Studies directed toward the total synthesis of lancifodilactone G: An expeditious route to the ABC subunit

Article abstract of DOI:10.1021/ol800418m

(Chemical Equation Presented) An efficient entry to the ABC network of lancifodilactone G is outlined. The C ring is constructed by way of enyne ring-closing metathesis. The AB component is established via a base-mediated biomimetic oxy-Michael addition-lactonization sequence.

Full text of DOI:10.1021/ol800418m

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2111-2113
Studies Directed toward the Total
Synthesis of Lancifodilactone G: An
Expeditious Route to the ABC Subunit
Leo A. Paquette* and Kwong Wah Lai
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette@chemisty.ohio-state.edu
Received February 22, 2008
ABSTRACT
An efficient entry to the ABC network of lancifodilactone G is outlined. The C ring is constructed by way of enyne ring-closing metathesis.
The AB component is established via a base-mediated biomimetic oxy-Michael addition-lactonization sequence.
Lancifodilactone G (1) is an architecturally novel, highly
oxygenated nortriterpenoid isolated from the medicinal plant
Schisandra lancifolia by Sun and co-workers in 2005 (Figure
1).1 Its structure and relative stereochemistry were determined
cytotoxicity against C8166 cells (CC50 > 200 g/mL) while
demonstrating anti-HIV activity with an EC50 ) 95.47 ( 14.19
g/mL and a selectivity index in the range of 1.82-2.46. In
addition, its intimidating molecular architecture constitutes a
significant challenge for chemical synthesis.
Lancifodilactone G features 8 rings with complicated
cyclic connectivity, 12 stereogenic centers, and 10 oxygen-
ated carbons. In addition, the highly congested F ring can
be expected to introduce significant complications during
construction. Other provocative characteristics of this mol-
ecule include the presence of an enol functional group and
a sensitive bis-spirocyclic moiety. These structural features
serve to make 1 a unique synthetic target. In this paper, we
report an expeditious synthesis of the ABC segment of
lancifodilactone G (1).
Figure 1. Chemical structure of lancifodilactone G.
Dissection of the ABC framework revealed that the furanyl
B ring is exceedingly rich in chirality, including two
on the basis of extensive one- and two-dimensional NMR
spectroscopy and mass spectral data, coupled with single-crystal
X-ray analysis.2 Its absolute configuration was recently ex-
trapolated from the biogenetic connectivity to its congener,
micrandilactone B.3 Lancifodilactone G (1) exerts minimal
(2) The original structural assignment for lancifodilactone G has been
revised, see: (a) Xiao, W.-L.; Zhu, H.-J.; Shen, Y.-H.; Li, R.-T.; Li, S.-H.;
Sun, H.-D.; Zheng, Y.-T.; Wang, R.-R.; Lu, Y.; Wang, C.; Zheng, Q. T.
Org. Lett. 2006, 8, 801.
(3) For the absolute configuration of micrandilactone B, see: (a) Huang,
S.-X.; Li, R.-T.; Liu, J.-P.; Lu, Y.; Chang, Y.; Lei, C.; Xiao, W.-L.; Yang,
L.-B.; Zheng, Q.-T.; Sun, H.-D Org. Lett. 2007, 9, 2079. (b) For preliminary
synthetic studies aimed at micrandilactone A, consult: Zhang, Y.-D.; Ren,
W.-W.; Lan, Y.; Xiao, Q.; Wang, K.; Xu, J.; Chen, J.-H.; Yang, Z. Org.
Lett. 2008, 10, 665.
(1) For the isolation and biological evaluation of lancifodilactone G,
see: (a) Xiao, W.-L.; Zhu, H.-J.; Shen, Y.-H.; Li, R.-T.; Li, S.-H.; Sun,
H.-D.; Zheng, Y.-T.; Wang, R.-R.; Lu, Y.; Wang, C.; Zheng, Q. T. Org.
Lett. 2005, 7, 2145.
10.1021/ol800418m CCC: $40.75
Published on Web 05/03/2008
2008 American Chemical Society

quaternary carbon centers (C4 and C10).4 Its fusion to the
7-membered C ring and lactonic A ring provides an inviting
scaffold for synthesis. A retrosynthetic perspective is depicted
in Scheme 1. We conceived that the AB component of
Scheme 2. Preparation of Enyne 5
Scheme 1. Retrosynthetic Analysis of Tricycle 2
primary alcohol functionality in 7 afforded aldehyde 8.10
Transformation of the aldehyde 4 to alkyne 5 was best realized
by the Miwa protocol using TMSCHN2 in combination with
n-BuLi.11 With the key compound 5 in hand, the stage was set
to perform the enyne ring-closing metathesis step (Scheme 3).
Scheme 3. Attempted Ring-Closing Metathesis of Enyne 5
tricycle 2 might be established through the base-mediated
biomimetic oxy-Michael addition-lactonization of diol 3 in
a stereoselective fashion.5 We anticipated that the Michael
acceptor component within 3 could be incorporated into the
endo-olefin of 4 using cross-metathesis technology.6 The
7-membered C ring would then be assembled by application
of enyne ring-closing metathesis7 involving 5, which in turn
could be derived from the known epoxy alcohol 6.8 It was
imperative that the starting material 6 imbed the requisite
stereochemistry at C4 and C5 and thus provide a superior
starting point to expedite matters.
The synthesis commenced with hydroxymethyl-guided ep-
oxide opening of 68 with the organocuprate reagent derived from
5-hexenylmagnesium bromide (Scheme 2).9 Diol 7 was formed
in a regio- and stereoselective manner. IBX oxidation of the
Unfortunately, all trials to effect the cyclization using either
the Grubbs II or Hoveyda catalyst system failed, and only
recovered starting material 5 was evidenced. To explain this
unanticipated failure, we propose a hydroxyl-inhibitory pathway
as shown in Scheme 3. This prior complexation of the
ruthenium catalyst to the alkyne moiety residing in 5 leads to
the presumably stable vinyl alkylidine 10, which eventually
retards the metathesis propagation and recycling steps (via 11
and 12). Therefore, we reasoned that masking the C4 hydroxyl
group in 5 might overcome the inhibitory problem, although
added steps would be required.
To our satisfaction, protection of the tertiary alcohol as its
TMS ether (5 f 13) followed by enyne ring-closing metathesis
proceeded smoothly under an ethylene atmosphere in refluxing
CH2Cl2 to give the 7-membered C ring product 4 in excellent
yield (Scheme 4). The next mission was to introduce the
(4) The carbon numbering is assigned according to the system of the
parent natural product in ref 1.
(5) For reviews on the biomimetic synthesis of natural products, see:
(a) Yoder, R. A.; Johnston, J. N. Chem. ReV. 2005, 105, 4730. (b) Beaudry,
C. M.; Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105, 4757.
(6) For reviews on cross-metathesis, see: (a) Chatterjee, A. K.; Grubbs,
R. H. Angew. Chem., Int. Ed. 2002, 41, 3171. (c) Choi, T.-L.; Lee, C. W.;
Chatterjee, A. K.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 10417. (d)
Chatter, A. K.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 3171, and
references cited therein.
(7) Reviews on enyne metathesis, see: (a) Chattopadhyay, S. K.;
Karmakar, S.; Biswas, T.; Majumdar, K. C.; Hahaman, H.; Roy, B.
Tetrahedron 2007, 63, 3919. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D
Angew. Chem., Int. Ed. 2005, 44, 4490. (c) Diver, S. T.; Giessert, A. J.
Chem. ReV. 2004, 104, 1317.
(8) Fontana, A. F.; Messina, R.; Spinella, A.; Cimino, G Tetrahedron
Lett. 2000, 41, 7559. The diastereopurity of 2 was further ascertained by
Mosher ester analysis (dr g 20:1)
(10) For IBX oxidation, see: (a) Frigerio, N.; Santagostino, M. Tetra-
hedron Lett. 1994, 35, 8019.
(9) (a) Juaristi, E.; Jimenez-Vazquez, H. A. J. Org. Chem. 1991, 56,
1623. (b) Samsel, E. G.; Kochi, J. K. Inorg. Chem. 1986, 25, 2450.
(11) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107.
2112
Org. Lett., Vol. 10, No. 11, 2008

Scheme 4
.
Preparation of Diol 14
Scheme 5. Biomimetic Synthesis of ABC ring 15
Michael acceptor by cross-metathesis technology involving the
Hoveyda catalyst and methyl acrylate. Indeed, the desired 14
was formed with reasonable efficiency and an impressive E-Z
selectivity of 20:1. At this point, we proceeded to set up the
oxidation level in 14 by means of regio- and diastereoselective
single-site dihydroxylation in the presence of (DHQD)2PHAL
as the accelerating ligand,12 followed by discharge of the acid-
sensitive TMS protecting group with a mixture of HCl in
methanol. This reaction sequence restored the hydroxyl func-
tionality at C10 and delivered the triol 15 in ca. 60% yield over
two steps. Chemoselective protection of the secondary alcohol
within 15 gave rise to the desired TBS ether 3.
With the key intermediate 3 in hand, we proceeded to trigger
the biomimetic cascade illustrated in Scheme 5 which consisted
of an intramolecular oxy-Michael addition initiated by potassium
tert-butoxide for closing up the 5-membered B ring as in 18,
followed by lactonization to build the remaining A ring and
cleanly afford the tricyclic 21. Particularly compelling is the
formation of a single diastereoisomer in this reaction. The
inherent selectivity of this process can be rationalized in terms
of a preference for forming conformer 17 in which the acrylate
side chain occupies a pseudoequatorial position, with attack by
the alkoxide occurring on the double bond (C1 position). In
contrast, conformer 16 is disfavored because of steric compres-
sion and poor alignment of the acrylate moiety. These consid-
erations also explain why the C-1 position of final product 21
possesses the R configuration.13 The crude product 21 was
directly treated with TBAF to induce desilylation and produce
the ABC tricycle 2 in 88% yield over two steps.
In summary, we have developed an efficacious access
route to the ABC segment of lancifodilactone G. The entire
sequence involves 11 steps and proceeds in 19% overall
yield. The prominent steps involved enyne ring-closing
metathesis, cross-metathesis, and a base-mediated biomimetic
oxy-Michael addition-lactonization sequence. In addition,
we uncovered a hydroxyl-inhibitory problem in the ring-
closing metathesis reaction. Progress toward completion of
the total synthesis of lancifodilactone G (1) is currently
underway in our laboratory.
Acknowledgment. We thank The Ohio State University for
partial financial support and Robert Dura (The Ohio State
University) for assistance with the NOE and 2D NMR experiments.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Under ligandless conditions, OsO4 led to a low reaction rate and
poor chemical yield. For chiral dihydroxylation catalysts in enantioselective
synthesis, see: (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B
Chem. ReV. 1994, 94, 2483. The stereochemistry of 15 was determined by
spectral comparison with the advanced compound 21.
OL800418M
(13) Diagnostic NOE enhancements between H-1 and H-19 and H-1
and H-30 were observed.
Org. Lett., Vol. 10, No. 11, 2008
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