Formal Synthesis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehydrative Alkoxylation

Article abstract of DOI:10.1002/chem.201700499

8-Membered cyclic ethers are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. The gold(I)-catalyzed intramolecular dehydrative alkoxylation of ω-hydroxy allylic alcohols was explored to stereoselectively construct α,α′-cis-oxocenes and further applied in a formal synthesis of (+)-laurencin. The gold(I)-catalyzed intramolecular dehydrative alkoxylation may constitute an alternative method for the synthesis of molecular building blocks and natural products that contain highly functionalized 8-membered cyclic ethers.

Full text of DOI:10.1002/chem.201700499

A Journal of
Accepted Article
Title: Formal Synthesis of (+)-Laurencin via a Gold(I)-Catalyzed
Intramolecular Dehydrative Alkoxylation
Authors: Megan L Lanier, Hyeri Park, Paramita Mukherjee, Jacob C
Timmerman, Anthony A Ribero, Ross A Widenhoefer, and
Jiyong Hong
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To be cited as: Chem. Eur. J. 10.1002/chem.201700499
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10.1002/chem.201700499
Chemistry - A European Journal
Formal Synthesis of (+)-Laurencin via a Gold(I)-Catalyzed Intramolecular Dehydrative
Alkoxylation
Megan L. Lanier,[a],†,§ Hyeri Park,[a],§ Paramita Mukherjee,[a] Jacob C. Timmerman,[a] Anthony A.
Ribeiro,[b] Ross A. Widenhoefer,[a],* and Jiyong Hong[a],*
[a] Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
[b] Duke University NMR Center and Department of Radiology, Duke University, Durham, North
Carolina 27710, United States
ABSTRACT: 8-Membered cyclic ethers are found in a wide range of natural products; however,
they are challenging synthetic targets due to enthalpic and entropic barriers. The gold(I)-catalyzed
intramolecular dehydrative alkoxylation of -hydroxy allylic alcohols was explored to
stereoselectively construct α,α΄-cis-oxocenes and applied in a formal synthesis of (+)-laurencin.
The gold(I)-catalyzed intramolecular dehydrative alkoxylation may constitute an alternative
method for the synthesis of molecular building blocks and natural products that contain highly
functionalized 8-membered cyclic ethers.
A number of areas associated with human health including natural products synthesis,
pharmaceutical development, and chemical biology depend on reliable and efficient methods for
the synthesis of a chemically diverse range of molecular building blocks and sub-structures. For
this reason, the development of general and selective carbon-carbon and carbon-heteroatom bond-
forming reactions, particularly those suited for application in complex molecular systems, has the
potential to positively impact these diverse and important areas of research.
8-Membered cyclic ethers are highly abundant in structurally or biologically intriguing
natural products (Figure 1). As a consequence, these 8-membered cyclic ethers have fueled
synthetic efforts to develop novel methodologies.[1] However, despite prolonged interest in the
area, effective methods for the stereoselective synthesis of 8-membered cyclic ethers are limited
most notably with respect to catalytic methods. Thus, there remains a great need to develop
catalytic and stereoselective methods for 8-membered cyclic ether synthesis that are applicable in
structurally complex natural product synthesis.
1
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Figure 1. Examples of naturally occurring 8-membered cyclic ethers.
The use of soluble gold complexes as catalysts for organic reactions has become
increasingly popular over the past decade.[2] Early work in this area focused on the application of
gold(III) halides as catalysts, but effort has increasingly shifted toward cationic gold(I) complexes,
which display excellent chemoselectivity and functional group compatibility. Over the past several
years, these cationic gold(I) complexes have emerged as particularly active catalysts for the regio-
and stereoselective functionalization of C=C bonds with carbon and heteroatom nucleophiles[3] to
form carbocycles, heterocycles, and hetero-functionalized building blocks from readily available
starting materials via highly atom-economical transformations.[4] Included among these
transformations is the formation of cyclic ethers through the gold(I)-catalyzed hydroalkoxylation
of allenes[3b, 5] or dehydrative alkoxylation of allylic alcohols.[6] However, application of these
methods to the synthesis of medium-sized cyclic ethers remains underexplored[7] and only a few
reports of the synthesis of an 8-membered cyclic ether via gold catalysis have been disclosed.[8]
Herein, we describe our investigation of the gold(I)-catalyzed intramolecular dehydrative
alkoxylation of -hydroxy allylic alcohols for the stereoselective preparation of α,α΄-cis-oxocenes
and application of the method in a stereoselective formal synthesis of (+)-laurencin (1, Figure 2).
2
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Figure 2. The gold(I)-catalyzed intramolecular dehydrative alkoxylation approach to a
stereoselective synthesis of (+)-laurencin (1).
Since oxocenes containing a 4,5- or 5,6-cis double bond or a functional group that can be
derived from a double bond are abundant in nature, initial studies to test the feasibility of the
gold(I)-catalyzed intramolecular dehydrative alkoxylation for a stereoselective oxocene synthesis
were completed with both monoallylic diols 2a and 2b possessing 4,5- and 5,6-cis-olefin,
respectively (Table 1).[9] Initially, 2a and 2b were subjected to (JohnPhos)AuCl (5 mol%) and
AgOTs (5 mol%) in dioxane at 25 °C for 24 h. Unfortunately, no product formation was observed.
After increasing the temperature to 100 and 50 °C, respectively, only trace amounts of a new
product were detected (entries 1 and 2). Changing the catalyst combination to IPrAuCl and AgClO4
did not show any improvement in reactivity at 25 °C; however, increasing the temperature to 50 °C
gave the desired oxocenes 3a and 3b, respectively, as single diastereomers (entries 3 and 4). The
gold(I)-catalyzed intramolecular dehydrative alkoxylation stereoselectively provided the α,α΄-cis-
oxecene 3b[10] through the more favorable conformation 2b-B and involved the outer sphere attack
of the nucleophile on a catalyst -complex. Prolonged reaction time did not show complete
consumption of the substrate in either case. Exchanging Ph3PAuCl for IPrAuCl yielded a complex
reaction mixture and microwave irradiation did not show any significant change in isolated yield
(entries 5 and 6).
Table 1. Synthesis of α,α′-cis-Oxecenes via the Gold(I)-Catalyzed Intramolecular Dehydrative
Alkoxylation.
3
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Product
(yield [%])
Entry Substrate Gold Catalyst
Silver Salt Temp [°C] Time [h]
1
2
3
4
5
6
2a
2b
2a
2b
2a
2a
(JohnPhos)AuCl AgOTs
(JohnPhos)AuCl AgOTs
25–100
25–50
25–50
25–50
25–80
50 μW
96
trace
96
trace
IPrAuCl
IPrAuCl
Ph3PAuCl
IPrAuCl
AgClO4
AgClO4
AgClO4
AgClO4
144
144
48
3a (18)[a]
3b (37)[a]
complex mixture
3a (17)[a]
50
[a] >20:1 dr
Since the active gold catalyst is formed in situ and it has been established that the silver
salt counteranion can significantly affect its reactivity,[11] various silver salts were examined (Table
2). Based on the preliminary studies, optimization of the silver salt was accomplished with 10 mol%
of IPrAuCl at 50 °C for 48 h. No reaction was observed with AgOTs and AgOAc (entries 1 and 2)
and reactivity increased in the order of AgAsF6, AgBF4, AgSbF6 and AgOTf, yielding up to 50%
α,α΄-cis-oxocene 3b. In order to rule out an acid-catalyzed mechanism, 2b was subjected to HOTf
(10 mol%) in dioxane at 50 °C for 48 h. The reaction resulted in roughly 62% conversion of 2b
with the desired oxocene 3b comprising around 6% of the reaction mixture. This result clearly
suggested that the cyclization reaction is not dependent on acid-catalysis, but is dependent on
gold(I)-catalysis. AgClO4 gave a lower yield (entry 7) under these conditions in comparison to
AgOTf. Interestingly, reducing the catalyst loading to 5 mol% gave a higher yield of 3b (28%,
entry 8). Reducing the temperature to 30 °C also resulted in a similar increase in isolated yield
(22%, entry 9). Unfortunately, this trend was not applicable to the most reactive silver salt, AgOTf,
and significantly lower yields were obtained (entries 10 and 11). Various solvents were also
screened; however, dioxane remained the most advantageous choice (entries 12–17).
4
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Table 2. Screening of Silver Salts and Solvents for the Gold(I)-Catalyzed Intramolecular
Dehydrative Alkoxylation.
Entry Silver Salt [mol%] Catalyst Loading [mol%] Solvent Temp [°C] Yield (%)[a]
1
AgOTs (10)
AgOAc (10)
AgAsF6 (10)
AgBF4 (10)
AgSbF6 (10)
AgOTf (10)
AgClO4 (10)
AgClO4 (5)
AgClO4 (10)
AgOTf (5)
10
10
10
10
10
10
10
5
dioxane 50
dioxane 50
dioxane 50
dioxane 50
dioxane 50
dioxane 50
dioxane 50
dioxane 50
dioxane 30
dioxane 50
dioxane 30
toluene 50
CH3CN 50
no reaction
2
no reaction
3
18
4
32
5
35
6
50
7
8
8
28
9
10
5
22
10
11
12
13
14
15
16
17
32
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
10
10
10
10
10
10
10
29
24
trace
14
THF
50
acetone 50
CH2Cl2 50
EtOAc 50
17
trace
trace
[a] >20:1 dr
Having screened the silver salt, catalyst loading, solvent, and temperature, the 5,6-cis-
olefin containing monoallylic diol 2b was subjected to IPrAuCl (10 mol%) and AgOTf (10 mol%)
in dioxane at 50 °C for 48 h to afford the desired α,α΄-cis-oxocene 3b in 50% yield (entry 6).[12]
These model studies suggested that the gold(I)-catalyzed intramolecular dehydrative alkoxylation
of -hydroxy allylic alcohols can be used to stereoselectively construct α,α΄-cis-oxocenes.[13,14]
Encouraged by the potential of the gold(I)-catalyzed dehydrative alkoxylation for the
stereoselective synthesis of α,α΄-cis-oxocenes, we embarked on a stereoselective formal synthesis
5
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of (+)-laurencin (1, Figure 3). (+)-Laurencin (1) was isolated from Laurencia glandulifera,
collected at Oshoro Bay (Hokkaido, Japan), by Irie et al. in 1965.[15] Key structural features of (+)-
laurencin (1), which were established through several reports,[16] include a 3,4,7,8-tetrahydro-2H-
oxocin core, a bromine atom as well as ethyl and 1-acetoxyhex-3-en-5-ynyl groups. Although 1
possesses only moderate activity as a drug metabolism inhibitor,[17] its preparation has been
extensively studied due to its unique structural features.[18,19,20]
Figure 3. Retrosynthetic plan for (+)-laurencin (1).
As illustrated in our retrosynthetic plan (Figure 3), (+)-laurencin (1) could be prepared
from the α-cyano ketone 4 following the known procedures.[19i] The α-cyano ketone 4 would be
obtained from the α,α΄-cis-oxocene 5 via the Wacker oxidation and subsequent α-cyanation. We
envisioned the α,α΄-cis-oxocene 5 would be accessed from the -hydroxy allylic alcohol 6 via the
key gold(I)-catalyzed intramolecular alkoxylation. The coupling of epoxide 7 and alkyne 8 would
provide 6 for the gold(I)-catalyzed intramolecular alkoxylation.
The synthesis began with preparation of the SEM-protected α-hydroxyepoxide 7 from the
tosylate 9 (Scheme 1). The CuI-mediated coupling of 9, which was prepared from (4R,5R)-2,2-
dimethyl-1,3-dioxolane-4,5-dimethanol,[21] and CH3Li followed by debenzylation provided the
alcohol 10 in 92% overall yield for two steps. Treatment of 10 with p-TsCl and acetonide
deprotection of the resulting tosylate under acidic conditions gave the diol 11 in 91% overall yield
for two steps. An initial two-step sequence in which epoxidation was achieved using K2CO3 and
MeOH/CH2Cl2 followed by treatment of the crude epoxide with NaH and SEMCl was somewhat
successful, giving the desired SEM-protected α-hydroxyepoxide 7 in 10% yield. However, there
were several drawbacks to this procedure, including prolonged reaction time for the epoxidation
and the potential volatility of the intermediate epoxide. It was hypothesized that the epoxidation
and SEM protection could be achieved in a single step using NaH as the base for both purposes,
hence eliminating the long reaction time for epoxidation and handling of the volatile epoxide prior
to protection. As depicted in Scheme 1, treatment of 11 with excess NaH and SEMCl gave 7
directly in 82% isolated yield.
6
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Scheme 1. Preparation of epoxide and alkyne.
For the synthesis of the terminal alkyne 8, we converted commercially available (E)-2-
butene-1,4-diol (12) to 13 via mono-SEM protection followed by bromination (Scheme 1). The
CuBr-mediated coupling of 13 and TMS-acetylene followed by TMS deprotection gave the desired
terminal alkyne 8 in 88% overall yield for two steps.
With both fragments in hand, the epoxide–alkyne coupling reaction was attempted
(Scheme 2). After examining several conditions, the coupling of alkyne 8 and epoxide 7 via
lithiation followed by transmetalation proceeded smoothly to afford the homopropargylic alcohol
14 in 67% yield.[22] The benzylation of 14 in the presence of TBAI gave the benzyl ether 15 in 91%
yield. Lindlar hydrogenation followed by bis-SEM deprotection afforded the -hydroxy allylic
alcohol 6 in 71% for two steps. With the key substrate in hand, we turned our attention to the
gold(I)-catalyzed intramolecular alkoxylation for preparation of the α,α΄-cis-oxocene core of 1.
When the optimized conditions from the model studies were applied to the key cyclization of 6,
the desired α,α΄-cis-oxocene 5 was obtained in 35% yield as a single diastereomer.[23] Based on
reports of gold(I)-catalyzed reactions “buffered” by bases such as NaHCO3 and CaCO3, it was
hypothesized that use of NaHCO3 to maintain the pH might suppress potential side reaction and
increase the yield of the cyclization reaction. We found that treatment of 5 with IPrAuCl (20 mol%),
AgSbF6 (20 mol%), and NaHCO3 in 1,2-dichloroethane at 50 °C yielded the desired α,α΄-cis-
oxocene 5 in 45% yield as a single diastereomer. The isolated yield of 6 still suffered due to
competing reaction pathways such as 4,5-cis-double bond isomerization and dimerization, but the
gold(I)-catalyzed intramolecular dehydrative alkoxylation proceeded with excellent
stereoselectivity (>20:1 dr). Moreover, the reaction is catalytic and complementary to existing
synthetic methods for 8-membered cyclic ethers.
To complete the formal synthesis of (+)-laurencin (1), a two-step sequence of Wacker
oxidation and α-cyanation was employed. The Wacker oxidation of 5 gave the desired methyl
ketone 16 in 51% yield (64% brsm), a moderate yield resulting from competitive aldehyde
formation (~10%). Treatment of 16 with LHMDS and p-TsCN yielded the known Kim’s α-cyano
7
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ketone 4[19i] in 55% yield. The spectral data of 4 were in good agreement with those in literature,
which constitutes a formal synthesis of (+)-laurencin (1).
Scheme 2. Formal synthesis of (+)-laurencin (1) via the gold(I)-catalyzed intramolecular
dehydrative alkoxylation of -hydroxy allylic alcohol.
In summary, the gold(I)-catalyzed intramolecular dehydrative alkoxylation of -hydroxy
allylic alcohols was explored for the stereoselective synthesis of α,α΄-cis-oxocenes and applied in
a formal synthesis of (+)-laurencin (1). The α,α΄-cis-oxocene core of (+)-laurencin (1) was
stereoselectively constructed from the readily available epoxide 7 and alkyne 8 via gold(I)-
catalyzed intramolecular dehydrative alkoxylation. We expect that the gold(I)-catalyzed
intramolecular dehydrative alkoxylation would be broadly applicable in stereoselective synthesis
of 8-membered cyclic ethers as well as other types of medium-sized cyclic ethers.
Supporting Information
General experimental procedures including spectroscopic and analytical data along with copies of
1H and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jiyong.hong@duke.edu; ross.widenhoefer@duke.edu.
Present Addresses
†Hammond High Magnet School, 45168 River Rd, Hammond, LA 70401, United States.
Author Contributions
8
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§ These authors contributed equally.
The manuscript was written through contributions of all authors. / All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENTS
We thank Professor Deukjoon Kim for helpful discussions and Dr. Te-ik Sohn ford the 2D NMR
spectra of 3b. We are grateful to the National Institutes of Health (National Institute of Allergy
and Infectious Diseases, 1R21AI128283-01) and Duke University for funding this work, to the
North Carolina Biotechnology Center (NCBC; Grant No. 2008-IDG-1010) for funding of the
NMR instrumentation, and to the National Science Foundation (NSF) MRI Program (Award ID
No. 0923097) for funding mass spectrometry instrumentation. M.L.L. was supported by the
NIGMS Pharmacological Sciences Training Program (NIH GM007105) and A.A.R. was
supported in part by NIH NCI P30-CA-14236, which is gratefully acknowledged. NMR spectra
were acquired at the Duke University NMR Spectroscopy Center funded by the NSF, the NIH, the
NC Biotechnology Center, and Duke University.
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Chemistry - A European Journal
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10
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