Total Synthesis of (-)-Neocosmosin A via Intramolecular Diels-Alder Reaction of 2-Pyrone

Article abstract of DOI:10.1021/acs.orglett.6b02575

A new synthetic route to (-)-neocosmosin A was devised by elaboration of intramolecular Diels-Alder (IMDA) cycloaddition of 2-pyrone containing a bromopropiolate group as the dienophile. The IMDA reaction was accompanied by cycloreversion of carbon dioxide to give benzannulated macrolide with two bromide groups at C14 and C16. Installation of the pinacolboryl groups and oxidations allowed completion of the total synthesis of (-)-neocosmosin A.

Full text of DOI:10.1021/acs.orglett.6b02575

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Neocosmosin A via Intramolecular Diels−Alder
Reaction of 2‑Pyrone
Joon-Ho Lee and Cheon-Gyu Cho*
Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro, Seongdong-gu,
Seoul 04763, Korea
S
* Supporting Information
ABSTRACT: A new synthetic route to (−)-neocosmosin A
was devised by elaboration of intramolecular Diels−Alder
(IMDA) cycloaddition of 2-pyrone containing a bromopro-
piolate group as the dienophile. The IMDA reaction was
accompanied by cycloreversion of carbon dioxide to give
benzannulated macrolide with two bromide groups at C14 and
C16. Installation of the pinacolboryl groups and oxidations
allowed completion of the total synthesis of (−)-neocosmosin
A.
esorcyclic acid lactones (RALs) are polyketide-derived
benzannulated macrolides, named for their β-resorcyclate
affinity for human opioid and cannabinoid receptors.5 The chiral
C2 carbinyl center, assigned incorrectly at the isolation,3a,b
proved to have S-configuration as underpinned by two
independent total syntheses led by Das6b and Banwell.6a In
both syntheses, ring closing metathesis was employed as a key
strategy. The RCM is no doubt an effective method for the
formation of a macrocycle but suffers from drawbacks arising
from the difficulties in controlling stereochemistry of the double
bond and finding proper reaction conditions, high catalyst costs,
issues with catalyst recovery/recycling, and necessary high
dilution conditions to suppress the undesired intermolecular
process.4
R
core structure fused to a 12- or 14-membered lactone ring
(Figure 1).1 They are synthesized in vivo by a variety of fungi
As a part of our ongoing study of 3,5-dibromo-2-pyrone
toward target oriented synthesis,7 we have devised a new
synthetic route that could allow rapid access to (−)-neocosmosin
A (Scheme 1). In this elaboration, the key bicyclolactone 2 would
be accessed from 2-pyrone 3 containing acrylate linked to the C3
position of the 2-pyrone through intramolecular Diels−Alder
cycloaddition (IMDA). Cycloreversion (retro-Diels−Alder) of
cycloadduct 2 and subsequent oxidative aromatization affords
benzomacrolactone 1. Introduction of the hydroxyl groups at
C14/C16 positions and methylation of the C14 hydroxyl group
allows completion of the synthesis.
To prove the concept, a racemic synthesis was first undertaken,
starting with the preparation of ( )-homoallylic alcohol 5 from
the readily accessible carboxylic acid 4 (Scheme 2).8 The
resulting alkyne 5 was then subjected to the Sonogashira
coupling reaction with 3,5-dibromo-2-pyrone 6 to give 3-alkynyl-
5-bromo-2-pyrone 7 in 86% yield.9 Subsequent mercury-
mediated hydration of alkyne 7 took place in a highly selective
manner at the desired alkyne carbon away from the 2-pyrone to
afford ketone 8 in 90% yield, as we expected from the possible
Figure 1. Selected resorcyclic acid lactones.
from acetone and malonate units via a series of Claisen
condensation reactions.2 Many of them exhibit intriguing
biological activities that include anticarcinogenic, antimalarial,
antifungal, and antibiotic properties.3 Several RAL compounds
are, in fact, currently under development for clinical applications.
Because of their potential values as new drug candidates,
invention of methods and/or routes that allow rapid and
divergent synthesis of RALs would be of significant interest.
However, literature survey unveils a rather short list in which the
strategies based on the ring-closing metathesis (RCM) or
macrolactonization reaction prevail.4,1c
Neocosmosin A is a recently found RAL, co-isolated with
neocosmosins B and C from the fungus Neocosmospora sp. (UM-
031509) in 2012.3a,b It was shown to have a strong binding
Received: August 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02575
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pinacolborane group. The IMDA reaction was eventually
effectuated by heating directly at 160 °C. However, the reaction
did not give the desired product 1, but gave 12, which was
identical to the product obtained from cycloadduct 11. In this
reaction, the initially formed cycloreversion product 13 under-
went β-elimination instead of oxidative aromatization (Scheme
3).12
Scheme 1. Retrosynthetic Analysis of Neocosmosin A
Scheme 3. IMDA of 2-Pyrone Acrylate with a Pinacolboranyl
Group
Scheme 2. IMDA of 2-Pyrone Connected with Acrylate as a
Model
To unravel the deborylation problem, 2-pyrone IMDA
precursor 15 with propiolate as a dienophile partner was
elaborated (Scheme 4). The extrusion of CO2 from the IMDA
Scheme 4. Preparation of 2-Pyrone IMDA Precursor with a
Bromopropiolate Group
adduct 15 would directly provid the key benzannulated
macrolactone 1 without oxidative aromatization reaction. We
opted to use a bromine group, considering the difficulty
associated with the installation of a pinacolboryl group in the
presence of a base-labile propiolate group13 as well as an
analogous literature precedent on the use of bromopropiolate as
the dienophile.14 Toward this, alcohol 8 was coupled with
propiolic acid to give propiolate 14 before the treatment with N-
bromosuccinimide (NBS) in the presence of AgNO3 to afford
IMDA precursor 15.15
In an effort to optimize the reaction, the IMDA reaction of 15
was subjected to both conventional and microwave heating
conditions at various temperatures in different solvents (Table
1). The microwave irradiation was conducted in the temperature
range from 140 to 200 °C. While the reaction finished very
rapidly within 30 min, the reaction yield hardly exceeded 40%,
even in the best case (entries 1−3). On the other hand, a product
yield of 48% was obtained on conventional heating in toluene at
150 °C (in sealed tube) under high dilution conditions (23 mM)
neighboring group participation of the 2-pyrone carbonyl
group.10 To probe the viability of the 2-pyrone IMDA strategy
involving such a long tether,11 2-pyrone 9 with a simple acrylate
group was prepared for a model study. When heated in refluxing
toluene under high dilution conditions (23 mM), the
corresponding cycloadduct 10 was obtained in 48% yield. To
effect the cycloreversion process, isolated 10 was heated in 1,2-
dichlorobenzene under reflux at 160 °C. Under the conditions,
the resulting cycloreversion product was found to undergo
oxidative aromatization, providing the corresponding benzoma-
crocyclic lactone 12 in 50% total yield.
Encouraged by the results, we prepared the IMDA precursor 3
containing a pinacolborane group as a synthetic equivalent of the
C16 hydroxyl group. Unfortunately, subjection to the conditions
effective for the model system 10 did not bring about the IMDA
reaction, presumably due to the steric impediment of the bulky
B
DOI: 10.1021/acs.orglett.6b02575
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Organic Letters
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Table 1. IMDA Reaction of Precursor 15
Scheme 5. Synthesis of Dibromobenzomacrolide (−)-16
a
entry
conditions
yield (%)
1
2
3
4
5
6
MW, o-dichlorobenzene, 140 °C, 10 min
MW, o-dichlorobenzene, 160 °C, 10 min
MW, o-dichlorobenzene, 200 °C, 10 min
toluene, 150 °C (sealed tube), 3 days
mesitylene, reflux (165 °C), 2 days
mesitylene, 0.5 equiv of BHT, reflux (165 °C), 2 days
33
35
15
48
56
64
a
All reactions were conducted at the concentration of 23 mM.
after 3 days (entry 4). The reaction in refluxing mesitylene
resulted in a slightly higher yield (56%, entry 5). Meaningful
increase in product yield (64%) was observed when the reaction
was conducted in the presence of 0.5 equiv of butylated
hydroxytoluene (BHT) as the radical scavenger (entry 6).
Having proved the effectiveness of our 2-pyrone IMDA
strategy, we ushered in the asymmetric synthesis of (−)-neo-
cosmosin A by preparing alkyne (−)-19 from aldehyde 1716 by
means of a Julia−Kocienski reaction with sulfone 18 (Scheme
5).17 Alkyne (−)-19 with opposite stereochemistry at the
carbinyl center was prepared in anticipation of configurational
inversion during the installation of the propiolate ester under
Mitsunobu conditions (vide infra). Subsequent Sonogashira
coupling reaction with 3,5-dibromo-2-pyrone (6) and mercury-
mediated hydration gave ketone (−)-8 in good overall yield. The
optical purity of (−)-8 was verified by Mosher ester analysis (see
Supporting Information). The same transformation can be
mediated by a Au catalyst, albeit in a slightly lower yield (80%;
see Supporting Information for details).18 Coupling reaction
with propiolic acid under Mitsunobu conditions gave propiolate
(+)-14 with inversion of configuration at the chiral carbinyl
center. Treatment with NBS in the presence of AgNO3 afforded
IMDA precursor (+)-15. Subsequent IMDA reaction under the
optimized conditions (except the concentration, vide infra)
afforded the corresponding macrocyclic lactone (+)-16 in 65%
yield. Note the reaction concentration, 0.1 M, is 10 times higher
than that of a typical RCM-based reaction, thereby it is more
readily adaptable to large-scale synthesis.
Scheme 6. End-Game Synthesis of (−)-Neocosmosin A
With a sufficient amount of dibromobenzo macrocyclic
lactone (+)-16 in hand, we surveyed the ways to convert the
aromatic bromides to phenolic hydroxyl groups (Scheme 6).
Direct installation of the hydroxyl groups by transition-metal-
catalyzed C−O coupling reactions were not compatible with the
base-labile macrocyclic lactone moiety. We chose to detour by
converting them into pinacolboryl groups. Toward this,
dibromide (+)-16 was subjected to the Miyaura conditions to
afford bispinacolborane 21.19 Subsequent oxidation of the
resulting borane compound 21 provided the resorcinol
(−)-2220 in 71% overall yield from (+)-16. Treatment with
MeI in the presence of K2CO3 allowed selective methylation at
the sterically less hindered C14 hydroxyl group to deliver
(−)-neocosmosin A in 78% yield. The spectroscopic data and
optical rotation of our synthetic neocosmosin A are consistent
with the literature values (see Supporting Information).3a,6
In summary, a new efficient synthetic route to (−)-neo-
cosmosin A was devised through the elaboration of intra-
molecular Diels−Alder cycloaddition of 2-pyrone connected to a
bromopropiolate group as the dienophile. Subsequent installa-
tion of two hydroxyl groups completed the synthesis of
(−)-neocosmosin A in a total of eight steps in 17% overall
yield from 3,5-dibromo-2-pyrone.
C
DOI: 10.1021/acs.orglett.6b02575
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Organic Letters
Letter
(11) (a) Shin, J.-T.; Hong, S.-C.; Shin, S.; Cho, C.-G. Org. Lett. 2006, 8,
3339. (b) Shin, J.-T.; Shin, S.; Cho, C.-G. Tetrahedron Lett. 2004, 45,
5857. For other examples, see: (c) Zhao, P.; Beaudry, C. M. Angew.
Chem., Int. Ed. 2014, 53, 10500. (d) Nelson, H. M.; Gordon, J. R.; Virgil,
S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2013, 52, 6699.
(12) It could be viewed as the reverse hydroboration as the
hydroboration is reversible at the temperatures greater than 160 °C.
Zweifel, G.; Brown, H. C. J. Am. Chem. Soc. 1964, 86, 393.
(13) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2005, 127, 3252.
(14) For the preparation of 3-bromopropiolate via transesterification
and IMDA reaction, see: Graetz, B. R.; Rychnovsky, S. D. Org. Lett.
2003, 5, 3357.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02575.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ccho@hanyang.ac.kr.
Notes
(15) Halbes-Letinois, U.; Weibel, J.-M.; Pale, P. Chem. Soc. Rev. 2007,
36, 759 and refs cited therein.
(16) Feldman, K. S.; Gonzalez, I. Y.; Glinkerman, C. M. J. Am. Chem.
Soc. 2014, 136, 15138.
The authors declare no competing financial interest.
(17) Lu, J.; Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron:
Asymmetry 2006, 17, 1066.
(18) For a recent review on hydration of alkyne, see: (a) Dorel, R.;
Echavarren, A. M. Chem. Rev. 2015, 115, 9028. (b) Brenzovich, W. E., Jr.
Angew. Chem., Int. Ed. 2012, 51, 8933. (c) Hintermann, L.; Labonne, A.
Synthesis 2007, 2007, 1121.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Research
Foundation of Korea (2014R1A5A1011165 and
2012M3A7B4049657).
(19) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508.
(20) (−)-22 is the enantiomer of naturally occurring monocillin IV.
REFERENCES
■
(1) For recent reports and reviews on RALs, see: (a) Ma, X.; Bolte, B.;
Banwell, M. G.; Willis, A. C. Org. Lett. 2016, 18, 4226. (b) Cookson, R.;
Barrett, T. N.; Barrett, A. G. M. Acc. Chem. Res. 2015, 48, 628. (c) Xu, J.;
Jiang, C.-s.; Zhang, Z.-l.; Ma, W.-q.; Guo, Y.-w. Acta Pharmacol. Sin.
2014, 35, 316. (d) Napolitano, C.; Murphy, P. V. Resorcylic Acid
Lactones. In Natural Lactones and Lactams: Synthesis, Occurrence and
Biological Activity; Janecki, T., Ed.; Wiley-VCH: Weinheim, Germany,
2014; Chapter 7. (e) Brase, S.; Encinas, A.; Keck, J.; Nising, C. F. Chem.
Rev. 2009, 109, 3903. (f) Winssinger, N.; Barluenga, S. Chem. Commun.
2007, 22.
(2) (a) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380.
(b) Birch, A.; Donovan, F. Aust. J. Chem. 1955, 8, 529.
(3) (a) Gao, J.; Radwan, M. M.; Leon, F.; Dale, O. R.; Husni, A. S.; Wu,
́
Y.; Lupien, S.; Wang, X.; Manly, S. P.; Hill, R. A.; Dugan, F. M.; Cutler,
H. G.; Cutler, S. J. J. Nat. Prod. 2013, 76, 2174. (b) Gao, J.; Radwan, M.
M.; Leon, F.; Dale, O. R.; Husni, A. S.; Wu, Y.; Lupien, S.; Wang, X.;
Manly, S. P.; Hill, R. A.; Dugan, F. M.; Cutler, H. G.; Cutler, S. J. Nat.
Prod. 2013, 76, 824. (c) Proisy, N.; Sharp, S. Y.; Boxall, K.; Connelly, S.;
Roe, S. M.; Prodromou, C.; Slawin, A. M. Z.; Pearl, L. H.; Workman, P.;
Moody, C. Chem. Biol. 2006, 13, 1203. (d) Hellwig, V.; Mayer-
Bartschmid, A. M.; Muller, H.; Greif, G.; Kleymann, G.; Zitzmann, W.;
Tichy, H.-V.; Stadler, M. J. Nat. Prod. 2003, 66, 829.
(4) For a review, see: Gradillas, A.; Per
Ed. 2006, 45, 6086.
́
ez-Castells, J. Angew. Chem., Int.
(5) Ahmad, S.; Dray, A. Curr. Opin. Investig. Drugs 2004, 5, 67.
(6) (a) Zhang, Y.; Dlugosch, M.; Jubermann, M.; Banwell, M. G.;
Ward, J. S. J. Org. Chem. 2015, 80, 4828. (b) Dachavaram, S. S.;
Kalyankar, K. B.; Das, S. Tetrahedron Lett. 2014, 55, 5629.
(7) (a) Shin, H.-S.; Jung, Y.-G.; Cho, H.-K.; Park, Y.-G.; Cho, C.-G.
Org. Lett. 2014, 16, 5718. (b) Cho, H.-K.; Lim, H.-Y.; Cho, C.-G. Org.
Lett. 2013, 15, 5806. (c) Jung, Y.-G.; Lee, S.-C.; Cho, H.-K.; Darvatkar,
N. B.; Song, J.-Y.; Cho, C.-G. Org. Lett. 2013, 15, 132. (d) Jung, Y.-K.;
Kang, H.-U.; Cho, H.-K.; Cho, C.-G. Org. Lett. 2011, 13, 5890.
(e) Chang, J. H.; Kang, H.-U.; Jung, I.-H.; Cho, C.-G. Org. Lett. 2010, 12,
2016. (f) Tam, N. T.; Jung, E.-J.; Cho, C.-G. Org. Lett. 2010, 12, 2012.
(g) Tam, N. T.; Cho, C.-G. Org. Lett. 2008, 10, 601. (h) Tam, N. T.;
Chang, J.; Jung, E.-J.; Cho, C.-G. J. Org. Chem. 2008, 73, 6258. (i) Shin,
I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303.
(j) Tam, N. T.; Cho, C.-G. Org. Lett. 2007, 9, 3391. (k) Kim, H.-Y.; Cho,
C.-G. Prog. Heterocycl. Chem. 2007, 18, 1. (l) Ryu, K.; Cho, Y.-S.; Cho,
C.-G. Org. Lett. 2006, 8, 3343. (m) Kim, W.-S.; Kim, H.-J.; Cho, C.-G. J.
Am. Chem. Soc. 2003, 125, 14288.
(8) Petri, A. F.; Kuhnert, S. M.; Scheufler, F.; Maier, M. E. Synthesis
2003, 2003, 0940.
(9) Lee, J.-H.; Park, J.-S.; Cho, C.-G. Org. Lett. 2002, 4, 1171.
(10) Wang, W.; Xu, B.; Hammond, G. B. J. Org. Chem. 2009, 74, 1640.
D
DOI: 10.1021/acs.orglett.6b02575
Org. Lett. XXXX, XXX, XXX−XXX