The importance of the bis-THF alcohol in drug discovery
has generated a significant interest in the synthesis. One
glycolaldehyde dimer (5) would serve as the ultimate
electrophile for the catalyzed reaction. In an ideal case, this
3
4
approach utilized substrate-controlled synthesis starting from
a chiral pool material like D-glyceraldehyde derivatives.
would give the target bis-THF alcohol (3) in a single step
from the most simple carbohydrate and 2,3-DHF.5
The equilibrium of glycolaldehyde (6) and its dimer (5)
3
b-d
The most notable synthesis along this approach is the recently
reported synthesis by Quaedflieg and co-workers starting
from S-2,3-O-isopropylideneglyceraldehyde.3b Generally,
good stereochemical control was reported with this approach.
Another approach involved the synthesis of the racemic form
6
has been a subject for several reports (Scheme 1). We
Scheme 1
3
a,e-g
of bis-THF alcohol followed by enzymatic resolution.
Despite the need for multiple steps to establish the relative
stereochemistry of the bicyclic structure prior to the enzy-
matic resolution, this synthetic approach has been demon-
strated to be highly practical. One such synthesis has been
3g
scaled up to tonnage quantity in production of 1. Recently,
Ghosh reported an asymmetric synthesis based on an anti-
3i
aldol reaction of an ester-derived titanium enolate. However,
this is still a substrate-controlled synthesis requiring a
stoichiometric amount of a chiral indanol.
Our goal was to achieve an efficient synthesis of the bis-
THF alcohol 3 in high optical purity through a short and
stereoselective synthesis employing catalytic reagent control
as shown in Figure 2. The bicyclic [2.2.0] ring structure of
anticipated that the cycloaddition would drive the equilibrium
from 5 to 6. The desired product 3 and diastereomeric
compound 7 correspond to the anti and syn additions of 4
to 6, respectively, prior to the ring closure.
We were initially drawn to the Evans pybox (8) and box
(
9) ligands because of their wide use in a variety of reactions
7
involving (benzyloxy)acetaldehyde. We were delighted to
find that a mixture of 2,3-DHF (4) and half equivalent of
glycolaldehyde dimer (5) in the presence of 2 mol % of
6 2
[Cu((S,S)-Ph-pybox)](SbF ) gave rise to a mixture of cyclo-
adducts 3 and 7 at ambient temperature. Both diastereo and
enantio selectivities were obtained by analysis of the crude
reaction mixture in a chiral GC with a racemic reference as
Figure 2. Strategy for asymmetric synthesis of bis-tetrahydrofuran
alcohol 3.
3g
1
well as an enantiomerically pure sample of 3. In H NMR
analysis, the doublets for the acetal H of 3 and 7 were well
separated and highly diagnostic at 5.7 and 5.9 ppm,
respectively. Although the diastereo (70:30 for 3/7) and
enantio (57:43 for 3 favoring the desired 3R-alcohol as
shown) selectivities were modest, the observation that the
skeleton of the bis-THF alcohols was established in a single
step prompted us to further examine the reaction. Also, the
desired diastereomer 3 resulting from anti addition of 4 to 6
was favored over the syn adduct 7, albeit in modest ratio.
This is in contrast with the extremely high syn selectivity
3
means that only one of the two bridge-head stereocenters
needs to be controlled, and the other stereocenter is formed
in the cyclization. This line of thinking led to postulation of
an oxonium-like intermediate A. The two stereocenters in
A would require the addition of 2,3-dihydrofuran (2,3-DHF,
4) to a complex of glycolaldehyde and the chiral catalyst
(
ML* ) in the anti fashion. The commercially available
2
(
3) (a) Surleraux, D. L. N. G.; Tahri, A.; Verschueren, W. G.; Pille, G.
M. E.; de Kock, H. A.; Jonckers, T. H. M.; Peeters, A.; De Meyer, S.;
Azijn, H.; Pauwels, R.; de Bethune, M.-P.; King, N. M.; Prabu-Jeyabalan,
M.; Schiffer, C. A.; Wigerinck, P. B. T. P. J. Med. Chem. 2005, 48, 1813.
(4) Glycolaldehyde dimer, commercially available from Sigma-Aldrich,
is used in food industry as a flavoring and browning agent and was
reportedly produced in large scale from the pyrolysis of sawdust: Stradal,
J. A.; Underwood, G. L. US Patent 5,393,542, 1995.
(
b) Quaedflieg, P. J. L. M.; Kesteleyn, B. R. R.; Wigerinck, P. B. T. P.;
Goyvaerts, N. M. F.; Vijn, R. J.; Liebregts, C. S. M.; Kooistra, J. H. M.
H.; Cusan, C. Org. Lett. 2005, 7, 5917. (c) Ghosh, A. K.; Leshchenko, S.;
Noetzel, M. J. Org. Chem. 2004, 69, 7822. (d) Ghosh, A. K.; Kincaid, J.
F.; Walters, D. E.; Chen Y.; Chaudhuri, N. C.; Thompson, W. J.; Culberson,
C.; Fitzgerald, P. M. D.; Lee, H. Y.; McKee, S. P.; Munson, P. M.; Duong,
T. T.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.; Axel, M. G.; Lin, J.;
Huff, J. R. J. Med. Chem. 1996, 39, 3278. (e) Ghosh, A. K.; Chen. Y.
Tetrahedron Lett. 1995, 36, 505. (f) Ghosh, A. K.; Thompson, W. J.;
Fitzgerald, P. M. D.; Culberson, J. C.; Axel, M. G.; McKee, S. P.; Huff, J.
R.; Anderson, P. S. J. Med. Chem. 1994, 37, 2506. (g) Roberts, J. C.;
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M.; Hirai, M.; Nagata, M.; Katoh, R.; Ogawa, R.; Ohta, A. Tetrahedron
Lett. 2001, 42, 4653. (i) Ghosh, A. K.; Li, J.; Perali, R. S. Synthesis 2006,
(5) During the preparation of this manuscript, we noted a publication
by Yu and co-workers in November 2007 using the same strategy: Yu, R.
H.; Polniaszek, R. P.; Becker, M. W.; Cook, C. M.; Yu, L. H. L. Org.
Process Res. DeV. 2007, 11, 972. Our work with a much higher anti
diastereoselectivity to avoid the need of oxidation-reduction for OH inversion
was independently conceived and presented in ACS ProSpectives Sympo-
sium on Process Chemistry, Boston, MA, in September, 2007.
(6) (a) George, W. O.; Collins, G. C. S. J. Chem. Soc, Phys. Org. 1971,
1352. (b) Stassinopoulou, C. I.; Zioudrou, C. Tetrahedron 1972, 28, 1257.
(c) Wolfe, J.; Nemeth, D.; Costero, A.; Rebek, J., Jr. J. Am. Chem. Soc.
1988, 110, 983. (d) Gennari, C.; Molinari, F.; Bartoletti, M.; Piarulli, U.;
Potenza, D. J. Org. Chem. 1991, 56, 3201.
(7) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos,
K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669.
3
015.
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