LETTER
Bicyclo[4.4.0]Decane Ring System of Valencanes
447
Table 3 Experimental Hydrogenations of Valencanes (continued)
O
X
X
*
O
R
R
R
3
: X = O; R = isopropylidene
4: X = O; R = isopropyl
5: X = O; R = isopropylidene
14: X = H, H; R = isopropyl
15: R = isopropyl
16: R = isopropylidene
1
1
1
1: X = O; R = isopropyl
2: X = H, H; R = isopropylidene
3: X = equatorial OH, axial H;
R = isopropylidene
Entry
Starting material
Reaction conditions
Product
15
1
1
4
5
16
16
H (1 bar), 5% Pd/C, EtOH, 3, 6, and 15 h
2
9-BBN, AcOH
15
Hydrogenation of (+)-nootkatone (3) and valencene (12) to ketonic products has been reported in other systems.
provided the trans-fused product, regardless of the condi- Surprisingly, the catalysts (iridium and rhodium) proved
1
7
tions and the reaction media generated (entries 1, 3, 4, 6, ineffective in these stereoselective reductions. Evans et
and 10). Suspicion was aimed at the isopropylidene group al. postulated that at low pressures, oxidative addition of
of (+)-nootkatone. Due to its accessibility, it would be hydrogen to the catalyst–substrate complex is rate deter-
first to undergo hydrogenation. It was proposed that this mining, resulting in the competitive alkene isomerization
isopropylidene group could coordinate to the metal cata- pathway. Although this problem could be circumvented in
lyst, ultimately influencing and directing the second hy- rhodium-catalyzed hydrogenations by increasing the hy-
drogen addition to come from the top face, thereby drogen pressure (>41.4 bar), no such improvements are
providing the trans-fused isomer almost exclusively. To observed with iridium catalysts (at high pressure, sub-
test this hypothesis, the terminal olefinic group of (+)- strate–catalyst complexation becomes rate determining,
nootkatone (3) was selectively reduced utilizing Wilkin- thereby attenuating isomerization.).17
1
5,16
son’s catalyst (entry 7).
The hydrogenation product,
From our perspective, one of the more interesting aspects
of the valencane framework, from a synthetic point of
view, is the underestimated steric influence imparted by
the C-4 methyl substituent.
1
1,12-dihydronootkatone (11), was subjected to both cat-
alytic hydrogenation (entry 8) and transfer hydrogenation
conditions (entry 9). Both methods provided the trans-iso-
mer exclusively, implying that this recurring result was
not a result of the isopropylidene’s influence, but actually
arose from the steric impact imparted by the C-4 methyl
substituent.
As alluded to earlier, this methyl group provides enough
steric congestion to hinder the coordination of the hydro-
gen-carrying species to the b-face thus deterring an other-
wise straightforward and well-documented chemical
transformation from occurring (Scheme 2).
In an attempt to test this hypothesis, 11,12-dihydronoot-
katone (11) was converted to its corresponding b,g-unsat-
urated ketal 15. Through this process, the steric effects
between the incoming reagent and the C-4 methyl group
would be reduced, opening the possibility for a cis-fused
ring junction upon the adsorption of hydrogen. Hydroge-
nation in acidic media (entry 12) did not occur to an ap-
preciable extent and the isomerization and regeneration of
H
trans-fused
O
cis-fused
4
Me
Me
H
O
M
H
H
O
H M
Me
1
1 became the competing and predominant reaction. Fur-
thermore, hydroboration with subsequent protonation of
Me
H
Me
1
5 resulted in a complex and inseparable mixture (entry
3). And, in the case of (+)-nootkatone’s deconjugated ac-
Me
1
O
etal 16, the b,g-olefin could not be reduced regardless of
the reaction conditions, or the duration of exposure to the
hydrogen source. As evidenced in entries 14 and 15, both
reaction resulted in the generation of 15 as the exclusive
product (entries 14 and 15).
H
O
H
Me
Me
Me
H
Me
Scheme 2 Influence of the C-4 methyl group on hydrogenation sel-
Efforts were then turned to the hydroxy-directed hydroge-
nation of 13, implementing Crabtree’s iridium catalyst.
Unfortunately, this transformation was plagued with ole-
fin isomerization, producing trans-THN as the exclusive
product. In hindsight, these results are supported by liter-
ature precedence, as it is known that alkene isomerization
ectivity
The hydrogenation of 17 (Scheme 4) would help to sub-
stantiate this claim. As illustrated (Scheme 3), the axial C-
4
methyl group, positioned away from the hydrogen-
delivery vehicle, should not have a steric impact on the
Synlett 2010, No. 3, 445–448 © Thieme Stuttgart · New York