First total synthesis of (+)-pentandranoic acid A

Article abstract of DOI:10.1016/j.tetlet.2012.04.080

The first total synthesis of (+)-pentandranoic acid A (1) was accomplished in 14 steps, starting from alcohol 3. Our synthesis features several key transformations, such as an ozonolysis-aldol cyclization-dehydration ring contraction sequence and a selective 1,4-diol oxidation, and provides an efficient synthetic route to this rare clerodane diterpenoid.

Full text of DOI:10.1016/j.tetlet.2012.04.080

Tetrahedron Letters 53 (2012) 3329–3332
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First total synthesis of (+)-pentandranoic acid A
⇑
Li Ren , Edward Piers
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of (+)-pentandranoic acid A (1) was accomplished in 14 steps, starting from
alcohol 3. Our synthesis features several key transformations, such as an ozonolysis-aldol cyclization-
dehydration ring contraction sequence and a selective 1,4-diol oxidation, and provides an efficient
synthetic route to this rare clerodane diterpenoid.
Received 9 April 2012
Revised 13 April 2012
Accepted 17 April 2012
Available online 24 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diterpenoid synthesis
Ring contraction
Selective diol oxidation
The isolation of (+)-pentandranoic acid A (1), a structurally no-
vel diterpenoid from the leaf extracts of the Callicarpa pentandra,
was first reported by Goh et al. in 2000.1 Plants of the genus
Callicarpa are known to have medicinal properties for the treat-
ment of rheumatism, stomach disorders, and intestinal troubles.2
The Malaysian species Callicarpa pentandra Roxb. (Verbenaceae),
as a liquid, is used for the treatment of the common cold in tradi-
tional Malaysian folk medicine.3 On the basis of a combination of
NMR and mass spectrometry studies, the structure of (+)-pentan-
dranoic acid A was proposed as 1 with the relative and absolute
stereochemistry shown (Fig. 1).1
The natural product is a trans-clerodane diterpenoid (2) with a
rare contraction of ring A. In addition to the novel scaffold, (+)-pent-
andranoic acid A (1) features four contiguous chiral centers, two of
which are quaternary, as well as several sensitive functionalities,
which can pose additional synthetic challenges. Its intriguing struc-
ture and important biological activities make (+)-pentandranoic
acid A (1) an attractive target. The Piers laboratory previously
developed a general synthetic route to the enantiomerically pure
cis- and trans-clerodane family of diterpenoids via annulation
sequences using bifunctional trialkylstannylcopper reagents.4
Although this strategy was successfully applied to clerodanes with
a 6,6-fused decalin framework (2), its utility in the construction of a
5,6-fused hydrindane has yet to be demonstrated. In this Letter, we
wish to report the application of this methodology to the hydrin-
dane scaffold and the first total synthesis of (+)-pentandranoic acid
A (1).
planning at the onset of our campaign. For example, the C-2 formyl
group can easily be oxidized or reduced under a variety of condi-
tions and would limit the choice of synthetic transformations if
introduced early. Furthermore, the unique enone moiety, a poten-
tial Michael acceptor, is a cause for greater concern (vide infra). In
addition to its perceived reactivity towards nucleophiles, the al-
kene can readily isomerize to a thermodynamically more favorable
isomer (between C-13 and C-14) in the presence of a base. Based
on these considerations, it was decided that the enone functional-
ity should be unveiled late in the synthesis.
It was envisioned that the enone precursor, allylic alcohol A,
could be prepared from addition of an appropriately functionalized
vinyl anion, such as B, to aldehyde C (Scheme 1). The C-2 formyl
group in (+)-pentandranoic acid A (1) was masked as a protected
alcohol at this stage which could be revealed at the end of the syn-
thesis. Construction of the trans-fused hydrindane framework was
envisioned to arise from ring contraction of a suitably decorated
decalin such as D. A series of manipulations, starting with oxida-
tive cleavage of the double bond between C-3 and C-4, followed
by an intramolecular aldol cyclization and dehydration were
planned for this key transformation.
O
14
13
11
8
11
COOH
H
H
1
1
17
17
16
2
3
2
10
OHC
3
8
A
The presence of sensitive functional groups, such as an aldehyde
and an enone in (+)-pentandranoic acid A (1), required careful
4
4
18
6
6
19
1
19
18
2
⇑
Corresponding author.
E-mail address: li.ren@arraybiopharma.com (L. Ren).
Figure 1. (+)-Pentandranoic acid
clerodane diterpenoids (2).
A (1) and general carbon skeleton of trans-
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.080

3330
L. Ren, E. Piers / Tetrahedron Letters 53 (2012) 3329–3332
O
OH
OH
OTBS
b, c
H
H
OR1
11
11
COOH
R2O
a
H
H
2
2
OHC
3
4
1
A
OTBS
OTBS
O
M
H
H
B
d
H
OR1
OHC
EEO
O
OR3
17
O
12
11
10
11
8
7
ring
contraction
H
1
O
2
3
OTBS
g, h
2
8
H
H
4
H
R2O
6
e, f
C
D
EEO
18
9
Scheme 1. Retrosynthetic analysis of (+)-pentandranoic acid A.
10
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole, DCM, 99%; (b) O3, Sudan
II, ꢀ78 °C, DCM/MeOH (9:1); (c) pyridine, Me2S, 0 °C; (d) neutral alumina, 4A
molecular sieves, 52%; (e) DIBAL, ꢀ78 °C, ether, 92%; (f) vinyl ethyl ether, PPTS,
DCM, 99%; (g) TBAF, THF, 98%; (h) Dess–Martin periodinane, DCM, 95%.
The synthesis of (+)-pentandranoic acid A (1) began with the
known alcohol 3, an advanced intermediate used in the total syn-
thesis of (ꢀ)-kolavenol and (ꢀ)-agelasine B4a (Scheme 3). Protec-
tion of alcohol 3 with TBSCl afforded the corresponding silyl
ether 4 in quantitative yield. Next, oxidation of the alkene was
evaluated. Treatment of alkene 4 with OsO4 under a variety of con-
ditions gave the desired diol 5 in low yield (20–30%), along with
decomposition of the starting material. In some cases, hydroxyl ke-
tone 6 was isolated as a minor product (Scheme 2). The formation
of ketone byproduct was observed in the dihydroxylation of steri-
cally hindered olefins.5 Direct cleavage of alkene 4 using RuCl3/
on the side chain. The requisite C-12 aldehyde 10 was obtained via
a two-step procedure, first removal of the TBS protecting group
with TBAF, followed by subsequent oxidation using Dess–Martin
periodinane.11
Originally, we planned to attach the side chain via a NiCl2/CrCl2
mediated Nozaki–Kishi reaction. (Scheme 4).12 Vinyl iodide 12
with a pendant methyl ester, which could be converted to the de-
sired acid by hydrolysis, was deemed to be a suitable coupling
partner. The feasibility of this strategy was tested with a model
compound 11. The coupling reaction proceeded reasonably well
and gave alcohol 13 in moderate yield (51%), which was oxidized
to enone 14 in 95% yield. Unfortunately, attempts to hydrolyze
the methyl ester of either 13 or 14 under a variety of conditions
failed, due to the various decomposition pathways shown in
Scheme 4. For example, saponification of 14 in the presence of a
base gave the Michael adduct (H) as predicted. Although this can
be avoided with alcohol 13, byproducts stemming from isomeriza-
tion (E), alkene migration (F) and lactonization (G) became pre-
dominate. Furthermore, vinyl iodides with more labile acid
protecting groups such as TBS or OCH2CCl3, failed to participate
in the Nozaki–Kishi coupling. These observations showcased the
delicate nature of this particular side chain.
6
NaIO4 was also attempted. Unfortunately, the desired ketoalde-
hyde 7 was obtained in low yield (20%) together with 6 as a
byproduct. These initial results highlighted the challenges associ-
ated with our plan to use the alkene as a synthetic handle for ring
contraction.
Ozonolysis was reported as an effective protocol for alkenes oxi-
dation in congested systems.7 To our delight, under the conditions
reported by Ward,8 the desired ketoaldehyde 7 was obtained effi-
ciently (Scheme 3). The unstable intermediate was immediately
subjected to an aldol condensation/dehydration sequence follow-
ing conditions reported by Corey and Tanabe to give aldehyde 8
in 52% overall yield.9 With the hydrindane core in hand, attaching
the enone side chain became the next focus. Towards this end, the
C-2 aldehyde was first reduced with DIBAL and the resulting allylic
alcohol was protected with an ethoxyethyl ether to afford 9 as an
inconsequential 1:1 mixture of diastereomers which were insepa-
rable by column chromatography.10 The judicious choice of the
ethoxyethyl ether as a C-3 hydroxyl protecting group was based
on considerations that it could be removed with mild acids, condi-
tions most likely to be compatible with the sensitive enone moiety
Since an ester was not a viable precursor for the desired acid in
this case, other alternatives were explored. Vinyl iodide 15 with a
R =
I
12
OTBS
OTBS
OTBS
CO2Me
b
R
H
R
CO2Me
H
H
H
R
CO2Me
"OsO4"
a
OH
13
O
11
O
+
14
HO
HO
O
HO
d
e
c
4
5
6
f
20-30%
OTBS
OTBS
O
H
H
OMe
CO2H
R
R
CO2H
R
CO2H
H
"RuCl3/NaIO4"
R
O
O
O
OH
O
O
4
7
E
F
H
G
20 %
Scheme 4. Reagents and conditions: (a) NiCl2, CrCl2, DMF, 51%; (b) TPAP, NMO,
Scheme 2. Initial ring contraction attempts.
DCM, 95%; (c) K2CO3, MeOH; (d) Ba(OH)2; MeOH; (e) NaSMe, DMPU; (f) BBr3, DCM.

L. Ren, E. Piers / Tetrahedron Letters 53 (2012) 3329–3332
3331
OH
13
O
14
12
I
OTBDPS
b
11
H
15
H
H
10
H
15
OTBDPS
EEO
EEO
a
16
OH
O
OH
O
OH
H
d, e
c
EEO
EEO
17
18
O
COOH
H
COOH
H
f, g
O
EEO
H
1
19
Scheme 5. Reagents and conditions: (a) t-BuLi, 15, ꢀ78 to ꢀ40 °C, then 10, ether, 94%; (b) TBAF, THF, 99%; (c) MnO2, ether, 65%; (d) Dess–Martin periodinane, DCM, 92%; (e)
NaClO2, NaH2PO4, t-BuOH, H2O, 2-methyl-2-butene, 90%; (f) PPTS, MeOH, 95%; (g) Dess–Martin periodinane, DCM, 99%.
TBDPS protected homoallylic alcohol eventually served as the
appropriate precursor to the side chain of (+)-pentandranoic acid
A (1) (Scheme 5). Addition of the vinyl lithium reagent derived
from metal-halide exchange between 15 and tert-butyl lithium
gave 16 as a 1:1 mixture of diastereomers at C-12 in 94% yield.13
Although alcohol 16 was produced in a non-selective manner, all
isomers were used in the synthesis of (+)-pentandranoic acid A
(1) as the newly generated chiral center was removed in the sub-
sequent oxidation step.
At this stage, the remaining transformations to complete the
side chain included oxidizing the secondary alcohol at C-12 as well
as deprotecting and converting the primary alcohol at C-15 to the
corresponding acid. Again, these seemingly trivial transformations
turned out be quite challenging in the context of our target. Fist,
the order of these two events was critical for success. It was deter-
mined that the C-12 hydroxyl group should be oxidized first to cir-
cumvent formation of the five-membered ring lactone byproduct
such as G during the conversion of the C-15 alcohol to the corre-
sponding acid. Thus, an effective protocol for converting 16 to
the hydroxyl enone 18 was needed. The most straight forward
way to accomplish this would be oxidation followed by silyl depro-
tection. Although the oxidation step occurred in high yield, re-
moval of the TBDPS protecting group under standard conditions
(TBAF, HF/pyridine, bases) led to decomposition, likely due to the
sensitivity of the enone moiety.
ing group was removed with a mild acid (PPTS)10 and the resulting
alcohol was oxidized to the aldehyde using Dess–Martin period-
inane to afford (+)-pentandranoic acid A (1).
The 1H NMR and 13C NMR spectra of the synthetic (+)-pentan-
dranoic acid A (1) were identical with those of the natural product.
Furthermore, the optical rotation value of our synthetic material
(½a 2D1
ꢁ
+47.2, c 0.5, CHCl3) agreed very well with the reported value
+44.9, c 0.86, CHCl3). Thus, our syn-
of the natural substance (½a D
ꢁ
thesis has confirmed the correct assignment of both the relative
and absolute configuration of (+)-pentandranoic acid A (1).
In summary, the first total synthesis of (+)-pentandranoic acid A
(1) was accomplished in 14 steps, starting from alcohol 3. This
synthetic procedure, which employs an ozonolysis-aldol cycliza-
tion-dehydration ring contraction sequence and a selective 1,4-diol
oxidation as key steps, offers a concise and efficient synthetic route
to this rare clerodane diterpenoid.
Acknowledgments
The author thanks NSERC Canada for funding. The author also
thanks Drs. Erick Hicken, Kevin Hunt and Weidong Liu for critical
review of the manuscript and helpful suggestions.
References and notes
Our backup strategy was to remove the silyl protecting group
first and then selectively oxidize the secondary C-12 hydroxyl
group in the presence of the primary C-15 hydroxyl group (Scheme
5). It is recognized that the C-12 hydroxyl group is an allylic alco-
hol and can be oxidized preferentially with a unique set of oxi-
dants.14 In practice, alcohol 16 was first treated with TBAF to
give 17 in quantitative yield. To our delight, stirring a solution of
diol 17 in ether with MnO2 at room temperature overnight affor-
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Dess–Martin periodinane, oxidized the primary hydroxyl group
(C-15) first which inevitably led to the formation of lactol and lac-
tone as major byproducts. With 18 in hand, the remaining steps of
the synthesis proceeded smoothly. Oxidation of the primary alco-
hol to the carboxylic acid was accomplished by sequential treat-
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ment with Dess–Martin periodinane and NaClO2 to produce
acid 19 in 83% yield over two steps. The ethoxyethyl ether protect-

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