Stereoselective, Ag-Catalyzed Cyclizations to Access Polysubstituted Pyran Ring Systems: Synthesis of C1-C12 Subunit of Madeirolide A

Article abstract of DOI:10.1021/acs.orglett.6b00414

The exploration into the scope of a silver-catalyzed cyclization (AgCC) of propargyl benzoates for accessing pyran ring systems has been reported. The impact of the degree of substitution, nature of the substitution on the carbon backbone/benzoate moiety,

Full text of DOI:10.1021/acs.orglett.6b00414

Letter
pubs.acs.org/OrgLett
Stereoselective, Ag-Catalyzed Cyclizations To Access Polysubstituted
Pyran Ring Systems: Synthesis of C1−C12 Subunit of Madeirolide A
Kazuhiro Watanabe,†,‡ Jinming Li,‡ Nagarathanam Veerasamy, Ankan Ghosh, and Rich G. Carter*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: The exploration into the scope of a silver-
catalyzed cyclization (AgCC) of propargyl benzoates for
accessing pyran ring systems has been reported. The impact of
the degree of substitution, nature of the substitution on the
carbon backbone/benzoate moiety, and stereochemistry has
been evaluated. The application of this methodology to the
synthesis of the C1−C12 southern fragment of madeirolide A is
disclosed.
Scheme 1. Background of Metal-Catalyzed THF Synthesis
and Select Natural Product Examples
ature produces a diverse array of polyketide natural
Nproducts that have shown interesting biological activity.
Many of these polyketides contain stereodefined, polysub-
stituted tetrahydrofurans and tetrahydropyrans (Scheme 1).
Consequently, a broad array of synthetic tools have been
developed to access these structural classes,1 including various
transition-metal-mediated processes. The use of allenyl alcohols
as suitable precursors has proven effective in metal-catalyzed
(primarily Au and Ag) methods for accessing dihydrofurans (eq
1)2 and dihydropyrans.3 Our laboratory has had a long-standing
interest in macrolides including those containing furan and
pyran ring systems.4 More recently, we have been focused on
the potential of silver-catalyzed cyclizations (AgCCs) with
propargyl benzoates for accessing furanyl ring systems (eq 2).5
This work was inspired by Shigemasa and other pioneering
authors in the area.6,7 In these transformations, the propargyl
benzoate 4 must first undergo metal-catalyzed rearrangement to
an allenyl enol ether 6 which then undergoes a second metal-
catalyzed process, this time a 5-endo cyclization to access a
presumed vinyl metallo intermediate 7 which subsequently
protodemetallates to give the final, dihydrofuranyl enol ether
product 8. We became intrigued by the potential of extending
this concept to access tetrahydropyrans using the correspond-
ing homopropargylic alcohols. Toste and co-workers demon-
strated the potential of phenolic-containing propargylic
benzoates for accessing enantioenriched benzopyrans.8 Kotika-
lapudi and Swamy utilized highly unsaturated propargyl
benzoate systems for access to dienyl pyran systems.9 In our
recent total synthesis of mandelalide A (9), we demonstrated
the first example of using a AgCC to access a cis-disubstituted
pyran moiety.5c Concurrent with our mandelalide A synthesis,
Furstner and co-workers reported a exo-cyclic version of this
̈
transformation in their synthesis of enigmazole A.10 Herein, we
disclose the exploration of a general method for accessing enol
benzoate-containing dihydropyrans and its application to the
Received: February 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00414
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
synthesis of the C1−C12 fragment of the antifungal macrolide
madeirolide A (10).11
Table 2. Exploration of Diastereoselective AgCC
We first sought to explore the impact of substitution on the
propargylic benzoate carbon12 in the AgCC process (Table 1).
Table 1. Exploration of Scope of AgCC
entry
substrate
conditions
% yield (dr)
entry
R
yield (%)
1
13a
13a
13a
13b
13b
13b
13c
13c
13c
13d
13d
13d
13e
13e
13e
PhH, reflux, 3.5 h
PhMe, reflux, 1.5 h
xylenes, reflux, 50 min
PhH, reflux, 4 h
92 (4.6:1)
93 (5.4:1)
93 (5.5:1)
79 (4.2:1)
87 (4.8:1)
86 (4.6:1)
93 (3.8:1)
94 (4.0:1)
90 (4.3:1)
77 (2.6:1)
93 (3.8:1)
91 (3.8:1)
13 (3.0:1)
45 (3.2:1)
62 (3.5:1)
a
b
c
d
e
f
Me
73
2
Et
76
3
Ph
decomp
89
4
−(CH2)4−
−(CH2)5−
5
PhMe, reflux, 5 h
xylenes, reflux, 50 min
PhH, reflux, 3.5 h
PhMe, reflux, 1.5 h
xylenes, reflux, 50 min
PhH, reflux, 2.5 h
PhMe, reflux, 1.5 h
xylenes, reflux, 30 min
PhH, reflux, 7 h
83
6
−(CH2)2−O−(CH2)2−
73
7
a
g
H
decomp
8
a
This result was observed in refluxing toluene (3 h) and xylenes (1 h).
No reaction was observed under refluxing benzene (4 h).
9
10
11
12
13
14
15
The optimum conditions for these cyclizations were in refluxing
benzene. The reaction proceeded faster at higher temperatures
(e.g., refluxing toluene or xylenes); however, slightly lower
yields were typically observed (ca. 5−10% lower). We were
pleased to see clean conversion with both the dimethyl
benzoate 11a and the diethyl variant 11b to their desired
products in 73% and 76% yield, respectively. Interestingly, the
diphenyl benzoate 11c proved problematic, as decomposition
was observed under the reaction conditions. We attribute this
outcome to the strong propensity of the benzoate moiety to
ionize to the corresponding 3° carbocation which would be
highly stabilized by the two phenyl substituents as well as the
alkyne. Cyclic systems (e.g., 11d−11f) worked smoothly to
provide the spirocyclic products in good to excellent yields
(73−89%). The absence of any substitution at the propargylic
benzoate carbon was problematic as the primary benzoate 11g
led to no reaction under refluxing benzene conditions and
decomposition at higher temperatures.
We next set out to study the impact of substituents on the
benzoate moiety in the cyclization (Table 2). We focused on
the disubstituted AgCC, as we recently demonstrated the utility
of this transformation in our mandelalide A synthesis.5c These
cyclization precursors were accessed from known chiral
building blocks.13 We observed a modest temperature depend-
ent stereoerosion in the cyclization process. Interestingly,
higher reaction temperatures appeared to have a slight, positive
impact on the stereochemical outcome of the process. The use
of more electron-rich benzoates (e.g., 13d) led to an increase in
the reaction rate, likely due to the increased nucleophilicity of
the benzoate to attack the silver-activated alkyne (entries 10−
12); however, a decrease in the overall selectivity was observed.
In contrast, the use of a more electron-deficient benzoate (13e)
led to dramatically lower yields and slightly reduced
diastereoselectivity (entries 13−15).
PhMe, reflux, 5 h
xylenes, reflux, 1 h
position. A series of cyclization precursors containing multiple
stereochemistries were studied. The stereoselectivities on
alcohols 17b−c were modest (5−6:1 dr), but the reactions
proceeded in generally good yields. Interestingly, the epimeric
alcohol stereochemistry 19 did produce the expected trans-
pyran ring 20, but in low diastereoselectivity (2:1 dr). This
example clearly demonstrates that significant stereochemical
scrambling is occurring on a similar time frame to cyclization.
The presence of a second propargylic stereocenter proved
beneficial, leading to excellent stereoconversion (20:1 dr) for
alcohol 21 to enol benzoate 22; however, the formation of a
dihydrofuran (DHF) byproduct 23 was also observed.14 The
use of tertiary alcohols produced nearly equal amounts of five-
and six-membered products. Finally, the use of the stereo-
chemically dense alcohol 27 did provide the target dihydropyr-
an 28.14 Crude NMR indicated a similar DHF byproduct was
also formed in nearly equal amounts (approximately 1:1);
however, this presumed DHF compound proved too unstable
to verify. Subsequent hydrolysis of the enol benzoate 28
provided the pyranone 29 in 20:1 dr.
With a firm knowledge of the reaction scope, we applied the
AgCC protocol to the synthesis of the C1−C12 fragment of
madeirolide A (Scheme 3). Starting from readily available vinyl
iodide 3015 and alkyne 31,5b Sonogashira cross-coupling
generated the enyne 32 in good yield. Shi epoxidation of
enyne 32 proceeded in excellent diastereoselectivity and good
overall yield. Subsequent ring opening at the propargylic
position was best accomplished using LiAlMe4/BF3·Et2O to
provide clean stereoconversion to alcohol 35. We were pleased
to see that the key AgCC proceeded in excellent
diastereoselectivity to provide the enol p-methoxybenzoate 36
in >20:1 dr along with a minor amount of the undesired DHF
37 in an approximately 1.4:1 ratio (36:37). The p-methoxy
Varying substitution of the carbon backbone led to
interesting results (Scheme 2).12 The use of a primary alcohol
as the terminal nucleophile (compound 15) in the AgCC
worked smoothly and in high yield. This result is in contrast to
the primary propargylic benzoate 11g which led to decom-
B
DOI: 10.1021/acs.orglett.6b00414
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Letter
Scheme 2. Exploration of Stereochemistry in AgCC
Scheme 3. AgCC for Accessing the C3−C7 THP Ring in
Madeirolide A
The completion of the southern, C1−C12 fragment of
madeirolide A is shown in Scheme 4. NaOMe cleavage5c of
the enol benzoate revealed the desired ketone with no
Scheme 4. Synthesis of the C1−C12 Subunit of Madeirolide A
group on the aromatic ring of the benzoate was essential for
obtaining reasonable yields. Interestingly, the DHF product14
was formed in greater quantities at lower temperatures,
indicating a higher activation barrier for isomerization of the
propargylic benzoate to the allene as compared to direct
cyclization by the alcohol to the activated alkyne. The DHF 37
proved unstable and decomposed partially under SiO2
purification conditions and upon storage in CDCl3.
C
DOI: 10.1021/acs.orglett.6b00414
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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stereoerosion at C3 or C6. Stereoselective reduction of the C5
ketone followed by attachment of the glycoside 4011b provided
product 41. Finally, buffered TBAF deprotection of the C10
OTIPS ether followed by DMP oxidation and Wittig
olefination introduced the key trans C10,11 alkene 42.
In summary, the scope of AgCC to access pyran ring systems
has been explored. The impact of the degree of substitution,
nature of substituents, and stereochemistry has been studied.
Extension of this work to the synthesis of the southern, C1−C12
subunit of madeirolide A has been demonstrated. Further work
exploring the AgCC reaction and its application in synthesis
will be reported in due course.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00414.
Complete experimental procedures (PDF)
1
Copies of H and 13C spectra for all new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rich.carter@oregonstate.edu.
Present Address
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1959. (b) Yeom, H.-S.; Yoon, S.-J.; Shin, S. Tetrahedron Lett. 2007, 48,
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†Tohoku Pharmaceutical University, 4-1-1 Komatsushima,
Aoba-ku, Sendai, 981-8558, Japan.
(8) Wang, Y.-M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.; Toste,
F. D. J. Am. Chem. Soc. 2011, 133, 12972−12975.
Author Contributions
‡K.W. and J.L. contributed equally.
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8012.
(10) Ahlers, A.; de Haro, T.; Gabor, B.; Furstner, A. Angew. Chem.,
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Notes
Int. Ed. 2016, 55, 1406−1411.
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2009. (b) Paterson, I.; Haslett, G. W. Org. Lett. 2013, 15, 1338−1341.
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provided in the Supporting Information.
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2009, 74, 8681−8689. (b) Bae, H. J.; Jeong, W.; Lee, J. H.; Rhee, Y. H.
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(14) A mechanistic explanation for the formation of unwanted DHP
byproduct is provided in the Supporting Information.
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Chem. Soc. 2009, 131, 17714−17718. (b) Huang, Z.; Negishi, E. Org.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Oregon State University.
K.W. acknowledges Tohoku Pharmaceutical University for
fellowship support. We thank Professor Claudia Maier and Dr.
Jeff Morre
́
(OSU) for mass spectrometric data.
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