Total synthesis of (+)-rubriflordilactone A

Article abstract of DOI:10.1002/anie.201506366

Two enantioselective total syntheses of the nortriterpenoid natural product rubriflordilactone A are described, which use palladium- or cobalt-catalyzed cyclizations to form the CDE rings, and converge on a late-stage synthetic intermediate. These key processes are set up through the convergent coupling of a common diyne component with appropriate AB-ring aldehydes, a strategy that sets the stage for the synthetic exploration of other members of this family of natural products. Two in one: Two enantioselective total syntheses of the nortriterpenoid natural product rubriflordilactone A are described, which use palladium- or cobalt-catalyzed cyclizations to converge on a late-stage synthetic intermediate. These key processes are set up through the coupling of a common diyne component with appropriate AB-ring aldehydes, a strategy that enables a broad exploration of this family of natural products, as well as synthetic analogues.

Full text of DOI:10.1002/anie.201506366

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201506366
German Edition: DOI: 10.1002/ange.201506366
Natural Product Synthesis
Total Synthesis of (+)-Rubriflordilactone A
Shermin S. Goh, Guilhem Chaubet, Birgit Gockel, Marie-Caroline A. Cordonnier,
Hannah Baars, Andrew W. Phillips, and Edward A. Anderson*
Abstract: Two enantioselective total syntheses of the nortriter-
penoid natural product rubriflordilactone A are described,
which use palladium- or cobalt-catalyzed cyclizations to form
the CDE rings, and converge on a late-stage synthetic
intermediate. These key processes are set up through the
convergent coupling of a common diyne component with
appropriate AB-ring aldehydes, a strategy that sets the stage for
the synthetic exploration of other members of this family of
natural products.
C
hinese herbal plants of the Schisandra and Kadsura genera
have afforded a rich diversity of structurally related nortri-
terpenoid natural products, which are characterized by
complex fused ring systems, a high degree of oxygenation,
and densely arrayed stereochemistry.[1] Many of these have
been found to exhibit bioactive properties, including promis-
ing levels of anti-HIV activity. Their attractive architectures
also represent a formidable synthetic challenge, first met in
2011 by Yang and co-workers in their synthesis of schindi-
lactone A.[2] This landmark achievement has recently been
complemented by an elegant asymmetric synthesis of rubri-
flordilactone A (1, Scheme 1) by Li et al., where a 6p-
electrocyclization was used to assemble the challenging
pentasubstituted D-ring arene;[3] and syntheses of the related
family members schilancitrilactones B and C, and propindi-
lactone G.[4] Herein, we describe two convergent enantiose-
lective total syntheses of rubriflordilactone A,[5] which are
distinct from previous work in that the CDE ring system at the
heart of the natural product framework is formed in a single
tricyclization step.[6,7] The two syntheses differ in the method
used to construct this CDE framework, which is achieved
under either palladium or cobalt catalysis; the products of
these key cyclizations converge on a common late-stage
intermediate.
Scheme 1. Retrosynthetic analysis of rubriflordilactone A.
phile 2 to an oxocarbenium ion in the final step. The latter
synthon would arise from lactol 3, which in turn would be
constructed from a bromoendiyne (4) or triyne (5) under
palladium or cobalt catalysis, respectively. Bromoendiyne 4
could be formed from the union of aldehyde 6[6a] with diyne 7,
the latter of which features two challenging contiguous
stereocenters. The synthesis of triyne 5 would also require 7
and the alkyne-bearing aldehyde 8. These two strategies
present different challenges: whilst palladium-catalyzed bro-
moendiyne cyclizations are established as efficient methods
for tricycle synthesis,[8,9] no applications of this method to
natural product total synthesis have been reported; and whilst
cobalt-catalyzed alkyne cyclotrimerization has a rich syn-
thetic history,[10] its use in the formation of seven-membered
rings (as in the C ring of rubriflordilactone A) is rare.
The synthesis of diyne 7 began with esterification of (S,E)-
pent-3-en-2-ol[11] with carboxylic acid 9 (Scheme 2).[12] Ire-
land–Claisen rearrangement of the resultant ester 10 led to
acid 11, a reaction that gave higher yield and diastereoselec-
tivity with the free lithium enolate (96%, > 20:1 d.r.)[13] than
with the silyl ketene acetal (92%, 9:1 d.r.).[12] Sequential
manipulations to convert the carboxylic acid in 11 into
benzyldimethylsilyl alkyne 12 (where Stork–Zhao olefina-
tion[14]/elimination proved the most effective means for
alkynylation), and then the para-methoxybenzyl ether into
a terminal alkyne gave 7, which is primed for addition to AB-
ring aldehydes 6 or 8.
Both strategies (Scheme 1) envisaged introduction of the
butenolide G ring through addition of a siloxyfuran nucleo-
[*] S. S. Goh, Dr. G. Chaubet, Dr. B. Gockel, M.-C. A. Cordonnier,
A. W. Phillips, Prof. E. A. Anderson
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: edward.anderson@chem.ox.ac.uk
H. Baars
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
The preparation of the alkyne-bearing aldehyde 8 offered
an opportunity to avoid the Stille coupling we had used to
install the bromoalkene sidechain in aldehyde 6.[6a] Its syn-
thesis commenced with ester 13 (Scheme 3), which was
converted into epoxide 14 through alkyne carbocupration[15]
with 3-trimethylsilylpropynylmagnesium bromide,[16] ester
reduction, and Sharpless asymmetric epoxidation (83%
over 3 steps, 92% ee).[17] Ring-opening of 14 with allylmag-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506366.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
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reproduction in any medium, provided the original work is properly
cited.
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nesium chloride,[18] followed by oxidation and b-lactone
formation, afforded 15 in good yield (74% over 4 steps).[19]
Double nucleophilic addition of methylmagnesium bromide
to the b-lactone smoothly installed the gem-dimethyl group of
the B ring (16);[20] oxidative cleavage of the terminal alkene in
16, methyl acetal formation, and oxidation of the remaining
primary alcohol afforded aldehyde regioisomers 17 and 18
(1.9:1 ratio, 72% yield from 16). The formation of this
separable mixture of aldehydes is inconsequential since both
were found to be suitable for conversion to the AB-ring
aldehyde 8. In the case of aldehyde 17, this was achieved
through Ando olefination/A-ring lactonization[21] and acetal
hydrolysis to give lactol 19. Pleasingly, exposure of this lactol
to methanolic potassium carbonate gave the AB-ring alde-
hyde 8 in quantitative yield through oxy-Michael addition.
From aldehyde 18, a similar sequence could be applied, which
proceeded via enoate 20 (Z/E = 2.5:1); acidic deprotection of
the acetal in 20 led to spontaneous lactonization to 19.
With the key diyne and aldehyde components in hand, we
now investigated their union and cyclizations to the ABC-
DE ring system of rubriflordilactone A (Scheme 4). We first
chose to explore the palladium-catalyzed route, which began
with addition of diyne 7 to bromoalkenyl aldehyde 6 to give
alcohol 21 (67%). Prior work in the group[6b] had shown that
protection of the propargylic alcohol would be required to
achieve high yields in the ensuing cyclization, and accordingly
a TBS ether was installed at this position. The resultant
bromoendiyne was then cyclized by treatment with [Pd-
(PPh3)4] (10 mol%) and triethylamine in acetonitrile, which
to our delight afforded the ABCDE-ring pentacycle 22 in
excellent yield (91%). Oxidation of the aryl benzyldimethyl-
silane to the corresponding phenol proceeded smoothly,[22]
and after benzylic deoxygenation, the fully functionalized
ABCDE framework 23 was revealed.
Scheme 2. Reagents and conditions: a) (S,E)-pent-3-en-2-ol, EDC·HCl,
Et3N, DMAP, THF, RT, 16 h, 81%; b) LiHMDS, Et3N/toluene (3:1),
À788C!RT, 5 h, 95%, d.r.>20:1; c) LDA, TMSCl/Et3N (1:1), THF,
À788C!08C, 3 h, 92%, d.r. 9:1; d) TMSCHN2, toluene/MeOH (5:1),
RT, 30 min, 88%; e) DIBALH, CH2Cl2, À788C!À308C, 2 h, 97%;
f) DMP, NaHCO3, CH2Cl2, 08C!RT, 1 h, 90%; g) [Ph3PCH2I]+IÀ,
NaHMDS, THF, À788C!RT; then NaHMDS, À788C!RT, 84%;
h) LiHMDS, THF, À788C, 30 min; then BnMe2SiCl, À788C!RT, 3 h,
98%; i) DDQ, CH2Cl2/H2O (4:1), RT, 1 h; j) DMP, NaHCO3, CH2Cl2,
08C!RT, 30 min, 83% (2 steps); k) CBr4, PPh3, CH2Cl2 À308C!08C,
1 h, 85%; l) nBuLi, THF, À788C!RT, 40 min, 98%. Bn=benzyl,
DIBALH=diisobutylaluminium hydride, DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMAP=4-dimethylaminopyridine,
DMP=Dess–Martin periodinane, EDC=1-Ethyl-3-(3-dimethylamino-
propyl)carbodiimide, HMDS=1,1,1,3,3,3-hexamethyldisilazane, LDA=
lithium diisopropylamide, PMB=para-methoxybenzyl, TMS=trimethyl-
silyl.
At this juncture, we elected to compare the palladium-
catalyzed cyclization route with the alternative cobalt-cata-
lyzed cyclotrimerization approach. Diyne 7 was therefore
instead combined with alkynyl aldehyde 8 to give triyne 24
(85%). We were excited to find that cyclotrimerization of 24
under microwave heating[6b, 23] successfully afforded penta-
cycle 25 (67%); this product could also be advanced to the
same ABCDE-ring structure 23 prepared via the palladium-
catalyzed route, through Tamao oxidation followed by
benzylic deoxygenation.[22] Notably, silylation of the propar-
gylic alcohol in 24 provides an alternative point of conver-
gence between the two routes, since the product of cyclo-
trimerization of the resultant silyl ether is pentacycle 22,
albeit obtained with slightly reduced efficiency compared to
cyclization of the free alcohol 24.[24]
Our two strategies had now converged on the late-stage
intermediate 23, and all that remained was elaboration of the
FG ring system. This was achieved in four steps (Scheme 5),
beginning with a two-step oxidative cleavage of the pendent
alkene in 23 to give the lactol 26 (in equilibrium with the
open-chain aldehyde). This lactol intercepts with the synthetic
route reported by the Li group,[3] who progressed 26 to the
natural product through the formation of a fluoropyran,
stereoselective coupling of which with a furanyl stannane
installed the butenolide G ring. With a view to avoiding the
Scheme 3. Reagents and conditions: a) TMSCaCCH2MgBr, CuBr·SMe2,
THF, À788C!À408C, 40 min; 13, À788C; b) DIBALH, CH2Cl2,
À788C!RT, 3 h, 90% (2 steps); c) Ti(OiPr)4, d-(À)-diethyl tartrate,
tBuOOH, 4 Š MS, CH2Cl2, À208C, 22 h, 92%, 92% ee; d) AllylMgBr,
THF, 08C, 10 min, 97%; e) SO3·py, DMSO, iPr2EtN, CH2Cl2, 08C!RT,
2 h; f) NaOCl, NaH2PO4, 2-methylbut-2-ene, tBuOH/H2O (3:1), RT,
18 h, 92% (2 steps); g) BOPCl, py, MeCN, RT, 3 h, 83%; h) MeMgBr,
THF, À58C!RT, 1.5 h, 64%+31% ketone, recycled to give 75%
overall; i) OsO4, NaIO4, 2,6-lutidine, dioxane/H2O (4.6:1), RT, 2 h,
88%; j) (Æ)-camphorsulfonic acid, MeOH, RT, 18 h, 98%; k) SO3·py,
DMSO, iPr2EtN, CH2Cl2, 0–108C, 1 h, 84%; l) (PhO)2POCH2CO2Et,
KHMDS, THF, 08C; m) TFA, CH2Cl2, 08C, 15 min, 47% (from 17, and
18); n) K2CO3, MeOH, RT, 2 h, 99%. BOPCl=bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride, MS=molecular sieves, py=pyridine, TBS=tert-
butyldimethylsilyl, TFA=trifluoroacetic acid.
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Scheme 4. Reagents and conditions: a) nBuLi, 7, À788C; then add 6, À788C!À108C, 2 h, 67%; b) TBSOTf, 2,6-lutidine, CH2Cl2, 08C!RT, 4 h
75%; c) [Pd(PPh3)4] (10 mol%), Et3N, MeCN, 808C, 18 h, 91%; d) TBAF, THF, RT, 30 min; then H2O2, KHCO3, MeOH, RT, 12 h; e) Et3SiH, ZnCl2,
CH2Cl2, RT, 3 h; then TBAF, THF, RT, 20 min, 51% (2 steps); f) nBuLi, 7, À788C; then add 8, À788C!À108C, 4 h, 85%; g) [CpCo(CO)2]
(20 mol%), PPh3 (40 mol%), PhCl, MW (300 W), 1508C, 25 min, 67%; h) TBAF, THF, RT, 30 min; then H2O2, KHCO3, MeOH, RT, 12 h, 84%;
i) Et3SiH, ZnCl2, CH2Cl2, RT, 3 h, 77%; j) TBSCl, imid., DMAP, CH2Cl2, RT, 6 h, 98%; k) [CpCo(CO)2] (20 mol%), PPh3 (40 mol%), PhCl, MW
(300 W), 1508C, 25 min, 54%. Cp=cyclopentadienyl, MW=microwave irradiation, OTf =trifluoromethanesulfonate, TBAF=tetra-n-butylammo-
nium fluoride.
Scheme 5. Reagents and conditions: a) OsO4 (2 mol%), NMO, acetone/H2O (3:1), RT, 3 h; b) NaIO4/SiO2, CH2Cl2, RT, 15 min, 85% (2 steps);
c) ZnCl2, SOCl2, CDCl3, RT, 3 h; d) 29, ZnCl2, CH2Cl2, À308C!RT, 12 h, 38% of 1 and 33% of 30 (2 steps). NMO=N-methylmorpholine-N-oxide,
TIPS=triisopropylsilyl.
25
D
use of a tin-based nucleophile, we explored alternative
methods to activate the lactol. This proved challenging, but
after some experimentation we found that chloropyran 27
could be prepared by treating lactol 26 with a mixture of
thionyl chloride and zinc(II) chloride.[25] This seemingly
straightforward transformation in fact proceeds via initial
and rapid formation of dimer 28, which over a period of 3 h is
converted into the targeted chloropyran 27 (see graph in
Scheme 5). This unstable intermediate was then reacted
directly with siloxyfuran 28 in the presence of zinc(II)
chloride and, to our delight, this reaction afforded rubriflor-
dilactone A along with its C23-epimer 30 in 71% yield (d.r.
ꢀ 1:1). It is notable that the facial selectivity of the addition of
the furan to the incipient oxocarbenium ion is excellent, since
these two separable diastereomers were the predominant
products formed in this addition. The spectroscopic data for
the synthetic rubriflordilactone A were found to be identical
to those for the natural product, with the exception of the
+ 58.3 (c = 0.114, MeOH); lit. ½aŠ ¼À58.1 (c = 0.114,
MeOH)).[5,26]
In conclusion, we have developed two synthetic strategies
that achieve enantioselective syntheses of rubriflordilac-
tone A. These employ palladium or cobalt catalysis to
assemble the ABCDE ring system as the key framework-
construction step. The routes are strategically highly con-
vergent because their common late-stage intermediate is just
four steps from the end of the synthesis. The modular nature
of the coupling between a functionalized diyne and AB-ring
aldehydes to assemble the cyclization substrates enables
a unified approach to other members of this fascinating family
of natural products, and offers a high degree of flexibility for
the synthesis of rubriflordilactone analogues.
Acknowledgements
specific rotation, which showed an equal and opposite value,
We thank the EPSRC for an Advanced Research Fellowship
(EAA) (EP/E055273/1) and additional funding (EP/K005391/
25
thus indicating that 1 is the unnatural enantiomer (½aŠ ¼
D
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Keywords: cyclotrimerization · domino reactions ·
natural products · total synthesis · transition metal catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12618–12621
Angew. Chem. 2015, 127, 12809–12812
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Carbohydr. Res. 1970, 14, 263.
[26] The specific rotation is also of opposite sign to that reported by
the Li group (see Ref. [3]), although both our group and the Li
group describe the synthesis of the same enantiomer of the
natural product. Personal communications with Prof. Li indicate
that, following re-measurement of the specific rotation of the Li
groupꢀs synthetic sample, the specific rotation reported in this
manuscript is correct.
Received: July 10, 2015
Published online: September 1, 2015
Angew. Chem. Int. Ed. 2015, 54, 12618 –12621
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12621