A general route to 5,6-seco-hexahydrodibenzopyrans and analogues: first total synthesis of (+)-Machaeridiol B and (+)-Machaeriol B

Article abstract of DOI:10.1016/j.tet.2006.10.067

A general and efficient route for the synthesis of 5,6-seco-hexahydrodibenzopyran and trans-hexahydrodibenzopyran analogues was established, via a highly regio- and stereoselective S_N2′ reaction of arylcyanocuprates to enol silyl ether of α,β-e

Full text of DOI:10.1016/j.tet.2006.10.067

Tetrahedron 63 (2007) 1014–1021
A general route to 5,6-seco-hexahydrodibenzopyrans
and analogues: first total synthesis of (D)-Machaeridiol B
and (D)-Machaeriol B
Qinggang Huang,a Qiaoling Wang,a Jiyue Zheng,a Jiyong Zhang,a Xinfu Pana
and Xuegong Shea,b,
*
aDepartment of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Tianshui South 222#, Lanzhou, Gansu 730000, PR China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, PR China
Received 12 September 2006; revised 24 October 2006; accepted 26 October 2006
Available online 29 November 2006
Abstract—A general and efficient route for the synthesis of 5,6-seco-hexahydrodibenzopyran and trans-hexahydrodibenzopyran analogues
was established, via a highly regio- and stereoselective SN20 reaction of arylcyanocuprates to enol silyl ether of a,b-epoxycyclohexanone. It
was applied to the first facile total synthesis of (+)-Machaeridiol B and (+)-Machaeriol B.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
hexahydrocannabinol).1 Quite a number of hexahydrodiben-
zopyran derivatives have been isolated from the stem bark
of Machaerium multiflorum Spruce (Fabaceae) (Fig. 1).2
These natural products generally were classified into two
classes according to their structural features, 5,6-seco-
hexahydrodibenzopyrans (HHDBP’s) Machaeridiols A–C
The dibenzopyran nucleus is a structural feature found in
a wide variety of products, including the tetrahydrodibenzo-
pyran derivatives (e.g., tetrahydrocannabinol, cannabidiol)
and hexahydrodibenzopyran derivatives (e.g., nonnatural
R
HO
H
HO
H
HO 2'
O
H
1'
1
6
3
4
6'
OH
*
*
*
*
OH
OH
8
R
H
H
H
9
Machaeridiol C
R= OH Machaeridiol A
R= H Machaeridiol B
5, 6-seco-HHDBP's nucleus
R
HO
H
HO
H
HO
H
3
1
6
O
4a
10a
6a
9
8
*
*
*
*
O
H
O
H
O
R
R
H
R= H Machaeriol C
R=OH Machaeriol D
R= OH Machaeriol A
R= H Machaeriol B
trans-HHDBP's nucleus
Figure 1. Representative members of 5,6-seco-HHDBP’s and trans-HHDBP’s.
* Corresponding author. E-mail: shexg@lzu.edu.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.067

Q. Huang et al. / Tetrahedron 63 (2007) 1014–1021
1015
HO
H
HO
H
HO
H
O
OH
O
HO
H
H
H
Machaeriol D
Machaeridiol B
Machaeriol B
Scheme 1. The structures of (+)-Machaeriol D, (+)-Machaeridiol B, and (+)-Machaeriol B.
and trans-HHDBP’s Machaeriols A–D. The characteristic
biological activities and challenging molecular architecture
of this class of natural products have stimulated synthetic
efforts directed toward their total syntheses. Many different
approaches3 have been employed for the construction of the
skeleton. Taking the key step of hexahydrodibenzopyrans’
formation into consideration, the methods can be generally
classified into two different strategies: (1) the intramolecular
Diels–Alder cycloadditions and (2) the acid-catalyzed con-
densation of phenols with citronellal. The two strategies
suffer from the general problem of formation of hexahydro-
dibenzopyrans derivatives that is difficult to prevent under
these conditions. In our recent work of the total synthesis
of (+)-Machaeriol D (Scheme 1),4 a tandem SN20-hydrolysis
reaction5 sequence successfully established four stereocen-
ters at the 5,6-seco-HHDBP’s nucleus enantioselectively.
To further explore the scope and generality of this strategy,
a variety of large arylcyanocuprates were examined under
the optimized conditions. In this paper, we detail our re-
sults for the SN20-hydrolysis reaction of substituted arylcya-
nocuprates. To highlight the method, the above synthetic
strategy was used to assemble (+)-Machaeridiol B and (+)-
Machaeriol B.
ether 5. Compound 6 could be achieved through methyl xan-
thating of the corresponding reduced product of 5 and reduc-
tion via Barton radical deoxygenation7 in 59% yield for three
steps. After the success of deoxygenation, the TBS protect-
ing group was removed with TBAF in refluxing THF for 12 h
in 98% yield.8 In the course of removing hydroxyl group,
Barton radical deoxygenation was first tried, however, the
desired product was isolated in low yield. After considerable
experiment, we settled on a sequence that involved convert-
ing 7 to the corresponding methyl sulfonate in quantitative
yield. Thus, treatment of this methyl sulfonate with lithium
aluminum hydride in refluxing ether under argon for 8 h
afforded the important compound 8 in 80% yield.9
Having successfully obtained the precursor 8 from 7, we pro-
ceeded to synthesize (+)-Machaeridiol B and (+)-Machaeriol
B. For deprotecting the MOM group without cyclization,
LiBF4,10a PPTS,10b and NaHSO4$SiO210c have been attemp-
ted, but all the attempts were unsuccessful to obtain the 5,6-
seco-HHDBP’s nucleus. Finally, we found that in CH3CN/
CH2Cl2 (2:1) treatment of 8 with AlCl3 and NaI at 0 ꢁC could
afford (+)-Machaeridiol B.10d As soon as the substrate 8
disappeared, the reaction was quenched with ice water. In
this case, (+)-Machaeridiol Bcouldbe achievedin 50% yield.
If we let the mixed reaction to react for longer time, (+)-
Machaeriol B was obtained in 90% yield. The spectral prop-
erties of our synthetic products are identical with the natural
products.2
2. Results and discussion
The SN20-hydrolysis reaction of enol silyl ether6 of a,b-ep-
oxycyclohexanone 14 with a variety of large arylcyanocup-
rates was found to be a very general route (Table 1). The
unstable adducts 3a–3g, which were immediately subjected
to mild hydrolysis to afford 4a–4g with the desired four ste-
reocenters, have been prepared by the SN20-hydrolysis reac-
tion of 2a–2g in satisfactory yields in two steps (70–79%).
When the ortho- and para-methoxy arylcyanocuprates (en-
tries 2 and 3) were used, the electronic effect on the benzene
ring was proved to be a tiny effect on the reaction. When ste-
rically demanding arylcyanocuprates (entries 4 and 5) were
used, the reactions also provided the desired products in
good yields. To our delight, we found that the conjugative ef-
fect on the benzene ring (entries 6 and 7) was very few that
the desired crucial compounds 4f and 4g could be obtained
in 76 and 70% yields, respectively. When the arylcyanocup-
rate reagents were prepared, we have found that the concen-
tration of Grignard reagents (0.5 M) is important. We have
also found that the temperature of mixed arylcyanocuprate
reactions should be well controlled at ꢀ40 ꢁC and then
warmed to 0 ꢁC until CuCN disappeared absolutely.
3. Conclusion
In summary, a strategy for the construction of 5,6-seco-
HHDBP’s was developed and found to be general for various
arylcyanocuprates to optically active enol silyl ether of a,b-
epoxycyclohexanone. Utility of this strategy, the first total
synthesis of (+)-Machaeridiol B and (+)-Machaeriol B has
been facilely completed. This result indicated that the
SN20-hydrolysis reaction was useful for the construction of
5,6-seco-HHDBP’s and trans-HHDBP’s skeletons, impor-
tant structural frameworks in a wide range of bioactive com-
pounds. Further study to apply the present methodology for
the synthesis of other natural products is in progress in our
laboratory and will be reported in due course.
4. Experimental
4.1. General
With the above results in hand, the synthesis of (+)-Machaeri-
diol B and (+)-Machaeriol B was conducted (Scheme 2). The
secondary hydroxyl of 4g was easily protected as its TBS
Oxygen- and moisture-sensitive reactions were carried out
under argon atmosphere. Solvents were purified and dried by
standard methods prior to use. All commercially available

1016
Q. Huang et al. / Tetrahedron 63 (2007) 1014–1021
Table 1. The SN20-hydrolysis reaction of 1 with various large arylcyanocuprates
TMS
O
OTMS
R1
R2
Ar
THF, -78 °C
+
BrMg(CN)Cu
O
R3
O
HO
R4
2a-2g
1
3a-3g
2a R1=R2=R3=R4=H
2b R1=OMe, R2=R3=R4=H
2c R3=OMe, R1=R2=R4=H
2d R1=R4=OMe, R2=R3=H
Ar
KF, MeOH
2e R1=R4=OMOM, R2=H, R3=CH2OTBS
2f R3=(CH=CH)Ph, R1=R2=R4=H
2g R3=(CH=CH)Ph, R1=R4=OMOM, R2=H
HO
4a-4g
Entry
ArCu(CN)MgBr
Productsa
Yieldb (two steps) (%)
O
H
1
2a
79
HO
HO
H
4a
O
H
MeO
2
3
2b
2c
76
71
H
4b
OMe
O
H
HO
H
4c
MeO
O
H
MeO
4
5
2d
75
74
HO
H
4d
MOMO
OTBS
O
H
OMOM
2e
HO
H
4e
Ph
O
H
6
2f
76
70
HO
HO
H
4f
Ph
MOMO
O
H
7
2g
OMOM
H
4g
a
All reactions were carried out with 2 equiv of the freshly-prepared arylcyanocuprates reagents in the presence of 1 (1 equiv) at ꢀ78 ꢁC, warming the reaction
mixture to ꢀ10 ꢁC over 45 min, stirring for an additional 3 h at ꢀ10 ꢁC to 0 ꢁC, leading to the silyl enol ethers, which were immediately subjected to mild
hydrolysis to afford a-aryl ketones.
Isolated yields.
b

Q. Huang et al. / Tetrahedron 63 (2007) 1014–1021
1017
MOMO
O
H
1) LiAlH4, -30 °C, THF
2) NaH, CS2, MeI, 50 °C
MOMO
O
imidazole, TBSCl
H
DMF, DMAP, 93%
3) AIBN (cat.), n-Bu3SnH,
toluene, 90 °C
OMOM
HO
OMOM
H
TBSO
H
5
59% for 3 steps
4g
MOMO
H
MOMO
H
1) MsCl, Et3N, CH2Cl2, 0 °C
TBAF, THF
2) LiAlH4, ether, reflux, 24h
78% for Two steps
OMOM
reflux, 12h, 98%
OMOM
TBSO
HO
H
H
6
7
HO
H
50%
OH
H
MOMO
H
(+)-Machaeridiol B
Acid
AlCl3, NaI, 0 °C
OMOM
CH3CN:CH2Cl2 (2:1)
H
HO
H
8
90%
O
H
(+)-Machaeriol B
Scheme 2. Total synthesis of (+)-Machaeridiol B and (+)-Machaeriol B.
reagents were used without further purification unless
otherwise noted. Column chromatography was performed
on silica gel (200–300 mesh). Optical rotations were
measured on a precision automated polarimeter. Infrared
(1 mmol) in dry THF (2 mL) by cannula under argon. The
reaction mixture was allowed to warm to ꢀ10 ꢁC to 0 ꢁC
for 3 h. Ether was added, and the organic phase was washed
with saturated aqueous NH4Cl, dried (NaSO4), and evapo-
rated. Flash chromatography of the residue over silica gel,
using first 30:1 petroleum ether/EtOAc and then 10:1 petro-
leum ether/EtOAc, gave 3a–3g as a colorless oil.
1
spectra were recorded on a FTIR spectrometer. H and 13C
NMR spectra were recorded on 300 and 400 MHz spectrom-
eters. Chemical shifts are reported as d values relative to
internal chloroform (d 7.26 for 1H and 77.0 for 13C).
4.3. Synthesis of b-hydroxy ketone 4a–4g
4.1.1. Formation of ArMgBr. The system with a magnetic
stir bar, reflux condenser, a stopcock, and a 25-mL addition
funnel was charged with magnesium dust (2.2 mmol),
evacuated, and placed under argon. 1,2-Dibromoethane
(0.01 mL) was added via syringe to the magnesium suspen-
sion in dry THF (1 ml) to initiate Grignard formation, and
then a solution of substrates of ArBr (2 mmol) in dry THF
(3 ml) was added dropwise via addition funnel to the reflux-
ing mixture. After addition the solution was refluxed for
45 min, at that time Mg had been dissolved.
To a solution of silyl enol ethers 3a–3g in MeOH was added
KF, and the mixture was stirred at room temperature for
1 h. The solvent was removed in vacuo, and water was
added. The resulting mixture was extracted with EtOAc
(3ꢂ20 mL). The combined organic phases were dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification
of the residue through column chromatography on silica
gel (petroleum/EtOAc, 5:1) afforded 4a–4g as a colorless
oil.
4.1.2. Formation of the Cuprate. The aryl magnesium bro-
mide solution was added to a stirred and cooled (ꢀ40 ꢁC)
mixture of CuCN (2 mmol) in dry THF (2 ml) under argon.
The reaction mixture was gradually warmed to homogeneity
(0 ꢁC).
4.3.1. (2S,3R,5S,6S)-3-Hydroxy-2-methyl-6-phenyl-5-
(prop-1-en-2-yl)cyclohexanone 4a (Table 1, entry 1).
1
[a]2D5 ꢀ35 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3):
d 7.19–7.31 (m, 3H), 7.00 (d, J¼7.8 Hz, 2H), 4.61 (s, 2H),
3.50–3.59 (m, 2H), 2.53–2.69 (m, 2H), 2.51 (m, 1H), 2.17–
2.24 (m, 1H), 2.01 (q, J¼12.0 Hz, 1H), 1.57 (s, 3H), 1.17
(d, J¼6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 208.2,
144.4, 136.3, 129.3, 127.9, 126.8, 113.4, 74.6, 60.1, 53.7,
46.9, 40.6, 18.4, 10.7. HRMS calcd for C16H21O2 [M+H]+:
245.1542; found: 245.1545.
4.2. Synthesis of silyl enol ether 3a–3g
To a solution of arylcyanocuprates reagents 2a–2g (2 mmol)
at ꢀ78 ꢁC was added a solution of enol silyl ether epoxides 1

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Q. Huang et al. / Tetrahedron 63 (2007) 1014–1021
4.3.2. (2S,3R,5S,6S)-3-Hydroxy-6-(2-methoxyphenyl)-2-
methyl-5-(prop-1-en-2-yl)cyclohexanone 4b (Table 1,
128.6, 127.5, 126.4, 116.4, 112.1, 106.2, 95.2, 94.6, 73.8,
56.0, 53.2, 49.7, 44.0, 40.1, 18.4, 11.2. HRMS calcd for
C28H38NO6 [M+NH4]+: 484.2699; found: 484.2694.
1
entry 2). [a]2D5 ꢀ40 (c 1.0, CHCl3); H NMR (300 MHz,
CDCl3): d 7.20 (td, J¼6.9, 2.4 Hz, 1H), 6.83–6.97 (m, 3H),
4.60 (t, J¼1.8 Hz, 2H), 4.00 (d, J¼11.7 Hz, 1H), 3.75 (s,
3H), 3.60 (t, J¼10.5 Hz, 1H), 2.79 (td, J¼12.3, 3.3 Hz,
1H), 2.50–2.60 (m, 1H), 2.17–2.26 (m, 2H), 2.00 (q,
J¼12.0 Hz, 1H), 1.59 (s, 3H), 1.20 (d, J¼6.6 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): d 207.9, 157.0, 145.1, 130.1,
127.9, 125.3, 120.2, 112.6, 110.4, 74.5, 55.3, 53.6, 45.3,
40.7, 18.4, 10.8. HRMS calcd for C17H23O3 [M+H]+:
275.1648; found: 275.1646.
4.4. Compound 5
To a solution of 4g (1.23 g, 2.64 mmol) and imidazole
(360 mg, 5.28 mmol) in dry DMF (2 mL) at room tempera-
ture were added TBSCl (480 mg, 3.17 mmol) and DMAP
(cat.), and stirred for 3 h. The reaction mixture was then
diluted with ether, washed with water and brine. The com-
bined organic solution was dried over anhydrous Na2SO4
and concentrated in vacuo. Purification of the residue by
column chromatography on silica gel (petroleum/EtOAc,
15:1) afforded 5 (1.43 g, 93%) as a colorless oil. [a]2D5 ꢀ27
(c 1.0, CHCl3); IR (KBr) 3399, 2931, 2856, 1713, 1603,
4.3.3. (2S,3R,5S,6S)-3-Hydroxy-6-(4-methoxyphenyl)-2-
methyl-5-(prop-1-en-2-yl)cyclohexanone 4c (Table 1,
1
entry 3). [a]2D5 ꢀ32 (c 1.0, CHCl3); H NMR (300 MHz,
1
CDCl3): d 6.92 (d, J¼9.0 Hz, 2H), 6.83 (d, J¼9.0 Hz, 2H),
4.62 (s, 2H), 3.77 (s, 3H), 3.53 (d, J¼12.9 Hz, 2H), 2.51–
2.64 (m, 3H), 2.17–2.23 (m, 1H), 2.03 (q, J¼12.0 Hz, 1H),
1.57 (s, 3H), 1.17 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 208.4, 158.3, 144.6, 130.2, 128.4, 113.4, 74.6,
59.3, 55.0, 53.7, 47.1, 40.6, 18.4, 10.7. HRMS calcd for
C17H23O3 [M+H]+: 275.1648; found: 275.1651.
1467, 1450, 1253, 1038, 837, 775, 692 cmꢀ1; H NMR
(400 MHz, CDCl3): d 7.50 (d, J¼8.0 Hz, 2H), 7.35 (t,
J¼8.0 Hz, 2H), 7.23–7.27 (m, 1H), 7.05 (d, J¼1.6 Hz, 2H),
6.97 (d, J¼3.2 Hz, 2H), 5.10–5.19 (m, 4H), 4.54 (d, J¼
4.0 Hz, 2H), 4.11 (d, J¼11.6 Hz, 1H), 3.68 (td, J¼10.4,
4 Hz, 1H), 3.49 (s, 3H), 3.46 (s, 3H), 3.11 (td, J¼12.4,
3.6 Hz, 1H), 2.43–2.47 (m, 1H), 1.99–2.12 (m, 2H), 1.70
(s, 3H), 1.19 (d, J¼6.8 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 3H),
0.13 (s, 3H); 13C NMR (100 MHz, CDCl3): d 207.4, 156.5,
156.1, 145.9, 137.6, 137.3, 128.8, 128.6, 127.5, 126.5, 116.7,
111.9, 106.5, 106.3, 95.2, 94.8, 74.6, 56.1, 56.0, 53.9, 49.9,
44.0, 40.9, 25.8, 18.4, 18.0, 11.8, ꢀ4.4, ꢀ4.7. HRMS calcd
for C34H52NO6 Si [M+NH4]+: 598.3606; found: 598.3602.
4.3.4. (2S,3R,5S,6S)-3-Hydroxy-6-(2,6-dimethoxy-
phenyl)-2-methyl-5-(prop-1-en-2-yl)cyclohexanone 4d
1
(Table 1, entry 4). [a]2D5 ꢀ28 (c 1.0, CHCl3); H NMR
(300 MHz, CDCl3): d 7.14 (t, J¼6.4 Hz, 1H), 6.51 (d, J¼
7.5 Hz, 2H), 4.45 (d, J¼11.1 Hz, 2H), 4.09 (d, J¼12.3 Hz,
1H), 3.72 (s, 6H), 3.10 (td, J¼12.6, 3.3 Hz, 1H), 2.31–2.38
(m, 1H), 2.25 (d, J¼4.2 Hz, 1H), 2.15 (dt, J¼12.9, 3.6 Hz,
1H), 2.03 (q, J¼12.0 Hz, 1H), 1.88 (s, 1H), 1.63 (s, 3H),
1.24 (d, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 207.7, 158.1, 146.0, 128.0, 115.3, 111.5, 104.5, 103.7,
73.9, 55.6, 53.2, 49.2, 43.9, 40.2, 17.9, 11.2. HRMS calcd
for C18H25O4 [M+H]+: 305.1754; found: 305.1753.
4.5. Compound 6
(1) To a slurry solution of compound 5 (0.72 g, 1.24 mmol) in
dry THF (5 mL) at ꢀ30 ꢁC was added slowly a solution of
LiAlH4 (51.8 mg, 1.36 mmol) in THF. The reaction mixture
was then stirred at this point for 1 h, judged by TLC. H2O
(1 mL) was added carefully. The resulting slurry was filtered
off and washed with EtOAc (100 mL). The combined organic
solution was dried over anhydrous Na2SO4 and concentrated
in vacuo. Purification of the residue by column chromato-
graphy on silica gel (petroleum/EtOAc, 10:1) afforded the al-
cohol (0.51 g, 70%) as a white amorphous solid. [a]2D5 ꢀ6 (c
1.0, CHCl3); IR (KBr) 3506, 2903, 1602, 1571, 1466, 1451,
4.3.5. (2S,3R,5S,6S)-3-Hydroxy-2-methyl-5-(prop-1-en-
2-yl)-6-(4-styrylphenyl)cyclohexanone 4f (Table 1, entry
6). [a]2D5 ꢀ26 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.50 (d, J¼8.0 Hz, 2H), 7.43 (d, J¼8.0 Hz, 2H), 7.36 (t,
J¼8.0 Hz, 2H), 7.25 (td, J¼8.4, 0.8 Hz 1H), 7.08 (s, 2H),
7.00 (d, J¼8.4 Hz, 2H), 4.63 (q, J¼1.6 Hz, 2H), 3.57–3.61
(m, 2H), 2.57–2.66 (m, 2H), 2.22–2.26 (m, 2H), 2.03 (q,
J¼12.0 Hz, 1H), 1.59 (s, 3H), 1.20 (d, J¼6.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 207.9, 144.3, 137.4, 135.9,
135.9, 129.7, 128.6, 128.5, 128.3, 127.5, 126.4, 126.2,
113.6, 74.7, 59.9, 53.8, 47.0, 40.6, 18.5, 10.7. HRMS calcd
for C24H27O2 [M+H]+: 347.2012; found: 347.2010.
1251, 1039, 922, 840, 773 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d 7.51 (d, J¼8.4 Hz, 2H), 7.36 (t, J¼8.0 Hz, 2H),
7.24–7.28 (m, 1H), 7.07 (d, J¼16.4 Hz, 1H), 7.02 (d, J¼
16.4 Hz, 1H), 6.98 (d, J¼8.0 Hz, 2H), 5.18–5.28 (m, 4H),
4.58 (s, 1H), 4.48 (d, J¼1.2 Hz, 1H), 3.76 (t, J¼9.6 Hz,
1H), 3.57 (s, 3H), 3.55 (s, 3H), 3.42 (t, J¼10.8 Hz, 2H),
3.03 (td, J¼12.0, 2.8 Hz, 1H), 1.87 (dt, J¼12.0, 4.0 Hz,
1H), 1.51–1.67(m, 6H), 1.18 (d, J¼6.4 Hz, 3H), 0.95
(s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 157.7, 157.2, 147.3, 137.5, 137.2, 128.8, 128.6,
128.5, 127.6, 126.5, 117.9, 110.6, 107.1, 106.6, 95.7, 94.6,
74.6, 74.4, 56.3, 56.2, 48.2, 46.0, 42.8, 41.7, 25.9, 18.7,
18.1, 15.2, ꢀ4.0, ꢀ4.6. HRMS calcd for C34H54NO6Si
[M+NH4]+: 576.3763; found: 576.3760.
4.3.6. (2S,3S,5R,6S)-2-(2,6-Bis(methoxymethoxy)-4-styryl-
phenyl)-5-hydroxy-6-methyl-3-(prop-1-en-2-yl)cyclo-
hexanone 4g (Table 1, entry 7). [a]2D5 ꢀ24 (c 1.0, CHCl3);
IR (KBr) 3463 (–OH), 2932, 1707, 1603, 1576, 1450, 1037,
1
922, 823, 753, 693 cmꢀ1; H NMR (400 MHz, CDCl3):
d 7.50 (d, J¼7.2 Hz, 2H), 7.35 (t, J¼7.6 Hz, 2H), 7.25 (t, J¼
7.6 Hz, 1H), 7.08 (s, 2H), 6.97 (s, 2H), 5.08–5.19 (m, 4H),
4.54 (d, J¼12.0 Hz, 2H), 4.09 (d, J¼12.0 Hz, 1H), 3.72 (td,
J¼10.8, 4.0 Hz, 1H), 3.46 (s, 6H), 3.13 (td, J¼12.4, 3.6 Hz,
1H), 2.38–2.42 (m, 1H), 2.20 (dt, J¼12.4, 3.6 Hz, 1H),
2.06 (d, J¼4.8 Hz, 1H), 1.99 (q, J¼12.0 Hz, 1H), 1.69
(s, 3H), 1.26 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 207.1, 156.5, 155.9, 145.5, 137.6, 137.2, 128.7,
(2) To a solution of this alcohol (0.51 g, 0.87 mmol) in dry
THF (6 mL) at room temperature was added NaH (57% sus-
pension in mineral oil, 109 mg, 2.18 mmol) under an argon
atmosphere. The reaction mixture was stirred for 30 min
before CS2 (1.5 mL) was introduced into the flask and was

Q. Huang et al. / Tetrahedron 63 (2007) 1014–1021
1019
heated to 50 ꢁC for 2 h. Then, MeI (0.54 mL, 8.7 mmol) was
added and stirred for another 5 h. After cooling to ambient
temperature, the reaction mixture was filtered and
concentrated. Purification of the residue by column chroma-
tography on silica gel (petroleum/EtOAc, 50:1) afforded the
xanthate ester (0.54 g, 93%) as a yellow oil. [a]2D5 +23 (c 1.0,
CHCl3); IR (KBr) 3388, 2953, 2930, 1602, 1574, 1466, 1220,
155.8, 148.1, 137.3, 136.5, 128.6, 128.3, 127.5, 126.4,
121.7, 110.2, 106.6, 106.5, 95.2, 94.6, 76.3, 56.1, 56.1,
46.2, 41.8, 40.6, 37.9, 37.3, 18.9, 18.3. HRMS calcd for
C28H40NO5 [M+NH4]+: 470.2949; found: 470.2943.
4.7. Compound 8
1
1044, 839, 774, 692 cmꢀ1; H NMR (400 MHz, CDCl3):
(1) To a solution of 7 (210 mg, 0.46 mmol) and triethylamine
(0.13 mL, 0.93 mmol) in CH2Cl2 (2 mL) at 0 ꢁC was added
MsCl (0.06 mL, 0.70 mmol) and stirred for 5 min. The reac-
tion was then quenched with water and extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were washed with
brine and dried over anhydrous Na2SO4, filtered, and evapo-
rate to dryness. Purification of the residue through column
chromatography on silica gel (petroleum/EtOAc, 5:2)
afforded methyl sulfonated compound (238 mg, 97%) as
a white amorphous solid. [a]2D5 ꢀ7 (c 1.0, CHCl3); IR
(KBr) 3372, 2925, 1733, 1602, 1450, 1354, 1172, 1039,
d 7.49 (d, J¼8.0 Hz, 2H), 7.34 (t, J¼8.0 Hz, 2H), 7.22–7.27
(m, 1H), 7.04 (d, J¼16.0 Hz, 1H), 6.98 (d, J¼16.0 Hz, 1H),
6.90 (s, 2H), 6.26 (t, J¼10.4 Hz, 1H), 5.17–5.28 (m, 4H),
4.66 (s, 1H), 4.53 (d, J¼1.2 Hz, 1H), 3.71 (t, J¼10.8 Hz,
1H), 3.62 (s, 3H), 3.57 (s, 3H), 3.51 (m, 1H), 3.18 (td,
J¼13.0, 2.8 Hz, 1H), 2.35 (s, 3H), 1.91 (m, 2H), 1.62–1.70
(m, 4H), 1.06 (d, J¼6.4 Hz, 3H), 0.95 (s, 9H), 0.13 (s, 6H);
13C NMR (100 MHz, CDCl3): d 215.7, 157.9, 156.9, 146.6,
137.4, 137.2, 128.8, 128.6, 128.3, 127.4, 126.4, 116.0, 111.2,
106.3, 106.1, 95.5, 95.3, 86.0, 73.9, 56.3, 56.2, 47.1, 42.7,
42.5, 41.4, 25.8, 18.7, 18.5, 18.0, 15.1, ꢀ4.0, ꢀ4.7. HRMS
for C36H53O6S2Si [M+H]+: 673.3054; found: 673.3051.
1
920, 823, 753 cmꢀ1; H NMR (400 MHz, CDCl3): d 7.48
(d, J¼7.6 Hz, 2H), 7.34 (t, J¼7.6 Hz, 2H), 7.22–7.27 (m,
1H), 7.04 (d, J¼16.0 Hz, 1H), 6.98 (d, J¼16.0 Hz, 1H),
6.95 (d, J¼12.0 Hz, 2H), 5.20–5.26 (m, 4H), 4.59 (s, 1H),
4.50 (s, 1H), 4.46 (s, 1H), 3.55 (s, 3H), 3.51 (s, 3H), 3.39 (t,
J¼8.4 Hz, 1H), 3.17 (t, J¼12.0 Hz, 1H), 3.05 (s, 3H), 2.26
(d, J¼12.0 Hz, 1H), 1.71–1.91 (m, 4H), 1.53 (s, 3H), 1.04
(d, J¼5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 157.4,
155.8, 146.8, 137.2, 136.8, 128.6, 128.5, 127.5, 126.5,
120.5, 111.1, 106.5, 95.2, 94.6, 87.4, 56.2, 56.1, 45.8, 39.3,
38.9, 38.1, 37.4, 36.9, 18.8, 18.5. HRMS calcd for
C29H42NO7S [M+NH4]+: 548.2682; found: 548.2724.
(3) To a solution of the xanthate ester (0.45 g, 0.67 mmol) in
dry toluene (2 mL) at room temperature were sequentially
added AIBN (cat.) and n-Bu3SnH (neat, 0.45 mL,
2.68 mmol) under an argon atmosphere. The mixture was
carefully deoxygenated by bubbling argon through it for
30 min. The reaction flask was then immersed into a pre-
heated oil bath (90 ꢁC) and the mixture was stirred at this
temperature for 30 min. After cooling to ambient tempera-
ture, the solvent was evaporated. Purification of the residue
by column chromatography on silica gel (petroleum/EtOAc,
30:1) afforded 6 (342 mg, 90%) as a white amorphous solid.
[a]2D5 ꢀ3 (c 1.0, CHCl3); IR (KBr) 3363, 2952, 2928, 1602,
(2) To a solution of this methyl sulfonated compound
(0.753 mg, 1.42 mmol) in dry ether (3 mL) was added lith-
ium aluminum hydride (0.267 mg, 5.68 mmol) under argon.
This mixture was stirred at the reflux temperature for 8 h,
cooled, and treated with saturated ammonium chloride solu-
tion. The inorganic solids were separated by filtration and
washed with ether (5ꢂ20 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and
filtered. The solvent was concentrated in vacuo. Purification
of the residue by column chromatography on silica gel (pe-
troleum/EtOAc, 50:1) afforded 8 (495 mg, 80%) as a white
amorphous solid. [a]2D5 +13 (c 1.0, CHCl3); IR (KBr) 3386,
2948, 2920, 1901, 1571, 1449, 1152, 1041, 923, 823,
1
1571, 1452, 1253, 1043, 924, 835, 773 cmꢀ1; H NMR
(400 MHz, CDCl3): d 7.48–7.54 (m, 2H), 7.31–7.39 (m,
2H), 7.22–7.27 (m, 1H), 7.06 (s, 2H), 6.94 (d, J¼10.8 Hz,
2H), 5.17–5.27 (m, 4H), 4.58 (s, 1H), 4.46 (s, 1H), 3.57 (s,
3H), 3.54 (s, 3H), 3.30–3.53 (m, 2H), 3.07 (t, J¼11.2 Hz,
1H), 1.50–1.89 (m, 1H), 1.74–11.77 (m, 1H), 1.51–1.64
(m, 6H), 0.97 (d, J¼6.4 Hz, 3H), 0.90 (m, 9H), 0.11 (s,
6H); 13C NMR (100 MHz, CDCl3): d 157.5, 155.8, 148.5,
137.3, 136.4, 128.7, 128.6, 128.3, 127.4, 126.4, 122.1,
110.0, 106.6, 95.3, 94.6, 77.0, 56.1, 46.4, 42.3, 40.9, 38.0,
37.4, 25.9, 19.1, 18.9, 18.1, ꢀ3.9, ꢀ4.6. HRMS calcd for
C34H51O5Si [M+H]+: 567.3507; found: 567.3500.
750 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 7.51 (d, J¼
8.0 Hz, 2H), 7.33 (t, J¼8.0 Hz, 2H), 7.25 (m, 1H), 7.05 (s,
2H), 6.96 (d, J¼4.4 Hz, 2H), 5.20–5.28 (m, 4H), 4.59 (d,
J¼2.4 Hz, 1H), 4.46 (d, J¼1.2 Hz, 1H), 3.57 (s, 3H), 3.52
(s, 3H), 3.37 (td, J¼11.2, 4.0 Hz, 1H), 2.96 (td, J¼12.0,
3.6 Hz, 1H), 1.62–1.82 (m, 5H), 1.59 (s, 3H), 1.46 (qd,
J¼13.2, 3.2 Hz, 1H), 1.12 (qd, J¼9.2, 3.6 Hz, 1H), 0.94
(m, 3H); 13C NMR (100 MHz, CDCl3): d 157.6, 155.7,
149.7, 137.4, 136.2, 128.8, 128.6, 128.1, 127.4, 126.4,
123.1, 109.5, 106.6, 95.2, 94.6, 56.1, 56.0, 47.6, 39.4, 38.4,
35.4, 33.3, 33.2, 22.6, 19.2. HRMS calcd for C28H40NO4
[M+NH4]+: 454.3000; found: 454.2996.
4.6. Compound 7
To a solution of protected 6 (1.39 g, 1.25 mmol) in dry THF
(10 mL) was added TBAF (1.16 g). The reaction mixturewas
stirred at ambient temperature for 12 h. The organic solution
was concentrated in vacuo and purification of the residue by
column chromatography on silica gel (petroleum/EtOAc,
5:2) afforded the alcohol 7 (1.25 g, 98%) as a white amor-
phous solid. [a]2D5 +10 (c 1.0, CHCl3); IR (KBr) 3396,
2950, 2926, 1601, 1571, 1449, 1152, 1040, 921, 824, 732,
693 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 7.48 (d, J¼
8.0 Hz, 2H), 7.34 (t, J¼8.0 Hz, 2H), 7.24 (t, J¼6.8 Hz,
1H), 7.06 (d, J¼2.8 Hz, 2H), 6.94 (s, 2H), 5.17–5.28 (m, 4H),
4.57 (s, 1H), 4.46 (s, 1H), 3.55 (s, 3H), 3.48 (s, 3H), 3.35–3.40
(m, 2H), 3.13 (t, J¼12.0 Hz, 1H), 1.99 (dt, J¼12.0, 3.2 Hz,
1H), 1.78 (q, J¼12.0 Hz, 1H), 1.46–1.69 (m, 7H), 1.05 (d,
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 157.4,
4.8. (D)-Machaeridiol B
To a solution of compound 8 (55 mg, 0.126 mmol) in
CH3CN/CH2Cl2 (2:1) at 0 ꢁC was added NaI (299 mg,
1.89 mmol) and AlCl3 (253 mg, 1.89 mmol). As soon as
compound 8 disappeared, the reaction was quenched with

1020
Q. Huang et al. / Tetrahedron 63 (2007) 1014–1021
(b) Gaoni, Y.; Mechoulam, R. J. Am. Chem. Soc. 1971, 93,
217; For natural cannabidiol (CBD), see: (c) Mechoulam, R.;
Shvo, Y. Tetrahedron 1963, 19, 2073; (d) Mechoulam, R.;
Gaoni, Y. Tetrahedron Lett. 1967, 1109; For nonnatural hexa-
hydrocannabinol (HHC), see: (e) Edery, H.; Grunfeld, Y.;
Ben-Zvi, Z.; Mechoulam, R. Ann. N.Y. Acad. Sci. 1971, 191,
40; (f) Mechoulam, R.; Lander, N.; Varkony, T. H.; Kimmel,
I.; Becker, O.; Ben-Zvi, Z. J. Med. Chem. 1980, 23, 1068.
2. Muhammad, I.; Li, X. C.; Jacob, M. R.; Tekwani, B. L.;
Dunbar, D. C.; Ferreira, D. J. Nat. Prod. 2003, 66, 804.
ice water and extracted with EtOAc (3ꢂ20 mL). The com-
bined organic layers were washed with brine, dried over an-
hydrous Na2SO4, filtered, and evaporated. Purification of the
residue through column chromatography on silica gel (petro-
leum/EtOAc, 4:1) afforded (+)-Machaeridiol B (22 mg,
50%) as a yellow amorphous solid. [a]2D5 +14.5 (c 0.53,
MeOH) {lit.2 [a]D25 +17.8 (c 0.53, MeOH)}; IR (KBr)
3386, 2919, 2851, 1612, 1578, 1449, 1424, 1370, 1254,
1
1117, 1020, 960, 749 cmꢀ1; H NMR (400 MHz, acetone-
d6): d 8.10 (s, 2H), 7.50–7.51 (m, 2H), 7.31–7.35 (m, 2H),
7.21–7.25 (m, 1H), 6.96 (m, 2H), 6.58 (d, J¼1.6 Hz, 1H),
6.53 (d, J¼1.6 Hz, 1H), 4.65 (d, J¼2.0 Hz, 1H), 4.37 (m,
1H), 3.34 (m, 1H), 3.14 (m, 1H), 1.78–1.86 (m, 1H), 1.74–
1.78 (m, 1H), 1.67–1.72 (m, 1H), 1.61(s, 3H), 1.58 (m,
1H), 1.41–1.54 (m, 2H), 1.05–1.45 (m, 1H), 0.91 (d, J¼
6.4 Hz, 3H); 13C NMR (100 MHz, acetone-d6): d 158.2,
156.6, 150.7, 138.6, 136.5, 129.9, 129.5, 128.1, 128.1,
127.2, 119.6, 109.9, 107.1, 106.2, 48.0, 40.0, 38.9, 36.2,
34.2, 34.0, 23.03, 19.5. HRMS calcd for C24H27O2
[MꢀH]+: 347.2011; found: 347.2017.
3. For total syntheses of THC and CBD, see: (a) Razdan, R. K.
The Total Synthesis of Natural Products; ApSimon, J., Ed.;
Wiley: New York, NY, 1981; Vol. 4, pp 185–262; (b)
Mechoulam, R.; McCallum, N. K.; Burstein, S. Chem. Rev.
1976, 76, 1; (c) Childers, W. E.; Pinnick, H. W. J. Org.
Chem. 1984, 49, 5276; (d) Crombie, L.; Crombie, W. M. L.;
Jamieson, S. V.; Palmer, C. J. J. Chem. Soc., Perkin Trans. 1
1988, 1243; (e) Evans, D. A.; Shaughnessy, E. A.; Barnes,
D. M. Tetrahedron Lett. 1997, 38, 3193; (f) Crombie, L.;
Crombie, W. M. L.; Palmer, C. J.; Jamieson, S. V.
Tetrahedron Lett. 1983, 24, 3129; (g) Rickards, R. W.;
Ronnenberg, H. J. Org. Chem. 1984, 49, 572; (h) Baek,
S.-H.; Srebnik, M.; Mechoulam, R. Tetrahedron Lett. 1985,
26, 1083; (i) Vaillancourt, V.; Albizati, K. F. J. Org. Chem.
1992, 57, 3627; For total syntheses of HHC, see: (j) Tietze,
L.-F.; Kiedrowski, G. v.; Berger, B. Angew. Chem., Int. Ed.
Engl. 1982, 21, 221; (k) Lu, Z.; Sato, N.; Inoue, S.; Sato, K.
Chem. Lett. 1992, 1237; (l) Casiraghi, G.; Cornia, M.;
Casnati, G.; Fava, G. G.; Belicchi, M. F. J. Chem. Soc., Chem.
Commun. 1986, 271; (m) Cornia, M.; Casiraghi, G.; Casnati,
G.; Zetta, L. Gazz. Chim. Ital. 1989, 119, 329; (n) Marino,
J. P.; Dax, S. L. J. Org. Chem. 1984, 49, 3671; (o) Talley, J. J.
J. Org. Chem. 1985, 50, 1695; (p) Wang, T.; Burgess, J. P.;
Reggio, P. H.; Seltzman, H. H. Synth. Commun. 2000, 30, 1431.
4. Wang, Q. L.; Huang, Q. G.; Chen, B.; Lu, J. P.; Wang, H.; She,
X. G.; Pan, X. F. Angew. Chem., Int. Ed. 2006, 22, 3651.
5. For a review on SN20 reaction, see: (a) Marshall, J. A. Chem.
Rev. 1989, 89, 1503; For recent references on SN20 reaction,
see: (b) Li, L.; Rayabarapu, D. K.; Nandi, M.; Cheng, C.
Org. Lett. 2003, 5, 1621; (c) Smith, A. B., III; Pitram, S. M.;
Gaunt, M. J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124,
4.9. (D)-Machaeriol B
To a solution of compound 8 (55 mg, 0126 mmol) in CH3CN/
CH2Cl2 (2:1) at 0 ꢁC were added NaI (299 mg, 1.89 mmol)
and AlCl3 (253 mg, 1.89 mmol), and the resulting mixture
was stirred for another 5 min. The reaction was quenched
with ice water and extracted with EtOAc (3ꢂ10 mL). The
combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and evaporated. Purifica-
tion of the residue through column chromatography on silica
gel (petroleum/EtOAc 5:1) afforded (+)-Machaeriol B
(40 mg, 90%) as a yellow amorphous solid. [a]2D5 +116 (c
0.36, MeOH) {lit.2 [a]2D5 +115.4 (c 0.39, MeOH)}; IR
(KBr) 3381, 2865–2976, 1614, 1509, 1451, 1420, 1355,
1323, 1267, 1138, 732 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 7.45 (d, J¼8.0 Hz, 2H), 7.33 (t, J¼8 Hz, 2H), 7.24 (t, J¼
7.2 Hz, 1H), 6.98 (d, J¼16.0 Hz, 1H), 6.89 (d, J¼16.0 Hz,
1H), 6.62 (d, J¼1.2 Hz, 1H), 6.40 (d, J¼1.2 Hz, 1H), 5.15
(s, 1H), 3.08 (d, J¼13.6 Hz, 1H), 2.51 (td, J¼9.8, 2.4 Hz,
1H), 1.84–1.87 (m, 2H), 1.64–1.66 (m, 1H), 1.50 (t, J¼
9.6 Hz, 1H), 1.41 (s, 3H), 1.12 (s, 3H), 0.95 (d, J¼6.8 Hz,
3H), 0.80 (q, J¼12.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 155.3, 155.1, 137.3, 136.7, 128.6, 128.5, 128.1,
127.5, 126.5, 113.0, 108.5, 105.6, 77.2, 49.0, 38.8, 35.6,
35.4, 32.8, 28.0, 27.7, 22.6, 19.0. HRMS calcd for
C24H27O2 [MꢀH]+: 347.2017; found: 347.2017.
ꢀ
14516; (d) Spino, C.; Beaulieu, C.; Lafreniere, J. J. Org.
Chem. 2000, 65, 7091; (e) Wang, X.; Wu, Y.; Jiang, S.;
Singh, G. J. Org. Chem. 2000, 65, 8146; (f) Xie, C.; Nowak,
P.; Kishi, Y. Org. Lett. 2002, 4, 4427; (g) Iura, Y.; Sugahara,
T.; Ogasawara, K. Org. Lett. 2001, 3, 291; (h) Harrington-
Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel,
P. Org. Lett. 2003, 5, 2111; (i) Soorukram, D.; Knochel, P.
Org. Lett. 2004, 6, 2409; (j) Calaza, M. I.; Yang, X.;
Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 529.
Acknowledgements
6. (a) Marino, J. P.; Hatanaka, N. J. Org. Chem. 1979, 44, 4467;
(b) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. J. Am.
We are grateful for the financial support by the NSFC (no.
20572037, 20572036, QT program). The Special Doctorial
Program Funds of the Ministry of Education of China
(20040730008), GanSu Science Foundation (no. 3ZS051-
A25-004), Program for New Century Excellent Talents in
University (NCET-05-0879) and the key grant project of
Chinese ministry of Education (no.105169).
ꢁ
Chem. Soc. 1981, 103, 2114; (c) Marino, J. P.; Jaen, J. C.
J. Am. Chem. Soc. 1982, 104, 3165; (d) Marino, J. P.; Kelly,
M. G. J. Org. Chem. 1981, 46, 4389; (e) Marino, J. P.;
Pradilla, F.; Laborde, E. J. Org. Chem. 1987, 52, 4898; (f)
Clive, D. L. J.; Wickens, P. L.; Silva, G. V. J. J. Org. Chem.
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Trans. 1 1975, 1574; (b) Barton, D. H. R.; Lobberding,
D. C. A.; Zard, S. Z. Tetrahedron 1986, 42, 2329; (c) For
a review, see: Crich, D.; Quintero, L. Chem. Rev. 1989, 89,
1413.
References and notes
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Mechoulam, R. J. Am. Chem. Soc. 1964, 86, 1646;

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