Thiocarbonyl Ylide Chemistry Enables a Concise Synthesis of (±)-Hippolachnin A

Article abstract of DOI:10.1021/jacs.7b06815

Hippolachnin A (1) is an antifungal polyketide that bristles with ethyl groups mounted onto a caged heterotricyclic core. It has shown potent activity against Cryptococcus neoformans, a yeast that can affect immunocompromised patients as an opportunistic pathogen. Herein we describe a concise, diversifiable, and scalable synthesis of (±)-hippolachnin A (1). It features a powerful photochemical opening step, a diastereoselective addition of an ethyl cuprate and an unusual strategy to install two additional ethyl groups that makes use of a thiocarbonyl ylide generated in situ.

Full text of DOI:10.1021/jacs.7b06815

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Communication
Thiocarbonyl Ylide Chemistry Enables a
Concise Synthesis of (±)-Hippolachnin A
Nils Winter, and Dirk Trauner
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06815 • Publication Date (Web): 28 Jul 2017
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Thiocarbonyl Ylide Chemistry Enables a Concise Synthesis of
(±)-Hippolachnin A
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Nils Wintera and Dirk Trauner*a,b
aDepartment of Chemistry, LudwigꢀMaximiliansꢀUniversität München, Butenandtstr. 5ꢀ13, 81377 Munich, Germany
bDepartment of Chemistry, New York University, Silver Center, 100 Washington Square East, Room 712, USA
Supporting Information Placeholder
ABSTRACT: Hippolachnin A (1) is an antifungal polyketide
that bristles with ethyl groups mounted onto a caged heterotricyꢀ
clic core. It has shown potent activity against Cryptococcus
neoformans, a yeast that can affect immunocompromised patients
as an opportunistic pathogen. Herein we describe a concise, diverꢀ
sifiable, and scalable synthesis of (±)ꢀhippolachnin A (1). It feaꢀ
tures a powerful photochemical opening step, a diastereoselective
addition of an ethyl cuprate and an unusual strategy to install two
additional ethyl groups that makes use of a thiocarbonyl ylide
generated in situ.
Opportunistic infections with ubiquitous fungi represent a maꢀ
jor challenge to the immunocompromised. The yeast Cryptococ-
cus neoformans, for instance, can cause lifeꢀthreatening meningiꢀ
tis and affect the lungs and skin of patients with advanced acꢀ
quired immunodeficiency syndrome (AIDS).[1] Indeed, cryptococꢀ
cosis is the second most common AIDSꢀrelated complication in
subꢀSaharan Africa. Although a combination of intravenously
applied amphotericin and oral flucytosin provides an effective
treatment, these drugs are associated with significant side effects,
difficult administration regimes, high costs, and the emergence of
resistance.[2] Therefore, the development of new drugs that target
C. neoformans and related opportunistic fungal pathogens remains
an important goal.
Scheme 1: Synthetic approaches to hippolachnin A
The synthesis of a presumed biomimetic precursor, compound 7,
which was isolated together with 1, was described by Ohira et al.
in 2005[7] and by Wu et al. in 2017.[8] However, irradiation of 7
with UV light did not yield 1 but only resulted in isomerization of
the vinylogous ester moiety.[8] Possibly, the desired cyclization
could be achieved using more biomimetic irradiation conditions,
as has been recently demonstrated with other marine natural
products.[9]
Hippolachnin A (1) could provide an important lead in this search.
It was recently isolated from the South China Sea marine sponge
Hippospongia lachne[3] and proved to be highly potent against
several pathogenic fungi, including C. neoformans (MIC = 0.41
ꢁM). Biosynthetically, it was identified as a polyketide of the
gracilioether family. While it bears structural similarities to other
members of this series, the 4ꢀ5ꢀ5 tricyclic core of hippolachnin A
is unique.[4] Presumed to be of photochemical origin, it features
six contiguous stereocenters and bears an unusual array of four
ethyl groups on its convex face.
We now report a concise synthesis of hippolachnin A that is
also based on a photochemical key step, albeit a decidedly nonꢀ
biomimetic one. Our retrosynthetic analysis is shown in Scheme
2. In a deviation from previous syntheses, we planned to close the
heterocyclic ring in 1 by Oꢀalkylation of an enolized βꢀketo ester
8.[10] The two vicinal ethyl groups would be installed by threeꢀ
component coupling involving an ethyl nucleophile, an ethyl
electrophile and the Michael acceptor 9. This key intermediate, in
Given its attractive molecular structure and potent bioactivity, it is
no surprise that hippolachnin A has attracted the attention of
several synthetic groups (Scheme 1). The first total synthesis was
achieved by Carreira in 2015.[5] In this case, the cyclobutane core
was formed via photochemical [2+2] cycloaddition of 3ꢀhexyne
(2) to cyclopentenone 3 and the heterocycle was installed using an
eneꢀtype cyclization. In 2016 Brown and Wood reported a collabꢀ
orative synthesis in which the cyclobutane was formed through a
[2+2+2] cycloaddition of quadricyclane (4) to either 5 or 6 and
the heterocycle through a lateꢀstage allylic CꢀH oxidation.[6]
Scheme 2: Retrosynthetic analysis of hippolachnin A
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Scheme 3: Total synthesis of hippolachnin A. KOtꢀBu=potassium tertꢀbutoxide, pꢀTSA= paraꢀtoluensulfonic acid,
KHMDS=potassium hexamethyldisilazide, DMF=dimethylformamide, DMPU=1,3ꢀdimethylꢀ3,4,5,6ꢀtetrahydroꢀ2(1H)ꢀ
pyrimidinone, DIBALꢀH=diisobutylaluminium hydride, DMP=DessꢀMartin periodinane, LDA=lithium diisopropylamide,
TBAB=tetrabutylammonium bromide, DCE=1,2ꢀdichloroethane.
turn, could be traced back to the known bicyclo[3.2.0]heptadiene
derivative 10, a photoisomer of the readily available tropolone
ether 11.
To overcome this issue, we turned to a cycloaddition chemistry.
We reasoned that the 1,3ꢀdipolar addition of thiocarbonyl ylide 16
to the more reactive double bond of 9, followed by reductive
desulfurization of the resulting tetrahydrothiophene, would deliver
both ethyl groups to the convex side.[18] To this end, we syntheꢀ
sized the sulfoxide 15 as a precursor of the highly reactive 16.
Compound 15 is a homologue of the parent reagent introduced by
Achiwa and was prepared in two steps from sodium sulfide and
1ꢀchloroethyl trimethylsilane (see Supporting Information).[19]
Indeed, heating of 15 in the presence of 9 afforded tetrahydrothioꢀ
phene 17 as a single diastereomer. Single crystal Xꢀray structure
Accordingly, our synthesis opens with the photochemical conꢀ
version of 11 into methoxy bicyclo[3.2.0]heptadienone 10
(Scheme 3). This unusual photochemical reaction has been studꢀ
ied in detail by Dauben et al. and proceeds via disrotatory 4πꢀ
electrocyclization of 11 to yield 12, which then undergoes an
excited state rearrangement to afford 10.[11] Stereoselective conjuꢀ
gate addition of ethyl cuprate[12] from the convex side to 10, folꢀ
lowed by Wittig olefination[13] and hydrolysis of the enol ether,[14]
gave rise to ketone 14 as a 10:1 mixture of Zꢀ and Eꢀisomers
analysis showed that the methyl groups adopt
a transꢀ
configuration with respect to the tetrahydrothiophene ring, which
can be explained by the stepwise nature of thiocarbonyl ylide
cycloadditions.[20]
(major isomer shown). Homologation of ketone 14 was then
[15]
achieved by formation of the vinyl triflate
and subsequent
carbomethoxylation.[16]
The final phase of our synthesis required the elongation of the
methyl ester into a βꢀketo ester and its closure to a tetrahydrofuran
to obtain the full carbon skeleton of hippolachnin A. Unfortunateꢀ
ly, all attempts at a crossed Claisen condensation or even hydrolyꢀ
sis of 17 failed, presumably due to steric hindrance.[21]. However,
a reductionꢀoxidation sequence gave rise to aldehyde 18 in good
yield. Aldol addition[22] of methyl acetate then afforded the correꢀ
sponding βꢀhydroxy ester, which could easily be oxidized to yield
βꢀketo ester 19. Formation of the tin enolate followed by chelaꢀ
tionꢀcontrolled trapping of the simultaneously generated tertiary
carbocation[10] gave rise to (Z)ꢀconfigured vinylogous carbonate
20.[23] Desulfurization with Raney nickel in THF[24] then provided
hippolachnin A. Overall, the synthesis proceeds in 12 steps from
the known bicyclo[3.2.0]heptane 10 and provides 1 on a 100 mg
scale.
The stage was now set for the introduction of the two remaining
ethyl groups. As outlined in our retrosynthesis (Scheme 1), we
planned to achieve this by addition of an ethyl nucleophile, folꢀ
lowed by alkylation with an ethyl electrophile. Ethyl cuprate
addition to unsaturated ester 9 indeed occurred with complete
regioꢀ and stereoselectivity at C10. However, the subsequent
deprotonation and alkylation with iodoethane only afforded a 1:2
mixture of diastereoisomers in favor of the desired isomer (see
Supporting Information).[17] Although the major isomer could be
easily converted into an advanced intermediate of the Woodꢀ
Brown synthesis,[6] we felt that such a low level of selectivity was
not acceptable for an efficient synthesis of 1.
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Our synthesis will serve as a platform for the development of
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more potent and more soluble antifungal agents as well as molecꢀ
ular probes with which to identify the biological target(s) of hipꢀ
polachnin A. It relies on a photoisomerization of a tropolone to
construct the bicyclic carbon core of the natural product. Asymꢀ
metric variants of this rearrangement have been described.[25] The
distinctive four ethyl substituents of 1 are introduced by a cuprate
conjugate addition, a Wittig olefination, followed by etherificaꢀ
tion, and a thiocarbonyl ylide cycloaddition, followed by eventual
reductive desulfurization. The latter amounts to the addition of an
alkane over an (electron poor) alkene. Despite its high strategic
value, this sequence has been rarely used in synthesis.[26] This
may be because, apart from the parent system, precursors of the
requisite thiocarbonyl ylides have not been widely available.
Future studies will expand on this chemistry and explore its useꢀ
fulness in the synthesis of hippolachnin A derivatives as well as
other complex natural products. Biological investigations of anaꢀ
logs of hippolachnin A, in particular compound 20 and its oxidaꢀ
tion products, are currently ongoing and will be reported in due
course.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of
charge on the ACS Publications website.
CIF file for compound 17 (CCDC 1563493).
CIF file for compound 20 (CCDC 1563492).
Experimental procedures, spectroscopic data and copies of NMRꢀ
spectra.
The CIF files are also available free from charge on
https://www.ccdc.cam.ac.uk/structures/.
AUTHOR INFORMATION
Corresponding Author
Department of Chemistry, LudwigꢀMaximiliansꢀUniversität Münꢀ
chen, Butenandtstr. 5ꢀ13, 81377 Munich, Germany
Present Addresses
Department of Chemistry, New York University, Silver Center,
100 Washington Square East, Room 712
(16) Magauer, T.; Mulzer, J. Tiefenbacher, K. Org. Lett. 2009, 11,
5306–5309.
(17) Meier, R.; Trauner, D. Angew. Chem. Int. Ed. 2016, 55,
11251–11255.
Notes
The authors declare no competing financial interest.
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Chem. Eur. J. 2003, 9, 2256–2263. (b) Huisgen, R.; Kalvinsch, I.;
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ACKNOWLEDGMENT
The authors would like to thank Henriette Lämmermann for exꢀ
perimental assistance and Dr. Peter Mayer for Xꢀray structure
analysis. Additionally, we would like to acknowledge the
Deutsche Forschungsgemeinschaft (SFB 749 and CIPSM) for
generous funding. Dr. Julius R. Reyes is acknowledged for excelꢀ
lent support with the preparation of this manuscript.
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