Enantioselective total synthesis of 13-O-brefeldin A

Article abstract of DOI:10.1016/j.tet.2008.09.065

An enantioselective route to the title compound, a heteroatom substituted close analogue of natural brefeldin A, is described. As a key step in the whole synthesis, concatenation of the lower chain and the cyclopentanone-upper chain moiety was achieved using a Rh-catalyzed Michael addition of a vinyl boronic acid to an enone, which effectively eliminated the problems encountered with the corresponding cuprate protocol and exemplified the potential of the strategy in synthesizing similar analogues.

Full text of DOI:10.1016/j.tet.2008.09.065

Tetrahedron 64 (2008) 11105–11109
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective total synthesis of 13-O-brefeldin A
*
Jian Gao, Yi-Xian Huang, Yikang Wu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective route to the title compound, a heteroatom substituted close analogue of natural
brefeldin A, is described. As a key step in the whole synthesis, concatenation of the lower chain and the
cyclopentanone-upper chain moiety was achieved using a Rh-catalyzed Michael addition of a vinyl
boronic acid to an enone, which effectively eliminated the problems encountered with the corresponding
cuprate protocol and exemplified the potential of the strategy in synthesizing similar analogues.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 August 2008
Received in revised form
20 September 2008
Accepted 23 September 2008
Available online 30 September 2008
Keywords:
Antibiotics
Michael additions
Natural products
Analogues
Heterocycles
1. Introduction
and propargyl bromide as the precursors for the lower chain. Be-
sides, as O- or S-alkylation, especially when using a reactive halide,
(þ)-Brefeldin A1 (1, BFA) is one of the natural products that have
attracted considerable attention in the synthetic community since the
late 1970s. To date, some 30 total/formal syntheses have already been
documented in the literature.2 Apart from its interesting molecular
architecture BFA’s significant antitumor, antiviral, antifungal, and
antimitotic activities are also important factors that stimulated re-
searchers to enter the area. Several investigations devoted to BFA’s
derivatives and analogues have already appeared.3 In a recent paper
we reported3i the 15-demethyl analogue of 1. Here we wish to describe
synthesis of 13-O-substituted BFA (2), a novel analogue that is not
accessible from natural BFA through partial structural modification.
is remarkably more facile than alkylation of a carbon atom, re-
placement of the C-13 with an oxygen or sulfur atom, therefore,
may facilitate the synthesis without causing drastic changes in
molecular size and shape of the end product. Should not this
change affect the bioactivities, such a more readily accessible lower
chain may be also used as a substitute for the all-carbon chain to
facilitate the synthesis of analogues modified in other positions.
These considerations urged us to synthesize 2.
In a recent paper,2m we described the first application of the Rh-
catalyzed4 Michael addition of vinyl boronic acids to enones in total
synthesis of natural products, where the union of the lower chain
(3a) of BFA and the enone 4 was achieved in 95% yield using only
0.03 mol % of [RhCl(COD)]2 (COD¼cycloocta-1,5-diene) as the cat-
alyst. As far as the synthesis of BFA is concerned, this Rh catalyst-
boronic acid approach enjoys a number of advantages over the
traditional cuprate protocol, including simple operations, low
sensitivity toward air and moisture, no need for the use of a large
excess of the optically active lower chain, and high reproducibility.
Indeed, when using the conventional cuprate protocol we were
frustrated at times by complete failure in obtaining the anticipated
Michael adduct while the optically active starting materials accu-
mulated through many steps of reactions were fully destroyed.
Such a problem appeared to be even more serious with the oxygen-
substituted lower chain (the cuprates closely related to 3b),
perhaps the presence of an alkoxy group at the allylic position
had some adverse effects. Encouraged by the success with
OH
4
OH
4
2
2
H
H
6
8
6
8
O
O
7
7
HO
HO
O
O
15
15
10
10
O
13
13
2 (+)-13-O-Brefeldin A
1 (+)-Brefeldin A
2. Results and discussion
Inspection of the BFA’s structure revealed that insertion of
a heteroatom at position 13 would make it possible to use lactate
* Corresponding author.
E-mail address: yikangwu@mail.sioc.ac.cn (Y. Wu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.065

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J. Gao et al. / Tetrahedron 64 (2008) 11105–11109
the all-carbon lower chain addition in total synthesis of 1, we de-
cided to examine the Rh-boronic acid approach (Scheme 1) in the
present investigation.
then reduced with SmI2/i-PrOH, which proved2m to be the best
reducing agent for the corresponding reduction in the synthesis of
1. In the present case, the desired 9a was also formed as the major
product as expected. The minor isomer 9b was readily separated
from 9a and could be converted into 9a through Mitsunobu in-
version using DEAD (diethyl azodicarboxylate)/Ph3P/p-nitro-
benzoic acid followed by alkaline hydrolysis.
OH
B
10
OBn
15
OH
13
H
H
O
HO
O
3a
Use of the ‘ate’ compounds prepared8 in situ from DIBAL-H/
n-BuLi and DIBAL-H/t-BuLi, respectively, to reduce 8 was also ex-
amined. As observed2m previously with the similar substrate in the
synthesis of 1, reduction under such conditions also afforded the
HO
HO
O
O
OTBS
H
1
OBn
OH
4
2
6
4
O
b-OH isomer 9b as the main product. When using DIBAL-H/n-BuLi
7
as reducing agent, the ratio of 9a/9b was ca. 1:5. With DIBAL-H/
t-BuLi, 9b was formed as the only detectable product in quantitative
yield after reaction in THF at ꢀ78 ꢁC for 30 min.
OH
B
10
OBn
15
8
13
O
10
15
O
HO
13
3b
2
When using boronic acid 11 as the lower chain, which contained
a sulfur instead of an oxygen atom at the allylic position, no Michael
adduct (12) was formed at all under otherwise identical conditions
(Scheme 3). The starting materials were essentially quantitatively
recovered. Increasing the amount of the added rhodium catalyst
did not lead to any changes.
Scheme 1.
As we have already developed a highly efficient route to the
enone 4,2m the main task before executing the Michael addition
depicted in Scheme 1 was to prepare the boronic acid 3b. To this
end, L
-ethyl lactate was protected5 with benzyl group and reduced6
to the corresponding alcohol using the literature procedures
(Scheme 2). The resultant 6 was alkylated with propargyl bromide/
NaH in DMF, giving alkyne 7.7
OTBS
OTBS
H
OBn
H
H
OBn
[RhCl(COD)]2
O
O
4
OBn
15
O
O
BnO
S
a
b
EtO
HO
OH
13
S
12
OBn
OH
OBn
B
5
HO
11
10
7
L-(-)-Lactate
6
c
Scheme 3.
OBn
OTBS
H
H
Compound 9a was then further elaborated into the end product
OBn
15
HO
B
d
e
13-O-BFA 2 as shown in Scheme 4. The hydroxyl group was first
masked as a TBS ether with TBSCl (t-butyl-dimethyl-silyl chloride)
in DMF (N,N’-dimethylformamide) in the presence of 2,6-lutidine.
The two benzyl protecting groups were removed under the con-
ditions9 of Liu, giving diol 14. The allylic hydroxyl group was se-
lectively oxidized into the corresponding aldehyde with activated
MnO2 in CH2Cl2,10 which on further treatment with NaClO2 in the
presence of NaH2PO4/methyl-2-butene11 afforded the hydroxyl
acid 15.
O
O
BnO
O
HO
3b
8
OTBS
OTBS
H
H
OBn
OBn
7
HO
7
HO
BnO
O
BnO
H
f
H
9a
O
9b
15%
75%
OTBS
OTBS
H
H
H
H
OBn
OTBS
OBn
H
H
a
g
OBn
BnO
TBSO
HO
BnO
O
BnO
O
PNBO
10
b
13
9a
O
Scheme 2. (a) Refs. 5,6; (b) NaH/propargyl bromide/DMF, 86% (Ref. 7); (c) (i) cat-
echolborane (neat)/70 ꢁC, (ii) H2O/rt, 89% from 7; (d) enone 4/[RhCl(COD)]2/MeOH/H2O
(6:1)/LiOH/rt/1 h, 92%; (e) SmI2/i-PrOH/THF/0 ꢁC/3 h; (f) DEAD/Ph3P/p-nitrobenzoic
acid/THF/rt/2 days, 89%; (g) NaOH/MeOH/rt/2 h, 91%.
OTBS
OTBS
H
H
H
OH
O
CO2H
HO
c
TBSO
TBSO
HO
H
O
O
15
14
Conversion of the terminal alkyne to corresponding vinyl bo-
ronic acid was achieved by the addition of catecholborane followed
by hydrolysis. As mention in the previous work, complete removal
of catechol at the work-up is of critical importance. Contamination
of 3b by traces of catechol may lead to complete failure in the
subsequent Rh-catalyzed Michael addition. Besides, compared with
the boronic acid involved in the synthesis of 1, the one in this work
(3b) is remarkably more unstable and thus should be used in the
next step immediately after its preparation.
In sharp contrast to the difficulty repeatedly encountered with
the corresponding cuprated-mediated Michael addition, the addi-
tion of 3b to 4 proceeded smoothly when using [RhCl(COD)]2 as the
catalyst, affording the adduct 8 in 92% yield. The C-7 ketone was
d
OH
H
OTBS
H
O
e
4
HO
7
TBSO
16
O
15
O
H
O
13-O-BFA
2
H
O
Scheme 4. (a)2,6-Lutidine/TBSCl/DMF/rt/24 h, 91%; (b)Li/naphthalene/THF/ꢀ30 ꢁC/3 h,
85%; (c) (i) MnO2/CH2Cl2/rt/4 h, (ii) t-BuOH/NaClO2/NaH2PO4/Me2C]CHMe/rt/2 h, 70%;
(d) MNBA/DMAP/4 Å MS/toluene/rt/20 h, 81%; (e) 2 N HCl/THF/H2O (1:1)/rt/48 h, 94%.
The macrolactonization was realized using the MNBA
(2-methyl-6-nitrobenzoic anhydride) protocol12 of Shiina, which in

J. Gao et al. / Tetrahedron 64 (2008) 11105–11109
11107
4.2. Synthesis of ketone 8 via Rh-mediated Michael addition
of 3b to enone 4
A solution of alcohol 6 (3.32 g, 20 mmol) in dry DMF (10 mL)
was added dropwise to a suspension of NaH (0.96 g, 60% suspen-
sion in mineral oil, 24 mmol, washed with hexane) in dry DMF
(70 mL) stirred at 0 ꢁC. The mixture was stirred at the same tem-
perature for 1 h before propargyl bromide (1.32 mL, 24 mmol) was
added dropwise. The stirring was continued at ambient tempera-
ture for 24 h (giving a dark mixture). Water (100 mL) was then
introduced. The mixture was extracted with Et2O (4ꢂ50 mL). The
combined organic layers were washed with water and brine before
being dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography on silica gel (1:10
24
EtOAc/PE) gave 7 as yellowish oil (3.50 g, 17.1 mmol, 86%). [a]
D
ꢀ4.3 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.42–7.25 (m, 5H),
4.62 (s, 2H), 4.20 (d, J¼2.1 Hz, 2H), 3.80–3.70 (m, 1H), 3.62–3.53 (m,
Figure 1. The ORTEP plot of 13-O-BFA (2).
2H), 2.43 (t, J¼2.3 Hz, 1H), 1.22 (d, J¼6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3)
d 128.4, 127.7, 127.5, 74.4, 73.8, 71.1, 58.6, 17.2.
our hands gave the most satisfactory results2m,13 in synthesis of 1
and antimycin A3b. Finally, the TBS protecting groups were hydro-
lyzed with 2 N HCl in THF/H2O to afford the end product 13-O-BFA
2.
Although initially compound 2 was obtained as an oil after
chromatography, it could be crystallized from MeOH. This property
made it possible to perform a single crystal X-ray crystallographic
analysis14 (Fig. 1).
A mixture of the above prepared 7 (774 mg, 3.79 mmol) and
catecholborane (neat, 0.43 mL, 3.98 mmol) was stirred at 70 ꢁC
(bath) under argon until TLC showed completion of the reaction (ca.
24 h). The mixture was cooled down to ambient temperature.
Water (10 mL) was then added. The mixture was vigorously stirred
for 5 min. The upper layer (aqueous) was then removed using
a pipette. This procedure was repeated for five times (until TLC
showed no catechol remained in the organic layer). The organic
phase was diluted with Et2O (25 mL), washed with water and brine,
and dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography on silica gel (1:3 EtOAc/
PE) gave the unstable 3b as a colorless oil (843 mg, 3.37 mmol,
3. Conclusions
89%). 1H NMR (300 MHz, CDCl3)
d 7.40–7.20 (m, 5H), 6.54 (dt,
As part of our efforts to develop new analogues of natural
brefeldin A for future study of the structure–activity relationships
(SAR), 13-O-BFA has been synthesized. Its single crystal X-ray
structure has also been determined. Unlike many derivatives/
analogues of BFA so far known, this novel heteroatom substituted
congener is not accessible from structural modification of the
natural BFA and thus might offer relevant SAR information not
attainable otherwise. The synthesis exploits the general strategy
recently developed by us for the natural product 1 itself, with the
key concatenation step achieved using the Rh-catalyzed4 Michael
addition of a vinyl boronic acid to an enone. Use of this protocol
here effectively eliminated the problems associated with the
conventional cuprate Michael addition and thus greatly facilitated
the whole synthesis. However, when the vinyl boronic acid con-
tained a sulfur instead of an oxygen atom at the allylic position the
Michael addition could not occur under otherwise the same
conditions.
J¼18.2, 4.6 Hz, 1H), 5.69 (dt, J¼18.3, 1.8 Hz, 1H), 4.63 (s, 1H), 4.62 (s,
1H), 4.11 (dd, J¼4.1, 2.7 Hz, 2H), 3.82–3.70 (m, 1H), 3.60–3.40 (m,
2H), 1.22 (d, J¼6.1 Hz, 3H); FTIR (film) 3291, 2927, 2871, 1643, 1603,
1512, 1472, 1373, 1259, 1236, 1097, 1057, 745, 698 cmꢀ1, which was
utilized immediately in the following step.
LiOH (7.3 mg, 0.174 mmol, 0.5 equiv) was added to a mixture of
the above prepared boronic acid 3b (104 mg, 0.416 mmol),
[RhCl(COD)]2 (5.1 mg, 0.01 mmol), and enone
4
(129 mg,
0.347 mmol) in MeOH/H2O (6:1, 2.1 mL). The mixture was stirred at
ambient temperature for 1 h before being concentrated on a rotary
evaporator. The residue was chromatographed on silica gel (1:12
EtOAc/PE) to afford 8 as a colorless oil (185 mg, 0.309 mmol, 92%).
28
[a
]
ꢀ49.3 (c 1.15, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.39–7.26
D
(m, 10H), 5.78–5.60 (m, 4H), 4.63 (s, 2H), 4.50 (s, 2H), 4.32 (d,
J¼6.6 Hz, 1H), 4.04–3.98 (m, 4H), 3.75 (quintet, J¼6.0 Hz, 1H), 3.52
(dd, J¼10.0, 6.0 Hz, 1H), 3.42 (dd, J¼10.0, 4.6 Hz, 1H), 2.89–2.75 (m,
1H), 2.54–2.33 (m, 2H), 2.25–1.90 (m, 3H), 1.18 (d, J¼6.3 Hz, 3H),
0.88 (s, 9H), 0.04 (s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, CDCl3)
4. Experimental
4.1. General
d 217.1, 138.9, 138.2, 135.0, 134.2, 128.4, 128.3, 127.6, 127.5, 127.3,
74.4, 74.0, 72.1, 71.5, 71.1, 70.7, 69.9, 49.3, 45.3, 40.9, 37.8, 25.9, 18.2,
17.2, ꢀ3.7, ꢀ4.7; FTIR (film) 2928, 2856, 1744, 1716, 1451, 1361, 1253,
1108, 972, 836 cmꢀ1; ESIMS m/z 601.3 ([MþNa]þ). MALDIHRMS
calcd for C35H50O5SiNa ([MþNa]þ): 601.3320; found: 601.3321.
The 1H NMR and 13C NMR spectra were recorded at ambient
temperature using a Varian Mercury 300 or a Bruker Avance 300
instrument (operating at 300 MHz for proton). The FTIR spectra
were scanned with a Nicolet Avatar 360 FTIR spectrometer. The
ESIMS and ESIHRMS/MALDIHRMS were recorded with a PE Mar-
iner API-TOF and an APEX III (7.0 T) FTMS mass spectrometer,
respectively. The melting points were uncorrected. Optical rota-
tions were recorded on a Jasco P-1030 polarimeter. Dry THF and
Et2O were distilled from Na/Ph2CO under N2 prior to use. Dry
DMF and CH2Cl2 were distilled over CaH2 under N2 prior to use.
PE (chromatography eluent) stands for petroleum ether (bp
60–90ꢁC).
4.3. SmI2 reduction of cyclopetanone 8 leading
to alcohols 9a/9b
A freshly prepared solution of SmI2 (0.1 M, 13 mL) in anhydrous
THF was added dropwise to a solution of ketone 8 (150 mg,
0.259 mmol) in anhydrous THF (2.0 mL) and i-PrOH (0.4 mL) stirred
to 0 ꢁC. The resulting blue solution was stirred at 0 ꢁC until TLC
showed completion of the reaction (ca. 3 h). Et2O (20 mL) and 1% aq
HCl (5.0 mL) were added. The mixture was stirred for another
15 min before the phases were separated. The aqueous layer was

11108
J. Gao et al. / Tetrahedron 64 (2008) 11105–11109
back extracted with Et2O. The combined organic layers were
washed successively with aq satd Na2S2O3, water and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography on silica gel (1:10 EtOAc/
PE) afforded 9a (the more polar component, 113 mg, 0.194 mmol,
75%) and 9b (the less polar component, 23 mg, 0.0396 mmol, 15%)
FTIR (film) 2927, 2855, 1723, 1607, 1496, 1453, 1350, 1274, 1118, 969,
837, 721, 697 cmꢀ1; ESIMS m/z 752.5 ([MþNa]þ). ESIHRMS calcd for
C42H55NO8SiNa ([MþNa]þ): 752.3589; found: 752.3577.
4.6. Conversion of 10 into 9a
as colorless oils.
A solution of NaOH (1.012 g, 2.525 mmol) in MeOH (4 mL) was
added to a solution of 10 (219 mg, 0.300 mmol) in MeOH (2 mL).
After completion of the addition, the mixture was stirred at am-
bient temperature until TLC showed completion of the reaction (ca.
2 h). Water (5 mL) was added. The mixture was concentrated on
28
Data for 9a: [
a
]
ꢀ14.7 (c 3.1, CHCl3); 1H NMR (300 MHz, CDCl3)
D
d
7.38–7.21 (m, 10H), 5.75–5.60 (m, 3H), 5.51 (dt, J¼15.4, 6.0 Hz,1H),
4.63 (s, 2H), 4.49 (s, 2H), 4.30–4.22 (m, 1H), 4.02–3.95 (m, 4H),
3.79–3.67 (m, 1H), 3.50 (dd, J¼9.8, 6.0 Hz, 1H), 3.39 (dd, J¼10.0,
5.5 Hz,1H), 2.39–2.53 (m, 1H), 2.22–2.10 (m, 1H), 2.03–1.86 (m, 2H),
1.65–1.37 (m, 2H), 1.20 (d, J¼6.8 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H),
a
rotary evaporator. The residue was extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were washed with water
and brine before being dried over anhydrous MgSO4. Removal of
the solvent by rotary evaporation and column chromatography on
silica gel (1:8 EtOAc/PE) gave 9a as a colorless oil (159 mg,
0.273 mmol, 91%). Data for 9a: see above.
0.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 139.0, 138.4, 138.1, 136.2,
128.4, 128.3, 127.7, 127.6, 127.5, 126.4, 126.1, 74.1, 74.0, 72.8, 72.2,
72.0, 71.9, 71.1, 70.2, 50.3, 42.7, 42.6, 35.2, 26.0, 18.2,17.4, ꢀ3.7, ꢀ4.7;
FTIR (film) 3364, 2927, 2855, 1454, 1373, 1257, 1093, 972, 835,
697 cmꢀ1
;
ESIMS m/z 603.5 ([MþNa]þ). ESIHRMS calcd for
C35H52O5SiNa ([MþNa]þ): 603.3476; found: 603.3466.
28
4.7. TBS protection of 9a leading to 13
Data for 9b: [
a
]
ꢀ8.9 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3)
D
d
7.35–7.15 (m, 10H), 5.70–5.43 (m, 4H), 4.54 (s, 2H), 4.42 (s, 2H),
A solution of 9a (120 mg, 0.207 mmol), 2,6-lutidine (0.05 mL,
0.414 mmol), and TBSCl (62 mg, 0.414 mmol) in anhydrous DMF
(1.0 mL) was stirred at ambient temperature for 24 h. Ice-water
(5.0 mL) was introduced. The mixture was extracted with Et2O
(3ꢂ25 mL). The combined ethereal phases were washed with aq
satd CuSO4, water and brine, dried over anhydrous Na2SO4. Re-
moval of the solvent on a rotary evaporator left a residue, which
4.20–4.04 (m, 2H), 3.40–3.85 (m, 4H), 3.73–3.60 (m, 1H), 3.45 (dd,
J¼10.0, 5.9 Hz, 1H), 3.33 (dd, J¼10.1, 4.7 Hz, 1H), 2.80 (br s, OH),
2.70–2.60 (m, 1H), 1.90–1.75 (m, 3H), 1.70–1.56 (m, 2H), 1.43–1.35
(m, 1H), 1.15 (d, J¼6.4 Hz, 3H), 0.93 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H);
13C NMR (75 MHz, CDCl3)
d 138.9, 138.2, 137.1, 135.6, 128.4, 128.3,
127.6, 127.4, 126.9, 126.2, 74.1, 73.9, 72.9, 72.4, 72.0, 71.8, 71.0, 69.9,
50.3, 43.3, 42.1, 34.8, 25.9, 18.2, 17.3, ꢀ3.8, ꢀ4.5; FTIR (film) 3466,
2929, 2856, 1454, 1362, 1255, 1100, 972, 836, 697 cmꢀ1; ESIMS m/z
603.4 ([MþNa]þ). ESIHRMS calcd for C35H52O5SiNa ([MþNa]þ):
603.3476; found: 603.3468.
was purified by flash column chromatography (1:25 EtOAc/PE) to
28
afford 13 as a colorless oil (131 mg, 0.188 mmol, 91%). [
a]
ꢀ15.8 (c
D
6.45, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.40–7.22 (m, 10H), 5.73–
5.60 (m, 3H), 5.48 (dt, J¼15.1, 6.2 Hz, 1H), 4.62 (s, 2H), 4.49 (s, 2H),
4.25–4.16 (m, 1H), 4.15–4.10 (m, 1H), 4.03–3.93 (m, 4H), 3.78–3.67
(m, 1H), 3.50 (dt, J¼10.2, 6.1 Hz, 1H), 3.39 (dt, J¼10.1, 4.8 Hz, 1H),
2.46–2.34 (m, 1H), 2.09–1.73 (m, 3H), 1.56–1.39 (m, 2H), 1.21 (d,
J¼6.5 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.04 (s, 3H), 0.02 (s, 6H), 0.01
4.4. LiAl(i-Bu)2(t-Bu)H reduction of 8 leading to 9b
t-BuLi (1.7 M in pentane, 2.1 mL, 3.6 mmol) was slowly added to
DIBAL-H (1.0 M in toluene, 3.6 mL, 3.6 mmol) stirred at 0 ꢁC under
argon to generate LiAl(i-Bu)2(t-Bu)H (0.63 M). The resultant clear
solution (0.63 M, 1.1 mL, 0.67 mmol) was then added to a solution
of 8 (95 mg, 0.165 mmol) in anhydrous THF (4.0 mL) stirred at
ꢀ78 ꢁC under argon. The solution was stirred at ꢀ78 ꢁC for 30 min
before being diluted with EtOAc (30 mL), washed with 5% aq HCl, aq
satd NaHCO3 and brine, and dried over anhydrous MgSO4. Removal
of the solvent on a rotary evaporator left 9b (the only product) as
a colorless oil (96 mg, 0.165 mmol, 100%). Data for 9b: see above.
(s, 3H); 13C NMR (75 MHz, CDCl3)
d 138.9, 138.5, 138.3, 136.5, 128.4,
128.3, 127.6, 127.5, 127.4, 126.1, 125.6, 73.9, 73.3, 72.3, 72.0, 71.7, 71.1,
70.1, 49.9, 43.1, 42.3, 35.0, 25.9, 18.1, 17.3, ꢀ3.7, ꢀ4.8; FTIR (film)
2928, 2855, 1736, 1471, 1361, 1251, 1110, 835, 774, 696 cmꢀ1; ESIMS
m/z 717.7 ([MþNa]þ). ESIHRMS calcd for C41H66O5Si2Na ([MþNa]þ):
717.4341; found: 717.4322.
4.8. Removal of the benzyl groups in 13 leading to 14
4.5. Conversion of 9b into 10
A solution of 13 (129 mg, 0.186 mmol) in anhydrous THF
(4.0 mL) was added to a freshly prepared solution of Li-naphthalene
in anhydrous THF (0.23 M, 12 mL) stirred at ꢀ30 ꢁC under argon.
The dark-green mixture was stirred at the same temperature for
3 h, when TLC showed completion of the reaction. Water was added
carefully, followed by Et2O (50 mL). The phases were separated. The
organic phase was washed with water and brine before being dried
over anhydrous Na2SO4. Removal of the solvent by rotary evapo-
With cooling (ice-water bath) and stirring, DEAD (216 mL,
1.383 mmol) was added dropwise to a solution of 9b (196 mg,
0.337 mmol), Ph3P (345 mg, 1.316 mmol), and p-nitrobenzoic acid
(212 mg, 2.282 mmol) in dry THF (6.7 mL). After completion of the
addition, the clear yellow solution was stirred at ambient temper-
ature until TLC showed completion of the reaction (ca. 2 days).
Solvent was removed by rotary evaporation. The residue was
ration and column chromatography on silica gel (1:3 EtOAc/PE)
27
chromatographed on silica gel (1:50 EtOAc/PE) to give 10 as a yel-
afforded 14 as a colorless oil (81 mg, 0.157 mmol, 85%). [
a
]
ꢀ16.4
D
(c 3.3, CHCl3); 1H NMR (300 MHz, CDCl3)
d 5.74–5.54 (m, 3H), 5.42
27
low sticky oil (219 mg, 0.300 mmol, 89%). [
a
]
D
ꢀ12.6 (c 2.95,
CHCl3); 1H NMR (300 MHz, CDCl3)
d
8.25 (d, J¼8.9 Hz, 2H), 8.15 (d,
(dt, J¼15.5, 6.4 Hz, 1H), 4.18 (quintet, J¼5.3 Hz, 1H), 4.08 (d,
J¼4.4 Hz, 2H), 4.02–3.85 (m, 4H), 3.41 (dd, J¼9.2, 2.6 Hz,1H), 3.23 (t,
J¼8.9 Hz, 1H), 2.28 (quintet, J¼8.4 Hz, 1H), 2.07–1.93 (m, 2H), 1.70
(dd, J¼8.6, 5.2 Hz, 2H), 1.44 (ddd, J¼13.3, 8.4, 5.5 Hz, 1H), 1.15 (d,
J¼6.4 Hz, 3H), 0.87 (s, 18H), 0.03 (m, 6H), ꢀ0.04 (s, 6H); 13C NMR
J¼9.1 Hz, 2H), 7.40–7.20 (m, 10H), 5.75–5.53 (m, 4H), 5.43–5.35 (m,
1H), 4.61 (s, 2H), 4.48 (s, 2H), 4.25–4.19 (m, 1H), 4.05–3.95 (m, 4H),
3.80–3.65 (m, 1H), 3.50 (dd, J¼9.8, 5.8 Hz, 1H), 3.39 (dd, J¼9.8,
4.7 Hz, 1H), 2.66–2.53 (m, 1H), 2.48ꢀ2.35 (m, 1H), 2.23–2.10 (m,
1H), 2.07–1.93 (m, 1H), 1.92–1.80 (m, 1H), 1.80–1.67 (m, 2H), 1.20 (d,
J¼6.4 Hz, 3H), 0.93 (s, 9H), 0.06 (s, 3H), 0.03 (s, 9H); 13C NMR
(75 MHz, CDCl3)
d 140.8, 134.7, 129.1, 125.0, 76.4, 75.5, 73.1, 72.2,
66.4, 62.8, 50.1, 43.4, 42.9, 38.0, 25.9, 18.6, 18.1, ꢀ3.7, ꢀ4.7; FTIR
(75 MHz, CDCl3)
d
164.3, 138.1, 136.4, 135.9, 135.6, 130.5, 128.3,
(film) 3404, 2928, 2855, 1472, 1361, 1254, 1107, 836, 775 cmꢀ1
;
128.2, 127.6, 127.5, 127.4, 126.8, 126.6, 123.4, 76.6, 74.1, 73.8, 72.0,
71.7, 71.6, 71.0, 70.0, 50.6, 42.3, 39.3, 32.1, 25.9, 18.1, 17.2, ꢀ3.7, ꢀ4.8;
ESIMS m/z 537.5 ([MþNa]þ). ESIHRMS calcd for C27H54O5Si2Na
([MþNa]þ): 537.3402; found: 537.3414.

J. Gao et al. / Tetrahedron 64 (2008) 11105–11109
11109
27
4.9. Oxidation of the allylic alcohol in 14 leading to 15
a white solid (14 mg, 0.0496 mmol, 91%). Mp 229–231 ꢁC; [
a
]
D
þ31.5 (c 0.08, MeOH); 1H NMR (300 MHz, CD3OD)
7.27 (dd, J¼17.7,
d
A suspension of activated MnO2 (170 mg, 1.955 mmol) and 14
(60 mg, 0.117 mmol) in anhydrous CH2Cl2 (5.0 mL) was stirred at
ambient temperature until TLC showed completion of the reaction
(ca. 4 h). The solids were filtered off (washing with CH2Cl2). The
filtrate and washings were combined and concentrated on a rotary
evaporator to give the crude intermediate aldehyde, which was
directly dissolved in t-BuOH (4.0 mL). To this solution were added
2-methyl-2-butene (0.26 mL) and a solution of NaH2PO4$H2O
(468 mg, 3.39 mmol) in water (1.2 mL). A solution of NaClO2 (97 mg,
1.07 mmol) in water (1.2 mL) was then added dropwise. After
completion of the addition, the mixture was stirred at ambient
temperature until TLC showed completion of the reaction (ca. 24 h).
The mixture was acidified with 2 N HCl to pH 2, extracted with Et2O
(3ꢂ25 mL). The combined organic layers were washed in turn with
water (10 mL) and brine (10 mL) before being dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
4.0 Hz, 1H), 5.87 (dd, J¼15.7, 1.7 Hz, 1H), 5.80 (ddd, J¼14.8, 10.1,
4.2 Hz,1H), 5.47 (dd, J¼15.2, 9.5 Hz,1H), 5.03 (ddd, J¼8.7, 6.7, 2.1 Hz,
1H), 4.23 (quintet, J¼5.1 Hz, 1H), 4.04 (ddd, J¼9.6, 3.9, 1.5 Hz, 1H),
3.91 (dd, J¼12.6, 4.3 Hz, 1H), 3.79 (dd, J¼12.6, 10.1 Hz, 1H), 3.63 (dd,
J¼11.3, 2.1 Hz, 1H), 3.48 (dd, J¼11.3, 8.7 Hz, 1H), 2.42 (quintet,
J¼8.9 Hz, 1H), 2.15 (ddd, J¼13.9, 8.8, 5.7 Hz, 1H), 2.03 (ddd, J¼12.5,
8.0, 4.0 Hz, 1H), 1.92 (quintet, J¼8.9 Hz, 1H), 1.81 (ddd, J¼14.0, 8.6,
6.3 Hz, 1H), 1.45 (ddd, J¼13.5, 7.3, 5.3 Hz, 1H), 1.18 (d, J¼6.6 Hz, 3H);
13C NMR (125 MHz, CD3OD)
d 168.6, 155.0, 142.4, 128.3, 119.2, 76.9,
74.3, 73.0, 72.6, 71.6, 53.3, 45.9, 44.3, 42.3, 16.5; FTIR (KBr): 3239,
2929, 2878, 1710, 1646, 1456, 1258, 1116, 1070, 975 cmꢀ1; ESIMS m/z
305.2 ([MþNa]þ). MALDIHRMS calcd for C15H22O5Na ([MþNa]þ):
305.1359; found: 305.1360.
Acknowledgements
chromatography on silica gel (1:2 EtOAc/PE) afforded 15 as a color-
This work was supported by the National Natural Science
Foundation of China (20372075, 20321202, 20672129, 20621062,
20772143) and the Chinese Academy of Sciences (‘Knowledge In-
novation’, KJCX2.YW.H08).
25
less oil (43 mg, 0.0813 mmol, 70%). [
(300 MHz, CDCl3)
a
]
ꢀ9.7 (c 0.9, CHCl3); 1H NMR
D
d
6.98 (dd, J¼15.7, 5.4 Hz, 1H), 5.95 (d, J¼15.8 Hz,
1H), 5.67 (dd, J¼15.2, 8.4 Hz, 1H), 5.49 (dt, J¼15.7, 6.0 Hz, 1H), 4.30–
4.23 (m, 1H), 4.23–4.15 (m, 1H), 4.04–3.90 (m, 3H), 3.42 (dd, J¼9.5,
2.9 Hz,1H), 3.27–3.17 (m,1H), 2.38 (quintet, J¼8.3 Hz,1H), 2.10–1.95
(m, 2H), 1.85–1.72 (m, 1H), 1.60–1.40 (m, 2H), 1.15 (d, J¼6.5 Hz, 3H),
0.92 (s, 9H), 0.86 (s, 9H), 0.05 (s, 3H), 0.03 (s, 6H), 0.01 (s, 3H); 13C
References and notes
1. Singleton, V. L.; Bohonos, N.; Ullstrup, A. J. Nature (London) 1958, 181, 1072–
1073.
NMR (75 MHz, CDCl3)
d 170.7, 153.2, 138.6, 125.6, 119.4, 75.5, 73.0,
2. (a) Corey, E. J.; Wollenberg, R. H. Tetrahedron Lett. 1976, 4705–4708; (b) For
syntheses of BFA before 1997, see a review: Kobayashi, Y.; Watatani, K. Yuki Gosei
Kagaku Kyokaishi 1997, 55, 110–120; Chem. Abstr. 1997, 126, 185901; For recent
total syntheses (from 1997 on) of BFA, see: (c) Haynes, R. K.; Lam, W. W.-L.; Yeung,
L. L.; Williams, I. D.; Ridley, A. C.; Starling, S. M.; Vonwiller, S. C.; Hambley, T. W.;
Lelandais, P. J. Org. Chem. 1997, 62, 4552–4553; (d) Wang, Y.; Romo, D. Org. Lett.
2002, 4, 3231–3234; (e) Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124,
9328–9329; (f) Suh, Y. G.; Jung, J.-K.; Seo, S.-Y.; Min, K.-H.; Shin, D.-Y.; Lee, Y.-S.;
Kim, S.-H.; Park, H.-J. J. Org. Chem. 2002, 67, 4127–4137; (g) Kim, D.; Lee, J.; Shim,
P. J.; Lim, J. I.; Doi, T.; Kim, S. J. Org. Chem. 2002, 67, 772–781; (h) Kim, D.; Lee, J.;
Shim, P. J.; Lim, J. I.; Jo, H.; Kim, S. J. Org. Chem. 2002, 67, 764–771; (i) Wu, Y.-K.;
Shen, X.; Yang, Y.-Q.; Hu, Q.; Huang, J.-H. Tetrahedron Lett. 2004, 45, 199–202; (j)
Wu, Y.-K.; Shen, X.; Yang, Y.-Q.; Hu, Q.; Huang, J.-H. J. Org. Chem. 2004, 69, 3857–
3865; (k) Seo, S.-Y.; Jung, J.-K.; Paek, S.-M.; Lee, Y.-S.; Kim, S.-H.; Suh, Y.-G.
Tetrahedron Lett. 2006, 47, 6527–6530 (formal synthesis); (l) Lin, W.; Zercher, C. K.
J. Org. Chem. 2007, 72, 4390–4395 (formal synthesis); (m) Wu, Y.-K.; Gao, J. Org.
Lett. 2008,10,1533–1536; (n) Legrand, F.; Archambaud, S.; Collet, S.; Aphecetche-
Julienne, K.; Guingant, A.; Evain, M. Synlett 2008, 389–393.
3. (a) Argade, A. B.; Haugwitz, R. D.; Devraj, R.; Kozlowski, J.; Fanwick, P. E.;
Cushman, M. J. Org. Chem. 1998, 63, 273–278; (b) Argade, A. B.; Devraj, R.;
Vroman, J. A.; Haugwitz, R. D.; Hollingshead, M.; Cushman, M. J. Med. Chem.
1998, 41, 3337–3346; (c) Zhu, J.-W.; Nagasawa, H.; Nagura, F.; Mohamad, S. B.;
Uto, Y.; Ohkura, K.; Hori, H. Bioorg. Med. Chem. 2000, 8, 455–463; (d) Zhu, J.-W.;
Hori, H.; Nojiri, H.; Tsukuda, T.; Taira, Z. Bioorg. Med. Chem. Lett. 1997, 7, 139–
144; (e) Weigele, M.; Loewe, M. F.; Poss, C. S.; Lazarova, T. (Ariad Pharmaceu-
ticals, USA). PCT Int. Appl. WO 9521614 A1, August 17, 1995, 54 pp; Chem. Abstr.
1996, 124, 8507; (f) Weigele, M.; Loewe, M. F.; Poss, C. S. (Ariad Pharmaceuti-
cals, USA). U.S. Patent 5,516,921 A, May 14, 1996, 14 pp; Chem. Abstr. 1996, 125,
58201; (g) Anadu, N. O.; Davisson, V. J.; Cushman, M. J. Med. Chem. 2006, 49,
3897–3900; (h) Hubscher, T.; Helmchen, G. Synlett 2006, 1323–1326; (i) Shen,
X.; Yang, Y.-Q.; Hu, Q.; Huang, J.-H.; Gao, J.; Wu, Y.-K. Chin. J. Chem. 2007, 25,
802–807.
71.8, 66.5, 49.2, 43.1, 42.5, 35.6, 25.9, 25.8,18.5,18.1, ꢀ4.0, ꢀ4.8, ꢀ4.9;
FTIR (film) 3445, 2930, 2857, 1699, 1659, 1472, 1256, 1105, 979, 837,
776 cmꢀ1; ESIMS m/z 551.5 ([MþNa]þ). MALDIHRMS calcd for
C27H52O6Si2Na ([MþNa]þ): 551.3244; found: 551.3243.
4.10. MNBA mediated lactonization of 15 leading to 16
A solution of hydroxyl acid 15 (18 mg, 0.034 mmol) in dry tol-
uene (6.0 mL) was added slowly (with the aid of a syringe pump)
over 4 h to a mixture of MNBA (18 mg, 0.051 mmol), DMAP (19 mg,
0.204 mmol) and activated 4 Å molecular sieves (405 mg) in dry
toluene (12 mL) stirred at ambient temperature. After completion
of the addition, the mixture was stirred at the same temperature for
20 h before being diluted with EtOAc (50 mL), washed in turn with
aq satd NaHCO3, water and brine, and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography on silica gel (1:50 EtOAc/PE) afforded 16 as
23
a colorless oil (14 mg, 0.0274 mmol, 80%). [
a
]
þ17.3 (c 0.85,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.17 (dd, J¼15.8, 4.0 Hz, 1H),
5.90 (dd, J¼15.8, 1.6 Hz, 1H), 5.63 (ddd, J¼14.5, 9.7, 4.2 Hz, 1H), 5.43
(dd, J¼15.2, 9.4 Hz, 1H), 5.20–5.08 (m, 1H), 4.24–4.17 (m, 1H), 4.04–
3.74 (m, 3H), 3.60 (dd, J¼11.2, 2.4 Hz, 1H), 3.46 (dd, J¼11.3, 7.9 Hz,
1H), 2.30–1.87 (m, 4H), 1.22 (d, J¼6.6 Hz, 3H), 0.91 (s, 9H), 0.87 (s,
9H), 0.07–0.01 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 166.2, 152.5,
140.8, 126.2, 118.9, 76.3, 73.3, 72.5, 71.8, 69.6, 52.7, 44.0, 43.6, 42.0,
29.7, 25.8, 18.1, 16.0, ꢀ4.2, ꢀ4.8, ꢀ5.0; FTIR (film) 2955, 2928, 2856,
1718, 1664, 1647, 1496, 1256, 1122, 1078, 971, 837, 775 cmꢀ1; ESIMS
m/z 533.5 ([MþNa]þ). ESIHRMS calcd for C27H50O5Si2Na
([MþNa]þ): 533.3089; found: 533.3088.
4. (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229–4231; (b)
de la Herran, G.; Mba, M.; Murcia, C.; Plumet, J.; Csaky, A. G. Org. Lett. 2005, 7,
1669–1671.
5. Ohkuma, T.; Koizumi, M.; Yoshida, M.; Noyori, R. Org. Lett. 2000, 2, 1749–1752.
6. Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247–3251.
7. Matijoska, A.; Eicher-Lorka, O.; Rastenyte, L. J. Chem. Res., Synop. 2003, 160–161.
8. (a) Bian, J.; Van Wingerden, M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 7428–
7429; (b) Kovacs, G.; Galambos, G.; Juvancz, Z. Synthesis 1977, 171–172.
9. Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38, 2253–2256.
10. Papadooulos, E. P.; Jarrar, A.; Issidorides, C. H. J. Org. Chem. 1966, 31, 615–616.
11. (a) Hillis, L. R.; Ronald, R. C. J. Org. Chem. 1985, 50, 470–473; (b) Bal, B. S.;
Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
12. (a) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535–7539; (b)
Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004, 69,
1822–1830.
4.11. Hydrolysis of TBS groups in 16 leading to 2 (13-O-BFA)
A solution of lactone 16 (27 mg, 0.0529 mmol) and aq HCl (2 N,
0.35 mL) in THF/H2O (1:1 v/v, 4 mL) was stirred at ambient tem-
perature for 48 h. Aq satd NaHCO3 (2.0 mL) was then added. The
mixture was extracted with Et2O (3ꢂ25 mL). The combined organic
phases were washed with water and brine, and dried over anhy-
drous Na2SO4. The solvent was removed by rotary evaporation. The
residue was recrystallized from MeOH to afford 13-O-BFA 2 as
13. Wu, Y.-K.; Yang, Y.-Q. J. Org. Chem. 2006, 71, 4296–4301.
14. The crystallographic data (CCDC 697371) has been deposited to the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; e-mail:
deposit@ccdc.cam.ac.uk.