Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates

Article abstract of DOI:10.1021/jacs.7b04086

We report a divergent and modular protocol for the preparation of acyclic molecular frameworks containing newly created quaternary carbon stereocenters. Central to this approach is a sequence composed of a (1) regioselective and -retentive preparation of allyloxycarbonyl-trapped fully substituted stereodefined amide enolates and of a (2) enantioselective palladium-catalyzed decarboxylative allylic alkylation reaction using a novel bisphosphine ligand.

Full text of DOI:10.1021/jacs.7b04086

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Article
Enantioselective Construction of Acyclic Quaternary Carbon
Stereocen-ters: Palladium-Catalyzed Decarboxylative
Allylic Alkylation of Fully-Substituted Amide Enolates
Pavel Starkov, Jared T. Moore, Douglas C Duquette, Brian M. Stoltz, and Ilan Marek
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Jun 2017
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Enantioselective Construction of Acyclic Quaternary Carbon Stereocen-
ters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully-
Substituted Amide Enolates
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Pavel Starkov,†,⊥,§ Jared T. Moore,‡,⊥ Douglas C. Duquette, ‡ Brian M. Stoltz, ‡,* Ilan Marek†,*
†The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry, and The Lise Meitner–Minerva Center for Compu-
tational Quantum Chemistry, Technion–Israel Institute of Technology, Technion City, Haifa 32000, Israel
‡Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California 91125, United States
Supporting Information Placeholder
9
lowed by a regioretentive in situ oxidation reaction. This
approach proved to be successful in preparation of new
compounds bearing quaternary carbon stereocenters using
aldol, Mannich, and allylic alkylation reactions, achiev-
ing good to excellent overall yields and exceptional dia-
stereoselectivities (Scheme 1B). Additionally, a highly
diastereoselective aldol reaction employing aliphatic alde-
hydes was possible using stereodefined fully-substituted
silyl ketene aminals and titanium-mediated Mukaiyama
aldol-type reaction conditions.9d Recent studies demon-
strated efficient preparation of stereochemically defined
acyclic fully substituted ketone enolates from simple vinyl
ABSTRACT: We report a divergent and modular protocol
for the preparation of acyclic molecular frameworks con-
taining newly created quaternary carbon stereocenters.
Central to this approach is a sequence composed of a (1)
regioselective and -retentive preparation of allyloxycar-
bonyl-trapped fully-substituted stereodefined amide eno-
lates and of a (2) enantioselective palladium-catalyzed
decarboxylative allylic alkylation reaction using a novel
bisphosphine ligand.
I. INTRODUCTION
The quaternary carbon stereocenter is a structure that
represents a minimalistic molecular framework with en-
hanced (bio)chemical stability and embedded propensity
to encode directionality in the three-dimensional space.
Over the past decade, several efficient approaches ad-
dressing de novo construction of cyclic quaternary carbon
10
carbamates in a single-pot operation (Scheme 1C).
As most of the above mentioned strategies relied on the
use of chiral auxiliaries, the remaining challenge was de-
velopment of catalytic enantioselective tranformations
,
11 12
to establish acyclic quaternary carbon centers via electro-
philic C-functionalization of fully substituted amide eno-
lates. The Stoltz group has extensively contributed to the
design of highly efficient catalysts for highly enantiose-
1
stereocenters have been developed; however, only a se-
lect few provide general access to such molecular struc-
2
tures in an acyclic setting. The prevailing majority of
13
lective allylic alkylation-type reactions, especially those
these methods heavily rely on the use of stereodefined
involving fully substituted cyclic allyl enol carbonates
trisubstituted alkenes as substrates for enantioselective
14
3
4
(Scheme 1D) en route to the synthesis of complex natu-
allylic substitution, conjugate addition, or nucleophilic
15
5
ral products. We envisaged developing a unified carbo-
allylation reactions.
metalation–enantioselective catalysis approach to access
de novo quaternary carbon stereocenters. Our approach
would involve implementing achiral acyclic amide eno-
lates in combination with enantioselective palladium-
catalyzed decarboxylative allylic alkylation technology
(Scheme 1E).
An alternative strategy, with potentially a broader syn-
thetic application, is enantioselective electrophilic func-
tionalization of fully substituted acyclic enolates. In this
context, regioselective formation of functionalized and
fully-substituted enolates is the center of renewed inter-
6
est, with several attractive strategies having been report-
Of special interest are the α-quaternary-amide and
-imide derivatives that this outlined strategy would pro-
duce. Activated amides are among the most widely uti-
lized carboxylic acid derivatives and have seen historical
synthetic use16 as well as more recent applications in cata-
lytic transformations. 17 Additionally, we surmised that
having the ability to tune the electronic and steric nature
of the amido functionality would be critical for the suc-
cess of the asymmetric catalysis. Thus, based on our past
ed for the preparation of β,β-disubstituted enolates of es-
7
8
ters and amides (albeit, largely using enantiomerically
enriched α,α-disubstituted carbonyl derivatives) (Scheme
1A).
The Marek group has previously reported a robust ste-
reoselective approach to the formation of polysubstituted
stereodefined acyclic enolates using a highly regioselec-
tive carbometalation of α-heterosubstituted alkynes fol-
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experience with catalytic enantioselective allylic alkyla- mentary methods. The initial method (Method A, Scheme
1
2
3
4
5
6
7
8
tions of lactam-derived enolates, we intentionally focused
our studies on amido-type enolate chemistry.14b,d This
supposition indeed proved to be true, as will be outlined
below.
2) consists of a regioselective carbometalation reaction of
ynecarbamates 1 using one equivalent of the Gilman rea-
gent (R4 CuLi) to result in the formation of nonsymmetric
2
18
vinyl alkyl cuprate species 2. Upon treatment with a
single equivalent of tert-butyl hydroperoxide (t-BuOOH),
a selective protonation of the residual R4 moiety of 2 oc-
curs to give a reactive heterocuprate intermediate.9 It sub-
sequently undergoes an intramolecular SN2 reaction (1,2-
metalate rearrangement) to provide the desired stereode-
fined copper(I) enolate. The final electrophilic trapping
by allyl chloroformate (AllocCl) gives allyloxycarbonyl-
protected polysubstituted amide enolate 3. Method A is
effective for substrates bearing cyclic carbamates such as
2-oxazolidinone and 2-benzoxazolinone (3a–3c) but is
much less efficient for acyclic carbamates. In the latter
case of acyclic ynecarbamate-derived products (e.g., 3d),
the regioselectivity of the carbometalation reaction is poor
and therefore, the overall efficiency of preparation of our
desired allyloxycarbonyl-protected polysubstituted amide
enolates 3 was less than optimal. As an alternative, a
copper-promoted carbomagnesiation reaction using Nor-
mant-type reagent (RMgBr/CuI in a 2:1 ratio)18 proved to
be highly regioselective in diethyl ether as solvent. Trap-
ping of the resulting vinyl magnesium species with mo-
lecular iodine leads to the formation of fully substituted
vinyl iodide 4 in excellent yields as a single constitutional
isomer (Method B, Scheme 2). The vinyl iodide is then
directly converted to the corresponding vinyl lithium spe-
cies by iodine–lithium exchange and regioretentively oxi-
Scheme 1. Preparation of polysubstituted enolates and con-
struction of quaternary stereocenters.
A. β,β’-disubstituted enolate of ester and amide
O
9
Me
O
Base
R*X
Me
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Me
R*X
Me
B. Combined carbometalation – oxidation then aldol, Mannich,
or alkylation processes
O
Et2OC
Xp
O
R2
R1
dr > 98:2
Br
CO2Et
OH
ArCHO
Ar
Xp
Xp
R2
R1
OM
Xp
R2
R1
dr 95:5
i. Carbometalation
ii. Oxidation
R1
Xp
TsHN
O
Xp = Chiral oxazolidinone
TsN=CHAr
Ar
iii. Silylation
iv. R3CHO
[Ti]
R1 R2
dr 94:6
OH
O
R3
Xp
R1 R2
dr > 98:2
C. Combined metalation – acylation /carbamoyl transfer /Mannich reaction
i. Metalation
ii. Acylation
iii. Carbamoyl transfer
iv. Mannich reaction
R1
TsHN
R4
O
O
NiPr2
R3
R2
OCb
R1 R2
O
dr 95:5:0:0
19
dized with an externally prepared oxenoid (t-BuOOLi).
D. Allylic alkylation reaction of fully substituted cyclic allyl enol carbonates
The resulting stereodefined fully substituted enolate is
then reacted with AllocCl to deliver well-diversified prod-
ucts 3d–3q in excellent yields as single isomers as shown
in Scheme 2.
O
O
O
R1
R1
[Pd], L*
O
n
ee > 90%
E. Palladium-catalyzed enantioselective decarboxylative allylic alkylation of
stereodefined acyclic enolates (this research)
O
O
R2
R1
O
O
[Pd], L*
NR3R4
NR3R4
R2
R1
2. RESULTS AND DISCUSSION
2.1 Stereodefined Acyclic Enol Carbonates. Our first
target was an efficient approach to stereodefined acyclic
allyloxycarbonyl-protected polysubstituted amide eno-
lates. Given the multiple potential challenges and pitfalls
of our strategy, we purposely limited the scope of the
study to substrates with the highest probability of success.
For the formation of stereodefined acyclic allyloxycar-
bonyl-protected polysubstituted amide enolates, we envi-
sioned that heteroatoms in proximity to the sites of reac-
tivity could interfere with the regio- and stereoselectivity
of the multistep organometallic process, and thus general-
ly limited our exploration to alkyl and aryl substituted
systems. To this end, we have developed two comple-
2
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in THF at –80 °C for 0.5 h] at –80 °C to –40 °C for 1 h, then AllocCl (4.0–
5.0 equiv) at –50 °C to 23 °C for 1 h, then 1 M HCl.
Scheme 2. Preparation of stereodefined acyclic allyloxycarbon-
yl polysubstituted amide enolates 3.
1
2
3
4
5
6
7
8
9
Method A
R4
R42CuLi
(1.2 equiv)
Cu
1. t-BuOOH, (1.2 equiv)
-78 °C, 30 min
R4
CO2R3
2.2 Asymmetric Pd-catalyzed Decarboxylative
Allylic Alkylation. With a library of acyclic substrates 3
in hand, we evaluated the enantioselective palladium-
catalyzed decarboxylative allylic allylation (Table 1).
Initially, the enantiomeric excess was determined directly
by using the decarboxylative allylic alkylation reaction
products 5 (on chiral SFC and HPLC); however, we opted
to include an additional olefin metathesis step that results
in products 6, which were more easily separable and gave
a greater UV signal strength on chiral SFC. We first ex-
amined a subset of solvents using the two PHOX ligands
(L1 and L2), known to achieve excellent enantioselectivi-
ties for the palladium-catalyzed asymmetric alkylation of
cyclic ketones. Surprisingly, for acyclic substrates 3a-d,
neither of these ligands achieved satisfactory level of en-
antiodiscrimination (for the full list of solvents and de-
tailed results, see Table S1 in Supporting Information).
The first promising results were obtained with C2-
symmetric bisphosphines ligands L3–L7 in THF (Table 1,
entries 1 to 5 and Table S2 in the Supporting Infor-
N
–30 to –10 °C
Et2O, 30 min
2. AllocCl
R1
R2
O
2
CO2R3
O
O
N
R2
R4
CO2R3
N
R2
3
R1
R1
1
Method B
R4MgBr (2 equiv)
CuI (1 equiv)
1. t-BuLi (2.0 equiv)
Et2O, –78 °C
2. t-BuOOLi, THF
I
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R4
CO2R3
N
–30 to –10 °C, Et2O, 1 h
then I2
R1
R2
3. AllocCl
4
O
O
O
O
O
O
O
O
O
O
O
Me
nBu
Me
N
N
N
O
O
O
O
n-Bu
Me
n-Bu
3c
3a
E:Z < 2:98
Method A, 70%
3b
E:Z > 98:2
Method A, 52%
E:Z < 2:98
Method A, 50%
O
O
O
O
O
O
O
O
O
Me
CO2Me
Me
CO2Et
Me
COOtBu
N
N
N
n-Bu
Bn
n-Bu
Bn
n-Bu
Bn
3d
E:Z < 2:98
Method A, 17%
Method B, 72%
3e
E:Z < 2:98
Method B, 56%
3f
E:Z < 2:98
Method B, 63%
20
mation). Increasing the bulk around the phosphine (L8),
which has been shown to have had a positive impact on
allylation of trisubstituted amide enolates with stilbene-
O
O
O
21
O
O
O
O
O
O
derived diamine-linked P,P-ligands, inhibited the reac-
Me
CO2Bn
Me
CO2Me
Me
CO2Me
tion with our fully-substituted enolates 3a and 3d (Table
1, entries 6 and 20). Interestingly, when the two alkyl
groups (R1 and R4) on the stereodefined acyclic al-
lyloxycarbonyl polysubstituted amide enolate were per-
mutated (c.f. 3a and 3b), opposite enantiomers were ob-
tained in lower enantiomeric excess (Table 1, cf. entries 3
and 7 vs. entries 4 and 8). These observations suggest that
the enolate geometry is likely conserved through the
course of the reaction and that the highest enantioselectiv-
ities are obtained when the smallest substituent is syn to
the allyloxycarbonyl group. Slightly better enantiodis-
crimination was observed when EtOAc was used as sol-
vent instead of THF (Table 1, entries 8 and 9). Benzoxa-
zolidinone 3c21 performed unsatisfactorily when compared
to the parent oxazolidinone 3a (Table 1, cf. entries 2 and
10 and entries 4 and 11). Far better enantioselectivities
were finally achieved with acyclic carbamate 3d using C2-
symmetric bisphosphine ligands L3–L7 (Table 1, entries
12–18) to reach an excellent enantiomeric excess of 94%
with the novel electron-deficient ligand L7 and EtOAc as
solvent (Table 1, entry 19). Using these optimized condi-
tions, we decreased the catalyst loading to 4 mol % of
Pd(dba)2 and ligand L7 loading to 7 mol % in EtOAc with
no loss in enantiodiscrimination.
N
N
N
n-Bu
Bn
n-Bu
Ar
n-Hex
Bn
3g
E:Z < 2:98
Method B, 78%
3h
Ar = 4-ClC6H4
3i
E:Z < 2:98
Method B, 81%
E:Z < 2:98
Method B, 63%
O
O
O
O
O
O
O
O
O
Me
CO2Me
Me
CO2Me
Et
CO2Me
N
N
N
TBSO
Bn
Ph
Bn
n-Bu
Bn
3j
E:Z < 2:98
Method B, 82%
3k
E:Z < 2:98
Method B, 61%
3l
E:Z < 2:98
Method B, 63%
O
O
O
O
O
O
O
O
O
Et
CO2Me
nPr
CO2Me
CO2Me
N
N
Ph
N
3
n-Bu
Bn
n-Hex
Bn
n-Hex
Bn
3m
E:Z < 2:98
Method B, 77%
3n
E:Z < 2:98
Method B, 73%
3o
E:Z < 2:98
Method B, 75%
O
O
O
O
O
O
O
O
O
Et
Et
n-Hex
3q
N
N
O
n-Bu
3p
E:Z < 2:98
E:Z < 2:98
Method B, 73%
Method B, 73%
a
Conditions: Method A; Ynecarbamate (1.0 equiv), CuBr·DMS (1.0–1.2
equiv), R4Li in hexanes or Et2O (2.0–2.4 equiv), in Et2O (ca. 0.1–0.5 M) at –
30 °C to –10 °C for 0.5 h, then ca. 5.5 M tBuOOH in decane (1.0–1.2 equiv)
at –80 °C for 0.5 h, then AllocCl (2.5–4.0 equiv) –80 °C to 23 °C for 1 h,
then 1 M HCl. Method B; step 1: Ynecarbamate (1.0 equiv), CuI (1.0
equiv), R4MgBr in Et2O (2.0 equiv), in Et2O (ca. 0.1–0.5 M) at –30 °C to –
10 °C for 1 h, then I2 (2.0 equiv) in THF at –20 °C to 0 °C for 15 min, then
sat. Na2S2O3. Step 2: Vinyl iodide (1 equiv), tBuLi (2.0–2.1 equiv), in Et2O
(0.1–0.3 M) at –80 °C for 15 min, then in situ prepared tBuOOLi [from ca.
5.5 M tBuOOH in decane (1.8–2.1 equiv) and MeLi in Et2O (2.0–2.3 equiv),
With an optimal asymmetric reaction protocol in hand,
we initiated an investigation into the scope of the enanti-
oselective alkylation. The nature of the N-substituents R2
and R3 of the acyclic carbamate substrate was probed by
measuring the enantioselectivity of the reaction as shown
in Scheme 3A. Gratifyingly, the scope of the reaction
3
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process appears to be fairly broad with respect to the R3
the R1 substituent from a butyl group (6d, 94% ee) to a
substituent on the carbamate group (COOR3 where R3 =
Me, Et, t-Bu and Bn; 3d–3g, respectively) and produced
reaction products 6d-g of uniformly high enantiomeric
excesses. Additionally, changing the R2 substituent from
N-benzyl to N-4-chlorophenyl produced α-quaternary am-
ide 6h in 90% ee.
hexyl or CH2CH2OTBS group did not alter the enantiose-
lectivity of the acyclic quaternary carbon center (94% ee
for 6i and 6j, Scheme 3B). However, when the R1 sub-
stituent is an aromatic group, the enantiodiscrimination is
moderately lower (76% ee for 6k). To a certain extent,
replacing the R4 substituent with an ethyl group was well
tolerated (82% and 94% ee for 6l and 6m, respectively),
while introduction of a bulkier (CH2)3Ph group resulted in
diminished enantiomeric excess (76% ee for 6n). In gen-
eral, there is a reasonable amount of functional group tol-
erance as well as structural flexibility at every variable
position in the new combined method. In certain cases the
chemical yields of the Pd-catalyzed allylic alkylation are
somewhat modest. This is likely due to a combination of
steric congestion and the opportunity for palladium-
enolates to proceed through multiple catalytic pathways
(inner sphere versus outer sphere alkylation chemistry),22
some of which do not productively lead to the desired
1
2
3
4
5
6
7
8
Table 1. Evaluation of ligands for palladium-catalyzed DAA of
acyclic allyloxycarbonyl polysubstituted amide enolates 3.a
9
O
CO2R3
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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O
R2
R1
R4
Pd(dba)2 (4-10 mol %)
L (7-12.5 mol %)
solvent, 23 °C, 24-72 h
5
O
O
R4
CO2R3
or
optional:
methyl acrylate
Grubbs's II (5 mol%)
40 °C, CH2Cl2, 24 h
N
O
R1
R2
CO2R3
3
MeO2C
N
R2
R1
R4
6
Ligands
R
O
O
O
O
NH HN
NH HN
O
N
23
product (e.g., enolate protonation, β-hydride elimina-
PPh2 Ph2P
PPh2 Ph2P
Ar2P
24
tion, etc.).
tBu
L1 R = H, Ar = Ph
L2 R = CF3, Ar = 4-CF3C6H4
L3
L4
Scheme 3. Access to all-carbon quaternary stereocenters in un-
biased acyclic systems with Alloc-trapped enolates.a
Ph
Ph
O
A.
L6 R = H, Ar = Ph
L7 R = CF3, Ar = 4-CF3C6H4
L8 R = H, Ar = 2-CH3C6H4
O
O
1. Pd(dba)2 (4 mol %)
O
O
NH HN
O
L7 (7 mol %)
O
O
NH HN
PAr2 Ar2P
EtOAc or THF, 25 °C, 24 h
CO2R3
Me
n-Bu
CO2R3
MeO2C
N
PPh2 Ph2P
N
2. methyl acrylate
Grubbs' II (6 mol%)
40 °C, CH2Cl2, 3 h
R2
R
R
R2
n-Bu
Me
6d-h
L5
3d-h
O
O
O
entry
substrate
ligand
solvent
ee
CO2Me
Ph
CO2Et
Ph
CO2tBu
MeO2C
N
MeO2C
N
MeO2C
N
n-Bu
6d
n-Bu
6e
n-Bu
Me
Me
Me
1
2
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3d
3d
3d
3d
3d
3d
3d
3d
3d
L3
L4
L5
L6
L7
L8
L5
L6
L6
L4
L6
L3
L4
L5
L5
L6
L6
L7
L7
L8
THF
THF
64
76
Ph
6f
62% and 85% yield
53% yield (2 steps)
94% ee
88% and 79% yield
70% yield (2 steps)
90% ee
85% and 80% yield
68% yield (2 steps)
94% ee
3
THF
-70
70
O
O
4
THF
CO2Me
CO2CH2Ph
Ph
MeO2C
N
MeO2C
N
5
THF
70
n-Bu
Me
n-Bu
6g
53% and 76% yield
40% yield (2 steps)
94% ee
Me
6h
6
THF
NR
46
Cl
62% and 80% yield
50% yield (2 steps)
90% ee
7
THF
8
THF
-30
-36
32
O
B.
1. Pd(dba)2 (4 mol %)
9
EtOAc
THF
O
L7 (7 mol %)
EtOAc or THF, 25 °C, 24 h
O
O
CO2Me
Ph
10
11
12
13
14
15
16
17
18
19
20
R4
CO2Me
MeO2C
N
2. methyl acrylate
Grubbs' II (6 mol%)
40 °C, CH2Cl2, 3 h
N
R1
R4
THF
50
R1
Ph
3i-n
6i-
n
THF
72
O
O
O
THF
74
CO2Me
CO2Me
Ph
CO2Me
Ph
MeO2C
N
MeO2C
N
MeO2C
N
THF
-60
-68
86
Me
Me
Me Ph
n-Hex Ph
EtOAc
THF
6i
6j
6k
OTBS
69% and 84% yield
58% yield (2 steps)
94% ee
77% and 78% yield
60% yield (2 steps)
76% ee
76% and 79% yield
60% yield (2 steps)
94% ee
EtOAc
THF
84
O
O
O
86
CO2Me
Ph
CO2Me
Ph
CO2Me
Ph
MeO2C
N
n-Bu
MeO2C
N
MeO2
C
N
EtOAc
THF
94
Et
Ph(CH2)2CH2
Et
n-Hex
n-Hex
NR
6l
6m
6n
76% and 85% yield
65% yield (2 steps)
82% ee
64% and 85% yield
54% yield (2 steps)
94% ee
56% and 84% yield
47% yield (2 steps)
76% ee
NR = no reaction
a
a
Conditions: polysubstituted amide (1.0 equiv), Pd(dba)2 (4–10 mol %),
ligand (7–12.5 mol %) in solvent (0.17 M) at 25 °C for 24–72h in glovebox.
Filtration through silica plug, optionally followed by methyl acrylate (10
equiv), Grubbs second generation catalyst (5 mol%) in CH2Cl2 (0.03 M) at
40 °C for 24 hours in glovebox. For details of individual experiments, see
Supporting Information.
Conditions: polysubstituted amide (1.0 equiv), Pd(dba)2 (4 mol %), lig-
and (7 mol %) in solvent (0.17 M) at 20 °C for 24 h in glovebox. Purifica-
tion (preparative TLC) followed by methyl acrylate (10 equiv), Grubbs
second generation catalyst (6 mol%) in CH2Cl2 (0.03 M) at 40 °C for 3 h in
glovebox. Yields are given for the individual steps as well as the overall 2
step yield.
We then turned our attention to altering the substituents
To determine the absolute configuration of the newly
formed quaternary carbon stereocenters in acyclic com-
at the α-carbon (Scheme 3B, i.e., R1 and R4). Changing
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pounds 5 and 6 (Scheme 4), we compared the optical rota-
tion of lactam 8, an easily accessible cyclic product result-
Funding Sources
No competing financial interests have been declared.
1
2
3
4
5
6
7
8
ing from simple manipulations of 5j with a previously
characterized derivative obtained by enantioselective de-
carboxylative allylic alkylation of cyclic allyl enol car-
bonate 7 (see Supporting Information for further de-
tails).14d As a result of this chemical structural correlation,
we determined that the absolute stereochemistry of acyclic
derivative 5j is S. All other acyclic amide products result-
ing from our new asymmetric alkylation reaction are as-
signed in Scheme 3 by analogy.
ACKNOWLEDGMENT
This research was supported by the Israel Science Founda-
tion administrated by the Israel Academy of Sciences and
Humanities (140/12), the Fund for Promotion of Research at
the Technion, the NIH-NIGMS (R01GM080269), and the
NSF (predoctoral research fellowship to D.C.D., No. DGE-
1144469). Research reported in this publication was sup-
ported by the NIH-NIGMS under Award Number
F32GM116304 (postdoctoral fellowship to J. Moore). The
content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health. I.M. is holder of the Sir Michael and
Lady Sobell Academic Chair (Technion). Dr. Mona Shahg-
holi (Caltech) and Naseem Torian (Caltech) are thanked for
mass spectrometry assistance. Dr. Scott Virgil (Caltech) is
thanked for instrumentation assistance and helpful discus-
sions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Determination of absolute stereochemistry.
O
O
O
1. NaOMe, NaOH
2. NaH, BnBr
1. NaOH
2. TBAF
Me
(S)
Me
CO2Me
O
N
N
N
(R)
3. MsCl, TEA
4. NaHMDS
Ph
Me
Ph
Ph
OTBS
7
98% ee
ref [14d]
5j
94% ee
8
from 5j: [α]D = +26° (S)
from [α]D = -30° (R)
7
:
3. CONCLUSION
In conclusion, we have developed a robust method for
the preparation of versatile molecular backbones contain-
ing a newly created quaternary carbon stereocenter in un-
biased acyclic systems. This was accomplished by the
unique combination of easily accessible, fully substituted
stereodefined amide enolates with the enantioselective
catalytic decarboxylative allylic alkylation reaction em-
ploying a novel electronically perturbed C2 symmetrical
bis-phosphine ligand. Finally, while the full synthetic
utility of the enantioenriched α-quaternary amides pre-
pared has yet to be realized, one can glean the implica-
tions of this chemistry from both past literature applica-
tions of these subunits as well as the simple sequence em-
ployed to determine absolute stereochemistry, resulting in
the preparation of lactam 8 (Scheme 4). Efforts to exploit
this new technology on the context of multi-step synthetic
chemistry will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
characterization data as Supporting Information is available
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10.1021/jacs.5b00000.
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AUTHOR INFORMATION
Corresponding Author
*stoltz@caltech.edu
*chilanm@tx.technion.ac.il
Author Contributions
⊥These authors contributed equally.
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Present Address
§Department of Chemistry and Biotechnology,
Tallinn University of Technology, Tallinn
12618, Estonia
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TOC graphic
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Highly Enantioselective
Pd-catalyzed Alkylation
Regioretentive
Oxidation
Regioselective
Carbometalation
O
O
O
O
O
I
O
R1
R2
O
O
O
R1
N
O
R1
N
N
O
N
O
R2
R2
R2
9
Simple
Starting
Materials
De Novo Quaternary
Stereocenter Synthesis
Full Control in
Acyclic Systems
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