Synergistic Gold and Copper Dual Catalysis for Intramolecular Glaser–Hay Coupling: Rapid Total Synthesis of Ivorenolide B

Article abstract of DOI:10.1002/ejoc.201800708

A synergistic dual catalysis approach involving gold and copper catalysts for the synthesis of macrolactones bearing 1,3-butadiynes through an intramolecular Glaser–Hay coupling reaction in good yield is described. This dual catalytic system exhibited good selectivity, reactivity and functional group tolerance. This unique process offers a paradigm shift: the potential as well as the versatility of this novel method is not only exemplified for the synthesis of macrolactones of different ring size but also for the rapid total synthesis of ivorenolide B, a new class of macrolides endowed with conjugated 1,3-diyne motif, having impressive immunosuppressive activities.

Full text of DOI:10.1002/ejoc.201800708

A Journal of
Accepted Article
Title: Synergistic Gold and Copper Dual Catalysis for Intramolecular
Glaser-Hay Coupling: Rapid Total Synthesis of Ivorenolide B
Authors: Debendra Kumar Mohapatra
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800708
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800708
Supported by

10.1002/ejoc.201800708
European Journal of Organic Chemistry
COMMUNICATION
Synergistic Gold and Copper Dual Catalysis for Intramolecular
Glaser-Hay Coupling: Rapid Total Synthesis of Ivorenolide B
Sudheer K. Rangaraju, Uma Maheshwar Gonela, Aala Kavita, Jhillu S. Yadav, and Debendra K.
Mohapatra*
Abstract: A synergistic dual catalysis approach involving gold and
copper catalysts for the synthesis of macrolactones bearing 1,3-
butadiynes through an intramolecular Glaser-Hay coupling reaction
in good yield is described. This dual catalytic system exhibited good
selectivity, reactivity and functional group tolerance. This unique
process offers a paradigm shift: the potential as well as the versatility
of this novel method is not only exemplified for the synthesis of
macrolactones of different ring size but also for the rapid total
synthesis of ivorenolide B, a new class of macrolides endowed with
conjugated 1,3-diyne motif, having impressive immunosuppressive
activities.
Metal mediated oxidative dimerization of terminal alkynes with
stoichiometric amount of copper was developed by Glaser[10]
about 150 years ago. Modified reactions such as Glaser-Hay[11]
and Cadiot-Chodkiewicz[12] coupling reactions were devloped
later to prepare unsymmetrical conjugated diynes. Cadiot-
Chodkiewicz coupling though powerful, often suffers from poor
selectivity and formation of homo-coupled byproducts. To
specifically address the problems related to optimizing
chemoselectivity in homo-coupling of alkynes, either of the
terminal alkynes should be immobilized on a solid support or
should be converted to a haloalkyne under high dilution
conditions. Less is known about the Glaser-Hay coupling for
macrolactonization, although recent studies by Collins et al.
disclosed a novel strategy employing copper catalysis and high
concentrations for the synthesis of macrocycles using a “phase
separation strategy”.[13] We disclose herein, the use of gold-
copper catalyst system to effect direct macrocyclization. So far
very few examples are reported to achieve intermolecular
Glaser-Hay coupling reaction with gold complexes.[14,15] One of
the alkynes behaves as an immobilized haloalkyne to form
heterodiynes in excellent yield under homogenous conditions.[14]
We envisioned that gold catalyst could form complex with one of
the alkynes[15] and behave like a haloalkyne or immobilized
alkyne leading to improve chemoselectivity via intramolecular
Glaser-Hay coupling for macrocyclization in an unprecedented
manner. However, to date, gold-catalyzed intramolecular
Glaser-Hay coupling was not utilized to synthesize diyne
containing macrolactones.
Macrocycles are widespread structural motifs present in natural
products,[1] pharmaceuticals,[2] material science compositions,[3]
and have profound importance in supramolecular chemistry.[4]
Among these, 1,3-butadiynes or di-acetylenic scaffolds occur
widely and to date, over one thousand naturally occurring
polynes were isolated and were found to display antibacterial,
anti-cancer,
anti-HIV,
antifungal
properties.[5]
Further,
conjugated diynes play an important role in the properties of
many functional materials, such as nonlinear plastics, fibers with
high density and strength, and liquid crystals.[6] A new class of
1,3-butadiyne macrolides ivorenolide A and B (Fig. 1) exhibiting
immunosuppressant activities was isolated from the species
Khaya ivorenis.[7] Immunosuppressive therapy usually has to
follow surgery to ensure the success of organ transplantation[8]
and also for treatment of autoimmune diseases, including
rheumatoid arthritis, systemic lupus erythematosus (SLE),
psoriasis, and multiple sclerosis.[9] Synthesis of conjugated
diynes especially unsymmetrical diynes, depicted below is of
clinical relevance.
Our investigations began with the macrocyclization of model
substrate ester 3, via intramolecular Glaser-Hay coupling of
terminal alkynes. Our initial screening results concerning
different metal catalysts and reagents are listed in Table 1.
Treatment of ester 3 under standard intermolecular Glaser-Hay
coupling
reaction
conditions[10,11]
for
macrocyclization
(CuCl/TMEDA), led to low yield of the required product along
with products resulting from polymerization (Table 1, entry 1).
Similarly, Pd-catalyzed[16] reaction also proceeded with low yield
although complete consumption of starting material (entry 3)
was observed. Macrocyclization under Shi’s conditions[15b]
afforded trace amount of lactone
4
accompanied with
decomposition of the starting material (entry 4 and 5). When the
ester was treated with the conditions reported by Corma et al., it
did not afford the required product (entry 6).[14] When we
employed catalytic amount of Au(I)/Cu(I) catalyst in combination
for the macrocyclization a yield of 49% was realized (entry 7). To
optimize these reaction conditions, different Au(I) catalysts were
screened. Increase of reaction yield as well as the catalyst
stability was observed with dppm(AuBr)2 (entry 7). When the
dppm(AuBr)2 was replaced with PPh3AuCl catalyst, gratifying
increase of the yield (68%) was observed (entry 8). Next,
different bases were screened.
Figure 1. Structures of Ivorenolide A (1) and B (2).
[*]
S. K. Rangaraju, U. M. Gonela, A. Kavita, Dr. J. S. Yadav, Dr. D. K.
Mohapatra
CSIR-Indian Institute of Chemical Technology
Hyderabad-500007 (INDIA)
E-mail: Mohapatra@iict.res.in
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800708
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Optimization of catalytic system[a]
In an effort to evaluate the generality of the optimized
conditions, the macrocyclization of other diynes with different
ring size was performed (Table 2). Change in the macrolactone
ring sizes from 14- to 24-membered ring (5-13), did not
significantly change the reaction yield except 14- and 15-
membered ring formation were found in moderate yield along
with oligomerized products in 11% and 7%, respectively (Table 2,
entry 1 and 2). During the investigation of the macrocyclization
of larger ring macrolactones, it was found that macrolactones
having ring sizes 16-20 at high concentrations afforded the
respective macrolactones in excellent yield. For 21- and 24-
membered macrolactones, the yield was 78% and 71%,
respectively.
Entry
Reaction conditions
Solvent
time
Yield(%)[b]
1
2
3
4
5
6
CuCl, TMEDA, O2
CuI, I2, DIPA
Toluene
Toluene
2 d
2 d
2 d
2 d
2 d
1 d
19
18
Pd(PPh3)2Cl2, CuI, I2, DIPA
PPh3AuCl, BAIB, Phen
dppm(AuBr)2, BAIB, Phen
THF
32
Table 2. Substrate scope of Au(I)/Cu(I)- intramolecular Glaser-Hay
Coupling.[a]
Acetonitrile
Acetonitrile
Acetonitrile
trace
trace
0
PPh3AuCl (10 mol%)
H
AuPPh3NTf2, selectofluor,
Na2CO3
CuI (30 mol%)
I2 (2.5 equiv)
m
O
m
O
O
7
8
dppm(AuBr)2, CuI, I2, DIPA
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
THF
2 d
2 d
3 d
3 d
3 d
3 d
3 d
2 d
2 d
49
68
0
O
PPh3AuCl, CuI, I2, DIPA
PPh3AuCl, CuI, I2, Na2CO3
PPh3AuCl, CuI, I2, K2CO3
PPh3AuCl, CuI, I2, Cs2CO3
PPh3AuCl, CuI, I2, Et3N
PPh3AuCl, CuI, I2, py.
DIPA (1.2 equiv)
Tolune, 24-48 h, rt
H
9
n
10
11
12
13
14
15
0
0
14
15
O
2.
1.
3.
<20
<20
45
71
O
O
O
5
6
/69%
/61%
PPh3AuCl, CuI, I2, TMEDA
PPh3AuCl, CuI, I2, DIPA
O
4.
O
THF
16
17
O
16
17
18
19
PPh3AuCl, CuI, I2, DIPA
PPh3AuCl, CuCl, I2, DIPA
PPh3AuCl, CuCl2, I2, DIPA
PPh3AuCl, CuI, DIPA/O2
Toluene
Toluene
Toluene
Toluene
2 d
2 d
2 d
3 d
86
66
O
8
/83%
7
/74%
39
O
18
19
trace
6.
5.
7.
O
O
20
21
PPh3AuCl, AgOTf, I2, DIPA
AuCl3, CuI, I2, DIPA
Toluene
Toluene
Toluene
1 d
1.5 d
2 d
trace
trace
79
O
10
/79%
9
/85%
22[c]
PPh3AuCl, CuI, I2, DIPA
8.
21
12
20
O
O
[a] Reaction conditions: 3 (0.1 mmol), catalyst (10 mol%), cocatalyst (30
mol%), base (1.2 equiv), oxidant (2.5 equiv), and solvent (10.0 mL) at rt for 24-
72 h. [b] Yield of Isolated product with 0.1 mmol scale. [c] The reaction was
carried out on one gram scale.
O
O
11
/81%
9.
/78%
No product was formed with inorganic bases (entry 9-11) and
among organic bases (Et3N, pyridine, TMEDA, DIPA), DIPA was
found to be the best base leading too good yields (entry 12-15).
An investigation of the impact of solvents showed that toluene
worked best for the smooth conversion of diynes to
corresponding macrolactones in the presence of 10 mol%
PPh3AuCl (10 mol%), CuI (30 mol%), I2 (2.5 equiv.) and DIPA
(1.2 equiv.), producing 4 in 86% yield (entry 16). Screening of
different copper catalysts revealed low yield of the
macrocyclization obtained with other co-catalysts such as CuCl,
CuCl2 and AgOTf. When Au(III) catalyst was used in place of
Au(I) catalyst, a trace amount of 4 was observed (entry 21). The
above optimized condition was also used for gram scale
synthesis to afford compound 4 in 79% yield (entry 22).
24
O
O
13
/71%
[a] The reaction was carried out on a 0.05 mmol scale.
While the precise reaction mechanism is not yet known, a
plausible mechanism is shown in Figure 2. It is postulated that
homogenous gold catalysts in situ generates organogold
species which behaves like immobilized alkyne leading not only
to the heterocoupling under high concentrations (0.01 M) but
also enhances the yield of the macrolactone formation. The
pathway is proposed as follows: The alkyne in presences of
base and gold(I) catalyst forms the gold acetylide[15b] complex
and simultaneously other alkyne forms copper acetylide. The
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10.1002/ejoc.201800708
European Journal of Organic Chemistry
COMMUNICATION
oxidative transmetalation of the organocopper species to AuIII in
presence of molecular iodine lead to intermediate IV. Diisopropyl
amine assisted reductive elimination of AuIII bis-acetylide
complex yields the product with removal of AuI species and
continues the next catalytic cycle.
In our current work, the development of a Au(I)/Cu(I)-catalyzed
macrocyclization for the synthesis of ivorenolide
B was
envisaged through intramolecular Glaser-Hay coupling which
disconnects the molecule framework at conjugated 1,3-diyne
bond leading to terminal alkynes ester 14 as an advanced
intermediate for the formation of 17-membered macrolactone.
The linear ester fragment 14 could be prepared by coupling of
alcohol 15 and acid 16 under Yamaguchi conditions.[19]
Syntheses of both fragments were anticipated following a
reliable direct catalytic asymmetric alkynylation strategy starting
from PMB-protected 9-decyn-1-ol and propionaldehyde,
respectively.
The synthesis of carboxylic alkynyl synthons 16 commenced
from PMB-protected 9-decyn-1-ol. Hydroxymethylation[20]
followed by Z-selective partial reduction[21] of the acetylene was
performed to furnish Z-alcohol 19 in 79% yield over two steps.
Oxidation of allylic alcohol with Dess-Martin-periodinane
(DMP)[22] furnished the α,β-unsaturated aldehyde, which was
subjected to zinc-ProPhenol-catalyzed alkyne addition to provide
the propargyl alcohol 20 in 94% enantiomeric excess and with
91% yield.[23,24] At this juncture, in anticipation for a better result,
the substrate 20 (for results, see Table 3) was prepared by
BINOL-mediated alkyne addition,[25] oxidation followed by Noyori
asymmetric hydrogenation[26] and enzymatic kinetic resolution.[27]
The secondary hydroxyl group present in compound 20 was
obtained through zinc-ProPhenol catalyzed addition, was
protected as its TBDPS ether and treated with DDQ in CH2Cl2
(pH 7) to afford 21 in 89% yield over two steps. The primary
alcohol 21 was oxidized to acid under TEMPO/BAIB in
CH3CN:H2O (2:1) to obtain acid 16 in 89% yield.[28] With acid 16
in hand, the alkynylation of propionaldehyde was accomplished
under Trost’s conditions using zinc-ProPhenol as the chiral
ligand and adding trimethylsilylacetylene (TMSA) slowly over 1 h
at 0 oC to furnish alcohol 15 in 70% yield with 89% ee.
Figure 2. Possible mechanistic pathways.
To demonstrate the utility of the novel macrocyclization,
synthesis of the 17-membered macrolide ivorenolide B was
undertaken. Yue et al. and our group independently achieved
the total synthesis of ent-ivorenolide A (1) and ivorenolide A (1),
respectively, utilizing alkyne-alkyne cross-coupling followed by
macrolactonization.[7a,17] Collins et al. recently reported the
formal total synthesis of ivorenolide
A
by following
macrocyclization strategies under phase separation conditions
using continuous flow.[13a] Further, Yue et al. reported the first
total synthesis of ivorenolide B (2), which was achieved through
esterification followed by RCM.[7b] Furstner et al. reported the
second synthesis of ivorenolide B using ring-closing alkyne
metathesis (RCAM) based macrocyclization, which involved
highly unstable tetrayne precursors.[18]
Scheme 2. Synthesis of fragment 16.
Scheme 1. Retrosynthetic analysis of ivorenolide B.
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10.1002/ejoc.201800708
European Journal of Organic Chemistry
COMMUNICATION
Table 3. Optimization of reaction conditions
desired product in low yield (Table 4). Subsequent epoxidation
with m-CPBA was highly regio- and stereoselective to furnish
ivorenolide B (2) in 82% yield as a single isomer. All analytical
and spectral data of the synthetic ivorenolide B (2) were in full
agreement with those of the natural product reported in the
literature.[7b,18]
Entry
Reaction conditions
ee
Yield (%)
1
2
3
4
Me2Zn, (R,R)-Prophenol, Ph3P=O
Et2Zn, (R)-Binol, Ti(OiPr)4
Noyori asymmetric reduction
Novozym Enzymatic resolution
94
70
91
93
91
79
82
39
In summary, we have developed
a highly synergistic
Au(I)/Cu(I) dual catalytic system for intramolecular Glaser-Hay
coupling with linear terminal alkynes for the synthesis of
macrolactones. The gold/copper conditions also can be utilized
to promote macrocyclization of a wide range of macrocycles with
varying ring sizes in excellent yield. The versatility of the
protocol was demonstrated in the rapid asymmetric total
synthesis of ivorenolide B. Further applications of this method
are being researched.
Union of the alcohol fragment with the acid fragment was
achieved smoothly under Yamaguchi conditions to furnish ester
22 in 92% yield. Deprotection of all silyl groups using TBAF in
THF afforded 24 in 96% yield. The stage was set to perform the
macrocyclization using Au(I)/Cu(I) in presence of iodine and
DIPA in toluene. When intramolecular Glaser-Hay coupling was
tried with the linear terminal alkynes with the secondary hydroxyl
group protected as its TBDPS ether, macrocyclization occurred
and 25 was obtained in 67% yield after two days (see Table 4).
Acknowledgements ((optional))
We thank Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for financial support as part of the XII Five
Year plan programme under the title ORIGIN (CSC-0108).
Keywords: Glaser-Hay coupling • Ivorenolide • Natural products
• Macrocycle • Gold-Copper dual catalysis
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Scheme 3. Total synthesis of Ivorenolide B.
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R1
Reaction conditions
time (d)
Yield (%)
TBDPS
-H
-H
AuCl(Ph3P)/CuI/I2/DIPA
AuCl(Ph3P)/CuI/I2/DIPA
Pd(PPh3)2Cl2/CuI/I2/DIPA
CuCl, TMEDA, O2
2
1.5
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67
81
36
15
-H
2
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10.1002/ejoc.201800708
European Journal of Organic Chemistry
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Sudheer K. Rangaraju, Uma Maheshwar
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Synergistic Gold and Copper Dual
Catalysis for the Intramolecular
Glaser-Hay Coupling: Rapid Total
Synthesis of Ivorenolide B
Diyne macrocycles with different ring size were synthesized by developing a novel
dual catalysis approach involving gold and copper catalysts through an
intramolecular Glaser-Hay coupling reaction in good yield and demonstrated for a
rapid total synthesis of ivorenolide B, a new class of macrolides endowed with
conjugated 1,3-diyne motif, having impressive immunosuppressive activities.
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