Cross metathesis products (()-5a-f were further elabo-
rated into the olefin-ketocarbene cyclopropanation substrates
(()-7b-f by protection of the free allylic hydroxyl group
as silyl enol ethers (excellent to quantitative yields) followed
by diazo transfer with p-toluenesulfonyl azide also in
quantitative yields (Scheme 2).3 These intermediates were
stirred at 80 °C employing cyclohexane as solvent in the
presence of copper sulfate16 to generate the desired bicyclic
systems as chromatographically separable mixtures (see
Supporting Information) of diastereomers favoring the R
isomer (()-8 over the â isomer (()-9 in good to excellent
yields (Table 2, entries 1-3).
Table 2. Carbene-Mediated Intramolecular Cyclopropanation
Figure 1. Crystal structure of (()-2. Displacement ellipsoid plot
drawn at the 50% probability level. The crystal structure has been
deposited at the Cambridge Crystallographic Data Centre and has
been allocated the deposition number CCDC 295062.
entry product
R
time (h) yield (%), (endo/exo)
1
2
3
4
5
8b/9ba CH2OBn
41
22
22
48
48
75 (2.2/1)
62 (4/1)
95 (3.3/1)
0
8c/9cb Si(OEt)3
8d/9da CH2P(O)(OEt)2
8e/9ea P(O)(OEt)2
the bicyclo[3.1.0]hexane system (Scheme 3). This 1,3-dipolar
addition of diazo compounds and R,â-unsaturated olefins is
well documented in the literature.18
8f/9fa
CO2CH3
18 (1/1)
a R′ ) TBDPS; b R′ ) TBDMS.
Scheme 3
As previously reported, the stereochemical outcome of the
reaction can be rationalized in terms of steric hindrance
assuming that the transition state adopts a product-like
pseudoboat conformation.3 The rigid boat conformation of
the bicyclo[3.1.0]hexane system, which for this class of
compounds has been extensively confirmed by X-ray crystal-
lography and NMR analysis,1c,d,17 makes the assignment of
the stereochemistry particularly straightforward. For example,
in intermediate (()-8b, H-4 appears as a doublet of doublet
of doublets (J ) 8.4, 7.4, and 5.3 Hz). On the other hand,
when H-4 is R, as in intermediate (()-9b, the signal appears
as a doublet (J ) 4.9 Hz). In the latter case, two of the three
dihedral angles with vicinal protons are close to 90° so their
coupling constants approach zero. Both relative configura-
tions of C-4 and C-6 were validated by the X-ray structure
of the final product (()-2 (Figure 1).
The reaction outcome was completely different when the
starting olefin was substituted with electron-withdrawing
groups, such as componds (()-7e,f (Table 2, entries 4 and
5). In those cases, a noncatalyzed intramolecular 1,3-dipolar
cycloaddition pathway predominated over the carbene-
mediated cyclopropanation, and consequently bicyclic pyra-
zoline products (()-10e,f and (()-11f were prevalent over
The developed methodology was applied to the synthesis
of carbocyclic nucleosides (()-1 and (()-2. Bicyclic com-
pound (()-8b was used as starting material, and a convergent
approach through a Mitsunobu-type19 coupling was chosen
to assemble the target nucleoside. Compound (()-8b, which
was prepared on a 10 g scale with the same yield reported
in Tables 1 and 2, was reduced in a stepwise fashion by
first reducing the keto group with sodium borohydride and
then the ester by treatment with lithium aluminum hydride
to afford diol (()-13 in 75% overall yield (Scheme 4).2 After
selective benzoylation of the primary hydroxyl group, the
secondary alcohol was replaced by iodine with retention
of configuration (double inversion)1e to yield intermediate
(()-15. Compound (()-15 was subjected to elimination
conditions to generate intermediate (()-16, which after
deprotection of the secondary hydroxyl group yielded the
Mitsunobu coupling precursor (()-17.
(16) CuSO4 was employed as catalyst because it gave better diastereo-
isomeric ratios of R (()-8/â (()-9 in comparison to other catalysts, such
as Rh2(OAc)4, Cu(OTf) or Cu(acac)2, on this class of substrates (Moon, H.
R.; Marquez, V. E. Unpublished results).
(17) (a) Rodriguez, J. B.; Marquez, V. E.; Nicklaus, M. C.; Barchi, J. J.
Tetrahedron Lett. 1993, 34, 6233. (b) Rodriguez, J. B.; Marquez, V. E.;
Nicklaus, M. C.; Mitsuya, H.; Barchi, J. J. J. Med. Chem. 1994, 37, 3389.
(18) Huisgen, R. J. Org. Chem. 1976, 41, 403.
(19) (a) Mitsunobu, O. Synthesis 1981, 1, 1. (b) Marquez, V. E.; Tseng,
C. K. H.; Treanor, S. P.; Driscoll, J. S. Nucleosides Nucleotides 1987, 6,
239.
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