Direct carbon - Carbon bond formation via chemoselective soft enolization of thioesters: A remarkably simple and versatile crossed-claisen reaction applied to the synthesis of LY294002

Article abstract of DOI:10.1021/ol801498u

(Chemical Equation Presented) Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr ₂·OEt₂ and i-Pr₂NEt to give β-keto thloesters. Prior enolate formation is not required, and the reaction is conducted using untreated CH₂Cl₂ open to the air. The coupled products are stable synthetic equivalents of β-keto acids and can be converted directly into β-keto esters, β-keto amides, and β-diketones under mild conditions. The utility of this carbon-carbon bond-forming method is shown through the synthesis of the PI3-K inhibitor LY294002.

Full text of DOI:10.1021/ol801498u

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3809-3812
Direct Carbon-Carbon Bond Formation
via Chemoselective Soft Enolization of
Thioesters: A Remarkably Simple and
Versatile Crossed-Claisen Reaction
Applied to the Synthesis of LY294002
Guoqiang Zhou, Daniel Lim, and Don M. Coltart*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
don.coltart@duke.edu
Received July 2, 2008
ABSTRACT
Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr2·OEt2 and i-Pr2NEt to give
ꢀ-keto thioesters. Prior enolate formation is not required, and the reaction is conducted using untreated CH2Cl2 open to the air. The coupled
products are stable synthetic equivalents of ꢀ-keto acids and can be converted directly into ꢀ-keto esters, ꢀ-keto amides, and ꢀ-diketones
under mild conditions. The utility of this carbon-carbon bond-forming method is shown through the synthesis of the PI3-K inhibitor LY294002.
The crossed-Claisen coupling reaction is an essential
carbon-carbon bond-forming method.1 The ꢀ-keto ester
moiety produced is found in countless natural products,
pharmaceuticals, and other compounds in either its native
or derivatized form. Indeed, ꢀ-keto esters are unusually
versatile intermediates, providing access to a very wide array
of functionality. In the most general form of the crossed-
Claisen reaction, both the nucleophilic precursor and the
acylating component possess R-protons. However, in such
cases, four products may, in principle, result: two from self-
and two from crossed-coupling. Chemoselectivity is con-
trolled using prior enolate formation.1 While effective, the
stepwise procedures required to generate the enolates are
time-consuming, particularly if trapping is involved, and
require that all manipulations be conducted under anhydrous
conditions and, when strong bases are used, at low temper-
ature. Moreover, a large excess of enolate (( acylating agent)
is required for high conversion, making these transformations
inherently inefficient.1,2 Given the central role that ꢀ-keto
esters play in organic synthesis, it is clear that a simplified
and more efficient version of this transformation would be
beneficial. Herein, we report an efficient and operationally
simple direct crossed-Claisen coupling of thioesters and
N-acylbenzotriazoles via chemoselective soft enolization. The
(2) In a recent modification of the crossed-Claisen reaction, 1:1 mixtures
of esters and 2-substituted N-acyl-N-methylimidazolium chlorides were
treated with TiCl4 and Bu3N, lending some efficiency to the coupling.
Unfortunately, the reaction still requires anhydrous conditions and low
temperature, and a large excess (3 equiv) of TiCl4 is needed. See: Misake,
T.; Nagase, R.; Matsumoto, K.; Tanabe, Y. J. Am. Chem. Soc. 2005, 127,
(1) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed.; Wiley & Sons: Hoboken,
2007; Chapter 16. Benetti, S.; Romagnol, R.; De Risi, C.; Spalluto, G.;
Zanirato, V. Chem. ReV. 1995, 95, 1065–1114.
2854–2855
.
10.1021/ol801498u CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society

process does not require prior enolate formation and is
conducted using untreated, reagent-grade solvent open to the
air, thus providing a remarkably simple approach to this
important transformation. Moreover, due to their unusual
reactivity, the ꢀ-keto thioesters produced serve as stable
synthetic equivalents of ꢀ-keto acids and can be converted
directly into a variety of useful compounds under mild
conditions, in addition to those commonly obtained from
ꢀ-keto oxoesters. As a preliminary demonstration of the
utility of this method and the strategic advantage imparted
by the thioester function, a concise and high-yielding
synthesis of LY294002, a potent phosphoinositide 3-kinase
(PI3-K) inhibitor, is described.
Soft enolization provides an exceptionally mild and
operationally simple approach to direct carbon-carbon bond
formation.3,4 We anticipated that this mode of enolization
could provide the basis of a solution to the long-standing
problems associated with the crossed-Claisen coupling,
provided the nucleophilic precursor could be chemoselec-
tively enolized in the presence of the acylating agent. To
achieve this, we turned to the use of simple thioesters as the
enolate precursors.4a,b Our inspiration for this stems from
their pervasiveness in related biological processes. Nature’s
use of thioesters in forming carbon-carbon bonds is likely
due in large part to their enhanced acidity,5 which ensures
appreciable deprotonation by the weak bases found in
biological systems. Interestingly, in Nature’s version of the
crossed-Claisen condensation, such as in fatty acid synthesis
(Scheme 1), thioesters serve as both the enolate precursors
of chemoselective enolization that would avoid the additional
steps and difficulties associated with the laboratory prepara-
tion of MAHTs.7 Fortunately, as a result of prior work we
had conducted,4 we felt that chemoselective soft enolization
of a simple thioester could be achieved while in the presence
of an even more reactive acylating agent.
In our previous studies,4 we found that thioesters and
ketones are readily alkylated under soft enolization condi-
tions, whereas oxoesters, acid chlorides, and N-acylbenzo-
triazoles are not. These observations are consistent with the
notion that the propensity of the carbonyl species to enolize
is not determined by Brønsted acidity alone, but by a balance
between R-proton acidity and carbonyl Lewis basicity
(Figure 1). Thus, a carbonyl species that is strongly acidic
Figure 1. Qualitative relationship between Brønsted acidity, Lewis
basicity, and soft enolization.
and, correspondingly, weakly Lewis basic (e.g., acid chloride,
N-acylbenzotriazole) would be less prone to interaction with
the Lewis acid, as required of soft enolization.4c,d In contrast,
a somewhat less acidic species (e.g., thioester, ketone), being
more strongly Lewis basic, would be prone to such interac-
tion and, subsequently, enolization. However, there is a
tipping point on this side of the equation too: even though
oxoesters are more Lewis basic than thioesters, their rela-
tively low acidity decreases their susceptibility to soft
enolization.4a,b Thioesters and ketones appear to strike a near
ideal balance between Brønsted acidity and Lewis basicity
in the context of soft enolization. It is perhaps not surprising
then that thioesters are used in biological carbon-carbon
bond-forming processes employing soft enolization.
Scheme 1. Fatty Acid Biosynthesis (ACP ) Acyl-Carrier
Protein; KS ) ꢀ-Ketoacyl-ACPSynthase)
and acylating agents.6 While such reactions produce a single
crossed-product, chemoselective enolization is not achieved
by selective deprotonation. Instead, the intended thioester
enolate is formed via decarboxylation of the corresponding
malonic acid half-thioester (MAHT) (1). Although effective
in a biological context, we sought a more convenient mode
On the basis of the above observations, we anticipated
that the use of a thioester as the enolate precursor, in
combination with an acid chloride or N-acylbenzotriazole
as an acyl donor, should enable chemoselective enolization
leading to a controlled direct crossed-Claisen coupling. To
test this idea, we chose to use N-acylbenzotriazoles, which
are extremely inexpensive, versatile, and easily managed
(3) For pioneering applications of soft enolization in direct carbon-carbon
bond formation, see: Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985, 50,
2622–2624. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–
2626. Tirpak, R. E.; Olsen, R. S.; Rathke, M. W. J. Org. Chem. 1985, 50,
4877–4879
.
(4) See for example: (a) Yost, J. M.; Zhou, G.; Coltart, D. M Org. Lett.
2006, 8, 1503–1506. (b) Zhou, G.; Yost, J. M.; Coltart, D. M. Synthesis
2007, 478–482. (c) Lim, D.; Fang, F.; Zhou, G.; Coltart, D. M. Org. Lett.
2007, 9, 4139–4142. (d) Lim, D.; Zhou, G.; Livanos, A. E.; Fang, F.; Coltart,
(7) MAHTs have been used in the development of various carbon-
carbon bond forming methods. See for example: Kobuke, Y.; Yoshida, J. I.
Tetrahedron Lett. 1978, 367–370. Magdziak, D.; Lalic, G.; Lee, H. M.;
Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2005, 127,
7284–7285. Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46,
6841–6844.
D. M. Synthesis 2008, 2148–2152
.
(5) The pKa of the thioester R-proton has been reported to be 2 units
less than that of the corresponding oxoester. See: Bordwell, F. G.; Fried,
H. E. J. Org. Chem. 1991, 56, 4218–4223.
(6) Hill, A. M. Nat. Prod. Rep. 2006, 23, 256–320. O’Hagan, D. Nat.
Prod. Rep. 1992, 9, 447–479. O’Hagan, D. The Polyketide Metabolites;
Horwood, E., Ed.; Chichester, UK, 1991.
(8) For lead refs, see: Katritzky, A. R.; Wang, Z.; Wang, M.; Wilkerson,
C. R.; Hall, C. D.; Akhmedov, N. G. J. Org. Chem. 2004, 69, 6617–6622.
(b) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 1656–1665.
3810
Org. Lett., Vol. 10, No. 17, 2008

acylating agents.8,9 Gratifyingly, when N-acylbenzotriazole
5 and thioester 6 were combined in CH2Cl2 in the presence
of MgBr2·OEt2 and Hunig’s base (Table 1), the desired
Table 2. Direct Thioester Crossed-Claisen Coupling
Table 1. Comparison of the Direct Crossed-Claisen Coupling of
Various Thioesters and Oxoester 8 with 5
entry thio/oxoester ꢀ-keto thio/oxoester time (h) yield (%)
1
2
3
4
Y ) SPh (6)
Y ) OPh (8)
Y ) SEt (10)
Y ) SBn (12)
7
9
11
13
4
26
4
93
44
83
80
4
crossed coupling product was obtained in excellent yield
(93%). Neither the self-addition products nor the other
crossed-Claisen products were detected. To confirm our
suspicion regarding the importance of the thioesters in this
transformation, oxoester 8 was treated under analogous
conditions. In this case, only a relatively low yield (44%) of
ꢀ-keto oxoester (9) formed after an extended period of time,
thus confirming the superiority of thioesters in the transfor-
mation. The coupling reaction also proceeded with an S-ethyl
and an S-benzyl thioester (10 and 12, respectively), albeit
with somewhat lower yields.
One of the compelling features of conducting carbon-
carbon bond formation via soft enolization is the mildness
of the reaction conditions required. In avoiding the use of
strong bases, not only are low temperature requirements
overcome but also there is the need for an inert atmosphere
and the use of anhydrous conditions. To test that such
conditions would not be deleterious in the present situation,
the reaction between 5 and 6 was repeated, but this time
open to the air using untreated, reagent grade solvent. We
were pleased to find that under these very straightforward
conditions there was no change in the outcome of the reaction
in comparison to the use of an inert atmosphere and
anhydrous conditions.
Having established proof of concept in the direct thioester
crossed-Claisen coupling and confirming that it could be
conducted without the need for highly controlled conditions,
we investigated its scope (Table 2). In general, the transforma-
tion proceeded very well with a range of thioesters and
N-acylbenzotriazoles. The reaction conditions proved to be
compatible with a variety of functionality, including ester, acetal,
and R,ꢀ-unsaturated carbonyl compounds. Notably, it even
progressed quite well in the case of a very sterically hindered
R-silyloxy substituted N-acylbenzotriazole (entry 9).10
As demonstrated, the use of thioesters in the direct crossed-
Claisen coupling is advantageous in facilitating the reaction
relative to oxoesters. However, in addition, the presence of
the thioester moiety in the coupled product enables subse-
quent direct transformations that are not possible using ꢀ-keto
oxoesters. Consequently, the ꢀ-keto thioesters produced
provide a convenient and stable alternative to the use of
ꢀ-keto acids. For instance, esters were readily formed from
ꢀ-keto thioester 7 in high yield from alcohols using
AgCO2CF3 as a thiophilic promoter (Scheme 2).11 The use
of allylic alcohols (cf. 39 and 41) provides straightforward
access to Carroll rearrangement substrates (40 and 42). Direct
amidation12 was also possible from ꢀ-keto thioester 7, as
shown in the preparation of 43 and 45. An especially useful
transformation involving ꢀ-keto thioester product 17 is seen
in its conversion to ꢀ-diketone 46 using the Fukuyama
protocol.13 Overall, this transformation is equivalent to the
regioselective acylation of 3-heptanone which, under con-
ventional conditions, would be marginally selective at best.
Notably, this is the first report of a direct alkylation of a
ꢀ-keto thioester.
The usefulness of the present method in preparing ꢀ-keto
thioesters, along with the strategic advantage presented in
their synthetic equivalence to ꢀ-keto acids, was demonstrated
by a concise total synthesis of LY294002 (47), a potent and
(11) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, G. S.
J. Am. Chem. Soc. 1977, 99, 6756–6758.
(9) We have shown that O-Pfp esters are also excellent acylating agents
under soft enolization conditions (see refs 4c-d); however, given the relatively
high cost associated with their preparation, we have focused on N-acylbenzo-
(12) Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48,
1145–1174.
(13) Tokuyama, H.; Yokoshima, S.; Yamashita, T; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189–3192.
triazoles for this work
.
(10) Control experiments (cf. refs 4c, d) showed that epimerization had
(14) Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. J. Biol.
Chem. 1994, 269, 5241–5248.
not occurred during the formation of 31.
Org. Lett., Vol. 10, No. 17, 2008
3811

along with the established generality of our coupling method,
makes this a very simple and flexible approach to structural
analogues of LY294002 and related compounds. This should
be beneficial for ongoing and future drug development
initiatives involving PI3-K.15
Scheme 2. Direct Transformations of ꢀ-Keto Thioester 7 and 17
To test this synthetic strategy, we first prepared O-benzyl-
protected N-acylbenzotriazole 55 from commercially avail-
able 3-phenyl salicylic acid (52) (Scheme 4). Treatment of
Scheme 4. Synthesis of LY294002
specific inhibitor of PI3-K.14 PI3-Ks play prominent roles
in a variety of diseases including diabetes, cancer, and
chronic inflammation and have attracted considerable recent
interest as a new class of drug targets.15 Our plan for the
synthesis of 47 is shown in a general sense in Scheme 3.
55 and thioester 6 under the conditions developed above
smoothly generated ꢀ-keto thioester 56. The thioester func-
tion was then leveraged in the direct amidation reaction
leading to 57. Hydrogenolysis followed by treatment with
Tf2O generated the chromone core, thus providing LY294002
with an overall yield of 70%.16
Scheme 3
.
General Synthetic Strategy for the Synthesis of
LY294002 and Structural Analogues
In conclusion, we have developed an efficient direct
crossed-Claisen reaction between thioesters and N-acylben-
zotriazoles. The process does not require prior enolate
formation and is conducted using untreated, reagent-grade
solvent open to the air. In contrast to products obtained via
conventional Claisen condensations, the resulting ꢀ-keto
thioesters serve as stable synthetic equivalents of ꢀ-keto acids
and readily undergo direct conversion to esters, amides, and
ketones. The utility of this coupling procedure and the
strategic advantage resulting from the presence of the
thioester function have been demonstrated through the total
synthesis of LY294002.
Here, the direct crossed-Claisen coupling of a salicylic acid-
derived N-acylbenzotriazole and an aliphatic acid-derived
thioester is used to merge the two halves of the molecule
and is followed by late-stage chemoselective amidation and
cyclization. The timing of the amidation reaction (49 f 48),
Acknowledgment. This work was supported, in part, by
the ACS Petrolum Research Fund. G. Z. holds a C. R. Hauser
Fellowship from the Duke University Department of Chem-
istry.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(15) Ward, S.; Sotsios, Y.; Dowden, J.; Bruce, I.; Finan, P Chem. Biol.
2003, 10, 207–213. Ward, S. G.; Finan, P. Curr. Opin. Pharmacol. 2003,
3, 426–434. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.;
Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Mol. Cell 2000, 6, 909–
919.
(16) In an earlier synthesis, 47 was obtained from 52 in 33% overall
yield. See: Abbott, B.; Thompson, P. Aust. J. Chem. 2003, 56, 1099–1106.
OL801498U
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Org. Lett., Vol. 10, No. 17, 2008