Synthesis of the western fragment of pseudolarenone

Full text of DOI:10.1002/bkcs.10869

Communication
DOI: 10.1002/bkcs.10869
BULLETIN OF THE
M. H. Oh et al.
KOREAN CHEMICAL SOCIETY
Synthesis of the Western Fragment of Pseudolarenone
*
Moo Hyun Oh, Jin Woo Lee, Se Yun Jang, and Duck Hyung Lee
Department of Chemistry, Sogang University, Seoul, Republic of Korea. *E-mail: dhlee@sogang.ac.kr
Received May 20, 2016, Accepted June 15, 2016
Keywords: Pseudolarenone, Total synthesis, Nortriterpenoid, Piancatelli rearrangement, Aldol reaction
Pseudolarenone (1) was first isolated from the Pseudolarix
amabilis in 2013 by Zhang and coauthors. Structurally
11a as the major product in a ratio of >99:1 (entry 1 in
1
2+
+
Table 1). The use of the Mg ion instead of the Li ion
turned out to be crucial for the success of this reaction to
afford the desired product 4a in 80% yield (entry 3).
Conversion of lactone 4a into the target molecule 2 is
summarized in Scheme 3. Opening of the lactone ring in 4a
was performed by a combination of MeNH(OMe)∙HCl and
varying diterpenoid compounds with a range of moderately
useful bioactivities were separated from the root barks of
1,2
P. amabilis. In addition, the seeds of P. amabilis also
provided structurally novel triterpenoid lactones with potent
3
cytotoxicity (Figure 1).
Pseudolarenone (1) is a pentacyclic (5/11/5/6/5) nortriter-
AlMe in 80% yield, and two hydroxyl groups were pro-
3
penoid lactone and has a unique bicyclo[8.2.1]tridecane
tected with TBSOTf to furnish the Weinreb amide 12 in
80% yield. Reduction of amide 12 with LAH in 84% yield
was then followed by the Wittig olefination reaction of the
resulting aldehyde to afford the desired (E)-α,β-unsaturated
ester 3 in 97% yield. The ester 3 was converted to allyl
ether 13 by DIBAL reduction in 91% yield and subsequent
allylation reaction with allyl bromide and NaH in 99%
yield. Finally, selective deprotection of the bis-TBS ether
core with nine chiral centers. Actually, triterpenoid with an
4
11-membered ring is rarely found in the natural product.
We report herein the synthesis of the western fragment 2 of
pseudolarenone (1).
Retrosynthetic analysis for the fragment 2 is shown in
Scheme 1. The fragment 2 is prepared by reduction and
allylation reaction of α,β-unsaturated ester 3. The ester 3 is
obtained by the conversion of 4a to the Weinreb amide,
reduction to aldehyde, and HWE olefination. Intramolecular
cyclization, regio- and stereoselective aldol reaction pro-
vides the lactone 4a from the ethyl ester 5. Finally, the ester
13 with HF-pyridine in 60% yield and MnO oxidation of
2
the resulting allylic alcohol moiety in 88% yield led to the
completion of the synthesis of 2.
5
is likely to be accessible from the commercially available
furfural 6 by Lewis acid-catalyzed Piancatelli rearrange-
5
ment and isomerization reactions as key steps.
The synthesis of lactone 10a is summarized in Scheme 2.
β-Hydroxy ester 7 was readily prepared on a large scale by
Reformatsky reaction between ethyl bromoacetate and the
6
commercially available furfural 6 in 93% yield. After conver-
sion of the β-hydroxy ester 7 into a mixture of 8 and 5 via
Figure 1. Structure of pseudolarenone (1).
7
ZnCl -catalyzed Piancatelli rearrangement, the isomeriza-
2
tion of 8 took place in the presence of Et N and a catalytic
3
amount of chloral to provide α,β-unsaturated ketone 5 in
8
3
3% yield over two steps. The resulting hydroxyl group of
5
was treated with TBSCl, Et N, and DMAP to afford the
3
corresponding silyl ether adduct in 96% yield. Subse-
quently, stereoselective Luche reduction was carried out
successfully, providing the cis-allylic alcohol 9 as the major
9
product in 70% yield. The relative stereochemistry of cis-
allylic alcohol 9 was determined by the NOESY experi-
ment. Allylic alcohol 9 was transformed into lactone 10a
by NaOH-mediated hydrolysis of the ethyl ester and intra-
molecular cyclization of the resulting hydroxy acid with the
aid of acetic anhydride and Et N in 55% yield.
3
However, the aldol reaction between the lithium enolate
of 10a and acetone provided the undesired aldol product
Scheme 1. Retrosynthetic analysis of fragment 2.
Bull. Korean Chem. Soc. 2016
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
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BULLETIN OF THE
KOREAN CHEMICAL SOCIETY
Scheme 2. Synthesis of lactone 10a. (a) Ethyl bromoacetate, zinc
dust, TMSCl, Et
2
O, reflux, 3 h, 93%; (b) ZnCl
2 2
, 1,4-dioxane/H O
Scheme 3. Synthesis of the target molecule 2. (a) MeNH(OMe)
(1:7), reflux, 3 h; (c) chloral, Et
3
N, EtOAc, rt, 12 h, 33% (two
ꢀ
∙
HCl, AlMe , CH Cl , −10 C, 4 h, 80%; (b) TBSOTf, 2,6-luti-
steps); (d) TBSCl, Et
e) NaBH , CeCl
Á7H
3
N, DMAP, CH
O, MeOH, −78 C, 1 h, 70%; (f ) 1 N
2
Cl
2
,
rt, 9 h, 96%;
3
2
2
ꢀ ꢀ
dine, CH Cl , 0 C, 1 h, 80%; (c) LAH, Et O, −40 C, 1 h, 84%;
2 2 2
ꢀ
(
4
3
2
ꢀ
(d) Ph P=CHCO Et, toluene, reflux, 17 h, 97% (crude).
3 2
NaOH, EtOH, 0 C, 1 h, 100% (crude); (g) Ac
−
2
O, Et
3
N, CH
2
Cl
2
,
ꢀ
(e) DIBAL, CH Cl , −78 C, 2 h, 91%; (f ) allyl bromide, NaH,
2 2
ꢀ
15 C, 1 h, 55%.
ꢀ
THF, rt, 36 h, 99%; (g) HF-pyridine, pyridine, THF, 0 C, 2.5 h,
60%; (h) MnO , CH Cl , rt, 3 h, 88%.
Table 1. Regioselective aldol reaction of 10.
2
2
2
Supporting Information. Experimental details and other
information are available in the online version of this
article.
References
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b
Entry
Starting lactone
Additive
11:4
Yield (%)
1
2
3
10a
10b
10a
—
>99:1
85:15
11:89
—
—
80
—
.
MgBr
2
OEt
2
a
1
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4
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b
In conclusion, the synthesis of the western fragment 2 of
5
. G. Piancatelli, A. Scettri, S. Barbadoro, Tetrahedron Lett.
pseudolarenone (1) was accomplished in 16 steps. The key
steps are ZnCl -catalyzed Piancatelli rearrangement and
isomerization, and stereo- and regioselective aldol reaction.
1
976, 39, 3555.
2
6
7
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Acknowledgments. This research was assisted financially
by the National Research Foundation of Korea (NRF-2013-
R1A2A2A01067217). The instrument facilities of OCRC
were also helpful.
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Bull. Korean Chem. Soc. 2016
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