Highly diastereoselective synthesis of β-carboxy-γ-lactams and their ethyl esters via Sc(OTf)3-catalyzed imino Mukaiyama-aldol type reaction of 2,5-bis(trimethylsilyloxy)furan with imines

Article abstract of DOI:10.1021/jo070533r

(Chemical Equation Presented) Functionalized γ-lactams are found to be crucial intermediates in the synthesis of biologically important natural products. We herein described a highly diastereoselective synthesis of β-carboxy-γ-lactams and their ethyl este

Full text of DOI:10.1021/jo070533r

carbene catalyzed addition of enals to imines,4 addition of
homoenolates to imines,5 ring expansion of â-lactams,6 and
cycloaddition strategies.7
Recently, we have developed an alternative approach to
â-carboethoxy-γ-lactam synthesis. The methodology is based
on the reaction of bis(trimethylsilyloxy)-1,4-diethoxy-1,3-buta-
diene with imines via imino Mukaiyama-aldol type reaction
mediated by ZnCl2. Regarding the stereochemical outcome, the
relative stereochemistry of the carboethoxy group at C-â and
the aryl group at C-γ depends on the type of substituent on the
nitrogen atom of the imines (eq 1).8
Highly Diastereoselective Synthesis of
â-Carboxy-γ-lactams and Their Ethyl Esters via
Sc(OTf)3-Catalyzed Imino Mukaiyama-Aldol
Type Reaction of 2,5-Bis(trimethylsilyloxy)furan
with Imines
Manat Pohmakotr,* Nattawut Yotapan,
Patoomratana Tuchinda, Chutima Kuhakarn, and
Vichai Reutrakul*
Department of Chemistry, Faculty of Science, Mahidol
UniVersity, Rama 6 Road, Bangkok 10400, Thailand
scmpk@mahidol.ac.th; scVrt@mahidol.ac.th
ReceiVed March 15, 2007
We now report our findings on a highly diastereoselective
synthesis of the trans isomers of â-carboxy-γ-aryl-γ-lactams
and their ethyl esters from the reaction of 2,5-bis(trimethylsi-
lyloxy)furan (1) and imines catalyzed by Sc(OTf)3. The 2,5-
bis(trimethylsilyloxy)furan (1) was prepared according to the
previously reported procedure.9a It has been used for the
synthesis of γ-hydroxybutenolides9 and as diene for the Diels-
Alder reactions.10 With 2,5-bis(trimethylsilyloxy)furan (1) in
hand, we next examined the Lewis acid suitable for promoting
the reaction. A collection of Lewis acids, i.e., Ti(OiPr)4 and
M(OTf)x, were tested and N-benzylimine derived from benzal-
dehyde was selected as a model substrate (Table 1). Compound
1 was treated with a THF solution of imine 2a and Lewis acid
at -78 °C and the reaction was allowed to proceed at room
temperature (16 h). After being exposed to acidic aqueous
stirring (NH4Cl) at room temperature for 1 h followed by
conventional workup, it provided γ-lactamcarboxylic acid 3a
with excellent diastereoselectivity (99:1 of trans:cis), which was
Functionalized γ-lactams are found to be crucial intermedi-
ates in the synthesis of biologically important natural
products. We herein described a highly diastereoselective
synthesis of â-carboxy-γ-lactams and their ethyl ester
derivatives, in high yields with high diastereomeric ratio,
via the Mukaiyama-aldol type reaction of 2,5-bis(trimethysi-
lyloxy)furan with imines, employing Sc(OTf)3 as a catalyst.
The construction of γ-lactam functionality has been a topic
of great interest for many years since the γ-lactam unit is a
prominent structural feature found in a number of biologically
active natural products.1 In addition, functionalized γ-lactams
have also proven to be attractive synthetic targets, and crucial
intermediates in the synthesis of numerous natural products.1
Therefore, considerable efforts were directed to a great number
of synthetic approaches to γ-lactam synthons. As they are
considered the general methods for assembling γ-lactam unit,
they are based on Rh-catalyzed intramolecular C-H insertion
of diazo derivatives,2 Pd-catalyzed cyclization,3 N-heterocyclic
(3) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (b)
Shaughressy, K. H.; Hammann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
63, 6546-6553. (c) Craig, D.; Hyland, C. J. T.; Ward, S. E. Chem. Commun.
2005, 3439-3441. (d) Poli, G.; Giambastiani, G.; Malacria, M.; Thorimbert,
S. Tetrahedron Lett. 2001, 42, 6287-6289. (e) Madec, D.; Prestat, G.;
Martini, E.; Fristrup, P.; Poli, G.; Norrby, P. O. Org. Lett. 2005, 7, 995-
998.
(4) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131-3134 and references
cited therein.
(5) (a) Abbas, M.; Neuhaus, C.; Krebs, B.; Westermann, B. Synlett 2005,
473-476. (b) Okamoto, S.; Teng, X.; Fujii, S.; Takayama, Y.; Sato, F. J.
Am. Chem. Soc. 2001, 123, 3462-3471. (c) DiMauro, E.; Fry, A. J.
Tetrahedron Lett. 1999, 40, 7945-7949.
(6) 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, 1755-1757 and references
cited therein.
(7) See for examples: (a) Wang, Q.; Nara, S.; Padwa, A. Org. Lett. 2005,
7, 839-841. (b) Sun, P.-P.; Chang, M.-Y.; Chiang, M. Y.; Chang, N.-C.
Org. Lett. 2003, 5, 1761-1763.
(8) Pohmakotr, M.; Yotapan, N.; Tuchinda, P.; Kuhakarn, C.; Reutrakul,
V. Tetrahedron 2007, 63, 4328-4337.
(9) (a) Brownbridge, P.; Chan, T.-H. Tetrahedron Lett. 1980, 21, 3431-
3434. (b) Troll, T.; Schmid, K. Tetrahedron Lett. 1984, 25, 2981-2984.
(10) Taguchi, T.; Hosoda, A.; Tomizawa, G.; Kawara, A.; Masuo, T.;
Suda, Y.; Nakajima, M.; Kobayashi, Y. Chem. Pharm. Bull. 1987, 35, 909-
912.
(1) (a) Bergann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492-503. (b)
Barrett, A. G.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.;
Williams, D. J. J. Org. Chem. 1999, 64, 6005-6018. (c) Barrett, A. G. M.;
Head, J.; Smith, M. L.; Sotck, N. S.; White, A. J. P.; Williams, D. J. J.
Org. Chem. 1999, 64, 6005-6018. (d) Huang, P. Q.; Zheng, X.; Wang, S.
L.; Ye, J. L.; Jin, L. R.; Chen, Z. Tetrahedron: Asymmetry 1999, 10, 3309-
3317. (e) Aoki, S.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.; Tadano, K.
Bull. Chem. Soc. Jpn. 2004, 77, 1703-1716. (f) Aoki, S.-Y.; Tsukude, T.;
Miyazaki, Y.; Takao, K.; Tadano, K. Heterocycles 2006, 69, 49-54.
(2) (a) Yoon, C.-H.; Flanigan, D. L.; Chong, B.-D.; Jung, K.-W. J. Org.
Chem. 2002, 67, 6582-6585 and references cited therein. (b) Choi, M.
K.-W.; Yu, W.-Y.; Che, C. M. Org. Lett. 2005, 7, 1081-1084 and references
cited therein.
10.1021/jo070533r CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/17/2007
5016
J. Org. Chem. 2007, 72, 5016-5019

TABLE 1. Screening of Lewis Acids
TABLE 2. Sc(OTf)3-Catalyzed Reaction of Compound 1 with
Imines 2a-l
yield (%);b
trans:cisc
entry
Lewis acida
1
2
3
4
5
Ti(OiPr)4
Sc(OTf)3
Yb(OTf)3
Zn(OTf)2
In(OTf)3
60; 99:1
86; 99:1
67; 99:1
74; 99:1
80; 99:1
imine
lactam
3
yield (%);a
entry
2
Ar
trans:cisb
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
86; 99:1
72; 99:1
74; 99:1
65; 90:10
70; 99:1
89; 99:1
63; 99:1
75; 99:1
60; 80:20
70; 80:20
60; 80:20
65; 90:10
4-MeOC6H4
3-MeOC6H4
3,4-(MeO)2C6H3
4-MeC6H4
4-ClC6H4
4-NO2C6H4
2-furyl
C6H5
a 100 mol % for Ti(OiPr)4 and 5 mol % for M(OTf)x. b Isolated yields
after crystallization from iPrOH. c Determined by integration of the 1H NMR
(300 MHz) spectra of the crude products before crystallization.
1
determined by integration of the H NMR (300 MHz) spectra
of the crude product. Pure trans-3a, with yields ranging from
60% to 86% depending on the types of Lewis acid employed,
was obtained after single crystallization from PrOH. A sto-
10
11
12
2j
2k
2l
4-MeOC6H4
3,4-MeOC6H3
4-ClC6H4
3j
3k
3l
i
ichiometric amount of Ti(OiPr)4 showed moderate reactivity,
affording lactam 3a in moderate yield (60%, Table 1, entry 1).
Metal triflates, Yb(OTf)3, Zn(OTf)2, In(OTf)3, and Sc(OTf)3,
as catalysts gave better results (67-86%, Table 1, entries 2-5).
Among these, Sc(OTf)3 was found to be the best catalyst. In
addition, Sc(OTf)3-catalyzed Mukaiyama-aldol reactions and
imine activation are extensively documented.11
a Isolated yields of the acid or ethyl ester derivatives. b Determined by
integration of the 1H NMR (300 MHz) spectra of the crude lactamcarboxylic
acids before crystallization or exposure to esterification.
with lower yields and diminished diastereoselectivity (60-70%
yields with trans:cis ) 80:20 to 90:10; Table 2, entries 9-12).
These results are in sharp contrast to our earlier work on the
ZnCl2-catalyzed reaction of bis(trimethylsilyloxy)-1,4-diethoxy-
1,3-butadiene with N-benzyl- and N-phenylimimes (eq 1).8 It
is worth emphasizing that in the present work the trans isomer
is preferentially formed regardless of the type of substituent
(phenyl or benzyl) on the imine nitrogen. Even though the
diastereoselectivities are moderate in case of N-phenylamine,
pure diastereomer can be obtained by simple chromatographic
purification.
On the basis of our previous report and our current studies,
the possible mechanistic pathway of the imino Mukaiyama-aldol
reaction of 2,5-bis(trimethylsilyloxy)furan (1) and imines cata-
lyzed by Sc(OTf)3 is illustrated in Scheme 1. The reaction was
proposed to proceed via the staggered acyclic transition state.12
It is assumed that the Sc(OTf)3 occupied a coordination site on
the nitrogen atom of the imine such that it is cis to the Ar group
of the imine carbon. Now 2,5-bis(trimethylsilyloxy)furan (1)
can approach the imine by transition state 4A or 4B. It is
envisioned that the diastereoselectivity was governed by the
steric effect caused by repulsion interaction of the Sc(OTf)3 and
the carbon atom (Câ) of the furan ring. Therefore, transition
state 4A is more favorable by positioning the least steric
hydrogen atom at Câ of the furan ring being cis to the Sc(OTf)3,
leading preferably to trans γ-lactam after aqueous workup. The
reaction of N-phenylimines with compound 1 leading to lower
diastereoselection may result from slow cyclization due to the
low nucleophilicity of the nitrogen atom. Thus, the equilibration
at the stereogenic R-carbon adjacent to the anhydride group
occurred.
The Sc(OTf)3-catalyzed imino Mukaiyama-aldol type reaction
of 2,5-bis(trimethylsilyloxy)furan (1) was further studied with
other imine substrates and the results were summarized in
Table 2. The diastereomeric ratios in all cases as shown in Table
1
2 were established from the H NMR integration of the crude
materials of the γ-lactamcarboxylic acids. The γ-lactam products
were isolated either as the carboxylic acid derivative in the case
when the crystallization was allowed or as ethyl ester by
exposure of the crude mixture to SOCl2 (3 equiv) in ethanol,
-78 °C to room temperature for 5 h, followed by chromato-
graphic purification and crystallization. Measurement of the
diastereomeric ratios of the ethyl ester derivatives by 1H NMR
integration of the crude materials confirmed that no epimeriza-
tion took placed under the esterification reaction conditions
employed. Finally, relative stereochemistry of the γ-lactam
products was established and assigned by analogy with our
previous work.8 Generally, N-benzylimine substrates
(Table 2, entries 1-8) produced γ-lactam products with good
to moderate yields (63-89%) with high diastereoselectivity
(trans:cis ) 99:1) except for N-benzylimine derived from 3,4-
dimethoxybenzaldehyde (Table 2, entry 4, inseparable mixture
of trans:cis ) 90:10). From the experimental results, there is
no obvious relationship between the electron density of the Ar
group of the arylimine substrates and the yields of the corre-
sponding γ-lactam products. The reaction of N-phenylimime
also proceeded under the same reaction conditions, however,
(11) (a) Kobayashi, S. Eur. J. Org. Chem. 1999, 15-27. (b) Maity, B.
C.; Puranik, V. G.; Sarkar, A. Synlett 2002, 504-506. (c) France, S.; Shah,
M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem.
Soc. 2005, 127, 1206-1215. (d) Anderson, J. C.; Blake, A. J.; Howell, G.
P.; Wilson, C. J. Org. Chem. 2005, 70, 549-555.
(12) Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem. Eur. J. 2006,
12, 5082-5093.
J. Org. Chem, Vol. 72, No. 13, 2007 5017

SCHEME 1
1 mmol) in THF (2 mL) was added dropwise. The resulting mixture
was slowly warmed to room temperature and stirred overnight. After
16 h, saturated aqueous NH4Cl (2 mL) was added and the mixture
was stirred at room temperature for 1 h before it was extracted
with EtOAc (3 × 30 mL). The combined organic layers were
washed with water (3 × 30 mL) and brine (30 mL) and dried over
anhydrous Na2SO4. After removal of the solvents, the diastereomeric
ratio of the crude γ-lactamcarboxylic acid 3a was determined by
1H NMR integration to consist of a 99:1 mixture of trans:cis isomer.
A pure trans isomer of 3a was obtained after single crystallization
from iPrOH (0.253 g, 86%, mp 171-172 °C). 1H NMR (300 MHz,
CDCl3) δ 7.45-6.95 (m, 10H), 5.09 (d, J ) 14.7 Hz, 1H), 4.63 (d,
J ) 5.6 Hz, 1H), 3.47 (d, J ) 14.7 Hz, 1H), 3.15-3.05 (m, 1H),
3.00-2.75 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 175.7, 173.0,
138.6, 135.4, 129.2, 128.7, 128.6, 128.4, 127.7, 127.0, 63.5, 45.6,
44.5, 33.5. IR (KBr) νmax 3448, 3033, 1731, 1655 cm-1. MS m/z
(%) relative intensity 296 ([M + 1]+, 5), 295 ([M]+, 30), 204 (100),
147 (22), 146 (51), 132 (29), 119 (19), 118 (60), 117 (13), 115
(22), 104 (45), 91 (42), 77 (11), 65 (14). HRMS (ESI-TOF) calcd
for C18H17NO3Na [M + Na]+ 318.1106, found 318.1110.
Preparation of Ethyl 5-Oxo-1,2-diphenylpyrrolidine-3-car-
boxylate (3i). To a 50 mL round-bottomed flask charged with Sc-
(OTf)3 (49 mg, 0.05 mmol) was added a solution of imine 2i
(0.185 g, 1 mmol) in THF (1 mL) at room temperature. The mixture
was further stirred at room temperature under an argon atmosphere
for 30 min. The mixture was brought to -78 °C (dry ice-acetone)
and a solution of 2,5-bis(trimethylsilyloxy)furan (1) (0.244 g,
1 mmol) in THF (2 mL) was added dropwise. The resulting mixture
was slowly warmed to room temperature and stirred overnight. After
16 h, saturated aqueous NH4Cl (2 mL) was added and the mixture
was stirred at room temperature for 1 h before it was extracted
with EtOAc (3 × 30 mL). The combined organic layers were
washed with water (3 × 30 mL) and brine (30 mL) and dried over
anhydrous Na2SO4. After removal of the solvents, the diastereomeric
In summary, we have developed an efficient and highly
diastereoselective synthesis of â-carboxy-γ-aryl-γ-lactams and
their ethyl esters from the reaction of 2,5-bis(trimethylsilyloxy)-
furan and imines catalyzed by Sc(OTf)3. The methodology offers
an alternative and efficient method for the synthesis of func-
tionalized γ-lactams in terms of simplicity of the procedure,
readily available starting materials, mild reaction conditions,
and high diastereoselectivity. A study of the enantioselective
synthesis of this type of γ-lactam is currently underway.
1
ratio of the crude γ-lactamcarboxylic acid was determined by H
NMR integration to consist of an 80:20 mixture of trans:cis isomers.
The ethyl ester derivative was then prepared according to General
Procedure A: Thionyl chloride (0.2 mL, 3 mmol) was added
dropwise to a stirred -78 °C dry EtOH (20 mL) solution. To this
mixture was added a solution of a crude γ-lactamcarboxylic acid
in dry EtOH (5 mL). The reaction mixture was allowed to warm
to room temperature under an argon atmosphere. After 5 h, EtOH
was removed (aspirator). The residue was quenched by slow
addition of saturated aqueous Na2CO3 at 0 °C. The aqueous layer
was extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with H2O (25 mL) and brine (25 mL), dried
(Na2SO4), filtered, and concentrated. A crude ethyl ester residue
was purified by preparative thin-layer chromatography (SiO2, 20%
EtOAc in hexanes, triple runs). The higher Rf was trans-3i (0.161
g, 52%, a pale yellow solid, mp 115-116 °C). 1H NMR (300 MHz,
CDCl3) δ 7.39 (d, J ) 7.6 Hz, 2H), 7.35-7.19 (m, 7H), 7.06 (t, J
) 7.5 Hz, 1H), 5.53 (d, Jtrans ) 4.6 Hz, 1H), 4.22 (q, J ) 7.1 Hz,
2H), 3.20-2.80 (m, 3H), 1.27 (t, J ) 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 172.15, 172.09, 139.7, 137.5, 129.0, 128.7,
128.2, 126.1, 125.3, 122.7, 65.8, 61.6, 46.4, 34.3, 14.1. IR (CHCl3)
νmax 1731 (CdO of ester), 1698 (CdO of amide) cm-1. MS m/z
(%) relative intensity 310 ([M + 1]+, 24), 309 ([M]+ 97), 236 (100),
208 (99), 180 (71), 91 (24), 77 (38), 50 (11). Anal. Calcd for C19H19-
NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.79; H, 6.25; N,
Experimental Section
General Procedure for the Reaction of 2,5-Bis(trimethylsi-
lyloxy)furan (1) with Imines, Using Sc(OTf)3 as a Catalyst.
To a 50 mL round-bottomed flask charged with Sc(OTf)3 (49 mg,
0.05 mmol) was added a solution of imine (1 mmol) in THF
(1 mL) at room temperature. The mixture was further stirred at
room temperature under an argon atmosphere for 30 min. The
mixture was brought to -78 °C (dry ice-acetone) and a solution
of 2,5-bis(trimethylsilyloxy)furan (1) (0.244 g, 1 mmol) in THF
(2 mL) was added dropwise. The resulting mixture was slowly
warmed to room temperature and stirred overnight. After 16 h,
saturated aqueous NH4Cl (2 mL) was added and the mixture was
stirred at room temperature for 1 h before it was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with water (3 × 30 mL) and brine (30 mL) and dried over
anhydrous Na2SO4. Removal of solvents (aspirator then vacuo)
yielded a crude γ-lactamcarboxylic acid whose diastereomeric ratio
1
was determined by H NMR integration. The crude material was
purified by crystallization to yield the acid derivative or conversion
to ethyl ester derivative (SOCl2, EtOH, -78 °C to rt) before
chromatographic purification when the crystallization of the first
formed acid was found difficult.
1
4.41. The lower Rf was cis-3i (25 mg, 8%, a pale yellow oil). H
NMR (300 MHz, CDCl3) δ 7.42 (d, J ) 7.9 Hz, 2H) 7.35-7.10
(m, 7H), 7.06 (t, J ) 7.3 Hz, 1H), 5.48 (d, Jcis ) 8.8 Hz, 1H),
3.88-3.65 (m, 3H), 3.32 (dd, J ) 17.3, 10.2 Hz, 1H), 2.72 (dd, J
) 17.3, 8.8 Hz, 1H), 0.99 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 172.7, 169.5, 137.8, 136.2, 128.7, 128.62, 128.60, 127.0,
125.3, 122.1, 65.1, 61.0, 43.7, 32.9, 13.7. IR (neat) νmax 1732 (Cd
O of ester), 1707 (CdO of amide) cm-1. MS m/z (%) relative
Preparation of 1-Benzyl-5-oxo-2-phenylpyrrolidine-3-car-
boxylic Acid (3a). To a 50 mL round-bottomed flask charged with
Sc(OTf)3 (49 mg, 0.05 mmol) was added a solution of imine 2a
(0.195 g, 1 mmol) in THF (1 mL) at room temperature. The mixture
was further stirred at room temperature under an argon atmosphere
for 30 min. The mixture was brought to -78 °C (dry ice-acetone)
and a solution of 2,5-bis(trimethylsilyloxy)furan (1) (0.244 g,
5018 J. Org. Chem., Vol. 72, No. 13, 2007

intensity 310 ([M + 1]+, 29), 309 ([M]+, 75), 281 (51), 236 (100),
208 (78), 91 (21), 77 (33), 65 (3). HRMS (ESI-TOF) calcd for
C19H19NO3Na [M + Na]+ 332.1263, found 332.1263.
Fund to M.P. (BRG 49800005) and to V.R. (Senior Research
Scholar) is gratefully acknowledged.
Supporting Information Available: Experimental details and
characterization data of compound 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the Center for
Innovation in Chemistry: Postgraduate Education and Research
Program in Chemistry (PERCH-CIC) and the Thailand Research
JO070533R
J. Org. Chem, Vol. 72, No. 13, 2007 5019