Total synthesis of (-)-funebrine via Au-catalyzed regio- and stereoselective γ-butyrolactonization of allenylsilane

Article abstract of DOI:10.1016/j.tetlet.2011.08.050

The stereoselective total synthesis of (-)-funebrine from 2-butyn-1-ol was described. The crucial steps in the synthesis involved the stereoselective enolate Claisen rearrangement of the (S)-α-acyloxy-α-alkynylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the Paal-Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.

Full text of DOI:10.1016/j.tetlet.2011.08.050

Tetrahedron Letters 52 (2011) 5744–5746
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Total synthesis of (ꢀ)-funebrine via Au-catalyzed regio- and stereoselective
c-butyrolactonization of allenylsilane
⇑
⇑
Takuya Okada, Kazuhiko Sakaguchi , Tetsuro Shinada, Yasufumi Ohfune
Graduate School of Science, Osaka City University, Sugimoto, Osaka 558 8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 31 August 2011
The stereoselective total synthesis of (ꢀ)-funebrine from 2-butyn-1-ol was described. The crucial steps in
the synthesis involved the stereoselective enolate Claisen rearrangement of the (S)- -acyloxy- -alky-
a
a
nylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the
Paal–Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Funebrine
Au-catalyzed lactonization
Allenylsilane
c
-Butyrolactone
Paal–Knorr pyrrole condensation
The
c
-butyrolactones are often found as a core substructure in
Our preliminary studies indicated that the conversion of 6a
(Si = TBS) into 5 was accompanied by a troublesome epimerization
at C3 to give a 1:1 mixture of diastereomers 50 (Scheme 2). The
undesired epimerization occurred during the removal of the TBS
many biologically active natural products. (ꢀ)-Funebrine (1),1 iso-
lated in 1984 from the flowers of Quararibea funebris, is a represen-
tative example of this class of natural products. This flower was used
as a folk medicine for treating various diseases while the biological
activity of 1 had not yet been elucidated. The structure is character-
group from the a-silyl ketone 9 which was prepared by the hydro-
lysis of 6a with Na2CO3.5 To avoid the troublesome epimerization
at C3, we chose 6b possessing a dimethylphenylsilyl (Me2PhSi)
group, since this group is sterically less bulky than the TBS group
and is readily removed under mild reaction conditions.
ized by the highly functionalized
contiguous stereogenic centers including an amino group on the
c-butyrolactone core with three
lactone ring. Only two total syntheses of
1 including an
enantioselective version have been reported.2 Herein, we report
(S)-a-Acyloxysilane 8 (>95% ee) was prepared from the com-
the stereoselective total synthesis of (ꢀ)-1 via the silyl group-
mercially available 2-butyn-1-ol by the following sequence of reac-
tions (Scheme 3): (1) the reverse-Brook rearrangement of 2-butyn-
1-ol (93%), (2) the Mukaiyama oxidation6 of the resulting alcohol
10 (79%), (3) asymmetric reduction of the silyl ketone 11 using
(+)-B-chlorodiisopinocamphenylborane (DIP-Cl),7 and (4) conden-
sation with Boc-Gly (2 steps, 87%). The enolate Claisen rearrange-
ment of 8 gave the allenylsilane 7 (50%) with an excellent
diastereoselectivity (>20:1).4 The Au-catalyzed lactonization of 7
was performed using 3 mol % of [(Ph3PAu)3]OBF4 to give the de-
directed Au-catalyzed regio- and stereoselective
tion of the allenylsilane.
c-butyrolactoniza-
Ishibashi and co-workers reported the synthesis of 1 based on
the coupling of the 2-amino -butyrolactone 3 with the symmetri-
c
cal diketone 4a (P = P0) to construct the pyrrole core 2. We consid-
ered that the use of the unsymmetrical 1,4-diketone 4b (P – P0)
would be advantageous in view of the efficient synthesis of an
aldehyde 2 in comparison with the use of 4a.2 In a preceding paper,
we described the Au-catalyzed conversion of the optically active
sired trans
c-butyrolactone 6b in 69% yield. The catalyst loading
(S,aS)-
ethylene-
rearrangement of the (S)-
the -butyrolactone 6 possessed both the requisite stereochemis-
try and functional groups on the lactone ring, this can be a plausi-
ble precursor for the synthesis of the key -butyrolactone 3 via the
a
-allenylsilane 7 to the (2S,3S)-2-amino-3-methyl-4-silylm-
-butyrolactone 6, prepared from the enolate Claisen
-acyloxy-
-alkynylsilane 8.3,4 Since
could be reduced to 1 mol % by the addition of 20 mol % of i-Pr2NEt.
The fact that the observed dr had dropped to 10:18 as compared to
that of the TBS group (>20:1) suggested that the decrease in the
steric bulkiness of the silyl group significantly affected the diaste-
c
a
a
c
reoselectivity of the c
-lactonization.3 The treatment of the lactone
c
6b with aqueous Na2CO3 simultaneously occurred with the lactone
opening and the removal of the Me2PhSi group in a one-pot oper-
ation to give the methyl ester 5 as a single diastereomer after the
CH2N2 treatment (71%, 2 steps).
stereoselective reduction of 5 (Scheme 1).
Next, we examined the reduction of methyl ketone 5 to (4R)-
amino lactone 3. Initial attempts using the substrate-controlled
⇑
Corresponding authors.
E-mail address: sakaguch@sci.osaka-cu.ac.jp (K. Sakaguchi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.050

T. Okada et al. / Tetrahedron Letters 52 (2011) 5744–5746
5745
O
O
CO2Me
NHBoc
S
O
R
3
O
O
NH2
stereoselective
S
O
3
O
O
reduction
N
5
N
N
O
+
HO
HO
O
O O
hydrolysis
(-)-1
2
desilylation
PO
OP'
4a: P = P'
4b: P P'
O
O
S
NHBoc
O
[3,3]
cat Au
CO2H
O
S
NHBoc
Si
[(Ph3PAu)3O]BF4
Si
•
S
aS
S
NHBoc
Si
LDA, ZnCl2
6a: Si = TBS
8
7
6b: Si = Me2PhSi
Scheme 1.
The 1,4-diketone 4b possessing the TES and THP protected
1) Na2CO3
acetone, H2O
TBAF
AcOH
O
3
CO2Me
NHBoc
O
CO2Me
NHBoc
hydroxymethyl groups, which can be selectively removed upon
the exposure to fluoride ion or under acidic conditions, was syn-
thesized from commercially available 5-hydroxymethyl furfural
(Scheme 4). After the protection of the hydroxy group with the
THP group, reduction of the aldehyde followed by the protection
of the resulting alcohol with the TES group to give 13 (3 steps,
quant). Oxidation of the furan with anhydrous mCPBA11 furnished
the enone 14 (51%), which, upon reduction with Zn/AcOH, afforded
the unsymmetrical 1,4-diketone 4b (75%).
TBS
6a
THF
64%
2) CH2N2, Et2O
quant.
9
5' dr = 1 : 1
Scheme 2.
methods, that is, Felkin–Anh type or chelation-controlled reduc-
tion using hydride reagents, were not satisfactory enough to give
a mixture of the desired (4R)- and undesired (4S)-lactones 12
(4R/4S = 3:1–1:20).9 Therefore, we turned our attention to the
use of a chiral oxazaborolidine for the reagent-controlled reduc-
tion. We found that (S)-Me-oxazaborolidine10 solved this problem
by producing (4R)-12 as the major isomer (82%, dr = 10:1). The re-
moval of the Boc group gave (2S,3S,4R)-3-HCl (quant., >95% ee,
dr = 10:1). Since both undesired (4S)-isomers contaminated in 12
and 3 were inseparable under chromatographic as well as recrys-
tallization conditions, respectively, further transformations were
performed as the mixture (10:1).
With the diketone 4b in hand, we next examined the Paal–
Knorr pyrrole condensation with the 2-amino-c-lactone 3, pre-
pared in situ from 3-HCl and Et3N (Scheme 5). The reaction was
successfully performed by refluxing the mixture in CH2Cl2 in the
presence of 5 equiv of AcOH.11 The addition of TBAF to the reaction
mixture effected the selective removal of the TES group to give the
pyrrole 15 with a protection-free alcohol in 67% yield. The oxida-
tion of 15 followed by the removal of the THP group gave (ꢀ)-fune-
bral (2) (2 steps, 64%).12 The minor isomer could be removed at this
stage by column chromatography on silica gel. Finally, the imine
O
PhSNHt-Bu
NCS, K2CO3
OH
Me2PhSiCl
n-BuLi
OH
Me2PhSi
Me2PhSi
then t-BuLi
93%
79%
10
11
O
O
NHBoc
1) (+)-DIPCl
CO2H
LDA
Me2PhSi
•
2) Boc-Gly
EDCI, DMAP
87%(2 steps)
Me2PhSi
NHBoc
dr = >20 : 1
ZnCl2
50%
(S)-8 >95% ee
7
[(Ph3PAu) 3O]BF4
(1 mol%)
O
O
1) Na2CO3
O
O
CO2Me
NHBoc
acetone, H2O
iPr2NEt (20 mol%)
NHBoc
Me2PhSi
2) CH2N2
CH2Cl2
69%
5
71% (2 steps)
6b
O
(S)-Me-oxazaborolidine
BH3-SMe2
12N HCl
O
O
4
NH2-HCl
NHBoc
MeOH, rt
quant.
then Et3N
82%
3-HCl dr = 10 : 1
12 dr = 10 : 1
>95% ee (MTPA amide)
Scheme 3.

5746
T. Okada et al. / Tetrahedron Letters 52 (2011) 5744–5746
1) DHP, PPTS
2) NaBH4
3) TESCl, Et3N
quant. (3 steps)
O
O
mCPBA
O
O
O
1) Dess-Martin
periodinane
THPO
OTES
HO
51%
O
O
O
80%
13
N
N
2) p-TsOH-H2O
EtOH, 66%
O O
EtO
O O
THPO
OH
Zn, AcOH
THPO
OTES
ethyl ether of 2
THPO
OTES
75%
15
14
4b
Scheme 6.
Scheme 4.
Acknowledgments
This study was financially supported by
(16201045 and 19201045) for Scientific Research from the Japan
Society of the Promotion of Science (JSPS).
1) Dess-Martin
periodinane
O
N
O
a
Grant-in-Aid
4b
O
O
AcOH, Et3N
80%
NH2-HCl
CH2Cl2, reflux
then TBAF
67%
2) p-TsOH-H2O
2-PrOH, 81%
THPO
OH
15 dr = 10:1
3-HCl dr = 10 : 1
Supplementary data
O
O
O
Supplementary data (full experimental details and characteriza-
tion data of all synthetic compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2011.08.050.
3-HCl (dr = 10 : 1)
O
Et3N
O
N
N
N
O
neat, 130 °C, 5 min
81%
HO
HO
O
(-)-funebral (2)
(-)-funebrine (1)
References and notes
Scheme 5.
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Forsyth, D. A.; Le Quesne, P. W. J. Org. Chem. 1999, 64, 2657–2666.
3. See the preceding paper.
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formation was accomplished by the condensation of 2 with 3 dur-
ing heating at 130 °C2a to give (ꢀ)-1 in 81% yield. All the spectral
data including the optical rotation of synthetic 1 (½a D23
ꢀ69.2 (c
ꢁ
1.00, CHCl3)) were in good agreement with those of the authentic
5. The methanolysis of 6a using K2CO3 in MeOH gave
9 as a mixture of
data (½a 2D6
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ꢀ71.3 (c 1.00, CHCl3)).2a
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8. The 2,3-trans- and cis diastereomers 6b (10:1) were separated by column
chromatography on silica gel.
In summary, the stereoselective synthesis of (ꢀ)-funebrine (1)
was achieved from the commercially available 2-butyn-1-ol in 14
steps. The synthesis is highlighted by the construction of the two
contiguous stereocenters at C2 and C3 by the enolate Claisen rear-
rangement of the (S)-a-acyloxy-a-alkynylsilane 8 and the Au-cat-
alyzed lactonization of the resulting allenylsilane 7. The pyrrole
ring was constructed by the condensation of the unsymmetrical
1,4-diketone 4b with the 2-amino-c-lactone 3 under mild reaction
conditions, which enabled the efficient conversion of the resulting
pyrrole 15 to the natural funebrine (1). The biological evaluation of
1 is currently in progress in our laboratories.
9. The (4R)-12/(4S)-12 ratios using several reducing reagents were as follows: L-
selectride (1:20), super hydride (1:2), NaBH4 (3:1), and Zn(BH4)2 (1.5:1).
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12. Using EtOH instead of 2-PrOH as the solvent during the removal of the THP
group, the ethyl ether of 2 was obtained in 66% yield (Scheme 6).