Acetoxy Meldrum's acid: A versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/ol2011242

Acetoxy Meldrum's acid can serve as a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation. The reaction of this nucleophile with various meso and racemic electrophiles afforded alkylated products in high yields and enantiopur

Full text of DOI:10.1021/ol2011242

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3222–3225
Acetoxy Meldrum’s Acid: A Versatile Acyl
Anion Equivalent in the Pd-Catalyzed
Asymmetric Allylic Alkylation
Barry M. Trost,* Maksim Osipov, Philip S. J. Kaib, and Mark T. Sorum
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received April 27, 2011
ABSTRACT
Acetoxy Meldrum’s acid can serve as a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation. The reaction of this
nucleophile with various meso and racemic electrophiles afforded alkylated products in high yields and enantiopurities. These enantioenriched
products are versatile intermediates that can be further functionalized using nitrogen- and oxygen-centered nucleophiles, affording versatile
scaffolds for the synthesis of nucleoside analogues. These scaffolds were used to complete formal syntheses of the anti-HIV drugs carbovir,
abacavir, and the antibiotic aristeromycin.
The high therapeutic value of nucleoside analogues in
the treatment of viral infections including hepatitis, the
herpes virus, and HIV is unquestionable.1 Nucleoside
analogues inhibit viral replication by acting as nonspecific
chain terminators during DNA transcription. However,
the high propensity for resistance caused by viral mutation
necessitates the development of new nucleoside ana-
logues.2 Current methods for the synthesis of furanose
nucleoside analogues rely on carbohydrate precursors,
which are only available as the D-enantiomer from natural
sources.3 The use of highly oxygenated carbohydrate
starting materials also requires the extensive use of protect-
ing groups which reduces synthetic efficiency (Figure 1).
Carbanucleosides, which contain a methylene group in
place of the furanose oxygen, are synthesized using chiral
pool strategies and enzymatic resolution, limiting access to
both enantiomers.4
Recently, L-nucleosides have gained increased attention
for their potent antiviral activity. These compounds fre-
quently display lower toxicity, and higher activity due to
their greater metabolic stability compared to D-nucleo-
sides.5 Hence, the development of methods that provide
ready access to both enantiomers of nucleoside analogues
is desirable.
Generally, nucleoside analogues contain a hydroxy-
methylene side chain on the “sugar” moiety. This function-
ality can be installed through the reaction of an aldehyde
with a nucleophile.3b,6 However, installation of a hydro-
xymethylene unit in an umpolung manner, using an acyl
anion equivalent, remains a difficult transformation. Acyl
(1) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(b) Simons, C. Nucleoside Mimetics: Their Chemistry and Biological
Properties; Gordon and Breach Science Publishers: Amsterdam, 2001.
(2) Kiertiburanakul, S.; Sungkanuparph, S. Curr. HIV Res. 2009, 7,
273.
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C. A. M.; Kurteva, V. B. Chem. Rev. 2000, 109, 6809. (c) Schneller, S. W.
Curr. Top. Med. Chem. 2002, 2, 1087.
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ꢀ
39, 1017. (b) Gosselin, G.; Mathe, C. Antiviral Res. 2006, 71, 276.
(3) (a) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319.
(b) Vorbruggen, H.; Ruh-Pohlenz, C. Handbook of Nucleoside Synthesis;
John Wiley & Sons: New York, 2001.
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Chem. 2003, 68, 139. (b) Cesario, C.; Miller, M. J. Org. Lett. 2009, 11,
1293.
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10.1021/ol2011242
Published on Web 05/26/2011
2011 American Chemical Society

anion equivalents provide a method to construct CÀC
bonds by reversing the inherent electrophilic reactivity of a
carbonyl group.7 While dithianes8 as well as other acyl
anions, have been studied extensively in this capacity, their
asymmetric introduction, remains a challenge.9
We began our studies by investigating the reaction of
meso dicarbonate 2a with acetoxy Meldrum’s acid (1)
(Table 1, entry 1). Treatment of this system with 2.5 mol
% Pd2(dba)3•CHCl3 and (R,R)-L1 in 1,2-dichloroethane
(DCE) with Cs2CO3 as a base afforded the alkylated
product 3a in 99% yield and 99% ee. Reaction of the
five-membered dicarbonate14 2b under the same reaction
conditions employing (R,R)-L2 as ligand provided the
alkylated product 3b in 97% yield and 98% ee (entry 2).
Likewise, the meso dihydrofuran15 2c reacted smoothly to
generate the alkylated dihydrofuran 3c in 90% yield and
92% ee (entry 3). The success of the five-membered ring
meso electrophiles is noteworthy due to their utility as
building blocks in the synthesis of both carbocyclic and
heterocyclic nucleoside analogues, respectively (vide infra).
Additionally, 3b and 3c were easily prepared on gram scale
without deterioration of yields or enantiopurities. Reac-
tion of the tropone-derived meso dicarbonate 2d pro-
vided the substituted product 3d in 78% yield and 90% ee
Figure 1. Strategies to access nucleoside analogues.
Table 1. Scope of Electrophiles in the Pd-AAA with Acetoxy
Meldrum’s Acid (1)a
The Pd-catalyzed asymmetric allylic alkylation (Pd-AAA)
is a powerful method for the stereoselective construction
of CÀC and CÀX bonds.10 In the past, the Pd-AAA has
been used to construct nucleosides and their analogues by
employing purine and pyrimidine nucleophiles.11 How-
ever, use of an acyl anion equivalent in the Pd-AAA to ac-
cess nucleoside analogues as well as other chiral scaffolds
containing this functionality remains under studied. We
imagined that acetoxy Meldrum’s acid (1) could serve as a
good nucleophile and a general acyl anion equivalent in such
processes under mildly basic conditions.12 Simple hydrolysis
of the acetonide functionality followed by oxidative decar-
boxylation with ceric ammonium nitrate (CAN) should
unmask the carboxylic acid functionality (Figure 1).13 This
carboxylic acid handle could be reduced to the corresponding
aldehyde or hydroxymethylene as needed. Inspired by the
significance of nucleoside analogues, we envisioned that
the use of acetoxy Meldrum’s acid as an acyl anion equiva-
lent, and its application to the Pd-AAA would provide
an enabling method for the rapid assembly of both enantio-
mers of carbocyclic and heterocyclic nucleoside analogues
(Figure 1).
(7) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(8) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
(9) (a) Aggarwal, V. K.; Esquivel-Zamora, B. N. J. Org. Chem. 2002,
€
67, 8618. (b) Seemann, M.; Scholler, M.; Kudis, S.; Helmchen, G. Eur. J.
Org. Chem. 2003, 2122. (c) Johnson, J. S. Curr. Opin. Drug Discovery
Dev. 2007, 10, 691. (d) Hashimoto, T.; Hirose, M.; Maruoka, K. J. Am.
€
Chem. Soc. 2008, 130, 7556. (e) Forster, S.; Tverskoy, O.; Helmchen, G.
Synlett 2008, 2803.
(10) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (c) Trost,
B. M. J. Org. Chem. 2004, 69, 5813. (d) Trost, B. M.; Machacek, M. R.;
Aponick, A. Acc. Chem. Res. 2006, 39, 747. (e) Trost, B. M.; Fandrick,
D. R. Aldrichimica Acta 2007, 40, 59.
(11) (a) Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114,
8745. (b) Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037. (c)
Trost, B. M.; Kallander, L. S. J. Org. Chem. 1999, 64, 5427. (d) Trost,
B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122,
5947.
a All reactions were performed with 1.0 equiv of 1, 1.0 equiv of of
electrophile 2, and 1.1 equiv of Cs2CO3, 0.25 M in DCE at ambient
temperature. b Isolated yield. c %ee was determined by chiral HPLC.
d (R,R)-L2 was used.
(12) Schank, K.; Blattner, R. Chem. Ber. 1981, 114, 1958.
Org. Lett., Vol. 13, No. 12, 2011
3223

(entry 4). Both carbonate and ester-leaving groups could
be utilized in this transformation to afford the desired
products in high yields and enantiopurities.
yield and 99% ee (entry 7). In all cases examined, the
alkylation product was obtained exclusively as a single
regio- and diastereoisomer.
To provide a wide range of functionalized scaffolds for
the synthesis of nucleoside analogues, the products 3b and
3c were alkylated a second time using a diastereoselective
Pd-catalyzed allylic substitution. In this reaction, the use of
enantiopure ligands was not necessary, since the chiral
center established in the initial Pd-AAA would dictate the
diastereoselectivity of the second alkylation. Both 3b and
3c were selected for their abilities to serve as scaffolds for a
large number of nucleoside analogues. Both nitrogen-
(Table 2, entries 1À6) and oxygen-centered (entry 7)
nucleophiles were successfully utilized and afforded the
substituted products (5aÀg) in high yields as a single
diastereomer. Both pyrrole 4a and phthalimide 4b under-
went substitution with chiral cyclopentene 3b in near-
quantitative yields to afford cyclopentenes 5a and 5b
(entries 1 and 2). Substitution of dihydrofuran 3c with
6-chloropurine (4c) to afford 5c (entry 3) is important, as it
provides an appropriately functionalized intermediate for
the synthesis of several purine-derived nucleoside analo-
gues through manipulation of the dihydrofuran olefin and
purine side chain. Reaction of cyclopentene 3b with tria-
zole 4d provided 5d (entry 4) in 74% yield, which contains
the carbon skeleton of several biologically activeanalogues
of the broad-spectrum antiviral agent ribavirin.16 Cou-
pling of dihydrofuran 3c with 2-hydroxypyrimidine•HCl
(4f) provided 5f (entry 6), which contains the carbon
skeleton for the DNA methylation inhibitor zebularine.17
Table 2. Pd-Catalyzed Allylic Substitutionsa
Scheme 1. Formal Syntheses of Carbovir, Abacavir, and Aris-
teromycin
a All reactions were performed with 1.0 equiv of 3, 1.0 equiv of 4, and
1.1 equiv of Cs2CO3, 0.25 M in DCE at ambient temperature. b Isolated
yield. c Performed using 5 mol % Pd2(dba)3•CHCl3, 15 mol % (()-L1,
10 mol % Bu3SnOAc with 3.0 equiv of NEt3 in THF. d Performed
in THF in the absence of base. e Performed using
5 mol %
Pd2(dba)3•CHCl3, 15 mol % (()-L1, with 3.0 equiv of NEt3 in THF.
With conditions developed for meso electrophiles, we
turned our attention to racemic substrates. Treatment of
racemic cyclohexenyl benzoate rac-2e with acetoxy Mel-
drum’s acid (1) under conditions used for meso electro-
philes provided the alkylated product 3e in 91% yield and
99% ee (entry 5). Incorporating substitution on the cyclo-
hexene ring had little effect on the transformation, and rac-
2f was alkylated to 3f in 81% yield and 99% ee (entry 6).
Likewise, C2 symmetric tetracarbonate 2gwas examined in
the transformation and provided the product 3g in 75%
Pd-catalyzed substitution of cyclopentene 3b with
TMSN3 (4e) generated allyl azide 5e in 99% yield (entry
5). This compound was used to complete the formal
syntheses of several biologically active nucleoside analo-
gues (Scheme 1). Basic hydrolysis of allyl azide 5e with
LiOH followed by oxidative decarboxylation with CAN
(16) Noble, S. N.; Beddall, N. E.; Beveridge, A. J.; Marr, C. L. P.;
Mo, C. L.; Myers, P. L.; Penn, C. R.; Storer, R.; Woods, J. M. Nucleo-
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1984, 106, 3797.
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3224
Org. Lett., Vol. 13, No. 12, 2011

and methylation of the liberated carboxylic acid with
TMSCHN2 provided ester 6 in 67% yield over three steps.
Reduction of the ester and azide functionalities with
LiAlH4 yielded the corresponding amino alcohol that
was acylated directly with acetic anhydride to afford
acetylated amino alcohol 7 in 91% yield over two steps.
Acetylated amino alcohol 7 is a known intermediate in the
synthesis of the HIV drugs carbovir,18 abacavir,19 and the
antibiotic aristeromycin.20
In conclusion, we have developed acetoxy Meldrum’s
acid (1) as a versatile nucleophile and acyl anion equiva-
lent in the Pd-AAA. Both meso and racemic electro-
philes reacted with acetoxy Meldrum’s acid (1) to
provide the desired alkylated products in high yields
and enantiopurities in a chemo-, regio-, and diastereo-
selective fashion. The products from the Pd-AAA were
then subjected to a second Pd-catalyzed allylic substitu-
tion using both nitrogen- and oxygen-centered nucleo-
philes. Formal syntheses of carbovir, abacavir, and
aristeromycin were completed to demonstrate an appli-
cation of this method in short syntheses of carbanucleo-
side analogues.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health (GM33049)
for their generous support of our programs. M.O. thanks
the John Stauffer Memorial Fellowship for financial sup-
port. P.S.J.K. thanks the BaCaTec, the Luise Prell Stiftung,
and the Richard-Winter-Stiftung for financial support.
Palladium salts were generously supplied by Johnson-
Matthey.
Supporting Information Available. Experimental de-
tails and spectral data for all unknown compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(19) Daluge, S. M.; Martin, M. T.; Sickles, B. R.; Livingston, D. A.
Nucleosides, Nucleotides Nucleic Acids 2000, 19, 297.
€
(20) Csuk, R.; Dorr, P. Tetrahedron 1995, 51, 5789.
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