Synthesis of novel unsaturated bicyclic lactams by ring-closing metathesis

Article abstract of DOI:10.1055/s-1999-2887

An efficient and versatile synthetic method for the preparation of novel unsaturated fused bicyclic lactams is described. The crucial step of the stereoselective approach is the ting-closing metathesis reaction. The 6,5-, 7,5- and 8,5-fused 1-aza-2-oxobicycloalkenes can be obtained in five steps and good overall yield.

Full text of DOI:10.1055/s-1999-2887

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LETTER
Synthesis of Novel Unsaturated Bicyclic Lactams by Ring-Closing Metathesis
Catharine E. Grossmith,1 Francesco Senia, Jürgen Wagner*
*Novartis Pharma AG, CH-4002 Basel, Switzerland
Fax +41.61.324.45.13; E-mail: juergen.wagner@pharma.novartis.com
Received 28 June 1999
dride preactivation methods. Other conditions, like EDC/
Abstract: An efficient and versatile synthetic method for the prep-
HOBT or DCC/DMAP, failed or gave lower yields.
aration of novel unsaturated fused bicyclic lactams is described.
The crucial step of the stereoselective approach is the ring-closing
metathesis reaction. The 6,5-, 7,5- and 8,5-fused 1-aza-2-oxobicy-
cloalkenes can be obtained in five steps and good overall yield.
Key words: bicyclic compounds, metathesis, lactams, ruthenium
Fused bicyclic systems play a very important role in the
field of drug discovery. They are often incorporated into
linear bioactive molecules in order to reduce the confor-
mational flexibility and/or to increase the metabolic sta-
bility of the parent substance.2 Due to their rigid
geometry, they are also useful tools to probe and elucidate
the structure-activity relationships. In that regard, a partic-
ularly attractive class of compounds are the fused bicyclic
lactams, or 1-aza-2-oxobicyclo[X.Y.0]alkanes. Several
structures, possessing various ring sizes, have already
been prepared and incorporated into pharmacologically
relevant peptides.3 However, very few efficient and versa-
tile synthetic routes exist so far. Therefore, new method-
ologies for their preparation are still in high demand.
In this paper, we disclose the preparation of a series of
novel unsaturated fused bicyclic lactams, which are of in-
terest as a new type of potentially useful building blocks.
The efficient stereoselective approach allows the synthe-
sis of 6,5-, 7,5- and 8,5-fused bicycles in five steps from
protected proline in good overall yield.
a) Electrolysis, 300 mA, MeOH, Bu4N+BF4 , b) Allyltrimethylsilane,
TiCl4, CH2Cl2, -20ºC, 46% from 1, c) CuBr·DMS, (Z)-1-lithio-1-pro-
pene, BF3·Et2O, Et2O, 69% from 1, d) HCl/Et2O, quant., e) RCO2H,
THF, iBuOCOCl, NMM, 50-93%.
-
The dienyl precursors 4 and 6 were prepared from protect-
ed proline 1 (Scheme 1). The electrochemical oxidation of
1, first described by Shono et al.,4 provided the C5-meth-
oxylated intermediate 2 in large quantities. Without puri-
fication, 2 was converted with high diastereoselectivity
(90%) into the allylproline derivative 3 using allyltrimeth-
ylsilane in the presence of TiCl4.5 The nucleophilic substi-
tution proceeded best at low temperature (-20ºC) and
gram quantities of intermediate 3 could be obtained as an
oil in 46% yield from 1. Alternatively, the vinylproline
derivative 5 with the opposite configuration at C5 could be
prepared from 2 by boron trifluoride mediated cuprate ad-
dition as described by McClure et al.6 Removal of the tert-
butoxycarbonyl protecting group from 3 or 5 with HCl in
Et2O gave quantitatively the desired amines. The coupling
of the hindered amines to various unsaturated carboxylic
acids afforded the dienyl precursors 4a-f and 6 in yields
varying from 50 to 93%. The coupling reaction proceeded
best by using either the acyl chloride or the mixed anhy-
Scheme 1
The results of the ring-closing metathesis reaction on in-
termediates 4a-f and 6 are summarized in Table 1.7 The
reactions were best carried out in refluxing CH2Cl2 using
freshly
prepared
ruthenium
catalyst
(Cl2(PCy3)2Ru=CHPh).8 In comparison, identical reac-
tions performed in C6H6 gave lower yields. In order to de-
termine the scope of our approach, we prepared bicyclic
lactams possessing three different ring sizes. The 6,5- and
7,5-fused bicyclic structures were obtained in excellent
1
yields (entries 1-4). H NMR analysis of the crude mix-
tures of these reactions indicated clean and quantitative
formation of the products 7-9. The substitution of one
double bond by an additional alkyl group did not influ-
ence the yield of the reactions (entries 2 and 3, 5 and 6).
The successful synthesis of lactam 9 showed that the ap-
proach is not limited to one stereochemistry at C5 (entry
Synlett 1999, No. 10, 1660–1662 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Unsaturated Bicyclic Lactams by Ring-Closing Metathesis
1661
be obtained in good to excellent yields. In addition, the
double bond can be located either in the C6-C7 or the C7-
C8 position. Bicycles 7, 9 and 11 are of particular interest.
Compound 7 has been used previously as a crucial inter-
mediate for the preparation of a tachykinin NK-2 receptor
antagonist.11 Bicycles 9 and 11 are potentially useful
dipeptide analogues because they possess the required
amino terminus. Finally, the double bond could be used to
introduce additional functional groups. Further work is
ongoing to determine the full potential of this methodolo-
gy.
Acknowledgement
We thank Julien France for the NMR measurements.
References and Notes
(1) Present address: C. E. Grossmith, University of Bath,
Claverton Down, Bath BA2 7AY, England.
(2) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244.
(3) For a recent comprehensive review, see: Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.D.
Tetrahedron 1997, 53, 12789 and references cited therein.
(4) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.;
Yamane, S.-I.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc.
1982, 104, 6697. Shono, T.; Matsumura, Y.; Tsubata, K. Org.
Synth. 1985, 63, 206.
(5) Shono, T.; Fujita, T.; Matsumura, Y. Chem. Lett. 1991, 81.
(6) McClure, K.F.; Renold, P.; Kemp, D.S. J. Org. Chem. 1995,
60, 454.
(7) Representative experimental procedure for the ring-closing
metathesis reaction: To a solution of 4 or 6 (0.2 mmol) in dry
CH2Cl2 (5 mL) was added the freshly prepared ruthenium
catalyst (10-15%) under nitrogen. The mixture was stirred
under reflux overnight. The solvent was evaporated and the
residue was purified by chromatography (SiO2 or RP-18). All
new compounds have been isolated in pure form and their
spectral data (MS, IR and NMR) were consistent with the
proposed structure.
Selected data for compound 7: 1H NMR (DMSO, 400 MHz) d
6.70 (m, 1H), 5.82 (dd, J = 10.0, 4.5 Hz, 1H), 4.37 (d, J = 9.0
Hz, 1H), 3.75 (m, 1H), 3.64 (s, 3H), 2.57 (m, 1H), 2.10-2.20
(m, 3H), 1.95 (m, 1H), 1.65 (m, 1H). 13C NMR (CDCl3, 100
MHz) d 28.6, 30.9, 32.1, 52.7, 57.3, 57.4, 125.8, 140.1, 163.8,
173.3. EI-MS m/z 195 (M)+, 136 (M-CO2CH3)+.
Selected data for compound 8: 1H NMR (CDCl3, 360 MHz) d
5.65 (m, 1H), 5.55 (m, 1H), 4.57 (dd, J = 7.0, 5.5 Hz, 1H), 4.30
(m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 2.88 (dd, J = 17.5, 9.0 Hz,
1H), 2.50 (m, 1H), 2.00-2.30 (m, 4H), 1.75 (m, 1H). ESI-MS
m/z 210 (M+H)+.
4). On the other hand, formation of the 8,5-fused bicyclic
lactams proceeded at a slower rate and complete conver-
sion could not be achieved. The difficulty of forming 8-
membered rings by metathesis is well known.9 Neverthe-
less, the presence of a rigid control element, the proline
ring, allowed the reaction to proceed in good yield.
Selected data for compound 9: 1H NMR (DMSO, 400 MHz) d
6.67 (d, J = 6.6 Hz, 1H), 5.68 (m, 1H), 5.60 (m, 1H), 4.88 (m,
1H), 4.72 (m, 1H), 4.42 (dd, J = 7.5, 3.0 Hz, 1H), 3.63 (s, 3H),
2.31-2.41 (m, 1H), 2.05-2.26 (m, 3H), 1.82-1.90 (m, 2H), 1.40
(s, 9H). 13C NMR (CDCl3, 100 MHz) d 28.0, 28.8, 32.9, 33.4,
51.3, 52.8, 56.1, 60.3, 79.9, 130.1, 130.5, 155.3, 171.0, 172.4.
EI-MS m/z 324 (M)+, 209.
Selected data for compound 10: 1H NMR (DMSO, 400 MHz)
d 5.67 (m, 1H), 5.53 (m, 1H), 4.45 (m, 1H), 4.23 (m, 1H), 3.58
(s, 3H), 2.80-2.89 (m, 1H), 2.52-2.66 (m, 2H), 1.97-2.30 (m,
5H), 1.70-1.83 (m, 2H). 13C NMR (CDCl3, 100 MHz) d 24.0,
25.8, 31.9, 32.9, 34.5, 51.0, 56.9, 59.1, 125.5, 128.7, 171.3,
172.0. ESI-MS m/z 224 (M+H)+.
In summary, we have developed an efficient and versatile
approach towards novel unsaturated fused bicyclic lac-
tams.10 The methodology described herein is of interest
because it is suitable for the preparation of a large array of
bicycles. Indeed, the 6,5-, 7,5- and 8,5-fused lactams can
Synlett 1999, No. 10, 1660–1662 ISSN 0936-5214 © Thieme Stuttgart · New York

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C. E. Grossmith et al.
LETTER
(10) For a related application of the ring-closing metathesis
Selected data for compound 11: 1H NMR (CDCl3, 360 MHz)
d 5.74 (m, 1H), 5.59 (m, 1H), 4.98 (m, 1H), 4.34 (dd, J = 7.0,
6.5 Hz, 1H), 4.28 (m, 1H), 3.74 (s, 3H), 2.86-3.02 (m, 2H),
2.12-2.29 (m, 4H), 1.75-1.86 (m, 2H), 1.45 (s, 9H). FAB-MS
m/z 339 (M+H)+, 283 (MH-C4H8)+, 239 (MH-Boc)H+.
reaction, see: Beal, L.M.; Moeller, K.D. Tetrahedron Lett.
1998, 39, 4639. For other types of bicyclic lactams, see:
Martin, S.F.; Chen, H.-J.; Courtney, A.K.; Liao, Y.; Plätzel,
M.; Ramser, M.N.; Wagman, A.S. Tetrahedron 1996, 52,
7251. Diedrichs, N.; Westermann, B. Synlett 1999, 7, 1127.
Tarling, C.A.; Holmes, A.B.; Markwell, R.E.; Pearson, N.D.
J. Chem. Soc., Perkin Trans. 1 1999, 1695.
(8) Schwab, P.; France, M.B.; Ziller, J.W.; Grubbs, R.H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. For recent reviews on
the ring-closing metathesis reaction, see: Amstrong, S.K. J.
Chem. Soc., Perkin Trans. I 1998, 371. Grubbs, R.H.; Chang,
S. Tetrahedron 1998, 54, 4413. Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2037. Grubbs, R.H.;
Miller, S.J.; Fu, G.C. Acc. Chem. Res. 1995, 28, 446.
(9) Extended reaction times up to 2 days, higher catalyst loadings
(20%) and various solvent systems (CH2Cl2, C6H6) did not
improve the conversion. Similar difficulties have been
encountered by others, see: Kirkland, T.A.; Grubbs, R.H. J.
Org. Chem. 1997, 62, 7310.
(11) Compound 7 has been prepared previously in 11 steps from L-
pyroglutamic acid: Hanessian, S.; Ronan, B.; Laoui, A.
Bioorg. Med. Chem. Lett. 1994, 4, 1397.
Article Identifier:
1437-2096,E;1999,0,10,1660,1662,ftx,en;G17199ST.pdf
Synlett 1999, No. 10, 1660–1662 ISSN 0936-5214 © Thieme Stuttgart · New York