Thionium ion initiated medium-sized ring formation: The total synthesis of asteriscunolide D

Article abstract of DOI:10.1021/ja210986f

The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.

Full text of DOI:10.1021/ja210986f

Communication
pubs.acs.org/JACS
Thionium Ion Initiated Medium-Sized Ring Formation: The Total
Synthesis of Asteriscunolide D
Barry M. Trost,* Aaron C. Burns, Mark J. Bartlett, Thomas Tautz, and Andrew H. Weiss
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
envisioned that a dimethyl(methylthio)sulfonium tetrafluor-
ABSTRACT: The first synthesis of the biologically active
humulene natural product asteriscunolide D has been
accomplished in nine steps without the use of protecting
groups. The challenging 11-membered ring was forged via
a diastereoselective thionium ion initiated cyclization,
which constitutes a formal aldol disconnection to form a
strained macrocycle. A stereospecific thioether activation−
elimination protocol was developed for selective E-olefin
formation, thus providing access to the most biologically
active asteriscunolide. The absolute stereochemical con-
figuration was established by the Zn-ProPhenol catalyzed
enantioselective addition of methyl propiolate to an
aliphatic aldehyde to afford a γ-hydroxy propiolate as a
handle for butenolide formation via Ru-catalyzed alkene−
alkyne coupling.
oborate (DMTSF)-mediated formal aldol disconnection could
provide a mild and irreversible pathway to the relatively
strained 11-membered ring (8→7, Figure 2). To the best of our
umulene (1)1 and humulene-derived natural products
Figure 2. Retrosynthetic analysis of 6.
2
H(e.g., 2) have been the focus of many synthetic studies
(Figure 1). This is due in part to the challenge of generating the
knowledge, an aldol addition has not been reported to effect
medium-sized carbocyclic ring formation.8,9 Previously our
group has noted that thionium ions behave as “super carbonyl”
equivalents and effectively react with nucleophilic olefins;10
however, medium-sized ring formation using this technology
has not been reported. Herein we disclose the first total
synthesis of asteriscunolide D (6) by implementation of this
strategy of a sulfur analog of an aldol addition.
As depicted by our retrosynthetic strategy (Figure 2), 11-
membered ring formation could be effected by implementation
of a chemoselective DMTSF-mediated cyclization (8→7). Such
a method would also be compatible with potentially labile
functional groups (e.g., the butenolide) and would complement
forty years of prior art in humulene-based 11-membered ring
formation.1 Subsequent activation of the thioether in 7 and
elimination would provide the requisite olefin. If the cyclization
process could be rendered diastereoselective, this would offer
the most likely opportunity for the development of a
stereospecific elimination event. The silyl enol ether 8 could
be accessed by thioacetal generation and subsequent enol ether
formation of a respective keto aldehyde. The butenolide moiety
could be obtained by utilization of a Ru-catalyzed alkene−
alkyne coupling of 9 with allyl alcohol to provide a transient
enol that would tautomerize to an aldehyde and concomitantly
Figure 1. Structures of humulene, zerumbone, and asteriscunolides
A−D.
11-membered ring, which has been described as a major
impediment in synthesis.3 Furthermore, many of these
compounds possess biological activity, and this has provided
motivation for their respective biological studies.4 More
specifically, asteriscunolides A−D5 (3−6) possess anticancer
activity, with 6 being the most potent toward the A-549
(human lung carcinoma), HT-29 (human colon carcinoma),
and MEL-28 (human melanoma) cell lines.6 Recently, 3 has
been found to induce apoptosis in human tumor cell lines.7 We
became interested in these targets (i.e., 3−6) because we
Received: November 22, 2011
Published: January 4, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
form the butenolide following engagement of the allylic alcohol
with the newly formed enoate carbonyl.11 The chiral
propargylic alcohol could be obtained using a chemoselective
Zn-ProPhenol catalyzed asymmetric methyl propiolate addition
to the keto aldehyde 10.12,13
Scheme 1. Synthesis of Asteriscunolide D (6)
Since the Zn-ProPhenol catalyzed enantioselective addition
of ketone enolates to aldehydes had been established, it was
unclear whether an enolizable ketone functional group, as in 10,
would be compatible with the reaction conditions.14 However,
unpublished concurrent efforts within our group indicated that
with respect to enantioselective additions of alkynes, enolizable
substrates function well as electrophiles (Table 1). Notably, it is
Table 1. Zn-ProPhenol Catalyzed Enantioselective Addition
a
of Methyl Propiolate to Aliphatic Aldehydes
a
(a) (MeO)2P(O)CH2C(O)CH2CH3 (1.0 equiv), LiCl (1.8 equiv), i-
Pr2NEt (1.8 equiv), CH3CN, 4 h, 91%. (b) (COCl)2 (1.5 equiv),
DMSO (3.0 equiv), Et3N (6.0 equiv), CH2Cl2, −78 °C, 99%. (c)
(S,S)-11 (20 mol %), Me2Zn (2.95 equiv), methyl propiolate (2.8
equiv), toluene, 4 °C, 36 h, 83% yield, 84% ee. (d) allyl alcohol (1.5
equiv), CpRu(CH3CN)3PF6 (5 mol %), CSA (0.25 equiv), THF,
acetone, 50 °C, 4.5 h, 55%. (e) thiophenol (2.0 equiv), BF3·Et2O (15
mol %), CH2Cl2, 15 h, 79%. (f) TMSOTf (1.4 equiv), i-Pr2NEt (1.5
equiv), CH2Cl2, 0 °C, 1.5 h, 90%, (g) DMTSF (1.2 equiv), 4 Å MS,
CH2Cl2, −30 °C, 1.5 h, 32−41%. (h) Me3OBF4 (1.8 equiv), CH2Cl2,
16 h; then i-Pr2NEt (1.8 equiv), 40 °C, 6 h, 82%.
a
Reactions were carried out with methyl propiolate (0.390 mmol, 1.2
equiv), aldehyde (0.325 mmol, 1.0 equiv), dimethyl zinc (0.488 mmol,
1.5 equiv), and (S,S)-11 (65.0 μmol, 20 mol %) in toluene (847 μL)
for 48 h at 4 °C. (S,S)-11 (32.5 μmol, 10 mol %) used.
b
possible to reduce the excess of dimethyl zinc and methyl
propiolate relative to our initial disclosures12 to access 12−14
with good yields and enantioselectivities. Encouraged by the
success of the addition of methyl propiolate to aliphatic
aldehydes, we set out to test whether this method would be
compatible with a ketone moiety of 10, which would provide
the most direct route to 9 (vide infra).
sized ring with nearly complete diastereoselectivity. Further-
more, recrystallization of 21 allowed for the structural
determination by X-ray crystallographic analysis and provided
a means to upgrade the ee from 84% to greater than 98%. In
contrast, recrystallization of asteriscunolide D did not provide
material with enhanced ee. Interestingly, thermal elimination of
the corresponding sulfoxide led to regioselective formation of
the β,γ-unsaturated ketone. In contrast to this result, alkylative
thioether elimination20 provided the geometrically pure E-
olefin present in 6. This result is consistent with the
cyclooctene studies of Cope et al.: Hoffman elimination
provides predominately E-cyclooctene (anti-elimination) while
Cope elimination gives only Z-cyclooctene (syn-elimination).21
It is also clear that racemization does not occur during the
elimination procedure, or at any stage of the synthesis, as the ee
of each intermediate was confirmed by chiral HPLC relative to
the racemic compounds (cf. Supporting Information (SI)). In
addition to disclosing the first synthesis of the most biologically
potent asteriscunolide member in nine steps from commercial
material, preliminary experiments (cf. SI) have demonstrated
that 6 can be isomerized to an approximately 3:3:1:1 mixture of
asteriscunolides A−D (PhSeSePh, hν) (cf. Figure 1, 3−6). This
The keto aldehyde 10 was prepared in three steps from
isobutyraldehyde. Aldol addition of isobutyraldehyde to
formaldehyde conveniently provided the β-hydroxy aldehyde
by precipitation of the dimer 15, which could be triturated and
used without further purification.15 As depicted in Scheme 1,
cracking of the dimer (60 °C, CH3CN) and subsequent HWE-
olefination using the Masamune−Roush conditions (dimethyl
2-oxobutanephosphonate)16 provided enone 16, which was
oxidized (Moffatt−Swern) to afford the aldehyde 10. Gratify-
ingly, 10 served as an excellent substrate in the chemoselective
Zn-ProPhenol catalyzed enantioselective addition with methyl
propiolate to provide the γ-hydroxy propiolate 9 in good yield
and enantiopurity. Treatment of 9 with catalytic CpRu-
(CH3CN)3PF6 and allyl alcohol effected the alkene−alkyne
coupling, directly providing the butenolide with the appended
aldehyde.11c Thioacetal formation and a Z-selective TMS-enol
ether formation17−19 (supported by NOE experiments)
afforded test substrate 19 for the DMTSF-mediated cyclization.
To our delight, the cyclization smoothly provided the medium-
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Journal of the American Chemical Society
Communication
(5) For the first reported isolation of 3, see: (a) San Feliciano, A. S.;
Barrero, A. F.; Medarde, M.; Miguel del Corral, J. M.; Ledesma, E.
Tetrahedron Lett. 1982, 23, 3097. For the subsequent isolation of 3−
6, see: (b) San Feliciano, A.; Barrero, A. F.; Medarde, M.; Miquel del
Corral, J. M.; Aramburu Aizpiri, A.; S.-Ferrando, F. Tetrahedron 1984,
40, 873. For the structural reassignment of 3 and 4, see: (c) San
Feliciano, A.; Barrero, A. F.; Medarde, M.; Miguel del Corral, J. M.;
Aramburu, A.; Perales, A.; Fayos, J.; S.-Ferrando, F. Tetrahedron 1985,
41, 5711.
speaks to the relatively similar thermodynamic stabilities of the
four olefin isomers and provides potential access to the
remaining asteriscunolides.22
In summary, the first synthesis of asteriscunolide D (6) has
been accomplished in nine steps without the use of protecting
groups. The challenging 11-membered ring was forged via a
diastereoselective DMTSF-mediated cyclization. The addition
of a silyl enol ether to a transient thionium intermediate
represents a mild and irreversible alternative to an intra-
molecular aldol addition, which would be complicated by facile
retro-aldol cleavage due to the inherent ring strain and the
kinetic lability of the β-hydroxy ketone product. The success of
this new macrocyclization protocol for such a difficult ring size
bodes well for its broad applicability as a versatile macro-
cyclization. In addition, a stereospecific elimination protocol
was identified allowing for the exclusive formation of the most
biologically active asteriscunolide. The absolute stereochemical
configuration of 6 was introduced by a chemoselective Zn-
ProPhenol catalyzed enantioselective addition of methyl
propiolate to an aliphatic aldehyde bearing an acidic ketone
functional group, thus providing a facile asymmetric synthesis
of butenolides in a direct two-step sequence when combined
with the Ru-catalyzed alkene−alkyne coupling. Extension of the
DMTSF-mediated cyclization strategy toward other bioactive
natural products containing medium-sized rings is currently
underway.
(6) Rauter, A. P.; Branco, I.; Bermejo, J.; Gonzal
Gravalos, M. D.; San Feliciano, A. Phytochemistry 2001, 56, 167.
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ez, A. G.; G.-
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(8) Rare examples involve macroaldolizations of substrates lacking
enolizeable α-CH bonds to form macroheterocycles; see: (a) Hayward,
C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
9345. (b) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.;
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(11) (a) Trost, B. M.; Muller, T. J. J.; Martinez, J. J. Am. Chem. Soc.
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ASSOCIATED CONTENT
■
(12) (a) Trost, B. M.; Weiss, A. H.; von Wagelin, A. J. J. Am. Chem.
Soc. 2006, 128, 8. (b) Trost, B. M.; Weiss, A. H. Org. Lett. 2006, 8,
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S
* Supporting Information
Experimental procedures and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) For alternative catalytic asymmetric additions of propiolate
nucleophiles to aldehydes, see: (a) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie,
R.-G.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 122. (b) Rajaram, A. R.;
Pu, L. Org. Lett. 2006, 8, 2019. (c) Lin, L.; Jiang, X.; Liu, W.; Qiu, L.;
Xu, Z.; Xu, J.; Chan, A. S. C.; Wang, R. Org. Lett. 2007, 9, 2329.
(d) Turlington, M.; DeBerardinis, A. M.; Pu, L. Org. Lett. 2009, 11,
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Tetrahedron: Asymmetry 2009, 20, 2733. (f) Kojima, N.; Nishijima, S.;
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AUTHOR INFORMATION
■
Corresponding Author
bmtrost@stanford.edu
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-0846427)
and the National Institutes of Health (GM-33049) for their
generous support of our programs. M.J.B. is grateful to Victoria
University of Wellington for a Ph.D. scholarship. We thank
Umicore for a generous gift of ruthenium salts.
(15) Tormakangas, O. P.; Saarenketo, P.; Koskinen, A. M. P. Org.
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Process Res. Dev. 2002, 6, 125.
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