Stereodivergent synthesis of β-lactams using thermal rearrangement of aminocyclobutenones

Article abstract of DOI:10.1021/ol901192y

In the present study, the stereodivergent synthesis of both cls- and trans-β-lactams is presented using the following three reactions: iminocyclobutenone formation, chemoselective reduction of imino groups, and thermal rearrangement of aminocyclobutenones

Full text of DOI:10.1021/ol901192y

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3266-3268
Stereodivergent Synthesis of ꢀ-Lactams
Using Thermal Rearrangement of
Aminocyclobutenones
Iwao Hachiya, Takuya Yoshitomi, Yukari Yamaguchi, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering,
Mie UniVersity, Tsu, Mie 514-8507, Japan
mshimizu@chem.mie-u.ac.jp
Received May 28, 2009
ABSTRACT
In the present study, the stereodivergent synthesis of both cis- and trans-ꢀ-lactams is presented using the following three reactions:
iminocyclobutenone formation, chemoselective reduction of imino groups, and thermal rearrangement of aminocyclobutenones as crucial
steps, in which the starting materials, iminocyclobutenones, were readily synthesized using conjugate addition reactions of alkynyl imines
with ketene silyl acetals in good yields.
New synthetic routes for ꢀ-lactams are of great importance
because of structure-activity relationship study and the
development of new derivatives in the ꢀ-lactam antibiotics.
It has been recognized that stereochemistry at the C-3 and
C-4 carbons of the ꢀ-lactam ring is involved in manifestations
of biological activity.1 The Staudinger reaction, the enolate-
imine condensations, and the cyclization of ꢀ-amino acids
or esters have been used for stereocontrolled constructions
of the C-3 and C-4 carbons of ꢀ-lactams.2 Although
numerous methods for the stereoselective synthesis of cis-
and trans-ꢀ-lactams have been reported, a single-step
synthesis of them from the same precursor has been highly
desired. We have focused on the reactivity at the ꢀ-position
of alkynyl imines3 and reported efficient synthetic methods
for 2-pyridones, iminopyridines, and aminopyridines using
conjugate addition reaction of active methine compounds to
alkynyl imines.4 During these investigations, we envisioned
an iminocyclobutenone synthesis by conjugate addition
reactions of alkynyl imines with ketene silyl acetals. Imi-
nocyclobutenones would be useful intermediates for the
synthesis of nitrogen-containing heterocycles by transforma-
tion including the thermal rearrangement of the cyclobuten-
one ring.5 This paper describes the stereodivergent synthesis
of both cis- and trans-ꢀ-lactams 8 using iminocyclobutenone
3 formation, chemoselective reduction of imino groups, and
thermal rearrangement of aminocyclobutenones 4 as crucial
steps (Scheme 1).
We first examined the aluminum chloride promoted
conjugate addition reaction of several alkynyl imines 1 with
ketene silyl acetals 2.6 Table 1 summarizes the results. The
alkynyl imines possessing heteroaromatic or aromatic groups
as the substituent R2 underwent conjugate addition reactions
(1) Chemistry and Biology of ꢀ-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic Press: New York, 1982; Vols. 1-3.
(2) For a review on the synthesis of ꢀ-lactams, see: Brandi, A.; Cicchi,
S.; Cordero, F. M. Chem. ReV. 2008, 108, 3988.
(4) Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun. 2009, 874.
(5) For a recent example of thermal rearrangement of cyclobutenones,
see: Harrowven, D. C.; Pascoe, D. D.; Guy, I. L. Angew. Chem., Int. Ed.
2007, 46, 425.
(3) For a review on the alkynyl imines in organic synthesis, see:
Stadnichuk, M. D.; Khramchikhin, A. V.; Piterskaya, Yu. L.; Suvorova,
I. V. Russ. J. Gen. Chem. 1999, 69, 593.
10.1021/ol901192y CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

Thermal rearrangement of aminocyclobutenones 4a-f in
toluene or octane at 110 °C proceeded to give the desired
ꢀ-lactams 8a-f in moderate to good yields with good cis-
selectivities.8 Table 2 summarizes the results.9
Scheme 1
.
Proposed Transformation of Iminocyclobutenones 3
into ꢀ-Lactams 8
Table 2. Thermal Rearrangement of Aminocyclobutenones into
ꢀ-Lactams
a
a
entry R1
R2
R3 time (h) 8 (yield %)b cis/transc
1d
2
3
4
5
Ph Ph
Ph 2-furyl
Ph Np
Ph 2-thienyl Me
Np Ph
Ph Ph
Me
Me
Me
24
45
40
48
48
48
8a (61)
8b (76)
8c (69)
8d (89)
8e (51)
8f (65)
80/20
74/26
75/25
79/21
79/21
80/20e
Table 1. Synthesis of Imino- and Aminocyclobutenones
Me
SEt
6
a Np ) 2-naphthyl. b Isolated yields. c Diastereomeric ratios were
determined by 1H NMR spectra. d Reaction performed in toluene. e A
geometrical mixture of the double bond.
a
a
entry R1
R2
imine R3
3 (yield %)b 4 (yield %)b
A plausible reaction mechanism for the thermal rearrange-
ment of aminocyclobutenones 4 into ꢀ-lactams 8 is shown
in Scheme 2. Aminoketene 5 would be generated by ring
1
2
3
4
5
6
7
Ph Ph
Ph 2-furyl
Ph Np
Ph 2-thienyl
Np Ph
Ph Ph
1a
1b
1c
1d
1e
1a
1c
Me 3a (82c, 71d) 4a (95e)
Me 3b (85c, 75d)
4b (67f)
4c (79e)
4d (78e)
4e (90g)
4f (89e,h
4g (84e,h
Me 3c (80c, 77d)
Me 3d (71d)
Me 3e (75c)
SEt 3f (78c)
SEt 3g (83c)
)
)
Scheme 2. Plausible Mechanism for the Thermal Rearrangement
Ph Np
a Np ) 2-naphthyl. b Isolated yields. c Ketene silyl acetals 2a and 2b
(3.0 equiv) were used. d Ketene silyl acetal 2a (1.5 equiv) was used. e AcCl
(1.5 equiv) was used. f AcCl (0.5 equiv) was used. g AcCl (1.0 equiv) was
used. h Diastereomeric ratio was 1/1.
to give the corresponding iminocyclobutenones 3a-d in
good to high yields (entries 1-4).7 Use of 1.5 equiv of 2a
slightly decreased the yields (entries 1-3). The reaction of
alkynyl imines 1a and 1c with the ketene silyl acetal 2b
having an ethanesulfenyl group gave iminocyclobutenones
3f and 3g in good yields (entries 6 and 7).
We next examined chemoselective reduction of iminocy-
clobutenones 3 having three reducible functional groups such
as imino, carbonyl, and alkenyl. When sodium cyanoboro-
hydride was used as a reducing reagent, the reduction of
iminocyclobutenones 3a-g in methanol in the presence of
acetyl chloride, which reacted with methanol to generate a
limited amount of hydrogen chloride in situ, proceeded
chemoselectively at room temperature to give the desired
aminocyclobutenones 4a-g in moderate to high yields
(Table 1).
opening of aminocyclobutenone 4 and undergo a cyclization
to give the enol intermediate 9. Protonation of the enol
intermediate 9 would occur from the less hindered face of
the enol to give cis-ꢀ-lactam 8 predominantly. The proton-
ation step is crucial regarding the cis-selectivity. Therefore,
several additives were investigated in the thermal rearrange-
ment of aminocyclobutenones 4c to improve the cis-
selectivity, and Table 3 summarizes the results. We first
examined several amines as a proton transfer additive.10
(6) The reactions using other Lewis acids such as TiCl4, ZrCl4, and
EtAlCl2 gave the iminocyclobutenone in yields ranging from 8% to
25%.
(8) Relative stereochemistry at C(3) -C(4) was determined on the basis
of the J3,4; coupling constants for cis-ꢀ-lactams are larger than those for
trans-isomers. See: Bouffard, F. A.; Johnston, D. B. R.; Christensen, B. G.
J. Org. Chem. 1980, 45, 1130.
(7) The reaction of an alkynyl imine 1 possessing an aliphatic group as
n
the substituent R1 (R1 ) Bu, R2 ) Ph) gave the δ-lactam instead of the
(9) Among the solvents examined, such as toluene, xylene, octane, and
chlorobenzene, octane was found to be the most effective.
ꢀ-lactam.
Org. Lett., Vol. 11, No. 15, 2009
3267

Table 3. Effect of Additive in the Thermal Rearrangement
Table 4. Diastereoselective Synthesis of ꢀ-Lactams by Thermal
Rearrangement of Aminocyclobutenones
additivea
equiv 8c (yield%)b cis/transc
b
b
entry
basea
R1
R2
8 (yield%)c
cis/transd
entry
1e
2
3
6
6
6
6
6
7
7
7
7
7
Ph
Ph
Ph
Ph
Np
Ph
Ph
Ph
Ph
Np
Ph
2-furyl
Np
2-thienyl
Ph
Ph
2-furyl
Np
2-thienyl
Ph
8a (80)
8b (99)
8c (93)
8d (77)
8e (85)
8a (78)
8b (80)
8c (59)
8d (59)
8e (75)
98/2
82/18
97/3
94/6
95/5
3/97
2/98
2/98
2/98
3/97
1
2
3
4
5
6
7
8
9
none
proton sponge
DABCO
N-methylmorpholine
1,4-dimethylpiperazine (6) 1.0
69
71
99
61
98
93
90
93
31
59
67
98
41
75/25
89/11
83/17
83/17
94/6
97/3
97/3
97/3
33/67
2/98
1.0
1.0
1.0
4
5
6e
7
6
6
2.0
3.0
1.0
1.0
1.0
0.5
0.2
1.0
1,4-diethylpiperazine
DBN
8
9
10
10 DBU (7)
11
12
7
7
30/70
54/46
79/21
a 1,4-Dimethylpiperazine (6) (2.0 equiv) or DBU (7) (1.0 equiv) was
used. b Np ) 2-naphthyl. c Isolated yields. d Diastereomeric ratios were
determined by H NMR spectra. e Reaction performed in toluene.
1
13 BHT
a BHT)2,6-di-tert-butyl-4-methylphenol.b Isolatedyields.c Diastereomeric
ratios were determined by H NMR spectra.
1
selectivities. ꢀ-Lactams are the most important nitrogen-
containing compounds because of their biological activities12
as well as their use as versatile building blocks.13 The present
method offers an attractive alternative ꢀ-lactam synthesis
because aminocyclobutenones can be easily prepared from
readily available starting materials.
Among the amines tested, 1,4-dimethylpiperazine (6) and
1,4-diethylpiperazine were found to be the most effective
regarding both the cis-selectivity and the yield (entries
1-8).11 On the other hand, thermal rearrangement in the
presence of stronger bases such as DBN and DBU (7) gave
the ꢀ-lactam 8c with trans-selectivity (entries 9 and 10).
When isomerization of cis-ꢀ-lactam 8c into the trans-
counterpart 8c was examined in octane with DBU (7), trans-
ꢀ-lactam 8c was obtained in 91% yield along with the
recovered cis-ꢀ-lactam 8c in 2% yield (eq 1). Use of a
substoichiometric amount of DBU (7) did not give good
trans-selectivities (entries 11 and 12). These results suggest
that cis-ꢀ-lactam 8c would be kinetically produced and then
isomerize into the thermodynamically more stable trans
ꢀ-lactam 8c. Use of 2,6-di-tert-butyl-4-methylphennol (BHT)
as an acidic additive was not effective (entry 13).
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research (B) and Priority Areas from
MEXT and JSPS.
Supporting Information Available: Experimental pro-
cedures and product characterization for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL901192Y
(10) Tang reported that an appropriate amine was essential in the
Kinugasa reaction to control both diastereo- and enantioselectivities, in
which the amine might coordinate to the copper and relay the chirality to
the product; see: Ye, M.-C.; Zhou, J.; Tang, Y. J. Org. Chem. 2006, 71,
3576. For a similar aminoketene intermediate, see: Ahn, C.; Kennington,
J. W., Jr.; DeShong, P. J. Org. Chem. 1994, 59, 6282. Fu indicated that the
Kinugasa reaction would proceed through ring-opening fragmentation to a
ketene, followed by recyclization, where the role of the amine was thought
to be both deprotonation of an acetylene with copper catalyst to generate
the copper acetylide and protonation of the enolate; see: Shintani, R.; Fu,
G. C. Angew. Chem., Int. Ed. 2003, 42, 4082.
(11) Regarding the role of 1,4-dimethylpiperazine (6), we presume the
formation of a bulky proton source shown.
We next examined a diastereoselective synthesis of a
variety of ꢀ-lactams, and the results are summarized in Table
4. Whereas use of 1,4-dimethylpiperazine (6) gave ꢀ-lactams
8a-e in good to high yields with good to high cis-
selectivities (entries 1-5), DBU (7) effected formation of
their trans-counterparts 8a-e in moderate to good yields with
excellent selectivities (entries 6-10).
In conclusion, we found that the thermal rearrangement
of aminocyclobutenones in the presence of an appropriate
amine produced either cis- or trans-ꢀ-lactams with high
(12) For a review on the biological activity of ꢀ-lactams, see: von
Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Ha¨bich, D. Angew.
Chem., Int. Ed. 2006, 45, 5072.
(13) For a review on the ꢀ-lactam synthon method, see: Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, 107, 4437.
3268
Org. Lett., Vol. 11, No. 15, 2009