Ring-Closing Metathesis with Vicinal Dibromoalkenes as Protected Alkynes: A Synthetic Approach to Macrocyclic Enynes

Article abstract of DOI:10.1021/acs.orglett.5b02595

A new strategy to access macrocyclic enynes was developed. To block undesired ene-yne cyclization pathways, alkynes were protected via bromination and the resultant acyclic vic-(E)-dibromotrienes participated in selective ene-ene ring closing metathesis reactions. Zinc-promoted deprotection of (E)-dibromodienes provided macrocyclic enynes in high yields.

Full text of DOI:10.1021/acs.orglett.5b02595

Letter
pubs.acs.org/OrgLett
Ring-Closing Metathesis with Vicinal Dibromoalkenes as Protected
Alkynes: A Synthetic Approach to Macrocyclic Enynes
Sedef Karabiyikoglu,† Robert G. Iafe,‡ and Craig A. Merlic*,†
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
‡Department of Chemistry and Biochemistry, California State University, San Marcos, California 92078, United States
S
* Supporting Information
ABSTRACT: A new strategy to access macrocyclic enynes was
developed. To block undesired ene−yne cyclization pathways, alkynes
were protected via bromination and the resultant acyclic vic-(E)-
dibromotrienes participated in selective ene−ene ring closing
metathesis reactions. Zinc-promoted deprotection of (E)-dibromo-
dienes provided macrocyclic enynes in high yields.
yclic enynes gained importance with interest in annulene
plexes.29 In fact, we tested the synthesis of dicobalt complex 4
without success (Table 1). Cyclic enyne 4 was formed in yields
C
chemistry in the 1960s,1 and their significance increased as
novel biologically active natural products were discovered.2
Enyne rings constitute the core of potent antitumor anti-
biotics3−8 and cytotoxic alkaloids.9 Cyclic enynes were also used
in natural product syntheses10 and transannular rearrange-
ments.11 These discoveries stimulated studies on the con-
struction of enyne rings. Traditional syntheses encompass
functionalized acyclic enynes participating in intramolecular
transformations.10a,12−15 Other methods involved introduction
of alkyne or alkene units via cycloelimination reactions16,17 and
intermolecular processes involving double coupling18,19 or
substitution.20 However, these methods suffer from tedious
substrate preparations, low yields, and limited product scope.
Ring-closing metathesis (RCM) is one of the most powerful
tools in organic synthesis,21 so ene−ene RCM of dienynes could
be an efficient alternative for the preparation of macrocyclic
enynes. However, a thermodynamically favored ene−yne RCM
pathway is preferred in transformations with an ene−ene vs ene−
yne reactivity competition.22,23 Few exceptions are observed for
this chemoselectivity.10d,24−26 Indeed, our attempts at RCM of
dienyne 1 led to low yields of enyne 2 (Scheme 1).
Table 1. Synthesis of Cyclic Enyne Complex 4
a
b
entry
solvent
°C
h
catalyst (equiv)
yield (%)
1
2
3
4
5
6
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
40
25
0
12
12
12
24
24
72
Grubbs I (0.02)
Grubbs I (0.05)
Grubbs II (0.05)
Grubbs I (0.05)
Grubbs I (0.15)
Grubbs I (0.10)
12
0
0
0
14
13
a
Grubbs I = (PCy3)2Cl2Ru = CHPh (Grubbs’ 1st generation), Grubbs
II = (PCy3)(C20H26N2)Cl2Ru = CHPh (Grubbs’ second generation).
b
1
Yields were determined by H NMR and only the Z isomer was
observed.30
even lower than the yield of metal-free enyne 2 from an RCM
reaction of “unprotected” dienyne 1 (Scheme 1). The destructive
effects of CO on catalysis were clear, and development of an
alternative protection method was essential.
Scheme 1. Synthesis of Cyclic Enyne 2
RCM reactivity is principally determined by olefin substitution
patterns. Trisubstituted alkenes have low reactivity and
tetrasubstituted alkenes have almost no metathesis reactivity,
especially for initiation.21a,31 We utilized this low reactivity as the
basis for an alkyne protection strategy. We proposed that
tetrasubstituted vic-dibromoalkenes with general structure 8
would serve as protected alkynes and be inert in metathesis
reactions32 while being deprotected via zinc-promoted elimi-
nation (Scheme 2).30 Since its discovery in the late 1800s, alkyne
bromination has had limited use as a protection method.33 In this
regard, our strategy provides an interesting example of this tactic.
Attempting to circumvent this reactivity {Co2(CO)6}−alkyne
complexes were employed as protected alkynes in
RCM.10c,22a−c,25b,27 However, this often led to side reactions,
high catalyst loadings, and poor yields. Most metathesis reactions
require heat,21a and {Co2(CO)6}−dienynes complexes readily
undergo thermal Pauson−Khand reactions.22c,27e,28 More
importantly, these complexes can release π-acidic CO which
reacts with the catalyst leading to metathesis-inactive com-
Received: September 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02595
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Preparation and Enyne Synthesis
Table 3. Synthesis of Protected Cyclic Diene 9c
b
a
entry
cd
solvent
°C
h
catalyst (equiv)
yield, % (E/Z)
,
1
2
3
4
5
6
CH2Cl2
DCE
40
85
40
40
85
40
12
36
12
36
36
12
Grubbs I (0.05)
Grubbs I (0.05)
Grubbs II (0.05)
Grubbs I (0.10)
Grubbs I (0.10)
Grubbs II (0.10)
2 (100:0)
9 (1.7:1)
50 (1:5.3)
54 (1.7:1)
2 (100:0)
90 (1:5)
cd
,
d
e
CH2Cl2
CH2Cl2
DCE
RCM of 8a was tested to synthesize the 10-membered-ring
product 9a (Table 2). However, mixtures of polar polyether
oligomers were formed instead of the target molecule possibly
due to its high ring strain.
cde
, ,
e
CH2Cl2
a
Yields are of isolated products.30 E/Z ratios were determined by
b
c
NMR spectroscopy. DCE = 1,2-dichloroethane. For entries 1, 2, and
5, 90%, 78%, and 68% of 8c were recovered, respectively. [8c] =
0.002 M. [8c] = 0.004 M.
d
Table 2. Optimization of the RCM Reaction
e
a
entry
solvent
°C
h
catalyst (equiv)
9b, yield, % (E/Z)
b
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
40
40
40
12
12
12
12
12
Grubbs I (0.20)
Grubbs II (0.05)
Grubbs I (0.05)
Grubbs III (0.05)
Grubbs II (0.05)
30 (8:1)
b
2
0
c
3
69 (2.5:1)
10 (100:0)
0
cd
,
4
c
5
a
Yields are of isolated products.30 E/Z ratios were determined by
b
c
d
NMR spectroscopy. [8b] = 0.005 M. [8b] = 0.002 M. Grubbs III =
C31H38Cl2N2ORu (Hoveyda−Grubbs second generation).34b
To avoid oligomerization, we considered larger rings, so triene
8b was tested in RCM reactions (Table 2). At rt with the Grubbs
I catalyst, the target ring was formed in a 30% yield (Table 2,
entry 1), but with a high catalyst loading of 20%. A trial with the
more reactive34a Grubbs II catalyst at rt failed to form 9b and
instead gave a mixture of decomposition products (entry 2).
Since the alkyne protecting group is heat-tolerant, we tested the
RCM of 8b in refluxing CH2Cl2 with the Grubbs I catalyst and
the reaction gave 9b in a 69% yield (entry 3). In refluxing DCM,
Grubbs III34b was less effective (entry 4) while Grubbs II gave a
complex mixture of metathesis products (entry 5).
All-carbon rings have less ring strain compared to ether
analogs, as C−C σ-bonds are longer than C−O σ-bonds.20b
Thus, although 10-membered-ring 9a failed to form, we tested
the synthesis of 10-membered-ring 9c (Table 3). In contrast to
8a, 8c was resistant to oligomerization, but it exhibited low RCM
reactivity. Optimal conditions for formation of macrocycle 9b
only afforded trace amounts of 9c (Table 3, entry 1). Higher
temperatures and longer reaction times did not improve the yield
(entry 2). To increase the metathesis reaction rate, both the
substrate concentration and catalyst loading were increased
(entries 4−6). Under these conditions with the more active
Grubbs II catalyst, ring 9c was obtained in a 90% yield (entry 6).
The stereoselectivity of the catalysts were opposite which might
reflect kinetic versus theromdanamic control and has precedent
in the formation of a 10-membered lactone.35
Figure 1. Synthesis of protected macrocycles via RCM. Yields are of
isolated products.30 E/Z ratios were determined by H and 13C NMR
1
spectroscopy. For 9c, conditions in Table 3, entry 6 were used.
cyclic sulfonamide (9e). Tetrasubstituted vic-dibromoalkenes
were excellent protecting groups, as each reaction proceeded
smoothly providing only the terminal ene−ene RCM product.
The RCM was not limited to formation of medium rings, as 19-
membered 9g and 16-membered 9h were synthesized
successfully in 65% and 87% yields, respectively (Figure 1).
1
The H NMR spectra of 9b−f and h exhibited unexpected
diastereotopicity for protons α and β to the dibromoalkene
units.30 This was attributed to rigidity imposed by the bromine
atoms restricting rotations leading to favored conformations with
the geminal protons and esters located in different environments.
Larger and less strained 9g did not exhibit such behavior. The Z-
isomer of 9c was interesting, as the 1H NMR displayed two sets
of multiplets for the vinyl protons, suggesting it exists as a
mixture of two planar chiral conformers and interconversion
between the enantiomeric conformers is slow on the NMR time
scale.25 To support these proposals, quantum-chemical simu-
lations were performed.30 Calculated chemical shifts and
coupling constants based on populations of conformers were
in good agreement with the experimental spectra.
Using the optimized RCM conditions for 9b and 9c, a variety
of dibromotrienes were prepared and reacted to obtain protected
macrocycles in good to high yields (Figure 1).30
The structural scope of these RCM processes includes all
carbon diene rings (9c, 9d), cyclic ethers (9b, 9f, 9g, 9h), and a
Stereoselective synthesis of large rings via metathesis is
challenging, although stereoselective RCM catalysts for macro-
cyclization were recently reported.36,37 Traditional metathesis
catalysts lack kinetic selectivity, as E/Z ratios are determined by
B
DOI: 10.1021/acs.orglett.5b02595
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the stabilities of the macrocycles based on ring size and/or
substitution patterns.36,37 RCM of dibromotrienes 8 exhibited
similar behavior. While formation of symmetric 16-membered
9h showed no stereoselectivity, 13-membered 9b and 19-
membered 9g formed with a modest 2.5:1 E/Z ratio. There is a
pronounced allylic chalcogen effect38 in macrocyclization RCM.
Under identical conditions, 12-membered rings 9d and 9f
formed as single isomers, but with opposite selectivity. Substrates
with allyl ether linkages (8b, 8f, 8g) gave E macrocyclic isomers
as the sole or major isomer (Figure 1).
Scheme 3. Pt(II)-Catalyzed Cycloisomerization Reactions
Macrocyclic dienes 9b−h were then subjected to deprotection.
Zn metal effectively promoted elimination reactions and cyclic
enynes were formed in high yields (Figure 2).
The isomeric ratio of 10g was preserved in cycloisomerization to
11g, and NMR spectra confirmed that the 3,4-dihydropyran ring
11g was preferred over a tetrahydrofuran ring (11g′).
In conclusion, a new strategy to access macrocyclic enynes was
developed. Vicinal-dibromo tetrasubstituted alkenes were
excellent protected alkynes, and (E)-dibromotrienes participated
in selective ene−ene RCM reactions. The RCM reactions were
general, tolerated high temperatures, and used low catalyst
loadings. Diverse macrocyclic enynes in various ring sizes were
prepared in high yields by Zn-promoted deprotection reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 2. Synthesis of enyne macrocycles. Yields are of isolated
products.30 E/Z ratios were determined by NMR spectroscopy. For 10c,
heating in a sealed tube at 60 °C for 4 d achieved complete consumption
of 9c where only the Z isomer was isolated in a 78% yield.30
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02595.
Experimental details and spectral data for isolated
products (PDF)
NMR spectra (PDF)
Calculations (PDF)
Isomeric distributions were not affected by deprotection, as
the E/Z ratios were maintained. Rings with allyl and homoallyl
moieties (10b−g) are typically inaccessible by RCM of
unprotected acyclic dienynes since ene−yne RCM is pre-
ferred.22,23 This method is superior to the Co2(CO)6−alkyne
protection method which suffered from low yields and catalyst
deactivation. Macrocycles 2 and 4 were initially synthesized in
very low yields while our approach provided 2 in a 79% overall
yield (Figures 1, 2). Zn-promoted deprotection of strained ring
9c afforded the pure Z isomer of 10c in a 93% yield based upon
initial Z isomer content (Figure 2). Deslongchamps reported the
preparation of E- and Z-isomers of enyne 10c via intramolecular
SN2 reactions.12b Our method was more efficient, by requiring
fewer steps and giving a higher yield.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: merlic@chem.ucla.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank UCLA for support of this work and Materia for
generous donations of catalysts.
■
Pt-catalyzed intramolecular cyclopropanations of allyl prop-
argyl ethers39,40 and transannular cycloisomerizations of 1,5-
enyne rings with propargylic alkoxy substituents11a were
reported. Inspired by these studies, we subjected macrocycles
10f and 10g to Pt(II)-catalyzed rearrangements, and tricyclic
enol ethers 11f and 11g were obtained in good yields (Scheme
3).30
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DOI: 10.1021/acs.orglett.5b02595
Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.5b02595
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