Schneideret al.,Science 367 , 676–681 (2020) 7 February 2020 1of5
ORGANIC CHEMISTRY
Total synthesis of the complex taxane
diterpene canataxpropellane
Fabian Schneider, Konstantin Samarin, Simone Zanella, Tanja Gaich*
Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent
congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane
exhibits a taxane skeleton with three additional transannular C–C bonds, resulting in a total of six
contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation
of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of
(–)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding
to 29 steps from commercial material. The core structure of the (–)-canataxpropellane (2) was assembled in
twostepsusingaDiels–Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was
introduced by designing chiral siloxanes to serve as auxiliaries in the Diels–Alder reaction.
T
axane diterpenes ( 1 – 3 ) are a medicinally
vital family of natural products exhibiting
potent anticancer activity ( 4 – 6 )thatwere
originally isolated from slow-growing
evergreen shrubs in the genusTaxus,
commonly known as yews. In 1994, major
synthetic efforts ( 7 – 15 ) culminated in the first
total syntheses of the most prominent anti-
cancer drug, Taxol ( 1 )( 4 – 6 )(Fig.1A),byHolton
( 7 , 8 ) and Nicolaou ( 9 ), which turned out to
be one of the top-selling anticancer drugs
(peak sales in 1999 of 1.5 billion USD) over
the past three decades ( 16 ). Ever since, differ-
entTaxusspecies have been screened for their
constituents and >500 taxanes have been iso-
lated to date [for a comprehensive review,
see ( 3 )]. Their structures are classified into 11
groups on the basis of their carbon ring sys-
tems ( 3 ). Among them, (–)-canataxpropellane
( 2 ) was isolated fromTaxus canadensis( 17 )
and represents a member of the complex tax-
ane group (Fig. 1B). This highly oxygenated
diterpene is one of the most intricate and
complex natural products that has ever been
isolated. As in the case of its sibling, Taxol, and
other taxane diterpenes, it suffers from ex-
tremely inefficient sourcing from its natural
producer, thus preventing biological and phar-
maceutical investigations to this day.
(–)-Canataxpropellane ( 2 ) comprises a hepta-
cyclic [5,5,5,4,6,6,6] carbon framework (Fig. 1C).
It is densely functionalized and highly oxidized
(five hydroxyl groups; one ketone), containing
only two CH 2 groups. Among the features dis-
tinguishing the compound’s structural complex-
ityarethefollowing:(i)itistheonlynatural
product harboring two propellanes ( 18 )simul-
taneously {see the colored portions of the
structures in Fig. 1CI(a [3.3.2]-propellane)
andII(a [4.4.2]-propellane)}; (ii) it contains
12 contiguous stereocenters (Fig. 1CIII)in-
cluding five quaternarycenters, four of which
reside in a cyclobutane ring (Fig. 1CIV); and
(iii) except for two carbon atoms (6 and 14), its
backbone consists exclusively of neopentylic
motifs (Fig. 1CIV). The retrosynthetic analysis
of (–)-canataxpropellane ( 2 ) (Fig. 2) required a
completely different design than those in any of
the previous works ( 7 – 15 )becauseofthedis-
tinctive and intricate structural features dis-
played by ( 2 ). Our analysis leads to dialdehyde
3 by disconnecting cyclopentane A in 2 through
a pinacol-coupling reaction between C9 and
C10. Dialdehyde 3 couldbeobtainedbyfunc-
tionalization of the B-ring in 4 , including in-
troduction of the quaternary stereocenter at
C8 and stereoselective hydroxylation of C5
(marked blue in 4 ). Disconnection of the cy-
clobutane ring in 4 would give aromatic com-
pound 5. This disconnection represented
by far the biggest synthetic challenge in this
synthesis, requiring a transformation capable of
not only closing a cyclobutane ring, but at the
same time establishing four quaternary stereo-
centers (C3, C4, C11, and C12) at once. For this
purpose, an alkene-arene-ortho-photocycloaddi-
tion ( 19 , 20 ) of aromatic compound 5 was
designed. This transformation would further-
more accomplish dearomatization of ring B
in photoprecursor 5. Compound 5 could be
efficiently disconnected using an intermo-
lecular Diels–Alder reaction to give 6 and 7.
The starting materials 6 and 7 of this [4+2]
cycloaddition are simple and easily accessi-
ble buildingblocks.
We devised a racemic and an enantiopure
synthesis of ( 2 ). Both syntheses started from
known lactone 8 (see Fig. 3) prepared on deca-
gram scale in three steps (90% overall, no
chromatographic purifications; see the mate-
rials and methods). Deprotonation of 8 and
trapping with tert-butyl trimethylsilyl chloride
(TBS-Cl) gave isobenzofuran diene 6 in situ,
to which dieneophile 7 (prepared in three
steps) was added to afford Diels–Alder adduct 5
in 71% yield with excellent diastereoselec-tivity (endo/exo= 100:1). Thisendo-selectivity
was prerequisite for the application of the
alkene-arene-ortho-photocycloaddition in the
next step. Thecisrelation of the oxygen bridge
and protons in the endo-Diels–Alder product
(Fig. 3, blue) brings the olefin ring (C11–C12)
and the aromatic ring (C3–C4) in close proxim-
ity, thus enabling the photoreaction. By con-
trast, in the minorexo-Diels–Alder product,
the olefin and aromatic rings (Fig. 3, red) are
blocked from reacting with each other in [2+2]
fashion. Irradiation of 5 - (endo)(l=254nm)
in acetonitrile yielded 50% of the cage-like
compound 4. To push the photoequilibrium,
5 was separated from 4 and resubmitted to
the photoreaction twice to give overall 73%
of photoadduct 4. The alkene-arene-ortho-
photocycloaddition proved to be scalable and
produced decagrams of the cage-like com-
pound 4. Photo-adduct 4 was thus accessed
in only two steps (from known compounds 7
and 8 ) and already contained the [4.4.2]-
propellane, all four quaternary stereocenters
of the cyclobutane, and the de-aromatized
B-ring. The next task was a framework func-
tionalization (Fig. 3), which first required open-
ing of the lactol in 4. However, after extensive
experimentation, we were not able to selec-
tively open the bridgehead lactol at the O–C20
bond (Fig. 3, blue) under any conditions. In-
stead, compound 4 exclusively underwent
fragmentation of the C14–C20 bond (retro-
aldol reaction; Fig. 3, red) when treated with
tetrabutylammonium fluoride in THF to give
keto-lactone 9. At this tipping point in the
synthesis, we realized that this unwanted frag-
mentation of C14–C20 was potentially capa-
ble of opening the tenacious O–C20 bond by
translactonization. For this purpose, the keto-
group in 9 was reduced with complete stereo-
selectivity to the corresponding alcohol at C13
by calcium borohydride [Ca(BH 4 ) 2 • 2THF] ( 21 )
in dichloromethane. Fortunately, this alco-
hol underwent the desired translactoniza-
tion in situ to afford hydroxyl-lactone 10 ,thus
opening the critical O–C20 bond.
In addition to cleaving the bridgehead
O–C20 bond, this transformation also served to
differentiate the C2 alcohol, which was subse-
quently protected with methoxymethylene
chloride (MOMCl) to give compound 11 in 73%
yield over three steps. Reduction of 11 with
lithiumaluminumhydride(LiAlH 4 ), followed
by Swern oxidation, yieldedbis-carbonyl 12.
When 12 was subjected to basic conditions
(KOtBu; 5:1 THF:tBuOH), an intramolecular
aldol reaction reestablished the C14–C20 bond
with complete diastereoselectivity and formed
cage structure 13 in 53% isolated yields from
11 .Compound 13 was confirmed by single-
crystal x-ray analysis to contain all functional
groups and stereocenters of the cage motif
correctly in place, matching canataxpropellane
( 2 ). With compound 13 in hand, we introducedRESEARCH
Department of Chemistry, University of Konstanz, 78467
Konstanz, Germany.
*Corresponding author. Email: [email protected]