Total synthesis of amphilectane-type diterpenoid (±)-7- isocyanoamphilecta-11(20),15-diene

Article abstract of DOI:10.1055/s-0030-1259514

The total synthesis of amphilectane-type diterpenoid (±)-7- isocyanoamphilecta-11(20),15-diene, isolated from the tropical marine sponge Cymbastela hooperi, was achieved. The synthesis involves construction of a cis-decalin ring by an intramolecular Diels-Alder reaction and construction of an all-trans-perhydrophenalene ring by an intramolecular Michael reaction as the key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259514

LETTER
547
Total Synthesis of Amphilectane-Type Diterpenoid ( )-7-Isocyanoamphilecta-
11(20),15-diene
Synthesis of
(
)-7-
i
Isocya
r
olecta-11(20)a
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(42)6763073; E-mail: miyaokah@toyaku.ac.jp
Received 8 December 2010
nalene ring by an intramolecular Michael reaction as the
Abstract: The total synthesis of amphilectane-type diterpenoid ( )-
key steps.
7-isocyanoamphilecta-11(20),15-diene, isolated from the tropical
marine sponge Cymbastela hooperi, was achieved. The synthesis
involves construction of a cis-decalin ring by an intramolecular
Diels–Alder reaction and construction of an all-trans-perhydro-
phenalene ring by an intramolecular Michael reaction as the key
steps.
N
C
H
7
8
H
11 H13
12
4
20
H
1
3
Key words: total synthesis, 7-isocyanoamphilecta-11(20),15-
diene, isocyanide, intramolecular Diels–Alder reaction, intramolec-
ular Michael reaction
15H
7-isocyanoamphilecta-11(20),15-diene (1)
Figure 1 Structure of 7-isocyanoamphilecta-11(20),15-diene
A variety of amphilectane-type diterpenoids, which pos-
sess the structurally interesting tricyclic carbon (amphi-
lectane) skeleton, have been isolated from marine
invertebrates.1–19 Amphilectane-type diterpenoids have
demonstrated a broad range of biological activities includ-
ing antimicrobial,1,2,5,14 anti-inflammatory,3,4,7,12,13,18 anti-
malarial,8,13,19 cytotoxic,9,13 antituberculosis,10,11,13 and
antiviral.13 Amphilectane-type diterpenoids have been
classified into two groups on the basis of shared structural
features; the pseudopterosin group,3,4,6,7,10–15,17,18 which
possess an aromatic ring, and the amphilectane
group,1,2,5,8,9,16,19 which possess a perhydrophenalene ring.
Our synthetic strategy is presented in Scheme 1. An exo-
selective intramolecular Diels–Alder reaction of triene A,
obtained from ( )-trans-3-allyl-4-methyltetrahydro-2H-
pyran-2-one (2),35 affords cis-decalin B. Following con-
version of cis-decalin B to a,b-unsaturated ester C, an in-
tramolecular Michael reaction of a,b-unsaturated ester C
affords the all-trans-perhydrophenalene derivative D.
Diketone D is then converted to 7-isocyanoamphilecta-
11(20),15-diene (1) by introduction of an isocyano group.
O
O
7-Isocyanoamphilecta-11(20),15-diene (1) is an amphi-
lectane-type diterpenoid isolated from the tropical marine
sponge Cymbastela hooperi, collected in Australia on the
Kelso Reef (Figure 1).8 7-Isocyanoamphilecta-11(20),15-
diene (1) has an all-trans-perhydrophenalene ring system
and includes an isocyano group. The relative configuration
of 1 was demonstrated by single-crystal X-ray analysis. 7-
Isocyanoamphilecta-11(20),15-diene (1) moderately in-
hibits proliferation of the malaria parasite Plasmodium
falciparum.8 The biological activities and unique structur-
al features of amphilectane-type diterpenoids have
prompted synthetic chemists to undertake their chemical
synthesis.20–45 However, most investigations to date have
dealt with the syntheses of pseudopterosins,20–34 and few
synthetic studies have been reported for amphilec-
tanes.33,34 The authors achieved the total synthesis of ( )-
7-isocyanoamphilecta-11(20),15-diene (1) via construc-
tion of a cis-decalin ring by an intramolecular Diels–Alder
reaction and construction of an all-trans-perhydrophe-
O
H
H
O
H
TBSO
TBSO
H
2
RO
RO
A
B
O
H
O
H
H
H
H
H
H
H
1
O
O
RO2C
RO2C
C
D
Scheme 1 Synthetic strategy for 7-isocyanoamphilecta-11(20),15-
diene (1)
trans-Decalin 12 was synthesized from ( )-trans-3-allyl-
4-methyltetrahydro-2H-pyran-2-one (2)35 via an intramo-
lecular Diels–Alder reaction (Scheme 2). Lactone 235 was
reduced with DIBAL-H to the hemiacetal, which was then
treated with benzyl alcohol and TsOH36 to give benzyl ac-
etal 3 as a diastereomeric mixture (3:2). Hydroboration–
oxidation of the terminal olefin in 3 afforded the primary
SYNLETT 2011, No. 4, pp 0547–0550
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2011
DOI: 10.1055/s-0030-1259514; Art ID: U10810ST
© Georg Thieme Verlag Stuttgart · New York

548
H. Miyaoka, Y. Okubo
LETTER
alcohol, and the hydroxy group was protected to give TBS ( )-7-Isocyanoamphilecta-11(20),15-diene (1) was syn-
ether 4. Hydrogenolysis of benzyl acetal in the presence of thesized from trans-decalin 12 via construction of an all-
37
Pd(OH)2 gave hemiacetal 5. Hemiacetal 5 was treated trans-perhydrophenalene skeleton by an intramolecular
with allyl magnesium bromide to afford the diol as a dia- Michael reaction (Scheme 3). The Tr group in trans-deca-
stereomeric mixture (5:3), and the primary hydroxy group lin 12 was removed by hydrogenolysis to give the primary
was then protected to give triphenylmethyl (Tr) ether 6. alcohol and was followed by oxidation of the alcohol with
The secondary hydroxy group in 6 was protected as an IBX to give aldehyde 13. Aldehyde 13 was treated with
acetyl group, and ozonolysis of the terminal olefin fol- Wittig reagent (Ph3P=CHCO2Me) to afford (E)-a,b-un-
lowed by treatment with Me2S and DBU resulted in b- saturated ester 14 as the sole product. a,b-Unsaturated
elimination of the acetoxy group to give a,b-unsaturated ester 14 was treated with pyrrolidine to afford thermody-
aldehyde 7 (E/Z > 20:1). Aldehyde 7 was methylated with namically stable all-trans-perhydrophenalene 15 as the
methyl magnesium bromide, and the resulting secondary sole product in 66% yield via an intramolecular Michael
alcohol was converted to acetate 8. Following deprotec- reaction.40 The relative configuration of 15 was unambig-
tion of the TBS group in 8 with TBAF, the primary alco- uously determined by X-ray crystallographic analysis
hol was oxidized with 2-iodoxybenzoic acid (IBX)38 to (Figure 2).
give aldehyde 9. Vinylation of aldehyde 9 with vinyl mag-
Treatment of a,b-unsaturated ester 14 with LHMDS un-
nesium bromide afforded the diol and was followed by
expectedly resulted in C–C bond formation between C-1
oxidation with IBX to give bis(enones) 10. Bis(enones) 10
and C-6 to afford tricyclic compound 16 as the sole prod-
uct (Figure 3). The relative configuration of 16 was deter-
mined by X-ray crystallographic analysis.
was treated with TBSOTf and DIPEA in CH2Cl2 to give
cis-decalin 11 as the sole product in 86% yield via regi-
oselective silyl enol etherification and an endo-selective
intramolecular Diels–Alder reaction. This is the first ex-
Diketone 15 was treated with Wittig reagent (Ph3P=CH2)
to afford mono exo-olefin 17. The carbonyl group at C-11
in diketone 15 remained unchanged following treatment
ample of a decalin ring being constructed by consecutive
reactions comprising the regioselective enolization of
with Wittig reagent. This low reactivity may have resulted
bis(enones) and intramolecular Diels–Alder cycloaddi-
from steric hindrance around the carbonyl group at C-11.
Consequently, introduction of the exo-olefin was per-
formed by Peterson olefination. Ketone 17 was treated
with trimethylsilylmethyllithium, prepared from (trimeth-
tion.39 cis-Decalin 11 was treated with TBAF to give the
diketone, and isomerization at C-8 with DIPEA in CH2Cl2
to give trans-decalin 12 as the sole product. The isomer-
ization of cis-decalin to trans-decalin occurred under ther-
ylsilylmethyl)tributylstannum and butyllithium,41 to give
modynamic control.
a mixture of carboxylic acid 18 and methyl ketone 19.
Carboxylic acid 18 was easily converted to methyl ketone
OTBS
H
OTBS
H
OTBS
H
BnO
OH
BnO
OH
a, b
c, d
e
f, g
2
O
O
O
TrO
3
5
4
6
OTBS
H
OTBS
OHC
H
h, i
j, k
l, m
H
OHC
TrO
AcO
AcO
TrO
TrO
8
9
7
(E/Z > 20:1)
O
O
H
O
H
H
H
8
n, o
p
q, r
H
H
O
TBSO
TrO
O
H
TrO
TrO
12
11
10
Scheme 2 Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C; (b) BnOH, TsOH, PhH, reflux, 81% (2 steps); (c) BH3·THF, THF, 0 °C,
then NaOH, H2O2; (d) TBSCl, imidazole, DMF, 93% (2 steps); (e) H2, Pd(OH)2, EtOAc, 86%; (f) CH2=CHCH2MgBr, Et2O, 0 °C, 90%; (g)
TrCl, pyridine, 87%; (h) Ac2O, pyridine; (i) O3, pyridine, CH2Cl2–MeOH, –78 °C, then Me2S, DBU, 87% (2 steps); (j) MeMgBr, THF, 0 °C;
(k) Ac2O, pyridine, 97% (2 steps); (l) TBAF, THF; (m) IBX, DMSO–THF, 90% (2 steps); (n) CH2=CHMgBr, THF, 0 °C, 87%; (o) IBX,
DMSO–THF, 88%; (p) TBSOTf, DIPEA, CH2Cl2, 0 °C to r.t., 86%; (q) TBAF, AcOH, THF; (r) DIPEA, CH2Cl2, 95% (2 steps).
Synlett 2011, No. 4, 547–550 © Thieme Stuttgart · New York

LETTER
Synthesis of ( )-7-Isocyanoamphilecta-11(20),15-diene
549
Figure 3 Synthesis of tricyclic compound 16 and ORTEP drawing
of 16
Figure 2 ORTEP drawing of 15
19 via conversion to the Weinreb amide42 and methyla-
tion. Regio- and diastereoselective aziridination43 of exo-
olefine 19 led to the desired b-aziridine 20 as a major
product (b/a > 20:1) in 53% yield based on recovered
starting material. Methyl ketone 20 was converted into the
exo-olefin by Wittig reaction and aziridine was reduced
amine, and subsequent formylation with acetic formic an-
hydride followed by dehydration with TsCl and pyridine
afforded ( )-7-isocyanoamphilecta-11(20),15-diene (1).
Spectral data of synthetic ( )-7-isocyanoamphilecta-
11(20),15-diene (1) were identical with the reported data
of natural 7-isocyanoamphilecta-11(20),15-diene (1),8
thus confirming the first total synthesis of ( )-7-isocyano-
amphilecta-11(20),15-diene.
44
by treatment with LiBHEt3 to afford tosylamide 21 in
72% yield (2 steps). Reductive removal of the tosyl group
in tosylamide 21 with sodium naphtalenide45 provided the
O
O
H
O
H
H
a, b
c
d
11 H
H
H
H
12
O
O
O
H
H
H
MeO2C
OHC
MeO2C
H
15
14
13
H
H
H
H
H
O
H
H
H
H
H
H
H
H
H
O
e
f, g
+
Me
O
H
MeO2C
H
H
H
MeO2C
HO2C
H
H
H
19
17
18
O
h, i
NHTs
NTs
H
H
H
H
H
H
H
H
H
j
k, l
m–o
19
1
H
21
20
O
(β/α > 20:1)
Scheme 3 Reagents and conditions: (a) H2, Pd(OH)2, EtOAc; (b) IBX, DMSO–THF, 64% (2 steps); (c) Ph3P=CHCO2Me, THF, 91%; (d)
pyrrolidine, CH2Cl2, 66%; (e) Ph3P=CH2, THF, 0 °C, 88%; (f) Bu3SnCH2TMS, BuLi, THF, –78 °C; (g) HCl, THF; 18: 34% (2 steps), 19: 31%
(2 steps); (h) HN(OMe)Me·HCl, EDC·HCl, Et3N, CH2Cl2, 0 °C; (i) MeMgBr, THF, 0 °C, quant. (2 steps); (j) PhI=NTs, Cu(OTf)2, MS 4 Å,
MeCN–CH2Cl2, 0 °C, 53% (BRSM); (k) Ph3P=CH2, THF, 0 °C; (l) LiBHEt3, THF, 0 °C, 72% (2 steps); (m) sodium naphthalenide, THF, 0 °C;
(n) acetic formic anhydride, CH2Cl2; (o) TsCl, pyridine, CH2Cl2, 79% (3 steps).
Synlett 2011, No. 4, 547–550 © Thieme Stuttgart · New York

550
H. Miyaoka, Y. Okubo
LETTER
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