Catalytic Asymmetric Synthesis of Ketene Heterodimer β-Lactones: Scope and Limitations

Article abstract of DOI:10.1021/acs.joc.6b01481

In this article we describe extensive studies of the catalytic asymmetric heterodimerization of ketenes to give ketene heterodimer β-lactones. The optimal catalytic system was determined to be a cinchona alkaloid derivative (TMS-quinine or Me-quinidine). The desired ketene heterodimer β-lactones were obtained in good to excellent yields (up to 90%), with excellent levels of enantioselectivity (≥90% ee for 33 Z and E isomer examples), good to excellent (Z)-olefin isomer selectivity (≥90:10 for 20 examples), and excellent regioselectivity (only one regioisomer formed). Full details of catalyst development studies, catalyst loading investigations, substrate scope exploration, protocol innovations (including double in situ ketene generation for 7 examples), and an application to a cinnabaramide A intermediate are described. The addition of lithium perchlorate (1-2 equiv) as an additive to the alkaloid catalyst system was found to favor formation of the E isomer of the ketene heterodimer. Ten examples were formed with moderate to excellent (E)-olefin isomer selectivity (74:25 to 97:3) and with excellent enantioselectivity (84-98% ee).

Full text of DOI:10.1021/acs.joc.6b01481

Article
pubs.acs.org/joc
Catalytic Asymmetric Synthesis of Ketene Heterodimer
β‑Lactones: Scope and Limitations
Shi Chen, Ahmad A. Ibrahim, Nicholas J. Peraino, Divya Nalla, Mukulesh Mondal,
Maxwell Van Raaphorst, and Nessan J. Kerrigan*
Department of Chemistry, Oakland University, 2200 North Squirrel Road, Rochester, Michigan 48309-4477, United States
S
* Supporting Information
ABSTRACT: In this article we describe extensive studies of
the catalytic asymmetric heterodimerization of ketenes to give
ketene heterodimer β-lactones. The optimal catalytic system
was determined to be a cinchona alkaloid derivative (TMS-
quinine or Me-quinidine). The desired ketene heterodimer
β-lactones were obtained in good to excellent yields (up to
90%), with excellent levels of enantioselectivity (≥90% ee for
33 Z and E isomer examples), good to excellent (Z)-olefin
isomer selectivity (≥90:10 for 20 examples), and excellent
regioselectivity (only one regioisomer formed). Full details of
catalyst development studies, catalyst loading investigations,
substrate scope exploration, protocol innovations (including double in situ ketene generation for 7 examples), and an application
to a cinnabaramide A intermediate are described. The addition of lithium perchlorate (1−2 equiv) as an additive to the alkaloid
catalyst system was found to favor formation of the E isomer of the ketene heterodimer. Ten examples were formed with
moderate to excellent (E)-olefin isomer selectivity (74:25 to 97:3) and with excellent enantioselectivity (84−98% ee).
the alkaloid catalyst (Scheme 2). In that way regioselective
ketene heterodimerization was ensured, while donor ketene
homodimerization was limited or reduced to a manageable
level. We found that acceptor ketene homodimerization was
never an issue if a ketene of attenuated reactivity was chosen for
the acceptor role: e.g. an alkylarylketene, diarylketene, dialkyl-
ketene, or TMS-ketene.
In this article we disclose full details of our catalyst
optimization/development studies, catalyst loading investiga-
tions, and substrate scope evaluation as well as an explora-
tion of a double in situ ketene generation variant, olefin stereo-
selectivity studies (switching selectivity to favor E isomer), and
stereochemical models.
INTRODUCTION
■
Historically, the goal of developing methods for selective
ketene heterodimerization (cross-dimerization of two different
ketenes) to provide access to ketene heterodimer β-lactones
has proved an elusive target (Scheme 1).1−6 Given the exten-
sive use of enantioenriched β-lactones in synthetic activities, we
were motivated to address this problem.5,7−9 The obstacles to
the attainment of such a goal have included the difficulty of
achieving regioselective formation of the desired ketene
heterodimer (two possible ketene heterodimer β-lactones),
competing ketene homodimerization (two possible ketene
homodimer β-lactones), and inability to control exocyclic olefin
stereoselectivity (E vs Z isomer).6 Finally, the ability to access
one enantiomer of the desired ketene heterodimer β-lactone
has become an important and necessary target, especially if the
ketene heterodimerization reaction is to be considered a viable
method for natural product and drug molecule synthetic appli-
cations.
Recently, we reported the first method to address all of these
difficulties in a practical manner (Schemes 1 and 2).10 We
determined that an alkaloid derivative catalytic system was
capable of effecting a regioselective and enantioselective hetero-
dimerization of ketenes to provide access to ketene hetero-
dimer β-lactones in up to 99% ee, with excellent regioselectivity
(only one ketene heterodimer observed), and with very good to
excellent olefin stereoselectivity (Z:E up to >97:3). Key to the
success of our protocol was the slow addition of the more
reactive ketene precursor (donor ketene precursor) to a solu-
tion containing the less reactive ketene (acceptor ketene) and
RESULTS AND DISCUSSION
■
We began our optimization of the ketene heterodimerization
methodology with the goal of preparing methylphenylketene-
derived heterodimer (Z)-3a in high enantiomeric excess (Table 1).
This involved examining the reaction of methylphenylketene,
which would act as the less reactive ketene (acceptor ketene),
with methylketene (generated in situ from propionyl chloride),
which would act as the more reactive ketene (donor ketene). We
had previously had success in developing a disubstituted ketene
(ketoketene) homodimerization reaction and related reactions
through the use of phosphine catalysis.11 However, phosphine
catalysts (Binaphane, Josiphos, and PBu3) were found to be too
Received: June 21, 2016
© XXXX American Chemical Society
A
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Scheme 1. Development of Ketene Heterodimerization
Table 1. Optimization of Reaction Conditions in
Alkaloid-Catalyzed Heterodimerization of Ketenes
a
addition
time of
yield (%)
(conversn
b
entry
catalyst
TMSQ
AcCl (h)
solvent
(%)) ee (%)
1
2
1
1
1
1
8
8
8
8
8
8
8
8
8
8
8
8
8
THF
0
TMSQ
MeQ
CH2Cl2
(40)
(50)
(65)
65
nd
nd
nd
c
3
d
CH2Cl2
4
MeQ
CH2Cl2
e
5
6
7
8
9
MeQ
CH2Cl2
83
94
93
e
TMSQ
(DHQ)2PHAL
QT
CH2Cl2
57
CH2Cl2
38
CH2Cl2
<5
43
nd
13
61
72
NBzQ
CH2Cl2
10 PhQ
CH2Cl2
39
11 BzQ
CH2Cl2
55
e
12 MeQd
13 MeQd
14 MeQd
15 MeQd
16 MeQd
17 MeQd
CH2Cl2
64
98
91
89
91
36
5
THF
47
PhCH3
35
CH2Cl2 (−78 °C)
CH2Cl2 (0 °C)
CH2Cl2 (room temp)
50
20
15
a
Only one heterodimer regioisomer observed by GC-MS and 1H
Scheme 2. Initial Mechanistic Proposal for Catalytic
Asymmetric Heterodimerization of Ketenes
NMR analysis of crude for entries 5,6 and 12 (Z:E ratio >97:3 as
determined by GC-MS and 1H NMR analysis). Definitions of
catalysts:
b
c
ee determined by chiral HPLC. Entries 1−3: 0.13 M concentration
d
of acceptor ketene in solvent. Entries 4−17: 0.25 M concentration of
acceptor ketene in solvent. MeQ and TMSQ afforded the R
e
active to facilitate the desired heterodimerization, leading
generally to oligomerization of the donor ketene or suffering
from catalyst deactivation under in situ ketene generation
conditions. Inspired by Calter’s work on the alkaloid-catalyzed
ketene homodimerization reaction, we proceeded to evaluate
cinchona alkaloid derivatives as promoters of the ketene hetero-
dimerization reaction.12−14 During control experiments it
became apparent that the alkaloid catalysts were incapable of
catalyzing the homodimerization of less reactive ketenes
(methylphenylketene or dimethylketene) to any great extent
(<10% conv at best). This outcome suggested to us a strategy
for promoting a selective ketene heterodimerization reaction:
the alkaloid catalyst would be mixed with a less reactive ketene
(the acceptor ketene, e.g. a disubstituted ketene or TMS-ketene)
enantiomer of 3a, while MeQd provided the S enantiomer of 3a.
acyl chloride precursor (the donor ketene) would be added
slowly to the reaction solution (Scheme 2). In this way, donor
ketene homodimerization would be minimized, as the donor
ketene would be generated slowly over time and as a result kept
in low concentrations at all times. Regioselective heterodime-
rization would also be enabled, as the more reactive donor
ketene would be more likely to form the critical ammonium
enolate intermediate. Once donor ketene ammonium enolate
formation occurred, it would encounter an excess amount of
acceptor ketene molecules rather than donor ketene molecules,
and hence a regioselective ketene heterodimerization would be
favored. An enantioselective reaction would also be expected,
and Hunig’s base, and a solution of a more reactive ketene or
̈
B
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given the high enantioselectivity observed in Calter’s alkaloid-
catalyzed homodimerization of methylketene and alkaloid-
catalyzed reaction of monosubstituted ketenes with a variety
of electrophiles (e.g., with iminoesters in Lectka’s β-lactam syn-
thesis).7c,13
Table 2. Catalyst Loading Studies in Alkaloid-Catalyzed
Heterodimerization of Ketenes
a
Early in optimization, we determined that it was essential to
add propionyl chloride over 8 h via syringe pump to a CH2Cl2
solution of methylphenylketene, the alkaloid catalyst (Me-
quinidine or Me-quinine/TMS-quinine), and Hunig’s base, in
̈
catalyst loading
(mol %)
reaction time
(h)
order to achieve optimal yields of the desired ketene hetero-
dimer (ca. 60−65%) (Table 1, entries 5, 6, and 12). This reac-
tion setup minimized competing methylketene homodimeriza-
tion.
b
c
entry
yield (%) ee (%)
Z:E
d
1
2
3
4
5
10
5
24
24
24
24
48
64 (87)
72
98
94
93
87
82
>97:3
96:4
96:4
97:3
96:4
2.5
1
52
57
53
Many alkaloid catalysts used in this study were prepared
through one-step literature procedures described by the groups
of Calter (TMSQ and TMSQd), Gaunt (MeQ and MeQd),
and Lectka (BzQ), while others were commercially available
((DHQ)2PHAL).12−14 TMS- and Me-protected alkaloid cata-
lysts were determined to provide very good to excellent
enantioselectivity in ketene heterodimerization, with TMS-
quinine (TMSQ) or Me-quinine (MeQ) providing access to
the R enantiomer, and the pseudoenantiomeric Me-quinidine
(MeQd) providing access to the S enantiomer (Table 1, entries
5, 6, and 12). Surprisingly, bifunctional catalysts possessing a
H-bonding donor group as well as the nucleophilic quinuclidine
nitrogen (e.g., benzamidoquinine and thiourea-quinine catalyst,
entries 8 and 9) provided poor enantioselectivity and reactivity.
Ph-quinine and Lectka’s Bz-quinine provided lower levels of
asymmetric induction in comparison to Me-quinine or TMS-
quinine (entries 10 and 11) and were not explored further.
CH2Cl2 was found to be superior to all other reaction
solvents (e.g., toluene and THF) in facilitating optimal con-
version to the desired ketene heterodimer (Table 1, entry 12 vs
entries 13 and 14). However, it was notable that very good
levels of enantioselection could be obtained in most solvents
examined (e.g., entries 12−14: 89−98% ee). The best levels of
enantioselectivity were observed when the reaction was con-
ducted at −25 °C (entry 12), while significantly lower
enantioselectivity was observed at 0 °C (entry 16) and virtually
racemic product was obtained when the reaction was con-
ducted at room temperature (entry 17). We speculate that
0.5
a
Only one heterodimer regioisomer observed in all cases by GC-MS
b
c
and 1H NMR analysis of crude. ee determined by chiral HPLC. Z:E
d
ratio determined by GC-MS analysis. 4 mmol scale.
We then proceeded to evaluate the substrate scope of the
reaction through variation of both the acceptor ketene and
donor ketene structure (Table 3). Significant variation in donor
ketene structure was tolerated, with methylketene, ethylketene,
n-propylketene, n-butylketene, and acetoxyketene all working
well. However, benzyloxyketene, phenoxyketene, N-phthaloyl-
ketene, and isopropylketene failed as donor ketenes for various
reasons, including incomplete ketene generation under the
reaction conditions (isopropylketene) and oligomerization of
the ketene under the reaction conditions (e.g., benzyloxyke-
tene). A variety of alkylarylketenes, including methylphenylke-
tene, ethylphenylketene, n-butylphenylketene, dimethylketene,
diphenylketene, and TMS-ketene (see Table 4) were found to
function as effective acceptor ketenes. However, dialkylketenes
as acceptor ketenes gave mixed results; therefore, although
dimethylketene performed excellently as an acceptor ketene
(Table 3, entries 8, 9, 22, and 23), cyclohexylmethylketene, iso-
propylmethylketene, and isobutylmethylketene generally gave
lower yields (20−40%) and variable levels of olefin stereo-
selectivity (Z:E = ca. 1:1 to 7:1).
In most cases, good to excellent enantioselectivity was
obtained (70 to >99% ee), with good to excellent levels of
olefin isomer selectivity (Z:E from 84:16 to >97:3 for 17
examples). Occasionally lower enantioselectivity (e.g., 73% ee
for Table 3, entry 3) was encountered when Me-quinine was
used as the catalyst, and this was attributed to the sterically
smaller O-methylated group providing reduced enantiofacial
shielding of the ammonium enolate intermediate I (Scheme 2).
This situation could be rectified by substituting TMS-quinine
for Me-quinine, leading to significantly higher enantioselectivity
(e.g., 93% ee for entry 4 vs 73% for entry 3), albeit at the cost of
lower yield (33%, entry 13) or lower Z:E selectivity (74:26 for
entry 13).
Hunig’s base-mediated racemization of the ketene heterodimer
̈
occurs more readily at temperatures above −25 °C. A control
experiment involving the subjection of enantioenriched ketene
heterodimer 3a (94% ee) to typical reaction conditions at room
temperature for 24 h seemed to confirm this hypothesis, as
significant racemization had occurred (ee decreased to 15%).
For the optimized examples (entries 5, 6 and 12), complete
regioselectivity for the desired ketene heterodimer 3a, as deter-
1
mined by GC-MS and H NMR analysis of the crude product,
was observed (Table 1). In addition, the desired heterodimer
was obtained as a single olefin isomer (>97:3 favoring the
Z isomer) (entries 5, 6, and 12).
In the case of ethylphenylketene (Table 3, entries 3 and 4),
the relatively lower (Z)-olefin isomer stereoselectivity may be
due to reversible protonation−deprotonation of putative inter-
The level of catalyst loading was examined for the Me-
quinidine case. Remarkably, it was determined that the reaction
could be run at as low as 0.5 mol % loading (Table 2, entry 5)
without significant reduction in yield of ketene heterodimer,
albeit with somewhat attenuated enantioselectivity (82% ee vs
98% ee for 10 mol % loading). A reasonable compromise of
acceptable yield and enantioselectivity (52% yield and 93% ee)
may be attained if a loading of 2.5 mol % is employed (Table 2,
entry 3).
mediate II by the ammonium salt of Hunig’s base (Scheme 2).
̈
Interestingly the level of isomerization appears to have some
dependence on the catalyst used (90:10 for MeQ vs 69:31 for
TMSQ, entries 3 and 4). Subjecting ketene heterodimer (+)-3b
(Z:E = 90:10) to standard reaction conditions (TMS-quinine,
propionyl chloride, Hunig’s base, at −25 °C in the presence or
absence of LiClO4) did not lead to any significant change in
̈
C
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a
Table 3. Substrate Scope of Heterodimerization of Monosubstituted Ketenes with Disubstituted Ketenes
b
c
entry
(+)-/(−)-3
cat.
R1
R2
Ph
R3
yield (%)
57
ee (%)
Z:E
d
1
(+)-3a
TMSQ
MeQd
MeQ
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Et
94
98
73
93
98
96
96
91
95
>99
>99
70
80
95
72
95
74
88
94
76
95
76
91
nd
>97:3
>97:3
90:10
69:31
84:16
e
2
(−)-3a
(+)-3b
(+)-3b
(−)-3b
(−)-3c
(+)-3c
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
TMS
64 (87)
3
57
60
62
61
60
79
90
43
40
73
33
65
4
TMSQ
MeQd
TMSQ
MeQd
MeQ
Et
5
Et
6
Ph
Ph
Me
Me
Me
Me
Et
7
f h
8
(+)-3d −
f h
9
(−)-3d −
MeQd
TMSQ
MeQd
MeQ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
(+)-3e
(−)-3e
(+)-3f
(+)-3f
(−)-3f
(R)-3g
(S)-3g
(R)-3h
(R)-3h
(S)-3h
(R)-3i
(S)-3i
>97:3
>97:3
91:9
Et
Et
TMSQ
MeQd
MeQ
Et
Et
74:26
87:13
93:7
Et
Et
i
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
OAc
OAc
Me
Et
61
i
MeQd
MeQ
Et
37
83:17
>97:3
97:3
Me
Me
Me
Et
54
55
64
TMSQ
MeQd
MeQ
>97:3
93:7
i
51
MeQd
MeQ
Et
43
52
57
50
84:16
j
(+)-3j
Me
Me
Me
j
(−)-3j
MeQd
MeQd
k
(+)-3k
78:22
a
b
c
Only one heterodimer regioisomer observed in all cases by GC-MS analysis of crudes and NMR analysis of 3. ee determined by chiral HPLC. Z:E
d
e
ratio determined by GC-MS or 1H NMR analysis. Sign of specific rotation: + enantiomer or − enantiomer. Reaction conducted on 4 mmol scale.
f
g
h
In these cases 2 equiv of LiClO4 was used as an additive. Isolated as Weinreb amide derivative 4 due to volatility of heterodimer. 20 mol % of
i
catalyst used. Isolated yield for two steps after conversion to acid 5 through Pd/C-catalyzed hydrogenolysis (characterized as acid; see the
Supporting Information and ref 20 for details). Isolated as Weinreb amide 4 due to susceptibility to decomposition on silica gel. 1 equiv of LiClO4
j
k
was used as an additive.
Table 4. Scope of Alkaloid-Catalyzed Heterodimerization of
Two Monosubstituted Ketenes
For dimethylketene-derived ketene heterodimers (Table 3
entries 8 and 9), it was found necessary to carry out hetero-
dimerizations in the presence of LiClO4 (2 equiv) in order to
limit competing homodimerization of methylketene. For most
examples (e.g., entries 1−7) an excess of donor ketene acyl
chloride (2.0 equiv) was used to effect full conversion to the
desired ketene heterodimer. As a result, the amount of ketene
homodimer formed as a side product for the latter examples
ranged from ca. 20−40% conversion (by GC-MS analysis of
crudes). On the other hand, for examples requiring equimolar
to excess molar amounts of acceptor ketene (e.g., entries 8, 9,
22, and 23, requiring only 0.5−1.0 equiv of acyl chloride), <1%
donor ketene homodimer was afforded, as determined by
GC-MS analysis of the crude products. Formation of ketene
homodimer derived from acceptor ketene was never observed
in any of our studies. Furthermore, only one heterodimer
regioisomer was observed in all cases, as determined by GC-MS
a
b
c
entry (+)-/(−)-3
catalyst
R1
Me
R2
yield (%)
ee (%)
1
2
3
4
5
6
7
(+)-3l
(−)-3l
(−)-3m
(+)-3m
(−)-3n
(+)-3n
3o
TMSQ
MeQd
TMSQ
MeQd
TMSQ
MeQd
MeQd
TMS
TMS
TMS
TMS
TMS
TMS
H
67
75
44
49
53
55
95
98
97
98
97
95
nd
Me
d
d
d
d
Cl-Et
Cl-Et
n-Hex
n-Hex
n-Hex
e
(18)
a
b
Sign of specific rotation: + enantiomer or − enantiomer. Only one
1
heterodimer regioisomer observed in all cases by GC-MS analysis of crudes
and NMR analysis of 3. Z:E ratio >97:3 in all cases. ee determined by
chiral HPLC or GC. 20 mol % of catalyst used. Percent conversion
by GC-MS to desired ketene heterodimer, not isolated.
and H NMR analysis of the crudes.
c
Having determined that the ketene heterodimerization
reaction was very efficient at providing access to heterodimers
derived from the reaction of monosubstituted ketenes with
disubstituted ketenes, we were motivated to investigate the more
daunting challenge of cross-dimerization of two monosubstituted
d
e
Z:E selectivity, ruling out isomerization of olefin geometry in
the heterodimer product.
D
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ketenes (Table 4). Such heterodimers had already received
some attention for use in applications toward the synthesis of
complex molecules (e.g., salinosporamide A by Romo’s group),
and so a method that would provide enantioselective access to
this class of heterodimer would be expected to have immediate
applications.5 For this purpose we sought an acceptor ketene
that would be unlikely to undergo homodimerization or indeed
to act as a donor ketene and so issues over the control of
regioselectivity and acceptor ketene homodimerization would
be eliminated. We had previously found that TMS-ketene was
incapable of undergoing catalytic homodimerization under
either alkaloid or even phosphine catalysis. We surmised that
the failure of homodimerization under nucleophile-catalyzed
conditions was due to the low reactivity of onium enolate
intermediate I (Scheme 2) derived from TMS-ketene. The
well-precedented stabilization of α anions by silicon was
presumed to be the underlying reason for the low reactivity of
the onium enolate.15 In light of the failed homodimerization
results, TMS-ketene appeared to be an ideal candidate for the
role of acceptor ketene, provided it could be subjected to reac-
tion with a more reactive ammonium enolate (intermediate I).
This was proven, as TMS-ketene was found to perform
excellently in its role as acceptor ketene to provide access to
heterodimers derived from methylketene, 2-chloroethylketene,
and n-hexylketene (Table 4, entries 1−6). All of the desired
ketene heterodimers were formed with excellent enantioselec-
tivity and complete regioselectivity (Table 4, entries 1−6).
In some cases (Table 4, entries 3 and 4), yields somewhat
lower (44−49%) than those for previous heterodimerizations
were obtained, due to competing homodimerization of the
donor ketene. The actual amount of donor ketene homodimer
formed depended upon the amount of acyl chloride used. Not
surprisingly, most homodimer (comprising 20−40% of crude
product) was formed in those reactions where an excess of
donor ketene acyl chloride (up to 2 equiv) was employed
(Table 4, entries 1−4). The least amount of donor ketene
homodimer (<10% of crude product) was observed in those
cases where an excess of acceptor ketene (up to 2 equiv) was
used (entries 5 and 6). The use of less donor ketene and
slower addition (12 h for entries 5 and 6) of the acyl chloride
precursor acted to minimize the formation of homodimer.
Conveniently, donor ketene homodimer (e.g., methylketene
homodimer in entries 1 and 2) was volatile enough to be
removed under high vacuum in many cases. Alternatively, the
desired heterodimer was separated from donor ketene homo-
dimer (e.g., entries 3 and 4) by flash column chromatography
through a plug of neutral silica (see the Experimental Section
for details).
Scheme 3. Application of Enantioenriched Ketene
Heterodimer to Synthesis of Cinnabaramide A Intermediate
Scheme 4. Mechanism for Formation of Z Isomer
(B3LYP/6-31+G(d,p) level of theory) was employed to cal-
culate reaction coordinates for the methyl quinidine catalyzed
heterodimerization of methylketene with ethylphenylketene (to
give ketene heterodimer (S,Z)-3b).16,17
In our earlier communication we proposed a mechanism
(Schemes 2 and 4) where an ammonium enolate (intermediate I)
would be formed stereoselectively as the (Z)-enolate due to the
alkaloid catalyst (Me-quinidine) adding to the less sterically
hindered side of the methylketene.10 Our more recent calcul-
ations (see the Supporting Information) support this proposal
and are in qualitative agreement with the results of Lectka’s
earlier molecular mechanics study on alkaloid-catalyzed
β-lactam formation.13,16 The free energy of the (Z)-enolate
(intermediate I) was found to be 8.86 kcal mol−1 lower in
energy then the (E)-enolate, indicating that essentially all of the
first enolate exists in the Z isomer form. From there we consid-
ered a number of possibilities for the reaction of intermediate I
((Z)-enolate) with the acceptor ketene (ethylphenylketene).
One mechanistic route involves an aldol-type process which
gives rise to ammonium enolate (intermediate II), and fol-
lowing lactonization, (S,Z)-3b is afforded (Schemes 2 and 4).
Alternatively, the reaction may proceed through a concerted
asynchronous [2 + 2] cycloaddition of intermediate I with
ethylphenylketene, via transition state II (TS II) (Scheme 4).18
Precedent for concerted substitution (rather than stepwise
addition−elimination) at the carbonyl of certain carboxylic acid
derivatives is known and has been proposed when a good
leaving group is bonded to the carbonyl.19
The advantage of using pregenerated TMS-ketene as accep-
tor ketene (entries 1−6) was emphasized as follows. Cross-
dimerization of two simple in situ generated monosubstituted
ketenes (n-hexylketene with ketene) led to a complex mixture
of homodimers and heterodimers, with the desired ketene
heterodimer accounting for only 18% of the product mixture
(as determined by GC-MS analysis, Table 4 entry 7).
Heterodimers 3m,n were of particular interest, given their
anticipated potential as intermediates for the synthesis of
salinosporamide A and cinnabaramide A.5 A cinnabaramide A
intermediate was efficiently accessed through ring opening of
ketene heterodimer (−)-3h with a serine derivative (Scheme 3).
Reaction Mechanism. Possible intermediates in the
catalytic cycle for the formation of ketene heterodimer (S,Z)-
3b are depicted in Scheme 4. Density functional theory
Stereochemical Models. We propose that enantioselec-
tion is determined in the transition state for the reaction of
the ammonium enolate (intermediate I) with ethylphenylke-
tene (Figure 1). Calculations showed that approach of
E
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Article
would be useful for synthetic applications involving different
diastereomers of dipropionate or deoxypropionate deriva-
tives.8e,20 Interestingly, when LiClO4 (1−2 equiv) was added
to the catalytic system, we noted a change in olefin geometry
selectivity from favoring the Z isomer to favoring formation of
the E isomer (e.g., Table 3, entries 3 and 5, in comparison with
Table 5, entries 1 and 2).21 A number of other lithium salt
additives and Lewis acids (LiI, LiBr, LiCl, LiBF4, ZnCl2, and
MgCl2) were investigated, but none of them gave results as
good as those with lithium perchlorate. The desired products
were generally obtained in >70% yield, with Z:E selectivity
ranging from 26:74 to 3:97 and with good to excellent enan-
tioselectivity (84−98% ee). The best levels of (E)-olefin
selectivity were obtained for isobutylphenylketene as acceptor
ketene, presumably due to the greater steric bulk of the isobutyl
group in comparison to the unbranched ethyl or n-butyl group
(Table 5, entries 5, 6, 9, and 10 vs entries 1−4, 7, and 8).
Unfortunately, the procedure failed for the synthesis of
(E)-ketene heterodimers derived from methylphenylketene,
with low olefin isomer selectivity being obtained (e.g., for 3a,
Z:E = 66:34).
Figure 1. Stereochemical model: calculated transition states II for
formation of (Z)-ketene heterodimer.
We surmise that the role of LiClO4 is to stabilize enolate
intermediates (Scheme 5). Due to the intermediacy of a
relatively long lived lithium enolate intermediate II, it is pos-
sible for equilibration of olefin geometry to occur (Scheme 5).
We propose that the change in olefin selectivity involves equil-
ibration of the second enolate intermediate (intermediate II)
through reversible protonation−deprotonation by protonated
ethylphenylketene to the re face of the ammonium enolate of
intermediate I (Z isomer) was nearly 2 kcal mol−1 lower in
energy than the competing si face approach (Figure 1, tran-
sition state II re face and si face). This corresponds well with
the observed enantioselectivity of 98% ee for formation of
(−)-3b (Table 3, entry 5). The formation of a significant
amount of E isomer (16% for (−)-3b) in the reaction may be
rationalized by a transition state which is calculated to be just
0.65 kcal mol−1 higher in energy than transition state II re
face leading to (Z)-ketene heterodimer (see the Supporting
Information). Again, this energy difference (predicting a Z:E
ratio of 79:21) correlates well with the experimentally deter-
mined Z:E ratio of 84:16 for the formation of (Z)-(−)-3b
(Table 3, entry 5).
Hunig’s base/Hunig’s base to afford mainly the E isomer of
̈
̈
intermediate II. Subsequent lactonization via tetrahedral
intermediate III would provide the ketene heterodimer as the
E isomer.
Double in Situ Ketene Generation. From a practical
standpoint the availability of a double in situ ketene generation
variant, which would preclude the need to pregenerate and
handle the acceptor ketene, would be highly desirable. Such a
process would allow chemists to use two commercially available
acyl chlorides to assemble enantioenriched ketene heterodimers
and thus bypass the need to isolate, purify, and handle
Synthesis of (E)-Ketene Heterodimers. Having the
potential to access both olefin isomers of a given heterodimer
a
Table 5. Asymmetric Synthesis of (E)-Ketene Heterodimers
b
c
d
entry
(+)-/(−)-3
catalyst
R1
R2
Et
R3
yield (%)
ee (%)
Z:E
1
2
(+)-3p
(−)-3p
(+)-3q
(−)-3q
(+)-3r
(−)-3r
(+)-3s
(−)-3s
(−)-3t
(+)-3t
TMSQ
MeQd
TMSQ
MeQd
TMSQ
MeQd
TMSQ
MeQd
TMSQ
MeQd
Me
Me
Me
Me
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
56
57
69
78
78
83
86
86
76
88
85
94
84
92
96
98
93
88
97
98
16:84
13:87
24:76
26:74
4:96
Et
e
3
n-Bu
n-Bu
i-Bu
i-Bu
Et
e
4
5
6
7
8
3:97
26:74
24:76
6:94
Et
Et
e
9
Et
i-Bu
i-Bu
e
10
Et
5:95
a
b
Only one heterodimer regioisomer observed in all cases by GC-MS analysis of crudes and NMR analysis of 3. Sign of specific rotation: +
c
d
1
enantiomer or − enantiomer. ee determined by chiral HPLC. Z:E ratio determined by GC-MS analysis of crudes and confirmed by H NMR
analysis. In these cases 1 equiv of LiClO4 was used as an additive.
e
F
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Article
Even with this modification, a distinct drop in yield was noted
due to incomplete acceptor ketene generation. Overall, these
results demonstrate the great promise of the method and
suggest that the scope of the process could be increased in the
future to include more exotic nonisolable acceptor ketenes.
Applications. To demonstrate that ketene heterodimers 3
can act as surrogates for aldol construction, (−)-4d (derived
from 3d) underwent a highly diastereoselective reduction
through reaction with KEt3BH to afford β-hydroxyamide
(+)-8d with excellent diastereoselectivity (dr >99:1), and
with virtually no loss of enantiomeric integrity (94% ee)
(Scheme 6).10,22 In addition, we have recently demonstrated
that ketene heterodimers may be conveniently converted into
anti-deoxypropionate derivatives 5, through a simple Pd/C-
catalyzed hydrogenolysis procedure (Scheme 6).20 Such struc-
tural motifs have found widespread use in the synthesis of
polyketide natural products and drug molecules. Moreover,
simple deoxypropionate derivatives often possess interesting
intrinsic biological activity.23,24 For example, (+)-5a was readily
reduced to alcohol (+)-9a (93%, dr 4:1), a molecule which
displays biological activity in its own right (Scheme 6).23
Scheme 5. Proposed Mechanism for Formation of E Isomer
CONCLUSION
■
In summary, we have developed a catalytic asymmetric
heterodimerization of ketenes of wide substrate scope that
allows even two different monosubstituted ketenes to be cross-
dimerized with excellent enantioselectivity (33 examples
with ≥90% ee), good to excellent (Z)-olefin isomer selectivity
(84:16 to >99:1), and excellent regioselectivity (only one hetero-
dimer formed in all cases). Moderate to excellent (E)-olefin
isomer selectivity (74:25 to 97:3) along with excellent enan-
tioselectivity (84−98% ee) could also be accomplished through
use of lithium perchlorate as an additive. Catalyst loading studies
suggest that the reaction can be run on as a low a loading as
0.5 mol %, without significant reduction in yield and only slight
reduction in enantioselectivity, which is very competitive in
comparison to other organocatalytic processes.25 Furthermore,
a double in situ ketene generation protocol displays promise,
as seven examples proceeded with excellent enantioselectivity
and moderate to good yields. Studies are currently underway to
moisture-sensitive acceptor ketenes. In situ generation of the
acceptor ketene as well as of the donor ketene was investigated
for seven different examples (Table 6). (−)-3a was formed with
comparable yield (61%) and with slightly lower enantiomeric
excess (91% ee) in comparison to those when pregenerated
methylphenylketene was used (Table 6, entry 1 vs Table 3,
entry 2). Indeed, in all cases examined high enantioselectivity
(>90% ee) comparable to that obtained using pregenerated
acceptor ketene was observed (Table 6 vs Table 3). Signif-
icantly, the reaction could be performed with a lower catalyst
loading (2.5 mol %), without any decrease in yield, diastereo-
selectivity, or enantioselectivity (Table 6, entry 2). However,
for examples involving ethylphenylketene as acceptor ketene, a
longer ketene generation time was required (12 h at room
temperature), in order to provide reasonable yields (35−48%)
of the desired ketene heterodimer (Table 6, entries 4, 6, and 7).
a
Table 6. Double in Situ Generation of Ketenes
b
c
d
entry
catalyst (amt (mol %))
R1
R2
R3
yield (%)
ee (%)
Z:E
3
e
1
2
3
4
5
6
7
MeQd (10)
MeQd (2.5)
TMSQ (10)
MeQd (10)
MeQd (10)
MeQd (10)
Me
Me
Me
Me
Et
Me
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Et
61
74
67
48
71
35
41
91
92
>97:3
99:1
(−) -3a
e
(−) -3a
e
93
99:1
(+) -3a
95
78:22
98:2
(−)-3b
(−)-3e
(−)-3f
(E)-(−)-3p
Me
Et
97
Et
97
86:14
33:67
f
MeQd (10)
Me
Ph
>99
a
b
c
Only one heterodimer regioisomer observed in all cases by GC-MS analysis of crudes and NMR analysis of 3. Isolated yield for both isomers. ee
d
e
f
determined by chiral HPLC. Z:E ratio determined by GC-MS analysis. Sign of specific rotation: + enantiomer or − enantiomer. Reaction
conducted in the presence of 2 equiv of LiClO4.
G
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Scheme 6. Access to Dipropionate and Deoxypropionate Synthons
Method A for Ketene Heterodimerization. Acyl chloride in
dichloromethane was added over the indicated time via syringe pump
apply the new methodology to the asymmetric synthesis of
biologically interesting molecules.
to a solution of ketene, Hunig’s base, and alkaloid catalyst in dichloro-
̈
methane at −25 °C, and the mixture was stirred for the indicated time.
Method B for Ketene Heterodimerization. Acyl chloride in
dichloromethane was added over the indicated time via syringe pump
EXPERIMENTAL SECTION
General Considerations. THF was freshly distilled from
benzophenone ketyl radical under nitrogen prior to use, while Hunig’s
■
to a solution of ketene, Hunig’s base, LiClO , and alkaloid catalyst in
̈
̈
4
dichloromethane/ether solution at −25 °C, and the mixture was
base (diisopropylethylamine) was distilled from calcium hydride and
N,N-dimethylethylamine was distilled from potassium hydroxide under
nitrogen.26 Most anhydrous solvents (dichloromethane and diethyl
ether) were obtained by passing through activated alumina columns
on a solvent purification system. Zinc dust (<10 μm), lithium
perchlorate, n-butyllithium (2.5 M in hexane), LiAlH4 (1.0 M in
Et2O), potassium triethylborohydride (1.0 M in THF), 2-phenyl-
propanoic acid, 2-phenylbutanoic acid, diphenylacetyl chloride,
phenylacetic acid, ethylethynyl ether, and 2-pyridone were purchased
and used as received. Propionyl chloride, butyryl chloride, aceto-
xyacetyl chloride, 4-chlorobutyryl chloride, hexanoyl chloride, octanoyl
chloride, valeroyl chloride, and trimethylsilyl chloride were purchased
and distilled prior to use.26 Iatrobeads (neutral silica, 60 μM particle
size), and TLC plates (UV254, 250 μM) were used as received.
Methylphenylketene, ethylphenylketene, n-butylphenylketene, isobu-
tylphenylketene, diphenylketene, dimethylketene, and TMS-ketene
were prepared according to literature procedures.27 TMS-quinine, Me-
quinidine, and Me-quinine were synthesized according to literature
procedures.28 (R)-Allyl-3-(benzyloxy)-2-(4-methoxybenzylamino)-
propanoate (6) was synthesized according to a literature procedure.5
NMR spectra were recorded on a 400 spectrometer (400 MHz for
1H and 100 MHz for 13C). NMR chemical shifts were reported relative
stirred for the indicated time.
Method C for Ketene Heterodimerization (in Situ Gener-
ation of both Acceptor and Donor Ketene). Hunig’s base was
̈
added to a solution of 2-phenylpropionyl chloride or 2-phenylbutyryl
chloride in CH2Cl2 at the indicated temperature, and the mixture
was stirred for the indicated time. The reaction mixture was cooled to
−25 °C, Me-quinidine in CH2Cl2 was added, and propionyl chloride
or butyryl chloride in CH2Cl2 was added over 8 h via syringe pump.
The reaction mixture was stirred for 12 h at −25 °C.
Previous Compound Characterization. Compounds (+)-3a,
(−)-3a, (+)-3b, (−)-3b, (+)-3c, (−)-3c, (+)-3l, (−)-3l, (+)-3m,
(−)-3m, (+)-3n, (−)-3n, (+)-(E)-3p, (−)-(E)-3p, (+)-(E)-3r, and
(−)-(E)-3r were fully characterized as previously described.10 Weinreb
amides (+)-4d, (−)-4d, (+)-4j, and (−)-4j were obtained from the
corresponding ketene heterodimers (3d,j) through Weinreb amine
ring opening, and the amides were fully characterized as previously
described.10 Carboxylic acids (+)-5g, (−)-5g, (+)-5h, (−)-5h, (+)-5i,
and (−)-5i were obtained from the corresponding ketene hetero-
dimers (3g−i) through Pd/C-catalyzed hydrogenolysis, and the acids
were fully characterized as previously described.20 Compounds (+)-5a,
(+)-8d, and (+)-9a were prepared and characterized as previously
described.10,20
1
to TMS (0 ppm) for H and to CDCl3 (77.23 ppm) for 13C spectra.
(R,Z)-3-Ethyl-4-(1-phenylethylidene)oxetan-2-one ((+)-(Z)-
3e) (Method A). Butyryl chloride (255 mg, 2.39 mmol) in dichloro-
methane (1.0 mL) was added over 8 h to a solution of methylphenyl-
High-resolution mass spectra were obtained on an Accurate Mass
Q-TOF LC-MS instrument with ESI as the ionization method. Low-
resolution mass spectra were recorded on a GC-MS instrument
equipped with a mass selective detector and using a GC column
(30 m, 0.25 mm i.d.). IR spectra were recorded on an IR spectrometer.
Optical rotations were measured on an automatic polarimeter.
Chiral high-performance liquid chromatography analysis (HPLC)
was performed using AD, OD-H, OB-H, and AS-H columns (25 ×
0.46 cm) on an HPLC instrument attached with diode array detector
(deuterium lamp, 190−600 nm) with HPLC-grade isopropyl alcohol
and hexanes as the eluting solvents. Enantiomeric excesses were deter-
mined at λ 254 or 225 nm (details given for each compound). Chiral
gas chromatography analysis (GC) was performed using a Chiraldex
B-DM fused silica capillary column (30 m × 0.25 mm × 0.12 μm film
thickness) on a gas chromatograph instrument.
ketene (158 mg, 1.20 mmol), Hunig’s base (309 mg, 2.39 mmol), and
̈
TMS-quinine (47 mg, 0.12 mmol) in dichloromethane (3.7 mL) at
−25 °C. The reaction mixture was stirred at this temperature for
another 16 h before being concentrated under reduced pressure to
about 1 mL. The solution was diluted with 1% EtOAc/hexane
(10 mL) and passed through a plug of neutral silica (12 g), with 1%
EtOAc/hexane (300 mL) as eluent. The solvent was removed under
reduced pressure, and (+)-(Z)-3e was isolated as a colorless oil
(104 mg, 43%), with a Z:E ratio of >97:3 as determined by GC-MS
analysis: HPLC analysis >99% ee (Daicel Chiralcel OB-H column;
1 mL/min; solvent system 10% isopropyl alcohol in hexane; retention
times 9.7 min (major)); [α]D23 = +7.6 (c = 0.42, CH2Cl2); IR (thin film)
H
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Article
1
2973, 2936, 1705, 1654, 1453, 1377, 1228, 1066, 698 cm−1; H NMR
(400 MHz, CDCl3, TMS) δ 7.56−7.50 (m, 2H), 7.43−7.35 (m, 2H),
7.32−7.25 (m, 1H), 4.30 (dd, J = 7.1, 5.0 Hz, 1H), 2.13−1.93
(m, 2H), 2.03 (s, 3H), 1.15 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.4, 141.4, 136.3, 128.6, 127.4, 127.3, 108.8, 56.7, 20.5,
15.5, 10.3; (M + H)+ HRMS m/z calcd for (C13H15O2)+ 203.1072,
found 203.1073.
(m, 2H), 7.33−7.22 (m, 2H), 4.26 (dd, J = 7.0, 4.8 Hz, 1H), 2.60−
2.30 (m, 2H), 2.14−1.90 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H), 1.06 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 141.0, 134.8,
128.6, 128.0, 127.4, 115.8, 56.1, 23.2, 20.6, 13.7, 10.3; (M + H)+
HRMS m/z calcd for (C14H17O2)+ 217.1229, found 217.1221.
(R,Z)-4-(1-Phenylpropylidene)-3-propyloxetan-2-one ((R,Z)-3g)
(Method A). Valeroyl chloride (230 mg, 1.91 mmol) in dichloro-
methane (0.9 mL) was added over 8 h to a solution of ethylphenyl-
(S,Z)-3-Ethyl-4-(1-phenylethylidene)oxetan-2-one ((−)-(Z)-3e)
(Method A). Butyryl chloride (562 mg, 5.27 mmol) in dichloro-
methane (1.0 mL) was added over 8 h to a solution of methylphenyl-
ketene (139 mg, 0.95 mmol), Hunig’s base (247 mg, 1.91 mmol), and
̈
Me-quinine (33 mg, 0.098 mmol) in dichloromethane (1.1 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 1 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (7 g), with
1% EtOAc/hexane (300 mL) as eluent. The solvent was removed
under reduced pressure, and (R,Z)-3g was isolated as a colorless oil
(92% conversion by GC-MS), with a Z:E ratio of 93:7 as determined
by GC-MS analysis: HPLC analysis 72% ee (Daicel Chiralpak OD-H
column; 1 mL/min; solvent system 2% isopropyl alcohol in hexane;
retention times 5.7 min (minor), 10.6 min (major)). (R,Z)-3g (84 mg)
was subjected to Pd/C-catalyzed hydrogenolysis to provide carboxylic
acid (−)-5g (56 mg, 61% for two steps), which was fully characterized
as previously described.20
ketene (348 mg, 2.64 mmol), Hunig’s base (945 mg, 5.27 mmol), and
̈
Me-quinidine (89 mg, 0.26 mmol) in dichloromethane (9.4 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 2 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (15 g),
with 1% EtOAc/hexane (200 mL) and 5% EtOAc/hexane (100 mL)
as eluents. The solvent was removed under reduced pressure, and
(−)-(Z)-3e was isolated as a colorless oil (213 mg, 40%)%), with a Z:E
ratio of >97:3 as determined by GC-MS analysis: HPLC analysis >99%
ee (Daicel Chiralpak OB-H column; 1 mL/min; solvent system 10%
isopropyl alcohol in hexane; retention times 6.4 min (major)], [α]D23
=
−5.8 (c = 1.24, CH2Cl2); IR (thin film) 2973, 2935, 1705, 1657, 1448,
1377, 1067, 699 cm−1; H NMR (400 MHz, CDCl3, TMS) δ 7.58−
1
(S,Z)-4-(1-Phenylpropylidene)-3-propyloxetan-2-one ((S,Z)-3g)
(Method A). Valeroyl chloride (230 mg, 1.91 mmol) in dichloro-
methane (1.0 mL) was added over 8 h to a solution of ethylphenyl-
7.48 (m, 2H), 7.46−7.33 (m, 2H), 7.32−7.21 (m, 1H), 4.30 (app t,
J = 5.4 Hz, 1H), 2.15−1.91 (m, 2H), 2.02 (s, 3H), 1.15 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 141.4, 136.3, 128.6,
127.4, 127.3, 108.8, 56.6, 20.5, 15.5, 10.3; (M + H)+ HRMS m/z calcd
for (C13H15O2)+ 203.1072, found 203.1070.
ketene (139 mg, 0.95 mmol), Hunig’s base (247 mg, 1.91 mmol), and
̈
Me-quinidine (33 mg, 0.098 mmol) in dichloromethane (1.0 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 1 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (5 g), with
1% EtOAc/hexane (300 mL) as eluent. The solvent was removed
under reduced pressure, and (S,Z)-3g was isolated as a colorless oil
(83% conversion by GC-MS) with a Z:E ratio of 83:17 as determined
by GC-MS analysis: HPLC analysis 95% ee (Daicel Chiralpak OD-H
column; 1 mL/min; solvent system 2% isopropyl alcohol in hexane;
retention times 5.7 min (major), 10.8 min (minor)). (S,Z)-3g (42 mg)
was subjected to Pd/C-catalyzed hydrogenolysis to provide carboxylic
acid (+)-5g (19 mg, 37% for 2 steps), which was fully characterized as
previously described.20
(R,Z)-3-Ethyl-4-(1-phenylpropylidene)oxetan-2-one ((+)-(Z)-3f)
(Method A). Butyryl chloride (227 mg, 2.13 mmol) in dichloro-
methane (0.6 mL) was added over 8 h to a solution of ethylphenyl-
ketene (155 mg, 1.06 mmol), Hunig’s base (275 mg, 2.13 mmol), and
̈
Me-quinine (36 mg, 0.11 mmol) in dichloromethane (1.6 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction was concentrated under reduced pressure
to about 1 mL. The solution was diluted with 1% EtOAc/hexane
(10 mL) and passed through a plug of neutral silica (14 g), with 1%
EtOAc/hexane (300 mL) as eluent. The solvent was removed under
reduced pressure, and (+)-(Z)-3f was isolated as a colorless oil
(167 mg, 73%), with a Z:E ratio of 91:9 as determined by GC-MS
analysis: HPLC analysis 70% ee (Daicel Chiralpak OD-H column;
1 mL/min; solvent system 2% isopropyl alcohol in hexane; retention
times 6.2 min (minor), 10.9 min (major)); [α]2D3 = +5.9 (c = 0.22,
CH2Cl2); IR (thin film) 2972, 2939, 1709, 1664, 1455, 1383, 1273,
(R,Z)-3-Butyl-4-(1-phenylethylidene)oxetan-2-one ((R,Z)-3h)
(Method A). Hexanoyl chloride (369 mg, 2.74 mmol) in dichloro-
methane (0.8 mL) was added over 8 h to a solution of methylphenyl-
ketene (181 mg, 1.37 mmol), Hunig’s base (354 mg, 2.74 mmol),
̈
1224, 1093, 699 cm−1; H NMR (400 MHz, CDCl3, TMS) δ 7.52−
1
and Me-quinine (46 mg, 0.14 mmol) in dichloromethane (2.1 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 1 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (10 g),
with 1% EtOAc/hexane (300 mL) as eluent. The solvent was removed
under reduced pressure, and (R,Z)-3h was isolated as a colorless oil
(170 mg, 54%), with a Z:E ratio of >97:3 as determined by GC-MS
analysis: HPLC analysis 74% ee (Daicel Chiralpak OD-H column;
1 mL/min; solvent system 2% isopropyl alcohol in hexane; retention
times 5.5 min (minor), 8.6 min (major)). (R,Z)-3h was subjected to
Pd/C-catalyzed hydrogenolysis to provide carboxylic acid (−)-5h,
which was fully characterized as previously described.20
7.45 (m, 1H), 7.45−7.36 (m, 2H), 7.35−7.25 (m, 2H), 4.27 (dd, J =
7.3, 4.8 Hz, 1H), 2.61−2.33 (m, 2H), 2.17−1.92 (m, 2H), 1.18 (t, J =
7.4 Hz, 3H), 1.08 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
169.4, 141.0, 134.8, 128.5, 128.0, 127.3, 115.7, 56.0, 23.1, 20.5, 13.6,
10.2; (M + H)+ HRMS m/z calcd for (C14H17O2)+ 217.1229, found
217.1223.
(S,Z)-3-Ethyl-4-(1-phenylpropylidene)oxetan-2-one ((−)-(Z)-3f)
(Method A). Butyryl chloride (234 mg, 2.20 mmol) in dichloro-
methane (1.0 mL) was added over 8 h to a solution of ethylphenyl-
ketene (160 mg, 1.10 mmol), Hunig’s base (284 mg, 2.20 mmol), and
̈
Me-quinidine (37 mg, 0.11 mmol) in dichloromethane (3.4 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After this time the reaction mixture was concentrated under
reduced pressure to about 1 mL. The solution was diluted with 1%
EtOAc/hexane (10 mL) and passed through a plug of neutral silica
(14 g), with 1% EtOAc/hexane (200 mL) and 10% EtOAc/hexane
(100 mL) as eluents. The solvent was removed under reduced
pressure, and (−)-(Z)-3f was isolated as a colorless oil (154 mg, 65%),
with a Z:E ratio of 87:13 as determined by GC-MS analysis: HPLC
analysis 95% ee (Daicel Chiralpak OD-H column; 1 mL/min; solvent
system 2% isopropyl alcohol in hexane; retention times 6.1 min
(major), 10.8 min (minor)); [α]2D3 = −3.8 (c = 0.19, CH2Cl2); IR (thin
film) 2972, 2938, 1720, 1450, 1383, 1270, 1226, 1106, 699 cm−1;
1H NMR (400 MHz, CDCl3, TMS) δ 7.53−7.43 (m, 1H), 7.43−7.33
(R,Z)-3-Butyl-4-(1-phenylethylidene)oxetan-2-one ((R,Z)-3h)
(Method A). Hexanoyl chloride (298 mg, 2.21 mmol) in dichloro-
methane (1.1 mL) was added over 8 h to a solution of methylphenyl-
ketene (146 mg, 1.11 mmol), Hunig’s base (286 mg, 2.21 mmol), and
̈
TMS-quinine (44 mg, 0.11 mmol) in dichloromethane (1.3 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 1 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (5 g), with
1% EtOAc/hexane (300 mL) as eluent. The solvent was removed
under reduced pressure, and (R,Z)-3h was isolated as a colorless oil
(142 mg, 55%), with a Z:E ratio of 97:3 as determined by GC-MS
I
DOI: 10.1021/acs.joc.6b01481
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
analysis: HPLC analysis 88% ee (Daicel Chiralpak OD-H column;
1 mL/min; solvent system 2% isopropyl alcohol in hexane; retention
times 5.6 min (minor), 8.7 min (major)). (R,Z)-3h was subjected to
Pd/C-catalyzed hydrogenolysis to provide carboxylic acid (−)-5h,
which was fully characterized as previously described.20
(S,Z)-3-Butyl-4-(1-phenylethylidene)oxetan-2-one ((S,Z)-3h)
(Method A). Hexanoyl chloride (369 mg, 2.74 mmol) in dichloro-
methane (0.8 mL) was added over 8 h to a solution of methylphenyl-
concentrated under reduced pressure to about 1 mL. The solution
was diluted with pentane (10 mL) and passed through a plug of
neutral silica (5 g), with 25% CH2Cl2/pentane (200 mL) as eluent.
The solvent was removed, and (+)-3k was isolated as a colorless liquid
(36 mg, 50%), with a Z:E ratio of 78:22 as determined by GC-MS
analysis: [α]2D3 = +5.0 (c = 0.16, CH2Cl2); IR (thin film) 2957, 2925,
2855, 1730, 1600, 1461, 1404, 1379, 1273, 1183, 1122, 1072, 841
1
cm−1; H NMR (400 MHz, CDCl3, TMS) for major diastereomer δ
ketene (181 mg, 1.37 mmol), Hunig’s base (354 mg, 2.74 mmol), and
̈
4.06 (q, J = 7.6 Hz, 1H), 1.67 (s, 3H), 1.51 (d, J = 7.6 Hz, 3H), 0.17
(s, 9H); 13C NMR (100 MHz, CDCl3) for major diastereomer δ
171.2, 151.2, 105.2, 49.5, 13.9, 12.4, −1.2; (M + H)+ HRMS m/z calcd
for (C9H17O2Si)+ 185.0998, found 185.0996.
(R,E)-3-Methyl-4-(1-phenylpentylidene)oxetan-2-one
((+)-(E)-3q) (Method B). LiClO4 (85 mg, 0.80 mmol) dissolved in
Et2O (0.8 mL) was added to a solution of n-butylphenylketene
(139 mg, 0.80 mmol) and TMS-quinine (32 mg, 0.08 mmol) in
Me-quinidine (46 mg, 0.14 mmol) in dichloromethane (2.1 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction was concentrated under reduced pressure
to about 1 mL. The solution was diluted with 1% EtOAc/hexane
(10 mL) and passed through a plug of neutral silica (5 g), with 1%
EtOAc/hexane (300 mL) as eluent. The solvent was removed under
reduced pressure, and (S,Z)-3h was isolated as a colorless oil (202 mg,
64%), with a Z:E ratio of >97:3 as determined by GC-MS analysis:
HPLC analysis 94% ee (Daicel Chiralpak OD-H column; 1 mL/min;
solvent system 2% isopropyl alcohol in hexane; retention times
5.5 min (major), 8.7 min (minor)). (S,Z)-3h was subjected to Pd/C-
catalyzed hydrogenolysis to provide carboxylic acid (+)-5h, which was
fully characterized as previously described.20
dichloromethane (0.8 mL) at −25 °C. Hunig’s base (207 mg,
̈
1.60 mmol) was then added to the solution. Propionyl chloride
(148 mg, 1.60 mmol) in dichloromethane (0.9 mL) was added over 8
h to the above solution at −25 °C, and the mixture was stirred at this
temperature for another 16 h. The reaction was quenched by the
addition of water (20 mL), the layers were separated, and the aqueous
layer was extracted with dichloromethane (2 × 20 mL). The combined
organic layers were dried over anhydrous Na2SO4, and the filtered
solution was concentrated under reduced pressure to about 1 mL. The
solution was diluted with 1% EtOAc/hexane (10 mL) and passed
through a plug of neutral silica (5 g), with hexane (50 mL) and then
1% EtOAc/hexane (200 mL) as eluents. The solvent was removed
under reduced pressure, and (+)-(E)-3q was isolated as a colorless oil
(127 mg, 69%), with a Z:E ratio of 24:76 as determined by GC-MS
analysis: HPLC analysis 84% ee (Daicel Chiralpak OD-H column;
1 mL/min; solvent system 2% isopropyl alcohol in hexane; retention
times 6.9 min (minor), 11.7 min (major)); [α]2D3 = +5.9 (c = 0.16,
CH2Cl2); IR (thin film) 2957, 2931, 2872, 1709, 1600, 1495, 1448,
(R,Z)-3-Butyl-4-(1-phenylpropylidene)oxetan-2-one ((R,Z)-3i)
(Method A). Hexanoyl chloride (301 mg, 2.23 mmol) in dichloro-
methane (0.9 mL) was added over 8 h to a solution of ethylphenyl-
ketene (163 mg, 1.12 mmol), Hunig’s base (289 mg, 2.23 mmol), and
̈
Me-quinine (38 mg, 0.11 mmol) in dichloromethane (1.4 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 1 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (7 g), with
1% EtOAc/hexane (250 mL) as eluent. The solvent was removed
under reduced pressure, and (R,Z)-3i was isolated as a colorless oil
(95% conversion by GC-MS), with a Z:E ratio of 93:7 as determined
by GC-MS analysis: HPLC analysis 76% ee (Daicel Chiralpak OD-H
column; 1 mL/min; solvent system 2% isopropyl alcohol in hexane;
retention times 5.2 min (minor), 9.5 min (major)). (R,Z)-3i (46 mg)
was subjected to Pd/C-catalyzed hydrogenolysis to provide carboxylic
acid (−)-5i (25 mg, 51% for two steps), which was fully characterized
as previously described.20
1
1378, 1290, 1203, 1181, 1062, 1041, 922, 868, 770, 699 cm−1; H
NMR (400 MHz, CDCl3, TMS) for major diastereomer δ 7.43−7.30
(m, 2H), 7.30−7.19 (m, 3H), 4.21 (q, J = 7.6 Hz, 1H), 2.67−2.52
(m, 1H), 2.52−2.40 (m, 1H), 1.46−1.20 (m, 4H), 1.16 (d, J = 7.6 Hz,
3H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) for major
diastereomer δ 170.5, 144.1, 136.6, 128.8, 127.9, 127.5, 116.3, 49.1,
30.1, 29.1, 22.5, 14.0, 11.7; (M + H)+ HRMS m/z calcd for
(C15H19O2)+: 231.1385, found 231.1382.
(S,E)-3-Methyl-4-(1-phenylpentylidene)oxetan-2-one
((−)-(E)-3q) (Method B). LiClO4 (92 mg, 0.86 mmol) dissolved in
Et2O (0.9 mL) was added to a solution of n-butylphenylketene
(150 mg, 0.86 mmol) and Me-quinidine (29 mg, 0.086 mmol) in
(S,Z)-3-Butyl-4-(1-phenylpropylidene)oxetan-2-one ((S,Z)-3i)
(Method A). Hexanoyl chloride (301 mg, 2.23 mmol) in dichloro-
methane (0.9 mL) was added over 8 h to a solution of ethylphenyl-
ketene (163 mg, 1.12 mmol), Hunig’s base (289 mg, 2.23 mmol), and
̈
Me-quinidine (38 mg, 0.11 mmol) in dichloromethane (1.4 mL) at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction mixture was concentrated under reduced
pressure to about 1 mL. The solution was diluted with 1% EtOAc/
hexane (10 mL) and passed through a plug of neutral silica (7 g), with
hexane (100 mL) and 1% EtOAc/hexane (200 mL) as eluents. The
solvent was removed under reduced pressure, and (S,Z)-3i was iso-
lated as a colorless oil (117 mg, 43%), with a Z:E ratio of 84:16 as
determined by GC-MS analysis: HPLC analysis 95% ee (Daicel
Chiralpak OD-H column; 1 mL/min; solvent system 2% isopropyl
alcohol in hexane; retention times 5.1 min (major), 9.5 min (minor)).
(S,Z)-3i was subjected to Pd/C-catalyzed hydrogenolysis to provide
carboxylic acid (+)-5i, which was fully characterized as previously
described.20
dichloromethane (0.9 mL) at −25 °C. Hunig’s base (224 mg, 1.73
̈
mmol) was then added to the solution. Propionyl chloride (160 mg,
1.73 mmol) in dichloromethane (1.1 mL) was added over 8 h to the
above solution at −25 °C, and the mixture was stirred at this temper-
ature for another 16 h. After 16 h the reaction was quenched by the
addition of water (20 mL). The layers were separated and the aqueous
layer was extracted with dichloromethane (2 × 20 mL). The combined
organic layers were dried over anhydrous Na2SO4 and the reaction was
concentrated under reduced pressure to about 1 mL. The solution was
diluted with 1% EtOAc/hexane (10 mL) and passed through a plug of
neutral silica (5 g), eluting with hexane (50 mL), and then 1% EtOAc/
hexane (200 mL). The solvent was removed under reduced pressure
and (−)-E-3q was isolated as a colorless oil (154 mg, 78%), with a Z:E
ratio of 26:74 as determined by GC-MS analysis: HPLC analysis 92%
ee (Daicel Chiralpak OD-H column; 1 mL/min; solvent system 2%
isopropyl alcohol in hexane; retention times 7.4 min (major), 13.1 min
(minor)); [α]2D3 = −3.1 (c = 0.16, CH2Cl2); IR (thin film) 2957, 2931,
2872, 1714, 1600, 1496, 1449, 1379, 1256, 1211, 1185, 1126, 1071,
(S)-3-Methyl-4-(1-(trimethylsilyl)ethylidene)oxetan-2-one
((+)-3k) (Method B). LiClO4 (42 mg, 0.39 mmol) dissolved in Et2O
(0.4 mL) was added to a solution of TMS-methylketene (100 mg,
0.78 mmol) and Me-quinidine (13 mg, 0.038 mmol) in dichloro-
methane (0.6 mL) at −25 °C. Hunig’s base (51 mg, 0.39 mmol) was
̈
then added to the solution. Propionyl chloride (36 mg, 0.39 mmol) in
dichloromethane (0.6 mL) was added over 8 h to the above solution at
−25 °C, and the mixture was stirred at this temperature for a further
16 h. The reaction was quenched by the addition of water (20 mL).
The layers were separated, and the aqueous layer was extracted with
dichloromethane (2 × 20 mL). The combined organic layers were
dried over anhydrous Na2SO4, and the filtered solution was
1
1025, 922, 868, 770, 699 cm−1; H NMR (400 MHz, CDCl3, TMS)
for major diastereomer δ 7.42−7.31 (m, 2H), 7.31−7.20 (m, 3H), 4.21
(q, J = 7.6 Hz, 1H), 2.66−2.53 (m, 1H), 2.53−2.41 (m, 1H), 1.46−
1.20 (m, 4H), 1.16 (d, J = 7.6 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) for major diastereomer δ 170.5, 144.1,
J
DOI: 10.1021/acs.joc.6b01481
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The Journal of Organic Chemistry
Article
136.6, 128.8, 127.9, 127.5, 116.3, 49.1, 30.1, 29.1, 22.5, 14.0, 11.7; (M +
H)+ HRMS m/z calcd for (C15H19O2)+ 231.1385, found 231.1384.
(R,E)-3-Ethyl-4-(1-phenylpropylidene)oxetan-2-one ((+)-(E)-
3s) (Method B). LiClO4 (361 mg, 3.40 mmol) dissolved in Et2O
(1.6 mL) was added to a solution of ethylphenylketene (248 mg,
1.70 mmol) and TMS-quinine (67 mg, 0.17 mmol) in dichloro-
dichloromethane (2 × 20 mL). The combined organic layers were
dried over anhydrous Na2SO4, and the filtered solution was
concentrated under reduced pressure to about 1 mL. The solution
was diluted with 1% EtOAc/hexane (10 mL) and passed through a plug
of neutral silica (15 g), with 1% EtOAc/hexane (300 mL) as eluent. The
solvent was removed under reduced pressure, and (−)-(E)-3t was
isolated as a colorless oil (231 mg, 76%), with a Z:E ratio of 6:94 as
determined by GC-MS analysis: HPLC analysis 97% ee (Daicel
Chiralpak AS-H column; 1 mL/min; solvent system 2% isopropyl
alcohol in hexane; retention times 3.8 min (minor), 5.7 min (major));
[α]2D3 = −6.0 (c = 0.10, CH2Cl2); IR (thin film) 2958, 2935, 1706, 1600,
1495, 1386, 1283, 1178, 699 cm−1; 1H NMR (400 MHz, CDCl3, TMS)
δ 7.41−7.33 (m, 2H), 7.33−7.28 (m, 1H), 7.28−7.22 (m, 2H), 4.26
(dd, J = 7.1, 5.0 Hz, 1H), 2.45 (d, J = 7.4 Hz, 2H), 1.74−1.55 (m, 2H),
1.55−1.40 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H),
0.87 (d, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 142.7,
136.9, 128.8, 127.8, 127.5, 116.0, 55.4, 38.4, 26.8, 23.0, 21.9, 19.5, 10.1;
(M + H)+ HRMS m/z calcd for (C16H21O2)+ 245.1542, found 245.1538.
(S,E)-3-Ethyl-4-(3-methyl-1-phenylbutylidene)oxetan-2-one
((+)-(E)-3t) (Method B). LiClO4 (133 mg, 1.25 mmol) dissolved in
Et2O (1.3 mL) was added to a solution of isobutylphenylketene
(217 mg, 1.25 mmol) and Me-quinidine (43 mg, 0.13 mmol) in
methane (2.2 mL) at −25 °C. Hunig’s base (349 mg, 3.40 mmol) was
̈
then added to the solution. Butyryl chloride (362 mg, 3.40 mmol) in
dichloromethane (1.0 mL) was added over 8 h to the above solution at
−25 °C, and the mixture was stirred at this temperature for a further
16 h. The reaction was quenched by the addition of water (20 mL).
The layers were separated, and the aqueous layer was extracted with
dichloromethane (2 × 20 mL). The combined organic layers were
dried over anhydrous Na2SO4, and the filtered solution was concen-
trated under reduced pressure to about 1 mL. The solution was diluted
with 1% EtOAc/hexane (10 mL) and passed through a plug of neutral
silica (10 g), with 1% EtOAc/hexane (250 mL) as eluent. The solvent
was removed under reduced pressure, and (R,E)-3s was isolated as a
colorless oil (315 mg, 86%), with a Z:E ratio of 26:74 as determined
by GC-MS analysis: HPLC analysis 93% ee (Daicel Chiralpak OD-H
column; 1 mL/min; solvent system 2% isopropyl alcohol in hexane;
retention times 4.7 min (minor), 5.1 min (major)); [α]2D3 = +7.8
(c = 1.58, CH2Cl2); IR (thin film) 2968, 2935, 1704, 1494, 1385, 1275,
1178, 698 cm−1; 1H NMR (400 MHz, CDCl3, TMS) for major
diastereomer δ 7.42−7.34 (m, 2H), 7.33−7.23 (m, 3H), 4.26 (dd, J =
6.9, 4.4 Hz, 1H), 2.73−2.60 (m, 1H), 2.59−2.44 (m, 1H), 1.71−1.57
(m, 1H), 1.57−1.42 (m, 1H), 1.05 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) for major diastereomer δ
169.9, 141.8, 136.4, 128.8, 127.7, 127.5, 118.1, 55.5, 22.8, 19.4, 13.0,
10.1; (M + H)+ HRMS m/z calcd for (C14H17O2)+ 217.1229, found
217.1226.
dichloromethane (1.9 mL) at −25 °C. Hunig’s base (323 mg,
̈
2.50 mmol) was then added to the solution. Butyryl chloride (266 mg,
2.50 mmol) in dichloromethane (0.6 mL) was added over 8 h to the
above solution at −25 °C, and the mixture was stirred at this tem-
perature for another 16 h. After 16 h the reaction was quenched by the
addition of water (20 mL). The layers were separated, and the aqueous
layer was extracted with dichloromethane (2 × 20 mL). The combined
organic layers were dried over anhydrous Na2SO4, and the filtered
solution was concentrated under reduced pressure to about 1 mL. The
solution was diluted with 1% EtOAc/hexane (10 mL) and passed
through a plug of neutral silica (15 g), with 1% EtOAc/hexane
(300 mL) as eluent. The solvent was removed under reduced pressure,
and (+)-(E)-3t was isolated as a colorless oil (268 mg, 88%), with a
Z:E ratio of 5:95 as determined by GC-MS analysis: HPLC analysis
98% ee (Daicel Chiralpak AS-H column; 1 mL/min; solvent system
2% isopropyl alcohol in hexane; retention times 5.6 min (minor),
3.8 min (major)); [α]2D3 = +33.5 (c = 0.50, CH2Cl2); IR (thin film)
(S,E)-3-Ethyl-4-(1-phenylpropylidene)oxetan-2-one ((−)-(E)-
3s) (Method B). LiClO4 (361 mg, 3.40 mmol) dissolved in Et2O
(1.6 mL) was added to a solution of ethylphenylketene (248 mg,
1.70 mmol) and Me-quinidine (57 mg, 0.17 mmol) in dichloro-
methane (2.2 mL) at −25 °C. Hunig’s base (349 mg, 3.40 mmol) was
̈
then added to the solution. Butyryl chloride (362 mg, 3.40 mmol) in
dichloromethane (1.0 mL) was added over 8 h to the above solution at
−25 °C, and the mixture was stirred at this temperature for another
16 h. After 16 h the reaction was quenched by the addition of water
(20 mL). The layers were separated, and the aqueous layer was
extracted with dichloromethane (2 × 20 mL). The combined organic
layers were dried over anhydrous Na2SO4, and the filtered solution was
concentrated under reduced pressure to about 1 mL. The solution was
diluted with 1% EtOAc/hexane (10 mL) and passed through a plug of
neutral silica (10 g), with 1% EtOAc/hexane (250 mL) as eluent. The
solvent was removed under reduced pressure, and (−)-(E)-3s was
isolated as a colorless oil (315 mg, 86%), with a Z:E ratio of 24:76 as
determined by GC-MS analysis: HPLC analysis 88% ee (Daicel
Chiralpak OD-H column; 1 mL/min; solvent system 2% isopropyl
alcohol in hexane; retention times 5.1 min (minor), 4.7 min (major));
[α]2D3 = −5.7 (c = 0.60, CH2Cl2); IR (thin film) 2968, 2930, 1701,
1494, 1382, 1274, 1174, 701 cm−1; 1H NMR (400 MHz, CDCl3,
TMS) for major diastereomer δ 7.42−7.34 (m, 2H), 7.33−7.22
(m, 3H), 4.26 (dd, J = 6.7, 4.9 Hz, 1H), 2.73−2.60 (m, 1H), 2.58−
2.45 (m, 1H), 1.70−1.57 (m, 1H), 1.56−1.43 (m, 1H), 1.05 (t, J =
7.5 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
for major diastereomer δ 169.9, 141.8, 136.4, 128.8, 127.7, 127.5,
118.1, 55.5, 22.8, 19.4, 13.0, 10.1; (M + H)+ HRMS m/z calcd for
(C14H17O2)+ 217.1229, found 217.1225.
1
2968, 2935, 1703, 1600, 1495, 1382, 1272, 1183, 697 cm−1; H NMR
(400 MHz, CDCl3, TMS) δ 7.41−7.33 (m, 2H), 7.33−7.28 (m, 1H),
7.28−7.21 (m, 2H), 4.27 (app t, J = 5.2 Hz, 1H), 2.45 (d, J = 7.3 Hz,
2H), 1.74−1.54 (m, 2H), 1.54−1.41 (m, 1H), 0.94 (d, J = 6.6 Hz,
3H), 0.89 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.0, 142.7, 136.9, 128.8, 127.8, 127.5, 116.1,
55.4, 38.5, 26.8, 23.0, 22.0, 19.6, 10.1; (M + H)+ HRMS m/z calcd for
(C16H21O2)+: 245.1542, found 245.1540.
Formation of (−)-3a through in Situ Generation of both
Acceptor and Donor Ketene with 2.5 mol % Catalyst Loading
(Method C). Hunig’s base (593 mg, 4.59 mmol) was added to a
̈
solution of 2-phenylpropionyl chloride (257 mg, 1.53 mmol) in
CH2Cl2 (4.2 mL) at room temperature. The reaction mixture was
stirred at room temperature for 2 h, and then the reaction mixture was
cooled to −25 °C. Me-quinidine (13 mg, 0.038 mmol) in CH2Cl2
(0.9 mL) was then added to the reaction mixture, followed by
propionyl chloride (283 mg, 3.06 mmol) in CH2Cl2 (0.9 mL), which
was added over 8 h via syringe pump. The reaction mixture was stirred
for 12 h at −25 °C and then was quenched by adding deionized water
(5 mL). The layers were separated, the aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), the combined organics were dried over
anhydrous sodium sulfate, and the filtered solution was concentrated
under reduced pressure to about 3 mL. The solution was diluted with
1% EtOAc/hexane (15 mL) and passed through a plug of neutral silica
(6 g), with hexane (50 mL) and 1% EtOAc/hexane (200 mL) as
eluents. The solvent was removed under reduced pressure, and (−)-3a
was isolated as a colorless oil (212 mg, 74%), with a Z:E ratio of 99:1
as determined by GC-MS analysis: HPLC analysis 92% ee (Daicel
Chiralpak OB-H column; 1 mL/min; solvent system 10% isopropyl
alcohol in hexane; retention times 9.1 min (major), 16.3 min
(R,E)-3-Ethyl-4-(3-methyl-1-phenylbutylidene)oxetan-2-one
((−)-(E)-3t) (Method B). LiClO4 (133 mg, 1.25 mmol) dissolved in
Et2O (1.3 mL) was added to a solution of isobutylphenylketene
(217 mg, 1.25 mmol) and TMS-quinine (50 mg, 0.13 mmol) in dichloro-
methane (1.9 mL) at −25 °C. Hunig’s base (323 mg, 2.50 mmol) was
̈
then added to the solution. Butyryl chloride (266 mg, 2.50 mmol) in
dichloromethane (0.6 mL) was added over 8 h to the above solution at
−25 °C, and the mixture was stirred at this temperature for another 16 h.
The reaction was quenched by the addition of water (20 mL), the
layers were separated, and the aqueous layer was extracted with
K
DOI: 10.1021/acs.joc.6b01481
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The Journal of Organic Chemistry
Article
(minor)); [α]2D3 = −20.2 (c = 0.042, CH2Cl2); NMR spectra matched
(minor)); [α]2D3 = −7.9 (c = 1.02, CH2Cl2); NMR spectra matched
those of (−)-3e previously prepared.10
those of (−)-3a previously described.10
Formation of (−)-3f through in Situ Generation of Both
Formation of (+)-3a through in Situ Generation of both
Acceptor and Donor Ketene (Method C). Hunig’s base (354 mg,
Acceptor and Donor Ketene (Method C). Hunig’s base (1527 mg,
̈
̈
2.74 mmol) was added to a solution of 2-phenylbutanoyl chloride
(166 mg, 0.91 mmol) in CH2Cl2 (2.5 mL) at room temperature. The
reaction mixture was stirred for 12 h at room temperature, and then
the reaction mixture was cooled to −25 °C. Me-quinidine (31 mg,
0.092 mmol) in CH2Cl2 (0.4 mL) was then added to the reaction
mixture, followed by butyryl chloride (194 mg, 1.82 mmol) in CH2Cl2
(0.8 mL), which was added over 8 h via syringe pump. The reaction
mixture was stirred for 12 h at −25 °C and then was quenched
by adding deionized water (5 mL). The layers were separated, the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL), the combined
organics were dried over anhydrous sodium sulfate, and the filtered
solution was concentrated under reduced pressure to about 3 mL.
The solution was diluted with 1% EtOAc/hexane (15 mL) and passed
through a plug of neutral silica (5 g) with 1% EtOAc/hexane
(300 mL) as eluent. The solvent was removed under reduced pressure,
and (−)-3f was isolated as a colorless oil (69 mg, 35%), with a Z:E
ratio of 86:14 as determined by GC-MS analysis: HPLC analysis
97% ee (Daicel Chiralpak OD-H column; 1 mL/min; solvent system
2% isopropyl alcohol in hexane; retention times 6.0 min (major),
10.4 min (minor)); [α]D23 = −3.4 (c = 1.32, CH2Cl2); NMR spectra
matched those of (−)-3f previously prepared.10
11.82 mmol) was added to a solution of 2-phenylpropionyl chloride
(662 mg, 3.94 mmol) in CH2Cl2 (10.8 mL) at room temperature. The
reaction mixture was stirred at room temperature for 2 h, and then the
reaction mixture was cooled to −25 °C. TMS-quinine (156 mg,
0.39 mmol) in CH2Cl2 (4.2 mL) was then added to the reaction mix-
ture, followed by propionyl chloride (729 mg, 7.88 mmol) in CH2Cl2
(0.6 mL), which was added over 8 h via syringe pump. The reaction
mixture was stirred for 12 h at −25 °C and then was quenched by
adding deionized water (5 mL). The layers were separated, the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL), the combined
organics were dried over anhydrous sodium sulfate, and the filtered
solution was concentrated under reduced pressure to about 3 mL.
The solution was diluted with 1% EtOAc/hexane (15 mL) and passed
through a plug of neutral silica (16 g), with 1% EtOAc/hexane
(500 mL) as eluent. The solvent was removed under reduced pressure,
and (+)-3a was isolated as a colorless oil (496 mg, 67%), with a Z:E
ratio of 99:1 as determined by GC-MS analysis: HPLC analysis 93% ee
(Daicel Chiralpak OB-H column; 1 mL/min; solvent system 10%
isopropyl alcohol in hexane; retention times 9.3 min (minor), 15.7 min
(major)); [α]2D3 = +18.0 (c = 0.064, CH2Cl2); NMR spectra matched
those of (+)-3a previously reported.10
Formation of (S,E)-(E)-3p through in Situ Generation of Both
Formation of (−)-3b through in Situ Generation of both
Acceptor and Donor Ketene (Method C). Hunig’s base (309 mg,
̈
Acceptor and Donor Ketene (Method C). Hunig’s base (360 mg,
̈
3.94 mmol) was added to a solution of 2-phenylbutanoyl chloride
(239 mg, 1.31 mmol) in CH2Cl2 (3.7 mL) at room temperature. The
reaction mixture was stirred for 12 h at room temperature, and then
the reaction mixture was cooled to −25 °C. Me-quinidine (44 mg,
0.13 mmol) in CH2Cl2 (0.8 mL) and LiClO4 (279 mg, 2.62 mmol) in
Et2O (2.6 mL) were then added to the reaction mixture, followed by
propionyl chloride (243 mg, 2.63 mmol) in CH2Cl2 (0.8 mL), which
was added over 8 h via syringe pump. The reaction mixture was stirred
for 12 h at −25 °C and then was quenched by adding deionized water
(5 mL). The layers were separated, the aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), the combined organics were dried over
anhydrous sodium sulfate, and the filtered solution was concentrated
under reduced pressure to about 3 mL. The solution was diluted with
1% EtOAc/hexane (15 mL) and passed through a plug of neutral silica
(9 g), with hexane (50 mL) and 1% EtOAc/hexane (300 mL) as
eluents. The solvent was removed under reduced pressure, and (−)-E-
3p was isolated as a colorless oil (109 mg, 41%), with a Z:E ratio of
33:67 as determined by GC-MS analysis: HPLC analysis >99% ee
(Daicel Chiralpak OB-H column; 1 mL/min; solvent system 2%
isopropyl alcohol in hexane; retention times 6.3 min (major))); NMR
spectra matched those of (−)-E-3p previously prepared.10
2.79 mmol) was added to a solution of 2-phenylbutanoyl chloride
(169 mg, 0.93 mmol) in CH2Cl2 (2.5 mL) at room temperature. The
reaction mixture was stirred for 12 h at room temperature, and then
the reaction mixture was cooled to −25 °C. Me-quinidine (31 mg,
0.092 mmol) in CH2Cl2 (0.4 mL) was then added to the reaction
mixture, followed by propionyl chloride (172 mg, 1.86 mmol) in
CH2Cl2 (0.8 mL), which was added over 8 h via syringe pump. The
reaction mixture was stirred for 12 h at −25 °C and then was
quenched by adding deionized water (5 mL). The layers were
separated, the aqueous layer was extracted with CH2Cl2 (3 × 5 mL),
the combined organics were dried over anhydrous sodium sulfate, and
the filtered solution was concentrated under reduced pressure to about
3 mL. The solution was diluted with 1% EtOAc/hexane (15 mL) and
passed through a plug of neutral silica (5 g), with 1% EtOAc/hexane
(300 mL) as eluent. The solvent was removed under reduced pressure,
and (−)-3b was isolated as a colorless oil (90 mg, 48%), with a Z:E
ratio of 78:22 as determined by GC-MS analysis: HPLC analysis 95%
ee (Daicel Chiralpak OB-H column; 1 mL/min; solvent system 2%
isopropyl alcohol in hexane; retention times 10.6 min (major), 23.3
min (minor)); [α]2D3 = −12.1 (c = 0.26, CH2Cl2); NMR spectra
matched those of (−)-3b as previously described.10
(R)-Allyl 2-((R)-2-Acetyl-N-(4-methoxybenzyl)octanamido)-3-
(benzyloxy)propanoate ((+)-7). (−)-3n (28 mg, 0.12 mmol), serine
derivative 65 (82 mg, 0.23 mmol), and 2-pyridone (23 mg, 0.24 mmol)
were dissolved in THF (0.6 mL) and stirred at 50 °C for 55 h. After
this time, the reaction mixture was cooled to room temperature, TBAF
(0.23 mL, 0.23 mmol, 1 M solution in THF) was added, and the
reaction mixture was stirred for 10 min before water (5 mL) was
added. The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were dried
over anhydrous sodium sulfate, and the solvent was removed under
reduced pressure. The crude was purified by column chromatography
with gradient elution (10−15% EtOAc/Hexane) to afford (+)-7 as a
Formation of (−)-3e through in Situ Generation of both
Acceptor and Donor Ketene (Method C). Hunig’s base (307 mg,
̈
2.38 mmol) was added to a solution of 2-phenylpropionyl chloride
(133 mg, 0.79 mmol) in CH2Cl2 (2.1 mL) at room temperature. The
reaction mixture was stirred for 2 h at room temperature, and then the
reaction mixture was cooled to −25 °C. Me-quinidine (27 mg,
0.08 mmol) in CH2Cl2 (0.3 mL) was then added to the reaction
mixture, followed by butyryl chloride (169 mg, 1.59 mmol) in CH2Cl2
(0.8 mL), which was added over 8 h via syringe pump. The reaction
mixture was stirred for 12 h at −25 °C and then was quenched by
adding deionized water (5 mL). The layers were separated, the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL), the combined
organics were dried over anhydrous sodium sulfate, and the filtered
solution was concentrated under reduced pressure to about 3 mL.
The solution was diluted with 1% EtOAc/hexane (15 mL) and passed
through a plug of neutral silica (5 g), with 1% EtOAc/hexane
(300 mL) as eluent. The solvent was removed under reduced pressure,
and (−)-3e was isolated as a colorless oil (113 mg, 71%), with a Z:E
ratio of 98:2 as determined by GC-MS analysis: HPLC analysis 97% ee
(Daicel Chiralpak OB-H column; 1 mL/min; solvent system 10%
isopropyl alcohol in hexane; retention times 6.4 min (major), 9.9 min
1
colorless oil (50 mg, 82%) with dr 3:1 as determined by H NMR
(diastereomers are separable by column chromatography): [α]D23
=
+25.5 (c = 0.09, CH2Cl2) for a diastereomerically enriched sample (dr
1
9:1); IR (thin film) 2165, 1737, 1645 cm−1; H NMR for the major
diastereomer (400 MHz, CDCl3, TMS) δ 7.34−7.14 (m, 9H), 6.85 (d,
J = 8.8 Hz, 2H), 5.93−5.83 (m, 1H), 5.33−5.22 (m, 2H), 4.83 (d, J =
17.2 Hz, 1H), 4.66−4.54 (m, 4H), 4.40 (d, J = 3.2 Hz, 2H), 4.04−3.92
(m, 2H), 3.80 (s, 3H), 3.51 (dd, J = 5.6, 8.0 Hz, 1H), 2.12 (s, 3H),
2.03−2.91 (m, 1H), 1.72−1.65 (m, 1H), 1.35−1.24 (m, 6H), 0.85 (t,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) for the major
L
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diastereomer δ 205.3, 170.7, 168.7, 159.4, 137.9, 132.0, 128.9, 128.6,
128.3, 127.9, 127.8, 118.9, 114.3, 73.6, 68.7, 66.2, 59.9, 59.0, 55.5, 51.8,
31.7, 29.8, 29.2, 27.7, 27.1, 22.8, 14.2; (M + H)+ HRMS m/z calcd for
(C31H42NO6)+ 524.3007, found 524.3003.
NMR facilities at Oakland University, and CHE-1048719 for
LC-MS facilities at Oakland University.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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Spectroscopic data and chromatograms for all new
compounds (PDF)
Computational data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for N.J.K.: kerrigan@oakland.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Science Foundation
and the National Institutes of Health: Grant Nos. CHE-1213638,
CHE-1463728, and R15GM107800 to N.J.K., CHE-0821487 for
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