One-pot synthesis of chiral α-methylene-γ-lactams with excellent diastereoselectivities and enantioselectivities

Article abstract of DOI:10.1021/ol102148b

An efficient one-pot asymmetric synthesis of highly substituted γ-lactams containing α-methylene groups has been successfully developed. A wide range of γ-lactams could be obtained in high yields with excellent diastereomeric ratios of up to 99:1 in favor

Full text of DOI:10.1021/ol102148b

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5154-5157
One-Pot Synthesis of Chiral
r-Methylene-γ-lactams with Excellent
Diastereoselectivities and
Enantioselectivities
An Shen,† Min Liu,† Zhen-Shan Jia,† Ming-Hua Xu,*,†,‡ and Guo-Qiang Lin*,†
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China, and Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
lingq@mail.sioc.ac.cn; xumh@mail.sioc.ac.cn
Received September 9, 2010
ABSTRACT
An efficient one-pot asymmetric synthesis of highly substituted γ-lactams containing r-methylene groups has been successfully developed.
A wide range of γ-lactams could be obtained in high yields with excellent diastereomeric ratios of up to 99:1 in favor of trans isomers. In
particular, excellent enantioselectivities of the two newly formed stereogenic centers with up to 99% ee were observed.
R-Methylene-γ-lactams are key structural units occurring in
a wide variety of biologically active natural products.1-6
Compared with their isosteric replacement R-methylene-γ-
lactones, they are frequently used as DNA polymerase
inhibitors, nuclear vitamin D receptor inhibitors, or cellular
steroidal inhibitors7 due to their similar bioactivities in
antibacterial, anti-inflammatory, and antianaphylactic proper-
ties, however with much lower toxic side effects.1,8,9
Because of their excellent activities for potential drug
candidates as well as their role as significant building blocks
for the total synthesis of a series of targeted compounds,
the construction of R-methylene-γ-lactam skeletons has
received much attention over the past three decades.10-16
The representative asymmetric synthetic approaches to
γ-lactams include the cyclization of nitrogen radicals,11 the
cycloaddition reaction,12 the transition-metal-catalyzed in-
tramolecular carbenoid C-H insertion,13 the ring expansion
of ꢀ-lactams,14 NHC-catalyzed addition of enals to imines,15
and tandem sequence aza-Michael/intramolecular nucleo-
philic substitution.16 In addition to these methods, there are
some indirect approaches based on using chiral reagents such
as bis-π-allylpalladium complexes17 or chiral ꢀ-alkoxycar-
bonylallylboronates,18 providing the precursors of γ-lactams.
† Shanghai Institute of Organic Chemistry.
‡ Shanghai Institute of Materia Medica.
(1) Janecki, T.; Blaszczyk, E.; Studzian, K.; Janecka, A.; Krajewska,
U.; Rosalski, M. J. Med. Chem. 2005, 48, 3516
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Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.; Velankar, M.;
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10.1021/ol102148b  2010 American Chemical Society
Published on Web 10/27/2010

For example, Villie´ras10i reported a synthesis of γ-lactams
with two examples, by addition of ꢀ-functional crotylzinc
reagents to chiral N-R-aminoesters in 60% yield, 92% de,
and in 86% yield, 100% de, respectively. However, more
steps were needed including reduction and acidic cleavage
to remove the auxiliary for achieving the final products.
Despite the fact that considerable efforts have been made, a
more efficient, reliable, and convenient route to R-methylene-
γ-lactams is still in high demand.
Scheme 1
.
Asymmetric Allylation Using Different Allyl
Regents
Previously, we have reported our achievements about the
aza-Barbier reaction for asymmetric synthesis of various
important chiral amines.19 For example, we reported a highly
diastereoselective synthesis of chiral homoallylic amines by
Zn-mediated allylation of chiral N-tert-butanesulfinyl imines
at room temperature (Scheme 1, 2a, R1 ) R2 ) H). By
simply turning the reaction conditions, a remarkable stereo-
control was provided, affording the products R/S-3a in good
yields and with up to 99:1 dr.19a Moreover, when 3-ben-
zoyloxyallyl bromide (Scheme 1, 2b, R1 ) OBz, R2 ) H)
or 3-arylallyl bromide (Scheme 1, 2c, R1 ) Ar, R2 ) H)
was used, a direct R-hydroxyallylation or cinnamylation
of imines 1 in a highly stereoselective manner was
observed.19b-d In the meantime, a dramatic LiCl effect was
found on the stereocontrol so that DMF could be used as
solvent to replace the unpleasant HMPA.19d In our continu-
ous interest to explore the utilities of chiral sulfinyl auxiliary,
we envisioned whether it was possible to use ꢀ,γ-disubsti-
tuted allyl bromide (Scheme 1, 2e, R1 ) Me, R2 ) CO2Et)
for setting up another interesting class of homoallylic amines
3 with two adjacent chiral centers simultaneously and which
by subjecting to further cyclization would yield the chiral
R-methylene-γ-lactams 5 in a one-pot varient. In this work,
we disclose our success on such an efficient synthesis with
high yields and excellent diastereo- and enantioselectivities.
Our initial investigation commenced with the reaction
between the model substrates (R)-N-tert-butanesulfinyl imine
1a and ethyl 2-(bromomethyl)acrylate (Table 1, 2d, R1 ) H,
Table 1. Initial Attempts in Reaction Conditions Screening
(10) (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc.
2004, 126, 6230. (b) Reddy, L. R.; Fournier, J.-F.; Subba Reddy, B. V.;
Corey, E. J. J. Am. Chem. Soc. 2005, 127, 8974. (c) Ooi, H.; Ishibashi, N.;
Iwabuchi, Y.; Ishihara, J.; Hatakeyama, S. J. Org. Chem. 2004, 69, 7765.
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Ed 2008, 47, 2294. (e) Krawczyk, H.; Albrecht, L.; Wojciechowski, J.;
Wolf, W. M.; Krajewska, U.; Rozalski, M. Tetrahedron 2008, 42, 6307.
(f) Alami, N. E.; Belaud, C.; Ville´ras, J. Tetrahedron Lett. 1987, 28, 59.
(g) Dembele, Y. A.; Belaud, C.; Hitchcock, P.; Villie´ras, J. Tetrahedron:
Asymmetry 1992, 3, 351. (h) Dembele, Y. A.; Belaud, C.; Villie´ras, J.
Tetrahedron: Asymmetry 1992, 3, 511. (i) Nyzam, V.; Belaud, C.;
Zammattio, F.; Villie´ras, J. Tetrahedron: Asymmetry 1996, 7, 1835. (j)
Choudhury, P. K.; Foubelo, F.; Yus, M. J. Org. Chem. 1999, 64, 3376. (k)
Tanaka, K.; Yoda, H.; Kaji, A. Synthesis 1985, 84. (l) Beji, F.; Lebreton,
J.; Villie´ras, J.; Amri, H. Tetrahedron 2001, 57, 9959. (m) Lee, K. Y.;
Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48, 2007.
solvent and
additiveb
Zn/2d
entrya
time (h) (equiv) yield (%)c de (%)d
1
2
3
4
5
6
7
8
5 mL of THFe
5 mL of DMFe
5 mL of DMF
5 mL of HMPAf
2 mL of DMF
1 mL of DMF
0.5 mL of DMF
5 mL of DMF
1 mL of DMF
1 mL of DMF
1 mL of DMFg
8
11
11
11
12
12
11
18
75
11
11
2
2
2
2
2
2
2
2
2
3
3
87
94
48
23
76
81
86
45
79
94
88
-68
52
96
93
99
99
96
96
97
97
98
(11) (a) Mackiewicz, P.; Furstoss, R.; Wage&, B.; Cote, R.; Lessard, J.
J. Org. Chem. 1978, 43, 3746. (b) Callier-Dublanchet, A. C.; Quiclet-Sire,
B.; Zard, S. Z. Tetrahedron Lett. 1995, 36, 8791.
(12) (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293. (b)
Groaning, M. D.; Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1998, 63,
5517. (c) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434.
(d) Romero, A.; Woerpel, K. A. Org. Lett. 2006, 8, 2127. (e) Sun, P.-P.;
Chang, M. Y.; Chiang, M. Y.; Chang, N. C. Org. Lett. 2003, 5, 1761. (f)
Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999.
(13) (a) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (b)
Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (c) Taber,
D. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 3, p 1045. (d) Choi, M. K. W.;
Yu, W. Y.; Che, C. M. Org. Lett. 2005, 7, 1081. (e) Zhou, C. Y.; Che,
C. M. J. Am. Chem. Soc. 2007, 129, 5828.
9
10
11
a Reaction was performed with 0.2 mmol of 1a, Zn/2d, and additive in
dry solvent at rt. b 2 equiv of LiCl was used as additive unless otherwise
d
noted. c Isolated yield. Determined by H NMR of the product. 3d was
converted to the lactam to determine its configuration and confirm its
diastereomeric excess (see Supporting Information). e Without any additive.
f 10 µL of H2O was used as additive. g None-predried DMF was used.
1
(14) (a) Van Brabandt, W.; De Kimpe, N. J. Org. Chem. 2005, 70, 3369.
(b) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005,
7, 3981. (c) Park, J.-H.; Ha, J. R.; Oh, S. J.; Kim, J. A.; Shin, D.-S.; Won,
T. J.; Lam, Y. F.; Ahn, C. Tetrahedron Lett. 2005, 46, 1755.
R2 ) CO2Et). According to our previous reports, different kinds
of solvents were tested in this reation. Unfortunately, the
diastereomeric excesses of products were not satisfactory when
THF and DMF were used as solvents (Table 1, entries 1 and
2). When DMF was employed in combination with 2 equiv of
(15) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
(16) Comesse, S.; Sanselme, M.; Da¨ıch, A. J. Org. Chem. 2008, 73,
5566.
(17) Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 3562.
Org. Lett., Vol. 12, No. 22, 2010
5155

LiCl as an additive, excellent diastereomeric excess (96%) was
observed, however with much lower yield (Table 1, entry 3).
With the HMPA system, an analogous result was obtained
(Table 1, entry 4). On the basis of the eximious diastereomeric
excess in the DMF and LiCl system, further study on improving
the reaction yield was taken into consideration. By increasing
the substrate concentration, to our delight, improved yields were
obtained (Table 1, entries 3 vs 5-7). In addition, extension of
the reaction time did not seem to affect the yield (Table 1, entry
3 vs 8 and entry 6 vs 9). Remarkably, excellent yield and
diastereomeric excess could be achieved simultaneously when
the amounts of Zn and allyl bromide 2d were increased to 3
equiv (Table 1, entry 10). Untreated DMF was also proven to
be a suitable solvent, retaining a similar yield and diastereomeric
excess (Table 1, entry 11).
treatment of imine 1a and allyl bromide 2e, followed by
cyclization to yield the product 4e immediately, which was
then treatd with HCl-dioxane to afford 5e upon removal of
the auxiliary. Thus, the one-pot synthesis of 5e could be
realized (Scheme 2, route C).
Due to the dramatic effect of anhydrous LiCl in this
reaction (Table 1), further investigation was taken to optimize
the reaction conditions on LiCl loading (Table 2).
Table 2. Effect of the Loading of Anhydrous LiCl
Encouraged by the above success, we subsequently turned
the extension to γ-methyl substituted allyl bromide by using
(Z)-ethyl 2-(bromomethyl)butenoate 2e for investigating the
reaction with substrate (R)-N-tert-butanesulfinyl imine 1a
under the optimal reaction conditions (Table 1, entry 10).
Although we failed to obtain the expectant product 3e under
the selected conditions, we were pleased to see that 4e, a
ring-closed product of 3e, was produced. Upon removal of
the sulfinyl auxiliary, 4e could be easily transformed to highly
functionalized R-methylene-γ-lactam 5e in 83% yield and
92% ee (Scheme 2, route A). Then it was found that under
entrya
LiCl (equiv)
yield (%)b
ee (%)c
trans:cisc
1
2
3
4
-
1
3
5
43
40
91
86
12
32
96
99
99:1
99:1
99:1
99:1
a Reaction was performed with imine 1a (0.2 mmol), Zn, and allyl
bromide 2e (0.6 mmol) and anhydrous LiCl in 1 mL of dry DMF at rt and
was then treated with 1 N HCl-dioxane (0.5 mL). b Isolated yield.
c Determined by chiral HPLC analysis.
As shown in Table 2, very poor result (43% yield and
12% ee) was observed when the reaction occurred in the
absence of LiCl (Table 2, entry 1). The presence of LiCl
exerted a remarkable impact on enantioselectivities (Table
2, entries 1-4). The best result was given when 5 equiv of
LiCl was used where 5e was obtained in 99% ee and 99:1
dr (Table 2, entry 4).
Scheme 2. Different Process to 5e
The relative configuration of 5e was established to be trans by
NOE analysis. Since the attempt to have the single crystal of 5e
was unsuccessful, it was turned to use its precursor 4e or analogues.
Fortunately, with the crystal of the analogue 4m obtained, the
absolute configuration of the two newly generated stereocenters
in 4m was unambiguously determined to be (9R,10R) (Figure 1).
Thus, treatment of (R)-N-tert-butanesulfinyl imine 1a with
(Z)-ethyl 2-(bromomethyl) butenoate 2e in the presence of
the presence of 1-5 equiv of water the same reation occurred
to afford 3e in 89% yield and 89% de. As an alternative
way, 3e could also be cyclized to yield γ-lactam 5e in about
80% yield (Scheme 2, route B). These results indicated that
under the reaction process 3e was formed first upon the
(18) (a) Chataigner, I.; Zammattio, F.; Lebreton, J.; Villie´ras, J.
Tetrahedron 2008, 64, 2441. (b) Elford, T. G.; Hall, D. G. Tetrahedron
Lett. 2008, 49, 6995.
(19) (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979.
(b) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res.
2008, 41, 831. (c) Liu, M.; Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Chem.sEur.
J. 2009, 15, 10217. (d) Liu, M.; Shen, A.; Sun, X.-W.; Deng, F.; Xu, M.-
H.; Lin, G.-Q. Chem. Commun. 2010, DOI: 10.1039/C0CC03230A.
Figure 1. X-ray crystal structure of 4m.
Org. Lett., Vol. 12, No. 22, 2010
5156

3 equiv of Zn and 5 equiv of LiCl at room temperature in
DMF followed by treatment of 1 N HCl could give almost
pure (R,R)-trans-5e in a one-pot manner.
After successful establishment of the reaction conditions
for the one-pot synthesis of R-methylene-γ-lactam, we paid
attention to the investigation of the reaction generality. As
summarized in Table 3, a variety of (R)-N-tert-butanesulfinyl
imines 1 were examined to react with allzyl bromide 2 in
DMF in the presence of Zn (3 equiv) and LiCl (5 equiv).
Gratifyingly, all reactions proceeded smoothly at room
temperature to afford the expected products 5 with excellent
enantioselectivities (up to 99% ee) and diastereoselectivities
as well (trans:cis ) 97:3 to 99:1). Good yields were observed
in the cases of aromatic and heterocyclic substrates. Both
electron-donating and -withdrawing groups on the phenyl
ring of imines did not seem to affect the yields and
stereoselectivities significantly (Table 3, entries 1-2 and
5-13). As an exception, the substrate with a 4-CF3 sub-
stituent afforded relatively lower yield due to its low
reactivity in cyclization but still retained the 96% enantio-
meric excess (Table 3, entry 14). More interestingly, when
aliphatic substrates were subjected to the reaction, the same
levels of excellent enantioselectivities were observed, albeit
the isolated yields were somehow moderate with slow
conversion (Table 3, entries 3-4 and 15-17).
Table 3. Diastereoselective Synthesis of
R-Methylene-γ-lactamsa
In summary, we have developed an efficient and facile
one-pot approach for the asymmetric synthesis of highly
substituted γ-lactam compounds containing R-methylene
groups through Zn-promoted aza-Barbier-type allylations of
(R)-N-tert-butanesulfinyl imines with allzyl bromide in DMF
at room temperature. The reaction is well-tolerated; various
aromatic and aliphatic imines could act as suitable substrates
and display excellent diastereo- and enantioselectivities. Our
access to chiral R-methylene-γ-lactams, which is a key
scaffold in a wide variety of bioactive natural products and
synthetic medicines, provides a valuable tool for synthetic
chemistry.
yield
ee
entryb
1
R
2
5
(%)c trans:cisd (%)d
1
2
3
4
5
6
7
8
1a C6H5
2d 5a
2d 5b
2d 5c
2d 5d
2e 5e
2e 5f
2e 5g
2e 5h
2e 5i
2e 5j
2e 5k
2e 5l
85
77
70
69
86
75
82
89
82
85
79
73
-
-
-
-
97
95
98
98
99
98
99
99
98
95
98
98
94
96
92
92
95
1b 4-MeOC6H4
1c C6H5CH2CH2
1d cyclohexyl
1a C6H5
1b 4-MeOC6H4
1e ꢀ-naphthyl
1f 2-furanyl
1g 2-CH3C6H4
1h 4-CH3C6H4
99.5:0.5
99.8:0.2
99.5:0.5
96.6:3.4
98.8:1.2
99:1e
9
10
11
12
13
14
15
16
17
1i
1j
4-BrC6H4
4-FC6H4
99:1e
97.1:2.9
99.7:0.3f
99.6:0.4f
99.4:0.6
99.1:0.9
98.2:1.8
Acknowledgment. Financial support from the Major State
Basic Research Development Program (2010CB833302),
Chinese Academy of Sciences KJCX2-YW-H-07, and the
Shanghai Municipal Committee of Science and Technology
(09JC1417300) is acknowledged.
1k 2,4-(MeO)2C6H3 2e 5m 78
1l
4-CF3C6H4
2e 5n
2e 5o
2e 5p
2e 5q
51
59
70
64
1c C6H5CH2CH2
1m C6H5CHdCH
1n (CH3)2CHCH2
a In most cases, uncyclized product was found in a minor amount (about
5-10%). b Reaction was performed with imine 1 (0.2 mmol), Zn, and allyl
bromide 2 (0.6 mmol) and anhydrous LiCl (1.0 mmol) in 1 mL of dry
DMF at rt and was then treated with 1 N HCl-dioxane (0.5 mL). c Isolated
yield. d Determined by chiral HPLC analysis unless otherwise noted.
e Determined by 1H NMR of the product.18b f Determined by LC-MS
analysis.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR and HPLC
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL102148B
Org. Lett., Vol. 12, No. 22, 2010
5157