Total Synthesis of trans-Resorcylide via Macrocyclic Stille Carbonylation

Article abstract of DOI:10.1038/s41429-019-0145-4

The resorcylic macrolides are important natural products with a wide range of remarkable biological activities. So far, most of the reported resorcylic macrolide syntheses use either macrolactonization or ring closing metathesis to build the corresponding macrocycle. In continuation of our efforts in developing novel carbonylation reactions to facilitate natural product total synthesis, we report herein a total synthesis of trans-resorcylide (1) featuring a palladium-catalyzed macrocyclic Stille carbonylation to build its 12-membered macrocycle.

Full text of DOI:10.1038/s41429-019-0145-4

The Journal of Antibiotics
https://doi.org/10.1038/s41429-019-0145-4
SPECIAL FEATURE: BRIEF COMMUNICATION
Total Synthesis of trans-Resorcylide via Macrocyclic Stille
Carbonylation
1
Yiyang Luo1 Xianglin Yin1 Mingji Dai
●
●
Received: 8 December 2018 / Revised: 26 December 2018 / Accepted: 28 December 2018
© The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2019
Abstract
The resorcylic macrolides are important natural products with a wide range of remarkable biological activities. So far, most
of the reported resorcylic macrolide syntheses use either macrolactonization or ring closing metathesis to build the
corresponding macrocycle. In continuation of our efforts in developing novel carbonylation reactions to facilitate natural
product total synthesis, we report herein a total synthesis of trans-resorcylide (1) featuring a palladium-catalyzed
macrocyclic Stille carbonylation to build its 12-membered macrocycle.
The resorcylic macrolide is an important family of natural
products featuring a 6-alkyl-2,4-dihydroxybenzoic acid (the
β-resorcylate moiety) fused with a macrocyclic lactone ring.
These resorcylic macrolides have demonstrated a wide
range of important biological activities. For example, trans-
resorcylide (1, Fig. 1) and cis-resorcylide (2) are plant
growth inhibitors [1, 2]. Radicicol (3) was originally iso-
lated from Monicillium nordinii in 1953 [3] and has shown
antibiotic anticancer activity. It was later discovered as a
potent and selective heat shock protein 90 (Hsp90) inhibitor
with IC50 of 20 nM [4]. Hsp90 is a chaperon protein and has
been an important therapeutic target for developing new
cancer treatment. Monocillin VI (4) was recently isolated
from the cultures of Paecilomyces sp. SC0924. It exhibited
potent growth inhibition activity against quite a few cancer
cell lines including MCF-7, A549, and Hela cells as well as
antifungal activity against Peronophythora litchi [5].
These resorcylic macrolides, due to their diverse struc-
tures and remarkable biological activities, have garnered a
significant amount of synthetic attention. For example,
Couladouros et al. reported the first total synthesis of trans-
resorcylide (1) and cis-resorcylide (2) in 2004 [6]. Miller and
Mennen reported a formal synthesis of trans-resorcylide (1)
in 2007 [7]. Tsuji et al. synthesized dehydroxy-trans-resor-
cylide by an intramolecular alkylation [8]. Radicicol (3) has
been synthesized by the groups of Lett [9, 10], Danishefsky
[11–13], and Winssinger [14]. The Danishefsky group also
synthesized cycloproparadicicol to improve the corre-
sponding pharmacokinetics and reduce nonspecific toxicities
[15]. The key for synthesizing these resorcylic macrolides is
to construct the β-resorcylate moiety and the macrolactone
moiety. While most of the syntheses relied on starting
materials already equipped with the resorcylate core,
Danishefsky and co-workers reported a remarkable Diels-
Alder reaction of strained ynolides to build the β-resorcylate
moiety. For the macrolactone moiety, macrolactonization
and ring closing metathesis are the two common strategies to
form the desired macrolactones. Notably, in Miller’s formal
synthesis of trans-resorcylide (1), an acyl-anion equivalent
macrocyclization was used to build the corresponding
macrocycle.
Dedication: This article is dedicated to Professor Samuel J.
Danishefsky for his great scientific contributions to total synthesis of
highly complex and biologically important natural products.
Supplementary information The online version of this article (https://
doi.org/10.1038/s41429-019-0145-4) contains supplementary
material, which is available to authorized users.
Our group has been developing novel palladium-
catalyzed carbonylation reactions to facilitate the total
synthesis of complex natural product [16, 17]. For
example, we have developed a palladium-catalyzed
alkoxycarbonylative macrolactonization to streamline the
synthesis of tetrahydropyran/tetrahydrofuran-containing
bridged macrolactones including 9-demethylneopeltolide
* Mingji Dai
mjdai@purdue.edu
1
Department of Chemistry, Center for Cancer Research, and
Institute for Drug Discovery, Purdue University, 720 Clinic Drive,
West Lafayette, IN 47907, USA

Y. Luo et al.
A. Selected resorcylic macrolides
Fig. 1 Selected resorcylic
macrolides and our synthetic
plan via macrocyclic Stille
carbonylation
Me
O
H
O
O
O
OH
O
O
Me
O
OH
Me
H
Me
HO
O
HO
O
O
HO
O
Cl
HO
trans-Resorcylide (1)
OH
O
O
OH
cis-Resorcylide (2)
Monocillin VI (4)
Radicicol (3)
B. Synthetic plan via macrocyclic Stille carbonylation
Me
Me
HO
Me
OH
O
OR
O
O
OR
Pd cat.
O
O
Cl
OH
Cl
8
HO
RO
RO
O
C
7
O
SnBu3
SnBu3
5
6
[18]. This effective method was also used as the key step
in Harran’s total synthesis of callyspongiolide [19]. An
intramolecular carbonylative Heck macrolactonization has
been realized and utilized by us to streamline the total
synthesis of spinosyn A [20]. We also developed a novel
palladium-catalyzed carbonylative spirolactonization of
hydroxycyclopropanols to synthesize oxaspirolactone-
esterification of acyl chloride 19 and secondary alcohol 14 to
synthesize the macrocyclic Stille carbonylation precursor 20.
Our synthesis of 14 started from known bromide 9 [26], which
was treated with Mg metal and 1,2-dibromoethane followed by
transmetalation with CuI. The resulting cuprate reagent
underwent regioselective epoxide ring opening with epoxide 10
to afford alcohol 11 in 74% yield. After removal of the TMS
group with Cs2CO3 in MeOH, the terminal alkyne was sub-
sequently converted to alkynyl stannane via deprotonation with
nBuLi followed by trapping the acetylide with nBu3SnCl.
Stereoselective reduction of the internal alkyne with the
Schwartz’s reagent gave cis-vinylstannane 14 in good yield.
We then synthesized known benzoic acid 18 from commer-
cially available starting material 15. Vilsmeier-Haack for-
mylation accompanied by in situ chlorodehydration gave
aldehyde 16 in quantitative yield. Due to the difficulties we
encountered in removing the methyl groups at a late stage, the
two methyl ethers were switched to benzyl ethers via a
sequence of BBr3 deprotection and benzylation with BnBr in
presence of Cs2CO3 in acetone. The resulting benzyl protected
aldehyde 17 was then oxidized to benzoic acid 18, which was
subsequently converted to acyl chloride 19 with the treatment
of oxalyl chloride and DMF in DCM. Acyl chloride 19,
without further purification was reacted with alcohol 14 to
deliver the Stille carbonylation precursor 20 in modest yield.
With 20 in hand, we investigated various reaction condi-
tions for the macrocyclic Stille carbonylation and were sur-
prised to discover that, under the reaction conditions of 10 mol
% of Pd(PPh3)4 and 20 mol% of P(2-furyl)3 under balloon
pressure of carbon monoxide in p-dioxane at 80 °C, macro-
cyclic product 21 with a trans-enone was obtained in 36%
yield while compound 20 contains a cis-vinylstannane moiety.
The expected macrocyclic cis-enone was not isolated. We
didn’t observe the direct intramolecular Stille cross coupling
containing
C12-oxygenated
labdanolic
diterpenes
α-levantanolide and α-levantenolide [21] and stemona
alkaloids bisdehydroneostemoninine and bisdehy-
drostemoninine [22]. Very recently, we have used a
palladium-catalyzed hydrocarbonylative lactonization to
synthesize three rare abies sesquiterpenoids, which in turn
enabled the identification of novel selective covalent
inhibitors of oncogenic protein tyrosine phosphatase
SHP2 and elucidation of DNA polymerase epsilon subunit
3 (POLE3) as one of their potential cellular targets [23]. In
this context, we considered the possibility of developing a
palladium-catalyzed macrocyclic Stille carbonylation to
build the desired macrocyclic enone moiety of these
resorcylic macrolides (cf. 1-4) by converting
vinylstannane-containing benzyl chloride 6 to macro-
cyclic enone 5. Macrocyclic Stille carbonylation has been
rarely used in total synthesis [24, 25] and no macrocyclic
Stille carbonylation of benzyl chloride has been reported
so far. Therefore, we hope to develop a new strategy to
access these important resorcylic macrolides and gen-
eralize the macrocyclic Stille carbonylation for macro-
cyclic enone synthesis.
We chose cis-resorcylide (2) as the initial target molecule to
test the hypothesis of using the macrocyclic Stille carbonylation
to build the corresponding macrocycle. For this purpose, ben-
zyl chloride 20 (Scheme 1b) with an intramolecularly tethered
vinylstannane need to be prepared. We planned to use an

Total Synthesis of trans-Resorcylide via Macrocyclic Stille Carbonylation
A. Synthesis of 14
Mg, BrCH2CH2Br
THF, 55 °C, 1 h
Cs2CO3
OH
OH
TMS
Br
O
MeOH, overnight
66%
then CuI,
Me
Me
TMS
Me
(10)
9
12
11
THF, r.t., 1 h
74%
OH
Cp2ZrHCl, then H2O
nBuLi, nBu3SnCl
OH
SnBu3
Me
THF, -78 °C to r.t., overnight
66%
THF, r.t., 2 h
66%
Me
SnBu3
14
13
B. Total synthesis
OMeO
OBn O
OMe
i. BBr3, DCM, -78 °C to r.t.
POCl3, DMF
overnight; 95%
H
H
Cl
0 °C to 75 °C, 2 h
100%
Cl
OH
ii. BnBr, Cs2CO3, acetone
r.t., overnight
MeO
BnO
MeO
16
17
15
91%
OBn O
OBn O
Cl
NaClO2, NH2SO3H
(COCl)2, DMF
DCM, 0 °C to r.t., 1 h
TEA, 14, DCM
OH
Cl
acetone/DMSO/H2O
0 °C, 0.5 h
Cl
0 °C to r.t., 2 h
52%
BnO
BnO
18
19
56%
Me
Me
Me
OBn O
Pd(PPh3)4 (10 mol%)
P(2-furyl)3 (20 mol%)
CO (balloon)
O
O
OH
BnO
O
Cl
O
O
BCl3, DCM
BnO
p-dioxane, 80 °C
overnight
-78 °C, 0.5 h
97%
HO
BnO
Bu3Sn
O
O
21
36%
trans-Resorcylide (1)
20
Scheme 1 Total synthesis of trans-resorcylide (1)
product too. The detailed reaction mechanism for the formation
of the macrocyclic trans-enone was not fully understood at this
stage. One hypothesis is that the macrocyclic cis-enone was
initially formed, but then quickly isomerized to the trans one
under the carbonylation reaction conditions via either a rever-
sible Michael-type addition with PPh3 and/or P(2-furyl)3 as the
nucleophile at the relative high reaction temperature or a Pd-
catalyzed isomerization probably involving in situ formed Pd-
H species. Removal of the two benzyl groups with the treat-
ment of BCl3 at −78 °C in DCM [27] completed the total
synthesis of trans-resorcylide (1). Notably, removal of these
two benzyl groups was nontrivial at all. Couladouros and co-
workers had experienced difficulties in converting 21 to trans-
resorcylide (1) directly and developed a three-step detour. In
our case, the use of solid NaHCO3 and methanol to quench the
final benzyl deprotection at low temperature is important and
the use of aqueous NaHCO3 solution led to decomposition of
In summary, we have developed a total synthesis of
trans-resorcylide (1). The synthesis features a palladium-
catalyzed macrocyclic Stille carbonylation to build the 12-
membered macrocycle. Notably, while intermediate 20
contains a cis-vinylstannane, the palladium-catalyzed mac-
rocyclic Stille carbonylation delivered product 21 with a
trans-enone moiety. We are currently using the macrocyclic
Stille carbonylation strategy to synthesize other family
members of the resorcylic macrolides as well as probe
molecules to understand their mode of actions.
Acknowledgements This research was supported by NIH R35
GM128570. We thank unrestricted grants from Eli Lilly and Amgen.
The NIH P30 CA023168 is acknowledged for supporting shared NMR
resources to Purdue Center for Cancer Research.
Compliance with ethical standards
1
the final product. The H NMR, 13C NMR, and other spec-
troscopic data of our synthetic trans-resorcylide (1) match well
Conflict of interest The authors declare that they have no conflict of
with the reported ones.
interest.

Y. Luo et al.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
14. Barluenga S, Moulin E, Lopez P, Winssinger N. Solution‐ and
solid‐phase synthesis of radicicol (monorden) and pochonin C.
Chem – Eur J. 2005;11:4935–52.
15. Yamamoto K, Garbaccio RM, Stachel SJ, Solit DB, Chiosis G,
Rosen N, Danishefsky SJ. Total synthesis as a resource in the
discovery of potentially valuable antitumor agents: cyclopropar-
adicicol. Angew Chem Int Ed. 2003;42:1280–4.
16. Bai Y, Davis DC, Dai M. Natural product synthesis via palladium-
catalyzed carbonylation. J Org Chem. 2017;82:2319–28.
17. Ma K, Martin BS, Yin X, Dai M. Natural product syntheses via
carbonylative cyclizations. Nat Prod Rep. 2019;36:174–219.
18. Bai Y, Davis DC, Dai M. Synthesis of Tetrahydropyran/Tetra-
hydrofuran‐Containing Macrolides by Palladium‐Catalyzed
Alkoxycarbonylative Macrolactonizations. Angew Chem Int Ed.
2014;53:6519–22.
References
1. Oyama H, Sassa T, Ikeda M. Structures of new plant growth
inhibitors, trans-and cis-resorcylide. Agric Biol Chem.
1978;42:2407–9.
2. Barrow CJ. New macrocyclic lactones from a Penicillium species.
J Nat Prod. 1997;60:1023–5.
3. Delmotte P, Delmotte-Plaquee J. A new antifungal substance of
fungal origin. Nature. 1953;171:344.
4. Chiosis G, Lucas B, Huezo H, Solit D, Basso A, Rosen N.
Development of purine-scaffold small molecule inhibitors of
Hsp90. Curr Cancer Drug Tar. 2003;3:371–6.
19. Manoni F, Rumo C, Li L, Harran PG. Unconventional fragment
usage enables a concise total synthesis of (−)-callyspongiolide.
J Am Chem Soc. 2018;140:1280–4.
5. Xu L, Wu P, Xue J, Molnar I, Wei X. Antifungal and cytotoxic β-
resorcylic acid lactones from a paecilomyces species. J Nat Prod.
2017;80:2215–23.
20. Bai Y, Shen X, Li Y, Dai M. Total synthesis of (−)-spinosyn A
6. Couladouros EA, Mihou AP, Bouzas EA. First total synthesis of
trans-and cis-resorcylide: remarkable hydrogen-bond-controlled,
stereospecific ring-closing metathesis. Org Lett. 2004;6:977–80.
7. Mennen SM, Miller SJ. Development of a bio-inspired acyl-anion
equivalent macrocyclization and synthesis of a trans-resorcylide
precursor. J Org Chem. 2007;72:5260–9.
8. Takahashi T, Minami I, Tsuji J. Synthesis of dehydroxy-trans-
resorcylide by intramolecular alkylation of the protected cyano-
hydrin using a butadiene telomer as a building block. Tetrahedron
Lett. 1981;22:2651–4.
9. Lampilas M, Lett R. Convergent stereospecific total synthesis of
monochiral Monocillin I related macrolides. Tetrahedron Lett.
1992;33:773–6.
10. Lampilas M, Lett R. Convergent stereospecific total synthesis of
Monocillin I and Monorden (or Radicicol). Tetrahedron Lett.
1992;33:777–80.
via carbonylative macrolactonization.
2016;138:10838–41.
J Am Chem Soc.
21. Davis DC, Walker KL, Hu C, Zare RN, Waymouth RM, Dai M.
Catalytic carbonylative spirolactonization of hydro-
xycyclopropanols. J Am Chem Soc. 2016;138:10693–9.
22. Ma K, Yin X, Dai M. Total syntheses of bisdehydroneostemoninine
and bisdehydrostemoninine by catalytic carbonylative spir-
olactonization. Angew Chem Int Ed. 2018;57:15209–12.
23. Davis DC, Hoch DG, Wu L, Abegg D, Martin BS, Zhang Z,
Adibekian A, Dai M. Total synthesis, biological evaluation, and
target identification of rare abies sesquiterpenoids. J Am Chem
Soc. 2018;140:17465–73.
24. Gyorkos AC, Stille JK, Hegedus LS. The total synthesis of ( )-epi-
jatrophone and ( )-jatrophone using palladium-catalyzed carbo-
nylative coupling of vinyl triflates with vinyl stannanes as the
macrocycle-forming step. J Am Chem Soc. 1990;112:8465–72.
25. Houghton TJ, Choi S, Rawal VH. Efficient assembly of the
phomactin core via two different macrocyclization protocols. Org
Lett. 2001;3:3615–7.
11. Garbaccio RM, Stachel SJ, Baeschlin DK, Danishefsky SJ. Con-
cise asymmetric syntheses of radicicol and monocillin I. J Am
Chem Soc. 2001;123:10903–8.
12. Garbaccio RM, Danishefsky SJ. Efficient asymmetric synthesis of
radicicol dimethyl ether: a novel application of ring-forming olefin
metathesis. Org Lett. 2000;2:3127–9.
13. Geng X, Yang Z, Danishefsky SJ. Synthetic development of
radicicol and cycloproparadicicol: highly promising anticancer
agents targeting Hsp90. Synlett. 2004;8:1325–33.
26. Simon M, Karaghiosoff K, Knochel P. Diastereoselective intra-
molecular carbolithiations of stereodefined secondary alkyllithiums
bearing a remote alkynylsilane. Org Lett. 2018;20:3518–21.
27. Choe H, Cho H, Ko H, Lee J. Total synthesis of (+)-pochonin D
and (+)-monocillin II via chemo-and regioselective intramolecular
nitrile oxide cycloaddition. Org Lett. 2017;19:6004–7.