upon dehydroformylation were transformed
with modest regioselectivities (1j and 1k); however, steric congestion favored terminal olefins
over trisubstituted products (1l). Nonetheless,
trisubstituted olefins were generated from
substrates containing a single syn-b-hydrogen
such as 1m.
Next, we applied this protocol to generate structurally complex olefins from natural products
(Fig. 3C). By dehydroformylation of a (+)-sclareolide
derivative, we accessed a carbon-based scaffold
2n containing an exocyclic diene adjacent to a
quaternary center. This product is a key interme-
diate in the synthesis of several terpenes. Fur-
thermore, (+)-sclareolide is an inexpensive and
readily available precursor, whereas typical pre-
cursors such as (+)-manool and (–)-polygodial
have either been discontinued by commercial
suppliers or are available only in milligram quan-
tities ( 27).
To study the chemoselectivity of dehydroformylation, we examined steroid and macrolide substrates (Fig. 3C). Deoxycholic acid derivative 2o
was prepared without protection of the hydroxyl
groups, despite the potential for alcohol oxidation under Rh catalysis ( 28, 29). Thus, activation
of the aldehyde C–H bond occurred with high
chemoselectivity to initiate C–C bond cleavage.
Smooth dehydroformylation of the antibiotic
spiramycin I to generate macrolide 2p highlights
the tolerance of this method to many functional
groups, including dienes, amines, ethers, esters,
and acetals. In this case, dehydroformylation
introduced an exocyclic olefin that dramatically
altered the topology of the macrolide.
The yohimbinoid family of indole alkaloids has
often served as a testing ground for methodology
( 30). Padwa reported the de novo synthesis of
racemic yohimbenone in 11 steps from methyl 3-
indolylacetate ( 31). By using dehydroformylation
as a key step, we prepared (+)-yohimbenone in
three steps from commercially available and
inexpensive (+)-yohimbine. Conversion of ester
7a to b-hydroxy aldehyde 7b was achieved in
87% yield by LiAlH4 reduction followed by
58 2 JANUARY 2015 • VOL 347 ISSUE 6217 sciencemag.org SCIENCE
Fig. 3. Applications of dehydroformylation. (A) General conditions for transfer hydroformylation. (B) Substrate scope. (C) Natural product derivatization.
(D) Three-step synthesis of (+)-yohimbenone. Yields are of isolated materials and mixtures of regioisomers where indicated. rr is the regioisomeric ratio; rr
values were determined by 1H NMR analysis of the reaction mixtures. The yields of 2e and 2k were determined by 1H NMR analysis of the reaction mixtures
using durene as an internal standard. See the supplementary materials for details.