A synthetic study of briarane-type marine diterpenoid, pachyclavulide B

Article abstract of DOI:10.1016/j.tetlet.2005.12.099

Enantioselective preparation of the six-membered ring of pachyclavulide B, a briarane-type diterpenoid, was achieved. The key step is desymmetrization of an achiral symmetric substrate by enantiogroup- and diastereoselective epoxidation. The asymmetric ep

Full text of DOI:10.1016/j.tetlet.2005.12.099

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1483–1486
A synthetic study of briarane-type marine diterpenoid,
pachyclavulide B
Junya Iwasaki, Hisanaka Ito,* Mitsutake Nakamura and Kazuo Iguchi*
School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 2 November 2005; revised 30 November 2005; accepted 1 December 2005
Abstract—Enantioselective preparation of the six-membered ring of pachyclavulide B, a briarane-type diterpenoid, was achieved.
The key step is desymmetrization of an achiral symmetric substrate by enantiogroup- and diastereoselective epoxidation. The asym-
metric epoxidation proceeded with up to 99% de and 94% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
OAc
Pachyclavulide B (1) isolated from the Okinawan soft
coral Pachyclavularia violacea by our group is a bri-
arane-type diterpenoid containing eight chiral centers
and a highly oxygenated tricyclic system,1 and it exhibi-
ted moderate growth-inhibitory activity against cancer
cells (SNB-75) of the central nervous system. Over 350
of the briarane-type diterpenoids were isolated from
various organisms.2,3 Details of various attractive bio-
logical activities of several of these compounds were
reported. Synthetic studies of briarane-type diterpenoids
were reported by several groups;4 however, total synthesis
has not yet been reported. Therefore, the total synthesis
of pachyclavulide B (1) was examined because 1 would
be converted easily to other briarane-type diterpenoids.
We report here the enantioselective synthesis of the six-
membered ring fragment through enantiogroup- and
diastereoselective epoxidation.
AcO
OH OH
OH
OTBDPS
H
O
H
HO
AcO
O
2
pachyclavulide B (1)
O
Enantiogroup Selective
Asymmetric Epoxidation
CO2R
CO2R
3
4
Scheme 1. Retrosynthetic analysis of pachyclavulide B.
could be synthesized through enantiogroup and diaste-
reoselective asymmetric epoxidation of achiral substrate
4. Compound 4 can be easily prepared by Birch reduc-
tion of 2,6-dimethylbenzoic acid.
Our synthetic plan of pachyclavulide B (1) is shown in
Scheme 1. Construction of the 10-membered ring would
be achieved through elongation of the carbon chain of 2
and ring-closing reaction. Therefore, compound 2 was
selected for a key intermediate. During consideration
of the preparation of 2, we found that compound 2
has a latent symmetric feature. Compound 2 could be
prepared from compound 3 by carbon–carbon bond
forming reaction with the construction of the quater-
nary carbon on the cyclohexene ring. Compound 3
Prior to the synthesis of 2, we examined the enantio-
group- and diastereoselective epoxidation of symmetric
1,4-cyclohexadiene derivatives.5 In this reaction system,
both enantiogroup selectivity and diastereoselectivity
were important, that is, the reagent attacks not only
from the Re or Si face of the tri-substituted carbon–car-
bon double bond but also from the less hindered site
to avoid the steric repulsion of the substituent such as
an alkoxycarbonyl or alkoxymethylene group. The
substrate was prepared from 2,6-dimethylbenzoic acid
through Birch reduction as shown in Scheme 2. All reac-
tions were carried out in excellent yield. The asymmetric
epoxidation of these substrates was examined using a
*
Corresponding authors. Tel.: +81 426 76 5473; fax: +81 426 76 7282
(H.I.); tel.: +81 426 76 7273; fax: +81 426 76 7282 (K.I.); e-mail
addresses: itohisa@ls.toyaku.ac.jp; onocerin@ls.toyaku.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.099

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J. Iwasaki et al. / Tetrahedron Letters 47 (2006) 1483–1486
point, the absolute stereochemistry of epoxides was
a
b or c
CO H
tentatively assigned based on mechanistic consideration
reported by Shi et al.5,6 We also confirmed the absolute
stereochemistry of epoxide ent-3b after converting to
compound 9 (vide infra).
CO H
CO R
2
2
2
4a
4b: R = Me
4c: R = TBDPS
d
e
4b
As mentioned above, asymmetric epoxidation was
achieved to obtain the mono-epoxide 3 with up to 99%
de and 94% ee. At first, we tried to convert 3c to com-
pound 8 through a reduction–protection sequence. The
epoxide moiety on 3c, however, was decomposed under
the reduction condition because relatively strong reduc-
tion condition was required to reduce the TBDPS ester
due to the steric repulsion of the TBDPS group. There-
fore, we employed 3b for the synthetic study of pachy-
clavulide B (1). The asymmetric epoxidation of 4b was
performed by the use of the enantiomer of 7 as a catal-
yst, which was prepared from D-sorbose,6 to give com-
pound ent-3b in 44% yield with 81% de and 87% ee
(Scheme 3). The reduction of the methoxycarbonyl
group successively proceeded to give an alcohol by using
DIBAL–H in 93% yield. After the protection of the
hydroxyl group with the TBDPS group, compound 8
was purified by recrystallization and almost enantiome-
rically pure 8 (99% ee) was obtained. Compound 8 was
converted to allylic alcohol derivative 9 by treating with
Et2AlTMP.8 The absolute stereochemistry of com-
pound 9 was determined after conversion to MTPA
esters by the Kusumi–Kakisawa method.9 For the
construction of the quaternary center on the cyclohex-
ene ring, intramolecular radical cyclization was per-
formed.10 The substrate 10 was prepared by treating 9
with ethyl vinyl ether in the presence of NIS in 80%
yield.11 Although the yield was unsatisfactory (32%
yield), the intramolecular radical cyclization proceeded
OH
OTBDPS
5a
5b
Scheme 2. Preparation of the substrates for epoxidation. Reagents and
conditions: (a) Na, NH3, EtOH, À50 °C, 96%; (b) CH2N2, ether, 0 °C,
quant; (c) TBDPSCl, imidazole, CH2Cl2, rt, quant; (d) LAH, THF,
0 °C, 97%; (e) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 98%.
chiral ketone as a catalyst with Oxone developed by Shi
et al.6 and the results are shown in Table 1.
For optimization of the reaction conditions, a catalyst 7,
which was prepared from D-fructose,6 was employed to
provide the antipode of the desired mono-epoxide. In
the case of substrate 4b, the yield was strongly depen-
dent on the amount of the catalyst (entries 1 and 2).
In the presence of 50 mol % of the catalyst, compound
3b7 was obtained in 55% yield with 75% de and 87%
ee. The use of 100 mol % of the catalyst increased the
de to 82% but the yield was significantly decreased
(44% yield, entry 3). A more bulky substituent (TBDPS)
was employed to increase the diastereoselectivity (entries
4–6). The reaction of 4c proceeded to provide 3c in
70% yield with excellent diastereoselectivity (99% de)
and enantioselectivity (94% ee) in the presence of 100
mol % of the catalyst (entry 6). We also examined a silyl-
oxymethyl substituent; however, the diastereoselectivi-
ties were not satisfactory (entries 7 and 8). At this
Table 1. Enantiogroup and diastereoselective asymmetric epoxidationa
O
O
O
O
O
O
Oxone
7
R
R
(MeO) CH /CH CN/H O
2
2
3
2
O
pH 10.5, -10 oC
4b: CO Me
3b: CO Me
2
2
4c: CO TBDPS
3c: CO TBDPS
6b: CH OTBDPS
2
2
2
5b: CH OTBDPS
2
Entry
Substrate
Cat (mol %)
Time (h)
Product
Yield (%)b
de (%)c
ee (%)d,e
1
2
3
4
5
6
7
8
4b
4b
4b
4c
4c
4c
5b
5b
30
50
100
30
50
100
50
2
3b
3b
3b
3c
3c
3c
6b
6b
27 (52)
55 (58)
44
37 (69)
56 (76)
70 (93)
56 (67)
49 (59)
75
75
82
99
99
99
75
83
88
87
87
93
93
94
84
84
4.5
4.5
2
3.5
6
3.5
3.5
100
a Reaction conditions were reported by Shi et al.
b Isolated yield. Numbers in parentheses were conversion yield after recovery of the substrate.
c De was determined by 1H NMR.
d Ee was determined for major diastereomer.
e Ee was determined by CHIRALCEL OJ-H for 3b, CHIRALPAK AD-H for 3c and CHIRALPAK AS-H for 6b.

J. Iwasaki et al. / Tetrahedron Letters 47 (2006) 1483–1486
1485
OH
O
O
d
a
b,c
OTBDPS
OTBDPS
CO Me
CO Me
2
2
ent-3b (87% ee)
4b
8 (99% ee)
9
OEt
OEt
O
I
O
O
O
e
f
h,i,j
g
OTBDPS
OTBDPS
OTBDPS
11
10
12
OH OH
O
OH
O
O
OH
OTBDPS
m
k,l
H
OTBDPS
OTBDPS
14
13
2
Scheme 3. Reagents and conditions: (a) ent-7, Oxone, CH3CN–DMM, 44%; (b) DIBAL–H, toluene, À78 °C, 93%; (c) TBDPSCl, imidazole, CH2Cl2,
rt, quant; (d) Et2AlTMP, toluene, 0 °C, 97%; (e) ethyl vinyl ether, NIS, CH2Cl2, À20 to 0 °C, 80%; (f) Bu3SnH, AIBN, toluene, 100 °C, 32%; (g)
Jones reagent, acetone, rt, 94%; (h) TBAF, THF, rt, 99%; (i) LDA, 2-(phenylsulfonyl)-3-phenyloxaziridine, THF, À30 to À10 °C, 62%; (j) TBDPSCl,
imidazole, DMF, rt, 90%; (k) LiAlH4, THF, rt; (l) NaIO4, THF–H2O, rt, then aq NaHCO3, THF–MeOH, rt, two steps 74%; (m) vinylmagnesium
chloride, THF, 0 °C, quant.
Nucleophile
TBDPSO
H
H
TBDPSO
H
O
H
O
O
O
Mg
R
15
Figure 2.
Figure 1. NOE correlations of 15.
the Si face of the carbonyl group to avoid the steric
repulsion of the TBDPS group to create an (S) chiral
center bearing a hydroxyl group.
to give compound 11 along with a significant amount of
iodine-reduced and 6-endo cyclized products.12 For the
conversion of compound 11 to aldehyde 14 with one car-
bon degradation, the acetal moiety of 11 was directly
oxidized to a lactone using Jones reagent and 12 was
obtained in 94% yield. The incorporation of a hydroxyl
group at the a-position of lactone 12 was found to be
difficult due to the steric repulsion of the TBDPS group;
however, the reaction proceeded in a diastereoselective
manner (>95% de) after removal of the TBDPS group.
Although the stereochemistry of the product 13 was
not determined, it could be speculated that the Davis
reagent13 approached from the convex face of lithium
enolate of 12. After conversion of 13 to a diol derivative,
oxidative cleavage was achieved by treating with NaIO4
and aldehyde 14 was obtained.
The enantioselective preparation of key intermediate 2
for the synthesis of the briarane-type diterpenoid,
pachyclavulide B (1), was achieved. Enantiogroup and
distereoselective epoxidation of the symmetric substrate
succeeded to give the optically active mono-epoxide.
Work on the total synthesis of pachyclavulide B and
related briarane-type diterpenoids is now under way.
References and notes
1. Iwasaki, J.; Ito, H.; Aoyagi, M.; Sato, Y.; Iguchi, K. J.
Nat. Prod., in press.
2. For reviews of briarane-type diterpenoid, see: (a) Sung,
P.-J.; Sheu, J.-H.; Xu, J.-P. Heterocycles 2002, 57, 535–
579; (b) Sung, P.-J.; Chang, P.-C.; Fang, L.-S.; Sheu,
J.-H.; Chen, W.-C.; Chen, Y.-P.; Lin, M.-L. Heterocycles
2005, 55, 195–204.
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68, 1328–1335; (b) Iwagawa, T.; Nishitani, N.; Nakatani,
M.; Doe, M.; Morimoto, Y.; Takemura, K. J. Nat. Prod.
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Xiao, Z.-H.; Li, Q.-X. Helv. Chim. Acta 2005, 88, 2349–
2354; (d) Iwagawa, T.; Babazono, K.; Okamura, H.;
Nakatani, M.; Doe, M.; Morimoto, Y.; Shiro, M.;
Takemura, K. Heterocycles 2005, 65, 2083–2093; (e) Lin,
The diastereoselective addition reaction of vinylmagne-
sium chloride to 14 was achieved to give compound 2
as a single diastereomer in quantitative yield.14 The ste-
reochemistry of 2 was determined by NOESY spectra
after conversion of 2 to compound 15 as shown in Fig-
ure 1.
The mechanism of the diastereoselectivity was specu-
lated as shown in Figure 2. The chelation of magnesium
between the carbonyl oxygen and the hydroxyl group on
the cyclohexene ring fixed the conformation of the alde-
hyde carbonyl group. The nucleophile approached from

1486
J. Iwasaki et al. / Tetrahedron Letters 47 (2006) 1483–1486
Y.-C.; Huang, Y.-L.; Khalil, A. T.; Chen, M.-H.; Shen,
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maniam, R. P.; Moss, D. K.; Wyatt, J. K.; Spence, J. D.
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5. Recently, Shi et al. reported enantiogroup and diastereo-
selective epoxidation via kinetic resolution and desym-
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Zhang, J.-R.; Tang, Y.; Burke, C.; Shi, Y. J. Org. Chem.
2005, 70, 2904–2911.
11. White, J. D.; Blakemore, P. R.; Green, N. J.; Hauser, E.
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12. We also examined triethylborane-induced radical cycliza-
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obtained. See: (a) Villar, F.; Equey, O.; Renaud, P. Org.
Lett. 2000, 2, 1061–1064; (b) Fujita, K.; Nakamura, T.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123,
3137–3138; (c) Takami, K.; Mikami, S.; Yorimitsu, H.;
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6635.
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Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org.
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7. Compound 3b: Colorless oil. [a]D +154.0 (c 1.0, CHCl3)
(87% ee). IR (film) m cmÀ1; 2968, 2912, 1741, 1454, 1435.
1H NMR (300 MHz, CDCl3) d 1.37 (3H, s), 1.68 (3H, br
s), 2.51–2.68 (2H, m), 3.18 (1H, s), 3.34 (1H, s), 3.73 (3H,
s), 5.33 (1H, br s). 13C NMR (75 MHz, CDCl3) d 20.9,
22.3, 26.4, 52.2, 52.9, 57.5, 58.1, 119.2, 128.3, 172.2.
HRESIMS Calcd for C10H15O3 (M+H)+ 183.1021, found
183.1013.
8. Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.;
Linnane, P.; Tavares, F.; Lynch, V. Tetrahedron 1999,
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9. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096.
14. Compound 2: Colorless oil. [a]D +83.7 (c 0.95, CHCl3). IR
(film) m cmÀ1; 3307, 2930, 2857, 1590, 1471, 1455, 1428. 1H
NMR (300 MHz, CDCl3) d 1.04 (9H, s), 1.11 (3H, s), 1.50
(3H, br s), 2.14 (1H, br s), 2.15 (1H, br d, J = 18.5 Hz),
2.43 (1H, br d, J = 18.5 Hz), 3.15 (1H, d, J = 2.2 Hz), 3.32
(1H, br d, J = 6.0 Hz), 3.70 (1H, dd, J = 4.7, 11.1 Hz),
3.78 (1H, dd, J = 3.1, 11.1 Hz), 4.27 (1H, td, J = 5.7,
7.4 Hz), 4.44 (1H, d, J = 7.4 Hz), 5.17 (1H, dd, J = 1.7,
18.0 Hz), 5.19 (1H, dd, J = 1.7, 10.6 Hz), 5.41 (1H, br s),
5.87 (1H, ddd, J = 7.4, 10.6, 18.0 Hz), 7.37–7.42 (6H, m),
7.64–7.68 (4H, m). 13C NMR (75 MHz, CDCl3) d 15.4,
19.1, 22.3, 26.8, 32.3, 42.2, 47.5, 61.9, 73.2, 77.6, 117.6,
121.3, 127.6, 127.7, 129.7, 132.6, 133.1, 133.3, 135.6, 135.7,
137.3. HRESIMS Calcd for C28H39O3Si (M+H)+
451.2668, found 451.2645.
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Okawara, M. J. Am. Chem. Soc. 1982, 104, 5564–5566; (b)
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