Enantioselective syntheses of bicyclic lactams based on iridium-catalyzed asymmetric allylic substitution and heck cyclization

Article abstract of DOI:10.1002/ejoc.201301813

A sequence of reactions that include an iridium-catalyzed regio- and enantioselective allylic amination, the formation of an amide, a ruthenium-catalyzed ring-closing metathesis, and an intramolecular Heck reaction allows for the preparation of [3,3,1]- and [4,3,1]-bicyclic amides. The target compounds have a nitrogen atom at the bridgehead, a nonplanar amide moiety, and a stereogenic center at the one-carbon bridge.

Full text of DOI:10.1002/ejoc.201301813

FULL PAPER
DOI: 10.1002/ejoc.201301813
Enantioselective Syntheses of Bicyclic Lactams Based on Iridium-Catalyzed
Asymmetric Allylic Substitution and Heck Cyclization
Gedu Satyanarayana*[a][‡] and Günter Helmchen*[a]
Keywords: Asymmetric catalysis / Synthetic methods / Lactams / Cyclization / Enantioselectivity / Iridium / Palladium
A sequence of reactions that include an iridium-catalyzed re-
gio- and enantioselective allylic amination, the formation of
an amide, a ruthenium-catalyzed ring-closing metathesis,
and an intramolecular Heck reaction allows for the prepara-
tion of [3,3,1]- and [4,3,1]-bicyclic amides. The target com-
pounds have a nitrogen atom at the bridgehead, a nonplanar
amide moiety, and a stereogenic center at the one-carbon
bridge.
Dibenzoazocine 2 was prepared by using a Friedel–
Crafts dual cyclization as the key step,[4b] whereas amine 3
was obtained through the condensation of 1-azabicy-
clo[3,3,1]-nonan-4-one, sulfur, and tert-butylcyanoacetate
followed by aromatization.[5] The preparation of the core
structure of bridged amine 4 was accomplished by a ceric
ammonium nitrate (CAN) mediated radical-initiated ring-
opening followed by a ring-closing reaction sequence that
started from azabicyclo[3.1.0]hexane-1-ol.[6,7] Bicyclic lact-
ams with the nitrogen atom at the bridgehead position have
been elegantly accessed, in particular, through a ring-clos-
ing metathesis (RCM) followed by an intramolecular Heck
reaction.[8]
Introduction
Bridged heterocyclic systems that have nitrogen at the
bridgehead position are of interest because of their known
and potential biological properties.[1,2] For example, the
alkaloid quinine (1, see Figure 1) has antipyretic, anti-
malarial, analgesic, and anti-inflammatory effects,[3] and di-
benzo[c,f]azocine 2 is known to be active with regard to the
central nervous system (CNS).[4] Methanothieno[2,3-c]-
azocine 3 and structurally related compounds are inhibitors
of protein tyrosine phosphatases,[5] and benzazocine 4 is an
inhibitor of biogenic amine transporters.[6]
The latter strategy was adopted by us in conjunction with
an iridium-catalyzed enantioselective allylic amination to
provide the starting materials. Thus (see Scheme 1), our
route to bicyclic lactam E involves an intramolecular Heck
reaction of enamide D, which in turn can be obtained by an
Ir-catalyzed allylic amination between 2-bromobenzylamine
(B) and carbonate A followed by amide formation with vin-
ylacetic acid (C) and a ring-closing metathesis reaction.
Figure 1. Structures of biologically active bicyclic heterocycles that
containing nitrogen in the bridgehead position.
[a] Organisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
E-mail: g.helmchen@oci.uni-heidelberg.de
http://www.uni-heidelberg.de/institute/fak12/OC/helmch/
[‡] Current address: 544205 Indian Institute of Technology (IIT)
Hyderabad, Ordnance Factory Estate (ODF),
Yeddumailaram 502205, Medak District, Andhra Pradesh,
India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301813.
Scheme 1. Strategy for an enantioselective route to bicyclic
lactam D.
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Enantioselective Syntheses of Bicyclic Lactams
carried out by using the described catalyst system {i.e.,
[Ir(COD)]2 (2 mol-%)/L* (4 mol-%), TBD (1,5,7-triazabicy-
clo[4.4.0]dec-5-ene, 8 mol-%), dry tetrahydrofuran (THF)},
and the reaction temperatures were optimized. Branched
amines 6 were obtained in good yields and excellent
enantioselectivity (Ͼ90%ee). The linear allylic amines were
not detected, which is likely a result of a diallylation process
that occurs faster with the linear than the branched
monoallylation products. The absolute configurations of
the allylic substitution products 6 were assigned on the ba-
sis of a valid rule,[10b,10e] that is thus far without exception.
The coupling reaction between secondary amines 6a–6d
and 3-butenoic acid with N,NЈ- dicyclohexylcarbodiimide
(DCC) and a catalytic amount of 4-(dimethylamino)pyr-
idine (DMAP) gave dienamides 8a–8d (see Scheme 2). The
ring-closing metathesis of dienamide 8 by treatment with
5 mol-% of Grubbs I catalyst in refluxing dichloromethane
furnished the cyclic products 9 in near quantitative overall
yields from 6.[17]
Results and Discussion
The Ir-catalyzed allylic substitution reaction, which was
introduced in 1997,[9] has emerged as a versatile tool for
enantioselective synthesis.[10] High degrees of regio- and
enantioselectivity that favor branched substitution products
can be obtained. The reactions, of particular interest, are
those with N-nucleophiles, that is, aliphatic amines,[11]
amides,[12] and anilines[13] to give branched allylic amines,
which are often well-suited as starting materials for alkaloid
syntheses.[14] In the most often used version of allylic amin-
ation, the catalyst is prepared from [Ir(COD)Cl]2 (COD =
1,5-cyclooctadiene) and chiral phosphoramidite L*, which
is activated by base. Commercially available L1[15] and often
superior L2[16] and L3[16] were employed as ligands (see Fig-
ure 2).
For the intramolecular Heck reaction[18] of bromides 9,
the reported reaction conditions for similar substrates were
initially employed.[10] Thus, upon subjecting a mixture of
enamide 9b, Pd(PPh3)2Cl2 (20 mol-%), Et3N (10 equiv.),
and dry N,N-dimethylformamide (DMF, 0.03 m) to micro-
wave irradiation (300 W) at 110 °C for 1 h, bicyclic lactams
10b (52%) and 11b (14%) were obtained (see Scheme 3 and
Table 2, Entry 1). These products arise from the insertion
of the intermediary aryl-palladium species into the double
Figure 2. Ligands used for allylic amination.
The reactions between carbonates 5 and (o-bromo- bond that is anti or syn to the R (ethyl) group. With catalyst
phenyl)methylamine as the nucleophile (see Table 1) were Pd(OAc)2/PPh3 (10 mol-%), similar results were obtained
Table 1. Ir-catalyzed asymmetric allylic amination of carbonates 5.[a]
Entry
Carbonate
L*
Time [h]
Temp. [°C]
% Yield[b]
% ee[c]
1
2
3
4
5
6
7
8
5a
5a
5a
5b
5b
5b
5b
5c
5c
5c
5d
5d
5d
L2
ent-L2
L3
4
7
7
20
20
15
20
3
4
4
6.5
5.5
6.5
50
r.t.
50
r.t.
r.t.
r.t.
50[e]
50
50
50
50
50
73
78
75
72
71
69
74
60
54
63
83
86
88
96[d]
95[d]
96[d]
93
93
95
93
96
93
95
L2
ent-L2
L3
L3
L2
ent-L2
L3
L2
ent-L2
L3
9
10
11
12
13
98
94
97
50
[a] Reactions were carried out according to GP1 (method A: Ir/L*/TBD, 2:4:8 mol-%; see Exp. Section). [b] Isolated yields of branched
1
amination products 6. Regioselectivity was determined by H NMR analysis of the crude product. [c] Enantiomeric excess values were
determined by chiral HPLC analysis. [d] In the case of 6a, it was not possible to measure the ee values by chiral HPLC or chiral GC
analysis, and, hence, those were measured by using dienamide 8a. [e] Reactions were conducted at 50 °C for 3 h and then continued at
room temp for 15–17 h.
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G. Satyanarayana, G. Helmchen
FULL PAPER
(see Table 2, Entries 2–4). The catalyst Pd(OAc)2/(Ϯ)-
BINAP (10 mol-%) was ineffective and led to 80% recovery
of the starting material 9b (see Table 2, Entry 5). With
either Pd(dppf)2Cl2 [10 or 20 mol-%, dppf = 1,1Ј-bis(di-
phenylphosphino)ferrocene] or Pd(PPh3)2Cl2 (20 mol-%) as
catalysts under various concentrations, the yields were poor
to moderate (see Table 2, Entries 6–12). Gratifyingly, a low
concentration of 0.03 m in conjunction with Pd(dppf)2Cl2
(10 or 20 mol-%) as the catalyst consistently afforded good
results (see Table 2, Entries 13–15).
Cyclization reactions of other enamides 9 were carried
out using the optimal conditions for 9b. In general, the re-
sults were similar to those obtained for 9b (see Table 3). In
the case of the amide 9d, the catalysts Pd(PPh3)2Cl2 and
Pd(OAc)2/PPh3 afforded results as good as those obtained
with Pd(dppf)2Cl2 (see Table 3 Entries 5–8). Characteriza-
tions of minor isomers 11a, 11c, 11d as well as 12a, 12c,
and 12d were carried out with the accumulated material.
The structure of 10d was confirmed by single-crystal X-
ray diffraction analysis. As expected, the relative orientation
of the phenyl group that is present at the bridging carbon
is anti to the other aromatic ring, and the nitrogen attains
a twisted nonplanar amide bond[19] (see Figure 3).
Scheme 2. Synthesis of pyridinones 9 (Tr = triphenylmethyl).
Finally, the synthesis of a one-carbon homologated bicy-
clic lactam was carried out. The coupling reaction between
amine 6b and 4-pentenoic acid by treatment with DCC gave
dienamide 8bb in high yield. The ring-closing metathesis
reaction with Grubbs I catalyst under the previously opti-
mized conditions failed to furnish amide 9bb. However, em-
ploying Grubbs II catalyst resulted in a nearly quantitative
yield (see Scheme 4). The key intramolecular Heck reaction
furnished bicyclic lactams 10bb and 11bb as major and
minor isomers, respectively. Neither a reduction of the
double bond nor a double-bond shift into the α,β-position
were observed.
Scheme 3. Pd-catalyzed cyclization of 9 to give bicyclic lactams 10–
12.
Table 2. Screening of conditions for the Pd-catalyzed cyclization of 9b to give 10b–12b according to Scheme 3.[a,b]
Entry Catalyst [mol-%]
Conc. [M]
Temp. [°C]
Time [h]
% Recovered
% Yield[c]
11b
9b
10b
12b
1[d]
Pd(PPh3)2Cl2 (20)
Pd(OAc)2/PPh3 (10)[f]
Pd(OAc)2/PPh3 (10)[f]
Pd(OAc)2/PPh3 (10)[f]
Pd(OAc)2/(Ϯ) BINAP (10)[h]
Pd(dppf)2Cl2 (20)
Pd(dppf)2Cl2 (20)
Pd(dppf)2Cl2 (20)
Pd(PPh3)2Cl2 (20)
Pd(PPh3)2Cl2 (20)
Pd(dppf)2Cl2 (10)
Pd(dppf)2Cl2 (10)
Pd(dppf)2Cl2 (10)
Pd(dppf)2Cl2 (20)
Pd(dppf)2Cl2 (20)
0.03
0.06
0.1
0.03
0.03
0.1
0.03
0.1
0.1
110
80
1
1.5
1
2
2
1.5
1.16
0.5
0.66
0.66
1.5
24
2
0.5
0.66
–
38
–
–
80
–
100
–
–
–
–
52
45
52
53
–
37
–
42
11
34
49
47
62
60
59
14
8
–
18
–
–
–
–
–
11
6
–
–
–
–
–
–
–
–
–
–
5
14
8
3
4
2[e]
3[e]
120
100
100
120
120
120
120
100
100
100
100
120
120
4[g]
5[g]
6[e]
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
0.1
0.06
0.06
0.03
0.03
0.03
–
–
–
–
–
8
6
11
[a] DMF was used as the solvent, except that toluene was used for Entry 7. [b] Reactions were conducted under microwave irradiation,
except that conventional heating was used for Entry 12. [c] Isolated yields of pure products. [d] NEt3 (10 equiv.) was used as base.
[e] Cs2CO3 (3–4 equiv.) was used as base. [f] PPh3 (20 mol-%) was used. [g] NEt3 (5 equiv.) was used as base. [h] (Ϯ)-BINAP [2,2Ј-bis(di-
phenylphospino)-1,1Ј-binapthyl, 20 mol-%] was used.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Enantioselective Syntheses of Bicyclic Lactams
Table 3. Pd-catalyzed Heck cyclization according to Scheme 3.[a]
Entry
Reaction conditions
Products [% yield][b,c]
1[d]
2[d]
3[d]
4[d]
5[d]
6[d]
7[d]
8[e]
Pd(dppf)2Cl2 (20 mol-%), 120 °C, 0.5 h
Pd(dppf)2Cl2 (20 mol-%), 120 °C, 0.41 h
Pd(dppf)2Cl2 (10 mol-%), 100 °C, 2 h
Pd(dppf)2Cl2 (20 mol-%), 120 °C, 1 h
Pd(PPh3)2Cl2 (10 mol-%), 110 °C, 1.5 h
Pd(dppf)2Cl2 (20 mol-%), 120 °C, 0.66 h
Pd(dppf)2Cl2 (20 mol-%), 120 °C, 1 h
Pd(OAc)2/PPh3 (10 mol-%), 120 °C, 1.5 h
10a (53)
10a (58)
10b (62)
10c (58)
10d (70)
10d (60)
10d (70)
10d (63)
11a (5)
12a (3)
12a (2)
12b (8)
12c (3)
12d (5)
12d (5)
12d (4)
12d (3)
11a (7)
11b (8)
11c (14)
–
–
–
–
[a] Solvent: DMF, c(9) = 0.03 m, microwave irridiation. [b] Isolated yields of chromatographically pure products. [c] We were unable to
collect data for isomer 11d. [d] NEt3 (10 equiv.) was used as base. [e] NEt3 (5 equiv.) was used as base.
Experimental Section
1
General Methods: The H NMR spectroscopic data were recorded
with a Bruker AC 300 (300 MHz) or Bruker Avance 500 (500 MHz)
spectrometer at room temp. with the samples dissolved in CDCl3.
Chemical shifts are reported in δ units relative to CHCl3 (δH
=
7.26 ppm), TMS (δH = 0.00 ppm), or toluene [δH = 2.11 ppm (cen-
tral line of the quintet)]. The 13C NMR spectroscopic data were
recorded with a Bruker AC 300 (75 MHz) or Bruker Avance 500
(125 MHz) spectrometer at room temp. with the sample dissolved
in CDCl3. Chemical shifts are reported in δ units relative to CDCl3
[δC = 77.16 ppm (central line of the triplet)]. The abbreviations used
throughout are s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), m (multiplet), and br. s (broad singlet). The assignment
Figure 3. X-ray crystal structure of 10d.[20]
1
1
of the signals was confirmed by H,1H-COSY, H,13C-COSY, and
DEPT spectroscopic analyses. Numbers of atoms were derived by
using ACD/ChemSketch, and the numbers are provided in the Sup-
porting Information with the spectra. Optical rotations were mea-
sured in a thermostatted cuvette (1 dm) by using a mercury lamp
with a Perkin–Elmer 341 Polarimeter. Concentration (c) is given in
g per 100 mL. HRMS were recorded with a JEOL JMS-700 instru-
ment (EI and FAB) or a Bruker ApexQe instrument (ESI). Elemen-
tal analyses were carried out at the Organisch-Chemisches Institut,
Universität Heidelberg. Enantiomeric excess values were deter-
mined by chiral GC analysis with the HP 5890 instrument or by
chiral HPLC analysis with the HP 1090 or HP 1100 instrument.
For HPLC, the columns from Daicel that were used are Chiralpak
AD-H (250ϫ4.6 mm, 5 μm) with the guard cartridge AD-H
(10ϫ4 mm, 5 μm) and Chiralpak AS-H (250ϫ4.6 mm, 5 μm) with
the guard cartridge AS-H (10ϫ4 mm, 5 μm). For GC, a permethyl
β-cyclodextrin column by Chrompack (WCOT fused silica, Cp-
Cyclodextrin-B-236-M-19, 25 mϫ0.25 mm) was used. For prepar-
ative HPLC, a Gilson-305 pump coupled with a Knauser UV de-
tector 2600 and a silica gel column (Latek, silica, 5μ, 21ϫ250 mm)
were used. All microwave experiments were carried out using CEM
Discover LabmateTM instrument [method: Chem. DriverTM soft-
ware, with microwave vials (10 mL), closed vessel, power: 300 W,
temperature: 100–120 °C (25 to 120 min)]. All reactions were car-
ried out in glassware that was dried with a heat gun under argon.
Success with any of the following procedures for the iridium-cata-
lyzed allylic substitutions required dry THF (content of H2O
Ͻ30 mg/L, Karl Fischer titration). Anhydrous TBD is hygroscopic
and, hence, was stored in a desiccator over KOH (alternatevely
small amounts were stored under argon in a Schlenk tube), and
measuring its mass was carried out rapidly.
Scheme 4. Synthesis of bicyclic lactams 10bb and 11bb starting
from amine 6b.
Conclusions
In summary, we have developed an efficient enantioselec-
tive synthesis of bicyclic lactams with nitrogen at the
bridgehead position and, as a consequence, a twisted non-
planar amide group. The highly regio- and enantioselective
Ir-catalyzed allylic amination and Pd-catalyzed intramolec-
ular Heck reactions were employed as the key steps.
General Procedure (GP1) for Iridium-Catalyzed Allylic Substitu-
tions: Under argon, a Schlenk tube was dried with a heat gun and
then charged with a solution of [Ir(COD)Cl]2 (13.4 mg, 20 μmol)
and the chiral ligand L* (40 μmol) in dry THF (1.0 mL, content of
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G. Satyanarayana, G. Helmchen
H2O Ͻ30 mg/L, Karl-Fischer titration). Anhydrous TBD (11.1 mg, 254.0539. C12H16BrN (254.17): calcd. C 56.71, H 6.35, Br 31.44, N
FULL PAPER
80 μmol) was added, and the mixture was stirred for 5 min (for L2)
or 30 min (for L3). Carbonate 5 (1 mmol) and 2-bromobenzyl-
amine (1.1–1.2 mmol) were then added, and the mixture was stirred
at the stated temperature (r.t.–50 °C) and time, at which either com-
plete conversion or no further conversion was detected by TLC
or GC–MS analysis. For the workup procedure, the mixture was
concentrated in vacuo. The regioselectivity of the reaction was de-
termined by 1H NMR analysis of the crude product or by isolating
the regioisomers. Purification by flash chromatography on silica gel
afforded pure amination product 6.
5.51; found C 56.61, H 6.32, Br 31.23, N 5.43.
(–)-(R)-N-(2-Bromobenzyl)-1-(trityloxy)but-3-en-2-amine [(–)-(R)-
6c]: GP1 was carried out with [Ir(COD)Cl]2 (26.8 mg, 40 μmol),
(R,R,aR)-L3 (45.6 mg, 80 μmol), anhydrous TBD (22.3 mg,
160 μmol), carbonate 5c (776.9 mg, 2 mmol), and 2-bromobenzyl-
amine (409.3 mg, 2.2 mmol) in dry THF (2 mL) at 50 °C for 4 h.
For TLC, Rf (6c) = 0.50, Rf (5c) = 0.60 (petroleum ether/ethyl acet-
ate, 6:1; KMnO4). Purification of the crude product by flash
chromatography on silica (40 g; petroleum ether/ethyl acetate, from
96:4 to 9:1) gave (–)-(R)-6c (627 mg, 63%) as a yellow oil. [α]2D0
=
(+)-(S)-N-(2-Bromobenzyl)but-3-en-2-amine [(+)-(S)-6a]: GP1 was
carried out with [Ir(COD)Cl]2 (53.7 mg, 80 μmol), (R,R,aR)-L3
(91.1 mg, 160 μmol), anhydrous TBD (44.5 mg, 320 μmol), carb-
onate 5a (520 mg, 4 mmol), and 2-bromobenzylamine (818.6 mg,
4.4 mmol) in dry THF (4 mL) at 50 °C for 7 h. For TLC, Rf (6a)
= 0.20–0.40, Rf (5a) = 0.80 (petroleum ether/ethyl acetate, 4:1;
KMnO4). Purification of the crude product by flash chromatog-
raphy on silica (50 g; petroleum ether/ethyl acetate, from 95:5 to
4:1) gave (+)-(S)-6a (720 mg, 75%) as a yellow oil. [α]2D0 = +1.1 (c
= 1.01, CHCl3); 96%ee. In this particular case, it was not possible
to measure the ee value directly, and it was measured after the DCC
coupling reaction to give 8a. 1H NMR (300 MHz, CDCl3): δ =
7.53 (dd, J = 8.0, 1.1 Hz, 1 H, 3Ј-H), 7.38 (dd, J = 7.6, 1.6 Hz, 1
H, 6Ј-H), 7.27 (ddd, J = 7.4, 7.4, 1.1 Hz, 1 H, 5Ј-H), 7.11 (ddd, J
= 7.6, 7.6, 1.7 Hz, 1 H, 4Ј-H), 5.74 (ddd, J = 17.3, 10.0, 7.5 Hz, 1
H, 3-H), 5.15 (dd, J = 17.2, 1.6 Hz, 1 H, 4-HZ), 5.09 (dd, J = 10.1,
1.7 Hz, 1 H, 4-HE), 3.87 (d, J = 13.7 Hz, 1 H, N-CH2a-Ar), 3.76
(d, J = 13.7 Hz, 1 H, N-CH2b-Ar), 3.21 (dq, J = 7.0, 6.7 Hz, 1 H,
2-H), 1.19 (d, J = 6.4 Hz, 3 H, 1-H), 1.55 (s, 1 H, NH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 142.6 (d, C-3), 139.6 (s, C-1Ј), 132.9
(d, C-3Ј), 130.6 (d, C-6Ј), 128.6 (d, C-4Ј), 127.5 (d, C-5Ј), 124.1 (s,
C-2Ј), 115.0 (t, C-4), 56.1 (d, C-2), 51.5 (t, N-CH2-Ar), 22.0 (q, C-
1) ppm. HRMS (ESI+): calcd. for C11H1579BrN+ [M + H]+
240.0382; found 240.0383; calcd. for C11H1581BrN+ [M + H]+
242.0362; found 242.0362. C11H14BrN (240.14): calcd. C 55.02, H
5.88, Br 33.27, N 5.83; found C 54.78, H 5.83, Br 32.98, N 5.73.
–21.9 (c = 1.17, CHCl3); 95%ee by HPLC. HPLC [Chiralpak AD-
H (250ϫ4.6 mm, 5 μm) with guard cartridge AD-H (10ϫ4 mm,
5 μm), n-hexane/2-propanol (98:2), 0.5 mL/min]: tR = 10.45 min
[(+)-(S)-6c] and tR = 11.48 min [(–)-(R)-6c]. 1H NMR (300 MHz,
CDCl3): δ = 7.55 (dd, J = 7.7, 1.1 Hz, 1 H, 3ЈЈ-H), 7.50–7.32 (m,
6 H, trityl-H), 7.36 (dd, J = 7.5, 1.6 Hz, 1 H, 6ЈЈ-H), 7.33–7.13 (m,
10 H, 5ЈЈ-H, trityl-H), 7.11 (ddd, J = 7.6, 7.6, 1.6 Hz, 1 H, 4ЈЈ-H),
5.62 (ddd, J = 17.3, 10.1, 7.2 Hz, 1 H, 3-H), 5.19 (dd, J = 17.4,
1.3 Hz, 1 H, 4-HZ), 5.14 (ddd, J = 10.1, 7.2, 1.6 Hz, 1 H, 4-HE),
3.88 (d, J = 13.9 Hz, 1 H, N-CH2a-Ar), 3.73 (d, J = 13.9 Hz, 1 H,
N-CH2b-Ar), 3.30–3.03 (m, 2 H, 1-H), 3.23 (ddd, J = 7.9, 7.9,
3.7 Hz, 1 H, 2-H), 2.31 (s, 1 H, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 144.1 (s, 3 C, C-1Ј), 139.6 (s, C-1ЈЈ), 138.0 (d, C-3),
133.0 (d, C-3ЈЈ), 130.6 (d, C-6ЈЈ), 128.8 (d, 6 C, trityl-C), 128.6 (d,
C-4ЈЈ), 127.9 (d, 6 C, trityl-Ph-C), 127.4 (d, C-5ЈЈ), 127.1 (d, 3 C,
C-4Ј), 124.3 (s, C-2ЈЈ), 117.9 (t, C-4), 86.8 [s, O-C-(Ph)3], 66.7 (t,
C-1), 60.8 (d, C-2), 51.2 (t, N-CH2-Ar) ppm. HRMS (ESI+): calcd.
for C30H2979BrNO+ [M + H]+ 498.1427; found 498.1428; calcd. for
C30H2881BrNONa+ [M
+
Na]+ 520.1246; found 520.1248.
C30H28BrNO (498.45): calcd. C 72.29, H 5.66, Br 16.03, N 2.81;
found C 72.01, H 5.76, Br 16.05, N 2.74.
(–)-(R)-N-(2-Bromobenzyl)-1-phenylprop-2-en-1-amine [(–)-(R)-6d]:
GP1 was carried out with [Ir(COD)Cl]2 (53.7 mg, 80 μmol),
(R,R,aR)-L3 (91.1 mg, 160 μmol), anhydrous TBD (44.5 mg,
320 μmol), carbonate 5d (768 mg, 4 mmol), and 2-bromobenzyl-
amine (818.6 mg, 4.4 mmol) in dry THF (4 mL) at 50 °C for 6.5 h.
For TLC, Rf (6d) = 0.50, Rf (5d) = 0.50 (petroleum ether/ethyl
acetate, 9:1; KMnO4). Purification of the crude product by flash
chromatography on silica (50 g; petroleum ether to petroleum
ether/ethyl acetate, 95:5) gave (–)-(R)-6d (1.06 g, 88%) as a yellow
oil. [α]2D0 = –2.7 (c = 0.99, CHCl3); 97%ee by HPLC. HPLC [Chi-
ralpak AS-H (250ϫ4.6 mm, 5 μm) with guard cartridge AS-H
(10ϫ4 mm, 5 μm), n-hexane/2-propanol (99.9:0.1) and 1% dieth-
(–)-(S)-N-(2-Bromobenzyl)pent-1-en-3-amine [(–)-(S)-6b]: GP1 was
carried out with [Ir(COD)Cl]2 (53.7 mg, 80 μmol), (R,R,aR)-L3
(91.1 mg, 160 μmol), anhydrous TBD (44.5 mg, 320 μmol), carb-
onate 5b (576 mg, 4 mmol), and 2-bromobenzylamine (818.6 mg,
4.4 mmol) in dry THF (4 mL) at 50 °C for 3 h and then at room
temperature for 17 h. For TLC, Rf (6b) = 0.20–0.40, Rf (5b) = 0.80
(petroleum ether/ethyl acetate, 7:3; KMnO4). Purification of the
crude product by flash chromatography on silica (50 g; petroleum
ether/ethyl acetate, from 95:5 to 4:1) gave (–)-(S)-6b (755 mg, 74%)
as a yellow oil. [α]2D0 = –8.3 (c = 1.02, CHCl3); 93%ee by HPLC.
HPLC [Chiralpak AD-H (250ϫ4.6 mm, 5 μm) with guard car-
tridge AD-H (10ϫ4 mm, 5 μm), n-hexane/2-propanol (99:1) and
0.1% diethylamine, 0.5 mL/min]: tR = 9.93 min [(+)-(R)-6b] and tR
= 10.47 min [(–)-(S)-6b]. 1H NMR (300 MHz, CDCl3): δ = 7.53
(dd, J = 7.9, 1.1 Hz, 1 H, 3Ј-H), 7.38 (dd, J = 7.5, 1.7 Hz, 1 H, 6Ј-
H), 7.27 (ddd, J = 7.4, 7.4, 1.3 Hz, 1 H, 5Ј-H), 7.11 (ddd, J = 7.6,
7.6, 1.7 Hz, 1 H, 4Ј-H), 5.64 (ddd, J = 16.9, 10.4, 8.2 Hz, 1 H, 2-
H), 5.17 (dd, J = 10.5, 1.8 Hz, 1 H, 3-HE), 5.14 (ddd, J = 16.9, 1.8,
0.7 Hz, 1 H, 3-HZ), 3.89 (d, J = 13.7 Hz, 1 H, N-CH2a-Ar), 3.73
(d, J = 13.7 Hz, 1 H, N-CH2b-Ar), 2.92 (ddd, J = 8.0, 7.9, 5.7 Hz,
1 H, 1-H), 1.68–1.32 (m, 2 H, 4-H), 1.63 (s, 1 H, NH), 0.88 (t, J =
7.4 Hz, 3 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.2 (d,
C-2), 139.7 (s, C-1Ј), 132.9 (d, C-3Ј), 130.7 (d, C-6Ј), 128.6 (d, C-
4Ј), 127.5 (d, C-5Ј), 124.2 (s, C-2Ј), 116.5 (t, C-3), 62.9 (d, C-1),
ylamine, 0.5 mL/min]: tR = 12.09 min [(+)-(S)-6d] and tR
=
1
13.20 min [(–)-(R)-6d]. H NMR (300 MHz, CDCl3): δ = 7.52 (dd,
J = 8.0, 1.1 Hz, 1 H, 3ЈЈ-H), 7.44–7.15 (m, 7 H, 6ЈЈ-H, 5ЈЈ-H, Ar-
H), 7.09 (ddd, J = 7.7, 7.6, 1.8 Hz, 1 H, 4ЈЈ-H), 5.95 (ddd, J = 17.2,
10.1, 7.1 Hz, 1 H, 2-H), 5.23 (ddd, J = 17.1, 1.3, 1.2 Hz, 1 H, 3-
HZ), 5.12 (ddd, J = 10.1, 1.4, 0.8 Hz, 1 H, 3-HE), 4.19 (d, J =
7.2 Hz, 1 H, 1-H), 3.83 (d, J = 14.0 Hz, 1 H, N-CH2a-Ar), 3.77 (d,
J = 14.0 Hz, 1 H, N-CH2b-Ar), 1.86 (s, 1 H, NH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 142.7 (s, C-1Ј), 141.0 (d, C-2), 139.4 (s, C-
1ЈЈ), 132.9 (d, C-3ЈЈ), 130.6 (d, C-6ЈЈ), 128.7 (d, 3 C, C-4ЈЈ, Ar-C),
127.5 (d, 2 C, Ar-C), 127.4 (d, C-5ЈЈ), 127.4 (d, C-4Ј), 124.1 (s, C-
2ЈЈ), 115.4 (t, C-3), 65.2 (d, C-1), 51.5 (t, N-CH2-Ar) ppm. HRMS
(ESI+): calcd. for C16H1779BrN+ [M + H]+ 302.0539; found
302.0540. C16H16BrN (302.21): calcd. C 63.59, H 5.34, Br 26.44, N
4.63; found C 63.42, H 5.34, Br 26.71, N 4.58.
General Procedure (GP2) for DCC Coupling Reaction: A cold (0 °C)
51.4 (t, N-CH2-Ar), 28.6 (t, C-4), 10.5 (q, C-5) ppm. HRMS solution of amine 6 (1 mmol) in dry dichloromethane (4–6 mL) un-
(ESI+): calcd. for C12H1779BrN+ [M + H]+ 254.0539; found
der argon was treated with DCC (1.1–1.2 mmol), DMAP (5–
2246
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2242–2252

Enantioselective Syntheses of Bicyclic Lactams
10 mol-%), and then vinylacetic acid or 4-pentenoic acid (1.1–
1.2 mmol). The mixture was slowly warmed to room temperature
and was then stirred for 15–72 h. The reaction mixture was filtered
through Celite in a short column (12ϫ3 cm), which was rinsed
with diethyl ether. The filtrate was concentrated in vacuo, and the
residue of crude 8 was purified by flash chromatography on silica.
and 135.9 (d) [CH=CH2], 132.9 (d) and 132.5 (d) [C-3ЈЈЈ], 131.9 (d)
and 131.8 (d) [CH=CH2], 128.9 (d) and 128.7 (d) [C-4ЈЈЈ], 128.2 (d)
and 127.9 (d) [C-6ЈЈЈ], 127.6 (d) and 127.4 (d) [C-5ЈЈЈ], 122.4 (s) and
122.2 (s) [C-2ЈЈЈ], 118.3 (t) and 118.2 (t) [CH=CH2], 118.0 (t) and
117.3 (t) [CH=CH2], 62.0 (d) and 58.7 (d) [C-1Ј], 48.3 (t) and 45.7
(t) [N-CH2-Ar], 39.4 (t, C-2), 25.6 (t) and 24.8 (t) [C-1ЈЈ], 11.2 (q)
a n d 1 1 . 0 ( q ) [ C - 2 Ј Ј ] p p m . H R M S ( E S I + ) : c a l c d . fo r
C16H2179BrNO+ [M + H]+ 322.0801; found 322.0803; calcd. for
C16H2079BrNONa+ [M + Na]+ 344.0620; found 344.0623.
C16H20BrNO (322.24): calcd. C 59.64, H 6.26, Br 24.80, N 4.35;
found C 59.69, H 6.26, Br 24.74, N 4.38.
(–)-N-(2-Bromobenzyl)-N-[(S)-1-methylprop-2-en-1-yl]but-3-en-
amide [(–)-(S)-8a]: GP2 was carried out with amine (S)-6a (590 mg,
2.46 mmol), dry dichloromethane (9 mL), DCC (608.6 mg,
2.95 mmol), DMAP (30.0 mg, 10 mol-%), and vinylacetic acid
(254 mg, 2.95 mmol) at r.t. for 26 h. For TLC, Rf (8a) = 0.45, Rf
(6a) = 0.20–0.40 (petroleum ether/ethyl acetate, 4:1; KMnO4). The
reaction mixture was filtered through Celite (12ϫ3 cm) with di-
ethyl ether (50 mL), and the filtrate was concentrated in vacuo.
Purification of the crude product by flash chromatography on silica
(50 g; petroleum ether/ethyl acetate, from 95:5 to 4:1) gave (–)-(S)-
8a (680 mg, 90%) as a yellow oil. [α]2D0 = –45.9 (c = 0.99, CHCl3);
96%ee by HPLC. HPLC [Chiralpak AS-H (250ϫ4.6 mm, 5 μm)
(–)-N-(2-Bromobenzyl)-N-{(R)-1-[(trityloxy)methyl]prop-2-en-1-
yl}but-3-enamide [(–)-(R)-8c]: GP2 was carried out with amine (R)-
6c (1.02 g, 2.05 mmol), dry dichloromethane (6.83 mL), DCC
(507.1 mg, 2.46 mmol), DMAP (12.5 mg, 10 mol-%), and vinylace-
tic acid (211.6 mg, 2.46 mmol) at r.t. for 23 h. For TLC, Rf (8c) =
0.50, Rf (6c) = 0.52 (petroleum ether/ethyl acetate, 4:1; KMnO4).
The reaction mixture was filtered through Celite (12ϫ3 cm) with
with guard cartridge AS-H (10ϫ4 mm, 5 μm), n-hexane/2-prop- diethyl ether (50 mL), and the filtrate was concentrated in vacuo.
anol (95:5), 0.5 mL/min]: tR = 28.45 min [(–)-(S)-8a] and tR
=
Purification of the crude product by flash chromatography on silica
33.64 min [(+)-(R)-8a]. 1H NMR (500 MHz, CDCl3, signals from
rotamers): δ = 7.56 (d, J = 8.0 Hz) and 7.48 (d, J = 8.0 Hz) [1 H,
(50 g; petroleum ether/ethyl acetate, from 95:5 to 6:1) gave (–)-(R)-
8c (1.10 g, 95%) as a yellow oil. [α]2D0 = –14.5 (c = 0.66, CHCl3);
1
3ЈЈЈ-H], 7.31 (dd, J = 7.4, 7.4 Hz) and 7.22 (dd, J = 7.4, 7.4 Hz) [1 95%ee. H NMR (300 MHz, CDCl3, signals from rotamers): δ =
H, 5ЈЈЈ-H], 7.22 (d, J = 7.4 Hz) and 7.12 (d, J = 7.7 Hz) [1 H, 6ЈЈЈ-
H], 7.15 (dd, J = 7.7, 7.7 Hz) and 7.06 (dd, J = 7.5, 7.5 Hz) [1 H,
7.52 (d, J = 8.0 Hz) and 7.45 (d, J = 8.0 Hz) [1 H, 3ЈЈЈЈ-H], 7.70–
6.80 (m, 18 H, 4ЈЈЈЈ-H, 5ЈЈЈЈ-H, 6ЈЈЈЈ-H, trityl-ArH), 6.24–5.80 (m,
4ЈЈЈ-H], 6.16–5.88 (m, 1 H, CH=CH2), 5.88–5.70 (m, 1 H, 1 H, CH=CH2), 5.83 (ddd, J = 17.2, 10.4, 6.8 Hz) and 5.62 (ddd,
CH=CH2), 5.46–5.31 (m) and 4.68–4.54 (m) [1 H, 1Ј-H], 5.33–5.06 J = 16.9, 10.9, 5.8 Hz) [1 H, CH=CH2], 5.40–4.90 (m, 4 H, 2
(m) and 5.01 (d, J = 17.3 Hz) [4 H, 2 CH=CH2], 4.73 (d, J =
16.7 Hz), 4.42 (d, J = 18.7 Hz), 4.37 (d, J = 18.7 Hz) and 4.33 (d,
CH=CH2), 5.35–5.10 (m) and 4.80–4.54 (m) [1 H, 1Ј-H], 4.70–4.30
(m, 2 H, N-CH2-Ar), 3.63–2.80 (m, 4 H, 1ЈЈ-H, 2-H) ppm. 13C
J = 16.7 Hz) [2 H, N-CH2-Ar], 3.43–3.23 (m) and 3.05–2.86 (m) [2 NMR (75 MHz, CDCl3): δ = 172.2 (s, C-1), 143.7 (s) and 143.5 (s)
H, 2-H], 1.20 (d, J = 7.1 Hz) and 1.19 (d, J = 7.1 Hz) [3 H, 1ЈЈ- [3 C, C-1ЈЈЈ], 137.0 (s) and 136.8 (s) [C-1ЈЈЈЈ], 133.7 (d) and 133.6
H] ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0 (s) and 171.7 (s)
[C-1], 137.7 (d) and 137.7 (d) [CH=CH2], 137.1 (s) [C-1ЈЈЈ], 133.0
(d) and 132.5 (d) [C-3ЈЈЈ], 131.8 (d) and 131.7 (d) [CH=CH2], 128.9
(d) and 128.1 (d) [C-4ЈЈЈ], 128.1 (d) and 127.7 (d) [C-5ЈЈЈ], 127.5 (d)
(d) [CH=CH2], 132.7 (d) and 132.3 (d) [C-3ЈЈЈЈ], 131.9 (d) and 131.7
(d) [CH=CH2], 128.7 (d) and 128.6 (d) [6 C, trityl-Ph-C], 128.0 (d)
and 127.9 (d) [6 C, trityl-Ph-C], 127.8 (d) and 127.6 (d) [C-4ЈЈЈ],
127.3 (d) and 127.3 (d) [C-5ЈЈЈЈ], 127.1 (d, 3 C, C-4ЈЈЈ), 127.3 (d)
and 127.4 (d) [C-6ЈЈЈ], 122.3 (s) and 122.2 (s) [C-2ЈЈЈ], 118.2 (t) and and 126.9 (d) [C-6ЈЈЈЈ], 122.3 (s) and 122.1 (s) [C-2ЈЈЈЈ], 118.9 (t)
118.0 (t) [CH=CH2], 116.6 (t) and 116.3 (t) [CH=CH2], 55.0 (d) and 118.4 (t) [CH=CH2], 118.2 (t) and 118.0 (t) [CH=CH2], 87.5
and 51.4 (d) [C-1Ј], 47.7 (t) and 45.7 (t) [N-CH2-Ar], 39.3 (t, C-
2), 18.2 (q) and 16.5 (q) [C-1ЈЈ] ppm. HRMS (ESI+): calcd. for
C15H1879BrNO+ [M + H]+ 308.0644; found 308.0649; calcd. for
C15H1881BrNO+ [M + H]+ 310.0624; found 310.0629. C15H18BrNO
(308.21): calcd. C 58.45, H 5.89, Br 25.92, N 4.54; found C 58.31,
H 5.85, Br 25.65, N 4.82.
(s) and 87.0 (s) [O-C-trityl], 64.0 (t) and 63.6 (t) [C-1ЈЈ], 60.1 (d)
and 57.6 (d) [C-1Ј], 49.9 (t) and 46.1 (t) [N-CH2-Ar], 39.3 (t, C-
2) ppm. HRMS (ESI+): calcd. for C34H3379BrNO2 [M + H]+
+
566.1689; found 566.1694; calcd. for C34H3279BrNO2Na+ [M +
Na]+ 588.1509; found 588.1513.
(+)-N-(2-Bromobenzyl)-N-[(1R)-1-phenylprop-2-en-1-yl]but-3-en-
(–)-N-(2-Bromobenzyl)-N-[(S)-1-ethylprop-2-en-1-yl]but-3-enamide amide [(+)-(R)-8d]: GP2 was carried out with amine (R)-6d
[(–)-(S)-8b]: GP2 was carried out with amine (S)-6b (660 mg, (920 mg, 3.04 mmol), dry dichloromethane (10 mL), DCC
2.60 mmol), dry dichloromethane (10 mL), DCC (643.3 mg, (753.8 mg, 3.65 mmol), DMAP (18.6 mg, 5 mol-%), and vinylacetic
3.12 mmol), DMAP (31.7 mg, 10 mol-%), and vinylacetic acid
(268.4 mg, 3.12 mmol) at r.t. for 20 h. For TLC, Rf (8b) = 0.65, Rf
(6b) = 0.20–0.40 (petroleum ether/ethyl acetate, 7:3; KMnO4). The
reaction mixture was filtered through Celite (12ϫ3 cm) with di-
ethyl ether (50 mL), and the filtrate was concentrated in vacuo.
Purification of the crude product by flash chromatography on silica
(50 g; petroleum ether/ethyl acetate, from 9:1 to 4:1) gave (–)-(S)-
8b (820 mg, 98%) as a yellow oil. [α]2D0 = –32.5 (c = 1.00, CHCl3);
acid (314.5 mg, 3.65 mmol) at r.t. for 23 h. For TLC, Rf (8d) = 0.30,
Rf (6d) = 0.50 (petroleum ether/ethyl acetate, 9:1; KMnO4). The
reaction mixture was then filtered through Celite (12ϫ3 cm) with
diethyl ether (50 mL), and the filtrate was concentrated in vacuo.
Purification of the crude product by flash chromatography on silica
(50 g; petroleum ether/ethyl acetate, from 95:5 to 6:1) gave (+)-(R)-
8d (1.020 g, 90%) as a yellow oil. [α]2D0 = +22.7 (c = 1.15, CHCl3);
1
97%ee. H NMR (300 MHz, CDCl3, signals from rotamers): δ =
7.47 (d, J = 7.7 Hz) and 7.36 (d, J = 8.0 Hz) [1 H, 3ЈЈЈ-H], 7.40–
1
95%ee. H NMR (300 MHz, CDCl3, signals from rotamers): δ =
7.55 (d, J = 7.7 Hz) and 7.47 (d, J = 7.7 Hz) [1 H, 3ЈЈЈ-H], 7.40– 6.86 (m, 8 H, 4ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H, Ar-H), 6.47 (d, J = 6.6 Hz)
6.94 (m, 3 H, 4ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H), 6.20–5.82 (m, 1 H, CH=CH2),
5.82–5.60 (m, 1 H, CH=CH2), 5.33–4.86 (m, 4 H, 2 CH=CH2),
5.08–4.84 (m) and 4.32–4.18 (m) [1 H, 1Ј-H], 4.70–4.38 (m, 2 H,
and 5.67 (d, J = 4.8 Hz) [1 H, 1Ј-H], 6.25–5.85 (m, 2 H, 2
CH=CH2), 5.46–4.90 (m, 4 H, 2 CH=CH2), 4.90–4.30 (m, 2 H, N-
CH2-Ar), 3.32 (d, J = 5.8 Hz) and 3.01 (d, J = 6.7 HZ) [2 H, 2-
N-CH2-Ar), 3.32 (d, J = 6.4 Hz) and 3.70–2.80 (m) [2 H, 2-H], H] ppm. 13C NMR (75 MHz, CDCl3): δ = 172.1 (s, C-1), 138.7 (s)
1.72–1.48 (m, 2 H, 1ЈЈ-H), 0.88 (t, J = 7.4 Hz) and 0.85 (t, J =
and 137.8 (s) [C-1ЈЈ], 136.8 (s) and 136.4 (s) [C-1ЈЈЈ], 135.0 (d) and
134.8 (d) [CH=CH2], 132.7 (d) and 132.3 (d) [C-3ЈЈЈ], 131.9 (d) and
7.5 Hz) [3 H, 2ЈЈ-H] ppm. 13C NMR (75 MHz, CDCl3): δ = 172.0
(s) and 172.0 (s) [C-1], 137.5 (s) and 136.9 (s) [C-1ЈЈЈ], 136.1 (d) 131.6 (d) [CH=CH2], 128.7 (d) and 128.4 (d) [C-4ЈЈЈ], 128.6 (d, 2
Eur. J. Org. Chem. 2014, 2242–2252
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2247

G. Satyanarayana, G. Helmchen
FULL PAPER
C, Ph-C), 128.1 (d) and 128.0 (d) [2 C, Ph-C], 127.9 (d) and 127.7
(d) [C-5ЈЈЈ], 127.7 (d, C-6ЈЈЈ), 127.4 (d) and 127.1 (d) [C-4ЈЈ], 122.3
168.3 (s, C-2), 136.2 (s, C-1ЈЈ), 132.9 (d, C-3ЈЈ), 128.8 (d, C-4ЈЈ),
128.6 (d, C-6ЈЈ), 127.9 (d, C-5ЈЈ), 127.8 (d, C-5), 123.5 (s, C-2ЈЈ),
(s) and 121.9 (s) [C-2ЈЈЈ], 119.4 (t, CH=CH2), 118.3 (t, CH=CH2), 121.6 (d, C-4), 53.7 (d, C-6), 47.1 (t, N-CH2-Ar), 32.2 (t, C-3), 20.9
63.8 (d) and 60.1 (d) [C-1Ј], 49.1 (t) and 47.6 (t) [N-CH2-Ar], (q, C-1Ј) ppm. HRMS (ESI+): calcd. for C13H1579BrNO+
39.5 (t) and 39.2 (t) [C-2] ppm. HRMS (ESI+): calcd. for
C20H2179BrNO+ [M + H]+ 370.0801; found 370.0806; calcd. for
C20H2079BrNONa+ [M + Na]+ 392.0620; found 392.0626.
C20H20BrNO (370.28): calcd. C 64.87, H 5.44, Br 21.58, N 3.78;
found C 64.88, H 5.49, Br 21.50, N 3.75.
[M + H]+ 280.0331; found 280.0336; calcd. for C13H1479BrNONa+
[M + Na]+ 302.0151; found 302.0156.
(–)-(6S)-1-(2-Bromobenzyl)-6-ethyl-3,6-dihydropyridin-2(1H)-one
[(–)-(S)-9b]: GP3 was carried out with dienamide 8b (450 mg,
1.40 mmol), dichloromethane (47 mL, 0.03 m), and Grubbs I cata-
lyst (57.5 mg, 5 mol-%) for 2 h. For TLC, Rf (9b) = 0.28, Rf (8b) =
0.55 (petroleum ether/ethyl acetate, 7:3; KMnO4). Purification of
(–)-N-(2-Bromobenzyl)-N-[(1S)-1-ethylprop-2-en-1-yl]pent-4-en-
amide [(–)-(S)-8bb]: GP2 was carried out with amine (S)-6b
(630 mg, 2.48 mmol), dry dichloromethane (8 mL), DCC the crude product by flash chromatography on silica (35 g; petro-
(614.2 mg, 2.98 mmol), DMAP (15.1 mg, 5 mol-%), and 4-pen- leum ether/ethyl acetate, from 9:1 to 3:2) gave (–)-(S)-9b (410 mg,
tenoic acid (298 mg, 2.98 mmol) at r.t. for 15 h. For TLC, Rf (8bb) 100%) as a brownish viscous liquid. [α]2D0 = –1.2 (c = 1.05, CHCl3);
= 0.70, Rf (6b) = 0.20–0.40 (petroleum ether/ethyl acetate, 4:1;
KMnO4). The reaction mixture was then filtered through Celite
(12ϫ3 cm) with diethyl ether (50 mL), and the filtrate was concen-
trated in vacuo. Purification of the crude product by flash
chromatography on silica (50 g; petroleum ether to petroleum
ether/ethyl acetate, from 9:1 to 4:1) gave (–)-(S)-8bb (764 mg, 92%)
93 % ee). 1H NMR (300 MHz, CDCl3): δ = 7.53 (dd, J = 7.9,
1.1 Hz, 1 H, 3ЈЈ-H), 7.26 (ddd, J = 7.8, 7.1, 1.1 Hz, 1 H, 5ЈЈ-H),
7.17 (dd, J = 7.8, 1.6 Hz, 1 H, 6ЈЈ-H), 7.11 (ddd, J = 7.5, 7.5,
1.8 Hz, 1 H, 4ЈЈ-H), 5.87 (dddd, J = 10.1, 3.9, 3.2, 0.8 Hz, 1 H, 4-
H), 5.70 (dddd, J = 10.0, 4.2, 2.0, 2.0 Hz, 1 H, 5-H), 5.38 (d, J =
16.0 Hz, 1 H, N-CH2a-Ar), 4.21 (d, J = 16.0 Hz, 1 H, N-CH2b-Ar),
3.86 (dddd, J = 10.5, 6.8, 3.3, 0.6 Hz, 1 H, 6-H), 3.16–2.95 (m, 2
as a yellow oil. [α]2D0 = –24.9 (c = 0.85, CHCl3); 93%ee. H NMR
1
(300 MHz, CDCl3, signals from rotamers): δ = 7.54 (d, J = 8.05 Hz) H, 3-H), 1.80 (dqd, J = 14.3, 7.2, 7.1 Hz, 1 H, 1Ј-Ha), 1.62 (dqd,
and 7.48 (d, J = 8.0 Hz) [1 H, 3ЈЈЈ-H], 7.36–6.97 (m, 3 H, 4ЈЈЈ-H,
J = 14.4, 7.3, 3.0 Hz, I H, 1Ј-Hb), 0.84 (t, J = 7.3 Hz, 3 H, 2Ј-
5ЈЈЈ-H, 6ЈЈ-H), 6.04–5.60 (m, 2 H, 2 CH=CH2), 5.36–4.84 (m, 4 H, H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.8 (s, C-2), 136.1 (s,
2 CH=CH2), 5.20–4.88 (m) and 4.34–4.14 (m) [1 H, 1Ј-H], 4.72– C-1ЈЈ), 132.9 (d, C-3ЈЈ), 128.8 (d, C-4ЈЈ), 128.7 (d, C-6ЈЈ), 127.8 (d,
4.28 (m, 2 H, N-CH2-Ar), 2.72–2.18 (m, 4 H, 2-H, 3-H), 1.73–1.44 C-5ЈЈ), 125.8 (d, C-5), 123.6 (s, C-2ЈЈ), 123.1 (d, C-4), 58.2 (d, C-
(m, 2 H, 1ЈЈ-H), 0.89 (t, J = 7.1 Hz) and 0.86 (t, J = 6.9 Hz) [3 H,
6), 46.6 (t, N-CH2-Ar), 32.7 (t, C-3), 26.4 (t, C-1Ј), 7.8 (q, C-
2ЈЈ-H] ppm. 13C NMR (75 MHz, CDCl3): δ = 173.4 (s) and 173.2 2Ј) ppm. HRMS (ESI+): calcd. for C14H1779BrNO+ [M + H]+
(s) [C-1], 137.7 (d) and 137.5 (d) [CH=CH2], 137.0 (s, C-1ЈЈЈ), 136.3 294.0488; found 294.0489; calcd. for C14H1679BrNONa+ [M + Na]
(d) and 136.1 (d) [CH=CH2], 132.9 (d) and 132.5 (d) [C-3ЈЈЈ], 128.8
(d) and 128.7 (d) [C-4ЈЈЈ], 128.2 (d) and 128.0 (d) [C-5ЈЈЈ], 127.6 (d)
and 127.4 (d) [C-6ЈЈЈ], 122.4 (s) and 122.2 (s) [C-2ЈЈЈ], 118.2 (t) and
117.2 (t) [CH=CH2], 115.5 (t) [CH=CH2], 62.0 (d) and 58.7 (d) [C-
1Ј], 48.3 (t) and 45.8 (t) [N-CH2-Ar], 33.2 (t, C-2), 29.6 (t) and 29.5
(t) [C-3], 25.7 (t) and 24.8 (t) [C-1ЈЈ], 11.3 (q) and 11.1 (q) [C-
2ЈЈ] ppm. HRMS (ESI+): calcd. for C17H2379BrNO+ [M + H]+
336.0957; found 336.0959; calcd. for C17H2279BrNONa+ [M +
Na]+ 358.0777; found 358.0779. C17H22BrNO (336.27): calcd. C
60.72, H 6.59, Br 23.76, N 4.17; found C 60.76, H 6.62, Br 23.77,
N 4.18.
+ 316.0307; found 316.0309. C14H16BrNO (294.19): calcd. C 57.16,
H 5.48, Br 27.16, N 4.76; found C 57.25, H 5.45, Br 27.21, N 4.76.
(+)-(6R)-1-(2-Bromobenzyl)-6-[(trityloxy)methyl]-3,6-dihydro-
pyridin-2(1H)-one [(+)-(R)-9c]: GP3 was carried out with dienamide
8c (950 mg, 2.56 mmol), dichloromethane (85.5 mL, 0.03 m), and
Grubbs I catalyst (63.33 mg, 3 mol-%) for 5 h. For TLC, Rf (9c) =
0.34, Rf (8c) = 0.72 (petroleum ether/ethyl acetate, 3:2; KMnO4).
Purification of the crude product by flash chromatography on silica
(40 g; petroleum ether/ethyl acetate, from 9:1 to 7:3) gave (+)-(R)-
9c (800 mg, 91%) as a brownish viscous liquid. [α]2D0 = +47.5 (c =
1
1.10, CHCl3); 95%ee. H NMR (300 MHz, CDCl3): δ = 7.48 (dd,
General Procedure (GP3) for Ring-Closing Metathesis Reaction: A
solution of dienamide 8 in dry dichloromethane (0.03 m) under ar-
gon was treated with Grubbs I catalyst (for six-membered ring for-
mation) or Grubbs II catalyst (for seven-membered ring formation,
3–5 mol-%). The solution was heated at reflux for 2–5 h and was
then concentrated in vacuo. The residue was subjected to flash col-
umn chromatography on silica to give 9.
J = 7.9, 1.3 Hz, 1 H, 3ЈЈ-H), 7.45–7.34 (m, 6 H, trityl-Ph-H), 7.36–
7.12 (m, 10 H, 5Ј-H, trityl-Ph-H), 7.06 (ddd, J = 7.7, 7.7, 1.5 Hz,
1 H, 4ЈЈ-H), 7.00 (dd, J = 7.5, 1.3 Hz, 1 H, 6ЈЈ-H), 5.97 (ddd, J =
9.9, 3.8, 2.7 Hz, 1 H, 4-H), 5.77 (ddd, J = 9.9, 4.6, 2.4 Hz, 1 H, 5-
H), 5.27 (d, J = 16.5 Hz, 1 H, N-CH2a-Ar), 4.04 (d, J = 16.5 Hz,
1 H, N-CH2b-Ar), 3.90–3.70 (m, 1 H, 6-H), 3.33 (dd, J = 10.1,
4.2 Hz, 1 H, CH2a-O), 3.25 (dd, J = 10.1, 4.2 Hz, 1 H, CH2b-O),
3.25–2.98 (m, 2 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.0 (s, C-2), 143.7 (s, 3 C, C-1Ј), 135.9 (s, C-1ЈЈ), 132.9 (d, C-3ЈЈ),
128.7 (d, 6 C, trityl-Ph-C), 128.7 (d, C-4ЈЈ), 128.2 (d, C-6ЈЈ), 128.0
(d, 6 C, trityl-Ph-C), 127.7 (d, C-5ЈЈ), 127.3 (d, 3 C, C-4Ј), 124.7
(d, C-5), 124.5 (d, C-4), 123.5 (s, C-2ЈЈ), 87.3 [s, (Ph)3C-C-O], 64.0,
(t, CH2-O), 58.0 (d, C-6), 47.7 (t, N-CH2-Ar), 33.0 (t, C-3) ppm.
(–)-(6S)-1-(2-Bromobenzyl)-6-methyl-3,6-dihydropyridin-2(1H)-one
[(–)-(S)-9a]: GP3 was carried out with dienamide 8a (700 mg,
2.27 mmol), dichloromethane (76 mL, 0.03 m), and Grubbs I cata-
lyst (56.1 mg, 3 mol-%) for 2.5 h. For TLC, Rf (9a) = 0.30, Rf (8a)
= 0.60 (petroleum ether/ethyl acetate, 3:2; KMnO4). Purification of
the crude product by flash chromatography on silica (40 g; petro-
leum ether/ethyl acetate, from 4:1 to 3:2) gave (–)-(S)-9a (610 mg,
96%) as a brownish viscous liquid. [α]2D0 = –3.7 (c = 1.02, CHCl3);
96%ee. 1H NMR (300 MHz, CDCl3): δ = 7.53 (dd, J = 7.9, 1.0 Hz,
1 H, 3ЈЈ-H), 7.25 (ddd, J = 7.8, 7.0, 1.2 Hz, 1 H, 5ЈЈ-H), 7.16 (dd,
J = 7.6, 1.2 Hz, 1 H, 6ЈЈ-H), 7.10 (ddd, J = 7.6, 7.5, 1.5 Hz, 1 H,
+
HRMS (ESI+): calcd. for C32H2979BrNO2 [M + H]+ 538.1376;
found 538.1381; calcd. for C32H2879BrNO2Na+ [M + Na]+
560.1196; found 560.1200. C32H28BrNO2 (538.47): calcd. C 71.38,
H 5.24, Br 14.84, N 2.60; found C 71.68, H 5.34, Br 14.57, N 2.51.
(+)-(6R)-1-(2-Bromobenzyl)-6-phenyl-3,6-dihydropyridin-2(1H)-one
4ЈЈ-H), 5.84–5.66 (m, 2 H, 4-H, 5-H), 5.25 (d, J = 16.1 Hz, 1 H, [(+)-(R)-9d]: GP3 was carried out with dienamide 8d (820 mg,
N-CH2a-Ar), 4.36 (d, J = 16.1 Hz, 1 H, N-CH2b-Ar), 3.89 (dddd, 2.21 mmol), dichloromethane (74 mL, 0.03 m), and Grubbs I cata-
J = 9.9, 9.9, 6.5, 3.3 Hz, 1 H, 6-H), 3.13–3.00 (m, 2 H, 3-H), 1.28 lyst (91.1 mg, 5 mol-%) for 2.5 h. For TLC, Rf (9d) = 0.34, Rf (8d)
(d, J = 6.5 Hz, 3 H, 1Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
= 0.68 (petroleum ether/ethyl acetate, 3:2; KMnO4). Purification of
2248
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2242–2252

Enantioselective Syntheses of Bicyclic Lactams
the crude product by flash chromatography on silica (40 g; petro-
leum ether/ethyl acetate, from 6:1 to 3:2) gave (+)-(R)-9d (720 mg,
95%) as a brownish viscous liquid. [α]2D0 = +92.0 (c = 0.92, CHCl3);
97%ee. 1H NMR (300 MHz, CDCl3): δ = 7.52 (dd, J = 7.9, 1.3 Hz,
azocin-3-one [(+)-(6S,11S)-12a]: GP4 was carried out with cyclic
enamide 9a (58.0 mg, 0.21 mmol), Pd(dppf)Cl2 (30.4 mg, 20 mol-
%), triethylamine (209.6 mg, 2.1 mmol), and dry DMF (6.9 mL,
0.03 m). The capped vial was irradiated with a microwave at 120 °C
1 H, 3ЈЈ-H), 7.43–7.20 (m, 4 H, 5ЈЈ-H, 3Ј-H, 4Ј-H, 5Ј-H), 7.23–7.12 for 2 min followed by a 40 min hold time at 120 °C. For TLC, Rf
(m, 3 H, 6ЈЈ-H, 2Ј-H, 6Ј-H), 7.11 (ddd, J = 7.7, 7.5, 1.5 Hz, 1 H, (10a, 11a, 12a) = 0.60, Rf (9a) = 0.30 (petroleum ether/ethyl acetate,
4ЈЈ-H), 5.90–5.66 (m, 2 H, 4-H, 5-H), 5.39 (d, J = 16.0 Hz, 1 H, 3:2; KMnO4). After cooling to room temp., water (20 mL) was
N-CH2a-Ar), 4.83 (dd, J = 7.1, 3.5 Hz, 1 H, 6-H), 3.86 (d, J = added, and the resulting mixture was extracted with ethyl acetate
16.1 Hz, 1 H, N-CH2b-Ar), 3.40–3.10 (m, 2 H, 3-H) ppm. 13C (3ϫ 15 mL). The combined organic layers were dried with Na2SO4
NMR (75 MHz, CDCl3): δ = 168.1 (s, C-2), 139.9 (s, C-1Ј), 135.7
(s, C-1ЈЈ), 133.0 (d, C-3ЈЈ), 129.1 (d, 2 C, C-3Ј, C-5Ј), 128.9 (d, 2 C,
C-4ЈЈ, C-6ЈЈ), 128.4 (d, C-4Ј), 127.7 (d, C-5ЈЈ), 127.1 (d, 2 C, C-2Ј,
and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica (25 g; petroleum ether/ethyl acet-
ate, 4:1) to give a mixture of the three products (28 mg, 68%, 10a/
C-6Ј), 126.6 (d, C-5), 123.7 (s, C-2ЈЈ), 120.9 (d, C-4), 62.7 (d, C-6), 11a/12a, 86:10:4). Separation was accomplished by preparative
47.2 (t, N-CH2-Ar), 32.3 (t, C-3) ppm. HRMS (ESI+): calcd. for HPLC (pentane/ethyl acetate, 4:1) to give first (–)-(6S,11S)-10a
C18H1779BrNO+ [M + H]+ 342.0488; found 342.0491; calcd. for
(24 mg, 58%), then (+)-(6R,11S)-11a (3 mg, 7%), and finally (+)-
C1 8 H1 6 7 9 BrNOK+ [M + K]+ 380.0047; found 380.0050. (6S,11S)-12a (1 mg, 2%).
C18H16BrNO (342.23): calcd. C 63.17, H 4.71, Br 23.35, N 4.09;
found C 63.25, H 4.83, Br 23.07, N 3.82.
(–)-(6S,11S)-10a: [α]2D0 = –356 (c = 0.85, CHCl3); 96%ee. 1H NMR
(500 MHz, CDCl3): δ = 7.20 (ddd, J = 7.4, 7.4, 1.4 Hz, 1 H, 8-H),
7.15 (dd, J = 7.1, 7.1 Hz, 1 H, 9-H), 7.08 (d, J = 7.4 Hz, 1 H, 10-
H), 7.01 (d, J = 7.4 Hz, 1 H, 7-H), 6.98 (ddd, J = 9.2, 7.0, 2.1 Hz,
1 H, 5-H), 6.05 (d, J = 9.3 Hz, 1 H, 4-H), 4.81 (d, J = 16.5 Hz, 1
H, 1-Ha), 4.37 (d, J = 16.5 Hz, 1 H, 1-Hb), 3.85–3.71 (m, 1 H, 11-
H), 3.22 (d, J = 6.9 Hz, 1 H, 6-H), 1.48 (d, J = 6.9 Hz, 3 H, 1Ј-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.8 (s, C-3), 146.9
(d, C-5), 138.3 (s, C-10a), 135.1 (s, C-6a), 128.7 (d, C-10), 127.7 (d,
C-7), 127.6 (d, C-8), 126.9 (d, C-9), 126.1 (d, C-4), 55.6 (d, C-11),
54.7 (t, C-1), 40.4 (d, C-6), 18.3 (q, C-1Ј) ppm. HRMS (ESI+):
calcd. for C13H13NONa+ [M + Na]+ 222.0889; found 222.0889.
C13H13NO (199.25): calcd. C 78.36, H 6.58, N 7.03; found C 78.07,
H 6.63, N 6.83.
(+)-(7S)-1-(2-Bromobenzyl)-7-ethyl-1,3,4,7-tetrahydro-2H-azepin-2-
one [(+)-(S)-9bb]: GP3 was carried out with dienamide 8bb
(700 mg, 2.08 mmol), dichloromethane (69 mL, 0.03 m), and
Grubbs II catalyst (53.1 mg, 3 mol-%) for 5 h. For TLC, Rf (9bb) =
0.30, Rf (8bb) = 0.70 (petroleum ether/ethyl acetate, 7:3; KMnO4).
Purification of the crude product by flash chromatography on silica
(40 g; petroleum ether to petroleum ether/ethyl acetate, from 6:1 to
3:2) gave (+)-(S)-9bb (630 mg, 98%) as a brownish viscous liquid.
[α]2D0 = +31.8 (c = 1.12, CHCl3); 93%ee. 1H NMR (300 MHz,
CDCl3): δ = 7.52 (dd, J = 7.9, 1.28 Hz, 1 H, 3ЈЈ-H), 7.25 (ddd, J
= 7.3, 7.1, 0.7 Hz, 1 H, 5ЈЈ-H), 7.18 (dd, J = 7.9, 1.6 Hz, 1 H, 6ЈЈ-
H), 7.10 (ddd, J = 7.8, 7.2, 1.4 Hz, 1 H, 4ЈЈ-H), 5.83 (dddd, J =
11.7, 5.8, 1.1, 0.8 Hz, 1 H, 5-H), 5.65 (dddd, J = 11.6, 7.0, 2.8,
1.4 Hz, 1 H, 6-H), 5.32 (d, J = 16.1 Hz, 1 H, N-CH2a-Ar), 4.14 (d,
J = 16.1 Hz, 1 H, N-CH2b-Ar), 3.59 (ddd, J = 7.3, 7.3, 7.3 Hz, 1
H, 7-H), 2.94 (ddd, J = 12.9, 12.9, 3.9 Hz, 1 H, 3-Ha), 2.66 (dddd,
J = 13.1, 5.3, 2.9, 1.0 Hz, 1 H, 3-Hb), 2.60–2.20 (m, 2 H, 4-H),
2.05–1.72 (m, 2 H, 1Ј-H), 1.01 (t, J = 7.3 Hz, 3 H, 2Ј-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 174.4 (s, C-2), 136.8 (s, C-1ЈЈ), 132.7
(d, C-3ЈЈ), 129.9 (d, C-5), 128.7 (d, C-6), 128.6 (d, C-4ЈЈ), 128.3 (d,
C-6ЈЈ), 127.7 (d, C-5ЈЈ), 123.3 (s, C-2ЈЈ), 60.3 (d, C-7), 52.0 (t, N-
CH2-Ar), 35.6 (t, C-3), 29.6 (t, C-1Ј), 24.6 (t, C-4), 11.9 (q, C-
2Ј) ppm. HRMS (ESI+): calcd. for C30H3679Br2N2O2Na+ [2M +
Na]+ 637.1030; found 637.1045. C15H18BrNO (308.21): calcd. C
58.45, H 5.89, Br 25.92, N 4.54; found C 58.44, H 5.93, Br 25.73,
N 4.50.
(+)-(6R,11S)-11a: [α]2D0 = +370 (c = 0.60, CHCl3); 96%ee. 1H NMR
(300 MHz, CDCl3): δ = 7.24 (dd, J = 9.1, 6.6 Hz, 1 H, 5-H), 7.20
(ddd, J = 7.0, 7.0, 2.0 Hz, 1 H, 8-H), 7.15 (ddd, J = 7.1, 7.1, 1.6 Hz,
1 H, 9-H), 7.07 (dd, J = 7.2, 1.7 Hz, 1 H, 10-H), 6.98 (d, J = 6.8,
1.6 Hz, 1 H, 7-H), 6.00 (d, J = 9.2 Hz, 1 H, 4-H), 4.67 (d, J =
17.2 Hz, 1 H, 1-Ha), 4.29 (d, J = 17.2 Hz, 1 H, 1-Hb), 4.05 (qd, J
= 7.0, 0.8 Hz, 1 H, 11-H), 3.05 (d, J = 6.7 Hz, 1 H, 6-H), 1.32 (d,
J = 7.0 Hz, 3 H, 1Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
178.1 (s, C-3), 152.8 (d, C-5), 134.5 (s, C-6a), 133.7 (s, C-10a), 130.0
(d, C-10), 127.5 (d, C-8), 127.2 (d, C-7), 127.1 (d, C-9), 125.1 (d,
C-4), 54.1 (d, C-11), 46.1 (t, C-1), 40.1 (d, C-6), 16.0 (q, C-1Ј) ppm.
HRMS (ESI+): calcd. for C26H26N2O2Na+ [2M + Na]+ 421.1886;
found 421.1894.
1
(+)-(6S,11S)-12a: H NMR (300 MHz, CDCl3): δ = 7.25–7.00 (m,
General Procedure (GP4) for Intramolecular Heck Reactions: To an
oven-dried microwave vial that was equipped with a magnetic stir-
ring bar and the cyclic product 9 (1 mmol) under argon were added
Pd(PPh3)2Cl2 or Pd(dppf)Cl2 (10–20 mol-%), triethylamine
(10 mmol), and dry DMF (0.03 m). The capped vial was placed in
the microwave reactor Discover CEM and irradiated at 100–120 °C
for 2 min followed by a 25–120 min hold time at 100–120 °C. The
reaction mixture was cooled to room temp. and was then treated
with either H2O or saturated NH4Cl solution. The aqueous layer
was extracted with ethyl acetate. The combined organic layers were
dried with Na2SO4 and concentrated in vacuo. The crude products
(i.e., 10, 11, and 12) were purified by flash column chromatography
on silica (petroleum ether/ethyl acetate) or, if necessary, preparative
HPLC (pentane/ethyl acetate).
3 H, Ar-H), 7.03 (dd, J = 6.8, 1.8 Hz, 1 H, 10-H), 5.17 (d, J =
15.8 Hz, 1 H, 1-Ha), 4.15 (d, J = 15.8 Hz, 1 H, 1-Hb), 3.72 (qd, J
= 7.1, 1.8 Hz, 1 H, 11-H), 3.12 (dd, J = 7.5, 2.2 Hz, 1 H, 6-H),
2.72–2.45 (m, 2 H, 4-Ha, 5-Ha), 2.44–2.23 (m, 1 H, 4-Hb), 2.10–
1.85 (m, 1 H, 5-Hb), 1.48 (d, J = 7.0 Hz, 3 H, 1Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 184.3 (s, C-3), 141.9 (s, C-10a), 136.7 (s, C-
6a), 129.9 (d, Ar-C), 127.2 (d, Ar-C), 126.9 (d, Ar-C), 126.7 (d, C-
10), 56.6 (d, C-11), 55.7 (t, C-1), 39.5 (d, C-6), 29.8 (t, C-4), 26.9
(t, C-5), 18.2 (q, C-1Ј) ppm. HRMS (ESI+): calcd. for C13H16NO+
[M + H]+ 202.1226; found 202.1229; calcd. for C13H15NONa+ [M
+ Na]+ 224.1046; found 224.1049.
(–)-(6S,11S)-11-Ethyl-1,6-dihydro-3H-2,6-methano-2-benzazocin-3-
one [(–)-(6S,11S)-10b], (+)-(6R,11S)-11-Ethyl-1,6-dihydro-3H-2,6-
methano-2-benzazocin-3-one [(+)-(6R,11S)-11b], and (+)-(6S,11S)-
11-Ethyl-1,4,5,6-tetrahydro-3H-2,6-methano-2-benzazocin-3-one
[(+)-(6S,11S)-12b]: GP4 was carried out with enamide 9b (60 mg,
0.20 mmol), Pd(dppf)Cl2 (29.9 mg, 20 mol-%), triethylamine
(206.5 mg, 2.04 mmol), and dry DMF (6.8 mL, 0.03 m). The
(–)-(6S,11S)-11-Methyl-1,6-dihydro-3H-2,6-methano-2-benzazocin-
3-one [(–)-(6S,11S)-10a], (+)-(6R,11S)-11-Methyl-1,6-dihydro-3H-
2,6-methano-2-benzazocin-3-one [(+)-(6R,11S)-11a], and (+)-
(6S,11S)-11-Methyl-1,4,5,6-tetrahydro-3H-2,6-methano-2-benz-
Eur. J. Org. Chem. 2014, 2242–2252
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2249

G. Satyanarayana, G. Helmchen
FULL PAPER
capped vial was irradiated with a microwave at 120 °C for 2 min
Pd(dppf)Cl2 (17.2 mg, 20 mol-%), triethylamine (118.5 mg,
followed by a 40 min hold time at 120 °C. For TLC, Rf (10b, 11b, 1.2 mmol), and dry DMF (3.9 mL, 0.03 m). The capped vial was
12b) = 0.70, Rf (9b) = 0.35 (petroleum ether/ethyl acetate, 3:2; irradiated with a microwave at 120 °C for 2 min followed by a 1 h
KMnO4). The cooled reaction mixture was treated with H2O
(20 mL), and the resulting solution was extracted with ethyl acetate
(3ϫ 15 mL). The combined organic layers were dried with Na2SO4
and concentrated in vacuo. The residue was subjected to flash col-
umn chromatography on silica (25 g; petroleum ether/ethyl acetate,
4:1) to give a mixture of the three products (32 mg, 74%, 10b/11b/
12b, 79:15:6). Separation was accomplished by preparative HPLC
(pentane/ethyl acetate, 4:1) to elute first (–)-(6S,11S)-10b (25 mg,
59%), then (+)-(6R,11S)-11b (5 mg, 11%), and finally (+)-(6S,11S)-
12b (2 mg, 4%).
hold time at 120 °C. For TLC, Rf (10c, 11c, 12c) = 0.72, Rf (9c) =
0.34 (petroleum ether/ethyl acetate, 3:2; KMnO4). The cooled reac-
tion mixture was diluted with H2O (20 mL), and the resulting solu-
tion was extracted with ethyl acetate (3ϫ 15 mL). The combined
organic layers were dried with Na2SO4 and concentrated in vacuo.
Flash column chromatography on silica (25 g; petroleum ether/
ethyl acetate, 4:1) gave a mixture of the three products (40 mg,
75%, 10c/11c/12c, 77:18:4). Separation was accomplished by repar-
ative HPLC (pentane/ethyl acetate, 4:1) to elute first (–)-(6S,11R)-
10c (31 mg, 58%), then (+)-(6R,11R)-11c (7 mg, 14%), and finally
(+)-(6S,11R)-12c (2 mg, 3%), as brown viscous oils.
(–)-(6S,11S)-10b: [α]2D0 = –317 (c = 0.92, CHCl3); 93%ee. 1H NMR
(300 MHz, CDCl3): δ = 7.20 (ddd, J = 7.1, 7.1, 1.8 Hz, 1 H, 8-H), (–)-(6S,11R)-10c: [α]2D0 = –143 (c = 0.96, CHCl3); 95%ee. 1H NMR
7.15 (dd, J = 7.1, 6.4 Hz, 1 H, 9-H), 7.09 (dd, J = 7.1, 1.6 Hz, 1
H, 10-H), 7.01 (d, J = 8.0 Hz, 1 H, 7-H), 6.96 (ddd, J = 9.2, 7.0,
(300 MHz, CDCl3): δ = 7.52–7.32 (m, 6 H, trityl-H), 7.35–7.08 (m,
12 H, 8-H, 9-H, 10-H, trityl-H), 6.98 (d, J = 7.2 Hz, 1 H, 7-H),
2.1 Hz, 1 H, 5-H), 6.03 (d, J = 9.15 Hz, 1 H, 4-H), 4.85 (d, J = 6.81 (ddd, J = 9.1, 6.9, 2.0 Hz, 1 H, 5-H), 5.78 (d, J = 9.2 Hz, 1
16.5 Hz, 1 H, 1-Ha), 4.34 (d, J = 16.5 Hz, 1 H, 1-Hb), 3.52–3.38 H, 4-H), 4.78 (d, J = 16.2 Hz, 1 H, 1-Ha), 4.32 (d, J = 16.2 Hz, 1
(m, 1 H, 11-H), 3.29 (d, J = 6.6 Hz, 1 H, 6-H), 2.08–1.85 (m, 1 H, H, 1-Hb), 3.93–3.78 (m, 1 H, 11-H), 3.57 (dd, J = 9.2, 5.8 Hz, 1 H,
1Ј-Ha), 1.86–1.65 (m, 1 H, 1Ј-Hb), 1.01 (t, J = 7.5 Hz, 3 H, 2Ј-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.7 (s, C-3), 146.4 (d,
C-5), 138.3 (s, C-10a), 135.5 (s, C-6a), 128.8 (d, C-10), 127.6 (d, C-
7), 127.6 (d, C-8), 126.9 (d, C-9), 126.4 (d, C-4), 62.0 (d, C-11),
54.8 (t, C-1), 38.4 (d, C-6), 25.1 (t, C-1Ј), 11.3 (q, C-2Ј) ppm.
HRMS (ESI+): calcd. for C14H16NO+ [M + H]+ 214.1226; found
214.1227; calcd. for C14H15NOK+ [M + K]+ 252.0785; found
252.0786. C14H15NO (213.27): calcd. C 78.84, H 7.09, N 6.57;
found C 78.58, H 7.09, N 6.49.
1Ј-Ha), 3.55 (d, J = 5.8 Hz, 1 H, 6-H), 3.37 (dd, J = 9.2, 9.2 Hz, 1
H, 1Ј-Hb) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.4 (s, C-3),
146.4 (d, C-5), 143.8 (s, 3 C, C-1ЈЈ), 137.7 (s, C-10a), 135.2 (s, C-
6a), 129.0 (d, C-10), 128.7 (d, 6 C, trityl-Ph-C), 128.0 (d, 6 C, trityl-
Ph-C), 127.6 (d, 2 C, C-7, C-8), 127.3 (d, 3 C, C-4ЈЈ), 126.9 (d, C-
9), 125.6 (d, C-4), 86.9 [s, O-C(Ph)3], 62.8 (t, C-1Ј), 59.7 (d, C-
11), 54.5 (t, C-1), 36.5 (d, C-6) ppm. HRMS (ESI+): calcd. for
C32H28NO2 [M + H]+ 458.2115; found 458.2118; calcd. for
+
C32H27NO2Na+ [M + Na]+ 480.1934; found 480.1940; calcd. for
C32H27NO2K+ [M + K]+ 496.1673; found 496.1680. C32H27NO2
(457.56): calcd. C 84.00, H 5.95, N 3.06; found C 83.98, H 6.05, N
3.02.
(+)-(6R,11S)-11b: [α]2D0 = +302 (c = 0.91, CHCl3); 93%ee. 1H NMR
(300 MHz, CDCl3): δ = 7.30 (dd, J = 7.4, 2.3 Hz, 1 H, 5-H), 7.21
(ddd, J = 7.0, 7.0, 2.0 Hz, 1 H, 8-H), 7.19 (dd, J = 7.3, 7.3, 1.5 Hz,
1 H, 9-H), 7.12 (dd, J = 7.2, 1.7 Hz, 1 H, 10-H), 7.02 (d, J = 6.7,
[(+)-(6R,11R)-11c]: [α]2D0 = +110 (c = 1.08, CHCl3); 95%ee. 1H
1.6 Hz, 1 H, 7-H), 6.05 (d, J = 9.2 Hz, 1 H, 4-H), 4.72 (d, J = NMR (300 MHz, CDCl3): δ = 7.44–6.98 (m, 19 H, trityl-H, Ar-H,
17.3 Hz, 1 H, 1-Ha), 4.27 (d, J = 17.3 Hz, 1 H, 1-Hb), 3.79 (ddd, J 5-H), 6.86–6.73 (m, 1 H, Ar-H), 6.01 (d, J = 9.2 Hz, 1 H, 4-H),
= 8.0, 7.3, 0.7 Hz, 1 H, 11-H), 3.16 (d, J = 6.7 Hz, 1 H, 6-H), 1.77 4.53 (d, J = 17.3 Hz, 1 H, 1-Ha), 4.12 (dd, J = 7.6 and 6.1 Hz, 1
(ddq, J = 14.2, 7.6, 7.5 Hz, 1 H, 1Ј-Ha), 1.61 (ddq, J = 14.3, 7.2,
H, 11-H), 3.86 (d, J = 17.3 Hz, 1 H, 1-Hb), 3.44 (d, J = 8.9 Hz, 1
7.2 Hz, 1 H, 1Ј-Hb), 1.09 (t, J = 7.4 Hz, 3 H, 2Ј-H) ppm. 13C NMR H, 6-H), 3.38 (dd, J = 9.1, 3.5 Hz, 1 H, 1Ј-Ha), 3.33 (dd, J = 8.9,
(75 MHz, CDCl3): δ = 178.3 (s, C-3), 152.8 (d, C-5), 134.8 (s, C-
6a), 133.9 (s, C-10a), 129.8 (d, C-10), 127.5 (d, C-8), 127.2 (d, C-
7), 127.1 (d, C-9), 125.2 (d, C-4), 60.4 (d, C-11), 46.3 (t, C-1), 38.7
(d, C-6), 22.9 (t, C-1Ј), 10.8 (q, C-2Ј) ppm. HRMS (ESI+): calcd.
for C14H16NO+ [M + H]+ 214.1226; found 214.1229; calcd. for
C28H30N2O2Na+ [2M + Na]+ 449.2199; found 449.2208.
8.9 Hz, 1 H, 1Ј-Hb) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.8
(s, C-3), 152.6 (d, C-5), 143.6 (s, 3 C, C-1ЈЈ), 134.2 (s, C-6a), 133.6
(s, C-10a), 129.7 (d, C-7), 128.6 (d, 6 C, trityl-Ph-C), 127.9 (d, 6 C,
trityl-Ph-C), 127.5 (d, C-10), 127.2 (d, 3 C, C-4ЈЈ), 127.1 (d, Ar-C),
127.1 (d, Ar-C), 125.2 (d, C-4), 86.9 [s, O-C(Ph)3], 61.8 (t, C-1Ј),
58.4 (d, C-11), 47.3 (t, C-1), 36.8 (d, C-6) ppm. HRMS (ESI+):
+
calcd. for C32H28NO2 [M + H]+ 458.2115; found 458.2125; calcd.
1
(+)-(6S,11S)-12b: H NMR (300 MHz, CDCl3): δ = 7.25–7.01 (m,
for C64H54N2O4Na+ [2M + Na]+ 937.3976; found 937.3997.
3 H, Ar-H), 7.04 (dd, J = 6.4, 2.1 Hz, 1 H, 10-H), 5.20 (d, J =
15.8 Hz, 1 H, 1-Ha), 4.12 (d, J = 15.8 Hz, 1 H, 1-Hb), 3.40 (dd, J
= 7.6, 7.6 Hz, 1 H, 11-H), 3.19 (dd, J = 7.4, 2.2 Hz, 1 H, 6-H),
[(+)-(6S,11R)-12c]: 1H NMR (300 MHz, CDCl3): δ = 7.57–7.39 (m,
6 H, trityl-Ph-H), 7.40–7.03 (m, 12 H, Ar-H, trityl-Ph-H), 7.03 (dd,
2.70–2.40 (m, 2 H, 4-Ha, 5-Ha), 2.31 (dd, J = 15.1, 9.2 Hz, 1 H, 4- J = 6.9, 2.0 Hz, 1 H, Ar-H), 5.17 (d, J = 15.9 Hz, 1 H, 1-Ha), 4.19
Hb), 2.10–1.60 (m, 3 H, 5-Hb, 1Ј-H), 1.07 (t, J = 7.4 Hz, 3 H, 2Ј-
(d, J = 15.9 Hz, 1 H, 1-Hb), 3.87 (dd, J = 6.4, 6.4 Hz, 1 H, 11-H),
3.57 (dd, J = 9.2, 5.5 Hz, 1 H, 1Ј-Ha), 3.38–3.21 (m, 2 H, 1Ј-Hb, 6-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 184.2 (s, C-3), 142.0 (s,
C-10a), 137.0 (s, C-6a), 130.0 (d, Ar-C), 127.2 (d, Ar-C), 127.0 (d, H), 2.30–1.87 (m, 3 H, 5-Ha, 4-H), 1.90–1.88 (m, 1 H, 5-Hb) ppm.
Ar-C), 126.7 (d, C-10), 63.6 (d, C-11), 56.1 (t, C-1), 38.1 (d, C-6),
13C NMR (75 MHz, CDCl3): δ = 183.9 (s, C-3), 143.8 (s, 3 C, C-
30.0 (t, C-4), 27.1 (t, C-5), 25.2 (t, C-1Ј), 11.9 (q, C-2Ј) ppm. HRMS 1ЈЈ), 141.6 (s, C-10a), 136.7 (s, C-6a), 130.1 (d, Ar-C), 128.7 (d, 6
(ESI+): calcd. for C14H18NO+ [M + H]+ 216.1383; found 216.1385; C, trityl-C), 128.1 (d, 6 C, trityl-C), 127.4 (d, 3 C, C-4ЈЈ), 127.2 (d,
calcd. for C28H34N2O2Na+ [2M + Na]+ 453.2512; found 453.2519.
Ar-C), 126.9 (d, Ar-C), 126.8 (d, C-10), 86.9 [s, O-C(Ph)3], 63.9 (t,
C-1Ј), 61.6 (d, C-11), 55.8 (t, C-1), 36.8 (d, C-6), 30.1 (t, C-4), 27.1
(–)-(6S,11R)-11-[(Trityloxy)methyl]-1,6-dihydro-3H-2,6-methano-
2-benzazocin-3-one [(–)-(6S,11R)-10c], (+)-(6R,11R)-11-[(Trityl-
oxy)methyl]-1,6-dihydro-3H-2,6-methano-2-benzazocin-3-one [(+)-
(6R,11R)-11c], and (+)-(6S,11R)-11-[(Trityloxy)methyl]-1,4,5,6-
tetrahydro-3H-2,6-methano-2-benzazocin-3-one [(+)-(6S,11R)-12c]:
GP4 was carried out with enamide 9c (63 mg, 0.12 mmol),
(t, C-5) ppm. HRMS (ESI+): calcd. for C32H30NO2 [M + H]+
+
460.2271; found 460.2279; calcd. for C32H29NO2Na+ [M + Na]+
482.2090; found 482.2100.
(–)-(6S,11R)-11-Phenyl-1,6-dihydro-3H-2,6-methano-2-benzazocin-
3-one [(–)-(6S,11R)-10d] and (+)-(6S,11R)-11-Phenyl-1,4,5,6-tetra-
2250
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2242–2252

Enantioselective Syntheses of Bicyclic Lactams
hydro-3H-2,6-methano-2-benzazocin-3-one [(+)-(6S,11R)-12d]: GP4
was carried out with enamide 9d (62 mg, 0.18 mmol), Pd(dppf)Cl2
11.1, 5.7, 3.3 Hz, 1 H, 6-H), 5.62 (dddd, J = 11.0, 8.9, 2.0, 2.0 Hz,
1 H, 5-H), 5.40 (d, J = 16.8 Hz, 1 H, 1-Ha), 4.35 (dd, J = 8.9,
(26.6 mg, 20 mol-%), triethylamine (183.4 mg, 1.8 mmol), and dry 6.4 Hz, 1 H, 12-H), 3.98 (d, J = 16.6 Hz, 1 H, 1-Hb), 3.81 (ddd, J
DMF (6.04 mL, 0.03 m). The capped vial was irradiated with a mi-
crowave at 120 °C for 2 min followed by a 1 h hold time at 120 °C.
= 16.4, 5.7, 2.7 Hz, 1 H, 4-Ha), 3.22 (br. s, 1 H, 7-H), 2.87 (dd, J
= 16.5, 8.7 Hz, 1 H, 4-Hb), 1.73 (ddq, J = 16.1, 7.2, 7.2 Hz, 1 H,
For TLC, Rf (10d, 11d, 12d) = 0.70, Rf (9d) = 0.34 (petroleum 1Ј-Ha), 1.56 (ddq, J = 13.9, 7.0, 6.9 Hz, 1 H, 1Ј-Hb), 1.03 (t, J =
ether/ethyl acetate, 3:2; KMnO4). The cooled reaction mixture was
treated with H2O (20 mL), and the resulting solution was extracted
with ethyl acetate (3ϫ 15 mL). The combined organic layers were
dried with Na2SO4 and concentrated in vacuo. Flash column
chromatography on silica (25 g; petroleum ether/ethyl acetate, 4:1)
gave a mixture of the three products (36 mg, 76%, 10d/11d/12d,
7.4 Hz, 3 H, 2Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.3 (s,
C-3), 134.7 (s, d, C-11a, C-5), 134.2 (s, C-7a), 129.5 (d, Ar-C), 126.9
(d, Ar-C), 126.7 (d, Ar-C), 126.4 (d, Ar-C), 120.5 (d, C-6), 56.1 (d,
C-12), 42.1 (d, C-7), 40.9 (t, C-1), 35.9 (t, C-4), 23.5 (t, C-1Ј), 11.2
(q, C-2Ј) ppm. HRMS (ESI+): calcd. for C15H18NO+ [M + H]+
228.1383; found 228.1386; calcd. for C30H34N2O2Na+ [2M + Na]+
92:2:6). Preparative HPLC (pentane/ethyl acetate, 4:1) gave first 477.2512; found 477.2522.
(–)-(6S,11R)-10d (33 mg, 70%) as solid (recrystallized from petro-
leum ether/dichloromethane) followed by (+)-(6S,11R)-12d (2 mg,
(+)-(7R,12S)-11bb: 1H NMR (300 MHz, CDCl3): δ = 7.28–6.99 (m,
4 H, Ar-H), 6.23–6.00 (m, 2 H, 5-H, 6-H), 5.40 (d, J = 16.7 Hz, 1
H, 1-Ha), 4.23–4.01 (m, 1 H, 12-H), 4.12 (dd, J = 16.7 Hz, 1 H, 1-
Hb), 3.11 (dd, J = 10.2, 2.9 Hz, 1 H, 7-H), 2.94 (ddd, J = 18.2,
10.3, 6.0 Hz, 1 H, 4-Ha), 2.50–2.30 (m, 1 H, 4-Hb), 1.70 (ddq, J =
14.4, 9.0, 7.2 Hz, 1 H, 1Ј-Ha), 1.53 (ddq, J = 14.0, 7.1, 7.0 Hz, 1
H, 1Ј-Hb), 0.98 (t, J = 7.4 Hz, 3 H, 2Ј-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.0 (s, C-3), 139.1 (s, C-11a), 136.6 (d, C-6), 133.4
(s, C-7a), 130.1 (d, Ar-C), 127.2 (d, Ar-C), 126.6 (d, Ar-C), 126.5
(d, Ar-C), 126.4 (d, C-6), 57.0 (d, C-12), 42.4 (d, C-1), 41.0 (t, C-
7), 36.1 (t, C-4), 23.4 (t, C-1Ј), 11.4 (q, C-2Ј) ppm. HRMS (ESI+):
calcd. for C30H34N2O2Na+ [2M + Na]+ 477.2512; found 477.2519.
4%), as a semisolid.
(–)-(6S,11R)-10d: M.p. 171–172 °C; [α]2D0 = –187 (c = 0.96, CHCl3);
1
97%ee. H NMR (300 MHz, CDCl3): δ = 7.50–7.28 (m, 4 H, Ar-
H, Ph-H), 7.32–7.14 (m, 4 H, Ar-H, Ph-H), 7.08 (d, J = 6.7 Hz, 1
H, 7-H), 6.84 (ddd, J = 9.2, 6.8, 1.9 Hz, 1 H, 5-H), 5.87 (d, J =
9.4 Hz, 1 H, 4-H), 5.04 (d, J = 16.5 Hz, 1 H, 1-Ha), 4.92 (s, 1 H,
11-H), 4.49 (d, J = 16.5 Hz, 1 H, 1-Hb), 3.92 (dd, J = 6.8, 1.9 Hz,
1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.7 (s, C-3),
146.8 (d, C-5), 139.5 (s, C-1Ј), 137.3 (s, C-10a), 135.5 (s, C-6a),
129.0 (d, C-10), 128.6 (d, 2 C, Ph-C), 127.8 (d, C-4Ј), 127.7 (d, C-
7), 127.1 (d, C-8), 127.0 (d, C-9), 126.9 (d, C-4), 126.6 (d, 2 C, Ph-
C), 61.8 (d, C-11), 54.3 (t, C-1), 39.5 (d, C-6) ppm. HRMS (ESI+):
calcd. for C18H16NO+ [M + H]+ 262.1226; found 262.1229; calcd.
for C18H15NONa+ [M + Na]+ 284.1046; found 284.1049.
C18H15NO (261.32): calcd. C 82.73, H 5.79, N 5.36; found C 82.43,
H 5.77, N 5.43.
(+)-(6S,11R)-12d: 1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J =
8.0 Hz, 2 H, 2Ј-H, 6Ј-H), 7.42 (dd, J = 7.5, 7.5 Hz, 2 H, 3Ј-H, 5Ј-
H), 7.40–7.03 (m, 5 H, Ar-H, Ph-H), 5.41 (d, J = 16.1 Hz, 1 H, 1-
Ha), 4.81 (s, 1 H, 11-H), 4.30 (d, J = 16.1 Hz, 1 H, 1-Hb), 3.93 (dd,
J = 8.8, 1.8 Hz, 1 H, 6-H), 2.70–2.38 (m, 1 H, 5-Ha), 2.30–1.70 (m,
3 H, 5-Hb, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 184.1 (s,
C-3), 141.6 (s, C-10a), 139.6 (s, C-1Ј), 136.6 (s, C-6a), 130.1 (d, Ar-
C), 129.1 (d, 2 C, C-2Ј, C-6Ј), 127.4 (d, Ar-C), 127.3 (d, C-4Ј),
127.0 (d, C-10), 127.0 (d, Ar-C), 125.2 (d, 2 C, C-3Ј, C-5Ј), 62.6 (d,
C-11), 54.5 (t, C-1), 37.9 (d, C-6), 30.7 (t, C-4), 27.9 (t, C-5) ppm.
HRMS (ESI+): calcd. for C18H18NO+ [M + H]+ 264.1383; found
264.1386; calcd. for C18H17NOK+ [M + K]+ 302.0942; found
302.0946; calcd. for C36H34N2O2K+ [2M + K]+ 565.2252; found
565.2262.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of HPLC data for compounds 5b–5d and 8a as well as
1
X-ray crystal data for 10d and H and 13C NMR spectra.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (SFB 623) and the Fonds der Chemischen Industrie. Dr.
Frank Rominger is thanked for the crystal structure analysis.
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subjected to flash column chromatography on silica (25 g; petro-
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isomer (+)-(7S,12S)-10bb (38 mg, 72 %) and then (+)-(7R,12S)-
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Eur. J. Org. Chem. 2014, 2242–2252
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2251

G. Satyanarayana, G. Helmchen
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Received: December 5, 2013
Published Online: February 12, 2014
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