An Efficient Directed Claisen Reaction Allows for Rapid Construction of 5,6-Disubstituted 1,3-Dioxin-4-ones

Article abstract of DOI:10.1055/s-0034-1378822

An efficient directed Claisen reaction between tert-butyl propionate and phenyl propionate is described. This enables a practical synthesis of 6-ethyl-2,2,5-trimethyl-4H-1,3-dioxin-4-one and thereby (Z)-[(4-ethylidene-2,2,5-trimethyl-4H-1,3-dioxin-6-yl)oxy]trimethylsilane, a key building block in our synthesis of macrolide antibiotics. The three-step route elaborated for the preparation of the latter substance requires no chromatography and is amenable to large-scale synthesis.

Full text of DOI:10.1055/s-0034-1378822

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2709–2712
psp
2709
Z. Zhang et al.
PSP
Synthesis
An Efficient Directed Claisen Reaction Allows for Rapid Construction
of 5,6-Disubstituted 1,3-Dioxin-4-ones
Ziyang Zhang
OLi
Yoshiaki Kitamura
Andrew G. Myers*
Me
Ot-Bu
Me
O
Me
O
LiHMDS
O
O
1 equiv
2 steps
(1.05 equiv)
Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, MA 02138, USA
myers@chemistry.harvard.edu
Me
Me
Ot-Bu
+
O
OTMS
86%
Me
Me
Me
OPh
1.05 equiv
30-g scale
70% overall yield
chromatography-free
Received: 01.07.2015
Accepted after revision: 09.07.2015
Published online: 03.08.2015
ed the desired product 3 in 60–65% yield, but its purifica-
tion was complicated by the presence of γ-monomethylated
and α,α,γ-trimethylated by-products, which were difficult
to separate.
DOI: 10.1055/s-0034-1378822; Art ID: ss-2015-m0409-psp
Abstract An efficient directed Claisen reaction between tert-butyl
propionate and phenyl propionate is described. This enables a practical
synthesis of 6-ethyl-2,2,5-trimethyl-4H-1,3-dioxin-4-one and thereby
(Z)-[(4-ethylidene-2,2,5-trimethyl-4H-1,3-dioxin-6-yl)oxy]trimethylsi-
lane, a key building block in our synthesis of macrolide antibiotics. The
three-step route elaborated for the preparation of the latter substance
requires no chromatography and is amenable to large-scale synthesis.
Me
O
Me
O
Me
O
Me
O
O
O
Me
Ot-Bu
Me
Me
Me
O
OTMS
Me
Me
1
2
3
Key words directed Claisen reaction, β-keto ester synthesis, phenyl
ester substrate, synthesis of substituted dioxinones, macrolide antibiot-
Scheme 1 Retrosynthetic route to 1
ics
O
O
NaH, n-BuLi;
O
O
We have developed a practical synthetic route to macro-
lide antibiotics that involves the highly convergent assem-
bly of eight simple building blocks. To enable large-scale
synthesis of macrolide antibiotic candidates for potential
clinical development, it is essential that each of our simple
molecular building blocks be available in large quantities
from readily available commodity chemicals. One essential
building block is (Z)-[(4-ethylidene-2,2,5-trimethyl-4H-1,3-
dioxin-6-yl)oxy]trimethylsilane (1). Here we detail a direct-
ed Claisen strategy that permits a practical, large-scale syn-
thesis of this substance.
Kato and co-workers have reported a facile method for
the synthesis of 2,2-dimethyl-1,3-dioxinones from β-keto
tert-butyl esters, acetic anhydride, acetone, and sulfuric
acid.1 To implement this method to synthesize the dioxi-
none 2 an access to the tert-butyl ester 3 is required
(Scheme 1). A two-step sequential γ-, then α-dimethylation
of tert-butyl acetoacetate has been reported to produce 3 in
51% yield,2 but a shorter and more efficient sequence was
sought. We found that a single-step α,γ-dimethylation of
tert-butyl acetoacetate (Scheme 2) was feasible and afford-
MeI
Me
Ot-Bu
60–65%
Me
Ot-Bu
Me
3
Scheme 2 A single-step synthesis of 3
In light of previous successes in other laboratories3 as
well as ours4 employing phenyl esters as substrates in intra-
molecular Claisen condensations, we envisioned that 3
might be assembled efficiently by a directed Claisen reac-
tion between tert-butyl propionate and phenyl propionate.
Two prior examples each of nonenolizable5 and enolizable6
phenyl esters as condensation partners in directed Claisen
reactions are summarized graphically in Scheme 3. Where-
as condensations of nonenolizable phenyl esters can be
conducted with equimolar amounts of the two coupling
partners (Scheme 3, A), in the examples of directed Claisen
reactions with enolizable phenyl esters as electrophiles an
excess of either the enolate or the phenyl ester was neces-
sary (Scheme 3, B). In the protocol detailed herein, efficient
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2709–2712

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Z. Zhang et al.
PSP
Synthesis
coupling between tert-butyl propionate and phenyl propio-
nate was achieved using just a 5% excess of the latter reac-
tant.
high yield, and is believed to serve to deprotonate the β-
keto tert-butyl ester product as it is formed, preventing
nonproductive consumption of the tert-butyl ester enolate.
The use of additional base in Claisen couplings has been re-
ported previously by Ohta and co-workers7 for condensa-
tions between the lithium enolate of tert-butyl acetate and
methyl or ethyl alkanoates, although in these examples
slow addition of an excess of the nucleophilic ester compo-
nent (2 equiv) and base (2.5 equiv) was required. The use of
an extra equivalent of base had also earlier been shown to
be beneficial in improving the yield of certain intramolecu-
lar Claisen cyclization reactions that we investigated as part
of our research on the synthesis of tetracyclines.4c The im-
portant role of the phenyl ester substrate in the present
transformation merits brief comment. Its high reactivity as
a Claisen substrate permits rapid condensation to occur
even at –78 °C without enolate exchange (deprotonation of
phenyl propionate by lithium tert-butyl propionate). In ad-
dition, the acidity of the phenol by-product permits its fac-
ile removal by base extraction. By contrast, when the con-
densation of lithium tert-butyl propionate was attempted
with benzyl propionate at –78 °C no reaction was observed
at that temperature, and at warmer temperatures where
condensation did proceed, self-condensation of benzyl pro-
pionate was observed as well as the desired cross-coupling
product 3.
A. directed Claisen reactions with non-enolizable phenyl esters
CO2Men
CO2Men
t-Bu
LDA (1 equiv)
O
CO2Men
MenO2C
t-Bu
O
PhO
O
(1 equiv)
(1 equiv)
91%5a
O
O
CO2Me
+
MeO
NaH (4 equiv)
N
Me
PhO
N
Me
MeSO2
(1 equiv)
MeSO2
(1.05 equiv)
62%5b
B. directed Claisen reactions with enolizable phenyl esters
Me
Me
Me
Me
O
O
O
H
O
H
LDA (1.2 equiv)
O
O
O
O
O
Me
Me
O
Me
Me
O
CO2Et
COMe
O
O
O
CO2Et
PhO
Me
LDA, LiHMDS;
Me
Me
60%6a
OTBS
Ot-Bu
(1 equiv)
(2 equiv)
Ot-Bu
then
Me
O
Me
O
O
O
OPh
LiHMDS (2 equiv)
3
Me
t-BuO
t-BuO
Me
86%
O
OTBS
H2SO4, Ac2O
acetone
OMe
80%6b
Me
(2 equiv)
PhO
99%
OMe
(1 equiv)
Me
O
Me
O
Me
O
Me
O
LDA, TMSCl
87%
Scheme 3 Previous examples of directed Claisen reactions with phenyl
ester electrophiles
Me
Me
OTMS
O
Me
Me
2
As shown in Scheme 4 below, addition of tert-butyl pro-
pionate (1 equiv, 30.7 g) to a solution of LDA (1.025 equiv)
in THF at –78 °C followed immediately in sequence by addi-
tions of a freshly prepared solution of lithium hexameth-
yldisilazide (1.0 M, 1.05 equiv) in THF and a solution of phe-
nyl propionate in THF (5.0 M, 1.05 equiv) led to complete
and clean directed condensation within one hour at –78 °C,
as determined by TLC analysis. Extractive isolation (includ-
ing a basic aqueous wash to remove the by-product phenol)
and concentration afforded the crude Claisen product in
1
Scheme 4 Large-scale synthesis of 1 by directed Claisen reaction
Treatment of a solution of the (unpurified) product 3 in
acetone (6.8 M) with acetic anhydride (3.0 equiv) and con-
centrated sulfuric acid (1.0 equiv) at 23 °C for five hours, as
specified by Kato et al.,1 afforded 2,2,6-trimethyl-5-ethyl-
1,3-dioxin-4-one (2) in quantitative yield as a colorless liq-
uid. If desired, this product can be purified by distillation,
although the crude product is quite pure. Further transfor-
mation of 2 into the corresponding trimethylsilyl enol ether
1 was easily achieved by enolization at –78 °C with LDA (1.2
equiv) followed by addition of freshly distilled chloro-
1
86% yield (37.8 g). H NMR analysis showed that the prod-
uct was free from detectable impurities; it was therefore
used without further purification. Inclusion of one equiva-
lent of lithium hexamethyldisilazide was key to achieving a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2709–2712

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Z. Zhang et al.
PSP
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trimethylsilane (1.2 equiv). Extractive isolation and distilla-
tion afforded pure (Z)-1 in 87% yield. The E-stereoisomer is
not formed, presumably as a consequence of an unfavorable
A1,3 steric repulsion that would be present between the
methyl groups in that isomer. Pure (Z)-1 has been found to
be stable to storage in neat form at –15 °C for at least one
year.
The three-step sequence described above requires no
chromatography and is amenable to large-scale synthesis.
We have conducted this sequence several times over to af-
ford 30-gram batches of pure (Z)-1 in an overall yield of
~70% from tert-butyl propionate. We believe that the proto-
cols reported here may be of value in the preparation of
other Claisen products and thereby substituted 1,3-dioxi-
nones.
at –78 °C (dry ice/acetone bath). The resulting colorless solution was
stirred at –78 °C for 15 min. A solution of tert-butyl propionate (30.7
g, 236 mmol, 1 equiv) in THF (50 mL) was added dropwise via cannu-
la. The resulting pale yellow solution was stirred at –78 °C for 15 min,
then the freshly prepared solution of lithium hexamethyldisilazide
(vide supra) was added dropwise via cannula. Immediately following
completed addition, a solution of phenyl propionate (37.2 g, 248
mmol) in THF (50 mL) was added dropwise via cannula. The resulting
solution was stirred at –78 °C for 1 h. Sat. aq NH4Cl (200 mL), H2O
(400 mL), and Et2O (400 mL) were added sequentially, and the mix-
ture was allowed to warm to 23 °C with stirring. The layers were sep-
arated and the aqueous layer was extracted with Et2O (2 × 300 mL). To
the combined organic layers was added 2 M aq NaOH (500 mL), and
the biphasic mixture was stirred vigorously for 2 h. The layers were
separated and the organic layer was washed with H2O (500 mL) fol-
lowed by brine (500 mL). The organic layer was dried (MgSO4) and
concentrated under reduced pressure [rotary evaporation, 30 °C (wa-
ter bath)/~40 mmHg] to provide 3 as a pale yellow oil; yield: 37.8 g
(86%).
FTIR (neat): 2980 (m), 1735 (s), 1715 (s), 1369 (m), 1155 (s), 847 (m),
735 cm–1 (m).
1H NMR (600 MHz, CDCl3): δ = 3.42 (q, J = 7.3 Hz, 2 H), 2.64–2.46 (m, 1
H), 1.45 (s, 9 H), 1.29 (d, J = 6.6 Hz, 3 H), 1.08 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 206.8, 169.8, 81.6, 53.6, 34.5, 27.9,
12.7, 7.7.
All reactions were performed in flame-dried glassware fitted with
rubber septa under a positive pressure of argon, unless otherwise
noted. Air- and moisture-sensitive liquids were transferred via sy-
ringe or stainless steel cannula. Solutions were concentrated by rota-
ry evaporation below 35 °C. Analytical TLC was performed using glass
plates pre-coated with silica gel (0.25 mm, 60 Å pore size, 230−400
mesh, Merck KGA) impregnated with a fluorescent indicator (254
nm). TLC plates were visualized by exposure to ultraviolet light (UV),
then were stained by submersion in a 10% solution of phosphomolyb-
dic acid (PMA) in EtOH, followed by brief heating on a hot plate.
HRMS (ESI): m/z calcd for (C10H18O3 + Na)+: 209.1148; found:
209.1148.
6-Ethyl-2,2,5-trimethyl-4H-1,3-dioxin-4-one (2)
Commercial solvents and reagents were used as received with the fol-
lowing exceptions. Hexamethyldisilazine (HMDS), i-Pr2NH, and
Me3SiCl were distilled from CaH2 under an atmosphere of N2 at 760
mmHg. Et2O, and THF were purified by passage through Al2O3 under
argon by the method of Pangborn et al.8 The molarity of solutions of
n-BuLi was determined by titration against diphenylacetic acid as an
indicator (average of three determinations).9
1H and 13C NMR spectra were recorded on Varian INOVA 500 (500
MHz/125 MHz) or INOVA 600 (600 MHz/150 MHz) NMR spectrome-
ter at 23 °C. Proton chemical shifts are expressed in parts per million
(ppm, δ scale) and are referenced to residual protium in the NMR sol-
vent (CHCl3: δ = 7.26). Carbon chemical shifts are expressed in parts
per million (ppm, δ scale) and are referenced to the carbon resonance
of the NMR solvent (CDCl3: δ = 77.0). Data are represented as follows:
chemical shift, multiplicity (standard abbreviations), coupling con-
stant (J) in hertz (Hz), and integration. IR spectra were obtained using
a Shimadzu 8400S FT-IR spectrophotometer referenced to a polysty-
rene standard. Data are represented as follows: frequency of absorp-
tion (cm–1), and intensity of absorption (s = strong, m = medium).
High-resolution mass spectra were obtained at the Harvard Universi-
ty Mass Spectrometry Facility using a Bruker micrOTOF-QII mass
spectrometer.
Ac2O (55.3 mL, 586 mmol, 3.00 equiv) was added dropwise via addi-
tion funnel to a solution of tert-butyl 2-methyl-3-oxopentanoate (3;
36.4 g, 195 mmol, 1 equiv) in acetone (28.7 mL, 391 mmol, 2.00
equiv) at 0 °C (ice-water bath). Concd H2SO4 (10.4 mL, 195 mmol, 1.00
equiv) was then added to the ice-cold solution dropwise over 15 min
via addition funnel. The reaction solution was allowed to warm to
23 °C and stirred at that temperature for 5 h. The mixture was poured
into a 3 L flask containing Et2O (1 L) and sat. aq NaHCO3 (1.6 L). The
biphasic mixture was stirred for 2 h and the layers were separated.
The organic layer was washed with sat. aq NaHCO3 (2 × 1 L) followed
by brine (1 L). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure [rotary evaporation, 30 °C (water bath)/~40
mmHg] to provide 2 as a colorless oil; yield: 32.8 g (99%). The prod-
uct, if desired, can be distilled under reduced pressure (70 °C/0.5
mmHg, ~75% yield).
FTIR (neat): 2991 (m), 1720 (s), 1643 (s), 1388 (s), 1377 (s), 1361 (s),
1267 (s), 1205 (s), 1150 (s), 1080 (s), 981 (s), 862 (m), 767 cm–1 (s).
1H NMR (600 MHz, CDCl3): δ = 2.30 (q, J = 7.6 Hz, 2 H), 1.82 (s, 3 H),
1.65 (s, 6 H), 1.12 (t, J = 7.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 166.7, 162.8, 104.5, 99.3, 24.9, 24.2,
10.2, 9.7.
HRMS (ESI): m/z calcd for (C9H14O3 + H)+: 171.1016; found: 171.1023.
tert-Butyl 2-Methyl-3-oxopentanoate (3)
A solution of n-BuLi in hexanes (2.34 M, 106 mL, 248 mmol, 1.05
equiv) was added dropwise via cannula to an ice-cooled solution of
hexamethyldisilazane (51.9 mL, 248 mmol, 1.05 equiv) in THF (90
mL). The resulting colorless solution was stirred at 0 °C for 30 min.
The resulting solution of lithium hexamethyldisilazide was used
within 1 h. In a separate flask, a solution of n-BuLi in hexanes (2.34 M,
103 mL, 242 mmol, 1.025 equiv) was added dropwise via cannula to a
solution of i-Pr2NH (34.5 mL, 242 mmol, 1.025 equiv) in THF (104 mL)
(Z)-[(4-Ethylidene-2,2,5-trimethyl-4H-1,3-dioxin-6-
yl)oxy]trimethylsilane (1)
A solution of n-BuLi in hexanes (2.32 M, 76 mL, 176 mmol, 1.20
equiv) was added dropwise via cannula to a solution of i-Pr2NH (25.1
mL, 176 mmol, 1.20 equiv) in THF (210 mL) at –78 °C (dry ice/acetone
bath). The reaction flask was transferred to an ice bath and stirring
was continued for 15 min. The reaction flask was cooled to –78 °C,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2709–2712

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Z. Zhang et al.
PSP
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and a solution of 6-ethyl-2,2,5-trimethyl-4H-1,3-dioxin-4-one (2;
25.0 g, 147 mmol, 1 equiv) in THF (50 mL) was added dropwise via
cannula; the transfer was quantitated with additional THF (6 mL). The
reaction mixture was stirred for 1 h at –78 °C, then Me3SiCl (22.5 mL,
176 mmol, 1.20 equiv) was added dropwise via syringe. After stirring
for 3 h at –78 °C, the cooling bath was removed and the reaction mix-
ture was allowed to warm to 23 °C, whereupon it was then concen-
trated under reduced pressure [rotary evaporation, 30 °C (water
bath)/~40 mmHg]. The residue was diluted with anhydrous pentane
(100 mL) and the resulting suspension was filtered through a sintered
glass funnel (medium porosity, 10–15 μm pore size). The filtrate was
concentrated to afford a yellow residue, which was purified by vacu-
um distillation (63–67 °C/0.2 mmHg) to afford 1 as a colorless oil;
yield: 31.0 g (87%).
ty. Z.Z. is a Howard Hughes Medical Institute International Student
Research Fellow.
References
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FTIR (neat): 2997 (m), 1678 (s), 1253 (s), 1170 (m), 910 (s), 885 (s),
846 (s), 730 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 4.40 (q, J = 6.9 Hz, 1 H), 1.66 (d, J = 6.9
Hz, 3 H), 1.63 (s, 3 H), 1.52 (s, 6 H), 0.24 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 147.9, 147.2, 101.0, 95.0, 82.1, 24.7,
9.9, 9.1, 0.5.
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HRMS (ESI): m/z calcd for (C12H22O3Si + H)+: 243.1411; found:
243.1416.
(7) Ohta, S.; Shimabayashi, A.; Hayakawa, S.; Sumino, M.; Okamoto,
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Acknowledgment
(8) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
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We most gratefully acknowledge funding from Alastair and Celine
Mactaggart, from a private family foundation, and from the Blavatnik
Biomedical Accelerator Program at Harvard University. Y.K. acknowl-
edges support from the Engineering Promotion Fund of Gifu Universi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2709–2712