Formation of Carbon Quaternary Stereogenic Center in Acyclic Systems via a Sequence of Carbometalation-Intramolecular Cyclization-Silicon Activation

Article abstract of DOI:10.1055/s-0035-1561666

The diastereoselective carbometalation reaction of cyclopropenyl esters followed by reaction with acylsilanes provides γ-silylated lactones that undergo a 'sila-Grob' fragmentation to give pyrone enolates as a new source of acyclic δ-diketones, δ-keto acid, and δ-keto ester derivatives possessing a quaternary stereocenter.

Full text of DOI:10.1055/s-0035-1561666

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
M. Preshel-Zlatsin et al.
Paper
Synthesis
Formation of Carbon Quaternary Stereogenic Center in Acyclic
Systems via a Sequence of Carbometalation–Intramolecular
Cyclization–Silicon Activation
Maya Preshel-Zlatsin
Fa-Guang Zhang
Guillaume Eppe
Ilan Marek*
1)
Li, EDA
THF, 0 °C, 2.5 h
2) NuH, 0 °C to rt, 3 h
then H3O+
O
O
SiMe3
R3
O
R3
R2
R2
R1
11 examples
yields up to 91%
single-pot
operation
Nu
O
R1
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of
Chemistry and The Lise Meitner-Minerva Center for Computational Quan-
tum Chemistry, Technion-Israel Institute of Technology, Technion City,
Haifa 32000, Israel
chilanm@tx.technion.ac.il
Dedicated to the memory of Jean Normant, a wonderful teacher and truly inspirational colleague
Received: 13.04.2016
Accepted after revision: 20.05.2016
Published online: 10.06.2016
regio- and diastereoselective copper-catalyzed carbomag-
nesiation reaction of cyclopropenyl amide leading to the
formation of diastereoisomerically pure cyclopropyl mag-
nesium species 2;12 (ii) addition of acylsilane giving the cor-
responding α-trimethylsilyl metal alkoxide 3 as a single
diastereoisomer that undergoes, by simple addition of THF,
(iii) Zn Brook rearrangement13 with inversion of configura-
tion at the benzylic carbon center;14 (iv) followed by a selec-
tive ring cleavage15 of organometallic species 4 into the cor-
responding silyl enol ether 5 as a single geometrical isomer
after addition of water. Acidic hydrolysis provided, in a
single-pot operation from 1, the formation of δ-keto amide
6 possessing the quaternary carbon stereocenter in high
enantiomeric ratio.10
Although the described sequence of Scheme 1 is very ef-
ficient, we soon realized that any subsequent chemical
transformations of the amide function in the presence of
the ketone functional group (R3 = aryl, alkyl) would be chal-
lenging. To solve this potential issue of chemoselectivity,
we have then decided to develop an alternative approach
that should give an easy access to either δ-diketo 7, δ-keto
acid 8, and δ-keto ester 9 derivatives (Scheme 2). This new
sequence would also start from the easily accessible cyclo-
propenyl ester 10, easily accessible in enantiomerically en-
riched form,11 that would undergo the known diastereose-
lective carbometalation reaction as described in Scheme
2.12 However, upon addition of acylsilane, the diastereoiso-
merically pure α-silyl carbinol intermediate 11 would un-
dergo cyclization by intramolecular nucleophilic attack of
the alkoxide on the ester moiety providing bicyclic lactone
12. If, indeed, this reaction were to happen, one would then
need to trigger a fragmentation of the lactone 12 by activa-
tion of the C–Si bond into α-pyrone derivatives 13 that
DOI: 10.1055/s-0035-1561666; Art ID: ss-2016-c0205-op
Abstract The diastereoselective carbometalation reaction of cyclopro-
penyl esters followed by reaction with acylsilanes provides γ-silylated
lactones that undergo a ‘sila-Grob’ fragmentation to give pyrone eno-
lates as a new source of acyclic δ-diketones, δ-keto acid, and δ-keto es-
ter derivatives possessing a quaternary stereocenter.
Key words quaternary carbon stereocenters, carbometalation, cyclo-
propenes, silicon activation, fragmentation
In the last few decades, we have witnessed remarkable
accomplishments for the efficient creation of new carbon–
carbon bonds in acyclic systems en route to complex molec-
ular frameworks.1 In this context, single-pot operations
combining several steps that collectively provide the same
increase of complexity as multistep processes are of high
value.2 Particularly interesting would be the development
of one-pot strategies leading to the formation of enantio-
merically enriched quaternary carbon stereocenters in acy-
clic systems.3 If one wants to reach these goals in a single-
pot operation with the creation of several C–C bonds,4 poly-
functional intermediates such as bismetalated,5 carben-
oids,6 and oxenoids7 species may be used, but perfect con-
trol of the reactivity and selectivity of those species is
needed.8 One additional bifunctional intermediate that
could provide quaternary stereocenters with the same in-
crease of complexity as multistep processes was found in
the anionic migration of a silyl group from a carbon to an
oxygen, namely the Brook rearrangement,9 as described in
Scheme 1.10 This one-pot procedure for the transformation
of enantiomerically enriched cyclopropenyl amide11 1 into
acyclic δ-keto amide 6 proceeds through a sequence of: (i)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
M. Preshel-Zlatsin et al.
Paper
Synthesis
1. carbometalation
2. addition of acylsilane
3. Brook rearrangement
4. β-fragmentation
5. hydrolysis
O
NMe2
O
R3
R2
R1
Me2N
O
single-pot operation
R1
er 95:5
formation of a quaternary carbon stereocenter
2 new C–C bonds
1
6
60–72%
er 95:5
R2[M]
[M]
O
O
O
O
NMe2
[M]
Me2N
R2
Me2N
R2
O
[M]
C
H
SiMe3
R3
O
OSiMe3
R3
OSiMe3
R3
SiMe3
R1
R2
R3
R1 R2
Me2N
then
H2O
R1
R1
H
H
H
2
3
4
5
selective
diastereoselective
reaction with acylsilane
Brook rearrangement with
inversion of configuration
fragmentation,
stereodefined
silyl enol ether
syn-diastereoselective
carbometalation
Scheme 1 Brook rearrangement as a trigger for the ring opening of strained carbocycle
would then be able to react with a large range of nucleop-
hiles to provide the corresponding δ-keto acid 7, δ-keto es-
ter 8, and δ-diketo 9 derivatives as described in Scheme 2.
We were pleased to observe that the best experimental
conditions described for the diastereoselective carbometa-
lation reaction of cyclopropenyl amide10 could be similarly
applied to cyclopropenyl ester 10 and subsequent addition
of various acylsilanes directly gave the lactone 12a–f in
good overall yield as unique diastereoisomers as described
in Scheme 3. The formation of a unique diastereoisomer for
12 results from the diastereoselectivity of the carbometala-
tion reaction (control of the stereochemistry in C1–C2) and
reaction with acylsilane (control of the stereochemistry in
C3). The stereochemistry of 12 has been deduced from X-
ray crystal structure analysis of a structurally related com-
pound and the diastereoisomeric ratio by 1H NMR.10
1) R2MgBr (1 equiv), LiCl (1 equiv)
O
O
OEt
O
SiMe3
R3
CuBr•SMe2 (5 mol%)
R2
toluene, –50 °C
3
2
R1 1
R1
O
Proposed new targets
2)
10
12
R3
SiMe3
O
O
R3
O
R3
O
R3
R4
O
HO
O
R4O
R2
R2
R2
O
O
O
O
R1
R1
R1
O
O
SiMe3
Ph
SiMe3
Ph
SiMe3
Tol
7
8
9
Me
Bu
Me
Hex
Me
Et
12a
12b
54%
12c
65%
New proposed sequence
52%
dr >97:3:0:0:0:0:0:0
dr >97:3:0:0:0:0:0:0
dr >97:3:0:0:0:0:0:0
syn-diastereoselective
carbometalation and
reaction with acylsilane
lactonization
O
O
O
O
O
O
SiMe3
Tol
SiMe3
Tol
SiMe3
Tol
MgBr
Me
Bu
Me
Me
O
O
EtO
R2
O
SiR4
R3
O
OEt
O
3
SiR4
3
Hex
PhCH2
R2
R1
12d
95%
dr 94:6:0:0:0:0:0:0
12e
70%
dr >97:3:0:0:0:0:0:0
12f
40%
dr >97:3:0:0:0:0:0:0
R3
R1
R1
H
H
12
10
11
Scheme 3 Formation of lactone 12 via the carbometalation of cyclo-
propenyl ester followed by addition of acylsilane
carbon–silicon
activation
O
O
Having in hand the diastereoenriched lactones 12a–f,
the next step towards the formation of the acyclic frag-
ments 7–9 possessing the quaternary carbon stereocenters
was the transformation of 12 into the α-pyrone 13 via the
addition of a nucleophile (Scheme 2). One obvious potential
pitfall would be the reaction of the nucleophile on the car-
bonyl group of the lactone to provide back the cyclopropyl
R2
R1
O
R3
R4
O
R2
R1
ring-opening
reaction
R3
7 R4 = alkyl
8 R4 = OH
9 R4 = OR
13
Scheme 2 Proposed targets and synthetic plan
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
M. Preshel-Zlatsin et al.
Paper
Synthesis
ring derivative 11. However, we were confident that reac-
tions on the carbonyl group would be difficult as both dia-
stereotopic faces of the carbonyl group were shielded by
substituents of the quaternary stereocenter on one hand
and by the substituents of the original acylsilane on the
other.
R4MgBr
Et2O, 0 °C, 3 h
O
Me
Bu
O
Ph
O
R4
O
Me
7a–c
Bu
Ph
13b
Bu
Ph
Ph
Me
We were indeed pleased to observe that the addition of
commercially available lithium acetylide, ethylenediamine
complex (EDA) trigger selectively the ‘sila-Grob’-type frag-
mentation reaction,16 leading to α-pyrones 13 as described
in Scheme 4. It should be emphasized that α-pyrones are
well-known secondary metabolites from microorganisms
such as streptomycetes, having a role in spore germination,
pseudomonads, fungi, and as bacterial signaling mole-
cules.17
Bu
Me
O
O
Bu
Me
O
O
7b
71%
7a
88%
Ph
Ph
Bu
O
Me
O
7c
71%
Scheme 5 Ring opening of α-pyrones en route to acyclic δ-diketo prod-
ucts 7
O
O
Li, EDA
To further improve efficiency, we then decided to pre-
pare the desired acyclic δ-keto acids 8 as well as δ-keto es-
ters 9 in a single-pot operation directly from the bicyclic
lactone 12. To reach this goal, two rings need to be opened
O
SiMe3
R3
R2
R1
R2
THF, 0 °C, 2.5 h
1
O
then H3O+
Li, EDA
1
R1 12
13
R3
O
O
SiMe3
R3
O
Li, EDA
THF, 0 °C, 2.5 h
1)
O
SiMe3
R3
R2
R1
O
O
R3
R2
R1
2) R4OH, 0 °C to rt, 3 h
then H3O+
R4O
1
R2
O
R1
12
8a–f, 9a–e
O
O
O
Li, EDA
Me
Me
Me
Et
Me
Bu
O
O
O
O
H
O
Li
R4OH
O
Hex
PhCH2
R2
R1
R2
R1
+ R4OLi
Ph
Ph
Ph
Ph
13a
85%
13b
85%
13c
72%
13d
92%
O
O
R3
R3
O
O
O
O
O
Me
Et
Me
Bu
Me
Me
Ph
Ph
O
O
O
HOOC
HOOC
Hex
PhCH2
Et
Bu
8b
82%
Me
Me
O
O
O
O
Tol
Tol
Tol
13e
79%
13f
68%
13g
67%
13h Tol
8a
64%
75%
Ph
Tol
HOOC
HOOC
Scheme 4 Synthesis of α-pyrones 13
Me
PhCH2
Et
Me
8c
8d
In all cases, the α-pyrones were obtained in excellent
yields. Interestingly, other alkyllithiums species such as n-
BuLi, MeLi, or alkylmagnesium bromides, such as MeMgBr,
as well as various sources of fluoride anion (CsF, Bu4NF, KF)
in different conditions and solvents provided only traces of
α-pyrones, underlining again not only the difficulty for a
nucleophile to reach the carbonyl group of the lactone but
also to activate the silicon. Only non-bulky and reactive or-
ganolithium species, such as alkynyllithium, could promote
this ‘sila-Grob’ fragmentation. It was then obvious that the
addition of a nucleophile to the carbonyl group of the α-py-
rones 13 should be an easy process and indeed addition of
alkylmagnesium bromides to 13b gave the corresponding
acyclic δ-diketones 7a–c possessing a quaternary carbon
stereocenter in very good yields (Scheme 5).
82%
91%
Tol
Tol
HOOC
HOOC
Me
PhCH2
Hex
O
O
Me
8e
89%
8f
66%
Ph
Ph
Ph
MeOOC
MeOOC
MeOOC
Bu
Hex
Me
Me
O
O
O
O
9a
70%
9b
65%
Tol
iPrOOC
Et Me
Et
Me
9c
67%
9d
50%
Ph
iPrOOC
Bu
O
Me
9e
61%
Scheme 6 One-pot conversion of lactone 12 into acyclic δ-keto acid 8
and δ-keto ester 9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
M. Preshel-Zlatsin et al.
Paper
Synthesis
consecutively. Treatment of the initial lactone 12 with
alkynyllithium species promotes the first ring opening of
the cyclopropyl ring to afford the pyrone lithium enolate in-
termediate. Then, the success of this strategy resides in the
introduction of a second reagent that would not only pro-
tonate the pyrone enolate but also generates in situ a nucle-
ophile that would subsequently react with the carbonyl of
the pyrone to promote the second ring opening. Pleasingly,
the addition of water or alcohol could fulfill these two re-
quirements and provide the formation of either acyclic car-
boxylic acids 8 or esters 9 in excellent overall yields
(Scheme 6).
to –25 °C. The reaction was quenched with aq NH4Cl–NH4OH solu-
tion. The aqueous layer was washed with Et2O (3 × 5 mL) and the
combined organic layers were dried (Na2SO4).
(1S*,4S*,5R*,6R*)-6-Butyl-6-methyl-4-phenyl-4-(trimethylsilyl)-3-
oxabicyclo[3.1.0]hexan-2-one (12a)
White solid; yield: 164 mg (0.59 mmol, 52%); Rf = 0.3 (hexane/Et2O,
4:1); mp 65 °C.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.21 (m, 2 H), 7.15–7.11 (m, 3 H),
2.27 (d, J = 6.4 Hz, 1 H), 2.01 (d, J = 6.4 Hz, 1 H), 1.33–1.27 (m, 3 H),
1.26–1.21 (m, 2 H), 1.17–1.13 (m, 1 H), 0.85 (t, J = 7.1 Hz, 3 H), 0.61 (s,
3 H), –0.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.20, 140.97, 127.86, 125.94, 84.97,
In conclusion, the diastereoselective carbometalation
reaction of cyclopropenyl ester followed by reaction with
acylsilane provides a lactone that undergo a ‘sila-Grob’
fragmentation to give pyrone enolate as a new source of δ-
diketones 7, δ-keto acids 8, and δ-keto esters 9 possessing
an acyclic quaternary stereocenter.
39.98, 33.95, 32.80, 28.53, 28.16, 22.79, 14.39, 14.00, –4.83.
HRMS (ESI): m/z [M + H]+ calcd for C19H28O2Si + H: 317.1931; found:
316.8995.
(1S*,4S*,5R*,6R*)-6-Hexyl-6-methyl-4-phenyl-4-(trimethylsilyl)-3-
oxabicyclo[3.1.0]hexan-2-one (12b)
White solid; yield: 186 mg (0.54 mmol, 54%); Rf = 0.3 (hexane/Et2O,
4:1); mp 80 °C.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.21 (m, 3 H), 7.15–7.12 (m, 2 H),
2.22 (d, J = 6.4 Hz, 1 H), 2.01 (d, J = 6.4 Hz, 1 H), 1.32–1.31 (m, 3 H),
1.28–1.27 (m, 1 H), 1.27–1.24 (m, 4 H), 1.22–1.20 (m, 2 H), 0.82 (t, J =
6.8 Hz, 3 H), 0.61 (s, 3 H), –0.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.43, 141.15, 128.04, 126.12,
125.45, 85.17, 40.48, 34.17, 32.97, 31.94, 29.57, 28.39, 26.55, 22.81,
14.57, 14.26, –4.64.
All reactions involving organometallic compounds were carried out in
flame-dried glassware under positive pressure of argon in dry sol-
vents under anhydrous conditions using standard Schlenk techniques,
unless otherwise stated. Progress of the reactions was monitored by
analytical TLC using Merck pre-coated silica gel glass plates with F254
indicator. Visualization of spots was accomplished by using UV light
(254 nm), p-anisaldehyde, phosphomolybdic acid (PMA), or KMnO4
stain. All organometallic compounds, dry solvents, and reagents were
transferred using plastic single-use syringes and oven-dried stainless
steel needles. The purification of crude mixtures was accomplished
either by Celite 535 filter aid (Aldrich) or by preparative flash column
chromatography on silica gel 60 Å (Aldrich) using gradient mixtures
of either Et2O/n-pentane or n-hexane. Yields refer to chromatography
and spectroscopically pure compounds, unless otherwise indicated.
1H and 13C NMR spectra were measured in CDCl3 solution at r.t. on a
Bruker Avance AVII400 (400 MHz 1H, 100 MHz 13C) spectrometer. THF
and Et2O were purified and dried immediately prior to use by an In-
novative Technology Pure-Solv PS-MD-2 solvent purifier (alumina
columns) and kept under positive pressure of N2 (99.9999% purity
grade). CH2Cl2, toluene, and Et3N were freshly distilled from CaH2,
Na/benzophenone, and CaSO4, respectively, prior to use. n-BuLi (2.5 M
in hexanes), t-BuLi (1.7 M in pentane), MeLi (1.6 M in Et2O), MeMgBr
HRMS (APCI): m/z [M + H]+ calcd for C21H32O2Si + H: 345.2244; found:
345.2258.
(1S*,4S*,5R*,6R*)-6-Ethyl-6-methyl-4-(p-tolyl)-4-(trimethylsilyl)-
3-oxabicyclo[3.1.0]hexan-2-one (12c)
White solid; yield: 196 mg (0.65 mmol, 65%); Rf = 0.3 (hexane/Et2O,
4:1); mp 67 °C.
1H NMR (400 MHz, CDCl3): δ = 7.10–7.09 (m, 4 H), 2.32 (s, 3 H), 2.24
(d, J = 6.4 Hz, 1 H), 2.05 (d, J = 6.4 Hz, 1 H), 1.43–1.41 (m, 1 H), 1.25–
1.22 (m, 1 H), 0.97 (t, J = 7.4 Hz, 3 H), 0.67 (s, 3 H), 0.04 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.53, 137.98, 135.62, 128.72,
124.99, 85.15, 33.98, 33.17, 32.82, 29.12, 21.19, 14.04, 10.82, –4.66.
HRMS (APCI): m/z [M + H]+ calcd for C18H26O2Si + H: 303.1775; found:
303.1804.
(3.0
M in Et2O), lithium acetylide, ethylenediamine complex,
Rh2(OAc)4, CuI, and CuBr·SMe2, were purchased from Aldrich without
further purification. Other chemical compounds were purchased
from commercial suppliers and were purified if needed according to
suitable procedures. The cyclopropenyl esters18 and acylsilanes19
were synthesized according to known procedures.
(1S*,4S*,5R*,6R*)-6-Butyl-6-methyl-4-(p-tolyl)-4-(trimethylsilyl)-
3-oxabicyclo[3.1.0]hexan-2-one (12d)
White solid; yield: 313 mg (1.31 mmol, 95%); Rf = 0.3 (hexane/Et2O,
4:1); mp 70 °C.
1H NMR (400 MHz, CDCl3): δ = 7.15–7.07 (m, 4 H), 2.33 (s, 3 H), 2.24
(d, J = 6.4 Hz, 1 H), 2.05 (d, J = 6.4 Hz, 1 H), 1.39–1.23 (m, 6 H), 0.90 (t,
J = 7.1 Hz, 3 H), 0.67 (s, 3 H), 0.04 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.61, 137.96, 135.63, 128.74, 85.27,
40.20, 34.11, 33.00, 28.72, 28.30, 22.99, 21.21, 14.60, 14.19, –4.64.
Bicyclic Lactones 12; General Procedure
LiCl (1.2 mmol) was added to a 3-neck flask prior to flame-drying.
CuBr·SMe2 (5 mol%) was added and diluted in dry toluene (4 mL).
Then, the mixture was cooled to –50 °C, MeMgBr (1.2 mmol) was
added dropwise, and the mixture was stirred for 15 min at this tem-
perature. The appropriate cyclopropenyl ester 10 (1.5 mmol) diluted
in toluene (1 mL) was added dropwise and the mixture was allowed
to warm to –35 °C. Then, the appropriate acylsilane (1.0 mmol) was
added dropwise and the mixture was stirred for 2.5 h while warming
(1S*,4S*,5R*,6R*)-6-Hexyl-6-methyl-4-(p-tolyl)-4-(trimethylsilyl)-
3-oxabicyclo[3.1.0]hexan-2-one (12e)
White solid; yield: 250 mg (0.70 mmol, 70%); Rf = 0.3 (hexane/Et2O,
4:1); mp 75 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
M. Preshel-Zlatsin et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.10–7.08 (m, 4 H), 2.33 (s, 3 H), 2.24
(d, J = 6.4 Hz, 1 H), 2.05 (d, J = 6.4 Hz, 1 H), 1.37–1.32 (m, 4 H), 1.29–
1.26 (m, 6 H), 0.89 (t, J = 6.7 Hz, 3 H), 0.67 (s, 3 H), 0.05 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.55, 137.99, 135.63, 128.74,
125.73, 85.23, 40.51, 34.14, 32.98, 31.95, 29.58, 28.32, 26.55, 22.81,
21.22, 14.60, 14.26, –4.63.
4-Hexyl-4-methyl-6-phenyl-3,4-dihydro-2H-pyran-2-one (13c)
Yellow oil; yield: 98 mg (0.36 mmol, 72%); Rf = 0.3 (hexane/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 6.6 Hz, 2 H), 7.37–7.35 (m, 3
H), 5.66 (s, 1 H), 2.60 (d, J = 15.6 Hz, 1 H), 2.47 (d, J = 15.6 Hz, 1 H),
1.47–1.43 (m, 2 H), 1.35–1.33 (m, 8 H), 1.28 (s, 3 H), 0.87 (t, J = 6.0 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 167.17, 148.80, 132.60, 129.05,
128.63, 124.72, 110.51, 41.61, 41.58, 34.79, 31.87, 29.93, 26.54, 24.41,
22.77, 14.21.
HRMS (APCI): m/z [M + H]+ calcd for C22H34O2Si + H: 359.2401; found:
359.2414.
(1S*,4S*,5R*,6R*)-6-Benzyl-6-methyl-4-(p-tolyl)-4-(trimethylsi-
lyl)-3-oxabicyclo[3.1.0]hexan-2-one (12f)
HRMS (APCI): m/z [M + H]+ calcd for C18H24O2 + H: 273.1849; found:
273.2020.
White solid; yield: 146 mg (0.40 mmol, 40%); Rf = 0.3 (hexane/Et2O,
4:1); mp 122 °C.
4-Benzyl-4-methyl-6-phenyl-3,4-dihydro-2H-pyran-2-one (13d)
1H NMR (400 MHz, CDCl3): δ = 7.31–7.27 (m, 2 H), 7.25–7.21 (m, 2 H),
7.14–7.12 (m, 2 H), 6.94–6.88 (m, 3 H), 2.70 (d, J = 13.9 Hz, 1 H), 2.54
(d, J = 13.9 Hz, 1 H), 2.41 (d, J = 6.5 Hz, 1 H), 2.25 (d, J = 6.5 Hz, 1 H),
2.24 (s, 3 H), 0.63 (s, 3 H), –0.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.00, 137.72, 137.21, 135.33,
129.19, 128.30, 126.65, 85.00, 45.26, 32.90, 32.14, 28.26, 20.83, 14.87,
–4.99.
Yellow oil; yield: 127 mg (0.46 mmol, 92%); Rf = 0.3 (hexane/Et2O,
4:1).
1H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 7.8, 1.6 Hz, 2 H), 7.36–7.34
(m, 3 H), 7.29–7.25 (m, 3 H), 7.14 (dd, J = 6.4 Hz, 2 H), 5.64 (s, 1 H),
2.74 (s, 2 H), 2.65 (d, J = 15.6 Hz, 1 H), 2.45 (d, J = 15.6 Hz, 1 H), 1.24 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 168.63, 149.02, 136.65, 132.53,
130.63, 129.20, 128.68, 128.40, 127.07, 124.81, 109.99, 47.10, 41.41,
35.92, 26.38.
HRMS (APCI): m/z [M + H]+ calcd for C23H28O2Si + H: 365.1931; found:
365.1943.
HRMS (APCI): m/z [M + H]+ calcd for C19H18O2 + H: 279.1380; found:
279.1389.
α-Pyrones 13; General Procedure from Bicyclic Lactones 12
Lithium acetylide ethylenediamine complex (approx. 2 mmol) was
added to a weighed flask and the flask was weighed again. THF was
added (15 mL) and the solution was cooled using an ice bath. The ap-
propriate bicyclic lactone 12 (0.5 mmol, 1/3 equiv from the lithium
acetylide, EDA complex weighed) diluted in THF (2 mL) was added
dropwise and the mixture was stirred at this temperature following
the reaction by TLC (full consumption of starting material after 2.5 h).
The reaction was quenched with aq NH4Cl solution. The aqueous lay-
er was washed with Et2O (3 × 15 mL), and the combined organic lay-
ers were dried (Na2SO4).
4-Ethyl-4-methyl-6-(p-tolyl)-3,4-dihydro-2H-pyran-2-one (13e)
Yellow oil; yield: 91 mg (0.39 mmol, 79%); Rf = 0.3 (hexane/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.1
Hz, 2 H), 5.59 (s, 1 H), 2.57 (d, J = 15.6 Hz, 1 H), 2.45 (d, J = 15.6 Hz, 1
H), 2.36 (s, 3 H), 1.52–1.49 (m, 2 H), 1.16 (s, 3 H), 0.93 (t, J = 7.5 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 169.33, 149.02, 139.06, 129.79,
129.30, 124.62, 109.21, 41.19, 34.94, 34.04, 26.04, 21.38, 8.76.
HRMS (APCI): m/z [M + H]+ calcd for C15H18O2 + H: 231.1380; found:
231.1385.
4-Ethyl-4-methyl-6-phenyl-3,4-dihydro-2H-pyran-2-one (13a)
Yellow oil; yield: 92 mg (0.42 mmol, 85%); Rf = 0.3 (hexane/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 7.62 (dd, J = 8.0, 1.4 Hz, 2 H), 7.39–7.33
(m, 3 H), 5.65 (s, 1 H), 2.59 (d, J = 15.6 Hz, 1 H), 2.47 (d, J = 15.6 Hz, 1
H), 1.55–1.49 (m, 2 H), 1.17 (s, 3 H), 0.94 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.87, 148.65, 132.26, 128.75,
128.32, 124.40, 109.83, 40.82, 34.70, 33.70, 25.69, 8.46.
4-Butyl-4-methyl-6-(p-tolyl)-3,4-dihydro-2H-pyran-2-one (13f)
Yellow oil; yield: 88 mg (0.34 mmol, 68%); Rf = 0.3 (hexane/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.1
Hz, 2 H), 5.60 (s, 1 H), 2.59 (d, J = 15.6 Hz, 1 H), 2.46 (d, J = 15.6 Hz, 1
H), 2.36 (s, 3 H), 1.57–1.44 (m, 2 H), 1.32–1.28 (m, 4 H), 1.17 (s, 3 H),
0.90 (t, J = 6.7 Hz, 3 H).
HRMS (APCI): m/z [M + H]+ calcd for C14H16O2 + H: 217.1223; found:
217.1225.
13C NMR (100 MHz, CDCl3): δ = 169.38, 148.86, 139.09, 129.82,
129.33, 124.64, 109.60, 41.69, 41.36, 34.71, 26.63, 23.38, 21.42, 14.17.
HRMS (APCI): m/z [M + H]+ calcd for C17H22O2 + H: 259.1693; found:
4-Butyl-4-methyl-6-phenyl-3,4-dihydro-2H-pyran-2-one (13b)
Yellow oil; yield: 104 mg (0.42 mmol, 85%); Rf = 0.3 (hexane/Et2O,
259.1904.
4:1).
1H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 8.1, 1.5 Hz, 2 H), 7.32–7.28
(m, 3 H), 5.61 (s, 1 H), 2.54 (d, J = 15.6 Hz, 1 H), 2.41 (d, J = 15.6 Hz, 1
H), 1.45–1.36 (m, 2 H), 1.28–1.25 (m, 4 H), 1.13 (s, 3 H), 0.86 (t, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.02, 148.68, 132.50, 128.95,
128.53, 124.61, 110.39, 41.49, 41.18, 34.64, 26.50, 26.44, 23.25, 14.04.
4-Hexyl-4-methyl-6-(p-tolyl)-3,4-dihydro-2H-pyran-2-one (13g)
Yellow oil; yield: 96 mg (0.33 mmol, 67%); Rf = 0.3 (hexane/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 10.8
Hz, 2 H), 5.59 (s, 1 H), 2.58 (d, J = 15.6 Hz, 1 H), 2.45 (d, J = 15.6 Hz, 1
H), 2.36 (s, 3 H), 1.47–1.43 (m, 2 H), 1.28–1.26 (m, 8 H), 1.17 (s, 3 H),
0.87 (t, J = 6.4 Hz, 3 H).
HRMS (APCI): m/z [M + H]+ calcd for C16H20O2 + H: 245.1536; found:
245.1559.
13C NMR (100 MHz, CDCl3): δ = 169.39, 148.86, 139.09, 129.83,
129.34, 124.64, 109.62, 41.64, 34.75, 31.89, 29.98, 26.61, 24.43, 22.79,
21.43, 14.24.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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M. Preshel-Zlatsin et al.
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Synthesis
HRMS (APCI): m/z [M + H]+ calcd for C19H26O2 + H: 287.2006; found:
287.2218.
2.63 (d, J = 17.2 Hz, 1 H), 2.55 (d, J = 17.2 Hz, 1 H), 2.48 (t, J = 7.6 Hz, 2
H), 2.27 (t, J = 7.3 Hz, 2 H), 1.81–1.70 (m, 2 H), 1.45–1.36 (m, 2 H),
1.19–1.08 (m, 4 H), 1.00 (s, 3 H), 0.78 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.86, 200.61, 141.79, 138.45,
132.79, 128.54, 128.53, 128.40, 128.04, 125.94, 77.48, 77.16, 76.84,
49.77, 44.95, 43.57, 40.64, 35.67, 35.14, 26.03, 25.89, 25.21, 23.39,
14.20.
HRMS (APCI): m/z [M + H]+ calcd for C25H32O2 + H: 365.2475; found:
365.2498.
4-Benzyl-4-methyl-6-(p-tolyl)-3,4-dihydro-2H-pyran-2-one (13h)
Yellow oil; yield: 109 mg (0.37 mmol, 75%); Rf = 0.3 (hexane/Et2O,
4:1).
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.1 Hz, 2 H), 7.21 (t, J = 6.8
Hz, 3 H), 7.11–7.07 (m, 4 H), 5.52 (s, 1 H), 2.66 (s, 2 H), 2.58 (d, J = 15.6
Hz, 1 H), 2.38 (d, J = 15.6 Hz, 1 H), 2.29 (s, 3 H), 1.15 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.79, 149.07, 139.23, 136.73,
130.63, 129.74, 129.37, 128.37, 127.02, 124.73, 109.08, 47.14, 41.47,
35.86, 26.42, 21.42.
HRMS (APCI): m/z [M + H]+ calcd for C20H20O2 + H: 293.1536; found:
293.1545.
Acyclic Acids 8; General Procedure from Bicyclic Lactones 12
Lithium acetylide, ethylenediamine complex (approx. 1 mmol) was
added to a weighed flask and the flask was weighed again. THF (1 mL)
was added and the solution was cooled to 0 °C using an ice bath. The
appropriate bicyclic lactone 12 (0.5 mmol, 1/3 equiv from the lithium
acetylide, EDA complex weighed) diluted in THF (1 mL) was added
dropwise and stirred at this temperature following the reaction by
TLC (full consumption of the starting material after 2.5 h). Then, sat.
aq KOH solution was added and the mixture was stirred for an addi-
tional hour. The aqueous layer was washed with EtOAc (5 × 3 mL). The
aqueous layers were combined and few drops of concd HCl were add-
ed (pH 1), the aqueous layer was then washed with CH2Cl2 (5 × 3 mL).
The combined organic layers were dried (Na2SO4).
Acyclic Diketones 7; General Procedure from α-Pyrone 13b
The α-pyrone 13b (98 mg, 0.4 mmol, 1.0 equiv) was charged in dried
flask with dry Et2O (8 mL). Then Grignard reagent (0.48 mmol, 1.2
equiv) was added dropwise at 0 °C under argon and the mixture was
stirred at this temperature for 3 h. The reaction was quenched with 1
M HCl and extracted with Et2O. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The crude
product was purified by chromatography (silica gel, hexane/Et2O).
3-Ethyl-3-methyl-5-oxo-5-phenylpentanoic Acid (8a)
3-Butyl-3-methyl-1-phenylhexane-1,5-dione (7a)
Colorless oil; yield: 0.08 mmol, 64%); Rf = 0.2 (hexane/Et2O, 1:1).
Colorless oil; yield: 92 mg (0.35 mmol, 88%); Rf = 0.4 (hexane/Et2O,
6:1).
1H NMR (400 MHz, CDCl3): δ = 8.69 (bs), 7.95 (d, J = 7.4 Hz, 2 H), 7.54
(t, J = 7.3 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 3.12–3.10 (m, 2 H), 2.61 (d,
J = 14.4 Hz, 1 H), 2.55 (d, J = 14.4 Hz, 1 H), 1.52–1.48 (m, 2 H), 1.10 (s,
3 H), 0.87 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 201.10, 138.22, 133.34, 128.77,
128.35, 44.79, 42.93, 36.33, 33.27, 25.19, 8.29.
1H NMR (400 MHz, CDCl3): δ = 7.95–7.81 (m, 2 H), 7.48 (t, J = 7.3 Hz, 1
H), 7.39 (t, J = 7.5 Hz, 2 H), 3.18 (d, J = 16.6 Hz, 1 H), 3.10 (d, J = 16.6
Hz, 1 H), 2.74 (d, J = 17.3 Hz, 1 H), 2.65 (d, J = 17.3 Hz, 1 H), 2.04 (s, 3
H), 1.51–1.42 (m, 2 H), 1.24–1.13 (m, 4 H), 1.06 (s, 3 H), 0.83 (t, J = 7.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 208.99, 200.59, 138.43, 132.79,
128.53, 128.01, 50.45, 44.86, 40.55, 35.61, 31.88, 25.99, 25.80, 23.37,
14.16.
HRMS (ESI): m/z [M + H]+ calcd for C14H18O3 + H: 235.1329; found:
235.2642.
3-Methyl-3-(2-oxo-2-phenylethyl)heptanoic Acid (8b)
HRMS (ESI): m/z [M + H]+ calcd for C17H24O2 + H: 261.1849; found:
261.1851.
Colorless oil; yield: 159 mg (0.70 mmol, 82%); Rf = 0.2 (hexane/Et2O,
1:1).
1H NMR (400 MHz, CDCl3): δ = 9.62 (bs), 7.94–7.92 (m, 2 H), 7.56–7.52
(t, J = 7.4 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 2 H), 3.17–3.08 (m, 2 H), 2.65 (d,
J = 14.6 Hz, 1 H), 2.58 (d, J = 14.6 Hz, 1 H), 1.55–1.47 (m, 2 H), 1.22–
1.20 (m, 4 H), 1.13 (s, 3 H), 0.87 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.20, 177.96, 137.95, 132.81,
128.36, 127.86, 44.76, 42.78, 40.09, 35.54, 25.70, 25.32, 23.04, 13.85.
3-Butyl-3-methyl-1-phenylnonane-1,5-dione (7b)
Colorless oil; yield: 85 mg (0.28 mmol, 71%); Rf = 0.5 (hexane/Et2O,
6:1).
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.2 Hz, 2 H), 7.45 (t, J = 7.3
Hz, 1 H), 7.35 (t, J = 7.5 Hz, 2 H), 3.16 (d, J = 16.6 Hz, 1 H), 3.07 (d, J =
16.6 Hz, 1 H), 2.66 (d, J = 17.2 Hz, 1 H), 2.58 (d, J = 17.2 Hz, 1 H), 2.27
(t, J = 7.4 Hz, 2 H), 1.42 (dd, J = 15.1, 7.3 Hz, 4 H), 1.17 (dt, J = 14.4, 8.8
Hz, 6 H), 1.02 (s, 3 H), 0.79 (t, J = 7.3 Hz, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H22O3 + H: 263.1642; found:
263.1640.
13C NMR (100 MHz, CDCl3): δ = 211.46, 200.68, 138.51, 132.79,
128.56, 128.06, 77.48, 77.16, 76.84, 49.72, 45.01, 44.29, 40.64, 35.71,
26.06, 25.93, 25.90, 23.42, 22.39, 14.21, 13.96.
3-Benzyl-3-methyl-5-oxo-5-phenylpentanoic Acid (8c)
Colorless oil; yield: 29 mg (0.10 mmol, 82%); Rf = 0.2 (hexane/Et2O,
1:1).
HRMS (ESI): m/z [M + H]+ calcd for C20H30O2 + H: 303.2319; found:
303.2332.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.3 Hz, 2 H), 7.47 (t, J = 7.4
Hz, 1 H), 7.36 (t, J = 7.7 Hz, 2 H), 7.20–7.18 (m, 3 H), 7.08 (d, J = 6.5 Hz,
2 H), 3.08–2.97 (m, 2 H), 2.90 (d, J = 13.2 Hz, 1 H), 2.81 (d, J = 13.2 Hz,
1 H), 2.69 (d, J = 14.9 Hz, 1 H), 2.49 (d, J = 14.9 Hz, 1 H), 1.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.92, 177.72, 138.45, 137.94,
133.61, 131.30, 129.08, 128.55, 128.53, 126.95, 46.32, 44.86, 43.00,
37.11, 25.92.
3-Butyl-3-methyl-1,8-diphenyloctane-1,5-dione (7c)
Colorless oil; yield: 103 mg (0.28 mmol, 71%); Rf = 0.4 (hexane/Et2O,
6:1).
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 7.3 Hz, 2 H), 7.42 (t, J = 7.3
Hz, 1 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.17 (t, J = 7.4 Hz, 2 H), 7.07 (dd, J =
13.6, 7.2 Hz, 3 H), 3.14 (d, J = 16.6 Hz, 1 H), 3.06 (d, J = 16.6 Hz, 1 H),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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M. Preshel-Zlatsin et al.
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Synthesis
HRMS (APCI): m/z [M + H]+ calcd for C19H20O3 + H: 297.1485; found:
297.1497.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.4 Hz, 2 H), 7.52 (t, J = 7.3
Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 3.59 (s, 3 H), 3.16 (d, J = 14.7 Hz, 1 H),
3.08 (d, J = 16.8 Hz, 1 H), 2.61 (d, J = 14.7 Hz, 1 H), 2.55 (d, J = 14.7 Hz,
1 H), 1.55–1.49 (m, 2 H), 1.27–1.25 (m, 4 H), 1.13 (s, 3 H), 0.87 (t, J =
6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.66, 172.72, 138.21, 138.21,
132.59, 128.34, 127.77, 50.96, 44.90, 42.60, 40.03, 35.48, 25.79, 25.35,
23.13, 13.92.
3-Ethyl-3-methyl-5-oxo-5-(p-tolyl)pentanoic Acid (8d)
Colorless oil; yield: 21 mg (0.08 mmol, 91%); Rf = 0.2 (hexane/Et2O,
1:1).
1H NMR (400 MHz, CDCl3): δ = 8.62 (bs), 7.79 (d, J = 8.1 Hz, 2 H), 7.25
(d, J = 8.3 Hz, 2 H), 3.00 (s, 2 H), 2.48 (d, J = 14.2 Hz, 1 H), 2.42 (d, J =
14.2 Hz, 1 H), 2.34 (s, 3 H), 1.49–1.45 (m, 2 H), 1.02 (s, 3 H), 0.80 (t, J =
7.4 Hz, 3 H).
HRMS (APCI): m/z [M + H]+ calcd for C17H24O3 + H: 277.1798; found:
277.1864.
13C NMR (100 MHz, CDCl3): δ = 201.47, 176.77, 144.71, 135.99,
129.81, 128.94, 44.98, 43.49, 36.86, 33.71, 25.57, 22.13, 8.62.
Methyl 3-Methyl-3-(2-oxo-2-phenylethyl)nonanoate (9b)
Colorless oil; yield: 53 mg (0.17 mmol, 65%); Rf = 0.3 (hexane/Et2O,
7:3).
HRMS (ESI): m/z [M + H]+ calcd for C15H20O3 + H: 249.1485; found:
249.1736.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.3 Hz, 2 H), 7.54 (t, J = 7.3
Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 3.60 (s, 3 H), 3.16 (d, J = 16.8 Hz, 1 H),
3.08 (d, J = 16.8 Hz, 1 H), 2.61 (d, J = 14.7 Hz, 1 H), 2.54 (d, J = 14.7 Hz,
1 H), 1.56–1.49 (m, 2 H), 1.29–1.24 (m, 8 H), 1.13 (s, 3 H), 0.86 (t, J =
6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.69, 172.73, 138.23, 132.59,
128.35, 127.78, 50.98, 44.92, 42.62, 40.34, 35.54, 31.65, 29.74, 25.36,
23.54, 22.48, 13.92.
3-Methyl-3-[2-oxo-2-(p-tolyl)ethyl]nonanoic Acid (8e)
Colorless oil; yield: 48 mg (0.16 mmol, 89%); Rf = 0.2 (hexane/Et2O,
1:1).
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.1
Hz, 2 H), 3.36 (m, 2 H), 2.87 (d, J = 14.3 Hz, 1 H), 2.74 (d, J = 14.3 Hz, 1
H), 2.69 (s, 3 H), 1.78–1.71 (m, 2 H), 1.53–1.51 (m, 8 H), 1.39 (s, 3 H),
1.13 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 201.26, 177.42, 144.63, 136.00,
129.78, 128.88, 43.74, 42.41, 36.63, 32.23, 30.29, 26.13, 23.08, 22.11,
14.54.
HRMS (APCI): m/z [M + H]+ calcd for C19H28O3 + H: 305.2111; found:
305.2145.
Methyl 3-Ethyl-3-methyl-5-oxo-5-(p-tolyl)pentanoate (9c)
Colorless oil; yield: 50 mg (0.19 mmol, 67%); Rf = 0.3 (hexane/Et2O,
7:3).
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.18 (t, J = 7.4
Hz, 2 H), 3.52 (s, 3 H), 3.04 (d, J = 16.5 Hz, 1 H), 2.97 (d, J = 16.5 Hz, 1
H), 2.53 (d, J = 14.7 Hz, 1 H), 2.46 (d, J = 14.7 Hz, 1 H), 2.33 (s, 3 H),
1.53–1.49 (m, 2 H), 1.04 (s, 3 H), 0.86 (t, J = 7.5 Hz, 3 H).
3-Benzyl-3-methyl-5-oxo-5-(p-tolyl)pentanoic Acid (8f)
Colorless oil; yield: 41 mg (0.13 mmol, 66%); Rf = 0.2 (hexane/Et2O,
1:1).
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.1 Hz, 2 H), 7.55–7.49 (m, 5
H), 7.43 (d, J = 6.6 Hz, 2 H), 3.39 (d, J = 16.6 Hz, 1 H), 3.30 (d, J = 16.6
Hz, 1 H), 3.22 (d, J = 28.3, 13.2 Hz, 1 H), 3.16 (d, J = 28.3, 13.2 Hz, 1 H),
3.00 (d, J = 14.7 Hz, 1 H), 2.82 (d, J = 14.7 Hz, 1 H), 2.68 (s, 3 H), 1.38 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 199.35, 172.76, 143.34, 135.75,
129.03, 127.96, 50.99, 44.35, 42.25, 35.70, 32.66, 24.78, 21.44, 8.00.
HRMS (APCI): m/z [M + H]+ calcd for C16H22O3 + H: 263.1642; found:
263.2108.
13C NMR (100 MHz, CDCl3): δ = 200.66, 176.74, 144.35, 137.59,
135.59, 131.02, 129.49, 128.49, 128.22, 126.62, 46.14, 44.44, 37.01,
25.66, 21.81.
HRMS (APCI): m/z [M + H]+ calcd for C20H22O3 + H: 311.1642; found:
Isopropyl 3-Ethyl-3-methyl-5-oxo-5-phenylpentanoate (9d)
311.1644.
Colorless oil; yield: 17 mg (0.06 mmol, 50%).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.2 Hz, 2 H), 7.53 (t, J = 7.3
Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 4.96 (dt, J = 12.5, 6.3 Hz, 1 H), 3.15 (d,
J = 16.7 Hz, 1 H), 3.07 (d, J = 16.7 Hz, 1 H), 2.54 (d, J = 14.3 Hz, 1 H),
2.48 (d, J = 14.3 Hz, 1 H), 1.59–1.55 (m, 2 H), 1.16 (dd, J = 6.3, 0.6 Hz, 6
H), 1.11 (s, 3 H), 0.87 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.28, 172.45, 138.88, 133.23,
128.99, 128.43, 67.72, 45.33, 43.41, 36.40, 33.29, 25.41, 22.34, 22.32,
8.65.
Acyclic Esters 9; General Procedure from Bicyclic Lactones 12
Lithium acetylide, ethylenediamine complex (approx. 1 mmol) was
added to a weighed flask and the flask was weighed again. THF (1 mL)
was added and the solution was cooled to 0 °C using an ice bath. The
appropriate bicyclic lactone 12 (0.5 mmol, 1/3 equiv from the lithium
acetylide, EDA complex weighed) diluted in THF (1 mL) was added
dropwise and stirred at this temperature following the reaction by
TLC (full consumption of the starting material after 2.5 h). Then, ei-
ther aq i-PrOH or 3 M NaOMe in MeOH was added and the mixture
was stirred for 1.5 h. The aqueous layer was washed with Et2O (3 × 5
mL) and the combined organic layers were dried (Na2SO4).
Isopropyl 3-Methyl-3-(2-oxo-2-phenylethyl)heptanoate (9e)
Colorless oil; yield: 30 mg (0.10 mmol, 61%).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.2 Hz, 2 H), 7.53 (t, J = 7.3
Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 4.96 (dt, J = 12.5, 6.3 Hz, 1 H), 3.16 (d,
J = 16.8 Hz, 1 H), 3.07 (d, J = 16.8 Hz, 1 H), 2.55 (d, J = 14.3 Hz, 1 H),
2.49 (d, J = 14.3 Hz, 1 H), 1.53–1.49 (m, 2 H), 1.26–1.25 (m, 4 H), 1.16
(d, J = 6.2 Hz, 6 H), 1.13 (s, 3 H), 0.87 (t, J = 6.7 Hz, 3 H).
Methyl 3-Methyl-3-(2-oxo-2-phenylethyl)heptanoate (9a)
Colorless oil; yield: 79 mg (0.29 mmol, 70%); Rf = 0.3 (hexane/Et2O,
7:3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
M. Preshel-Zlatsin et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 199.91, 172.09, 138.55, 132.87,
128.64, 128.08, 67.36, 45.44, 43.50, 40.35, 35.88, 26.11, 25.66, 23.47,
22.00, 14.27.
(8) Marek, I.; Masarwa, A.; Delaye, P.-O.; Leibeling, M. Angew. Chem.
Int. Ed. 2015, 54, 414.
(9) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
(10) Zhang, F.-G.; Eppe, G.; Marek, I. Angew. Chem. Int. Ed. 2016, 55,
714.
(11) For the enantioselective cyclopropenylation of alkynes, see:
(a) Briones, J. F.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134,
11916. (b) Uehara, M.; Suematsu, H.; Yasutomi, Y.; Katsuki, T.
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S.; Wojitas, L.; Zhang, X. P. J. Am. Chem. Soc. 2011, 133, 3304.
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10.1039/C5CS00897B. (b) Didier, D.; Delaye, P.-O.; Simaan, M.;
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Acknowledgment
This research was supported by the European Research Council under
the European Community’s Seventh Framework Program (ERC grant
agreement no. 338912). F.-G.Z. was supported in part by a fellowship
of the Israel Council for Higher Education and by the Technion Fund
for Cooperation with Far Eastern Universities. I.M. is holder of the Sir
Michael and Lady Sobell Academic Chair.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H