Asymmetric Synthesis of Spiro β-Lactams via a Squaramide- Catalyzed Sulfa-Michael Addition/Desymmetrization Protocol

Article abstract of DOI:10.1002/adsc.201600554

An efficient asymmetric synthesis of spirocyclohexenone β-lactams bearing three contiguous stereocenters has been achieved in moderate to good yields and high stereoselectivities. The protocol involves the combination of a squaramide-catalyzed sulfa-Micha

Full text of DOI:10.1002/adsc.201600554

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DOI: 10.1002/adsc.201600554
Asymmetric Synthesis of Spiro b-Lactams via a Squaramide-
Catalyzed Sulfa-Michael Addition/Desymmetrization Protocol
a
a
a
b
b
˘
Pankaj Chauhan, Suruchi Mahajan, Ugur Kaya, Arto Valkonen, Kari Rissanen,
and Dieter Endersa,*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
a
Fax : (+49)-241–809–2127; e-mail: enders@rwth-aachen.de
Department of Chemistry, Nanoscience Center, University of Jyvaskyla, 40014 JYU, Finland
b
Received: May 23, 2016; Revised: July 8, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600554.
Abstract: An efficient asymmetric synthesis of spi-
rocyclohexenone b-lactams bearing three contigu-
ous stereocenters has been achieved in moderate to
good yields and high stereoselectivities. The proto-
col involves the combination of a squaramide-cata-
lyzed sulfa-Michael addition under desymmetriza-
tion via a dynamic kinetic resolution of racemic 2,5-
cyclohexadienones.
for the organocatalytic asymmetric synthesis of b-lac-
tams, mostly relying on the Staudinger reaction.[10] As
an alternative, we herein realized the synthesis of
spiro b-lactams via a desymmetrization of the racemic
2,5-cyclohexadienone b-lactams. The cyclohex-2-
enones are well-established building blocks for the
synthesis of a wide array of natural products and syn-
thetic bioactive compounds.[11] The metal and organo-
catalyzed desymmetrization of 2,5-cyclohexadienones
has emerged as an efficient strategy to obtain enantio-
pure cyclohex-2-enones.[12] The major emphasis during
the asymmetric desymmetrization process was on the
intramolecular addition reaction,[13] whereas the inter-
Keywords: asymmetric synthesis; desymmetriza-
tion; b-lactams; organocatalysis; spiro compounds;
sulfa-Michael addition
molecular desymmetrization of cyclohexadienones re-
[14]
mained less explored,
especially for the synthesis
of spiro compounds. Recently, Wangꢀs group reported
The b-lactam (2-azetidinone) ring is one of the most an organocatalytic asymmetric desymmetrization of
attractive and highly studied heterocycles in chemis- prochiral spirooxindoles containing a cyclohexadien-
try, biology and medicine, especially due to the pres-
ACHTUNGTRENNUNG
ence of this heterocyclic core in numerous antibiotics, lyzed by
a
representing an important class of modern pharma- (Scheme 1).[14b] To the best of our knowledge, there is
ceuticals.[1] The antibiotic properties and other inter-
esting bioactivities of these heterocycles have led to
the development of new b-lactam systems. Due to the
frequent occurrence of spirocycles in natural products
and biologically active molecules, the asymmetric syn-
thesis of spiro compounds has always been a major
area of research among synthetic organic chemists.[2]
The spirocyclic b-lactams have also emerged as impor-
tant candidates for biological evaluations.[3] The spiro
b-lactams I[4] and II[5] have been identified as potent
cholesterol absorption inhibitors, whereas b-lactam
III[6] is an antiviral agent (Figure 1). The spiro b-lac-
tams IV show b-lactamase inhibitor activity[7] and V
serves as a precursor for the synthesis of glutamine
synthetase inhibitors, i.e., tabtoxinine b-lactam.[8]
In recent years numerous methods have been estab-
lished for the synthesis of enantiopure b-lactams.[9]
However, there is only a limited number of examples Figure 1. Biologically active spiro b-lactams.
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Table 1. Catalyst screening.[a]
Scheme 1. Organocatalytic intermolecular desymmetrization
of 2,5-cyclohexadienones.
no report on the catalytic asymmetric synthesis of
spiro cyclohexene b-lactams.
Due to the pharmaceutical significance of b-lactams
and cyclohex-2-enones, we herein report a highly ste-
reoselective sulfa-Michael addition/desymmetrization
protocol, which leads to the formation of spirocyclo-
hexene b-lactams.
We envisaged that if a racemic 2,5-cyclohexadien-
ACHTUNGTRENNUNG
one 1[15] would be subjected to a sulfa-Michael addi-
tion (SMA)[16] in the presence of a bifunctional hydro-
gen-bonding catalyst[17] it could undergo a desymmetri-
zation combined with a dynamic kinetic resolution
[18]
(DKR)
to provide the spiro b-lactam 3 in high dia-
stereo- and enantiomeric excess (Scheme 1).
To confirm our hypothesis, we started our investiga-
tion with the sulfa-Michael addition of thiophenol 2a
to the racemic 2,5-cyclohexadienone 1a catalyzed by
2 mol% of various bifunctional hydrogen bonding or-
ganocatalysts. Initially, the reaction was catalyzed by
the squaramide C1, which led to the formation of
a single diastereomer of the desired product 3a in
58% yield with 91:9 er. After further screening of dif-
ferent squaramide catalysts C2–C11, the squaramide
C3 was identified as the best catalyst, as it provided
55% yield with an er of 92:8. The thioureas C12, C13
and a dimeric Cinchona alkaloid C14 gave lower
yields and enantioselectivities than the squaramide
catalysts (Table 1).
[a]
Reaction conditions: 0.22 mmol of 1a, 0.20 mmol of 2a,
2 mol% of catalyst and 1 mL of CH2Cl2 at room tempera-
ture.
Further optimization of the reaction conditions
were carried out through solvent screening (Table 2,
With the optimized reaction conditions in our hand,
entries 1–8), which revealed that the reaction in 1,4- we evaluated the substrate scope and the limitations
dioxane provides the best er of 93:7 (entry 8). The of this transformation by screening various 2,5-cyclo-
screening of various additives (entries 9–12) showed hexadienones and thiols (Table 3). The reaction works
that using molecular sieves resulted in an improve- very well with electron-neutral aryl thiols, however,
ment of the enantiomeric ratio. The lowering of the with 2-naphthyl thiol a lower yield and er of 3b com-
reaction temperature and a longer reaction time pro- pared to 3a was observed. The thiophenol derivatives
vided a better yield of up to 76% and an enantiomeric bearing electron-releasing groups provided good
ratio of up to 95:5 (entries 13 and 14).
yields and enantiomeric ratios of 3c–e with the excep-
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Table 2. Optimization studies.[a]
the optimized conditions to afford the b-lactam 3u in
49% yield, 5:1 dr and 92:8 er.
The synthetic utility of this transformation was
demonstrated by the chemo- and diastereoselective
reduction of the ketone group of 3a to the alcohol 4
bearing four stereogenic centers with a high dr value
(Scheme 2).
[c]
Entry
Solvent
Additive
Yield [%][b]
er
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
ClCH2CH2Cl
toluene
p-xylene
–
–
–
–
–
–
–
–
55
37
51
42
52
59
63
56
64
58
51
49
71
76
92:8
91:9
89:11
89:11
88:12
88:12
90:10
93:7
94:6
94:6
93:7
91:9
THF
MTBE
Scheme 2. Chemoselective reduction of 3a.
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
4ꢂ MS
3ꢂ MS
Na2SO4
MgSO4
4ꢂ MS
4ꢂ MS
10
11
12
13[d]
14[e]
The absolute configuration of the spiro b-lactam
products 3a–u was assigned as 3R,4S,9R by X-ray
crystallographic analysis of 3j with an er of >99:1
(Figure 2).[19]
95:5
95:5
On the basis of the observed absolute configuration
of the products, a mechanism of this transformation
may be proposed (Scheme 3). The plausible transition
state involves the hydrogen bonding activation of the
(R)-enantiomer of the dienone with the squaramide
moiety of the catalyst for the attack of the sulfur nu-
cleophile, which in turn is activated by the tertiary
amine of the catalyst via deprotonation to provide
product 3a (TS 1). The possibility of the (S)-enantio-
mer of the substrate to form the product is less due to
[a]
Reaction conditions: 0.22 mmol of 1a, 0.20 mmol of 2a,
2 mol% of catalyst C3 and 1 mL of solvent at room tem-
perature.
Yield 3a isolated after column chromatography.
Enantiomeric ratio determined by HPLC on a chiral sta-
tionary phase.
[b]
[c]
[d]
[e]
The reaction was carried out at 138C for 3 days.
The reaction was carried out at 138C for 4 days.
tion of 2-methoxythiophenol, which gave 3f only in the steric repulsion between the ester group and the
38% yield but with a high er of 95:5. The thiophenol incoming S-nucleophile and hence (S)-1 undergoes
derivatives bearing electron-withdrawing groups led a rapid transformation to (R)-1 in the presence of the
to the formation of the desired products 3g–k in 41– catalyst via deprotonation of the acidic proton.
51% yield with 88:12–92:8 er. In these cases, only
In conclusion, we have developed an efficient
a slight improvement in the product yields was ob- method to procure diastereomerically pure and highly
served when using a higher catalyst loading of enantio-enriched spirocyclohexenone b-lactams bear-
5 mol%. We further tested a heteroaryl thiol, which ing three contiguous stereocenters via desymmetriza-
provided 3l in 46% yields and acceptable er of 89:11. tion of 2,5-cyclohexadiones through a sulfa-Michael
After the screening of thiols, different 2,5-cyclohexa- addition/dynamic kinetic resolution process catalyzed
dienones were tested. Using a methyl ester instead of by a low loading of a squaramide. The reaction can
ethyl ester led to the formation of the desired prod-
ucts 3m–q in good yields (except 2-methoxythiophe-
nol) and high enantioselectivities (90:10–96:4 er). The
2,5-cyclohexadienone derivatives bearing different N-
protecting groups such as an electron-withdrawing
and an electron-releasing substituent at the aryl ring
as well as a heteroaryl group were also tolerated and
provided the respective products 3r–t in 72–80% yield
and 93:7 er The gram-scale reaction of thiophenol
with 1a worked very well to provide 3a with some-
what lower yield and a similar level of stereoselectiv-
ity. The 2,5-cyclohexadienone bearing a cyano group
instead of the ester function also reacts well under Figure 2. X-Ray crystal structure of 3j.
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Table 3. Substrate scope.[a]
[a]
Reaction conditions: 0.44 mmol of 1, 0.4 mmol of 2, 2 mol% of catalyst C3 in 3 mL of 1,4-dioxane and 200 mg of 4 ꢂ mo-
lecular sieves.
[b]
[c]
The results obtained for a gram scale reaction at 3.5 mmol.
The results obtained with 5 mol% of catalyst.
thiol 2 (1.0 equiv., 0.4 mmol) was added and the stirring was
continued for 4 days at the same temperature. The crude
product was directly purified by flash column chromatogra-
phy (n-hexane/EtOAc=7:3) to afford the spiro b-lactams
3a–3u.
be scaled up to a gram level and the enantioselectivity
can be improved through a single crystallization.
Experimental Section
General Procedure
Acknowledgements
In a 10-mL reaction tube equipped with a magnetic stirring
bar, the 2,5-cyclohexadienone 1 (1.1 equiv., 0.44 mmol), cat-
alyst C3 (2 mol%) and 4ꢂ molecular sieves (200 mg) were
stirred in 1,4-dioxane (3.0 mL) at 138C. After 5 minutes,
A.V. and K.R. gratefully acknowledge the Academy of Fin-
land (KR: grant nos. 263256 and 265328) for financial sup-
port.
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York, 1993; pp 295–368; b) C. Palomo, J. M. Aizpurua,
I. Ganboa, M. Oiarbide, Eur. J. Org. Chem. 1999, 3223–
3235; c) C. Palomo, J. M. Aizpurua, I. Ganboa, M.
Oiarbide, Curr. Med. Chem. 2004, 11, 1837–1872;
d) C. R. Pitts, T. Lectka, Chem. Rev. 2014, 114, 7930–
7953.
[10] a) H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356,
51–123; for selected examples of organocatalytic asym-
metric syntheses of b-lactams, see: b) A. E. Taggi,
A. M. Hafez, H. Wack, B. Young, W. J. Drury, T.
Lectka, J. Am. Chem. Soc. 2000, 122, 7831–7832;
c) A. M. Hafez, A. E. Taggi, H. Wack, W. J. Drury III,
T. Lectka, Org. Lett. 2000, 2, 3963–3965; d) A. E. Taggi,
A. M. Hafez, H. Wack, B. Young, D. Ferraris, T.
Lectka, J. Am. Chem. Soc. 2002, 124, 6626–6635;
e) Y. R. Zhang, L. He, X. Wu, P. L. Shao, S. Ye, Org.
Lett. 2008, 10, 277–280; f) N. Duguet, C. D. Campbell,
A. M. Slawin, A. D. Smith, Org. Biomol. Chem. 2008,
6, 1108–1113; g) S. Chen, E. C. Salo, K. A. Wheeler,
N. J. Kerrigan, Org. Lett. 2012, 14, 1784–1787.
[11] For reviews, see: a) M. A. Varner, R. B. Grossman, Tet-
rahedron 1999, 55, 13867–13867; b) X. Y. J. Wang, P. Li,
Org. Biomol. Chem. 2014, 12, 2499–2513.
[12] For recent reviews on the desymmetrization of cyclo-
hexadienones, see: a) G. Maertens, M.-A. Menard, S.
Canesi, Synthesis 2014, 46, 1573–1582; b) K. A. Kalsta-
bakken, A. M. Harned, Tetrahedron 2014, 70, 9571–
9585.
Scheme 3. Plausible mechanism.
References
[13] a) K. Kondo, M. Sodeoka, M. Mori, M. Shibasaki, Tet-
rahedron Lett. 1993, 34, 4219–4222; b) K. Kondo, M.
Sodeoka, M. Mori, M. Shibasaki, Synthesis 1993, 920–
930; c) R. Imbos, A. J. Minnaard, B. L. Feringa, J. Am.
Chem. Soc. 2002, 124, 184–185; d) R.; Imbos, A. J. Min-
naard, B. L. Feringa, Dalton Trans. 2003, 2017–2023;
e) Y. Hayashi, H. Gotoh, T. Tamura, H. Yamaguchi, R.
Masui, M. Shoji, J. Am. Chem. Soc. 2005, 127, 16028–
16029; f) Q. Liu, T. Rovis, J. Am. Chem. Soc. 2006, 128,
2552–2553; g) N. T. Vo, R. D. M. Pace, F. OꢀHara, M. J.
Gaunt, J. Am. Chem. Soc. 2008, 130, 404–405; h) R.
Leon, A. Jawalekar, T. Redert, M. J. Gaunt, Chem. Sci.
2011, 2, 1487–1490; i) Q. Gu, S.-L. You, Chem. Sci.
2011, 2, 1519–1522; j) Q. Gu, S.-L. You, Org. Lett. 2011,
13, 5192–5195; k) S. Takizawa, T. M. N. Nguyen, A.
Grossmann, D. Enders, H. Sasai, Angew. Chem. 2012,
124, 5519–5522; Angew. Chem. Int. Ed. 2012, 51, 5423–
5426; l) M.-Q. Jia, S.-L. You, Chem. Commun. 2012, 48,
6363–6365; m) D. M. Rubush, M. A. Morges, B. J. Rose,
D. H. Thamm, T. Rovis, J. Am. Chem. Soc. 2012, 134,
13554–13557; n) M.-Q. Jia, C. Liu, S.-L. You, J. Org.
Chem. 2012, 77, 10996–11001; o) S. Takizawa, T. M.-N.
Nguyen, A. Grossmann, M. Suzuki, D. Enders, H.
Sasai, Tetrahedron 2013, 69, 1202–1209; p) M.-Q. Jia,
S.-L. You, Synlett 2013, 1201–1204; q) W. Wu, X. Li, H.
Huang, X. Yuan, J. Lu, K. Zhu, J. Ye, Angew. Chem.
2013, 125, 1787–1791; Angew. Chem. Int. Ed. 2013, 52,
1743–1747; r) D. M. Rubush, T Rovis, Synlett 2014,
713–717; s) F. Li, J. Wang, M. Xu, X. Zhao, X. Zhou,
W.-X. Zhao, L. Liu, Org. Biomol. Chem. 2016, DOI:
10.1039/c6ob00281a.
[1] a) J. F. Fisher, S. O. Meroueh, S. Mobashery, Chem.
Rev. 2005, 105, 395–424; b) S. M. Drawz, R. A.
Bonomo, Clin. Microbiol. Rev. 2010, 23, 160–201.
[2] For recent reviews on the stereoselective synthesis of
spirocyclic compounds, see: a) B. M. Trost, M. K.
Brennan, Synthesis 2009, 3003–3025; b) R. Rios, Chem.
Soc. Rev. 2012, 41, 1060–1074; c) A. Nakazakia, S. Ko-
bayashi, Synlett 2012, 1427–1445; d) A. K. Franz, N. V.
Hanhan, N. R. Ball-Jones, ACS Catal. 2013, 3, 540–553;
e) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas III, ACS
Catal. 2014, 4, 743–762; f) Y. Zheng, C. M. Tice, S. B.
Singh, Bioorg. Med. Chem. Lett. 2014, 24, 3673–3682.
[3] a) S. S. Bari, A. Bhalla, Top. Heterocycl. Chem. 2010,
22, 49–99; b) A. A. C. Cativiela, M. Parls, J. M. Peregri-
na, Tetrahedron: Asymmetry 1995, 6, 1409–1418.
[4] a) L.-Y. Chen, A. Zaks, S. Chackalamannil, S. Dugar, J.
Org. Chem. 1996, 61, 8341–8343; b) G. Wu, W. Tormos,
J. Org. Chem. 1997, 62, 6412–6414.
[5] a) F. Benfatti, G. Cardillo, L. Gentilucci, A. Tolomelli,
Eur. J. Org. Chem. 2007, 3199–3205; b) F. Benfatti, G.
Cardillo, L. Gentilucci, A. Tolomelli, Bioorg. Med.
Chem. Lett. 2007, 17, 1946–1950.
[6] J. W. Skiles, D. McNeil, Tetrahedron Lett. 1990, 31,
7277–7280.
[7] a) B. W. Bycroft, R. E. Shute, M. J. Begley, J. Chem.
Soc. Chem. Commun. 1988, 274–276; b) B. W. Bycroft,
L. Gledhill, R. E. Shute, P. Williams, J. Chem. Soc.
Chem. Commun. 1988, 1610–1612.
[8] J. E. Baldwin, M. Otsuka, P. M. Wallace, Tetrahedron
1986, 42, 3097–3110.
[9] a) G. I. Georg, V. T. Ravikumar, in: The Organic
Chemistry of b-Lactams, (Ed.: G. I. Georg), VCH, New
[14] a) R. Imbos, M. H. G. Brilman, M. Pineschi, B. L. Fer-
inga, Org. Lett. 1999, 1, 623–626; b) L. Yao, K. Liu, H.-
Y. Tao, G.-F. Qiu, X. Zhou, C.-J. Wang, Chem.
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Commun. 2013, 6078–6080; c) N. Miyamae, N. Wata-
nabe, M. Moritaka, K. Nakano, Y. Ichikawa, H. Kotsu-
ki, Org. Biomol. Chem. 2014, 12, 5847–5855; d) Y. Na-
ganawa, M. Kawagishi, J. Ito, H. Nishiyama, Angew.
Chem. 2016, 128, 6987–6990; Angew. Chem. Int. Ed.
2016, 55, 6873–6876.
jan, U. Kaya, D. Hack, D. Enders, Adv. Synth. Catal.
2015, 357, 253–281; d) X. Fang, C.-J. Wang, Chem.
Commun. 2014, 51, 1185–1197.
[18] For selected reviews on organocatalytic DKR, see:
a) H. Pellissier, Adv. Synth. Catal. 2011, 353, 659–676;
b) M. Rachwalski, N. Vermue, F. P. J. T. Rutjes, Chem.
Soc. Rev. 2013, 42, 9268–9282; c) H. Pellesier, Tetrahe-
dron 2016, DOI: 10.1016/j.tet.2016.04.053.
[15] J. Liang, J. Chen, F. Du, X. Zeng, L. Li, H. Zhang, Org.
Lett. 2009, 11, 2820–2823.
[16] For reviews on sulfa-Michael reactions, see: a) D.
Enders, K. Lꢃttgen, A. A. Narine, Synthesis 2007, 959–
980; b) P. Chauhan, S. Mahajan, D. Enders, Chem. Rev.
2014, 114, 8807–8864.
[17] For selected reviews on the bifunctional hydrogen-
bonding organocatalysts, see: a) J. Alemꢄn, A. Parra,
H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17,
6890–6899; b) R. I. Storer, C. Aciro, L. H. Jones, Chem.
Soc. Rev. 2011, 40, 2330–2346; c) P. Chauhan, S. Maha-
[19] The crystals of enantiopure 3j were obtained from
ethyl acetate:n-hexane (1:1) upon slow evaporation/sol-
vent diffusion. CCDC 1476009 (3j) contains the supple-
mentary crystallographic data for this paper. These
data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. For more data,
see the Supporting Information.
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Asymmetric Synthesis of Spiro b-Lactams via
a Squaramide-Catalyzed Sulfa-Michael Addition/
Desymmetrization Protocol
7
Adv. Synth. Catal. 2016, 358, 1 – 7
˘
Pankaj Chauhan, Suruchi Mahajan, Ugur Kaya,
Arto Valkonen, Kari Rissanen, Dieter Enders*
Adv. Synth. Catal. 0000, 000, 0 – 0
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