Angewandte
Chemie
isomers.[7] These four compounds served as controls for the
success of our exercise.
passifloricin. Demixing of M-6b provided the other four
isomers (not shown). All eight isomers of 6 were deprotected
individually by exposure to 3n HCl in EtOH. Products 1 were
purified by flash chromatography and normal-phase HPLC to
provide the eight-member library including (ent)-passifloricin
A (5S,7R,9R,12R-1) and its seven diastereomers with R
configurations at C12 and all the possible configurations at
C5, C7, and C9.[10]
Unlike previous libraries that we have made with remote
stereocenters,[1c] each member of this library exhibited unique
1H and 13C NMR spectra. Samples of passifloricin and three
isomers from Marco and co-workers[7b] were identical to the
four expected products 1 in our library, thus demonstrating
that the tagging and demixing process was successful. The
exercise confirms the stereostructure of passifloricin by
rigorously proving that it is not any of the other seven
possible stereoisomers.
This strategy of fluorous mixture synthesis with the
introduction and tagging of stereocenters en route is a
powerful new approach to making stereoisomer libraries
with significant savings in effort. The mixture synthesis phase
of this work required only 18 chemical reactions, whereas the
same synthesis conducted in serial fashion would have
required 44 reactions. The route also economizes tags, as
four pairs of isomers were made by using three tags, only two
of which were fluorous. Eight isomers could be made in a
single mixture with five tags, 16 isomers with 9 tags, and so on.
Central to this approach is the approximate additivity of the
fluorine content of the tags as expressed by elution order in
the demixing. Although demonstrated in an en route setting,
the tactic of using multiple tags is equally applicable in
settings in which pretagged building blocks are assembled.[11]
Enantiopure allyl silyl ether (R)-2 (> 99% ee) was
subjected to a sequence of hydroboration and oxidation.
Half of the resulting aldehyde was treated with the (R,R)-DH
reagent, and the resulting alcohol (82%, d.r. = 98:2) was
tagged with fluorous triisopropylsilyl trifluoromethanesulfo-
nate (FTIPSOTf) bearing a C4F9 group (81%).[9] The other
half was treated with the (S,S)-DH reagent, and the alcohol
F
(83%, d.r. = 2:98) was tagged with the TIPS group bearing
C3F7 (95%). The resulting quasi-diastereomers were mixed to
make M-3 for the second cycle.
The terminal carbon atom of the allyl group is not needed
in cycle 2, so the aldehyde was generated by oxidative
cleavage (OsO4/N-methylmorpholine N-oxide (NMO), then
NaIO4, 73%) of M-3. Now division and allylation as above (91
and 88%, respectively) were followed by tagging; the product
from the (R,R)-DH reagent received the new “null” (non-
fluorous) TIPS tag (90%), and the product from the (S,S)-DH
reagent received the repeat C3F7 tag. The resulting pair of
two-compound mixtures was mixed to make a four-compound
mixture of quasi-diastereomers M-4 in preparation for
cycle 3.
Cycle 3 was identical to cycle 2 through oxidation (73%)
and allylation (93 and 80%) but was then interrupted to
complete the synthesis. The resulting two mixtures of four
compounds M-5a,b were acylated with cinnamoyl chloride
(83 and 78%), and the crude products were directly subjected
to ring-closing metathesis with the second-generation Grubbs
catalyst[6,7] (85 and 92%). This process provided the full
stereoisomer library of protected passifloricins as two mix-
tures of four compounds M-6a,b.
The product structures and retention times for the
preparative demixing of M-6a are shown in Scheme 2. The
Received: January 4, 2006
Published online: March 9, 2006
Keywords: allylation · asymmetric synthesis · fluorous tags ·
.
mixture synthesis · separation tags
[1]a) Z. Luo, Q. Zhang, Y. Oderaotoshi, D. P. Curran, Science 2001,
291, 1766 – 1769; short reviews: b) W. Zhang, Arkivoc 2004, 101 –
109; c) Q. Zhang, D. P. Curran, Chem. Eur. J. 2005, 11, 4866 –
4880.
[2]a) D. P. Curran, T. Furukawa, Org. Lett. 2002, 4, 2233 – 2235;
b) W. Zhang, Z. Luo, C. H.-T. Chen, D. P. Curran, J. Am. Chem.
Soc. 2002, 124, 10443 – 10450; c) Q. Zhang, H. Lu, C. Richard,
D. P. Curran, J. Am. Chem. Soc. 2004, 126, 36 – 37; d) S.
Dandapani, M. Jeske, D. P. Curran, Proc. Natl. Acad. Sci. USA
2004, 101, 12,008 – 12,012; e) S. Manku, D. P. Curran, J. Comb.
Chem. 2005, 7, 63 – 68.
Scheme 2. Demixing of M-6a by fluorous HPLC: the quasi-diastereo-
mers emerge in order of increasing total fluorine content.
[3]D. P. Curran in The Handbook of Fluorous Chemistry (Eds.:
J. A. Gladysz, D. P. Curran, I. T. Horvµth), Wiley-VCH, Wein-
heim, 2004, pp. 101 – 127; and D. P. Curran in The Handbook of
Fluorous Chemistry (Eds.: J. A. Gladysz, D. P. Curran, I. T.
Horvµth), Wiley-VCH, Weinheim, 2004, pp. 128 – 156.
[4]a) Redundant tagging: S. Manku, D. P. Curran, J. Org. Chem.
2005, 70, 4470 – 4473; b) double tagging with fluorous and
oligoethylene glycol tags: C. S. Wilcox, V. Gudipati, H. Lu, S.
Turkyilmaz, D. P. Curran, Angew. Chem. 2005, 117, 7098 – 7100;
Angew. Chem. Int. Ed. 2005, 44, 6938 – 6940.
samples were injected on a PF-C8 fluorous HPLC column,[9]
which was eluted over 60 minutes with a gradient from 80%
MeCN/water to 100% MeCN. The approximate additivity of
the fluorine content of the tags was indeed observed, with the
quasi-isomer of 6 bearing 7 fluorine atoms emerging first,
followed in turn by those with 9, 14, and 16 fluorine atoms.
These four major fractions were collected and concentrated to
provide the four individual, protected quasi-isomers of
Angew. Chem. Int. Ed. 2006, 45, 2423 –2426
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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