Journal of the American Chemical Society
Communication
length (Figure 1b). Disconnections solely between the
junctions of the bicyclic core should then promote a shorter
synthesis of 1.
this case enabling tactic. Here we report its successful
implementation in a concise synthesis of 1 (Scheme 1). 2
5
Dimethylation of (R)-carvone was achieved in one or
26
With this strategic goal in mind, we encoded the oxidations
of 1 with alkenes to arrive at carbocycle 2, which might derive
two steps, although the latter procedure was employed on a
30 g (200 mmol) scale. The magnesium enolate of 3 was
formed by deprotonation with NaHMDS in the presence of
1
,3,5,22
from (R)-carvone
via annulation of methyl 2-oxobuta-
anhydrous MgCl ; subsequent addition of methyl 2-oxobuta-
2
noate at −78 °C gave the aldol addition product 4 in 67% yield
with excellent diastereoselectivity (>20:1) at C1 and
inconsequential 3.3:1 diastereoselectivity at C9. Use of lithium,
sodium, potassium, or zinc enolates gave diminished to no
yield of 4. The reaction was quenched at −78 °C to avoid
retro-aldol decomposition that occurs above −20 °C. This
unusual aldol reaction occurs with high regio- and diaster-
eoselectivity to form a quaternary carbon (C1) and a
neopentyl alcohol (C9). Our working model posits an efficient
relay of stereochemical information from the C4 stereocenter
to C1 by avoidance of a 1,3-diaxial interaction between the
axial C5 methyl group and methyl 2-oxobutanoate in the aldol
addition transition state (Figure 3b). In contrast, use of trans-
α-methylcarvone (13), i.e., mono methylation, resulted in a
Figure 2. Chemical background and synthetic plan.
23
embedded into the starting materials, with the exception of
the C15 carboxylate. Our decision to decrease C15 to the
methyl oxidation state was informed by problems encountered
1
:12 diastereomeric mixture favoring the opposite and
unproductive diastereomer (14). An extended enolate could
not be formed with either (R)-carvone or cis-α-methylcarvone,
and use of Corey’s hydrazone alkylation procedure gave no
4
−7,9−11
in the literature
with C10/C15 translactonization and
1
intramolecular epoxide opening at higher oxidation states of
C15. However, we quickly discovered that a single methyl
group on carvone led to the incorrect stereoisomer (13 → 14;
see Figure 3a). Instead, we found that geminal dimethylation
enabled the efficient synthesis of 2 in only four steps. The
challenge then became discovery of a late-stage stereoselective
aldol addition product.
Alternative tactics that replaced one of the Me groups with a
Br, Cl, or CN group were plagued by poor stereocontrol in the
formation of the C5 stereocenter and subsequent failure of the
aldol addition through proton transfer, elimination, and
aromatization pathways (Figure 3c). Symmetrical substitution
24
6
at C5 with silylhydroxymethylene (R SiOCH −), methyl
3
2
ester, or nitrile groups required multiple steps for installation,
and the aldol addition still failed. Since the inclusion of an extra
C5 methyl group enabled installation of all 15 carbon atoms of
the picrotoxinin skeleton with the correct regio- and
stereochemistry in just two steps without need for C5
stereocontrol, we continued forward with a plan to excise the
extra C5 methyl group at a late stagea risky but ultimately
successful decision.
Neopentyl alcohol 4 was converted to 5 by SOCl -induced
2
27
elimination. These conditions proved uniquely able to
eliminate both diastereomers of the sterically congested C9
alcohol 4. A vinylogous intramolecular 5-exo-trig aldol addition
reaction yielded 2 in 90% yield upon treatment of 5 with LDA
at 0 °C and warming to 23 °C. This reaction failed with the
alkene derived from 14 because of competitive deprotonation
and epimerization pathways.
Facile and scalable access to 2 allowed extensive inter-
rogation of the remaining alkene oxidations. First, bromoether-
1
,5,9
ification
with NBS proved entirely selective for the
isopropene group and delivered an 11:1 diastereomeric
mixture of 6. This dual-purpose bromoetherification served
1
2,13
to protect the Δ
isopropenyl alkene and lock the
conformation of 2 to promote lactonization at C10 and
directed oxidation of the C5 methyl groups. Epoxidation of 6
initially suffered poor diastereocontrol under nucleophilic
epoxidation conditions (e.g., alkali metal peroxides) and low
conversion with electrophilic epoxidation reagents (e.g.,
DMDO, trifluoroperacetic acid). Although mCPBA alone
was insufficient to react with 6, we found that the use of
KHCO with mCPBA in a biphasic mixture of CH Cl and
3
2
2
Figure 3. Importance of the extra methyl group in 2.
H O at 23 °C afforded 7 with high diastereoselectivity in 84%
2
B
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX