Isothiourea-mediated stereoselective C-acylation of silyl ketene acetals

Article abstract of DOI:10.1021/ol1008747

Isothiourea DHPB promotes the diastereoselective C-acylation of silyl ketene acetals with anhydrides or benzoyl fluoride, giving 3-acyl-3-aryl or 3-acyl-3-alkylfuranones in excellent yields and stereoselectivities (up to 99:1 dr).

Full text of DOI:10.1021/ol1008747

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2660-2663
Isothiourea-Mediated Stereoselective
C-Acylation of Silyl Ketene Acetals
Philip A. Woods,† Louis C. Morrill,† Tomas Lebl,† Alexandra M. Z. Slawin,†
Ryan A. Bragg,‡ and Andrew D. Smith*,†
EaStCHEM, School of Chemistry, UniVersity of St Andrews, North Haugh, St. Andrews
KY16 9ST, U.K., and AstraZeneca UK Ltd., Mereside, Alderley Park, Macclesfield,
Cheshire SK10 4TG, U.K.
ads10@st-andrews.ac.uk
Received April 16, 2010
ABSTRACT
Isothiourea DHPB promotes the diastereoselective C-acylation of silyl ketene acetals with anhydrides or benzoyl fluoride, giving 3-acyl-3-aryl
or 3-acyl-3-alkylfuranones in excellent yields and stereoselectivities (up to 99:1 dr).
Stereoselective methods for the C-acylation of enolates or
their equivalents offer synthetic access to versatile building
blocks in organic synthesis. While a number of catalytic
asymmetric Steglich1 and Black rearrangements2 of hetero-
cyclic carbonate derivatives have been developed that deliver
C-carboxyl derivatives in high ee, few methodologies have
been delineated that can effect the direct C-acylation of
enolates.3 Central to the problems associated with this
transformation is the propensity for competitive O- and
C-acylation processes, typically leading to mixtures of O-
and C-acylated products.4 Strategies to solve these issues
such as Lewis acid promoted C-acylation of enolsilanes5 or
TBAF promoted C-acylation of silyl enol ethers6 have been
reported. As an alternative approach, Fu and Mermerian have
elegantly shown that planar chiral PPY derivative 2 promotes
the catalytic enantioselective C-acetylation of both cyclic and
acyclic silyl ketene acetals bearing an R-aryl or R-alkenyl
substituent with acetic anhydride.7 Building upon this
precedent, we proposed to identify a Lewis base8 that would
† University of St Andrews.
‡ AstraZeneca UK Ltd.
(3) Cyanoformates promote the direct C-carboxylation of enolates; for
examples, see: Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425–
5428. Crabtree, S. R.; Alex Chu, W. L.; Mander, L. N. Synlett 1990, 169–
170.
(1) Steglich, W.; Ho¨fle, G. Tetrahedron Lett. 1970, 11, 4727–4730. For
asymmetric versions of this reaction, see: Ruble, J. C.; Fu, G. C. J. Am.
Chem. Soc. 1998, 120, 11532–11533. Shaw, S. A.; Aleman, P.; Vedejs, E.
J. Am. Chem. Soc. 2003, 125, 13368–13369. Shaw, S. A.; Aleman, P.;
Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128,
925–934. Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett. 2006,
8, 769–772. Seitzberg, J. G.; Dissing, C.; Søtofte, I.; Norrby, P.-O.;
Johannsen, M. J. Org. Chem. 2005, 70, 8332–8337. Busto, E.; Gotor-
Ferna´ndez, V.; Gotor, V. AdV. Synth. Catal. 2006, 348, 2626–2632. For an
asymmetric acetyl group rearrangement, see: Dietz, F. R.; Gröger, H.
Synthesis 2009, 24, 4208–4218.
(4) Caine, D. In Carbon-Carbon Bond Formation; Augustine, R. L.,
Ed.; Marcel Dekker: New York, 1979; Vol. 1, pp 250-258.
(5) For example, see: Fleming, I.; Iqbal, J.; Krebs, E.-P. Tetrahedron
1983, 39, 841–846. Le Roux, C.; Mandrou, S.; Dubac, J. J. Org. Chem.
1996, 61, 3885–3887.
(6) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Tetrahedron
Lett. 2002, 43, 2945–2948.
(7) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 4050–
4051. Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 5604–
5607. For a related reaction involving silyl ketene imines and anhydrides,
see: Mermerian, A. H.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 949–
952.
(2) Black, T. H.; Arrivo, S. M.; Schumm, J. S.; Knobeloch, J. M. J.
Org. Chem. 1987, 52, 5425–5403. Hills, I. D.; Fu, G. C. Angew. Chem.,
Int. Ed. 2003, 42, 3921–3924. Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am.
Chem. Soc. 2009, 131, 14–15.
10.1021/ol1008747  2010 American Chemical Society
Published on Web 05/11/2010

lead to the efficient C-acylation of silyl ketene acetals9,10
and to subsequently develop a general and highly diastereo-
selective version of this process for the preparation of
stereodefined 3-acyl-3-aryl or 3-acyl-3-alkylfuranones 5 from
silyl ketene acetals such as 4 (Figure 1). This methodology
Figure 2. Screening Lewis base reactivity for the C-acylation of
silyl ketene acetal 6 with acetic anhydride.
Table 1. Diastereoselective Isothiourea Promoted C-Acylation
of Silyl Ketene Acetal 16
Figure 1. Proposed Lewis base promoted stereoselective C-
acylation of silyl ketene acetals.
would be complementary to alternative approaches to these
valuable building blocks such as the asymmetric alkylation
or conjugate addition of 1,3-dicarbonyl species.11
Initial studies probed the effectiveness of a range of com-
mercially available or readily prepared Lewis bases to promote
the C-acylation of a model substrate, silyl ketene acetal 6, with
acetic anhydride. Under standardized conditions, amidines such
as DBN 9, DBU 10, and dihydroimidazo[1,2-a]pyridine (DHIP)
11, as well as N-methylimidazole (NMI) 12 and guanidine 13,
entry
t (°C)
acyl source
R
dr
yield (%)
1
2
3
4
5
6
7
8
rt
0
(MeCO)2O
(MeCO)2O
(MeCO)2O
(MeCO)2O
(MeCO)2O
(EtCO)2O
(i-PrCO)2O
PhCOF
Me
Me
Me
Me
Me
Et
93/7
94/6
95/5
96/4
98/2
97/3
95/5
>98/2
-20
-40
-78 to rt
-78 to rt
-78 to rt
-78 to rt
(8) For a review of Lewis base mediated reaction processes, see:
Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–
1638.
78
78
75
65
i-Pr
Ph
(9) For the DMAP promoted O-benzoylation of silyl enol ethers with
benzoyl fluoride and DMAP mediated C-benzoylation of silyl ketene acetals
with benzoyl fluoride, see: Poisson, T.; Dalla, V.; Papamicae¨l, C.; Dupas,
G.; Marsais, F.; Levacher, V. Synlett 2007, 381–386.
(10) For examples of our previous research program concerned with
applications of Lewis bases in organocatalysis, see: Thomson, J. E.; Rix,
K.; Smith, A. D. Org. Lett. 2006, 8, 3785–3788. Thomson, J. E.; Campbell,
C. D.; Concello´n, C.; Duguet, N.; Rix, K.; Slawin, A. M. Z.; Smith, A. D.
J. Org. Chem. 2008, 73, 2784–2791. Campbell, C. D.; Duguet, N.;
Gallagher, K. A.; Thomson, J. E.; Lindsay, A. G.; O’Donoghue, A. C.;
Smith, A. D. Chem. Commun. 2008, 3528–3530. Duguet, N.; Campbell,
C. D.; Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108–
1113. Thomson, J. E.; Kyle, A. F.; Concello´n, C.; Gallagher, K. A.; Lenden,
P.; Morrill, L. C.; Miller, A. J.; Joannesse, C.; Slawin, A. M. Z.; Smith,
A. D. Synthesis 2008, 2805–2818. Concello´n, C.; Duguet, N.; Smith, A. D.
AdV. Synth. Catal. 2009, 351, 3001–3009. For a stoichiometric asymmetric
oxindole synthesis promoted by a nitrone, see: Duguet, N.; Slawin, A. M. Z.;
Smith, A. D. Org. Lett. 2009, 11, 3858–3861.
gave only modest conversions (<55%) to the desired C-acetyl
product 7, giving significant quantities of lactone 8.12 Further
catalyst evaluation probed the use of isothioureas 2,3,6,7-
tetrahydro-5H-thiazolo[3,2-a]pyrimidine (THTP) 14 and 3,4-
dihydro-2H-pyrimido[2,1-b]benzothiazole (DHPB) 15, recently
shown to be excellent O-acylation13 and C-carboxyl transfer
(12) We assume that lactone 8 arises as a result of hydrolysis of
unreacted silyl ketene acetal upon exposure to air or moisture upon
workup.
(11) For examples of catalytic asymmetric alkylations of ꢀ-keto esters,
see: Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997,
119, 7879–7880. Ooi, T.; Miki, T.; Fukumoto, K.; Maruoka, K. AdV. Synth.
Catal. 2006, 348, 1539–1542. For catalytic asymmetric Michael reactions
of ꢀ-keto esters, see: Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem.
Soc. 2002, 124, 11240–11241. Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli,
A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew.
Chem., Int. Ed. 2006, 45, 4966–4970.
(13) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006, 47, 4347–
4350. Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9, 37–40.
(14) For our previous work using DHPB as a catalyst for O- to
C-carboxyl transfer, see: Joannesse, C.; Simal, C.; Concello´n, C.; Thomson,
J. E.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem.
2008, 6, 2900–2907. For an asymmetric version of this reaction with chiral
isothioureas, see: Joannesse, C.; Johnston, C. P.; Concello´n, C.; Simal, C.;
Philp, D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914–8918.
Org. Lett., Vol. 12, No. 11, 2010
2661

isothiourea DHPB 15 showing the optimal conversion of the
Lewis bases tested, giving C-acetyl 7 that was isolated in 90%
yield (Figure 2).
Having identified isothiourea DHPB 15 as an efficient
C-acetylation catalyst, the development of a general and
stereoselective C-acylation protocol was investigated.15
Treatment of silyl ketene acetal 16 with isothiourea 15 and
acetic anhydride at rt proceeded to give C-acetyl 17 in
excellent yield and with high stereoselectivity (dr ) 93/7).
Subsequent variation of reaction temperature gave optimal
stereoselectivity, giving C-acetyl 17 in 98/2 dr, the relative
configuration within which was confirmed by NOESY
analysis.16 This protocol proved equally applicable to
alternative anhydrides, with propionic and isobutyric anhy-
dride giving the corresponding C-acyl derivatives 18 and 19,
respectively, with excellent stereoselectivities (dr 97/3 and
95/5, respectively). The use of benzoyl fluoride in this
reaction protocol was also developed, giving C-benzoyl 20
in excellent yield and stereoselectivity (dr >98/2) (Table 1).17
Consistent with Fu’s proposal,7 our current mechanistic
hypothesis for this transformation requires initial formation of
Figure 3. Proposed mechanism for the diastereoselective isothiourea
promoted C-acylation of silyl ketene acetals.
catalysts,14 in this protocol. Both isothioureas gave markedly
improved levels of C-acylation (>85% conversion to 7), with
Table 2. Scope of the DHPB Promoted Diastereoselective C-Acylation of Silyl Ketene Acetals
a
b
1
1
Diastereomeric ratios were determined from inspection of the H NMR spectra of the crude reaction mixtures. Ratios were determined from the H
NMR spectra of the isolated products.
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Org. Lett., Vol. 12, No. 11, 2010

The scope of this protocol was next demonstrated, through
variation of both the C(3)- and C(5)-substituents within the silyl
ketene acetal, as well as the use of anhydrides and benzoyl
fluoride as the acyl source.20 Isothiourea DHPB promotes
efficient C-acylation with C(3)-aryl and heteroaryl substitution,
giving good to excellent levels of stereoselectivity in all cases
(dr up to >98/2). C(5)-Methyl, ethyl, or n-butyl substituents all
provide high levels of diastereocontrol (dr up to 99/1) in this
reaction sequence. Notably, this protocol also tolerates C(3)-
benzyl substitution, allowing acylation with acetic anhydride
or propionic anhydride, generating lactones 41 and 42 in 87%
and 57% yield and 91/9 and 84/16 dr, respectively (Table 2).21
The relative configuration within 36 was proven by X-ray
crystallography (Figure 4),22 with the relative configuration
within 25, 29, 33, 37, and 41 also assigned by NOESY analysis.
In conclusion, we have shown that isothiourea DHPB 15
promotes the efficient C-acylation of silyl ketene acetals with
high levels of stereoselectivity (up to 99/1 dr) using a range
of anhydrides or benzoyl fluoride as the acylating agents.
Ongoing studies within this laboratory are directed toward
the demonstration of catalytic asymmetric versions of related
reaction protocols and developing alternative uses of isothio-
ureas in asymmetric catalysis.
Figure 4. Molecular representation of the X-ray crystal structure
of furanone 36.
an activated acyl-isothiourionium ion 21 from the reaction of
DHPB and the anhydride or benzoyl fluoride, with desilyation
of the silyl ketene acetal promoted by either the carboxylate or
fluoride counterion generating enolate 22. Subsequent C-
acylation of enolate 22, anti to the stereodirecting C(5)-
substituent,18 generates the C-acyl product 24 with high
diastereoselectivity and regenerates DHPB 15 (Figure 3).19
Acknowledgment. The authors would like to thank the
Royal Society for a University Research Fellowship (A.D.S.),
AstraZeneca (P.A.W.) for funding, and the EPSRC National
Mass Spectrometry Service Centre (Swansea).
(15) For diastereoselective C-acylations using chiral auxiliaries, see:
Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am. Chem.
Soc. 1984, 106, 1154–1156. Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1984, 25, 6015–6016.
Supporting Information Available: Experimental pro-
cedures plus spectroscopic data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) See Supporting Information for full details.
(17) The use of benzoic anhydride in this protocol gave excellent
conversion to 20 in >98/2 dr, but 20 proved difficult to purify to homogeneity
in this case because of co-elution with excess benzoic anhydride.
(18) For select examples of highly diastereoselective alkylations of
butyrolactones that proceed anti to a C(5)-stereodirecting group (typical dr
>95/5), see: Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. Chem. Lett. 1981,
1621–1624. Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. J. Org. Chem.
1988, 53, 4094–4098.
OL1008747
(20) Reactions were typically performed with 0.5 mmol of the requisite
silyl ketene acetal. For one example, we have demonstrated that scaling to
5 mmol furnishes 25 in similar yield and dr (87% yield, 98/2 dr).
(21) Benzoyl fluoride or isobutyric anhydride with DHPB gave only
low conversion to the corresponding C-acyl products.
(22) Crystallographic data for 36 has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
772460.
(19) While this simplistic model accounts for the observed sense of
stereoselectivity, the lowest energy conformations of neither the presumed
enolate nor the C-acyl isothiouronium intermediate, or the transition state
for the reaction, have yet been calculated computationally. Efforts towards
this goal are currently under further investigation.
Org. Lett., Vol. 12, No. 11, 2010
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