Light-mediated total synthesis of 17-deoxyprovidencin

Article abstract of DOI:10.1002/anie.201400617

An asymmetric synthesis of the diterpenoid 17-deoxyprovidencin is described. Key steps include an aldol addition, a base-catalyzed Wipf-type furan formation, a Z-selective ring-closing metathesis for macrocyclization, a photochemical E/Z isomerization to a highly strained and conformationally restricted ring system, and the stereoselective formation of two epoxides on the ring. Photochemistry is the key: An asymmetric synthesis of the diterpenoid 17-deoxyprovidencin is described. Key steps include an aldol addition, a base-catalyzed Wipf-type furan formation, a Z-selective ring-closing metathesis for macrocyclization, a photoinduced Z/E isomerization to a highly strained conformationally restricted ring system, and the stereoselective formation of two epoxides on the macrocycle.

Full text of DOI:10.1002/anie.201400617

Angewandte
Chemie
DOI: 10.1002/anie.201400617
Total Synthesis
Light-Mediated Total Synthesis of 17-Deoxyprovidencin**
Nina Toelle, Harald Weinstabl, Tanja Gaich, and Johann Mulzer*
Abstract: An asymmetric synthesis of the diterpenoid 17-
deoxyprovidencin is described. Key steps include an aldol
addition, a base-catalyzed Wipf-type furan formation, a Z-
selective ring-closing metathesis for macrocyclization, a photo-
chemical E/Z isomerization to a highly strained and conforma-
tionally restricted ring system, and the stereoselective forma-
tion of two epoxides on the ring.
a D-7,8 trans epoxide in the macrocyclic ring.[3] The crystal
structure[2] of 1 reveals a perpendicular arrangement of
butenolide and furan in the macrocycle; the high ring strain
of this macrocycle makes it impossible to build a Dreiding
model without breaking any bonds. Evidently, the ring strain
is mainly due to the trans arrangement of the D-7,8 epoxide
and the rigid angle of 1448 between the C7 and C2 appendages
around the furan ring.
T
he class of furanocembranoids offers a diverse range of
The complex and unusual molecular architecture renders
1 an attractive and yet elusive synthetic target.[4,5] In
particular, a recent report by White and Jana has disclosed
significant headway, yet underlined the difficulties in closing
the highly strained macrocyclic ring.[6]
Considering the biosynthesis of this compound from
bipinnatin J, we suggest in contrast to previous assump-
tions[1,4c] that the cyclobutane ring is closed through a cationic
cyclization of I-1 to form I-2 and I-3 (Figure 2). E/Z Isome-
rization to I-4, as indicated by the formation of acerosolide
(Figure 1), and further oxidations may lead to 17-deoxy
derivative 2 as a direct precursor to 1.
structurally and biologically interesting natural compounds.[1]
In 2003, a highly oxygenated furanobutenolide-based cem-
brane named providencin (1) was isolated from the Caribbean
sea plume Pseudopterogorgia kallos (Bielschowsky, 1918) by
the Rodriguez group.[2] The biosynthesis of 1 is unknown,
even though bipinnatin J has been shown to be a plausible
precursor.[1] In terms of its biological properties, 1 exhibits
moderate activity against human breast cancer and lung and
CNS cancer cell lines. The relative configuration was deter-
mined by single-crystal X-ray analysis, but the absolute
configuration has remained unknown (Figure 1). Compared
to other members of the furanocembranoid family, 1 contains
two unusual structural features: a cyclobutanol moiety and
Figure 1. 17-Deoxyprovidencin, providencin, and two related furano-
cembranoids.
Figure 2. Hypothesis for the biosynthetic formation of 1.
[*] Dr. N. Toelle,[+] Dr. H. Weinstabl,[+] Prof. Dr. J. Mulzer
Universitꢀt Wien, Institute fꢁr Organische Chemie
Wꢀhringer Strasse 38, 1090 Wien (Austria)
Herein, we report a synthesis of 2. Our retrosynthetic plan
(Figure 3) is based on precursor 3, which should be accessible
from 2 by formal removal of the epoxides and subsequent
modifications on the cyclobutane moiety. Intermediate 3
should arise from the connection of the two main fragments 4
and 5 through an aldol addition[7] and ring-closing metathesis
(RCM).[8] The olefin geometry was of minor concern, as we
hoped to achieve Z/E double-bond interconversion by
standard methods.
Dr. T. Gaich
Leibniz Universitꢀt Hannover, Institut fꢁr Organische Chemie
Schneiderberg 1B, 30167 Hannover (Germany)
[+] These authors contributed equally to this work.
[**] N.T. is grateful to the Austrian FWF (Fonds zur Fçrderung der
Wissenschaften) for a Lise Meitner fellowship (M1322). We also
thank Hanspeter Kaehlig, Lothar Brecker, and Susanne Felsinger for
the recording and help with the interpretation of NMR data and
Vladimir Arion and Alexander Roller for crystal-structure analysis of
27a.
The preparation of 4 started from the known non-racemic
compound 6,[5] which was converted into diol 7 by ozonolysis
and reduction (Scheme 1). The differentiation of the primary
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400617.
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Figure 3. Retrosynthetic analysis of 2.
Scheme 2. Preparation of building block 5. DIC=diisopropylcarbodi-
imide, DMAP=4-N,N-dimethylaminopyridine, LDA=lithium diiso-
propylamide.
(Scheme 2). In situ treatment with the dianion of phenyl-
selenyl acetic acid (17) furnished seco acid 18, which was
cyclized to 5 under Steglich conditions.[10]
Deprotonation of 5 with LDA and addition of aldehyde 4
provided the aldol adduct as a mixture of four diastereomers.
Oxidative elimination of selenide led to a mixture of the
epimeric alcohols 19a/b. For practical use, large-scale RCM[8]
was performed with this mixture, which resulted in the
formation of the Z olefins 20a/b as a readily separable
diastereomeric mixture in a 1.5:1 ratio. Acetylation of 20a
with acetic anhydride led to 21 (Scheme 3). Alternatively,
Scheme 1. Preparation of fragment 4. IBX=2-iodoxybenzoic acid,
MMTrCl=tris(4-methoxyphenyl)methylchloride, PPTS=pyridinium
p-toluenesulfonate, TIPS=triisopropylsilyl.
OH groups was achieved by selective monotritylation of the
less hindered position to give intermediate 8. Oxidation led to
the corresponding aldehyde, which underwent base-catalyzed
in situ isomerization to trans diastereomer 9. A Reformatsky
reaction with bromoacatete followed by oxidation furnished
ketoester 10 in excellent overall yield. Alkylation of 10 with
propargyl iodide 11 led to 12, which was cyclized to vinylfuran
13 under base catalysis.[9] Detritylation and oxidation with
IBX gave aldehyde 4.
Selenolactone 5 was prepared from (R)-glycidyl tosylate
(14) by cuprate addition to furnish alcohol 15, which was
converted into epoxide 16 with retention of the configuration
Scheme 3. Preparation of macrocycle 21. DIPEA=diisopropylethyl-
amine, Grubbs II cat.=[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyli-
dene]dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium.
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alcohols 19a and 19b were separated, and 19a was cyclized to
20a, whereas 19b was converted directly into 21 through
a Mitsunobu inversion[11] and subsequent RCM. All attempts
to isomerize either the Z olefins 20a/b or acetate 21 to their
E isomers failed.[5a]
Therefore, we proceeded with the formation of the D-
11,12 epoxide. Treatment of 20a with hydrogen peroxide
under basic conditions gave a diastereomerically pure com-
pound, which we thought to be epoxy alcohol 22 (Scheme 4).
Scheme 5. Formation of epoxide 27, photoinduced Z/E isomerization,
and further elaboration to 17-deoxyprovidencin (2). b.r.s.m.=based on
recovered starting material, DMDO=dimethyldioxirane, TBAF=tetra-
butylammonium fluoride.
dichloride 27a.[13a,b] Irradiation of 27 with UV-B light resulted
in the desired Z/E isomerization[14] to olefin 28. The use of
Pyrex glass was crucial, because it cuts off UV wavelengths
below 300 nm. The UV absorption maximum of 27 lies at
306 nm, whereas 28 absorbs below 300 nm and is thus not
subjected to further photoreactions. With quartz glass, the
irradiation produced unidentifiable product mixtures.
Scheme 4. Unexpected formation of ketone 23.
Treatment with acetic anhydride, however, failed to produce
the expected epoxy acetate and furnished ketone 23 instead,
which was unambiguously characterized by 1H and 13C NMR
spectroscopy. Presumably, 1,4-addition of a hydroperoxide
anion to 21 had led to 24 through the elimination of acetate. A
second 1,4-attack of the hydroperoxide anion generated
epoxy hydroperoxide 25, which was converted into acetate
26 when treated with acetic anhydride. Finally, elimination of
acetic acid under the basic conditions furnished ketone 23.
In contrast, when acetate 21 was subjected to the
conditions developed by Node et al.,[12] epoxy acetate 27
was formed diastereoselectively (Scheme 5); this intermedi-
ated was characterized by single-crystal diffraction of the 7,8-
The 1H NMR spectra of 27 and 28 were characteristically
different. For 28, typical line broadening indicated the
formation of atropisomers at room temperature. Heating to
758C furnished sufficiently sharp signals, so that NOE
measurements were feasible to provide evidence for the
E configuration of the olefin.[13a] Interestingly, no photo-
chemical 1,3-sigmatropic ring contraction (Rodriguez–Pat-
tenden rearrangement)[15] to pseudopterane 30 was observed.
For the further elaboration of 28 towards 2, the sequence
of steps was carefully orchestrated. Thus, 16-ketone 29 was
first generated by deprotection and oxidation. Now, it was
possible to perform the stereoselective epoxidation of the D-
7,8 olefin with DMDO.[16] Finally, the exocyclic double bond
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at the C16 position was installed by Wittig methylenation.
Using this sequence, 17-deoxyprovidencin (2) was obtained.
A careful NOE analysis confirmed the correct configuration
of the D-7,8 epoxide,[13a] which means that despite (or owing
to) the restricted conformational flexibility of the macrocyclic
periphery, the DMDO attack has occurred at the desired
outside face of the olefin.
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[13] a) For details, see the Supporting Information; b) CCDC 981166
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
In conclusion, we have presented a synthesis of 17-
deoxyprovidencin (2) in 17 steps along the longest linear
sequence with an overall yield of 1.6%. Key steps include an
aldol addition with subsequent oxidative elimination of
selenide, a Z-selective RCM macrocyclization, a photo-
induced Z/E isomerization to a highly strained conforma-
tionally restricted ring system, and a stereoselective epox-
idation of the E olefin. To corroborate our biosynthetic
hypothesis, various allylic oxidations[17] at the C17 position,
including enzymatic hydroxylations,[18] remain to be per-
formed.
Experimental Section
Synthesis of the E-configured pentacycle 28: The Z-configured
macrocycle 27 (233 mg, 396 mmol, 1.00 equiv) was dissolved in
anhydrous degassed acetonitrile (75 mL, 190 mLmmolÀ1) and filled
in Pyrex tubes (d = 1 cm). The solution was further degassed, sealed
with a septum and parafilm, and irradiated with UV-B light for 2 ꢀ
40 min without further heating (monitored by TLC, cooling). After
the second irradiation, the solvent was removed under reduced
pressure, and the crude product was subjected to column chromatog-
raphy (hexanes/ethyl acetate 5:1 to 3:1) to yield 31% of the desired
E-configured macrocycle 28 along with 34% of starting material. Rf
(hexanes/ethylacetate = 3:1, CAM): 27: 0.38 shiny lilac 256 nm, stains.
28: 0.26 extinct. 256 nm, stains. 1H NMR (600 MHz, [D8]-toluene,
348.1 K): d = 6.42 (d, J = 1.3 Hz, 1H); 5.84 (s, 1H); 5.41 (d, J =
10.3 Hz, 1H); 4.40 (dd, J = 5.4, 5.4 Hz, 1H); 4.06 (dd, J = 4.0,
2.5 Hz, 1H); 3.88 (q, J = 9.2 Hz, 1H); 3.52 (m, 2H); 3.49 (s, 3H);
2.99 (m, 1H); 2.48 (dd, J = 12.3, 8.6 Hz, 1H); 2.28 (dd, J = 13.9,
3.9 Hz, 1H); 2.16 (m, 3H); 1.73 (s, 3H); 1.60 (s, 3H); 1.08 ppm (m,
21H). HRMS (ESI): m/z calcd for C31H44O8Si [M]+: 588.2755; found:
588.2748.
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Received: January 20, 2014
Published online: March 6, 2014
Keywords: furanocembranoids · macrocycles · metathesis ·
.
photoisomerization · total synthesis
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