Conception and evolution of stereocontrolled strategies toward functionalized 8-aryloctanoic acids related to the total synthesis of aliskiren

Article abstract of DOI:10.1021/jo5015195

A detailed account is given describing the approaches used toward the total synthesis of aliskiren. In particular, ring-closing metathesis with the Hoveyda-Grubbs catalyst accelerates the formation of a 9-membered lactone from an (R)-ester. The diastereom

Full text of DOI:10.1021/jo5015195

Article
pubs.acs.org/joc
Conception and Evolution of Stereocontrolled Strategies toward
Functionalized 8‑Aryloctanoic Acids Related to the Total Synthesis
of Aliskiren
Stephen Hanessian,* Etienne Chenard, Sebastien Guesne, and Jean-Philippe Cusson
́
́
́
́ ́ ́
Department of Chemistry, Universite de Montreal, CP6128 Succursale A, Centre-ville, Montreal, Quebec H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: A detailed account is given describing the
approaches used toward the total synthesis of aliskiren. In
particular, ring-closing metathesis with the Hoveyda−Grubbs
catalyst accelerates the formation of a 9-membered lactone
from an (R)-ester. The diastereomeric (S)-ester leads to the
formation of dimeric dilactones, which were characterized by
X-ray analysis and chemical conversions.
INTRODUCTION
■
The regulation of arterial blood pressure is a complex
physiological process with important implications in the
pathogenesis of cardiovascular diseases.1 Among these, hyper-
tension is considered to be a high risk factor and associated with
incidences of stroke and kidney failure. A natural substance
produced by the kidney, named renin, was known to have a
hypertensive effect in experimental animals as far back as 1898.2
Since then, pioneering efforts in cardiovascular medicine have
advanced the frontiers of antihypertensive research, culminating
with the availability of drugs to control the disease.3 The aspartyl
protease renin is part of the renin angiotensin system (RAS),
known to be a regulator of blood pressure and electrolyte
balance.4 Stimulation of the RAS leads to the release of renin
from the kidney, whereupon a series of proteolytic events take
place ultimately forming vasoconstricting peptides.5 Thus, renin
cleaves a Leu-Val peptide linkage in its endogenous sub-
strate angiotensinogen, releasing the decapeptide angiotensin I
(Figure 1A). A second enzyme in the RAS, angiotensin-converting
enzyme (ACE), then cleaves two amino acids from angiotensin I
to give the vasoconstricting octapeptide angiotensin II. On the
basis of these observations, the inhibition of renin as the first and
rate-limiting step in the RAS cycle was considered to be a viable
and attractive strategy in the quest toward discovery of novel
antihypertensives working by a unique mechanism.6 Indeed,
major advances toward this goal have been made during the past
three decades.7 Unfortunately, and in spite of achieving highly
effective in vivo inhibition of renin with beneficial antihyperten-
sive action, such activities had to be terminated in a number of
pharmaceutical companies primarily due to issues dealing with
cost of production and bioavailability. Nevertheless, the synthesis
of minimally peptidic potent inhibitors, such as CGP-38960
(Figure 1B), was admirably guided by structure-based design
relying on valuable information gleaned from cocrystal structures
Figure 1. (A) Scissile Leu-Val bond in angiotensinogen by the en-
zyme renin. (B) First-generation peptidic inhibitor. (C) Structure of
aliskiren.
with human recombinant renin.8 Although active investigations
toward the synthesis of new renin inhibitors had somewhat
waned, a new class of nonpeptidic 8-aryloctanoic acid amides was
Received: July 11, 2014
Published: October 6, 2014
© 2014 American Chemical Society
9531
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
Figure 2. Early prototypes of renin inhibitors: (A) L-mandelic acid as starting chiron; (B and C) L-pyroglutamic acid as starting chiron and source of
nitrogen (Dieckmann and phosphate extension routes).
found to have highly promising activity.9 Further refinement in
this series by scientists at Ciba-Geigy (Pharma) in Basel led to
aliskiren (1), which is presently marketed by Novartis for the
BACKGROUND
■
Among the many research collaborations with pharmaceutical
companies, none are more challenging than when an academic is
treatment of hypertension under the trade name Tekturna
(Figure 1C).10 The cocrystal structure analysis of aliskiren in
complex with renin revealed the characteristic interactions of the
hydroxyethylene segment with aspartic acid residue and unique
binding interactions of the hydrophobic moieties.11 Of particular
significance in optimizing the inhibitory activity was the
truncation of segments corresponding to the P2 and P4 site in
the original inhibitors such as CGP-38560 by directly linking
P1 and P3 (Figure 1). Compared to the previous generation of
renin inhibitors, often possessing heterocyclic appendages near
the hydroxyethylene subunit,10 aliskiren represents a structurally
simple ω-aryloctanoic acid amide harboring four stereogenic
carbon atoms (Figure 1). Further SAR studies also demonstrat-
ed an improvement of the affinity at the P2′ site when the
n-butylamide was exchanged for a 3-amino-2,2-dimethylpropio-
namide unit.12 Already, considerable interest has been generated
in the clinical aspects of aliskiren, a first-in-class, orally active
antihypertensive.13
asked to contribute to an active project with the prospects of
developing a viable synthesis of a molecule of interest.14
Encouraged by such an opportunity, we first explored a
stereocontrolled approach to a bioactive prototype of aliskiren,
starting with L-mandelic acid (Figure 2A).15 In the following
years, we were motivated to devise strategies avoiding the use of
azide as a source of the C-5 nitrogen atom (aliskiren numbering)
for safety considerations in an eventual scale-up operation.
Further consideration to our mandate was to avoid the use of
chiral auxiliaries to create stereogenic carbon atoms with
required substituents for cost and possibly IP reasons. Faced
with these restrictions, we devised two stereocontrolled
approaches to 2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoic
acids exemplified by 3, starting with the readily available
L-pyroglutamic acid as a chiron16 (Figure 2B and 2C). In addition
to providing the source of the nitrogen atom, the inher-
ent stereochemistry in the starting chiron served to control
the sequential stereocontrolled introduction of appropriate
functionality.
9532
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
Since our initial efforts toward the stereocontrolled synthesis
of aliskiren,15,16 there has been a plethora of reports particularly
in the patent literature17 describing a variety of approaches to
intermediates and analogues. In a brief overview, we shall
distinguish those involving approaches18 or formal syntheses19
from those pertaining to actual total syntheses20 of aliskiren.21 In
the majority of these syntheses, extensive use was made of the
Scheme 1. Shorter Route to an Advanced Intermediate in the
Speedel Process
Evans22 and Schollkopf23 chiral auxiliaries to secure the C-2/C-7
̈
isopropyl and C-4/C-5 amino alcohol groups, respectively, in
high enantio- or diastereoselectivity. Alternative approaches are
described in several patents.17,24 For example, the key building
blocks used in the Speedel process25 for the synthesis of aliskiren
are shown in Figure 3. Intermediate A was obtained by an
benzylic carbon (Scheme 1).27 A cross-metathesis reaction with
ester 5 led to the advanced Speedel intermediate 6 in five linear
steps and 38% overall yield from 4-methoxy-3-(methoxypropoxy)-
1-bromobenzene.
Nine-Membered Lactone Route toward Aliskiren. As is
clear from the preceding section, a major challenge in devising
synthetic approaches to aliskiren is the introduction of the C-2/
C-7 isopropyl groups and the C-4/C-5 amino alcohol subunit in
the 8-aryloctanoic acid framework with high stereocontrol
(Figure 1C). Added to this is the desire to devise a relatively
shorter route compared to existing reports, including those in the
patent literature. We recently reported an 11-step total synthesis
of aliskiren starting with a single chiral progenitor (Figure 4).28
Figure 3. Key building blocks in the Speedel process toward aliskiren.
asymmetric catalytic hydrogenation of an α,β-unsaturated
precursor in >95% ee starting from a racemic dialkoxyphenyl
propionate precursor (total of seven steps). The enantiopure
chlorovinyl intermediate B was prepared from the racemic
ester via pig liver esterase resolution in 47% yield, after
distillation. The undesired enantiomeric carboxylic acid was
recycled by epimerization, esterification, and repeated enzyme
treatment (total three steps to B from methyl isobutyrate in
one pass). Intermediate C was prepared from acid A in three
steps. Coupling of C and B was accomplished via the
corresponding Grignard reagent derived from B in the presence
of FeIII acetylacetonate to give D in 75% yield. Subsequent
steps involving hydrolysis to the acid, bromolactonization,
epoxide formation, lactonization, mesylation, and azide displace-
ment gave the azidolactone precursor E. Condensation with
3-amino-2,2-dimethylpropionamide, followed by hydrogenation
and crystallization, gave aliskiren fumarate (total of 10 steps
from D). Improvements in the bromolactonization step have also
been reported.24
In the past, chiral auxiliaries were used to access intermediates
such as C and D (Figure 3).18−20,22 In spite of this invaluable
method, all of the reported syntheses comprise numerous steps
to access the building blocks individually and prior to engaging
them in a stepwise assembly. Furthermore, except for some of the
patented processes, none of the published papers provide
experimental details leading to aliskiren.
Recently, we reported on an efficient synthesis of intermediate
4 adopting an extension of the Stoltz26 catalytic asymmetric
transposition of an allylic enolcarbonate derived from the
corresponding aryl ketone precursor followed by reduction at the
Figure 4. Nine-membered lactone route to aliskiren from a common
chiron.
Thus, (2S)-2-isopropyl-4-pentenal 8, easily prepared from the
acid 7,28 was converted to a 6:1 mixture of diastereomeric
benzylic alcohols H, which was used to assemble the ester G.
Ring-closing metathesis in the presence of the Grubbs I
catalyst29,30 gave the 9-membered lactone F (Figure 4). Regio-
and stereoselective introduction of an amino and an alcohol
group provided the entirely functionalized 8-aryloctanoic acid
framework of aliskiren and of selected amide variants. In this
paper, we elaborate on various aspects of this synthesis,
particularly with regard to the preparation and functionalization
of the 9-membered lactones using a ring-closing metathesis en
route toward aliskiren.
9533
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
Scheme 2. Synthesis of the 9-Membered Lactones
6:1 mixture of 17 and 18, the cyclization was completed within
19 h at 50 °C to give 21 in 72% yield (Table 1, entry 13). We were
at first intrigued by the observation that only the (R)-esters
15 and 17 were transformed to the corresponding lactones 19
and 21, respectively. At the time of execution, reports of the
formation of 9-membered functionalized lactones by ring-closing
metathesis were sparse.36,37
RESULTS AND DISCUSSION
■
Synthesis of the 9-Membered Lactone. Initially, we
focused on the 4-methoxy analogue (3, Figure 4) in order to
explore aspects of stereoselectivity and conditions for the ring-
closing metathesis. As will become evident, it was important to
attempt the ring-closing metathesis reaction with a higher
proportion of the (R)-ester derived from alcohol diastereomer
11 (Scheme 2).31
Functionalization of the 9-Membered Lactone. Our
next task was to explore methods for the regio- and stereo-
selective introduction of an amino alcohol unit on the double
bond of lactones 19 and 21. We surmised that in the presence of
Attempts to add various organometallic derivatives of 9 (X =
Br; M = Mg-n-Bu; TMEDA; Mg-n-Bu inverse addition; Mg-n-Bu,
CeCl3; Li, CeCl3; Et2ZnLi; Mg(n-Bu)2Li) to the aldehyde 8
resulted in modest to low yields and unsatisfactory ratios. After
extensive trials, the best ratio of inseparable diastereomers 11 and
12 favoring the (R)-lactone was obtained with a mixed Mg/Li
Grignard reagent described by Inoue32 in 68% yield. Application
of the same protocol to the aliskiren aryl moiety 10 led to a better
ratio of 13 and 14 (5−8:1) of diastereomers. Esterification by the
Yamaguchi method33 afforded the diastereomeric mixture of
esters 15:16 and 17:18, maintaining the same ratios, respectively.
In our original report, we had utilized the Grubbs first-generation
catalyst due to its availability at time. A 5 mol % loading in a
10 mM solution of the esters 15:16 or 17:18 in toluene led, after
78 h at room temperature, to the intended lactones 19 and 21, in
65% and 81% yield, respectively. In this process, the mixture of
esters was first stirred with Ti(O-i-Pr)4 for 24 h before adding the
catalyst. Then, to ensure complete conversion of the (R)-esters
15 and 17, an additional 5−10 mol % of the first genera-
tion Grubbs catalyst was added every 24 h. In the absence of
Ti(O-i-Pr)4, the low yield of the cyclization was attributed to the
coordination of the Ru catalyst to the proximal ester carbonyl
group.34 The results of the cyclization of different batches of
diastereomeric esters under different conditions and catalysts are
shown in Table 1. Starting with an ester mixture enriched in the
(R)-isomer, we obtained the (R)-lactone in 71% yield in the
presence of the first-generation Grubbs catalyst (G1) at room
temperature (Table 1, entry 9). Using a 4:1 mixture of esters
15 and 16 in the presence of the second-generation Hoveyda−
Grubbs catalyst (H−G2)35 at reflux resulted in the formation of
19 within 20 min in 64% yield (Table 1, entry 8). Ultimately,
utilizing the second-generation Hoveyda−Grubbs catalyst and a
38
NBS, CuI, and TsNH2 a bromonium ion (27) would be
attacked to give the corresponding vicinally substituted
9-membered lactone 23 (arbitrary regio- and stereochemistry,
Scheme 3). Instead, the products formed with a good conversion
were found to be the bromolactones 24 and 25 in a ratio of 3.9:1
arising from an intramolecular attack of the carboxylate released
by concomitant formation of quinonoid intermediates followed
by an anti attack of TsNH2 relative to the bulky isopropyl group.
The structures of 24 and 25 were assigned by detailed NMR
studies. The bromolactone structure (25) was also confirmed by
X-ray crystallography. Reductive cleavage of the benzylic
sulfonamide group in the mixture of 24 and 25 with Et3SiH
and trifluoroacetic acid gave the bromolactone 26 in a good
overall yield from 19.
Next, we converted the 9-membered lactone 19 into the
corresponding epoxide 28 (Scheme 4). The major product with
the designated stereochemistry as shown was formed in excellent
yield at 0 °C or room temperature. Surprisingly, treatment with
NaN3−NH4Cl in methoxyethanol or Bu4NN3 in refluxing
toluene gave back starting epoxide. Upon treatment with
Et3SiH and trifluoroacetic acid, it was expected that the benzylic
carbon oxygen bond would be cleaved. Instead, a mixture of the
three products 29, 30, and 31 (6:1:1 ratio) was obtained whose
structures are proposed on the basis of detailed NOE studies.31
plausible mechanism is shown in Scheme 4.
A
Dihydroxylation of 19 under standard conditions led to the
dihydroxy lactone 32 and the dibenzoate 33 after benzoylation,28
whose structures and stereochemistry was confirmed by X-ray
analysis,31 validating a trajectory of approach that would be opposed
9534
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
Table 1. Formation of the 9-Membered Lactones 19 and 21
a
entry
ester dr
R
cat.
G2
add.
time
temp (°C)
yield (%)
1
3:1
3:1
3:1
3:1
2:1
4:1
4:1
4:1
7:1
2:1
8:1
8:1
5:1
H
H
H
H
H
H
H
H
H
H
1 d
2 d
rt
0
43
57
58
49
65
67
64
71
44
65
2
G2
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
rt
3
G1
2 d
rt
4
G1
3 d
rt
5
G1
3 d
rt
6
G1
3 d
rt
7
G2
40 min
20 min
3 d
reflux
reflux
rt
8
H−G2
G1
9
Ti(O-i-Pr)4
b
10
11
12
13
H−G2
G1
20 h
reflux
rt
O(CH2)3OCH3
O(CH2)3OCH3
O(CH2)3OCH3
Ti(O-i-Pr)4
Ti(O-i-Pr)4
3 d
c
G1
3−4 d
16 h
rt
81
H−G2
50
72
a
b
c
Isolated yield. Conversion was completed within 20 h. An extra 5 mol % of the catalyst was added if no further progress was noticed by TLC. G1,
G2, and H−G2 refer to Grubbs first generation, Grubbs second generation, and Hoveyda−Grubbs 2nd generation catalyst.
Scheme 3. Attempted Bromoamination of the Macrocyclic Lactone 19
to the orientation of the resident C-8 4-methoxyphenyl group
(Scheme 5).28 Although this stereochemical outcome could not be
predicted a priori in a quasi C2-symmetrical 9-membered lactone
with respect to the orientation of the isopropyl groups at C-2 and C-
7 such as in 19, it became clear that C-8 aryl group may have exerted
a steric influence in the dihydroxylation step.
Encouraged by this result, we attempted a Du Bois
aziridination reaction,39 expecting to obtain the aziridine with
the “up” orientation. We would then attempt a solvolysis with an
appropriate carboxylic acid, hoping for a regioselective opening
at the C-4 position, thereby generating the vicinal trans-amino
alcohol (Scheme 6).
9535
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
Scheme 4. Epoxidation of the Lactone 19 and Further Transformations
Scheme 5. Diastereoselective Dihydroxylation of Lactone 1928
acidification and N-protection led to the known N-Boc lactone
41 (Scheme 6).16b,40
Completion of the Total Synthesis of Aliskiren. To test
the compatibility of the sulfamate group under amide forming
conditions from the lactone 37, we were pleased that treatment
with n-butylamine in the presence of AlMe3 gave an excellent
yield of the n-butylamine derivative 42 (Scheme 7). However, the
same conditions to form an amide failed with the sterically
demanding neopentylic 3-amino-2,2-dimethylpropionamide
(ADPA). The utility of 2-hydroxypyridine as an activator in
amide formation is well documented.41 In fact, this method is
claimed to work in high yield in a number of patents describing
aliskiren.25,42 In our hands, the methods described for the N-Boc
derivative corresponding to the lactone 37 resulted in low yields.
Prolonged heating of 37 with ADPA in neat Et3N at 85 °C led to
a 61% yield of the desired amide 43, with recovery of starting
lactone. We then decided to convert the N-sulfamoyl group in
43 into an N-Boc group to give 44 in good overall yield. There
remained to cleave the benzylic amine bond and the N-Boc group
to complete the total synthesis of aliskiren. Thus, treatment of
44 with Na in liquid ammonia in the presence of t-BuOH
followed by acid cleavage of the N-Boc group gave aliskiren (1).
Overall, our linear synthesis comprised 11 steps and a 7%
unoptimized yield starting from aldehyde 8.28 After completion
of this work, Foley and Jamieson described a conceptually
innovative method for an acid-promoted aminolysis of lac-
tones that has since been applied toward the synthesis of
aliskiren.43,44
In the event, treatment of 19 and 21 individually with
trichloroethylsulfamate in the presence of Rh2(tfacam)4 and
PhI(OAc)2 according to Du Bois39 led to the desired aziridines
34 and 35 in excellent yields (Scheme 6). Suspecting the need for
a strong acid to activate the N-(trichloroethyl)sulfamoyl group in
the solvolysis, aziridines 34 and 35 were treated with a dilute
solution of trifluoroacetic acid in CH2Cl2. Remarkably, in both
cases, a double-ring contraction occurred to give the pyrrolidine
lactones 36 and 37, respectively, in excellent yields (Scheme 6).28
It should be noted that this simple solvolytic reaction produced
the desired (4S,5S) amino alcohol with exquisite regio- and
stereocontrol. Confirmation of the structure and stereochemistry
of 36 (hence 37) was obtained from the X-ray crystal structure of
the amide 38. Treatment of 36 with AlMe3 and n-butylamine
gave the amide 38 which was converted to the N-Boc analogue
40, accompanied by the lactone 39, the structure of which
was ascertained by X-ray crystallography.31 Alternatively,
alkaline hydrolysis of the sulfamate group in 37 followed by
What about the (S)-Lactones 20 and 22? We previously
commented on the exquisite selectivity of the Grubbs metathesis
reaction with the first-generation catalyst. In fact, using an
9536
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
Scheme 6. Elaboration of 9-Membered Lactones via Aziridination and Ring Contraction
Scheme 7. Completion of the Synthesis of Aliskiren (1)
9537
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
inseparable mixture of the diastereomeric esters 15 and 16
(as well as 17 and 18) led to a single diastereomer in each case
involving the cyclization of the (R)-esters to give the
9-membered lactones 19 and 21, respectively (Scheme 2). The
other diastereomeric esters 16 (and 18) were recovered in poor
yield and contaminated with some other metathesis side
products. To further study the fate of the (S)-ester 16, we
prepared it in a stereoselective manner (Scheme 8). Thus, allylic
transposition of allyl enolcarbonate 46 in the presence of
Pd2(dba)3 catalyst, (S)-t-BuPHOX ligand,26,45 and BHT as
additive27 led to the ketone 48 in good yield and acceptable
enantiomeric excess (average of 90% yield and 88 to 91% ee).
The same ketone was also prepared by arylation of the Weinreb
amide derivative 47 of (2S)-isopropylbuta-4-enoic acid 7
independently prepared via an Evans22 or MacMillan28,46
asymmetric allylation. Reduction with a slow addition of
DIBAL-H, keeping the temperature at −78 °C, led quantitatively
to the (S)-alcohol 12 with a diastereomeric ratio of >20:1.
Esterification with the acid 7 using the Yamaguchi method33
led to 16.
In the presence of 5 mol % of the second-generation
Hoveyda−Grubbs catalyst (H-G2) at 10 mM in refluxing
toluene, the (S)-ester 16 yielded 30% of the C2-symmetrical
trans−trans bis-unsaturated dilactone 49 and a mixture of non-
symmetric dilactones as double-bond isomers 50 (Scheme 9).
The structure of 49 was also confirmed by single-crystal X-ray
analysis. Reductive cleavage of the benzylic ester bonds in 49 led
to the acid 51, which is a known intermediate in the Speedel
process for the synthesis of aliskiren.24,25 Controlled catalytic
hydrogenation of the double bonds in 49 led to the saturated
dilactone 53, which upon reductive cleavage in acidic media
yielded acid 54. Alternatively, hydrogenation of the mixture of
isomers corresponding to dilactones 50 afforded the head-
to-head dilactone 52 (Scheme 9).
Scheme 8. Catalytic Asymmetric Synthesis of (S)-Ester 16
Judging from the results using the Grubbs first-generation
catalyst (G1) with the (R)-esters 15 and 17 (10 mol % catalyst,
72 h, rt, toluene at 10 mM concentration), we speculate that
the formation of the corresponding 9-membered lactones 19
(and 21) can be attributed to the contribution of cooperative
stereochemical, stereoelectronic, and conformational effects
leading first to alkylidene Ru complexes (exemplified by the
structure 15a as one of the two possible intermediates).
Presumably, the olefinic termini are favorably aligned with
minimal steric interaction to lead to the Ru-metallacycle
15b, which eventually collapses to the intended lactone 19
(Scheme 10A). In contrast, the transition state starting with
the (S)-ester 16 will be subject to a significant steric clash
between the isopropyl and aromatic moieties, thereby slowing
Scheme 9. Cross-Metathesis Reaction of the (S)-Ester 16 and Reductive Cleavage of Macrocylic Dilactones
9538
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
a
Scheme 10. Possible Ru-Metallacyclic Intermediates
a
(A) First-generation Grubbs (G1) and second-generation Hoveyda−Grubbs (H−G2) catalysts at 10 mM (72 h at rt and 20 min, toluene reflux,
respectively). (B) H−G2 catalyst at 1 mM (6 h, toluene reflux) and 10 mM (24 h, toluene reflux). (C) H−G2 catalyst at 10 mM (24 h, toluene
reflux). Only one alkylidene Ru-intermediate is shown.
Scheme 11. Aziridination and Double-Ring Contraction of the (S)-Lactone 20
down the reaction (Scheme 10B). The same conclusion would
also apply in the case of ester 18.
Finally, we subjected the (S)-lactone 20 to an aziridination
reaction to give 55 in 25% yield with recovery of starting
material (Scheme 11). TFA-induced double-ring contraction
as for the (R)-lactone 19 (Scheme 6) gave the known lac-
tone 36 in 88% yield. Presumably, the activation of the
N-sulfamoyl aziridine lactone in either 9-membered lactones
engendered participation by the electron-rich aryl moiety
to give a quinonoid oxocarbenium ion which underwent
regioselective intramolecular attack liberating the sulfamate
group (Scheme 12). The latter would attack the quinonoid
benzylic carbon atom with high antiselectivity with regard to
In the presence of the more robust second-generation
Hoveyda−Grubbs catalyst (H−G2 5 mol %, at a concentration
of 10 mM in toluene at 110 °C for 20 min), the (R)-ester 15 in a
mixture containing the (S)-ester 16 as the minor isomer is
converted to lactone 19 in 64% yield. Under the same conditions,
the minor (S)-ester 16 undergoes direct dimerization to the
macrocyclic dilactones 49 and 50, which were not reverted to
starting material under these conditions (Scheme 10B). This was
corroborated with the enantioenriched (S)-ester 16 (Scheme 9).
Surprisingly, when the reaction was performed at a concentra-
tion of 1 mM instead of 10 mM, in refluxing toluene for 6 h,
the (S)-ester 16 led to the elusive (S)-lactone 20 in 53%
yield, accompanied by the usual dimers 49 and 50 (∼24%)
(Scheme 10B). The structure of 20 was confirmed by X-ray
crystallography.31 When heated at reflux temperature in 10 mM
in toluene for 24 h in the presence of the second-generation
Hoveyda−Grubbs catalyst (H−G2), the (S)-lactone 20 was
rapidly converted to the lactones 49 and 50. At a concentration of
1 mM, a diastereomeric mixture of 15 and 16 led to the
corresponding lactones 19 and 20 respectively, accompanied by
the dimers 49 and 50.
Scheme 12. Proposed Double-Ring Contraction
Mechanism28
Intrigued by this observation, we subjected the (R)-lactone
19 to the same reaction conditions, only to find that dimerization
to 49 and 50 had also taken place (Scheme 10A). We can
conclude that, depending on the concentration, the catalyst,
and temperature, the (R)-lactone 19 and (S)-lactone 20 are
the kinetic products. Dimerization during ring-closing metathesis
has been previously reported.47
9539
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
1177, 1038 cm−1; HRMS (ESI-TOF) m/z calcd for C15H22NaO2
[M + Na]+ 257.1512, found [M + Na]+ 257.1516.
the C-7 isopropyl substituent leading to the observed pyrro-
lidine lactone 36.28
(S)-(1S,2S)-2-Isopropyl-1-(4-methoxyphenyl)pent-4-en-1-yl-
2-isopropylpent-4-enoate (Ester 16). Triethylamine (70 μL, 0.51
mmol, 1.2 equiv), 2,4,6-trichlorobenzoyl chloride (80 μL, 0.51 mmol,
1.2 equiv), and 4-(dimethylamino)pyridine (62 mg, 0.51 mmol, 1.2
equiv) were successively added to a solution of acid 7 (64 mg, 0.45
mmol, 1.05 equiv) in dry toluene (3 mL) at 0 °C. The resulting white
slurry was stirred at 0 °C for 10 min during which the white slurry turned
yellow. A solution of alcohol 12 (0.10 g, 0.43 mmol, 1.0 equiv) in dry
toluene (1 mL) was added to the reaction vessel containing the yellow
slurry in a dropwise manner at 0 °C. The flask that contained alcohol
12 was rinsed three times with dry toluene (1 mL), and the reaction
mixture was allowed to warm to room temperature and monitored by
TLC analysis until no more starting material was observed (Around 4 h
at room temperature). The solvent was removed, and the resulting
yellow solid was taken up in ethyl acetate (10 mL) and H2O (10 mL).
The aqueous layer was separated and extracted with ethyl acetate (3 ×
10 mL). The combined organic layers were successively washed with a
10% aqueous solution of acid citric (10 mL) and a saturated aqueous
solution of sodium bicarbonate (10 mL). The organic layer was dried
over magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 2.5 cm × 14.0 cm; 1:19
diethyl ether/hexanes) to yield ester 16 (110 mg, 72%) as an oil: Rf =
0.53 (1:9 diethyl ether/hexanes); [α]2D0 − 58 (c 2.0, CDCl3); 1H NMR
(300 MHz, CDCl3) δ 7.26−7.21 (m, 2H), 6.87−6.77 (m, 2H), 5.79−
5.58 (m, 2H), 5.57−5.37 (m, 1H), 5.05−4.91 (m, 2H), 4.87−4.73
(m, 2H), 3.79 (s, 3H), 2.39−2.14 (m, 3H), 2.12−1.71 (m, 5H), 0.96−
0.89 (m, 6H), 0.84 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 174.4, 159.1, 138.3, 136.2, 132.4, 129.1,
116.6, 115.4, 113.5, 77.1, 55.3, 52.8, 48.7, 34.0, 30.9, 30.7, 27.2, 21.2,
20.5, 20.3, 18.0; IR (neat) 3075, 2957, 2931, 2873, 2837, 1728, 1612,
1513, 1249, 1169, 1035 cm−1; HRMS (ESI-TOF) m/z calcd for
C23H34NaO3 [M + Na]+ 381.2400, found [M + Na]+381.2400.
CONCLUSION
■
In conclusion, we have provided a detailed account of various
approaches leading to the total synthesis of the antihypertensive
marketed drug aliskiren. Ring-closing metathesis using the
Grubbs (G1 and G2) and Hoveyda−Grubbs (H−G2) catalysts
with stereochemically distinct esters carrying terminal allyl
moieties led to 9-membered lactones which were further
elaborated to aliskiren and its p-methoxyphenyl congener. The
formation of 9-membered lactones from diastereomeric (R)- and
(S)-esters 15 and 16 were found to be concentration dependent
and favored at a concentration of 1 mM in toluene using the
Hoveyda−Grubbs second-generation catalyst (H−G2). At
higher concentrations, the (R)-ester 15 afforded the expected
9-membered lactone, while the (S)-ester 16 led to a mixture of
macrocyclic dilactones. Further studies focusing on the nature
and stereochemistry of substituents in related cyclizations by
ring-closing metathesis are in progress and will be reported in
due course.
EXPERIMENTAL SECTION
■
General Procedure. All reactions were performed in oven-dried
glassware under an argon atmosphere using dry, deoxygenated solvents.
Dichloromethane and toluene were dried by passage through an
activated alumina column under argon (solvent drying system (SDS)).
Reagents were purchased and used without further purification.
Reactions were monitored by analytical thin-layer chromatography
(TLC) carried out on 0.25 mm silica plates that were visualized under a
UV lamp (254 nm) and developed by staining with ceric ammonium
molybdate, p-anisaldehyde, and/or potassium permanganate solution.
Flash column chromatography was performed using silica (particle size
40−63 μm, 230−400 mesh) at increased pressure. FTIR are reported
in reciprocal centimeters (cm−1). NMR spectra (1H, 13C, DEPT 135,
COSY, HMQC, NOESY) were recorded at either 300, 400, 500, or
Lactone 20. Hoveyda−Grubbs second-generation catalyst (3 mg,
0.048 mmol, 0.06 equiv) was added to a solution of 16 (30 mg, 0.084
mmol, 1.0 equiv, dr 20:1) in dry toluene (84 mL), and the mixture was
stirred at reflux for 6 h. The reaction mixture was cooled to room
temperature, then an excess of ethyl vinyl ether was added and gently
evaporated. The residue was purified by flash chromatography (silica gel,
1.5 cm diameter ×20.0 cm height, 1:50 ethyl acetate/hexanes) to yield
1
700 MHz. Chemical shifts for H NMR spectra are recorded in parts
20 (16 mg, 53%) as pure white crystals: mp 89−91 °C; Rf = 0.55 (1:9
per million relative to trimethylsilane (TMS, δ = 0.00 ppm) with the
solvent resonance as the internal standard (CH3Cl, δ = 7.26 ppm). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, p = pentet, h = hextet, m = multiplet, and
br = broad), coupling constants in hertz (Hz), integration (xH).
Chemical shifts for 13C NMR spectra are recorded in parts per million
using the central peak of CDCl3 (δ = 77.16 ppm) as the internal
standard. Optical rotations were determined with a polarimeter at
589 nm using a 1 dm cell at ambient temperature and are reported in
units of deg·cm3·g−1·dm−1. Melting points are given as ranges and are
reported in °C.
(1S,2S)-2-Isopropyl-1-(4-methoxyphenyl)pent-4-en-1-ol
(12). A solution of 1.5 M of DIBAL-H in toluene (1.8 mL, 2.7 mmol,
1.5 equiv) was added in a slow dropwise manner to a solution of ketone
48 (0.42 g, 1.8 mmol, 1.0 equiv) in THF (10 mL) at −78 °C. The
solution was kept at −78 °C for at least 3 h and then allowed to slowly
warm to room temperature. Silica gel was added until the reaction
mixture stopped to generate bubbles. The mixture was filtered on a silica
pad (silica gel, 2.5 cm diameter ×4.0 cm height; 5 V diethyl ether, then
2 V ethyl acetate) to yield alcohol 12 (0.40 g, 95%, dr >20:1) as a
colorless oil: Rf = 0.11 (1:9, diethyl ether:hexanes); [α]2D0 −12 (c 3.0,
CDCl3) (from ketone 48 with 83% ee, prepared with the PdAAA
protocol27); 1H NMR (400 MHz, CDCl3) δ 7.28−7.23 (m, 2H), 6.89−
6.85 (m, 2H), 5.53 (ddt, J = 17.1, 10.1, 7.1 Hz, 1H), 4.88−4.79 (m, 2H),
4.58 (dd, J = 7.7, 3.3 Hz, 1H), 3.81 (s, 3H), 2.16−2.04 (m, 1H), 2.04−
1.95 (m, 1H), 1.92−1.83 (m, 1H), 1.74−1.68 (m, 1H), 1.67 (dd, J = 3.4,
0.4 Hz, 1H), 0.98−0.93 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 159.2,
138.9, 136.5, 128.1, 115.1, 113.9, 75.9, 55.4, 50.6, 31.3, 27.2, 21.5, 18.4;
IR (neat) 3454, 3005, 2962, 2940, 2880, 2845, 1615, 1515, 1468, 1248,
1
diethyl ether/hexanes); [α]20 −119 (c 0.5, CDCl3); H NMR (400
D
MHz, CDCl3) δ 7.28 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 5.74−
5.64 (m, 1H), 5.55 (ddd, J = 11.0, 10.9, 6.1 Hz, 1H), 3.80 (s, 2H), 3.10−
3.00 (m, 1H), 2.87−2.77 (m, 1H), 2.48 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H),
2.23−2.10 (m, 1H), 2.00 (dq, J = 13.5, 6.7 Hz, 1H), 1.90−1.81 (m, 1H),
1.48 (dq, J = 13.2, 6.6 Hz, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.84−0.79 (m,
J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 174.9, 159.1, 133.5,
131.0, 128.4 (2H), 126.2, 113.9 (2H), 78.2, 55.4, 50.7, 49.5, 28.8, 26.9,
26.5, 23.4, 22.4, 21.9, 20.3, 19.0; IR (neat) 3008, 2956, 2871, 2836, 1735,
1612, 1513, 1463, 1386, 1367, 1247, 1158, 1112, 1030 cm−1; HRMS
(ESI-TOF) m/z calcd C21H31O3 [M + H]+ 331.2268, found [M + H]+
331.2259.
Lactone 21. See ref 28. Also prepared from addition of Hoveyda−
Grubbs second-generation catalyst (4 mg, 0.0064 mmol, 0.06 equiv) to a
solution of esters 17:18 (52 mg, 0.11 mmol, 1.0 equiv, dr 5:1) in dry
toluene (9 mL) with stirring at 50 °C for 2 h. The reaction mixture was
cooled to room temperature, filtered on silica and a Fluorisil pad, and
then rinsed using 50% ethyl acetate/hexanes. The residue was purified
by flash chromatography (silica gel, 1.5 cm diameter × 20.0 cm height,
1:9 ethyl acetate/hexanes) to yield 21 (33 mg, 72%).
Lactones 24 and 25. A solution of NBS (29 mg, 0.16 mmol,
1.1 equiv) was added in a dropwise manner to a mixture of lactone 19
(47 mg, 0.14 mmol, 1 equiv), copper(I) iodide (3 mg, 0.015, 0.11 equiv),
and p-toluenesulfonamide (26 mg, 0.15 mmol, 1.1 equiv) in
dichloromethane (3 mL). The mixture was stirred at room temperature
for 4 h, and then H2O (4 mL) was added in a round-bottom flask
covered with aluminum foil. The mixture was diluted with ethyl acetate
(15 mL) and stirred for a few minutes, and then layers were separated.
9540
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
The aqueous layer was back-extracted with ethyl acetate (5 mL), and the
organic layers were combined, washed with brine (10 mL), dried over
sodium sulfate, and concentrated. A diastereomeric ratio of 3.9:1 was
observed by 1H NMR of the crude mixture. The residue was purified by
flash chromatography (silica gel, 1.5 cm diameter ×21 cm height, 1:9 to
1:4 ethyl acetate/hexanes) to yield the lactone 24 (42 mg, 52%) as a
white solid along with impure fractions of 25, which could be obtained as
a pure white solid by recrystallization in methanol. Also, starting from
63 mg (0.19 mmol, 1 equiv) of lactone 19, 14 mg (13%) of lactone
25 could be obtained pure by flash chromatography (silica gel, 2.5 cm ×
20 cm, 0 to 1:19 ethyl acetate/hexanes) and 64 mg of impure lactone
24 which was repurified by flash chromatography (silica gel, 1.5 cm
diameter × 20 cm height, 1:4 ethyl acetate/hexanes) to yield the pure
lactone 24 (40 mg, 36%).
Epoxide 28. m-CPBA (77%) (65 mg, 0.29 mmol, 1.9 equiv) was
added to a solution of lactone 19 (51 mg, 0.15 mmol, 1.0 equiv) in
dichloromethane (1 mL), and the reaction mixture was stirred for 1 h at
room temperature. The solution was diluted with diethyl ether (5 mL)
and washed with a saturated aqueous solution of sodium bicarbonate
(2 × 10 mL). The organic layer was dried over magnesium sulfate,
filtered, and concentrated to yield 47 mg of the crude epoxide 28 (dr
10:1) as a gel: Rf = 0.52 (1:4, ethyl acetate/hexanes). Only the major
diastereomer is reported: 1H NMR (300 MHz, CDCl3) δ 7.33−7.27 (m,
2H), 6.92−6.85 (m, 2H), 5.75 (d, J = 11.1 Hz, 1H), 3.81 (s, 3H), 3.29−
3.20 (m, 1H), 3.04 (ddd, J = 10.7, 3.7, 1.8 Hz, 1H), 2.60−2.50 (m, 1H),
2.25 (ddd, J = 11.4, 5.2, 1.9 Hz, 1H), 2.21−2.07 (m, 1H), 2.07−1.93 (m,
2H), 1.58−1.38 (m, 2H), 1.03 (d, J = 6.5 Hz, 3H), 0.99−0.92 (m, 1H),
0.89 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 174.7, 159.6, 131.7, 128.9 (2C),
114.0 (2C), 78.0, 61.0, 55.4, 55.4, 52.7, 48.6, 28.5, 27.0, 26.5, 25.0, 22.0,
21.8, 19.7, 15.9; IR (neat) 3004, 2967, 2947, 2936, 2929, 2880, 1733,
1519, 1466, 1393, 1375, 1277, 1252, 1204, 1179, 1122, 1117, 1038 cm−1;
HRMS (ESI-TOF) m/z calcd for C21H31O4 [M + H]+ 347.2217, found
[M + H]+ 347.2204 and calcd for C21H30NaO4 [M + Na]+ 369.2036,
found [M + Na]+ 369.2029.
Lactones 29, 30, and 31. To a solution of the crude epoxide 28
(47 mg) in dichloromethane (1 mL) was added trifluoroacetic acid
(60 μL). The solution was stirred 10 min,a nd then the reaction was
stopped by adding a saturated aqueous solution of sodium bicarbonate
(5 mL) followed by ethyl acetate (10 mL). The organic layer was washed
with a saturated aqueous solution of sodium bicarbonate (5 mL), dried
over magnesium sulfate, filtered, and concentrated. A ratio of 6:1:1 was
observed in the 1H NMR spectrum of the crude mixture. The residue was
purified by flash chromatography (silica gel, 2.0 cm diameter × 20.0 cm
height, 1:19 ethyl acetate:hexanes) to yield lactones 29 (15 mg, 29%) +
30 (4 mg, 8%) + 31 (4 mg, 8%) + 7 mg of mixed fractions. All lactones
produced from this reaction were clear oils.
Lactone 24: Rf = 0.29 (1:4 ethyl acetate/hexanes); (recrystallized
from 2-propanol) mp 113−115 °C; [α]2D0 +49 (c 0.5, CHCl3); 1H NMR
(700 MHz, CDCl3) δ 7.42−7.39 (m, 2H), 7.03 (d, J = 8.0 Hz, 2H),
6.91−6.88 (m, 2H), 6.63−6.60 (m, 2H), 5.34 (d, J = 7.7 Hz, 1H), 4.45−
4.43 (m, 1H), 4.20 (dd, J = 9.2, 8.1 Hz, 1H), 4.16 (ddd, J = 9.0, 4.4,
1.5 Hz, 1H), 3.73 (s, 3H), 2.96 (ddd, J = 11.3, 7.6, 3.8 Hz, 1H), 2.58−
2.51 (m, 1H), 2.31 (s, 3H), 2.31−2.27 (m, 1H), 2.11 (ddd, J = 14.4, 11.2,
3.1 Hz, 1H), 2.03 (ddd, J = 14.7, 9.2, 5.4 Hz, 1H), 1.81−1.77 (m, 1H),
1.69 (ddd, J = 14.9, 4.4 Hz, 1H), 1.47−1.42 (m, 1H), 0.97 (d, J = 7.0 Hz,
3H), 0.95 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.71 (d, J =
6.8 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 170.9, 158.8, 142.6, 138.2,
132.5, 129.2 (2C), 128.1 (2C), 127.1 (2C), 113.8 (2C), 81.1, 60.5, 55.4,
50.0, 45.7, 42.9, 32.0, 30.2, 29.2, 28.1, 21.7, 21.6, 19.7, 18.5, 16.2; IR
(neat) 3252, 2958, 2923, 2852, 1732, 1704, 1612, 1514, 1463, 1443,
1325, 1248, 1218, 1179, 1160, 1093, 1046 cm−1; HRMS (ESI-TOF) m/
z
calcd for C28H3879BrNNaO5S [M + Na]+ 602.1546, found [M + Na]+
602.1517.
Lactone 25: Rf = 0.21 (1:4 ethyl acetate/hexanes); (gradual dec)
(recrystallized from ethanol) mp 151−167 °C; [α]2D0 −56 (c 0.5,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.48−7.44 (m, 2H), 7.07−7.03
(m, 2H), 6.92−6.86 (m, 2H), 6.65−6.59 (m, 2H), 5.30 (d, J = 8.5 Hz,
1H), 4.19−4.16 (m, 1H), 4.12−4.07 (m, 1H), 3.69 (s, 3H), 2.76−2.66
(m, 2H), 2.40−2.29 (m, 4H), 2.29−2.21 (m, 1H), 2.07 (ddd, J = 14.6,
8.2, 3.4 Hz, 1H), 1.66 (ddd, J = 14.4, 9.4, 1.5 Hz, 1H), 1.63−1.55
(m, 1H), 1.50−1.43 (m, 1H), 1.40 (ddd, J = 14.4, 9.3, 5.0 Hz, 1H), 1.00
(d, J = 7.0 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H),
0.69 (d, J = 6.8 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 171.3, 159.3,
143.1, 137.5, 132.3, 129.3 (2C), 128.3 (2C), 127.3 (2C), 114.0 (2C),
78.8, 60.4, 55.3, 49.0, 45.7, 42.9, 31.7, 30.3, 29.5, 28.1, 22.0, 21.6, 19.5,
18.1, 16.0; IR (neat) 3273, 2966, 2930, 2860, 2880, 1740, 1727, 1667,
1615, 1518, 1467, 1449 1329, 1256, 1183, 1161, 1052, 1041 cm−1;
HRMS (ESI-TOF) m/z calcd for C28H3879BrNNaO5S [M + Na]+
602.1546, found [M + Na]+ 602.1535.
Lactone 26. Starting from the lactone 19 (66 mg, 0.20 mmol, 1.0
equiv), the bromosulfonamidation protocol was followed and the crude
mixture of the bromosulfonamides 24:25 (dr 3.9:1) was dissolved in
dichloromethane and cooled to 0 °C. Triethylsilane (0.16 mL, 1.0 mmol,
5.0 equiv) was added to the solution followed by TFA (0.1 mL). The
solution was allowed to slowly reach room temperature, and the
progress of the reaction was monitored by TLC. Volatiles were removed
under vacuum with a rotary evaporator, and the residue was purified by
flash chromatography (silica gel, 2.0 cm diameter ×20 cm height, 1:9
ethyl acetate/hexanes) to yield bromolactone 26 (62 mg, 75%, 2 steps)
as an oil: Rf = 0.43 (1:4, ethyl acetate/hexanes); [α]2D0 +11 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.15−7.01 (m, 2H), 6.89−6.75
(m, 2H), 4.26−4.20 (m, 1H), 3.77 (s, 3H), 3.70 (ddd, J = 6.8, 5.2, 1.0 Hz,
1H), 2.79 (ddd, J = 11.3, 7.8, 3.9 Hz, 1H), 2.71 (dd, J = 13.8, 5.2 Hz, 1H),
2.54−2.33 (m, 2H), 2.13 (ddd, J = 14.6, 7.8, 3.4 Hz, 1H), 1.85−1.53 (m,
5H), 0.96−0.91 (m, 6H), 0.88 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 171.5, 158.2, 133.4, 129.9 (2C),
114.1 (2C), 79.3, 55.4, 49.9, 42.8, 41.7, 37.8, 36.2, 31.21, 30.23, 29.3,
19.7, 19.6, 18.4, 18.3; IR (neat) 2966, 2940, 2879, 1736, 1615, 1515,
1468, 1249, 1226, 1209, 1180, 1069, 1041 cm−1; HRMS (ESI-TOF) m/
z calcd for C21H3179BrNaO3 [M + Na]+ 433.1349, found [M + Na]+
433.1340.
Lactone 29: Rf = 0.41 (1:4 ethyl acetate/hexanes); [α]2D0 +14 (c 1.5,
CHCl3); 1H NMR (700 MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.89−6.86
(m, 2H), 4.53−4.43 (m, 1H), 4.25 (d, J = 10.5 Hz, 1H), 3.89−3.87 (m,
1H), 3.80 (s, 3H), 2.81 (ddd, J = 11.5, 7.3, 3.8 Hz, 1H), 2.59−2.52 (m,
1H), 2.17−2.11 (m, 1H), 2.08 (ddd, J = 14.0, 7.3, 3.9 Hz, 1H), 2.00−
1.93 (m, 1H), 1.74 (ddd, J = 14.3, 12.5, 2.3 Hz, 1H), 1.64 (ddd, J = 14.4,
12.9, 2.8 Hz, 1H), 1.43−1.36 (m, 1H), 0.93−0.90 (m, 6H), 0.78 (d, J =
7.0 Hz, 3H), 0.74 (d, J = 6.9 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ
173.9, 159.6, 132.7, 128.6 (2C), 114.1 (2C), 83.2, 76.1, 70.5, 55.4, 41.0,
39.7, 29.0, 28.3, 26.4, 25.8, 20.9, 19.8, 17.9, 15.9; IR (neat) 3018, 3003,
2965, 2954, 2941, 2935, 2923, 2913, 2905, 2881, 2844, 1724, 1617,
1590, 1518, 1469, 1446, 1391, 1373, 1367, 1350, 1248, 1226, 1175,
1157, 1129, 1082, 1056, 1030, 1007 cm−1; HRMS (ESI-TOF) m/z calcd
for C21H30O4 [M + H]+ 347.2217, found [M + H]+ 347.2225 and calcd
for C21H30NaO4 [M + Na]+ 369.2036, found [M + Na]+ 369.2044.
Lactone 30: Rf = 0.46 (1:4 ethyl acetate/hexanes); [α]2D0 +39 (c 0.4,
CHCl3); 1H NMR (700 MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.88−6.85
(m, 2H), 4.50 (ddd, J = 9.3, 3.2, 2.1 Hz, 1H), 4.41 (d, J = 9.3 Hz, 1H),
4.08 (ddd, J = 9.2, 5.0, 2.0 Hz, 1H), 3.79 (s, 3H), 2.70 (ddd, J = 9.8, 9.3,
5.0 Hz, 1H), 2.22 (ddd, J = 13.1, 10.0, 3.3 Hz, 1H), 2.20−2.13 (m, 2H),
2.13−2.06 (m, 2H), 1.92 (ddd, J = 12.4, 9.3 Hz, 1H), 1.60−1.53 (m,
1H), 0.96 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H), 0.89 (d, J =
6.0 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ
179.8, 159.6, 133.2, 128.7 (2C), 114.0 (2C), 85.8, 79.6, 79.4, 55.4, 52.4,
45.4, 31.7, 29.0, 28.6, 26.3, 22.0, 20.6, 19.6, 18.1; IR (neat) 3000, 2967,
2931, 2907, 2899, 2889, 2878, 2859, 1771, 1619, 1519, 1471, 1374,
1251, 1178, 1110, 1093, 1036 cm−1; HRMS (ESI-TOF) m/z calcd for
C21H31O4 [M + H]+ 347.2217, found [M + H]+ 347.2220 and calcd for
C21H30NaO4 [M + Na]+ 369.2036, found [M + Na]+ 369.2042.
Lactone 31: Rf = 0.31 (1:4 ethyl acetate/hexanes); [α]2D0 −2 (c 0.4,
CHCl3); 1H NMR (700 MHz, CDCl3) δ 7.26−7.23 (m, 2H), 6.87−6.84
(m, 2H), 4.57 (d, J = 9.3 Hz, 1H), 4.36−4.32 (m, 1H), 4.25−4.20 (m,
1H), 3.79 (s, 3H), 2.61−2.56 (m, 1H), 2.21−2.15 (m, 2H), 2.15−2.12
(m, 1H), 2.12−2.07 (m, 1H), 2.05−1.95 (m, 1H), 1.84−1.77 (m, 1H),
1.71−1.64 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H),
0.90 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H); 13C NMR (176 MHz,
CDCl3) δ 178.0, 159.3, 134.3, 128.5 (2C), 113.9 (2C), 85.0, 79.9, 78.7,
9541
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
55.4, 54.1, 46.9, 31.8, 28.9, 27.9, 26.3, 22.4, 20.8, 19.6, 18.5; IR (neat)
3006, 2966, 2928, 2906, 2897, 2878, 2864, 2858, 2834, 2818, 1770,
1618, 1518, 1469, 1251, 1177, 1038, 1001, 981, 828, 763 cm−1; HRMS
(ESI-TOF) m/z calcd for C21H31O4 [M + H]+ 347.2217, found
[M + H]+ 347.2223 and calcd for C21H30NaO4 [M + Na]+ 369.2036 and
[M + Na]+ 369.2044.
Lactone Diol 32. N-Methylmorpholine N-oxide (53 mg, 0.45 mmol,
1.5 equiv) was added to a solution of lactone 15 (0.1 g, 0.3 mmol,
1 equiv) in acetone (2.4 mL) and distilled water (0.6 mL) at 0 °C, a 2.5
wt % solution of osmium tetra oxide in 2-methyl-2-propanol (0.2 mL,
0.02 mmol, 0.05 equiv) was added, and the reaction mixture was allowed
to warm to room temperature. After 1 h of stirring, the reaction media
was poured into a cold solution of ethyl acetate (2 mL) and a saturated
aqueous solution of sodium thiosulfate (2 mL). The aqueous layer was
separated and back-extracted with ethyl acetate (3 × 2 mL). The
combined organic layers were dried over sodium sulfate, filtered, and
concentrated to leave 102 mg of a black oil which was purified by flash
chromatography (silica gel, 1.5 cm × 20 cm; 2:3 ethyl acetate/hexanes)
to yield diol 32 (89 mg, 81%, dr 9:1) as a colorless oil.
by flash chromatography (silica gel, 1:4 ethyl acetate/hexanes) to yield
the known amide 4028 (90 mg, 31%) (Rf = 0.57, 2:3 ethyl acetate/
hexanes) as a colorless oil and lactone 39 (40 mg, 16%) (Rf = 0.37, 2:3
ethyl acetate/hexanes) as a white solid, which was recrystallized from
diffusing hexanes to a solution of lactone 39 in a minimal amount of
ethyl acetate: mp 140 to 143 °C; [α]2D0 +14 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.22 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H),
4.60−4.25 (m, 2H), 4.20−4.05 (m, 1H), 3.79 (s, 1H), 4.70−4.55 (m,
1H), 2.40−2.10 (m, 4H), 2.00−1.80 (m, 1H), 1.73 (br s, 2H), 1.50−
1.10 (br m, 9H), 1.04 (d, J = 6.8 Hz, 3H), 0.97−0.90 (m, 6H), 0.82 (d,
J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 178.1, 158.4, 136.0,
127.9, 113.7, 80.3, 65.7, 60.0, 55.3, 52.5, 45.1, 29.2, 28.3, 28.2, 27.8, 27.4,
22.2, 20.7, 18.6, 17.8; IR (neat) 2959, 2930, 2874, 2837, 1772, 1690,
1613, 1513, 1466, 1386, 1366, 1245, 1170, 1101, 1033 cm−1; HRMS
(ESI-TOF) m/z calcd for C26H40NO5 [M + H]+ 446.2901, found
[M + H]+ 446.2891 and calcd for C26H39NNaO5 [M + Na]+ 468.2720,
found [M + Na]+ 468.2729.
Lactone 41. An aqueous 1 M solution of LiOH (1.4 mL, 1.4 mmol,
10 equiv) was added to a solution of lactone 37 (88 mg, 0.14 mmol, 1.0
equiv) in DME (1.4 mL) at 0 °C. The reaction mixture was allowed to
reach room temperature and monitored by TLC and MS. The mixture
was then acidified with a 1 M HCl solution in MeOH to pH = 3−4, and
volatiles were removed under vacuum with a rotary evaporator to give
312 mg of the crude mixture.
Diol 32 was also prepared using the same protocol, with 4 wt %
solution of osmium tetraoxide in H2O in 91% yield and an estimated dr
of 6:1 by NMR. The oil was recrystallized from ethyl acetate:hexanes
(1:4) to give white needles with an estimated dr of 7:1; mp 96 to 106 °C;
1
Rf = 0.2 (2:3 ethyl acetate/hexanes): H NMR (300 MHz, CDCl3) δ
7.32−7.26 (m, 0.27H), 7.26−7.20 (m, estimated to ∼1.6H), 6.88−6.82
(m, 2H), 5.68 (d, J = 11.0 Hz, 1H), 4.50 (d, J = 6.5 Hz, 1H), 3.84−3.69
(m, 4H), 2.47 (s, 2H), 2.29 (ddd, J = 15.9, 6.8, 2.7 Hz, 1H), 2.24−2.01
(m, 2H), 1.92−1.58 (m, 3H), 1.55−1.45 (m, 0.21H), 1.45−1.30 (m,
1H), 1.24−1.08 (m, 1H), 0.98 (d, J = 6.1 Hz, 3H), 0.92−0.71 (m,
9H).Only the major diastereomer is reported for the 13C NMR. 13C
NMR (75 MHz, CDCl3) δ 175.1, 159.7, 131.0, 128.7, 114.1, 78.8, 77.9,
69.0, 55.4, 53.2, 48.4, 31.6, 30.1, 27.5, 26.9, 21.5, 21.3, 20.2, 15.3; IR
(neat) 3394, 2867, 2945, 2881, 1730, 1617, 1519, 1467, 1253, 1179,
1052, 1036 cm−1; HRMS (ESI-TOF) m/z calcd for C21H32NaO5 [M +
Na]+ 387.2142, found [M + Na]+ 387.2126.
Pyrrolidine Lactone 36. A dry round-bottomed flask was charged
with 8 mg (0.014 mmol, 1.0 equiv) of 55, a magnetic stirrer and 0.5 mL
of dry dichloromethane ([55] = 0.028 M) were introduced via a glass
syringe then added 5 drops of trifluoroacetic acid. The solution was
stirred and monitored by TLC analysis (20:80 ethyl acetate−hexanes,
CAM). After 10 min, when TLC analysis showed no more starting
material, the trifluoroacetic acid and dichloromethane were first
removed under reduced pressure at room temperature to leave yellow
oil which was purified by flash column chromatography (silica gel,
1.5 cm × 20 cm; 1:19 ethyl acetate−hexanes) to yield 7 mg (0.0123
mmol, 88%) of the titled compound 36 as a yellow oil: Rf = 0.44 (1:9
ethyl acetate:hexanes); [α]2D0 +21 (c 0.7, CDCl3); 1H NMR (400 MHz,
CDCl3) δ 7.33−7−31 (m, 2H), 6.89−6.86 (m, 2H), 4.57−4.52 (m,
2H), 4.34 (d, J = 11.2 Hz, 2H), 4.23 (dd, 5.2 and 8.4 Hz, 1H), 3.78 (s,
3H), 2.64 (ddd, J = 5.6, 7.6, 10.0 Hz, 1H), 2.56−2.47 (m, 1H), 2.41−
2.34 (m, 1H), 2.21−2.05 (m, 3H), 1.95 (dd, J = 6.4, 12.8 Hz, 1H), 1.71−
1.62 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.91
(d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H).
Lactone 39. Zn(Cu) (0.18 g, 2.8 mmol, 5.0 equiv) was added to
a solution of amide 38 (0.36 g, 0.56 mmol, 1.0 equiv) in methanol/ethyl
acetate (1 mL, 1:1 v/v) and stirred at room temperature. The reaction
was monitored by MS. The mixture was filtered on Celite, rinsed with a
minimal amount of MeOH, and concentrated. The resulting solid was
dissolved in dry MeOH (5 mL) and cooled to 0 °C, and AcCl (0.36 mL)
was added. The solution was allowed to reach room temperature
and stirred 24 h. The solvent was removed under vacuum with a
rotary evaporator, and the resulting white solid was dissolved in CH2Cl2
(2 mL). To this last were added H2O (2 mL), Boc2O (0.16 g, 0.73 mmol,
1.3 equiv), K2CO3 (0.39 g, 2.8 mmol, 5.0 equiv), and TBAB (43 mg, 0.11
mmol, 0.2 equiv). The mixture was stirred at room temperature and
monitored by TLC. An excess of imidazole was added, and then the
mixture was acidified to a pH = 3−4, with a 10% solution of citric acid.
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 10 mL). The organic layers were combined, dried
over sodium sulfate, filtered, and concentrated. The residue was purified
Boc2O (0.10 g, 0.48 mmol, 2.4 equiv) was added to a mixture of the
crude deprotected intermediate (0.18 g, estimated to 0.20 mmol, 1.0
equiv) in dichloromethane (1 mL) and H2O (1 mL) at 0 °C. K2CO3
(0.26 g, 1.9 mmol, 10 equiv) and TBAB (24 mg, 74 μmol, 0.37 equiv)
were added, and the mixture was allowed to reach room temperature.
The mixture was stirred for 16 h at room temperature, and then the
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 × 2 mL), and the organic layers were combined, dried over sodium
sulfate, filtered, and concentrated. The residue was purified via flash
chromatography (silica gel, 1:9 ethyl acetate:hexanes) to yield Boc-
protected lactone 41 (105 mg, >95%) as a colorless oil: [α]2D0 −70
(c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.01 (s, 1H), 6.85−6.72
(m, 2H), 4.82 (s, 1H), 4.35−3.95 (m, 4H), 3.83 (s, 3H), 3.62−3.48 (m,
2H), 3.36−3.28 (m, 3H), 2.66−2.53 (m, 1H), 2.35−2.02 (m, 5H),
1.99−1.56 (m, 4H), 1.35−1.10 (m, 9H), 1.04 (d, J = 6.9 Hz, 3H), 0.93
(d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 177.64, 155.42, 148.26, 148.15, 119.86,
111.86, 111.19, 80.12, 79.22, 69.73, 66.32, 66.29, 61.11, 58.76, 56.14,
46.86, 29.60, 28.59, 28.31, 27.90, 27.66, 21.88, 20.72, 18.36, 18.28; IR
(NaCl) 2961, 2874, 2835, 1770, 1682, 1515, 1469, 1391, 1260, 1143,
1028 cm−1; HRMS (ESI-TOF) m/z calcd for C30H47NNaO7 [M + Na]+
556.3245, found [M + Na]+ 556.3241.
Amide 42. A 2 M solution of AlMe3 in toluene (0.1 mL, 0.2 mmol,
5 equiv) was added to a solution of n-butylamine (20 μL, 0.20 mmol,
5.0 equiv) in dichloromethane (1 mL), and the mixture was stirred at
room temperature for 5 min. The resulting solution was transferred to a
solution of lactone 37 (25 mg, 40 μmol, 1.0 equiv) in dichloromethane
(1 mL), and the solution was stirred at room temperature overnight and
then quenched with a saturated solution of ammonium chloride
(10 mL). The organic phase was separated, and the aqueous phase was
extracted with dichloromethane (3 × 10 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 1:4 ethyl
acetate/hexanes) to yield amide 42 (25 mg, 87%) as a colorless oil: Rf =
(0.31, 2:3 ethyl acetate/hexanes); [α]2D0 + 11 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.07 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.3, 2.0 Hz,
1H), 6.79 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 5.7 Hz, 1H), 4.55 (d, J = 9.2 Hz,
1H), 4.44 (q, J = 10.8 Hz, 2H), 4.16−4.07 (m, 2H), 4.00−3.93 (m, 1H),
3.83 (s, 3H), 3.65−3.57 (m, 3H), 3.37 (s, 3H), 3.34−3.24 (m, 1H),
3.23−3.13 (m, 1H), 2.34−2.25 (m, 1H), 2.17−2.07 (m, 3H), 2.00−1.83
(m, 4H), 1.75−1.67 (m, 1H), 1.60 (ddd, J = 13.5, 10.4, 2.8 Hz, 1H),
1.51−1.44 (m, 2H), 1.38−1.28 (m, 3H), 0.97−0.86 (m, 12H), 0.83 (d,
J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 175.4, 149.2, 148.7,
134.2, 120.1, 112.6, 111.6, 93.9, 77.6, 71.4, 69.9, 69.7, 67.7, 66.2, 58.8,
56.1, 53.4, 51.5, 39.3, 35.1, 32.0, 30.6, 30.4, 29.6, 28.7, 22.1, 21.3, 20.6,
20.3, 18.5, 13.9; IR (NaCl) 3330, 3012, 2960, 2931, 2874, 1634, 1516,
9542
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
1464, 1373, 1261, 1183, 1000 cm−1; HRMS (ESI-TOF) m/z calcd for
C31H52Cl3N2O8S [M + H]+ 717.2505, found [M + H]+ 717.2524 and
calcd for C31H51Cl3N2NaO8S [M + Na]+ 739.2324, found [M + Na]+
739.2341.
1733, 1513, 1465, 1248, 1148, 1035 cm−1; HRMS (ESI-TOF) m/z calcd
for C42H64NO6 [M + NH4]+ 678.4728, found [M + NH4]+ 678.4721.
Other fractions were combined to give 28 mg of mixture of head-to-
head isomers 50.
(S)-2-Isopropyl-N-methoxy-N-methylpent-4-enamide (47).
EDC (0.71 g, 3.7 mmol, 1.1 equiv) was added to a solution of acid 7
(0.50 g, 3.5 mmol, 1 equiv) in dichloromethane (15 mL) at 0 °C,
followed by triethylamine (0.59 mL, 4.2 mmol, 1.2 equiv), N,O-
dimethylhydroxylamine hydrochloride, and a small chip of DMAP. The
reaction mixture was allowed to slowly reach room temperature and
stirred for 16 h. Volatiles were removed under vacuum with a rotary
evaporator, and the resulting residue was partitioned between ethyl
acetate (10 mL) and H2O (10 mL). The aqueous layer was back-
extracted twice with ethyl acetate (2 × 10 mL), and the organic layers
were combined, washed with a saturated aqueous solution of sodium
bicarbonate (3 × 10 mL), dried over sodium sulfate, and concentrated.
The residue was purified by flash chromatography (silica gel, 2.5 cm
diameter × 20 cm height, 1:4 ethyl acetate/hexanes) to yield 47 (0.46 g,
70%) as an oil: Rf = 0.7 (3:7, ethyl acetate/hexanes) [α]2D0 +8 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.74 (ddt, J = 17.2, 10.2, 7.1 Hz,
1H), 5.05 (ddt, J = 17.0, 1.8, 1.2 Hz, 1H), 5.00−4.90 (m, 1H), 3.66 (s,
3H), 3.18 (s, 3H), 2.69 (br s, 1H), 2.43−2.23 (m, 2H), 1.96−1.82 (m,
1H), 0.96 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H); (residual
chloroform signal was set at 77.9 ppm); 13C NMR (75 MHz, CDCl3) δ
177.6, 137.3, 117.0, 62.1, 48.2, 35.1, 32.8, 31.4, 21.9, 21.8; IR (neat)
3077, 2961, 2873, 2820, 1661, 1464, 1440, 1416, 1385, 1337, 1321,
1177, 1116, 1085; HRMS (ESI-TOF) m/z calcd for C10H20NO2
[M + H]+ 186.1489, found [M + H]+ 186.1482.
(2S,7R,E)-2-Isopropyl-7-(4-methoxybenzyl)-8-methylnon-4-
enoic Acid (Acid 51). TFA (3 drops) was added to a solution of
dilactone 49 (17 mg, 0.026 mmol, 1.0 equiv) and triethylsilane (0.10 mL,
0.63 mmol, 24 equiv) in dichloromethane (1 mL). The solution was
stirred at room temperature for 10 min. Volatiles were removed under
vacuum with a rotary evaporator, and the residue was purified by flash
chromatography (silica gel, 1.5 cm diameter × 20 cm height, 100 mL of
hexanes then 1:19 ethyl acetate/hexanes) to yield acid 51 (12 mg, 71%)
as a clear oil: Rf = 0.14 (1:9 ethyl acetate/hexanes); [α]2D0 +27 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 10.74 (s, 1H), 7.07−7.02
(m, 2H), 6.83−6.78 (m, 2H), 5.47−5.29 (m, 2H), 3.78 (s, 3H), 2.50
(dd, J = 13.8, 6.6 Hz, 1H), 2.36 (dd, J = 13.8, 8.0 Hz, 1H), 2.31−2.12
(m, 3H), 2.00−1.80 (m, 3H), 1.76−1.62 (m, 1H), 1.53−1.40 (m, 1H),
1.00−0.92 (m, 6H), 0.88 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 180.6, 157.7, 134.2, 132.0, 130.1, 128.3,
113.7, 55.4, 52.7, 46.4, 35.7, 33.0, 32.7, 30.1, 28.3, 20.4, 20.3, 19.3, 19.0;
IR (neat) 2956, 2925, 2871, 1703, 1511, 1244, 1176, 1038 cm−1; HRMS
(ESI-TOF) m/z calcd for C21H36NO3 [M + NH4]+ 350.2690, found
[M + NH4]+ 350.2688 and calcd for C21H32NaO3 [M + Na]+ 355.2244,
found [M + Na]+ 355.2248.
Dilactone 52. Pd/C (cat) was added to a solution of the mixture of
isomers 50 (28 mg) in methanol/ethyl acetate (6 mL, 1:1). The
suspension was purged with H2 and stirred 24 h. The mixture was then
filtered on Celite and concentrated to afford a residue which was purified
by flash chromatography (silica gel, 1.5 cm diameter × 20 cm height,
1:9 ethyl acetate/hexanes) to yield dilactone 52 (20 mg, 30% over two
steps) as a clear oil: Rf = 0.33 (1:9 ethyl acetate/hexanes); [α]2D0 −64
(S)-2-Isopropyl-1-(4-methoxyphenyl)pent-4-en-1-one (48).27
A solution of 1.6 M n-BuLi in hexane (1.35 mL, 2.16 mmol, 1.03 equiv)
was added to a solution of 4-bromoanisole (0.26 mL, 2.1 mmol, 1.0
equiv) in tetrahydrofuran (8 mL) at −78 °C. The solution was stirred at
−78 °C for 40−60 min, and then a solution of 47 (0.46 g, 2.5 mmol, 1.2
equiv) in tetrahydrofuran (2−3 mL) was added in a dropwise manner.
The reaction mixture was allowed to warm to room temperature, stirred
for 1 h, and then quenched with water (10 mL). The organic layer was
separated from the aqueous layer. The aqueous layer was extracted with
diethyl ether (2 × 10 mL). Organic solutions were combined, washed
with brine (2 × 10 mL), dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography (silica
gel, 2.5 cm diameter × 13 cm height; 1:9 diethyl ether/hexanes) to yield
ketone 48 (0.40 g, 83%) as a clear oil: Rf = 0.47 (1:4 ethyl acetate/
hexanes); [α]2D0 +38 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.93
(d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.69 (ddt, J = 17.0, 10.1,
7.0 Hz, 1H), 4.99 (d, J = 17.0 Hz, 1H), 4.89 (d, J = 10.1 Hz, 1H), 3.87
(s, 3H), 3.29 (ddd, J = 10.2, 6.8, 3.9 Hz, 1H), 2.64−2.45 (m, 1H), 2.38−
2.21 (m, 1H), 2.16−1.91 (m, J = 6.7 Hz, 1H), 0.98−0.88 (m, 6H);13C
NMR (75 MHz, CDCl3) δ 202.4, 163.4, 136.6, 131.5, 130.6 (2C), 116.3,
113.8 (2C), 55.6, 52.0, 33.4, 30.8, 21.4, 19.7; IR (neat) 3076, 2960, 2934,
2872, 2840, 1670, 1640, 1599, 1576, 1509, 1463, 1439, 1419, 1388, 1370,
1308, 1259, 1211, 1170, 1114, 1031 cm−1; HRMS (ESI-TOF) m/z calcd
for C15H21O2 [M+ H]+ 233.1536, found [M+ H]+ 233.1530 and calcd for
C15H20NaO2 [M + Na]+ 255.1356, found [M + Na]+ 255.1345.
Dilactone 49. Hoveyda−Grubbs’ second-generation catalyst (6 mg,
0.01 mmol, 0.05 equiv) was added to a solution of ester 16 (70 mg, 0.20,
1.0 equiv) in toluene (20 mL), and the mixture was heated to reflux for
24 h. The solution was concentrated by blowing air in the flask. The
residue was purified by flash chromatography (silica gel, 2.0 cm
diameter × 20 cm height, 0:100 to 3:97 ethyl acetate/hexanes) to yield
the dilactone 49 (20 mg, 30%): Rf = 0.2 (1:9 ethyl acetate/hexanes); re-
crystallization from methanol gave white crystals; mp 191−198 °C; [α]D20
−48 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.22−7.13 (m, 4H),
6.91−6.78 (m, 4H), 6.14 (d, J = 2.7 Hz, 2H), 5.75−5.60 (m, 2H), 5.54−
5.35 (m, 2H), 3.80 (s, 6H), 2.54−2.27 (m, 4H), 2.21 (ddd, J = 11.2, 7.9,
3.6 Hz, 2H), 2.14−1.94 (m, 4H), 1.94−1.70 (m, 4H), 1.52−1.42 (m,
2H), 0.98 (d, J = 6.7 Hz, 6H), 0.94 (d, J = 6.9 Hz, 6H), 0.90 (d, J =
6.6 Hz, 6H), 0.78 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
174.8, 158.6, 132.8, 131.4, 130.0, 127.3, 113.5, 75.3, 55.4, 54.4, 50.1,
34.5, 31.5, 28.2, 25.7, 23.3, 21.2, 20.6, 18.0; IR (neat) 2956, 2932, 2873,
1
(c 0.5, CHCl3); H NMR (300 MHz, CDCl3) δ 7.19−7.11 (m, 4H),
6.90−6.83 (m, 4H), 6.05 (d, J = 1.5 Hz, 2H), 3.79 (s, 6H), 2.22 (td, J =
8.7, 2.8 Hz, 2H), 2.00−1.82 (m, 2H), 1.82−1.27 (m, 20H), 0.96−0.84
(m, 18H), 0.81 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
175.3, 158.7, 132.4, 127.5, 113.6, 76.2, 55.3, 52.7, 50.3, 30.3, 29.7, 29.5,
27.0, 26.9, 25.8, 23.0, 21.5, 20.0, 18.6; IR (neat) 2953, 2934, 2868, 1730,
1608, 1507, 1461, 1379, 1295, 1250, 1172, 1118, 1035 cm−1; HRMS
(ESI-TOF) m/z calcd for C42H64NaO6 [M + Na]+ 687.4595, found
[M + Na]+ 687.4580.
(2S,7R)-2-Isopropyl-7-(4-methoxybenzyl)-8-methylnonanoic
Acid (Acid 54). Pd/C (cat) was added to a solution of dilactone 49
(4 mg, 0.006 mmol, 1 equiv) in methanol (0.5 mL) and ethyl acetate
(0.05 mL). The suspension was purged with H2, and the reaction was
stirred under H2 atmosphere (H2 balloon). The reaction was monitored
by TLC: Rf = 0.31 (1:9 ethyl acetate/hexanes). When completed, the
mixture was filtered through Celite and concentrated to afford 4 mg
1
of the crude dilactone 53: H NMR (300 MHz, CDCl3) δ 7.18−7.09
(m, 2H), 6.88−6.75 (m, 2H), 6.14 (d, J = 1.8 Hz, 1H), 3.77 (s, 3H),
2.15−2.03 (m, 1H), 1.91−1.10 (m, 11H), 0.92 (d, J = 6.7 Hz, 6H), 0.83
(d, J = 6.6 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H); HRMS (ESI-TOF) m/z
calcd for C42H64NaO6 [M + Na]+ 687.4595, found [M + Na]+ 687.4576.
TFA (3 drops) was added to a solution of the crude dilactone 53
(4 mg, 0.006 mmol, 1 equiv) and triethylsilane (0.1 mL, 0.63 mmol, 100
equiv) in dichloromethane (1 mL). The solution was stirred at room
temperature for 10 min. Volatiles were removed under vacuum with a
rotary evaporator, and the residue was purified by flash chromatography
(silica gel, 1.5 cm diameter × 20 cm height, 100 mL of hexanes then
1:19 ethyl acetate:hexanes) to yield acid 54 (3 mg, 75%): [α]2D0 +16
(c 0.3, CDCl3); 1H NMR (500 MHz, CDCl3) δ 9.45 (s, 1H), 7.10−7.02
(m, 2H), 6.84−6.76 (m, 2H), 3.78 (s, 3H), 2.51 (dd, J = 13.7, 6.7 Hz,
1H), 2.35 (dd, J = 13.7, 7.8 Hz, 1H), 2.17−2.03 (m, 1H), 1.94−1.79 (m,
1H), 1.75−1.62 (m, 1H), 1.62−1.49 (m, 2H), 1.49−1.36 (m, 2H),
1.36−1.08 (m, 5H), 0.96−0.92 (m, 6H), 0.88 (d, J = 6.9 Hz, 3H), 0.84
(d, J = 6.9 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 179.6, 157.7, 134.5,
130.1, 113.7, 55.4, 52.4, 46.1, 36.3, 30.6, 29.6, 29.5, 28.6, 28.4, 27.7, 20.6,
20.3, 19.3, 16.9; 13C NMR (101 MHz, CDCl3) δ 181.5, 157.7, 134.4,
130.1, 113.7, 55.4, 52.6, 46.1, 36.3, 30.6, 29.5, 29.4, 28.6, 28.2, 27.7, 20.6,
20.2, 19.3, 18.8; IR (neat) 2925, 2860, 1704, 1511, 1461, 1375, 1245,
9543
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
1178, 1038 cm−1; HRMS (ESI_NEG) calcd for C21H33O3 [M − H]−
(6) (a) Kobori, H.; Nangaku, M.; Navar, L. G.; Nishiyama, A.
Pharmacol. Rev. 2007, 59, 251. (b) Wood, J. M.; Stanton, J. L.; Hofbauer,
K. G. J. Enzym. Inhib. 1981, 1, 169. (c) For a historical perspective, see:
Peart, W. S. Proc. R. Soc., B 1969, 173, 317. (d) Skeggs, L. T., Jr.; Kahn, J.
R.; Lentz, K.; Shumway, N. P. J. Exp. Med. 1957, 106, 439.
(7) See, for examples: (a) Kasani, A.; Subedi, R.; Stier, M.; Holsworth,
D. D.; Maiti, S. N. Heterocycles 2007, 73, 47. (b) Tice, C. M. Annu. Rep.
Med. Chem. 2006, 41, 155. (c) Rosenberg, S. H.; Kleinert, H. D. Pharm.
Biotechnol. 1998, 11, 7. (d) Rosenberg, S. H. Prog. Med. Chem. 1995, 32,
37. (e) Greenlee, W. J. Med. Res. Rev. 1990, 2, 173.
(8) (a) Sielecki, A. R.; Hayakawa, K.; Fujinaga, M.; Murphy, M. E. P.;
Fraser, M.; Muir, A. K.; Carilli, C. T.; Lewicki, J. A.; Baxter, J. D.; James,
M. N. G. Science 1989, 243, 1346. (b) Dhanaraj, V.; Dealwis, C. G.;
Frazao, C.; Badasso, M.; Sibanda, B. L.; Tickle, I. J.; Cooper, J. B.;
Driessen, H. P.; Newman, M.; Aguilar, C.; Wood, S. P.; Blundell, T. L.;
Hobart, P. M.; Geoghegan, K. F.; Ammirati, M. J.; Danley, D. E.;
O’Connor, B. A.; Hoover, D. J. Nature 1992, 357, 466.
(9) For reviews, see: (a) Maibaum, J.; Feldman, D. L. Annu. Rep. Med.
Chem. 2009, 44, 105. (b) Jensen, C.; Herold, P.; Brunner, H. R. Nat. Rev.
Drug Discovery 2008, 7, 399. (c) Siragy, H. M.; Kar, S.; Kirkpatrick, P.
Nat. Rev. Drug Discovery 2007, 6, 779.
333.2435, found [M-H]− 333.2440.
Lactone 55. 2,2,2-Trichloroethylsulfamate (14 mg, 0.061 mmol,
1.1 equiv) was added to a solution of lactone 20 (18 mg, 0.055 mmol,
1.0 equiv) in toluene (0.3 mL) followed by magnesium oxide (6 mg,
0.15 mmol, 2.7 equiv) and rhodium trifluoroacetamide dimer (2 mg,
0.003 mmol, 0.04 equiv). The resulting pale blue slurry was cooled to
0 °C, diacetoxyiodobenzene (27 mg 0.083 mmol, 1.5 equiv) was added,
and the reaction was slowly warmed to room temperature. The progress
of the reaction was monitored by TLC analysis (30:70 ethyl acetate−
hexanes, CAM). After 20 h of stirring at room temperature, TLC
analysis showed no more conversion. The reaction mixture was diluted
with dichloromethane, filtered through a pad of Celite, and then washed
with dichloromethane (3 × 10 mL). The solvent was removed under
reduced pressure to leave a brown oil which was purified by flash column
chromatography (silica gel, 1.5 cm diameter ×20.0 cm height, 1:19 ethyl
acetate/hexanes) to yield compound 55 (8 mg, 0.014 mmol; 25%) and
starting material 20 (8 mg, 0.024 mmol, yield based on recovered
starting material: 47%): Rf = 0.27 (1:9 ethyl acetate/hexanes); [α]2D0 −19
(c 0.8, CDCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.7 Hz, 1H),
6.89 (d, J = 8.7 Hz, 1H), 5.85 (d, J = 6.3 Hz, 1H), 4.80 (s, 1H), 3.81
(s, 1H), 2.94 (ddd, J = 12.2, 6.8, 2.6 Hz, 1H), 2.81 (ddd, J = 10.1, 6.8, 3.0
Hz, 1H), 2.48−2.39 (m, 1H), 2.32−2.25 (m, 1H), 2.21−1.99 (m, 1H),
1.97−1.87 (m, J = 14.6, 11.3, 6.2 Hz, 1H), 1.51−1.41 (m, 1H), 1.03 (t,
J = 6.8 Hz, 3H), 0.88 (d, J = 6.6 Hz, 2H), 0.77 (d, J = 6.6 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 173.2, 159.8, 129.2, 128.9, 114.1, 93.1, 79.5,
77.1, 55.4, 49.1, 48.1, 44.1, 43.6, 29.6, 26.9, 26.0, 23.4, 22.6, 21.7, 20.2,
19.7; IR (neat) 2959, 2931, 2873, 2839, 1733, 1612, 1515, 1464, 1369,
1250, 1178, 1118 cm−1; HRMS (ESI-TOF) m/z calcd for
C23H33NO6SCl3 [M + H]+ 556.1089, found [M + H]+ 556.1075.
(10) (a) Webb, R. L.; Schiering, N.; Sedrani, R.; Maibaum, J. J. Med.
Chem. 2010, 53, 7490. (b) Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger,
H.; Goschke, R.; Cohen, N. C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood,
J. M.; Gruetter, M. G. Chem. Biol. 2000, 7, 493.
(11) (a) Wood, J. M.; Maibaum, J.; Rahuel, J.; Grutter, M. G.; Cohen,
̈
N.-C.; Rasetti, V.; Ruger, H.; Goschke, R.; Stutz, S.; Fuhrer, W.;
̈
̈
Schilling, W.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H.-P.;
Schnell, C. R.; Herold, P.; Mah, R.; Jensen, C.; O’Brien, E.; Stanton, A.;
Bedigian, M. P. Biochem. Biophys. Res. Commun. 2003, 308, 698.
(b) Rahuel, J.; Priestle, J. P.; Gruetter, M. G. J. Struct. Biol. 1991, 107,
227.
ASSOCIATED CONTENT
■
S
* Supporting Information
(12) Maibaum, J.; Stutz, S.; Goschke, R.; Rigollier, P.; Yamaguchi, Y.;
̈
1H and 13C NMR spectra of new compounds as well as X-ray
crystallography reports and CIF files for compounds 20, 25, 32,
33, 39, and 49. This material is available free of charge via the
Internet at http://pubs.acs.org.
Cumin, F.; Rahuel, J.; Baum, H.-P.; Cohen, N.-C.; Schnell, C. R.; Fuhrer,
W.; Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50,
4832.
(13) See, for example: (a) Morganti, A.; Lonati, C. J. Nephrol. 2011, 24,
541. (b) Wal, P.; Wal, A.; Rai, A. K.; Dixit, A. J. Pharm. Bioallied Sci. 2011,
3, 189. (c) Mohamed Saleem, T. S.; Jain, A.; Tarani, P.; Ravi, V.;
Gauthaman, K. Syst. Rev. Pharm. 2010, 1, 93. (d) Price, L. Drugs Context
2008, 4, 105. (e) Allikmetz, K. Vasc. Health Risk Manag. 2007, 3, 809.
(f) Fisher, N. D.; Hollenberg, N. K. Exp. Opin. Investig. Drugs 2001, 10,
417.
AUTHOR INFORMATION
Corresponding Author
*E-mail: stephen.hanessian@umontreal.ca.
■
Notes
(14) See, for example: Hanessian, S. Chem. Med. Chem. 2006, 1, 1300.
(15) Hanessian, S.; Raghavan, S. Bioorg. Med. Chem. Lett. 1994, 4, 1697.
(16) (a) Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem. 2002,
67, 4261. (b) For related approaches, see: Acemoglu, M.; Grimler, D.;
Sedelmeier, G. WO 045420 A3, 2007.
(17) For a summary, see: Yokokawa, F.; Maibaum, J. Expert Opin. Ther.
Patents 2008, 18, 581 and references cited therein.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSERC and FQRNT.
We thank Robert D. Giacometti and Benoıt Deschen
̂
̂
es-Simard
for X-ray crystallographic analyses.
(18) See, for example: (a) Goschke, R.; Stutz, S.; Heinzelmann, W.;
̈
Maibaum, J. Helv. Chim. Acta 2003, 86, 2848. (b) Dondoni, A.; De
Lathauwer, G.; Perrone, D. Tetrahedron Lett. 2001, 42, 4819.
REFERENCES
■
(1) (a) Braunwald’s Heart Disease: Review and Assessment; Lilly, L. S.,
Ed.; Elsevier Health Sciences: New York, 2012. (b) Pathophysiology of
Heart Disease; Lilly, L. S., Ed.; Lippincott Williams & Wilkins: New York,
2011. (c) Chilton, R. J. J. Am. Osteopath. Assoc. 2004, 104 (9), S5.
(2) Tigerstedt, R.; Bergman, P. G. Skand. Arch. Physiol. 1898, 8, 223.
(3) White, W. B. Am. J. Med. 2005, 118, 695.
(4) (a) Skeggs, L. T.; Doven, F. E.; Levins, M.; Lentz, K.; Kahn, J. R. In
The Renin-Agiotensin System; Johnson, J. A., Anderson, R. R., Eds.;
Plenum Press: New York, 1980; p 1. (b) McGregor, G. A.; Markandu, N.
D.; Roulston, J. E.; Jones, J. C.; Morton, J. J. Nature 1981, 291, 329.
(c) Reid, I. A.; Morris, B. J.; Ganong, W. F. Annu. Rev. Physiol. 1978, 40,
377.
(c) Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A. Tetrahedron
Lett. 2000, 41, 10091. (d) Rueger, H.; Stutz, S.; Goschke, R.; Spindler,
F.; Maibaum, J. Tetrahedron Lett. 2000, 41, 10085.
̈
̈
̈
(19) (a) Neelam, U. K.; Gangula, S.; Reddy, V. P.; Bandichhor, R.
Chem. Biol. Interface 2013, 3, 14. (b) Lindsay, K. B.; Skrydstrup, T. J. Org.
Chem. 2006, 71, 4766.
(20) (a) Mascia, S.; Heider, P. L.; Zhang, H.; Lakerveld, R.; Benyahia,
B.; Barton, P. I.; Braatz, R. D.; Cooney, C. L.; Evans, J. M.; Jamison, T. F.;
Jensen, K. F.; Myerson, A. S.; Trout, B. L. Angew. Chem., Int. Ed. 2013,
52, 12359. (b) Nam, G.; Ko, S. Y. Helv. Chim. Acta 2012, 95, 1937.
(c) Slade, J.; Liu, H.; Prashad, M.; Prasad, K. Tetrahedron Lett. 2011, 52,
4349. (d) Dong, H.; Zhang, Z.-L.; Huang, J.-H.; Ma, R.; Chen, S.-H.; Li,
G. Tetrahedron Lett. 2005, 46, 6337.
(5) Foundling, S. I.; Cooper, J.; Watson, F. E.; Cleasby, A.; Pearl, L. H.;
Sibanda, B. L.; Hemmings, A.; Wood, S. P.; Blundell, T. L.; Valler, M. J.;
Norey, C. G.; Kay, J.; Boger, J.; Dunn, B. M.; Leckie, B. J.; Jones, D. M.;
Atrash, B.; Hallett, A.; Szelke, M. Nature 1987, 327, 349.
(21) Cee, V. J. In Modern Drug Synthesis; Li, J. J., Johnson, D. S., Eds.; J.
Wiley & Sons: Hoboken, NJ, 2010; Chapter 11.
9544
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545

The Journal of Organic Chemistry
Article
(22) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737. (b) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem.
Soc. 1981, 103, 2127. (c) Evans, D. A.; Takacs, J. M. Tetrahedron Lett.
1980, 21, 4233.
(46) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582.
(47) (a) Thiel, O. R.; Ackermann, L.; Furstner, A. Org. Lett. 2001, 3,
̈
449. (b) Kozmin, Sergey A.; Adams, C. M.; Paone, D. V.; Smith, A. B.,
III. J. Am. Chem. Soc. 2000, 122, 4984.
(23) (a) Sckhollkopf, U.; Westphalen, K.-O.; Schroder, J.; Horn, K.
̈
̈
Liebigs Ann. Chem. 1988, 781. (b) Schollkopf, U. Pure Appl. Chem. 1983,
55, 1799.
̈
(24) See, for example: (a) Milan, S. US Patent 0296100A1, 2012.
(b) Satyanarayna Reddy, M.; Thirumalai Rajan, S.; Eswaraiah, S.; Venkat
Reddy, G.; Rama Subba Reddy, K.; Sahadeva Reddy, M. WO 148392 A1,
2011. (c) Kidemet, D.; Zupet, R.; Smodis, J.; Stefane, B.; Pozgan, F. EP
2189442A1, 2010. (d) Meier, V.; Reuter, K.; Stolz, F.; Wedel, T. WO
049837 A1, 2009.
(25) (a) Herold, P.; Stutz, S. EP 1303478B1, 2004. (b) Herold, P.;
Stutz, S. WO 0202487 A1, 2002. (c) Herold, P.; Stutz, S. WO 02092828
A3, 2002. (d) Herold, P.; Stutz, S.; Spindler, F. WO 0202508 A1, 2002.
(e) See also: Boogers, J. A. F.; Felfer, U.; Kotthaus, M.; Lefort, L.;
Steinbauer, G.; de Vries, A. H. M.; de Vries, J. G. Org. Process Res. Dev.
2007, 11, 585. (f) Sturm, T.; Weissensteiner, W.; Spindler, F. Adv. Synth.
Catal. 2003, 345, 160.
(26) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(27) Hanessian, S.; Chen
(28) Hanessian, S.; Guesne,
́
ard, E. Org. Lett. 2012, 14, 3222.
́
S.; Chenard, E. Org. Lett. 2010, 12, 1816.
́
(29) For a relevant review, see: (a) Handbook of Metathesis; Grubbs, R.
H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1−3. (b) Schwab, P.;
Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
(30) (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4592. (b) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(31) See the Supporting Information
(32) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333.
(33) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(34) For examples of the use of Ti(O-i-Pr)4 in metathesis reactions,
see: (a) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.;
Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81. (b) Furstner, A.;
̈
Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130.
(35) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791.
(36) For example, see: (a) Shiina, I. Chem. Rev. 2007, 107, 239.
(b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(37) For recent studies on the influence of substituent in ring-closing
metathesis to form 9-membered lactone, see: (a) Ramírez-Fernan
́
dez, J.;
Collado, I. G.; Hernandez-Galan, R. Synlett 2008, 339. (b) Takahashi,
́
́
T.; Wataqnabe, H.; Kitahara, T. Heterocycles 2002, 58, 99. (c) Baba, Y.;
Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.;
Takemoto, Y. J. Org. Chem. 2001, 66, 81.
(38) Thakur, V. V.; Talluri, S. K.; Sudalai, A. Org. Lett. 2003, 5, 861.
(39) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672.
(40) Ramarao, C.; Michel, P. T.; Navakoti, R.; Nandipati, R. D.; Rao,
R.; WO 064790 A1, 2011.
(41) Openshaw, H. T.; Whittaker, N. J. Chem. Soc. C 1969, 89.
(42) Mickel, S. J.; Sedelmeier, G.; Hirt, H.; Schafer, F.; Foulkes, M. WO
̈
131304, 2006.
(43) Foley, M. A.; Jamison, T. F. Org. Process Res. Dev. 2010, 14, 1177.
(44) (a) Arena, G.; Barreca, G.; Carcone, L.; Cini, E.; Marras, G.;
Nedden, H. G.; Rasparini, M.; Roseblade, S.; Russo, A.; Taddei, M.;
Zanotti-Geraso, A. Adv. Synth. Catal. 2013, 355, 1449. (b) Taddei, M.;
Russo, A.; Cini, E.; Riva, R.; Rasparini, M.; Carcone, L.; Banfi, L.; Vitale,
R.; Roseblade, S.; Zanotti-Gerosa, A. WO 151442 A2, 2011.
(45) For reviews, see: (a) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature
2008, 455, 323. (b) Mohr, J. T.; Stoltz, B. M. Chem.Asian J. 2007, 2,
1476. (c) You, S.-L.; Dai, L.-X. Angew. Chem., Int. Ed. 2006, 45, 5246.
For the design, synthesis, and reactivity of chiral phosphinooxazolines
(PHOX) ligands, see: (d) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336 and references cited therein. (e) Williams, J. M. J. Synlett 1996,
705.
9545
dx.doi.org/10.1021/jo5015195 | J. Org. Chem. 2014, 79, 9531−9545