favor of the desired and more reactive C2 po-
sition. Final hydrogenation of the benzylidene
acetal delivered (±)-canataxpropellane ( 2 ). In
the isolation report of (–)-canataxpropellane
( 2 )fromT. canadensis( 19 ), an apparent con-
formational isomerismof the natural product,
was described, with two compounds apparent
in the^1 H-nuclear magnetic resonance (NMR)
spectrum (major and minor). Our spectral
data (^1 H,^13 C, COSY, HSQC, HMBC, and NOESY)
are in full accordance with the reported“major
conformer”(see the supplementary materials)
but we did not observe the second set of signals
representing the“minor conformer.”Given the
rigidity of 2 and the fact that the dipropellane
structure allows for very little conformational
flexibility, we conclude that the second signal
setobservedintheisolationstudylikelycorre-
sponds to a naturally occurring, closely related
derivative of (–)-canataxpropellane ( 2 )thathas
yet to be identified. Having accomplished the
racemic synthesis of the natural product, we
performed its enantioselective synthesis. For
this purpose, enantioselectivity needs to be
introduced during the Diels–Alder reaction to
product 5. However, we found that 5 itself
is extremely sensitive toward a wide range
of Lewis and Brønsted acids even in catalytic
amounts, leading to rapid degradation of the
material. Therefore, many literature-reported
methods of asymmetric Diels–Alder reactions,
such as chiral Lewis acid catalysis ( 25 )or
iminium catalysis ( 26 ), were found to be im-
practical for our system. We therefore turnedour attention toward chiral silyl chlorides to
form a chiral isobenzofuran species as a chiral
analog to 6 (Fig. 5). After screening a broad
spectrum of chiral silyl groups, we found
a,a,a′,a′-tetraaryl-1,3-dioxolan-4,5-dimethanol
(TADDOL) ( 27 )–based 27 to be the best choice,
although the diastereoselectivity in the Diels–
Alder reaction was modest (1.5:1 =28:29)
for the desired stereoisomer 28 .Theuseof
TADDOL 27 proved to be advantageous be-
cause the products 28 and 29 could be readily
separated by column chromatography. Alkene-
arene-ortho-photocycloaddition and retro-aldol
reaction of 28 under the previously investi-
gated conditions delivered the enantiopure
intermediate (–)- 9. The absolute configura-
tionwas assigned by determination of FlackSchneideret al.,Science 367 , 676–681 (2020) 7 February 2020 4of5
Fig. 4. Total synthesis of (–)-canataxpropellane (2) part II: B-ring
elaboration, pinacol coupling, and end game to (2).Reagents and conditions:
- Dimethoxybenzylidene [PhCH(OMe) 2 ] (5.0 equiv.), CH 3 CN, para-
toluenesulfonic acid (PTSA) (5 mol %), r.t.,96%. 14. Lithium tri-sec-butylborohydride
(L-selectride) (1.1 equiv.), THF–78°C, 99%. 15. Potassiumhexamethyldisilazide
(KHMDS) (1.5 equiv.), Comin’s reagent (A) (2.0 equiv.),–78°C,THF,83%.16.
NEt 3 (3.0 equiv.), CO, palladium tetrakis triphenylphosphine [Pd(PPh 3 ) 4 (10 mol %)],
N,N-dimethylformamide (DMF), MeOH, 89% r.t. 17. Magnesium turnings
(Mg)(20.0equiv.),MeOH,r.t.,88%.18.KHMDS(1.5equiv.),crownether[18]-crown-
6(1.5equiv.),THF–78°C,methyliodide(excess),95%.19.LiAlH 4 (2.0 equiv.),
THF, 0°C, then tetrabutylammonium fluoride (TBAF) (1.5 equiv.), r.t., THF, 83%.- Oxalyl chloride (8.0 equiv.), DMSO (16.0 equiv.), NEt^3 (24.0 equiv.),
CH 2 Cl 2 ,–78°C. 21. TiCl 4 (20.0 equiv.), THF 0°C, zinc dust (Zn), (40.0 equiv.),
pyridine (20.0 equiv.), 55%. 22. Pyridine, acetic anhydride (Ac 2 O) (20.0 equiv.),
N,N-dimethylaminopyridine (DMAP), (2,5 mol%), CH 2 Cl 2 ,79%.23.
2-Bromo-1,3,2-benzodioxaborole [BrB(catechol)] (5.0 equiv.), CH 2 Cl 2 ,0°C,
56% and 44%. 24. MeOH r.t., potassium carbonate (K 2 CO 3 ) (4.0 equiv.),
67%. 25. Pyridine, acetic anhydride (Ac 2 O) (1.1 equiv.), DMAP, (2,5 mol %),
0°C, CH 2 Cl 2 , 45%. 26. Palladium on charcoal (Pd/C 10 wt %) (0.30 mol %),
MeOH r.t., hydrogen (H 2 ), 97%.
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