Asymmetric synthesis of δ-substituted α,β-unsaturated δ-lactams by ring closing metathesis of enantiomerically pure N-acryloyl-homoallylic amines

Article abstract of DOI:10.1021/jo0703000

(Chemical Equation Presented) Optically pure secondary homoallylic amines, obtained by highly diastereoselective addition of allylmetal reagents to imines derived from chiral amines, were N-dealkylated, and the primary amines were converted to N-acryloyl

Full text of DOI:10.1021/jo0703000

Asymmetric Synthesis of δ-Substituted r,â-Unsaturated δ-Lactams
by Ring Closing Metathesis of Enantiomerically Pure
N-Acryloyl-homoallylic Amines
Claudio Fiorelli and Diego Savoia*
Dipartimento di Chimica “G. Ciamician”, UniVersita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
diego.saVoia@unibo.it
ReceiVed February 13, 2007
Optically pure secondary homoallylic amines, obtained by highly diastereoselective addition of allylmetal
reagents to imines derived from chiral amines, were N-dealkylated, and the primary amines were converted
to N-acryloyl amides. Then, ring closing metathesis gave δ-substituted δ-lactams in good overall yields.
Introduction
an unsaturated organometallic reagent to an imine and the
subsequent N-alkylation with an unsaturated alkyl halide. In
this case, asymmetric induction in the carbon-carbon bond
formation (imine addition) can be achieved by three different
methodologies exploiting (a) substrate induced diastereoselec-
tivity (SID),6 where the chirality is present in the imine,
generally in the C-substituent, and is retained in the product;
(b) auxiliary induced diastereoselectivity (AID), where the
chirality is present in the imine, generally in the N-substituent,
that is removed in a successive step; and (c) reagent induced
stereoselectivity (RIS),7 where the asymmetric induction is
provided by a chiral ligand that is bound to the metal by covalent
bond(s) or by Lewis acid-base interaction(s).
The AID approach to the synthesis of substituted piperidines
is illustrated in Scheme 1. It involves the C-allylation of chiral
imine 1 to give the homoallylic amine 2 and successive
N-allylation to give the 5-aza-1,7-diene 3. The absolute con-
figuration of the new stereocenter R to N formed in the
allylmetalation step is controlled by the chiral auxiliary (N-
The ring closing metathesis (RCM) of 1,n-dienes is a powerful
and versatile technique for the construction of carbocyclic and
heterocyclic compounds.1 In particular, this methodology has
been exploited for the synthesis of azaheterocycles, as witnessed
by several reviews dealing with the synthesis of natural
compounds (e.g., piperidine and pyrrolidine alkaloids,2,3 dipep-
tide mimetics,4 and â-lactams of non-classical structure).5 The
required azadiene for the RCM reaction can be prepared by a
plethora of methods. A simple route involves the addition of
(1) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c)
Phillips, A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75. (d) Schrock, R,
R.: Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (e) Schmidt,
B.; Hermanns, J. Curr. Org. Chem. 2006, 10, 1363. (f) Michaut, A.;
Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740. (g) Gradillas, A.;
Pe´rez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086.
(2) (a) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2002, 3693. (b)
Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199. (c) Moody, C. J.
Chem. Commun. 2004, 1341-1351.
(3) For recent reports, see: (a) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett.
2005, 7, 871. (b) Pedrosa. R.; Andre´s, C.; Gutie´rrez-Loriente, A.; Nieto,
X. Eur. J. Org. Chem. 2005, 2449. (c) Welter, C.; Moreno, R. M.; Streiff,
S.; Helmchen, G. Org. Biomol. Chem. 2005, 3, 3266. (d) Weihofen, R.;
Dahnz, A.; Tverskoy, O.; Helmchen, G. Chem. Commun. 2005, 3541. (e)
Cren, S.; Wilson, C.; Thomas, N. R. Org. Lett. 2005, 7, 3521. (f) Gagnon,
D.; Lauzon, S.; Godbout, C.; Spino, C. Org. Lett. 2005, 7, 4769. (g)
Kuznetsov, N. Y.; Khrustalev, V. N.; Godovikov, I. A.; Bubnov, Y. N.
Eur. J. Org. Chem. 2006, 113.
(6) (-)-epi-Deoxoprosopinine has been synthesized through RCM by
the SID approach: Felpin, F.-X.; Boubekeur, K.; Lebreton, J. Eur. J. Org.
Chem. 2003, 4518.
(7) (a) Addition of (-)-B-allyldiisopinocampheylborane to N-alumi-
noimines afforded the homoallylic amines with 68-90% e.e., then N-
allylation with ethyl[(2-acetyloxy)methyl]acrylate and RCM afforded
functionalized tetrahydropyridine-3-carboxylates: Ramachandran, P. V.;
Burghardt, T. E.; Bland-Berry, L. J. Org. Chem. 2005, 70, 7911. (b)
γ-Lactams were synthesized by the same methodology: Ramachandran,
P. V.; Burghardt, T. E. Chem.sEur. J. 2005, 11, 4387.
(4) Maison, W.; Prenzel, A. H. G. P. Synthesis 2005, 1031.
(5) Alcaide, B.; Almendros, P. Curr. Org. Chem. 2002, 6, 245.
10.1021/jo0703000 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/11/2007
6022
J. Org. Chem. 2007, 72, 6022-6028

Synthesis of δ-Substituted R,â-Unsaturated δ-Lactams
SCHEME 1
the N-protected tetrahydropyridine 5, hydrogenation, and final
N-deprotection.10 N-Acetyl-(-)-coniine was similarly prepared
in seven steps; in the first of them, the addition of lithiated allyl
phenyl sulfone to enantiopure N-p-toluenesulfinyl butyraldimine
occurred with low diastereoselectivity, affording a mixture of
three diastereomeric branched homoallylic amines with a 1:1:3
ratio.11,12
On the basis of these reports, we considered that there was
room for improvement. Above all, we foresaw a significant
variant in the synthetic sequence by the conversion of the
secondary homoallylic amine 2 to the acryloyl amide 4 (Scheme
1), as the N-acryloyl substituent provides at the same time a
two carbon fragment to the ring being constructed and acts as
a protective group of the amine function in the RCM step leading
to the R,â-unsaturated δ-lactams 6. The latter compounds are
precursors of the saturated piperidines 8 by a plethora of
methodologies.
R,â-Unsaturated δ-lactams have been previously prepared by
RCM reactions.13,14 For example, an unsymmetrically δ,δ-
disubstituted R,â-unsaturated δ-lactam, precursor of a disub-
stituted piperidine NK1 antagonist, was prepared from N-(t-
butylsulfinyl)ketimine by a route analogous to that described
in Scheme 1, involving the addition of allylmagnesium chloride
(63% yield, d.r. 9:1).13k Alternatively, homoallylic amines were
prepared from optically pure homoallylic alcohols through
substitution by an azide ion in HMPA,13f and by the addition
of vinylmagnesium chloride to (S)-N-Boc-phenylalaninal,13n
then, in both cases, reaction with acryloyl chloride and RCM
reaction led to polysubstituted lactams.
In principle, following routes analogous to those described
in Scheme 1, either the size and/or the position of the double
bond of the unsaturated lactams can be varied by the proper
choice of the ω-alkenylmetal reagent and the ω-alkenyl/alkenoyl
halide. However, the synthesis of six-membered rings takes
substituent). When the allylmetal reagent bears a γ-substituent
(R2), two stereocenters are formed, whose relative stereochem-
istry is determined by the (E) or (Z) geometry of the substituted
allylmetal reagent. In the first report of this approach,8 (-)-
pipecoline, (-)-coniine, and (-)-2-phenylpiperidine were syn-
thesized beginning from imines derived from (R)-1-phenyleth-
ylamine and acetaldehyde, butyraldehyde, and benzaldehyde,
respectively, exploiting in the first step the zinc-mediated Barbier
allylation procedure we previously developed for imines derived
from (S)-valine esters.9 After N-allylation of the homoallylic
amines 2 thus obtained gave 3 (R ) R*), the RCM reaction
catalyzed by the first generation Grubbs ruthenium benzylidene
complex afforded the tetrahydropyridines 5 (R ) R*) as a
mixture of diastereomers (d.r. <85:15), which were separated
by column chromatography. Finally, hydrogenation of the alkene
and concomitant hydrogenolysis of the N-substituent afforded
the piperidines 7 (R2 to R4 ) H). (-)-Coniine and (R)-2-
phenylpiperidine also have been synthesized by an analogous
route that used (S)- and (R)-(O)-(1-phenylbutyl)hydroxylamine
as the chiral auxiliaries in the appropriate oximes, which
underwent the addition of allylmagnesium bromide with good
stereocontrol (de 87 and 91%, respectively).10 A longer route
involves the removal of the chiral auxiliary from the homoallylic
amine 2, protection of the amine function (e.g., as a carbamate),
N-allylation to give the N-protected azadiene 3, RCM to give
(11) Kumareswaran, R.; Hassner, A. Tetrahedron: Asymmetry 2001, 12,
2269.
(12) Azaheterocycles have been prepared by an analogous route begin-
ning from chiral cyclic N-acyliminium ions and exploiting the RCM of the
derived azadienes: (a) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett.
2000, 41, 4113. (b) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron 2001,
57, 5393. (c) El-Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R. R. Eur.
J. Org. Chem. 2002, 4137.
(13) (a) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997,
38, 677 and Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2000, 41,
4413. (b) Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org. Chem. 2002, 68,
62. (c) Ma, S.; Ni, B. Org. Lett. 2002, 4, 639. (d) Gille, S.; Ferry, A.;
Billard, T.; Langlois, B. R. J. Org. Chem. 2003, 68, 8932. (e) Danieli, B.;
Lesma, G.; Passerella, D.; Sacchetti, A.; Silvani, A.; Virdis, A. Org. Lett.
2004, 6, 493. (f) Ma, S.; Ni, B. Chem.sEur. J. 2004, 10, 3286. (g) Ma, S.;
Ni, B.; Liang, Z. J. Org. Chem. 2004, 69, 6305. (h) Krelaus, R.;
Westermann, B. Tetrahedron Lett. 2004, 45, 5987. (i) Wijdeven, M. A.;
Botman, P. N. M.; Wijtmans, R.; Schoemaker, H. E.; Rutjes, F. P. J. T.;
Blaauw, R. H. Org. Lett. 2005, 7, 4005. (j) De Matteis, V.; van Delft, F.
L.; Tiebes, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2006, 1166. (k) Xiao,
D.; Wang, C.; Palani, A.; Reichard, G.; Aslanian, R.; Shih, N.-Y.; Buevich,
A. Tetrahedron: Asymmetry 2006, 17, 2596. (l) Lesma, G.; Danieli, B.;
Sacchetti, A.; Silvani, A. J. Org. Chem. 2006, 71, 3317. (m) Cardona, W.;
Quin˜ones, W.; Robledo, S.; Ve´lez, I. D.; Murga, J.; Garc´ıa-Fontanet, J.;
Carda, M.; Cardona, D.; Echeverri, F. Tetrahedron 2006, 62, 4086. (n) Niida,
A.; Mizumoto, M.; Narumi, T.; Inokuchi, E.; Oishi, S.; Ohno, H.; Otaka,
A.; Kitaura, K.; Fujii, N. J. Org. Chem. 2006, 71, 4118. (o) Deiters, A.;
Pettersson, M.; Martin, S. J. J. Org. Chem. 2006, 71, 6547.
(14) Diastereoselective addition of allyl- and alkenylmetal reagents to
chiral cyclic N-acyliminium ions (SID) has been used in analogous routes
to differently sized bicyclic lactams: (a) Beal, L. M.; Liu, B.; Chu, W.;
Moeller, K. D. Tetrahedron 2000, 56, 10113. (b) Harris, P. W. R.; Brimble,
M. A.; Gluckman, P. D. Org. Lett. 2003, 5, 1847. (c) Hanessian, S.; Sailes,
H.; Munro, A.; Therrien, E. J. Org. Chem. 2003, 68, 7219. (d) Manzoni,
L.; Colombo, M.; Scolastico, C. Tetrahedron Lett. 2004, 45, 2623.
(8) Pachamutu, K.; Vankar, Y. D. J. Organomet. Chem. 2001, 624, 339.
(9) (a) Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Chem. Soc., Chem.
Commun. 1993, 1542. (b) Basile, T.; Bocoum, A.; Savoia, D.; Umani-
Ronchi, A. J. Org. Chem. 1994, 59, 7766.
(10) Hunt, J. C. A.; Laurent, P.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 2002, 2378.
J. Org. Chem, Vol. 72, No. 16, 2007 6023

Fiorelli and Savoia
SCHEME 2
advantage of the higher reactivity and ready availability of the
allylic organometallic reagents and allyl/acryloyl halides. In this
paper, we describe the successful synthesis of δ-substituted R,â-
unsaturated δ-lactams by the general route described in Scheme
1 (1 to 6 through 4).15 It is worthwhile observing that although
a plethora of methods is available for the synthesis of R,â-
unsaturated δ-lactams,16 we could find in the literature only a
few reports of optically pure δ-substituted R,â-unsaturated
δ-lactams 6, having R1 ) (R)-CO2Me,13a (S)-CO2Me,16a (R)-
[(3R,5S)-1-Cbz-5-(acetoxymethyl)piperidin-3-yl),13e (S)-CH2-
CO2Me,13k (S)-n-C15H31,13l (S)-CO2H,16u and (S)-CO2tBu (N-
Boc derivative).16t
Obviously, the usefulness of our synthetic route is based on
the capability of achieving the highest possible diastereoselec-
tivity in the first allylmetalation step. In this respect, the choice
of the chiral auxiliary (amine) is of paramount importance and
should be based also on the nature of the starting aldehyde.17
A variety of optically pure primary amines (including amino
acid esters and amides and â-amino alcohols), hydrazines,
hydroxylamines, and sulfinamides is available for this purpose,
and each of them often provides an excellent diastereoselectivity
in organometallic additions, particularly with allylmetal reagents,
as thoroughly described in recent reviews.17,18
Results and Discussion
The actual route followed for the synthesis of δ-substituted
R,â-unsaturated δ-lactams is described in Scheme 2. In par-
ticular, we exploited (S)-valine methyl ester for the preparation
of the homoallylic amines 13 from the precursor imines 9. We
previously achieved high to complete stereocontrol in this crucial
step by the addition of allylcopper, -tin, -lead, and -zinc reagents
to a variety of aromatic and aliphatic imines in anhydrous
tetrahydrofuran (THF) at low temperature (Grignard protocol).19
We also described a convenient Barbier protocol, which relies
on the reaction of imines with allyl bromide and zinc and a
catalytic amount (generally 10 mol %) of cerium trichloride
heptahydrate in anhydrous THF at 0 °C.9 The hydrated cerium
salt may have different roles in the process, but above all, it
prevents the retroallylation reaction, so preserving the stereo-
chemical purity of the homoallylic zinc amide produced. As a
matter of fact, complete or almost complete diastereoselectivities
were obtained with aromatic and aliphatic imines (e.g., the
benzaldimine 9a). Subsequently, other authors reported that this
Barbier protocol worked efficiently and diastereoselectively with
substituted allylic bromides and with 4-hydroxybenzaldimine
and its O-substituted derivatives, suitable substrates for the
preparation of supported chiral catalysts.20 More recently, the
same procedure has been efficiently applied to imines derived
from 2-thiophenecarboxaldehyde and several R-aminoacid
esters, as well as 9h; moreover, such addition reactions
employing diimines or triimines with a polycyclic aromatic core
produced chiral multiallylic dendritic amines with a similar
diastereoselectivity.21 On this basis, we decided to implement
the stereoselective synthesis of new homoallylic amines 10b-l
by applying our Barbier protocol to the imines 9b-l, derived
from either aromatic and aliphatic aldehydes. The primary
homoallylic amine precursors of 13a-l were then obtained by
efficient reduction of the ester group by lithium aluminum
hydride to give the intermediate aminoalcohols 12 and removal
of the N-substituent (Scheme 2 and Table 1).
(15) Complementary approach to the preparation of racemic ω-substituted
lactams involves the cross metathesis of N-protected unsaturated amines
(e.g., allylic and homoallylic amines) and acrylates or ω-unsaturated esters,
following by a cyclization step: Gebauer, J.; Dewi, P.; Blechert, S.
Tetrahedron Lett. 2005, 46, 43.
(16) Cyclization reactions: (a) Marson, C. M.; Grabowska, U.; Fallah,
A.; Walsgrove, T.; Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1994,
59, 291. (b) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron Lett. 2001, 42,
3483. (c) Beck, B.; Picard, A.; Herdtweck, E.; Do¨mling, A. Org. Lett. 2004,
6, 39. (d) Huang, X.; Zhou, H.; Chen, W. J. Org. Chem. 2004, 69, 839.
Isomerization of â,γ-unsaturated δ-lactams: (e) Zhang, S.; Liebeskind, L.
S. J. Org. Chem. 1999, 64, 4042. (f) Knight, J. G.; Tchabanenko, K.
Tetrahedron 2002, 58, 6659. (g) Tinarelli, A.; Paolucci, C. J. Org. Chem.
2006, 71, 6630. Cycloadditions to imines: (h) Danishefsky, S.; Vogel, C.
J. Org. Chem. 1986, 51, 3915. (i) Brandstadter, S. M.; Ojima, I.; Hirai, K.
Tetrahedron Lett. 1987, 613. (j) Bennett, D. M.; Okamoto, I.; Danheiser,
R. L. Org. Lett. 1999, 1, 641. (k) Cardillo, G.; Fabbroni, S.; Gentilucci, L.;
Perciaccante, R.; Piccinelli, F.; Tolomelli, A. Tetrahedron 2004, 60, 5031.
Elimination reaction from R- or â-hetero-substituted δ-lactams: (l) Herdeis,
C.; Kaschinski, C.; Karla, R. Tetrahedron: Asymmetry 1996, 7, 867. (m)
Ecija, M.; Diez, A.; Rubiralta, M.; Casamitjana, N.; Kogan, M. J.; Giralt,
E. J. Org. Chem. 2003, 68, 9541. (n) Marin, J.; Didierjean, C.; Aubry, A.;
Casimir, J.-R.; Briand, J.-P.; Guichard, G. J. Org. Chem. 2004, 69, 130.
(o) Li, Y.; Rauschel, F. M. Bioorg. Chem. 2005, 33, 470. (p) Garcia, E.;
Lete, E.; Sotomayor, N. J. Org. Chem. 2006, 71, 6776. Cyclocarbonylation
of â-allenic sulfonamides: (q) Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang,
J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851. Diels-Alder reactions: (r)
J?rgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (s) Buonora, P.;
Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099.
The results of the Barbier allylmetalation of imines 9a-l,
derived from the valine methyl ester, are reported in Table 1.
In almost all cases, as expected, we observed complete or almost
(17) Alvaro, G.; Savoia, D. Synlett 2002, 651.
(18) (a) Puentes, C. O.; Kouznetsov, V. J. Heterocyclic Chem. 2002,
29, 595. (b) Ding, H.; Friestad, G. F. Synthesis 2005, 2815.
(19) (a) Bocoum, A.; Boga, C.; Savoia, D.; Umani-Ronchi, A. Tetra-
hedron Lett. 1991, 32, 1367. (b) Alvaro, G.; Savoia, D. Tetrahedron:
Asymmetry 1996, 7, 2083. (c) Alvaro, G.; Pacioni, P.; Savoia, D. Chem.s
Eur. J. 1997, 3, 726.
(20) (a) El-Shehawy, A. A.; Omara, M. A.; Ito, K.; Itsuno, S. Synlett
1998, 367. (b) Itsuno, S.; El-Shehawy, A. A.; Abdelaal, M. Y.; Ito, K. New
J. Chem. 1998, 775. (c) Itsuno, S.; El-Shehawy, A. A. Polym. AdV. Technol.
2001, 12, 670.
(21) Wang, H.; Wang, J.-L.; Yuan, S.-C.; Pei, J.; Pei, W.-W. Tetrahedron
2005, 61, 8465.
6024 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of δ-Substituted R,â-Unsaturated δ-Lactams
TABLE 1. Synthesis of Secondary Homoallylic Amines 10a and
TABLE 2. Synthesis of â-Aminoalcohols 12k,ma from Imines
11k,m
â-Aminoalcohols 12b from Imines 9
imine 9, R
10
d.r.c
yield (%)d 12 from 10 (yield %)d
imine 11, R
allylmetal
12
d.r.b
yield (%)c
9a, Ph
9b, 4-ClPh
9c, 4-FPh
10a 100:0
10b >99:1
10c >99:1
10d >99:1
86
78
80
87
76
91
65
86
80f
88
95g
79
98
98
92
98
94
100
92
100
100
71
11k, 2-quinolyl
11k, 2-quinolyl
11m, 2-pyridyl
allylZnBr
allylMgCl
allylMgCld
12k
12k
12m
80:20
90:10
99:1
45
45
87
9d, 4-MeOPh
a Reactions were performed on 5-10 mmol of imine; allylmetal (2 equiv),
THF, -78 °C, 3 h. b Determined by 1H NMR analysis of the crude product.
c Yield of the pure prevalent diastereomer isolated by column chromatog-
raphy. d Reaction described in ref 22a.
9e, 3,4,5-(MeO)3Ph 10e >99:1
9f, 2-naphthyl
9g, 2-furyl
9h, 2-thienyl
9i, ferrocenyl
9j, 3-pyridyl
9k, 2-quinolyl
9l, cyclohexyl
10f >99:1
10g >99:1
10h >99:1
10i >99:1e
10j >99:1
10k 66:34
10l >99:1
TABLE 3. Two-Step Preparation of Acryloyl Amides 13 from
â-Aminoalcohols 12
90
12, R
methoda
product 13
yield (%)b
a Reactions were performed on 5-10 mmol of imine by the Barbier
protocol using allylBr (1.5 equiv), Zn (2 equiv), CeCl3-7H2O (0.1 equiv),
THF, 0 °C, 1 h. b Reaction conditions: LiAlH4 (2 equiv vs 10), THF, -10
°C, 1 h. c Determined by GC-MS and 1H NMR analysis of the crude product.
d Yield of product isolated by flash chromatography. e Product was not eluted
12a, Ph
12b, 4-ClPh
12c, 4-FPh
A
A
A
A
A
A
B
B
A
A
B
C
B
13a
13b
13c
13d
13e
13f
13g
13h
13i
74
75
78
87
77
90
80
67
87
70
69
62
50
12d, 4-MeOPh
12e, 3,4,5-(MeO)3Ph
12f, 2-naphthyl
12g, 2-furyl
12h, 2-thienyl
12i, ferrocenyl
12j, 3-pyridyl
12k, 2-quinolyl
12l, cyclohexyl
12m, 2-pyridyl
1
by GC-MS; an impurity, detected in <5% amount by H NMR analysis,
could not be identified. f Pure diastereomer was obtained by crystallization
of the crude product from MeOH. g No attempt was made to separate the
diastereomers.
13j
13k
13l
complete diastereoselectivity (d.r. >99:1) and high yield of the
desired homoallylic amines 10, which were purified from small
amounts or traces of starting materials and, especially for the
reaction on the p-fluorophenylimine 9c, products coming from
over-reaction (attack on the ester group). A low diastereose-
lectivity was obtained with the 2-quinolineimine 9k (d.r. 66:
34), and no attempt was made to separate the two diastereomers.
The low stereocontrol obtained with 9k is in accord with the
outcomes of organometallic additions to analogous 2-pyridine-
imines and can be explained by the capability of these imines
to form N,N′-chelated complexes with the organometallic
reagent in competition with the rigid N,O-chelated complexes
that can be formed by the intervention of the chiral auxiliary.
In the N,N′-chelated complexes, the N-substituent (chiral
auxiliary) is free to rotate along the N-C* bond, so increasing
the number of reactive conformers.
We previously reported that valine methyl ester is not the
best auxiliary for the addition of the preformed allylmetal
reagent to 2-pyridineimine at low temperature. The allylation
reaction carried out by cerium-catalyzed or other Barbier
protocols gave even worse results in terms of diastereoselec-
tivity. We also reported that O-silyl-protected (S)-valinol was
an excellent and convenient chiral auxiliary for the addition of
organolithium, Grignard, and organozincate reagents to the
imines 11.22 In particular, it provided better stereocontrol than
valine esters for the allylzincation of bidentate imines, especially
those derived from 2-pyridinealdehyde. Protection of the valinol
OH group is opportune, otherwise, an excess of organometallic
reagent, a longer reaction time, and a higher temperature are
required, and consequently, a lower diastereoselectivity is often
obtained, as we observed, for example, in the Zn-mediated
Barbier reaction on the benzaldimine 10a.9a
13m
a Method A: (1) H5IO6, MeNH2, MeOH and (2) acryloyl chloride,
Na2CO3, acetone. Method B: (1) H5IO6, MeNH2, MeOH and (2) acryloyl
chloride, triethylamine, DMAP (cat.). Method C: (1) lead tetraacetate and
hydroxylamine hydrochloride and (2) acryloyl chloride, Na2CO3, acetone.
b Yield of pure product after column chromatography.
with ammonium fluoride in protic solvent; hence, it is more
conveniently used than the O-methyl or O-benzyl protections
reported by other authors.13,18 Moreover, the valinol-derived
N-substituent can be directly removed from the amine 12 by
an oxidative cleavage, whereas reduction of the ester group step
of the secondary amine 10 is an additional step when starting
from the imine 9. Hence, we carried out the allylmetalation of
the 2-quinolineimine 11k using either allylzinc bromide or
allylmagnesium chloride (Table 2). However, the homoallylic
amine 12k was obtained with a diasteromeric ratio not exceeding
90:10 after a routine desilylation step, markedly differing from
the almost complete diastereoselectivity obtained for the 2-py-
ridine derivative 12m.22a The prevalent diastereomer was then
isolated in moderate yield by column chromatography.
The diastereomerically pure â-aminoalcohols 12 were then
subjected to cleavage of the auxiliary group (N-substituent) by
an oxidative protocol using periodic acid in the presence of
methylamine. The crude primary homoallylic amines were not
purified but instead were directly converted to N-acryloyl amides
13 by routine procedures using acryloyl chloride and different
bases (i.e., sodium carbonate in acetone (procedure A) or
triethylamine in the presence of a catalytic amount of 4-dim-
ethylaminopyridine (DMAP)). Only in the case of the aliphatic
amine 12l was the cleavage of the N-substituent preferably
achieved with lead tetraacetate (LTA), and the primary amine
was then reacted with acryloyl chloride/sodium carbonate/
acetone (procedure C). By these two-step procedures, the
unsaturated amides 13 were obtained with good overall yields
(Table 3).
It should also be noted that the O-silyl protection is easily
introduced, as well as easily removed, to obtain the secondary
homoallylic amines 12 by a simple acidic hydrolysis or treatment
(22) (a) Alvaro, G.; Martelli, G.; Savoia, D. J. Chem. Soc., Perkin Trans.
1 1998, 775. (b) Alvaro, G.; Martelli, G.; Savoia, D.; Zoffoli, A. Synthesis
1998, 1773. (c) Ferioli, F.; Fiorelli, C.; Martelli, G.; Monari, M.; Savoia,
D.; Tobaldin, P. Eur. J. Org. Chem. 2005, 1016. (d) Savoia, D.; Alvaro,
G.; Di Fabio, R.; Fiorelli, C.; Gualandi, A.; Monari, M.; Piccinelli, F. AdV.
Synth. Catal. 2006, 348, 1883.
The unsaturated amides 13 were then subjected to the RCM
reactions to prepare the six-membered R,â-unsaturated lactams
14 (Scheme 2) exploiting the commercially available, widely
J. Org. Chem, Vol. 72, No. 16, 2007 6025

Fiorelli and Savoia
TABLE 4. Synthesis of δ-Substituted r,â-Unsaturated δ-Lactams
14 by RCM of N-(3-Buten-1-yl) Acryloyl Amides 13a
SCHEME 3
acryloyl
amides 13
II
(mol %) solvent additive (equiv) lactam yield (%)b
13a, Ph
13b, 4-ClPh
13c, 4-FPh
5
5
5
5
5
5
5
5
5
5
5
5
10
5
5
5
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene
CH2Cl2
CH2Cl2
CH2Cl2
benzene
14a
14b
14c
14d
14e
14f
14g
14h
14i
76
72
77
77c
69c
80c
60
62
78
0
13d, 4-MeOPh
13e, 3,4,5-(MeO)3Ph
13f, 2-naphthyl
13g, 2-furyl
13h, 2-thienyl
13i, ferrocenyl
13j, 3-pyridyl
13j, 3-pyridyl
13k, 2-quinolyl
13k, 2-quinolyl
13l, c-Hx
14j
14j
TFA (2.5)
TFA (2.5)
70
0
14k
14k
14l
14m
14m
14m
40d
82
0
13m, 2-pyridyl
13m, 2-pyridyl
13m, 2-pyridyl
TFA (2.5)
HCl (1)
TFA (2.5)
0
0
a Reactions were carried out using the Grubbs’ catalyst II for 3 h at the
reflux temperature of the solvent. b Yield of product purified by column
chromatography. c Using 2 mol % of the catalyst incomplete ring closure
was observed after 3 h. d About 80% conversion of the starting diene was
1
determined by H NMR analysis.
used ruthenium benzylidene complexes (i.e., the first and second
generation Grubbs’ catalysts I and II, respectively). Preliminary
attempts carried out using I were not satisfactory, whereas II
generally performed well, so the latter catalyst was chosen for
the subsequent reactions. The results of the metathesis reactions
performed on the unsaturated amides 13 are reported in Table
4.
tion/desulfurization of the thiophene ring23 of 14h would lead
to the n-butyl-substituted lactam 14 (R ) n-Bu, Scheme 2);
this route should be preferable to the alternative one beginning
from pentaneimines 9 or 11 (R ) n-Bu, Scheme 2), as linear
aliphatic aldimines are less easily prepared than aromatic imines.
The synthetic sequence described for the preparation of
δ-aryl-δ-lactams from mono-imines was then applied to the
synthesis of the C2-symmetric dilactams 21 and 22, where the
two rings are connected through a 1,3-disubstituted benzene ring
or 2,6-disubstituted pyridine ring (Scheme 3). The diimine 15
derived from isophtalaldehyde and the (S)-valine methyl ester
was allylated by the Barbier protocol and gave the expected
di-homoallylic amine 17 in good yield and with almost complete
diastereoselectivity. Reduction of the ester groups to alcohol,
oxidative cleavage, and reaction of the primary amines with
acryloyl chloride gave the unsaturated diamide 19, and then
RCM gave the dilactam 21 in satisfactory overall yield. On the
other hand, the imine 16 was prepared by condensation of 2,6-
pyridinedicarbaldehyde and (S)-valinol, followed by silylation
of the hydroxyl groups. The Grignard protocol using allylzinc
bromide at low temperature gave the di-homoallylic amine 18
with d.r. 96:4, and the pure prevalent diastereomer was obtained
in 70% yield after column chromatography. Removal of the
chiral auxiliaries and N,N′-diacroylation gave the unsaturated
diamide 20. We were delighted, and surprised, to observe that
the double RCM reaction in the presence of TFA (2.5 equiv)
was successful for this compound, despite the failure previously
In most cases, good results were obtained by working with 5
mol % of catalyst in dichloromethane solution at the reflux
temperature. Following the progress of the reaction by TLC or
GC-MS analysis, the disappearance of the starting compound
13 was observed after 3 h. After usual workup, the expected
products 14 were isolated in good yields after separation from
minor amounts of byproducts by medium-pressure column
chromatography. However, in the case of pyridyl containing
substrates, the reaction did not work in the usual conditions.
The 3-pyridyl derivative 13j could be converted to the corre-
sponding unsaturated lactam 14j in 70% yield only in the
presence of 2.5 equiv of trifluoroacetic acid (TFA). However,
for the 2-quinolyl and 2-pyridyl derivatives 13k and 13m,
respectively, even the latter conditions did not allow for their
satisfactory conversion. Surprisingly, the 2-quinolyl-substituted
lactam 14k was obtained in 40% yield by working in refluxing
benzene in the absence of TFA. Instead, the 2-pyridyl-substituted
lactam 14m could not be obtained from 13m working either in
dichloromethane in the presence of TFA or HCl or in benzene
in the presence of TFA.
It should be observed that the furyl-substituted lactam 14g
can be converted to the carboxy-substituted analogue 14 (R )
CO2H, Scheme 2) and then the corresponding ester13a via routine
oxidation of the furan ring.22b Similarly, Nickel-Raney reduc-
(23) (a) Rajappa, S. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Pergamon Press: Oxford, 1984; Vol. 4, Ch. 3.14, pp 776-779.
6026 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of δ-Substituted R,â-Unsaturated δ-Lactams
The preparation of racemic lactams 13a26 and 14a16c has been
previously reported. The novel imines were prepared by the same
procedures described previously.
observed for the mono-amide 13m, although an increased
amount of catalyst (10 mol %) was required to obtain the
dilactam 22 in a satisfactory yield. Actually, we cannot explain
the positive effect of TFA in the latter reaction.
Barbier Allylation of Imines 9. Zinc dust (1.31 g, 20 mmol)
was added in small portions to a solution of the imine 9 (10 mmol),
allyl bromide (1.8 g, 1.3 mL, 15 mmol), and CeCl3·7H2O (0.372 g,
1 mmol) in anhydrous THF (15 mL) at 0 °C, and the mixture was
then stirred at room temperature. The reactions were monitored by
TLC and GC-MS analyses and were usually complete within 1.5
h. To the mixture was added saturated aqueous NH4Cl (10 mL)
and 40% NH3 (10 mL), and the organic phase was extracted with
Et2O (2 × 15 mL). The combined ethereal layers were dried over
Na2SO4 and concentrated at reduced pressure to give an oily residue,
which was subjected to flash chromatography eluting with cyclo-
hexane/ethyl acetate mixtures. Starting from the diimine 15, 2-fold
amounts of reagents were required.
Reduction of Amino Esters 10 with LiAlH4. A solution of the
amino ester 10 (5 mmol) in anhydrous THF was added dropwise
to a suspension of LiAlH4 (0.38 g, 10 mmol) in THF (10 mL) and
cooled with an ice/NaCl bath. After 1 h, the reaction was quenched
with 2.5 M NaOH (10 mL) (Caution: this is a Very exothermic
reaction) and then H2O (10 mL), and the organic phase was
extracted with Et2O (2 × 15 mL). The combined ethereal layers
were dried over Na2SO4 and concentrated at reduced pressure to
give the products 12, which were used as obtained in the successive
step. Starting from 17, 2-fold amounts of reagents were required.
Organometallic Addition to Imines 11 and 16. A solution of
allyl bromide (1.3 mL, 1.8 g, 15 mmol) in anhydrous THF (20
mL) was added dropwise to a stirred suspension of zinc dust (1.31
g, 20 mmol) in THF (8 mL). The reaction was exothermic, and the
rate of addition must be controlled to maintain the temperature
below 50 °C. After the addition was complete, the mixture was
stirred for 1 h and then stirring was stopped to allow the zinc dust
to deposit on the bottom of the flask. The solution was taken by a
syringe and transferred into an addition funnel and finally added
dropwise to a solution of the imine 11 (5 mL) in dry THF cooled
at -78 °C. The reaction was monitored by TLC and GC-MS
analyses, and the O-trimethylsilyl amino alcohol was obtained by
the usual workup. The crude product was dissolved in Et2O (5 mL)
and treated with 1 M HCl (10 mL) for 1 h, then 2.5 M NaOH was
added until pH 11 was reached, and the organic material was
extracted with Et2O (2 × 10 mL). The combined ethereal layers
were dried over Na2SO4, concentrated at reduced pressure, and
subjected to flash chromatography eluting with cyclohexane/ethyl
acetate mixtures. Starting from the diimine 16, 2-fold amounts of
reagents were required.
Preparation of Propenamides from â-Amino Alcohols. Pro-
cedure A. The amino alcohols 12a-j (1 mmol) were dissolved in
a mixture of MeOH (15 mL) and THF (5 mL), then 40% aqueous
MeNH2 (12 mL) was added. A solution of H5IO6 (0.80 g, 3.5 mmol)
in H2O (15 mL) was added dropwise with stirring. The reaction
was slightly exothermic. The reaction was monitored by TLC and
GC-MS analyses. When the reaction appeared complete (1-3 h),
the mixture was concentrated at reduced pressure to remove most
of the MeOH, and H2O (15 mL) was added. The organic phase
was extracted with Et2O (2 × 20 mL), and the combined ethereal
layers were dried over Na2SO4 and concentrated at reduced pressure.
The residue was dissolved in acetone, and Na2CO3 (0.37 g, 3 mmol)
dissolved in 5 mL of H2O was added. To the vigorously stirred
mixture, at 0 °C, was added dropwise acryloyl chloride (0.18 g,
163 µL, 2 mmol) dissolved in acetone (10 mL). The reaction was
monitored by TLC and GC-MS analyses, and when it appeared
complete (ca. 2 h), most of the solvent was evaporated at reduced
pressure, H2O (15 mL) was added, and the organic phase was
extracted with Et2O (2 × 15 mL). The combined ethereal layers
were dried over Na2SO4 and concentrated at reduced pressure, and
Conclusion
The stereoselective synthesis of simple δ-substituted R,â-
unsaturated δ-lactams has been accomplished starting from
readily available materials: aldehydes, optically pure primary
amines, allyl halides (allylmetal compounds), and acryloyl
chloride, which were assembled by established methodologies
allowing the easy and efficient formation of a carbon-nitrogen
bond (imine formation) and three carbon-carbon bonds. In
particular, the highly diastereoselective formation of the C5-
C6 bond has been accomplished by two alternative protocols
for the allylmetalation of chiral imines, which were obtained
from (S)-valine methyl ester or (S)-valinol. Then, after removal
of the N-substituent and N-acroylation of the primary homoal-
lylic amine, the unsaturated lactam ring was built by a ring
closing metathesis reaction.
As noted in the Introduction, a C5 substituent could be
introduced diastereoselectively by using a γ-substituted allyl-
metal reagent, so forming two new stereocenters by combined
auxiliary induced and simple diastereoselectivities. Moreover,
the versatility of this route is further enhanced by the possibility
of using the unsaturated lactams to construct more substituted/
functionalized nitrogen heterocycles as the conjugated alkene
and amide functions can undergo further transformations. For
example, nucleophilic conjugate addition and reduction of the
lactam carbonyl group can be sequentially used to prepare cis-
and/or trans-2,4-disubstituted piperidines,24 a structural motif
that is present in a number of biologically and pharmacologically
active compounds.25
It should also be remarked that the C2-symmetric 2,6-
disubstituted pyridine 22 is an appealing compound, with
potential utility as a ligand in asymmetric synthesis and catalysis,
for two reasons. First of all, owing to the presence of the basic
pyridine nitrogen, it is capable of coordinating a metal center
in either bidentate and terdentate fashion. Second, the acidity
of the N-H lactam bonds could be exploited in asymmetric
catalytic reactions involving the formation of metal amide(s)
intermediates. Moreover, there is ample scope to convert 22 to
a series of N,N,N-terdentate ligands by transformations of the
R,â-unsaturated lactam groups.
Experimental Section
The following compounds have been previously described: 9a,
9d,9b 9h,21 9k,22c 10a,9b 10d,9b 10h,21 10j,9b 12a,9b 12g,22b and 16.22d
(24) (a) Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron Lett. 2002, 43,
1991. (b) Hanessian, S.; van Otterloo, W. A. L.; Nilsson, I.; Bauer, U.
Tetrahedron Lett. 2002, 43, 1995. Also see ref 16r.
(25) See, for example: (a) Birkenmeyer, R. D.; Kroll, S. J.; Lewis, C.;
Stern, K. F.; Zurenko, G. E. J. Med. Chem. 1984, 27, 216. (b) Keenan, T.
P.; Yaeger, D.; Holt, D. A. Tetrahedron: Asymmetry 1999, 10, 4331. (c)
Wacker, D. A.; Santella, J. B., III; Gardner, D. S.; Varnesw, J. G.; Estrella,
M.; De Lucca, G. V.; Ko, S. S.; Tanabe, K.; Watson, P. S.; Welch, P. K.;
Covington, M.; Stowell, N. C.; Wadman, E. A.; Davies, P.; Solomon, K.
A.; Newton, R. C.; Trainor, G. L.; Friedman, S. M.; Decicco, C. P.; Duncia,
J. V. Bioorg. Med. Chem. Lett. 2002, 12, 1745. (d) Rocco, V. P.; Spinazze,
P. G.; Kohn, T. J.; Honigschmidt, N. A.; Nelson, D. L.; Wainscott, D. B.;
Ahmad, L. J.; Shaw, J.; Threlkeld, P. G.; Wong, D. T.; Takeuchi, K. Bioorg.
Med. Chem. Lett. 2004, 14, 2653. (e) Kauffmann, G. S.; Watson, P. S.;
Nugent, W. A. J. Org. Chem. 2006, 71, 8975.
(26) Vankar, Y. D.; Kumaravel, G.; Rao, C. T. Synth. Commun. 1989,
19, 2181.
J. Org. Chem, Vol. 72, No. 16, 2007 6027

Fiorelli and Savoia
the residue was subjected to flash chromatography to give the pure
amides 13a-j. Compound 19 was similarly obtained from 17 by
using 2-fold amounts of reagents.
Preparation of R,â-Unsaturated δ-Lactams. The unsaturated
amide (1 mmol) was dissolved in anhydrous CH2Cl2 or C6H6 (5
mL), and TFA (0.29 g, 192 µL, 2.5 mmol) was added for 13j,k
and 20. The solution was degassed by bubbling a stream of Ar
through it, Ru-complex II (0.042 g, 0.05 mmol) was added, and
the solution was again deaerated and heated to reflux. The progress
of the reaction was monitored by TLC analysis, and the disappear-
ance of the starting material was observed within 3 h. The solvent
was removed at reduced pressure, and the residue was subjected
to flash chromatography.
Procedure B. Cleavage of the N-substituent of 12k,m was
conducted as described previously, then the crude primary amine
was dissolved in THF (10 mL), and triethylamine (0.15 g, 0.21
mL) and DMAP (0.01 g) were added. To the vigorously stirred
mixture at 0 °C was added dropwise acryloyl chloride (0.13 g, 0.12
mL, 1.5 mmol) dissolved in THF (10 mL), and a white precipitate
formed immediately. The reaction was monitored by TLC and GC-
MS analyses. The solvent was removed at reduced pressure, and
the crude product was subjected to flash chromatography to give
the pure amide 13k,m. Compound 20 was similarly obtained from
18 by using the proper amounts of reagents.
Procedure C. The amino alcohol 12l (0.63 mmol) was dissolved
in a 1:1 MeOH/CH2Cl2 mixture (6 mL), and then lead tetraacetate
(0.33 g, 0.75 mmol) was added to the stirred solution and cooled
to 0 °C. When TLC analysis showed complete consumption of the
starting material, hydroxylamine hydrochloride (0.04 g, 6.3 mmol)
was adde, and the mixture was vigorously stirred for 3 h. H2O (5
mL) was added, and the insoluble material was filtered off, then
the organic phase was extracted with Et2O (2 × 10 mL). The
combined ethereal layers were dried over Na2SO4 and concentrated
at reduced pressure to yield the crude primary amine, which was
converted into the amide 13l as described in procedure A.
Acknowledgment. This work was carried out in the field
of the Prin Project: “Sintesi e Stereocontrollo di Molecole
Organiche per lo Sviluppo di Metodologie Innovative”. We also
thank the University of Bologna for financial support.
Supporting Information Available: General methods, analyti-
cal data, and copies of 1H and 13C NMR spectra for all new
compounds prepared. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0703000
6028 J. Org. Chem., Vol. 72, No. 16, 2007