3
424
P.-L. Boudreault et al. / Tetrahedron Letters 56 (2015) 3423–3427
1
3
are implicated in numerous clinical indications including cancer,
O
OH
O
1
4
15
Alzheimer’s disease,
cardiovascular disease,
immune and
OH
C3H7
H
O
1
6
17
18
Butyric anhydride
Et3N, DMAP
O
C3H7
C3H7
inflammatory diseases, metabolic disorders, stroke, and ath-
H
1
9
erosclerosis. While relatively little is known about the PKC iso-
form selectivities of the PKC active diterpenes, some agents have
shown promising PKC selective activity and therapeutic potential.
Gnidimacrin (NSC 252940),20 for example, is a member of the
daphnane family and shows potent antitumor activity against
murine tumors in vivo and several human tumor cell lines
in vitro. Importantly, gnidimacrin is proposed to operate by acti-
vation of PKC bII, arresting the cell cycle at the G1 phase through
inhibition of cyclin-dependent kinase-2 (cdk2) activity in human
K562 leukemia cells.
OH
CH2Cl2
OH
82%
O
O
O HO
OH
1
O HO
2
0
20
2
TrCl, Pyridine
5
0°C, 12h
72%
2
1
O
OH
O
OH
C3H
O
7
O
C3H7
Butyric Acid
EDCI, DMAP
H
H
OH
Et3N, CH2Cl2
OH
Studies on the modes of action and therapeutic potential of tigli-
ane and daphnane diterpenes have been hampered by their scarce
and often variable supply, high cost (generally >$50/mg), difficulty
in accessing sources due to geopolitical issues, and challenges asso-
ciated with their synthesis and chemical modification. To date,
O HO
81%
OTrt
O HO
OTrt
.01% HClO4
3
4
0
MeOH, 85%
phorbol2 is the only tigliane and resiniferatoxin is the only
2
23
O
O
O
O
O
C3H7
H
O
daphnane for which total syntheses have been reported. A semi-
C3H7
H
O
O
C3H7
C3H7
2
4
synthesis of prostratin from phorbol has also been reported,
enabling synthetic access to more potent analogs now being stud-
TBDPSCl
2
5
OH
Pyr., DMAP
OH
OH
ied as latency reversing agents in strategies to eradicate HIV. In
011, we also reported a study directed at producing an advanced
daphnane precursor that could be used to synthetically access most
members of the large daphnane diterpene family. This ‘gateway
strategy’ resulted in the synthesis of a general precursor to poten-
tially >70 daphnanes and led to the synthesis of des-epoxy-yuan-
6
9%
O HO
2
O HO
OTBDPS
6
5
Scheme 2. Synthesis of PTBu 3, C20-trityl PDBu 4, and C20-TBDPS PDBu 6.
4
huapin. This study also led to the identification of PKC as a target
for yuanhuapin and the additional finding that des-epoxy-yuanhua-
converted to PDBu (5) by a standard three-step procedure
(Scheme 2). Direct epoxidation of PDBu or a C20 protected deriva-
tive led to b-face epoxidation, consistent with our yuanhuapin
(daphnane) study and the earlier report of Hecker and Schmidt
on the tigliane phorbol triacetate (Scheme 1). This is consistent
with the phorbol B-ring assuming a conformation with a fold
between C4 and C8 and thus a more accessible convex b-face. In
cases where a direct epoxidation gives the undesired stereoisomer,
one can often produce the desired epoxide isomer by using a two-
step procedure in which a bromine is delivered to the more acces-
sible substrate face to form a bromonium ion which with water
would give a halohydrin whose closure in base would give the
i
pin is a potent PKC modulator with a K of 1.6 nM.
4
In the course of our studies on yuanhuapin, we found that epox-
idation of des-epoxy-yuanhuapin resulted in exclusive formation of
C6,C7-epi-yuanhuapin. In other words, epoxidation of the C6,C7
double bond occurred exclusively on the b-face. Notwithstanding
the presence of the a-epoxide in most daphnanes, this epoxidation
problem and stereochemistry have received little attention. Tyler
and Howden have reported that under conditions similar to the
ones used with des-epoxy-yuanhuapin to make the b-epoxide,
a-epoxide. This
stands in contrast to the yuanhuapin study and an earlier report
2
6
phorbol 12,13-dibenzoate was converted to the
4
28
complementary epoxide stereochemistry. However, when PDBu
by Hecker and Schmidt that epoxidation of phorbol 12,13,20-triac-
2
5 is treated with Br in a mixture of acetone and water (1:1), it
undergoes preferential oxidation to the C20 aldehyde with only a
small amount of the desired bromohydrin (<5%) being formed.
2
7
etate proceeds on the b-face of the C6,C7 double bond (Scheme 1).
Given that over 90 members of the daphnane family possess an
a
-
epoxide and that epoxidation would preferably be done as a final
synthetic step when most delicate functionalities would be in place,
we sought, as described herein, to determine the intrinsic facial
selectivity for direct epoxidations of such complex targets and to
develop mild strategies to selectively access either epoxide as
needed for synthesis and structure-function studies.
2
The same results were observed using NBS instead of Br on the
same substrate. It was expected that the C20 butyric acid ester 2
could prevent this oxidation. However, the reaction with PTBu 2
and 1.3 equiv of NBS was very slow and again when heated led
to aldehyde formation presumably by hydrolysis of the primary
ester and subsequent allylic alcohol oxidation.
To establish a reliable protocol for stereoselective epoxidation
of tiglianes and daphnanes, the readily available phorbol 12,13-
dibutyrate (PDBu, 5) was selected as our test system. Phorbol (1)
itself was obtained from abundantly available croton oil by first
hydrolyzing various naturally occurring ester derivatives in the
oil and extracting the resultant free phorbol in 1.6% yield after flash
chromatography (see Supporting information). Phorbol was then
Another useful reagent for bromonium ion formation is N-bro-
2
9
moacetamide (NBA). NBA has been used in steroid syntheses to
produce epoxides complementary in stereochemistry to those
3
0
obtained with peroxyacids such as mCPBA. In our case, the same
conditions (NBA in dioxane/water and a catalytic amount of HClO
4
)
led again to the C20 aldehyde and many other unidentified prod-
ucts, likely resulting from acid-catalyzed opening of the cyclopro-
pane (D) ring. In 2002, White reported the formation of
bromohydrins from silyl ether protected allylic alcohols using
NBS/H O in THF. This procedure proceeds without deprotection
2
OAc
8
OAc
8
31
OAc
OAc
and oxidation of the alcohol. To test this method, we prepared
the C20-TBDPS PDBu 6 from phorbol in 4 steps (Scheme 2). Unfor-
tunately, the reported conditions also led to oxidation of 6 to the
C20 aldehyde, proceeding in 6 h at 0 °C and in nearly quantitative
yield. The same results were observed with a trityl protecting
group (Table 1).
H
H
mCPBA
4
OH
4
OH
O HO
O HO
O
OAc
OAc
Scheme 1. Hecker’s b-face epoxidation of phorbol-triacetate.27