Stereocontrolled total synthesis of polygalolide A

Article abstract of DOI:10.1002/asia.201300362

The total synthesis of polygalolide A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramo

Full text of DOI:10.1002/asia.201300362

FULL PAPER
DOI: 10.1002/asia.201300362
Stereocontrolled Total Synthesis of Polygalolide A
Hitomi Yamada,[a] Masaatsu Adachi,*[a] Minoru Isobe,[a, b] and Toshio Nishikawa*[a]
Abstract: The total synthesis of polyga-
lolide A, a secondary metabolite that
was isolated from a Chinese medicinal
plant, is reported. A key issue in this
synthesis was construction of an
lation did not occur under the condi-
tions found from model experiments,
further examination revealed that the
combination of trimethylsilyl trifluoro-
tion played a crucial role in the stereo-
control of this reaction. The product
was further transformed into a tetracy-
clic compound as follows: The vinyl
ether and acetylenic moieties were re-
duced and the siloxy group was re-
moved with a Barton–McCombie reac-
tion. The construction of the six-mem-
bered ether and the g-lactone provided
the tetracyclic compound. Finally,
a phenolic moiety was introduced by
using a Mukaiyama aldol reaction to
furnish polygalolide A.
methanesulfonate
(TMSOTf)
and
oxabicyclo
N
2,4,6-collidine successfully afforded the
desired product as a single diastereo-
mer. The siloxy group at the C3 posi-
solved by the development of an intra-
molecular Ferrier-type C-glycosylation
of a glucal with siloxyfuran as an inter-
nal nucleophile. The substrate was pre-
pared from d-glucal by the introduc-
tion of trimethylsilylacetylene and si-
loxyfuran groups. Although C-glycosy-
Keywords: glycosylation · heterocy-
cles · natural products · polygalo-
lides · total synthesis
Introduction
Polygalolides A (1) and B (2) were isolated by Wei and co-
workers in 2003 from the powdered dried roots and stems
of the folk medicinal plant Polygala fallax Hemsl. (Polygala-
ceae) and is used as a tonic or as an antihepatitis drug
(Scheme 1).[1] Extensive spectroscopic analysis has revealed
that these two molecules represent a new type of phenolic
compound with a distinctive tetracyclic substructure that is
characterized by
a
highly substituted oxabicyclo-
ACHTUNGTRENNUNG[3.2.1]octanone skeleton, contiguous quaternary stereogenic
Scheme 1. Structures of polygalolides A (1) and B (2).
centers that are fused with a g-lactone, and a six-membered
ether. Although the biological activities of compounds 1 and
2 have not yet been reported, their characteristic structures
have attracted considerable interest in the field of organic
synthesis. The absolute configuration of the polygalolides
was established by their first total synthesis in 2006 by Ha-
shimoto, Nakamura, and co-workers,[2] who constructed the
lar 1,3-dipolar cycloaddition of carbonyl ylide. A compari-
son of the [a]D values of these synthesized compounds with
those of natural polygalolides led them to suggest that these
natural products might be biosynthesized in their near-race-
mic forms. Snider, Hashimoto, and co-workers also reported
a formal total synthesis by using the [5+2] cycloaddition of
oxidopyrylium ylide as a key step.[3] Herein, we report the
full details of our efforts toward the total synthesis of poly-
galolide A (1), through the development of an intramolecu-
lar Ferrier-type C-glycosylation of a glucal modified with si-
oxabicycloACHTUNGTRENNUNG[3.2.1]octanone skeleton by using an intramolecu-
[a] H. Yamada, Dr. M. Adachi, Prof. Dr. M. Isobe,
Prof. Dr. T. Nishikawa
Laboratory of Organic Chemistry
Graduate School of Bioagricultural Sciences
Nagoya University
Chikusa, Nagoya 464-8601 (Japan)
Fax : (+81)52-789-4111
loxyfuran as
a key step for the construction of the
oxabicyclo
AHCTUNGTRENNUNG
E-mail: madachi@agr.nagoya-u.ac.jp
nisikawa@agr.nagoya-u.ac.jp
Results and Discussion
[b] Prof. Dr. M. Isobe
Initial Synthetic Plan for Polygalolide A (1)
Department of Chemistry
National Tsing Hua University
Hsinchu 30013 (Taiwan)
We planned to synthesize polygalolide A (1) from tetracyclic
intermediate 3, which was employed by Hashimoto, Naka-
mura, and co-workers in their total synthesis[2] (Scheme 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300362.
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Masaatsu Adachi, Toshio Nishikawa et al.
cosylation reactions might be
explained by steric repulsion
between the H7 and H10
atoms in transition state TS-
1 of the resulting oxocarbeni-
um ion. The instability of the
ketene silyl acetal moiety
under the glycosylation condi-
tions might also be another
reason for these unsuccessful
results. These analyses led us
to design glucal 14, which pos-
sessed a siloxyfuran moiety as
an alternative nucleophile
(Scheme 4) for the C-glycosy-
lation reaction with the aim of
Scheme 2. Retrosynthetic analysis of polygalolide A (1).
The g-lactone and six-membered ether moieties in inter-
mediate 3 would be transformed from a tricyclic compound
A with an oxabicycloACTHNUTRGNE[NUG 3.2.1]octene skeleton. We envisaged
enhancing its stability and minimizing steric hindrance.
A new model precursor 14 was synthesized from tri-O-
acetyl-d-glucal (7), a commercially available starting materi-
al (Scheme 4). Deacetylation of compound 7 with NaOMe
followed by regioselective silylation of the resulting triol
with TBSCl afforded bis-TBS ether 8. Benzylation of the re-
maining hydroxy group and selective desilylation of the pri-
mary TBS group with hydrogen fluoride pyridine gave alco-
hol 9. A g-lactone unit was introduced by oxidation of the
primary alcohol and Wittig reaction of the resulting alde-
hyde with compound 10 provided lactone 11 in good yield.
Isomerization of the olefin was best carried out by treat-
ment with Wilkinson’s catalyst and Et3SiH in toluene to
yield the desired furanone 12. Finally, the TBS ether of com-
pound 12 was transformed into the corresponding benzoate
in two steps, including desilylation and benzoylation, under
the mild conditions developed by Oriyama and co-workers
(BzCl, TMEDA, 08C).[12] Treatment of compound 13 with
TBSOTf and LHMDS gave siloxyfuran 14, which was then
immediately used in the C-glycosylation reaction without
purification because of its instability.
that compound A would be synthesized from glucal deriva-
tive C through: a) The generation of oxocarbenium ion B
through Lewis acid-promoted activation of the ester group
and migration of the double bond (so-called Ferrier rear-
rangement); b) partial ring inversion from the 4C1-conformer
1
À
into the C4-conformer; and c) an intramolecular C C bond-
forming reaction (so-called C-glycosylation[5–7]) to yield
oxabicycloACHTUNGTRENNUNG
[3.2.1]octene A in a one-pot manner.[8] The pre-
cursor C, which possessed a nucleophilic moiety, would be
prepared from d-glucal (4). Because a few examples of in-
tramolecular C-glycosylation reactions have been reported,[9]
we began with a model experiment for examining the feasi-
bility of this synthetic strategy.
Model Experiments for the Construction of the
OxabicycloACTHNUGRTENUNG[3.2.1]octene Skeleton
To examine the intramolecular C-glycosylation reaction, g-
butyrolactone-derived silyl enolate 5[10] was prepared as
a model compound without a substituent at the C8 position
(C; Scheme 2, R=H) and then exposed to conventional
conditions for the C-glycosylation reaction. However, all of
the attempted intramolecular C-glycosylation reactions with
various Lewis acids, such as TMSOTf, TiCl4, and BF3·OEt2,
When compound 14 was treated with SnCl4 in the pres-
ence of 4 ꢁ M.S. at À788C, followed by gradually increasing
the reaction temperature to À308C, a complex mixture of
products was obtained (Table 1, entry 1). The reaction with
ZnCl2 solely provided oxabicycloACHTUNTRGNEUNG[3.2.1]octene 16 in 10%
overall yield over two steps (Table 1, entry 2). Fortunately,
further experimentation led us to find that TiCl4 and
BF3·OEt2 were optimal Lewis acids for the production of
the oxabicycloACHTUNTRGNEUNG[3.2.1]octene; when compound 14 was treated
with 1.5 equivalents of TiCl4, oxabicyclic products 15 and 16
were obtained in 24% and
did not give the desired oxabicycloACTHUNTGRNEUNG[3.2.1]octene 6, but rather
a complex mixture of products was afforded, although the
oxocarbenium ion was generated through activation of the
benzoate (Scheme 3).[11] The lack of success of these C-gly-
49% overall yield, respectively,
over two steps (Table 1,
entry 4).[13] The C-glycosylation
reaction with BF3·OEt2 pro-
ceeded smoothly to give com-
pounds 15 and 16 in 37% and
38% overall yield, respectively,
over two steps (Table 1,
entry 5). The reason for the
Scheme 3. Intramolecular Ferrier-type C-glycosylation for the construction of the oxabicyclo
ton of polygalolides.
ACHTUNGTREN[NUGN 3.2.1] core skele-
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Masaatsu Adachi, Toshio Nishikawa et al.
tion. This auxiliary should be
easy to prepare and securely
remove and it must be compat-
ible with the C-glycosylation
conditions. Based on these
considerations, we modified
our synthetic plan for polygalo-
lide A (1), as shown in
Scheme 5, and designed a new
precursor 19 for the intramo-
lecular C-glycosylation reac-
tion, which possessed a siloxy
group at the C3 position with
an S configuration and an acet-
ylene group at the C8 position.
The acetylenic moiety was an-
ticipated to be the synthetic
equivalent of a hydroxymethyl
group at the C8 position and
would stabilize an oxocarbeni-
um ion intermediate. The pre-
cursor 19 would be synthesized
from a commercially available
d-glucal (4) by the introduc-
tion of the acetylenic and silox-
yfuran moieties at the C8 and
C2 positions, respectively. In
the C-glycosylation of com-
pound 19, considering unfavor-
able 1,3-allylic strain between
the two siloxy groups in transi-
tion state TS-4, more-stable
transition state TS-5 would
preferentially yield the desired
Scheme 4. Synthesis of model precursor siloxyfuran 14 and oxabicycloACTHNUTRGNEU[GN 3.2.1]octene through intramolecular Fer-
rier-type C-glycosylation. Reagents and conditions: a) NaOMe, MeOH, RT, 0.4 h; b) TBSCl, imidazole, DMF,
08C, 11 h, 73% over 2 steps; c) NaH, BnBr, TBAI, DMF, À5 to 58C, 9 h, 92%; d) HF·Py, THF, 08C, 4 h, 74%
in 2 cycles; e) IBX, DMSO, RT, 6 h; f) compound 10, CH2Cl2, 08C to RT, 3 h, 79% over 2 steps; g) [RhCl-
ACHTUNGTRENNUNG(PPh3)3], Et3SiH, toluene, 608C, 1.5 h, 92%; h) TBAF, AcOH, THF, 08C to RT, 22 h, 78%; i) BzCl, TMEDA,
CH2Cl2, 08C, 0.6 h, 65%; j) LHMDS, THF, À788C, 1 h; then TBSOTf, À208C, 1 h; k) see Table 1. Ac=acetyl,
TBS=tert-butyldimethylsilyl, Bn=benzyl, TBAI=tetrabutylammonium iodide, Py=pyridine, IBX=2-iodoxy-
benzoic acid, TBAF=tetrabutylammonium fluoride, Bz=benzoyl, TMEDA=N,N,N’,N’-tetramethylethylene-
diamine, LHMDS=lithium bis(trimethylsilyl)amide, Tf=trifluoromethanesulfonyl, M.S.=molecular sieves.
Table 1. Intramolecular Ferrier-type C-glycosylation of compound 14.[a]
Entry
Lewis acid
t [h]
Yield [%][b]
16
oxabicycloACTHNUTRGNEUG[N 3.2.1]octene 18. In our newly designed synthetic
15
route, compound 18 would be transformed into tricyclic
compound 17 by deoxygenation at the C3 position. Con-
struction of six-membered ether and the g-lactone would
afford tetracyclic intermediate 3.
1
2
3
4
5
SnCl4
ZnCl2
TMSOTf
TiCl4
4
13
4
5
4
0
0
0
24
37
0
10
0
49
38
Siloxyfuran 19, a precursor for the C-glycosylation, was
synthesized from d-glucal (4) (Scheme 6). Hydroxy groups
at the C3 and C6 positions were protected as TIPS ether
and benzylation of the remaining secondary alcohol gave
compound 20. Construction of the ene-yne moiety of com-
pound 24 was achieved in a two-step procedure, that is, the
addition of an acetylide to a lactone derivative and subse-
quent dehydration, as follows: The direct oxidation of com-
pound 20 with pyridinium chlorochromate (PCC)[14] provid-
ed the required lactone 22 in 51% yield, along with a signifi-
cant amount of byproducts. Thus, the stepwise preparation
of compound 22 was examined next. Hydration of com-
pound 20 with triphenylphosphine hydrobromide in CH2Cl2
and water[15] gave hemiacetal 21, which was oxidized with
PCC to provide lactone 22 in good overall yield. The addi-
tion of lithium trimethylsilylacetylide gave hemiacetal 23 in
high yield, however, dehydration of compound 23 did not
readily give enyne 24 under conditions with either phospho-
BF3·OEt2
[a] The reaction was performed with a Lewis acid (1.5 equiv) and 4 ꢁ
M.S. in CH2Cl2 for the indicated time. [b] Yield of isolated product over
2 steps. TMS=trimethylsilyl.
low stereoselectivity of the C-glycosylation reaction might
be due to be the small energy difference between two possi-
ble transition states, TS-2 and TS-3, which leads to oxabicy-
clic products 15 and 16, respectively.
Modified Synthetic Plan for Polygalolide A (1)
With efficient access to the oxabicycloACTHNUTRGNEUNG[3.2.1]octene skeleton
secured, the remaining issue was the stereocontrol at the C2
position. We envisaged that the configuration at the C2 posi-
tion could be controlled by introducing a bulky auxiliary at
the C3 position of a precursor for the C-glycosylation reac-
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direct synthesis of compound
18 was difficult. Therefore, we
would synthesize compound 18
in steps from compound 31
through compound 19, and the
preparation of compound 19
from compound 31 was reex-
amined. Finally, TBSOTf and
Et3N in Et2O (instead of di-
chloromethane) was found to
be the optimal conditions, thus
giving the desired compound
19 in 98% yield.
According to the conditions
developed in the model experi-
ment, the intramolecular C-
glycosylation of siloxyfuran 19
was investigated (Table 2). The
siloxyfuran 19 was treated with
a Lewis acid, such as TiCl4 or
BF3·OEt2, in CH2Cl2 to give
a complex mixture of products
Scheme 5. Modified synthetic plan for polygalolide A (1).
rus oxychloride or Burgess reagent because of the steric hin-
drance around the tertiary alcohol. In contrast, the dehydra-
tion of compound 23 with TFA in the presence of 4 ꢁ M.S.
proceeded smoothly to furnish compound 24. After the
TIPS group on the primary alcohol was selectively desilylat-
ed by using hydrogen fluoride pyridine, oxidation with IBX
afforded aldehyde 26. The addition of lithiosiloxyfuran,[16] as
prepared from bromofuran 27 with nBuLi, was best carried
out in the presence of ZnCl2 to afford adduct 28 as a single
product.[17] Because of its instability, the adduct 28 was im-
mediately hydrolyzed with TFA in Et2O and furanone 29
was isolated in 65% yield over two steps as a single diaste-
reomer.[18] The stereochemical outcome of this addition
might be explained as follows: On the pretreatment of com-
pound 26 with ZnCl2, the carbonyl oxygen atom and the
ring oxygen atom of the glucal would chelate to the zinc
cation and, thus, the nucleophile would approach from the
less-hindered side.
(Table 2, entries 1 and 2). Attempted C-glycosylations with
other conventional Lewis acids also failed to give the ex-
pected oxabicyclic product 18. These results might be due to
instability of the highly functionalized precursor 19, which
possessed the siloxy substituent at the C3 position. Next, the
conditions (TBSOTf, Et3N, in CH2Cl2) that were incidentally
found for the direct production of compound 18 from ace-
tate 31 were examined in detail for the C-glycosylation reac-
tion. The possibility of TfOH as a “real” activator was ex-
cluded by the following experiment: Treatment of com-
pound 19 with TfOH in the presence of Et3N at À208C only
provided a small amount of the oxabicyclic product 18 in
11% yield (Table 2, entry 3). After extensive attempts by
employing a combination of TBSOTf and Et3N, we were
pleased to find that the exposure of the siloxyfuran 19 to an
equimolar ratio of TBSOTf (3.5 equiv) and Et3N (3.5 equiv)
An acetyl group was introduced as a leaving group at the
C6 position for the intramolecular Ferrier-type C-glycosyla-
tion reaction. The TIPS group of compound 29 was depro-
tected with hydrogen fluoride pyridine in THF to give diol
30 in 87% yield after two cycles. The regioselective acetyla-
tion proceeded smoothly under the conditions reported by
Vedejs et al.[19] (acetic anhydride in the presence of a catalyt-
ic amount of nBu3P at À408C) to afford the desired acetate
31 in 78% yield after two cycles.[20] Fortunately, when siloxy-
furan 19 was prepared from the resulting acetate 31 by
treatment with TBSOTf and Et3N in dichloromethane,
oxabicycloACHTUNGTRENNUNG[3.2.1]octene 18, the desired product, was inciden-
tally obtained in 16% yield as a single diastereomer. The
structure of compound 18 was unambiguously confirmed by
X-ray crystallographic analysis (Figure 1).[21] This unexpect-
ed but successful result encouraged us to examine the C-gly-
cosylation conditions from compound 31; however, the
Figure 1. ORTEP of compound 18.
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Masaatsu Adachi, Toshio Nishikawa et al.
Table 2. Synthesis of oxabicyclo
Ferrier-type C-glycosylation.
ACHTUNGTRENUN[NG 3.2.1]octene 18 through intramolecular
Entry
Acid
Base
Yield [%][c]
1
2
TiCl4
BF3·OEt2
TfOH
TBSOTf
TBSOTf
TBSOTf
TBSOTf
TBSOTf
TMSOTf
–
–
0
0
3[a]
4[b]
5[b]
6[b]
7[b]
8[b]
9[b]
Et3N
Et3N
DIEA
11
61
59
54
72
0
DTBMP
2,4,6-collidine
DMAP
2,4,6-collidine
83
[a] The reaction was performed with TfOH (9.0 equiv) and E3N
(9.0 equiv) in CH2Cl2. [b] The reaction was performed with a Lewis acid
(3.5 equiv) and a base (3.5 equiv) in CH2Cl2. [c] Yield of isolated com-
pound 18. DIEA=N,N-diisopropylethylamine, DTBMP=2,6-di-tert-
butyl-4-methylpyridine, DMAP=N,N-dimethyl-4-aminopyridine.
in CH2Cl2 at À208C provided compound 18 in 61% yield as
a single diastereomer (Table 2, entry 4). The C-glycosylation
of compound 19 also proceeded smoothly in the presence of
a base, such as N,N-diisopropylethylamine (DIEA), 2,6-di-
tert-butyl-4-methylpyridine (DTBMP), or 2,4,6-collidine,
thus giving oxabicyclic product 18 in good yields (Table 2,
entries 5–7). On the other hand, the reaction of siloxyfuran
19 with an equimolar ratio of TBSOTf and N,N-dimethyl-4-
aminopyridine (DMAP) provided a complex mixture of
products (Table 2, entry 8). Finally, an equimolar ratio of
TMSOTf (3.5 equiv) and 2,4,6-collidine (3.5 equiv) in
CH2Cl2 at À208C were found to be the optimal conditions
for the intramolecular C-glycosylation, thus providing com-
pound 18 in 83% yield as a single diastereomer (Table 2,
entry 9). The exclusive production of compound 18 as
a single diastereomer indicates a crucial role of the siloxy
substituent at the C3 position of compound 19, as expected.
In this C-glycosylation reaction, a silylammonium or silyl-
pyridinium triflate[22] might be generated and serve as an
active promoter, which would selectively activate the acetyl
group of compound 19. This developed C-glycosylation reac-
tion allows the gram-scale synthesis of oxabicyclo-
Scheme 6. Synthesis of siloxyfuran 19 as a precursor for the intramolecu-
lar Ferrier-type C-glycosylation reaction. Reagents and conditions:
a) TIPSCl, imidazole, DMF, 08C to RT, 18 h; b) NaH, BnBr, TBAI,
DMF, 08C, 2.5 h, 80% over 2 steps; c) Ph3P·HBr, CH2Cl2/water (37:1),
RT, 13.8 h, 82%; d) PCC, NaOAc, 4 ꢁ M.S., CH2Cl2, RT, 1.5 h, 91%;
e) trimethylsilylacetylene, nBuLi, THF, À788C, 0.8 h, 93%; f) TFA, 4 ꢁ
M.S., CH2Cl2, 08C to RT, 24 h, 77%; g) HF·Py, THF, À58C, 4.8 h, 72%
(recovered starting material, 19%); h) IBX, DMSO, RT, 9.6 h, 89%;
i) bromofuran 27, nBuLi, ZnCl2, THF, À788C, 1.3 h; j) TFA, Et2O, 0 8C,
10 h, 65% over 2 steps; k) HF·Py, THF, 08C, 24 h, 87% in 2 cycles;
l) Ac2O, nBu3P, MeCN, À408C, 11.5 h, 78% in 2 cycles; m) TBSOTf,
Et3N, Et2O, À58C, 50 min, 98%; n) TBSOTf, Et3N, CH2Cl2, 08C, 20 min,
16%. TIPS=triisopropylsilyl, PCC=pyridinium chlorochromate, TFA=
trifluoroacetic acid.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tricyclic compound 17, according to the synthetic plan
shown in Scheme 5. Because the direct reduction of the
vinyl ether moiety in compound 18 was unsuccessful, its
two-step transformation into g-lactone 33 through hemiace-
tal 32 was examined (Scheme 7). Hydrolysis of compound
18 with LiOH was followed by reduction of the resulting
[23]
hemiacetal 32 with Et3SiH and BF3·OEt2 in the presence
of 4 ꢁ M.S. to give the desired g-lactone 33 in 43% yield,
along with methyl ketone 34 in 41% yield as a byproduct.
At this stage, the oxygen functionality at the C3 position
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Masaatsu Adachi, Toshio Nishikawa et al.
Scheme 8. Alternative synthetic route to tricyclic spiro compound 17. Re-
agents and conditions: a) H2, Pd/CaCO3, quinoline, EtOAc, RT, 30 min;
b) BF3·OEt2, Et3SiH, 4 ꢁ M.S., CH2Cl2, 08C to RT, 42 h, 73% over
2 steps; c) TBAF, AcOH, THF, 08C, 3.5 h; d) CS2, nBuLi, THF, 08C,
30 min; then MeI, 08C, 10 min, 63% over 2 steps; e) nBu3SnH, AIBN,
toluene, 1108C, 1 h, 57%.
along with diene 39 in 52% yield as a byproduct.[25] Further
experiments revealed that the undesired diene 39 was gener-
ated from compound 17; exposure of compound 17 to the
same conditions for 1.5 h provided compound 39 in 90%
yield as a single diastereomer, whereas this transformation
did not occur in the absence of nBu3SnH and AIBN. These
results indicated that the tributylstannyl radical that was
generated from nBu3SnH and AIBN might cause the trans-
formation.[26] In fact, the brief exposure of xanthate 38 to
a small amount of the stannyl radical was crucial for pre-
venting the production of undesired compound 39. Finally,
nBu3SnH in the presence of AIBN (10 mol%) at 1108C for
1 h were found to be the optimal conditions for the success-
ful deoxygenation to give compound 17 without the forma-
tion of compound 39. As a result, we established an efficient
accessible route to spiro compound 17.
For the total synthesis of polygalolide A (1), the next task
was the transformation of compound 17 into tetracyclic lac-
tone 3 (Scheme 9). Deprotection of the benzyl group of
compound 17 was best achieved by treatment with FeCl3 in
CH2Cl2 to provide the allylic alcohol,[27] which was oxidized
with MnO2 to give enone 41 in 64% yield over two steps. To
construct a six-membered ether by oxy-Michael addition,
hydrolysis of the lactone was examined. Basic conditions,
such as NaOMe, tBuOK, or LiOH, did not provide the oxy-
Michael product, even under refluxing conditions. We found
that the use of Cs2CO3 and MeOH was indispensable for the
hydrolysis and oxy-Michael addition reactions; treatment
with Cs2CO3 in aqueous THF and MeOH at room tempera-
ture gave the desired alcohol intermediate, which spontane-
ously underwent the oxy-Michael addition. The carboxylic
acid of the product was treated with MeI and K2CO3 to
afford methyl ester 42. Ozonolysis of the vinyl group was
followed by chemoselective reduction of the resulting alde-
Scheme 7. Synthesis of tricyclic spiro compound 17. Reagents and condi-
tions: a) LiOH·H2O, THF/water (3:1), 08C to RT, 6.5 h, 75%;
b) BF3·OEt2, Et3SiH, 4 ꢁ M.S., CH2Cl2, 08C to RT, 2 h, 43% over 2 steps
for compound 33, 41% over 2 steps for compound 34; c) TBAF, AcOH,
THF, 08C, 10 min; d) CS2, nBuLi, THF, À108C to RT, 1.7 h; then MeI,
RT, 1 h, 71% over 2 steps; e) nBu3SnH, AIBN, toluene, 1108C, 1 h; then
p-TsOH·H2O, 0 8C to RT, 16 h, 48%. AIBN=2,2’-azobisisobutyronitrile,
Ts=toluenesulfonyl.
was removed by using Barton–McCombie deoxygenation.[24]
The TBS group was deprotected and then xanthate 35 was
prepared by treatment with nBuLi, CS2, and MeI. The deox-
ygenation of compound 35 with nBu3SnH in the presence of
AIBN at 1108C gave vinyl stannane 36, which was subjected
to protodestannylation with p-TsOH to furnish the desired
spiro compound 17 in 48% yield. This route enabled us to
synthesize compound 17; however, the generation of by-
product 34 could not be completely prevented. Because this
result might be due to the presence of the acetylenic moiety
adjacent to the hemiacetal, we slightly modified the synthet-
ic route by including a transformation of the acetylenic
moiety of compound 32 into an alkene group prior to silane
reduction, as described below.
The partial hydrogenation of compound 32 in the pres-
ence of Lindlar’s catalyst and subsequent reduction with
Et3SiH and BF3·OEt2 afforded alkene 37 in 73% overall
yield over two steps without the formation of any byprod-
ucts (Scheme 8). According to the above procedure, com-
pound 37 was transformed into xanthate 38 in two steps.
Barton–McCombie deoxygenation of compound 38 with
nBu3SnH in the presence of AIBN (40 mol%) at 1108C for
1.5 h gave the desired spiro compound 17 in 13% yield,
hyde in the presence of the ketone with LiAlHACTHNUGTRENUNG(OtBu)3 to
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Masaatsu Adachi, Toshio Nishikawa et al.
forded oxabicycloACTHNUTRGNEUNG[3.2.1]octene 18 with the correct quaterna-
ry stereogenic centers in 83% yield. The successful produc-
tion of a single diastereomer indicated that the siloxy group
at the C3 position played a crucial role in the stereocontrol
of this reaction, as expected. Although several problems
were encountered in the transformation of oxabicyclic prod-
uct 18 into tetracyclic intermediate 3, we have established
a successful route as follows: The vinyl ether and acetylenic
moieties in compound 18 were reduced and the oxygen
functionality at the C3 position was removed by using
Barton–McCombie deoxygenation to provide tricyclic spiro
compound 17. The six-membered ether was constructed by
hydrolysis of the lactone moiety and spontaneous oxy-Mi-
chael addition. Ozonolysis of the vinyl group was followed
by chemoselective reduction of the resulting aldehyde to
give tetracyclic intermediate 3. Finally, a phenolic moiety
was introduced by a Mukaiyama aldol reaction to furnish
polygalolide A (1). This method should be applicable to the
synthesis of analogues of polygalolide and natural products
that contain an oxabicyclo skeleton.
Scheme 9. Total synthesis of polygalolide A (1). Reagents and conditions:
a) FeCl3, CH2Cl2, RT, 30 min; b) MnO2, CH2Cl2, RT, 13 h, 64% over
2 steps; c) Cs2CO3, THF/MeOH/water (2:1:1), 08C, 11 h; d) MeI, K2CO3,
DMF, 08C, 6.6 h, 70% over 2 steps; e) O3, CH2Cl2, À788C, 15 min; then
Me2S; f) LiAlH
G
g) TMSOTf, Et3N, CH2Cl2, 08C, 7.5 h; h) dimethyl acetal 43, TMSOTf,
3 ꢁ M.S., CH2Cl2, À788C, 40 min; i) DBU, CH2Cl2, 08C, 35 min, 54%
over 3 steps; j) sat. aq. NaHCO3, MeOH, RT, 21 h, quant. DBU=1,8-
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene.
Experimental Section
provide the primary alcohol, which underwent spontaneous
lactonization to yield the desired tetracyclic lactone 3.[2] Fi-
nally, according to the procedure of Hashimoto and co-
workers,[2] compound 3 was transformed into polygalolide A
(1) through Mukaiyama-aldol-type condensation with di-
methyl acetal 43 and then deprotection of the acetate. The
spectroscopic data of the synthesized compound were identi-
cal to those of natural polygalolide A (1) with the exception
of the value of optical rotation.[1] The synthetic [a]D value
(=À491, c=0.0226 in MeOH) was also consistent with that
reported by Hashimoto and co-workers (=À499.9, c=0.022
in MeOH).[2]
For experimental procedures, please see the Supporting Information.
Acknowledgements
This work was financially supported by Grants-in-Aid for Scientific Re-
search, a Global COE program from the Japan Society for the Promotion
of Science (JSPS), a Program for Leading Graduate Schools “Integrative
Graduate Education and Research in Green Natural Sciences” (MEXT),
and a SUNBOR grant from the Suntory Institute for Bioorganic Re-
search. H.Y. is grateful for
a Daiko Foundation Scholarship and
a Nagoya University Scholarship for outstanding graduate students. We
thank Dr. K. Yoza (Bruker AXS) for performing the X-ray crystallo-
graphic analysis. We also gratefully acknowledge Prof. S. Hashimoto
(Hokkaido University) and Prof. S. Nakamura (Nagoya City University)
for providing the spectra of tetracyclic compound 3 and polygalolide A
(1).
Conclusions
For the construction of the oxabicycloACTHNUTRGNE[NUG 3.2.1] structure,
a core skeleton of polygalolide A (1), we have developed an
intramolecular Ferrier-type C-glycosylation. Initial model
experiments of the key reaction of a glucal 14-modified si-
loxyfuran as an internal nucleophile led us to find that TiCl4
and BF3·OEt2 were effective Lewis acids, thus giving a mix-
ture of oxabicyclic products 15 and 16 in high yield but with
low stereoselectivity. For the total synthesis of polygaloli-
de A (1), we modified this intramolecular C-glycosylation
reaction to control the configuration at the C2 position. The
salient feature of this C-glycosylation reaction was the intro-
duction of a siloxy substituent at the C3 position as a tempo-
rary auxiliary into precursor 19, which was synthesized from
d-glucal by the introduction of trimethylsilylacetylene and
siloxyfuran groups. Although the optimal conditions in the
model experiments did not lead to the C-glycosylation of
compound 19, further examination led us to find that the
combination of TMSOTf and 2,4,6-collidine successfully af-
[1] W. Ma, X. Wei, T. Ling, H. Xie, W. Zhou, J. Nat. Prod. 2003, 66,
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[4] For a preliminary communication on the total synthesis of polygalo-
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Lett. 2011, 13, 6532–6535.
[5] For recent reviews on C-glycosylation, see: a) M. H. D. Postema,
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M. Isobe in Glycoscience, 2nd ed. (Eds.: B. Fraser-Reid, K. Tatsuta,
K, J. Thiem), Springer, Berlin, 2008, pp. 756–811.
Chem. Asian J. 2013, 8, 1428 – 1435
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Masaatsu Adachi, Toshio Nishikawa et al.
[6] a) Y. Ichikawa, M. Isobe, M. Konobe, T. Goto, Carbohydr. Res.
1987, 171, 193–199; b) R. Saeeng, U. Sirion, P. Sahakitpichan, M.
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[20] On the other hand, selective benzoylation at the C6 position of diol
30 was unsuccessful under the conditions used in the model experi-
ment.
[21] CCDC 836367 (18) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[22] a) T. J. Barton, C. R. Tully, J. Org. Chem. 1978, 43, 3649–3653; b) S.
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[8] Because the construction of the oxabicycloACTHNUTRGENUG[N 3.2.1] skeleton involves
[23] M. D. Lewis, J. K. Cha, Y. Kishi, J. Am. Chem. Soc. 1982, 104, 4976–
4978.
[24] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans.
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À
C C bond formation at the anomeric position by using an oxocarbe-
nium ion that is generated from a glycal derivative, we termed it
“intramolecular C-glycosylation”.
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um ion by using carbohydrate derivatives and related compounds,
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[10] Model compound 5 was prepared from a commercially available d-
glucal (4) in nine steps.
[25] The structure of compound 39 was determined by extensive NMR
À
analysis. The newly formed C C bond was undoubtedly determined
by HMBC correlation between the H6 and C2 atoms. The configu-
ration at the newly generated stereogenic center of the C2 position
was determined by NOESY correlations.
[26] The mechanism for the formation of diene 39 is proposed as de-
scribed below: In the first step, compound 17 reacts with the stannyl
À
radical, followed by the cleavage of a C C bond to provide an a-
carbonyl radical intermediate. In the second step, the stable radical
can overlap at the C6 or C8 positions with the p orbital of the diene
À
[11] The atom numbering used herein corresponds to that of polygalo-
lides.
[12] T. Sano, K. Ohashi, T. Oriyama, Synthesis 1999, 1141–1144.
[13] The structures of compounds 15 and 16 were determined by exten-
moiety in the transition state. In this case, the radical C C bond-
forming reaction predominantly proceeds at the C6 position to give
the rearranged product 39. This stereochemical outcome might be
explained by steric hindrance at two possible transition states (TS-6
and TS-7). The steric repulsion between the hydrogen atom at the
C5 position and the methylene group of the lactone moiety lead to
transition state TS-7, thus yielding compound 39.
À
sive analysis of their NMR spectra. The newly formed C C bonds
were confirmed by HMBC correlation and the configurations at the
C2 position of compounds 15 and 16 were determined by NOESY
correlation.
[27] Deprotection of the benzyl group of compound 17 was problematic:
Deprotection with BBr3 gave a complex mixture of products. When
compound 17 was treated with 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ), allylic alcohol was obtained in moderate yield,
along with a considerable amount of the starting material 17, even
when an excess of the reagents was employed.
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[18] Although the stereochemistry of the generated asymmetric center at
the C3 position was not determined at this stage, the configuration
was finally confirmed to be S by X-ray crystallographic analysis of
oxabicycloACHTUNGTRENNUNG[3.2.1]octene 18.
[19] a) E. Vedejs, S. T. Diver, J. Am. Chem. Soc. 1993, 115, 3358–3359;
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Received: March 19, 2013
Published online: May 13, 2013
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