7520
J . Org. Chem. 1997, 62, 7520-7521
been postulated to derive from strong Zr-Zr bonding.11
Ster eoselective “P in a col” Cou p lin g of
One electron reduction capability does exist for 4. This
was demonstrated by its reaction with 6-bromo-1-hexene,
which gave, following D2O workup, 1-hexene-d and meth-
ylcyclopentane-d (1:1), or with 4-(2-bromophenyl)-1-
butene which gave, following D2O workup, 1-methylin-
dane-d, consistent with a radical mechanism for activation
of the C-Br bond. Significantly, while in situ generated
3 reacts rapidly with 6-bromo-1-hexene (reaction time
1-10 min at room temperature8), 4 requires 7-10 h at
room temperature for reaction completion. It may be that
dissociation of 4 to 3, or the creation of a vacant site on
4 by dissociation of a chloride ligand, is rate determining,
overall, for reaction with the alkyl halide.
2,3-O-Isop r op ylid en e-D-glycer a ld eh yd e
Michael C. Barden and J effrey Schwartz*
Department of Chemistry, Princeton University,
Princeton, New J ersey 08544-1009
Received J une 4, 1997
The use of carbohydrate-derived aldehydes as building
blocks for stereoselective synthesis of polyhydroxylated
alkyl moieties1,2 can be an important alternative to other
methods which might involve sequential linking of hy-
droxymethylene units. Pinacol coupling of sugar-derived
aldehydes represents one such general, alternative meth-
odology. However, while various low-valent metallic
complexes are capable of effecting pinacol coupling of
aliphatic aldehydes,3 few of these accomplish the desired
transformation with high stereoselectivity, except where
considerations of large steric bulk or remote substrate
coordination are involved.4 We recently reported5 that the
simple Ti(III) reagent (Cp2TiCl)2 (1)6 can accomplish
highly stereoselective pinacol coupling of aromatic and
unsaturated aldehydes, likely via a reactive monomer (2),
which is readily obtained by dimer dissociation.7 How-
ever, this species was not effective for analogous coupling
of aliphatic aldehydes. Both halogen atom abstraction
from an aliphatic halide and pinacol coupling involve
reduction of the substrate, and in situ generated Cp2-
Zr(III)Cl8 (3) is far more reactive than 2 for halogen atom
abstraction from aliphatic halides.9 Therefore, we ex-
amined the possibility that a Zr(III) reagent could effect
pinacol coupling of a relatively unreactive aliphatic
Ti(III) dimer 1 reacts rapidly with benzaldehyde, even
below room temperature, to accomplish diastereoselective
pinacol coupling;5 however, a similar procedure using 4
and benzaldehyde occurred only slowly, even at room
temperature, to give a mixture of hydrobenzoins (dl:meso
) 65:35).12 The low rate of reactivity of 4 compared with
1 and the consequently higher temperature required to
effect pinacol coupling (with attendant lower coupling
stereoselectivity) suggest that, as for alkyl halide activa-
tion, dissociation of 4 to 3, or the creation of a vacant
site by dissociation of a chloride ligand, might be rate
determining for pinacol coupling, overall. The inherent
reactivity of Zr(III) as a reducing agent, however, is
greater than that of Ti(III): whereas 1 did not ap-
preciably react with aliphatic aldehydes or ketones at
room temperature, 4 readily coupled such species, albeit
slowly. Significantly, 4 could accomplish pinacol coupling
of 2,3-di-O-isopropylidene-D-glyceraldehyde with good
stereoselectivity. Analysis by NMR showed a 1:1 mixture
of the di-O-isopropylidene derivatives of mannitol13 and
iditol13 if the reaction was performed at room tempera-
ture. However, if reagents were mixed at -78 °C, and
then the mixture was allowed to warm only to 0 °C, then
1,2:5,6-di-O-isopropylidene-D-mannitol was the dominant
product (mannitol:iditol > 7:1) (Scheme 1). The stereo-
selectivity of pinacol coupling observed for this simple
carbohydrate suggests that similar procedures might be
applicable for efficient preparation of higher carbohydrate
derivatives, for use in synthesis of end products with
interesting biological properties.1,2 Accordingly, we are
examining methods for the activation of the Zr(III) dimer.
10
aldehyde. Indeed we find that (Cp2ZrCl)2 (4) can be
used to pinacol couple a simple aliphatic aldehyde, for
example 2,3-O-isopropylidene-D-glyceraldehyde, in good
yield and with high diastereoselectivity, in a process
which might involve reactive monomer 3.
Reduction of Cp2ZrCl2 with 10% Na(Hg) gives 4 as a
deep red, oxygen sensitive complex. While Ti(III) dimer
1 is easily dissociated to monomer 2 by reaction with a
broad range of donor ligands or coordinating solvents,7
these ligands (even in excess) failed to cleave 4 to
monomeric 3 in any quantity readily detectable by EPR
analysis; indeed, the observed diamagnetism of 4 has
(1) For example, see, Secrist, J . A., II; Barnes, K. O.; Wu, S.-R. In
Trends in Synthetic Carbohydrate Chemistry; Horton, D., Hawkins,
L. D., McGarvey, G. J ., Eds.; ACS Symposium Series 386; American
Chemical Society: Washington, DC, 1989; Ch. 5.
(2) For example, see, (a) Ikemoto, N.; Schreiber, S. L. J . Am. Chem.
Soc. 1992, 114, 2524-2536. (b) Marshall, J . A.; Beaudoin, S. J . Org.
Chem. 1994, 59, 6614-6619.
(3) For example, see, (a) Takahara, P. M.; Freudenberger, J . H.;
Konradi, A. W.; Pedersen, S. F. Tetrahedron Lett. 1989, 30, 7177-
7180. (b) Freudenberger, J . H.; Konradi, A. W.; Pedersen, S. F. J . Am.
Chem. Soc. 1989, 111, 8014-8016.
(4) (a) Konradi, A. W.; Pedersen, S. F. J . Org. Chem. 1990, 55, 4506-
4508. (b) Kempf, D. J .; Sowin, T. J .; Doherty, E. M.; Hannick, S. M.;
Cadavoci, L.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck, D.
W. J . Org. Chem. 1992, 57, 5692-5700. (c) Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F.; Giaroni, P. J . Org. Chem. 1992, 57, 782-
784.
Exp er im en ta l Section
Reduction procedures were performed under inert atmo-
sphere. Organic substrates were purchased from Aldrich Chemi-
cal and were purified prior to use. Solvents were distilled from
sodium benzophenone ketyl. NMR spectra were recorded on a
General Electric QE300 (300 MHz) spectrometer. EPR spectra
were recorded on a Bruker ESP 300 spectrometer with g-values
referenced to 2,2-di(4-tert-octylphenyl)-1-picrylhydrazyl (DOPH)
as internal standard (sealed capillary, g ) 2.004). The EPR
spectrometer was routinely operated at microwave powers of
0.2-0.5 mW; no saturation was observed. Field modulations
were kept below 0.2 G in order to ensure full resolution of the
(5) Barden, M. C.; Schwartz, J . J . Am. Chem. Soc. 1996, 118, 5484-
5485.
(11) Fochi, G.; Guidi, G.; Floriani, C. J . Chem. Soc., Dalton Trans.
1984, 1253-1256.
(6) Coutts, R. S. P.; Wailes, P. C.; Martin, R. L. J . Organomet. Chem.
1973, 47, 375-382.
(7) Green, M. L. H.; Lucas, C. R. J . Chem. Soc., Dalton Trans. 1972,
1000-1003.
(8) G. M. Williams, Ph. D. Thesis, Princeton University, 1981.
(9) Barden, M. C.; Xu, M.; Schwartz, J . Unpublished results.
(10) See, Cuenca, T.; Royo, P. J . Organomet. Chem. 1985, 293, 61-
67.
(12) Fu¨rstner, A.; Csuk, R.; Rohrer, C.; Weidmann, H. J . Chem. Soc.,
Perkin Trans. 1 1988, 1729-1835.
(13) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
1991, 56, 4056-4058.
(14) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J . Am. Chem.
Soc. 1986, 108, 810-819.
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