Table 1. Synthesis of Spirocyclic Models
Figure 2. Synthetic approach to halichlorine and pinnaic acid.
independently with the C5 center arising from homoserine
while a suitable C-ring surrogate 6 would be prepared from
cyclopentanone.5
In this report, we describe the construction of model
azaspiro systems from cyclic ketones using an imine alky-
lation/ring-closing metathesis methodology.6 The proposed
route to 4a,b involves an initial condensation of amine 7
with ketones 6a or 6b to provide the highly substituted
imines. Stereoselective addition of an allylmetal would
produce the acyclic dienes 5a,b with the correct relative
stereochemistry at C9. Ring-closing metathesis (5 f 4) was
targeted for the key cyclization through closure of the C6-
C7 bond.7
To test the viability of this strategy and explore its
generality, we examined a series of model dienes 10a-f.
For the initial series, allylamine was selected as a model of
amine 7 and was condensed with the cyclic ketones 9a-e
with removal of water (molecular sieves).
The condensation was monitored until complete (NMR),
and the crude imines reacted without the benefit of further
purification. A number of allyl additions to the ketimines
were examined including allylsilane, allylstannane, and
allylzinc reagents which reacted either sluggishly or failed
to react. However, it was found that addition of allylmag-
nesium bromide8 at ambient temperature gave the dienes
10a-f 9 in overall good yields (75-90%). With a route to
the dienes assured, studies of the amine spirocyclization
reaction followed (Table 1).
However, it has been demonstrated that ammonium salts are
tolerated by the ruthenium catalyst Cl2(PCy3)2RudCHPh
12.10 Since for our plan it was considered desirable to avoid
the use of protecting group strategies during the assembly
of the spirocyclic moiety, we first examined cyclization of
the free secondary amines in the presence of p-toluene-
sulfonic acid (Table 1).
Exposure to 1.1 equiv of pTSA and catalyst 12 (10 mol
%) were employed as the standard reaction conditions. Ring-
closed products formed cleanly, but reaction progress halted
after 1-2 days, probably owing to destruction of the catalyst.
Additional catalyst was added in portions (20-30 mol % of
total) to eventually drive the reaction to completion (75-
90% average yields). We were pleased to observe that the
spirocyclic ring closures could be effected without blocking
the secondary nitrogen although these transformations would
ultimately involve higher catalyst loading and longer reaction
times than typical methathesis reactions.
Free amines are typically incompatible with metathesis
reactions owing to catalyst inhibition by the basic nitrogen.
(5) These compounds have been prepared from cyclopentanone by (i)
Claisen rearrangement of the E or Z crotyl enol ether (Mikami, K.;
Takahashi, K.; Nakai, T.; Uchimaru, T. J. Am. Chem. Soc. 1994, 116,
10948), (ii) ozone, NaBH4, (iii) 1 equiv of TBSCl, imidazole, (iv) PCC.
(6) For a Claisen rearrangement/methathesis approach to spirocycles,
see: Tanner, D.; Hagberg, L.; Poulsen, A. Tetrahedron 1999, 55, 1427.
(7) For reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (b) Wright, D. L. Curr. Org. Chem. 1999, 3, 211. (c) Phillips, A.
J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75.
(8) This addition seems to be specific for allyl Grignard; attempts to
add vinyl or butenyl only resulted in metalloenamine formation.
(9) Addition to ketone 9e gave diastereomers 10e and 10f in a 2:1 ratio.
The identity was determined by observing NOE’s on compound 10e from
the allyl group to the axial protons on the adjacent carbons.
(10) Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856.
1848
Org. Lett., Vol. 2, No. 13, 2000