Total syntheses of (+)-polygalolide A and (+)-polygalolide B: Elucidation of the absolute stereochemistry and biogenetic implications

Article abstract of DOI:10.1002/chem.201200542

The total syntheses of (+)-polygalolide A and (+)-polygalolide B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated

Full text of DOI:10.1002/chem.201200542

DOI: 10.1002/chem.201200542
Total Syntheses of (+)-Polygalolide A and (+)-Polygalolide B: Elucidation of
the Absolute Stereochemistry and Biogenetic Implications
Yukihito Sugano,[a] Fumiaki Kikuchi,[a] Akinori Toita,[a] Seiichi Nakamura,*[a, b] and
Shunichi Hashimoto*[a]
Abstract: The total syntheses of
(+)-polygalolide A and (+)-polygalol-
ACHTUNGTRENNUNGide B have been completed by using
a carbonyl ylide cycloaddition strategy.
Three of the four stereocenters, includ-
ing two consecutive tetrasubstituted
carbon atoms at C2 and C8, were in-
corporated through internal asymmet-
ric induction from the stereocenter at
G
E
carbonyl ylide precursor based on
a hetero-Michael reaction. This ap-
proach requires 18 steps, and the natu-
ral products were obtained in 9.8 and
9.3% overall yields. Comparison of
specific rotations of the synthetic mate-
rials and natural products suggests that
polygalolides are biosynthesized in
nearly racemic forms through a [5+2]
cycloaddition between a fructose-de-
rived oxypyrylium zwitterion with an
isoprene derivative.
C7 by a [Rh2ACHTUNGTRENNUNG(OAc)4]-catalyzed carbon-
yl ylide formation/intramolecular 1,3-
dipolar cycloaddition sequence. The
Introduction
ous quaternary stereogenic centers at C2 and C8, compelled
us to embark on a program aimed at their total synthesis.
Very recently, the total synthesis of polygalolide A through
an intramolecular C-glycosylation was reported by Adachi
and Nishikawa and co-workers.[4] In this article, we describe
the details of our total synthesis of polygalolides A (1) and
B (2) by a carbonyl ylide cycloaddition strategy, a prelimi-
In exploring the EtOH percolate of the powdered dried
roots and stems of Polygala fallax Hemsl. (Polygalaceae),
a folk medicinal plant distributed in southern China that is
used as a tonic and antihepatitis agent, Wei and co-workers
isolated two phenolic constituents, along with three known
xanthones.[1,2] Whereas the structure and relative stereo-
chemistry of these compounds, named polygalolides A (1)
and B (2), were determined on the basis of NMR studies,
the absolute stereochemistry was not established. It is well-
known that a,b-unsaturated styryl ketones possess cytotoxic
activity due to their propensity to participate in Michael ad-
dition reactions with cellular thiols,[3] but the detailed phar-
macological properties of 1 and 2 have not been reported.
The unusual molecular architecture of these molecules,
which includes a trioxatetracyclic ring system and contigu-
AHCTUNGTRENNUNG
nary account of which was published in 2006.[5] The results
of this study suggest that these natural products are synthe-
sized in the medicinal plant through a [5+2] cycloaddition in
near-racemic form.
[a] Dr. Y. Sugano, Dr. F. Kikuchi, A. Toita, Prof. Dr. S. Nakamura,
Prof. Dr. S. Hashimoto
Results and Discussion
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita 12, Nishi 6, Kita-ku
Sapporo 060-0812 (Japan)
Fax : (+81)11-706-4981
Retrosynthetic analysis: The structures of polygalolides A
(1) and B (2) are characterized by a 5,10,13-trioxatetracy-
clo[6.5.1.04,12.08,12]tetradecane-2,9-dione core with an array
of four stereogenic centers, including contiguous tetrasubsti-
tuted carbon atoms at C2 and C8, and the only difference
between these natural products resides at C17. We then
planned to install the arylmethylidene moiety late in the
synthesis by an aldol reaction or a related variant, because
the implementation of this strategy would allow the incorpo-
ration of a variety of substituents into a common, fully ela-
borated intermediate 3 (Scheme 1). The scission of the lac-
E-mail: hsmt@pharm.hokudai.ac.jp
[b] Prof. Dr. S. Nakamura
Present address: Graduate School of Pharmaceutical Sciences
Nagoya City University
3-1 Tanabe-dori, Mizuho-ku
Nagoya 467-8603 (Japan)
E-mail: nakamura@phar.nagoya-cu.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200542.
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Chem. Eur. J. 2012, 18, 9682 – 9690

FULL PAPER
Scheme 2. Attempted synthesis of a-diazoketone 6. Reagents and condi-
tions: a) allyl bromide 9, NaH, THF/DMF (10:1), 1.5 h; b) I2, NaHCO3,
aq. acetone, ꢀ258C, 5 min; c) NaClO2, NaH2PO4, 2-methyl-2-butene, aq.
tBuOH, 6 h; d) (Boc)2O, DMAP, tBuOH, 1 h; e) H2, 10% Pd/C, EtOAc,
13 h; f) Bu4NF, AcOH, THF, 15 h; g) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢀ78 to 08C, then Me2N=CH2I, DBU, 20 h; h) NaClO2, NaH2PO4, 2-
methyl-2-butene, aq. tBuOH, 7 h; i) MeI, K2CO3, acetone, 14 h; j) AcOH/
THF/H2O (3:1:1), 408C, 6 h; k) TBDPSCl, imidazole, CH2Cl2, 20 min;
l) Dess–Martin periodinane, CH2Cl2, 1 h; m) TFA/CH2Cl2 (1:10), 08C,
1 h; n) ClCO2iBu, Et3N, Et2O, 0 8C, 15 min, then CH2N2, 90 min. THF=
tetrahydrofuran; DMF=N,N-dimethylformamide; Boc=tert-butoxycar-
bonyl; DMSO=dimethyl sulfoxide.
Scheme 1. Retrosynthetic analysis of polygalolides. TBDPS=tert-butyldi-
phenylsilyl.
tone ring provided tricyclic compound 5, which was envi-
sioned to arise from a-diazoketone 6 through a carbonyl
ylide formation/intramolecular 1,3-dipolar cycloaddition se-
quence triggered by a rhodium(II) catalyst.[6–8] Diazoketone
6 could be prepared from tert-butyl ester 7, which could be
traced back to alcohol 8,[9] readily obtained from d-arabi-
nose.
Synthesis of carbonyl ylide precursor: An attempt to pre-
pare carbonyl ylide precursor 6 from d-arabinose-derived
alcohol 8 is depicted in Scheme 2. Although O-alkylation of
alcohol 8 with 4-(tert-butyldiphenylsilyloxy)-1-iodobutane[10]
resulted in low yield (32%) and production of a large
amount of an elimination product, the use of allyl bromide
9[11] as the alkylating agent provided allyl ether 10 in 98%
yield. Oxidative hydrolysis of dithioacetal 10 with iodine in
the presence of NaHCO3 in acetone[12] furnished aldehyde
11 in 88% yield, which was transformed into tert-butyl ester
serve as a dipolarophile in the key cycloaddition reaction,
was installed by employing a slight modification of the pro-
tocol reported by Ogasawara and co-workers;[15] Eschen-
moserꢁs
salt
and
1,8-diazabicycloACTHNGUTRENNU[G 5.4.0]undec-7-ene
(DBU)[16] were added to the reaction mixture, wherein alco-
hol 14 underwent a Swern oxidation.[17] The resultant enal
15 was further oxidized with NaClO2 and treated with MeI
under basic conditions to provide methyl ester 16 in 79%
yield in two steps. The acetonide group needed to be re-
moved at this stage. A complicating aspect of this deprotec-
tion was competitive cleavage of the tert-butyl ester fol-
lowed by the formation of a five-membered lactone. After
considerable experimentation, we found that exposure of
acetonide 16 to aqueous AcOH in tetrahydrofuran (THF) at
408C effected the desired transformation to give diol 17 in
85% yield. However, careful control of the temperature was
required to access 17, because lactone formation was ob-
[13]
12 in 80% yield in two steps by oxidation with NaClO2
and esterification with (Boc)2O in the presence of a catalytic
amount of 4-(N,N-dimethylamino)pyridine (DMAP).[14] Cat-
alytic hydrogenation of the C2=C10 double bond in 12 using
10% Pd/C was followed by desilylation with AcOH-buf-
fered Bu4NF to give alcohol 14 in 91% yield in two steps.
At this juncture, the C2=C3 double bond, which would
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9683

S. Nakamura, S. Hashimoto et al.
served at temperatures above 458C under these conditions.
Selective silylation of the primary hydroxyl group at C9 with
TBDPSCl was followed by Dess–Martin oxidation[18] to pro-
vide g-ketoester 7 in 88% yield in two steps. The tert-butyl
ester in 7 was uneventfully deprotected upon exposure to
trifluoroacetic acid (TFA) in CH2Cl2 at 08C in preparation
for the one-carbon homologation. Because acid chlorides
derived from g-ketocarboxylic acids have been reported to
exist as cyclic pseudochlorides,[19] an attempt to convert the
product into a-diazoketone 6 was performed as a two-step,
one-flask procedure, whereby an intermediate mixed anhy-
dride was formed from isobutyl chloroformate in Et2O at
08C before treatment with excess diazomethane. Although
the mixed anhydride moiety could be transformed into the
corresponding a-diazoketone, the reaction was accompanied
by a [3+2] cycloaddition of diazomethane to the enoate
moiety, producing dihydropyrazole 19 in 25% yield in two
steps. We attribute this result to the high reactivity of the
enoate moiety toward cycloaddition. To prevent this unde-
sired cycloaddition, we elected to carry this portion of the
molecule in a reduced oxidation state.
55% yield in two steps. It is noteworthy that the 1H and
13C NMR spectra of the g-ketocarboxylic acid intermediate
indicated that one discernible tautomer existed as a 3.7:1
mixture of diastereomers in CDCl3. This observation re-
vealed a large equilibrium preference for the “closed” hemi-
acylal structure 25, despite the potential for ring–chain tau-
tomerism. The modest yield of the overall process might be
a result of this tautomerization of 25, which could prevent
the quantitative formation of the mixed anhydride.
Construction of the trioxatetracyclic ring system: Having
completed the synthesis of a-diazoketone 26, we then ad-
dressed the critical carbonyl ylide formation/intramolecular
1,3-dipolar cycloaddition sequence. The reaction involved
the dropwise addition of a solution of a-diazoketone 26
over a 3 min period to a solution of 5 mol% RhII catalyst.
We first investigated a [Rh2ACHTNUTRGENNUG(OAc)4]-catalyzed reaction in
toluene. Although the a-diazoketone was consumed within
1 h at room temperature, a complex mixture of products was
obtained (Table 1, entry 1). In contrast, intermolecular reac-
Enal 15 was then reduced with NaBH4 in EtOH at 08C to
give allyl alcohol 20 in 95% yield, which was transformed
into its 4-methoxyphenyl (PMP) ether 21 in 78% yield
through mesylation followed by a nucleophilic substitution
with 4-methoxyphenol in MeCN heated to reflux
(Scheme 3). Conversion of acetonide 21 into g-ketoester
Table 1. Intramolecular 1,3-dipolar cycloaddition triggered by a RhII cat-
alyst.
Entry RhII catalyst
Solvent
T
t
Yield
[8C]
ACHTUNGTRENN[UNG min] [%]
1
2
3
4
5
6
7
8
9
N
(OAc)4]
toluene
toluene
toluene
benzene
25 60
complex mixture
60
110
80
5
5
5
5
5
5
5
5
5
36
68
57
31
A
80
100
100
100
100
100
73
trace
complex mixture
PhCF3
PhCF3
PhCF3
24
41
10
Scheme 3. Synthesis of a-diazoketone 26. Reagents and conditions:
a) NaBH4, EtOH, 08C, 30 min; b) MsCl, Et3N, CH2Cl2, 08C, 10 min; c) 4-
MeOC6H4OH, K2CO3, MeCN, reflux, 6 h; d) AcOH/THF/H2O (3:1:1),
408C, 4 h; e) TBDPSCl, imidazole, CH2Cl2, 1 h; f) Dess–Martin periodi-
nane, CH2Cl2, 1 h; g) TFA/CH2Cl2 (1:10), 08C, 1 h; h) ClCO2iBu, Et3N,
Et2O, 0 8C, 10 min, then CH2N2, 90 min. Ms=methanesulfonyl.
tion with dimethyl acetylenedicarboxylate (DMAD) oc-
curred under identical conditions to give a 2:1 mixture of cy-
cloadducts 29 in 51% yield [Eq. (1)]. This result clearly indi-
cates the formation of carbonyl ylide 27 from 26 under
these conditions. We speculate that a) the carbonyl ylide 27
cannot adopt the folded conformation 27a at room tempera-
ture and/or b) compared to DMAD, the unactivated 1,1-di-
24[20] proceeded uneventfully over three steps (hydrolytic re-
moval of the acetonide, selective silylation of the primary al-
cohol, and Dess–Martin oxidation) in 81% overall yield.
After exposure of the tert-butyl ester 24 to TFA, the corre-
sponding mixed anhydride was generated in situ and treated
with diazomethane to give the target a-diazoketone 26 in
AHCTUNGTREGsNNUN ubstituted olefin in 26 is not sufficiently reactive as a dipo-
larophile. This hypothesis was validated by the observation
that when the reaction was performed at 608C, the desired
cycloadduct 28[20] was formed as a single isomer in 36%
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Chem. Eur. J. 2012, 18, 9682 – 9690

Syntheses of (+)-Polygalolides A and B
FULL PAPER
Scheme 4. Synthesis of tetracyclic lactone 3. Reagents and conditions:
yield (Table 1, entry 2), and by the finding that the product
yield was improved to 68% by an increase in reaction tem-
perature to 1108C (Table 1, entry 3). Solvent screening re-
vealed that aromatic solvents were superior to dichloro-
ethane and that a,a,a-trifluorotoluene was the optimal sol-
vent[21] for this transformation due to the low electron densi-
ty of the aromatic ring, which could prevent formation of cy-
a) (NH4)2Ce
ACHTUGNTRENN(UNG NO3)6, pyridine, aq. MeCN, 08C, 2 h; b) Dess–Martin per-
AHCTUNTGERNiGNUN odinane, CH2Cl2, 2 h; c) NaClO2, NaH2PO4, 2-methyl-2-butene, aq.
tBuOH, 6 h; d) CH2N2, Et2O, 0 8C, 30 min; e) Bu4NF, AcOH, THF, 20 h.
yield, which, upon further oxidation with NaClO2 and subse-
quent esterification with CH2N2, gave methyl ester 5 in 85%
yield in two steps. Finally, treatment of TBDPS ether 5 with
AcOH-buffered Bu4NF in THF effected desilylation and lac-
tonization to provide tetracyclic compound 3 in 93% yield.
cloheptatriene byproduct 30 resulting from
a Bꢂchner
reaction (Table 1, entries 3–6). A series of rhodium(II) com-
plexes were next evaluated for their ability to catalyze the
reaction in a,a,a-trifluorotoluene at 1008C. Although the
reaction of a-diazoketone 26 proceeded to completion
within 5 min in all cases, employment of catalysts other than
Completion of the total synthesis of polygalolides A and B:
Having constructed the common tetracyclic core of the nat-
ural products, all that remained to complete the total syn-
thesis was installation of the arylmethylidene moiety. We
first performed exploratory experiments using cycloadduct
28 lacking the lactone ring (Scheme 5). An attempt to
couple ketone 28 and triisopropylsilyl (TIPS)-protected va-
nillin 34[24] under basic conditions resulted in no reaction
and clean recovery of starting materials. Deuterium quench-
[Rh2ACHTUNGTRENNUNG(OAc)4] resulted in low yield (Table 1, entries 6–10).
Under the optimized conditions, the cycloaddition could be
performed on a 500 mg scale in 70% yield. It is noteworthy
that three of the four stereocenters (C2, C4, and C8) in the
natural products were established in a single operation
through internal asymmetric induction from the C7 stereo-
center. Interestingly, 1H NMR NOE correlation between
C6-Ha and C7-H suggested that the dihydropyranone ring in
cycloadduct 28 would adopt a boat-like conformation in
which the Ha-C6-C7-H dihedral angle is approximately 908
(Figure 1). This conformational analysis was supported by
1
ing experiments and H NMR spectroscopic analysis of the
crude product revealed that lithium enolate 33 was generat-
ed from ketone 28 upon treatment with lithium diisopro
ACHTUNGTRENNUNGpyl-
AHCTUNGTRENNUNG
a stereoselective manner to produce 36. However, apprecia-
ble deuterium loss and epimerization during purification of
36 by preparative thin-layer chromatography (TLC) were
observed, suggesting that tricyclic ketone 28 is prone to eno-
lization. Although the exact origin of this propensity is un-
clear at the present time, it was speculated that the aldol
product 35 underwent retro aldolization upon warming to
room temperature after quenching with saturated aqueous
NH4Cl. Switching protection of the phenolic C16 hydroxyl
group from a TIPS ether to an acetate gave aldol adduct 39,
although analysis of the unpurified reaction mixture by
1H NMR spectroscopy revealed approximately 10% conver-
sion. Furthermore, changing the metal counterion to zinc re-
sulted in an increase in conversion to approximately 20%
Figure 1. NOE interactions observed with cycloadduct 28.
observed vicinal coupling constants between the C6 and C7
protons (JACHTUNGTRENNUNG(6a,7)=0 Hz and JACHTUNGTRENN(UGN 6b,7)=9.0 Hz).
With the cycloadduct 28 in hand, the remaining opera-
tions necessary for construction of the tetracyclic ring
system involved the formation of the five-membered lac-
tone. Oxidative removal of the PMP group with cerium(IV)
ammonium nitrate (CAN)[22] buffered with pyridine[23] in
aqueous MeCN, furnished alcohol 31 in 91% yield
(Scheme 4). The resultant alcohol 31 was oxidized with
Dess–Martin periodinane to afford aldehyde 32 in 92%
1
(as judged by H NMR spectroscopic analysis). However, we
were disappointed to find that aldol product 39 reverted to
the starting materials 28 and 38a[25] during purification by
silica gel. From these results, a decision was made to trap
the alkoxide formed by the aldol reaction in situ with an
electrophile such as Ac2O to prevent the retro aldol reac-
tion.
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9685

S. Nakamura, S. Hashimoto et al.
in CH2Cl2 for 24 h, affording enone 41a as a 5:1 mixture of
E/Z isomers.[26] It should be noted that these isomers were
in equilibrium, as judged by two-dimensional TLC. For this
reason, only low-molecular-weight impurities such as excess
aldehyde 38a were removed by gel permeation chromatog-
raphy at this stage for the final deprotection event. Deacety-
lation of 41a was successfully performed with K2CO3 in
MeOH to afford polygalolide A (1) in 75% yield for the
three-step sequence. No evidence for the presence of the
(Z)-stereoisomer of 1 was found, suggesting that olefin iso-
merization occurred during deacetylation. This speculation
was supported by an experiment using acetate 41a (E/Z=
1:4), wherein polygalolide A (1) was obtained as the sole
product.
Following the same reaction sequence, polygalolide B (2)
could be synthesized from ketone 3 and aldehyde 38b,[27]
however, the overall yield was only 49%. The low efficiency
of the sequence was caused by incomplete conversion of the
aldol coupling, wherein enol acetate 42 was obtained in ap-
proximately 20% yield. Whereas this result could be attrib-
uted to the poor electrophilicity of 38b, the use of aldehyde
having a trifluoromethanesulfonate at C16 instead of 38b
gave polygalolide B in 35% overall yield (aldol reaction, b-
elimination and deprotection of the trifluoromethanesulfon-
yl (Tf) group with Bu4NF[28] in THF).[29] We considered that
the application of an irreversible reaction could improve the
efficacy of the coupling process. Thus, tetracyclic ketone 3
was converted into the corresponding trimethylsilyl (TMS)
enol ether 43 using TMSOTf and Et3N in preparation for
the Mukaiyama aldol-type reaction (Scheme 7).[30]
Scheme 5. Exploratory experiments using ketone 28. Reagents and condi-
tions: a) LDA, THF, ꢀ788C, then aldehyde 34; b) LDA, THF, ꢀ788C,
then D2O, ꢀ788C to RT; c) SiO2, EtOAc/hexane; d) LDA, ZnCl2, THF,
ꢀ788C, then aldehyde 38a.
Gratifyingly, desired product 40a could be obtained when
the zinc enolate derived from tetracyclic ketone 3 was react-
ed with aldehyde 38a at ꢀ788C for 30 min, followed by ad-
dition of Ac2O and gradual warming to room temperature
(Scheme 6). Because purification of b-acetoxyketone 40a by
silica gel chromatography caused partial elimination of the
C12 acetoxy group (probably due to the enolization-prone
carbonyl group), the crude mixture was exposed to silica gel
Scheme 7. Conversion of tetracyclic ketone 3 to polygalolides A (1) and
B (2) through a Mukaiyama aldol-type reaction. Reagents and condi-
tions: a) TMSOTf, Et3N, CH2Cl2, 08C, 5 h; b) acetal 44a or 44b
(2 equiv), TMSOTf, pulverized 3 ꢃ MS, CH2Cl2, 08C, 15 min; c) DBU,
CH2Cl2, 10 min; d) K2CO3, MeOH. MS=molecular sieves.
Scheme 6. Completion of the total synthesis of polygalolides A (1) and B
(2). Reagents and conditions: a) LDA, ZnCl2, THF, ꢀ788C, 1 h, aldehyde
38a or 38b (2 equiv), 30 min, then Ac2O, ꢀ788C to RT, 16 h; b) SiO2,
CH2Cl2, 24 h; c) K2CO3, MeOH.
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Syntheses of (+)-Polygalolides A and B
FULL PAPER
Initial attempts to couple silyl enol ether 43 with dimethyl
acetal 44a by either BF3·OEt2, (iPrO)TiCl3 or ScACTHNUGTRENUNG(OTf)3 met
with failure. After considerable experimentation, we found
that the TMSOTf-promoted reaction[31] proceeded at ꢀ788C
to give coupling product 45a[32] in 70% yield from ketone 3.
The yield of the two-step process was improved to 85% at
a higher temperature of 08C (Scheme 7). Elimination of the
methoxy group was effected by short exposure (10 min) of
the product 45a to DBU in CH2Cl2,[33] and subsequent de-
acetylation using K2CO3 in MeOH gave polygalolide A (1)
in 88% yield in two steps. In the same manner, and in ap-
proximately the same yields, silyl enol ether 43 was united
with dimethyl acetal 44b[34] and the product 45b was ad-
vanced to polygalolide B (2) (Scheme 7). Although applica-
tion of the Mukaiyama aldol-type reaction did not offer ad-
vantages in the synthesis of 1, the overall yield from 3 to 2
(71%) could be dramatically improved by applying the four-
step sequence.
Scheme 8. Synthetic plan based on conjugate addition of an alcohol nu-
cleophile.
the synthetic route to g-ketoester 24 (Scheme 8). In this
regard, Mulzer and co-workers reported diastereoselective
conjugate addition reactions of sodium alkoxides to enoate
47, wherein the preferential formation of syn adducts was
documented.[35] However, the corresponding alcohols were
employed as solvents in all cases, and the reaction with
a less reactive alkoxide (sodium benzylate) resulted in only
modest diastereoselectivity (syn/anti=76:24) due to the high
temperature (ꢀ108C) that was required for the reaction to
take place. The difficulty of using solid 48 as a solvent to-
gether with the lack of sufficient reactivity of the alkoxide
derived from 48 for the reaction at low temperatures
prompted us to explore the optimal conditions for the reac-
tion of enoate (ꢀ)-47[36,37] with alcohol 48.[39]
The synthetic compounds proved to be identical to natu-
ral products as judged by 1H and 13C NMR, IR, UV and
HRMS analyses. Their specific rotations were equal in sign;
however, the magnitudes ([a]D =ꢀ499.9 (c=0.022 in
MeOH) and ꢀ505.2 (c=0.018 in MeOH), respectively)
were inconsistent with those observed for natural polygalol-
ides A and B ([a]D =ꢀ14.4 (c=0.018 in MeOH) and ꢀ21.3
(c=0.015 in MeOH), respectively), indicating the possibility
that the natural products are biosynthesized in near-racemic
form.
Initial attempts to effect the reaction using NaH as a base
in either THF or 1,2-dimethoxyethane (DME) at ꢀ238C
and at a concentration of the enoate (ꢀ)-47 of 0.1m provid-
ed a mixture of coupling products 49a and ent-21 in moder-
ate combined yield and poor stereoselection (Table 2, en-
tries 1 and 2). Solvent screening revealed that, although low
yields were obtained, good to high syn selectivities were
achieved in Et2O, toluene, and CH2Cl2, with CH2Cl2 being
the optimal solvent (49a/ent-21=27.0:1; Table 2, entries 3–
5); it should be noted that CH2Cl2 is not normally used in
this type of reaction.[40] Despite the improvement in chemi-
cal yield (21!60%), the use of elevated temperature led to
Improved synthesis of intermediate 24: Although the stereo-
controlled total synthesis could be realized by taking ad-
vantage of the carbonyl ylide cycloaddition strategy, the
overall length (29 steps from d-arabinose) left room for im-
provement. We therefore wanted to develop an improved
synthesis of polygalolides. Because the length of the se-
quence was due, in part, to the transformations required for
installation of the C2=C3 olefin that functioned as a dipolar-
ophile in the 1,3-dipolar cycloaddition, we considered that
conjugate addition of alcohol 48 to enoate 47 would shorten
Table 2. Conjugate addition of alcohol 48 to enoate (ꢀ)-47.
Entry
Base
[equiv]
Solvent
c
T
t
Yield Recov. Ratio[a]
[m] [8C] [h] [%] [%] 49a/
(ꢀ)-47 ent-21
Entry
Base
ACHTUNGTRNE[NUNG equiv]
Solvent
c
T
t
Yield Recov. Ratio[a]
[m] [8C] [h] [%] [%] 49a/
(ꢀ)-47 ent-21
U
1
2
3
4
5
6
NaH 1.5 THF
NaH 1.5 DME
NaH 1.5 Et2O
0.1 ꢀ23
4
4
55
61
23
21
27
33
75
24
1:1.5
1:2.1
6.3:1
13.5:1
27.0:1
6.0:1
7
8
BuLi 1.5 CH2Cl2 0.1 ꢀ23
48
–
100
16
17
25
17
12
–
0.1 ꢀ23
KH
0.3 CH2Cl2 0.1 ꢀ23
48 76
48 79
48 70
72 77
8.3:1
26.7:1
22.9:1
20.7:1
16.6:1
0.1 ꢀ23 24 39
9[b]
10
11
12
NaH 3.0 CH2Cl2 0.1 ꢀ23
NaH 1.5 CH2Cl2 0.2 ꢀ23
NaH 1.5 CH2Cl2 0.2 ꢀ23
NaH 1.5 toluene 0.1 ꢀ23 24 45
NaH 1.5 CH2Cl2 0.1 ꢀ23 48 21
NaH 1.5 CH2Cl2 0.1
0
48 60
NaH 1.5 CH2Cl2 0.2 ꢀ23 144 82
[a] Determined by HPLC analysis (column, Zorbaxꢄ Sil, 4.6ꢅ250 mm; eluent, 6% THF in hexane; flow rate, 1.0 mLminꢀ1); tR =18.6 (ent-21, anti),
21.4 min (49a, syn). [b] Using 3 equiv of alcohol 48. (Recov.=recovered).
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S. Nakamura, S. Hashimoto et al.
a decline in the stereoselectivity (Table 2, entries 5 vs. 6). Of
the bases screened, NaH proved the best in terms of stereo-
selectivity (Table 2, entries 6–8). When the amounts of both
alcohol 48 and NaH were increased from 1.5 to 3.0 equiv,
a higher yield (79%) was obtained (Table 2, entries 5 vs. 9).
Chemical yield (70%, 93% based on recovered starting ma-
terial) was also improved by increasing the concentration of
enoate (ꢀ)-47 from 0.1 to 0.2m (Table 2, entry 10). From
these results, we decided to perform the reaction at a con-
centration of 0.2m using 1.5 equiv of alcohol 48 for reasons
of synthetic economy. It is noteworthy that erosion of the
syn selectivity was observed with extended reaction times
(Table 2, entries 10–12), indicating that the excellent selec-
tivity comes about as a result of kinetic control.[41]
higher efficiency (49 vs. 21% overall yield) compared with
the previous route.
Plausible biosynthetic pathway: Given the lack of informa-
tion in the literature regarding the biosynthesis of polygal
ACHTUNGTRENNUNGol-
AHCTUNGTREGiNNUN des, a search for natural products with similar molecular ar-
chitecture was performed. Although the CAS database con-
tains no records of tetracyclic compounds similar to polygal-
AHCTUNGTREUNoGNN lACHTUNTRGNEGiNU des, the 8-oxabicycloACHTNUGTRNE[NUGN 3.2.1]octan-2-one skeleton, which is
a partial structure of polygalolides, could be found in three
natural products 54–56 (Figure 2).[44] We also found that ex-
As is reported in the literature,[35] the stereochemical
course of the hetero-Michael reaction can be rationalized by
Felkin–Anh model A, wherein the electron-withdrawing
alkoxy group is aligned anti to the forming bond and the
sterically unencumbered hydrogen atom occupies the out-
side position (Scheme 9). Because enolate 50, thus formed,
Figure 2. Natural products having an 8-oxabicyclo
eton.
ACHTUNGERTN[NUNG 3.2.1]octan-2-one skel-
tremely short, racemic syntheses of these molecules had
been reported by Snider and Grabowski.[45] They demon-
strated that [5+2] cycloaddition of an oxypyrylium zwitter-
ion,[46,47] generated from a pyranulose derivative, with either
styrenes or a cinnamate ester proceeded in a regio- and dia-
Scheme 9. Stereochemical model for the predominant formation of syn-
isomer 49a.
stereoselective manner to provide 8-oxabicycloACHTNUTRGNE[NUG 3.2.1]oct-3-
en-2-one derivatives, which were deprotected to give natural
products 54–56 in 24, 27 and 13% overall yields, respective-
ly. Because the pyranulose derivative is generated by dehy-
dration and oxidation of fructose, they suggested that these
natural products would be biosynthesized by similar [5+2]
cycloaddition of achiral compounds, and that the small De
for 54 and the small [a]D values for 55 and 56 indicate asym-
metric induction during cycloadditions in chiral environ-
ments. Recently, Peterson and co-workers reported that
compound 54 was obtained from glucose, glycine, and ferulic
acid in a simulated baking model system.[48] This result sug-
gests that, under these conditions, the oxypyrylium zwitter-
ion was generated from glucose and glycine by Amadori
degradation followed by dehydration and cyclization, and
was trapped by 2-methoxy-4-vinylphenol, a decarboxylated
product of ferulic acid. On the basis of the reasonable pro-
posal by the Snider group, we speculated that polygalolides
could be synthesized in the medicinal plant through cyclo-
is capable of internal chelation with the b-heteroatom, isom-
ACHTUNGTRENNUNGerization through a retro-Michael reaction is presumably re-
tarded by the use of a nonpolar solvent such as CH2Cl2,
leading to the predominant formation of syn-isomer 49a.[42]
After chromatographic separation of adducts 49a and ent-
21, major isomer 49a was subjected to the same series of
transformations that was performed on acetonide 21, to
afford 24 in 73% overall yield (Scheme 10). Ketone 24, thus
obtained, was identical in all respects to the material pre-
pared by using the previous sequence. The improved route
to ketone 24 proceeds with 11 fewer steps and considerably
AHCTUNGTREGaNNNU ddition of oxypyrylium zwitterion 57 with an isoprene de-
rivative such as 58, followed by intramolecular hetero-Mi-
chael addition, lactone formation, and aldol reaction with
vanillin derivative 46 (Scheme 11). Our results clearly reveal
that poor enantiofacial differentiation (3–4% ee) occurs in
the cycloaddition event.[49] After the publication of our pre-
liminary communication in 2006,[5] a biomimetic, two-step
synthetic approach to tetracyclic compound (ꢁ)-3 was devel-
oped by the Snider group.[50,51]
Scheme 10. Conversion of 49a into ketone 24. Reagents and conditions:
a) AcOH/THF/H2O (3:1:1), 408C, 6 h; b) TBDPSCl, imidazole, CH2Cl2,
30 min; c) Dess–Martin periodinane, CH2Cl2, 1 h.
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Syntheses of (+)-Polygalolides A and B
FULL PAPER
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Conclusion
Stereocontrolled total synthesis of polygalolides A (1) and B
(2) has been achieved. The synthesis proceeded in 25 steps
and produced polygalolides A (1) and B (2) in 6.4 and 6.1%
overall yields, respectively, from known alcohol 8 (4.2 and
4.0% overall yields, respectively, 29 steps from d-arabinose).
The synthesis illustrates the power of the carbonyl ylide cy-
cloaddition methodology, which enables rapid assembly of
the unusual dioxatricyclic ring system, which is otherwise
difficult to construct. The synthetic sequence could be great-
ly shortened by exploiting the hetero-Michael reaction of
the alkoxide nucleophile, wherein the use of CH2Cl2 as a sol-
vent plays a pivotal role in achieving high syn selectivity. To
the best of our knowledge, this is the first report of a dia-
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ACHTUNGTRENNUNGstereoselective, intermolecular hetero-Michael reaction of
an alkoxide to an enoate without using an excess amount of
alcohol. The improved route is much more efficient in terms
of overall yield than the previous approach. As a conse-
quence, total syntheses of polygalolide A (1) and B (2) can
be realized in 16 steps with overall yields of 13 and 12%, re-
spectively, from known enoate (ꢀ)-47 (9.8 and 9.3% overall
yields, respectively, 18 steps from commercially available
(ꢀ)-methyl (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate) by
this route.
Comparison of the specific rotations indicates that the
natural products would be biosynthesized in near-racemic
form. Our total synthesis serves to provide a stereochemical
insight into the biogenesis of this class of natural products.
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Acknowledgements
This research was supported in part by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We also acknowledge the Japan Society for the Pro-
motion of Science for graduate fellowships to Y. S. We are grateful to
Professor Xiaoyi Wei for providing spectra of natural products. We thank
Ms. Hiroko Matsumoto, Ms. Akiko Maeda, Ms. Seiko Oka, Ms. Miwa
Kiuchi, and Mr. Tomohiro Hirose of the Center for Instrumental Analy-
sis, Hokkaido University, for technical assistance in mass and elemental
analysis.
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9689

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enolized with NaN
G
treatment with sodium alkoxide derived from 48 (1.5 equiv) at
ꢀ238C for 96 and 48 h, respectively. Nearly identical ratios (1:1.8
and 1:2, respectively) of isomers 49a and ent-21 were obtained
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[42] Compared with (E)-enoate (ꢀ)-47, the reaction of the correspond-
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the optimal conditions. Even after 144 h, a diastereomeric mixture
of adducts 49a and ent-21 was obtained in only 43% yield in a ratio
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[33] Prolonged exposure of 45a to DBU led to partial formation of (Z)-
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[34] Dimethyl acetal 44b was prepared in 91% yield from 4-hydroxy-
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CH2Cl2, 12 h.
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dioxolane-4-carboxylate by using the Takacs procedure[38] in 77%
yield over two steps.
[49] Catalytic asymmetric synthesis of compounds 54 and 55 revealed
that these natural products are also biosynthesized in near-racemic
form; see references [8r,8s].
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[39] Alcohol 48 was prepared from 4-methoxyphenol by the following
two-step sequence: 1) NaH (1.1 equiv), 3-bromo-2-bromomethyl-1-
propene (2.5 equiv), DMF, 1.5 h, 55%; 2) In (1.2 equiv), HCHO
(7.5 equiv), aq. THF, 48 h, 91%.
Received: February 18, 2012
Revised: May 2, 2012
Published online: July 3, 2012
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Chem. Eur. J. 2012, 18, 9682 – 9690