Synthesis of 3-oxaterpenoids and its application in the total synthesis of (±)-moluccanic acid methyl ester

Full text of DOI:10.1002/anie.201205981

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Chemie
DOI: 10.1002/anie.201205981
Synthetic Methods
Synthesis of 3-Oxaterpenoids and Its Application in the Total Synthesis
of (Æ)-Moluccanic Acid Methyl Ester**
Bin Li, Yin-Chang Lai, Yujun Zhao, Yiu-Hang Wong, Zhi-Liang Shen, and Teck-Peng Loh*
3-Oxaterpenoids represent an important class of plant-based
natural products and drugs, are oxidative metabolites of
terpenoids,[1] and exhibit interesting biological activities and
pharmaceutical potentials (Figure 1).[2–4] For example, salvi-
Scheme 1. Proposed mechanism for Prins reaction initiated polyene
cyclization.
3-oxaterpenoids in a straightforward manner (Scheme 1).[9]
We envisaged that a Prins reaction, the classic method to form
a THP ring,[10] might serve to initiate the cascade cyclization
to provide the anticipated 3-oxaterpenoids.
To test our hypothesis, we focused on an intermolecular
reaction between (E)-3-methyl-6-arylhex-3-en-1-ol (1a) and
benzaldehyde, mediated by different Lewis acids (Table 1).
Upon extensive investigtion, InBr3 and CH2Cl2 were found to
be the optimal catalyst and solvent, respectively, for the
Figure 1. Selected examples of 3-oxaterpenoids.
norin A (A)[2] is a selective k-opioid-receptor agonist, com-
pound B[3] is a mild toxin to brine shrimp, and compound C[4]
shows significant cytotoxic activity. Captivated by the intri-
cate polycyclic structure and diverse bioactivities of 3-
oxaterpenoids, and inspired by Natureꢀs uncanny workman-
ship in constructing them, we were very interested in the
development of efficient methods to complement the biosyn-
thesis. Herein, we report the preparation of 3-oxaterpenoids
and its application in the total synthesis of (Æ)-moluccanic
acid methyl ester, through a cascade of Prins reaction and
polyene cyclization (Scheme 1).[5]
Table 1: InBr3-catalyzed Prins–polyene cyclization with different carbonyl
substrates.[a,b]
Although methods to construct terpenoid skeletons are
well established,[6,7] there is no strategy to access 3-oxaterpe-
noids directly. As part of our ongoing efforts to develop
intermolecular polyene cyclization,[8] we hypothesized that
a modified intermolecular polyene cyclization might furnish
[*] Prof. T. P. Loh
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
B. Li, Y. C. Lai, Y. H. Wong, Z. L. Shen, Prof. T. P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637616 (Singapore)
E-mail: teckpeng@ntu.edu.sg
Dr. Y. Zhao
Departments of Internal Medicine, University of Michigan
Ann Arbor, MI 48109 (USA)
[**] We thank Dr. Yong-Xin Li for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and the Singa-
pore Ministry of Education Academic Research Fund Tier 2
(MOE2010- T2-2-067 and MOE2011-T2-1-013) for financial support.
[a] Conditions: InBr3 (0.06 mmol) was added to a solution of 1a
(0.2 mmol), 2 (0.24 mmol), and 4 ꢀ molecular sieves (0.2 g) in
anhydrous CH2Cl2 (2 mL) at RT. [b] Yields of isolated products. [c] 2-X-
1,1-diethoxyethane was used instead of the corresponding aldehyde.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205981.
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Table 2: InBr3-catalyzed Prins–polyene cyclization to 3-oxaterpenoid.[a]
transfomation at room temperature.[11,12] Gratifyingly, the
corresponding product 3a was obtained in 88% yield as
a single isomer.
With the optimized conditions in hand, the scope of this
Prins reaction initiated polyene cyclization (Prins–polyene
cyclization) was subsequently investigated (Table 1). The
reaction is compatible with a wide range of carbonyl
substrates. Both aryl and heteroaryl aldehydes reacted
efficiently and gave the desired products (3a–c) in good to
high yields (71–88%). Similarly, a,b-unsaturated aldehydes
performed well to deliver 3-oxaterpenoids 3d and 3e in 87%
and 90% yields, respectively. In addition, aliphatic aldehydes
also proved to be suitable substrates for the transformation
and led to the desired products (3 f and 3g) in excellent yields.
Sterically demanding aliphatic aldehydes did not suffer from
decreased reactivity and the desired products (3h and 3i)
were obtained in high yields (88% and 79%, respectively). In
the case of benzyloxyacetaldehyde, a functionalized aliphatic
aldehyde, the yield of product 3j was slightly lower (66%). It
is notable that 2-chloro-1,1-diethoxyethane and 2-bromo-1,1-
diethoxyethane are also reactive substrates, which afforded
3k and 3l, respectively, the alkyl halide moiety of which can
be readily functionalized. Although ketones are generally
considered to be mediocre substrates in Prins reactions,[13]
acetone and cyclohexanone are good substrates for this
cascade cyclization and provided 3m and 3o, respectively, in
high yields. When the optically pure aldehyde 2n was used for
this reaction (Scheme 2), a single diastereomer 3n was
obtained in good yield (74%), and its absolute stereochem-
istry was assigned based on single-crystal X-ray analysis.[17]
After identification of both aldehydes and ketones as
suitable substrates for the Prins–polyene cyclization, we
further investigated the reactivity of various homoallylic
alcohols toward benzaldehyde (Table 2). Regardless of the
presence of electron-donating (Table 2, entries 1–3) or elec-
tron-withdrawing (entry 4) groups on the phenyl ring, the
reaction provided the desired products in high yield (> 80%).
Satisfying results were also obtained when homoallylic
alcohols that were tethered to a furan (Table 2, entry 5) and
an indole moiety (entry 6) were used. The reaction of
[a] Conditions: see Table 1. [b] All yields are isolated yields. [c] 100 mol%
InBr3 was used in this reaction. The stereoselectivity of alkene is 3:1,
which is determined by 1H NMR.
substrate 1h, the terminating group of which is an internal
alkyne (Table 2, entry 7), gave product 4h, possessing
a unique cyclopentane ring fused to a THP ring, in 68%
yield.[14] Interestingly, secondary alcohol 1i (Table 2, entry 8)
reacted equally well and gave the desired product in 75%
yield as a single isomer.
Scheme 2. Prins–polyene cyclization with aldehyde 2n and single-
crystal X-ray structure of cyclization product 3n (thermal ellipsoids at
50% probability).
2
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In view of the cationic character of the Prins–polyene
cyclization and our previous studies on bio-inspired polyene
cyclization, we envisioned that tetracylic and pentacyclic
scaffolds might be accessible (Table 3).[8,15] To our delight,
when dienes that were tethered to arenes were used as
substrates, the tetracylic products (4j–4k) were obtained in
good yields (> 80%) as single isomers (Table 3, entries 1–3).
Figure 2. Single-crystal X-ray structure of 4j (thermal ellipsoids at 50%
Table 3: InBr3-catalyzed Prins–polyene cyclization to tetracyclic and
probability).
pentacyclic rings.[a]
progressed to apply the strategy in natural product synthesis.
The products of Prins–polyene cyclization share the 1,2-trans-
tetrahydronaphthalene scaffold, which is commonly found in
terpenoids, and have thus considerable value for the synthesis
of such compounds. For example, both the cyclization product
5 and (Æ)-moluccanic acid methyl ester (10) consist of
a highly functionalized 1,2-trans-tetrahydronaphthalene core
(Scheme 3). We envisioned that compound 10 can be
synthesized from 5 through suitable manipulation of the
(chloromethyl)pyran moiety of the latter. Firstly, chloroace-
taldehyde dimethyl acetal and 1c underwent Prins–polyene
cyclization to afford key intermediate 5 in 64% yield. The
cyclized product 5 was treated with sodium hydride to give the
E2 elimination product, which was then subjected to a solution
of HBr in acetone to afford bromo-substituted ketone 6 in
55% yield. The installation of a terminal alkene group on 6
was not possible through a Wittig reaction, however, this
problem was solved by employing a Tebbe reaction, and
olefination product 7 was thus obtained in 71% yield.[16]
[a] Conditions: see Table 1. [b] Yields of isolated products.
The relative stereochemistry of 4j was determined by single-
crystal X-ray analysis (Figure 2).[18] When 1m, a diene
tethered to an indole moiety as the terminating group, was
employed as the substrate, the reaction proceeded well and
a pentacyclic compound 4m was obtained in 66% yield as
a single isomer. It is worth mentionioning that through the
impressive cyclization of 1n, which occurred in a single step,
three cyclohexane rings and one THP ring were formed, thus
leading to the isolation of the single isomer 4n in 59% yield
(Table 3, entry 5).
Scheme 3. Synthesis of (Æ)-moluccanic acid methyl ester. a) 30 mol%
InBr3, chloroacetaldehyde dimethyl acetal, CH2Cl2, 64% yield; b) NaH,
DMF, 1308C; then HBr, acetone, 55% yield; c) Tebbe reagent, toluene,
72% yield; d) NaCN, [18]crown-6, CH3CN, 67% yield; e) KOH,
MeOH/H2O=4:1, 608C; f) DCC, MeOH, THF, 58% yield over two
steps; g) BCl3, TBAI, CH2Cl2, 71% yield. DMF=N,N-dimethylforma-
mide, DCC=dicyclohexylcarbodiimide, TBAI=tetra-n-butylammonium
iodide.
Having successfully established an intermolecular poly-
ene cyclization to construct 3-oxaterpenoid skeletons, we
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polyolefinic alcohol substrates. Catalytic amounts of InBr3
(30 mol%) were used and excellent diastereoselectivity was
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provides an alternative, concise way to synthesize 3-oxater-
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terpenoid synthesis. The usefulness of this strategy has been
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Received: July 26, 2012
Published online: && &&, &&&&
Keywords: cyclization · indium bromide · polyenes ·
.
Prins reaction · terpenoids
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Communications
Synthetic Methods
B. Li, Y. C. Lai, Y. Zhao, Y. H. Wong,
Z. L. Shen, T. P. Loh*
&&&& — &&&&
Synthesis of 3-Oxaterpenoids and Its
Application in the Total Synthesis of (Æ)-
Moluccanic Acid Methyl Ester
Cascades: An InBr3-catalyzed intermolec-
ular polyene cyclization initiated by
a Prins reaction provides a concise
approach to 3-oxaterpenoid derivatives.
The reaction is compatible with various
aldehydes, ketones, and polyolefin–alco-
hol substrates. In addition, the first total
synthesis of (Æ)-moluccanic acid methyl
ester was achieved in seven steps by
using such a Prins–polyene cyclization as
the key step.
6
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