Total Synthesis of (-)-Isoamericanin A and (+)-Isoamericanol A

Article abstract of DOI:10.1002/ejoc.201301363

The enantioselective total synthesis of the biologically active 1,4-benzodioxane lignans isoamericanin A (2) and isoamericanol A (3) has been achieved in 11 and 12 steps, respectively. These benzodioxane lignan natural products, and others that contain 9-hydroxymethyl group, show a wide range of biological properties. The 1,4-benzodioxane ring was formed by an acid-catalysed cyclisation, which gave the desired trans isomer exclusively. This method will allow the synthesis of a number of benzodioxane compounds containing a 9-hydroxymethyl group The total syntheses of (-)-isoamericanin A and (+)-isoamericanol A are described. The key steps were a Mitsunobu etherification and the acid-catalysed formation of the 1,4-benzodioxane moiety with exclusive formation of the desired trans isomer.

Full text of DOI:10.1002/ejoc.201301363

FULL PAPER
DOI: 10.1002/ejoc.201301363
Total Synthesis of (–)-Isoamericanin A and (+)-Isoamericanol A
Lisa I. Pilkington[a] and David Barker*[a]
Keywords: Natural products / Total synthesis / Chiral pool / Oxygen heterocycles / Lignan
The enantioselective total synthesis of the biologically active
1,4-benzodioxane lignans isoamericanin A (2) and isoamer-
icanol A (3) has been achieved in 11 and 12 steps, respec-
tively. These benzodioxane lignan natural products, and
others that contain 9-hydroxymethyl group, show a wide
range of biological properties. The 1,4-benzodioxane ring
was formed by an acid-catalysed cyclisation, which gave the
desired trans isomer exclusively. This method will allow the
synthesis of a number of benzodioxane compounds contain-
ing a 9-hydroxymethyl group
activity has been of particular interest in recent years due
to the fact that silybin A (1), one of the major components
Introduction
1,4-Benzodioxanes, in particular those with
a 9-hy- of silymarin (milk thistle extract) – a popular liver protect-
droxymethyl group, have been found to have a range of ant that has been used in traditional medicine for centu-
interesting pharmacological activities including cytotoxic, ries,[7,8] has demonstrated anti-HCV (hepatitis C) effects as
antimicrobial, and hepaprotective activities, and this makes well as in vitro inhibition of T-cell proliferation (Fig-
them desirable synthetic targets.[1–6] Their hepaprotective ure 1).[9]
Figure 1. Selected 1,4-benzodioxane natural products.
Additionally, isoamericanin A (2) has been shown to be
a prostaglandin I2 inducer.[10] Isoamericanol A (3) has been
[a] School of Chemical Sciences, The University of Auckland,
shown to enhance neurite sprouting, and also to increase
choline acetyltransferase (ChAT) activity in a primary cul-
ture of foetal rat cerebral hemisphere cells, which indicates
that it has neutrotrophic activity.[11,12]
23 Symonds St, Auckland, New Zealand
E-mail: d.barker@auckland.ac.nz
http://www.chemistry.auckland.ac.nz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301363.
Eur. J. Org. Chem. 2014, 1037–1046
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. I. Pilkington, D. Barker
FULL PAPER
Isoamericanin A (2) was first isolated in 1987 by Hase-
gawa et al.[10] from Phytolacca americana, and isoamer-
icanol A (3) was isolated five years later from the same
plant by the same group.[11] Both of these compounds were
isolated together with their associated regioisomers ameri-
canin A (4) and americanol A (5), respectively, and have
since been isolated from a range of trees and plants.[13–15]
The coupling of phenoxy radicals in the biosynthesis of 1,4-
benzodioxane natural products is generally not controlled
by enzymes, so compounds of this class are often found
as racemic mixtures.[16,17] Some natural 1,4-benzodioxanes,
though, have been found in enantiomerically pure form in
nature, including the closely related nitidanin (6)[18] and ai-
phanol (7).[19] The most studied family of such compounds
is the eusiderin family [e.g., eusiderin A (8)], and interest-
ingly, in some cases, both enantiomers have been iso-
lated.[20]
Results and Discussion
We began with the synthesis of phenol 12 (Scheme 1).
Salicylaldehyde (13) was protected with a MOM (meth-
oxymethyl) group in an excellent yield to give aldehyde 14,
which then underwent a Dakin oxidation to give mono-
protected catechol 15. Selective bromination of 15 with N-
bromosuccinimide (NBS) at 0 °C provided bromophenol 12
in an overall yield of 78% over four steps from salicylalde-
hyde (13).
Recently, we published the first asymmetric synthesis of
members of the eusiderin family of 1,4-benzodioxanes.
These compounds are structurally similar to the isoamer-
icanins, but there are a few key differences, the most signifi-
cant of which is that the 9-hydroxymethyl group of the
isoamericanins is replaced by a 9-methyl group in the eusid-
erin family.[21] Previous syntheses of lignans containing a 9-
hydroxymethyl group did not easily allow variations to be
made.[22–25] We wanted an adaptable synthetic route that
could be used to prepare both 2 and 3, and that would
also allow the synthesis of analogues of the natural product.
Similar 1,4-benzodioxanes, such as nitidanin (6) and ai-
phanol (7), that contain the 9-hydroxymethyl group should
also be accessible (Figure 2).
Scheme 1. Synthesis of phenol 12 (DIPEA = diisopropylethyl-
amine, mCPBA = meta-chloroperbenzoic acid).
To test our proposed route to aldehyde 10, we decided to
use the more readily available l-serine (16), which would, if
successful, give the enantiomer of 10, and could eventually
be replicated using the more expensive d-serine. The synthe-
sis of Mitsunobu coupling partner 11 therefore began with
diazotisation of l-serine (16), which gave diol 17 with reten-
tion of stereochemistry (Scheme 2).[26,27] Esterification of 17
gave the corresponding methyl ester (i.e., 18), the primary
alcohol of which was selectively protected with the bulky
TBDPS (tert-butyldiphenylsilyl) group to give 11a in 44%
yield over the three steps from 16.
Figure 2. Retrosynthetic analysis of isoamericanin-type products.
Scheme 2. Synthesis of alcohols 11a and 11b.
As 2 and 3 differ only in the side-chain, we thought that
if we could introduce this at a later stage of the synthesis,
When the Mitsunobu reaction between 11a and 12 was
we could synthesise both natural products from a common attempted using DIAD (diisopropyl azodicarboxylate), no
starting material that would be formed from an acid-cata- product was obtained, even after extended reaction times
lysed cyclisation of alcohol 9. Alcohol 9 would be made by (Scheme 3). We have previously shown that these conditions
the addition of an aryllithium species to aldehyde 10, itself give high yields of phenolic ethers when 11 is replaced with
formed from the product of the Mitsunobu reaction be- ethyl lactate, which has a methyl rather than a –CH2OSiR3
tween d-serine derived alcohol 11 and phenol 12.
group.[21] Therefore, to investigate whether the failure of
1038
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Total Synthesis of (–)-Isoamericanin A and (+)-Isoamericanol A
this reaction was due to steric hindrance, TES-protected mental to the reaction. Therefore the synthesis was contin-
(TES = triethylsilyl) alcohol 11b (synthesised from 18 using ued with TIPS-protected alcohol 20b. The Mitsunobu reac-
conditions similar to those used for 11a) was subjected to tion between 20b and the required phenol (i.e., 12) success-
the same Mitsunobu conditions. But unfortunately, this was fully gave the desired ether (i.e., 25) in 66% yield.
unsuccessful. To investigate whether the ortho substituent
in 12 was impeding the reaction, 4-bromophenol was
treated with both 11a and 11b; once again no reaction was
observed. However, when alcohol 11a was subjected to Mit-
sunobu conditions with benzoic acid, ester 19 was obtained
in 87% yield. This result indicates that while alcohols 11 do
not undergo Mitsunobu reactions with phenols, they are
able to react with more reactive coupling partners such as
carboxylic acids.
Scheme 4. Mitsunobu reactions of alcohol 20.
Having successfully prepared ether 25, the synthesis was
Scheme 3. Mitsunobu reactions of 11a and 11b.
continued with the removal of the PMB protecting group
using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to
give alcohol 26 in 80% yield (Scheme 5). Oxidation of 26
with Dess–Martin periodinane (DMP) gave the desired al-
dehyde (i.e., 10). The aryllithium species formed by the lithi-
ation of bromide 27[29] with tBuLi was added to 10 to give
an inseparable 2.5:1 mixture of anti and syn alcohols 28a
and 28b. Alcohols 28a and 28b were then heated at reflux
with an acidic resin, which resulted in the removal of all of
the protecting groups and concomitant cyclisation to give
the highly polar 1,4-benzodioxane 29. This compound was
immediately tri-protected to give 1,4-benzodioxane 30 in
58% yield over two steps. The NMR spectrum of 30 showed
only trace amounts of the cis product, indicating that this
cyclisation heavily favours the formation of the trans iso-
mer. This is in contrast to the similar cyclisation in the syn-
thesis of the eusiderin natural products. In that case, while
After the lack of success in the first route, a revised syn-
thetic plan was devised. We thought that instead of serine
derived alcohol 11, a glycerol derivative 20 Ϫ the enantio-
mer of which has been shown to undergo Mitsunobu reac-
tions,[28] could be used in the hope that it would successfully
couple with phenol 12 (Figure 3). The product of this cou-
pling could then be converted into aldehyde 10.
Figure 3. Revised retrosynthesis of 10.
To begin this revised synthesis, alcohol 21 was protected the formation of the trans isomer was favoured, ca. 20% of
as its PMB (p-methoxybenzyl) ether to give 22 in an excel- the cis isomer was formed as well.[21] This observation re-
lent 95% yield (Scheme 4). Deprotection of the acetonide flects findings associated with 1,4-benzoidoxane natural
group gave diol 23, which was selectively protected at the products Ϫ both trans and cis 1,4-benzoidoxanes with a 9-
primary alcohol with a TBDPS group to give 20a in 52% methyl group are found in nature (although the trans com-
yield. In an attempt to improve the yield of the protection pounds are more common), whereas only a very few cis
step, 23 was also protected with a TIPS (triisopropylsilyl) americanin-type compounds have been isolated.[30] It is pro-
ether to give 20b in an improved 79% yield. To test the posed that the highly selective formation trans isomer 29 is
compatibility of alcohols 16a and 16b in the Mitsunobu due to an intermediate quinonemethide, formed under the
reaction with phenols, they were first subjected to the reac- acidic conditions, which allows the reversible cleavage of the
tion with 4-bromophenol. Satisfyingly, ether 24b was ob- C-3–O-4 bond, resulting in the formation of the more stable
tained in 62% yield, showing the utility of alcohol 20b for trans isomer.[31]
this transformation. Alcohol 20a gave the corresponding
To install the side-chain required for the natural prod-
ether (i.e., 24a) in a lower 37% yield, which shows that in- ucts, bromide 30 was lithiated, and dry DMF was added to
creased steric bulk adjacent to the reaction centre was detri- give aldehyde 31. A Wittig reaction of 31 gave triprotected
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L. I. Pilkington, D. Barker
FULL PAPER
Scheme 5. Synthesis of isoamericanin A (2) and isoamericanol A (3). TBAF = tetrabutylammonium fluoride.
isoamericanin A 32 in a 21% yield, 100% based on reco-
vered starting material (brsm). Efforts to improve this yield
Experimental Section
General Methods: All reactions were carried out under a nitrogen
atmosphere in dry, freshly distilled solvents unless otherwise noted.
All optical rotation measurements were determined at 20 °C at the
sodium D line (λ = 589 nm, 0.1 dm cell). All NMR spectra were
recorded with a 400 MHz spectrometer. Chemical shifts were cal-
ibrated using the solvent peak of chloroform (δ = 7.26 ppm for 1H,
by performing the reaction at higher temperatures and/or
in high-pressure reaction vessels, gave 32 in a reduced yield
together with some degradation products. Therefore ad-
ditional 32 was obtained simply by repeated Wittig reac-
tions of recovered 31. Finally, deprotection of the TIPS
groups yielded isoamericanin A (2) in an excellent yield.
Reduction of isoamericanin A (2) with NaBH4 gave
isoamericanol A (3). The spectroscopic data for both 2 and
3 matched the literature values.[13]
1
and δ = 77.0 ppm for 13C spectra). H NMR spectroscopic data is
reported as chemical shift (δ), multiplicity (s singlet, d doublet, t
triplet, q quartet, m multiplet, br. broad peak, qd quartet of dou-
blets, dt doublet of triplets), coupling constant (J [Hz]), relative
integral, and assignment of the atom. 13C NMR spectroscopic data
are reported as chemical shift (δ) and assignment of the atom.
NMR spectral assignments were carried out using HSQC and
HMBC spectra. The numbering of the natural products (i.e., 2 and
3) and 1,4-benzodioxane 32 was done according to lignan no-
menclature, which numbers each lignan fragment from C-1 to C-
9.[32] High-resolution mass spectroscopy (HRMS) was carried out
by either chemical ionisation (CI) or electrospray ionisation (ESI)
with a MicroTOF-Q mass spectrometer. Unless otherwise noted,
chemical reagents were used as purchased.
Conclusions
The asymmetric total synthesis of isoamerincanin A (2)
and isoamericanol A (3) has been achieved. While the
method using serine-derived alcohol 11 failed at the stage
of the Mitsunobu coupling with phenol 12, modification of
the synthesis to use glycerol derivative 20b was successful,
and allowed the synthesis of the required aldehyde (i.e., 10).
Addition of aryl compound 27 in a lithiation reaction, and
cyclisation of the resulting alcohols, gave 1,4-benzodioxane
29, which was ultimately converted into the natural prod-
ucts (i.e., 2 and 3) by manipulation of the side-chain and
protecting groups. This method could be applied to the syn-
thesis of range of natural 1,4-benzodioxanes with a 9-hy-
droxymethyl functionality, as well as associated analogues.
2-(Methoxymethoxy)benzaldehyde
(14):
DIPEA
(23.4 mL,
0.131 mol) and then MOMCl (8.8 mL, 0.082 mol) were added to
salicylaldehyde (13; 4.0 g, 0.033 mol) in CH2Cl2 (120 mL) at room
temperature under an atmosphere of nitrogen. The mixture was
stirred at room temperature for 20 h. Sat. aq. NH4Cl (80 mL) was
added, and the organic layer was separated. The aqueous layer was
further extracted with CH2Cl2 (3ϫ 80 mL), the combined organic
extracts were dried (MgSO4), and the solvent was removed in
vacuo. The crude product was purified by flash chromatography
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Total Synthesis of (–)-Isoamericanin A and (+)-Isoamericanol A
(9:1, n-hexanes, ethyl acetate) to give compound 14 (5.31 g, 98%)
as a pale yellow oil. Rf (4:1, n-hexanes, ethyl acetate): 0.50. 1H
temperature and stirred for a further 17 h, and then it was concen-
trated in vacuo. Acetone was added to the white residue, and the
NMR (400 MHz, CDCl3; Me4Si): δ = 3.53 (s, 3 H, OMe), 5.31 (s, resulting suspension was filtered to remove inorganic salts. The fil-
2 H, OCH2O), 7.07 (t, J = 7.6 Hz, 1 H, 5-H), 7.21 (d, J = 8.4 Hz, trate was concentrated in vacuo. A mixture of acetone and CHCl3
1 H, 3-H), 7.51–7.55 (m, 1 H, 4-H), 7.83 (dd, J = 2.0, 7.6 Hz, 1 H,
6-H), 10.51 (d, J = 1.2 Hz, 1 H, CHO) ppm. 13C NMR (100 MHz,
CDCl3): δ = 56.5 (OMe), 94.6 (OCH2O), 115.0 (C-3), 121.8 (C-5),
125.5 (C-1), 128.3 (C-6), 135.8 (C-4), 159.6 (C-2), 189.7 (q, CHO)
(1:1; 20 mL) was added, and the mixture was concentrated in
vacuo. This was repeated three times to remove the H2O to give
crude (S)-glyceric acid 17 (5.45 g) as a yellow oil, which was used
without further purification.
1
ppm. The H NMR spectroscopic data was in agreement with lit-
Methyl (S)-Glycerate (18): A mixture of crude (S)-glyceric acid (17;
2.5 g), MeOH (50 mL), and freshly prepared methanolic HCl (1 m;
9.5 mL) was stirred at room temperature under an atmosphere of
nitrogen for 1.5 h. Trimethyl orthoformate (5.16 mL, 47 mmol) was
added, and the mixture was stirred at room temperature for 17 h.
The solution was then concentrated in vacuo to give crude methyl
(S)-glycerate (18; 2.88 g) as a pale yellow oil, which was used with-
out further purification. A small analytical sample was purified by
flash chromatography (5:1, n-hexanes, ethyl acetate). [α]D = –11.2
(c = 0.50, MeOH); [ref.[35] –8.4 (c = 0.44, MeOH)]. 1H NMR
(400 MHz, CDCl3; Me4Si): δ = 3.79 (s, 3 H, OMe), 3.85 (dd, J =
3.2, 11.2 Hz, 1 H, 3-Ha) 3.90 (dd, J = 3.2, 11.2 Hz, 1 H, 3-Hb),
4.34 (t, J = 3.2 Hz, 1 H, 2-H), 4.97 (br. s, 2 H, 2 OH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 52.4 (OMe), 63.8 (C-3), 71.7 (C-2),
erature values.[33]
2-(Methoxymethoxy)phenol (15): mCPBA (1.28 g, 5.7 mmol) was
added to a solution of aldehyde 14 (0.68 g, 4.1 mmol) in CH2Cl2
(15 mL) at room temperature under an atmosphere of nitrogen,
and the reaction mixture was stirred for 48 h. The flask was cooled
to 0 °C, and the white precipitate was removed by filtration through
Celite. The organic filtrate was diluted with CH2Cl2 (10 mL) and
washed with satd. aq. Na2S2O3 (15 mL), satd. aq. NaHCO3
(15 mL), and brine (15 mL). The organic layer was dried (Na2SO4),
and the solvent was removed in vacuo. The residue was suspended
in a solution of KOH (0.5 g) in methanol (20 mL), and the mixture
was stirred at room temperature for 5 h. The resulting solution was
added to HCl (2 m; 10 mL), and the mixture was extracted with
ethyl acetate (3ϫ 20 mL). The combined organic extracts were
washed with satd. aq. Na2CO3 (10 mL) and brine (10 mL), and
dried (Na2SO4), and the solvent was removed in vacuo. The crude
product was purified by flash chromatography (9:1, n-hexanes,
ethyl acetate) to give compound 15 (0.56 g, 88%) as a colourless
oil. Rf (4:1, n-hexanes, ethyl acetate): 0.39. 1H NMR (400 MHz,
CDCl3; Me4Si): δ = 3.52 (s, 3 H, OMe), 5.20 (s, 2 H, OCH2O), 5.92
(br. s, 1 H, OH), 6.80–6.84 (m, 1 H, 4-H), 6.93–6.95 (m, 2 H, 5-H,
6-H), 7.07 (dd, J = 1.2, 8.0 Hz, 1 H, 3-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 56.4 (OMe), 96.0 (OCH2O), 115.4 (C-3),
115.6 (C-6), 120.3 (C-4), 123.2 (C-5), 144.5 (C-2), 146.4 (C-1) ppm.
1
173.2 (C-1) ppm. The H and 13C NMR spectroscopic data was in
agreement with literature values.[35]
Methyl
(S)-2-Hydroxy-3-(tert-butyldiphenylsilanoxy)propionate
(11a): Imidazole (2.54 g, 37 mmol) was added to a solution of crude
methyl (S)-glycerate 18 (2.50 g) in CH2Cl2 (104 mL) at room tem-
perature under an atmosphere of nitrogen. After the solid had dis-
solved, the reaction mixture was cooled to –42 °C, and TBDPSCl
(5.82 mL, 22 mmol) was added. The reaction mixture was stirred
at –42 °C for 1 h, and then satd. aq. NH4Cl (40 mL) was added.
The solution was allowed to warm to room temperature. The mix-
ture was extracted with CH2Cl2 (3ϫ 30 mL), the combined organic
extracts were dried (MgSO4), and the solvent was removed in
vacuo. The crude product was purified by flash chromatography
(19:1, n-hexanes, ethyl acetate, to 9:1, n-hexanes, ethyl acetate) to
give compound 11a (2.51 g) as a colourless oil. Rf (4:1, n-hexanes,
ethyl acetate): 0.50. [α]D = +22.2 (c = 1.54, CHCl3); [ref.[36] +22.8
1
The H NMR spectroscopic data was in agreement with literature
values.[34]
4-Bromo-2-(methoxymethoxy)phenol (12):
A solution of NBS
(4.14 g, 0.023 mol) in DMF (35 mL) was added to a stirred solution
of phenol 15 (3.59 g, 0.023 mol) in DMF (35 mL) at 0 °C under an
atmosphere of nitrogen, and the resulting mixture was stirred at
this temperature for 30 min. Ice-cold water (50 mL) was then
added, and the mixture was allowed to warm to room temperature.
The aqueous mixture was extracted with diethyl ether (3ϫ 40 mL),
and the combined organic extracts were washed with water (30 mL)
and brine (30 mL), and dried (Na2SO4), and the solvent was re-
moved in vacuo. The crude product was purified by flash
chromatography (3:1, n-hexanes, ethyl acetate) to give compound
12 (4.92 g, 91%) as an orange oil. Rf (4:1, n-hexanes, ethyl acetate):
1
(c = 1.9, CHCl3)]. H NMR (400 MHz, CDCl3; Me4Si): δ = 1.04
[s, 9 H, SiC(Ph)2C(CH3)3], 3.12 (d, J = 8.0 Hz, 1 H, OH), 3.79 (s,
3 H, OMe), 3.91 (qd, J = 2.8, 10.4 Hz, 1 H, 3-H), 4.23–4.26 (m, 1
H, 2-H), 7.36–7.44 (m, 6 H, ArH), 7.61–7.69 (m, 4 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 19.3 [SiC(Ph)2C(CH3)3], 26.7
[SiC(Ph)2C(CH3)3], 52.4 (OMe), 65.8 (C-3), 71.9 (C-2), 127.7 (Ar-
C), 127.8 (Ar-C), 129.8 (Ar-C), 132.9 (q, Ar-C), 133.0 (q, Ar-C),
135.5 (Ar-C), 135.6 (Ar-C), 173.3 (C-1) ppm. The 1H and 13C
NMR spectroscopic data was in agreement with literature values.[37]
0.32. IR (neat): ν = 3438 (OH), 2941, 1494, 1263, 1155 (C–O),
˜
Methyl (S)-2-Hydroxy-3-(triethylsilanoxy)propionate (11b): Imid-
azole (0.51 g, 7.5 mmol) was added to a solution of crude methyl
(S)-glycerate (18; 0.50 g, 4.2 mmol) in CH2Cl2 (20 mL) at room
temperature under an atmosphere of nitrogen. After the solid had
dissolved, the reaction mixture was cooled to –42 °C, and TESCl
(0.75 mL, 4.5 mmol) was added. The reaction mixture was stirred
at –42 °C for 1 h, and then satd. aq. NH4Cl (15 mL) was added.
The solution was allowed to warm to room temperature. The reac-
tion mixture was extracted with CH2Cl2 (3ϫ 15 mL), the combined
organic extracts were dried (MgSO4), and the solvent was removed
in vacuo. The crude product was purified by flash chromatography
982 cm–1. 1H NMR (400 MHz, CDCl3; Me4Si): δ = 3.52 (s, 3
H,OMe), 5.19 (s, 2 H, OCH2O), 5.83 (s, 1 H, OH), 6.81 (d, J =
8.4 Hz, 1 H, 6-H), 7.03 (dd, J = 2.4, 8.4 Hz, 1 H, 5-H), 7.23 (d, J
= 2.4 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 56.5
(OMe), 96.1 (OCH2O), 111.5 (C-4), 116.5 (C-6), 118.7 (C-3), 125.9
(C-5), 145.1 (C-2), 145.6 (C-1) ppm. MS (ESI+): m/z (%) = 257
(100) [M(81Br) + Na+], 255 (95) [M(79Br) + Na+], 177 (25), 114
(50). HRMS (ESI+): calcd. for C8H981BrNaO3 [M
+
Na]+
256.9607; found 256.9606; calcd. for C8H979BrNaO3 [M + Na]+
254.9627; found 254.9627.
(S)-Glyceric Acid (17): A solution of NaNO2 (5.53 g, 80 mmol) in (9:1, n-hexanes, ethyl acetate) to give compound 11b (0.094 g, 11%)
H2O (100 mL) was slowly added to a solution of (S)-serine (16; as a pale yellow oil. [α]D = –2.75 (c = 0.80, CHCl ). IR (neat): ν =
4.20 g, 40 mmol) in HCl (0.4 m; 200 mL), at –10 °C. After the ad- 3481 (OH), 2954, 2878, 1746 (C=O), 1119 (C–O) cm–1. H NMR
dition was complete, the mixture was allowed to warm to room (400 MHz, CDCl3; Me4Si): δ = 0.57–0.69 [m, 9 H, Si(CH2CH3)3],
˜
3
1
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L. I. Pilkington, D. Barker
0.92–0.99 [m, 6 H, Si(CH2CH3)3], 3.15 (br. s, 1 H, OH), 3.78 (s, 3 with CH2Cl2 (3 ϫ 30 mL), the combined organic extracts were
FULL PAPER
H, OMe), 3.86 (qd, J = 3.2, 10.4 Hz, 2 H, 3-H), 4.22 (t, J = 3.2 Hz,
dried (MgSO4), and the solvent was removed in vacuo to give com-
pound 23 (2.99 g, 91%) as a colourless oil, which was used without
1 H, 2-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 4.2 [Si-
(CH2CH3)3], 6.4 [Si(CH2CH3)3], 52.2 (OMe), 64.6 (C-3), 71.9 (C- further purification. Rf (4:1, n-hexanes, ethyl acetate): 0.04. [α]D
=
1
2), 173.0 (C-1) ppm. MS (ESI+): m/z (%) = 257 (100) [M + Na+].
HRMS (ESI+): calcd. for C10H22NaO4Si [M + Na]+ 257.1180;
found 257.1180.
–0.73 (c = 2.48, CHCl3); [ref.[38] –0.7 (c = 2.48, CHCl3)]. H NMR
(400 MHz, CDCl3; Me4Si): δ = 2.17 (br. s, 1 H, OH), 2.61 (br. s, 1
H, OH), 3.49 (dd, J = 6.0, 10.0 Hz, 1 H, 3-Ha), 3.54 (dd, J = 6.0,
10.0 Hz, 1 H, 3-Hb), 3.60 (dd, J = 5.6, 11.2 Hz, 1 H, 1-Ha), 3.68
(dd, J = 4.0, 11.2 Hz, 1 H, 1-Hb), 3.81 (s, 3 H, OMe), 3.85–3.90
(m, 1 H, 2-H), 4.48 (s, 2 H, ArCH2), 6.88–6.90 (m, 2 H, 3Ј-H),
7.23–7.27 (m, 2 H, 2Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
55.3 (OMe), 64.1 (C-1), 70.5 (C-2), 71.5 (C-3), 73.3 (ArCH2), 113.9
(R)-3-(tert-Butyldiphenylsilyloxy)-1-methoxy-1-oxopropan-2-yl
Benzoate (19): DIAD (0.14 mL, 0.72 mmol) was added to a solu-
tion of benzoic acid (0.050 g, 0.41 mmol), alcohol 11a (0.260 g,
0.72 mmol), and PPh3 (0.188 g, 0.72 mmol) in THF at 0 °C under
an atmosphere of nitrogen. The solution was allowed to warm to
room temperature and stirred for 3.5 h. The solvent was then re-
moved in vacuo. The crude product was purified by flash
chromatography (19:1, n-hexanes, ethyl acetate) to give compound
19 (0.164 g, 87%) as a white solid. Rf (4:1, n-hexanes, ethyl acetate):
1
(C-3Ј), 129.4 (C-2Ј), 129.7 (C-1Ј), 159.4 (C-4Ј) ppm. The H NMR
spectroscopic data was in agreement with literature values.[38]
(S)-1-(tert-Butyldiphenylsilyloxy)-3-(4Ј-methoxybenzyloxy)propan-
2-ol (20a): TBDPSCl (0.49 mL, 1.87 mmol) was slowly added to
a solution of diol 23 (0.33 g, 1.55 mmol) and imidazole (0.28 g,
4.0 mmol) in DMF (10 mL) at room temperature under an atmo-
sphere of nitrogen. The mixture was stirred for 16 h, then it was
concentrated in vacuo, and the resulting residue was dissolved in
CH2Cl2/water (1:1; 20 mL). The layers were separated, and the
aqueous layer was further extracted with CH2Cl2 (2ϫ 15 mL). The
combined organic extracts were dried (MgSO4), and the solvent
was removed in vacuo. The crude product was purified by flash
chromatography (14:1, n-hexanes, ethyl acetate) to give compound
20a (0.361 g, 52%) as a colourless oil. Rf (4:1, n-hexanes, ethyl acet-
ate): 0.50. [α]D = –1.40 (c = 5.00, CHCl3). [ref.[39] of enantiomer,
0.61, m.p. 84–86 °C. [α]D = +20.5 (c = 1.02, CHCl ). IR (neat): ν
˜
3
= 3072, 2932, 1725 (C=O), 1270, 1104 (C–O), 701 cm–1. H NMR
1
(400 MHz, CDCl3; Me4Si): δ = 1.05 [s, 9 H, SiC(Ph)2C(CH3)3], 3.77
(s, 3 H, OMe), 4.10 (dd, J = 2.8, 10.8 Hz, 1 H, 3-Ha), 4.23 (dd, J
= 5.2, 11.8 Hz, 1 H, 3-Hb), 5.46 (q, J = 10.8 Hz, 1 H, 2-H), 7.33–
7.46 (m, 8 H, ArH), 7.55–7.59 (m, 1 H, ArH), 7.66–7.72 (m, 4 H,
ArH), 8.08 (dd, J = 1.6, 8.4 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.2 [SiC(Ph)2C(CH3)3], 26.5 [SiC-
(Ph)2C(CH3)3], 52.3 (OMe), 63.5 (C-3), 73.8 (C-2), 127.7 (Ar-C),
127.7 (Ar-C), 128.3 (C-3Ј), 129.4 (C-1Ј), 129.8 (Ar-C), 129.8 (Ar-
C), 129.9 (C-2Ј), 132.9 (q, Ar-C), 132.9 (q, Ar-C), 133.3 (C-4Ј),
135.5 (Ar-C), 135.5 (Ar-C), 165.9 (PhCOO), 168.5 (C-1) ppm. MS
(ESI+): m/z (%) = 485 (100) [M + Na+], 413 (15), 360 (40). HRMS
(ESI+): calcd. for C27H30NaO5Si [M + Na]+ 485.1755; found
485.1750.
1
+3.6 (c = 1.00, CHCl3)]. H NMR (400 MHz, CDCl3; Me4Si): δ =
1.05 [s, 9 H, SiC(Ph)2C(CH3)3], 2.45 (d, J = 5.2 Hz, 1 H, OH),
3.52–3.56 (m, 2 H, 3-H), 3.70 (d, J = 5.2 Hz, 2 H, 1-H), 3.80 (s, 3
H, OMe), 3.88–3.92 (m, 1 H, 2-H), 4.46 (s, 2 H, OCH2), 6.85 (d, J
= 8.8 Hz, 2 H, 3Ј-H), 7.21 (d, J = 8.8 Hz, 2 H, 2Ј-H), 7.35–7.45
(m, 6 H, ArH), 7.63–7.66 (m, 4 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.3 [SiC(Ph)2C(CH3)3], 26.8 [SiC-
(Ph)2C(CH3)3], 55.3 (OMe), 64.8 (C-1), 70.7 (C-2), 70.8 (C-3), 73.1
(OCH2), 113.8 (C-3Ј), 127.7 (Ar-C), 129.3 (Ar-C), 129.8 (C-2Ј),
130.1 (q, C-1Ј), 133.2 (q, Ar-C), 135.6 (Ar-C), 159.3 (q, C-4Ј) ppm.
(S)-4-[(4Ј-Methoxybenzyloxy)methyl]-2,2-dimethyl-1,3-dioxolane
(22): A solution of (S)-2,2-dimethyl-4-{[(4-methoxyphenyl)meth-
oxy]-methyl}-1,3-dioxolane (21; 2.0 g, 0.015 mol) in dry THF
(10 mL) was added to a stirred slurry of KOtBu (1.87 g, 0.017 mol)
in dry THF (20 mL) at 0 °C under an atmosphere of nitrogen. The
mixture was stirred at 0 °C for 30 min, and then 4-methoxybenzyl
chloride (2.26 mL, 0.017 mol) was added. The mixture was allowed
to warm to room temperature and stirred for 48 h. The solvent was
evaporated, and the residue was treated with water (30 mL) and
extracted with diethyl ether (3ϫ 40 mL). The combined organic
extracts were dried (Na2SO4), and the solvent was removed in
vacuo. The crude product was purified by flash chromatography
(9:1, n-hexanes, ethyl acetate) to give compound 22 (3.63 g, 95%)
1
The H NMR spectroscopic data was in agreement with literature
values.[40]
(S)-1-(Triisopropylsilyloxy)-3-(4-methoxybenzyloxy)propan-2-ol
(20b): TIPSCl (2.74 mL, 0.013 mol) was slowly added to a solution
of diol 23 (2.61 g, 0.012 mol) and imidazole (1.26 g, 0.018 mol) in
DMF (25 mL) at room temperature under an atmosphere of nitro-
gen. The mixture was stirred for 22 h, then it was concentrated in
vacuo, and the resulting residue was dissolved in EtOAc/water (1:1;
40 mL). The layers were separated, and the organic extract was
washed well with water (20 mL) and then brine (20 mL), then it
was dried (MgSO4), and the solvent was removed in vacuo. The
crude product was purified by flash chromatography (9:1, n-hex-
anes, ethyl acetate) to give compound 20b (3.56 g, 79%) as a pale
yellow oil. Rf (4:1, n-hexanes, ethyl acetate): 0.43. [α]D = +0.94 (c
= 3.52, CHCl3). [ref.[28] of enantiomer –0.86 (c = 3.47, CHCl3)]. 1H
NMR (400 MHz, CDCl3; Me4Si): δ = 1.05 {d, J = 5.2 Hz, 18 H,
Si[CH(CH3)2]3}, 1.08–1.13 {m, 3 H, Si[CH(CH3)2]3}, 2.52 (d, J =
4.8 Hz, 1 H, OH), 3.48–3.56 (m, 2 H, 3-H), 3.72 (dd, J = 2.8,
5.2 Hz, 2 H, 1-H), 3.80 (s, 3 H, OMe), 3.82–3.87 (m, 1 H, 2-H),
4.48 (s, 2 H, OCH2), 6.86 (d, J = 8.8 Hz, 2 H, 3Ј-H), 7.24 (d, J =
as a pale yellow oil. Rf (4:1, n-hexanes, ethyl acetate): 0.54. [α]D
=
+21.42 (c = 2.04, CHCl3); [ref.[38] +23 (c = 2.00, CHCl3)]. 1H NMR
(400 MHz, CDCl3; Me4Si): δ = 1.36 (s, 3 H, CH3), 1.42 (s, 3 H,
CH3), 3.42 (dd, J = 5.6, 9.6 Hz, 1 H, 4-CHaO), 3.51 (dd, J = 5.6,
9.6 Hz, 1 H, 4-CHbO), 3.71 (dd, J = 6.2, 8.4 Hz, 1 H, 5-Ha) 3.80
(s, 3 H, OMe), 4.02 (dd, J = 6.2, 8.4 Hz, 1 H, 5-Hb), 4.25 (q, J =
6.2 Hz, 1 H, 4-H), 4.46 (d, J = 11.6 Hz, 1 H, ArCHa), 4.51 (d, J =
11.6 Hz, 1 H, ArCHb), 6.86 (d, J = 8.6 Hz, 2 H, 3Ј-H), 7.24 (d, J
= 8.6 Hz, 2 H, 2Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.3
(CH3), 26.8 (CH3), 55.3 (OMe), 66.9 (C-5), 70.8 (4-CH2O), 73.2
(OCH2Ar), 74.7 (C-4), 109.4 (C-2), 113.8 (C-3Ј), 129.4 (C-2Ј), 130.0
1
(C-1Ј), 159.3 (C-4Ј) ppm. The H NMR spectroscopic data was in
agreement with literature values.[38]
(R)-3-(4Ј-Methoxybenzyloxy)propane-1,2-diol (23): HCl (1 m; 9 mL) 8.8 Hz, 2 H, 2Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.9
was added to acetonide 22 (3.90 g, 0.015 mol) in THF (18 mL) at
room temperature, and the resulting solution was stirred for 23 h.
The reaction mixture was neutralised with satd. aq. NaHCO3, and
the solvents were evaporated in vacuo. The residue was extracted
{Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 55.3 (OMe), 64.3 (C-1),
70.7 (C-2), 70.8 (C-3), 73.1 (OCH2), 113.8 (C-3Ј), 129.4 (C-2Ј),
1
130.2 (C-1Ј), 159.3 (C-4Ј) ppm. The H NMR spectroscopic data
was in agreement with literature values.[28]
1042
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1037–1046

Total Synthesis of (–)-Isoamericanin A and (+)-Isoamericanol A
(R)-[2-(4Ј-Bromophenoxy)-3-(4ЈЈ-methoxybenzyloxy)propoxy]tert-
butyldiphenylsilane (24a): DIAD (0.022 mL, 0.111 mmol) was
added to 4-bromophenol (0.011 g, 0.063 mmol), alcohol 20a
(0.050 g, 0.111 mmol), and PPh3 (0.029 g, 0.111 mmol) in toluene
(5 mL) at 0 °C under an atmosphere of nitrogen. The solution was
allowed to warm to room temperature and stirred for 20 h, and
then the solvent was removed in vacuo. The crude product was
purified by flash chromatography (n-hexanes, to 19:1, n-hexanes,
ethyl acetate) to give compound 24a (0.014 g, 37%) as a colourless
CHCl ). IR (neat): ν = 2940, 2865, 1465, 1249, 1155, (C–O),
˜
3
990 cm–1. 1H NMR (400 MHz, CDCl3; Me4Si): δ = 1.02 {d, J =
5.2 Hz, 18 H, Si[CH(CH3)2]3}, 1.03–1.08 {m, 3 H, Si[CH(CH3)2]3},
3.47 (s, 3 H, OCH2OCH3), 3.65 (dd, J = 2.4, 10.4 Hz, 1 H, 3-Ha),
3.73 (dd, J = 2.4, 10.4 Hz, 1 H, 3-Hb), 3.80 (s, 3 H, OMe), 3.91 (d,
J = 5.6 Hz, 2 H, 1-H), 4.35–4.39 (m, 1 H, 2-H), 4.48 (s, 2 H,
OCH2), 5.13 (s, 2 H, OCH2OCH3), 6.84–6.86 (m, 2 H, 2ЈЈ-H), 6.91
(d, J = 8.8 Hz, 1 H, 6Ј-H), 7.02 (dd, J = 2.4, 8.8 Hz, 1 H, 5Ј-H),
7.20–7.22 (m, 2 H, 3ЈЈ-H), 7.24 (d, J = 2.4 Hz, 1 H, 3Ј-H) ppm.
oil. Rf (4:1, n-hexanes, ethyl acetate): 0.70. [α]D = +7.54 (c = 1.34, 13C NMR (100 MHz, CDCl3): δ = 11.9 {Si[CH(CH3)2]3}, 17.9
CHCl ). IR (neat): ν = 3071, 2932, 1513, 1486, 1244, 1110 (C–O),
{Si[CH(CH3)2]3}, 55.2 (OMe), 56.3 (OCH2OCH3), 62.7 (C-1), 68.9
(C-3), 73.1 (OCH2), 80.4 (C-2), 95.7 (OCH2OCH3), 113.6 (C-4Ј),
113.7 (C-2ЈЈ), 118.9 (C-6Ј), 120.9 (C-3Ј), 125.3 (C-5Ј), 129.3 (C-3ЈЈ),
130.2 (C-1ЈЈ), 148.1 (C-1Ј), 148.7 (C-2Ј), 159.2 (C-4ЈЈ) ppm. MS
˜
3
822, 704 cm–1. H NMR (400 MHz, CDCl3; Me4Si): δ = 1.01 [s, 9
1
H, SiC(Ph)2C(CH3)3], 3.65 (dd, J = 2.4, 10.4 Hz, 1 H, 3-H), 3.74
(dd, J = 2.4, 10.4 Hz, 1 H, 3-H), 3.80 (s, 3 H, OMe), 3.82–3.88 (m,
2 H, 1-H), 4.36–4.41 (m, 1 H, 2-H), 4.48 (s, 2 H, OCH2), 6.68–6.71 (ESI+): m/z (%) = 607 (15) [M(81Br) + Na+], 605 (14) [M(79Br) +
(m, 2 H, 2Ј-H), 6.84–6.86 (m, 2 H, 3ЈЈ-H), 7.19–7.21 (m, 2 H, 2ЈЈ- Na+ ] , 4 1 3 ( 1 00 ) , 3 6 0 ( 3 0 ) . H R M S ( E S I + ) : c a l c d . fo r
H), 7.25–7.28 (m, 2 H, 3Ј-H), 7.31–7.37 (m, 4 H, Ar-H), 7.39–7.45 C28H4381BrNaO6Si [M + Na]+ 607.1886; found 607.1886; calcd. for
(m, 2 H, Ar-H), 7.59–7.64 (m, 4 H, Ar-H) ppm. 13C NMR C28H4379BrNaO6Si [M + Na]+ 605.1904; found 605.1903.
(100 MHz, CDCl3): δ = 19.2 [SiC(Ph)2C(CH3)3], 26.8 [SiC-
(R)-2-[4Ј-Bromo-2Ј-(methoxymethoxy)phenoxy]-3-(triisopropyl-
silyloxy)propan-1-ol (26): DDQ (0.89 g, 3.89 mmol) was added to a
solution of ether 25 (1.89 g, 3.25 mmol) in a rapidly stirred mixture
of CH2Cl2 (80 mL) and water (80 mL), and the mixture was stirred
at room temperature for 1.5 h. The resulting solution was washed
with portions of satd. aq. NaHCO3 until the washings were colour-
less. The combined organic extracts were dried (MgSO4), and the
solvent was removed in vacuo. The crude product was purified by
flash chromatography (14:1, n-hexanes, ethyl acetate) to give com-
pound 26 (1.20 g, 80%) as a pale yellow oil. Rf (4:1, n-hexanes,
(Ph)2C(CH3)3], 55.3 (OMe), 62.6 (C-1), 68.8 (C-3), 73.2 (OCH2),
78.3 (C-2), 113.1 (C-4Ј), 113.8 (C-3ЈЈ), 117.9 (C-2Ј), 127.7 (Ar-C),
127.7 (Ar-C), 129.3 (C-2ЈЈ), 129.7 (Ar-C), 129.8 (Ar-C), 130.1 (C-
1ЈЈ), 132.2 (C-3Ј), 133.1 (q, Ar-C), 133.3 (q, Ar-C), 135.6 (Ar-C),
135.6 (Ar-C), 157.4 (C-1Ј), 159.2 (C-4ЈЈ) ppm. MS (ESI+): m/z (%)
= 629 (95) [M(81Br) + Na+], 627 (100) [M(79Br) + Na+], 391 (60).
HRMS (ESI+): calcd. for C33H3781BrNaO4Si [M + Na]+ 629.1518;
found 629.1509; calcd. for C33H3779BrNaO4Si [M + Na]+ 627.1537;
found 627.1532.
(R)-[2-(4ЈЈ-Bromophenoxy)-3-(4Ј-methoxybenzyloxy)propoxy]tri-
isopropylsilane (24b): DIAD (0.10 mL, 0.51 mmol) was added to 4-
bromophenol (0.050 g, 0.29 mmol), alcohol 20b (0.186 g,
0.51 mmol), and PPh3 (0.133 g, 0.51 mmol) in toluene (10 mL) at
0 °C under an atmosphere of nitrogen. The solution was allowed
to warm to room temperature and stirred for 23 h, and then the
solvent was removed in vacuo. The crude product was purified by
flash chromatography (19:1, n-hexanes, ethyl acetate) to give com-
pound 24b (0.094 g, 62%) as a colourless oil. Rf (4:1, n-hexanes,
ethyl acetate): 0.25. [α]D = +28.5 (c = 0.57, CHCl ). IR (neat): ν =
˜
3
3466 (OH), 2866, 1492, 1252, 1083 (C–O), 985, 882 cm–1. 1H NMR
(400 MHz, CDCl3; Me4Si): δ = 1.05 {d, J = 5.2 Hz, 18 H,
Si[CH(CH3)2]3}, 1.07–1.14 {m, 3 H, Si[CH(CH3)2]3}, 2.79 (t, J =
6.8 Hz, 1 H, OH), 3.50 (s, 3 H, OMe), 3.80–3.84 (m, 2 H, 1-H),
3.88 (dd, J = 6.4, 10.4 Hz, 1 H, 3-Ha), 3.96 (dd, J = 6.4, 10.4 Hz,
1 H, 3-Hb), 4.18–4.23 (m, 1 H, 2-H), 5.16 (q, J = 6.8 Hz, 2 H,
-OCH2OMe), 6.98 (d, J = 8.4 Hz, 1 H, 6Ј-H), 7.07 (dd, J = 2.4,
8.4 Hz, 1 H, 5Ј-H), 7.27 (d, J = 2.4 Hz, 1 H, 3Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.9 {Si[CH(CH3)2]3}, 17.9 {Si[CH-
(CH3)2]3}, 56.5 (OMe), 62.4 (C-1), 62.9 (C-3), 83.0 (C-2), 95.7
(OCH2OMe), 114.9 (C-4Ј), 120.4 (C-3Ј), 120.5 (C-6Ј), 125.6 (C-5Ј),
147.7 (C-1Ј), 149.1 (C-2Ј) ppm. MS (ESI+): m/z (%) = 487 (100)
[M(81Br) + Na+], 485 (85) [M(79Br) + Na+]. HRMS (ESI+): calcd.
for C20H3581BrNaO5Si [M + Na]+ 487.1310; found 487.1309; calcd.
for C20H3579BrNaO5Si [M + Na]+ 485.1329; found 485.1330.
ethyl acetate): 0.78. [α]D = +4.41 (c = 1.86, CHCl ). IR (neat): ν =
˜
3
2939, 2865, 1486, 1241, 1068, 820, 684 cm–1. H NMR (400 MHz,
1
CDCl3; Me4Si): δ = 1.02 {d, J = 5.2 Hz, 18 H, Si[CH(CH3)2]3},
1.04–1.09 {m, 3 H, Si[CH(CH3)2]3}, 3.62 (dd, J = 2.4, 10.4 Hz, 1
H, 3-Ha), 3.71 (dd, J = 2.4, 10.4 Hz, 1 H, 3-Hb), 3.79 (s, 3 H, OMe),
3.87 (dd, J = 2.0, 5.4 Hz, 2 H, 1-H), 4.37–4.42 (m, 1 H, 2-H), 4.48
(s, 2 H, OCH2), 6.83–6.87 (m, 4 H, 2Ј-H and 3ЈЈ-H), 7.20–7.24 (m,
2 H, 2ЈЈ-H), 7.30–7.35 (m, 2 H, 3Ј-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.9 {Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 55.2
(OMe), 62.6 (C-1), 68.8 (C-3), 73.1 (OCH2), 78.9 (C-2), 113.1 (C-
4Ј), 113.7 (C-3ЈЈ), 118.0 (C-2Ј), 129.3 (C-2ЈЈ), 130.1 (C-1ЈЈ), 132.1
(C-3Ј), 157.6 (C-1Ј), 159.2 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 547
(95) [M(81Br) + Na+], 545 (100) [M(79Br) + Na+], 360 (45), 114
(25). HRMS (ESI+): calcd. for C26H3981BrNaO4Si [M + Na]+
547.1674; found 547.1671; calcd. for C26H3979BrNaO4Si [M +
Na]+ 545.1693; found 545.1683.
(S)-2-[4Ј-Bromo-2Ј-(methoxymethoxy)phenoxy]-3-(triisopropyl-
silyloxy)propanal (10): Dess–Martin periodinane (1.92 g, 4.5 mmol)
was added to a stirred solution of alcohol 26 (2.09 g, 4.5 mmol) in
CH2Cl2 (150 mL). The reaction mixture was left open to air and
stirred at room temperature for 16 h. Sat. aq. Na2S2O5 (40 mL) was
added, followed by satd. aq. NaHCO3 (40 mL). The mixture was
shaken until no further gas was evolved. The layers were separated,
and the aqueous layer was further extracted with CH2Cl2 (3 ϫ
30 mL). The combined organic extracts were washed with brine
(30 mL) and dried (MgSO4), and the solvent was removed in vacuo.
The crude product was purified by flash chromatography (14:1, n-
hexanes, ethyl acetate) to give compound 10 (1.46 g, 70%) as a
yellow oil. Rf (4:1, n-hexanes, ethyl acetate): 0.43. [α]D = +0.84 (c
(R)-{2-[4Ј-Bromo-2Ј-(methoxymethoxy)phenoxy]-3-(4ЈЈ-methoxy-
benzyloxy)propoxy}triisopropylsilane (25): DIAD (3.30 mL,
17 mmol) was added to a mixture of phenol 12 (3.44 g, 15 mmol),
alcohol 20b (4.94 g, 13 mmol), and PPh3 (4.40 g, 17 mmol) in THF
(120 mL) at 0 °C under an atmosphere of nitrogen. The solution
was allowed to warm to room temperature and stirred for 3 d, and
then the solvent was removed in vacuo. The crude product was
purified by flash chromatography (n-hexanes, to 19:1, n-hexanes,
ethyl acetate) to give compound 25 (5.15 g, 66%) as a colourless
= 0.72, CHCl ). IR (neat): ν = 2866, 1737 (C=O), 1491, 1134, 985
˜
3
(C–O), 882, 685 cm–1. 1H NMR (400 MHz, CDCl3; Me4Si): δ =
1.05 {d, J = 5.2 Hz, 18 H, Si[CH(CH3)2]3}, 1.08–1.13 {m, 3 H,
Si[CH(CH3)2]3}, 3.48 (s, 3 H, OMe), 4.15–4.17 (m, 2 H, 3-H), 4.43–
oil. Rf (4:1, n-hexanes, ethyl acetate): 0.63. [α]D = +1.82 (c = 1.10, 4.46 (m, 1 H, 2-H), 5.17 (s, 2 H, OCH2OMe), 6.84 (d, J = 8.4 Hz,
Eur. J. Org. Chem. 2014, 1037–1046
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1043

L. I. Pilkington, D. Barker
FULL PAPER
1 H, 6Ј-H), 7.03 (dd, J = 2.4, 8.4 Hz, 1 H, 5Ј-H), 7.29 (d, J =
(2S,3S)-6-Bromo-2-[(triisopropylsilyl)oxymethyl]-3-{3Ј,4Ј-bis[(tri-
2.4 Hz, 1 H, 3Ј-H), 9.85 (d, J = 1.6 Hz, 1 H, CHO) ppm. 13C NMR isopropylsilyl)oxy]phenyl}-1,4-benzodioxane (30): A mixture of diols
(100 MHz, CDCl3): δ = 11.8 {Si[CH(CH3)2]3}, 17.8 {Si[CH- 28a and 28b (0.168 g, 0.26 mmol) and Amberlyst 15 (0.10 g) in dry
(CH3)2]3}, 56.4 (OMe), 63.5 (C-3), 85.4 (C-2), 95.3 (OCH2OMe),
toluene (12 mL) was heated at 80 °C under an atmosphere of nitro-
115.3 (C-4Ј), 119.6 (C-6Ј), 120.2 (C-3Ј), 125.2 (C-5Ј), 147.2 (C-1Ј), gen for 18 h. The solution was cooled and filtered, and the solvent
148.6 (C-2Ј), 201.6 (CHO) ppm. MS (ESI+): m/z (%) = 485 (15)
was removed in vacuo. The crude product (i.e., 29) was used with-
out further purification. TIPSCl (0.17 mL, 0.80 mmol) was slowly
[M(81Br) + Na+], 483 (15) [M(79Br) + Na+], 360 (35), 301 (80), 114
(100). HRMS (ESI+): calcd. for C20H3381BrNaO5Si [M + added to a solution of triol 29 (90.0 mg, 0.26 mmol), DMAP
Na]+ 485.1163; found 485.1165; calcd. for C20H3379BrNaO5Si [M
+ Na]+ 483.1173; found 483.1174.
(0.3 mg, 0.026 mmol), and triethylamine (0.16 mL, 1.15 mmol) in
dry DMF (12 mL), at 0 °C under an atmosphere of nitrogen. The
solution was allowed to warm to room temperature and stirred for
2 d. The reaction mixture was concentrated in vacuo, and the re-
sulting residue was dissolved in a CH2Cl2/water mixture (1:1;
10 mL). The layers were separated, and the aqueous layer was fur-
ther extracted with CH2Cl2 (2ϫ 10 mL). The combined organic
extracts were dried (MgSO4), and the solvent was removed in
vacuo. The crude product was purified by flash chromatography
(n-hexanes, to 39:1, n-hexanes, ethyl acetate) to give compound 30
(0.121 g, 58% over two steps) as a pale yellow oil. Rf (4:1, n-hex-
(1R,2S)-1-[3ЈЈ,4ЈЈ-Bis(methoxymethoxy)phenyl]-2-[4Ј-bromo-2Ј-
(methoxymethoxy)phenoxy]-3-(triisopropylsilyloxy)propan-1-ol
(28a) and (1S,2S)-1-[3ЈЈ,4ЈЈ-Bis(methoxymethoxy)phenyl]-2-[4Ј-
bromo-2Ј-(methoxymethoxy)phenoxy]-3-(triisopropylsilyloxy)-
propan-1-ol (28b): tBuLi (1.4 m in THF; 0.12 mL, 0.17 mmol) was
added to a stirred solution of bromide 27 (24.0 mg, 0.086 mmol) in
dry THF (2.0 mL) at –78 °C under an atmosphere of nitrogen. Af-
ter 2 min, a solution of aldehyde 10 (33.0 mg, 0.072 mmol) in THF
(3 mL) was added slowly. The mixture was stirred at –78 °C for 1 h,
then it was allowed to warm to room temperature and left for a
further 23 h. Sat. aq. NH4Cl (3 mL) was added, and the aqueous
mixture was extracted with ethyl acetate (3ϫ 5 mL). The combined
organic extracts were dried (MgSO4), and the solvent was removed
in vacuo. The crude product was purified by flash chromatography
(4:1, n-hexanes, ethyl acetate) to give an inseparable 2.5:1 mixture
of compounds 28a and 28b (29.4 mg, 63%) as a colourless oil. Rf
anes, ethyl acetate): 0.93. [α]D = +6.92 (c = 1.07, CHCl3). IR (neat):
1
ν = 2942, 2867, 1487, 1275 (C–O), 883 cm–1. H NMR (400 MHz,
˜
CDCl3; Me4Si): δ = 1.02–1.12 {m, 54 H, 3 Si[CH(CH3)2]3}, 1.20–
1.32 {m, 9 H, 3 Si[CH(CH3)2]3}, 3.59 (dd, J = 3.6, 11.2 Hz, 1 H,
CHaOTIPS), 3.87 (dd, J = 3.6, 11.2 Hz, 1 H, CHbOTIPS), 3.95–
3.98 (m, 1 H, 2-H), 4.98 (d, J = 7.2 Hz, 1 H, 3-H), 6.77 (d, J =
8.8 Hz, 1 H, 8-H), 6.81–6.85 (m, 3 H, 2Ј-H, 5Ј-H, 6Ј-H), 6.95 (dd,
J = 2.4, 8.8 Hz, 1 H, 7-H), 7.08 (d, J = 2.4 Hz, 1 H, 5-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 11.9 {Si[CH(CH3)2]3}, 13.2
{Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3},
17.9 {Si[CH(CH3)2]3}, 62.3 (CH2OTIPS), 75.4 (C-3), 78.5 (C-2),
112.4 (C-6), 118.2 (C-8), 118.7 (C-5Ј), 119.8 (C-2Ј or C-6Ј), 120.1
(C-5), 120.3 (C-2Ј or C-6Ј), 124.1 (C-7), 129.0 (C-1Ј), 143.0 (C-8a),
144.6 (C-4a), 147.2 (C-3Ј or C-4Ј), 147.5 (C-3Ј or C-4Ј) ppm. MS
(APCI+): m/z (%) = 845 (5) [M(81Br) + Na+], 843 (4) [M(79Br) +
Na+], 391 (100). HRMS (ESI+): calcd. for C42H7381BrNaO5Si3 [M
+ Na]+ 845.3824; found 845.3819; calcd. for C42H7379BrNaO5Si3
[M + Na]+ 843.3841; found 843.3837.
(4:1, n-hexanes, ethyl acetate): 0.13. IR (neat): ν = 3475 (OH), 2941,
˜
1493, 1255, 1155, 1126, 991 (C–O), 883cm–1. Data for 28a: 1H
NMR (400 MHz, CDCl3; Me4Si): δ = 1.02 {d, J = 5.2 Hz, 18 H,
Si[CH(CH3)2]3}, 1.03–1.08 {m, 3 H, Si[CH(CH3)2]3}, 3.48 (s, 3 H,
OMe), 3.48 (s, 3 H, OMe), 3.50 (s, 3 H, OMe), 3.84 (dd, J = 5.6,
10.8 Hz, 1 H, 3-Ha), 3.88 (br. s, 1 H, OH), 3.96 (dd, J = 5.6,
10.8 Hz, 1 H, 3-Hb), 4.27 (m, 1 H, 2-H), 4.91 (t, J = 4.4 Hz, 1 H,
1-H), 5.14 (s, 2 H, OCH2OMe), 5.19 (s, 2 H, OCH2OMe), 5.21 (s,
2 H, OCH2OMe), 6.88 (d, J = 8.8 Hz, 1 H, 6Ј-H), 6.98 (dd, J =
2.0, 8.8 Hz, 1 H, 6ЈЈ-H), 7.02 (dd, J = 2.0, 8.8 Hz, 1 H, 5Ј-H), 7.09
(d, J = 8.8 Hz, 1 H, 5ЈЈ-H), 7.22 (d, J = 2.0 Hz, 1 H, 2ЈЈ-H), 7.25
(d, J = 2.0 Hz, 1 H, 3Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ (2S,3S)-6-Formyl-2-[(triisopropylsilyl)oxymethyl]-3-{3Ј,4Ј-bis[(tri-
= 11.8 {Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 56.1 (OMe), 56.2 isopropylsilyl)oxy]phenyl}-1,4-benzodioxane (31): tBuLi (1.4 m in
(OMe), 56.4 (OMe), 63.2 (C-3), 73.9 (C-1), 85.2 (C-2), 95.4 (OCH2- THF; 0.026 mL, 0.037 mmol) was added to a solution of bromide
OMe), 95.5 (OCH2OMe), 95.6 (OCH2OMe), 114.7 (C-4Ј), 115.1 30 (11.0 mg, 0.014 mmol) in THF (1.0 mL) at –78 °C under an at-
(C-2ЈЈ), 116.5 (C-5ЈЈ), 120.2 (C-3Ј), 120.6 (C-6Ј), 120.8 (C-6ЈЈ), mosphere of nitrogen. After 1 min, dry DMF (0.023 mL,
125.4 (C-5Ј), 134.6 (C-1ЈЈ), 146.7 (C-4ЈЈ), 147.2 (C-3ЈЈ), 147.7 (C-
1Ј), 149.2 (C-2Ј) ppm. Data for 28b: H NMR (400 MHz, CDCl3; 30 min. It was then allowed to warm to room temperature and left
Me4Si): δ = 1.00 {d, J = 5.2 Hz, 18 H, Si[CH(CH3)2]3}, 1.03–1.06 for a further 30 min. Sat. aq. NH4Cl (3 mL) was added, and the
0.29 mmol) was added, and the mixture was stirred at –78 °C for
1
{m, 3 H, Si[CH(CH3)2]3}, 3.48 (s, 3 H, OMe), 3.50 (s, 3 H, OMe),
aqueous mixture was extracted with ethyl acetate (3ϫ 5 mL). The
3.51 (s, 3 H, OMe), 3.79 (dd, J = 5.6, 10.8 Hz, 1 H, 3-Ha), 3.84 combined organic extracts were dried (MgSO4), and the solvent
(dd, J = 5.6, 10.8 Hz, 1 H, 3-Hb), 3.91 (br. d, J = 3.2 Hz, 1 H, was removed in vacuo. The crude product was purified by flash
OH), 4.15–4.20 (m, 1 H, 2-H), 4.83 (dd, J = 2.4, 6.4 Hz, 1 H, 1-
H), 5.18 (s, 2 H, OCH2OMe), 5.19 (s, 2 H, OCH2OMe), 5.20 (s, 2
chromatography (39:1, n-hexanes, ethyl acetate) to give compound
31 (9.9 mg, 71%) as a colourless oil. Rf (4:1, n-hexanes, ethyl acet-
H, OCH2OMe), 6.97 (dd, J = 2.0, 8.8 Hz, 1 H, 6ЈЈ-H), 7.02 (dd, J ate): 0.82. [α]D = +4.89 (c = 0.42, CHCl ). IR (neat): ν = 2942,
˜
3
= 2.0, 8.8 Hz, 1 H, 5Ј-H), 7.03 (d, J = 8.8 Hz, 1 H, 6Ј-H), 7.09 (d,
J = 8.8 Hz, 1 H, 5ЈЈ-H), 7.18 (d, J = 2.0 Hz, 1 H, 2ЈЈ-H), 7.25 (d,
J = 2.0 Hz, 1 H, 3Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
2868, 1697 (C=O), 1506 (C=C), 1280, 1114 (C–O), 883, 683 cm–1.
1H NMR (400 MHz, CDCl3; Me4Si): δ = 1.03–1.12 {m, 54 H, 3
Si[CH(CH3)2]3}, 1.21–1.33 {m, 9 H, 3 Si[CH(CH3)2]3}, 3.62 (dd, J
11.8 {Si[CH(CH3)2]3}, 17.8 {Si[CH(CH3)2]3}, 56.1 (OMe), 56.2 = 3.6, 11.2 Hz, 1 H, CHaOTIPS), 3.92 (dd, J = 3.6, 11.2 Hz, 1 H,
(OMe), 56.5 (OMe), 63.1 (C-3), 73.3 (C-1), 87.8 (C-2), 95.5 (OCH2- CHbOTIPS), 4.06–4.09 (m, 1 H, 2-H), 5.00 (d, J = 6.8 Hz, 1 H, 3-
OMe), 95.5 (OCH2OMe), 95.7 (OCH2OMe), 114.6 (C-4Ј), 115.4 H), 6.84 (m, 3 H, 2Ј-H, 5Ј-H, 6Ј-H), 7.02 (d, J = 8.0 Hz, 1 H, 8-
(C-2ЈЈ), 116.7 (C-5ЈЈ), 120.0 (C-3Ј), 120.5 (C-6Ј), 121.1 (C-6ЈЈ), H), 7.43 (dd, J = 1.6, 6.8 Hz, 1 H, 7-H), 7.47 (d, J = 2.0 Hz, 1 H,
125.4 (C-5Ј), 134.7 (C-1ЈЈ), 146.7 (C-4ЈЈ), 147.3 (C-3ЈЈ), 148.5 (C-
1Ј), 149.2 (C-2Ј) ppm. MS (ESI+): m/z (%) = 699 (50) [M(81Br) +
K+], 697 (45) [M(79Br) + K+], 683 (40) [M(81Br) + Na+], 681 (35)
[M(7 9 Br) + Na+ ], 298 (100). HRMS (ESI+ ): calcd. for
C30H4781BrKO9Si [M + K]+ 699.1786; found 699.1789.
5-H), 9.84 (s, 1 H, CHO) ppm. 13C NMR (100 MHz, CDCl3): δ =
11.9 {Si[CH(CH3)2]3}, 13.2 {Si[CH(CH3)2]3}, 17.9 {Si[CH-
(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 62.3
(CH2OTIPS), 75.4 (C-3), 79.2 (C-2), 117.4 (C-8), 118.5 (C-5), 118.8
(C-5Ј), 119.8 (C-2Ј or C-6Ј), 120.4 (C-2Ј or C-6Ј), 124.1 (C-7), 128.6
1044
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1037–1046

Total Synthesis of (–)-Isoamericanin A and (+)-Isoamericanol A
(C-1Ј), 130.4 (C-6), 144.2 (C-4a), 147.3 (C-3Ј or C-4Ј), 147.7 (C-3Ј Water (0.2 mL) was added, and then the MeOH was removed in
or C-4Ј), 149.5 (C-8a), 190.8 (C=O) ppm. MS (ESI+): m/z (%) =
793 (20) [M + Na+], 449 (100). HRMS (ESI+): calcd. for
C43H74NaO6Si3 [M + Na]+ 793.4685; found 793.4693.
vacuo. The aqueous mixture was extracted with diethyl ether (3ϫ
2 mL). The combined organic extracts were dried (MgSO4), and
the solvent was removed in vacuo. The crude product was purified
by flash chromatography (17:3, CHCl3, methanol) to give com-
pound 3 (1.3 mg, 59%) as a white film. Rf (17:3, CHCl3, MeOH):
0.38. [α]D = +6.25 (c = 0.08, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 3.47 (dd, J = 4.0, 12.8 Hz, 1 H, 9-H), 3.65 (dd, J =
2.4, 12.4 Hz, 1 H, 9-H), 3.98–4.01 (m, 1 H, 8-H), 4.18 (dd, J = 1.6,
6.0 Hz, 2 H, 9Ј-H), 6.17 (dt, J = 6.0, 16.0 Hz, 1 H, 8Ј-H), 6.47 (d,
J = 16.0 Hz, 1 H, 7Ј-H), 6.75 (dd, J = 2.0, 8.0 Hz, 1 H, 6-H), 6.79
(d, J = 8.0 Hz, 1 H, 5-H), 6.85 (d, J = 2.0 Hz, 1 H, 2-H), 6.88 (d,
J = 8.4 Hz, 1 H, 5Ј-H), 6.91 (dd, J = 2.0, 8.4 Hz, 1 H, 6Ј-H), 6.96
(J = 2.0 Hz, 1 H, 2Ј-H) ppm. 13C NMR (100 MHz, CD3OD): δ =
62.1 (C-9), 63.8 (C-9Ј), 77.7 (C-7), 80.1 (C-8), 115.5, 115.6 (C-2 and
C-2Ј), 116.3 (C-5), 118.0 (C-5Ј), 120.3 (C-6 and C-6Ј), 128.2 (C-8Ј),
129.9 (C-1), 131.4 (C-7Ј), 132.1 (C-1Ј), 144.6 (C-3Ј), 145.4 (C-4Ј),
146.6 (C-3), 147.4 (C-4) ppm. The 1H and 13C NMR spectroscopic
data was in agreement with literature values.[13]
Tri(triisopropylsilyl)isoamericanin A (32): (Triphenylphosphor-
anylidene)acetaldehyde (7.8 mg, 0.026 mmol) was added to a solu-
tion of aldehyde 31 (18.0 mg, 0.023 mmol) in dry toluene (3 mL)
at room temperature under an atmosphere of nitrogen. The solu-
tion was heated at reflux for 2 d, and then the solvent was removed
in vacuo. The crude product was purified by flash chromatography
(39:1, n-hexanes, ethyl acetate) to give compound 32 [3.9 mg, 21%
(100% based on recovered starting material)] as a yellow oil. Rf
(4:1, n-hexanes, ethyl acetate): 0.75. [α]D = +7.40 (c = 0.96, CHCl3).
IR (neat): ν = 2939, 2867, 1679 (C=O), 1507 (C=C), 1288, 1122
˜
(C–O), 883, 684 cm–1. 1H NMR (400 MHz, CDCl3; Me4Si): δ =
1.05–1.12 {m, 54 H, 3 Si[CH(CH3)2]3}, 1.23–1.32 {m, 9 H, 3
Si[CH(CH3)2]3}, 3.62 (dd, J = 3.6, 11.2 Hz, 1 H, CHaOTIPS), 3.91
(dd, J = 2.8, 11.2 Hz, 1 H, CHbOTIPS), 4.03–4.07 (m, 1 H, 8-H),
5.00 (d, J = 7.2 Hz, 1 H, 7-H), 6.55 (dd, J = 8.0, 16.0 Hz, 1 H, 8Ј-
H), 6.84–6.87 (m, 3 H, 2-H, 5-H, 6-H), 6.95 (d, J = 8.4 Hz, 1 H,
5Ј-H), 7.10 (dd, J = 2.0, 8.4 Hz, 1 H, 6Ј-H), 7.18 (d, J = 2.0 Hz, 1
H, 2Ј-H), 7.36 (d, J = 16.0 Hz, 1 H, 7Ј-H), 9.64 (d, J = 8.0 Hz, 1
H, 9Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.9 {Si[CH-
(CH3)2]3}, 13.2 {Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 17.9
{Si[CH(CH3)2]3}, 18.0 {Si[CH(CH3)2]3}, 62.3 (CH2OTIPS), 75.4
(C-7), 79.0 (C-8), 117.0 (C-2Ј), 117.5 (C-5Ј), 118.8, 119.9, 120.3 (C-
2, C-5 and C-6), 122.7 (C-6Ј), 126.9 (C-8Ј), 127.4 (C-1Ј), 128.8 (C-
1), 144.2 (C-3Ј), 146.8 (C-3 or C-4), 147.3 (C-4Ј), 147.7 (C-3 or C-
4), 152.8 (C-7Ј), 193.7 (C-9Ј) ppm. MS (ESI+): m/z (%) = 819 (60)
[M + Na+], 797 (100) [MH+], 663 (50), 338 (60). HRMS (ESI+):
calcd. for C45H77O6Si3 [M + Na]+ 797.5022; found 797.5023. Reco-
vered 31 (14.4 mg, 0.019 mmol) was also obtained in a separate
fraction.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all compounds,
and experimental procedure for the synthesis of aryl bromide 27.
Acknowledgments
We acknowledge the Royal Society of New Zealand Marsden Fund
for funding this research and the University of Auckland for ad-
ditional financial assistance and a doctoral scholarship (L. I. P.).
Isoamericanin A (2): TBAF (1.0 m in THF; 0.054 mL, 0.054 mmol)
was added to a solution of aldehyde 32 (9.5 mg, 0.012 mmol) in
THF (2 mL) at 0 °C under an atmosphere of nitrogen. The solution
was allowed to warm to room temperature and stirred for 5 min.
The mixture was then recooled to 0 °C, and satd. aq. NH4Cl (2 mL)
was added. The mixture was extracted with ethyl acetate (3 ϫ
3 mL). The combined organic extracts were washed with water
(3 mL) and brine (3 mL), and dried (MgSO4), and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography (17:3, CHCl3, MeOH) to give compound 2
(3.1 mg, 97%) as pale yellow crystals. Rf (17:3, CHCl3, MeOH):
0.50, m.p. 173–176 °C [ref.[13] m.p. 172–175 °C]. [α]D = –15.56 (c =
0.45, MeOH). 1H NMR (400 MHz, CD3OD): δ = 3.48 (dd, J =
4.4, 12.4 Hz, 1 H, 9-H), 3.69 (dd, J = 2.4, 12.0 Hz, 1 H, 9-H), 4.07–
4.11 (m, 1 H, 8-H), 4.85 (d, J = 8.0 Hz, 1 H, 7-H), 6.61 (dd, J =
8.0, 16.0 Hz, 1 H, 8Ј-H), 6.79 (dd, J = 2.0, 8.0 Hz, 1 H, 6-H), 6.81
(d, J = 8.0 Hz, 1 H, 5-H), 6.87 (d, J = 2.0 Hz, 1 H, 2-H), 7.02 (d,
J = 8.4 Hz, 1 H, 5Ј-H), 7.22 (dd, J = 2.4, 8.4 Hz, 1 H, 6Ј-H), 7.26
(d, J = 2.4 Hz, 1 H, 2Ј-H), 7.56 (d, J = 16.0 Hz, 1 H, 7Ј-H), 9.58
(d, J = 8.0 Hz, 1 H, 9Ј-H) ppm. 13C NMR (100 MHz, CD3OD): δ
= 61.9 (C-9), 77.6 (C-7), 80.5 (C-8), 115.6 (C-2), 116.4 (C-5), 118.2
(C-2Ј), 118.6 (C-5Ј), 120.4 (C-6), 124.0 (C-6Ј), 127.8 (C-8Ј), 129.1
(C-1 and C-1Ј), 145.7 (C-3Ј), 146.7 (C-3), 147.3 (C-4), 148.2 (C-4Ј),
155.3 (C-7Ј), 196.0 (C-9Ј) ppm. The 1H and 13C NMR spectro-
scopic data was in agreement with literature values.[13]
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1045

L. I. Pilkington, D. Barker
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