Radical-based asymmetric synthesis: an iterative approach to 1, 3, 5, ... (2n + 1) polyols.

Article abstract of DOI:10.1021/ol990188v

[formula: see text] A conceptually novel approach to 1, 3, 5, ... (2n + 1) polyols based on iterative stereo-controlled homologation of chiral hydroxyalkyl radicals is reported. Starting from alpha-keto ester precursors, the general sequence of (1) ketone

Full text of DOI:10.1021/ol990188v

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1057-1059
Radical-Based Asymmetric Synthesis:
An Iterative Approach to 1, 3, 5, ...
(2n + 1) Polyols
Philip Garner* and James T. Anderson
Department of Chemistry, Case Western ReserVe UniVersity,
CleVeland, Ohio 44106-7078
ppg@po.cwru.edu
Received July 23, 1999
ABSTRACT
A conceptually novel approach to 1, 3, 5, ... (2n + 1) polyols based on iterative stereocontrolled homologation of chiral hydroxyalkyl radicals
is reported. Starting from r-keto ester precursors, the general sequence of (1) ketone reduction, (2) auxiliary attachment, (3) saponification,
(4) Barton esterification, and (5) radical addition provided the two-carbon homologue in 70−80% overall yield. The simplicity and generality of
this iterative strategy for 1, 3, 5, ... (2n + 1) polyol synthesis suggests an attractive alternative for the preparation of molecules containing this
structural motif.
The 1, 3, 5, ... (2n + 1) polyol array is a structural theme
found in many macrolide antibiotics (cf., roflamycoin in
Figure 1) that continues to attract the attention of synthetic
demonstrated over the years,3 despite the successful applica-
tion of iterative strategies to other molecules made up of
repeating subunits (polypeptides and oligonucleotides, for
example). We now report an iterative approach to 1, 3, 5, ...
(2n + 1) polyols based on the stereocontrolled homologation
of chiral hydroxyalkyl radicals.4 Advantages of this protocol
include (1) chemical reactions that are high-yielding and
convenient to perform, (2) the ability to introduce either (R)-
or (S)-configured secondary alcohols selectively during the
C-C bond-forming event, and (3) use of multifunctional and
reusable chiral auxiliaries derived from D-glucose. The
chemistry described herein may also be amenable to eventual
polymer-supported synthesis of 1, 3, 5, ... (2n + 1) polyols.
Figure 1.
(3) (a) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719. (b) Ma,
P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem.
1982, 47, 1378. (c) Nicolaou, K. C.; Uenishi, J. J. Chem.. Soc., Chem.
Commun. 1982, 1292. (d) Lipshutz, B. H.; Kozlowski, J. A. J. Org. Chem.
1984, 49, 1147. (e) Rychnovsky, S. D.; Griesgraber, G. J. Org. Chem. 1992,
57, 1559. (f) Palomo, C.; Aizpurua, J. M.; Urchegui, R.; Garc´ıa, J. M. J.
Org. Chem. 1993, 58, 1646. (g) Mori, Y.; Asai, M.; Okumura, A.; Furukawa,
H. Tetrahedron 1995, 51, 5299. (h) Kiyooka, S.; Yamaguchi, T.; Maeda,
H.; Kira, H.; Hena, M. A.; Horiike, M. Tetrahedron Lett. 1997, 38, 3553.
(i) Paterson, I.; Wallace, D. J.; Gibson, K. R. J. Org. Chem. 1997, 38, 8911.
(4) (a) Garner, P. P.; Cox, P. B.; Klippenstein, S. J. J. Am. Chem. Soc.
1995, 117, 4183. (b) Garner, P.; Leslie, R.; Anderson, J. T. J. Org. Chem.
1996, 61, 6754.
chemists.1 Perhaps the simplest and most general retrosyn-
thetic disconnection of any 1, 3, 5, ... (2n + 1) polyol system
of variable stereochemistry would follow Nature’s iterative
use of two-carbon (acetate) building blocks.2 Surprisingly
few iterative 1, 3, 5, ... (2n + 1) polyol syntheses have been
(1) (a) Oishi, T.; Nakata, T. Synthesis 1990, 635. (b) Rychnovsky, S. D.
Chem. ReV. 1995, 95, 2021.
(2) Aparicio, J. F.; Colina, A. J.; Ceballos, E.; Martin, J. F. J. Biol. Chem.
1999, 274, 10133.
10.1021/ol990188v CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/04/1999

Scheme 1
Scheme 2
The sequence (Scheme 1) begins with an O-glycosylated
R-hydroxy acid such as 1, which is readily prepared from
the corresponding R-hydroxy ester and D-glucal derivative
25 using chemistry that we have previously described (ref
4). Since the substrate’s stereocenter will be lost during
radical formation, the configurational integrity of the starting
R-hydroxy ester has no bearing on subsequent chemistry.
Note that the chiral auxiliary used differs from our original
version in that C-6 is now fully substituted (CH2OBn f
CMe2OBn). This modification leads to enhanced stereocon-
trol in accord with an earlier study6 yet also retains other
favorable properties such as exclusive formation of the
R-anomer during glycosylation and increased stability of the
2-deoxyglucoside. Application of our improved Barton
esterification protocol7 resulted in fast (<30 min) and
quantitative conversion to 3 which was then photolyzed using
a sunlamp in the presence of excess ethyl trifluoroacetoxy-
acrylate (4), an easily prepared compound which is known8
to be an efficient radical trap. The initial adduct 5 was not
isolated but hydrolyzed directly (in situ?) to produce the
R-keto ester 6 in 80-90% yield after flash chromatography.
The diasteoselectivity was on the order of 10/1 when the
radical addition was performed at 0 °C but can be raised
significantly simply by going to lower reaction temperatures
(diasteoselectivity >20/1 at -78 °C). The absolute config-
uration shown for the newly formed stereocenter in 6 is that
expected from our previously proposed TS model (see ref
4a).
stereocenter. Introduction of a second D-auxiliary followed
by ester saponification led to the carboxylic acids 8.
Subjection of these free acids to HOTT-mediated Barton
esterification followed by photolytic radical addition to a 10-
fold excess of 4 resulted in the clean formation of “DD” or
“syn” product 9. Access to the complementary “DL” or “anti”
product 12 was effected using the same chemistry but simply
employing the easily obtainable pseudo-antipodal glucal 1010
instead of 2 in the “aux-on” step. It should be mentioned
that no evidence of â-anomer formation was detected during
the introduction of either the D- or L-auxiliaries. The overall
yield of both sequences was 70-80% and the diastereo-
selectivity (at 0 °C) was about 10/1 as judged by H NMR
integration.
Conclusive proof of structure came from the conversion11
of 9 and 12 to the diastereomeric acetonides 13 and 15
followed by analysis of their respective 13C NMR spectra
according to Rychnovsky (see Figure 2).12 The complemen-
1
The iterative homologation sequence (Scheme 2)9 com-
menced with the reduction of 6 by NaBH4 to produce a
mixture of diastereomeric R-hydroxy esters 7 in nearly
quantitative yield. (Recall that the configuration at this center
is irrelevant.) At this point, the synthetic path diverged
depending on what configuration was desired at the incipient
(5) Prepared in 24% overall yield from inexpensive ($0.20/g) D-(+)-
glucurono-6,3-lactone via the following six-step sequence: (1) MeOH,
catalytic NaOMe; (2) Ac2O, catalytic HClO4; (3) 30 wt % HBr/AcOH; (4)
Zn dust, CuSO4‚5H2O, buffered aqueous HOAc; (5) excess MeMgCl, THF,
0 °C f rt; (6) NaH, BnBr, Bu4NI, DMSO. See: Fehlhaber, H.-W.; Snatzke,
G.; Vlahov, I. Liebigs Ann. Chem. 1987, 637.
Figure 2.
(6) Garner, P.; Anderson, J. T. Tetrahedron Lett. 1997, 38, 6647.
(7) HOTT ) (S-1-oxido-2-pyridinyl) 1,1,3,3-tetramethylthiouronium
hexafluorophosphate: Garner, P.; Anderson, J. T.; Dey, S.; Youngs, W. J.;
Galat, K. J. Org. Chem. 1998, 63, 5732.
(8) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. Cs. Tetrahedron 1995,
51, 1867.
tary stereochemical course of these two routes (6 f 9 and
6 f 12) showed that the radical additions are exclusively
under auxiliary control. Accordingly, it should be possible
1058
Org. Lett., Vol. 1, No. 7, 1999

to access any polyol configuration by proper choice of
auxiliary. This sequence also allowed for efficient recovery
of the D- and L-auxiliaries in the form of their respective
thioglycosides 14 and 16, which can be recycled back to
the starting glucals (cf., ref 4b). It is noteworthy that the
iterative homologation protocol described here allows for
ready differentiation of the polyol chain termini and internal
hydroxyl functions, as would be required for the synthesis
of roflamycoin. In this context, the chiral auxiliaries are
multifunctional in that they may also serve as acid-labile
protecting groups during subsequent synthetic operations.
The simplicity and generality of this iterative strategy for 1,
3, 5, ... (2n + 1) polyol synthesis suggest an attractive
alternative for the synthesis of molecules containing this
structural motif.
Acknowledgment. This work was supported by the
National Science Foundation under grant CHE-9616632.
Special thanks to the Orlando Research Group (Complex
Carbohydrate Research Center, University of Georgia) for
performing the MALDI-TOF mass spectrometry. The mass
spectrometer was obtained with funds from NIH grant S10
RR12013.
(9) General iterative homologation protocol (6 f 9 or 12): (1) NaBH4
(0.25 equiv, 0.1 M)/EtOH, 0 °C, 5 min; (2) glucal 2 or 10 (1.5 equiv, 0.2
M), HBr‚PPh3 (5 mol %)/DCM, RT; flash chromatography; (3) 1 N aqueous
NaOH (6 equiv)/1:1 THF-iPrOH; (4) HOTT (1.5 equiv, 0.1 M), Et3N (3.0
equiv), DMAP (0.1 equiv)/3:1 THF-MeCN, 30 min, rt; (5) add trap 4 (10
equiv), hν (sun lamp), <30 min, 0 °C.; concentrate then SiO2/EtOAc; flash
chromatography.
(10) Prepared in 27% overall yield from very inexpensive ($0.08/g) R-D-
glucoheptonic γ-lactone via the following nine-step sequence: (1) PhCHO,
catalytic HCl; (2) aqueous NaIO4; (3) hot 1 N HCl; (4) MeOH, catalytic
NaOMe; (5) Ac2O, catalytic HClO4; (6) 30 wt % HBr/AcOH; (7) Zn dust,
CuSO4‚5H2O, buffered aqueous HOAc; (8) excess MeMgCl, THF, 0 °C
f rt; (9) NaH, MeI, THF.
(11) Synthetic sequence for 9 f 13 (42% overall yield) and 12 f 15
(35% overall yield): (1) LAH/THF; (2) aqueous NaIO4; (3) NaBH4/MeOH;
(4) Ac2O-pyridine; (5) PhSH, BF3‚OEt2 (isolate 14 and/or 16 by flash
chromatography, 86-88% yield); (6) DMP, catalytic TsOH.
(12) Rychnovsky, S. D.; Griesgraber, G.; Schlegel, R. J. Am. Chem. Soc.
1995, 117, 197.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1-16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL990188V
Org. Lett., Vol. 1, No. 7, 1999
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