De novo asymmetric synthesis of daumone via a palladium-catalyzed glycosylation

Article abstract of DOI:10.1021/ol051383e

(Chemical Equation Presented) The enantioselective syntheses of daumone and two analogues have been achieved in seven to eight steps. This route relies upon a diasteroselective palladium-catalyzed glycosylation reaction for the formation of the anomeric b

Full text of DOI:10.1021/ol051383e

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3921-3924
De Novo Asymmetric Synthesis of
Daumone via a Palladium-Catalyzed
Glycosylation
Haibing Guo and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received June 13, 2005
ABSTRACT
The enantioselective syntheses of daumone and two analogues have been achieved in seven to eight steps. This route relies upon a
diasteroselective palladium-catalyzed glycosylation reaction for the formation of the anomeric bond. The asymmetry of the sugar and aglycone
portion of daumone were introduced by Noyori reduction of an acylfuran and a propargyl ketone. A highly diastereoselective epoxidation and
reductive ring opening established the desired C-2 and C-4 stereochemistry of daumone.
The recently purified pheromone daumone (1) has attracted
significant attention for its ability to induce a dauer stage in
Caenorhabditis elegans.1 When C. elegans enter this dauer
stage, they are capable of enduring various severe environ-
mental conditions (e.g., overpopulation and starvation).2
Because the C. elegans in the dauer stage appear not to
age and experience extended lifetimes, there has been great
interest in understanding the biochemical mechanism by
which daumone regulates this process.3 These studies have
been significantly limited by the fact that neither pure
daumone was available nor was the chemical structure of
daumone known.4 Recently, this problem has been alleviated
by the extensive work of Jeong et al., who have isolated,
characterized, and completed the total synthesis of daumone.
Due to its fascinating biological activity, we desired access
to synthetic samples of daumone, as well as several
analogues.
In particular, we were also interested in preparing daumone
via a de novo route that would take advantage of our recently
developed palladium-catalyzed glycosylation reaction.5,6 This
route should allow for access not only to the desired natural
product for biological study but also to analogues. Herein
we report our successful endeavors toward the de novo
synthesis of daumone, as well as a C-2 deoxy-analogue and
a C-3 oxygenated analogue.
While in terms of overall efficiency the Jeong synthesis
of daumone set quite a high standard (Scheme 1), it did not
Scheme 1. Jeong’s Approach to Daumone (1)
(1) Viney, M. F.; Franks, N. R. Naturwissenschaften 2004, 91, 123-
124.
(2) (a) Bargmann, C. I.; Horvitz, H. R. Science 1991, 251, 1243-1246.
(b) Gordon, J. W.; Riddle DeV. Biol. 1984, 102, 368-378. (c) Cassada, R.
C.; Russell, R. L. DeV. Biol. 1975, 46, 326-342.
(3) (a) Apfeld, J.; Kenyon, C. Nature 1999, 402, 804-809. (b) Bird, D.
M.; Opperman, C. H. J. Nematol. 1998, 30, 299-308.
(4) Jeong, P.-Y.; Jung, M.; Yim, Y.-H.; Kim, H.; Kim, K.; Paik, Y.-K.
Nature 2005, 433, 541-545.
meet all of our requirements. In particular, we wanted a route
that allowed for the late-stage introduction of a hydride.7
The Jeong route to daumone derives the asymmetry from
10.1021/ol051383e CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/06/2005

chiral fragments, these being L-rhamnose and (R)-propylene
oxide. In contrast, we looked to prepare daumone from
achiral starting materials using asymmetric catalysis to set
the asymmetry without losing any overall efficiency.8 Hence,
this synthetic endeavor should serve as an excellent test to
our de novo asymmetric approach to carbohydrate containing
natural products.5
Scheme 3. Synthesis of Aglycone Precursor 6
Retrosynthetically, we envisioned the 3-deoxy-L-rhamnose
of daumone being derived from a diastereoselective alkene
hydration and ketone reduction of the pyranone ring in 4
(Scheme 2). The glycosidic bond of pyranone 4 could be
Scheme 2. Daumone (1) Retrosynthesis
lithium acetylide of 10 with acetic anhydride (76%). Expo-
sure of the propagyl ketone 10 to our modified Noyori
conditions10 provided excellent yield (81%) of propargyl
alcohol 11 with high enantiomeric purity (>96% ee). Finally,
the triple bond in 11 was cleanly reduced (H2, 10% Pd/C)
to give a good yield of 6 (82%, 63% overall yield from
alkyne 9).
With a reliable route to optically pure aglycone pre-
cursor 6 in hand, we next looked into the preparation of its
pyranone coupling partner 5 (Scheme 4). This was quite
stereoselectively installed by a palladium-catalyzed coup-
ling of the pyranone 5 and alcohol 6. Finally, it was
envisioned that the absolute stereochemistry of both 5 and
6 could be established by applying two Noyori reduc-
tions of acylfuran 7 and propargyl ketone 8, respectively.9
Because this route couples two chiral subunits, it requires
that both Noyori reactions occur with nearly complete
enantiocontrol.
Scheme 4. Synthesisof R-Pyranone 5
The synthesis of the aglycone precursor 6 begins with
4-pentynol 9 (Scheme 3), which was protected to give
TBS-ether 10 with TBSCl/imidazole in DMF (99%). The
terminal alkyne in 10 was converted into propargyl ke-
tone 8 by two procedures. Either metalation of 10 with
n-BuLi and then quenching with acetaldehyde followed by
MnO2 oxidation (98%) or in one step by quenching the
(5) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406-12407. (b) Babu, R. S.; M. Zhou; O’Doherty, G. A. J. Am. Chem.
Soc. 2004, 126, 3428-3429. (c) Babu, R. S.; O’Doherty, G. A. J.
Carbohydr. Chem. 2005, 24, 169-177.
(6) For the work of others, see: (a) Comely, A. C.; Eelkema, R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 8714-
8715. (b) Kim, H.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 1336-
1337.
easily accomplished by use of an Achmatowicz reaction
of furan alcohol 12.11 Once again employing the Noyori
(7) We envisioned that by incorporating a late-stage ketone reduction
the new route would be amenable to the incorporation of a tritium label.
For similar examples of label incorporation, see: Weigel, T. M.; Liu,
H.-W. Tetrahedron Lett. 1988, 29, 4221-4224.
(8) For alterative approaches to sugars, see: (a) McDonald, F. E.; Reddy,
K. S.; Diaz, Y. J. Am. Chem. Soc. 2000, 122, 4304-4309. (b) McDonald,
F. E.; Wu, M. Org. Lett. 2002, 4, 3979-3981.
(9) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522. (b) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2001, 40, 40-73.
(10) Previously, we have shown that a lower ratio of HCO2H/Et3N (1:1
instead of 2:1) was required for the Noyori reduction of compounds with
primary TBS groups; see: Li, M.; Scott, J. G.; O’Doherty, G. A.
Tetrahedron Lett. 2004, 45, 1005-1009.
3922
Org. Lett., Vol. 7, No. 18, 2005

reduction, with the enantiomeric catalyst, the furan alcohol
12 can be prepared from acylfuran in very high enantio-
meric excess (93% yield and >96% ee).12 Treating furan
alcohol 12 with typical Achmatowicz conditions (NBS in
THF/H2O) gave a good yield of the ring-expanded pyranone
product 13 (91%). The hemiacetal of 13 was then diaste-
reoselectively acylated with (Boc)2O to provide the Boc-
protected pyranone 5 in excellent overall yield (66%) from
acylfuran 7.
the epoxide 15 was regioselectivly opened with LiAlH4 to
form 16 in 88% yield.14
By combining the ketone reduction with the epoxide
opening reaction, we achieved a one-step conversion of
epoxy-enone 14 to diol 16 (Scheme 6). Thus, exposing 14
Scheme 6. Conversion of 13 to Daumone (1)
As outlined in Scheme 5, we next investigated the
glycosylation reaction of alcohol 6 with pyranone 5 followed
Scheme 5. Palladium-Catalyzed Glycosylation and
Postglycosylation Transformation
to LiAlH4 at -78 °C followed by warming to room
temperature cleanly provided 16 in an 86% yield.15 With
the required stereochemistry of daumone installed in 16, all
that remained was the deprotection of the TBS-ether and
the chemoselective oxidation of the primary alcohol to
the carboxylic acid. This deprotection was most easily
accomplished by exposing 16 to TBAF (98%). Finally, the
triol 17 was cleanly oxidized to daumone (1) using a catalytic
TEMPO procedure (61%).16 We found that the spectral data
for synthetic daumone (1) matched what was reported for
the isolated natural product in terms of IR, 1H and 13C NMR,
and optical rotation.4,17
by the subsequent conversion of the product enone 4 to the
3-deoxy-L-rhamnose 16. Thus, exposing a CH2Cl2 solution
of 5 and 6 to 5% palladium(0) and 10% triphenylphosphine
provided an excellent yield (94%) of pyranone 4 as a single
diastereomer.5 Treating the glycosylated product 4 with
hydrogen peroxide in the presence of a catalytic amount of
base (10 mol % NaOH) diastereoselectively epoxidized the
enone of 4, producing epoxy-enone 14 in 81% yield.13 In an
equally diastereoselective fashion, the ketone of 14 was
reduced with NaBH4 (-78 to -20 °C) to form the equatorial
alcohol 15 (93%). Taking advantage of an internal delivery
of a hydride anion via chelation to the C-4 hydroxyl group,
This de novo approach to daumone, was also amenable
for the preparation of sugar analogues (Scheme 7). Thus,
(14) For other examples of epoxide-opening reactions with LiAlH4, see
ref 7 and: Mastihubova, M.; Biely, P. Tetrahedron Lett. 2001, 42, 9065-
9067.
(15) As a prelude to our tritium labeling studies, epoxyketone 14 was
treated with LiAlD4, which cleanly afforded the bis-deuterated diol 16-
(D2).
(11) An Achmatowicz reaction is the oxidative rearrangement of furfuryl
alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones; see: (a) Ach-
matowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-176. For its use
in carbohydrate synthesis, see: refs 5, 10, 12 and: (b) Balachari, D.;
O’Doherty, G. A. Org. Lett. 2000, 2, 863-866. (c) Balachari, D.; O’Doherty,
G. A. Org. Lett. 2000, 2, 4033-4036.
(12) For other examples of the Noyori reduction of acylfurans, see ref
10 and: (a) Haukaas, M. H.; O’Doherty G. A. Org. Lett. 2001, 3, 3899-
3992. (b) Li, M.; O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 6407-
6411.
(16) For other examples of a catalytic TEMPO oxidation to form
carboxylic acids in unprotected carbohydrates see: a) Ying, L.; Gervay-
Hague, J. Carbohydrate Res. 2003, 338, 835-841. (b) Bragd, P. L.;
Besemer, A. C.; Bekkum, H. V. Carbohydr. Polym. 2002, 49, 397-406.
(17) Optical rotation for our synthetic daumone (1) was -85 (c 1.15),
which was slightly higher than the previously reported [R]D of -82 (c 0.1).
Both values were measured in methanol.
(13) Jung, M. E.; Pontillo, J. J. Org. Chem. 2002, 67, 6848-6851.
Org. Lett., Vol. 7, No. 18, 2005
3923

4). Similarly, the pyran double bond of 18 was diastereo-
selectively oxidized to the rhamnose isomer 20 (96% yield),
which as before was deprotected (98%) and oxidized (55%)
to the C-3 hydroxy daumone analogue 21 in good overall
yield (42% yield from enone 4).
Scheme 7. Syntheses of Daumone Analogues 18 and 19
In conclusion, a short de novo asymmetric synthesis of
daumone (1) has been developed. This highly enantio- and
diastereocontrolled route illustrates the utility of a palladium-
catalyzed glycosylation reaction for synthesis, as well as the
Noyori reductions of two ketones. This approach provided
both daumone (1) along with two analogues C-2 deoxy-
daumone 19 and C-3 hydroxy-daumone 21 in 26, 33, and
26% overall yields from acylfuran 7, respectively.18 It is also
worth noting that this route provided daumone in very
comparable efficiency to the previous carbohydrate-based
approach; however, this de novo approach started from
achiral sources and required the use of only one protecting
group. Further application of this approach to other members
of this class of natural product synthesis and biological testing
is ongoing.
Acknowledgment. We are grateful to NIH (GM63150)
and NSF (CHE-0415469) for the support of our research
program and NSF-EPSCoR (0314742) for a 600 MHz NMR
at WVU.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new com-
pounds can be found in Supporting Information. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
both the C-2 deoxy- and the C-3 hydroxy-daumone (19 and
21, respectively) were prepared from the palladium glyco-
sylation product 4. Simply reducing the enone with NaBH4
provided allylic alcohol 18 as a single diasteromer and in
78% yield. The alcohol 18 was converted to the deoxy-
analogue 19 by means of a diimide reduction of the pyran
double bond followed by TBS-ether deprotection and oxida-
tion to the carboxylic acid 19 (53% overall yield from enone
OL051383E
(18) These overall yields for 1, 19, and 21 are very similar from pentynol
9 (24, 31, and 25%, respectively).
3924
Org. Lett., Vol. 7, No. 18, 2005