Asymmetric iodolactamization induced by chiral oxazolidine auxiliary

Article abstract of DOI:10.1021/jo0488006

Asymmetric iodolactamization reactions of unsaturated amides with oxazolidines as the chiral auxiliaries were investigated. With (4S)-4-((2R)-2-butyl)-2,2-dimethyloxazolidine as the auxiliary and LiH as the base, a number of unsaturated amides underwent i

Full text of DOI:10.1021/jo0488006

Asymmetric Iodolactamization Induced by Chiral Oxazolidine
Auxiliary
Meihua Shen and Chaozhong Li*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. China
clig@mail.sioc.ac.cn
Received July 15, 2004
Asymmetric iodolactamization reactions of unsaturated amides with oxazolidines as the chiral
auxiliaries were investigated. With (4S)-4-((2R)-2-butyl)-2,2-dimethyloxazolidine as the auxiliary
and LiH as the base, a number of unsaturated amides underwent iodolactamization smoothly to
afford the corresponding γ- and δ-lactams in 30-98% yield with de values up to 97%.
Introduction
our surprise, has been systematically examined. Only two
separate examples of substrate-controlled asymmetric
iodolactamization have been reported.9,10 Takahata et al.
reported the asymmetric synthesis of statine via stereo-
selective iodolactamization of a chiral â-hydroxythioimi-
date.9 Knapp treated 3(S)-hydroxy-4-pentenamide with
excess TMSOTf/Et3N and iodine to generate the corre-
sponding asymmetric γ-lactam, which served as the
intermediate in the synthesis of (-)-slaframine.10 Nev-
ertheless, these two examples demonstrated the great
potential of asymmetric iodolactamization in natural
product synthesis and urged us to develop efficient and
general methods for asymmetric iodolactamization. We
here report the first chiral-auxiliary-induced iodolactam-
ization leading to the asymmetric syntheses of γ- and
δ-lactams.
Halocyclizations of unsaturated compounds have been
well established as an indispensable tool in the synthesis
of heterocyclic compounds and continue to be pursued
with a growing interest in their asymmetric reactions.1
Among them, the most widely studied type of reaction is
iodolactonization. Asymmetric iodolactonization reactions
have been carried out via substrate-controlled 1,3-induc-
tion2 or with the aid of chiral auxiliaries3 or chiral ligands
such as amines.4
Compared to iodolactonization, iodolactamization is
much less investigated. This is because the halocycliza-
tion of amides usually produces lactones rather than
lactams.1 To achieve lactamization, methods such as N,O-
bis-silylation,5 N-tosyl or N-alkoxycarbonyl substitution,6
and use of a strong base7 have been developed. More
recently, Taguchi et al. reported the efficient iodoami-
nocyclization with BuLi or LiAl(OBut)4 as the base.8
Whereas asymmetric iodolactonization continues to be
actively pursued,2-4 no asymmetric iodolactamization, to
Results and Discussion
Asymmetric oxazolidines and oxazolidinones are widely
used as chiral auxiliaries in many reactions such as
asymmetric free radical R-alkylation of carboxamides.11,12
They are readily prepared from 1,2-amino alcohols, which
in turn are available from the corresponding R-amino
acids. Thus, we designed models 1 and 2 with oxazo-
lidines and oxazolidinones as the chiral auxiliaries,
respectively. Substrates 1 could be easily prepared in
high yields in a one-pot procedure from their parent
amide 313 by its reaction with oxalyl chloride followed
by the addition of oxazolidines.14
(1) For reviews, see: (a) Cardillo, G.; Orena, M. Tetrahedron 1990,
46, 3321. (b) Harding, K. E.; Tiner, T. H. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol.
4, p 363. (c) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681.
(2) For the latest examples, see: Blot, V.; Reboul, V.; Metzner, P.
J. Org. Chem. 2004, 69, 1196.
(3) Moon, H.-S.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N. E.;
Kurth, M. J. J. Org. Chem. 1994, 59, 6504.
(4) (a) Haas, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297. (b)
Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J.
Org. Chem. 2004, 69, 2874.
(5) (a) Knapp, S.; Rodriques, K. E.; Levorse, A. T.; Ornaf, R. M.
Tetrahedron Lett. 1985, 26, 1803. (b) Knapp, S.; Levorse, A. T. J. Org.
Chem. 1988, 53, 4006. (c) Knapp, S.; Gibson, F. S. Org. Synth. 1992,
70, 101. (d) Kanpp, S. In Advances in Heterocyclic Natural Product
Synthesis; JAI Press: Greenwich, 1996; Vol. 3, p 57.
(6) (a) Biloski, A. J.; Wood, R. D.; Ganem, B. J. Am. Chem. Soc. 1982,
104, 3233. (b) Rajendra, G.; Miller, M. J. Tetrahedron Lett. 1985, 26,
5385. (c) Rajendra, G.; Miller, M. J. Tetrahedron Lett. 1987, 28, 6257.
(d) Rajendra, G.; Miller, M. J. J. Org. Chem. 1987, 52, 4471.
(7) Boeckman, R. K., Jr.; Connell, B. T. J. Am. Chem. Soc. 1995,
117, 12368.
(9) Takahata, H.; Yamazaki, K.; Takamatsu, T.; Yamazaki, T.;
Momose, T. J. Org. Chem. 1990, 55, 3947.
(10) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802.
(11) For a review, see: Porter, N. A. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
Germany, 2001; Vol. 1, p 416.
(12) For recent examples, see: (a) Sibi, M. P.; Rheault, T. R.;
Chandramouli, S. V.; Jasperse, C. P. J. Am. Chem. Soc. 2002, 124,
2924. (b) Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-x. J. Org. Chem.
2002, 67, 1738. (c) Sibi, M. P.; Chen, J.; Rheault, T. R. Org. Lett. 2001,
3, 3679.
(13) Brown, R. F.; vanGulick, N. M. J. Am. Chem. Soc. 1955, 77,
1092.
(8) (a) Kitagawa, O.; Fujita, M.; Li, H.; Taguchi, T. Tetrahedron Lett.
1997, 38, 615. (b) Fujita, M.; Kitagawa, O.; Suzuki, T.; Taguchi, T. J.
Org. Chem. 1997, 62, 7330.
10.1021/jo0488006 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/12/2004
7906
J. Org. Chem. 2004, 69, 7906-7909

Asymmetric Iodolactamization
TABLE 1. Synthesis of 6a-e via Iodolactamization of
1a-e with BuLi as Base
substrate
R
yield (%)a
de (%)b
1a
1b
1c
1d
1e
iPr
tBu
Bn
42
40
20
24
30
85
75
>99
>99
95
iPrCH2
To ensure the efficient iodolactamization for 1 and 2,
we first prepared dimethylaminocarbonyl-substituted
amide 4 as the model substrate and subjected it to the
reaction with iodine according to Taguchi’s procedure.8
Thus, treatment of 4 with BuLi at 0 °C followed by the
addition of iodine at room temperature afforded the
expected cyclization product 5 in 76% yield (eq 1).
2(R)-butyl
a Isolated yield based on 1. b Determined by 1H NMR of the
crude product 6 and by HPLC of their phenylsulfide derivatives.
See text.
TABLE 2. Effect of Base on the Cyclization of 1e
entry
base
yield (%)a
de (%)b
1
2
3
4
5
6
BuLi
30
38
25
37
72
67
95
94
90
70
70
78
LDA
LiAl(OtBu)4
tBuOK
NaH
LiH
a Isolated yield based on 1. b Determined by 1H NMR of the
crude product 6 and by HPLC of their phenylsulfide derivatives.
See text.
As the yield of 5 was acceptable, we carried out the
reactions of 1a-e under the above experimental condi-
tions, trying to find the best chiral auxiliary for the
asymmetric induction in the cyclization products 6a-e
(eq 2). The results are summarized in Table 1.
Compared to the substrate 4, 1a-e gave rather low
yields of cyclization products. This prompted us to take
measures to improve the yields of 6. Apparently the
critical factor in the reaction is the base, as also indicated
by Taguchi et al.8 We chose 1e to optimize the reaction
conditions. Thus, 1e was treated with a base in THF at
0 °C for 1 h followed by the addition of iodine at room
temperature. The results are illustrated in Table 2.
As can be seen from Table 1, excellent diastereoselec-
tivity was observed in the cases of 1c-e. The products
6a-e were converted to the corresponding phenylsulfide
by reaction with PhSH/K2CO3 at room temperature, and
HPLC analyses confirmed the de values measured by 1H
NMR. Furthermore, the nucleophilic substitution of 6a
(85% de) with PhSH in the presence of K2CO3 followed
by subsequent hydrolysis with KOH afforded lactam 7
in quantitative yield with 84% ee determined by chiral
HPLC (eq 3). In the meantime, the corresponding chiral
1,2-amino alcohol was recovered quantitatively. This
result not only further confirmed the de values deter-
As indicated in Table 2, sodium hydride or lithium
hydride gave high yields of the expected product. How-
ever, the diastereoselectivity was lowered. We suspected
that the high de values in other cases (Table 1 and entries
1-3, Table 2) probably resulted from the instability of
the minor isomers with high steric hindrance under those
experimental conditions. The differences between metal
hydrides and other bases such as BuLi might also be
attributed to the steric hindrance in substrates 1, which
required the base to be of the least bulkiness.
We also tested the effect of Lewis acids in the above
reaction with NaH as the base. Unfortunately, it turned
out that the addition of Lewis acids screened did not help
improve the diastereoselectivity. For example, with the
presence of Ti(OiPr)4 (1 equiv), the iodolactamization of
1e afforded 6e in 60% yield with a 71% de. With the
addition of MgBr2‚OEt2 (2 equiv), 1e was partially
decomposed. After the usual workup, only 48% of the
starting material was recovered and no expected cycliza-
tion product could be isolated. Other Lewis acids such
as Zn(OTf)2 showed no effect on the outcome of iodolac-
tamization of 1e or led to the decomposition of 1e.
1
mined by H NMR but also demonstrated the potential
of the above methodology in organic synthesis. The new
stereogenic center in the preferred isomers is in R
configuration as evidenced by the X-ray structure of 6c
(see Supporting Information).
With LiH or NaH as the base, we rechecked the effect
of R groups in 1 on the asymmetric induction. However,
for 1c (R ) Bn) and 1d (R ) PrCH2), no significant
We also prepared the corresponding oxazolidinone
substrates 2 (R ) Bn). However, its reaction with iodine
and a base such as BuLi failed to give the expected
cyclization product, and the starting material simply
decomposed to the corresponding 2,2-dimethylpentenoic
acid.
i
improvement in the yields of cyclization could be ob-
served, probably because they were more bulky in
structure than 1e. As a comparison, the iodolactamiza-
tion of 4 afforded 5 in 98% yield with LiH as the base.
It is worth mentioning here that we also explored
extensively the possible 5-exo amidyl radical cyclization
(14) Speziale, A.; Smith, L.; Fedder, J. J. Org. Chem. 1965, 30, 4306.
J. Org. Chem, Vol. 69, No. 23, 2004 7907

Shen and Li
TABLE 3. Iodolactamization of 1e and 8-13
10 with no substitution at R-carbonyl position, the
cyclization yields were moderate. On the other hand, with
R-disubstituted hexenamides 11-13, the iodolactamiza-
tion products 17-19 were obtained in excellent yields
(90-98%). Good to excellent diastereoselectivities (59-
97% de) were observed. The best asymmetric induction
was observed in the case of 13 with a cyclopentyl
substitution, probably as a result of its relatively rigid
conformation.
The above selectivity is possibly rationalized by the
transition state conformations A and B. In the chairlike
transition state model A, the olefinic moiety and the sec-
butyl group lie at the opposite faces of the imide plane
to avoid steric repulsion, whereas the two groups are at
the same face in model B. Therefore, model A should be
more favorable than B. Thus, the new chiral center
formed is preferentially in the R configuration.
Conclusion
We have demonstrated for the first time a relatively
efficient model for chiral-auxiliary-induced asymmetric
iodolactamization. With LiH as the base and the ap-
propriate oxazolidine as the chiral auxiliary, both γ- and
δ-lactams can be achieved in high yield with good to
excellent diastereoselectivity. Moreover, the cyclization
products could undergo further transformations and
subsequent hydrolysis without loss of diastereoselectivity,
thus making the above strategy of important application
in organic synthesis.
a
b Isolated yield. c Determined by 1H NMR (300
MHz) of the crude product. d Determined by HPLC.
Experimental Section
reactions15,16 of 1 under various experimental conditions
(tBuOCl/I2,17 PhI(OAc)2/I2/tBuOH,18 etc.). Unfortunately,
our attempt failed and only iodolactonization occurred
in most cases.
On the basis of the above efforts, we concluded that
the optimized condition for the asymmetric iodolactam-
ization was to use 2(S)-butyl-substituted oxazolidine (as
in 1e) as the chiral auxiliary and to use NaH or LiH as
the base. Thus, we carried out the iodolactamization
reactions of unsaturated amides 8-13 with LiH as the
base. The results are summarized in Table 3.
Preparation of 1e. Typical Procedure. Oxalyl chloride
(1.45 mL, 17 mmol) in ethylene dichloride (5 mL) was added
to 2,2-dimethyl-4-pentenamide (1.52 g, 12 mmol) in ethylene
dichloride (30 mL) at 0 °C. The solution was allowed to warm
to room temperature and then refluxed with stirring for 24 h.
The resulting mixture was concentrated under reduced pres-
sure to leave the residue as 2,2-dimethyl-pent-4-enoyl isocy-
anate, which was directly used without further purification.
To (4S)-4-((2R)-2-butyl)-2,2-dimethyloxazolidine19 (1.57 g, 10
mmol) in dry dichloromethane (30 mL) was added the above
isocyanate (1.53 g, 10 mmol) in dry dichloromethane (10 mL),
and the resulting solution was stirred for 4 h at room
temperature. After removal of the solvent, the crude product
was purified by column chromatography on silica gel with
hexane-acetone (20:1) as the eluent to give the pure 1e as a
As indicated in Table 3, both γ-lactams and δ-lactams
could be achieved in this manner. For substrates 9 and
colorless oil: yield 2.52 g (85%); [R]25 ) +24.7 (c 1.00, CH3-
D
(15) For reviews, see: (a) Esker, J.; Newcomb, M. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New
York, 1993; Vol. 58, p 1. (b) Fallis, A. G.; Brinza, I. M. Tetrahedron
1997, 53, 17543. (c) Stella, L. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001;
Vol. 2, p 407.
(16) For the latest examples, see: (a) Nicolaou, K. C.; Baran, P. S.;
Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J.
Am. Chem. Soc. 2002, 124, 2233. (b) Gagosz, F.; Moutrille, C.; Zard,
S. Z. Org. Lett. 2002, 4, 2707.
(17) Barton, D. H. R.; Beckwith, A. L. J.; Goosen, A. J. Chem. Soc.
1965, 181.
(18) Concepcion, J. I.; Francisco, C. G.; Hernandez, R.; Salazar, J.
A.; Suarez, E. Tetrahedron Lett. 1984, 25, 1953.
COCH3); 1H NMR (300 MHz, CDCl3) δ 0.76-0.83 (6H, m),
0.90-1.05 (1H, m), 1.14 (6H, s), 1.21-1.33 (1H, m), 1.49 (3H,
s), 1.59 (3H, s), 1.62-1.71 (1H, m), 2.18-2.32 (2H, m), 3.76-
3.80 (2H, m), 3.89-3.95 (1H, m), 5.00-5.05 (2H, m), 5.63-
5.75 (1H, m), 8.50 (1H, br); 13C NMR (CDCl3) δ 21.6, 23.1, 23.6,
24.5, 24.6, 25.6, 26.7, 42.6, 43.0, 44.2, 56.4, 67.1, 95.0, 118.6,
133.5, 150.1, 176.3; EIMS m/z (rel intensity) 295 (M+ - CH3,
4), 252 (7), 237 (6), 210 (21), 169 (10), 142 (100), 100 (24), 83
(19) Poter, N. A.; Bruhnke, J. D.; Wu, W.-X.; Rosenstein, I. J.;
Breyer, R. A. J. Am. Chem. Soc. 1991, 113, 7788.
7908 J. Org. Chem., Vol. 69, No. 23, 2004

Asymmetric Iodolactamization
(65). Anal. Calcd for C17H30N2O3: C, 65.77; H, 9.74; N, 9.02.
Found: C, 65.64; H, 9.70; N, 8.97.
55.2, 60.2, 64.1, 96.0, 150.7, 180.1. Minor isomer: 1H NMR
(300 MHz, CDCl3) δ 0.79-0.86 (6H, m), 1.02-1.22 (2H, m),
1.10 (3H, s), 1.17 (3H, s), 1.50 (3H, s), 1.62 (3H, s), 1.67-1.74
(1H, m), 1.94-2.13 (1H, m), 3.18-3.25 (1H, m), 3.47-3.51 (1H,
m), 3.73-3.78 (1H, m), 3.87-3.96 (2H, m), 4.04-4.09 (1H, m);
13C NMR (CDCl3) δ 6.7, 12.2, 14.3, 23.3, 24.2, 25.5, 26.0, 26.5,
37.2, 41.4, 41.9, 57.3, 60.2, 64.7, 95.8, 152.2, 179.5. EIMS m/z
(rel intensity) 421 (M+ - CH3, 33), 379 (28), 350 (100), 297
(69), 280 (70), 254 (65), 209 (33), 83 (81); HRMS calcd for
C16H26IN2O3 (M+ - CH3) 421.1055, found 421.1022.
Typical Procedure for Iodolactamization Reactions.
To a solution of 1e (124 mg, 0.4 mmol) in dry THF (10 mL)
was added LiH (98%, 9.73 mg, 1.2 mmol) at 0 °C under
nitrogen atmosphere. The mixture was stirred at 0 °C for 20
min, allowed to warm to room temperature, and stirred for
an additional 20 min. Iodine (305 mg, 1.2 mmol) was added,
and the resulting mixture was stirred at room temperature
for 15 h. Aqueous NaHSO3 solution (10 mL) was then added
with care. The two layers were separated, and the aqueous
phase was extracted with ethyl acetate (3 × 10 mL). The
combined organic layer was washed with brine (2 × 10 mL)
and then dried over anhydrous MgSO4. After removal of the
solvent, the crude product was purified by column chroma-
tography on silica gel with hexane-acetone (20:1) as the eluent
to give 6e as a white solid: yield 117 mg (67%). Major isomer:
1H NMR (300 MHz, CDCl3) δ 0.79-0.86 (6H, m), 1.02-1.22
(2H, m), 1.12 (3H, s), 1.15 (3H, s), 1.40-1.49 (1H, m), 1.46 (3H,
s), 1.64 (3H, s), 1.67-1.74 (1H, m), 2.26-2.32 (1H, m), 2.82-
2.89 (1H, m), 3.49 (1H, dd, J ) 3.4, 9.2 Hz), 3.77-3.82 (1H,
m), 3.87-3.96 (1H, m), 4.16-4.27 (2H, m); 13C NMR (CDCl3)
δ 6.7, 12.2, 14.5, 23.3, 24.2, 25.5, 25.7, 27.0, 37.2, 41.5, 41.9,
Acknowledgment. This project was supported by
the National Natural Science Foundation of China, by
the Shanghai Municipal Scientific Committee, and by
the Chinese Academy of Sciences.
Supporting Information Available: Synthesis and char-
acterization of compounds 1a-d, 4, 5, 6a-d, and 7-19 and
X-ray crystal structure of 6c in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0488006
J. Org. Chem, Vol. 69, No. 23, 2004 7909