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substrates and reaction sequences. As the initial phase of this
campaign, we selected crotophorbolone (1) as a target
molecule. Herein we report the total synthesis of 1 from
(R)-carvone (5) by employing a p-allyl Stille coupling
reaction and an a-alkoxy bridgehead radical mediated
cyclization for stereoselective construction of the common
C1–C12 tricycle.
C13 position in an anti-selective manner to the bulky
C14 isopropenyl group, leading to 7 as the major product
(d.r. = 5:1). The kinetic enolate generated from 7 by LiN(iPr)2
underwent the second aldol reaction with formaldehyde,
which was released in situ from B.[17] The exclusive stereose-
lectivity in forming the C8 center of 8 was again controlled by
the C14 substituent. After TIPS-protection of the primary
hydroxy group of 8, the conjugated C11–C12 double bond was
reduced under Birch conditions to produce the ketone 10 and
alcohol 10’ with the thermodynamically stable equatorial
C11 methyl group. The over-reduced 10’ was in turn oxidized
to 10 by TPAP.[18] Then, the sterically demanding lithiated
vinyl ether C added to the C9 ketone of 10 equatorially,
furnishing the pentasubstituted cyclohexane 11.
Next, the caged C9,C13’ bis(acetal) structure 16 was built
from 11 through a five-step functional-group manipulation.
Upon activation with CSA, the axial C9 alcohol of 11
participated in acetal exchange with the C13’ dimethyl
acetal to provide the oxabicyclo[2.2.2]octane 12 (d.r. = 1:1 at
C13’). The C9 O,Se-acetal was then constructed by conversion
of the C9 vinyl ether of 12.[8j] Thus, the vinyl ether 12 was
chemoselectively oxidized by mCPBA to the carboxylic acid
13 via the intermediacy of the hydroxy ketone. After
mesylation of 13, the mesyloxycarbonyl group of 14 was
converted into the PhSe group in a one-pot by Barton ester
formation[19] and subsequent photoirradiation in the presence
of (PhSe)2.[20] Removal of the TIPS group of 15, followed by
chromatographic separation, gave rise to (13’R)-16 and
(13’S)-16.
The three rings of 1, having five various oxygen-based
functionalities, present a daunting synthetic challenge (Sche-
me 1A). Crucial to the success of the total synthesis would be
efficient formation of the sterically congested C9–C10 bond
between the A- and C-rings. To realize this connection, we
decided to incorporate the intramolecular a-alkoxy bridge-
head radical reaction of 3, which was designed to possess the
cyclopentenone and O,Se-acetal moieties as the radical
acceptor and donor, respectively.[11] The stereochemically
defined and highly reactive bridgehead radical generated
from the oxabicyclo[2.2.2]octane 3 would undergo a 7-endo
cyclization into 2 with a C9 stereospecific connection of the
hindered bond. Appropriate C2 and C4 functionalizations of
the A-ring and oxidative cleavage of the C13–C13’ bond
would transform 2 into the target molecule 1. Accordingly,
this radical-based strategy would simplify the stereochemical
issues, because only two stereocenters (C4,C10) out of six
need to be introduced upon conversion from 3 into 1. The
skipped diene structure of the key intermediate 3 would be
synthesized from the achiral A-ring A and the chiral C-ring 4
by applying the p-allyl Stille coupling reaction. Pattern
recognition of the b-oriented isopropenyl cyclohexane sub-
structure within 4 led us to utilize (R)-carvone (5) as the
starting material.[12]
In this approach, the C10 stereocenter must be established
upon cyclization of the radical I (Scheme 1B). Since the five
chiral centers are concentrated on the C-ring moiety, the
stereochemical information of the C-ring of I must be
transmitted to the achiral A-ring to produce the correct
isomer IIIa instead of IIIb. Computational modeling studies
of II, an abbreviated structure of I, were thus performed to
predict the C10 stereoselectivity. Specifically, the two tran-
sition-states, TS-1 and TS-2, from II were simulated at the
UM06-2X/6-31G(d) level of theory.[13] TS-1, which leads to
the desired IVa, was found to be more stable than TS-2 by
4.1 kcalmolÀ1. Close inspection of the three-dimensional
structures of TS-1 and TS-2 suggested that the equatorially
oriented C11 methyl group influenced their energy differ-
ence. While the distances from H18 of the C11 methyl group
of TS-2 to H1 (2.00 ) and H2 (2.25 ) are both within the
sum of the van der Waals radii (2.40 ),[14] TS-1 possesses only
one such close contact [H18-1 (2.24 ), H18-10 (2.41 )]. On
the basis of the DFT calculations, we expected that the
C10 stereocenter would be controlled by the remote C11 ste-
reocenter in a 1,9-relationship.
The key intermediate 3 was prepared from (13’R)-16[21] by
stereoselective construction of the skipped diene structure.
The three-carbon extension from the aldehyde 17, which was
obtained by SO3·pyridine oxidation, was realized by nucleo-
philic addition of the vinyl lithium E, resulting in formation of
18. The two hydroxy groups of 18 were simultaneously
acetylated to afford 19. A reagent combination of Pd0 and
KOAc isomerized the disubstituted olefin 19 into the
trisubstituted olefin 20 by p-allyl formation and site-selective
addition of acetate to the less-congested primary position.[22]
After saponification of 20, the more exposed C20 hydroxy
group of the resultant diol 21 was regioselectively capped with
a bulky TIPS group, and the remaining C5 hydroxy group of
22 was chlorinated to give 4. These two transformations
enabled selective activation of C5 over C20 for the p-allyl
Stille coupling reaction.[23] However, the resulting C6–C7
geometry[24] of 4 was partially isomerized under the standard
thermal conditions for coupling with A.[25] After screening of
additives to avoid this unwanted reaction, CuTC[26] was found
to significantly accelerate and selectively promote the p-allyl
Stille coupling reaction. When 4 was treated with A, CuTC,
and K2CO3 in the presence of catalytic [Pd(PPh3)4] in DMF,
À
the C C bond formation proceeded, even at 08C, to afford 3
The synthesis commenced with conversion of (R)-carvone
(5) into 11 by introduction of the four new stereocenters (C8,
C9, C11, and C13; Scheme 2). Treatment of 5 with TMSCl and
MeMgBr in the presence of catalytic FeCl3 regioselectively
produced the dienoxysilane 6.[15] Subsequent vinylogous
Mukaiyama aldol reaction of 6 by the action of BF3·OEt2
with no geometrical alteration. Hence, the requisite cis rela-
tionship between the radical donor (C-ring) and acceptor (A-
ring) was secured at this stage.
Most importantly, the O,Se-acetal structure tolerated
various nucleophilic and transition-metal reagents from 15
to 3, yet functioned as the radical-generating functional
group. Treatment of 3 with (TMS)3SiH and V-40 (F) in
[16]
and CH(OMe)3 attached the dimethyl acetal group at the
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14457 –14461