Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utilizing organocopper-mediated reduction-alkylation and diastereoselectivity examination using DFT calculations

Article abstract of DOI:10.1021/jo060202z

We have carefully examined the organocopper-mediated reduction-alkylation of γ-acetoxy or γ,γ-difluoro-α,β-unsaturated- δ-lactams for the synthesis of (Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine mimetics. Reduction of acetates 2, 12, 14, a

Full text of DOI:10.1021/jo060202z

Synthesis of (Z)-Alkene and (E)-Fluoroalkene-Containing
Diketopiperazine Mimetics Utilizing Organocopper-Mediated
Reduction-Alkylation and Diastereoselectivity Examination Using
DFT Calculations
Ayumu Niida,† Makiko Mizumoto,† Tetsuo Narumi,† Eriko Inokuchi,† Shinya Oishi,†
Hiroaki Ohno,† Akira Otaka,†,‡ Kazuo Kitaura,† and Nobutaka Fujii*,†
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan, and
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima, Tokushima 770-8505, Japan
nfujii@pharm.kyoto-u.ac.jp
ReceiVed January 30, 2006
We have carefully examined the organocopper-mediated reduction-alkylation of γ-acetoxy or γ,γ-difluoro-
R,â-unsaturated-δ-lactams for the synthesis of (Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine
mimetics. Reduction of acetates 2, 12, 14, and difluorolactam 18 with higher-order cuprate reagents
(Me3CuLi2‚LiI‚3LiBr), followed by trapping the resulting metal dienolate with an electrophile in a one-
pot procedure gave R-alkylated-â,γ-unsaturated-δ-lactams in good yields. Because of side-chain steric
repulsion, we found that alkylation using relatively large electrophiles such as BnBr gave mostly 3,6-
trans isomers by kinetic trapping of metal enolates. On the other hand, MeI-mediated alkylations
predominantly provided the unexpected 3,6-cis isomers despite the presence of a bulky benzyl side chain.
Based on density functional theory calculations, we concluded that formation of the 3,6-cis isomers was
due to the occurrence of oxa-π-allyllithium complexes 29 and 31.
Introduction
fluoroalkene units in comparison with the simple (E)-alkenes.6,7
On the basis of our research on alkene-type dipeptide isosteres,
we envisioned that 3,6-dihydropiridin-2-ones could function as
potential 2,5-diketopiperazine mimetics in which a cis-peptide
bond has been replaced with a structurally similar (Z)-alkene8
or (E)-fluoroalkene unit (Figure 1).
2,5-Diketopiperazines, the smallest possible cyclic peptides
consisting of two R-amino acid residues, are often identified as
common structural motifs in a large number of natural and
artificial bioactive compounds.1 This highly constrained scaffold
is likely to serve as a privileged platform in medicinal chemistry.
The mimetics of 2,5-diketopiperazines could be novel scaffolds
for expanding the structural diversity of molecular libraries.
During the past decade, we have engaged in the development
of synthetic methodologies for (E)-alkene dipeptide isosteres2
as potential trans-peptide bond equivalents along with their
application to biologically active peptides.3-5 More recently,
we developed efficient synthetic strategies for (Z)-fluoroalkene
dipeptide isosteres possessing electrostatically favorable (Z)-
(1) (a) Bauer, K.; Gra¨f, K. J.; Faivre-Bauman, A.; Beier, S.; Tixier-Vidal,
A.; Kleinkauf, H. Nature 1978, 274, 174. (b) Shimazaki, N.; Shima, I.;
Hemmi, K.; Tsurumi, Y.; Hashimoto, M. Chem. Pharm. Bull. 1987, 35,
3527. (c) Prasad, C. Peptides 1995, 16, 151. (d) Weng, J. H.; Bado, A.;
Garbay, C.; Roques, B. P. Regul. Pept. 1996, 65, 3. (e) Kanoh, K.; Kohno,
S.; Katada, J.; Takahashi, J.; Uno, I.; Hayashi, Y. Bioorg. Med. Chem. 1999,
7, 1451. (f) Folkes, A.; Roe, M. B.; Sohal, S.; Golec, J.; Faint, R.; Brooks,
T.; Charlton, P. Bioorg. Med. Chem. Lett. 2001, 11, 2589. (g) Donkor, I.
O.; Sanders, M. L. Bioorg. Med. Chem. Lett. 2001, 11, 2647. (h) Maeda,
K.; Nakata, H.; Koh, Y.; Miyakawa, T.; Ogata, H.; Takeoka, Y.; Shibayama,
S.; Sagawa, K.; Fukushima, D.; Moravek, J.; Koyanagi, Y.; Mitsuya, H. J.
Virol. 2004, 78, 8654. (i) Nam, N.-H.; Ye, G.; Sun, G.; Parang, K. J. Med.
Chem. 2004, 47, 3131. (j) Borthwick, A. D.; Davies, D. E.; Exall, A. M.;
Livermore, D. G.; Sollis, S. L.; Nerozzi, F.; Allen, M. J.; Perren, M.; Shabbir,
S. S.; Woollard, P. M.; Wyatt, P. G. J. Med. Chem. 2005, 48, 6956.
* Corresponding author. Phone: +81-75-753-4551. Fax: +81-75-753-4570.
† Kyoto University.
‡ The University of Tokushima.
10.1021/jo060202z CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/02/2006
4118
J. Org. Chem. 2006, 71, 4118-4129

Synthesis of Diketopiperazine Mimetics
SCHEME 1
FIGURE 1. Diketopiperazine mimetics containing (Z)-alkene or (E)-
fluoroalkene units as cis-peptide bond equivalents.
Recently, we reported a stereoselective methodology to
prepare (Z)-alkene-containing diketopiperazine mimetics utiliz-
ing organocopper-mediated anti-SN2′ reactions of γ-phospho-
ryloxy-R,â-unsaturated-δ-lactams. Regio- and stereoselective
anti-SN2′ reactions of phosphate 1 using various organocopper
reagents proceeded smoothly to yield highly functionalized
diketopiperazine mimetics possessing the desired â,γ-alkene unit
(Scheme 1).9 This method enables the establishment of a chiral
center at the R-position, and it is useful for the divergent
synthesis of alkene-type diketopiperazine mimetics.
In the course of the above study, acetate 2 proved to be
susceptible to reduction with an organocopper reagent, whereas
2 is an inappropriate substrate for the organocopper-mediated
anti-SN2′ reaction. Treatment of 2 with Me3CuLi2‚LiI‚3LiBr
followed by quenching with aqueous acid afforded a reduced
product 4 in a high yield.10 It has also been reported that
treatment of γ,γ-difluoro-R,â-enoates with higher-order cuprates
gives the reduction products. Applications of this reaction to
the synthesis of (Z)-fluoroalkene dipeptide isosteres as trans-
amide bond mimetics have previously been described by us6,11
and others.12 Two consecutive single electron transfers from
higher-order cuprates to these substrates could be involved in
this reduction.6,11b,13 The metal dienolate intermediate 5 could
be trapped by electrophiles such as alkyl halides to provide
R-substituted diketopiperazine mimetics 6 (Scheme 2). We
envisioned that the organocopper-mediated reduction-alkylation
of γ-acetoxy- or γ,γ-difluoro-R,â-unsaturated-δ-lactams could
be used for the key step in constructing an R-chiral center of
(Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine mi-
metics. However, systematic studies on the reduction-alkylation
(2) (a) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1990, 29, 801.
(b) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Uyehara, T.;
Yamamoto, Y. J. Org. Chem. 1991, 56, 4370. (c) Ibuka, T.; Nakai, K.;
Habashita, H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 652. (d) Oishi, S.;
Tamamura, H.; Yamashita, M.; Odagaki, Y.; Hamanaka, N.; Otaka, A.;
Fujii, N. J. Chem. Soc., Perkin Trans. 1 2001, 2445. (e) Otaka, A.; Katagiri,
F.; Kinoshita, T.; Odagaki, Y.; Oishi, S.; Tamamura, H.; Hamanaka, N.;
Fujii, N. J. Org. Chem. 2002, 67, 6152. (f) Oishi, S.; Niida, A.; Kamano,
T.; Miwa, Y.; Taga, T.; Odagaki, Y.; Hamanaka, N.; Yamamoto, M.; Ajito,
K.; Tamamura, H.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1
2002, 1786.
(3) (a) Fujimoto, K.; Doi, R.; Hosotani, R.; Wada, M.; Lee, J.-U.;
Koshiba, T.; Ibuka, T.; Habashita, H.; Nakai, K.; Fujii, N.; Imamura, M.
Life Sci. 1997, 60, 29. (b) Kawaguchi, M.; Hosotani, R.; Ohishi, S.; Fujii,
N.; Tulachan, S. S.; Koizumi, M.; Toyoda, E.; Masui, T.; Nakajima, S.;
Tsuji, S.; Ida, J.; Fujimoto, K.; Wada, M.; Doi, R.; Imamura, M. Biochem.
Biophys. Res. Commun. 2001, 288, 711. (c) Tamamura, H.; Hiramatsu, K.;
Miyamoto, K.; Omagari, A.; Oishi, S.; Nakashima, H.; Yamamoto, N.;
Kuroda, Y.; Nakagawa, T.; Otaka, A.; Fujii, N. Bioorg. Med. Chem. Lett.
2002, 12, 923. (d) Oishi, S.; Kamano, T.; Niida, A.; Odagaki, Y.; Hamanaka,
N.; Yamamoto, M.; Ajito, K.; Tamamura, H.; Otaka, A.; Fujii, N. J. Org.
Chem. 2002, 67, 6162. (e) Tamamura, H.; Koh, Y.; Ueda, S.; Sasaki, Y.;
Yamasaki, T.; Aoki, M.; Maeda, K.; Watai, Y.; Arikuni, H.; Otaka, A.;
Mitsuya, H.; Fujii, N. J. Med. Chem. 2003, 46, 1764. (f) Tamamura, H.;
Hiramatsu, K.; Ueda, S.; Wang, Z.; Kusano, S.; Terakubo, S.; Trent, J. O.;
Peiper, S. C.; Yamamoto, N.; Nakashima, H.; Otaka, A.; Fujii, N. J. Med.
Chem. 2005, 48, 380.
(7) For fluoroalkene isosteres, see: (a) Abraham, R. J.; Ellison, S. L.
R.; Schonholzer, P.; Thomas, W. A. Tetrahedron 1986, 42, 2101. (b)
Allmendinger, T.; Furet, P.; Hungerbu¨hler, E. Tetrahedron Lett. 1990, 31,
7297. (c) Allmendinger, T.; Felder, E.; Hungerbu¨hler, E. Tetrahedron Lett.
1990, 31, 7301. (d) Boros, L. G.; De Corte, B.; Gimi, R. H.; Welch, J. T.;
Wu, Y.; Handschumacher, R. E. Tetrahedron Lett. 1994, 35, 6033. (e)
Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107. (f) Welch, J. T.;
Allmendinger, T. In Peptidomimetics Protocols; Kazmierski, W. M., Ed.;
Human Press: Totowa, NJ, 1999; pp 357-384. (g) Der Veken, P. V.;
Senten, K.; Kerte`sz, I.; De Meester, I.; Lambeir, A.-M.; Maes, M.-B.;
Scharpe´, S.; Haemers, A.; Augustyns, K. J. Med. Chem. 2005, 48, 1768.
(8) For the synthesis of 3,6-dihydropyridine-2-one, see: (a) Knight, J.
G.; Ainge, S. W.; Harm, A. M.; Harwood, S. J.; Maughan, H. I.; Armour,
D. R.; Hollinshead, D. M.; Jaxa-Chamiec, A. A. J. Am. Chem. Soc. 2000,
122, 2944. (b) Boucard, V.; Sauriat-Dorizon, H.; Guibe´, F. Tetrahedron
2002, 58, 7275. (c) Knight, J. G.; Tchabanenko, K. Tetrahedron 2002, 58,
6659. (d) Anderson, T. F.; Knight, J. G.; Tchabanenko, K. Tetrahedron
Lett. 2003, 44, 757.
(4) For alkene dipeptide isosteres, see: (a) Christos, T. E.; Arvanitis,
A.; Cain, G. A.; Johnson, A. L.; Pottorf, R. S.; Tam, S. W.; Schmidt, W.
K. Bioorg. Med. Chem. Lett. 1993, 3, 1035. (b) Bohnstedt, A. C.; Prasad,
J. V. N. V.; Rich, D. H. Tetrahedron Lett. 1993, 34, 5217. (c) Wai, J. S.;
Bamberger, D. L.; Fisher, T. E.; Graham, S. L.; Smith, R. L.; Gibbs, J. B.;
Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Kohl, N. E. Bioorg.
Med. Chem. 1994, 2, 939. (d) Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J.
Angew. Chem., Int. Ed. 2001, 40, 2824. (e) Wipf, P.; Xiao, J. Org. Lett.
2005, 7, 103. (f) Jenkins, C. L.; Vasbinder, M. M.; Miller, S. J.; Raines, R.
T. Org. Lett. 2005, 7, 2619.
(5) For amide bond isosteres, see: (a) Wipf, P.; Henninger, T. C.; Geib,
S. J. J. Org. Chem. 1998, 63, 6088. (b) Mutahi, M.; Nittoli, T.; Guo, L.;
Sieburth, S. M. J. Am. Chem. Soc. 2002, 124, 7363. (c) Melendez, R. E.;
Lubell, W. D. J. Am. Chem. Soc. 2004, 126, 6759. (d) Wang, X. J.; Xu, B.;
Mullins, A. B.; Neiler, F. K.; Etzkorn, F. A. J. Am. Chem. Soc. 2004, 126,
15533. (e) Wipf, P.; Stephenson, C. R. J. Org. Lett. 2005, 7, 1137. (f) Xiao,
J.; Weisblum, B.; Wipf, P. J. Am. Chem. Soc. 2005, 127, 5742.
(6) Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe, H.;
Kinoshita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org. Chem. 2004, 69,
1634.
(9) Niida, A.; Oishi, S.; Sasaki, Y.; Mizumoto, M.; Tamamura, H.; Fujii,
N.; Otaka, A. Tetrahedron Lett. 2005, 46, 4183.
(10) For the organocopper-mediated reduction of γ-substituted-R,â-
enoates, see: (a) Ibuka, T.; Aoyagi, T.; Yoneda, F. J. Chem. Soc., Chem.
Commun. 1985, 527. (b) Ibuka, T.; Aoyagi, T.; Yamamoto, Y. Chem.
Pharm. Bull. 1986, 34, 2417. (c) Takano, S.; Sekiguchi, Y.; Ogasawara, K.
J. Chem. Soc., Chem. Commun. 1988, 449. (d) Fujii, N.; Habashita, H.;
Shigemori, N.; Otaka, A.; Ibuka, T.; Tanaka, M.; Yamamoto, Y. Tetrahedron
Lett. 1991, 32, 4969. (e) Ibuka, T.; Yoshizawa, H.; Habashita, H.; Fujii,
N.; Chounan, Y.; Tanaka, M.; Yamamoto, Y. Tetrahedron Lett. 1992, 33,
3783.
(11) (a) Otaka, A.; Watanabe, H.; Mitsuyama, E.; Yukimasa, A.;
Tamamura H.; Fujii, N. Tetrahedron Lett. 2001, 42, 285. (b) Otaka, A.;
Watanabe, H.; Yukimasa, A.; Oishi, S.; Tamamura, H.; Fujii, N. Tetrahedron
Lett. 2001, 42, 5443.
(12) Okada, M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa, H.;
Taguchi, T. Chem. Lett. 2002, 28.
(13) (a) Chounan, Y.; Ibuka, T.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1994, 2003. (b) Chounan, Y.; Horino, H.; Ibuka, T.; Yamamoto,
Y. Bull. Chem. Soc. Jpn. 1997, 70, 1953.
J. Org. Chem, Vol. 71, No. 11, 2006 4119

Niida et al.
SCHEME 2
SCHEME 4 a
a Reagents and conditions: (i) DIBAL-H, CH2Cl2-toluene; (ii) (o-
MePhO)2P(O)CH2CO2t-Bu, NaI, DBU, THF; (iii) 4 M HCl-dioxane; (iv)
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), HOAt, (i-Pr)2NEt,
DMF; (v) MeI, NaH, THF.
SCHEME 3 a
8 with MeI in the presence of K2CO3 afforded N-methyl
sulfonamide 9a. The corresponding N-DMB (2,4-dimethoxy-
benzyl) derivative 9b was also synthesized by treatment of 8
with DMBOH under Mitsunobu conditions16 to examine the
effects of N-substitution against organocopper-mediated reduc-
tion-alkylation. After removal of the Ns group by treatment
with thiolate anion under basic conditions, the resulting second-
ary amines were acylated with acryloyl chloride. Subsequent
deprotection of O-TBS with TBAF followed by a ring-closing
metathesis reaction of the resulting 10 with Grubbs’ second-
generation catalyst17 proceeded smoothly at room temperature
to yield N-alkyl-γ-hydroxy-R,â-unsaturated-δ-lactams 11. Treat-
ment of 11 with Ac2O in the presence of pyridine and a catalytic
amount of DMAP gave acetates 2 and 12. Acetate 14, corre-
sponding to the diastereomer of 2 at the γ-position, was also
synthesized from allyl alcohol 1314 by a sequence of reactions
identical to those used for the preparation of 2.
The chiral â-amino acid ester 15,6 which could be synthesized
using a Reformatsky-Honda reaction,18 was chosen as a starting
material for the preparation of N-methyl-γ,γ-difluoro-R,â-unsatu-
rated-δ-lactam 18. After treatment of 15 with DIBAL-H, the
resulting aldehyde was subjected to (Z)-selective Horner-
Wadsworth-Emmons reaction19 to afford the (Z)-enoate 16 in
60% yield along with 15% of the isolated (E)-isomer. After
removal of the Boc and t-Bu groups of 16 using 4 M HCl in
dioxane, the resulting amino acid was cyclized with EDC to
yield δ-lactam 17. Treatment of lactam 17 with MeI and NaH
gave the desired γ,γ-difluoro-N-methyl-R,â-unsaturated-δ-lac-
tam 18.
Next we examined the organocopper-mediated reduction-
alkylation of acetates 2, 12, and 14 for the preparation of
diketopiperazine mimetics (Table 1). After reduction of acetate
2 with Me3CuLi2‚LiI‚3LiBr at -78 °C for 20 min, the reaction
mixture was treated with MeI to yield the R-methylated
diketopiperazine mimetics 19 in a good yield (entry 1). Contrary
to our expectation that this alkylation would favor the predomi-
nant formation of 3,6-trans isomers as a result of steric repulsion
a Reagents and conditions: (i) 4 M HCl-dioxane; (ii) Ns-Cl, 2,4,6-
collidine, CHCl3; (iii) TBSOTf, 2,6-lutidine, CH2Cl2; (iv) MeI, K2CO3,
DMF; (v) DMBOH, PPh3, DEAD, THF; (vi) HSCH2CO2H, LiOH, DMF;
(vii) CH2dCHCOCl, Et3N, CH2Cl2; (viii) tetrabutylammonium fluoride
(TBAF), THF; (ix) Grubbs’ second-generation catalyst, CH2Cl2; (x) Ac2O,
DMAP, pyridine, CHCl3. Abbreviations: Ns, 2-nitrobenzenesulfonyl; TBS,
tert-butyldimethylsilyl; DMB, 2,4-dimethoxybenzyl.
sequence of these lactams have yet to be carried out. In this
paper, we report the application of organocopper-mediated
reduction-alkylation sequences to the synthesis of (Z)-alkene-
or (E)-fluoroalkene-containing diketopiperazine mimetics, where
unexpected diastereoselectivity in the alkylation step was
observed. Density functional theory (DFT) calculations were
also carried out to attempt to address the diastereoselectivity in
this alkylation step.
Results and Discussion
(15) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Hidai, Y.; Kan, T.; Fukuyama, T. Chem. Pharm. Bull. 2000,
48, 1570.
(16) Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309.
(17) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Arisawa, M.; Theeraladanon, C.; Nishida, A.; Nakagawa, M.
Tetrahedron Lett. 2001, 42, 8029.
Synthesis of the requisite substrate, N-alkyl-γ-activated-R,â-
unsaturated-δ-lactams for organocopper-mediated reduction-
alkylation is summarized in Schemes 3 and 4. Conversion of
the N-protecting group of the chiral allyl alcohol 714 to N-Ns
(Ns ) 2-nitrobenzenesulfonyl),15 followed by O-protection with
a TBS group gave the N-Ns amide derivative 8. Treatment of
(18) Honda, T.; Wakabayashi, H.; Kanai, K. Chem. Pharm. Bull. 2002,
50, 307.
(19) Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem.
2000, 65, 4745.
(14) Hanson, G. J.; Lindberg, T. J. Org. Chem. 1985, 50, 5399.
4120 J. Org. Chem., Vol. 71, No. 11, 2006

Synthesis of Diketopiperazine Mimetics
TABLE 1. Organocopper-Mediated Reduction-Alkylation of
γ-Acetoxy-r,â-unsaturated-δ-lactams 2, 12, and 14
TABLE 2. Organocopper-Mediated Reduction-Alkylation of
γ,γ-Difluoro-r,â-unsaturated-δ-lactam 18
alkylation
productsd trans/
(%)
entry electrophilea conditionsb
solvent
cise
1
2
3
4
5
6
7
8
9
H+
MeI
MeI
MeOTf
MeOTf
BnBr
BnBr
MeI
THF/Et2O (4:1) 26 (77)
0 °C, 2 h THF/Et2O (4:1) 27 (60)
50:50
20:80
50:50
20:80
alkylation
productsc
(%)
trans/
cisd
entry substrate electrophilea
conditionsb
0 °C, 2 h Et2O
0 °C, 2 h THF/Et2O (4:1) 27 (75)
-78 °C, 2 h Et2O 27 (86)
27 (61)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
14
14
12
12
MeI
0 °C, 3 h
-78 °C, 2.5 h
0 °C, 2 h
19 (68)
20 (80)
21 (71)
22 (56)
23 (81)
19 (81)
20 (94)
24 (75)
25 (73)
15:85
90:10
86:14
100: 0
15:85e
21:79
88:12
13:87
74:26
BnBr
i-BuI
i-PrI
D2O (excess)
MeI
BnBr
MeI
BnBr
-78 °C, 2 h THF/Et2O (4:1) 28 (61) 100:0
-78 °C, 2 h Et2O 28 (46) 100:0
0 °C, 2 hc THF/Et2O (4:1) 27 (77)
0 °C, 2 hc Et2O
27 (62)
0 °C, 3 h
50:50
20:80
MeI
0 °C, 3 h
-78 °C, 3 h
0 °C, 3 h
a Eight equivalents were used. b Reduction was carried out with
Me3CuLi2‚LiI‚3LiBr (2 equiv) at -78 °C for 30 min before alkylation,
except for entries 8 and 9. c n-Bu3CuLi2‚LiI (2 equiv) was used as the
reducing reagent. d Combined isolated yields. e Ratios were calculated from
the isolated yields of both isomers.
-78 °C, 3 h
a Eight equivalents were used, except for entry 5. b Reduction was carried
out with Me3CuLi2‚LiI‚3LiBr (2 equiv) in THF-Et2O (4:1) at -78 °C for
20 min before alkylation. c Combined isolated yields. d Ratios were calcu-
1
lated from isolated yields of both isomers. e Ratio was determined by H
Me3CuLi2‚LiI‚3LiBr and alkyl halides proceeded with dia-
stereoselectivities similar to those observed in the reaction of
N-methyl acetates 2 and 14 to yield diketopiperazine mimetics
24 and 25.21 These could be important precursors for (Z)-alkene
dipeptide isosteres (entries 8 and 9).8b The results indicate that
N-alkyl substituents do not affect the diastereoselectivity of
alkylation.
NMR experiments.
between the substrate benzyl group and the incoming electro-
phile, the use of MeI as the electrophile gave the 3,6-cis-19 as
the main product (trans/cis ) 15:85). On the other hand,
alkylation with Bn-Br or i-BuI afforded the R-substituted
diketopiperazine mimetics 20 and 21, respectively, in good
yields, with the expected high 3,6-trans selectivity (entries 2
and 3). By using i-PrI, trans-22 was isolated as a sole product
(entry 4). Quenching the reaction with D2O preferentially gave
the 3,6-cis-R-deuteriodiketopiperazine mimetics 23 (trans/cis )
15:85). Therefore, in this reduction-alkylation system, relatively
bulky substituents such as Bn, i-Bu, and i-Pr groups were
introduced with 3,6-trans diastereoselectivity, while small
substituents such as Me and D tended to be introduced with
high 3,6-cis selectivity.20
The diastereomeric substrate 14 gave similar results to those
observed in the reaction of the acetate 2: alkylation with MeI
proceeded in a cis-selective manner, while the Bn group was
introduced with predominantly trans selectivity (entries 6 and
7). Thus, the configuration of the leaving group relative to the
benzyl substituent of 2 and 14 does not affect the diastereo-
selectivity of the alkylation step. These results suggest that
the reactions of both acetate 2 and acetate 14 proceed via the
same intermediates. The reactions of N-DMB acetate 12 with
Next, we examined the reaction of γ,γ-difluoro-R,â-unsatur-
ated-δ-lactam 18 in the organocopper-mediated reduction-
alkylation system (Table 2). Initially, it was confirmed that the
organocopper-mediated reduction proceeded smoothly to yield
lactam 26 (entry 1). In the same THF-Et2O (4:1) solvent system
as that used in the reduction-alkylation of acetates, alkylation
with MeI yielded (E)-fluoroalkene-containing diketopiperazine
mimetics 27 without diastereoselectivity (entry 2, trans/cis )
1:1). Of note, the use of Et2O as the reaction solvent dramatically
affected the product balance to yield cis-27 as the main product
(trans/cis ) 20:80, entry 3). The use of MeOTf instead of MeI
improved the chemical yield of 27, but this did not affect the
cis diastereoselectivity in Et2O (entries 4 and 5). In contrast,
benzylation gave only trans-27, regardless of the solvent
employed (entries 6 and 7).22,23 To probe the involvement of
the organocopper species in the diastereoselectivity of the
reduction-alkylation sequence, n-Bu3CuLi2‚LiI was used in
(21) Relative configurations of 25 could be assigned by the data of ref
8b. Structures of the diastereomeric pair of 24 were determined by the
observed chemical shift of the R-proton in H NMR experiments: trans-
24 (2.24 ppm) or trans-25 (2.46 ppm) vs cis-24 (2.85 ppm) or cis-25 (3.13
ppm).
(22) It was confirmed that trans-27 does not isomerize to cis-27 at 0 °C
for 2 h under the presence of Me3CuLi2‚LiI‚3LiBr in Et2O.
(23) Two R-protons of 26 were detected at 1.87 and 2.57 ppm in 1H
NMR measurements. The proton at 1.87 ppm is likely to be affected by
the anisotropic effect of the side chain phenyl ring, as in the case of alkene-
series compounds. The structures of each of the isomers of 27 were assigned
on the basis of the R-proton chemical shift: trans-27 (1.90 ppm) vs cis-27
(2.78 ppm). Compound 28 was assigned as a 3,6-trans isomer because the
observed R-proton chemical shift (2.14 ppm) was similar to trans-27 or
the upfield proton of 26.
1
(20) The absolute configurations of cis-19 or trans-20 were determined
to be (3R,6S) or (3S,6S) by X-ray analysis. On the basis of these results,
the relative configuration of the corresponding diastereomer trans-19 or
cis-20 was assigned. 1H NMR measurements of these diastereomeric pairs
indicated that the R-protons (3-position) of the 3,6-trans compounds
appeared about 0.6 ppm upfield from the corresponding R-protons of the
3,6-cis isomers as a result of the anisotropic effect of the side chain phenyl
ring. Structures of 21, 22, and 23 were determined on the basis of the
observed R-proton chemical shifts: trans-21 (2.07 ppm), trans-22 (2.14
ppm), trans-23 (2.12 ppm) vs cis-21 (2.76 ppm), cis-22 (2.81 ppm, obtained
in ref 9), and cis-23 (2.65 ppm). These assignments were supported by the
experiments on organocopper-mediated anti-SN2′ reactions of phosphate
derivatives. See ref 9.
J. Org. Chem, Vol. 71, No. 11, 2006 4121

Niida et al.
SCHEME 5
place of MeLi-derived organocopper as a reducing agent. This
showed that reduction with n-Bu3CuLi2‚LiI followed by alky-
lation with MeI also afforded the same results as those observed
using Me3CuLi2‚LiI‚3LiBr (entries 8 and 9). From these results,
we speculated that potential involvement of the organocopper
alkyl moiety in the alkylation diastereoselectivity could be
excluded.
To determine whether the metal dienolate (Cu or Li enolate)
played a critical role in the reaction mechanism, we next
examined alkylation of the Li dienolate (Scheme 5). Deproto-
nation of the reduction products 4 and 26 with LDA was carried
out, followed by electrophilic trapping of the Li dienolate with
MeI or BnBr.8d In these reactions, trends similar to those in the
organocopper-mediated reduction-alkylation sequence were
observed, where methylation proceeded with high cis selectivity,
while benzylation gave predominantly trans isomers.
FIGURE 2. ORTEP diagrams for the X-ray structures of cis-19 and
trans-20 (stereoviews).
On the basis of these results, we realized that diastereose-
lectivity in the organocopper-mediated reduction-alkylation was
determined at the alkylation step of the metal dienolate (Cu or
Li). Additionally, because essentially no differences were
observed in the alkylation diastereoselectivity between Li and
putative Cu dienolates, we performed DFT calculations24 on
the lithium dienolates using the Gaussian 98 program25 to probe
the mechanism leading to diastereoselectivity. Reactions of the
lithium dienolates from lactam 4 and fluorolactam 26 with MeBr
were chosen as model systems.
First, we examined local energy minima structures of lithium
dienolates from lactam 4 at the B3LYP/6-31G(d) level. The
X-ray analyses of cis-19 and trans-20 revealed that the re-face
of the lactam ring is covered by the side chain phenyl ring, as
depicted in Figure 2.26 Therefore, we performed calculations,
FIGURE 3. Optimized geometries of oxa-π-allyllithium complexes
29 and 30 in the gas phase at the B3LYP/6-31G(d) level (stereoviews).
(24) (a) Seminario, J. M., Politzer, P., Eds. Modern Density Functional
Theory. A Tool for Chemistry; Elsevier: New York, 1995; Vol. 2
(Theoretical and Computational Chemistry). (b) Koch, W.; Holthausen, M.
C. A Chemist’s Guide to Density Functional Theory; Wiley-VCH: Wein-
heim, Germany, 2000.
focusing particular attention on the phenyl ring orientation. As
a result, two oxa-π-allyllithium complexes 29 and 30 were
optimized as local minima reaction intermediates (Figure 3).
Calculations of the fluoro counterparts, which were obtained
from initial structures derived from 29 and 30, gave similar oxa-
π-allyllithium complexes 31 and 32, respectively, as local
minima structures.27 Relative energies of these intermediates
are shown in Figure 4. It was found that oxa-π-allyllithium
complexes 29 and 31, having the lithium cation on the same
(25) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.11; Gaussian,
Inc.: Pittsburgh, PA, 2001.
(27) For examples of the oxa-π-allyllithium complex in theoretical
studies, see: (a) Lynch, T. J.; Newcomb, M.; Bergbreiter, D. E.; Hall, M.
B. J. Org. Chem. 1980, 45, 5005. (b) Lambert, C.; Schleyer, P. v. R. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1129. (c) Kremer, T.; Schleyer, P. v. R.
Organometallics 1997, 16, 737. (d) Abbotto, A.; Streitwieser, A.; Schleyer,
P. v. R. J. Am. Chem. Soc. 1997, 119, 11255.
(26) The R-proton of trans-20 is supposed to be affected by the
anisotropic effect of the phenyl ring in the X-ray structure. This supports
the reliability of the above structure determinations.
4122 J. Org. Chem., Vol. 71, No. 11, 2006

Synthesis of Diketopiperazine Mimetics
FIGURE 4. Relative energies of oxa-π-allyl complexes 29-32 in the
gas phase at the B3LYP/6-31G(d) level.
FIGURE 6. Relative energies of complexes 33-36 in the gas phase
at the B3LYP/6-31G(d) level.
3LiBr, the thermodynamically stable oxa-π-allylmetal complex
A exists as the preferred reaction intermediate. The coordination
of MeI with A gives complex C, which is a precursor
intermediate of the 3,6-cis isomers. Such a route, via thermo-
dynamically more stable intermediates A and C leading to the
3,6-cis isomers, is thought to be preferable over alternate routes
in the reaction of the resulting metal dienolate with MeI or D2O.
In contrast, the approach of bulky alkyl halides from the same
side of the benzyl side chain would be difficult due to steric
repulsion. DFT calculations of complexes coordinated with
i-PrBr were performed next, and the results are shown in Figure
8. The calculations indicated that complex 37, derived from the
π-allyllithium intermediate 29, is thermodynamically more stable
than complex 38, derived from 30. However, the subsequent
alkylation step might be disturbed by the steric hindrance of
the i-Pr group (Figure 9). This implies that electrophilic trapping
with bulky alkyl halides such as i-PrI could be controlled in
the final step of the alkylation to yield 3,6-trans isomers as the
main products.
To demonstrate the importance of the phenyl ring on the
stabilization of oxa-π-allyllithium complexes, such as 29, we
carried out DFT calculations on alanine derivatives. Two oxa-
π-allyllithium complexes 39 and 40 were optimized at the
B3LYP/6-31G(d) level (Figure 10). In this case, complex 40,
having a lithium atom on the opposite face of the methyl side
chain, was slightly more stable as compared to complex 39. It
is clear that the interaction of the lithium cation with the phenyl
ring plays an important role in the stabilization of the phenyl-
alanine-derived complexes 29 and 31.
To verify the above DFT calculations, we carried out an
organocopper-mediated reduction-alkylation of the alanine-
derived substrate 4130 with MeI (Scheme 6). The predominant
product of the reaction was 3,6-cis-42.31 Furthermore, we
performed DFT calculations on plausible oxa-π-allyllithium
complexes 43 and 44 and found that complex 44, which is a
precursor of trans-42, is thermodynamically more stable than
complex 43 by 2.42 kcal/mol (Figure 11). This energy difference
is not responsible for the observed cis selectivity. These results
suggest that, in the methylation of the alanine-derived dienolate
43/44, other factors such as aggregate formation of metal
dienolate or activation energy on the methylation step may
contribute to the diastereoselectivity.32
FIGURE 5. Optimized geometries of complexes 33 and 34 in the gas
phase at the B3LYP/6-31G(d) level (stereoviews).
face of the benzyl side chain, were significantly more stable as
compared to the complexes 30 or 32 having the lithium cation
on the opposite face of the benzyl group, respectively (energy
difference: R ) H, 7.76 kcal/mol; R ) F, 6.78 kcal/mol). A
cation π-like interaction28 between the lithium cation and the
phenyl ring is likely to contribute to stabilization of the
complexes 29 and 31 over 30 and 32, respectively. Calculated
charge distributions of the lithium atoms were estimated as
follows: 29 (+0.261) versus 30 (+0.379) and 31 (+0.269)
versus 32 (+0.387). These results suggested that the lithium
cation interacts with the phenyl ring π-electrons.
Next, we carried out DFT calculations on the coordinated
complexes with MeBr-derived oxa-π-allyllithium intermediates
29-32.29 Local minima structures 33-36 were optimized, and
the relative energies were calculated at the B3LYP/6-31G(d)
level (Figures 5 and 6). The relative energies of complexes 33
and 35, which were formed from the stable oxa-π-allyllithium
complexes 29 or 31, were lower than those of complexes 34
and 36, derived from intermediates 30 and 32 (energy differ-
ence: RdH, 4.27 kcal/mol; RdF, 3.30 kcal/mol).
Finally, single-point energy calculations that included solvent
effects (polarizable continuum model; PCM)33 of optimized
structures 29-36 were performed to address the issue of
differential selectivity with lactam 18, depending on the solvents.
Energy differences based on calculated relative energy at the
B3LYP/6-31G(d) level in Et2O or THF model systems are
shown in Table 3. No significant changes of energy differences
From these calculations we derived a plausible explanation
for the observed diastereoselectivity in the organocopper-
mediated reduction-alkylation system, as shown in Figure 7.
After reduction of the lactams 2 and 18 with Me3CuLi2‚LiI‚
(28) (a) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303. (b)
Gokel, G. W.; Barbour, L. J.; Ferdani, R.; Hu, J. Acc. Chem. Res. 2002,
35, 878.
(30) Compound 41 was synthesized by a procedure similar to the
preparation of acetate 2. See Supporting Information.
(31) For structure determination of 42, see Supporting Information.
(29) Pratt, L. M.; Nguyeˆn, N. V.; Ramachandran, B. J. Org. Chem. 2005,
70, 4279.
J. Org. Chem, Vol. 71, No. 11, 2006 4123

Niida et al.
FIGURE 7. Plausible explanation for the unexpected cis selectivity of MeI in an organocopper-mediated reduction-alkylation system.
FIGURE 10. Optimized geometries of complexes 39 and 40 in the
gas phase at the B3LYP/6-31(d) level.
FIGURE 8. Optimized geometries of complexes 37 and 38 and their
relative energies in the gas phase at the B3LYP/6-31G(d) level.
FIGURE 9. Comparison of complexes 33 and 37 in the alkylation
step.
between 29, 31, 33 and 30, 32, 34, respectively, were observed
in any phase. It is worth noting that the energy difference
between the fluorinated intermediates 35 and 36 in THF was
1.30 kcal/mol, which is significantly smaller as compared to
that of the corresponding alkene-type intermediates 33 and 34
FIGURE 11. Optimized geometries of complexes 43 and 44 in the
gas phase at the B3LYP/6-31(d) level.
SCHEME 6
(32) The organocopper-mediated reduction-alkylation of N-methyl-
alanine-derived substrate a was also performed. This reaction proceeded
smoothly to yield R-methylated product b. HPLC analysis of the reaction
mixture indicated that the predominant product of this reaction was the
3,6-cis isomer, as in the case of the reaction of acetate 41. We could not
completely purify the product b and determine precise chemical yields as
a result of its highly volatile nature.
in THF (3.39 kcal/mol) or Et2O (3.37 kcal/mol). On the basis
of these data, the observed diastereoselectivity in the alkylation
of the difluorolactam 18 with MeI can be attributed to a small
(33) For the PCM, see: (a) Tomasi, J.; Persico, M. Chem. ReV. 1994,
94, 2027. (b) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998,
19, 404.
4124 J. Org. Chem., Vol. 71, No. 11, 2006

Synthesis of Diketopiperazine Mimetics
1
77-79 °C; [R]28 +40.5 (c 1.06, CHCl3); H NMR (270 MHz,
TABLE 3. Energy Differences between Corresponding
Intermediates in the Gas Phase, Et2O, or THF, as Estimated by
Single-Point Energy Calculations Using the PCM at the B3LYP/
6-31G(d) Level
D
CDCl3) δ 0.06 (s, 3H), 0.13 (s, 3H), 0.97 (s, 9H), 2.58 (dd, J )
13.8, 9.2 Hz, 1H), 2.99 (dd, J ) 13.8, 5.6 Hz, 1H), 3.63-3.75 (m,
1H), 4.25-4.33 (m, 1H), 5.02 (dt, J ) 10.5, 1.3 Hz, 1H), 5.18 (dt,
J ) 17.1, 1.3 Hz, 1H), 5.70 (d, J ) 7.6 Hz, 1H), 5.78 (ddd, J )
16.8, 10.2, 5.9 Hz, 1H), 6.95-7.05 (m, 5H), 7.45-7.80 (m, 4H);
13C NMR (100 MHz, CDCl3) δ -4.8, -4.2, 18.1, 25.8, 37.6, 62.0,
74.4, 116.8, 125.3, 126.5, 128.2, 129.0, 129.9, 132.6, 132.7, 135.0,
136.9, 137.5, 147.1. Anal. Calcd for C23H32N2O5SSi: C, 57.95; H,
6.77; N, 5.88. Found: C, 57.79; H, 6.61; N, 5.84.
∆Erel (kcal/mol)
E
E
rel30 -
Erel32 -
rel31
Erel34 -
rel33
Erel36 -
rel35
phase
rel29
E
E
E
gas
+7.76
+5.93
+6.28
+6.78
+4.62
+4.74
+4.27
+3.37
+3.39
+3.30
+1.78
+1.30
Et2Oa
THFa
(3S,4S)-3-[(tert-Butyl)dimethylsiloxy]-4-[N-methyl-N-(2-ni-
trobenzenesulfonyl)amino]-5-phenylpent-1-en (9a). To a stirred
solution of sulfonamide 8 (500 mg, 1.05 mmol) in DMF (5 mL)
was added K2CO3 (724 mg, 5.24 mmol) and MeI at 0 °C. After
stirring the mixture for 1 h at room temperature, the mixture was
extracted with EtOAc. The extract was washed with brine and dried
over MgSO4. Concentration under reduced pressure, followed by
flash chromatography over silica gel with n-hexanes-EtOAc
a Single-point energy calculations were performed without geometry
optimization under the PCM.
energy difference between C and D, as shown in Figure 7.
Furthermore, the larger energy differences between C and D in
THF could be an important controlling factor for the predomi-
nant formation of the 3,6-cis products via intermediate C.
(6:1), gave the title compound 9a (507 mg, 98.6%) as colorless
1
crystals: mp 74-75 °C; [R]33 -49.8 (c 1.02, CHCl3); H NMR
D
Conclusion
(270 MHz, CDCl3) δ 0.03 (s, 3H), 0.08 (s, 3H), 0.95 (s, 9H), 2.80
(dd, J ) 14.1, 8.7 Hz, 1H), 3.08 (s, 3H), 3.11 (dd, J ) 13.8, 6.2
Hz, 1H), 4.12-4.24 (m, 1H), 4.32-4.24 (m, 1H), 5.08 (d, J )
10.5, Hz, 1H), 5.19 (dt, J ) 17.1, 1.3 Hz, 1H), 5.90 (ddd, J )
17.1, 10.2, 6.9 Hz, 1H), 7.07-7.18 (m, 5H), 7.25-7.55 (m, 4H);
13C NMR (100 MHz, CDCl3) δ -4.8, -3.7, 18.3, 26.1, 31.6, 33.9,
64.1, 75.9, 117.1, 123.6, 126.4, 128.3, 128.9, 130.3, 131.1, 132.5,
133.0, 137.9, 147.8. Anal. Calcd for C24H34N2O5SSi: C, 58.75; H,
6.98; N, 5.71. Found: C, 58.71; H, 7.05; N, 5.69.
Taken together, the work reported herein demonstrates the
applicability of organocopper-mediated reduction-alkylation
methodology for the preparation of (Z)-alkene or (E)-fluoro-
alkene diketopiperazine mimetics. In this reaction system,
relatively bulky alkyl halides such as Bn-Br gave 3,6-trans
isomers as main products, while the reaction with MeI resulted
in predominant formation of the 3,6-cis isomers. DFT calcula-
tions suggested that oxa-π-allyllithium complexes 29 and 31,
which are stabilized by cation π-like interactions between the
neighboring phenyl ring of the lactam ring side chain and the
lithium cation, could be important reaction intermediates af-
fecting diastereoselectivity.
(3S,4S)-3-[(tert-Butyl)dimethylsiloxy]-4-[N-(2,4-dimethoxy-
benzyl)-N-(2-nitrobenzenesulfonyl)-amino]-5-phenylpent-1-en (9b).
To a stirred solution containing the sulfonamide 8 (200 mg 0.419
mmol), 2,4-dimethoxybenzyl alcohol (247 mg, 1.47 mmol), and
PPh3 (385 mg, 1.47 mmol) in THF (4 mL) was added dropwise
DEAD in toluene (40% solution, 660 µL, 1.47 mmol) at 0 °C under
argon, and the mixture was stirred overnight at room temperature.
Concentration under reduced pressure followed by flash chroma-
tography over silica gel with n-hexanes-EtOAc (5:1) gave the title
Experimental Section
General Method. Melting points are uncorrected. Chemical
compound 9b (238 mg, 90.6% yield) as a colorless oil: [R]28
1
shifts of the compounds, of which H and 13C NMR spectra were
D
1
-87.5 (c 0.38, CHCl3); H NMR (270 MHz, CDCl3) δ -0.01 (s,
recorded in CDCl3, are reported in parts per million downfield from
Me4Si (s ) singlet, d ) doublet, dd ) double doublet, ddd )
doublet of double doublet, t ) triplet, dt ) double triplet, dtd )
doublet of triple doublet, m ) multiplet). 19F NMR spectra were
referenced to the internal CFCl3 (δ 0.00 ppm). For flash chro-
matographies, Wakosil C-300 (silica gel for column chromatogra-
phy, Wako) was employed.
6H), 0.91 (s, 9H), 3.15 (d, J ) 7.2 Hz, 2H), 3.67 (s, 3H), 3.81 (s,
3H), 4.23 (dd, J ) 7.2, 3.3 Hz, 1H), 4.37 (dt, J ) 7.2, 3.3 Hz, 1H),
4.65 (d, J ) 15.8 Hz, 1H), 4.86 (d, J ) 15.8 Hz, 1H), 4.95-5.10
(m, 2H), 5.83 (ddd, J ) 17.1, 10.0, 7.3 Hz, 1H), 6.17 (d, J )
2.7 Hz, 1H), 6.32 (dd, J ) 8.5, 2.3 Hz, 1H), 7.14-7.58 (m,
10H); 13C NMR (100 MHz, CDCl3) δ -4.7, -3.4, 18.3, 26.1, 35.2,
45.2, 54.8, 55.4, 64.8, 66.6, 75.5, 97.7, 98.3, 103.6, 116.9, 117.4,
123.5, 126.1, 128.1, 129.2, 130.0, 130.9, 131.2, 131.6, 132.0, 135.0,
138.2, 138.5, 147.2, 157.9, 160.2; HRMS (FAB) m/z calcd for
C32H43N2O7SSi (MH+), 627.2560; found, 627.2575.
(3S,4S)-4-(N-Acryloyl-N-methylamino)-3-[(tert-butyl)dimeth-
ylsiloxy]-5-phenylpent-1-en (O-TBS Derivative of 10a). To a
stirred solution of the N-Me-sulfonamide 9a (507 mg, 1.03 mmol)
in DMF (3.6 mL) was added LiOH‚H2O (260 mg, 6.20 mmol) and
HSCH2CO2H (216 µL, 1.26 mmol) at 0 °C, and the mixture was
stirred for 2 h at room temperature. The mixture was extracted with
EtOAc. The extract was washed with saturated NaHCO3 and dried
over MgSO4. Concentration under reduced pressure gave oily
residues, which was dissolved in CH2Cl2 (5 mL). Et3N (720 µL,
5.17 mmol) and acryloyl chloride (336 µL, 1.01 mmol) were added
dropwise to the above solution at -20 °C, and the mixture was
stirred for 1.5 h at 0 °C under argon. Saturated NaHCO3 (2 mL)
was added to the above mixture at 0 °C, and the mixture was
extracted with EtOAc. The extract was washed successively with
saturated citric acid, brine, saturated NaHCO3, and brine and dried
over MgSO4. Concentration under reduced pressure, followed by
flash chromatography over silica gel with n-hexanes-EtOAc
(6:1), gave the title compound O-TBS-10a (316 mg, 83.8% yield)
as a colorless oil (rotamer mixture): [R]33D -51.3 (c 0.94, CHCl3);
(3S,4S)-3-[(tert-Butyl)dimethylsiloxy]-4-[N-(2-nitrobenzene-
sulfonyl)amino]-5-phenylpent-1-en (8). The allyl alcohol 7 (6.0
g, 21.6 mmol) was dissolved in 4 M HCl-dioxane (30 mL), and
the mixture was stirred for 1.5 h at room temperature. Concentration
under reduced pressure gave an oily residue, which was dissolved
in CHCl3 (20 mL). 2,4,6-Collidine (5.98 mL, 45.3 mmol) and a
solution of 2-nitrobenzenesulfonyl chloride (5.03 g, 22.7 mmol) in
CHCl3 (10 mL) were added to the above solution at 0 °C, and the
mixture was stirred for 5 h at room temperature. Saturated citric
acid (10 mL) was added to the mixture at 0 °C, and the mixture
was extracted with EtOAc. The extract was washed successively
with saturated citric acid, brine, saturated NaHCO3, and brine and
dried over MgSO4. Concentration under reduced pressure gave an
oily residue, which was dissolved in CH2Cl2 (40 mL). 2,6-lutidine
(6.54 mL, 56.2 mmol) and TBSOTf (6.44 mL, 28.1 mmol) were
added to the above solution at 0 °C, and the mixture was stirred
overnight at room temperature. Saturated NaHCO3 (15 mL) was
added to the mixture at 0 °C, and the mixture was extracted with
EtOAc. The extract was washed successively with saturated citric
acid, brine, saturated NaHCO3, and brine and dried over MgSO4.
Concentration under reduced pressure followed by flash chroma-
tography over silica gel with n-hexanes-EtOAc (6:1) gave the
title compound 8 (9.24 g, 89.5% yield) as colorless crystals: mp
J. Org. Chem, Vol. 71, No. 11, 2006 4125

Niida et al.
1H NMR (600 MHz at 323 K, CDCl3) δ 0.04 (s, 6H), 0.06 (s, 3H),
0.07 (s, 3H), 0.88 (s, 9H), 0.92 (9H), 2.81 (dd, J ) 14.3, 10.6 Hz,
1H), 2.84-2.90 (m, 1H), 2.87 (s, 3H), 2.91-2.97 (m, 1H), 2.94
(s, 3H), 3.02-3.08 (m, 1H), 4.02 (ddd, J ) 10.4, 6.2, 4.1 Hz, 1H),
4.20 (t, J ) 6.8 Hz, 1H), 4.40-4.50 (m, 1H), 4.65-4.80 (m, 1H),
5.15 (d, J ) 10.4 Hz, 1H), 5.24-5.30 (m, 3H), 5.33 (dd, J ) 10.8,
1.8 Hz, 1H), 5.52 (dd, J ) 10.5, 2.0 Hz, 1H), 5.75-5.90 (m, 3H),
6.10 (dd, J ) 16.8, 2.0 Hz, 1H), 6.18 (dd, J ) 17.0, 10.8 Hz, 1H),
6.36 (dd, J ) 16.8, 10.5 Hz, 1H), 7.05-7.26 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ -5.0, -4.9, -4.1, -3.9, 17.9, 18.0, 25.5,
25.6, 25.8, 28.3, 34.1, 34.8, 63.5, 73.6, 75.0, 75.4, 115.6, 117.4,
125.2, 125.8, 126.1, 126.2, 126.7, 127.9, 128.2, 128.4, 128.6, 129.0,
137.4, 138.0, 138.2, 138.4, 166.6, 168.2; HRMS (FAB) m/z calcd
for C21H34NO2Si (MH+), 360.2359; found, 360.2352.
131.0, 138.6, 138.9, 158.8, 161.1, 168.9; HRMS (FAB) m/z calcd
for C23H28NO4 (MH+), 382.2018; found, 382.2008.
(5S,6S)-6-Benzyl-5,6-dihydro-5-hydroxy-1-methylpyridin-2-
one (11a). To a solution of the acrylamide 10a (750 mg, 3.05 mmol)
in CH2Cl2 (20 mL) was added Grubbs’ second-generation catalyst
(129 mg, 0.152 mmol), and the mixture was stirred for 6 h at room
temperature under argon. Concentration under reduced pressure,
followed by flash chromatography over silica gel with n-hexanes-
EtOAc (1:1), gave the title compound 11a (558 mg, 84.2% yield)
as colorless crystals: mp 96-97 °C; [R]28D -137.1 (c 1.06, CHCl3);
1H NMR (270 MHz, CDCl3) δ 2.56 (s, 3H), 2.97 (dd, J ) 13.5,
9.2 Hz, 1H), 3.19 (dd, J ) 13.5, 4.6 Hz, 1H), 3.60-3.85 (m, 2H),
4.87 (m, 1H), 5.85 (d, J ) 9.8 Hz, 1H), 6.42 (d, J ) 9.8 Hz, 1H),
7.14-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 33.1, 35.1,
65.6, 66.7, 122.8, 126.2, 128.3, 129.2, 138.3, 143.7, 163.6. Anal.
Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.69;
H, 7.01; N, 6.37.
(5S,6S)-6-Benzyl-5,6-dihydro-1-[(2,4-dimethoxy)benzyl]-5-hy-
droxypyridin-2-one (11b). By the use of a procedure identical with
that described for the preparation of 11a from 10a, the acrylamide
10b (163 mg, 0.427 mmol) was converted into the title compound
11b (111 mg, 73.6% yield) as colorless crystals: mp 118-120 °C;
[R]22D -10.8 (c 0.65, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.93
(dd, J ) 13.4, 8.8 Hz, 1H), 3.07-3.17 (m, 1H), 3.17 (d, J ) 14.6
Hz, 1H), 3.20-3.42 (m, 1H), 3.69 (s, 3H), 3.74 (s, 3H), 3.79 (m,
1H), 4.68 (m, 1H), 4.82 (d, J ) 14.6 Hz, 1H), 5.81 (dd, J )
9.8, 2.2 Hz, 1H), 6.27-6.42 (m, 3H), 6.91 (d, J ) 8.0 Hz, 1H),
7.10-7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 33.0, 44.2,
55.0, 55.1, 61.8, 67.4, 76.6, 98.2, 103.8, 117.8, 123.1, 126.2, 128.3,
129.6, 130.8, 138.1, 143.6, 158.3, 160.1, 163.5. Anal. Calcd for
C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.33; H, 6.52;
N, 3.96.
(3S,4S)-4-(N-Acryloyl-N-methylamino)-5-phenylpent-1-en-3-
ol (10a). The acrylamide O-TBS-10a (116 mg, 0.322 mmol) was
dissolved in 1.0 M TBAF in THF (1 mL) at 0 °C, and the mixture
was stirred for 3 h at room temperature. The mixture was extracted
with EtOAc. The extract was washed with brine and dried over
MgSO4. Concentration under reduced pressure, followed by flash
chromatography over silica gel with n-hexanes-EtOAc (3:1), gave
the title compound 10a (78.2 mg, 98.9% yield) as a colorless oil
1
(rotamer mixture): [R]29 -92.2 (c 1.58, CHCl3); H NMR (600
D
MHz, CDCl3) δ 2.75 (s, 3H), 2.78 (dd, J ) 14.4, 10.5 Hz, 0.3H),
2.94 (dd, J ) 14.2, 4.1 Hz, 0.3H), 2.97 (s, 0.9H), 3.06 (dd, J )
14.0, 5.5 Hz, 1H), 3.10-3.30 (m, 1H), 4.01 (ddd, J ) 10.9, 7.4,
4.2 Hz, 0.3H), 4.22 (t, J ) 7.2 Hz, 0.3H), 4.26 (m, 1H), 5.16 (d,
J ) 10.5 Hz, 1H), 5.31 (d, J ) 10.3 Hz, 0.3H), 5.37 (dt, J ) 17.1,
1.4 Hz, 1H), 5.35-5.45 (m, 0.6H), 5.66 (dd, J ) 10.4, 1.7 Hz,
1H), 5.80-5.90 (m, 1.6H), 6.16 (dd, J ) 16.9, 10.8 Hz, 0.3H),
6.24 (dd, J ) 16.7, 1.3 Hz, 1H), 6.38 (dd, J ) 16.8, 10.4 Hz, 1H),
7.00-7.30 (m, 6.5H); 13C NMR (100 MHz, CDCl3) δ 28.1, 34.4,
34.9, 63.5, 73.5, 73.8, 115.6, 118.4, 126.0, 126.2, 126.5, 128.1,
128.2, 128.3, 128.4, 128.6, 128.7, 128.8, 137.3, 138.4, 168.0, 168.6;
HRMS (FAB) m/z calcd for C15H20NO2 (MH+), 246.1494; found,
246.1490.
(5S,6S)-5-Acetoxy-6-benzyl-5,6-dihydro-1-methylpyridin-2-
one (2). To a stirred solution of the alcohol 11a (458 mg, 2.10
mmol), pyridine (3.39 mL, 21.0 mmol), and DMAP (25.6 mg, 0.21
mmol) in CHCl3 (6 mL) was added dropwise Ac2O (1.98 mL, 3.68
mmol) at 0 °C, and the mixture was stirred for 1.5 h at 0 °C. H2O
(6 mL) was added to the above mixture at 0 °C, and the mixture
was extracted with EtOAc. The extract was washed successively
with saturated citric acid, brine, saturated NaHCO3, and brine and
dried over MgSO4. Concentration under reduced pressure, followed
by flash chromatography over silica gel with n-hexanes-EtOAc
(3S,4S)-4-[N-Acryloyl-N-(2,4-dimethoxybenzyl)amino]-3-[(tert-
butyl)dimethylsiloxy]-5-phenylpent-1-en (O-TBS Derivative of
10b). By the use of a procedure identical with that described for
the preparation of O-TBS-10a from 9a, the N-DMB sulfonamide
9b (159 mg, 0.253 mmol) was converted into the title compound
O-TBS-10b (76.2 mg, 60.7% yield) as a colorless oil (rotamer
mixture): [R]29 -67.7 (c 0.33, CHCl3); 1H NMR (600 MHz,
(2:1), gave the title compound 2 (490 mg, 90.0% yield) as color-
D
1
CDCl3, major isomer at 320 K) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.91
(s, 9H), 2.88 (dd, J ) 14.5, 5.5 Hz, 1H), 3.12 (m, 1H), 3.71 (s,
3H), 3.75 (s, 3H), 3.83 (m, 1H), 4.42 (d, J ) 17.8 Hz, 1H), 4.63
(m, 1H), 4.74 (d, J ) 17.7 Hz, 1H), 5.14 (d, J ) 10.3 Hz, 1H),
5.25 (d, J ) 17.1 Hz, 1H), 5.49 (dd, J ) 10.2, 1.7 Hz, 1H), 5.83
(ddd, J ) 17.1, 10.3, 6.8 Hz, 1H), 6.16 (dd, J ) 8.2, 1.6 Hz, 1H),
6.28-6.34 (m, 2H), 6.41 (dd, J ) 16.0, 10.0 Hz, 1H), 6.54 (d, J )
8.3 Hz, 1H), 6.95-7.20 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
-4.9, -4.0, -3.6, 18.0, 25.7, 34.7, 54.7, 55.2, 75.4, 97.9, 103.2,
116.3, 125.7, 127.3, 128.0, 128.1, 128.3, 128.5, 128.8, 129.0, 129.3,
138.9, 139.3, 157.2, 159.7, 167.9; HRMS (FAB) m/z calcd for
C29H42NO4Si (MH+), 496.2883; found, 496.2871.
less crystals: mp 55-57 °C; [R]25 -129.0 (c 1.26, CHCl3); H
D
NMR (600 MHz, CDCl3) δ 1.93 (s, 3H), 2.68 (s, 3H), 2.94 (dd, J
) 13.9, 7.4 Hz, 1H), 2.99 (dd, J ) 13.9, 6.2 Hz, 1H), 3.95-4.01
(m, 1H), 5.79 (dt, J ) 6.3, 2.3 Hz, 1H), 5.93 (dd, J ) 10.0, 2.5
Hz, 1H), 6.30 (dt, J ) 10.0, 1.8 Hz, 1H), 7.12-7.31 (m, 5H); 13
C
NMR (100 MHz, CDCl3) δ 20.5, 33.8, 34.4, 61.7, 69.4, 125.2,
126.6, 128.6, 129.2, 137.6, 137.9, 162.8, 170.0. Anal. Calcd for
C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.39; H, 6.62;
N, 5.33.
(5S,6S)-5-Acetoxy-6-benzyl-5,6-dihydro-1-(2,4-dimethoxy)-
benzylpyridin-2-one (12). By the use of a procedure identical with
that described for the preparation of 2 from 11a, the alcohol 11b
(545 mg, 1.54 mmol) was converted into the title compound 12
(3S,4S)-4-[N-Acryloyl-N-(2,4-dimethoxybenzyl)amino]-5
-phenylpent-1-en-3-ol (10b). By the use of a procedure identical
with that described for the preparation of 10a from O-TBS-10a,
the acrylamide O-TBS-10b (103 mg, 0.207 mmol) was converted
into the title compound 10b (70.0 mg, 88.6% yield) as a colorless
oil: [R]30D -65.2 (c 1.21, CHCl3); 1H NMR (600 MHz, CDCl3) δ
2.92 (dd, J ) 13.4, 7.2 Hz, 1H), 3.33 (dd, J ) 13.3, 7.9 Hz, 1H),
3.47 (m, 1H), 3.74 (s, 3H), 3.81 (s, 3H), 3.96 (m, 1H), 4.04 (m,
1H), 4.30 (d, J ) 15.6 Hz, 1H), 4.93 (d, J ) 10.4 Hz, 1H), 5.23
(d, J ) 17.0 Hz, 1H), 5.39 (m, 1H), 5.70 (dd, J ) 10.5, 1.5 Hz,
1H), 6.35 (dd, J ) 16.7, 1.9 Hz, 1H), 6.40-6.44 (m, 2H), 6.78
(dd, J ) 15.3, 10.6 Hz, 1H), 6.92 (d, J ) 8.7 Hz, 1H), 7.00-7.27
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 29.6, 34.7, 54.8, 55.4,
72.4, 98.5, 103.8, 114.3, 116.1, 126.2, 127.6, 128.3, 129.3, 129.4,
(583 mg, 95.5% yield) as a colorless oil: [R]22 +18.1 (c 1.38,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.82 (s, 3H), 2.93 (dd, J )
13.9, 7.3 Hz, 1H), 3.00 (dd, J ) 13.9, 6.6 Hz, 1H), 3.47 (d, J )
14.4 Hz, 1H), 3.77 (s, 3H), 3.82 (s, 3H), 4.20 (m, 1H), 4.78 (d, J
) 14.4 Hz, 1H), 5.65 (dt, J ) 6.3, 2.2 Hz, 1H), 5.93 (dd, J ) 10.0,
2.4 Hz, 1H), 6.24 (dt, J ) 10.0, 1.8 Hz, 1H), 6.37-6.46 (m, 2H),
7.05-7.33 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 14.2, 20.5,
34.3, 44.7, 55.3, 58.8, 69.9, 98.2, 103.9, 117.6, 125.2, 126.2, 128.3,
129.1, 131.4, 137.8, 137.9, 158.3, 160.1, 162.4, 169.5; HRMS
(FAB) m/z calcd for C23H26NO5 (MH+), 396.1811; found, 396.1819.
tert-Butyl (5R, 2Z)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-di-
fluoro-6-phenylhex-2-enoate (16). To a solution of the ester 15
(623 mg, 1.81 mmol) in CH2Cl2 (20 mL) was added dropwise a
4126 J. Org. Chem., Vol. 71, No. 11, 2006

Synthesis of Diketopiperazine Mimetics
solution of DIBAL-H in toluene (1.0 M, 3.63 mL, 3.63 mmol) at
-78 °C under argon, and the mixture was stirred for 30 min at
-78 °C. The reaction was quenched with saturated citric acid and
extracted with Et2O. The extract was washed with saturated citric
acid and brine and dried over MgSO4. Concentration under reduced
pressure gave an oily aldehyde, which was used immediately in
the next step without purification. To a stirred solution of
(o-MePhO)2P(O)CH2CO2t-Bu (563 mg, 1.63 mmol) in THF (10
mL) were added NaI (299 mg, 2.00 mmol) and DBU (271 µL,
1.82 mmol) at 0 °C under argon. After stirring for 10 min, a solution
of the above aldehyde in THF (10 mL) was added to the mixture
at -78 °C, and the mixture was stirred for 2 h at 0 °C. The reaction
was quenched with saturated NH4Cl and extracted with EtOAc.
The extract was washed with saturated citric acid, brine, 5%
NaHCO3, and brine and dried over MgSO4. Concentration under
reduced pressure, followed by flash chromatography over silica gel
with n-hexanes-EtOAc (14:1), gave the title compound 16 (440
128.9, 129.6, 130.7 (dd, J ) 12.4, 9.1 Hz), 131.3 (dd, J ) 34.8,
22.3 Hz), 135.6, 161.0; 19F NMR (376 MHz, CDCl3) δ -112.2
(dd, J ) 275, 8.3 Hz, 1F), -85.4 (dd, J ) 275, 14.4 Hz, 1F). Anal.
Calcd for C13H13NOF2: C, 65.81; H, 5.52; N, 5.90. Found: C,
65.65; H, 5.47; N, 5.83.
General Procedure for the Organocopper-Mediated Reduc-
tion. Synthesis of (6S)-6-Benzyl-3,6-dihydro-1-methylpyridin-
2-one (4). To a suspension of CuI (220 mg, 1.15 mmol) in THF
(4.5 mL) was added dropwise a solution of the MeLi‚LiBr complex
in Et2O (1.45 M, 2.38 mL, 3.46 mmol) at -78 °C under argon,
and the mixture was stirred for 10 min at 0 °C. To the solution of
organocopper reagent was added dropwise a solution of the acetate
2 (150 mg, 0.578 mmol) in THF (4.5 mL) at -78 °C, and the
mixture was stirred for 20 min at -78 °C. The reaction was
quenched at -78 °C by the addition of a 1:1 saturated NH4Cl-
28% NH4OH solution (20 mL), with additional stirring at room
temperature for 30 min. The mixture was extracted with Et2O, and
the extract was washed with H2O and dried over MgSO4.
Concentration under reduced pressure, followed by flash chroma-
tography over silica gel with n-hexanes-EtOAc (1:2), gave the
mg, 61.1% yield) as a colorless oil and the (E)-isomer (102 mg,
1
14.2% yield). Compound 16: [R]23 -94.3 (c 0.05, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 1.29 (s, 9H) 1.52 (s, 9H), 2.71 (dd, J
) 13.7, 11.0 Hz, 1H), 3.19 (d, J ) 14.4, 1H), 4.47-4.68 (m, 1H),
4.85 (d, J ) 9.5 Hz, 1H), 5.83-5.93 (m, 1H), 6.05 (d, J ) 12.7
Hz, 1H), 7.17-7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 27.9,
28.1, 34.5, 55.5 (dd, J ) 31.4, 24.8 Hz), 79.7, 82.3, 120.0 (t, J )
246 Hz), 126.5, 128.3, 129.3, 130.6 (t, J ) 28.1 Hz), 136.7, 155.1,
164.3; 19F NMR (376 MHz, CDCl3) δ -107.4 (ddt, J ) 250, 174,
16.5 Hz, 1F), -100.8 (dd, J ) 331, 252 Hz, 1F); HRMS (FAB)
m/z calcd for C21H30F2NO4 (MH+), 398.2143; found, 398.2151.
(6R)-6-Benzyl-5,5-difluoro-6-hydro-1H-pyridin-2-one (17). The
enoate 16 (150 mg, 0.377 mmol) was dissolved in 4 M HCl-
dioxane (6 mL) at 0 °C, and the mixture was stirred for 1 h at
room temperature. Concentration under reduced pressure gave oily
residues that dissolved in DMF (6 mL). To the above mixture were
successively added (i-Pr)2NEt (197 µL, 1.13 mmol), HOAt (154
mg, 1.13 mmol), and EDC‚HCl (217 µg, 1.13 mmol) at 0 °C, and
the mixture was stirred for 23 h at room temperature. After
concentration under reduced pressure, the residue was extracted
with EtOAc. The extract was washed with saturated citric acid,
brine, 5% NaHCO3, and brine and dried over MgSO4. Concentration
under reduced pressure, followed by flash chromatography over
silica gel with n-hexanes-EtOAc (4:1), gave the title compound
17 (61.4 mg, 73.0% yield) as colorless crystals: mp 78-80 °C;
[R]24D +78.4 (c 0.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.81
(dd, J ) 13.9, 11.5 Hz, 1H), 3.29 (dd, J ) 13.9, 3.2 Hz, 1H), 3.97-
4.08 (m, 1H), 5.43 (s, 1H), 6.18 (ddd, J ) 10.2, 2.2, 0.9 Hz, 1H),
6.59 (ddd, J ) 10.2, 7.6, 3.2 Hz, 1H), 7.20-7.42 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 33.6 (d, J ) 5.0 Hz), 57.4 (dd, J )
31.4, 27.1 Hz), 115.0 (dd, J ) 244, 236 Hz), 127.4, 129.0, 129.2,
130.2 (d, J ) 10.0 Hz), 133.8 (dd, J ) 30.6, 27.3 Hz), 134.6, 162.7;
19F NMR (376 MHz, CDCl3) δ -107.1 (d, J ) 281 Hz, 1F), -105.1
(dd, J ) 277, 18.6 Hz, 1F). Anal. Calcd for C12H11NOF2: C, 64.57;
H, 4.97; N, 6.27. Found: C, 64.65; H, 5.06; N, 6.25.
title compound 4 (95.6 mg, 82.1% yield) as colorless crystals: mp
1
55-56 °C; [R]21 +262.6 (c 1.12, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 2.14 (d, J ) 22.2 Hz, 1H), 2.68 (d, J ) 21.7 Hz, 1H),
2.88 (dd, J ) 13.4, 3.9 Hz, 1H), 2.94 (dd, J ) 13.4, 6.6 Hz, 1H),
3.11 (s, 3H), 4.08-4.15 (m, 1H), 5.62-5.71 (m, 2H), 7.05-7.09
(m, 2H), 7.21-7.29 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 31.8,
32.9, 39.4, 61.4, 123.6, 124.8, 126.6, 128.1, 129.8, 135.6, 168.4.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.43; H, 7.58; N, 6.89.
General Procedure for the Organocopper-Mediated Reduc-
tion-Alkylation. Synthesis of (3S,6S)-6-Benzyl-3,6-dihydro-1,3-
dimethylpyridin-2-one (trans-19) and (3R,6S)-6-Benzyl-3,6-
dihydro-1,3-dimethylpyridin-2-one (cis-19). To a suspension of
CuI (77.3 mg, 0.406 mmol) in THF (1.5 mL) was added dropwise
a solution of the MeLi‚LiBr complex in Et2O (1.33 M, 915 µL,
1.22 mmol) at -78 °C under argon, and the mixture was stirred
for 10 min at 0 °C. To the solution of organocopper reagent was
added dropwise a solution of the acetate 2 (52.8 mg, 0.203 mmol)
in THF (1.5 mL) at -78 °C, and the mixture was stirred for 20
min at -78 °C. To the above mixture was added MeI (101 µL,
1.62 mmol) at -78 °C, and the mixture was stirred for 3 h at 0 °C.
The reaction was quenched at -78 °C by the addition of a 1:1
saturated NH4Cl-28% NH4OH solution (2 mL), with additional
stirring at room temperature for 30 min. The mixture was extracted
with Et2O, and the extract was washed with H2O and dried over
MgSO4. Concentration under reduced pressure, followed by flash
chromatography over silica gel with n-hexanes-EtOAc (1:1), gave
the title compound trans-19 (4.4 mg, 10.1% yield) and cis-19 (25.3
mg, 57.8% yield) in order of elution. trans-19 (colorless oil): [R]23
D
+231.9 (c 0.207, CHCl3); 1H NMR (600 MHz, CDCl3) δ 1.16 (d,
J ) 7.5 Hz, 3H), 2.11-2.17 (m, 1H), 2.88 (dd, J ) 13.4, 3.7 Hz,
1H), 2.93 (dd, J ) 13.5, 6.6 Hz, 1H), 3.08 (s, 3H), 4.08-4.14 (m,
1H), 5.55 (dd, J ) 10.0, 2.1 Hz, 1H), 5.62 (ddd, J ) 9.9, 4.3, 2.9
Hz, 1H), 7.05-7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 17.7,
33.1, 34.9, 39.3, 61.6, 123.5, 126.3, 127.8, 129.5, 129.9, 135.5,
171.4; HRMS (FAB) m/z calcd for C14H18NO (MH+), 216.1388;
(6R)-6-Benzyl-5,5-difluoro-6-hydro-1-methylpyridin-2-one (18).
To a suspension of NaH (60% oil suspension, 5.6 mg, 0.140 mmol)
in THF (0.75 mL) was added the lactam 17 (26.7 mg, 0.120 mmol)
in THF (0.75 mL) at 0 °C under argon. After stirring for 2 h at 0
°C, MeI (15 µL, 0.241 mmol) was added to the above mixture,
and the resulting mixture was stirred for 2 h at room temperature.
The reaction was quenched with H2O (3 mL) at 0 °C and extracted
with EtOAc. The extract was washed with brine and dried over
MgSO4. Concentration under reduced pressure, followed by flash
chromatography over silica gel with n-hexanes-EtOAc (1:3), gave
found, 216.1389. cis-19 (colorless crystals): mp 134-135 °C;
1
[R]22 +198.8 (c 0.51, CHCl3); H NMR (600 MHz, CDCl3) δ
D
0.68 (d, J ) 7.4 Hz, 3H), 2.78 (m, 1H), 2.91 (d, J ) 5.1 Hz,
2H), 3.10 (s, 3H), 4.00-4.13 (m, 1H), 5.57 (ddd, J ) 10.1, 3.8,
0.6 Hz, 1H), 5.64 (ddd, J ) 10.1, 4.1, 0.9 Hz, 1H), 7.00-7.30 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 19.2, 33.1, 36.4, 40.1, 61.5,
123.2, 126.8, 128.2, 129.2, 129.9, 135.8, 171.7. Anal. Calcd for
C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 77.80; H, 7.96;
N, 6.35.
the title compound 18 (23.9 mg, 84.0% yield) as colorless
1
crystals: mp 48-50 °C; [R]25 -16.6 (c 0.06, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 2.71 (s, 3H), 2.89 (dd, J ) 13.9, 8.1 Hz,
1H), 3.15 (dt, J ) 13.9, 3.6 Hz, 1H), 3.89-3.95 (m, 1H), 6.04 (dt,
J ) 10.0, 2.9 Hz, 1H), 6.28 (ddt, J ) 10.0, 8.5, 1.6 Hz, 1H), 7.12-
7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 35.0, 36.0 (d, J )
5.8 Hz), 66.2 (t, J ) 28.1), 116.6 (dd, J ) 242, 239 Hz), 127.3,
(3S,6S)-3,6-Dibenzyl-3,6-dihydro-1-methylpyridin-2-one (trans-
20) and (3R,6S)-3,6-Dibenzyl-3,6-dihydro-1-methylpyridin-2-one
(cis-20). By the use of a procedure identical with that described
for the preparation of 19 from 2, organocopper-mediated reduction
J. Org. Chem, Vol. 71, No. 11, 2006 4127

Niida et al.
(-78 °C, 20 min)-alkylation with BnBr (176 µL, 1.48 mmol, -78
°C, 2.5 h) of acetate 2 (48.2 mg, 0.185 mmol) gave the title
compound trans-20 (38.9 mg, 72.1% yield) and cis-20 (4.8 mg,
0.15H), 2.65 (m, 0.85H), 2.88 (dd, J ) 13.5, 3.6 Hz, 1H), 2.93
(dd, J ) 13.5, 6.6 Hz, 1H), 3.10 (s, 3H), 4.10-4.13 (m, 1H), 5.64-
5.69 (m, 2H), 7.03-7.09 (m, 2H), 7.20-7.28 (m, 3H); HRMS
(FAB) m/z calcd for C13H15DNO (MH+), 203.1294; found, 203.1296.
(3S,6S)-6-Benzyl-3,6-dihydro-1-(2,4-dimethoxy)benzyl-3-
methylpyridin-2-one (trans-24) and (3R,6S)-6-Benzyl-3,6-dihy-
dro-1-(2,4-dimethoxy)benzyl-3-methylpyridin-2-one (cis-24). By
the use of a procedure identical with that described for the
preparation of 19 from 2, organocopper-mediated reduction (-78
°C, 20 min)-alkylation with MeI (63.4 µL, 1.02 mmol, 0 °C, 3 h)
of acetate 12 (50.4 mg, 0.127 mmol) gave the title compound trans-
8.9% yield). trans-20 (colorless crystals): mp 78-80 °C; [R]23
D
1
+231.8 (c 0.37, CHCl3); H NMR (600 MHz, CDCl3) δ 2.41 (m,
1H), 2.72 (dd, J ) 13.7, 9.3 Hz, 1H), 2.87 (d, J ) 5.27 Hz, 2H),
3.08 (s, 3H), 3.24 (d, J ) 13.7, 4.4 Hz, 1H), 3.98-4.02 (m, 1H),
5.50 (dd, J ) 10.3, 2.0 Hz, 1H), 5.57 (ddd, J ) 10.1, 4.1, 2.7 Hz,
1H), 7.02-7.27 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 33.2,
37.5, 39.5, 41.4, 61.4, 124.5, 126.1, 126.7, 126.9, 128.1, 128.2,
129.3, 129.8, 135.8, 139.1, 170.5. Anal. Calcd for C20H21NO: C,
82.44; H, 7.26; N, 4.81. Found: C, 82.34; H, 7.30; N, 4.70. cis-20
(colorless oil): [R]23D -15.2 (c 0.19, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 1.98 (dd, J ) 13.1, 9.3 Hz, 1H), 2.13 (dd, J ) 13.4, 7.7
Hz, 1H), 2.71 (dd, J ) 13.4, 3.7 Hz, 1H), 3.07 (s, 3H), 3.06-3.12
(m, 1H), 3.96-4.05 (m, 1H), 5.48 (dd, J ) 10.5, 3.7 Hz, 1H), 5.51
(dd, J ) 10.7, 3.6 Hz, 1H), 7.10-7.33 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 33.2, 39.5, 40.0, 43.3, 61.6, 124.5, 126.2, 126.3,
126.7, 128.1, 128.3, 129.5, 129.8, 136.2, 138.5, 170.1; HRMS
(FAB) m/z calcd for C20H22NO (MH+), 292.1701; found, 292.1695.
(3S,6S)-6-Benzyl-3,6-dihydro-1-methyl-3-(2-methylpropyl)py-
ridin-2-one (trans-21) and (3R,6S)-6-Benzyl-3,6-dihydro-1-meth-
yl-3-(2-methylpropyl)pyridin-2-one (cis-21). By the use of a
procedure identical with that described for the preparation of 19
from 2, organocopper-mediated reduction (-78 °C, 20 min)-
alkylation with i-BuI (152 µL, 1.31 mmol, 0 °C, 2 h) of acetate 2
(43.3 mg, 0.166 mmol) gave the title compound trans-21 (26.0 mg,
60.8% yield) and cis-21 (5.1 mg, 11.9% yield). trans-21 (colorless
oil): [R]24D +159.8 (c 1.46, CHCl3); 1H NMR (600 MHz, CDCl3)
δ 0.78 (d, J ) 6.5 Hz, 3H), 0.82 (d, J ) 6.5 Hz, 3H), 1.33 (ddd,
J ) 13.8, 8.8, 5.5 Hz, 1H), 1.64 (m, 1H), 1.72 (ddd, J ) 13.5, 8.8,
4.7 Hz, 1H), 2.07 (m, 1H), 2.91 (d, J ) 5.2 Hz, 2H), 3.08 (s, 3H),
4.08-4.13 (m, 1H), 5.63-5.65 (m, 2H), 7.06-7.10 (m, 2H), 7.20-
7.28 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 21.6, 23.1, 25.3,
33.3, 38.1, 39.5, 40.3, 61.4, 124.0, 126.7, 128.2, 129.9, 135.9, 171.8;
HRMS (FAB) m/z calcd for C17H24NO (MH+), 258.1858; found,
258.1859. cis-21 (colorless oil): [R]23D +42.6 (c 0.26, CHCl3); 1H
NMR (600 MHz, CDCl3) δ 0.32 (ddd, J ) 13.2, 9.9, 5.3 Hz, 1H),
0.76 (d, J ) 6.6 Hz, 3H), 0.81 (d, J ) 6.6 Hz, 3H), 1.17 (ddd, J )
13.2, 9.2, 5.5 Hz, 1H), 1.49-1.56 (m, 1H), 2.73-2,79 (m, 1H),
2.91 (d, J ) 5.2 Hz, 2H), 3.08 (s, 3H), 4.07-4.12 (m, 1H), 5.61
(ddd, J ) 10.2, 4.0, 0.5 Hz, 1H), 5.71 (ddd, J ) 10.2, 4.4, 0.9 Hz,
1H), 7.04-7.08 (m, 2H), 7.19-7.29 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 21.2, 23.1, 24.9, 33.1, 39.4, 40.1, 43.5, 61.6, 123.7, 126.8,
127.6, 128.2, 130.0, 135.8, 171.7; HRMS (FAB) m/z calcd for
C17H24NO (MH+), 258.1858; found, 258.1855.
24 (4.6 mg, 10.3% yield) and cis-24 (28.8 mg, 64.5% yield). trans-
1
24 (colorless oil): [R]20 -15.6 (c 0.26, CHCl3); H NMR (400
D
MHz, CDCl3) δ 1.20 (d, J ) 7.5 Hz, 3H), 2.19-2.28 (m, 1H),
2.86-2.97 (m, 2H), 3.79 (s, 3H), 3.84 (s, 3H), 4.00-4.13 (m, 1H),
4.27 (d, J ) 15.1 Hz, 1H), 5.32 (d, J ) 15.1 Hz, 1H), 5.52-5.61
(m, 2H), 6.39-6.52 (m, 2H), 7.03-7.33 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 17.9, 35.2, 39.3, 40.8, 55.4, 58.0, 98.3, 104.3, 117.8,
124.6, 126.5, 128.1, 129.9, 130.2, 136.4, 158.5, 160.1, 172.1; HRMS
(FAB) m/z calcd for C22H26NO3 (MH+), 352.1913; found, 352.1906.
cis-24: [R]21D -1.45 (c 1.37, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 0.79 (d, J ) 7.5 Hz, 3H), 2.80-2.90 (m, 1H), 2.91 (dd, J )
13.1, 7.3 Hz, 1H), 2.97 (dd, J ) 13.4, 3.9 Hz, 1H), 3.79 (s, 3H),
3.84 (s, 3H), 4.06-4.16 (m, 1H), 4.30 (d, J ) 14.9 Hz, 1H), 5.35
(d, J ) 14.9 Hz, 1H), 5.51 (dd, J ) 10.0, 4.1 Hz, 1H), 5.63 (dd, J
) 10.0, 4.1 Hz, 1H), 6.41-6.50 (m, 2H), 7.02-7.10 (m, 2H), 7.15-
7.30 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 19.3, 29.7, 36.9,
40.4, 55.4, 57.8, 98.3, 104.4, 117.7, 123.9, 126.6, 128.1, 128.8,
130.0, 130.6, 136.4, 158.6, 160.2, 172.1; HRMS (FAB) m/z calcd
for C22H26NO3 (MH+), 352.1913; found, 352.1919.
(3S,6S)-3,6-Dibenzyl-3,6-dihydro-1-(2,4-dimethoxy)benzylpy-
ridin-2-one (trans-25) and (3R,6S)-3,6-Dibenzyl-3,6-dihydro-1-
(2,4-dimethoxy)benzylpyridin-2-one (cis-25). By the use of a
procedure identical with that described for the preparation of 19
from 2, organocopper-mediated reduction (-78 °C, 20 min)-
alkylation with BnBr (120 µL, 1.01 mmol, -78 °C, 3 h) of acetate
12 (50.4 mg, 0.127 mmol) gave the title compound trans-25 (29.2
mg, 53.7% yield) and cis-25 (10.3 mg, 18.9% yield). Compound
cis-25 was identical to the compound characterized by Guibe´ et al.
(ref 8b). trans-25 (colorless oil): [R]23 +77.9 (c 0.68, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 2.42-2.50 (m, 1H), 2.87 (dd, J )
13.6, 8.5 Hz, 1H), 2.87-3.00 (m, 2H), 3.18 (dd, J ) 13.6, 4.4 Hz,
1H), 3.79 (s, 3H), 3.81 (s, 3H), 3.95-4.05 (m, 1H), 4.27 (d, J )
14.8 Hz, 1H), 5.33 (d, J ) 15.1 Hz, 1H), 5.49-5.60 (m, 2H), 6.37
(dd, J ) 8.6, 2.4 Hz, 1H), 6.44 (d, J ) 2.2 Hz, 1H), 6.88 (d, J )
8.3 Hz, 1H), 7.00-7.12 (m, 4H), 7.13-7.27 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 37.3, 39.3, 40.8, 41.5, 55.3, 57.8, 98.2, 104.4,
117.5, 125.2, 125.9, 126.5, 127.2, 128.0, 128.1, 129.5, 129.8, 129.9,
136.2, 139.2, 158.4, 160.0, 170.5; HRMS (FAB) m/z calcd for
C28H30NO3 (MH+), 428.2226; found, 428.2219.
(3S,6S)-6-Benzyl-3,6-dihydro-1-methyl-3-(methylethyl)pyri-
din-2-one (trans-22). By the use of a procedure identical with that
described for the preparation of 19 from 2, organocopper-mediated
reduction (-78 °C, 20 min)-alkylation with i-PrI (143 µL, 1.44
mmol, 0 °C, 3 h) of acetate 2 (46.7 mg, 0.180 mmol) gave the title
(6R)-6-Benzyl-3,6-dihydro-5-fluoro-1-methylpyridin-2-one (26).
By the use of a procedure identical with that described for the
preparation of 4 from 2, organocopper-mediated reduction of lactam
18 (23.2 mg, 0.0978 mmol) with Me3CuLi2‚LiI‚3LiBr (2 equiv) at
compound trans-22 (26 mg, 55,9% yield) as a colorless oil: [R]24
D
1
+1.91 (c 0.52, CHCl3); H NMR (600 MHz, CDCl3) δ 0.68 (d, J
) 6.8 Hz, 3H), 0.89 (d, J ) 7.1 Hz, 3H), 2.11-2.15 (m, 1H), 2.47-
2.54 (m, 1H), 2.88 (dd, J ) 13.4, 6.9 Hz, 1H), 2.93 (dd, J ) 13.4,
3.6 Hz, 1H), 3.10 (s, 3H), 4.10-4.15 (m, 1H), 5.61 (ddd, J ) 10.3,
1.5, 1.0 Hz, 1H), 5.71 (ddd, J ) 10.3, 3.5, 3.0 Hz, 1H), 7.07-7.28
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 17.6, 19.9, 29.1, 33.1,
39.6, 45.6, 61.0, 123.9, 125.3, 126.3, 127.8, 129.5, 135.6, 170.4;
HRMS (FAB) m/z calcd for C16H22NO (MH+), 244.1701; found,
244.1694.
-78 °C for 30 min gave the title compound 26 (16.5 mg, 76.8%
1
yield) as a colorless oil: [R]24 -13.3 (c 0.08, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 1.87 (ddt, J ) 20.9, 4.8, 3.4 Hz, 1H), 2.57
(dtd, J ) 20.9, 5.4, 2.0 Hz, 1H), 2.95 (ddd, J ) 14.1, 3.2, 1.3 Hz,
1H), 3.09 (s, 3H), 3.14 (dd, J ) 14.1, 4.2 Hz, 1H), 4.14-4.24 (m,
1H), 5.13 (ddd, J ) 13.6, 5.1, 2.4 Hz, 1H), 7.04-7.10 (m, 2H),
7.23-7.31 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 29.1 (d, J )
8.3 Hz), 33.0, 35.8, 59.8 (d, J ) 34.7 Hz), 99.9 (d, J ) 15.7 Hz),
127.2, 128.2, 130.0, 134.0, 152.8 (d, J ) 253 Hz), 167.9; 19F NMR
(376 MHz, CDCl3) δ -118.2 (dd, J ) 14.4, 6.2 Hz, 1F); HRMS
(FAB) m/z calcd for C13H15FNO (MH+), 220.1138; found, 220.1135.
(3R,6R)-6-Benzyl-3,6-dihydro-5-fluoro-1,3-dimethylpyridin-
2-one (trans-27) and (3S,6R)-6-Benzyl-3,6-dihydro-5-fluoro-1,3-
dimethylpyridin-2-one (cis-27). By the use of a procedure identical
with that described for the preparation of 19 from 2, organocopper-
(6S)-6-Benzyl-3-deuterio-3,6-dihydro-1-methylpyridin-2-
one (23). By the use of a procedure identical with that described
for the preparation of 4 from 2, after reduction of acetate 2 (25.5
mg, 0.098 mmol) with Me3CuLi2‚LiI‚3LiBr at -78 °C for 20 min,
treatment of the mixture with D2O (3 mL) gave the title compound
23 (16.0 mg, 80.7% yield) as a diastereomixture. The ratio of
1
diastereomers was determined by H NMR experiments (trans/cis
) 15:85). Compound 23: 1H NMR (600 MHz, CDCl3) δ 2.12 (m,
4128 J. Org. Chem., Vol. 71, No. 11, 2006

Synthesis of Diketopiperazine Mimetics
mediated reduction (-78 °C, 30 min)-alkylation with MeI (62.2
µL, 1.44 mmol, 0 °C, 2 h) of the lactam 18 (46.7 mg, 0.180 mmol)
in Et2O gave the title compound trans-27 (2.7 mg, 9.2% yield)
preparation of 19 from 2, organocopper-mediated reduction (-78
°C, 20 min)-alkylation with MeI (191 µL, 1.61 mmol, -78 °C, 2
h then 0 °C, 1 h) of lactam 41 (47.9 mg, 0.184 mmol) gave the
title compound 42 (21.4 mg, 54.0% combined yield, trans/cis )
13:87). The diastereo ratio was determined by 1H NMR. Each
isomer was separated by repetitious flash chromatography and
characterized. (3R,6S)-1-Benzyl-3,6-dihydro-3,6-dimethylpyri-
dine-2-one (cis-42). A colorless oil: [R]26D -103.3 (c 0.41, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.26 (d, J ) 6.6 Hz, 3H), 1.36 (d,
J ) 7.3 Hz, 3H), 3.00-3.12 (m, 1H), 3.78-3.90 (m, 1H), 4.06 (d,
J ) 15.4 Hz, 1H), 5.40 (d, J ) 15.1 Hz, 1H), 5.63 (dd, J ) 10.0,
3.6 Hz, 1H), 5.74 (dd, J ) 10.0, 4.4, 0.9 Hz, 1H), 7.20-7.35 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 20.8, 21.5, 36.9, 46.6, 52.6,
126.4, 127.2, 127.7, 128.5, 137.2, 171.8; HRMS (FAB) m/z calcd
for C14H18NO (MH+), 216.1388; found, 216.1383. (3S,6S)-1-
and cis-27 (15.0 mg, 51.1% yield). trans-27 (colorless oil): [R]25
D
1
+44.4 (c 0.05, CHCl3); H NMR (400 MHz, CDCl3) δ 1.10 (d, J
) 7.6 Hz, 3H), 1.87-1.92 (m, 1H), 2.94 (ddd, J ) 14.2, 2.9, 0.9
Hz, 1H), 3.08 (s, 3H), 3.15 (dd, J ) 14.2, 4.2 Hz, 1H), 4.19 (m,
1H), 5.05 (dd, J ) 14.2, 2.4 Hz, 1H), 7.02-7.10 (m, 2H), 7.22-
7.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 18.7, 32.9 (d, J )
8.3 Hz), 33.1, 35.7 (d, J ) 2.5 Hz), 60.2 (d, J ) 34.8 Hz), 106.2
(d, J ) 12.4 Hz), 127.2, 128.3, 130.0, 134.2, 152.4 (d, J ) 254
Hz), 171.2; 19F NMR (376 MHz, CDCl3) δ -119.5 (d, J ) 14.4
Hz, 1F); HRMS (FAB) m/z calcd for C14H17FNO (MH+), 234.1294;
1
found, 234.1291. cis-27: [R]25 +21.7 (c 0.05, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 0.35 (d, J ) 7.6 Hz, 3H), 2.75-2.81 (m,
1H), 2.94 (ddd, J ) 14.4, 4.4, 2.0 Hz, 1H), 3.10 (s, 3H), 3.12 (dd,
J ) 14.4, 4.1 Hz, 1H), 4.20 (dt, J ) 6.6, 3.2 Hz, 1H), 5.16 (dd, J
Benzyl-3,6-dihydro-3,6-dimethylpyridine-2-one (trans-42). A
1
colorless oil: [R]19 -58.9 (c 0.21, CHCl3); H NMR (400 MHz,
D
) 14.6, 4.4 Hz, 1H), 7.02-7.08 (m, 2H), 7.19-7.33 (m, 3H); 13
C
CDCl3) δ 1.24 (d, J ) 6.6 Hz, 3H), 1.39 (d, J ) 7.6 Hz, 3H),
2.98-3.10 (m, 1H), 3.80-3.92 (m, 2H), 4.05 (d, J ) 15.4 Hz,
1H), 5.41 (d, J ) 15.4 Hz, 1H), 5.62-5.69 (m, 2H), 7.19-7.40
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 18.5, 20.2, 35.3, 46.5,
52.8, 126.7, 127.2, 127.5, 128.0, 128.5, 137.4, 171.5; HRMS (FAB)
m/z calcd for C14H18NO (MH+), 216.1388; found, 216.1396.
NMR (100 MHz, CDCl3) δ 18.9 (d, J ) 1.6 Hz), 33.1, 34.7 (d, J
) 8.3 Hz), 35.6 (d, J ) 2.5 Hz), 59.8 (d, J ) 34.8 Hz), 105.7 (d,
J ) 12.4 Hz), 127.2, 128.3, 130.2, 134.2, 152.0 (d, J ) 252 Hz),
170.9; 19F NMR (376 MHz, CDCl3) δ -120.4 (d, J ) 14.5 Hz,
1F); HRMS (FAB) m/z calcd for C14H17FNO (MH+), 234.1294;
found, 234.1299.
DFT Calculations. DFT calculations were carried out on a SGI
Origin 3800 system within the Gaussian 98 package. All geometry
optimizations were performed by the B3LYP/6-31G(d) method. It
was confirmed that all optimized structures have no imaginary
frequencies by the frequency analysis at the B3LYP/6-31G(d) level.
It was also confirmed that optimization of complex 34 at the
B3LYP/6-31G(d,p) level gave a similar structure as in the case of
the use of B3LYP/6-31G(d) method.
(3R,6R)-3,6-Dibenzyl-3,6-dihydro-5-fluoro-1-methylpyridin-
2-one (28). By the use of a procedure identical with that described
for the preparation of 19 from 2, organocopper-mediated reduction
(-78 °C, 30 min)-alkylation with BnBr (191 µL, 1.61 mmol, -78
°C, 2 h) of lactam 18 (47.8 mg, 0.201 mmol) gave the title
compound 28 (38.1 mg, 61.3% yield) as a colorless oil: [R]26
D
+15.2 (c 0.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.12-2.16
(m, 1H), 2.61 (dd, J ) 13.7, 9.5 Hz, 1H), 2.89 (ddd, J ) 13.9, 2.9,
1.0 Hz, 1H), 3.07 (s, 3H), 3.11 (dd, J ) 14.1, 4.2 Hz, 1H), 3.15
(ddd, J ) 13.7, 4.1, 1.4 Hz, 1H), 4.09 (dt, J ) 7.1, 4.2 Hz, 1H),
4.98 (dd, J ) 14.6, 2.7 Hz, 1H), 6.98-7.06 (m, 4H), 7.12-7.28
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 33.2, 35.7 (d, J ) 3.3
Hz), 38.3, 39.6 (d, J ) 7.4 Hz), 59.8 (d, J ) 34.8 Hz), 103.4 (d,
J ) 14.1 Hz), 126.3, 127.1, 128.3, 129.2, 129.9, 134.1, 138.4, 152.7
(d, J ) 255 Hz), 169.7; 19F NMR (376 MHz, CDCl3) δ -117.7 (d,
J ) 14.5 Hz, 1F); HRMS (FAB) m/z calcd for C20H21FNO (MH+),
310.1607; found, 310.1607.
Acknowledgment. We thank Dr. Motoo Shiro, Rigaku
International Corporation, Japan, and Dr. Terrence R. Burke
Jr., NCI, NIH, USA, for X-ray analysis and for proofreading
this manuscript, respectively. Computation time was provided
by the Supercomputer Laboratory, Institute for Chemical
Research, Kyoto University. This research was supported in part
by 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science” a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and the Japan Health Science
Foundation. A.N. is grateful for Research Fellowships of the
JSPS for Young Scientists.
General Procedure for the Alkylation of â,γ-Unsaturated-
δ-Lactam with LDA/Alkyl Halide System. To a solition of
(i-Pr)2NH (45.3 µL, 0.322 mmol) in THF (1.25 mL) was added
n-BuLi in hexane (1.6 M, 170 µL, 0.273 mmol) at -78 °C under
argon. After stirring for 20 min at -78 °C, lactam 4 (50 mg, 0.248
mmol) in THF (0.75 mL) was added dropwise to the above mixture
and stirred for 30 min at -78 °C. To the above mixture, MeI (30.9
µL, 0.496 mmol) was added, and the mixture was stirred at -78
°C for 2 h, then at 0 °C for 1 h. The reaction was quenched with
saturated aq NH4Cl, followed by the usual workup, to yield trans-
19 (8.4 mg, 15.7% yield) and cis-19 (35.6% yield).
Supporting Information Available: Synthesis of acetate 14
and the alanine-derived substrate 41. Structure determination of
mimetics 42. CIF files of cis-19 and trans-20. Stereoviews, opti-
mized coordinates, and energies of oxa-π-allyl complexes. This ma-
terial is available free of charge via the Internet at http://pubs.acs.org.
(6S)-1-Benzyl-3,6-dihydro-3,6-dimethylpyridine-2-one (42).
By use of a procedure identical with that described for the
JO060202Z
J. Org. Chem, Vol. 71, No. 11, 2006 4129