Model studies for the stereoselective construction of the BC-ring of armatol F based on Ireland-Claisen rearrangement and relay ring-closing olefin metathesis

Article abstract of DOI:10.1016/j.tetlet.2010.06.103

Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a fused tricyclic ether moiety (BCD-ring) with an unusual cis ring junction at C18-C19 between the C- and D-rings. En route to the total synthesis of armatol F, the stereoselective construction of the C18 and C19 stereocenters by Ireland-Claisen rearrangement and the formation of the C-ring by relay ring-closing olefin metathesis were established through the synthesis of monocyclic (C-ring) and bicyclic (BC-ring) model compounds.

Full text of DOI:10.1016/j.tetlet.2010.06.103

Tetrahedron Letters 51 (2010) 4543–4546
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Model studies for the stereoselective construction of the BC-ring of armatol
F based on Ireland-Claisen rearrangement and relay ring-closing
olefin metathesis
a
a
Kenshu Fujiwara a, , Keita Tanaka , Yasushi Katagiri , Hidetoshi Kawai a,b, Takanori Suzuki a
*
a Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a fused tricyclic ether
moiety (BCD-ring) with an unusual cis ring junction at C18–C19 between the C- and D-rings. En route to
the total synthesis of armatol F, the stereoselective construction of the C18 and C19 stereocenters by Ire-
land-Claisen rearrangement and the formation of the C-ring by relay ring-closing olefin metathesis were
established through the synthesis of monocyclic (C-ring) and bicyclic (BC-ring) model compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 May 2010
Revised 17 June 2010
Accepted 21 June 2010
Available online 25 June 2010
Armatol F (1, Fig. 1), isolated from the red alga Chondria armata
by Ciavatta et al. as a polyether triterpene, is characterized by a sol-
itary oxepane (A-ring), a fused tricyclic ether moiety (BCD-ring),
and two bromo substituents at opposite ends of the molecule.1
The cis ring fusion at C18–C19 between the C- and D-rings of 1 is
unusual for naturally occurring fused polycyclic ethers.2,3 Although
the respective partial relative configurations of the A- and the BCD-
rings have been determined by NMR experiments, the full absolute
stereochemistry of 1 remains unclear. Since the unusual structure
of 1 has attracted our interest, we started a program toward the to-
tal synthesis and determination of full absolute configuration of 1.4
As a part of this program, the synthesis of the BCD-ring has been
studied. Herein, the stereoselective construction of the stereocen-
ters at C18 and C19 by Ireland-Claisen rearrangement5,6 and the
formation of the C-ring by relay ring-closing olefin metathesis,7
both of which were established through the synthesis of C-ring
model 2 and BC-ring model 3, are described.
The outline of the synthesis of C-ring model 2 and 15-Me-omit-
ted BC-ring model 3 is shown in Scheme 1 retrosynthetically. The
seven-membered ring (C-ring) formation, employing ring-closing
olefin metathesis (RCM) or relay RCM, was undertaken at the final
stage of the synthesis. The stereoselective construction of the con-
tiguous trisubstituted C18 and tetrasubstituted C19 stereocenters
of 4 and 5 relied on the Ireland-Claisen rearrangement of an E-3-
alkoxy-2-propenyl lactate (7 and 8), of which the chirality at
C16’ was transferred to C18 and C19 of the product (4 and 5) via
a presumed chair form transition state derived from a Z-ketene si-
lyl acetal intermediate (6). Lactate esters 7a,b and 8a,b were pre-
pared from alcohol 11 and lactic acid derivatives 9a,b and 10a,b.
Alcohol 11 was prepared from 1,2:5,6-di-O-isopropylidene-D-
mannitol (12) (Scheme 2).8 Oxidative cleavage of 12 with NaIO4,9
followed by the reaction with ethynyl magnesium bromide, pro-
duced 14 (60% over two steps), which was oxidized with IBX10 in
refluxing ethyl acetate to give 15.11 Conjugate addition of 4-
methoxybenzyl alcohol to 15 in the presence of PMe3 selectively
afforded E-enone 16 (51% over two steps).12 The enone was
diastereoselectively reduced to 1113 (ds >7:1, 93%) under Luche
conditions14 by the assistance of the neighboring chiral 2,2-di-
methyl-1,3-dioxolan-4-yl group.15
Simple lactic acids 9a and 9b were synthesized from R- and S-2-
bromopropionic acids (18), respectively, by substitution with 17
under basic conditions without the loss of optical purity (9a:
73%; 9b: 65%) (Scheme 3).16 The optical purities of 9a and 9b were
determined by NMR analysis of 19a and 19b derived from 9a and
9b with S-1-phenylethylamine. The absolute configurations of 9a
and 9b were confirmed by the X-ray crystallographic analysis of
19b.17
27
28
25 1 Me
Me OH
8
Me
24
7
11
O
A
O
B
Me
Br
H
26
10
Me
Me30
15 C
O
O
6
Me
18
19
3
D
OH
H
Me
Br
22
29
Armatol F (1)
H
O
B
11
H
H
C
O
15 C
O
OPMB
OPMB
18
19
18
19
14
H
CO Me
CO Me
2
Me
Me
2
29
29
C-Ring Model (2)
BC-Ring Model (3)
* Corresponding author. Tel.: +81 (0)11 706 2701; fax: +81 (0)11 706 4924.
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.103

4544
K. Fujiwara et al. / Tetrahedron Letters 51 (2010) 4543–4546
28Me
H
(a)
Me
(R)
11
O
O
(B)
11
H
H
OH
15
15
O
OPMB
18
18
Br
B
C
C
O
19
19
O R-18
O
Me
H
H
CO Me
Me
29
2
Ring-Closing
Olefin
Metathesis
NaH, THF (0.4 M)
reflux, 20 h
29
R1 R2
1
C-Ring Model (2)
BC-Ring Model (3)
OH
O
O
OH
17
(b) S-18, NaH, THF (0.4 M)
9a: R1=Me, R2=H (73%)
R3
reflux, 20 h
Ireland-Claisen
Rearrangement
OPMB
9b: R1=H, R2=Me (65%)
16'
H
18
17
16'
R3
H
O
O
11
H
1 R2
E
O
17
18
R
OPMB
EDCI•HCl
DMAP
CH2Cl2
(S)
14
H2N Ph
19
O
19
O
Me
H
H
Me
OR4
TMSO
CO Me
O
2
Z
R4
18
7a,b (acyclic)
8a,b (ring-fused)
4 (acyclic)
5 (ring-fused)
19
OPMB
E
O16'
R3
R1 R2
Me
6
H
(S)
N
Ph
O
a series:
R1=Me, R2=H
b series:
O
Me
OPMB
19a: R1=Me, R2=H (63%)
ORTEP diagram of 19b
19b: R1=H, R2=Me (53%)
R1=H, R2=Me
H
O
16'
HO
R1 R2
Scheme 3.
R1 R2
or
+
O
Me
Me
OH
OH
O
O
R3
H
O
O
O
LDA or KHMDS in THF at À78 °C for 10 or 30 min and then with
TMSCl at À78 °C, and the resulting ketene silyl acetal was rear-
ranged by warming to ambient temperature to produce carboxylic
acids, which were converted to 4x,y or 5x,y by methylation with
TMS-diazomethane. In the case of 7a and 7b, both LDA and KHMDS
produced desired 4x as a major product along with 4y (entries 1–
8). Increasing time of LDA exposure did not affect the selectivity of
4x but slightly decreased the yield (entries 1, 2, 5, and 6). Although
the treatment of 7a with KHMDS showed a good ratio of 4x (>20–
9a,b
10a,b
11
Scheme 1.
Me
O
NaIO4
pH 7 buffer
Me
OH
CHO
O
O
BrMg
THF
O
O
Me
CH2Cl2
23 °C, 1 h
O
Me
OH
12
Me
13
Me
0 °C, 1 h
60%
(a)
Me
(R)
(2 steps)
OH
PMBOH (2 eq)
PMe3 (1 eq)
CH2Cl2
IBX
AcOEt
Br
O
OH
O R-18
H
H
H
H
O
O
Me
15
O
O
O
NaH, 1,4-dioxane (0.2 M)
R1 R2
O
Me
14
Me
Me
0 °C, 2 h
reflux
8.5 h
OH
19
51%
(2 steps)
OH
O
65 °C, 2 d
O
(b) S-18, NaH
1,4-dioxane (0.2 M)
20
10a: R1=Me, R2=H (53%)
O
10b: R1=H, R2=Me (69%)
NaBH4
CeCl3•7H2O
65 °C, 2 d
OPMB
O
1-naphthol
EDCI•HCl
DMAP
11
O
Me
MeOH
–78 °C, 10 min
Me
1) OsO4
NMO
then
16
81%
93% (ds > 7:1)
EDCI•HCl
DMAP
OH
Me
H
NaIO4
O
O
O
O
Scheme 2.
Me
O
14
O
O
2) NaBH4
–20 °C
CH2Cl2
19
O
O
O
H
Me
17%
(4 steps)
HO
NpO
Similarly, lactic acids 10a and 10b were prepared from R- and
S-18, respectively, by the reaction with known 20,18 derived from
3) NaOH
NOE
23a
22a
21a (from 10a)
tri-O-acetyl-D
-glucal (10a: 53%; 10b: 69%) (Scheme 4).16 The ste-
Scheme 4.
reochemistry at C19 of 10a and 10b was determined by NMR anal-
ysis of lactone 23a, derived from 10a through a five-step process
[(i) esterification, (ii) dihydroxylation/oxidative cleavage, (iii)
reduction, (iv) hydrolysis, and (v) lactonization]. The presence of
an NOE between H14 and 19-CH3 of 23a indicated the S configura-
tion at C19 of 10a.
Alcohol 11 was esterified with 9a,b and 10a,b using EDCIÁHCl
and DMAP to afford 7a,b (as crude products) and 8a,b (89% and
97%), respectively (Scheme 5). Since simple esters 7a and 7b were
unstable, contrary to 8a and 8b, they were immediately used in the
next reaction without further purification.
PMBO
O
PMBO
EDCI•HCl
DMAP
H
9a,b
or
10a,b
O
R1 R2
R1 R2
or
11 +
O
CH2Cl2
23 °C
O
O
R3
R3
H
O
O
7a: R1=Me, R2=H
(crude)
8a: R1=Me, R2=H
(86%)
O
R3=
7b: R1=H, R2=Me
(crude)
8b: R1=H, R2=Me
(97%)
Me
O
Me
Selected results of the Ireland-Claisen rearrangement of 7a,b
and 8a,b are shown in Scheme 6. Each ester was treated with
Scheme 5.

K. Fujiwara et al. / Tetrahedron Letters 51 (2010) 4543–4546
4545
1) Base (3.0 eq), THF
–78 °C, Time
then
TMSCl (3.0 eq)
–78 → 25 °C, 1 h
Me
O
OH
H
1) 2 M HCl-THF (1:1)
24 °C, 2 h
R3
R3
Me
O
H
then pH 7 buffer
NaIO4, 24 °C, 0.5 h
O
H
7a,b
(crude)
or
H
O
O
H
OPMB
OPMB
R1
OPMB
OPMB
or
R1
O
O
2) TMSCHN2
PhH-MeOH
H
O
Me
2) NaBH4, CeCl3•7H2O
MeOH, –78 °C, 10 min
O
R2
4x,y
R2
5x,y
8a,b
CO2Me
CO2Me
Me
Me
O
98% (2 steps)
5x
28
x series: R1=CO2Me, R2=Me
y series: R1=Me, R2=CO2Me
Me
Br
R3=
24 (0.2 eq)
(CH2Cl)2
reflux, 24 h
O
NaH, TBAI
DMF–THF (2:1)
24 °C, 20 h
91%
O
Products
4/5 Yield (x+y) x : y
Entry Substrate
Base
Time
H
O
H
24 (0.1 eq)
(CH2Cl)2
O
Me
LDA
LDA
10 min
30 min
74%a
67%a
53%a
3 : 1
3 : 1
9 : 1
OPMB
H
18
1
2
3
4
4
4
5
5
14
OPMB
19
19
O
O
O
O
O
H3C
O
O
O
O
H
CO2Me
(S)
O
Me
29
NOEs
reflux, 4 h
73%
CO2Me
KHMDS 10 min
KHMDS 30 min
O
16%a >20 : 1
7a
3
Me
Me
Me
5
6
7
8
LDA
LDA
10 min
30 min
74%a
57%a
58%a
Decb
4 : 1
4 : 1
3 : 1
NDb
O
19
O
(R)
KHMDS 10 min
KHMDS 30 min
O
24 (0.2 eq)
(CH2Cl)2
H
O
O
7b
H
H
OPMB
OPMB
18
14
19
reflux, 22 h
8%
LDA
LDA
10 min
30 min
59%c
35%c
NRb
1 : 4
1 : 4
NDb
NDb
O
Me
O
Me
9
10
11
12
H
CO2Me
CO2Me
Me
30
19
NOE
5y
(S)
KHMDS 10 min
KHMDS 30 min
O
NRb
8a
Scheme 8.
dence of reactivity/stereoselectivity on the substrate structure
was observed, the Ireland-Claisen rearrangement producing the re-
quired stereochemistry at C18 and C19 for 1 was thus optimized by
applying the 10-min treatment with KHMDS to the 19R-lactate
substrate.
The cyclization of 4x and 4y by RCM with second-generation
Grubbs’ catalyst (24)19 in refluxing 1,2-dichloroethane smoothly
produced C-ring model 2 (67%) and 26 (69%), respectively (Scheme
7). The full absolute configurations of 2 and 26 as well as 4x and 4y
were elucidated by observation of NOE correlations in alcohols 25
(H18/19-CH3) and 27 (H18/H20), derived, respectively, from 2 and
26, and by application of the modified Mosher’s method20 to alco-
hols derived from 25 and 27 via TBS-protection and PMB-
detachment.
The attempt to cyclize 5x to BC-ring model 3 by RCM with 24
was unsuccessful (86% recovery of 5x), and the RCM of 5y only re-
sulted in a low yield of 19-epi-BC-ring model 30 (8%) (Scheme 8).
These results might be attributable to the steric congestion around
the double bond at C17. Therefore, the conversion of 5x to 3
employed a process including the removal of the bulky 2,2-di-
methyl-1,3-dioxolan-4-yl group and relay RCM, which was re-
ported to be effective for preparing sterically hindered cyclic
alkenes.7 Thus, one-pot acidic hydrolysis/oxidative diol cleavage,
followed by Luche reduction,14 transformed 5x to allyl alcohol 28
(overall 98%), which was reacted with allyl bromide to afford 29
(87%). Upon treatment with a catalytic amount of 24 in refluxing
1,2-dichloroethane, diallyl ether 29 was successfully cyclized to
BC-ring model 3 (73%). The stereochemistry of 3 and 30 was deter-
mined by the NOE correlations shown in Scheme 8 (3: H18/19-CH3,
H14/19-CH3, H14/H18; 30: H14/H18), thereby also confirming the
stereochemistry of rearrangement products 5x and 5y.
Me
13
14
15
16
LDA
LDA
10 min
30 min
66%c
62%c
53%c
26%c
1 : 4
1 : 4
19
(R)
KHMDS 10 min
KHMDS 30 min
9 : 1
O
8b
16 : 1
a
b
a three-step yield from 11. Dec: decomposition; NR: no reaction
(recovery of substrate); ND: not determined. c a two-step yield from 8.
Scheme 6.
MesN NMes
Ph
NOE
H
Cl
Cl
Ru
PCy3
LiAlH4
THF
OPMB
18
24 (0.1 eq)
19
4x
4y
2
O
(CH2Cl)2
reflux, 16 h
67%
0 °C
91%
H3C
OH
20
25
NOE
H
24 (0.1 eq)
(CH2Cl)2
H
LiAlH4
THF
OPMB
OPMB
18
19
O
O
Me
reflux, 24 h
69%
20
MeO2C
0 °C
87%
H2C
Me
26
OH
27
Scheme 7.
9:1), longer treatment of 7a or 7b with KHMDS decomposed the
substrate and decreased the yield (entries 3, 4, 7 and 8). It is nota-
ble that the LDA-promoted rearrangement of 8a and 8b afforded
undesired 5y as a major product (entries 9, 10, 13, and 14), con-
trary to the results from 7a and 7b. Interestingly, KHMDS was
effective for 8b to produce desired 5x with good selectively (16–
9:1) but was unproductive for 8a (entries 11, 12, 15, and 16). It
was also observed that the yield from 8b decreased with increasing
time of KHMDS exposure (entry 16). Although significant depen-
In conclusion, in our studies toward the total synthesis of arma-
tol F (1), a synthetic route including the stereoselective construc-
tion of the C18 and C19 stereocenters by Ireland-Claisen
rearrangement and the formation of the C-ring by relay RCM
was established through the synthesis of C-ring model 2 and

4546
K. Fujiwara et al. / Tetrahedron Letters 51 (2010) 4543–4546
6. For related approaches to b-alkoxyalkyl ethers using the Ireland-Claisen
rearrangement, see: (a) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 3465; (b) Sato, D.; Fujiwara, K.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2008, 49, 1514; (c) Fujiwara, K.; Kawamura, N.; Kawai, H.;
Suzuki, T. Tetrahedron Lett. 2009, 50, 1236.
7. Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 10210.
8. Goto, A.; Fujiwara, K.; Kawai, A.; Kawai, H.; Suzuki, T. Org. Lett. 2007, 9, 5373.
9. Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6.
15-Me-omitted BC-ring model 3. Further studies toward the total
synthesis of 1 are currently in progress.
Acknowledgments
We thank Dr. Eri Fukushi (GC–MS & NMR Laboratory, Graduate
School of Agriculture, Hokkaido University) for the measurements
of mass spectra. This work was supported by a Global COE Program
(B01: Catalysis as the Basis for Innovation in Materials Science) and
10. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
11. Auchus, R. J.; Covey, D. F.; Bork, V.; Schaefer, J. J. Biol. Chem. 1988, 263, 11640.
12. (a) Kuroda, H.; Tomita, I.; Endo, T. Polymer 1997, 38, 3655; (b) Inanaga, J.; Baba,
Y.; Hanamoto, T. Chem. Lett. 1993, 241.
13. The absolute configuration of the newly forming stereocenter (C16’) of 11 was
confirmed by applying the modified Mosher’s method20 to a saturated alcohol
obtained by conventional hydrogenation of 11.
a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology of Japanese
Government.
14. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
15. (a) Pikul, S.; Kozlowska, M.; Jurczak, J. Tetrahedron Lett. 1987, 28, 2627; (b)
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Supplementary data
Supplementary data associated (spectral data of 2, 25–27, 3, and
30) with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.06.103.
References and notes
17. Crystal data of 19b: C15H21NO2, M 771.74, orthorhombic P212121 (No. 19),
1. Ciavatta, M. L.; Wahidulla, S.; D’Souza, L.; Scognamiglio, G.; Cimino, G.
Tetrahedron 2001, 57, 617.
a = 5.306(1) Å, b = 15.353(3) Å, c = 16.913(4) Å, V = 1377.8(5) Å3, Dc
(Z = 4) = 1.192 g/cm3, T = 153 K,
l
= 0.78 cmÀ1. The final R value is 0.077 for
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2006, 8, 3663.
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336033 or e-mail: deposit@ccdc.cam.ac.uk]
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