Convergent synthesis of the [5-7-6-3] tetracyclic core of premyrsinane diterpenes

概要

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COMMUNICATION
Convergent Synthesis of the [5-7-6-3] Tetracyclic Core of
Premyrsinane Diterpenes
Received 00th January 20xx,
Accepted 00th January 20xx

Kohei Yoshinaga a and Satoshi Yokoshima*a

DOI: 10.1039/x0xx00000x

The [5-7-6-3] tetracyclic core of premyrsinane diterpenes was
convergently synthesized via the stereoselective three-component
coupling of a 2-propenyl unit, an enone, and an aldehyde,
followed by the relay ring-closing metathesis with conformation
control of the substrate to construct the 7-membered ring.
Premyrsinane diterpenes, which are the main ingredients
extracted from the Euphorbiaceae family of flowering plants,
have a [5-7-6-3] tetracyclic ring system (Figure 1a).1
Biogenetically, starting from geranylgeranyl pyrophosphate
(GGPP), the bicyclic casbane skeleton is first constructed, in
which a gem-dimethylcyclopropane is fused to a
cyclotetradecane ring. The cyclotetradecane ring is then
divided into a cyclopentane ring and a cycloundecane ring via a
transannular reaction, leading to the lathyrane skeleton
(Figure 1b). The cycloundecane ring is further divided in
several manners into a cyclohexane ring and a cycloheptane
ring, resulting in the formation of [5-6-7-3] and [5-7-6-3]
tetracyclic skeletons. Premyrsinane diterpenes belong to one
of these diverse ring systems. Some premyrsinane diterpenes
have an additional oxygen-containing ring as a cyclic ether or
acetal.
Highly oxidized diterpenes are attractive synthesis targets
because, in addition to construction of the skeletons, they
often present synthetic challenges of introducing oxygen
functionalities and controlling their reactivity.2 For
premyrsinane diterpenes, however, only a few synthetic
studies have been reported. Yamamura’s group reported a
synthesis of the core structure of premyrsinane diterpenes via
transannular reaction of an intermediate having the lathyrane
skeleton.3 Gao’s group reported the conversion of the
lathyrane skeleton into a premyrsinane skeleton via ironcatalyzed reductive olefin coupling.4 Herein, we report the
results of our study on the synthesis of premyrsinane
diterpenes.

Our retrosynthetic analysis is shown in Scheme 1. Oxygen
functionalities at C13 and C14 would be introduced on a C-C
double bond in I, which could be formed via a ring-closing
metathesis (RCM).5 The hydroxymethyl group at C6 would be
introduced by a reaction at the a-position of the carbonyl
group at C7. The requisite substrate II would, in turn, be
prepared by a three-component coupling reaction of aldehyde
III, enone IV, and 2-propenyl unit V via a sequence involving
1,4-addition and aldol reaction.6
a. premyrsinane diterpenes
O
OH
HO
H

AcO

H
BzO
AcO

n-PrO
OAc

H
AcO

OAc
AcO

H

H
O

i-BuO
AcO

euphorbiaproliferins I

H
AcO
H

falcatin P

OBz
OAc

b. biosynthetic pathway
OPP

premyrsinane
euphoractine
tigliane
jatropholane

GGPP

lathyrane skeleton

Figure 1. Premyrsinane diterpenes.

RO

O

OR

14 13

H

RO

[Cu]
V
H

H
RO
RO RO
premyrsinane diterpenes

RO

RO

H

O

O
IV

III

three-component
coupling

RO

14 13

6

School of Pharmaceutical Sciences, Nagoya University, Nagoya 4648601, Japan
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x

O

kandovanol ester

RO
a. Graduate

OBz
AcO

H
RO
RO RO
I

RO

H
RCM
&
hydroxymethylation

Scheme 1. Retrosynthetic analysis.

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H
6

RO

H
RO H
O
II

7

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COMMUNICATION

Journal Name

(R)-Me-CBS cat
BH3·THF (0.5 eq)

LDA, MeI
HMPA

O

OTBS

THF
−78 °C

O

2, 34%

1

OH
H

2) PDC, Celite
CH2Cl2/DMF
rt

7, 49%

HO

OTBS

THF
0 °C

OTBS
H

OTBS

THF, 0 °C

BnO

8, 51% (2 steps)

H

THF
0 °C to rt

Cl

OTBS
BnO

H

MeO
H

CH2Cl2
0 °C to rt

BnO

11, 95%

H

O

12, 86%

CaCO3

O

MeOH
H2O, rt

O
13

BnO

then
aq H2O2
aq NaOH, rt

Dess-Martin
periodinane
pyridine

OH

THF
50 °C

H

OH

6, 39% (2 steps)

MeO

NaIO4

PhS

BnO

TBAF

10, 90%

NaH
PhSH

(+)-3-carene

THF
50 °C

CH2Cl2
hexane
−78 to 0 °C

O

Ph

MeO

9, 78%

2 steps
ref 7

5

NaH
MeI

vinyl MgCl

BnO

O

OH

4, 91%

HO

O

ThexylBH2
THF
0 °C to reflux

DIBAL

toluene, rt

HO

3, 44%
er = 84:16

1) TBSCl
imidazole
CH2Cl2, 0 °C

OH

BnO

THF, 0 °C

OTBS

PhCH(OMe)2
PPTS

TBAF

neat
60 °C

S
Ph

O

O

O

15

14, 90%

16, 34% (2 steps)

Scheme 2. Preparation of the aldehyde and enone units.

Our synthesis commenced with the preparation of aldehyde 12
(Scheme 2). Methylation of known cyclopentenone 1 gave 2,
which was subjected to Corey-Bakshi-Shibata (CBS) reduction.7
Optical resolution occurred with moderate selectivity, and the
resultant allylic alcohol 3 was obtained in 44% yield with an
enantiomer ratio of 84:16. The absolute configuration of the
major enantiomer was determined by the modified Mosher’s
method.8 After removal of the tert-butyl(dimethyl)silyl (TBS)
group, the resultant 1,3-diol 4 was converted into benzylidene
acetal
5,
which
was
reductively
cleaved
with
diisobutylaluminum hydride (DIBAL) to form benzyl ether 6.
Hydroboration with thexylborane proceeded stereoselectively
to give diol 7, which, after protection of the primary alcohol
with a TBS group, was converted into ketone 8. Treatment
with vinyl magnesium chloride, followed by methylation of the
resultant tertiary alcohol, afforded ether 10. Removal of the
TBS group and subsequent oxidation with Dess-Martin
periodinane in the presence of pyridine furnished aldehyde 12.
We next prepared enone 16 starting from (+)-3-carene.
According to the reported procedure,9 (+)-3-carene was
converted into chloride 13 in two steps. Nucleophilic
substitution with a thiolate smoothly proceeded, and the
resultant sulfide 14 was oxidized with sodium periodate to give
sulfoxide 15 as a mixture of diastereomers, which included a
small amount of enone 16. When the mixture was heated at
60 °C in the presence of CaCO3, syn-elimination of the
sulfoxide smoothly occurred to afford enone 16.
With the desired aldehyde 12 and enone 16 in hand, we
turned our attention to the three-component coupling
reaction (Scheme 3). The 1,4-addition of a 2-propenyl copper
reagent to enone 16 proceeded at –78 °C to generate enolate
17, and addition of aldehyde 12 induced an aldol reaction to
produce diene 18 as a single diastereomer.10 The metathesis
reaction, however, did not occur and diene 18 was recovered
under conditions involving various Ru-based catalysts.11 These

results are attributed to the steric hindrance around the vinyl
or 2-propenyl groups.
MeO
H
Li

BnO

H

CuI

H

O

12

Et2O
−78 °C

O

O[Cu]

16

17

MeO

MeO

H

H

Ru cat

BnO

H
HO H
O

no reaction

19

BnO

H
HO H
O
18, 49%

Scheme 3. Three-component coupling.

To make it easier to approach the double bonds, we decided to
employ the relay ring-closing metathesis reaction (Scheme
4).12 For the relay metathesis, we prepared the requisite
substrate from ketone 8. Nucleophilic addition of enyne 20,13
followed by reduction of the resultant propargyl alcohol 21
with Red-Al, afforded E-olefin 22. Three-step conversions
including methylation, desilylation, and oxidation gave
aldehyde 24. The three-component coupling reaction using
aldehyde 24 also proceeded smoothly to give triene 25 in 46%
yield as a sole isomer.14 Attempted relay ring-closing
metathesis reactions of triene 25, however, did not produce
the desired product 19. Instead of the relay metathesis, cross
metathesis between the terminal C-C double bond to form
dimers, or isomerization of the terminal C-C double bond,15
was observed.

2 | J. Name., 2012, 00, 1-3

This journal is © The Royal Society of Chemistry 20xx

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COMMUNICATION
O

O
OTBS
BnO

O

20
n-BuLi
LaCl3

H

HO

THF
–78 to 0 °C

THF
−40 °C

OTBS
BnO

8

O

HO

Red-Al

OTBS
H

BnO

H
21, 82%

22, 57%
H

1) NaH, MeI
THF
50 °C

O

MeO

2) TBAF
THF
50 °C

OH
BnO

H

Dess-Martin
periodinane
pyridine
CH2Cl2
0 °C to rt

17

H

O[Cu]

Et2O
–78 °C

H
BnO

23, 90% (2 steps)

O

MeO

O

24, 90%

O

MeO

MeO

H

H

Ru cat

BnO

H
HO H
O

BnO
dimer or isomer

H
HO H
O

25, 46%

19

Scheme 4. Attempted relay ring-closing metathesis.

Hoping to change the conformation and the reactivity, we
converted the b-hydroxyketone moiety in 25 into a cyclic
acetal (Scheme 5). Reduction with sodium borohydride
(NaBH4) occurred from the less-hindered face to furnish a 1,3diol, which was reacted with benzaldehyde dimethyl acetal in
the presence of pyridinium p-toluenesulfonate (PPTS) to afford
benzylidene acetal 26.16 Upon treatment of 26 with Ru-based
catalyst 2717 in refluxing toluene in the presence of 1,4benzoquinone,15 to our delight, the relay ring-closing
metathesis reaction occurred to give a product with the [5-7-63] core (compound 28) in 42% yield. Under these conditions,
however, diene 29 was also produced in 26% yield via the relay
cross metathesis, instead of the relay ring-closing
metathesis.18,19 NOESY correlations and coupling constants (J
values) in 1H-NMR of 26 showed that the cyclopentane moiety,
which includes the diene unit, takes the axial position in the
six-membered ring of the benzylidene acetal. In this
conformation, the alkene moieties are apart from each other;
therefore,
the
ring-closing
metathesis
requires
a
conformational change of the six-membered ring so that the
cyclopentane moiety is situated in the equatorial position. If
the stereoselectivity in the reduction of ketone 25 could be

inverted, the cyclopentane moiety would take the equatorial
position in the six-membered ring of the resultant benzylidene
acetal. With these considerations in mind, we attempted
reduction of the ketone directed by the b-hydroxy group with
tetramethylammonium triacetoxyborohydride in a mixture of
acetic acid and acetonitrile.20 The reaction occurred
stereoselectively to furnish the desired diol 30, which was
converted into benzylidene acetal 31. ...