Palladium-catalyzed asymmetric alkylation in the synthesis of cyclopentanoid and cycloheptanoid core structures bearing all-carbon quaternary stereocenters

Article abstract of DOI:10.1016/j.tet.2011.10.031

General catalytic asymmetric routes toward cyclopentanoid and cycloheptanoid core structures embedded in numerous natural products have been developed. The central stereoselective transformation in our divergent strategies is the enantioselective decarboxylative alkylation of seven-membered β-ketoesters to form α-quaternary vinylogous esters. Recognition of the unusual reactivity of β-hydroxyketones resulting from the addition of hydride or organometallic reagents enabled divergent access to γ-quaternary acylcyclopentenes through a ring contraction pathway or γ-quaternary cycloheptenones through a carbonyl transposition pathway. Synthetic applications of these compounds were explored through the preparation of mono-, bi-, and tricyclic derivatives that can serve as valuable intermediates for the total synthesis of complex natural products. This work complements our previous work with cyclohexanoid systems.

Full text of DOI:10.1016/j.tet.2011.10.031

Tetrahedron 67 (2011) 10234e10248
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed asymmetric alkylation in the synthesis of cyclopentanoid
and cycloheptanoid core structures bearing all-carbon quaternary stereocenters
*
Allen Y. Hong, Nathan B. Bennett, Michael R. Krout, Thomas Jensen, Andrew M. Harned, Brian M. Stoltz
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
91125 CA, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
General catalytic asymmetric routes toward cyclopentanoid and cycloheptanoid core structures em-
bedded in numerous natural products have been developed. The central stereoselective transformation
Received 7 September 2011
Received in revised form 7 October 2011
Accepted 10 October 2011
Available online 19 October 2011
in our divergent strategies is the enantioselective decarboxylative alkylation of seven-membered
toesters to form -quaternary vinylogous esters. Recognition of the unusual reactivity of -hydrox-
yketones resulting from the addition of hydride or organometallic reagents enabled divergent access to
-quaternary acylcyclopentenes through a ring contraction pathway or -quaternary cycloheptenones
b-ke-
a
b
g
g
through a carbonyl transposition pathway. Synthetic applications of these compounds were explored
through the preparation of mono-, bi-, and tricyclic derivatives that can serve as valuable intermediates
for the total synthesis of complex natural products. This work complements our previous work with
cyclohexanoid systems.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
transformations (Fig. 2).6 During the course of this work, we ob-
served the unusual reactivity of
exploited a two-carbon ring contraction to provide a general syn-
thesis of
-quaternary acylcyclopentenes.7 With access to the iso-
meric five- and seven-membered enones, we prepared diverse
synthetic derivatives and polycyclic systems that can potentially
provide different entry points for synthetic routes toward complex
natural products.
b-hydroxycycloheptanones and
The stereoselective total synthesis of polycyclic natural products
depends greatly on the available tools for the efficient preparation
of small and medium sized rings in enantioenriched form.1 Facile
means to elaborate these monocyclic intermediates to fused,
bridged, and spirocyclic architectures within multiple ring systems
would significantly contribute to modern synthetic methods. While
many strategies have been developed for the preparation of six-
membered rings and their corresponding polycyclic derivatives,
approaches toward the synthesis of five- and seven-membered
rings would benefit from further development.
Guided by our continuing interest in the preparation of poly-
cyclic systems bearing all-carbon quaternary stereocenters using
Pd-catalyzed asymmetric alkylation chemistry,2e4 we sought to
prepare various chiral cyclic ketone building blocks for total syn-
thesis. Our investigation of six-membered ring substrates has
allowed us to achieve the total synthesis of a number of complex
natural products.5 Given our earlier success, we aimed to generalize
our approach and gain access to natural products containing chiral
cyclopentanoid and cycloheptanoid ring systems as a part of
a broader synthetic strategy (Fig. 1).
g
2. Results and discussion
2.1.
b-Ketoester synthesis and Pd-catalyzed asymmetric
alkylation reactions
Much of our past research on the asymmetric alkylation of cyclic
ketones2a,3,8d and vinylogous esters5bee,8aec,e focused on six-
membered rings, while transformations of larger rings were less
thoroughly investigated. We hoped to extend our work by exploring
asymmetric alkylations of seven-membered vinylogous esters. The
feasibility of various types of substrates for our asymmetric alkyl-
ation chemistry suggested that vinylogous ester 5 can be trans-
formed into silyl enol ether, enol carbonate, or
substrates, but we chose to prepare -ketoesters due totheir relative
stability and ease of further functionalization. To access a variety of
racemic -quaternary -ketoester substrates for Pd-catalyzed
b-ketoester
Our efforts led to the development of general strategies for the
b
preparation of
a-quaternary vinylogous esters and their conversion
to -quaternary cycloheptenones using StorkeDanheiser
g
a
b
asymmetric alkylation reactions, we required multi-gram quanti-
* Corresponding author. E-mail address: stoltz@caltech.edu (B.M. Stoltz).
tiesof 1,3-cycloheptanedione (4). Dione 4 iscommerciallyavailable,9
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.031

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10235
Fig. 1. Application of cyclopentanoid, cyclohexanoid, and cycloheptanoid cores toward stereoselective natural product total synthesis.
A
survey of several electronically differentiated PHOX
12,13
ligands2a,11 combined with Pd2(pmdba)3
in a number of dif-
ferent solvents using methyl-substituted
b
-ketoester 6a identified
the optimal parameters for this transformation (Table 1). Initial
conditions employed (S)-t-Bu-PHOX (L1, 6.25 mol %) and
Pd2(pmdba)3 (2.5 mol %) in THF and gave vinylogous ester 7a in 94%
yield and 84% ee (entry 1).14 Application of the same catalyst sys-
tem in other ethereal solvents, such as 1,4-dioxane, 2-methyl THF,
TBME, and Et2O led to only slight improvements in the enantiose-
lectivity of the reaction to give the desired product in up to 86% ee
(entries 2e5). Switching to aromatic solvents provided modest
increases in asymmetric induction, furnishing 7a in 91% yield and
88% ee in the case of toluene (entries 6 and 7).
Fig. 2. General access to enantioenriched cyclopentanoid and cycloheptanoid cores.
but we typically prepare it from cyclopentanone by the route of
Ragan and co-workers to facilitate large-scale synthesis.10 Treat-
ment of 4 with i-BuOH and catalytic PPTS under DeaneStark con-
ditions produced vinylogous ester 5 (Scheme 1).9 Acylation of 5 with
allyl cyanoformate following deprotonation with LDA enabled facile
installation of the requisite allyl ester functionality. Subsequent
enolate trapping with a variety of electrophiles under basic condi-
tions provided substrates containing alkyl, alkyne, alkene,1,3-diene,
vinyl chloride, nitrile, heteroarene, aldehyde, fluoride, silyl ether,
and ester functionalities in 61e88% yield over two to four steps
Table 1
Solvent and ligand effects on enantioselective decarboxylative allylationa
O
O
O
ligand (6.25 mol %)
Pd2(pmdba)3 (2.5 mol %)
O
solvent, 30 °C
i-BuO
i-BuO
6a
7a
(6aen). With these quaternary b-ketoesters in hand, we evaluated
the scope of Pd-catalyzed asymmetric alkylation reactions on seven-
membered ring vinylogousestersubstrates, focusingon methyl/allyl
substituted 6a for our optimization efforts.
Entry
Ligand
Solvent
THFe
1,4-Dioxane
2-Methyl THFe
TBMEe
Et2O
PhH
PhCH3
PhCH3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8d
9
L1
L1
L1
L1
L1
L1
L1
L2
L3
94
86
75
88
93
84
91
57
77
84
84
85
85
86
86
88
90
72
PhCH3
a
Conditions:
%)
b-ketoester 6a (1.0 equiv), Pd2(pmdba)3 (2.5 mol %), ligand
(6.25 mol
in
solvent
(0.1 M)
at
30
ꢀC;
pmdba¼4,40-
methoxydibenzylideneacetone.
b
Isolated yield.
Determined by chiral HPLC.
Increased catalyst loadings were required to achieve full conversion:
c
d
Pd2(pmdba)3 (5 mol %), L2 (12.5 mol %).
e
THF¼tetrahydrofuran, TBME¼tert-butyl methyl ether, 2-methyl THF¼2-methyl
Scheme 1. Synthesis of parent vinylogous ester 5 and b-ketoester substrates 6.
tetrahydrofuran.

10236
A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
under our standard conditions (entries 1 and 2). A variety of aro-
chiral ligands
CF3
matic and heteroaromatic functionality was well tolerated under
the reaction conditions (entries 3, 9e10). Additionally, unsaturated
functionality, such as alkynes, alkenes, and 1,3-dienes did not suffer
from competitive reaction pathways (entries 4e6). In the case of
vinyl chloride 6g, no products derived from oxidative addition into
the CeCl bond were observed (entry 7). Gratifyingly, N-basic
functionality, such as nitriles and pyridines could be carried
through the reaction without noticeable catalyst poisoning (entries
8 and 9). Perhaps the most intriguing result was the observation
that an unprotected aldehyde could be converted to the enan-
tioenriched product 7k in 90% yield and 80% ee, highlighting the
essentially neutral character of the reaction conditions (entry 11).
Tertiary fluoride products could also be obtained efficiently in 94%
yield and 91% ee (entry 12). Although most substrates underwent
smooth asymmetric alkylation, several substrates, such as silyl
ether 6m16 and benzoate ester 6n17 were not formed as efficiently
under the reaction conditions due to unproductive side reactions
(entries 13 and 14).
O
O
O
Ph2P
N
F3C
P
N
Ph2P
N
L1
(S)-t-Bu-PHOX
L2
L3
CF3
We next examined the impact of other PHOX ligands (L2 and L3)
in this medium. Electron deficient ligand L25b,15 displayed im-
proved enantioselectivity at the cost of higher catalyst loading and
lower yield (entry 8). Structural modification of the aryl phosphine
backbone was evaluated with ligand L3, but this proved to be less
effective, giving reduced yield and ee (entry 9). Of the three ligands,
L1 furnished the best overall results.
With optimal ligand and solvent conditions in hand, we ex-
plored asymmetric alkylation reactions of a variety of
-ketoesters (Table 2). Simple alkyl substitution performed well
a-substituted
b
Table 2
Scope of the Pd-catalyzed enantioselective alkylation of cyclic vinylogous estersa
2.2. Observation of unusual reactivity of
hydroxycycloheptanones
b-
O
O
O
R
R
(S)-t-Bu-PHOX (6.25 mol %)
Pd2(pmdba)3 (2.5 mol %)
O
With an assortment of asymmetric alkylation products in hand,
we next sought to perform a carbonyl transposition using methods
developed by Stork and Danheiser.18 Earlier experiments on the
hydride reduction of six-membered vinylogous ester 8 with sub-
sequent acid treatment gave enone 9 as expected (Scheme 2A).
However, to our surprise, application of identical reaction condi-
tions to the seven-membered analog (7a) gave poor yields of
cycloheptenone 3a (Scheme 2B). Only minor quantities of elimi-
nation product were observed even after prolonged stirring with
10% aqueous HCl. Closer inspection of the reaction mixture revealed
PhCH3, 30 °C
i-BuO
i-BuO
6
7
Entry
Substrate 6
R
Product 7
Yieldb (%)
eec (%)
1
2
3
4
5
6a
6b
6c
6d
6e
eCH3
eCH2CH3
eCH2Ph
7a
91
89
98
88
95
88
92
86
89
87
7b
7c
7d
7e
eCH2C^CH
eCH2CH2CH]CH2
b
-hydroxyketone 10a as the major product, suggesting that these
6
6f
7f
90
90
seven-membered rings display unique and unusual reactivity
compared to their six-membered ring counterparts.19e21
O
OH
A
LiAlH4
7
8
9
6g
6h
6i
7g
7h
7i
99
96
97
86
87
85
Et2O, 0 °C
Cl
then
i-BuO
O
O
10% aq HCl
eCH2CH2CN
8
9
no observable
β-hydroxyketone
92% yield
N
O
OH
B
LiAlH4
Et2O, 0 °C
d
Ts
then
i-BuO
O
O
10% aq HCl
N
10
6j
7j
98
83
7a
3a
10a
6% yield
87% yield
LiOt-Bu
H
O
O
t-BuOH, 40 °C
11
6k
7k
90
80
53% yield
1a
Scheme 2. Observation of the unusual reactivity of b-hydroxycycloheptanone 7a.
12
13
6l
6m
eF
7l
7m
94
66
91
58
eCH2OTBDPSd
Without initial success using acidic conditions, we reasoned
that -hydroxyketone 10a could potentially provide cyclo-
heptenone 3a under basic conditions through a -elimination
b
b
O
pathway (Scheme 2B). Attempts in this regard did not produce
enone 3a, but instead gave isomeric enone 1a that appeared to be
formed through an unexpected ring contraction pathway.22 Nota-
bly, this transformation serves as a rare example of a two-carbon
ring contraction.20,23,24
Upon consideration of the reaction mechanism, we believed
that this process occurred through an initial deprotonation of the
hydroxy moiety, followed by retro-aldol ring fragmentation to
14
6n
7n
75
57
O
Ph
a
Conditions:
6.25 mol
b-ketoester 6 (1.0 equiv), Pd2(pmdba)3 (2.5 mol %), (S)-t-Bu-PHOX
(L1,
%)
in
PhCH3
(0.1 M)
at
30
ꢀC;
pmdba¼4,40-
methoxydibenzylideneacetone.
b
Isolated yield.
Determined by chiral HPLC or SFC.
TBDPS¼tert-butyldiphenylsilyl, Ts¼4-toluenesulfonyl.
c
d

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10237
a ketoaldehyde enolate (Scheme 3). Subsequent isomerization to
2.3. Ring contraction strategy for preparing
acylcyclopentenes
g-quaternary
the more substituted enolate and aldol cyclization could lead to the
observed two-carbon ring contraction product 1a. Attempts to
isolate the intermediate ketoaldehyde 11a were unsuccessful, but
aldehyde peaks could be observed by 1H NMR in reactions that did
not proceed to full conversion. Subsequent experiments on more
Intrigued by our findings, we sought to develop a robust route to
g-quaternary acylcyclopentenes with many substitution patterns.
Exploring a number of bases, additives, solvents, and temperatures
for the ring contraction of -hydroxyketone 10a provided insight
substituted
b-hydroxyketones enabled isolation of linear uncycl-
b
ized intermediates and provided additional support for this re-
action mechanism (Scheme 6).
into the optimal parameters for the transformation (Table 3). Given
our early result using LiOt-Bu, we examined numerous aldol cy-
clization conditions with a variety of non-nucleophilic bases. We
observed that several tert-butoxides in t-BuOH and THF gave con-
version to the desired product (1a) in good yields (entries 1e4), but
noted that the rate of product formation was comparatively slower
with LiOt-Bu than with NaOt-Bu or KOt-Bu. The use of various hy-
droxides revealed a similar trend, where NaOH and KOH generated
acylcyclopentene 1a in 4 h with improved yields over their re-
spective tert-butoxides (entries 5 and 6). The relatively sluggish
reactivity of LiOH may be due to the lower solubility of this base in
THF, providing 1a in low yield with the formation of various in-
termediates (entry 7).
Table 3
Ring contraction reaction optimizationa
HO
Scheme 3. Proposed ring contraction mechanism.
conditions
+
O
O
O
To explore the general stability and reactivity of
ycycloheptanones, we examined simplified analogs that do not
possess the -quaternary stereocenter (Scheme 4). Following hy-
dride reduction, elimination to cyclohexenone 13 was observed for
the six-membered vinylogous ester 12, while -hydrox-
b-hydrox-
1a
10a
3a
a
not observed
b
Entry
Base
Additive
Solvent
T (ꢀC)
Yieldb (%)
ycycloheptanone 15 and volatile cycloheptenone 14 were observed
for seven-membered analog 5. In the seven-membered ring case,
a higher proportion of elimination product was observed when
compared to the more substituted analog. A milder aqueous acid
work-up may suffice to hydrolyze the isobutyl enol ether and en-
1
2
LiOt-Bu
LiOt-Bu
NaOt-Bu
KOt-Bu
NaOH
KOH
LiOH
LiOH
LiOH
d
t-BuOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
40
40
40
40
60
60
60
60
60
60
60
60
60
60
60
71
60
81
85
89
d
3
d
4e
5
d
d
6
7
8
9
10
11
12
13
14
15
d
87
d
19d
78
able isolation of the
b-hydroxycycloheptanone in higher yield in
t-BuOH
HFIPc
TFEc
d
this case. The ring contraction of
b
-hydroxycycloheptanone 15
87
under basic conditions proceeded smoothly to give volatile acyl-
cyclopentene 16. These observations suggest that the unusual two-
carbon ring contraction appears to be a general phenomenon re-
lated to seven-membered rings and motivated the development of
the ring contraction chemistry as a general approach to obtaining
chiral acylcyclopentene products.
LiOH
96
LiOCH2CF3
CsOH$H2O
Cs2CO3
Cs2CO3
Cs2CO3
90e
48
d
d
TFEc
61f
86
TFEc
100
a
Conditions:
b-hydroxyketone 10a (1.0 equiv), additive (1.5 equiv), base
(1.5 equiv), solvent (0.1 M) at indicated temperature for 9e24 h.
b
O
OH
GC yield using an internal standard at ꢁ98% conversion unless otherwise stated.
A
LiAlH4
c
HFIP¼1,1,1,3,3,3-hexafluoro-2-propanol; TFE¼2,2,2-trifluoroethanol.
Et2O, 0 °C
d
Several reaction intermediates observed by TLC and GC analysis; proceeded to
78% conversion.
then
i-BuO
O
O
e
10% aq HCl
Isolated yield.
12
13
no observable
f
Reaction did not reach completion at 24 h; proceeded to 67% conversion.
β-hydroxyketone
40% yield
To improve the yield of the reaction with LiOH as base, we in-
vestigated the effect of alcohol additives to facilitate the production
of mild, organic-soluble bases under the reaction conditions to
increase the efficiency of the transformation. The combination of t-
BuOH and LiOH in THF increased the yield of 1a to a similar level as
that observed with LiOt-Bu, although the reaction still proceeded
slowly (entry 8). Application of more acidic, non-nucleophilic al-
cohols such as hexafluoroisopropanol (HFIP) and trifluoroethanol
(TFE) demonstrated exceptional reactivity in combination with
LiOH and efficiently afforded 1a in high yields (entries 9 and 10).25
In particular, TFE enabled the production of 1a in 96% yield. Com-
O
OH
B
LiAlH4
Et2O, 0 °C
then
i-BuO
O
O
10% aq HCl
5
14
15
24% yield
46% yield
LiOH, TFE
O
THF, 60 °C
26
parable results with preformed LiOCH2CF3 suggest that this alk-
31% yield
16
oxide is the active base under the LiOH/TFE ring contraction
conditions (entry 11).
Scheme 4. Attempted StorkeDanheiser manipulations on unsubstituted rings.

10238
A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
Concurrent investigation of cesium bases reinforced the im-
none of the conditions surveyed for the ring contraction studies
generated the -elimination product, cycloheptenone 3a.
portance of alcohol additives for the in situ formation of organic-
soluble bases in ring contraction reactions. With CsOH$H2O and
Cs2CO3, product formation was inefficient due to low yield or
sluggish reactions (entries 12 and 13). The addition of TFE afforded
acylcyclopentene 1a in yields comparable to those of the LiOH/TFE
conditions (entry 14). Notably, ring contraction with Cs2CO3/TFE
can also be performed in acetonitrile as an alternative, non-ethereal
solvent with high efficiency (entry 15).27
While a number of bases are effective for the production of 1a in
excellent yields, we selected the combination of LiOH/TFE as our
standard conditions for reaction scope investigation due to the lower
cost and greater availability of base. The data from our study further
recognize the unique properties of these mild bases and suggest their
application may be examined in a broader context.28 Importantly,
b
With the optimal base promoted conditions in hand, we in-
vestigated the scope of the ring contraction chemistry with a variety
of substitution patterns21 (Table 4). Simple alkyl, aromatic, hetero-
aromatic substitution performed well under our standard conditions
(method A) in 84e95% yield (entries 1e6, 10). Additionally, vinyl
chlorides, nitriles, and indoles could be incorporated into the target
acylcyclopentenes in 85e92% yield (entries 7 and 8). Further studies
revealed that alternative aluminum hydrides such as DIBAL could be
employed in the generation of the intermediate b-hydroxyketone by
enabling more precise control of hydride stoichiometry. The use of
these modified conditions followed by oxalic acid work-up in meth-
anol (method B) facilitated the preparation of pyridine-containing
acylcyclopentene 1i in higher yield compared to method A (entry 9).
Table 4
Ring contraction substrate scopea,b,c,d,e
O
HO
R1
R1
LiOH
R2
R2
reduction
CF3CH2OH
R1
R2
conditions
A, B, C, or D
O
i-BuO
O
THF, 60 °C
7
10
1
Entry
Substrate 7
Reduction conditions
R1
R2
Product 1e
Yieldf (%)
1
2
3
4
5
7a
7b
7c
7d
7e
A
A
A
A
A
eCH3
eCH2CH3
eCH2Ph
eCH2C^CH
eCH2CH2CH]CH2
eCH2CH]CH2
eCH2CH]CH2
eCH2CH]CH2
eCH2CH]CH2
eCH2CH]CH2
1a
1b
1c
1d
1e
84
90
86
95
87
6
7f
A
eCH2CH]CH2
1f
91
7
8
9
7g
7h
7i
A
A
B
eCH2CH]CH2
eCH2CH]CH2
eCH2CH]CH2
1g
1h
1i
92
85
80
Cl
eCH2CH2CN
N
Ts
N
10
7j
A
eCH2CH]CH2
1j
87
11
12
7m
7og
C
C
eCH2OTBDPSi
e(CH2)3OTBDPSi
eCH2CH]CH2
eCH2CH]CH2
1m
1o
91
85
O
13
A
1p
81
O
i-BuO
7p
O
14
A
1q
87
O
i-BuO
7q
15
16
7n
7l
D
A
eOH
eF
eCH2CH]CH2
eCH2CH]CH2
1n
1l
25
0
hPrepared from 7a.
a
Reduction conditions A: vinylogous ester 7 (1.0 equiv), LiAlH4 (0.55 equiv) in Et2O (0.2 M) at 0 ꢀC, then 10% aqueous HCl quench.
b
c
d
e
f
Reduction conditions B: (1) vinylogous ester 7 (1.0 equiv), DIBAL (1.2 equiv) in PhCH3 (0.03 M) at ꢂ78 ꢀC; (2) oxalic acid$2H2O in MeOH (0.02 M).
Reduction conditions C: vinylogous ester 7 (1.0 equiv), CeCl3$7H2O (1.0 equiv), NaBH4 (3.0 equiv) in MeOH (0.02 M) at 0 ꢀC, then 10% aqueous HCl in Et2O at 0 ꢀC.
Reduction conditions D: vinylogous ester 7 (1.0 equiv), DIBAL (3.3 equiv) in PhCH3 (0.03 M) at ꢂ78 ꢀC; (2) 10% aqueous HCl in Et2O at 0 ꢀC.
Ring contraction conditions: b
-hydroxyketone 10 (1.0 equiv), CF3CH2OH (1.5 equiv), LiOH (1.5 equiv) in THF (0.1 M) at 60 ꢀC.
Isolated yield over 2e3 steps.
Prepared from 7k.
TBDPS¼tert-butyldiphenylsilyl, Ts¼4-toluenesulfonyl, DIBAL¼diisobutylaluminum hydride.
g
i

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10239
While various compounds could undergo the ring contraction
sequence with high efficiency, other substrates with more sensitive
functionality proved to be more challenging. To this end, we in-
vestigated the use of milder reduction conditions developed by
Luche29 to further increase the reaction scope. Silyl ether substrate
7m30 could be converted to the corresponding acylcyclopentene
1m in 86% yield using the LiAlH4 protocol (method A), but appli-
cation of Luche reaction conditions using (method C) enabled an
improvement to 91% yield (entry 11). The same conditions provided
the related silyl ether-containing acylcyclopentene 1o with a longer
carbon chain in 85% yield (entry 12).
electron-rich and sterically-crowded nature of the carbonyl elec-
trophile. Gratifyingly, excellent reactivity was achieved by in-
troducing CeCl3 to the reaction with the Grignard reagent,32
although a fair amount of the corresponding enone was pro-
duced in the transformation (Scheme 5B).33 Nevertheless, the
CeCl3 supplemented addition furnished a significantly improved
overall yield of addition products with good selectivity for
hydroxyketone 10r.
b
-
We next examined the ring contraction sequence with
b
-
hydroxyketone 10r (Scheme 6). Treatment of alcohol 10r with the
optimized ring contraction conditions using LiOH/TFE yielded
Our success in performing ring contractions with a variety of
substituents at the quaternary stereocenter encouraged studies
aimed at determining whether additional substitution patterns
could be introduced into the acylcyclopentene products. While
most substrates involved a variable group and an allyl fragment
positioned on the quaternary center, we were intrigued by the
possibility of performing the ring contraction chemistry with
other groups. Investigation of methyl and trans-propenyl
substituted vinylogous ester 7p using the standard LiOH/TFE
conditions showed that the chemistry was unaffected by modifi-
cation of the allyl fragment, giving product in 81% yield (entry 13).
Additionally, evaluation of spirocycle 7q also proceeded without
complications and afforded the desired product in 87% yield
(entry 14).
linear dione 11r without any of the b-substituted acylcyclopentene.
Even though the conditions did not afford the desired product, the
isolation of stable uncyclized intermediate 11r supports our pro-
posed retro-aldol fragmentation/aldol cyclization mechanism
(Scheme 3). By employing a stronger base such as KOt-Bu, both
steps of the rearrangement could be achieved to give acylcyclo-
pentene 1r. Furthermore, significantly reduced reaction times and
higher yields were achieved with microwave irradiation.
O
n-Bu
n-Bu OH
conditions
n-Bu
+
O
O
O
1r
10r
11r
Although many compounds performed well in the ring con-
traction sequence, certain substrates posed significant challenges.
Application of DIBAL reduction with 10% aqueous HCl work-up
LiOH, CF3CH2OH, THF, 60 °C, 3 h
71% yield
not observed
not observed
not observed
65% yield
KOt-Bu, THF, 60 °C, 22 h
KOt-Bu, THF, 85 °C,
μ
waves, 5 min
73% yield
(method D) and ring contraction of a-benzoate ester 7n enabled
access to tertiary hydroxyl acylcyclopentene 1n, but the yield was
relatively low in comparison to other substrates (entry 15). At-
tempts to prepare the corresponding tertiary fluoride 7l were un-
successful as no desired product was observed (entry 16). Under
the reaction conditions, both vinylogous esters led to more com-
plex reaction mixtures from unproductive side reactions in con-
trast to the typically high yielding transformations observed for
other substrates.
Scheme 6. Ring contraction screen on b-hydroxyketone 10r.
With a route to form a variety of acylcyclopentenes that possess
different substitution patterns, we were interested in increasing the
enantiopurity of these potentially useful intermediates. Formation
of the corresponding semicarbazone 18 enabled us to obtain ma-
terial in 98% ee after two recrystallizations (Scheme 7A). A high
yielding hydrolysis afforded enantioenriched acylcyclopentene 1a.
Further functionalization of semicarbazone 18 with 4-
iodobenzylamine provided crystals that allowed verification of ab-
solute stereochemistry by X-ray crystallography.34 To demonstrate
the viability of our method for large scale asymmetric synthesis, we
performed the asymmetric alkylation and ring contraction trans-
formations on multi-gram scale (Scheme 7B). Gratifyingly, our route
proved to be robust and reliable. Using 50 mmol of substrate (15 g),
we were able to achieve a 94% yield and 88% ee of our desired
asymmetric alkylationproduct. Notably, the increased reaction scale
permitted reduced catalyst loadings (1.25 mol % Pd2(pmdba)3 and
3.12 mol % (S)-t-Bu-PHOX, L1) and higher substrate concentrations
To obtain more functionalized acylcyclopentene products and
extend our methodology, we sought access to
b-substituted
acylcyclopentenes by replacing the hydride reduction step with
the addition of an organometallic reagent and applying the ring
contraction chemistry on the resulting tertiary b-hydroxyketones.
We selected a simple system for our initial investigations and
evaluated the reaction of n-butyl nucleophiles with vinylogous
ester 7a. Unfortunately, the addition of n-BuMgCl or n-BuLi
afforded a complex mixture of products and proceeded slowly
without reaching completion, consequently converting unreacted
starting material to dione 17 upon work-up with strong acid
(Scheme 5A).31 This low reactivity could be understood from the
(0.2 M). b-Ketoester 6a undergoes the asymmetric alkylation and
ring contraction protocol to furnish the desired acylcyclopentene in
69% overall yield over the three step sequence.
A. Organometallic Addition Product Distribution
O
O
conditions
mixture of n-Bu
+
2.4. Synthesis of acylcylopentene derivatives using site-
selective transformations
addition products
i-BuO
O
n-BuMgCl, THF, 23 °C
then 10% aq HCl
7a
17
n-BuLi, THF, 23 °C
With the ultimate goal of applying our methodology toward the
total synthesis of complex natural products, we set out to probe the
synthetic utility of various acylcyclopentenes prepared using our
ring contraction strategy. While acylcyclopentenes 1 are chiral
fragments with low molecular weights, they possess an array of
useful functionality that can be exploited for synthetic applications
through site-selective functionalizations (Fig. 3). Acylcyclopentenes
1 possess hard and soft electrophilic sites, a nucleophilic site,
a functional group handle in the form of an allyl group, and avariable
group, which we can installed through asymmetric alkylation.
then 10% aq HCl
B. CeCl3 Activated Reaction
O
n-Bu
n-Bu OH
CeCl3, n-BuMgCl
THF, 23 °C
+
then 10% aq HCl
i-BuO
O
O
7a
3r
10r
28% yield
65% yield
Scheme 5. Organometallic addition to vinylogous ester 7a.

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A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
hard electrophilic site (A)
O
(C) nucleophilic site
quaternary
stereocenter
(D) soft electrophilic site
(E) variable group
R
functional(B)
group handle
1
OH
NHTs
OH
N
N
(A)
(A)
(A)
20
21
22
92% yield
90% yield
74% yield
O
O
O
(B)
(B)
(B)
OH
O
O
H
23
24
25
Scheme 7. Confirmation of absolute stereochemistry and multi-gram scale reactions.
92% yield,
2 steps
80% yield,
2 steps
86% yield,
2 steps
O
O
O
(C)
(C)
(C)
Additionally, all of the acylcyclopentenes we have prepared bear an
all-carbon quaternary stereocenter or a fully substituted tertiary
center.
O
OH
N
We aimed to perform site-selective functionalizations to dem-
onstrate that a variety of derivatives could be prepared by recog-
nizing the rich functionality present in acylcyclopentene 1 (Fig. 3).
Selective functionalization of site A enabled access to tertiary al-
cohols, oximes, and hydrazones in 74e92% yield (20e22). Manip-
ulation of site B through olefin methathesis reactions with methyl
vinyl ketone or crotonaldehyde provided intermediate bis-enone or
enone-enal compounds in 90e95% yield as trans olefin isomers.
Chemoselective hydrogenation with Wilkinson’s catalyst reduced
the less substituted and less sterically hindered olefin in these
systems to form mono-enones 23 and 24 in 90e93% yield. Using
the insights gathered from these manipulations, we found it was
possible to perform chemoselective Heck and hydrogenation re-
actions to provide acylcyclopentene 25 bearing a pendent phenol in
86% yield over two steps. Through modification of site C, access to
carboxylic acids, Weinreb amides, and divinyl ketones were ach-
ieved (26e28). Additionally, functionalization of site D gave rise to
epoxide 29. Functionalization of this site was also demonstrated
26
27
28
77% yield,
2 steps
77% yield,
2 steps
77% yield,
2 steps
O
O
O
(E)
O
Ts
n-Bu
(D)
N
(D)
29
1r
1j
96% yield
(1:1 dr)
see Scheme 6
see Table 3
Fig. 3. Selective functionalizations on sites AeE of acylcyclopentenes 1.
with b-substituted acylcyclopentene 1r (Scheme 6). Lastly, varia-
intermediates that bear
a stronger resemblance to natural
tions at site E were accomplished by installing the appropriate
groups at an early stage during the asymmetric alkylation step
(Scheme 1 and Table 2).
products, we formed the triflate of Heck product 39 using Com-
ins’ reagent35 and subjected the compound to an intramolecular
Heck reaction using the HerrmanneBeller’s palladacycle 4036 to
obtain tricycle 41 with the cis-ring fusion (Scheme 8E). This key
tricycle contains all of the carbocyclic core of hamigerans C and D
with correct stereochemistry at the ring fusions.
Overall, our general strategy has enabled the synthesis of valu-
able chiral building blocks by taking advantage of the rich func-
tional group content embedded in acylcyclopentenes 1. Site-
selective manipulations on regions AeE can produce monocyclic
and polycyclic compounds with a large degree of structural varia-
tion. Our studies have provided valuable insight into the nature of
these compounds and we aim to apply our knowledge of these
promising synthetic intermediates in the total synthesis of complex
natural products.
To further increase the potential of these chiral building
blocks, we performed manipulations on a combination of sites to
arrive at more advanced synthetic intermediates (Scheme 8).
Hydroxydiene 31 was obtained from acylcyclopentene 1a by
performing a carbonyl epoxidation followed by fragmentation in
55% yield over two steps (Scheme 8A). Spirocyclic systems, such
as enones 32 and 34 can be obtained by performing an intra-
molecular DielseAlder using 1f or a ring closing metathesis of 1g
using GrubbseHoveyda third generation catalyst (Scheme 8B and
C). Additionally, phenolic indane 36 was generated in 57% yield
over four steps by exploiting an intermolecular DielseAlder re-
action with DMAD (Scheme 8D). To arrive at synthetic

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10241
Scheme 8. Functionalization of multiple acylcyclopentene reactive sites.
2.5. Carbonyl transposition approach to
cycloheptenones
g-quaternary
While pleased to discover the unusual reactivity of vinylogous
esters 7 that led to the synthesis of various acylcyclopentenes, we
maintained our interest in preparing enantioenriched
g-quater-
nary cycloheptenones and began reexamining reaction parame-
ters to this end. Initially, we identified conditions to obtain
cycloheptenone 3a in two steps by activation and elimination of
the hydroxy group at elevated temperatures, but ultimately de-
sired a more direct route from vinylogous ester 7a (Scheme 9A).
After considerable experimentation, we discovered fortuitously
that reduction and elimination using Luche conditions effectively
Scheme 9. Stepwise and one-pot formation of cycloheptenone 3a.
We again investigated the addition of n-BuMgCl to vinylogous ester
7a with CeCl3 additive, focusing on the impact of various quenching
parameters. While our previous studies showed that the formation of
furnished enone 3a with minimal b-hydroxyketone 10a (Scheme
9B). A number of factors may contribute to the reversed prod-
uct distribution, with methanol likely playing a large role.37 With
b
-hydroxyketone 10r was favored over cycloheptenone 3r (Schemes
10 and 11, path a vs path b), we reasoned that elevated temperatures
would promote dehydration of -hydroxyketone 10 to form cyclo-
heptenone 3 as the major product and simplify the product mixture
an effective route to enone 3a, we also sought to prepare
b-
substituted cycloheptenones through the addition of organome-
tallic reagents.
b

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A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
Table 5
Scope of organometallic addition/eliminationa
O
R
CeCl3,
R M
THF, 23 °C
then work-up
i-BuO
O
conditions
7a
3
Entry
R
M
Work-up conditionsb Product 3 Yieldc (%)
1
2
3
eMgCl
eMgBr
eMgBr
F
F
F
3r
3s
3t
84
73
93
Scheme 10. Synthesis of b-substituted cycloheptenones.
4
5
eMgBr
eMgBr
F
F
3u
3v
90
82
Scheme 11. General reaction mechanism for carbonyl transposition.
6
eMgBr
eLi
F
3w
3x
92
84
(Scheme 11, path c). Subsequent heating of the reaction to 60 ꢀC after
acid quench led to complete consumption of -hydroxyketone
7d
G
Ph
b
(Scheme 10). However, the desired cycloheptenone 3r was isolated as
a minor product along with the non-conjugated enone 42 in 76% yield
as a single olefin isomer. The prevalence of non-conjugated enone 42
again emphasizes the unusual reactivity of these seven-membered
ring systems. To revise our approach, we extensively screened mild
acidic work-up conditions to minimize the formation of side products
such as isomer 42. We ultimately discovered that a sodium phosphate
buffer quench followed by treatment of the crude enol ether38 with
dilute HCl in acetonitrile exclusively afforded desired cycloheptenone
3r (Scheme 10). Gratifyingly, a number of sp3-hybridized carbon nu-
cleophiles can be employed under these conditions, permitting the
preparation of allyl,39 homoallyl, and pentenyl substituted cyclo-
heptenones (Table 5, entries 1e6, method F).
8
eMgBr
eMgBr
H
H
3y
3z
97
66
9e
10
eLi
G
G
3aa
3ab
72
84
O
11
eMgCl
S
a
Conditions: vinylogous ester 7a (1.0 equiv), CeCl3 (2.5 equiv), RMgX or RLi
(3.0 equiv) in THF, 23 ꢀC then work-up by method F, G, or H.
We then turned our attention to sp and sp2-hybridized carbon
nucleophiles as part of our goal to prepare variably substituted
cycloheptenones. Attempts to apply the buffer and dilute acid
quenching parameters provided poor selectivity and often led to
complex mixtures of products. A thorough evaluation of work-up
b
Method F: (a) pH 6.5 Na3PO4 buffer (b) 6 mM HCl, CH3CN; method G: 10% w/w
aqueous HCl, 60 ꢀC; method H: 2 M H2SO4, 60 ꢀC.
c
Yield of isolated product.
Performed without CeCl3 additive.
Product was a 1.9:1 mixture of atropisomers.
d
e
conditions revealed that the desired unsaturated
b-substituted
(A) Buffer and Dilute Acid Parameters: sp3 carbon nucleophiles
cycloheptenones could be obtained by quenching the reactions
with concentrated strong acid followed by stirring at elevated
temperatures. Although investigated for sp3-hybridized carbon
nucleophiles, the strong acid work-up conditions are more suitable
for these reactions because the only possible elimination pathway
leads to conjugated enone 3. In this manner, the initial mixture of
R
O
CeCl3, RMgX or RLi
THF, 23 °C
then Na3PO4 buffer (pH 6.5)
then aq HCl (6 mM), CH3CN
O
i-BuO
7a
3
R = alkyl
enone and
b-hydroxyketone could be funneled to the desired
product (Scheme 11, paths b and c). By employing a HCl (method G)
or H2SO4 quench (method H), the synthesis of vinyl,40 alkynyl,41
aryl, and heteroaryl substituted enones was achieved in moderate
to excellent yield (Table 5, entries 7e11). Particularly noteworthy
was entry 9, where addition of an ortho-substituted Grignard re-
agent produced sterically congested cycloheptenone 3z.42
(B) Strong Acid Conditions: sp and sp2 carbon nucleophiles
O
R
CeCl3, RMgX or RLi
THF, 23 °C
then HCl or H2SO4
i-BuO
O
23 60 °C
7a
3
R = alkenyl, alkynyl, aryl
These results demonstrate that application of the appropriate
quenching parameters based on the type of carbon nucleophile
Scheme 12. Different work-up conditions for carbonyl transposition reactions em-
ploying sp3 versus sp/sp2 carbon nucleophiles.
employed is required for successful carbonyl transposition to
b-
substituted
g
-quaternary cycloheptenones (Scheme 12). For sp3-
2.6. Synthesis of cycloheptenone derivatives using transition-
metal catalyzed cyclizations
hybridized carbon nucleophiles, reaction work-up with buffer and
dilute acid maximizes enone yield and minimizes formation of
non-conjugated enone isomers. In contrast, reactions using sp and
sp2-hybridized carbon nucleophiles require strong acidic work-up
with heating for best results. Careful application of these general
Having produced a variety of cycloheptenones, we next turned
our attention to the preparation of a series of bi- and tricyclic
structures that would be valuable for total synthesis applications.
protocols provides access to diverse
cycloheptenones.
b-substituted g-quaternary
The incorporation of alkene functionality at the b-position allowed

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10243
rapid access to a series of [7en] fused ring systems through ring
closing metathesis with the -allyl fragment (Table 6). This trans-
formation enables the formation of disubstituted bicycles (43x, 43s,
43u, and 43w) from terminal alkenes in excellent yields (entries 1,
3, 5, and 8). Trisubstituted bicycles (43y, 43t, and 43v) are also
accessible through enyne ring-forming metathesis (entry 2) and
With two [7e6] bicyclic structures in hand, we next investigated
the preparation of other such bicycles with variable olefin posi-
tions. Addition of 3-butenylmagnesium bromide to trans-propenyl
vinylogous ester 7p followed by ring closing metathesis furnished
bicycle 44 with the alkene adjacent to the quaternary stereocenter
(Scheme 13A). Following the precedent of Fuchs,43 we envisioned
accessing bicycle 46 through a base-mediated migration from
enone 43s. However, treatment of skipped diene 43s with an amine
base at ambient temperature unexpectedly afforded diene 45 in-
stead (Scheme 13B). In the end, the alkene could be migrated in the
desired direction to generate diene 46 by running the reaction in
the presence of microwave irradiation. Overall, these methods al-
low for the preparation of [7e6] bicycles with variable olefin
substitution.
g
ring closing metathesis with 1,1-disubstituted alkene
b-sub-
stituents (entries 4 and 6). Additionally, both atropisomers of
cycloheptenone 3z converge to the [7e7e6] tricyclic enone (43z)
under the reaction conditions (entry 7).
Table 6
Formation of bi- and tricyclic systems through ring closing metathesisa
N
N
Cl
Ru
MgBr
A
R2
1. CeCl3, THF, 23 °C
Cl
then Na3PO4 buffer (pH 6.5)
O
O
33b
then HCl (6 mM), CH3CN
R1
n
2. Grubbs-Hoveyda
Grubbs Hoveyda
i-BuO
2nd generation (5 mol %)
PhH, 50 °C
O
2nd generation (5 mol %)
7p
44
O
O
PhH, 50 °C
70% yield, 2 steps
3
43
n = 0
3
B
Entry Substrate
R1
Product
Yieldb
conditions
3
43
(%)
+
O
O
O
45
43s
DBU, CH3CN, 23 °C
46
1c
3x
43x
R2¼H
93
Ph
R2
not observed
59% yield
73% yield
DBU, CH3CN, 180 °C, μwaves 16% yield
C
O
O
O
2
3y
3s
43y
43s
R2¼
99
91
Co2(CO)8
THF, 23 °C
H
H
+
then DMSO, 60 °C
3d
R2¼H
O
90% yield
R2
O
O
3y
47a
47b
3 : 1 d.r.
Scheme 13. Synthesis of additional [7e6] bicycles and [7e5e5] tricycles.
O
4d
5
3t
43t
R2¼Me
R2¼H
90
90
Recognition of the proximal enyne functionality of cyclo-
heptenone 3y prompted an investigation of a PausoneKhand
reaction to form more complex ring systems. Treatment of enone
3y with dicobalt octacarbonyl in the presence of dimethylsulf-
oxide44 generated the [7e5e5] tricycle in a 3:1 diastereomeric
ratio of 47a to 47b (Scheme 13C). Overall, our organometallic
addition and elimination strategy combined with the appropri-
ate work-up conditions facilitated the preparation of numerous
bi- and tricyclic systems with a wide array of substitution pat-
terns that may prove useful in the context of natural product
synthesis.
3u
43u
R2
O
6
3v
3z
43v
43z
R2¼Me
98
96
7e
O
2.7. Unified strategy for the synthesis of complex polycyclic
natural products
8
3w
43w
99
Our divergent approaches to the synthesis of acylcyclo-
pentenes 1 and cycloheptenones 3 from enantioenriched vinyl-
ogous esters 7 have provided the foundation for the preparation of
complex polycyclic molecules based on cyclopentanoid and
cycloheptanoid core structures (Fig. 4). Both [5e6] and [5e6e7]
fused polycyclic structures could be obtained from acylcyclo-
pentenes. Synthetic elaboration of cycloheptenones provided ac-
cess to [7e5], [7e6], [7e7], [7e8], [7e7e6], and [7e5e5] fused
structures. Additionally, [5e5], [5e6], and [7e6] spirocyclic
O
a
Conditions: cycloheptenone 3 (1.0 equiv) and GrubbseHoveyda second gener-
ation catalyst (33b, 5.0 mol %) in PhH, 50 ꢀC.
b
Yield of isolated product.
c
Conditions: cycloheptenone 3 (1.0 equiv) and Grubbs second generation catalyst
(0.2 mol %) in CH2Cl2, reflux.
d
1,4-Benzoquinone (10 mol %) added.
e
Performed in PhCH3.

10244
A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
Fig. 4. Representative fused and spirocyclic structures accessible by Pd-catalyzed asymmetric alkylation and successful application to natural product synthesis.
structures could be obtained using our synthetic approaches.
These examples significantly add to the collection of polycyclic
architectures accessible by elaboration of chiral six-membered
ring carbocycles or heterocycles 2. We have applied previously
developed methodology toward a number of polycyclic cyclo-
hexanoid natural products (Fig. 4) and similarly plan to exploit the
ring contraction and ketone transposition methodology in future
efforts toward cyclopentanoid and cycloheptanoid natural prod-
ucts.5 The work presented in this report will provide the foun-
dation for future efforts and enable a broader synthetic approach
to synthetic targets.
3. Conclusion
We have successfully developed general, enantioselective syn-
thetic routes toward
ternary cycloheptenones. The key stereoselective component
unifying this chemistry is the Pd-catalyzed asymmetric alkylation
of seven-membered vinylogous ester substrates to form a-quater-
nary vinylogous esters, for which we have demonstrated a broad
substrate scope with a variety of all-carbon and heteroatom-
containing functionality. These enantioenriched products were
transformed in a divergent manner to either facilitate a two-carbon
g-quaternary acylcyclopentenes and g-qua-

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10245
ring contraction to acylcyclopentenes or a carbonyl transposition to
Pd2(pmdba)3 (5.0 mg, 4.5
(4.4 mg, 11
m
mol, 2.5 mol %) and (S)-t-Bu-PHOX
cycloheptenones. Further synthetic elaboration of these products
has enabled access to five- and seven-membered ring systems that
are poised for further functionalization to bi- and tricyclic ring
systems. Overall, the described strategies provide broader access to
polycyclic ring systems and thus complement our previous work
with six-membered ring building blocks. Efforts to expand the
scope of these reactions, understand the key reaction mechanisms,
and apply the chiral products to the total synthesis of natural
products are the subject of future studies.
m
mol, 6.25 mol %) were placed in a 1 dram vial. The flask
was evacuated/backfilled with N2 (3 cycles, 10 min evacuation per
cycle). Toluene (1.3 mL, sparged with N2 for 1 h immediately before
use) was added and the black suspensionwas immersed in an oil bath
preheated to 30 ꢀC. After 30 min of stirring,
b-ketoester 6a (50.7 mg,
0.181 mmol, 1.00 equiv) was added as a solution in toluene (0.5 mL,
sparged with N2 immediately before use) using positive pressure
cannulation. The dark orange catalyst solution turned olive green
immediately upon addition of b-ketoester 6a. The reaction was stir-
red at 30 ꢀC for 21 h, allowed to cool to ambient temperature, filtered
through a silica gel plug (2ꢄ2 cm, Et2O), and concentrated under
reduced pressure. The crude oil was purified by preparative TLC (SiO2,
4:1 hexanes/EtOAc) to afford vinylogous ester 7a (38.8 mg,
0.164 mmol, 91% yield, 88% ee) as a pale yellow oil; Rf¼0.31 (3:1
4. Experimental
4.1. General
hexanes/Et2O); 1H NMR (500 MHz, CDCl3)
d
5.72 (dddd, J¼16.6, 10.5,
Unless otherwise stated, reactions were performed in flame-
dried glassware under an argon or nitrogen atmosphere using
dry, deoxygenated solvents. Reaction progress was monitored by
thin-layer chromatography (TLC). TLC was performed using E.
Merck silica gel 60 F254 precoated glass plates (0.25 mm) and vi-
sualized by UV fluorescence quenching, p-anisaldehyde, or KMnO4
staining. SiliaFlash P60 Academic Silica gel (particle size
7.3, 7.3 Hz,1H), 5.31 (s,1H), 5.05e5.00 (m, 2H), 3.50 (dd, J¼9.3, 6.6 Hz,
1H), 3.47 (dd, J¼9.3, 6.6 Hz, 1H), 2.53e2.42 (m, 2H), 2.38 (dd, J¼13.7,
7.1 Hz,1H), 2.20 (dd, J¼13.7, 7.8 Hz,1H), 1.98 (app sept, J¼6.6 Hz, 1H),
1.86e1.70 (m, 3H), 1.62e1.56 (m, 1H), 1.14 (s, 3H), 0.95 (d, J¼6.6 Hz,
6H); 13C NMR (125 MHz, CDCl3)
d 206.7,171.3,134.6,117.9,105.0, 74.5,
51.5, 45.4, 36.1, 35.2, 28.0, 25.2, 19.9, 19.3, 19.3; IR (neat film NaCl)
2960, 2933, 2873, 1614, 1470, 1387, 1192, 1171, 998, 912 cmꢂ1; HRMS
0.040e0.063 mm)
or
ICN
silica
gel
(particle
size
0.032e0.0653 mm) was used for flash column chromatography. 1H
NMR spectra were recorded on a Varian Mercury 300 MHz, a Var-
ian 400 MR 400 MHz, or a Varian Inova 500 MHz spectrometer and
(EIþ) m/z calcd for C15H24O2 [M]þꢅ: 236.1776; found 236.1767; ½a D25:6
ꢃ
ꢂ69.04 (c 1.08, CHCl3, 88.0% ee); HPLC conditions: 1% IPA in hexanes,
1.0 mL/min, OD-H column, tR (min): major¼6.30, minor¼7.26.
are reported relative to residual CHCl3 (d
7.26 ppm). 13C NMR
spectra are recorded on a Varian Mercury 300 MHz, a Varian
400 MR 400 MHz, or a Varian Inova 500 MHz spectrometer (at
75 MHz, 100 MHz, and 125 MHz, respectively) and are reported
4.3. Procedures for the ring contraction of vinylogous esters 7
4.3.1. General method A: lithium aluminum hydride reduction/10%
aqueous HCl hydrolysis.
relative to CDCl3 (d
77.16 ppm). 19F spectra were recorded on
a Varian Mercury 300 MHz or a Varian Inova 500 MHz spectrom-
eter (at 282 MHz and 470 MHz, respectively) and are reported
without the use of a reference peak. IR spectra were obtained using
a PerkineElmer Paragon 1000 or PerkineElmer Spectrum BXII
spectrometer using thin films deposited on NaCl plates and re-
ported in frequency of absorption (cmꢂ1). Optical rotations were
measured with a Jasco P-1010 or Jasco P-2000 polarimeter oper-
ating on the sodium D-line (589 nm) using a 100 mm path-length
O
HO
LiAlH4, Et2O, 0 °C
then 10% aq HCl
+
i-BuO
O
O
7a
10a
3a
6% yield
87% yield
cell and are reported as: ½a DT
ꢃ
(concentration in g/100 mL, solvent,
ee). Analytical chiral HPLC was performed with an Agilent 1100
A 500 mL round-bottom flask with magnetic stir bar was
charged with Et2O (150 mL) and cooled to 0 ꢀC in an ice/water
bath. LiAlH4 (806 mg, 21.2 mmol, 0.55 equiv) was added in one
portion. After 10 min, a solution of vinylogous ester 7a (9.13 g,
38.6 mmol, 1.00 equiv) in Et2O (43 mL) was added dropwise using
positive pressure cannulation. The gray suspension was stirred for
40 min and additional LiAlH4 (148 mg, 3.9 mmol, 0.10 equiv) was
added in one portion. After an additional 30 min of stirring at
0 ꢀC, the reaction was quenched by slow addition of aqueous HCl
(110 mL, 10% w/w). The resulting biphasic system was allowed to
warm to ambient temperature and stirred vigorously for 8.5 h.
The phases were separated and the aqueous phase was extracted
with Et2O (3ꢄ100 mL). The combined organic phases were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was azeotroped with toluene (3ꢄ20 mL) and
purified using flash column chromatography (SiO2, 5ꢄ15 cm,
Series HPLC utilizing
a
Chiralcel AD or OD-H column
(4.6 mmꢄ25 cm) obtained from Daicel Chemical Industries Ltd.
with visualization at 254 nm. Analytical chiral SFC was performed
with a Mettler Toledo SFC supercritical CO2 analytical chromatog-
raphy system with a Chiralcel AD-H column (4.6 mmꢄ25 cm) with
visualization at 254 nm/210 nm. Analytical chiral GC was per-
formed with an Agilent 6850 GC utilizing a GTA (30 mꢄ0.25 mm)
column (1.0 mL/min carrier gas flow). High-resolution mass spec-
tra (HRMS) were obtained from the Caltech Mass Spectral Facility
(EIþ or FABþ) or on an Agilent 6200 Series TOF with an Agilent
G1978A Multimode source in electrospray ionization (ESIþ), at-
mospheric pressure chemical ionization (APCIþ), or mixed ioniza-
tion mode (MM: ESIeAPCIþ).
9:1/3:1 hexanes/EtOAc, dry-loaded using Celite) to afford
b-
4.2. Procedures for the synthesis of enantioenriched
vinylogous esters 7 using enantioselective decarboxylative
alkylation reactions
hydroxyketone 10a (6.09 g, 33.41 mmol, 87% yield, 1.3:1 dr) as
a colorless semi-solid and cycloheptenone 3a (387 mg, 6% yield)
as a colorless oil.
4.2.1. Vinylogous ester 7a.
4.3.1.1. Cycloheptenone 3a.
O
O
O
Pd2(pmdba)3 (2.5 mol %)
(S)-t-Bu-PHOX (6.25 mol %)
O
i-BuO
i-BuO
PhCH3, 30 °C
O
6a
7a
91% yield, 88% ee
3a

10246
A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
Rf¼0.54 (7:3 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3)
d 6.04
117.8, 50.0, 45.3, 36.0, 29.7, 26.8, 25.6; IR (neat film NaCl) 3077,
2956, 2863, 1668, 1635, 1616, 1454, 1435, 1372, 1366, 1309, 1265,
(dd, J¼12.9, 0.7 Hz, 1H), 5.82 (d, J¼12.9 Hz, 1H), 5.75 (dddd, J¼17.1,
10.3, 7.8, 7.1 Hz, 1H), 5.10 (dddd, J¼10.3, 1.2, 1.2, 1.2 Hz, 1H),
5.08e5.03 (m, 1H), 2.65e2.52 (m, 2H), 2.19 (app dd, J¼13.7, 6.8 Hz,
1H), 2.11 (app dd, J¼13.7, 8.1 Hz, 1H), 1.84e1.76 (m, 3H), 1.68e1.63
1213, 1177, 993, 914, 862 cmꢂ1; HRMS (EIþ) m/z calcd for C11H17
O
[MþH]þꢅ: 165.1279; found 165.1281; ½a 2D1:4
þ17.30 (c 0.955,
ꢃ
CHCl3, 88.0% ee); GC conditions: 80 ꢀC isothermal, GTA column, tR
(min): major¼54.7, minor¼60.2.
(m, 1H), 1.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 204.7, 152.5, 133.8,
128.6. 118.6, 47.2, 45.1, 42.7, 38.2, 27.1, 18.4; IR (neat film NaCl) 3076,
3011, 2962, 2934, 2870, 1659, 1454, 1402, 1373, 1349, 1335, 1278,
1208, 1172, 997, 916, 874, 822, 772 cmꢂ1; HRMS (EIþ) m/z calcd for
4.4. Procedures for the carbonyl transposition of vinylogous
esters 7
C11H16O [M]þꢅ: 164.1201; found 164.1209; ½a 2D1:0
ꢂ9.55 (c 1.07,
ꢃ
CHCl3, 88.0% ee).
4.4.1. General method F: Grignard addition/Na3PO4 buffer quench/
dilute HCl work-up.
4.3.1.2.
b
-Hydroxyketone 10a.
HO
MgBr
1. CeCl3, THF, 23 °C
O
O
then Na3PO4 buffer
(pH 6.5)
10a
i-BuO
O
2. aq HCl (6 mM), CH3CN
Rf¼0.23 (7:3 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3)
d major
7a
3w
92% yield
epimer: 5.88 (dddd, J¼15.1, 9.0, 7.6, 7.6 Hz, 1H), 5.12e5.08 (m, 2H),
3.70 (dd, J¼4.9, 3.9 Hz, 1H), 2.86 (dd, J¼15.6, 1.7 Hz, 1H), 2.65 (dd,
J¼15.6, 7.3 Hz, 1H), 2.54e2.43 (m, 2H), 2.24 (dd, J¼13.7, 7.8 Hz,
1H), 2.07 (dd, J¼13.4, 7.3 Hz, 1H), 1.99 (dd, J¼15.9, 4.4 Hz, 1H),
1.82e1.69 (m, 2H), 1.45e1.41 (m, 1H), 0.96 (s, 3H); minor epimer:
5.83 (dddd, J¼14.9, 10.3, 7.6, 7.6 Hz, 1H), 5.12e5.06 (m, 2H), 3.68
(dd, J¼4.1, 2.4 Hz, 1H) 2.80 (dd, J¼15.4, 2.4 Hz, 1H), 2.74 (dd,
J¼15.4, 8.1 Hz 1H), 2.46e2.38 (m, 2H), 2.18 (dd, J¼13.9, 7.3 Hz,
1H), 2.09 (dd, J¼12.9, 7.8 Hz, 1H), 1.82e1.65 (m, 3H) 1.50e1.47 (m,
A 100 mL round-bottom flask equipped with a magnetic stir
bar was cycled into a glove box. The flask was loaded with
anhydrous cerium chloride (616.2 mg, 2.50 mmol, 2.50 equiv),
fitted with a septum, removed from the glove box, and con-
nected to an argon-filled Schlenk manifold. A portion of THF
(13 mL) was added, rinsing the cerium chloride to the bottom
of the flask. As the resulting thick white slurry was stirred,
a solution of pent-4-enylmagnesium bromide (8.6 mL, 0.35 M in
THF, 3.01 mmol, 3.01 equiv) was added and the mixture turned
gray. After 30 min of stirring, vinylogous ester 7a (236.3 mg,
1.00 mmol, 1.00 equiv) was cannula-transferred to the slurry
from a flame-dried 10 mL conical flask using several THF rinses
(3ꢄ4 mL; total THF added¼25 mL, 0.04 M). TLC analysis in-
dicated that no starting material remained after 5 min. After an
additional 10 min of stirring, the reaction was quenched with
pH 6.5 Na3PO4 buffer (20 mL). A thick gray emulsion formed.
The mixture was transferred to a separatory funnel where the
aqueous phase was extracted four times with Et2O. The com-
bined organics (150 mL) were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude oil was
transferred to a 20 mL scintillation vial and concentrated under
reduced pressure. A stir bar, CH3CN (2.0 mL), and aqueous HCl
(2.0 mL, 6 mM) were added to the vial. The resulting cloudy
solution was stirred vigorously for 30 min before being trans-
ferred to a separatory funnel where the aqueous phase was
extracted four times with Et2O. The combined organics (75 mL)
were dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude oil was purified by flash chroma-
tography (SiO2, 3ꢄ30 cm, 100% hexanes/1%/2%/5% EtOAc in
hexanes) to afford cycloheptenone 3w (214.2 mg, 0.92 mmol,
92% yield) as a clear colorless oil; Rf¼0.65 (30% EtOAc in hex-
1H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
d major epimer: 213.2,
135.0, 118.1, 72.9, 46.7, 44.9, 44.2, 41.0, 36.3, 21.9, 18.9; minor
epimer: 212.6, 134.2, 118.3, 73.3, 47.2, 42.8, 41.0, 35.9, 22.6, 18.7; IR
(neat film NaCl) 3436, 3074, 2932, 1692, 1638, 1443, 1403, 1380,
1352, 1318, 1246, 1168, 1106, 1069, 999, 913, 840 cmꢂ1; HRMS
(EIþ) m/z calcd for C11H18O2 [M]þꢅ: 182.1313; found 182.1307;
½
a 2D2:8
ꢃ
ꢂ57.10 (c 2.56, CHCl3, 88.0% ee).
4.3.2. General method E:
b
-hydroxyketone ring contraction.
O
HO
LiOH, TFE
THF, 60 °C
O
96% yield
1a
10a
Alcohol 10a (6.09 g, 33.4 mmol, 1.00 equiv) was dissolved in
THF (334 mL) in a 500 mL round-bottom flask. The solution was
treated with 2,2,2-trifluoroethanol (3.67 mL, 50.1 mmol,
1.50 equiv) and anhydrous LiOH (1.20 g, 50.1 mmol, 1.50 equiv).
The flask was fitted with a condenser, purged with N2, and
heated to 60 ꢀC using an oil bath. After 18 h of stirring, the sus-
pension was allowed to cool to ambient temperature, diluted
with Et2O (150 mL), dried over Na2SO4 (30 min of stirring), fil-
tered, and concentrated carefully under reduced pressure,
allowing for a film of ice to form on the outside of the flask. The
crude product was purified using flash column chromatography
(SiO2, 5ꢄ15 cm, 15:1 hexanes/Et2O) to afford acylcyclopentene 1a
(5.29 g, 32.2 mmol, 96% yield) as a colorless fragrant oil; Rf¼0.67
anes); 1H NMR (500 MHz, CDCl3)
d 5.88 (s, 1H), 5.79 (dddd,
J¼16.9, 10.2, 6.7, 6.7 Hz, 1H), 5.67e5.57 (m, 1H), 5.07e4.96 (m,
4H), 2.60e2.53 (m, 2H), 2.35 (dddd, J¼14.1, 6.7, 2.5, 1.2 Hz, 1H),
2.20e2.04 (m, 5H), 1.83e1.73 (m, 3H), 1.66e1.53 (m, 3H), 1.14 (s,
3H); 13C NMR (125 MHz, CDCl3)
d 205.3, 162.6, 138.2, 134.1,
128.8, 118.2, 115.3, 45.7, 45.2, 44.3, 38.7, 33.8, 33.5, 29.3, 25.7,
17.6; IR (neat film NaCl) 3076, 2975, 2937, 2870, 1652, 1611,
1456, 1415, 1380, 1343, 1257, 1218, 1179, 1110, 1071, 994,
913 cmꢂ1; HRMS (MM: ESIeAPCIþ) calcd for C16H25O [MþH]þ:
(8:2 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3)
d 6.45 (app t,
J¼1.7 Hz, 1H), 5.76 (dddd, J¼16.4, 10.7, 7.3, 7.3 Hz, 1H), 5.07e5.03
(m, 2H), 2.59e2.48 (m, 2H), 2.30 (s, 3H), 2.21e2.14 (m, 2H), 1.85
(ddd, J¼12.9, 8.3, 6.3 Hz, 1H), 1.64 (ddd, J¼12.9, 8.5, 6.1 Hz, 1H),
233.1900; found 233.1900;
88.0% ee).
½
a 2D5:0
ꢃ
ꢂ34.96 (c 1.46, CHCl3,
1.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 197.5, 151.9, 143.8, 134.9,

A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
10247
4.5. Procedures for synthesis of cycloheptenone derivatives
Supplementary data
43
Additional general information, procedures for the synthesis of
new compounds and ligands, procedures for general methods
AeI, and reaction screening protocols for asymmetric alkylation
and ring contraction; 1H NMR, 13C NMR, and IR spectra for com-
pounds L3, L4, 1n, 6l, 6n, 7l, 7n, 10n, 11r, 15, 17, 21, 22, 23, 24, 28,
42; HPLC traces for vinylogous esters 7l and 7n. Supplementary
data related to this article can be found online at doi:10.1016/
j.tet.2011.10.031.
4.5.1. General method I: ring closing metathesis.
N
N
Cl
Ru
Cl
O
33b
Grubbs Hoveyda
2nd Generation (5 mol %)
PhH, 50 °C
O
O
References and notes
3w
43w
99% yield
1. For a review discussing our strategy of using natural product structures to drive
the development of enantioselective catalysis, see: Mohr, J. T.; Krout, M. R.;
Stoltz, B. M. Nature 2008, 455, 323e332.
A 100 mL round-bottom flask equipped with a magnetic stir bar,
fitted with a water condenser, and connected to a Schlenk manifold
(through the condenser) was flame-dried three times, backfilling
with argon after each drying cycle. Once cool, the flask was loaded
with neat cycloheptenone 3w (50.0 mg, 0.22 mmol, 1.00 equiv) and
backfilled with argon twice. Benzene (1 h argon sparge before
use, 43 mL, 0.005 M) was added to the flask, followed by
GrubbseHoveyda second generation catalyst (6.7 mg, 0.011 mmol,
5 mol %). The solution color turned pale green with addition of
catalyst. The flask was lowered into a preheated oil bath (50 ꢀC).
The reaction was removed from the oil bath after 30 min, cooled to
room temperature (23 ꢀC), and quenched with ethyl vinyl ether
(1 mL). The reaction was filtered through a short silica gel plug
rinsing with Et2O and concentrated under reduced pressure. The
crude oil was purified twice by flash chromatography (SiO2, both
columns 2ꢄ28 cm, 100% hexanes/2%/5% EtOAc in hexanes) to
afford cycloheptenone 43w (43.5 mg, 0.21 mmol, 99% yield) as
a yellow oil; Rf¼0.56 (30% EtOAc in hexanes); 1H NMR (500 MHz,
2. For examples of asymmetric palladium-catalyzed reactions of cyclic ketone
enolates, see: (a) Ketone alkylation: Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc.
2004, 126, 15044e15045; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2005, 44, 6924e6927; (b) Behenna, D. C.; Mohr, J. T.;
ꢀ
Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak,
Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D. E.;
Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J., in
press, doi:10.1002/chem.201003383: (c) Enantioselective protonation: Mohr, J.
T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128,
11348e11349; Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett.
2008, 10, 1039e1042; (d) Conjugate addition/enolate alkylation cascade:
Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature Chem. 2010, 2, 192e196.
3. For examples of the asymmetric palladium-catalyzed alkylation of heterocyclic
ketone enolates, see: Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed.
2008, 47, 6873e6876.
4. For studies on the computational and experimental studies on the mechanism
of palladium-catalyzed asymmetric alkylation using the PHOX ligand scaffold,
see: (a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard,
J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876e11877; (b)
Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed.
2009, 48, 6840e6843.
5. For examples of the asymmetric alkylation of cyclic ketones and vinylogous
esters or thioesters in the context of natural product synthesis, see: (a)
McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738e7739; (b)
White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008,
130, 810e811; (c) Levine, S. R.; Krout, M. R.; Stoltz, B. M. Org. Lett. 2009, 11,
289e292; (d) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2009, 11,
293e295; (e) White, D. E.; Stewart, I. C.; Seashore-Ludlow, B. A.; Grubbs, R.
H.; Stoltz, B. M. Tetrahedron 2010, 66, 4668e4686; (f) Day, J. J.; McFadden, R.
M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed.
2011, 50, 6814e6818.
CDCl3)
d
5.77e5.70 (m, 1H), 5.65 (tdt, J¼10.4, 6.4, 1.3 Hz, 1H),
2.68e2.55 (m, 2H), 2.54e2.44 (m, 1H), 2.30e2.24 (m, 2H),
2.24e2.15 (m, 1H), 2.13e2.04 (m, 1H), 1.94e1.69 (m, 7H), 1.52e1.41
(m, 1H), 1.22 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 204.2, 165.6,
132.2,131.9,128.5, 49.0, 44.2, 39.8, 39.5, 35.5, 31.1, 27.0, 26.5,17.8; IR
(neat film NaCl) 3018, 2928, 2859, 1645, 1608, 1468, 1448, 1411,
1380, 1343, 1327, 1279, 1253, 1214, 1178, 1131, 1102, 1088, 1051, 1015,
987, 965, 937, 920, 899, 880, 845, 796, 777, 747 cmꢂ1; HRMS (MM:
ESIeAPCIþ) calcd for C14H21O [MþH]þ: 205.1587; found 205.1587;
6. For our initial communication on the addition of organometallic reagents to
chiral vinylogous esters to form g-quaternary cycloheptenones, see: Bennett, N.
B.; Hong, A. Y.; Harned, A. M.; Stoltz, B. M. Org. Biomol. Chem., in press, doi:10.
1039/C1OB06189E.
7. For our initial communication on the palladium catalyzed asymmetric alkyl-
½
a 2D5:0
ꢃ
ꢂ141.99 (c 1.01, CHCl3, 88% ee).
ation and ring contraction studies in the synthesis of g-quaternary acylcyclo-
pentenes, see: Hong, A. Y.; Krout, M. R.; Jensen, T.; Bennett, N. B.; Harned, A. M.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 2756e2760.
Acknowledgements
This publication is based on work supported by Award No. KUS-
11-006-02, made by King Abdullah University of Science and
Technology (KAUST). The authors wish to thank NIHeNIGMS
(R01M080269-01), Amgen, Abbott, Boehringer Ingelheim, and
Caltech for financial support. A.Y.H. thanks Roche for an Excellence
in Chemistry Award and Abbott for an Abbott Scholars Symposium
Award. M.R.K. acknowledges Eli Lilly for a predoctoral fellowship.
T.J. thanks the Danish Council for Independent Research/Natural
Sciences for a postdoctoral fellowship. Materia, Inc. is gratefully
acknowledged for the donation of metathesis catalysts. Lawrence
Henling and Dr. Michael Day are acknowledged for X-ray crystal-
lographic structure determination. The Bruker KAPPA APEXII X-ray
diffractometer used in this study was purchased via an NSF
CRIF:MU award to Caltech (CHE-0639094). Prof. Sarah Reisman, Dr.
Scott Virgil, Dr. Christopher Henry, and Dr. Nathaniel Sherden
contributed with helpful discussions. Dr. David VanderVelde and
Dr. Scott Ross are acknowledged for NMR assistance. The Varian
400 MR instrument used in this study was purchased via an NIH
award to Caltech (NIH RR027690). Dr. Mona Shahgholi and Naseem
Torian are acknowledged for high-resolution mass spectrometry
assistance.
8. Concurrent with our efforts, palladium-catalyzed asymmetric allylic alkylations
to form enantioenriched
a-quaternary cyclic ketones and vinylogous esters/
thioesters were reported by Trost. See: (a) Trost, B. M.; Pissot-Soldermann, C.;
Chen, I.; Schroeder, G. M. J. Am. Chem. Soc. 2004, 126, 4480e4481; (b) Trost, B.
M.; Schroeder, G. M. Chem.dEur. J. 2005, 11, 174e184; (c) Trost, B. M.; Pissot-
Soldermann, C.; Chen, I. Chem.dEur. J. 2005, 11, 951e959; (d) Trost, B. M.; Xu, J.
J. Am. Chem. Soc. 2005, 127, 2846e2847; (e) Trost, B. M.; Bream, R. N.; Xu, J.
Angew. Chem., Int. Ed. 2006, 45, 3109e3112.
9. 1,3-Cycloheptanedione (catalog #515981) and 3-isobutoxy-2-cyclohepten-1-
one (catalog #T271322) are commercially available from SigmaeAldrich. The
price of 1,3-cycloheptanedione is $40,000/mol. Adopted from Aldrich August
28th, 2011.
10. (a) Ragan, J. A.; Makowski, T. W.; am Ende, D. J.; Clifford, P. J.; Young, G. R.;
Conrad, A. K.; Eisenbeis, S. A. Org. Process Res. Dev. 1998, 2, 379e381; (b) Ragan,
J. A.; Murry, J. A.; Castaldi, M. J.; Conrad, A. K.; Jones, B. P.; Li, B.; Makowski, T.
W.; McDermott, R.; Sitter, B. J.; White, T. D.; Young, G. R. Org. Process Res. Dev.
2001, 5, 498e507; (c) Do, N.; McDermott, R. E.; Ragan, J. A. Org. Synth. 2008, 85,
138e146.
11. (a) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9,
2529e2531; (b) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86,
181e193.
12. (a) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J. Organomet. Chem.
1974, 65, 253e266; (b) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Org. Lett. 2004, 6,
4435e4438.
13. Pd2(pmdba)3 is preferable to Pd2(dba)3 in this reaction for ease of separation of
pmdba from the reaction products during purification. pmdba¼4,40-
Methoxydibenzylideneacetone.

10248
A.Y. Hong et al. / Tetrahedron 67 (2011) 10234e10248
14. Racemic products were obtained using Pd(PPh3)4 (5 mol %) or achiral PHOX
28. Fluorinated lithium alkoxides were recently used to promote Hor-
nereWadswortheEmmons olefinations of sensitive substrates, demonstrating
their mild reactivity: Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281e4283.
29. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226e2227.
ligand L4 (6.25 mol %) and Pd2(pmdba)3 (2.5 mol %) in toluene at 30 ꢀC.
30. Although we had success in preparing silyloxy acylcyclopentene 1p
from vinylogous ester 7p, we wondered whether it would be possible to
perform a ring contraction on aldehyde 7k. Under our standard condi-
tions, the intermediate ketodiol 10k can be obtained in 89% yield,
however the subsequent ring contraction proceeded in 62% yield to
O
Ph2P
N
L4
afford
a complex mixture of pyran diastereomers iii and uncyclized
acylcyclopentene 1k.
15. For a preparation of electron-deficient PHOX ligand L2 ((S)-p-(CF3)3-t-Bu-
PHOX), see: (a) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B.
M. Tetrahedron Lett. 2010, 51, 5550e5554.
H
O
OH
O
O
O
OH
16. The reaction with silyl-protected alcohol 6m afforded alkylation product 7m
and exocyclic enone i in 10% yield. A related silyl-protected alcohol substrate
did not display this type of elimination during an asymmetric de-
LiAlH , Et O, 0 °C
then 10% aq HCl
89% yield
LiOH, TFE
THF, 60 °C
O
i-BuO
O
carboxylative alkylation reaction on a six-membered ring
strate. See Ref. 2a.
b-ketoester sub-
62% yield
OH
7k
10k
iii
1:1 dr
1k
(5:1 mixture)
OTBDPS
OTBDPS
O
O
O
31. Analytically pure samples of dione 17 can be obtained from vinylogous ester 7a
by treatment with acid. See Supplementary data for details.
(S)-t-BuPHOX (6.25 mol %)
O
Pd (pmdba) (2.5 mol %)
32. The addition of cerium chloride to reactions with organolithium or Grignard
reagents has been shown to increase reactivity and reduce side reactions with
vinylogous ester systems, see: Crimmins, M. T.; Dedopoulou, D. Synth. Commun.
1992, 22, 1953e1958.
O
PhMe, 30 °C
i-BuO
i-BuO
i-BuO
6m
7m
i
66% yield
58% ee
10% yield
33. The increase in enone formation with the organometallic addition is likely due
to the higher stability of the tertiary carbocation (iv) compared to the sec-
ondary carbocation (v) formed along the reduction pathway.
17. The reaction with benzoate ester 6n afforded alkylation product 7n and en-
docyclic enone ii in 14% yield.
R
H
O
Ph
Ph
O
O
O
O
O
O
O
(S)-t-BuPHOX (6.25 mol %)
VS.
Pd (pmdba) (2.5 mol %)
i-BuO
i-BuO
O
v
iv
PhMe, 30 °C
i-BuO
i-BuO
i-BuO
3° carbocation
2° carbocation
6n
7n
ii
75% yield
57% ee
14% yield
34. Crystallographic data have been deposited at the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK and copies can be obtained on request, free of
charge, by quoting the publication citation and the deposition number
686849.
35. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299e6302.
36. Herrmann, W. A.; Brossmer, K. O.; Reisinger, C.-P.; Priermeier, T.; Beller, M.;
Fischer, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1845e1848.
18. Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775e1776.
19. Differences in ring conformational preferences can also be observed in the 1H
NMR spectra of 1,3-cyclohexadione (exclusively ketoenol form) and 1,3-
cycloheptadione (exclusively diketo form). See Ref. 10c.
20. For selected examples of the two-carbon ring contraction of seven-membered
carbocycles, see: (a) Frankel, J. J.; Julia, S.; Richard-Neuville, C. Bull. Soc. Chim. Fr.
1968, 4870e4875; (b) Jun, C.-H.; Moon, C. W.; Lim, S.-G.; Lee, H. Org. Lett. 2002,
4, 1595e1597.
37. Preferential
b-hydroxyketone formation is observed when the acidification of
the intermediate isobutyl enol ether is performed in diethyl ether instead of
methanol. See Table 4.
38. Attempts to purify the crude enol ether were challenging due to decomposition
21. Notably, 10a and related b-hydroxyketones 10aek, 10meq appear to undergo
minimal decomposition after several months of storage at room temperature
by TLC and 1H NMR analysis and immediate conversion to acylcyclopentenes 1a
is not necessary to achieve high yields.
to enone 3r and b-hydroxyketone 10r.
39. The yield of cycloheptenone 3s is lower than many related enones due to the
formation of several side products presumed to be non-conjugated alkene
isomers.
22. While a recent report shows a single example of a similar b-hydroxyketone, we
believe the unusual reactivity and synthetic potential of these compounds has not
been fully explored: Rinderhagen, H.; Mattay, J. Chem.dEur. J. 2004, 10, 851e874.
23. For an example of a photochemical two-carbon ring contraction of a macro-
cycle, see: Yang, Z.; Li, Y.; Pattenden, G. Tetrahedron 2010, 66, 6546e6549.
24. For examples of ring contractions of medium-sized ring heterocycles, see: (a)
Nasveschuk, C. G.; Rovis, T. Angew. Chem., Int. Ed. 2005, 44, 3264e3267; (b)
Nasveschuk, C. G.; Rovis, T. J. Org. Chem. 2008, 73, 612e617; (c) Nasveschuk, C.
G.; Rovis, T. Org. Biomol. Chem. 2008, 6, 240e254; (d) Baktharaman, S.; Afagh,
N.; Vandersteen, A.; Yudin, A. K. Org. Lett. 2010, 12, 240e243; (e) Dubovyk, I.;
Pichugin, D.; Yudin, A. K. Angew. Chem., Int. Ed. 2011, 50, 5924e5926; (f)
Volchkov, I.; Park, S.; Lee, D. Org. Lett. 2011, 13, 3530e3533; (g) Dubinina, G. G.;
Chain, W. J. Tetrahedron Lett. 2011, 52, 939e942.
40. Synthesis of the simple b-vinyl substituted enone proved challenging due to
the formation of a complex product mixture.
41. Quenching the alkynyl nucleophile addition with hydrochloric acid provided
a complex mixture of products, most notably one with an equivalent of HCl
added into the molecule. This issue was resolved by instead using sulfuric
acid.
42. Cycloheptenone 3aa is formed as a 1.9:1 mixture of atropisomers whose iso-
meric peaks coalesce in a variable temperature 1H NMR study. See Ref. 6 for
variable temperature 1H NMR experiment.
25. For a discussion of the properties of fluorinated alcohols and their use, see:
Begue, J.-P.; Bonnet-Delphon, D.; Crousse, B. Synlett 2004, 18e29.
26. A lithium alkoxide species is presumably generated in situ based on the fol-
lowing pKa values: (H2O¼15.7, TFE¼12.5, HFIP¼9.3 [water]; H2O¼31.2,
TFE¼23.5, HFIP¼18.2 [DMSO]); Bordwell, F. G. Acc. Chem. Res. 1988, 21,
456e463.
27. No reaction was observed with the following bases (with or without TFE ad-
ditive): DBU, TMG, Na2CO3, BaCO3, and CaH2. DBU¼1,8-diazabicyclo[5.4.0]un-
dec-7-ene, TMG¼1,1,3,3-tetramethylguanidine.
43. Jin, Z.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 5995e5996.
44. Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L. Organometallics
1993, 12, 220e223.