Stereoselective synthesis of seven-membered lactams and lactones on a carbohydrate scaffold using ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2009.03.125

We present here the application of Grubbs' 2nd generation catalyst for the ring-closing metathesis of electron-deficient α,β-unsaturated amides and esters leading to the synthesis of enantiopure azepinone and oxepinone derivatives on a carbohydrate glycos

Full text of DOI:10.1016/j.tetlet.2009.03.125

Tetrahedron Letters 50 (2009) 3657–3660
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of seven-membered lactams and lactones
on a carbohydrate scaffold using ring-closing metathesis
a,
Dominic L. Laventine a, Paul M. Cullis a, Marcos D. García a,b, , Paul R. Jenkins
*
*
a Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
b Departamento de Química Fundamental, Universidade da Coruña, Campus da Zapateira, A Coruña 15071, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here the application of Grubbs’ 2nd generation catalyst for the ring-closing metathesis of
electron-deficient ,b-unsaturated amides and esters leading to the synthesis of enantiopure azepinone
and oxepinone derivatives on a carbohydrate glycoside scaffold. The relative stereochemistries of the
compounds obtained were corroborated by X-ray crystallography, 1H NMR or deduced based on previ-
ously reported results. These compounds are designed as precursors of new polyhydroxylated heteroann-
ulated sugars with potential biological activity.
Received 12 January 2009
Revised 11 March 2009
Accepted 16 March 2009
Available online 21 March 2009
a
Keywords:
Azepinones
Ó 2009 Elsevier Ltd. All rights reserved.
Oxepinones
Carbohydrate annulations
Reductive amination
Ring-closing metathesis
The well-defined structural characteristics of carbohydrate cyc-
lic compounds (i.e., functional, stereochemical, topological and ste-
reoelectronic features) have enabled the exploitation of these as
advantageous scaffolds in the synthesis of chiral target molecules,1
contributing to the concept of the ‘Chiron Approach’ developed by
Hanessian.2 In this context, one of the key points of the above-
mentioned strategy is the ability to form enantiopure ring systems
from sugars.3 Our previous contributions to this area of carbohy-
drate annulation have involved the use of Robinson’s annulation,4
aldol condensation,5 radical cyclisation,6 and through the applica-
tion of these ideas to the synthesis of chiral taxoid models.7
We have been especially interested in the use of ring-closing
metathesis (RCM) for the synthesis of carbocyclic or heterocyclic
moieties fused to carbohydrates using Grubbs’ 1st generation cat-
alyst A.8 For example, annulated carbocycles of different ring sizes
1,9 spiro-annulated oxygen-containing compounds 29 or seven-
membered aza-heteroannulated sugar derivatives 3, 410 have been
previously synthesised by our group (Fig. 1).
(IC50 = 4.68 mM).11 Furthermore, we have found that the
3-N pyrrolidine derivative 6 displays the same pattern of selectiv-
ity (IC50 = 0.81 mM for b-galactosidase inhibition).12 The develop-
ment of new glycosidase inhibitors13 is a major area of research
due to their possible therapeutic applications, including treat-
ments for cancer, HIV and diabetes.14
In this context, the aim of this work was to extend the use of the
RCM methodology for the stereoselective synthesis of new and
more structurally challenging O/N-heteroannulated carbohydrate
derivatives of type I (Fig. 2), with the heterocyclic portion fused
OMe
OH
OMe
O
O
O
O
O
Ph
O
( )
n
Ph
O
H
n
( )
1 (n = 0, 1, 2, 3)
2 (n = 0, 1)
Besides the prospective use of these structures as privileged
scaffolds for the synthesis of enantiopure materials, the potential
biological applications of compounds such as 3 and 4 or related
structures can be exemplified by a recent paper by Vankar et al.
who reported the D-glucose and 1,4-dideoxymannohomonojirimy-
cin hybrid 5 (Fig. 2) to be a selective inhibitor of b-galactosidase
OMe
H
OMe
O
O
HO
HO
HO
H
H
N
HO
H
H
HN
3
4
OH
HO
* Corresponding authors. Tel.: +44 0 116 252 2124; fax: +44 0 116 252 3789
(P.R.J.).
Figure 1. Selected annulated sugar derivatives previously synthesised by our group
using Grubbs’ 1st generation catalyst A.8
E-mail addresses: mdgarcia@udc.es (M.D. García), kin@le.ac.uk (P.R. Jenkins).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.125

3658
D. L. Laventine et al. / Tetrahedron Letters 50 (2009) 3657–3660
only unreacted starting material. RCM performed upon 8 using
Fused sugar
scaffold
Grubbs’ 2nd generation catalyst produced a complex mixture of
new compounds (TLC analysis). This mixture was purified using
flash column chromatography to give two components. The spec-
trometric analyses (ESI-MS, 13C/1H NMR) of the first component
showed that an unresolved combination of various products was
present in a 66% yield, concordant with the existence of dimeric
products.17 Unfortunately, further separation of this mixture could
not be achieved. The second component eluted was identified as
the lactone 9. The doublet of doublets signal in the 1H NMR
(d = 5.99 ppm), assigned to H-9, had coupling constants of
11.8 Hz and 2.1 Hz; which are typical values for cis-vicinal double
bond couplings, and allylic couplings (see Scheme 2 for number-
ing). A doublet of doublets signal at 4.74 ppm, assigned to H-2,
showed the appropriate coupling constants (J2,3 = 11.0 Hz and
J1,2 = 3.6 Hz) confirming the expected geometry of the trans-ring
junction between the sugar derivative and the heterocycle.
1
O
OMe
H
O
OMe
H
HO
HO
H
X
HO
HO
H
H
H
OH
O
HN
N
HO
Target heteroannulated
sugars I : X = O, N-P
( P = protecting group)
5
OH
6
Figure 2. Examples of aza-heteroannulated sugars showing selective glycosidase
inhibition (511 and 612), and target compounds I.
to the sugar scaffold, either a seven-membered lactam (dihydroaz-
epinone) or lactone (dihydrooxepinone). These compounds are in-
tended to serve as starting materials for the synthesis of new
polyhydroxylated heteroannulated sugar derivatives as potential
glycosidase inhibitors. The presence of the alkene and carbonyl
groups in the proposed target compounds I increases the flexibility
for functionalisation of the seven-membered ring.
As shown in Scheme 1, starting from the unsaturated ketone II,
conversion of the carbonyl group to the appropriate alcohol or
amine and introduction of the acryloyl moiety, would produce
the corresponding diene III as a suitable substrate for the RCM
leading to the target compounds I.
The synthesis of the seven-membered lactams was envisaged
to be easier than that of the corresponding lactones, as the amide
carbonyl group is known to interfere less with the function of the
Grubbs’ catalyst than an ester carbonyl group. In addition, the
conjugated alkene bond in
a,b-unsaturated amides is not as elec-
tron-deficient as the corresponding related esters, due to the lone
pair of the nitrogen providing electron density to the conjugated
system.18 On this occasion, the amine functionality was intro-
duced via stereoselective reductive amination of the correspond-
ing carbonyl derivative followed by introduction of the acryloyl
moiety.
Scheme 3 shows the application of the designed methodology
for the successful synthesis of the trans-fused 2-N-dihydroazepi-
none derivative 13.16 The known compound 109b was stereoselec-
Due to the electron-deficient character of the
a,b-unsaturated
amides and esters III, the reaction conditions should be carefully
selected to achieve the RCM reaction. A priori, RCM can be success-
fully applied to acrylate derivates by means of Grubbs’ 2nd genera-
tion catalyst B8 or using the 1st generation catalyst A8 with an
appropriate Lewis acid as additive (in order to avoid coordination
of the carbonyl group with the Ru centre in the catalytic complex).15
The above-mentioned strategy was initially employed for the
synthesis of trans-fused 2-O seven-membered lactones (Scheme
2).16 The known alcohol 79b was reacted with acryloyl chloride
O
1
OMe
NH
O
OMe
O
O
O
i
2
Ph
O
and Et3N in CH2Cl2 affording the
a,b-unsaturated derivative 8 in
Ph
O
3
moderate yield. The first attempt to achieve the ring closure using
10
11
ii
Ph
catalyst A and Ti(iPrO)4 as additive,15 was unsuccessful yielding
RCM
X
OMe
Bn
O
X
OMe
O
O
O
O
O
O
H
iii
Bn
Ph
O
N
N
Ph
O
H
13
I
III
II
O
O
12
X = O, N-P
( P = protecting group)
Scheme 3. Reagents and conditions: (i) 8 equiv BnNH2, AcOH, THF, then NaBH3CN,
rt, 76%; (ii) acryloyl chloride, Et3N, dry CH2Cl2, 0 °C then rt, 66%; (iii) 0.05 equiv B,
CH2Cl2, reflux, 53%.
Scheme 1. Proposed retrosynthesis of dihydro-azepinones/oxepinones I using RCM
as the key step.
7
6
O
3
OMe
5
1
O
12
H
4
2
O
8
Ph
O
O
OMe
OH
H
O
OMe
O
11
O
O
O
i
ii
9
9
, 27%
10
Ph
O
H
H
Ph
O
+
7
8
O
Dimeric Products,
66%
Scheme 2. Reagents and conditions: (i) acryloyl chloride, Et3N, dry CH2Cl2, 0 °C then rt, 43%; (ii) 0.05 equiv B, CH2Cl2, reflux.

D. L. Laventine et al. / Tetrahedron Letters 50 (2009) 3657–3660
3659
coupling constants from the 1H NMR spectrum for 17 demon-
strated the cis geometry of the ring junction as well as the cis con-
figuration of the alkene.
In conclusion, we have successfully applied Grubbs’ 2nd gener-
ation catalyst B8 for the stereoselective construction by RCM of the
seven-membered enantiopure dihydroazepinones 13 and 17 start-
ing from the corresponding electron-deficient
a,b-unsaturated
amide. The use of this methodology for the RCM of the
a,b-unsat-
urated ester 8 yielded the expected dihydrooxepinone 9 accompa-
nied by an unresolved mixture of dimers. Work is in progress on
the synthesis of related polyhydroxylated heteroannulated sugars
for their further evaluation as glycosidase inhibitors.
Acknowledgments
Figure 3. MERcury ellipsoid projection (50% probability) of the molecular structure
of compound 13, with a random numbering scheme. Hydrogen atoms, except those
involved in the relative stereochemistry, are omitted for clarity.21
We would like to acknowledge the ESPRC and the University of
Leicester for financial support of this research. M.D.G. thanks the
Xunta de Galicia (‘programa Isidro Parga Pondal’ and ‘axudas para
estadías no estranxeiro’) for financial support. Many thanks to K.
Singh for X-ray data.
O
OMe
O
O
OMe
O
O
i
Supplementary data
Ph
O
O
Ph
O
HN
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.125.
Bn
14
15
ii
References and notes
OMe
O
1. (a) Inch, T . D. Adv. Carbohydr. Chest Biochem. 1972, 27, 191; (b) Fraser-Reid, B.
Acc. Chem. Res. 1975, 8, 192; (c) Hanessian, S. Acc. Chem. Res. 1979, 12, 159; (d)
Vasella, A. In Modern Synthetic Methods; Scheffold, R., Ed.; Otto Salle Verlag:
Frankfurt am Main, Germany, 1980; p 173.
2. Hanessian, S. In Total Synthesis of Natural Products: The ‘Chiron’ Approach;
Baldwin, J. E., Ed.; Pergamon Press: Oxford, 1983.
O
N
OMe
O
H
iii
Ph
O
Ph
O
H
Bn
N
O
Bn
16
3. (a) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779; (b) López, J. C. B.;
Fraser-Reid, B. J. Chem. Soc., Chem. Commun. 1997, 2251.
17
O
4. (a) Bonnert, R. V.; Jenkins, P. R. J. Chem. Soc., Chem. Commun. 1987, 6; (b)
Bonnert, R. V.; Howarth, J.; Jenkins, P. R.; Lawrence, N. J. J. Chem. Soc., Perkin
Trans. 1 1991, 1225.
5. (a) Wood, A. J. Chem. Soc., Chem. Commun. 1995, 1567; (b) Wood, A. J.; Holt, D.
J.; Dominguez, M.-C.; Jenkins, P. R. J. Org. Chem. 1998, 63, 8522.
6. (a) Bonnert, R. V.; Davies, M. J. Chem. Soc., Chem. Commun. 1987, 148; (b)
Bonnert, R. V.; Davies, M. J.; Howarth, J.; Jenkins, P. R.; Lawrence, N. J. J. Chem.
Soc., Perkin Trans. 1 1992, 27; (c) Wood, A. J.; Jenkins, P. R. Tetrahedron Lett.
1997, 38, 1853.
7. (a) Boa, A. N.; Clark, J.; Jenkins, P. R.; Lawrence, N. J. J. Chem. Soc., Chem.
Commun. 1993, 151; (b) Jenkins, P. R. Pure Appl. Chem. 1996, 68, 771.
8. Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, 2003; Vol. 2,
Chapter 2.
Scheme 4. Reagents and conditions: (i) 8 equiv BnNH2, AcOH, THF, then NaBH3CN,
rt, 65%; (ii) acryloyl chloride, Et3N, dry CH2Cl2, 0 °C then rt, 47%; (iii) 0.05 equiv 1,
CH2Cl2, reflux, 59%.
tively converted into the corresponding
a-amine 11 by reductive
amination using a large excess of benzylamine (8 equiv).19 The ste-
reochemistry at C-2, corroborated by measurement of the coupling
constants between H-2 and H-1/3, arises from a preferential attack
of the hydride from the opposite face of the methoxy group at
C-1.20 Further evidence of the identity of compound 11 was
obtained by X-ray crystallography after recrystallisation from 1:1
petroleum ether–diethyl ether. Introduction of the acryloyl moiety
followed by RCM using catalyst B,8 produced the expected target
compound 13 in a satisfactory overall yield.
N
N
PCy3
Ru
Ph
Cl
Cl
Cl
Ru
Cl
Ph
PCy3
APCy
X-ray crystallography confirmed the relative stereochemistry of
compound 13 (Fig. 3),21 showing that the trans geometry of ring
junction was maintained and proving the formation of the cis dou-
ble bond between C-9 and C-10. The corresponding coupling con-
stants in the 1H NMR of compound 13 were in accordance with
the postulated geometry.
In order to apply the synthetic strategy for the preparation of
the regioisomeric cis-fused 3-N-dihydroazepinone 17, reductive
amination of the known carbonyl derivative 149 produced only
3
B
Grubbs' 1st (A) and 2nd (B) generation catalysts.
9. (a) Holt, D. H.; Barker, W. D.; Jenkins, P. R.; Davies, D. L.; Garrat, S.; Fawcett, J.;
Russell, D. R.; Ghosh, S. Angew. Chem., Int. Ed. 1998, 37, 3298; (b) Holt, D. J.;
Barker, W. D.; Jenkins, P. R.; Panda, J.; Ghosh, S. J. Org. Chem. 2000, 65, 482.
10. Laventine, D. M.; Jenkins, P. R.; Cullis, P. M. Tetrahedron Lett. 2005, 46, 2295.
11. Kumar, A.; Rawal, G. K.; Vankar, Y. D. Tetrahedron 2008, 64, 2379.
12. Laventine, D. M. Ph. D. thesis, University of Leicester, April 2006.
13. (a) Stütz, A. E. In Iminosugars as Glycosidase Inhibitors—Nojirimycin and Beyond;
Wiley VCH: Weinheim, 1999; (b) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols,
M. Chem. Rev. 2002, 102, 515; (c) Heightman, T. D.; Vasella, A. T. Angew. Chem.,
Int. Ed. 1999, 38, 750.
the axial
a-amine 15 in 65% yield (Scheme 4). The geometry was
corroborated by the 1H NMR spectrum of 15 showing a coupling
constant of 3.6 Hz between H-2 and H-1/3 and is in agreement
with our previous results on the reductive amination of 14.10 Sub-
sequent acylation of 15 with acryloyl chloride, followed by RCM
using catalyst B8 produced the desired dihydroazepinone 17 in
satisfactory yield. Once more, measurement of the appropriate
14. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265.
15. For ring-closing metathesis reactions of acrylates, see: Fürstner, A.; Dierkes, T.
Org. Lett. 2000, 2, 2463. and references cited therein.
16. Full experimental details are presented as Supplementary data to this Letter.

3660
D. L. Laventine et al. / Tetrahedron Letters 50 (2009) 3657–3660
17. ESI-MS indicated that dimerised products arising from cross-metathesis and
subsequent RCM were present.
18. Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon, H.; Guibe, F. Synlett 2001, 37.
19. In our experience, a large excess of the amine is necessary in order to avoid the
21. CCDC 715631 and 715632 contain, respectively, the Supplementary
crystallographic data for compounds 11 and 13. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif or can be ordered from the
following address: Cambridge Crystallographic Data Centre, 12 Union Road,
reduction of the carbonyl group at C-2 producing the corresponding
as byproduct.
a-alcohol
Cambridge,
GB
CB2
1EZ;
Fax:
(+44)1223-336-033;
or
20. Yu, K. L.; Handa, S.; Tsang, R.; Fraser-Reid, B. Tetrahedron 1991, 47, 189.
deposit@ccdc.cam.ac.uk.