Synthesis of bicyclo[3.1.0]hexanes functionalized at the tip of the cyclopropane ring. Application to the synthesis of carbocyclic nucleosides

Article abstract of DOI:10.1021/ol052886n

A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross metathesis step designed to functionalize the appropriate terminal olefin of the bicyclo[3.1.0]hexane precursor and a c

Full text of DOI:10.1021/ol052886n

ORGANIC
LETTERS
2006
Vol. 8, No. 4
705-708
Synthesis of Bicyclo[3.1.0]hexanes
Functionalized at the Tip of the
Cyclopropane Ring. Application to the
Synthesis of Carbocyclic Nucleosides
Maria J. Comin,† Damon A. Parrish,‡ Jeffrey R. Deschamps,‡ and
Victor E. Marquez*,†
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer
Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702,
NaVal Research Laboratory, Washington, DC 20375
marquezV@mail.nih.goV
Received November 29, 2005
ABSTRACT
A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross
metathesis step designed to functionalize the appropriate terminal olefin of the bicyclo[3.1.0]hexane precursor and a carbene-mediated
intramolecular cyclopropanation reaction on the corresponding diazo intermediate. This combined methodology allowed the diastereoselective
introduction of chemically diverse substituents at the tip of the cyclopropane group, except in cases where the substituents consisted of
electron-withdrawing groups where a competing [3
+ 2] cycloaddition predominated.
To further explore structure-activity relationships on bicyclo-
[3.1.0]hexane nucleosides by functionalizing the tip of the
cyclopropane ring, the majority of published chemical
approaches appeared unsuitable,1 except for the intramo-
lecular carbene-mediated cyclopropanation approach recently
developed in our laboratory.2,3 This versatile reaction has
been successfully applied to the synthesis of optically active
bicyclo[3.1.0]hexane nucleosides using various approaches
such as starting with chiral compounds,4 employing chiral
auxilaries,5 and even incorporating chemico-enzymatic steps.2,3
On the other hand, relatively few examples describing the
use of chiral catalysts for the intramolecular cyclopropanation
of diazoketoesters have been reported, and the level of
enantiocontrol achieved has been rather low.6
† National Institutes of Health.
‡ Naval Research Laboratory.
(1) (a) Ezzitouni, A.; Marquez, V. E. J. Chem. Soc., Perkin Trans. 1
1997, 1073. (b) Ezzitouni, A.; Russ, P.; Marquez, V. E. J. Org. Chem.
1997, 62, 4870. (c) Altman, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G.
Tetrahedron Lett. 1994, 35, 2331. (d) Altman, K.-H.; Imwinkelried, R.;
Kesselring, R.; Rihs, G. Tetrahedron Lett. 1994, 35, 7625. (e) Choi, Y.;
George, C.; Comin, M. J.; Barchi Jr., J. J.; Kim, H. S.; Jacobson, K. A.;
Balzarini, J.; Mitsuya, H.; Boyer, P. L.; Hughes, S. H.; Marquez, V. E. J.
Med. Chem. 2003, 46, 3292.
With the aim of developing a general strategy for the
synthesis of bicyclo[3.1.0]hexanes substituted at the tip of
(4) (a) Gallos, J. K.; Massen, Z. S.; Kpftis, T.; Dellios, C. Tetrahedron
Lett. 2001, 42, 7489. (b) Joshi, B. V.; Moon, H. R.; Fettinger, J. C.; Marquez,
V. E.; Jacobson, K. A. J. Org. Chem. 2005, 70, 439.
(5) Tanimori, S.; Tsuboda, M.; He, M.; Nakayama, M. J. Synth. Commun.
1997, 27, 2371.
(6) (a) Pique´, C.; Fa¨hndrich, B.; Pfaltz, A. Synlett 1995, 491. (b) Doyle,
M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(2) Moon, H. R.; Ford, H., Jr.; Marquez, V. E. Org. Lett. 2000, 2, 3793.
(3) Yoshimura, Y.; Moon, H. R.; Choi, Y.; Marquez, V. E. J. Org. Chem.
2002, 67, 5938.
10.1021/ol052886n This article not subject to U.S. Copyright. Published 2006 by the American Chemical Society
Published on Web 01/27/2006

the cyclopropane ring, the use of a cross metathesis7 reaction
was envisioned (Scheme 1). The mild conditions and
Table 1. Cross Metathesis
Scheme 1
entry
product
R
time (h)
yield (%)d
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
CH2OAca,b
CH2OBna,b
Si(OEt)3
20
18
2
16
48
5
70
90
98
88
47
95
c
c
CH2P(O)(OEt)2
c
P(O)(OEt)2
b
CO2CH3
functional group tolerance of modern cross metathesis
methodologies were expected to allow the introduction of
chemically diverse substituents at the terminal olefin of the
bicyclo[3.1.0]hexane precursor. Then, an ensuing intramo-
lecular cyclopropanation reaction on the corresponding diazo
intermediate was anticipated to complete the formation of
the desired template. This combined methodology allowed
the diastereoselective introduction of chemically diverse sub-
stituents at the tip of the cyclopropane ring, except in cases
where the substituents consisted of electron-withdrawing
groups where a competing [3 + 2] cycloaddition predomi-
nated.
a The dimeric olefin was used as cross partner. b 2 equiv of cross partner
olefin were employed. c 5 equiv of cross partner olefin were employed.
d The trans isomer was the only one detected in all cases.
cross partners in the presence of either 2nd generation
Grubbs8 or Hoveyda-Grubbs9 catalysts (Table 1) to afford
the corresponding disubstituted olefins with excellent E-
selectivity and in high yields as mixtures of keto-enol
tautomers.10 In contrast, when the hydroxyl group was
protected as an acetate or as a silyl ether, no cross metathesis
reaction was observed and starting material was recovered
(data not shown). As has already been observed by other
groups using different substrates,11 the size of the allylic
substituent strongly modulates the outcome of the cross
metathesis reaction.
The substrate for the cross metathesis reaction was
prepared from ethyl acetoacetate (3) and acrolein as described
in Scheme 2.2 With intermediate (()-4 at hand, we initiated
Our initial efforts focused on elaborating the terminal
olefin to the corresponding allylic alcohol derivatives (entries
1 and 2). In these cases, the use of symmetric internal olefins
was found to be more efficient than simply using prop-2-
enyl acetate or 1-(phenylmethoxy)prop-2-ene.12 Reaction
with triethoxyvinylsilane (entry 3) was quantitative and fast.13
When olefin (()-4 was treated with diethoxyallylphospho-
nate, the cross product (()-5d was obtained stereoselectively
and in very good yield (88%, entry 4). On the other hand,
reaction with diethoxyphosphinovinyl-1-one yielded the
desired olefin in low yield (47%, entry 5),14 probably due to
its very low reactivity in cross metathesis reactions (no
homodimerization).15 Finally, reaction with methylacrylate
produced the desired olefin in high yield (entry 6).
Scheme 2
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(9) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(10) 1H and 13C NMR experiments show that a small amount of the enol
tautomer is always present in solution (see Supporting Information).
(11) (a) Chatterjee, A. K.; Choi, T.-l.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360. (b) Ghosh, A. K.; Gong, G. J. Am. Chem.
Soc. 2004, 126, 3704.
(12) O’Leary, D. J.; Blackwell, E. H.; Washenfelder, R. A.; Grubbs, R.
H. Tetrahedron Lett. 1998, 39, 7427.
(13) Pietraszuk, C.; Fisher, H.; Kujawa, M.; Marciniec, B. Tetrahedron
Lett. 2001, 42, 1175.
studies on the cross metathesis reaction. We found out that
free allylic alcohol (()-4 reacted smoothly with most olefin
(14) In this case, 50% of starting material (()-4 was recovered.
(15) Chatterjee, A. K.; Choi, T.-l.; Sanders, D. P.; Grubbs, R. H. Synlett
2001, 1034.
(7) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41,
3171.
706
Org. Lett., Vol. 8, No. 4, 2006

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.
Org. Lett., Vol. 8, No. 4, 2006
707

Scheme 4
Scheme 5
As shown in Scheme 5, treatment of compound (()-17
under Mitsunobu conditions employing 3N-benzoylthymine20
as nucleophile yielded, after hydrolysis of the benzoyl groups,
nucleoside precursor (()-18 in 37% overall yield.
The benzyl protecting group was then cleaved by treatment
with boron trichloride at low temperature to afford nucleoside
analogue (()-1 in high yield. Hydrogenation of the double
bond proceeded smoothly to give the thymidine analogue
(()-2 in quantitative yield.
This newly synthesized analogue provided adequate
crystals for X-ray analysis, and the crystal structure (Figure
1) validated all of the spectral assignments as well as the
base disposition (anti) and the pseudoboat conformation of
the carbocyclic ring.
analogues (()-1 and (()-2. The remarkable growth in the
area of asymmetric transition-metal-catalyzed cyclopropa-
nation reactions during the past few years21 bodes well for
the idea of attempting a catalytic asymmetric version of the
synthetic approach presented here. Future investigations on
these attempts will be published in due course.
Acknowledgment. The authors wish to thank Drs. James
A. Kelley and Christopher Lai of the Laboratory of Medicinal
Chemistry, NCI, for the high-resolution mass spectral data.
This research was supported in part by the Intramural
Research Program of the NIH, Center for Cancer Research,
NCI-Frederick.
Supporting Information Available: Experimental pro-
cedures and characterization data for all intermediates and
final products. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have developed a general strategy for
the synthesis of bicyclo[3.1.0]hexanes substituted at the tip
of the cyclopropane ring, employing simple starting ma-
terials. The synthetic potential of this strategy has been
demonstrated by the synthesis of carbocyclic nucleoside
OL052886N
(20) Cruickshank, K. A.; Jiricny, Reese, C. B. J. Tetrahedron Lett. 1984,
25, 681.
(21) (a) Maas, G. Chem. Soc. ReV. 2004, 33, 183. (b) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
708
Org. Lett., Vol. 8, No. 4, 2006