Versatile one-pot reductive alkylation of lactams/amides via amide activation: Application to the concise syntheses of bioactive alkaloids (±)-bgugaine, (±)-coniine, (+)-preussin, and (-)-cassine

Article abstract of DOI:10.1002/chem.201002054

Direct entry: One-pot reductive alkylation of lactams/amides with Grignard reagents has been realized via lactam/amide activation with Tf₂O. This method opens a direct entry to α-alkylated amines. The versatility of the method is illustrated by the concise syntheses of bioactive alkaloids (±)-bgugaine, (±)-coniine, (+)-preussin, and (?)-cassine.

Full text of DOI:10.1002/chem.201002054

DOI: 10.1002/chem.201002054
Versatile One-Pot Reductive Alkylation of Lactams/Amides via Amide
Activation: Application to the Concise Syntheses of Bioactive Alkaloids
(Æ)-Bgugaine, (Æ)-Coniine, (+)-Preussin, and (À)-Cassine
Kai-Jiong Xiao, Yu Wang, Ke-Yin Ye, and Pei-Qiang Huang*[a]
Efficiency is the central goal in organic synthesis.[1] To-
wards this goal, the development of one-pot multicompo-
nent reactions[2] and step-economy synthesis[3] constitute two
valuable approaches. In this context, we have recently re-
ported the first general one-pot method for the transforma-
tion of lactams and amides into the corresponding tert-alkyl-
amines[4] by bis-reductive alkylation with different organo-
metallic reagents (Scheme 1).[4a]
Figure 1. Selected naturally occurring a-substituted/a,a’-disubstituted pyr-
rolidine and piperidine alkaloids.
Scheme 1. Tf2O-Activated bis-reductive alkylation of lactams and amides.
Tf2O=Triflic anhydride; DTBMP=2,6-di-tert-butyl-4-methylpyridine.
lus ochraceus.[8] Moreover, a number of a,a’-disubstituted 3-
piperidinol alkaloids, such as (À)-cassine (5), (À)-spectaline
a-Substituted amines (sec-alkylamines), especially a-sub-
stituted pyrrolidines, piperidines and related ring systems,
are key structural features found in many bioactive alkaloids
and pharmaceutically relevant molecules.[5] For example,
(À)-irniine (1) and (À)-bgugaine (2) (Figure 1) are alkaloids
isolated from the tubers of Arisaum vulgare, which show an-
tibacterial activity against Gram-positive bacteria and anti-
mycotic activity against some Candida and Cryptococcus
strains;[6a] bgugaine (2) was also shown to be a strong hepa-
totoxin in rat and human liver cell cultures;[6b] (+)-coniine
(3) is one of the major toxic alkaloids present in poison
hemlock;[7] (+)-preussin (4) is a potent antifungal agent iso-
lated from fermentation broths of Preussia sp. and Aspergil-
(6), (+)-azimic acid (7), and (+)-carpamic acid (8), have
been isolated, and many of them showed important biologi-
cal activities.[5,9] As a conse-
quence, numerous synthetic
methods have been developed
for the syntheses of such ring
systems.[10] Among them, those
Scheme 2. General
one-pot
based on the reductive alkyla-
tion of lactams are quite attrac-
tive due to their flexibility and
versatility (Scheme 2).
transformation of lactams/
amides into the corresponding
a-alkylated amines.
For the transformation of a
lactam/amide into the corre-
sponding a-substituted amines, two approaches can be envi-
sioned, namely, mono-addition of an organometallic reagent
followed by a chemoselective reduction,[11–13] and partial re-
duction by a hydride followed by a chemoselective organo-
metallic reagent addition.[14] While both approaches have
been used in the syntheses of alkaloids, they are limited to
either special chelating substrates[11] or bicyclic lactams.[12,13]
Noteworthy is that, to the best of our knowledge, only one
case involved the transformation of an amide into the corre-
[a] K.-J. Xiao, Y. Wang, K.-Y. Ye, Prof. P.-Q. Huang
Department of Chemistry and
The Key Laboratory for Chemical Biology of Fujian Province
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen, Fujian 361005 (P. R. China)
Fax : (+86)592-2186400
E-mail: pqhuang@xmu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002054.
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Chem. Eur. J. 2010, 16, 12792 – 12796

COMMUNICATION
sponding a-substituted amine.[13a] Other drawbacks associat-
ed with some of the methods are low yields,[12b,c] epimeriza-
tion at a-position,[12j] or use of excess of highly toxic
NaBH3CN as the reducing agent.[11,12d,e] As a result, multi-
step transformations using either thioamides,[14c,15] lactim
ethers,[16] N-tert-butyl formamidines,[17] vinyl triflates,[18] or
N-acyl/N-alkoxycarbonyl derivatives[19–21] remain the most
reliable and widely adapted methods. Moreover, many a-
amidoalkylation methods are limited to silylated nucleo-
philes.[19]
(Table 2, entries 1–3). It is noteworthy that LiAlH4 can also
be replaced by NaBH4, which afforded the desired products
in comparable yields (Table 1, entry 8 and Table 2, entry 4).
To demonstrate the synthetic utility of this one-pot
method, the syntheses of bioactive alkaloids (Æ)-bgugaine
(2),[23] (Æ)-coniine (3),[24] (+)-preussin (4),[25] and (À)-cassine
(5)[26] were undertaken.
Table 2. Tf2O-Activated one-pot reductive alkylation of amides.
As a continuation of our interest in the development of
simple and efficient synthetic methodology,[4a,b] we now
report a direct and versatile one-pot method for the trans-
formation of lactams and amides into the corresponding a-
substituted amines by the reductive alkylation of lactams/
amides with Grignard reagents (Scheme 2), and the applica-
tion of this methodology to the concise syntheses of (Æ)-
bgugaine (2), (Æ)-coniine (3), (+)-preussin (4), and (À)-cas-
sine (5).
Entry
Substrate
R1 MgBr
M2-H
Product (Yield/%)[a]
1
2
3
4
15a (R=Me)
15a (R=Me)
15b (R=Ph)
15b (R=Ph)
EtMgBr
iPrMgBr
EtMgBr
EtMgBr
LiAlH4
LiAlH4
LiAlH4
NaBH4
16a (78); 17a (13)
16b (73); 17a (9)
16c (81); 17b (10)
16c (80); 17b (7)
[a] Isolated yield.
To achieve the required one-pot reaction under mild con-
ditions, a triflic anhydride (Tf2O)/2,6-di-tert-butyl-4-methyl-
pyridine (DTBMP) combination[22] was selected as the
amide activating system with Grignard reagents as alkylat-
ing agents and lithium aluminum hydride (LiAlH4) as a re-
ducing agent. It was found that when a CH2Cl2 solution of
lactam 9 (1.0 equiv) and DTBMP (1.2 equiv) was treated
successively with 1.2 equiv of Tf2O (À788C, 45 min),
1.0 equiv of ethylmagnesium bromide in Et2O (RT, 1 h), and
3.0 equiv of LiAlH4 (RT, 1 h), the desired 2-ethylpyrrolidine
11a was obtained in 82% yield, along with 8% yield of
amine 13 (Table 1, entry 1). Following the same procedure,
The syntheses of (Æ)-bgugaine (2) and (Æ)-coniine (3)
are illustrated in Scheme 3. Using the general procedure, re-
ductive n-tetradecylation of commercially available N-meth-
ylpyrrolidin-2-one (NMP, 18) produced (Æ)-bgugaine (2) in
75% yield. Catalytic hydrogenation of amine 12c, obtained
from the reductive n-propylation of lactam 10 (Table 1,
entry 6), gave coniine (3), isolated as its hydrochloride salt
in 85% yield. The physical and spectral data of the synthetic
products are in accordance with those reported for (Æ)-bgu-
gaine (2)[23d] and (Æ)-coniine (3),[24b] respectively.
Table 1. Tf2O-Activated one-pot reductive alkylation of lactams.
Entry
Substrate
R1 MgBr
M2-H
Product (Yield/%)[a]
1
2
3
4
5
6
7
8
9
9
9
9
10
10
10
9
EtMgBr
nBuMgBr
BnMgBr
PhMgBr
EtMgBr
iPrMgBr
BnMgBr
EtMgBr
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
NaBH4
11a (82); 13 (8)
11b (79); 13 (10)
11c (69); 13 (19)
11d (58); 13 (26)
12a (72) ; 14 (16)
12b (68); 14 (20)
12c (62); 14 (23)
11a (71); 13 (8)
Scheme 3. Concise syntheses of (Æ)-bgugaine (2) and (Æ)-coniine (3).
Encouraged by these results, we then focused on the ste-
reoselective total syntheses of (+)-preussin (4) and (À)-cas-
sine (5). Our retrosynthetic analysis is outlined in Scheme 4.
For the key one-pot reductive alkylations of lactams 19 and
20, two issues had to be addressed, namely, diastereoselec-
tivity and the use of a functionalized Grignard reagent. Lac-
tams 19 and 20 are easily available from (R)-glutamic acid
and (S)-malic acid, respectively, by the methods we have re-
ported previously.[27,28]
For the synthesis of (+)-preussin (4), the known lactam
(4S,5S)-19[27] was subjected to reductive alkylation with n-
nonylmagnesium bromide to give an inseparable mixture of
diastereomers 21a and 21b in 71% combined yield, with a
[a] Isolated yield.
the reactions of lactam 9 with n-butyl-, benzyl-, and phenyl-
Grignard reagents gave the corresponding pyrrolidines 11b–
d in 58–79% yield (Table 1, entries 2–4). Similar results
were obtained with lactam 10, which provided the corre-
sponding piperidines 12a–c in good yields (Table 1, en-
tries 5–7).
Similarly, the reductive alkylation of amides proceeded
smoothly to give the desired products in high yields
Chem. Eur. J. 2010, 16, 12792 – 12796
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P.-Q. Huang et al.
(À)-cassine (5) {m.p. 56–578C; lit.[30] m.p. 57–588C; [a]2D0
=
À1.2 (c = 0.5, EtOH); [a]2D0 = À15.4 (c = 0.5, CHCl3);
lit.[30] [a]2D0 = À0.6 (c = 8.0, EtOH)} in 88% yield. The H
1
and 13C NMR spectral data of our synthetic product are in
good agreement with those reported.[26e]
Scheme 4. Retrosynthetic analysis of (+)-preussin (4) and (À)-cassine
(5).
cis/trans ratio of 7.2:1 (Scheme 5). The cis/trans ratio was de-
termined by HPLC. The stereochemistry of the major prod-
uct was confirmed by its ultimate conversion into (+)-preus-
sin (4). To introduce the N-methyl group, the diastereomeric
mixture of pyrrolidine 21 was subjected to one-pot debenzy-
lation–urethanation [H2, l datm, 20% Pd(OH)2/C, (Boc)2O,
EtOH, RT, 48 h], and the N-tert-Boc derivative 22 was ob-
tained in 84% yield. The N-Boc group was then converted
into the corresponding N-methyl group by reduction with
LiAlH4, which afforded (+)-preussin (4) {[a]2D0 = +22.3 (c
= 1.0, CHCl3); lit.[8] [a]D20 = +22.0 (c = 1.0, CHCl3)} in
Scheme 6. Total synthesis of (À)-cassine (5).
In summary, a direct and versatile method for the one-pot
reductive alkylation of lactams/amides with Grignard re-
agents has been developed. This method opens a direct
entry to a-alkylated amines. The power of the methodology
is demonstrated by the concise syntheses of bioactive alka-
loids (Æ)-bgugaine (2), (Æ)-coniine (3), (+)-preussin (4),
and (À)-cassine (5). The syntheses of latter two alkaloids
allow the demonstration of the diastereoselectivity of the
method. Further application of this method to the total syn-
thesis of other alkaloids is under investigation.
1
93% yield. The H and 13C NMR spectral data of our syn-
thetic product are in good agreement with those reported.[8]
Experimental Section
General procedure for the reductive alkylation of lactams/amides: Tf2O
(1.2 equiv) was added dropwise to a cooled (À788C) solution of a
lactam/amide
(1.0 equiv)
and
2,6-di-tert-butyl-4-methylpyridine
(1.2 equiv) in CH2Cl2 and the resultant mixture was stirred at À788C for
45 min. A solution of RMgBr (1.0 equiv) in Et2O was added dropwise to
the resultant mixture. The mixture was allowed to warm slowly to RT
and stirred for 1 h. Then LiAlH4 (3.0 eq) or NaBH4 (3.0 equiv) was
added in one portion. After stirring for 1 h, the reaction was quenched
by careful addition of a 20% NaOH solution. After filtration, the filtrate
was dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash column chromatogra-
phy on SiO2 to afford the desired amine. Further experimental details
can be found in the Supporting Information.
Scheme 5. Total synthesis of (+)-preussin (4).
We next addressed the synthesis of (À)-cassine (5). To
this end, (5R,6R)-lactam 20, prepared following essentially
the procedure described for its enantiomer,[28] was subjected
to the one-pot reductive alkylation reaction by successive
treatment with Tf2O/DTBMP, Grignard reagent 23,[29] and
LiAlH4, which afforded a mixture of separable diastereo-
mers 24a and 24b in 3.5:1 ratio with a 62% combined yield
(Scheme 6). The stereochemistry of the major diastereomer
was confirmed by its ultimate conversion into (À)-cassine
(5). Deprotection of O-Bn and N-PMB in 24a under catalyt-
ic hydrogenolytic conditions [H2, l atm, 20% Pd(OH)2/C,
EtOH, RT, 48 h], followed by treatment of the resultant
crude product with aqueous HCl and neutralization, led to
Acknowledgements
The authors are grateful to the NSF of China (20832005) and the Nation-
al Basic Research Program (973 Program) of China (Grant No.
2010CB833200) for financial support.
Keywords: alkaloids
· amide activation · reduction ·
synthetic methods
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Chem. Eur. J. 2010, 16, 12792 – 12796

Versatile One-Pot Reductive Alkylation of Lactams and Amides
COMMUNICATION
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Received: July 20, 2010
Published online: October 11, 2010
12796
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Chem. Eur. J. 2010, 16, 12792 – 12796