Synthesis of enantiomerically pure bicyclic lactams

Article abstract of DOI:10.1055/s-1999-2747

Enantiomerically pure homologous 1-azabicyclo-[x.y.0]alkanones (x = 4-5, y = 4-7) can be synthesized by ring closing olefin metathesis using Grubbs' ruthenium catalyst. By starting from monocyclic lactams, the bicyclic products, even eight- and nine-membered rings, are formed in high yields. The monocyclic lactames can be obtained enantiomerically pure by enzyme-catalyzed kinetic resolution.

Full text of DOI:10.1055/s-1999-2747

LETTER
1127
Synthesis of Enantiomerically Pure Bicyclic Lactams
Nicole Diedrichs, Bernhard Westermann*
Universität Paderborn, Fachbereich für Chemie und Chemietechnik, 33095 Paderborn, Germany
Fax:+49 5251 603245, E-mail: bw@chemie.uni-paderborn.de
Received 22 April 1999
cyclic lactams can be prepared as we previously de-
scribed.7 Starting from β-keto esters 4a-e bearing an ω-
olefinic side chain at the quaternary carbon center, kinetic
resolution was carried out with pig liver esterase (PLE)
Abstract: Enantiomerically pure homologous 1-azabicyclo-
[x.y.0]alkanones (x = 4-5, y = 4-7) can be synthesized by ring clos-
ing olefin metathesis using Grubbs’ ruthenium catalyst. By starting
from monocyclic lactams, the bicyclic products, even eight- and
nine-membered rings, are formed in high yields. The monocyclic (Scheme 1). The products were isolated in high enantio-
lactames can be obtained enantiomerically pure by enzyme-cata-
lyzed kinetic resolution.
meric purities (ee > 98%). Subsequently, treatment of (–)-
4a-e with hydroxylamine afforded the corresponding E-
Key words: Grubbs’ catalyst, ring-closing olefin metathesis, PLE,
lactams, natural products
oximes in almost quantitative yield (E:Z ≥ 50:1). Conse-
quently, lactams (–)-7a-e were obtained via a stereo-
specific Beckmann-rearrangement. No racemization took
place during the Beckmann-rearrangement as determined
by 1H NMR employing chiral shift reagent Eu(tfc)3.8
Due to their ubiquity as frameworks in natural products,
the synthesis of 1-azabicyclo[x.y.0]alkane-alkaloids such
as 1 [4.4.0] or 2 [6.3.0] and [10.3.1] has attracted consid-
erable attention.1,2 In addition, these heterocycles 3 [5.4.0]
are useful candidates for the incorporation into small pep-
tides to induce certain secondary structural elements, e. g.
β turns.3 In retrospect, most of the numerous synthetic
strategies towards enantiomerically pure products report-
ed so far start from building blocks provided by the chiral
pool.4,5 By starting from naturally occurring and easily
available amino acids the number of derivatives allowing
the synthesis of a broad variety of differing ring sizes is
limited. Therefore, there is still need for a method by
which homologues can be prepared following a common
synthetic route.
O
O
O
CO2Et
CO2Et
CO2H
PLE
+
R
R
R
R = -(CH2)m-CH=CH2
n
n
n
a: n=1, m=1
b: n=1, m=2
c: n=1, m=3
d: n=1, m=4
e: n=2, m=1
(±)-
(–)-
4a-e
4a-e
5a-e
i : NH2OH, py
ii : p-TsOH, py
iii: silica gel, CH2Cl2
-CO2
O
O
n
R
NH
CO2Et
n
R
(–)-
(±)-
7a-e
6a-e
Scheme 1
OMe
MeO
N
N
H
H
H
PCy3
Ru
Cl
Cl
H
N
OH
O
N
Ph
N
PCy3
Br
3 mol%
CH2Cl2, rt
N
1
2
7a-e
Manzamine
Cryptopleurine
NaH, DMF, rt
75-92%
H
m
CO2Et
OMe
n
O
CO2t-Bu
8a-e
AcNH
O
N
O
S
N
H
N
N
OH
3
t-BuSH, toluene
65%
Bicyclic Turn
Dipeptide
n
m
H
CO2R
n,m=1
12
9a-e R=Et
NaOH
10 R=H
11 R=Cl
We now report a general method for the preparation of bi-
cyclic lactams using δ- and ε-lactams as conformational
constraint precursors in the ring closing olefin metathesis
(COCl)2
Scheme 2
employing
the
Grubbs’
catalyst
[Ru = CHPh(Cl)2(PCy3)2].6 Enantiomerically pure mono-
Synlett 1999, No. 07, 1127–1129 ISSN 0936-5214 © Thieme Stuttgart · New York

1128
N. Diedrichs, B. Westermann
LETTER
Transformation of 7 into the diolefinic compounds 8 was The results presented above show the power of the ring-
carried out with allyl bromide after deprotonation with closing metathesis by using Grubbs’ ruthenium catalyst.
NaH (Scheme 2). The intramolecular ring closing met- To the best of our knowledge, these results are among the
athesis reaction to form 9 was performed using 3 mol% of highest reported so far for the formation of 8- and 9-mem-
Grubbs’ ruthenium catalyst. After stirring in CH2Cl2 at bered rings. Due to the high degree of functionalization
room temperature, the cyclized products were isolated in these bicyclic lactams offer the possibility to be employed
high yields (see Table 1). Starting from valerolactams in natural product synthesis.
(n = 1), the reaction was completed after 1 – 12 hours. The
yields of isolated products ranged from 67% – 95%.9
Acknowledgement
These high yields were especially remarkable for the for-
N. D. appreciates the support by the Fonds der Chemischen Indu-
strie for a doctoral fellowship.
mation of 9-membered rings, which, in general, are not
easy to obtain.10 In addition, the formation of the new dou-
ble bond, which can be cis- or trans configurated for 9d
was highly selective. Indeed, the bicyclic product con-
tained only a cis-double bond.
References and Notes
(1) Buckley III, T. F.; Rapoport, H. J. Org. Chem. 1983, 48,
4222–4232.
(2) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Pätzel,
M.; Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52,
7251–7264.
By starting from caprolactam 7e (n = 2), the yield of cy-
clized product 9e was 77%, the reaction time was pro-
longed in comparison with the valerolactam derivatives.
(3) Colombo, L.; DiGiacomo, M.; Papeo, G.; Carugo, O.;
Scolastico, C.; Manzoni, L. Tetrahedron Lett. 1994, 35, 4031–
4034; Kolter, T.; Giannis, A. Angew. Chem. 1993, 105, 1303–
1326; Angew. Chem. Int. Ed. 1993, 32, 2036–2055 and cited
references.
Table 1 Synthesis of bicyclic lactams 9 by ring closing olefin me-
tathesis of 8.
(4) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825–1872
and cited references.
(5) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. Tetrahedron 1997, 53, 12789–12854 and cited
references.
(6) Grubbs, R. H.; Miller, S. J.; Fu, G. Acc. Chem. Res. 1995, 28,
446–452; Schuster, S.; Blechert, S. Angew. Chem. 1997, 109,
2124–2145; Angew. Chem. Int. Ed. 1997, 36, 2036–2055 and
cited references.
(7) Westermann, B.; Große-Scharmann, H.; Kortmann, I.
Tetrahedron: Asymmetry 1993, 4, 2119–2122.
(8) Gedrath, I.; Westermann, B. Synlett 1996, 665–666.
(9) General procedure for the preparation of lactams 9a-e:
To a solution of lactam 8a (550 mg, 2.2 mmol) in dry CH2Cl2
(200 ml) was added Ru = CHPh(Cl)2(PCy3)2 (52 mg, 0.07
mmol) and the reaction mixture was stirred at rt (time see
Table 1). After evaporation of the solvent at reduced pressure,
the residue was purified by chromatography on silica gel.
9a: TLC (petroleum/AcOEt, 1:1) RF = 0.10. – 1H NMR (200
MHz, CDCl3): δ = 1.23 (t, 3J 7.1 Hz, 3H, CH3), 1.59 – 1.91 (m,
3H, CH2), 2.18 – 2.56 (m, 4H, CH2), 2.76 – 2.88 (m, 1H, CH2),
3.65 – 3.75 (m, 1H, NCH2), 4.17 (q, 3J 7.1 Hz, 2H, OCH2),
4.38 – 4.49 (m, 1H, NCH2), 5.63 – 5.71 (m, 2H, CH = CH). –
13C NMR (50 MHz, CDCl3): δ 14.6, 17.9, 32.9, 34.6, 35.9,
42.4, 62.1, 63.9, 122.4, 124.8, 170.9, 173.4. – HR-MS (EI):
C12H17NO3: calcd. 223.1209 found 223.1214.
9b: TLC (petroleum/AcOEt, 1:1) RF = 0.13. – 1H NMR (200
MHz, CDCl3): δ 1.24 (t, 3J 7.1 Hz, 3H; CH3), 1.60 – 2.50 (m,
10H, CH2), 3.27 – 3.35 (m, 1H, NCH2), 4.18 (q, 3J 7.1 Hz, 2H,
OCH2), 4.61 – 4.80 (m, 1H, NCH2), 5.63 – 5.73 (m, 2H,
CH = CH). – 13C NMR (50 MHz, CDCl3): δ 14.6, 17.9, 24.4,
31.8, 32.3, 36.2 41.9, 62.0, 68.0, 128.0, 130.7, 170.0, 174.4. –
HR-MS (EI): C13H19NO3: calcd. 237.1365 found 237.1363.
9c: TLC (petroleum/AcOEt, 1:1) RF = 0.16. – 1H NMR (200
MHz, CDCl3): δ 1.24 (t, 3J 7.1 Hz, 3H, CH3), 1.49 – 2.56 (m,
12 H, CH2), 3.19 – 3.30 (m, 1H, NCH2), 4.17 (q, 3J 7.1 Hz, 2H,
OCH2), 4.84 – 4.95 (m, 1H, NCH2), 5.46 – 5.66 (m, 2H,
CH = CH). – 13C NMR (50 MHz, CDCl3): δ 14.6, 17.9, 22.1,
24.0, 30.3, 30.8, 32.6, 46.2, 62.1, 68.4, 126.6, 128.7, 170.9,
We also showed that lactam 9a can be decarboxylated us-
ing the Barton protocol, which is known to be stereoselec-
tive in rigid bicycles.11,12 Cleavage of the ethyl ester
(NaOH) of 9a afforded acid 10 in essentially quantitative
yield. After treatment with oxalyl chloride, the acid chlo-
ride 11 was directly coupled with N-hydroxy pyridine-2-
thione, which was exposed to t-butyl sulfide in toluene
(80 °C). Enantiomerically pure 12 was obtained in 65%
yield (9a → 12).
Synlett 1999, No. 07, 1127–1129 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
174.3. – HR-MS (EI): C14H21NO3: calcd. 251.1521 found
Synthesis of Enantiomerically Pure Bicyclic Lactams
1129
(10) Delgado, M.; Martin, J. D. Tetrahedron Lett. 1998, 38, 6299–
6300; Holt, D. J.; Barker, W. D.; Jenkins, P. R.; Davies, D. L.;
Garratt, S.; Fawcett, J.; Russell, D. R.; Ghosh, S. Angew.
Chem. 1998, 110, 3486–3488; Angew. Chem. Int. Ed. 1998,
37, 3298–3300; Tarling, C. A.; Holmes, A. B.; Markwell, R.
E.; Pearson, N. D. 216th ACS meeting, abstract 128 (orgn)
1998.
(11) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1983, 939–941.
(12) Grieco, P. A.; Abood, N. J. Chem. Soc., Chem. Commun.
1990, 410–412; Campbell, J. A.; Rapoport, H. J. Org. Chem.
1996, 61, 6313–6325.
251.1524.
9d: TLC (petroleum/AcOEt, 1:1) RF = 0.24. – 1H NMR (200
MHz, CDCl3): δ 1.30 (t, 3J 7.1 Hz, 3H, CH3), 1.37 – 2.62 (m,
10H, CH2), 3.48 (dd, J 10.9, 13.6 Hz, 1H, NCH2), 4.12 – 4.33
(m, 3H, OCH2, NCH2), 5.49 (ddd, J 6.8 Hz, 10.3 Hz, 1H,
CH = CH) 6.18 (ddd, J 6.2 Hz, 10.8 Hz, 1H, CH = CH). –
13C NMR (50 MHz, CDCl3): δ 14.7, 17.6, 18.4, 22.8, 23.9,
31.4, 32.2, 32.5, 41.5, 62.1, 70.9, 128.7, 130.2, 171.8, 174.8.
– HR-MS (EI): C15H23NO3: calcd. 265.1678 found 265.1685.
9e: TLC (petroleum/AcOEt, 1:1) RF = 0.27. – 1H NMR (200
MHz, CDCl3): δ 1.24 (t, 3J 7.1 Hz, 3H, CH3), 1.60 – 1.81 (m,
4H, CH2), 1.96 – 2.70 (m, 6H, CH2), 3.80 – 3.89 (m, 1H,
NCH2), 4.18 (q, 3J 7.1, 2H, OCH2), 4.39 (m, 1H, NCH2) 5.71
– 5.78 (m, 2H, CH = CH). – 13C NMR (50 MHz, CDCl3): δ
14.6, 21.3, 22.7, 36.5, 36.6, 37.9, 44.3, 62.0, 65.3, 123.5,
126.3, 173.6, 175.6. – HR-MS (EI): C13H19NO3: calcd.
237.1364 found 237.1362.
Article Identifier:
1437-2096,E;1999,0,07,1127,1129,ftx,en;G05599ST.pdf
Synlett 1999, No. 07, 1127–1129 ISSN 0936-5214 © Thieme Stuttgart · New York