Angular hydroxymethyl directed intramolecular Diels-Alder approach for the stereo- and regioselective synthesis of pimaraditerpenes

Article abstract of DOI:10.1016/j.tetlet.2004.08.161

The stereo- and regioselective synthetic route to pimaraditerpenes, employing an angular hydroxymethyl directed intramolecular Diels-Alder reaction of the decaline intermediate, has been developed. This synthetic approach allows prompt access to both natu

Full text of DOI:10.1016/j.tetlet.2004.08.161

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 8053–8056
Angular hydroxymethyl directed intramolecular Diels–Alder
approach for the stereo- and regioselective
synthesis of pimaraditerpenes
Nam Song Choi,a Jae-Kyung Jungb and Young-Ger Suha,*
aResearch Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong,
Kwanak-Gu, Seoul 151-742, Korea
bCollege of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea
Received 21 June 2004; revised 4 August 2004; accepted 30 August 2004
Available online 16 September 2004
Abstract—The stereo- and regioselective synthetic route to pimaraditerpenes, employing an angular hydroxymethyl directed
intramolecular Diels–Alder reaction of the decaline intermediate, has been developed. This synthetic approach allows prompt
access to both natural pimaraditerpenes and the unnatural regioisomers, which would be potentially new anti-inflammatory
pimaraditerpenes.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently, pimarane diterpenoidshave been attracting
13
synthetic and medicinal chemists because a variety of
new biological activitiesaswell astsructural diveristy
of these family have continuously been reported.1 In
particular, acanthoic acid (1), isolated from indigenous
Korean medicinal plants, Acanthopanax Koreanum
Nakai2 and its structural isomers such as 4 and 5 have
merged asone of the important pimarane diterpenoids
due to their anti-inflammatory related biological activi-
ties.3 Both natural and unnatural regioisomers revealed
an excellent suppressive activity of interleukin-1 (IL-1)
and tumor necrosis factor-a (TNF-a),3e,4 which are
major proinflammatory cytokines. We have also repor-
ted that the natural and synthetic pimarane diterpenoids
have cyclooxygenase-2 (COX-2) and nitric oxide (NO)
inhibitory activitiesaswell asanti-inflammatory
effect.3c,g
1
4
1
4
14
8
16
10
10
8
R
R
4 R = CO2H
5 R = Me
1 R = CO2H : Acanthoic acid
2 R = Me : (-)-Pimara-9(11),15-diene
3 R = CH2OH : (-)-Pimara-9(11),15-dien-19-ol
Figure 1.
securing substantial amount of pimarane diterpenoids
from natural sources, limited a rapid access to the struc-
turally diverse pimarane diterpenoids. Thus, the inter-
esting structural features and the important biological
activitiesof both natural and unnatural pimarane
diterpenoids prompted us to initiate synthetic studies
5
toward thisfamily.
In addition to the interesting pharmacological profiles,
this family consists of structurally unique tricyclic sys-
temsincluding unuusal trans-relationship between C-8
hydrogen and C-10 methyl group ashsown in Figure
1. However, few synthetic procedures for them, except
In recent year, Theodorakisand co-workersreported the
elegant total synthesis of (À)-acanthoic acid (1) and the
structural isomer 43e,6 using an intermolecular Diels–
Alder reaction7 although their synthesis suffered from
moderate face selectivity (3 ꢀ 4:1) in Diels–Alder cyclo-
addition, resulting in difficulty for separation of diaste-
reomers. We have also reported the total syntheses of
isopimarol diterpene.8 We herein report our more recent
progress on the stereo- and regioselective syntheses of
Keywords: Pimaraditerpene; Anti-inflammation; Intramolecular Diels–
Alder reaction.
*
Corresponding author. Tel.: +82 2 880 7875; fax: +82 2 888 0649;
e-mail: ygsuh@snu.ac.kr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.161

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N. S. Choi et al. / Tetrahedron Letters 45 (2004) 8053–8056
alcohol 9 in an excellent yield. The decalone 10 having
O
R1
R2
R3
R4
fully functionalized AB-ring skeleton of pimaradiene
wasconveniently prepared from the intermediate 9 in
94% overall yield via Barton–McCombie radical deoxy-
genation procedure.10
TBSO
OMe
HO
13
14
O
2
5
10
O
H
H
R1=Me,R 2=CO2R,R 3=R4=H
R1=R2=H,R 3=Me,R 4=CO2R
For the introduction of the diene moiety in B-ring
system, the direct vinyl addition to C-9 carbonyl of the
ketone 10 wasinitially attempted using vinyl Grignard
reagent. However, the desired vinyl addition did not
occur, presumably due to the steric hindrance. Thus,
we adapted the smaller alkylating reagent (e.g., ethynyl
Grignard reagent) in consideration of the steric environ-
ment of C-9 in the condensed structure of 10. In the
event, the bicyclic ketone 10 underwent facile Grignard
addition of ethynyl magnesium bromide to afford the
desired alkylation product, which was directly subjected
to partial hydrogenation (Pd/BaSO4, quinoline, H2) to
give the vinyl carbinol 11 in 80% overall yield. Finally,
the triene 7 asan intramolecular Diels–Alder precursor
wasobtained from the vinyl carbinol 11 via three-step
sequence (dehydration of vinyl carbinol 11 with
CuSO4,11 TBS deprotection with TBAF, and esterifica-
tion of the resulting alcohol with methacryloyl chloride).
6a
6b
7
8
Scheme 1. Retrosynthetic analysis.
pimarane diterpenoids, which was focused on the evalu-
ation of feasibility of our intramolecular strategy as
illustrated in Scheme 1.
In contemplating the synthesis of pimaradiene 2 and its
isomer 5, it wasenvisioned that C-ring with the correct
stereochemistries of C-8 and C-13/C-14 quaternary
carbon center9 could be constructed by the angular
hydroxymethyl directed Diels–Alder cycloaddition from
7 and the subsequent hydrolysis of the resulting adduct.
Such an approach would take advantage of the C-10
hydroxymethyl group to control the face selectivity of
the pivotal Diels–Alder reaction, resulting in perfect
stereocontrol of the quaternary carbon unit in C-ring.
With regard to the intramolecular Diels–Alder reaction,
we have already reported the practical synthesis of the
hydroxymethylated decalones,8c of which angular
hydroxymethyl group is stand point in our current syn-
thetic strategy. The requisite precursor 7 would be effi-
ciently prepared from the known bicyclic decalone 8.8c
With the requisite precursor 7 in hand, we intensively
investigated the angular hydroxymethyl directed Diels–
Alder cycloaddition. The results are summarized in
Table 1. The initial intramolecular Diels–Alder reaction
of the triene 7 in refluxing benzene produced a single
diastereomer 13,12 with a quite low yield mainly due to
slow reaction (entry 1). However, in addition to the effi-
cient C-ring formation, the intramolecular cycloaddition
provided a perfect stereoselectivity for two new stereo-
genic centers, compared to the moderate selectivity of
intermolecular version.6 Obviously, the perfect stereo-
control arises from endo-occupation of the tether7 as
well as a-face selectivity induced by the geometry of
the tether connected angular carbon moiety, which rules
out the steric interference of angular methyl in the inter-
molecular cycloaddition. Interestingly, the regioselectiv-
ity and the yield were quite dependent on the reaction
temperature although the unnatural regioisomer was
generally favored. The reaction in toluene in the sealed
Bearing in mind the intramolecular Diels–Alder
strategy, our studies toward the syntheses of pimara-
9(11),15-diene (2) and the regioisomer
5
were
commenced by preparation of the requisite Diels–Alder
precursor 7 from the hydroxymethylated decalone 8.
The introduction of the methyl substituent at C-4 and
the requisite stereochemistry of C-5 were executed via
reductive alkylation process, as shown in Scheme 2.
Treatment of the a,b-unsaturated ketone 8 with lithium
in liquid ammonia followed by alkylation with MeI gave
the corresponding alkylation product, which was
directly subjected to NaBH4 reduction to afford the
Table 1. Intramolecular Diels–Alder reaction of the triene 7
TBSO
OMe
TBSO
OMe
TBSO
O
O
c, d
a, b
O
H
O
O
O
O
HO
O
H
H
10
9
8
Diels-Alder
conditions
+
O
H
H
TBSO
OH
O
H
H
7
13
12
e, f
g - i
a
Entry ConditionsTime (h) (%Y)ields
Ratio (12:13)b
H
H
11
7
1
2
3
4
Benzene, 80°C
72
<10
72
0:1
Toluene, 110°C 72
1:3.5
1:10
1.2:1
Scheme 2. Reagentsand condition:s (a) Li/NH
(l), MeI, t-BuOH,
3
Toluene, 110°Cc 48
78
67
À78°C, 71%; (b) NaBH4, EtOH, 0°C, 99%; (c) NaH, CS2, HMPA,
imidazole, reflux, then MeI; (d) n-Bu3SnH, AIBN, xylene, reflux, 94%
from 9; (e) CHCMgBr, THF, 0°C, 81%; (f) Pd/BaSO4, H2, quinoline,
MeOH, 99%; (g) CuSO4, xylene, reflux, 75%; (h) TBAF, THF, 98%; (i)
methacryloyl chloride, Et3N, DMAP, THF, 0°C, 84%.
Xylene, 145°C
24
a Isolated yields after column chromatography.
b Measured by 400MHz 1H NMR.
c Sealed tube wasused.

N. S. Choi et al. / Tetrahedron Letters 45 (2004) 8053–8056
8055
attests to the significant synthetic utility of the angular
hydroxymethyl directed cycloaddition approach in
termsof the rapid accesto a variety of pimaraditerp-
enes. Considering necessity of incorporation and
removal of the regiocontrolling group (e.g., –SPh) in
the diene for the intermolecular cycloaddition, this
approach seems to be advantageous in synthetic effi-
ciency in spite of low regioselectivity for natural pimara-
diterpenes. As a synthetic application, the synthesis of
the isopimaradiene 5 has also been accomplished in
19% overall yield through 13 linear steps from the
known decalone 8. At present, improvement of the
regioselectivity of the key intramolecular Diels–Alder
reaction and development of novel anti-inflammatory
pimaraditerpenesby employing thisapproach are in
good progress and the successful results will be pub-
lished in due courses.
O
O
HO
HO
CO2Me
a
b,c
H
H
H
H
H
H
13
6b
14
TsO
d
e
H
H
H
H
15
5
Scheme 3. Reagentsand condition:s (a) NaOMe, MeOH, 95%; (b)
DIBAL, toluene, À78°C; (c) PPh3+CH3BrÀ, NaH, THF, 81% from 13;
(d) TsCl, pyridine, 100%; (e) NaI, Zn, HMPA, 110°C, 70%.
tube gave the optimum result (entry 3). Considering that
the type 2 intramolecular Diels–Alder reaction for the
tetherscontaining three to five atomsproduces
the meta-regioisomer7b such as 13, it isnoticeable that
the cycloaddition of 7 in xylene provided the reversed
regioselectivity (entry 4) favoring the para-regioisomer,
although the selectivity was not significant. Moreover,
the intermolecular cycloaddition of the diene 7 isknown
to produce only meta-regioisomer.6 Employing Lewis
acid such as Me2AlCl wasnot helpful for the improve-
ment of yield and regioselectivity. The general prefer-
ence of the unnatural regioisomer 13 islikely due to
the favorable orientation of the dienophile for 13 in
the type 2 intramolecular Diels–Alder reaction.7b,13
Acknowledgements
This research work was supported by the grant from
Center for Bioactive Molecular Hybrids, Yonsei
University.
References and notes
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The regioselectivity for the natural pimaraditerpene 2 is
expected being improved by a tether elongation as
reported in the precedents.7b However, at thistsage,
we were inspired by the recent report that the methyl
ester of the unnatural pimaraditepene 4, inhibitsup to
99% of TNF-a production at noncytotoxic concentra-
tion3e coupled with the perfect stereo- and regioselectiv-
ity of the intramolecular cycloaddition for 5, which is
not synthetically accessible from the natural product.
Thus, we decided to pursue the completion of total syn-
thesis of the isopimaradiene 5 in view of the medicinal
chemistry standpoint as shown in Scheme 3.
2. Kim, Y.-H.; Chung, B. S.; Sankawa, U. J. Nat. Prod.
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The lactone 13 wasopened with NaOMe to produce the
hydroxy ester 6b, which wastransformed into the corre-
sponding olefin 14 by DIBAL reduction and subsequent
Wittig olefination in 81% overall yield. Finally, tosyl-
ation of the primary alcohol 14, followed by reductive
cleavage of the resulting tosylate 15 using NaI and Zn,
provided the isopimaradiene 5 in 70% yield.14
In summary, we have developed an intramolecular
Diels–Alder route for the stereo- and regioselective syn-
thesis of pimaraditerpenes of structural diversity. As far
as we understand, it is the first example for the type
2 intramolecular Diels–Alder reaction of the bicyclic
system, in which the dienophile is directly tethered.
Although the regioselectivity for the natural pimaradi-
ene wasnot high aswe anticipated, the excellent stereo-
control of the C-8 and C-13/C-14 stereogenic centers as
well as the selective construction of pimaraditerpene
skeletons for both natural and unnatural regioisomers
4. For recent reviewsdealing with TNF- a and IL-1, see: (a)
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N. S. Choi et al. / Tetrahedron Letters 45 (2004) 8053–8056
5. Thiswork istaken in part from the Ph.D. Thesisof N. S.
Choi, Seoul National University, 1995.
12. The structure of the cycloadduct 13 wasconfirmed by an
extensive NMR studies including COSY, NOESY,
HMBC, and HMQC. 1H NMR (400MHz, CDCl3) of
the isomer 12: d 5.68–5.62 (m, 1H), 4.56 (d, 1H,
J = 11.2Hz), 3.52 (d, 1H, J = 11.2Hz), 2.20–1.16 (m,
16H), 1.15 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H). 1H NMR
(400MHz, CDCl3) of the isomer 13: d 5.61–5.55 (m, 1H),
4.71 (d, 1H, J = 11.2Hz), 3.60 (d, 1H, J = 11.2Hz), 2.14–
1.16 (m, 16H), 1.19 (s, 3H), 0.89 (s, 3H), 0.88 (s, 3H).
13. Taber, D. F. Intramolecular Diels–Alder and Alder Ene
Reactions; Springer: New York, 1984.
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Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vas-
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Int. Ed. 2001, 40, 820; (c) Fallis, A. G. Acc. Chem. Res.
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Type 2 intramolecular Diels–Alder reaction
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favorable less favorable
14. Spectral data of isopimaradiene 5. 1H NMR (CDCl3,
400MHz): d 5.91 (dd, 1H, J = 11.2, 16.8Hz), 5.45 (m, 1H),
5.06–4.92 (m, 2H), 2.28–1.08 (m, 16H), 1.03 (s, 3H), 0.98
(s, 3H), 0.96 (s, 3H), 0.90 (m, 3H). IR (CHCl3): 2960, 1460,
1375, 998, 910cmÀ1. LRMS (EI) m/z: 272 (M+). HRMS
(EI) calcd for C20H32 (M+) 272.2504, found 272.2495.