A highly conjunctive β-keto phosphonate: Application to the synthesis of pyridine alkaloids xestamines C, E, and H

Article abstract of DOI:10.1021/ol702590f

(Chemical Equation Presented) The synthesis of a novel β-keto γ-xanthyl phosphonate has been achieved. This highly conjunctive reagent has been utilized in a combination of radical and ionic reactions to create new carbon-carbon bonds. Its usefulness was

Full text of DOI:10.1021/ol702590f

ORGANIC
LETTERS
2008
Vol. 10, No. 2
253-256
A Highly Conjunctive
â-Keto
Phosphonate: Application to the
Synthesis of Pyridine Alkaloids
Xestamines C, E, and H
Matthieu Corbet, Michiel de Greef, and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, De´partement de Chimie,
Ecole Polytechnique, 91128 Palaiseau, France
zard@poly.polytechnique.fr
Received October 25, 2007
ABSTRACT
The synthesis of a novel
of radical and ionic reactions to create new carbon
â
-keto
γ
-xanthyl phosphonate has been achieved. This highly conjunctive reagent has been utilized in a combination
carbon bonds. Its usefulness was demonstrated by realizing the first total synthesis of
−
naturally occurring pyridine alkaloids xestamines C, E, and H.
Phosphonates bearing a keto function in the â position (â-
keto phosphonates) are of great interest in organic synthesis.
Of particular importance is their use in the Horner-
Wadsworth-Emmons (HWE) olefination.1 This well-known
modification of the Wittig reaction allows an easy access to
R,â-unsaturated ketones in either an intermolecular or
intramolecular fashion, and it has been shown many times
to be a useful tool in total synthesis.2 â-Keto phosphonates
are also valuable intermediates in the synthesis of hetero-
cyclic cores such as quinolines,3 pyrroles,4 pyrazoles,5 and
naphthydrines.6 Their synthesis is commonly achieved via
the Arbuzov reaction,7 the Michaelis-Becker reaction,8 or
by acylation of alkyl phosphonate anion.9 They can also be
formed from vinyl phosphates via a 1,3-phosphorus migra-
tion;10 this strategy, however, appears to be limited to the
formation of cyclic â-keto phosphonates.
Following our work on xanthate transfer radical chemis-
try,11 we envisioned synthesizing a â-keto phosphonate 2
(Scheme 1) that would be able to undergo both group transfer
Scheme 1. Synthesis of Key Xanthate 2
(1) For reviews, see: (a) Boutagy, J.; Thomas, R. Chem. ReV. 1974, 74,
87. (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(2) For recent examples, see: (a) Mata, E. G.; Thomas, E. J. J. Chem.
Soc. Perkin Trans. 1995, 1, 785. (b) Solladie´, G.; Wilb, N.; Bauder, C. J.
Org. Chem. 1999, 64, 5447. (c) Gosselin, F.; Lubell, W. D. J. Org. Chem.
2000, 65, 2163. (d) Lambert, W. T.; Hanson, G. H.; Benayoud, F.; Burke,
S. D. J. Org. Chem. 2005, 70, 9382. (e) Crimmins, M. T.; McDougall, P.
J.; Emmitte, K. A. Org. Lett. 2005, 7, 4033. (f) Nicolaou, K. C.; Nold, A.
L.; Milburn, R. R.; Schindler, C. S.; Cole, K. P.; Yamaguchi, J. J. Am.
Chem. Soc. 2007, 129, 1760.
(3) (a) Coppola, G. M. Synthesis 1988, 81. (b) Vasse, J.-L.; Goumain,
S.; Levacher, V.; Dupas, G.; Que´giner, G.; Bourguigno, J. Tetrahedron Lett.
2001, 42, 1871.
radical addition to olefins and HWE reaction with aldehydes
and ketones.
10.1021/ol702590f CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/28/2007

The synthesis of xanthate 2 was easily achieved in a 40%
overall yield starting from commercially available 1,3-
dichloroacetone via known â-keto phosphonate 1.12 With this
highly conjunctive reagent in hand, we hoped to generate
carbon-carbon bonds efficiently in both an ionic and a
radical fashion at the two extremities of this novel ketone.
Xanthate 2 afforded moderate to excellent yields of adducts
6a-k when treated with a substoichiometric amount of
lauroyl peroxide (DLP) (7.5-25 mol %) and the correspond-
ing olefin a-k (2-3 equiv) in refluxing 1,2-dichloroethane
(DCE). Examples include functionality that is widely used
in organic synthesis such as ketones (entry 11), esters (entries
1 and 9), nitriles (entry 3), N,O-protected amino acids (entry
10), silanes (entries 2 and 7). Complex heterocycles and
sugars (entries 4 and 5) were also tolerated.
We then turned our attention to the ability of these xanthate
adducts (or the corresponding reduced forms 6′j and 6′k from
6j and 6k)13 to undergo HWE olefination using sodium
hydride in THF (Table 2). We were glad to see that in most
Table 1. Radical Addition of Xanthate 2 to Olefins a-ka
Table 2. HWE Olefination of Some Selected Compoundsa
a
HWE reactions were performed using 1 equiv of NaH and 2 equiv of
aldehyde. b Xa ) SC(S)OEt. c Isolated yields.
cases the xanthate goup was stable under these conditions.
We encountered some difficulty, however, with xanthate
adduct 6i, which decomposed rapidly when treated with
a Addition reactions were performed by portionwise addition of DLP (5
mol %) every 90 min to a refluxing degassed 1 M solution of 2 (1 equiv)
in DCE in the presence of the olefin (2-3 equiv) until 2 had entirely reacted.
b Xa ) SC(S)OEt. c Isolated yields.
(9) (a) Theisen, P. D.; Heathcock, C. H. J. Org. Chem. 1988, 53, 2374.
(b) Narkunan, K.; Nagarajan, M. J. Org. Chem. 1994, 59, 6386.
(10) (a) Hammond, G. B.; Calogeropoulo, T.; Wiemer, D. F. Tetrahedron
Lett. 1986, 27, 4625. (b) Calogeropoulo, T.; Hammond, G. B.; Wiemer, D.
F. J. Org. Chem. 1987, 52, 4185. (c) An, Y.-Z.; An, J.; Wiemer, D. F. J.
Org. Chem. 1994, 59, 8197. (d) An, J.; Wilson, J. M.; An, Y.-Z.; Wiemer,
D. F. J. Org. Chem. 1996, 61, 4040. (e) Baker, T. J.; Wiemer, D. F. J. Org.
Chem. 1998, 63, 2613.
First, several examples of xanthate addition onto various
olefins were undertaken to investigate its scope (Table 1).
(4) Attanasi, O. A.; Filippone, P.; Giovagnoli, D.; Mei, A. Synthesis 1994,
181.
(5) Almirante, N.; Benicchio, A.; Cerri, A.; Fedrizzi, G.; Marazzi, G.;
Santagostino, M. Synlett 1999, 299.
(6) Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, P. J.
Org. Lett. 2001, 3, 1101.
(11) (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b)
Quiclet-Sire, B.; Zard, S. Z. Phosphorus Sulfur Silicon Relat. Elem. 1999,
153, 137. (c) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (d) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12, 6002.
(12) Corbel, B.; Medinger, L.; Haelters, J.-P.; Sturtz, G. Synthesis 1985,
1048.
(7) (a) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307. (b) Bhattacharya,
A. K.; Thyagarajan, G. Chem. ReV. 1981, 81, 415.
(8) Koh, Y. J.; Oh, D. Y. Tetrahedron Lett. 1993, 34, 2147.
(13) Xanthate reductions were performed with a combination of 2 equiv
of DLP in propan-2-ol (10 mL/mmol). See: Liard, A.; Quiclet-Sire, B.;
Zard, S. Z. Tetrahedron Lett. 1996, 37, 5877.
254
Org. Lett., Vol. 10, No. 2, 2008

sodium hydride. In addition, no intramolecular reaction
product was detected with xanthate adduct 6k under these
conditions. When the reaction was performed at reflux, we
observed the formation of trans-decalin 13 (entry 7) in a
70% isolated yield. Presumably, the strain incurred in
forming an 8-membered ring is too great for the expected
HWE pathway to occur. Anion equilibration at higher
temperature led to the formation of more accessible trans-
decalin 13. Subsequent HWE reaction with benzaldehyde
gave trans-decalin 14 in 92% yield (Scheme 2).
the niphatesine family,14c,15 the ikimine family,15b,16 or the
cribochaline family.17
Xestamine C was isolated from the Caribbean sponge
Xestospongia wiedenmayeri in 1990,18 and xestamine E was
isolated (along with inseparable xestamine D) in the Bahamas
from the sponge Calyx podatypa in 1991 as well as xestamine
H (along with inseparable xestamine G).19 Larock et al.
reported the first synthesis of a member of the xestamine
family (xestamine D) using palladium-catalyzed coupling of
3-iodopyridine, 1,13-tetradecadiene, and N,O-dimethylhy-
droxylamine.20 To our knowledge no other synthesis of any
xestamines has been realized.
Our work started with the straightforward synthesis of
N,O-dimethylhydroxylamines 15 and 16 starting from the
corresponding aldehydes (Scheme 3). (When n ) 7, the
Scheme 2. HWE Olefination of Unexpected Compound 13
Scheme 3. Synthesis of Olefinic
N,O-Dimethylhydroxylamines
We decided next to apply the key conjunctive reagent to
short and convergent syntheses of antimicrobial pyridine
alkaloids xestamines C (3), E (4), and H (5) (Figure 1).
aldehyde was prepared by oxidation of the corresponding
9-decen-1-ol using PCC in dichloromethane following the
reported procedure.21)
Treatment of these aldehydes with N-methoxyammonium
chloride and potassium carbonate in methanol gave the
corresponding oximes which were reduced with sodium
cyanoborohydride in acetic acid to afford O-methylhydroxy-
lamines. Subsequent N-methylation using NaH and methyl
iodide yielded the desired N,O-dimethylhydroxylamines 15
and 16 in 64% and 66% overall yield, respectively. They
were then submitted to the xanthate transfer radical reaction
with xanthate 2. These reactions proceeded smoothly under
the usual conditions to give the corresponding adducts 17
and 18 in 69 and 65% yield respectively. Reductive removal
of the xanthate groups was then readily accomplished using
DLP (2 equiv) in propan-2-ol (10 mL/mmol) to afford â-keto
phosphonates 19 and 20 in 80 and 83% yield, respectively
(Scheme 4). Horner-Wadsworth-Emmons olefination using
either 3-acetylpyridine (in refluxing THF) or nicotinaldehyde
(room temperature in THF) gave the corresponding R,â-
unsaturated carbonyl compounds 21 an 22 in good yield.
The lower yield obtained in the case of 21 can be explained
by the lower reactivity of the carbonyl in 3-acetylpyridine
as compared to that of nicotinaldehyde.
Figure 1. Retrosynthetic analysis of xestamines C, E, and H.
The xestamine family is part of a wide variety of naturally
occurring pyridine alkaloids such as the theonelladin family,14
(14) (a) Kobayashi, J.; Murayama, T.; Ohizumi, Y. Tetrahedron Lett.
1989, 30, 4833. (b) Rao, A. V.; Reddy, G. R.; Rao, B. V. J. Org. Chem.
1991, 56, 4545. (c) Teubner, A.; Gerlach, H. Liebigs Ann. Chem. 1993, 2,
161. (d) Tsunoda, T.; Uemoto, K.; Ohtani, T.; Kaku, H.; Ito, S. Tetrahedron
Lett. 1999, 40, 7359.
(15) (a) Kobayashi, J.; Murayama, T.; Kosuge, S.; Kanda, F.; Ishibashi,
M.; Kobayashi, H.; Ohizumi, Y.; Ohta, T.; Nozoe, S.; Sasaki, T. J. Chem.
Soc., Perkin Trans. 1990, 1, 3301. (b) Kobayashi, J.; Zeng, C. M.; Ishibashi,
M.; Shigemori, H.; Sasaki, T.; Mikami, Y. J. Chem. Soc., Perkin Trans.
1992, 1, 1291. (c) Rao, A. V. R.; Reddy, G. R. Tetrahedron Lett. 1993, 34,
8329. (d) Bracher, F.; Papke, T. J. Chem. Soc., Perkin Trans. 1995, 1, 2323.
(e) Bracher, F.; Papke, T. Monatsh. Chem. 1996, 127, 91.
Nevertheless, it is noteworthy that the â-keto phosphonate
allows a facile introduction of the methyl group R to the
pyridine ring for the synthesis of xestamine C. Moreover,
(18) Sakemi, S.; Totton, L. E.; Sun, H. H. J. Nat. Prod. 1990, 53, 995.
(19) Stierle, D. B.; Faulkner, D. J. J. Nat. Prod. 1991, 54, 1134.
(20) (a) Larock, R. C.; Wang, Y. Tetrahedron Lett. 2002, 43, 21. (b)
Wang, Y.; Dong, X.; Larock, R. C. J. Org. Chem. 2003, 68, 3090.
(21) Qin, X.; Tzvetkov, T.; Liu, X.; Lee, D.-C.; Yu, L.; Jacobs, D. C. J.
Am. Chem. Soc. 2004, 126, 13232.
(16) (a) Carroll, A. R.; Scheuer, P. J. Tetrahedron 1990, 46, 6637. (b)
Bracher, F.; Papke, T. Nat. Prod. Lett. 1994, 4, 223.
(17) Nicholas, G. M.; Molinski, T. F. Tetrahedron 2000, 56, 2921.
Org. Lett., Vol. 10, No. 2, 2008
255

Alcohols 23 and 24 were submitted to hydrogenation using
a platinum oxide catalyst to afford alcohols 25 and 26 in
99% yield. Subsequent tosylation using p-toluenesulfonyl
chloride (1.5 equiv), triethylamine (1.5 equiv), and catalytic
DMAP gave tosylates 27 and 28 in 77 and 75% yield,
respectively. Reduction with excess LAH (5 equiv) in dry
ether gave the final compounds, xestamines C (3) (94% yield)
and E (4) (96% yield).
Scheme 4. Key Steps in the Synthesis of Xestamines C and E
Finally, N-methylation of xestamine E using methyl iodide
in acetone afforded the N-methyl iodide salt, xestamine H
(5) in 65% yield (Scheme 6).
Scheme 6. Synthesis of Xestamine H
compounds 21 and 22 could easily provide access to various
analogues of xestamines C and E by further chemical
transformations of the R,â-unsaturated ketone moeity.
The last steps of the synthesis were achieved using
straightforward chemistry (Scheme 5). R,â-Unsaturated car-
In summary, we have developed a useful synthetic â-keto
γ-xanthyl phosphonate that is able to create two new
carbon-carbon bonds in both a radical and an ionic manner.
We have shown that it adds to various olefins in xanthate
radical transfer reactions and that the resultant compounds
undergo HWE olefination to form R,â-unsaturated ketones.
Moreover, we successfully demonstrated its high conjunc-
tivity by completing the first total synthesis of antimicrobial
xestamines C, E, and H. Their syntheses were achieved in
29%, 34%, and 22% overall yield, respectively, starting from
xanthate 2.
Scheme 5. Final Steps in the Synthesis of Xestamines C and
E
Acknowledgment. Partial financial support of this work
was provided by the Ministe`re de l’Enseignement Supe´rieur
et de la Recherche. M.C. thanks Dr. D. Woollaston (DCSO,
Ecole Polytechnique) for helpful discussions.
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
bonyl compounds 21 an 22 were reduced to the correspond-
ing allylic alcohols 23 and 24 in 95 and 98% yield
respectively, using Luche conditions.22
OL702590F
(22) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
256
Org. Lett., Vol. 10, No. 2, 2008