Versatile configuration-encoded strategy for rapid synthesis of 1,5-polyol stereoisomers

Article abstract of DOI:10.1021/ol1021417

The isolated stereogenic centers of 1,5-polyol-containing natural products present challenges to synthesis and structure determination. To address this problem, a configuration-encoded strategy defines each configuration within a simple 4-(arylsulfonyl)bu

Full text of DOI:10.1021/ol1021417

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5016-5019
Versatile Configuration-Encoded
Strategy for Rapid Synthesis of
1,5-Polyol Stereoisomers
Gregory K. Friestad* and Gopeekrishnan Sreenilayam
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242, United States
gregory-friestad@uiowa.edu
Received September 8, 2010
ABSTRACT
The isolated stereogenic centers of 1,5-polyol-containing natural products present challenges to synthesis and structure determination. To
address this problem, a configuration-encoded strategy defines each configuration within a simple 4-(arylsulfonyl)butyronitrile building block,
a repeat unit that is reliably and efficiently coupled in iterative fashion to afford 1,5-polyols of defined stereochemistry. For example, the
C27-C40 subunit of tetrafibricin is prepared in five steps and 42% yield. This strategy is amenable to rapid and unambiguous preparation of
all configurational permutations of 1,5-polyols with equal facility.
Chiral 1,5-polyol substructures are present in natural products
offering a wide range of biological activities (Figure 1), such
as tetrafibricin (nonpeptide fibrinogen receptor antagonist)1
and muricapentocin (selective cytotoxicity for colon cancer
cell line HT-29: ED50 71 ng/mL),2 as well as lydicamycin
(antibiotic active against multidrug resistant strains),3 sporm-
inarin B (antifungal),4 and amphidinol 3 (hemolytic and
antifungal).5
Configurational assignments of isolated stereogenic centers
in the 1,5-polyol sectors of these natural products present
significant challenges, and in fact, many related compounds
lack complete assignments of stereostructure.2-4,6,7
Application of aldol bond construction strategies8 to 1,5-
polyols would encounter daunting regio- and stereoselection
problems in dehydration of alternating hydroxyl functions. New
synthetic strategies tailored specifically for access to 1,5-polyols
(1) Isolation, structure, and biological activity: (a) Kamiyama, T.; Umino,
T.; Fujisaki, N.; Fujimori, K.; Satoh, T.; Yamashita, Y.; Ohshima, S.;
Watanabe, J.; Yokose, K. J. Antibiot. 1993, 46, 1039–1036. (b) Kobayashi,
Y.; Czechtizky, W.; Kishi, Y. Org. Lett. 2003, 5, 93–96. (c) Satoh, T.;
Kouns, W. C.; Yamashita, Y.; Kamiyama, T.; Steiner, B. Biochem. J. 1994,
301, 785–791. Synthetic studies: (d) Bouzbouz, S.; Cossy, J. Org. Lett.
2004, 6, 3469–3472. (e) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 533–
536. (f) Zhang, K.; Curran, D. P. Synlett 2010, 667–671.
(4) Mudur, S. V.; Gloer, J. B.; Wicklow, D. T. J. Antibiot. 2006, 59,
500–506
.
(5) (a) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J. Am.
Chem. Soc. 1991, 113, 9859–9861. (b) Murata, M.; Matsuoka, S.;
Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999, 121,
870–871. (c) Paquette, L. A.; Chang, S.-K. Org. Lett. 2005, 7, 3111–3114.
(d) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411–1414. (e)
(2) Kim, G.-S.; Zeng, L.; Alali, F.; Rogers, L. L.; Wu, F.-E.; McLaugh-
lin, J. L.; Sastrodihardjo, S. J. Nat. Prod. 1998, 61, 432–436.
(3) Hayakawa, Y.; Kanamaru, N.; Morisaki, N.; Seto, H. Tetrahedron
Lett. 1991, 32, 213–216. Tamotsu, F.; Keitaro, E.; Tomomitsu, S.; Hiroko,
H.; Hirayasu, O.; Noriko, S.; Takeshi, F.; Hideo, N.; Yasuhiro, I. J. Antibiot.
2002, 55, 873–880.
BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451–1454.
(6) Plaza, A.; Baker, H. L.; Bewley, C. A. J. Nat. Prod. 2008, 71, 473–
477
.
(7) A novel liposomal circular dichroism method has been devised to
address the difficult structural analyses: MacMillan, J. B.; Molinski, T. F.
J. Am. Chem. Soc. 2004, 126, 9944–9945
.
10.1021/ol1021417  2010 American Chemical Society
Published on Web 10/12/2010

Figure 1. Structures of representative 1,5-polyol-containing bioactive natural products. Asterisks denote unknown configurations.
have attracted significant interest, leading to development of
an iterative allylation and cross metathesis approach by Cossy
et al.9 and a bidirectional double allylboration by Roush et al.10
These approaches to 1,5-polyols generate new stereogenic
centers during C-C bond construction, which creates a number
of configurational assignment problems, as the integrity of
reagent control must be rigorously confirmed at each stage.
chain (Scheme 1). The olefin functionality generated in this
coupling could be retained or reduced, accommodating 1,5-
polyol targets both saturated and unsaturated (Figure 1).
Scheme 1
We sought a conceptually new approach to 1,5-polyols that
would meet the following objectives: (a) carbon-carbon bond
construction would occur without generating stereogenic centers,
(b) preparation of all relative configurations would be equally
facile, and (c) rapid assembly would be achieved with simple
reagents. With these criteria in mind, we devised a configura-
tion-encoded approach that defines the stereogenic center of
each hydroxyl group within separate modules, prepared with
both R and S configurations and designed for iterative as-
sembly.11 With hydroxyl configurations independent from the
coupling chemistry, the desired configuration would be simply
and unambiguously fixed during synthesis by the selection of
building blocks at each stage of the iterative coupling sequence.
This strategy-level innovation would not only permit versatile
application to targets of known configurations but also facilitate
stereochemical assignments of 1,5-polyol natural products
through synthesis. Here, we report initial studies which validate
this strategy and an application to a concise synthesis of the
C27-C40 portion of tetrafibricin.
To initiate experimental efforts, we carefully selected a
reliable method for the key C-C coupling which would link
the configuration-encoded building blocks. We selected
Julia-Kocienski olefination12 as a well-established C-C
bond construction that takes place under moderately basic
conditions compatible with a wide range of functionalities.
Accordingly, the four-carbon building block would need
sulfone and aldehyde functionalities at the two termini, and
oligomer synthesis would proceed via addition of the sulfone
to the aldehyde functionality upon the growing 1,5-polyol
Next, we identified a functional equivalent for the aldehyde,
orthogonal to both O-silylprotection and Julia-Kocienski olefi-
nation. After some disappointing preliminary studies using protec-
tion of the aldehyde as an acetal, we turned to a nitrile as a masked
aldehyde, to be revealed by DIBAL-H reduction. This called for
preparation of R-silyloxy-γ-sulfononitrile 1 (Scheme 2).
Scheme 2
(8) Reviews: (a) Bode, S. E.; Wolberg, M.; Muller, M. Synthesis 2006,
557–588. (b) Kimball, D. B.; Silks, L. A. Curr. Org. Chem. 2006, 10, 1975–
1992.
(9) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451–1454. (b) Also
see ref 1d.
(10) (a) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
13644–13645. (b) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411–
1414. (c) Also see ref 1e.
(11) Oishi, T.; Kanemoto, M.; Swasono, R.; Matsumori, N.; Murata,
M. Org. Lett. 2008, 10, 5203–5206.
(12) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
Org. Lett., Vol. 12, No. 21, 2010
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Synthesis of the configuration-encoded building blocks
(R)-1 and (S)-1 (Scheme 2) commenced with addition of
commercially available 1-phenyl-1H-tetrazol-5-thiol (PTSH)
to acrolein to afford aldehyde 2, which was then subjected
to asymmetric addition of trimethylsilyl cyanide in the
Scheme 3
13
presence of catalyst 3·Ti(Oi-Pr)4 to afford cyanohydrin 4
in 83-86% ee.14 Without further optimization, the asym-
metric cyanation on ca. 10 g scale afforded (R)-4 (99% yield)
and (S)-4 (96% yield), with ligand recoveries of 92 and 71%,
respectively. Protection of the hydroxyl group as a tert-
butyldimethylsilyl ether and S-oxidation (H2O2, 4 mol %
ammonium molybdate) furnished sulfone (S)-1 in an overall
yield of 88% from commercial materials. Recrystallization
of (R)- or (S)-1 furnished enantiopure material (60%
recovery, one crop).
The initial Julia-Kocienski couplings (Table 1) of 1 were
very clean and highly selective. Metalation of 1 (NaHMDS
obtained in 98% yield (E/Z > 98:2, entry 1). Aliphatic (entry
2) and R-silyloxy-substituted aliphatic aldehydes (entries
3-6) also coupled efficiently, regardless of whether 1,5-syn
or 1,5-anti relative configurations were formed (entries 5 and
6).
Table 1. Julia-Kocienski Couplings of (R)-1a
Next, the unveiling of the masked aldehyde was examined.
Upon exposure to DIBAL-H, nitrile reduction of 5 smoothly
released the aldehyde 10 in 91% yield (eq 1) for a second
iteration of the coupling sequence. This completes one full
iteration in overall 88% yield.
The iterative approach was next tested in three successive
couplings of lactaldehyde 11 with (R)-1. The first iteration
gave 1,5-diol 12 in 76% yield over two steps (E/Z > 98:2);
a second iteration and third coupling afforded 1,5,9-triol 13
(67%, two steps) and 1,5,9,13-tetrol 14, respectively. In the
second and third couplings, minor Z isomers were not
1
observed in H NMR spectra; they presumably form in
amounts less than 5% (by analogy with the first coupling).
Finally, we examined application of this strategy toward
synthesis of the C27-C40 fragment of tetrafibricin, a
nonpeptide fibrinogen receptor antagonist17 inhibiting platelet
aggregation by blocking glycoprotein interactions at the
platelet surface. Tetrafibricin is the subject of ongoing
synthetic efforts.1 The most advanced route reported to date
(13) Qin, Y. C.; Liu, L.; Pu, L. Org. Lett. 2005, 7, 2381–2383.
(14) Configurations were assigned via MPA esters: Louzao, I.; Seco,
J. M.; Quin˜oa´, E.; Riguera, R. Chem. Commun. 2006, 142, 2–1424.
(15) (a) A control experiment detected no loss of enantiopurity in (R)-1
after treatment with NaHMDS in THF and quenching with water. (b) Use
of NaHMDS in refluxing benzene for metallation of O-alkylcyanohydrin:
Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275–1276. (c) To
our knowledge, selective metallation and/or Julia coupling of a sulfone
bearing remote O-alkyl- or O-silylcyanohydrin functionality has not been
previously reported.
a Conditions: (R)-1, base (1.2 equiv, NaHMDS or KHMDS), -78 °C,
45 min; then aldehyde (1.0 equiv), -78 °C to ambient temperature, 3 h.
b KHMDS was employed. c NaHMDS was employed. d E/Z ratio measured
by integration of the 1H NMR spectrum. e 1H NMR peaks for the Z isomer
were not observed.
(16) Measurements of E/Z ratios were accomplished by integration of
an 1H NMR resonance attributed to an olefin proton of the minor Z isomer,
appearing upfield of the major olefin protons. In cases where such a
resonance could not be integrated (either not present or not resolved), the
ratio was recorded in Table 1 as >95:5.
or KHMDS, -78 °C)15 and coupling with a variety of
aldehydes afforded the expected adducts (E/Z ratios from
95:5 to >98:2, Table 1).16 With benzaldehyde, adduct 5 was
5018
Org. Lett., Vol. 12, No. 21, 2010

Scheme 4
is that of Curran, who reported syntheses of C1-C20 and
The approach employs asymmetric catalysis to install the
oxygen-bearing stereogenic centers, in contrast to existing
approaches using stoichiometric chiral reagents. The key
innovation in this 1,5-polyol synthesis is at the strategy level,
encoding the hydroxyl configuration within a simple repeat-
ing unit that is efficiently and cheaply prepared via a scalable
route. Using reliable Julia-Kocienski coupling, facile as-
sembly of all stereochemical permutations of any given 1,5-
polyol may be readily envisioned, with configurations
programmed by selection of building blocks.
C21-C40 fragments in 14 steps (2.2% yield) and 17 steps
(2.6% yield), respectively; fragment coupling has not been
reported.1f,18
From aldehyde 1519 (80% ee), we have prepared the
C27-C40 fragment of tetrafibricin in five steps and 42%
yield using two iterations of configuration-encoded Julia-
Kocienski coupling (Scheme 4). Coupling in the first iteration
gave 16a (E/Z ) 95:5, 1H NMR), and then reduction of the
nitrile function unveiled aldehyde 16b (78% yield, plus 14%
recovery of 16a) for the second iteration. Another coupling
with (S)-1 and reduction afforded 17b. Homologation with
a stabilized ylide afforded R,ꢀ-unsaturated aldehyde 18,
isolated as a single isomer in 89% yield, completing the
assembly of the C27-C40 carbon skeleton of tetrafibricin.
In this last step, the small quantities of minor isomers (5%
combined yield) indicated very high selectivities in all of
the Julia-Kocienski olefinations en route to 18, and by
analogy, those shown in Scheme 3.
Acknowledgment. We thank the University of Iowa for
support (MPSFP award to GKF, Graduate College Fellow-
ship to GS, and Faculty Scholar Award to GKF).
Supporting Information Available: Preparative and
characterization data for 1-18. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have designed a concise and extremely
efficient strategy for stereocontrolled synthesis of 1,5-polyols.
OL1021417
(17) Satoh, T.; Kouns, W. C.; Yamashita, Y.; Kamiyama, T.; Steiner,
B. Biochem. J. 1994, 301, 785–791.
(19) (a) Prepared from PMBOCH2CH2CHO by asymmetric cyanation
and reduction with DIBAL-H. See Supporting Information. (b)
PMBOCH2CH2CHO: Oka, T.; Murai, A. Tetrahedron 1998, 54, 1–20. Cink,
R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672–5673.
(18) Gudipati, V. Ph.D. Thesis, University of Pittsburgh, 2008. We thank
Professor Dennis Curran for providing a copy of this thesis.
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