Catalytic Macrocyclization Strategies Using Continuous Flow: Formal Total Synthesis of Ivorenolide A

Article abstract of DOI:10.1021/acs.joc.6b01500

A formal total synthesis of ivorenolide A has been accomplished employing a Z-selective olefin cross metathesis and a macrocyclic Glaser-Hay coupling as key steps. The macrocyclization protocol employed a phase separation/continuous flow manifold whose ad

Full text of DOI:10.1021/acs.joc.6b01500

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Article
Catalytic Macrocyclization Strategies Using Continuous
Flow: Formal Total Synthesis of Ivorenolide A
Mylène de Léséleuc, Eric Godin, Shawn Parisien-Collette, Alexandre Levesque, and Shawn K. Collins
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01500 • Publication Date (Web): 12 Jul 2016
Downloaded from http://pubs.acs.org on July 23, 2016
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Catalytic Macrocyclization Strategies Using
Continuous Flow: Formal Total Synthesis of
Ivorenolide A.
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§
§
Mylène de Léséleuc, Éric Godin, Shawn Parisien-Collette, Alexandre Lévesque and Shawn K.
Collins*
Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal,
CP 6128 Station Downtown, Montréal, Québec CANADA H3C 3J7
ABSTRACT A formal total synthesis of ivorenolide A has been accomplished employing a Zꢀ
selective olefin cross metathesis and a macrocyclic GlaserꢀHay coupling as key steps. The
macrocyclization protocol employed a phase separation/continuous flow manifold whose
advantages include catalysis, fast reaction times, high concentrations and facile scaleꢀup.
INTRODUCTION
Macrolides are a family of macrocyclic natural products having a wide array of biological
1
activities. From a synthetic perspective, several methods have evolved as the most popular
2
candidates for macrocyclization. Macrolactonization via stoichiometric activation of secoꢀacids,
3
such as the Yamaguchi protocol, is without a doubt the most popular method for constructing
the ester motif of macrolides. Another common synthetic route to form macrocycles involves
carbonꢀcarbon bond formation via transition metal catalysis, usually using olefin metathesis or
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crossꢀcoupling strategies. Despite the utility displayed by the above transformations, the
macrocyclizations are usually performed at low concentration, and rely upon slow addition
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techniques. Consequently, scaleꢀup of the target macrocycles becomes problematic, which is
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disappointing when promising biological activity is observed. The ivorenolides A and B are a
unique class of macrolides which possess 1,3ꢀdiyne motifs isolated from the stem bark of K.
ivorensis (Figure 1). Their immunosuppressive activities make them attractive targets for
medicinal chemistry investigations given the need for new immunosuppressants with improved
therapeutic profiles. Total syntheses of both the natural and unnatural enantiomers of ivorenolide
A have appeared in the literature, each exploiting a macrolactonization employing stoichiometric
activation strategies and high dilution and/or slow addition as the key macrocyclization step
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,8
(Figure 1). As such, the development of alternative methods for macrocyclization that would
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employ catalysis, high concentrations and facilitate scaleꢀup would be highly desirable. Our
group has put forth an alternative strategy for the synthesis of macrocycles via GlaserꢀHay
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coupling using a “phase separation” strategy. The protocol was shown to exploit aggregation
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effects caused by mixtures of poly(ethylene)glycol (PEG) coꢀsolvents. During the development
of the “phase separation” technology, it was apparent that the substrate scope explored to date
was limited, and did not address the influence of chiral centers, steric hindrance about the alkyne
reaction centers or tolerance to common protecting groups. In addition, no investigation of the
feasibility of scaleꢀup of complex macrocycles at the gram scale had been demonstrated. To
respond to the aforementioned questions, the formal total synthesis of ivorenolide A by
application of the “phase separation” strategy under continuous flow techniques is described
herein (Figure 1).
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Figure 1. Macrocyclization strategies via continuous flow towards ivorenolide A. Ring sizes are
in red.
RESULTS/DISCUSSION
The retrosynthetic analysis for the development of a phase separation/continuous flow
macrocyclization towards the synthesis of ivorenolide A aimed to prepare the 18ꢀmembered
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macrolactone 1 intermediate, which was previously prepared by Yadav and Yue as well as a
simplified model 1a (Figure 2). Envisioning the macrocyclization event arising from GlaserꢀHay
coupling of two terminal alkynes, the linear precursor 2 was selected as a target for the formation
of macrocycle 1, while the macrocyclization of the model 18ꢀmembered macrolactone 1a was
also imagined arising from GlaserꢀHay coupling of linear precursor 2a. Each ester (2 and 2a)
could be prepared from esterification of the alcohol 3 with a corresponding carboxylic acid
derivative.
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Figure 2. Retrosynthetic analysis towards the macrocyclic core of ivorenolide A (2→1) and a
simplified model (2a→1a). Ring sizes are in red.
The synthesis of alkynyl alcohol 3 commenced from TBSꢀprotected (S)ꢀmethyl lactate
Scheme 1). Reduction of the ester 5 to the corresponding aldehyde 6 using DIBALꢀH and
(
addition of the organolithium derived from trimethylsilyl acetylene afforded solely the desired
diastereomer. Subsequent MOMꢀprotection afforded the fully protected alkyne 7 in 52% yield
over two steps. Removal of both silyl protecting groups provided 3 in 94% yield. Esterification
of alcohol 3 using DCC/DMAP conditions with known carboxylic acid 8 provided the
macrocyclization precursor 2a in 75% yield.
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Scheme 1. Synthesis of alcohol 3 and diyne 2a analysis towards the macrocyclic core of
ivorenolide A (2→1) and a simplified model (2a→1a).
The carboxylic alkynyl synthon 1a required for the synthesis of macrocycle 1 was then
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envisioned arrising from a Zꢀselective cross metathesis process. The MOMꢀprotected substrate
racꢀ11 could be prepared in two steps via alkynylation of acrolein and subsequent protection
from MOMCl. To test the synthetic route, several cross metathesis reactions were evaluated on
the racemic, MOMꢀprotected secondary alcohol racꢀ11 (Scheme 2)
1
) n-BuLi (1 equiv)
RN
Ru
NR
Cl
OH
THF, -78 °C, 1 h
TIPS
2
) acrolein (1.2 equiv)
Cl
TIPS
rac-10
9
-
78 °C to 0 °C, 1 h
O
90%
MOMCl (2 equiv)
DIPEA (2 equiv)
R = o-tol 14
NR
CH Cl
2
2
0 to rt, 18 h
0%
N
8
CO2Me 12
( )7
CO Me
2
Ru
O
(
)7
O
catalyst
x mol %)
OMOM
(
O
N
OMOM
O
2
CH Cl2
TIPS
temperature (°C)
8 h
rac-13
rac-11
R = Mes 15a
R = DIPP 15b
1
TIPS
14 (2 mol %) [0.1 M] 21 °C, 47%, < 1% Z
1
1
5a (10 mol %) [0.5 M] 60 °C, 16%, 75% Z
5a (10 mol %) [0.5 M] 60 °C, 59%, 95% Z
Scheme 2. Optimization of a Zꢀselective cross metathesis to prepare racemic 13.
Cross metathesis was first evaluated with 1.0 equivalent of methyl ester 12 at room
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temperature using the StewartꢀGrubbs catalyst 14. The desired product racꢀ13 was obtained in
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7% yield and isolated as the pure Eꢀisomer. Next, two Ruꢀbased Zꢀselective catalysts were
1
5
evaluated, each having a different NHC in which the Nꢀaryl substituent differed. After a brief
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survey of reaction conditions, it was found that the DIPPꢀbearing catalyst 15b at 10 mol%, 60
°
C and at [0.5 M] afforded a 59% yield of the desired olefin racꢀ13, in excellent Zꢀselectivity
1
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(
95% Z). Cross metathesis using the mesityl catalyst 15a was not as selective (75% Z). With
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optimized conditions for the cross metathesis procedure in hand, the synthesis of the
enantioenriched carboxylic acid 16 was undertaken (Scheme 3). First the enantiomerically pure
alcohol 10 could be obtained via a previously reported CBS reduction, or via diastereomeric
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resolution. The alcohol 10 was protected as its MOM ether 11 in 94% yield and subsequently
subjected to Zꢀselective cross metathesis. To improve reproducibility at larger scales, an applied
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vacuum was used for removing ethylene. Consequently, the yield and selectivity of the reaction
remained reproducible at 43% (68% based on recovered starting material) and >95% Z with a
shorter reaction time (6 h vs. 18 h). With enantiopure olefin 13 in hand, desilylation was
performed using TBAF to provide the corresponding terminal alkyne in 92% yield (Scheme 3).
Saponification of the ester afforded the carboxylic acid 16 in 99% yield. Esterification of acid
16 with secondary alcohol 3 was promoted by reaction with DCC and DMAP to provide the
desired compound 2 in 62% yield.
Scheme 3. Synthesis of linear precursor 2 for macrocyclization to form the macrocyclic core of
ivorenolide A.
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With both key linear precursors in hand, attempted macrocyclization was performed first using
the simplified model 2a (Scheme 4). As such, the bisꢀalkyne 2a was cyclized under slow
addition conditions, using superꢀstoichiometric amounts of CuCl (12 equiv.) and ligand
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(
TMEDA, 20 equiv.) in refluxing toluene. Slow addition was performed over 36 h and the
refluxing reaction mixture (final concentration 0.2 mM) was left to stir for another 12 h to
promote conversion of all the starting material 2a. Macrocycle 1a was isolated following silica
gel chromatography in 36% yield. When identical reaction conditions were used to cyclize the
more complex macrocyclization precursor 2, the yield of the desired macrocycle 1 was higher at
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5%. Next, the macrocyclization precursors were subjected to phase separation conditions at
~
120 times the concentration employing reaction conditions previously developed for cyclization
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under microwave heating. For the cyclization of 2a, a 40% yield of macrocycle 1a was isolated.
Similar yields (30%) were also observed using the linear precursor 1. Each bisꢀalkyne was
observed to be sensitive to the basic conditions of the protocol for macrocyclization and it was
hoped that the precise control over temperature/reaction time using continuous flow would be
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advantageous. For the model precursor 2a, macrocyclizations under continuous flow
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conditions were evaluated with different ratios of PEG solvent to MeOH (Table 1). Based upon
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previous work, residence times of 1ꢀ2 h were selected for study. Consequently, a low flow rate
(0.167 mL/min) combined with a 20 mL reactor volume were necessary (two 10 mL reactor coils
were connected in series). In addition, since higher ratios of PEG /MeOH typically provide
4
00
higher selectivity for macrocyclization versus oligomerization, albeit with longer reaction times,
the optimization of the macrocyclization was conducted with a 2 h residence time. When
precursor 2a was cyclized at 120 °C, with a residence time of 2 h in PEG /MeOH (1:1) a 30%
4
00
yield of macrocycle 1a was isolated. Efforts to boost yields through increasing the ratio of
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PEG /MeOH to 4:1 resulted in lower yields, and a ratio of PEG /MeOH (8:1) required longer
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reaction times (4 h). Switching the solvent from PEG400 to PPG , a poly(propylene)glycol
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solvent previously demonstrated to be efficient in “phase separation”ꢀtype macrocyclizations,
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provided the best yield of macrocycle 1a (38ꢀ40% yield).
Scheme 4. Macrocyclizations under slow addition conditions (a) and macrocyclizations under
phase separation/microwave heating (b) to form macrocycles 1 and 1a. Ring sizes in red.
To demonstrate the feasibility of using the “phase separation” strategy alongside continuous
flow for large scale preparation of macrolide type macrocycles, the macrocyclization (2a→1a)
was repeated at gram scale and provided identical yields to what was observed at smaller scales
(50ꢀ150 mg). Gram scale cyclization of diyne 2a required 120 mL of the PPG :MeOH (2:1)
425
solvent mixture, while the equivalent slow addition experiment would have required >14 L of
PhMe. When a similar set of conditions were used for the macrocyclization of precursor 2
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possessing the additional Zꢀolefin and propargylic stereocenter, the best conditions surveyed
utilized 120 °C, with a residence time of 2 h in PEG /MeOH (1:1) for a 52% yield of
400
macrocycle 1. The higher yield of macrocycle 1 (52%) versus the model macrocycle 1a under
similar reaction conditions could be explained by the effects of the additional cisꢀolefin and
stereocenter in the respective precursor 2 versus 2a. The addition of the olefin and hydroxyl
motifs could promote a conformational bias to help bring the alkyne functionalities closer to one
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another. Consequently, the use of the phase separation/continuous flow conditions for the
preparation of the ivorenolide macrocycle 1 provided several advantages to using a traditional
slow addition type strategy. In addition to providing a similar yield (55 vs 52% of 1), reaction
under the phase separation/continuous flow manifold were catalytic as opposed to using superꢀ
stoichiometric quantities of ligand and metal source, the reaction time was significantly
shortened (48 vs 2 h) and the concentration was greater by more than two orders of magnitude
(0.2 vs 24 mM).
Table 1 Macrocyclizations using the phase separation strategy in continuous flow.
PEG
solvent
Ratio
(PEG:MeOH)
Temp.
(°C)
a
Yield (%)
macrocyclization 2a→1a
1:1 120
1
PEG400
30 (<5)
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PEG400
PEG400
PEG400
PPG425
2:1
4:1
8:1
2:1
120
120
120
120
26 (<5)
19 (24)
b
14 (18)
c
38ꢀ40
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macrocyclization 2→1
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PEG400
PEG400
PEG400
1:1
2:1
4:1
120
120
100
52 (0)
37 (<5)
27 (30)
a
b
Yields following chromatography. Recovered starting material in parentheses. 4 h reaction
time. Reactions performed at 80 or 100 °C afforded similar yields with small amounts of
unreacted 2a. For ease of purification, the reaction was kept at 120 °C. Ring sizes in red.
c
CONCLUSIONS
In summary, a formal total synthesis of ivorenolide A has been accomplished using a
macrocyclic catalytic oxidative coupling of terminal alkynes and a Zꢀselective cross metathesis
as key steps. Macrocyclization has been demonstrated employing a phase separation/continuous
flow method that is applicable to complex macrolides bearing chiral centers, steric hindrance
about the alkynes and common protecting groups. The macrocyclization also described for the
first time that continuous flow protocols allows for much more facile scaleꢀup that would be
highly problematic using high dilution strategies or microwave heating. The phase separation
strategy produced good yields of the desired macrocycles employing catalysis in place of
stoichiometric reagents, faster reaction times than the corresponding batch reactions and at
concentrations ~120X greater than the slow addition strategy.
Given the rarity of
macrocyclizations performed under continuous flow, and the importance of macrocycles in both
natural product synthesis and medicinal chemistry, the use of the phase separation/continuous
flow method would be expected to have significant impact.
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EXPERIMENTAL SECTION
All reactions that were carried out under anhydrous conditions were performed under an inert
o
argon or nitrogen atmosphere in glassware that had previously been dried overnight at 120 C or
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had been flame dried and cooled under a stream of argon or nitrogen. All chemical products
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obtained were reagent quality. Tridecꢀ12ꢀynoic acid , (
±
)ꢀ3ꢀhydroxyꢀ5ꢀ(triisopropylsilyl)pentꢀ1ꢀ
1
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enꢀ4ꢀyne, (3S)ꢀ3ꢀhydroxyꢀ5ꢀ(triisopropylsilyl)pentꢀ1ꢀenꢀ4ꢀyne and Methyl decꢀ9ꢀenoate were
prepared according to literature procedure. Anhydrous solvents (CH Cl , Et O, THF, DMF,
2
2
2
toluene, and nꢀhexane) were dried and deoxygenated. Isolated yields reflect the mass obtained
following flash column silica gel chromatography. Organic compounds were purified using the
2
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method reported by W. C. Still and using silica gel (40ꢀ63 nm; 230ꢀ240 mesh). Analytical thinꢀ
layer chromatography (TLC) was performed on glassꢀbacked silica gel 60 coated with a
fluorescence indicator. Visualization of TLC plate was performed by UV (254 nm), KMnO or
4
pꢀanisaldehyde stains. All mixed solvent eluents are reported as v/v solutions. Concentration
refers to removal of volatiles at low pressure on a rotary evaporator. All reported compounds
1
were homogeneous by thin layer chromatography (TLC) and by H NMR. NMR spectra were
taken in deuterated CDCl unless otherwise noted. Signals due to the solvent served as the
3
1
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internal standard (CHCl : δ 7.27 for H, δ 77.0 for C). The acquisition parameters are shown on
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all spectra. The H NMR chemical shifts and coupling constants were determined assuming firstꢀ
order behavior. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet),
t (triplet), app t (apparent triplet), q (quartet), app quin(apparent quintet), m (multiplet), br
(
broad); the list of couplings constants (J) corresponds to the order of the multiplicity
assignment.
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Methyl (S)ꢀ2ꢀ((tertꢀbutyldimethylsilyl)oxy)propanoate (5) TBSCl (8.68 g, 57.6 mmol, 1.2
equiv.) and imidazole (3.92 g, 57.6 mmol, 1.2 equiv.) were added to a solution of Methyl (S)ꢀ2ꢀ
hydroxypropanoate (4) (4.6 mL, 48.0 mmol, 1.0 equiv.) in CH Cl (120 mL) at 0 °C. The
2
2
0
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solution was stirred for 3 h at room temperature. Brine was then added and the organic and
aqueous layers were separated. The aqueous phase was extracted with CH Cl (3X) and the
2
2
combined organic phases were washed with brine, dried over anhydrous Na SO filtered and
2
4,
concentrated under reduced pressure. Flash chromatography (6% EtOAc in hexanes) was
performed to afford the product as a colorless oil (10.27 g, 98%). Spectral data were in
29
accordance with those previously reported in the literature.
(S)ꢀ2ꢀ((tertꢀbutyldimethylsilyl)oxy)propanal (6) DIBALꢀH 1 M in hexanes (20.0 mL, 20.0
mmol, 1.5 equiv.) was added dropwise to a solution of methyl (S)ꢀ2ꢀ((tertꢀ
butyldimethylsilyl)oxy)propanoate (5) (2.92 g, 13.35 mmol, 1.0 equiv.) in anhydrous Et O (45
2
mL) at ꢀ78 °C and stirred for 3 h. The solution was then quenched with a solution of sodium and
potassium tartrate and the organic and aqueous layers were separated. The aqueous layer was
extracted with Et O (3X). The combined organic layers were washed with brine, dried over
2
anhydrous Na SO , filtered and concentrated under reduced pressure. Flash chromatography
2
4
(
10% Et O in hexanes) was performed to afford the product as a colorless oil (1.92 g, 77%).
2
6
Spectral data were in accordance with those previously reported in the literature.
(3R,4S)ꢀ4ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ1ꢀ(trimethylsilyl)pentꢀ1ꢀynꢀ3ꢀol (S1) nꢀBuLi 1.35
M in THF (11.5 mL, 15.6 mmol, 1.5 equiv.) was added dropwise to a solution of
ethynyltrimethylsilane (2.2 mL, 15.6 mmol, 1.5 equiv.) in anhydrous THF (23 mL) at ꢀ78 °C.
The solution was stirred for 2 h at 0 °C. (S)ꢀ2ꢀ((tertꢀbutyldimethylsilyl)oxy)propanal (6) (1.96 g,
10.4 mmol, 1.0 equiv.) was added to the solution at ꢀ78 °C and stirred for an additional hour. The
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solution was then quenched with a solution of sodium and potassium tartrate. The resulting
mixture was vigorously stirred for 2 h before Et O (30 mL) was added to the mixture. The
2
organic and aqueous layers were separated. The aqueous layer was extracted with Et O (3X).
2
10
11
12
13
14
15
16
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The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered and
2
4
concentrated under reduced pressure. Flash chromatography (100% Hexanes to 4% EtOAc in
hexanes) was performed to afford exclusively the desired diastereoisomer as a white solid (1.55
30
g, 52%). Spectral data were in accordance with those previously reported in the literature.
(5R,6S)ꢀ6,8,8,9,9ꢀpentamethylꢀ5ꢀ((trimethylsilyl)ethynyl)ꢀ2,4,7ꢀtrioxaꢀ8ꢀsiladecane (7) In
a sealable tube, NaI (135 mg, 0,89 mmol, 10 mol%) was added to a solution of (3R,4S)ꢀ4ꢀ((tertꢀ
butyldimethylsilyl)oxy)ꢀ1ꢀ(trimethylsilyl)pentꢀ1ꢀynꢀ3ꢀol (S1) (2.58 g, 8.9 mmol, 1.0 equiv.) in
CH Cl (90 mL). The solution was cooled to 0 °C and iPr NEt (3.13 mL, 17.9 mmol, 2.0 equiv.)
2
2
2
and MOMCl (2.05 mL, 26.9 mmol, 3.0 equiv.) were added. The mixture was stirred for 18 h at
0 °C then quenched with water and the organic and aqueous layers were separated. The aqueous
layer was extracted with CH Cl (3X). The combined organic layers were washed with brine,
6
2
2
dried over anhydrous Na SO filtered and concentrated under reduced pressure. Flash
2
4,
chromatography (100% Hexanes to5 % EtOAc in hexanes) was performed to afford the product
as a yellow oil (2.97 g, 99%). Spectral data were in accordance with those previously reported in
7
the literature.
(2S,3R)ꢀ3ꢀ(methoxymethoxy)pentꢀ4ꢀynꢀ2ꢀol (3) TBAF (1 M in THF) (53.9 mL, 53.9 mmol,
6
equiv.) was added to a solution of (5R,6S)ꢀ6,8,8,9,9ꢀpentamethylꢀ5ꢀ((trimethylsilyl)ethynyl)ꢀ
,4,7ꢀtrioxaꢀ8ꢀsiladecane (7) (2.97 g, 9.0 mmol, 1.0 equiv.) in anhydrous THF (45 mL) and
2
stirred for 3 h at room temperature. The solution was then quenched with water and the organic
and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3X). The
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combined organic layers were washed with brine, dried over anhydrous Na SO filtered and
2
4,
concentrated under reduced pressure. Flash chromatography (30 % EtOAc in hexanes) was
1
performed to afford the product as a yellow oil (1.22 g, 94%). H NMR (400 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4.96 (d, J = 8 Hz, 1H), 4.70 (d, J = 8 Hz, 1H), 4.31ꢀ4.29 (m, 1H), 3.98ꢀ3.95 (m, 1H), 3.42 (s,
13
1
3H), 2.50 (d, J = 2 Hz, 1H), 2.38 (bs, 1H) 1.31 (d, J = 4 Hz, 3H) ppm. C{ H} NMR (75 MHz,
+
CDCl ) δ 94.4, 79.0, 75.8, 70.8, 69.1, 55.9, 18.1 ppm. HRMS (ESI ) m/z calculated for
3
+
C H NaO [M+Na] : 167.0679; found: 167.0675.
7
12
3
(2S,3R)ꢀ3ꢀ(methoxymethoxy)pentꢀ4ꢀynꢀ2ꢀyl tridecꢀ12ꢀynoate (2a) DCC (946 mg, 4.6 mmol,
equiv.), DMAP (840 mg, 6.9 mmol, 3 equiv.) and (2S,3R)ꢀ3ꢀ(methoxymethoxy)pentꢀ4ꢀynꢀ2ꢀol
2
(3) (331 mg, 2.3 mmol, 1 equiv.) were added to a solution of tridecꢀ12ꢀynoic acid (8) (723 mg,
3.4 mmol, 1.5 equiv.) in CH Cl (10 mL) and stirred for 18 h at room temperature. The solution
2
2
was then placed in the freezer for 12 h and the precipitated urea was filtered. Silica gel was
added to the filtrate and the slurry was concentrated under reduced pressure. Flash
chromatography (100% hexanes to 10% EtOAc in hexanes) was performed to afford the product
1
as a colorless oil (579 mg, 75%). H NMR (400 MHz, CDCl ) δ 5.1ꢀ5.10 (m, 1H), 4.92 (d, J =
3
6.8 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 4.42 (dd, J = 4 Hz, J = 2.1 Hz, 1H), 3.40 (s, 3H), 2.45 (d, J
=
2.2 Hz, 1H), 2.33 (t, J = 7.5 Hz, 2H), 2.19 (td, J = 7.1 Hz, J = 2.7 Hz, 2H), 1.95 (t, J = 2.7 Hz,
1
3
1
1
H), 1.65ꢀ1.61 (m, 2H), 1.56ꢀ1.49 (m, 2H), 1.40ꢀ1.28 (m, 15H) ppm. C{ H} NMR (75 MHz,
CDCl ) δ 173.1, 94.2, 84.8, 79.1, 75.0, 70.8, 68.0, 67.4, 55.7, 34.4, 29.40, 29.36, 29.2, 29.0 (2C),
3
+
+
2
8.7, 28.5, 24.9, 18.4, 15.1 ppm. HRMS (ESI ) m/z calculated for C H NO [M+NH ] :
20 36 4 4
3
54.2639; found: 354.2648.
3S)ꢀ3ꢀ(NꢀBocꢀLꢀphenylalanine)ꢀ5ꢀ(triisopropylsilyl)pentꢀ1ꢀenꢀ4ꢀyne (S2) DCC (2.74 g,
(
13.3 mmol, 2 equiv.), DMAP (2.43 g, 19.9 mmol, 3 equiv.) and (±)ꢀ3ꢀhydroxyꢀ5ꢀ
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(
triisopropylsilyl)pentꢀ1ꢀenꢀ4ꢀyne (racꢀ10) (1.58 g, 6.64 mmol, 1 equiv.) were added to a
solution of NꢀBocꢀLꢀphenylalanine (2.64 g, 9.96 mmol, 1.5 equiv.) in CH Cl (10 mL) and
2
2
stirred for 18 h at room temperature. The solution was then placed in the freezer for 12 h and the
precipitated urea was filtered. Silica gel was added to the filtrate and the slurry was concentrated
10
11
12
13
14
15
16
17
18
19
20
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23
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42
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47
48
49
50
51
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53
54
55
56
57
58
59
60
under reduced pressure. Flash chromatography (100% hexanes to 7% Et O in hexanes) was
2
1
performed to separate the diastereomers and isolate S2 as a colorless oil (923 mg, 29%). H
NMR (400 MHz, CDCl ) δ 7.29ꢀ7.15 (m, 5H), 5.92 (d, J = 4.4Hz, 1H), 5.98ꢀ5.81 (m, 1H), 5.61
3
(d, J = 13.7 Hz, 1H), 5.34 (d, J = 9.8Hz, 1H), 4.96 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 5.8 Hz, 1H),
13
1
3
.13ꢀ3.06 (m, 2H), 1.42 (s, 9H), 1.10ꢀ1.09 (m, 21 H) ppm. C{ H} NMR (100 MHz, CDCl ) δ
3
170.5, 155.0, 135.8, 132.5, 129.5, 129.4, 128.5, 127.0, 119.6, 119.4, 101.4, 89.7, 79.9, 65.6, 54.2,
+
37.9, 54.2, 37.9, 28.3, 18.5, 11.1 ppm. HRMS (ESI ) m/z calculated for C H NO SiNa
2
8
43
4
+
[
M+Na] : 508.2854; found: 508.2865.
±)ꢀ3ꢀhydroxyꢀ5ꢀ(triisopropylsilyl)pentꢀ1ꢀenꢀ4ꢀyne (10) The amino acid adduct (S3) (960
(
mg, 1.98 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (16 mL). Then LiOH (190 mg, 7.92
mmol, 4.0 equiv.) was added as an aqueous solution (4 mL). The reaction mixture was stirred at
o
65 C for 18 h. The reaction was then cooled to room temperature and HCl (1 M) was added until
the mixture was neutralized (pH = 7). Extraction with EtOAc (3 X 5 mL) was performed and the
combined organic phases were washed with brine (15 mL). The organic phase was dried over
Na SO and concentrated under reduced pressure to afford the desired product as a white solid
2
4
(421 mg, 89%). Spectral data were in accordance with those previously reported in the
1
8
literature.
(3S)ꢀ3ꢀ(methoxymethoxy)ꢀ5ꢀ(triisopropylsilyl)pentꢀ1ꢀenꢀ4ꢀyne (11) The alcohol (10) (1.50
g, 6.30 mmol, 1.00 equiv.) was dissolved in CH Cl (31 mL). iPr NEt (2.19 mL, 12.6 mmol,
2
2
2
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5
5
5
5
5
5
5
5
5
5
6
2
.00 equiv.) was added to the solution. MOMCl (0.96 mL, 12.6 mmol, 2.00 equiv.) was carefully
added at 0 °C and the reaction mixture was stirred at room temperature for 18 h. The reaction
was quenched by addition of water (20 mL) and extracted with CH Cl (2 x 15 mL). The
2
2
0
1
2
3
4
5
6
7
8
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1
2
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8
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4
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7
8
9
0
combined organic phases were washed with brine, dried over Na SO and concentrated under
2
4
reduced pressure. Flash chromatography (5% Et O in hexanes) was performed to obtain the
2
1
product as a colorless oil (1.42 g, 80%). H NMR (CDCl , 400 MHz) δ = 5.94 (ddd, J = 17.0 Hz,
3
10.2 Hz, 5.5 Hz, 1H), 5.56 (dt, J = 17.0 Hz, 1.2 Hz, 1H), 5.28 (dt, J = 10.2 Hz, 1.2 Hz, 1H), 4.98
(d, J = 6.7 Hz, 1H), 4.90 (dt, J = 5.5 Hz, 1.2 Hz, 1H), 4.68 (d, J = 6.7 Hz, 1H), 3.41 (s, 3H), 1.10ꢀ
13
1
1
.03 (m, 21H) ppm; C{ H} NMR (CDCl , 75 MHz) δ = 134.9, 117.7, 103.6, 93.7, 88.4, 66.7,
3
+
+
55.7, 18.6, 11.1 ppm; HRMS (ESI ) calculated for C H O SiNa [M + Na] 305.1907, found
16 30 2
3
1
305.1907.
Methyl (11S, 9Z)ꢀ11ꢀ(methoxymethoxy)ꢀ13ꢀ(triisopropylsilyl)tridecꢀ9ꢀenꢀ12ꢀynoate (13) A
flameꢀdried sealable tube was charged with CH Cl (2.75 mL), Methyl decꢀ9ꢀenoate (254 mg,
2
2
1.38 mmol, 1.00 equiv.) and ther ester (12) (390 mg, 1.38 mmol, 1.00 equiv.). The catalyst (15b)
(47 mg, 0.069 mmol, 0.05 equiv.) was added and the tube was sealed. The reaction mixture was
allowed to stir for 3 h at 60 °C. A second equivalent of Methyl decꢀ9ꢀenoate (12) (254 mg, 1.38
mmol, 1.00 equiv.) was added and the reaction mixture was allowed to stir for an additional 3 h.
During the reaction time, the mixture was put under vacuum for 5 seconds every hour to
eliminate the ethylene formed. After being cooled down to room temperature, silica was added
and the slurry was concentrated under reduced pressure. Flash chromatography (5 to 10% Et O
2
in hexanes) was performed to afford the product as a colorless oil (258 mg, 43% (68% BRSM),
1
>
95:5 Z : E). H NMR (CDCl , 400 MHz) δ = 5.64ꢀ5.52 (m, 2H), 5.14 (d, J = 8.2 Hz, 1H), 4.95
3
(d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 3.67 (s, 3H), 3.40 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H),
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13
1
2
.17ꢀ2.11 (m, 2H), 1.66ꢀ1.60 (m, 2H), 1.42ꢀ1.29 (m, 8 H), 1.11ꢀ1.05 (m, 21 H) ppm; C{ H}
NMR (CDCl , 100 MHz) δ = 174.2, 133.9, 127.1, 105.2, 93.3, 86.6 61.5, 55.6, 51.4, 34.1, 29.3,
3
+
2
9.11, 29.05, 29.03, 27.7, 24.9, 18.6. 11.1 ppm; HRMS (ESI ) calculated for C H O SiNa [M
2
5
46
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
3
2
+
Na] 461.3058, found 461.3063.
Methyl (11S, 9Z)ꢀ11ꢀ(methoxymethoxy)tridecꢀ9ꢀenꢀ12ꢀynoate (S3) The protected alkyne
13) (390 mg, 0.890 mmol, 1.00 equiv.) and THF (2.67 mL) was added to a flameꢀdried roundꢀ
(
bottom flask under N . TBAF (1 M in THF, 1.78 mL, 1.78 mmol, 2.0 equiv.) was slowly added
2
and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by
addition of H O (2 mL) and extracted with Et O (2 x 5 mL). The combined organic phases were
2
2
washed with H O (10 mL), dried over Na SO and concentrated under reduced pressure. Flash
2
2
4
chromatography (5% to 10% EtOAc in hexanes) was performed to afford the product as a
1
colorless oil (230 mg, 92%). H NMR (CDCl , 400 MHz) δ = 5.69ꢀ5.62 (m, 1H), 5.54ꢀ5.48 (m,
3
1
1
2
H), 5.13 (ddd, J = 8.8 Hz, 2.1 Hz, 0.9 Hz, 1H), 4.85 (d, J = 6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz,
H), 3.67 (s, 3H), 3.40 (s, 3H), 2.48 (d, J = 2.1 Hz, 1H), 2.30 (t, J = 7.5 Hz, 2H), 2.16ꢀ2.10 (m,
13
1
H), 1.66ꢀ1.58 (m, 2H), 1.43ꢀ1.29 (m, 8H) ppm; C{ H} NMR (CDCl , 100 MHz) δ = 174.2,
3
134.7, 126.4, 93.2, 81.8, 73.5, 60.5, 55.6, 51.4, 34.1, 29.2, 29.0 (2C), 28.9, 27.5, 24.9 ppm;
+
+
HRMS (ESI ) calculated for C H O Na [M + Na] 305.1723, found 305.1715.
1
6
26
4
(
9Z, 11S)ꢀ11ꢀ(methoxymethoxy)tridecꢀ9ꢀenꢀ12ꢀynoic acid (16) Methyl ester (S3) (251 mg,
0.890 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (4 mL). Then LiOH (85 mg, 3.56
mmol, 4.0 equiv.) was added as an aqueous solution (1 mL). The reaction mixture was stirred at
o
6
5 C for 18 h. The reaction was then cooled to room temperature and HCl (1 M) was added until
the mixture was neutralized (pH = 7). Extraction with EtOAc (3 X 5 mL) was performed and the
combined organic phases were washed with brine (15 mL). The organic phase was dried over
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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4
4
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5
5
5
5
5
5
5
5
5
6
Na SO and concentrated under reduced pressure to afford the desired product as a low melting
2
4
1
solid (238 mg, 99%). H NMR (CDCl , 400 MHz) δ = 5.66 (dt, J = 10.6, 7.5 Hz, 1H), 5.52 (m,
3
1
H), 5.13 (dd, J = 8.8, 2.2 Hz, 1H), 4.86 (d, J = 6.9 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 3.41 (s,
H), 2.48 (d, J = 2.2 Hz, 1H), 2.36 (t, J = 7.5 Hz, 2H), 2.16ꢀ2.11 (m, 2H), 1.64ꢀ1.62 (m, 2H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
3
1
1.42ꢀ1.33 (m, 8H) ppm; C{ H} NMR (CDCl , 100 MHz) δ = 179.8, 134.6, 126.3, 93.1, 81.6,
3
+
7
3.5, 60.5, 55.5, 33.9, 29.1, 28.9, 28.8 (2C), 27.4, 24.5 ppm; HRMS (ESI ) calculated for
+
C H O [M+H] : 267.1602, found 267.1609.
15
23
4
(2S, 3R)ꢀ3ꢀ(methoxymethoxy)pentꢀ4ꢀynꢀ2ꢀyl (S, Z)ꢀ11ꢀ(methoxymethoxy)tridecꢀ12ꢀynoate
2) DCC (472 mg, 2.29 mmol, 2 equiv.), DMAP (419 mg, 3.44 mmol, 3 equiv.) and (2S,3R)ꢀ3ꢀ
methoxymethoxy)pentꢀ4ꢀynꢀ2ꢀol (3) (165 mg, 1.15 mmol, 1 equiv.) were added to a solution of
(
(
(9Z, 11S)ꢀ11ꢀ(methoxymethoxy)tridecꢀ9ꢀenꢀ12ꢀynoic acid (307 mg, 1.15mmol, 1 equiv.) in
CH Cl (4 mL) and stirred for 18 h at room temperature. The solution was then placed in the
2
2
freezer for 12 h and the precipitated urea was filtered. Silica gel was added to the filtrate and the
slurry was concentrated under reduced pressure. Flash chromatography (100% hexanes to 20%
1
EtOAc in hexanes) was performed to afford the product as a colorless oil (282 mg, 62%). H
NMR (CDCl , 400 MHz) δ = 5.65 (dt, J = 11 Hz, 7.3 Hz, 1H), 5.51 (t, J = 8.9 Hz, 1H), 5.14ꢀ5.09
3
(m, 2H), 4.92 (d, J = 6.9 Hz, 1H), 4.85 (d, J = 6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz, 2H), 4.42 (dd, J =
3.8 Hz, 2.1 Hz, 1H), 3.40 (s, 3H), 3.39 (s, 3H), 2.47 (dd, J = 9.9 Hz, 2.1 Hz, 2H), 2.33 (t, J = 7.5
1
3
1
Hz, 2H), 2.17ꢀ2.10 (m, 2H), 1.66ꢀ1.60 (m, 2H), 1.39ꢀ1.29 (m, 11H) ppm; C{ H} NMR (CDCl ,
3
1
2
4
00 MHz) δ = 173.0, 134.7, 126.4, 94.2, 93.3, 81.8, 79.1, 75.0, 73.5, 70.8, 67.4, 55.6, 34.4, 29.2,
+
+
9.1, 29.0, 27.5, 24.9, 15.1 ppm; HRMS (ESI ) m/z calculated for C H NaO [M+Na] :
22 34
6
17.2248; found: 417.2260.
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(
17R,18S)ꢀ17ꢀ(methoxymethoxy)ꢀ18ꢀmethyloxacyclooctadecaꢀ13,15ꢀdiynꢀ2ꢀone (1a): Slow
Addition Procedure: To a tripleꢀneck roundꢀbottom flask equipped with a stirring bar and a
condenser, CuCl (154 mg, 1.56 mmol, 12 equiv.) and TMEDA (0.4 mL, 2.6 mmol, 20 equiv.)
was added to PhMe (550 mL). The mixture was stirred and warmed at 110 °C. To the mixture, a
solution of 2a (44 mg, 0.13 mmol, 1 equiv.) in PhMe (50 mL) was slowly added over 36 h (0.023
mL/min) with a syringe pump. The mixture was stirred and heated for an additional 12 h. The
reaction was then cooled down to room temperature and concentrated under reduced pressure.
Flash chromatography was performed (5% to 20% EtOAc in hexanes) to afford the desire
10
11
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13
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15
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17
18
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25
1
product as a colorless oil (15.6 mg, 36%). [α]D = ꢀꢀ0.221 (c = 0.0044, MeOH); H NMR (300
MHz, CDCl ) δ 5.04 (appquint, J = 6 Hz, 1H), 4.93 (d, J = 9 Hz, 1H), 4.61 (d, J = 6 Hz, 1H),
3
4
.30 (d, J = 6 Hz, 1H), 3.38 (s, 3H), 2.36ꢀ2.31 (m, 4H), 1.74ꢀ1.67 (m, 4H), 1.37ꢀ1.26 (m, 15H)
13
1
ppm. C{ H} NMR (75 MHz, CDCl ) δ 172.8, 94.2, 81.0, 71.4, 71.0, 70.7, 69.0, 65.1, 55.9,
3
+
35.3, 29.7, 29.2, 28.4, 27.5, 26.8, 26.3, 25.7, 24.9, 18.8, 17.4 ppm. HRMS (ESI ) m/z calculated
+
for C H NaO [M+Na] : 357.2036; found: 357.2029. Microwave Procedure: To a microwave
2
0
30
4
vial equipped with a stirring bar was dissolved the diyne 2a (41 mg, 0.12 mmol, 1 equiv.) in
MeOH. To the mixture was added polyethylene glycol 400 (3.75 mL), CuCl ·2H O (5 mg, 0.03
2
2
mmol, 25 mol %) and Ni(NO ) ·6H O (8.7 mg, 0.03 mmol, 25 mol %) and the mixture was
3
2
2
stirred at room temperature for 30 seconds or until the metals were solubilized. Oxygen was
bubbled in the solution for 5 min then TMEDA (0.09 mL, 0.6 mmol, 5 equiv.) and Et N (0.05
3
mL, 0.36 mmol, 3 equiv.) were added and the mixture was stirred at room temperature for an
additional 30 seconds. The vial was then sealed with a microwave cap. The reaction was warmed
to 100 °C for 3 h. The crude mixture was loaded directly onto silica gel for purification by
chromatography (10% to 20% EtOAc in hexanes) to afford the desire product as a colorless oil
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(
16 mg, 40%). Continuous Flow Procedure: To a 200 mL pearꢀshaped flask equipped with a
stirring bar, CuCl ·2H O (118 mg, 0.70 mmol, 25 mol%), Ni(NO ) ·6H O (204 mg, 0.70 mmol,
2
2
3 2
2
2
5 mol%), TMEDA (2.07 mL, 13.9 mmol, 5 equiv.) and Et N (1.16 mL, 8.34 mmol, 3 equiv.)
3
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was dissolved in MeOH (20 mL) and the mixture was stirred at room temperature for 30 seconds
or until the metals were solubilized. Poly(propylene glycol) 425 (77.2 mL) was added and the
mixture was stirred at room temperature for an additional 30 seconds. 2a (935 mg, 2.78 mmol, 1
equiv.) was dissolved in 18.6 mL of MeOH then added to the solution. The reaction mixture was
pumped into the flow reactor for a reaction time of 120 min (2 x 10 mL Stainless Steel reactors,
with a temperature controlled 27 cm length section of tubing between reactors) at a flow rate of
0
.167 mL/min at 120 °C. The flow reaction was conducted in a VapourTec R4 reactor and a R2+
pumping module. The continuous flow setup is ended with two inꢀline back pressures regulators
VapourTec 8 bar + IDEX 17 bar). Upon completion, the mixture was extracted with EtOAc,
(
washed with water and the combined organic phases were washed with brine. The organic phase
was dried over Na SO and concentrated under reduced pressure. The crude mixture was purified
2
4
by chromatography (5 to 10% EtOAc in hexanes) to afford the desire product as a yellowish oil
(353 mg, 38%).
(10Z,12S,17R,18S)ꢀ12,17ꢀdi(methoxymethoxy)ꢀ18ꢀmethyloxacyclooctadecꢀ10ꢀeneꢀ13,15ꢀ
diynꢀ2ꢀone (1): Slow Addition Procedure: To a tripleꢀneck roundꢀbottom flask equipped with a
stirring bar and a condenser, CuCl (119 mg, 1.2 mmol, 12 equiv.) and TMEDA (0.3 mL, 2.0
mmol, 20 equiv.) was added to PhMe (405 mL). The mixture was stirred and warmed at 110 °C.
To the mixture, a solution of 2 (40 mg, 0.10 mmol, 1 equiv.) in PhMe (50 mL) was slowly added
over 24 h (0.035 mL/min) with a syringe pump. The mixture was stirred and heated for an
additional 24 h. The reaction was then cooled down to room temperature and concentrated under
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reduced pressure. Flash chromatography was performed (5% to 20% EtOAc in hexanes) to
2
5
afford the desire product as a colorless oil (21.4 mg, 55%). [α]D = ꢀ62.1 (c = 0.00145, MeOH)
1
H NMR (400 MHz, CDCl ) δ 5.63ꢀ5.56 (td, J = 10.8, 5.5 Hz, 1H), 5.49 (app t, J = 10.9 Hz,
3
10
11
12
13
14
15
16
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18
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H), 5.20 (d, J = 8 Hz, 1H) 5.06ꢀ5.01 (m, 1H), 4.91 (d, J = 6.9 Hz, 1H), 4.81 (d, J = 6.7 Hz, 1H),
4.61 (t, J = 5.5 Hz, 1H), 4.28 (d, J = 7.7 Hz, 1H), 3.38 (s, 3H), 3.38 (s, 3H), 2.38ꢀ2.29 (m, 2H),
13
1
2.20ꢀ2.06 (m, 2H), 1.73ꢀ1.57 (m, 4H), 1.39ꢀ1.29 (m, 9H) ppm. C{ H} NMR (75 MHz, CDCl )
3
δ 172.8, 134.3, 126.5, 94.4, 93.6, 75.7, 70.6, 70.5, 69.5, 68.9, 61.5, 56.0, 55.7, 35.2, 29.7, 29.5,
2
9.4, 28.6, 28.5, 27.7, 25.4, 17.6 ppm. Spectral data were in accordance with those previously
12
reported in the literature. Microwave Procedure: To a microwave vial equipped with a stirring
bar was dissolved the diyne (38 mg, 0.10 mmol, 1 equiv.) in MeOH (1.05 mL). To the mixture
was added polyethylene glycol 400 (3.15 mL), CuCl ·2H O (4.2 mg, 0.025 mmol, 25 mol %)
2
2
and Ni(NO ) ·6H O (7 mg, 0.025 mmol, 25 mol %) and the mixture was stirred at room
3
2
2
temperature for 30 seconds or until the metals were solubilized. Oxygen was bubbled in the
solution for 5 min then TMEDA (0.07 mL, 0.5 mmol, 5 equiv.) and Et N (0.04 mL, 0.3 mmol, 3
3
equiv.) were added and the mixture was stirred at room temperature for an additional 30 seconds.
The vial was then sealed with a microwave cap. The reaction was warmed to 100 °C for 3 h. The
crude mixture was loaded directly onto silica gel for purification by chromatography (10 %
EtOAc in hexanes) to afford the desire product as a colorless oil (11.5 mg, 30%). Continuous
Flow Procedure: To a 20mLꢀreaction vial equipped with a stirring bar, CuCl ·2H O (3 mg,
2
2
0
.018 mmol) and Ni(NO ) ·6H O (5.2 mg, 0.018 mmol) was dissolved in MeOH (1.5 mL) and
3 2 2
the mixture was stirred at room temperature for 30 seconds or until the metals were solubilized.
Polyethylene glycol 400 (1.5 mL), TMEDA (0.05 mL, 0.33 mmol) and Et N (0.03 mL, 0.22
3
mmol) were added and the mixture was stirred at room temperature for an additional 30 seconds.
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Diyne 2 (19.9 mg, 0.051 mmol, 1 equiv.) was mixed 2 mL of the previous solution. The mixture
was stirred at room temperature until everything was soluble then taken into a syringe. The
reaction mixture was injected using a 2 mL injection loop into the flow reactor for a reaction
time of 120 min (2 x 10 mL Stainless Steel reactors, with a temperature controlled 27 cm length
section of tubing between reactors) at a flow rate of 0.167 mL/min at 120 °C. The flow reaction
was conducted in a VapourTec R4 reactor and a R2+ pumping module. The continuous flow
setup is ended with two inꢀline back pressures regulators (VapourTec 8 bar + IDEX 17 bar).
Upon completion, silica gel was added to the collection flask and the volatiles were removed
under vacuum. The crude mixture was purified by chromatography (20% EtOAc in hexanes) to
afford the desire product as a colorless oil (10.2 mg, 52%).
0
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AUTHOR INFORMATION
§
These authors contributed equally.
Corresponding Author
shawn.collins@umontreal.ca
ACKNOWLEDGMENT
The authors acknowledge the Natural Sciences and Engineering Research Council of Canada
(NSERC), Université de Montreal, the Centre for Green Chemistry and Catalysis (CGCC) and
the NSERC CREATE program in Continuous Flow Science for generous funding. The Canadian
Foundation for Innovation (CFI) is acknowledged for generous funding of the flow chemistry
infrastructure. EG thanks the FRQNT for a graduate scholarship. Materia Inc. is thanked for
generous donations of catalysts 14, 15a and 15b.
SUPPORTING INFORMATION
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Characterization data for all new compounds and optimization data for the Zꢀselective
metathesis. This material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
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(
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13) (a) Werrel, S.; Walker, J. C. L.; Donohoe, T. J. Tetrahedron Lett. 2015, 56, 5261ꢀ5268. (b)
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Grubbs, R. H. Angew. Chem. Int. Ed. 2015, 54, 5018 – 5024. (e) Meek, S. J.; O’Brien, R. V.;
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(
17) Endo, K.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 8525ꢀ8527.
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2013, 52, 8395ꢀ8400. An alternative route via diastereomeric separation was also used. See
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(19) Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H.
Nature 2011, 479, 88ꢀ93.
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21 (a) Porta, R.; Benaglia, M.; Puglisi, A. Org. Process Res. Dev. 2016, 20, 2ꢀ25. (b) Ley, S.
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(
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(
25) Shriver, D. F.; Drezdon, M. A. in The Manipulation of Air-Sensitive Compounds; Wileyꢀ
VCH: New York, 1986.
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(26) Lumbroso, A.; Abermil, N.; Breit, B. Chem. Sci., 2012, 3, 789ꢀ793.
(
(
(
27) Ranganathan, D.; Ranganathan, S.; Mehrotra, M. M. Tetrahedron 1980, 36, 1869ꢀ1875.
28) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923ꢀ2925.
29) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem., 1983, 48, 5180ꢀ5182.
(30) Marshall, J. A.; Bourbeau, M. P. Org. Lett., 2003, 5, 3197ꢀ3199.
(31) The same procedure was used for the synthesis of rac-11. The product was obtained as a
colorless oil (1.70 g, 80 %).
(32) A similar procedure was used for the synthesis of rac-13. The modifications were: the
reaction was run for 18 h, there was no second equivalent of ester added, no vacuum was
performed and 10 mol% catalyst was used. The product was obtained as a colorless oil (250 mg,
59 %).
TOC GRAPHIC
ACS Paragon Plus Environment
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