Metal-catalyzed syntheses of abridged CDE rings of rubriflordilactones A and B

Article abstract of DOI:10.1021/ol303041j

The development of complementary palladium- and cobalt-catalyzed approaches to tricyclic arylsilanes suitable for elaboration into the CDE ring systems of rubriflordilactones A and B is reported. Microwave conditions are required to effect a cobalt-catalyzed triyne cyclotrimerization, which critically depends on the substitution pattern of the triyne termini. Mild conditions to elaborate these arylsilanes to the CDE cores of the natural products are described.

Full text of DOI:10.1021/ol303041j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Catalyzed Syntheses of Abridged
CDE Rings of Rubriflordilactones A and B
Shermin S. Goh,† Hannah Baars,‡ Birgit Gockel,† and Edward A. Anderson*,†
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
OX1 3TA, U.K., and Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, D-52074 Aachen, Germany
edward.anderson@chem.ox.ac.uk
Received November 5, 2012
ABSTRACT
The development of complementary palladium- and cobalt-catalyzed approaches to tricyclic arylsilanes suitable for elaboration into the CDE ring
systems of rubriflordilactones A and B is reported. Microwave conditions are required to effect a cobalt-catalyzed triyne cyclotrimerization, which
critically depends on the substitution pattern of the triyne termini. Mild conditions to elaborate these arylsilanes to the CDE cores of the natural
products are described.
Rubriflordilactones A and B (Figure 1) are triterpenoid
natural products isolated from Schisandra rubriflora.1
Although related in structure and biosynthetic origin to
a large family of terpenoids isolated from this genus of
Chinese herbal plants,2 they are the only two which feature
aromatic D rings. These molecules have attracted attention
due to their anti-HIV properties, for which rubriflordilac-
tone B represents one of the more active family members
(EC50 = 9.75 μg mLꢀ1 for inhibition of HIV-induced
syncytium formation). Interestingly, rubriflordilactone A
shows limited antiviral activity, which may suggest a
structureꢀactivity relationship that depends on the CDEFG
framework of these molecules, rather than the AB rings
which are common to the two.
distinguished by the presence or absence of arene oxygena-
tion, and by the adjacent unsaturation that is featured in
the C ring of rubriflordilactone B. The synthetic challenge
posed by this family of natural products is highlighted by
the solitary total synthesis of (()-schindilactone A,3 despite
the numerous synthetic strategies that have been described.4
Our own studies focused on palladium-catalyzed cascade
cyclization of a bromoenediyne to form the CDE core,5
methodology which is well-established in the field of
palladium-catalyzed cascade reactions,6 but which has
not been applied in total synthesis. We report here refine-
ments of this strategy and an alternative cyclotrimerization
The centerpiece of the rubriflordilactone skeleton is the
aromatic D-ring, which is flanked by 7- and 5-membered
carbocycles (the C and E rings) and, in the case of rubri-
flordilactone A, a pyran. The two aromatic cores are
† University of Oxford.
‡ RWTH Aachen University.
(1) Xiao, W. L.; Yang, L. M.; Gong, N. B.; Wu, L.; Wang, R. R.; Pu,
J. X.; Li, X. L.; Huang, S. X.; Zheng, Y. T.; Li, R. T.; Lu, Y.; Zheng,
Q. T.; Sun, H. D. Org. Lett. 2006, 8, 991.
(2) Xiao, W. L.; Li, R. T.; Huang, S. X.; Pu, J. X.; Sun, H. D.
Nat. Prod. Rep. 2008, 25, 871.
Figure 1. Rubriflordilactone family of natural products.
r
10.1021/ol303041j
XXXX American Chemical Society

be obtained in good yields, with 4b being prepared via
ruthenium-catalyzed etherification of silane 4d.9,10
Scheme 1. Synthesis of Bromoendiynes 3aꢀe and 4aꢀe
With a selection of silylated bromoendiynes in hand, we
examined their palladium-catalyzed cyclization to tricyclic
arylsilanes (Table 1). This revealed that the free pro-
pargylic hydroxyl (3a) was indeed incompatible with the
cyclization conditions. However, the equivalent TBS ether
4a underwent successful cyclization (entries 1, 2). Of the
various alkynylsilanes, benzyldimethylsilane 4c proved
most effective, delivering 6c in 76% yield (entry 4). Hydro-
silane 4d did not survive the reaction conditions (entry 5),
possibly due to competitive oxidative addition into the
SiꢀH bond. Terminal alkyne 4e also decomposed (entry 6),
implying that a post-cyclization desilylation strategy would
be needed to access rubriflordilactone B.
Table 1. Cyclization of Bromoendiynes to Tricyclic Arylsilanes
approach to the CDE rings, the success of which depends
not only on the substitution pattern of the triyne substrate
but also on the mode of heating. We also detail elabora-
tion of the cyclized products to the different functional-
ities found in the rubriflordilactone CDE cores.
To this end, we synthesized a range of alkynylsilanes
suitable for cyclization (Scheme 1). This began with zipper
isomerization of hept-3-yn-1-ol,7 followed by an alkyne
bromoboration8/oxidation sequence to aldehyde 1, to
which was added a range of lithiated silyldiynes 2aꢀd
and the unsubstituted diyne 2e. While the isopropoxy
and dimethylsilane groups 2b and 2d were tolerated in this
addition, superior results were obtained with the trimethyl
and benzyldimethylsilanes 2a and 2c. Although it was not
yet clear whether the propargylic alcohol would require
protection during cyclization, the TBS ethers 4aꢀe could
entry
substrate
R
[Si]
TMS
product
yield (%)
1
2
3
4
5
6
3a
4a
4b
4c
4d
4e
H
5a
6a
6b
6c
6d
6e
dec.
62
TBS
TBS
TBS
TBS
TBS
TMS
SiMe2Oi-Pr
SiMe2Bn
SiMe2H
H
41
76
dec.
dec.
These cyclizations had revealed the scope and limita-
tions (with respect to the crucial silane substituent) of the
bromoendiyne route to rubriflordilactone-like tricyclic
arylsilanes. However, we were mindful of other methods
for the assembly of fused-ring arenes, such as alkyne cyclo-
trimerization. While this process has rich precedent in
synthesis11 and is well-known to tolerate simple alkynylsi-
lanes, its use in total synthesis for the preparation of rings
larger than 6-membered is, to our knowledge, unknown. It
was certainly unclear whether the nature of the substitu-
ents at the alkyne termini, which we presumed might direct
the order of events in the cyclotrimerization, would be of
importance.
(3) (a) Xiao, Q.; Ren, W. W.; Chen, Z. X.; Sun, T. W.; Li, Y.; Ye,
Q. D.; Gong, J. X.; Meng, F. K.; You, L.; Liu, Y. F.; Zhao, M. Z.; Xu,
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A screen of cyclotrimerization conditions was under-
taken using triyne 7a12 (featuring a TMS substituent at the
triyne terminus where 5-membered ring formation occurs)
with a particular focus on methods suitable for the
(5) Cordonnier, M.-C. A.; Kan, S. B. J.; Anderson, E. A. Chem.
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de Meijere, A. Eur. J. Org. Chem. 2008, 6152. (b) Henniges, H.; Meyer,
F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron
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Mohamud, M. M.; Ay, M. Tetrahedron Lett. 1992, 33, 3253. For recent
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(10) Attempted formation of 4c from 3c using TBSCl/imidazole led
to formation of a disiloxane at the alkyne terminus.
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Int. Ed. 1984, 23, 539. For a recent review, see: (b) Dominguez, G.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Cyclotrimerization of Triynes to Tricyclic Arylsilanesa
entry substrate
R1
TMS
R2
catalyst (mol %)
Rh(PPh3)3Cl (3)
solvent
temp (°C) time product yield (%) (conversion (%))
1
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7d
7c
7e
7f
H
PhMe/EtOH (10:3)
EtOHb
PhMeb
80
5.5 h
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5d
5c
5e
5f
dec (n.d.)
dec (n.d.)
10 (30)
2
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
SiMe2H
SiMe2Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Rh(PPh3)3Cl (10)
Co2(CO)8 (10)
80
24 h
3
110
20 h
4
CpCo(CO)2/2 PPh3 (100) dioxane
CpCo(CO)2/2 PPh3 (100) PhMe
100
48 h
10 (67)
5
110
24 h
30 (87)
6
CpCo(CO)2/2 PPh3 (20)
CpCo(CO)2/2 PPh3 (20)
CpCo(CO)2/2 PPh3 (20)
CpCo(CO)2/2 PPh3 (20)
PhCl
PhClb
PhClc
PhCl
150d
150d
150d
150d
150d
150d
150f
150d
150d
150d
150d
30 min
30 min
30 min
15 min
25 min
25 min
25 min
25 min
25 min
25 min
25 min
67 (100)
55 (100)
53 (100)
63 (73)
7
8
9
10
11
12
13
14
15
16
CpCo(CO)2/2 PPh3 (20) PhCl
CpCo(CO)2/2 PPh3 (20) PhCl
CpCo(CO)2/2 PPh3 (20) PhCl
CpCo(CO)2/2 PPh3 (20) PhCl
CpCo(CO)2/2 PPh3 (20) PhCl
80 (100)
19 (47)e
70 (86)e
20 (100)
87 (100)
10 (100)
trace
CpCo(CO)2/2 PPh3 (20)
PhCl
PhCl
H
TMS CpCo(CO)2/2 PPh3 (20)
a Reaction conditions: 7 (30 mg) in degassed solvent; Concentration, unless otherwise stated: Rh(PPh3)3Cl, 0.05 M; Co2(CO)8, 0.1 M; CpCo(CO)2/2
PPh3, 0.04 M. b 0.1 M. c 0.02 M. d MW power: 150 W. e Performed using 210 mg of 7. f MW power: 300 W.
formation of 7-membered rings (Table 2). Our survey
began with Wilkinson’s catalyst, but despite a precedent
for the formation of a benzannulated bridged 7-membered
ring,11e only decomposition was observed (entries 1, 2).
The use of cobalt catalysts led to some success, with small
amounts of arene 5a isolated using dicobalt octacarbonyl
(entry 3), albeit with incomplete conversion; similar results
were obtained with stoichiometric amounts of CpCo(CO)2/
PPh3, a reagent which had enabled the formation of a
benzooxepane (entries 4, 5).13 To our delight, significant
improvement was observed on moving to microwave
irradiation.14 While the role of microwave heating in
cyclotrimerization remains the subject of some debate,15
its benefit was clear, with reaction at 150 °C proceeding to
completion in 30 min using 20 mol % of catalyst, afford-
ing 5a in 67% yield (entry 6). Although varying the con-
centration did not lead to further improvement (entries 7, 8),
the reaction time proved to be critical: incomplete conver-
sion was observed after 15 min, but with an optimized
irradation period of 25 min, 5a was produced in 80% yield
(entries 9, 10). Both conversion and yield diminished on
scale-up. However, this problem could be solved by increas-
ing the microwave power to 300 W, which gave 5a in 70%
yield (entries 11, 12).
A series of other triynes were examined to determine the
effect of position and nature of the silane substituent.
Whereas hydrosilane 7d gave a poor return of arylsilane
5d, benzyldimethylsilane 7c delivered 5c in an excellent
87% yield (entries 13, 14). From a mechanistic perspective,
itis of interestthattheunsubstitutedtriyne7e, and triyne7f
(in which the silyl substituent is installed at the 1,8-diyne
terminus), gave low yields or only a trace product, imply-
ing that a sterically demanding substituent at R1, but not
R2, is crucial (entries 15, 16). In contrast to the bromoen-
diyne cyclizations, protection of the propargylic alcohol
was not necessary.
These successful cyclizations may be explained by two
possible mechanistic pathways (Scheme 2).16 The first
initiates with kinetically favored complexation of the
1,6-diyne, leading to cobaltacycle 8. Intramolecular [4 þ 2]
cycloaddition with the remote unsubstituted alkyne in 8
then outcompetes intermolecular reaction with another
molecule of substrate, unless the substrate is also unsub-
stituted at the 1,6-diyne terminus (as in 7e and 7f) or,
worse, substituted at the 1,8-diyne terminus (7f). Alter-
natively, complexation of the 1,8-diyne (which might be ex-
pected to be favored by silylation of the 1,6-diyne terminus)
leads to cobaltacycle 9, the alkyne of which, due to its
shorter tether, is then able to compete successfully with
intermolecular reactions, affording 5.
(13) (a) Stara, I. G.; Stary, I.; Kollarovic, A.; Teply, F.; Saman, D.;
Tichy, M. J. Org. Chem. 1998, 63, 4046. (b) Stara, I. G.; Alexandrova, Z.;
Teply, F.; Sehnal, P.; Stary, I.; Saman, D.; Budesinsky, M.; Cvacka, J.
Org. Lett. 2005, 7, 2547.
(14) Nicolaus, N.; Strauss, S.; Neudorfl, J. M.; Prokop, A.; Schmalz,
H. G. Org. Lett. 2009, 11, 341.
With a range of tricyclic arylsilanes in hand from both
methodologies, we proceeded to study the divergent func-
tionalization of the CD rings, in order to establish strategies
(15) (a) Dallinger, D.; Irfan, M.; Suljanovic, A.; Kappe, C. O. J. Org.
Chem. 2010, 75, 5278. (b) Rodriguez, A. M.; Cebrian, C.; Prieto, P.;
Garcia, J. I.; de la Hoz, A.; Diaz-Ortiz, A. Chem.;Eur. J. 2012, 18, 6217.
(16) Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria, M.;
Aubert, C. J. Am. Chem. Soc. 2007, 129, 8860.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Synthesis of an Abridged CDE Core of
Rubriflordilactone B
Scheme 2. Mechanistic Alternatives for Cyclotrimerization
ZnCl2
equiv
TMSCl
equiv
time
(h)
product
ratioa
yield
(%)b
entry
substrate
1
2
3
4
6a
6a
5a
5a
1.5
3.0
1.5
3.0
2.0
3.0
2.0
3.0
2
20
2
90:10
15:85
100:0
46:54
78
69
99
66
20
Scheme 3. Synthesis of an Abridged CDE Core of Rubriflordi-
lactone A
a Ratio of 10:11 based on integration of the 1H NMR spectrum of the
crude reaction mixture. b Isolated yield of 10 and 11.
for the synthesis of either rubriflordilactone. We first
investigated the CDE core of rubriflordilactone B, which
would arise from desilylation, and elimination of the
benzylic oxygen substituent. We were somewhat sur-
prised to find that the arylsilane in 6a was unaffected by
a range of fluoride sources (e.g., TBAF, CsF), with only
benzylic TBS ether cleavage observed upon heating.
Acidic conditions (e.g., TFA/CH2Cl2, CSA/methanol)
were also ineffective, although, in the latter case, metha-
nolic substitution of the benzylic silyl ether was observed.
This suggested that benzylic elimination might be facile,
and pleasingly treatment of 6a with ZnCl2/TMSCl
yielded 10 (Table 3, entry 1).17 10 could be desilylated
using in situ generated TMSI to give 11,18 the tricyclic core
of rubriflordilactone B, in 78% yield over two steps. By
increasing the reaction time and reagent quantities, 6a
could be converted directly into 11 (entry 2), although this
never proceeded to completion. This sequence could
equally be applied to benzyl alcohol 5a, delivering 11 in
an excellent 99% yield (entry 3).
We anticipated that the CDE core of rubriflordilactone
A could be obtained from tricyclic arylsilanes 6b or 6c by
Tamao oxidation,19 then benzylic reduction. In the event,
oxidation of isopropoxydimethyl silane 6b with catalytic
TBAF was possible (Scheme 3, Step 1, conditions A)20 but
required heating and gave moderate yields of phenol 12. A
sequenced procedure was needed for the oxidation of
benzyl dimethylsilane 6c, with TBAF-mediated silanol
formation preceding addition of H2O2;21 simultaneous
addition of all reagentsgavethis silanol as the sole product.
Using this protocol with 2.1 equiv of TBAF (which was
essential for the reaction to proceed to completion) gave 12
in 92% yield (Step 1, conditions B).
Finally, benzylic deoxygenation was investigated. We
were delighted to find that ionic hydrogenation of phenol
12 with TFA/triethylsilane afforded the tricyclic core 13 of
rubriflordilactone A, along with small amounts of the
(separable) phenolic TES ether (Step 2, conditions C).
The milder ionization conditions of ZnCl2 also proved
successful, giving 13 in 80% yield (Step 2, conditions D).
In summary, we have developed two transition
metal-catalyzed routes to prepare tricyclic arylsilanes
which are model precursors to the CDE rings of rubri-
flordilactones A and B. Highlights include the use of
microwave-promoted cyclotrimerization to forge the
challenging 7-membered C ring and the discovery of sub-
stituent effects which are critical to this reaction, an
arylsilane oxidation which effectively employs alkynylsilanes
as masked phenols, and the development of mild conditions
for tricycle elaboration into the natural product cores.
Acknowledgment. We thank the EPSRC for an Ad-
vanced Research Fellowship (E.A.A.) (EP/E055273/1),
A*STAR for a National Science Scholarship (S.S.G.),
and the postdoctoral support through a fellowship from
the German Academic Exchange Service (DAAD) (B.G.).
(17) Peng, Z.-Y.; Ma, F.-F.; Zhu, L.-F.; Xie, X.-M.; Zhang, Z. J. Org.
Chem. 2009, 74, 6855.
Supporting Information Available. Experimental pro-
1
cedures, and copies of H and 13C NMR spectra. This
(18) Radner, F.; Wistrand, L.-G. Tetrahedron Lett. 1995, 36, 5093.
(19) Tamao, K. Proc. Jpn. Acad. Ser. B 2008, 84, 123.
(20) (a) Bracegirdle, S.; Anderson, E. A. Chem. Commun. 2010, 46,
3454. (b) Rayment, E. J.; Summerhill, N.; Anderson, E. A. J. Org. Chem.
2012, 77, 7052.
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 7502.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX