Synthesis of ornithine lactams via diastereoselective photocyclization of 2-amino-4-oxo-4-phenyl-butanoyl amines

Article abstract of DOI:10.1016/S0957-4166(98)00472-8

The diastereoselective synthesis of ornithine lactams 6-9 via photoinduced ε-hydrogen ion followed by cyclization of the corresponding 1,6-biradicals is described. A highly asymmetric 1,4-induction is observed.

Full text of DOI:10.1016/S0957-4166(98)00472-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4459–4473
Synthesis of ornithine lactams via diastereoselective
photocyclization of 2-amino-4-oxo-4-phenyl-butanoyl amines
Ute Lindemann, Dirk Wulff-Molder and Pablo Wessig ∗
Institut für Chemie, Humboldt-Universität zu Berlin, Hessische Strasse 1-2, D-10115 Berlin, Germany
Received 2 November 1998; accepted 23 November 1998
Abstract
The diastereoselective synthesis of ornithine lactams 6–9 via photoinduced ε-hydrogen abstraction followed
by cyclization of the corresponding 1,6-biradicals is described. A highly asymmetric 1,4-induction is observed.
© 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
In recent years, diastereoselective photocyclization reactions have been developed as key steps in the
synthesis of biologically interesting compounds.1–4 The advantage of such ring closure reactions is the
formation of a C–C bond, possibly along with two new asymmetric centers.
In an earlier report, we described the cyclization of 4-oxo-4-phenyl-butanoyl amines to δ-lactams
via photoinduced hydrogen abstraction from the ε-position.5 Herein we report the synthesis of N-
protected (ꢀ)-2-amino- and (S)-2-amino-4-oxo-4-phenyl-butanoyl amines and their diastereoselective
photocyclization to ornithine lactams. The interest in mono- and bicyclic ornithine lactams has grown in
recent years owing to their utility as β-turn mimetics in peptide chemistry.6–8
2. Results and discussion
2.1. Synthesis of (ꢀ)-2-trifluoroacetylamino- and (S)-2-benzyloxycarbonylamino-4-oxo-4-phenyl-
butanoyl amines 3 and 7
Trifluoroacetyl-protected amino acid 1 was synthesized in two steps, starting with L-aspartic acid
according to the literature.9–11 The appropriate amides 3 were afforded via the in situ generated acid
∗
Corresponding author. E-mail: pablo=wessig@rz.hu-berlin.de
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00472-8

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chloride12 (Eq. 1, Table 1) and under these conditions complete racemization occurs presumably as a
result of the base-induced formation of a 5-oxo-1,3-oxazole from the acid chloride.13,14
(1)
Table 1
Isolated yields of amides (ꢀ)-3 and (S)-5
We therefore decided to change the protecting group of amides 3. The deprotection of acid 1 with
NaOH to afford the known β-benzoylalanine 415 could be accomplished in gram amounts (Eq. 2).
Compound 4 was then protected with benzyloxycarbonyl chloride, followed by coupling with amines
2, using TBTU16 (Eq. 2, Table 1). Amides 5 were afforded with enantiomeric excesses >95%.
(2)
2.2. Photocyclization of amides 3 and 5 to ornithine lactams 6–9
For the following stage, we turned our attention to the investigation of the photocyclization of amides
3 and 5. Irradiation of these compounds yielded the corresponding ornithine lactams 6–9 as a result of
an intramolecular ε-hydrogen abstraction (Eqs. 3 and 4). Remarkably, this reaction yields in both cases
only two (6 and 7; 8 and 9) of the four possible diastereomers. Ornithine lactams 6 and 8 are the major
products (Table 2).
(3)

U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
4461
(4)
Table 2
Yields* and diastereoselectivities of ornithine lactams 6–9
The amine substituent in reactants 3 and 5 effects a 1,4-induction on the newly formed stereocenter
at the bridge head carbon atom of bicyclic products 6–9. Thus, the methine proton on this carbon atom
assumes a trans-position in relation to the protected amino groups in all photoproducts. The influence of
1,3-induction on the formation of the second new stereocenter is only moderate.
The relative configuration of products 6 and 7 and the absolute configuration of bicyclic compounds 8
and 9 were assigned by coupling constants in the 1H NMR spectra and by NOE experiments. Coupling
constants between HA and HB (9.4–13.2 Hz) and between HA and HC (3.0–7.0 Hz) indicate that proton
HA assumes a pseudo-axial position at the 6-ring. The results of NOE experiments are summarized in
Fig. 1. Indeed, an NOE effect between protons HA and HC was observed for all ornithine lactams 6–9.
The broken line marks a small NOE effect between the aromatic ortho-protons with HD of products 6
and 8. This is smaller than that found with HB of these compounds.
Figure 1. Observed NOE effects of ornithine lactams 6–9*
Additionally, the structure of product 6b was established by X-ray analysis of compound 10 (Fig. 2),
which was obtained after removal of the Tfa-group using NaBH4.17 The investigated crystal contained
only one enantiomer (space group: P212121). The small distance (2.33 Å) between H19 and H27 in the X-
ray structure of 10 explains the NOE effect between the similiar protons HA and HD, which was observed
for all ornithine lactams 6–9.

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Figure 2. X-Ray structure of deprotected amine derivative 10
Possible conformations of the triplet 1-hydroxyl-1,6-biradicals, which are formed by ε-hydrogen
abstraction after irradiation, were calculated in order to explain the observed diastereoselectivities of the
photocyclization. Fig. 3, shows the calculated structure of a low energy conformer of the biradical, which
reflects convenient conditions for cyclization. The calculation was performed with the MM+ force field
(Hyperchem). As seen in Fig. 3, a hydrogen bond between the hydroxyl group and the carbonyl oxygen
atom of the amino-protecting group was found (formyl group was used to simplify the calculations). Its
distance was calculated as 2.2 Å.
Products 6–9 were formed by combination of the two radical centers I and II from the Re-site.
Presumably, the reason for this exclusive selectivity is the preferred conformation, as shown in Fig. 3,
around the C–C bond between the stereogenic center and the amide carbon atom (black marked bond).
The hydrogen atom H-2, the smallest substituent at the stereocenter, prefers a syn-orientation to H-1.
This conformation involves the smallest amount of unfavorable steric interactions.
The conformational analysis of the N-alanyl-pyrrolidine-2-yl radical used as a model system, per-
formed on a semi-empirical level (UHF/PM3), confirms that the energetically preferred conformer is
characterized by a syn-orientation of the hydrogen atoms H-4 and H-5. The structure shown in Fig. 4
corresponds to the global minimum with a dihedral angle (N–C–C–N) of 150°.
The formation of both possible products 6 and 7/8 and 9 by radical combination from the Re-site
can be explained by two contradictory effects. The intramolecular hydrogen bond can influence the
diastereoselectivity of radical combination. The major products 6 and 8 are formed from the biradical
conformation with the hydrogen bridge shown in Fig. 3.
In contrast, in these cases the steric hindrance between the hydrogen atom H-3 opposite the radical
center I and the phenyl ring at the radical center II influences the cyclization (see Fig. 3). We have
already discussed such an effect for the diastereoselective photocyclization of 4-oxo-4-phenyl-butanoyl

U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
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Figure 3. Calculated structure of 1,6-biradical
Figure 4. Calculated structure and conformational analysis of N-alanyl-pyrrolidine-2-yl radical

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U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
amines.5 The steric repulsion during the formation of the C–C bond is smaller if the hydrogen atom
H-3 interacts with the smaller hydroxyl group as opposed to the aromatic moiety. This steric interaction
could be the force for breaking of the hydrogen bridge and rotation around the C–C bond between the
radical center II and the neighboring CH2 group to yield ornithine lactams 7 and 9. Thus, the observed
diastereoselectivities show that the calculated intramolecular hydrogen bond does not completely offset
the steric shielding of the radical center I by the opposite hydrogen H-3.
In conclusion, we have reported the photocyclization of 2-amino-4-oxo-4-phenyl-butanoyl amines 3
and 5, affording diastereoselectively ornithine lactams 6–9. The effective asymmetric 1,4-induction is
explained with a preferred conformation of the corresponding 1,6-biradicals, which is caused by the
dominant influence of the amino-substituents.
3. Experimental
TLC was performed on alumina sheets with silica gel 60 F254 (Merck), detected by UV light. Silica
gel 40–63 µm (Merck) and a mobile phase of dichloromethane:methanol (v/v) were used for flash
chromatography (FC). High-pressure liquid chromatography (HPLC) was performed on an analytical
SIX [NH2] column (150×3.3 mm, 5 µm, Laboratorni Pristroje) under the following conditions: flow 1
ml/min, mobile phase n-hexane:2-propanol, 95:5 (v/v), UV detection at 220 and 230 nm. Enantiomeric
excesses of amines 3b and 5b were determined on an OD-Chiralcel column (Daicel), detected by
Chiralizer (IBZ Messelektronik). The uncorrected melting points (m.p.s) were determined on a Boetius
micro melting point apparatus (Wagema). IR spectra were taken with a Perkin–Elmer 881 (solids as KBr
pellets, oils on NaCl plates). NMR spectra were recorded with a Bruker DPX300 (1H 300 MHz, 13C 75.5
MHz), using SiMe4 as an internal standard (0 ppm). EI-mass spectra were taken with a Hewlett Packard
5995 A, 70 eV at 293–593 K.
3.1. General procedure for the synthesis of 2-trifluoroacetylamino-4-oxo-4-phenyl-butanoyl amines 3
(S)-2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoic acid 19–11 (20.0 mmol) dissolved in dried
CH2Cl2 (100 ml) was treated with Na2CO3 (32.0 mmol) at 0°C. A solution of dichloromethylmethyl-
ether (25.0 mmol) in dried CH2Cl2 (20 ml) was added at this temperature. After stirring for 2.5 h at 0°C,
the amine 2 (40.0 mmol), dissolved in CH2Cl2 (20 ml), was added dropwise to the reaction mixture. The
solution was stirred for 12 h at room temperature, then the precipitate was filtered off. The filtrate was
washed with water, with diluted HCl, again with water, with saturated NaHCO3 solution and again with
water. Products 3 were afforded by flash chromatography after drying the organic layer over MgSO4 and
removal of the solvent in vacuo.
3.1.1. 2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoyl azetidine 3a
(S)-2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoic acid 19–11 (1.00 g, 3.63 mmol) was treated with
an ethanolic solution of azetidine 2a, which was afforded by stirring of azetidine hydrochloride (0.42 g,
4.54 mmol) with t-BuOK (0.50 g, 4.54 mmol) in absolute ethanol (50 ml) for 30 min. Purification by FC
(CH2Cl2:MeOH, 10:1) afforded 3a (Rf=0.55) as a white solid (524 mg, 44%).
M.p.=104–106°C; IR (KBr): ν=3227, 1723, 1678, 1635, 1211, 1186, 1156 cm−1; 1H NMR (300 MHz,
CDCl3): δ=8.24 (m, 1H, NH), 7.98–7.35 (m, 5H, arom. H), 5.11–5.03 (m, 1H, 2-CH), 4.66–4.40 (m,
2H), 4.12–4.98 (m, 2H), 3.72 (dd, J=8.9, 17.7, 1H, 3-CHAHB), 3.39 (dd, J=4.1, 17.7, 1H, 3-CHAHB),
2.40–2.30 (m, 2H, CH2); 13C NMR (75.5 MHz, CDCl3): δ=196.8 (s, C-1), 169.1 (s, C-4), 157.0 (q,

U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
4465
CF3), 135.8 (s, arom. C), 133.7, 128.7, 128.0 (d, arom. CH), 51.1 (t, N–CH2), 48.3 (t, N–CH2), 45.1 (d,
C-2), 40.3 (t, C-3), 15.3 (t, CH2); MS (EI, 70 eV): m/z (%)=328 (1), [M+] 105 (74), [{CO–Ph}+] 84 (58),
[{CO–azetidinyl}+] 77 (55), [Ph+] 69 (14), 56 (100) [{azetidinyl}+]. Anal. calcd for C15H15N2O3F3: C
54.88, H 4.61, N 8.53; found: C 55.31, H 4.95, N 8.17.
3.1.2. 2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoyl pyrrolidine 3b
The reaction of (S)-2-trifluoroacetylamino-4-oxo-4-phenyl-butanoic acid 19–11 (5.50 g, 20.0 mmol)
with pyrrolidine 2b (2.06 ml, 25.0 mmol) yielded after FC (CH2Cl2:MeOH, 100:3) 3b (Rf=0.46,
CH2Cl2:MeOH, 100:4) as a white solid (3.86 g, 66%).
M.p.=141–143°C; UV/vis (MeCN): λmax (lg ε)=242.0 (4.16), 278.5 (3.05), 318.5 (2.28); IR (KBr):
ν=3223, 1715, 1679, 1627, 1201, 1185, 1167, 1153 cm−1; 1H NMR (300 MHz, CDCl3): δ=8.22–8.14 (m,
1H, NH), 7.98–7.38 (m, 5H, arom. H), 5.37–5.30 (m, 2H, 2-CH), 3.93–3.67 (m, 3H, CH2–N–CHAHB),
3.49–3.38 (m, 3H, N–CHAHB, 3-CH2), 2.07–1.84 (m, 4H, 2×CH2); 13C NMR (75.5 MHz, CDCl3):
δ=196.7 (s, C-1), 168.0 (s, C-4), 156.7 (q, CF3), 136.0 (s, arom. C), 133.6, 128.7, 128.0 (d, arom.
CH), 47.9 (d, 2-C), 46.9 (t, N–CH2), 46.4 (t, N–CH2), 41.0 (t, C-3), 25.9 (t, CH2), 24.1 (t, CH2); MS
(EI, 70 eV): m/z (%)=342 (0), [M+] 244 (0.5), [M+−{CO–pyrrolidinyl}] 105 (48), [{CO–Ph}+] 98 (79),
[{CO–pyrrolidinyl}+] 77 (60), [Ph+] 70 (100) [{pyrrolidinyl}+]. Anal. calcd for C16H17N2O3F3: C 56.14,
H 5.01, N 8.18; found: C 56.40, H 4.50, N 8.10.
3.1.3. 2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoyl piperidine 3c
(S)-2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoic acid 19–11 (1.50 g, 5.45 mmol) was treated with
piperidine 2c (0.67 ml, 6.81 mmol). Purification by FC (CH2Cl2:MeOH, 100:4) gave 3c (Rf=0.50) as a
white solid (1.38 g, 71%).
1
M.p.=137–139°C; IR (KBr): ν=1719, 1684, 1622, 1211 cm−1; H NMR (300 MHz, CDCl3):
δ=8.04–7.42 (m, 6H, arom. H, NH), 5.52 (dt, J=5.2, 7.8, 1H, 2-CH), 3.66–3.44 (m, 5H, CH2–N–CH2,
3-CHAHB), 3.39 (dd, J=5.2, 17.1, 1H, 3-CHAHB), 1.84–1.44 (m, 6H, 3×CH2); 13C NMR (75.5 MHz,
CDCl3): δ=196.5 (s, C-1), 167.7 (s, C-4), 156.7, 156.2 (q, CF3), 136.1 (s, arom. C), 133.7, 128.7, 128.1
(d, arom. CH), 47.1 (t, N–CH2), 46.0 (d, C-2), 43.8 (t, N–CH2), 41.1 (t, C-3), 26.2 (t, CH2), 25.4 (t,
CH2), 24.3 (t, CH2); MS (EI, 70 eV): m/z (%)=356 (0.6), [M+] 112 (100), [{CO–piperidinyl}+] 105 (52),
[{CO–Ph}+] 84 (64), [{piperidinyl}+] 77 (52), [Ph+] 69 (75).
3.1.4. 2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoyl azepanine 3d
Reaction of (S)-2-trifluoroacetylamino-4-oxo-4-phenyl-butanoic acid 19–11 (1.50 g, 5.45 mmol) with
hexamethylenimine 2d (0.77 ml, 6.81 mmol), followed by FC (CH2Cl2:MeOH, 100:4), afforded 3d
(Rf=0.52) as a white solid (972 mg, 48%).
M.p.=132–134°C; IR (KBr): ν=3230, 1717, 1685, 1620, 1212, 1183, 1156 cm−1; 1H NMR (300 MHz,
CDCl3): δ=7.98–7.39 (m, 5H, arom. H), 7.80 (d, J=8.7, 1H, NH), 5.50 (dt, J=5.3, 8.1, 1H, 2-CH),
3.79–3.55 (m, 4H), 3.45–3.37 (m, 2H), 1.93–1.51 (m, 8H, 4×CH2); 13C NMR (75.5 MHz, CDCl3):
δ=196.5 (s, C-1), 169.2 (s, C-4), 156.7, 156.2 (q, CF3), 136.2 (s, arom. C), 133.6, 128.7, 128.1 (d, arom.
CH), 48.1 (t, N–CH2), 46.8 (t, N–CH2), 46.4 (d, C-2), 41.3 (t, C-3), 28.8 (t, CH2), 27.2 (t, CH2), 27.1
(t, CH2), 26.5 (t, CH2); MS (EI, 70 eV): m/z (%)=370 (3), [M+] 265 (22), [M+–{CO–Ph}] 126 (100),
[{CO–azepanyl}+] 105 (51), [{CO–Ph}+] 98 (45), [{azepanyl}+] 83 (18), 77 (39), [Ph+] 55 (60).

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3.2. (S)-2-Amino-4-oxo-4-phenyl-butanoic acid 4
(S)-2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoic acid 19–11 (35.13 g, 122 mmol) was stirred with
NaOH (12.15 g, 305 mmol) in water (400 ml) for 4 h. At 0°C the mixture was acidified with HCl:water
(1:10) to pH=4. The precipitate was filtered off. This procedure was repeated and the precipitate collected.
After drying the white solid, 415 (30.8 g, 80%) was afforded (Rf=0.62, EtOH:H2O:NH3, 20:5:2).
M.p.=60–62°C; [α]D20 +4.6 (c 1, H2O); IR (KBr): ν=3518, 3450, 1684, 1623, 1596, 1411, 1349 cm−1;
1H NMR (300 MHz, D2O): δ=7.93–7.45 (m, 5H, arom. H), 4.11–4.08 (m, 1H, 2-H), 3.69–3.66 (m, 2H,
3-CH2); 13C NMR (75.5 MHz, D2O): δ=205.9 (s, C-4), 174.1 (s, CO), 170.6 (s, CO), 135.7 (s, arom. C),
134.9, 129.3, 128.6 (d, arom. CH), 50.8 (d, C-2), 39.0 (t, C-3); MS (EI, 70 eV): m/z (%)=193 (0), [M+]
105 (100), [{CO–Ph}+] 77 (69), [Ph+] 51 (40), 44 (58).
3.3. (S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoic acid 11
NaOH (5.40 g, 5% excess) was dissolved in water (120 ml) and (S)-2-amino-4-oxo-4-phenyl-butanoic
acid 415 (12.0 g, 62.2 mmol) was added followed by benzyloxycarbonylchloride (9.60 ml, 57.1 mmol)
at 0°C. The mixture was stirred for 48 h at room temperature. Ethyl acetate was then added. The non-
separated water layer was treated with 9 N aq. HCl until no precipitate formed. The organic layer was
separated, dried over MgSO4 and the solvent removed under reduced pressure. Product 11 (15.2 g, 75%)
was isolated as viscous oil.
[α]D20 +44.9 (c 1, CH2Cl2); IR (KBr): ν=3544, 3067, 3033, 1723, 1689, 1521, 1509, 1215, 1064, 755,
1
688 cm−1; H NMR (300 MHz, CDCl3): δ=10.01 (s, 1H, OH), 7.93–7.31 (m, 10H, arom. H), 5.99 (d,
J=8.3, 1H, NH), 5.09 (s, 2H, Ph–CH2), 4.82–4.79 (m, 1H, 2-CH), 3.76 (dd, J=3.8, 18.1, 1H, CHAHB),
3.56 (dd, J=3.8, 18.1, 1H, CHAHB); 13C NMR (75.5 MHz, CDCl3): δ=197.7 (s, C-4), 176.1 (s, C-1),
156.3 (s, COO), 135.9, 135.7 (s, arom. C), 133.8, 128.7, 128.5, 128.2, 128.1, 128.0 (d, arom. CH), 67.2
(t, Ph–CH2), 49.8 (d, C-2), 40.7 (t, C-3); MS (EI, 70 eV): m/z (%)=327 (0), [M+] 305 (0.3), 108 (48), 107
(31), 105 (100), [{CO–Ph}+] 91 (92), [{CH2–Ph}+] 79 (95), 77 (91), [Ph+] 65 (21), 51 (49).
3.4. General procedure for the synthesis of 2-benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl amines
5
(S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoic acid 4 (4.00 mmol), TBTU (4.40 mmol) and
EtN(i-Pr)2 (8.00 mmol or 12.0 mmol in the case of amine hydrochloride) were stirred in CH2Cl2 (25 ml)
at 0°C for 15 min. Then amine 2 (4.00 mmol) in 10 ml solvent was added dropwise. After stirring for
0.5–4 h, the reaction mixture was washed with citric acid in water (3×), with water (1×), with saturated
NaHCO3 solution (3×) and with water (1×). The organic layer was dried over MgSO4. Removal of the
solvent in vacuo followed by purification by FC afforded amide 5.
3.4.1. (S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl azetidine 5a
The reaction of (S)-2-benzyloxycarbonylamino-4-oxo-4-phenyl-butanoic acid 11 (1.42 g, 4.33 mmol)
with azetidine hydrochloride 2a·HCl (0.40 g, 4.33 mmol) gave, after purification by FC (Rf=0.22,
CH2Cl2:MeOH, 100:4), product 5a (50 mg, 8%) as a viscous oil.
[α]D20 −12.0 (c 0.5, CH2Cl2); IR (KBr): ν=3421, 1719, 1682, 1651, 1634 cm−1; 1H NMR (300 MHz,
CDCl3): δ=7.95–7.30 (m, 10H, arom. H), 5.65 (d, J=9.0, 1H, NH), 5.10 (s, 2H, Ph–CH), 4.86–4.78 (m,
1H, 2-CH), 4.52–4.42 (m, 2H), 4.52–4.42 (m, 2H), 3.51 (dd, J=7.9, 17.3, 1H, 3-CHAHB), 3.40 (dd, J=4.1,
17.3, 1H, 3-CHAHB), 2.33–2.26 (m, 2H, CH2); 13C NMR (75.5 MHz, CDCl3): δ=197.6 (s, C-1), 170.4

U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
4467
(s, C-4), 136.3 136.2 (s, arom. C), 133.5, 128.6, 128.5, 128.2, 128.1 (d, arom. CH), 67.0 (t, Ph–CH2), 51.0
(t, N–CH2), 48.2 (t, N–CH2), 46.9 (d, C-2), 41.3 (t, C-3), 15.4 (t, CH2); MS (EI, 70 eV): m/z (%)=366
(1), [M+] 105 (71), [{CO–Ph}+] 91 (100), [{CH2–Ph}+] 77 (20), [Ph+] 56 (23) [{azetidinyl}+].
3.4.2. (S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl pyrrolidine 5b
(S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoic acid 11 (1.44 g, 4.39 mmol) was treated with
pyrrolidine 2b (0.36 ml, 4.39 mmol), providing, after purification by FC (Rf=0.44, CH2Cl2:MeOH,
100:4), product 5b (1.11 g, 67%) as a viscous oil.
20
[α]D −34.1 (c 1, CH2Cl2); UV/vis (MeCN): λmax (lg ε)=242.0 (4.10), 278.0 (3.00), 311.5 (2.02);
IR (KBr): ν=3262, 1717, 1683, 1628, 1449, 746, 692 cm−1; 1H NMR (300 MHz, CDCl3): δ=8.00–7.26
(m, 10H, arom. H), 5.81–5.66 (m, 1H, NH), 5.09 (m, 3H, 2-CH, Ph–CH2), 3.88–3.58 (m, 3H), 3.44–3.30
(m, 3H), 1.98–1.72 (m, 4H, 2×CH2); 13C NMR (75.5 MHz, CDCl3): δ=197.9 (s, C-1), 169.7 (s, C-4),
156.0 (q, COO), 136.8, 136.6 (s, arom. C), 133.8, 129.0, 128.9, 128.6, 128.5 (d, arom. CH), 67.4 (t,
Ph–CH2), 49.6 (d, C-2), 47.1 (t, N–CH2), 46.5 (t, N–CH2), 42.4 (t, C-3), 26.4 (t, CH2), 24.6 (t, CH2);
MS (EI, 70 eV): m/z (%)=380 (0.4), [M+] 105 (71), [{CO–Ph}+] 98 (24), [{CO–pyrrolidinyl}+] 91 (100),
[{CH2–Ph}+] 77 (16), [Ph+] 70 (48), [{pyrrolidinyl}+] 55 (21).
3.4.3. (S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl piperidine 5c
The reaction of (S)-2-benzyloxycarbonylamino-4-oxo-4-phenyl-butanoic acid 11 (1.01 g, 3.09 mmol)
with piperidine 2c (0.31 ml, 3.09 mmol), followed by purification by FC (Rf=0.31, CH2Cl2:MeOH,
100:4), yielded product 5c (780 mg, 79%) as a viscous oil.
[α]D −25.5 (c 1, CH2Cl2); IR (KBr): ν=3267, 2938, 1715, 1684, 1626, 1448, 691 cm−1; 1H NMR
20
(300 MHz, CDCl3): δ=7.97–7.27 (m, 10H, arom. H), 5.89–5.83 (m, 1H, NH), 5.33–5.28 (m, 1H, 2-
CH), 5.08 (s, 2H, Ph–CH2), 3.69–3.48 (m, 5H, CH2–N–CH2, 3-CHAHB), 3.29 (dd, J=4.5, 17.0, 1H,
3-CHAHB), 1.72–1.45 (m, 6H, 3×CH2); 13C NMR (75.5 MHz, CDCl3): δ=197.3 (s, C-1), 163.1 (s, C-
4), 155.5 (q, COO), 136.4, 136.2 (s, arom. C), 133.2, 128.5, 128.4, 128.1, 128.0 (d, arom. CH), 66.9
(t, Ph–CH2), 47.1 (d, C-2), 47.0 (d, N–CH2), 43.5 (t, N–CH2), 41.9 (t, C-3), 26.2 (t, CH2), 25.5 (t,
CH2), 24.4 (t, CH2); MS (EI, 70 eV): m/z (%)=394 (0.5), [M+] 112 (23), [{CO–piperidinyl}+] 105 (79),
[{CO–Ph}+] 91 (100), [{CH2–Ph}+] 84 (42), [{piperidinyl}+] 77 (20), [Ph+] 69 (22).
3.4.4. (S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl azepanine 5d
(S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoic acid 11 (1.24 g, 3.78 mmol) was treated with
hexamethylenimine 2d (0.43 ml, 3.78 mmol). Purification by FC (Rf=0.42, CH2Cl2:MeOH, 100:4) gave
product 5d (1.23 g, 80%) as a viscous oil.
[α]D20 −28.8 (c 1, CH2Cl2); IR (KBr): ν=3412, 3266, 2928, 1715, 1683, 1626, 1284, 1241, 1213 cm−1;
1H NMR (300 MHz, CDCl3): δ=8.03–7.26 (m, 10H, arom. H), 6.01 (d, J=9.4, 1H, NH), 5.37–5.22 (m,
1H, 2-CH), 5.08 (s, 2H, Ph–CH2), 3.85–3.40 (m, 5H, 2×N–CH2, 3-CHAHB), 3.29 (dd, J=4.5, 17.3, 1H,
3-CHAHB), 2.01–1.48 (m, 8H, 4×CH2); 13C NMR (75.5 MHz, CDCl3): δ=197.3 (s, C-1), 170.6 (s, C-4),
155.5 (q, COO), 136.3, 136.2 (s, arom. C), 133.1, 128.4, 128.3, 128.0 (d, arom. CH), 66.9 (CH2–Ph),
47.9 (t, N–CH2), 47.3 (d, C-2), 46.3 (t, N–CH2), 42.1 (t, C-3), 28.7 (t, CH2), 27.2 (t, CH2), 26.9 (t,
CH2), 26.6 (t, CH2); MS (EI, 70 eV): m/z (%)=408 (0.4), [M+] 126 (13), [{CO–azepanyl}+] 105 (69),
[{CO–Ph}+] 98 (28), [{azepanyl}+] 91 (100), [{CH2–Ph}+] 77 (17), [Ph+] 53 (28).

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3.5. General procedure for the photocyclization of amides 3 and 5
Irradiation of amides 3 and 5 was performed in dichloromethane with concentrations of nearly 1
mg/ml, using a 150 W high pressure mercury arc lamp. The solutions were degassed with argon
for 30 min before irradiation, and stirred during irradiation. The products were separated by flash
chromatography.
3.5.1. (3S,5R,5aR)-(ꢀ)-3-Trifluoroacetylamino-5-hydroxy-5-phenyl-1-aza-bicyclo[4.2.0]octan-2-one
6a and (3S,5S,5aR)-(ꢀ)-3-trifluoroacetylamino-5-hydroxy-5-phenyl-1-aza-bicyclo[4.2.0]octan-2-one
7a
Irradiation of 2-trifluoroacetylamino-4-oxo-4-phenyl-butanoyl azetidine 3a (83 mg, 0.25 mmol) was
performed in dichloromethane (120 ml). Purification by FC (CH2Cl2:MeOH, 100:3) yielded 6a (29 mg,
35%), 9 mg (11%) of 7a and a mixture of 6a and 7a (18 mg, 22%) as white solids.
6a: m.p.=50–52°C; IR (KBr): ν=3394, 1723, 1712, 1701, 1685, 1673, 1669, 1653, 1642, 1172, 1164
cm−1; 1H NMR (300 MHz, CDCl3): δ=7.72 (s, 1H, NH), 7.35–7.21 (m, 5H, arom. H), 4.83–4.71 (m, 2H,
3-H, 5a-H), 3.86–3.81 (m, 2H, 7-CH2), 2.73 (dd, J=4.0, 13.2, 1H, 4-CHAHB), 2.31 (dd, J=12.4, 13.2,
1H, 4-CHAHB), 1.87–1.69 (m, 3H, OH, 6-CH2); 13C NMR (75.5 MHz, CDCl3): δ=169.6 (s, C-2), 141.4
(s, arom. C), 128.7, 128.3, 125.2 (d, arom. CH), 74.2 (s, C-5), 73.1 (d, C-5a), 48.6 (t, C-7), 47.2 (d, C-3),
38.4 (t, CH2), 26.4 (t, CH2); MS (EI, 70 eV): m/z (%)=328 (0.3), [M+] 105 (44), 91 (5), 84 (17), 77 (30),
[Ph+] 69 (14), 56 (100).
7a: m.p.=71–73°C; IR (KBr): ν=3389, 2923, 1721, 1710, 1666, 1659, 1641, 1214, 1183, 1161 cm−1;
1H NMR (300 MHz, CDCl3): δ=7.64 (m, 1H, NH), 7.33–7.24 (m, 5H, arom. H), 4.71 (dd, J=5.6, 8.3,
1H, 5a-H), 4.51–4.45 (m, 1H, 3-H), 4.15–4.09 (m, 1H, 7-CHAHB), 3.94–3.89 (m, 1H, 7-CHAHB), 3.28
(s, 1H, OH), 3.02 (dd, J=10.2, 15.4, 1H, 4-CHAHB), 2.43–2.34 (m, 1H, 6-CHAHB), 2.30–2.22 (m, 1H,
6-CHAHB), 2.14 (dd, J=3.0, 15.4, 1H, 4-CHAHB); 13C NMR (75.5 MHz, CDCl3): δ=171.1 (s, C-2),
140.5 (s, arom. C), 128.7, 128.1, 125.1 (d, arom. CH), 72.5 (s, C-5), 71.4 (d, C-5a), 49.5 (t, C-7), 46.8
(d, C-3), 44.4 (t, C-4), 19.2 (t, CH2); MS (EI, 70 eV): m/z (%)=328 (1), [M+] 105 (59), 91 (9), 84 (13),
77 (31), [Ph+] 69 (17), 56 (100).
3.5.2. (6S,8R,8aR)-(ꢀ)-6-Trifluoroacetylamino-8-hydroxy-8-phenyl-perhydro-indolizin-5-one 6b and
(6S,8S,8aR)-(ꢀ)-6-trifluoroacetylamino-8-hydroxy-8-phenyl-perhydro-indolizin-5-one 7b
2-Trifluoroacetylamino-4-oxo-4-phenyl-butanoyl pyrrolidine 3b (515 mg, 1.50 mmol) was irradiated
in dichloromethane (500 ml). A white solid 6b (282 mg, 55%) and a 1:0.57 mixture of 6b and 7b (109
mg, 21%) were isolated by FC (CH2Cl2:MeOH, 100:3).
1
6b: m.p.=69–71°C; IR (KBr): ν=3377, 1723, 1656, 1214, 1179, 1165 cm−1; H NMR (300 MHz,
CDCl3): δ=7.86 (s, 1H, NH), 7.36–7.29 (m, 5H, arom. H), 4.86–4.78 (m, 1H, 6-H), 3.89 (t, J=7.2, 1H,
8a-H), 3.53–3.34 (m, 3H, 3-CH2, OH), 2.97 (dd, J=6.4, 13.9, 1H, 7-CHAHB), 2.28 (dd, J=11.8, 13.9,
1H, 7-CHAHB), 1.98–1.58 (m, 2H), 1.41–1.22 (m, 2H); 13C NMR (75.5 MHz, CDCl3): δ=167.0 (s, C-5),
143.7 (s, arom. C), 128.3, 127.8, 125.5 (d, arom. CH), 74.5 (s, C-8), 65.9 (d, C-8a), 48.9 (d, C-6), 45.4
(t, C-3), 42.9 (t, C-7), 28.0 (t, CH2), 22.5 (t, CH2); MS (EI, 70 eV): m/z (%)=342 (1), [M+] 105 (12), 77
(12), [Ph+] 70 (100), 28 (12). Anal. calcd for C16H17N2O3F3: C 56.14, H 5.01, N 8.18; found C 55.99,
H 5.06, N 8.02.
7b: 1H NMR (300 MHz, CDCl3): δ=8.05 (s, 1H, NH), 7.49–7.20 (m, 5H, arom. H), 4.72–4.63 (m, 1H,
6-H), 3.93 (t, J=7.3, 1H, 8a-H), 3.69–3.48 (m, 3H, 3-CH2, OH), 3.08 (dd, J=9.4, 15.1, 1H, 7-CHAHB),
2.06 (dd, J=6.4, 15.1, 1H, 7-CHAHB), 1.94–1.53 (m, 4H, 1-CH2, 2-CH2); 13C NMR (75.5 MHz, CDCl3):

U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
4469
δ=166.7 (s, C-5), 143.3 (s, arom. C), 128.2, 124.8 (d, arom. CH), 73.1 (s, C-8), 66.1 (d, C-8a), 48.3 (d,
C-6), 47.0 (t, C-3), 44.4 (t, C-7), 26.3 (t, CH2), 23.0 (t, CH2).
3.5.3. (1R,3S,9aR)-(ꢀ)-3-Trifluoroacetylamino-1-hydroxy-1-phenyl-perhydro-quinolizin-4-one 6c and
(1S,3S,9aR)-3-trifluoroacetylamino-1-hydroxy-1-phenyl-perhydro-quinolizin-4-one 7c
Photoreaction of 2-trifluoroacetylamino-4-oxo-4-phenyl-butanoyl piperidine 3c (207 mg, 0.58 mmol)
in dichloromethane (230 ml) afforded, after purification by FC (CH2Cl2:MeOH, 100:3), a white solid 6c
(109 mg, 53%) and product 7c (30 mg, 15%) as a viscous oil.
1
6c: m.p.=187–190°C; IR (KBr): ν=3462, 1702, 1622, 1211, 1200, 1151 cm−1; H NMR (300 MHz,
CDCl3): δ=7.71–7.66 (m, 1H, NH), 7.39–7.31 (m, 5H, arom. H), 4.83–4.75 (m, 1H, 3-H), 4.65–4.60 (m,
1H, 6-CHAHB), 3.50 (d, J=12.4, 1H, 9a-H), 3.22 (s, 1H, OH), 2.86 (ddd, J=1.1, 5.9, 11.8, 1H, 2-CHAHB),
2.59–2.51 (m, 2H, 6-CHAHB, 2-CHAHB), 1.78–0.88 (m, 6H, 7-CH2, 8-CH2, 9-CH2); 13C NMR (75.5
MHz, CDCl3): δ=165.2 (s, C-4), 157.7 (q, CF3), 143.2 (s, arom. C), 128.7, 128.4, 125.3 (d, arom. CH),
73.2 (s, C-1), 68.4 (d, C-9a), 49.1 (d, C-3), 45.6 (t, C-6), 33.1 (t, C-2), 30.5 (t, CH2), 25.2 (t, CH2), 25.0
(t, CH2); MS (EI, 70 eV): m/z (%)=356 (0.3), [M+] 236 (6), 112 (5), 105 (18), 77 (19), [Ph+] 63 (12), 55
(20). Anal. calcd for C17H19N2O3F3: C 57.31, H 5.38, N 7.82; found: C 56.93, H 5.60, N 6.35.
7c: IR (KBr): ν=3401, 1731, 1620, 1167, 1025 cm−1; 1H NMR (300 MHz, DMSO-d6 ): δ=8.88–8.85
(m, 1H, NH), 7.79–7.27 (m, 5H, arom. H), 5.55 (s, 1H, OH), 4.67–4.62 (m, 1H, 6-CHAHB), 4.08–4.00
(m, 1H, 3-H), 3.71 (dd, 1H, 9a-H), 2.73–2.65 (m, 1H, 6-CHAHB), 2.41–2.38 (m, 2H, 2-CH2), 1.96–1.51
(m, 6H, 7-CH2, 8-CH2, 9-CH2); 13C NMR (75.5 MHz, DMSO-d6): δ=164.2 (s, C-4), 144.0 (s, arom.
C), 128.3, 127.5, 125.6 (d, arom. CH), 70.0 (s, C-1), 64.2 (d, C-9a), 47.8 (d, C-3), 44.1 (t, C-6), 37.0 (t,
C-2), 27.2 (t, CH2), 25.1 (t, CH2), 24.4 (t, CH2); MS (EI, 70 eV): m/z (%)=356 (1), [M+] 236 (9), 105
(19), 84 (100), 77 (16), [Ph+] 69 (13), 66 (52).
3.5.4. (1R,3S,10aR)-(ꢀ)-3-Trifluoroacetylamino-1-hydroxy-1-phenyl-perhydro-pyrido[1,2-a]azepin-
4-one
6d
and
(1S,3S,10aR)-(ꢀ)-3-trifluoroacetylamino-1-hydroxy-1-phenyl-perhydro-pyrido-
[1,2-a]azepin-4-one 7d
Irradiation of 2-trifluoroacetylamino-4-oxo-4-phenyl-butanoyl azepanine 3d (126 mg, 0.34 mmol) in
dichloromethane (120 ml), followed by purification by FC (CH2Cl2:MeOH, 100:3), gave 6d (60 mg,
48%) and 7d (16 mg, 9%) as white solids.
1
6d: m.p.=221–223°C; IR (KBr): ν=3437, 1705, 1620, 1220, 1190, 1154 cm−1; H NMR (300 MHz,
CDCl3): δ=7.92–7.88 (m, 1H, NH), 7.36–7.28 (m, 5H, arom. H), 4.77–4.71 (m, 1H, 3-H), 3.71–3.64
(m, 1H, 6-CHAHB), 3.62 (dd, J=3.4, 11.7, 1H, 10a-H), 3.50–3.42 (m, 1H, 6-CHAHB), 3.30 (s, 1H, OH),
2.80 (dd, J=6.4, 13.6, 1H, 2-CHAHB), 2.48 (dd, J=12.1, 13.6, 1H, 2-CHAHB), 1.96–1.04 (m, 8H, 7-
CH2, 8-CH2, 9-CH2, 10-CH2); 13C NMR (75.5 MHz, CDCl3): δ=168.3 (s, C-4), 157.6, 157.1 (q, CF3),
143.7 (s, arom. C), 128.5, 127.9, 125.3 (d, arom. CH), 74.5 (s, C-1), 68.5 (d, C-10a), 49.1 (d, C-3), 46.2
(t, C-6), 38.4 (t, C-2), 30.5 (t, CH2), 27.8 (t, CH2), 27.2 (t, CH2), 26.6 (t, CH2); MS (EI, 70 eV): m/z
(%)=370 (9), [M+] 265 (25), 250 (10), 126 (11), 105 (22), 98 (100), 77 (23), [Ph+] 69 (18). Anal. calcd
for C18H21N2O3F3: C 58.37, H 5.72, N 7.56; found: C 57.75, H 5.48, N 7.34.
1
7d: m.p.=66–68°C; IR (KBr): ν=3369, 1718, 1640, 1212, 1187, 1163 cm−1; H NMR (300 MHz,
CDCl3): δ=7.86–7.80 (m, 1H, NH), 7.49–7.27 (m, 5H, arom. H), 4.79–4.68 (m, 1H, 3-H), 4.63–4.56 (m,
1H, 6-CHAHB), 3.64 (dd, J=3.2, J=11.4, 1H, 10a-H), 3.23 (dd, J=7.0, 14.0, 1H, 2-CHAHB), 3.10–3.02
(m, 1H, 6-CHAHB), 2.30 (s, 1H, OH), 2.22–2.16 (m, 1H), 1.89–1.11 (m, 8H, 2-CHAHB); 13C NMR (75.5
MHz, CDCl3): δ=169.0 (s, C-4), 144.8 (s, arom. C), 128.7, 127.6, 124.6 (d, arom. CH), 67.0 (d, C-3),
49.1 (d, C-10a), 45.6 (t, C-2), 43.6 (t, C-6), 30.0 (t, CH2), 29.1 (t, CH2), 27.9 (t, CH2), 25.1 (t, CH2);

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U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
MS (EI, 70 eV): m/z (%)=370 (2), [M+] 265 (10), 126 (19), 105 (45), 98 (100), 82 (18), 77 (45), [Ph+]
68 (31).
3.5.5. (3S,5R,5aR)-3-Benzyloxycarbonylamino-5-hydroxy-5-phenyl-1-aza-bicyclo[4.2.0]octan-2-one
8a and (3S,5S,5aR)-3-benzyloxycarbonylamino-5-hydroxy-5-phenyl-1-aza-bicyclo[4.2.0]octan-2-one
9a
(S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl azetidine 5a (100 mg, 0.27 mmol) was irra-
diated in dichloromethane (120 ml). Purification by FC (CH2Cl2:MeOH, 100:2) afforded products 8a (30
mg, 30%), 9a (10 mg, 10%) and a 2:1 mixture of 8a and 9a (20 mg, 20%) as viscous oils.
20
1
8a: [α]D +78.5 (c 0.5, CH2Cl2); IR (NaCl): ν=3399, 1716, 1650, 1216, 699 cm−1; H NMR (300
MHz, CDCl3): δ=7.44–7.32 (m, 10H, arom. H), 6.12 (d, J=4.9, 1H, NH), 4.97 (s, 2H, Ph–CH2),
4.81–4.87 (m, 1H, 5a-H), 4.69–4.62 (m, 1H, 3-H), 3.87–3.82 (m, 2H, 7-CH2), 3.45–3.42 (m, 1H, OH),
2.73 (dd, J=4.1, 13.6, 1H, 4-CHAHB), 2.35 (dd, J=12.6, 13.6, 1H, 4-CHAHB), 1.86–1.73 (m, 2H, 6-
CH2); 13C NMR (75.5 MHz, CDCl3): δ=171.0 (s, C-2), 155.9 (s, CO–O), 142.1, 136.3 (s, arom. C),
128.6, 128.5, 128.3, 128.1, 128.0, 125.4 (d, arom. CH), 74.3 (s, C-5), 72.8 (d, C-5a), 66.8 (t, Ph–CH2),
48.2 (t, C-7), 47.8 (d, C-3), 40.4 (t, C-4), 26.0 (t, C-6); MS (EI, 70 eV): m/z (%)=366 (1), [M+] 105 (45),
91 (100), [{Ph–CH2}+] 77 (18), [Ph+] 65 (13), 56 (71).
9a: [α]D +11.4 (c 0.2, CH2Cl2); IR (NaCl): ν=3401, 2925, 1706, 1651 cm−1; 1H NMR (300 MHz,
20
CDCl3): δ=7.46–7.29 (m, 10H, arom. H), 5.89 (d, J=6.0, 1H, NH), 5.12 (s, 2H, Ph–CH2), 4.74–4.69
(m, 1H, 5a-H), 4.28–4.16 (m, 2H, 3-H, 7-CHAHB), 3.96–3.88 (m, 2H, OH, 7-CHAHB), 2.99 (dd, J=4.7,
15.4, 1H, 4-CHAHB), 2.51–2.44 (m, 1H, 6-CHAHB), 2.31 (dd, J=1.4, 15.4, 1H, 4-CHAHB), 2.19–2.13
(m, 1H, 6-CHAHB); 13C NMR (75.5 MHz, CDCl3): δ=172.2 (s, C-2), 156.8 (s, CO–O), 141.5, 136.1 (s,
arom. C), 128.6, 128.5, 127.8, 125.4 (d, arom. CH), 72.0 (s, C-5), 71.6 (d, C-5a), 67.0 (t, Ph–CH2), 49.4
(t, C-7), 45.0 (t, C-4), 38.6 (d, C-3), 18.9 (t, C-6); MS (EI, 70 eV): m/z (%)=366 (8), [M+] 148 (11), 105
(62), 91 (100), [{Ph–CH2}+] 77 (21), [Ph+] 65 (14), 56 (99).
3.5.6. (6S,8R,8aR)-6-Benzyloxycarbonylamino-8-hydroxy-8-phenyl-perhydro-indolizin-5-one 8b and
(6S,8S,8aR)-6-benzyloxycarbonylamino-8-hydroxy-8-phenyl-perhydro-indolizin-5-one 9b
Photocyclization of (S)-2-benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl pyrrolidine 5b (440 mg,
1.16 mmol) was performed in dichloromethane (500 ml). White solids 8b (110 mg, 25%), 9b (20 mg,
5%) and a 3:1 mixture of 8b and 9b (123 mg, 28%) were isolated by FC (CH2Cl2:MeOH, 100:2).
8b: m.p.=57–58°C; [α]D20 +121.7 (c 1, CH2Cl2); IR (KBr): ν=3396, 1708, 1653, 1453 cm−1; 1H NMR
(300 MHz, CDCl3): δ=7.35–7.26 (m, 10H, arom. H), 6.17 (d, J=4.9, 1H, NH), 5.03 (s, 2H, Ph–CH2),
4.71–4.63 (m, 1H, 6-H), 3.89–3.85 (m, 1H, 8a-H), 3.70 (s, 1H, OH), 3.47–3.34 (m, 2H, 3-CH2), 2.90
(dd, J=6.6, 14.1, 1H, 7-CHAHB), 2.26 (dd, J=11.9, 14.1, 1H, 7-CHAHB), 1.83–1.72 (m, 1H, 1-CHAHB),
1.61–1.50 (m, 1H, 2-CHAHB), 1.40–1.29 (m, 1H, 1-CHAHB), 1.22–1.12 (m, 1H, 2-CHAHB); 13C NMR
(75.5 MHz, CDCl3): δ=168.4 (s, C-5), 156.2 (s, CO–O), 144.3, 136.3 (s, arom. C), 128.5, 128.1, 128.0,
127.9, 127.4, 125.7 (d, arom. CH), 74.6 (s, C-8), 66.9 (t, Ph–CH2), 65.5 (d, C-8a), 49.7 (d, C-6), 45.2
(t, C-7, C-3), 27.7 (t, CH2), 22.7 (t, CH2); MS (EI, 70 eV): m/z (%)=380 (0.1), [M+] 105 (22), 91 (37),
[{Ph–CH2}+] 77 (10), [Ph+] 70 (100).
20
9b: m.p.=50–52°C; [α]D +12.0 (c 0.5, CH2Cl2); IR (KBr): ν=3410, 1714, 1701, 1652, 1641 cm−1;
1H NMR (300 MHz, CDCl3): δ=7.55–7.25 (m, 10H, arom. H), 6.13 (d, J=6.0, 1H, NH), 5.11 (s, 2H,
Ph–CH2), 4.35–4.27 (m, 1H, 6-H), 3.86–3.81 (m, 2H, 8a-H, OH), 3.59, 3.55 (m, 2H, 2-CH2), 3.02
(dd, J=9.8, 15.1, 1H, 7-CHAHB), 2.08 (dd, J=6.0, 15.1, 1H, 7-CHAHB), 1.95–1.84 (m, 2H), 1.78–1.67
(m, 1H), 1.59–1.50 (m, 1H, 1-CHAHB); 13C NMR (75.5 MHz, CDCl3): δ=168.0 (s, C-5), 156.8 (s,
CO–O), 144.1, 136.2 (s, arom. C), 128.5, 128.4, 128.1, 127.3, 125.0 (d, arom. CH), 72.7 (s, C-8), 67.1 (t,

U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
4471
Ph–CH2), 66.0 (d, C-8a), 49.4 (d, C-6), 46.9 (t, C-7), 45.6 (t, C-3), 26.3 (t, CH2), 23.1 (t, CH2); MS (EI,
70 eV): m/z (%)=380 (0.2), [M+] 105 (24), 91 (39), [{Ph–CH2}+] 77 (9), [Ph+] 70 (100).
3.5.7. (1R,3S,9aR)-3-Benzyloxycarbonylamino-1-hydroxy-1-phenyl-perhydro-quinolizin-4-one 8c and
(1S,3S,9aR)-3-benzyloxycarbonylamino-1-hydroxy-1-phenyl-perhydro-quinolizin-4-one 9c
(S)-2-Benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl piperidine 5c (527 mg, 1.34 mmol) was
irradiated in dichloromethane (500 ml). Purification by FC (twice, CH2Cl2:MeOH, 100:2 and 100:1)
yielded white solids 8c (151 mg, 29%) and 9c (40 mg, 5%).
8c: m.p.=80–83°C; [α]D20 +27.5 (c 1, CH2Cl2); IR (KBr): ν=3398, 1711, 1698, 1632, 1247 cm−1; 1H
NMR (300 MHz, CDCl3): δ=7.41–7.31 (m, 10H, arom. H), 5.92 (s, 1H, NH), 5.00 (s, 2H, Ph–CH2),
4.60–4.48 (m, 2H, 3-H, 6-CHAHB), 4.25–4.13 (m, 1H, OH), 3.46–3.35 (m, 1H, 9a-H), 2.63–2.53 (m,
2H, 2-CH2), 2.46–2.32 (m, 1H, 6-CHAHB), 1.76–1.62 (m, 1H), 1.58–1.23 (m, 3H), 1.17–0.96 (m, 1H),
0.94–0.83 (m, 1H); 13C NMR (75.5 MHz, CDCl3): δ=166.6 (s, C-4), 156.6 (s, CO–O), 143.9, 136.3 (s,
arom. C), 128.4, 128.0, 127.9, 125.5 (d, arom. CH), 73.0 (s, C-1), 68.3 (d, C-9a), 66.6 (t, Ph–CH2), 49.3
(d, C-3), 45.4 (t, C-6), 34.4 (t, C-2), 30.0 (t, CH2), 25.2 (t, CH2), 25.0 (t, CH2); MS (EI, 70 eV): m/z
(%)=394 (0.1), [M+] 105 (24), 91 (48), [{Ph–CH2}+] 84 (100), 77 (12) [Ph+].
9c: m.p.=42–45°C; [α]D −35.4 (c 0.5, CH2Cl2); IR (KBr): ν=3412, 2927, 1716, 1631 cm−1; H
NMR (300 MHz, CDCl3): δ=7.45–7.32 (m, 10H, arom. H), 5.89 (s, 1H, NH), 5.07 (s, 2H, Ph–CH2),
4.65–4.58 (m, 1H, 6-CHAHB), 4.13–4.02 (m, 1H, 3-H), 3.68–3.60 (m, 1H, 9a-H), 2.78–2.60 (m, 3H, 6-
20
1
CHAHB, 2-CHAHB, OH), 2.27–2.12 (m, 1H, 2-CHAHB), 1.87–1.26 (m, 6H, 7-CH2, 8-CH2, 9-CH2); 13
C
NMR (75.5 MHz, CDCl3): δ=167.6 (s, C-4), 156.2 (s, CO–O), 144.1, 136.3 (s, arom. C), 128.7, 128.4,
128.0, 127.9, 124.9 (d, arom. CH), 72.6 (s, C-1), 66.9 (t, Ph–CH2), 64.6 (d, C-9a), 49.7 (d, C-3), 45.7 (t,
C-6), 40.1 (t, C-2), 25.8 (t, CH2), 24.6 (t, CH2), 23.6 (t, CH2); MS (EI, 70 eV): m/z (%)=394 (0.1), [M+]
105 (30), 91 (60), [{Ph–CH2}+] 84 (100), 77 (14), [Ph+] 55 (11).
3.5.8. (1R,3S,10aR)-3-Benzyloxycarbonylamino-1-hydroxy-1-phenyl-perhydro-pyrido[1,2-a]azepin-
4-one
8d
and
(1S,3S,10aR)-3-benzyloxycarbonylamino-1-hydroxy-1-phenyl-perhydro-pyrido-
[1,2-a]azepin-4-one 9d
Irradiation of (S)-2-benzyloxycarbonylamino-4-oxo-4-phenyl-butanoyl azepanine 5d (450 mg, 1.10
mmol) in dichloromethane (500 ml) gave white solids 8d (283 mg, 63%) and 9d (66 mg, 15%) after
purification by FC (CH2Cl2:MeOH, 100:2).
8d: m.p.=76–78°C; [α]D +74.5 (c 1, CH2Cl2); IR (KBr): ν=3397, 2932, 1713, 1630, 699 cm−1; 1H
20
NMR (300 MHz, CDCl3): δ=7.35–7.28 (m, 10H, arom. H), 6.08 (s, 1H, NH), 5.29 (s, 2H, Ph–CH2),
4.60–4.52 (m, 1H, 3-H), 3.84 (s, 1H, OH), 3.78–3.65 (m, 1H, 6-CHAHB), 3.65–3.56 (m, 1H, 10a-H),
3.39–3.33 (m, 1H, 6-CHAHB), 2.71 (dd, J=6.0, 13.9, 1H, 2-CHAHB), 2.44 (dd, J=12.4, 13.9, 1H, 2-
CHAHB), 1.96–1.85 (m, 1H), 1.75–1.54 (m, 1H), 1.38–1.24 (m, 1H), 1.07–0.99 (m, 1H); 13C NMR (75.5
MHz, CDCl3): δ=169.9 (s, C-4), 156.3 (s, CO–O), 144.4, 136.3 (s, arom. C), 128.4, 128.2, 128.0, 127.9,
127.5, 125.4 (d, arom. CH), 74.5 (s, C-1), 68.4 (d, C-10a), 66.8 (t, Ph–CH2), 49.6 (d, C-3), 45.6 (t, C-6),
40.4 (t, C-2), 30.2 (t, CH2), 28.2 (t, CH2), 27.4 (t, CH2), 26.8 (t, CH2); MS (EI, 70 eV): m/z (%)=408 (1),
[M+] 105 (33), 98 (100), 91 (65), [{Ph–CH2}+] 77 (11) [Ph+].
20
9d: m.p.=54–57°C; [α]D +2.4 (c 1, CH2Cl2); IR (KBr): ν=3404, 1715, 1689, 1656, 699 cm−1;
1H NMR (300 MHz, CDCl3): δ=7.51–7.28 (m, 10H, arom. H), 6.13–6.11 (m, 1H, NH), 5.12 (s, 2H,
Ph–CH2), 4.64–4.57 (m, 2H, 3-H, 6-CHAHB), 3.63–3.59 (m, 1H, 10a-H), 3.16 (dd, J=6.6, 13.6, 1H, 2-
CHAHB), 3.06–2.98 (m, 1H, 6-CHAHB), 2.21–2.17 (m, 1H, OH), 1.90–1.12 (m, 9H, 2-CHAHB, 7-CH2,
8-CH2, 9-CH2, 10-CH2); 13C NMR (75.5 MHz, CDCl3): δ=170.5 (s, C-4), 156.1 (s, CO–O), 145.4,
136.3 (s, arom. C), 128.7, 128.5, 128.3, 128.1, 127.9, 127.2, 124.6 (d, arom. CH), 76.3 (s, C-1), 67.0 (d,

4472
U. Lindemann et al. / Tetrahedron: Asymmetry 9 (1998) 4459–4473
C-10a), 66.8 (t, Ph–CH2), 50.2 (d, C-3), 47.2 (t, C-2), 43.3 (t, C-6), 30.1 (t, CH2), 29.2 (t, CH2), 27.9 (t,
CH2), 25.1 (t, CH2); MS (EI, 70 eV): m/z (%)=408 (1), [M+] 105 (41), 98 (100), 91 (73), [{Ph–CH2}+]
79 (12), 77 (26) [Ph+].
3.5.9. (6S,8R,8aR)-(ꢀ)-3-Amino-8-hydroxy-8-phenyl-hexahydro-indolizin-5-one 10
According to the literature12 (6S,8R,8aR)-(ꢀ)-3-trifluoroacetylamino-8-hydroxy-8-phenyl-hexahydro-
indolizin-5-one 6b (350 mg, 1.00 mmol) was treated with NaBH4 (151 mg, 4 mmol) in 5 ml absolute
EtOH at 0°C. After stirring for 2 h, acetone (5 ml) was added, followed by stirring for 20 min. The solvent
was removed under reduced pressure. The residue was dissolved in K2CO3 solution and extracted with
dichloromethane (3×). Drying of the organic layer over MgSO4 followed by removal of the solvent in
vacuo afforded 10 (210 mg, 85%) as a white solid.
M.p.=176°C; IR (KBr): ν=1657 cm−1; 1H NMR (300 MHz, CDCl3): δ=7.36–7.25 (m, 5H, arom. H),
3.88–3.80 (m, 2H, 6-H, 8a-H), 3.48–3.29 (m, 2H, 3-CH2), 3.50 (dd, J=6.4, 13.9, 1H, 7-CHAHB), 2.35
(s, 1H, OH), 2.24 (dd, J=12.0, 13.9, 1H, 7-CHAHB), 1.80–1.69 (m, 1H, 1-CHAHB), 1.59–1.50 (m, 1H,
2-CHAHB), 1.39–1.13 (m, 2H, 1-CHAHB, 2-CHAHB); 13C NMR (75.5 MHz, CDCl3): δ=172.2 (s, C-5),
144.6 (s, arom. C), 128.2, 127.5, 125.6 (d, arom. CH), 74.7 (s, C-8), 65.7 (d, C-8a), 49.4 (d, C-6), 45.8 (t,
C-7), 45.0 (t, C-3), 27.9 (t, CH2), 22.6 (t, CH2); MS (EI, 70 eV): m/z (%)=246 (0.1), [M+] 148 (7), 124
(14), 105 (16), 77 (16), [Ph+] 70 (100), 44 (12). Anal. calcd for C14H17N2O4: C 68.27, H 7.37, N 11.37;
found: C 67.83, H 7.52, N 11.09.
Crystals suitable for X-ray structure determination have been grown from dichloromethane.
C14H18N2O2, M=246 g mol−1. Orthorhombic, a=5.8640(10), b=8.2110(10), c=26.397(4) Å, α=90,
β=90, γ=90°, V=1271.0(3) Å3, space group P212121, Z=4, density (calculated)=1.287 g cm−1.
Crystal size 1.90×0.38×0.15 mm. F(000)=528, T=200(2) K, wavelength=0.71069 Å. Absorption
coefficient 0.087 mm−1, extinction coefficient 0.010(6), theta range for data collection 2.60–24.16°,
index range −6≤h≤6, −9≤k≤9, −30≤l≤30. Collected reflections 9014, independent reflections 2029,
[R(int)=0.0654] data/restraints/parameters 2026/0/236, goodness of fit F2 1.072. Final R indices [I>2
sigma (I)]: R1=0.0352, wR2=0.0882. R indices (all data): R1=0.0375, wR2=0.0913. Largest difference
peak and hole 0.393 to −0.153 Å−3. Refinement method: full-matrix least-squares on F2. Further
details of the crystal structure investigations are available from the Fachinformationszentrum Karlsruhe,
D-76344 Eggenstein-Leopoldshafen (Germany), on quoting the depository numbers CSD-410326.
Acknowledgements
We gratefully thank the Deutsche Forschungsgemeinschaft for financial support.
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