Stereoselective double ring closing metathesis reactions in the synthesis of spirocyclic compounds

Article abstract of DOI:10.1016/S0040-4039(00)00095-2

The first diastereoselective double ring closing metathesis reaction to afford a spirocyclic compound is reported. Cyclisation of amino acid derived tetraenes 7 selectively afforded spirocyclic compounds 8. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00095-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2027–2029
Stereoselective double ring closing metathesis reactions in the
synthesis of spirocyclic compounds
Debra J. Wallace,∗ Cameron J. Cowden, Derek J. Kennedy, Michael S. Ashwood,
Ian F. Cottrell and Ulf-H. Dolling †
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon,
Hertfordshire, EN11 9BU, UK
Received 17 December 1999; accepted 11 January 2000
Abstract
The first diastereoselective double ring closing metathesis reaction to afford a spirocyclic compound is reported.
Cyclisation of amino acid derived tetraenes 7 selectively afforded spirocyclic compounds 8. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: ring closing metathesis; stereoselective; spirocyclic.
The ring closing metathesis (RCM) reaction has recently evolved to become a major tool for synthetic
organic chemists. This is largely due to the introduction of the well defined molybdenum and ruthenium
catalysts developed by Schrock1 and Grubbs,2 respectively. The RCM has now been applied to a range
of synthetic targets with great success.3 Despite this surge in interest, reports of double RCM reactions
are still rare4 although the possibility of forming two rings, in a single reaction, offers great scope for the
rapid synthesis of complex cyclic systems.
As part of our ongoing program to develop selective NK-1 receptor antagonists5 we required a
convenient synthesis of compounds with general structure 1 (Scheme 1). We were attracted to the
Scheme 1.
∗
†
Corresponding author. Tel: 44 1992 452145; fax: 44 1992 470437; e-mail: debra_wallace@merck.com (D. J. Wallace)
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00095-2
tetl 16368

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possibility of forming the spirocyclic rings of such a compound in a single step using a double RCM. For
instance, the double RCM reaction of tetraene 2 could afford spirodiene 3. This approach would require
the existing stereocentre in 2 to differentiate the enantiotopic vinyl groups. While diastereoselectivity has
been achieved in a double RCM reaction to form a decalin system,4b to the best of our knowledge, only
achiral spirocyclic compounds have previously been accessed in this way.4d In this paper we report our
preliminary studies on the first diastereoselective double RCM to give a spirocyclic compound.
A range of N-tosyl protected metathesis precursors were synthesised from commercially available
amino acid esters as outlined in Scheme 2. Reaction of the hydrochloride salts 4a–d with tosyl chlo-
ride and triethylamine afforded the N-tosyl esters 5a–d in good yields. Cerium-mediated addition of
vinylmagnesium bromide to these esters gave the tertiary alcohols 6a–d in moderate yields. Subsequent
allylation on oxygen and nitrogen was then achieved in a single step to give the tetraenes 7a–d in excellent
yields.6
Scheme 2. Reagents and conditions: (a) TsCl, Et3N, THF, 20°C, 16 h; (b) vinylmagnesium bromide, CeCl3, THF, 0°C, 1 h; (c)
NaH, THF, DMPU, allyl bromide, 20°C, 16 h; (d) RuCl2(PCy3)2_CHPh, CHCl3, 20°C, 2 h
The optimum conditions for the key double RCM reaction were treatment of a 0.05 M chloroform
solution of the tetraene with 5–7 mol% of the Grubbs catalyst at room temperature. This led to
complete consumption of the starting material within 2 h and in all cases the easily separable spirocyclic
compounds 8a–d and 9a–d were isolated in good to excellent yields.6 We were gratified to find that the
diastereoselectivity was strongly in favour of the desired 5R,6S isomers 8a–d and surprisingly was not
affected by the alkyl substituent.
The stereochemistry of the products was elucidated by NOE studies (Fig. 1), which also indicated that
the C6 substituent adopted a pseudoaxial position. Interactions between the C6 equatorial proton and a
C2 proton in the major isomer (e.g. shown for 8d), or the C4 proton and, for 9d, the benzylic protons in
the minor isomer allowed for stereochemical assignment.
Fig. 1.

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In conclusion, we have reported the first example of a diastereoselective double RCM reaction to form
a spirocyclic compound. Further studies on the scope of this reaction and the factors controlling the
stereochemical induction are underway and will be reported in due course.
References
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Ed. Engl. 1999, 38, 129. (c) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8628. (d) Bassindale, M. J.;
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Swain, C. J.; Williams, B. J. International Patent WO97/49710, 1997.
6. All new compounds gave satisfactory spectroscopic and HRMS data.