Total synthesis of (+)-machaeriols B and C and of their enantiomers with a cannabinoid structure

Article abstract of DOI:10.1002/hlca.200900014

An efficient and concise synthesis of the biologically interesting (+)-machaeriol B (2) and its enantiomer 5 was accomplished from O-phenylhydroxylamine (7) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)-machaeriol C (3) a

Full text of DOI:10.1002/hlca.200900014

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Helvetica Chimica Acta – Vol. 92 (2009)
Total Synthesis of (þ)-Machaeriols B and C and of Their Enantiomers with a
Cannabinoid Structure
by Hee Jin Leea), Yong Rok Lee*a), and Sung Hong Kimb)
a) School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
(phone: þ 82-53-810-2529; fax: þ 82-53-810-4631; e-mail: yrlee@yu.ac.kr)
b) Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 702-701, Korea
An efficient and concise synthesis of the biologically interesting (þ)-machaeriol B (2) and its
enantiomer 5 was accomplished from O-phenylhydroxylamine (7) in four steps (Scheme 2). In addition,
the first total synthesis of natural (þ)-machaeriol C (3) and its enantiomer 6 was achieved from the
readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5
involved benzofuran formation through a [3,3]-sigmatropic rearrangement and trans-hexahydrodiben-
zopyran formation by a domino aldol-type/hetero-Diels – Alder reaction. In the case of 3 and 6, the key
steps were stilbene formation by a Horner– Wadsworth – Emmons reaction and trans-hexahydrodiben-
zopyran formation by domino reactions.
Introduction. – (þ)-Machaeriols A (1), B (2), C (3), and D (4), bearing the
cannabinoid structure, were recently isolated from the bark of the Machaerium
multiflorum spruce (Fig.) located in Loreto and Peru [1]. They have been reported to
have potential in vitro antimicrobial activity against Staphylococcus aureus (IC50 [mg/
ml]: 1, 15.0; 2, 5.0; 3, 0.7; 4, 25.0) and methicillin-resistant S. aureus (IC50 [mg/ml]: 1,
10.0; 2, 4.5; 3, 0.7; 4, 30.0) [1]. They also showed potent in vitro antimalarial activity
against Plasmodium falciparum D6 (IC50 (3) ¼ 3.0 mg/ml) and W2 clones (IC50 (3) ¼
3.7 mg/ml) [1]. These important biological activities have led to the development of a
variety of synthetic approaches to these natural products. The first syntheses of
machaeriol A (1) and machaeriol B (2) were reported by Avery and co-workers starting
from phloroglucinol (¼ benzene-1,3,5-triol) through a hetero Diels – Alder cyclization
and Suzuki coupling reaction as the key steps with 34% (7 steps) and 32% (7 steps)
overall yields, respectively [2]. Another total synthesis of (þ)-machaeriol A (1) was
accomplished starting from the synthesized enol silyl ether of a,b-epoxycyclohexanone
through an SN2’ reaction to an aryl cyanocuprate as the key step with an overall yield of
26% (10 steps) [3]. Recently, (þ)-machaeriol D (4) was also synthesized starting from
4-bromo-2,4-dihydroxybenzoic acid in 12% overall yield (17 steps) by She, Pan, and co-
workers [4]. Although synthetic approaches to (þ)-machaeriols A (1), B (2), and D (4)
have been reported, there is still a demand for a more concise and efficient method for
synthesizing these biologically interesting natural products. In particular, no total
synthesis of natural (þ)-machaeriol C (3) or its enantiomer 6 has been reported thus
far.
Results and Discussion. – We developed a new and useful methodology for
preparing a variety of benzopyrans using the ethylenediamine diacetate (EDDA)
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Figure. Natural products 1 – 4 isolated from Machaerium multiflorum and unnatural products 5 – 6 with
cannabinoid structure
catalyzed reactions of resorcinols (¼ benzene-1,3-diols) to a,b-unsaturated aldehydes
[5]. These reactions involve cycloadditions through 6p-electrocyclization or hetero-
Diels – Alder reactions [5]. This methodology provides a rapid route for the synthesis of
benzopyran derivatives with a variety of substituents on the pyranyl moiety.
Recently, we also developed a new and useful methodology for preparing a variety
of cannabinoid analogues by the reaction of resorcinols with optically pure citronellals
(¼ 3,7-dimethyloct-6-enals) in the presence of EDDA and Et3N as a co-catalyst [6]. By
using this methodology as a key-step, we described the synthesis of (þ)-machaeriol A
(1) starting from 3,5-dimethoxybenzaldehyde [7]. As an extension of our work, we now
report the total syntheses of natural (þ)-machaeriols B (2) and C (3) and of their
unnatural enantiomers (ꢀ)-machaeriols B (5) and C (6), respectively.
Scheme 1 shows the retrosynthetic analysis for (þ)-machaeriol B (2). (þ)-
Machaeriol B (2) can be prepared from stemofuran A (11) and (ꢀ)-(3S)-citronellal
(12a) through a hetero-Diels – Alder reaction. Stemofuran A (11) can be readily
generated from O-phenylhydroxylamine (7) and 3,5-bis(benzoyloxy)acetophenone
(¼1-[3,5-bis(benzoyloxy)phenyl]ethanone; 8).
Scheme 2 shows a concise synthetic approach to natural (þ)-machaeriol B (2) and
its unnatural enantiomer 5. The precursor 11 for the total syntheses of 2 and 5 was
obtained by a known method [8]. Thus, the condensation of O-phenylhydroxylamine
(7) with 3,5-bis(dibenzoyloxy)acetophenone (8) in the presence of conc. HCl in EtOH
gave the oxime ether 9 in 93% yield. The latter was treated with trifluoroacetyl triflate
(CF3C(¼O)OS(¼O)2CF3 ¼ TFAT, 5.0 equiv.) and N,N-dimethylpyridin-4-amine
(DMAP, 3.0 equiv.) in CH2Cl2 at room temperature to afford the desired cycloadduct

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Scheme 1. Retrosynthetic Analysis for Natural (þ)-Machaeriol B (2)
Scheme 2. Total Synthesis of Natural (þ)-Machaeriol B (2) and Its Enantiomer 5
10 in 95% yield and as the sole product, via a [3,3]-sigmatropic rearrangement which is
the well-known oxa-variant of Fischerꢂs indole synthesis. Removal of the two benzoyl
groups from 10 with LiAlH4 in ether at room temperature afforded stemofuran (11) in
90% yield. Stemofuran (¼ 5-(benzofuran-2-yl)benzene-1,3-diol; 11), bearing a benzo-
furan moiety, was isolated from Stemona collinsae, distributed mainly in southeast Asia
[9]. This plant has been used in traditional medicine in China and Japan to treat

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inflammatory-related diseases [10], with the extracts from the fleshy tuberous roots still
used to treat respiratory disorders, including pulmonary tuberculosis, antiasthmatic,
and bronchitis. The extracts also kill insects and worms [11]. Benzofuranylbenzenediol
11 has also been shown to have potent antibacterial and antifungal activity [9].
Then the formation of the hexahydrodibenzopyran moiety of 2 and 5 from 11 in the
presence of EDDA/Et3N was investigated (Scheme 2). Treatment of 11 with (ꢀ)-(S)-
citronellal (12a; [a]2D5 ¼ ꢀ15.0 (neat)) in the presence of EDDA (20 mol-%)/Et3N
(2.0 ml) in refluxing xylene gave (þ)-machaeriol B (2) in 65% yield. (synthetic 2:
[a]2D5 ¼ þ113.1 (c ¼ 0.14, MeOH); [1b]: [a]2D5 ¼ þ113.7 (c ¼ 0.53, MeOH)). The
spectroscopic data of the synthetic 2 are in good agreement with the reported data
[1b]. Conversely, the corresponding treatment of 11 with (þ)-(R)-citronellal (12b;
[a]2D5 ¼ þ12.5, neat) gave (ꢀ)-machaeriol B (5) in 63% yield (synthetic 5: [a]2D5 ¼ ꢀ99.7
(c ¼ 0.45, MeOH)).
Scheme 3 shows the mechanism for the formation of (þ)-machaeriol B (2) through
a domino aldol-type/hetero-Diels – Alder reaction. Citronellal 12a was first protonated
at the aldehyde function by EDDA and then attacked by stemofuran (11) to yield an
intermediate 13. Shigemasa and co-workers first suggested such a process for the
formation of aldol-type products in a Ca(OH)2-mediated reaction of resorcinol with
enals [12]. The dehydration of intermediate 13 in the presence of EDDA/Et3N afforded
o-quinone methide 14. The stereospecificity of the formation of product 2 might be
explained by the pseudo-equatorial conformation of the Me group of 14 in the coplanar
structure of the chair-like transition state. In the subsequent hetero-Diels – Alder
reaction of o-quinone methide 14, the exo-transition state must be energetically more
favorable than the endo-transition state [13]. This is in good agreement with Marino
and Dax [14] and Korthals and Wulff [15], who reported the syntheses of
hexahydrocannabinol and hexahydrodibenzopyran by the intramolecular hetero-
Diels – Alder cycloaddition of an o-quinone methide.
Scheme 3. Mechanism for the Formation of (þ)-Machaeriol B (2)
Next, the syntheses of natural (ꢀ)-machaeriol C (3) and its enantiomer 6 were
achieved as shown in Scheme 4. The readily available ester 15 [16] was converted into
the corresponding iodide 16 by the sequence of reduction, mesylation, and iodination in
80% yield (3 steps). Compound 16 was then treated with triethyl phosphite in xylene at
1008 to give phosphonate 17 in 97% yield [17]. The Horner – Wadsworth – Emmons

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Scheme 4. Total Synthesis of Natural (þ)-Machaeriol C (3) and Its Enantiomer 6
reaction of 17 with benzaldehyde 18 [18] (prepared from salicylaldehyde) in the
presence of potassium tert-butoxide in THF, gave the desired coupling product 19 in
78% yield. Removal of the two protecting MeOCH2 groups of 19 with conc. HCl in
MeOH at room temperature afforded diol 20 in 72% yield. Reaction of compound 20
with (ꢀ)-(S)-citronellal (12a) in the presence of EDDA (20 mol-%)/Et3N (2.0 ml) in

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refluxing xylene gave adduct 21 (60%). Removal of the silyl protecting group with
Bu4NF afforded (þ)-machaeriol C (3) in 97% yield (synthesized 3: [a]2D5 ¼ þ118.2 (c ¼
0.34, MeOH); [1b]: [a]2D5 ¼ þ117.4 (c ¼ 1.01, MeOH)). The spectroscopic data of the
synthetic 3 was in agreement with the reported data [1b]. The corresponding treatment
of 20 with (þ)-(R)-citronellal (12b; [a]2D5 ¼ þ12.5, neat) (!22 (59%)), followed by
deprotection provided unnatural (ꢀ)-machaeriol C (6) in 95% yield (synthetic 6:
[a]2D5 ¼ ꢀ104.0 (c ¼ 0.26, MeOH)).
Conclusions. – Efficient and concise syntheses of the biologically interesting (þ)-
machaeriol B (2) and its enantiomer 5 were carried out starting from O-phenyl-
hydroxylamine (7) and 3,5-bis(benzoyloxy)acetophenone (8). Additionally, the first
total synthesis of natural (þ)-machaeriol C (3) and its enantiomer 6 was accomplished
from readily available ester 15. The key strategies in the syntheses of 2 and 5 involved
the benzofuran formation of oxime ether 9 through a [3,3]-sigmatropic rearrangement
which is the well-known oxa-variant of Fischerꢂs indole synthesis, and the trans-
hexahydrodibenzopyran formation of stemofuran (11) by a domino aldol-type/hetero-
Diels – Alder reaction. In the case of (þ)-machaeriol C (3) and its enantiomer 6, the key
steps were stilbene formation by a Horner – Wadsworth – Emmons reaction and trans-
hexahydrodibenzopyran formation by a domino reaction. These synthetic routes are
expected to be widely used in the synthesis of other natural products including
cannabinoid analogues.
This work was supported by the Yeungnam University research grants in 208-A-356-017.
Experimental Part
General. All experiments were carried out under N2. Column chromatography (CC): silica gel 9385
(Merck). Thin-layer chromatography (TLC): pre-coated silica gel plates (Art. 5554) with a fluorescent
indicator. FT-IR Spectra: Jasco-FTIR-5300 spectrophotometer. 1H- and 13C-NMR Spectra: Bruker-
ARX-300 spectrometer; CDCl3 or CD3OD solns.; d in ppm rel. to the solvent chemical shift, J in Hz. EI-
MS (70 eV) and HR-MS: the spectra were carried out at the Korea Basic Science Institute; in m/z.
(1E)-1-[3,5-Bis(benzoyloxy)phenyl]ethanone O-Phenyloxime (9). To a soln. of O-phenylhydroxyl-
amine (7; 0.327 g, 3.0 mmol) in EtOH (10 ml) were added 3,5-bis(benzoyloxy)acetophenone (8; 1.080 g,
3.0 mmol) and conc. HCl soln. (0.10 ml) at r.t. After being stirred at r.t. for 10 h, the mixture was
concentrated and the residue purified by CC (SiO2, hexane/AcOEt 10 :1): 1.259 g (93%) of 9. White
solid. M.p. 87 – 888. IR (KBr): 3461, 3098, 1740, 1593, 1483, 1453, 1431, 1335, 1312, 1265, 1202, 1134, 1082,
1
1067, 1024, 953, 901, 878, 762. H-NMR (CDCl3, 300 MHz): 8.42 (d, J ¼ 8.1, 4 H); 7.86 – 7.84 (m, 2 H);
7.80 (d, J ¼ 2.0, 2 H); 7.76 – 7.71 (m, 4 H); 7.53 – 7.46 (m, 5 H); 7.28 – 7.22 (m, 1 H); 2.67 (s, 3 H). 13C-NMR
(CDCl3, 75 MHz): 164.7; 159.3; 156.0; 151.4; 138.2; 133.8; 130.2; 129.3; 129.1; 128.6; 122.4; 117.3; 117.1;
114.9; 13.2. EI-MS: 451 (2, Mþ), 360 (6), 359 (32), 358 (72), 105 (100), 94 (5), 77 (25). HR-MS: 451.1417
(Mþ, C28H21NOþ5 ; calc. 451.1420).
5-(Benzofuran-2-yl)benzene-1,3-diol 1,3-Dibenzoate (10). To a soln. of 9 (0.902 g, 2.0 mmol) in
CH2Cl2 (20 ml) were added DMAP (0.734 g, 6.0 mmol) and TFAT (2.460 g, 10.0 mmol) at r.t. After being
stirred at r.t. for 10 h, the mixture was diluted with H2O (30 ml) and extracted with CH2Cl2 (3 ꢁ 40 ml).
The org. layer was washed with brine (30 ml), dried (MgSO4), and concentrated, and the residue purified
by CC (SiO2, hexane/AcOEt 5 :1): 0.826 g (95%) of 10. White solid. M.p. 148 – 1508. IR (KBr): 3097,
1744, 1620, 1599, 1451, 1258, 1130, 1063, 1024, 953, 882, 800, 747. 1H-NMR (CDCl3, 300 MHz): 8.27 – 8.25
(d, J ¼ 8.1, 4 H); 7.71 – 7.67 (m, 4 H); 7.64 – 7.52 (m, 6 H); 7.36 – 7.22 (m, 3 H); 7.11 (s, 1 H). 13C-NMR
(CDCl3, 75 MHz): 164.7; 155.0; 154.0; 151.8; 133.9; 132.7; 130.3; 129.1; 128.9; 128.7; 124.9; 123.2; 121.2;

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Helvetica Chimica Acta – Vol. 92 (2009)
115.7; 111.3; 102.9. EI-MS: 434 (46, Mþ), 358 (4), 330 (3), 106 (8), 105 (100), 77 (24). HR-MS: 434.1151
(Mþ, C28H18Oþ5 ; calc. 434.1154).
Stemofuran A (¼ 5-(Benzofuran-2-yl)benzene-1,3-diol; 11). A suspension of LiAlH4 (0.228 g,
6.0 mmol) in dry Et2O (20 ml) was cooled to 08 and treated dropwise with 10 (0.651 g, 1.5 mmol) in dry
Et2O (5 ml). After stirring at r.t. for 2 h, the mixture was quenched at 08 by the addition of H2O (30 ml)
and 2n HCl (50 ml). The mixture was extracted with AcOEt (3 ꢁ 40 ml), the org. layer washed with brine
(30 ml), dried (MgSO4), and concentrated, and the residue purified by CC (SiO2, hexane/AcOEt 3 :1):
0.306 g (90%) of 11. Yellow solid. M.p. 181 – 1828. IR (KBr): 3331, 1620, 1579, 1449, 1358, 1246, 1148, 999,
953, 853, 833, 801, 748. 1H-NMR (CD3OD, 300 MHz): 7.46 (d, J ¼ 8.0, 1 H); 7.38 (d, J ¼ 8.0, 1 H); 7.18 –
7.06 (m, 2 H); 6.93 (d, J ¼ 1.5, 1 H); 6.74 (d, J ¼ 1.5, 2 H); 6.20 (t, J ¼ 1.5, 1 H); 4.78 (br. s, 2 H).
13C-NMR (CD3OD, 75 MHz): 160.0; 157.4; 156.1; 133.4; 130.5; 125.3; 124.0; 121.9; 111.8; 104.5; 104.1;
102.3. EI-MS: 226 (100, Mþ), 197 (11), 181 (2), 169 (3), 152 (4), 151 (3), 150 (4), 141 (4), 139 (3), 115
(5), 113 (5). HR-MS: 226.0631 (Mþ, C14H10O3þ ; calc. 226.0630).
(þ)-Machaeriol B (¼(6aS,9S,10aS)-3-(Benzofuran-2-yl]-6a,7,8,9,10,10a-hexahydro-6,6,9-trimethyl-
6H-dibenzo[b,d]pyran-1-ol; 2). To a soln. of 11 (0.101 g, 0.4 mmol) and (ꢀ)-(S)-citronellal (12a; [a]D25
¼
ꢀ15.0, neat; 0.136 g, 0.9 mmol) in xylene (10 ml) was added ethylenediamine diacetate (0.016 g) and
Et3N (2 ml) at r.t. The mixture was stirred in refluxing xylene for 48 h. The solvent was evaporated and
the oily residue purified by CC (SiO2, hexane/AcOEt 5 :1): 0.104 g (65%) of 2. Brown solid. M.p. 92 –
938. [a]2D5 ¼ þ113.1 (c ¼ 0.14, MeOH). IR (KBr): 3393, 2922, 1622, 1564, 1452, 1422, 1358, 1250, 1142,
1040, 965, 883, 902, 750. 1H-NMR (CDCl3, 300 MHz): 7.51 (d, J ¼ 7.4, 1 H); 7.44 (d, J ¼ 7.8, 1 H); 7.25 –
7.15 (m, 2 H); 6.90 (d, J ¼ 1.5, 1 H); 6.86 (s, 1 H); 6.77 (d, J ¼ 1.5, 1 H); 5.11 (s, 1 H); 3.05 (d, J ¼ 12.9,
1 H); 2.49 (dd, J ¼ 13.0, 11.1, 1 H); 1.85 – 1.82 (m, 2 H); 1.68 – 1.56 (m, 1 H); 1.51 – 1.42 (m, 1 H); 1.38 (s,
3 H); 1.13 – 1.05 (m, 2 H); 1.07 (s, 3 H); 0.93 (d, J ¼ 6.6, 3 H); 0.87 – 0.76 (m, 1 H). 13C-NMR (CDCl3,
75 MHz): 156.0; 155.8; 155.2; 130.0; 129.7; 124.5; 123.3; 121.3; 114.4; 111.5; 107.5; 104.4; 101.6; 77.9; 49.5;
39.2; 36.1; 35.9; 33.3; 28.5; 28.1; 23.0; 19.5. EI-MS: 362 (100, Mþ), 347 (7), 320 (5), 319 (22), 279 (14), 277
(12), 263 (70), 240 (7), 239 (39), 226 (13). HR-MS: 362.1885 (Mþ, C24H26O3þ ; calc. 362.1882).
(ꢀ)-Machaeriol B (¼(6aR,9R,10aR)-3-(Benzofuran-2-yl)-6a,7,8,9,10,10a-hexahydro-6,6,9-trimeth-
yl-6H-dibenzo[b,d]pyran-1-ol; 5). As described for 2 with 11 (0.100 g, 0.4 mmol) and (þ)-(R)-citronellal
(12b; [a]2D5 ¼ þ12.5, neat; 0.136 g, 0.9 mmol): 0.101 g (63%) of 5. Brown solid. M.p. 181 – 1828. [a]2D5
ꢀ99.7 (c ¼ 0.45, MeOH).
¼
1-(Iodomethyl)-3,5-bis(methoxymethoxy)benzene (16). To a suspension of LiAlH4 (0.417 g,
11.0 mmol) in Et2O (40 ml) at 08 was added dropwise ester 15 (2.563 g, 10.0 mmol) in Et2O (3 ml).
The mixture was stirred at r.t. for 3 h and then quenched by addition of ice water (30 ml). The mixture
was acidified with 2n HCl (30 ml) and extracted with AcOEt (3 ꢁ 40 ml), the org. layer washed with H2O
(30 ml) and brine (30 ml), dried (MgSO4), and concentrated, and the residue purified by CC (SiO2,
hexane/AcOEt 5 :1): 2.191 g (95%) of 3,5-bis(methoxymethoxy)benzenemethanol. Liquid. IR (neat):
1
2955, 2830, 2732, 1702, 1600, 1465, 1389, 1297, 1214, 1153, 1084, 1033, 927, 856, 726. H-NMR (CDCl3,
300 MHz): 9.88 (s, 1 H); 7.18 (s, 2 H); 6.94 (s, 1 H); 5.18 (s, 4 H); 3.46 (s, 6 H). 13C-NMR (CDCl3,
75 MHz): 191.6; 158.7; 138.4; 111.1; 110.4; 90.4; 56.2.
Methanesulfonyl chloride (0.916 g, 8.0 mmol) was added dropwise to a soln. of the above
benzenemethanol (1.789 g, 7.8 mmol) and N,N-diisopropylethylamine (2.012 g, 15.6 mmol) in CH2Cl2
(30 ml) at 08. The mixture was stirred at r.t. for 10 h and then quenched by addition of H2O (30 ml). The
mixture was extracted with AcOEt (3 ꢁ 40 ml) and the combined org. layer washed with NH4Cl soln.
(30 ml), H2O (30 ml), and brine (30 ml), dried (MgSO4), and concentrated. The resulting residue and
NaI (3.507 g, 23.4 mmol) were stirred in acetone (50 ml) for 10 h. After solvent evaporation, the oily
residue was purified by CC (SiO2, hexane/AcOEt 5 :1): 2.188 g (83%) of 16. Liquid. IR (neat): 3022,
2935, 1601, 1457, 1364, 1179, 1151, 1024, 967, 867, 808, 744. 1H-NMR (CDCl3, 300 MHz): 6.70 (s, 2 H); 6.60
(s, 1 H); 5.12 (s, 4 H); 4.35 (s, 2 H); 3.45 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 158.2; 141.2; 110.0; 104.4;
94.4; 56.0; 5.2. HR-FAB-MS: 339.0091 ([M þ H]þ, C11H16IO4þ; calc. 339.0093).
{[3,5-Bis(methoxymethoxy)phenyl]methyl}phosphonic Acid Diethyl Ester (17). To a soln. of 16
(2.025 g, 6.0 mmol) in xylene (10 ml) was added triethyl phosphite (1 ml) at r.t. The mixture was heated
at 1008 for 7 h. After removal of the solvent, the oily residue was purified by CC (SiO2, hexane/AcOEt
1:1): 2.024 g (97% of 17). Liquid. IR (neat): 3457, 2982, 1602, 1464, 1400, 1150, 1029, 965, 857, 792.

Helvetica Chimica Acta – Vol. 92 (2009)
1411
1H-NMR (CDCl3, 300 MHz): 6.61 – 6.58 (m, 3 H); 5.10 (m, 4 H); 4.05 – 3.95 (m, 4 H); 3.42 (s, 6 H); 3.01
(d, J(P,H) ¼ 21.6, 2 H); 1.26 – 1.21 (m, 6 H). 13C-NMR (CDCl3, 75 MHz): 158.1; 133.6; 111.1; 103.4; 94.3;
62.1; 55.9; 33.9 (d, J(C,P) ¼ 138.1); 16.2. EI-MS: 348 (100, Mþ), 318 (28), 317 (22), 316 (94), 315 (27), 287
(42), 271 (25), 232 (24), 229 (20), 160 (21). HR-MS: 348.1335 (Mþ, C15H25O7Pþ; calc. 348.1338).
(E)-3’,5’-Bis(methoxymethoxy)-2-[(triisopropylsilyl)oxy]stilbene (¼1,3-Bis(methoxymethoxy)-5-
{(1E)-2-{2-{(tris(1-methylethyl)silyl]oxy}phenyl}ethenyl}benzene; 19). To a soln. of 17 (1.045 g,
t
3.0 mmol) and aldehyde 18 (0.891 g, 3.2 mmol) in THF (30 ml) was added BuOK (0.717 g, 6.4 mmol)
at 08. The mixture was stirred at 08 for 30 min and then quenched by addition of H2O (30 ml). The
mixture was extracted with AcOEt (3 ꢁ 30 ml), the combined org. layer washed with NH4Cl soln.
(30 ml), H2O (30 ml), and brine (30 ml), dried (MgSO4), and concentrated, and the oily residue purified
by CC (SiO2, hexane/AcOEt 4 :1): 1.180 g (78%) of 19. Liquid. IR (neat): 2949, 2867, 1596, 1481, 1265,
1149, 1082, 1035, 922, 756, 684. 1H-NMR (CDCl3, 300 MHz): 7.59 (d, J ¼ 7.5, 1 H); 7.56 (d, J ¼ 16.5, 1 H);
7.12 (dd, J ¼ 7.8, 7.5, 1 H); 6.98 (d, J ¼ 16.5, 1 H); 6.93 (dd, J ¼ 8.1, 7.8, 1 H); 6.88 (br. s, 2 H); 6.84 (d, J ¼
8.1, 1 H); 6.63 (br. s, 1 H); 5.18 (s, 4 H); 3.49 (s, 6 H); 1.37 – 1.30 (m, 3 H); 1.16 – 1.11 (m, 18 H).
13C-NMR (CDCl3, 75 MHz): 158.5; 153.7; 140.2; 128.6; 127.9; 126.0; 124.6; 121.2; 119.1; 107.8; 104.3; 94.5;
56.0; 18.1; 17.7; 13.0. EI-MS: 472 (100, Mþ), 429 (15), 397 (31), 367 (18), 365 (18), 353 (13), 337 (10), 335
(13), 323 (16), 251 (14), 237 (14), 235 (36), 165 (17), 161 (13), 145 (19), 131 (35), 117 (10), 103 (31), 75
(34), 61 (14). HR-MS: 472.2646 (Mþ, C27H40O5Siþ; calc. 472.2645).
(E)-2-[(Triisopropylsilyl)oxy]stilbene-3’,5’-diol (¼ 5-{(1E)-2-{2-{[Tris(1-methylethyl)silyl]oxy}phe-
nyl}ethenyl}benzene-1,3-diol; 20). To a soln. of 19 (0.993 g, 2.1 mmol) in MeOH (10 ml) was added
conc. HCl soln. (5 drops), and the mixture was stirred at r.t. for 10 h. After removal of the solvent, the
oily residue was diluted with H2O (30 ml) and the mixture extracted with AcOEt (3 ꢁ 40 ml). The
combined org. layer was washed with sat. NaHCO3 soln. (30 ml), H2O (30 ml) and brine (30 ml), dried
(MgSO4), and concentrated and the oily residue was purified by CC (SiO2, hexane/AcOEt 4 :1): 0.581 g
(72%) of 20. Liquid. IR (neat): 3392, 2946, 2865, 1597, 1482, 1485, 1344, 1264, 1152, 1003, 920, 833, 680.
1H-NMR (CDCl3, 300 MHz): 7.54 (d, J ¼ 7.8, 1 H); 7.48 (d, J ¼ 16.5, 1 H); 7.10 (dd, J ¼ 8.1, 7.8, 1 H); 6.90
(d, J ¼ 16.5, 1 H); 6.87 (dd, J ¼ 8.1, 7.2, 1 H); 6.82 (d, J ¼ 7.2, 1 H); 6.55 (d, J ¼ 2.1, 2 H); 6.25 (t, J ¼ 2.1,
1 H); 1.35 – 1.28 (m, 3 H); 1.13 – 1.11 (m, 18 H). 13C-NMR (CDCl3, 75 MHz): 157.0; 153.7; 140.7; 128.6;
128.1; 127.7; 126.2; 124.8; 121.1; 119.1; 106.0; 102.0; 18.0; 13.0. EI-MS: 384 (78, Mþ), 342 (27), 341 (100),
300 (11), 299 (48), 257 (11), 255 (13), 251 (18), 217 (19), 189 (14), 175 (12), 165 (11), 161 (23), 143 (9),
135 (8), 59 (8). HR-MS: 384.2122 (Mþ, C23H32O3Siþ; calc. 384.2121).
(6aS,9S,10aS)-6a,7,8,9,10,10a-Hexahydro-6,6,9-trimethyl-3-{(1E)-2-{2-{(tris(1-methylethyl)silyl]oxy}-
phenyl}ethenyl}-6H-dibenzo[b,d]pyran-1-ol (21). As described for 2, with 20 (0.231 g, 0.5 mmol), (ꢀ)-
(S)-citronellal (12a; [a]D ¼ ꢀ15.08, neat; 0.154 g, 1.0 mmol) xylene (10 ml), ethylenediamine diacetate
(0.018 g), and Et3N (2 ml). CC (SiO2, hexane/AcOEt 15 :1) gave 0.156 g (60%) of 21. Liquid. [a]D25
¼
þ84. 6, (c ¼ 0.60, MeOH). IR (neat): 3412, 2945, 2866, 1614, 1567, 1481, 1455, 1263, 1141, 918, 880,
750, 685. 1H-NMR (CDCl3, 300 MHz): 7.54 (d, J ¼ 7.8, 1 H); 7.44 (d, J ¼ 16.5, 1 H); 7.10 (dd, J ¼ 7.8, 7.5,
1 H); 6.92 (dd, J ¼ 7.5, 7.2, 1 H); 6.87 (d, J ¼ 16.5, 1 H); 6.83 (d, J ¼ 7.2, 1 H); 6.57 (br. s, 1 H); 6.42 (br. s,
1 H); 4.98 (br. s, 1 H); 3.07 (d, J ¼ 12.6, 1 H); 2.50 (dd, J ¼ 12.6, 10.8, 1 H) 1.87 – 1.84 (m, 2 H); 1.69 – 1.58
(m, 1 H); 1.52 – 1.44 (m, 1 H); 1.40 (s, 3 H); 1.37 – 1.28 (m, 3 H); 1.15 – 1.09 (m, 2 H); 1.14 (d, J ¼ 7.2,
18 H); 1.09 (s, 3 H); 0.95 (d, J ¼ 6.3, 3 H); 0.90 – 0.78 (m, 1 H). 13C-NMR (CDCl3, 75 MHz): 155.4, 155.1,
153.5; 137.4; 128.4; 128.2; 127.9; 126.3; 123.7; 121.1; 119.0; 112.6; 108.9; 105.1; 76.6; 49.1; 38.9; 35.7; 35.5;
32.9; 28.0; 27.7; 22.6; 19.0; 18.1; 13.0. EI-MS: 520 (100, Mþ), 478 (31), 477 (80), 472 (19), 354 (13), 353
(43), 341 (14), 311 (17), 189 (16), 161 (23), 149 (15), 129 (28), 83 (11), 81 (13), 71 (14), 69 (240), 57 (21).
HR-MS: 520.3376 (Mþ, C33H48O3Siþ; calc. 520.3373).
(þ)-Machaeriol C (¼(6aS,9S,10aS)-6a,7,8,9,10,10a-Hexahydro-3-[(1E)-2-(2-hydroxyphenyl)ethen-
yl]-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol; 3). To a soln. of 21 (0.104 g, 0.2 mmol) in THF (10 ml)
was added 1m Bu4NF in THF (0.6 ml), and the mixture was stirred at r.t. for 5 h. The mixture was
quenched by addition of sat. NH4Cl soln. (30 ml) and extracted with AcOEt (3 ꢁ 40 ml). The combined
org. layer was washed with H2O (30 ml) and brine (30 ml), dried (MgSO4), and concentrated, and the
oily residue purified by CC (SiO2, hexane/AcOEt 5 :1): 0.071 g (97%) of 3. Brown solid. M.p. 105 – 1068.
[a]2D5 ¼ þ118.2 (c ¼ 0.34, MeOH). IR (KBr): 3409, 2925, 1612, 1569, 1453, 1422, 1263, 1092, 1039, 870,
806, 746. 1H-NMR (CDCl3, 300 MHz): 7.43 (d, J ¼ 7.5, 1 H); 7.22 (d, J ¼ 16.2, 1 H); 7.08 (dd, J ¼ 7.5, 7.2,

1412
Helvetica Chimica Acta – Vol. 92 (2009)
1 H); 6.88 (dd, J ¼ 7.8, 7.2, 1 H); 6.85 (d, J ¼ 16.2, 1 H); 6.76 (d, J ¼ 7.8, 1 H); 6.56 (br. s, 1 H); 6.41 (br. s,
1 H); 5.28 (br. s, 2 H); 3.04 (d, J ¼ 12.3, 1 H); 2.47 (dd, J ¼ 12.3, 11.1, 1 H); 1. 84 – 1.81 (m, 2 H); 1.71 –
1.52 (m, 1 H); 1.50 – 1.41 (m, 1 H); 1.37 (s, 3 H); 1.12 – 1.02 (m, 2 H); 1.05 (s, 3 H); 0.92 (d, J ¼ 6.6, 3 H);
0.81 – 0.69 (m, 1 H). 13C-NMR (CDCl3, 75 MHz): 155.7, 155.6; 153.5; 137.5; 129.9; 129.1; 127.5; 125.2;
123.2; 121.6; 116.5; 113.5; 109.3; 105.8; 77.9; 49.6; 39.3; 36.1; 35.9; 33.3; 28.5; 28.2; 23.0; 22.5; 19.5. EI-MS:
364 (82, Mþ), 355 (27), 346 (12), 321 (28), 279 (32), 241 (43), 221 (25), 167 (40), 150 (11), 149 (100), 147
(17), 129 (12), 73 (10), 71 (13), 69 (10), 57 (17). HR-MS: 364.2042 (Mþ, C24H28O3þ ; calc. 364.2038).
(6aR,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-6,6,9-trimethyl-3-{(1E)-2-{2-{[tris(1-methylethyl)silyl]ox-
y}phenyl}ethenyl}-6H-dibenzo[b,d]pyran-1-ol (22). As described for 2, with 20 (0.154 g, 0.4 mmol), (þ)-
(R)-citronellal (12b; [a]D ¼ þ12.5, neat; 0.123 g, 0.8 mmol), xylene (10 ml), ethylenediamine diacetate
(0.014 g), and Et3N (2 ml). CC (SiO2, hexane/AcOEt 15 :1) gave 0.123 g (59%) of 22. Liquid. [a]D25
ꢀ74.4 (c ¼ 0.65, MeOH).
¼
(ꢀ)-Machaeriol C (¼(6aR,9R,10aR)-6a,7,8,9,10,10a-Hexahydro-3-[(1E)-2-(2-hydroxyphenyl)ethen-
yl]-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol; 6). As described for 3, with 22 (0.102 g, 0.2 mmol), THF
(10 ml), and 1m Bu4NF in THF (0.6 ml). CC (SiO2, hexane/AcOEt 5 :1) gave 0.064 g (95%) of 6. [a]D25
ꢀ104.0 (c ¼ 0.26, MeOH).
¼
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Received January 15, 2009