Enantioselective synthesis of the individual stereoisomers of a brassinolide mimetic

Article abstract of DOI:10.1016/j.tetasy.2004.01.029

The syntheses of all four stereoisomers of a nonsteroidal mimetic of the phytohormone brassinolide are reported. These are: (+)-(6S,7R,6′S, 7′)-, (-)-(6R,7S,6′R,7′)-, (+)-(6S,7R,6′R,7′)-, and (-)-(6R,7S,6′S,7′R)-1-[1-(4,6,7-trihydroxy-5,6,7,8- tetrahydron

Full text of DOI:10.1016/j.tetasy.2004.01.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 873–880
Enantioselective synthesis of the individual stereoisomers
of a brassinolide mimetic
Thomas G. Back,a,* Michael A. Bey,a Masood Parveza and Richard P. Pharisb
aDepartment of Chemistry, University of Calgary, 2500 University Drive, NW, Calgary, Alberta, Canada T2N 1N4
bDepartment of Biological Sciences, University of Calgary, 2500 University Drive, NW, Calgary, Alberta, Canada T2N 1N4
Received 11 December 2003; accepted 20 January 2004
Abstract—The syntheses of all four stereoisomers of a nonsteroidal mimetic of the phytohormone brassinolide are reported. These
are: (+)-(6S,7R,60S,70R)-, ())-(6R,7S,60R,70S)-, (+)-(6S,7R,60R,70S)-, and ())-(6R,7S,60S,70R)-1-[1-(4,6,7-trihydroxy-5,6,7,8-tetra-
hydronaphthyl)]-2-[10-(60,70-dihydroxy-50,60,70,80-tetrahydronaphthyl)]ethyne.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the high cost of brassinosteroids, commercial applica-
tions nevertheless remain very limited.
Brassinolide 1 is a phytohormone that was first isolated
from Brassica napus pollen in 1979 by Grove et al.,1 who
elucidated its structure and reported that 1 displayed
biological activity at doses as low as 1 ng per individual
plant when applied exogenously to certain plant species.
Since then, a variety of other naturally-occurring bras-
sinosteroids have been discovered, although 1 is gener-
ally considered to be the most potent member of this
family. Brassinolide and its congeners have been re-
ported to increase the yields of numerous commercially
important crops, as well as to improve their resistance to
stress caused by temperature extremes, drought, and
salinity.2–4 Extensive studies have been directed toward
the natural occurrence, biosynthesis, metabolism,
molecular biology, physiological effects, and potential
practical applications of these compounds.2–4 Although
several synthetic approaches to 1 and other brassino-
steroids have made these compounds available,5–7 the
high cost of synthetic brassinosteroids and their very
low natural abundance in plants have created formida-
ble obstacles to their large-scale preparation and com-
mercial exploitation. The discovery of more strongly
bioactive synthetic derivatives,8 as well as the synergy of
brassinosteroids with less expensive auxins such as
indole-3-acetic acid (IAA) and naphthaleneacetic acid
(NAA),9–11 have lowered the threshold of detectable
activity to ca. 1 pg/plant. While these advances mitigate
Structure–activity relationships (SAR) of brassinoster-
oids have been investigated by several groups12–17 and
considerable insight has been gained into the structural
requirements of highly bioactive brassinosteroids. As
part of such studies, we have prepared several dozen
modified analogues12 and subjected them to the rice leaf
lamina inclination bioassay,9 a technique that provides a
rapid and highly sensitive method for comparing the
bioactivities of various brassinosteroid structures. Based
on the results of SAR studies, we recently designed a
series of nonsteroidal mimetics of 1 that contain sub-
units bearing key functional groups mimicking those of
1. The subunits are joined by rigid linkers of appropriate
length, thereby generating structures that allow super-
imposition of the key substituents upon their counter-
parts in the minimum energy conformation of 1.18 In
addition to the diol groups, the presence of a polar
functionality on the B-ring is necessary for bioactivity.19
Although the lactone moiety of 1 is optimal for this
purpose, bioactivity is also observed in brassinosteroids
containing other polar groups, including C-6 alcohols
and ketones.19;20 The relatively simple structures of the
mimetics facilitates their synthesis, thus potentially
lowering their cost compared to that of natural bras-
sinosteroids. Among the first series of mimetic structures
that were synthesized and subjected to the rice leaf
lamina bioassay, two compounds, 2 and 3, displayed
significant bioactivity when coapplied with IAA. They
comprise the first nonsteroidal mimetics of brassino-
lide.18
* Corresponding author. Tel.: +1-403-220-6256; fax: +1-403-289-9488;
e-mail: tgback@ucalgary.ca
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.029

874
T. G. Back et al. / Tetrahedron: Asymmetry 15 (2004) 873–880
OH
HO
OH
Mimetic 2a
OH
HO
OH
HO
O
O
OH
O
OH
HO
OH
Brassinolide 1
OH
Mimetic 3a
OH
O
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
OH
OH
(-)-2a
Figure 1. Stereoisomers of mimetic 2 and the superimposability of key groups (shown in bold) of mimetics 2a and 3a with those of brassinolide 1.
OH
OH
(+)-2a
(+)-2b
(-)-2b
Figure 1 shows the respective stereoisomers of two such
mimetics 2a and 3a, where close superimposition of the
two vicinal diol moieties is possible with those of 1.
Moreover, the phenolic hydroxyl or ketone groups of 2a
and 3a, respectively, superimpose upon the lactone
moiety of 1. However, both 2 and 3 were originally
obtained and assayed as mixtures of inseparable stereo-
isomers. Since individual stereoisomers often have
strikingly different biological properties, we considered it
of importance to synthesize and assay each stereoisomer
separately. Herein we report the diastereo- and enantio-
selective preparation of all four stereoisomers of mimetic
2 (two diastereomers 2a and 2b, each consisting of a pair
of enantiomers).
2. Results and discussion
Subunits 5 and 8, containing the key vicinal cis-diol
moieties, were first prepared from iodide 421 and acetate
7,22 respectively, by Sharpless asymmetric dihydroxyl-
ation.23 Unfortunately, enantioselectivity was too low for
the purpose at hand. Thus, the asymmetric dihydroxyl-
ation of 4 with AD-mix-a and AD-mix-b (as purchased
from the Aldrich Chemical Co.) afforded enantiomeric
excesses (eeÕs) of 74% for ())-5 and 70% for (+)-5,
respectively. The similar treatment of 7 with AD-mix-a
and AD-mix-b provided eeÕs of 50% for ())-8 and 58%
for (+)-8, respectively. The racemic diols 518 and 824
were therefore obtained by nonasymmetric osmium
tetroxide-catalyzed dihydroxylation and resolved via
their diesters 6 and 9, prepared with (R)- and (S)-(O)-
acetylmandelic acid (AMA),25 as shown in Scheme 1. In
each case, the less soluble mandelate diastereomer was
subjected to repeated recrystallization until NMR
analysis revealed the absence of the more soluble dia-
stereomer. The absolute configurations of the diol car-
binol stereocenters of mandelates ())-6 and ())-9 were
established by X-ray crystallography with their ORTEP
diagrams shown in Figures 2 and 3, respectively. Crys-
tallographic data (excluding structure factors) for
structures ())-6 and ())-9 herein have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 225578 and
OH
OH
HO
HO
O
Brassinolide 1
O
O
H
OH
OH
OH
OH
H
H
HO
HO
HO
HO
H
O
OH
2 (mixture of cis-diol
3 (mixture of cis-diol
isomers)
isomers)

T. G. Back et al. / Tetrahedron: Asymmetry 15 (2004) 873–880
875
OAc
O
Ph
KOH
MeOH
R
1. DCC, DMAP,
(R)-AMA
O
O
OH
OH
R
S
2. Recrystallization
from EtOH
R
Ph
I
I
O
OH
OH
1. DCC, DMAP,
OAc
OAc
(-)-6 32%
(-)-5 98%
OsO4
NMO
O
I
I
Ph
S
4
(+/-)-5 87%
KOH
MeOH
OH
OH
O
O
(S)-AMA
S
R
2. Recrystallization
from EtOH
S
Ph
I
I
O
OAc
(+)-6 25%
(+)-5 93%
OAc
O
R
Ph
1. DCC, DMAP,
(R)-AMA
KOH
MeOH
O
R
S
O
HO
2. Recrystallization
from MeOH
HO
R
OAc
Ph
OH
O
HO
HO
OAc
OAc
(-)-10 95%
(-)-9 26%
OsO4
NMO
OAc
AcO
O
7
Ph
S
(+/-)-8 86%
KOH
MeOH
1. DCC, DMAP,
(S)-AMA
HO
HO
O
S
R
2. Recrystallization
from EtOH
O
S
OAc
OH
OAc
Ph
O
AMA =
Ph
CO2H
OAc
(+)-9 23%
(+)-10 93%
Scheme 1.
Figure 2. ORTEP diagram of ())-6.
Figure 3. ORTEP diagram of ())-9.

876
T. G. Back et al. / Tetrahedron: Asymmetry 15 (2004) 873–880
CCDC 225577, respectively. The enantioenriched diols 5
and 8, obtained via asymmetric dihydroxylation, could
also be used similarly in the preparation of esters 6 and
9, respectively. Saponification of the ester groups of
resolved 6 and 9 then afforded the pure enantiomers of
the required diol 5 and triol 10.
PdCl2(PPh3)2
CuI, Et3N
(+)-11 + (+)-14
OH
OH
With the pure enantiomers of the subunits in hand, we
proceeded to couple them with the required acetylenic
linker to afford the respective stereoisomers (+)-2a, ())-
2a, (+)-2b, and ())-2b. Thus, iodides ())-5 and (+)-5
were converted to the corresponding acetylenes ())-11
and (+)-11, respectively, by means of Sonogashira
reactions26–28 (Scheme 2), while ())-10 and (+)-10 were
protected and iodinated with iodine monochloride29 as
shown in Scheme 3. A second Sonogashira coupling of
each possible combination of (+)- and ())-11 with (+)-
and ())-14, followed by deprotection, then afforded the
desired products 2a–d (Scheme 4).
1. TBAF
(+)-2a 79%
2. TFA-
MeOH
O
O
OTBS
(+)-15a 71%
Similarly,
(-)-11 + (-)-14
(-)-11 + (+)-14
(+)-11 + (-)-14
(-)-2a 63% overall
(+)-2b 77% overall
(-)-2b 79% overall
Scheme 4.
OH
OH
1. PdCl2(PPh3)2
CuI, Et3N
levels. The mimetics were also examined (through co-
application) with regard to their effects on the bending
activity induced by brassinolide and IAA. Surprisingly,
when applied at a dose equal to, or higher than the dose
of brassinolide, the mimetics displayed the ability either
to enhance synergistically the activity of coapplied
brassinolide or to function as antagonists of brassino-
lideÕs promotive activity, depending on both the dose of
brassinolide and of the mimetic. A more detailed
investigation of this unexpectedly complex biological
behavior of the individual stereoisomers, is currently in
progress.
Me3Si
H
(-)-5
2. TBAF
H
(-)-11 92%
similarly
(+)-11 94%
(+)-5
Scheme 2.
(MeO)2CMe2
p-TsOH
O
(-)-10
3. Experimental
3.1. General
O
OH
(-)-12 73%
t-BuMe2SiCl
imidazole
DMF
ICl
Na2CO3
MeOH
I
NMR spectra were recorded in CDCl3, with residual
chloroform as the standard, unless otherwise noted.
Mass spectra were obtained using EI at 70 eV. An A. H.
Thomas hot-stage apparatus was used to measure
melting points, which are uncorrected. Optical rotations
were determined on a Rudolph Autopol IV polarimeter
at 22 °C.
O
O
OH
(+)-13 96%
I
O
O
3.2. ())-(6R,7S)-6,7-Bis[(R)-O-acetylmandeloxy]-1-iodo-
5,6,7,8-tetrahydronaphthalene ())-6
OTBS
(+)-14 76%
The racemic diol 518 (816 mg, 2.81 mmol), 4-dimethyl-
aminopyridine (34 mg, 10 mol %), and (R)-O-acetyl-
mandelic acid25 (1.15 g, 5.92 mmol) were stirred in
dichloromethane (40 mL). The resulting slurry was
cooled in an ice/water bath and dicyclohexylcarbodi-
imide (1.22 g, 5.91 mmol) in dichloromethane (15 mL)
added dropwise over 1 h. The reaction mixture was
allowed to reach ambient temperature while stirring
overnight. It was filtered, washed with Na2CO3 solution,
brine, dried over MgSO4, and evaporated in vacuo to
leave a colorless solid foam. Multiple recrystallizations
similarly
(-)-14 19% overall
(+)-10
Scheme 3.
Preliminary bioassay results using the rice leaf lamina
inclination assay of 2a–d indicated that bioactivity was
not confined to any single stereoisomer. Thus, three of
the mimetics (+)-2a, (+)-2b, and ())-2b, when coapplied
with IAA, showed modest, but variable promotive
effects on leaf lamina bending, but only at higher dose

T. G. Back et al. / Tetrahedron: Asymmetry 15 (2004) 873–880
877
(absolute ethanol) furnished 580 mg (32%) of diester ())-
3.6. ( )-(cis)-1-Acetoxy-5,6,7,8-tetrahydro-6,7-naphthal-
enediol 8
6 as white needles: ½aꢀ ¼ )100 (c 1.0, CH3OH); mp 113–
D
115 °C; IR (film) 1749, 1230, 1056 cmꢁ1
;
1H NMR
(200 MHz) d 7.69 (d, J ¼ 8:7 Hz, 1H), 7.45–7.28 (m,
10H), 7.08 (d, J ¼ 8:7 Hz, 1H), 6.87 (t, J ¼ 8:6 Hz, 1H),
5.86 (s, 1H), 5.77 (s, 1H), 5.37–5.21 (m, 2H), 3.19–3.11
(m, 2H), 2.87–2.58 (m, 2H), 2.18 (s, 3H), 2.07 (s, 3H);
13C NMR (50 MHz) d 170.2, 169.8, 168.0, 167.8, 137.4,
134.5, 133.8, 133.4, 129.2, 129.1, 128.7, 128.6, 128.0,
127.4, 127.3, 101.7, 74.4, 74.3, 70.6, 70.1, 38.1, 32.0,
20.5, 20.3; MS, m=z (relative intensity, %) 388 (5), 254
(6), 203 (9), 178 (6), 128 (100), 89 (64). Anal. Calcd for
C30H27IO8: C, 56.09%; H, 4.24%. Found: C, 56.12%; H,
3.98%.
Osmium tetroxide (156 lL of a 0.39 M solution in tert-
butanol, 0.061 mmol), N-methylmorpholine N-oxide
(1.57 g, 13.4 mmol), and water (220 lL, 12.2 mmol) were
added to a solution of 5,8-dihydro-1-naphthyl acetate
718 (2.29 g, 12.2 mmol) in acetone (75 mL). The solution
was stirred for 18 h, after which sodium thiosulfate
(250 mg) and Florisil (500 mg) were added and stirring
then continued for a further 3 h. The mixture was fil-
tered through Celite, the filtrate evaporated in vacuo,
and the residue subjected to flash chromatography
(elution with 50% ethyl acetate–hexanes) to give 2.33 g
(86%) of diol ( )-8;24 mp 144–145 °C (from acetone–
1
benzene); IR (Nujol) 3339, 1744, 1077, 1050 cmꢁ1; H
3.3. (+)-(6S,7R)-6,7-Bis[(S)-O-acetylmandeloxy]-1-iodo-
5,6,7,8-tetrahydronaphthalene (+)-6
NMR (200 MHz) (CD3OD) d 7.15 (t, J ¼ 8:4 Hz, 1H),
7.00 (d, J ¼ 8:2 Hz, 1H), 6.84 (d, J ¼ 8:2 Hz, 1H), 4.03
(m, 2H), 3.11–2.63 (m, 4H), 2.30 (s, 3H); 13C NMR
(50 MHz) (CD3OD) d 173.4, 153.1, 139.7, 130.3, 130.2,
130.1, 123.0, 72.4, 72.1, 37.8, 32.4, 23.2; MS, m=z (rel-
ative intensity, %) 222 (Mþ, 5), 204 (6), 180 (43), 162
(100), 133 (24), 120 (38). Anal. Calcd for C12H14O4: C,
64.85%; H, 6.35%. Found: C, 64.71%; H, 6.12%.
Racemic 5 was treated with (S)-O-acetylmandelic acid25
as in the preceding procedure to afford, after multiple
recrystallizations, 25% of diester (+)-6 as white needles:
½aꢀ ¼ +99.8 (c 1.0, CH3OH); mp 113–115 °C; IR (film)
D
1
1748, 1228, 1053 cmꢁ1; H NMR (200 MHz) d 7.69 (d,
J ¼ 8:7 Hz, 1H), 7.45–7.28 (m, 10H), 7.08 (d,
J ¼ 8:7 Hz, 1H), 6.87 (t, J ¼ 8:6 Hz, 1H), 5.86 (s, 1H),
5.77 (s, 1H), 5.37–5.21 (m, 2H), 3.19–3.11 (m, 2H), 2.87–
2.58 (m, 2H), 2.18 (s, 3H), 2.07 (s, 3H); 13C NMR
(50 MHz) d 170.2, 169.8, 168.0, 167.8, 137.4, 134.4,
133.7, 133.4, 129.1, 129.0, 128.8, 128.7, 128.0, 127.4,
127.2, 101.7, 74.4, 74.3, 70.6, 70.1, 38.1, 32.0, 20.5, 20.3;
MS, m=z (relative intensity, %) 388 (16), 254 (20), 203
(29), 178 (17), 128 (100), 89 (46). Anal. Calcd for
C30H27IO8: C, 56.09%; H, 4.24%. Found: C, 56.14%; H,
3.94%.
3.7. ())-(6R,7S)-1-Acetoxy-6,7-bis[(R)-O-acetylmandel-
oxy]-5,6,7, 8-tetrahydronaphthalene ())-9
Diol ( )-8 (2.73 g, 12.3 mmol), 4-dimethylaminopyridine
(150 mg, 1.23 mmol), and (R)-O-acetylmandelic acid25
(5.01 g, 25.8 mmol) were dissolved in dichloromethane
(125 mL) and the resulting slurry was cooled in an
ice/water bath. Dicyclohexylcarbodiimide (5.32 g,
25.8 mmol) in dichloromethane (65 mL) was added
dropwise over 1 h. The reaction mixture was stirred
overnight at ambient temperature. The resulting slurry
was filtered, the filtrate washed with Na2CO3 solution
and brine, dried over MgSO4, and evaporated in vacuo
to leave a colorless solid foam. Multiple recrystalliza-
tions (from methanol) furnished 1.81 g (26%) of triester
3.4. ())-(6R,7S)-1-Iodo-5,6,7,8-tetrahydro-6,7-naphthal-
enediol ())-5
Potassium hydroxide (1.64 g, 29.2 mmol) was added to a
slurry of ester ())-6 (2.35 g, 3.66 mmol) in methanol
(45 mL). The mixture was stirred for 2 h and the
resulting homogeneous solution evaporated in vacuo.
The residue was taken up in NaHCO3 solution and ex-
tracted several times with ethyl acetate. The combined
organic layers were washed with brine, dried over
Na2SO4, evaporated in vacuo, and subjected to flash
chromatography (elution with 80% ethyl acetate–hex-
anes) to give 1.04 g (98%) of diol ())-5 as a white solid:
())-9 as white needles; ½aꢀ ¼ )92.1 (c 1.0, acetone); mp
D
142–144 °C; IR (film) 1749, 1230, 1209, 1056, 1028 cmꢁ1
;
1H NMR (200 MHz) d 7.41–7.30 (m, 10H), 7.19 (t,
J ¼ 8:2 Hz, 1H), 6.98 (d, J ¼ 8:1 Hz, 1H), 6.91 (d,
J ¼ 8:1 Hz, 1H), 5.84 (s, 1H), 5.75 (s, 1H), 5.31 (m, 2H),
3.18 (m, 2H), 2.65 (m, 2H), 2.27 (s, 3H), 2.16 (s, 3H),
1.98 (s, 3H); 13C NMR (50 MHz) d 170.3, 169.9, 168.7,
168.0, 167.8, 148.9, 133.9, 133.5, 133.4, 129.1, 128.9,
128.7, 128.6, 127.4, 127.3, 127.2, 126.5, 124.4, 119.9,
74.5, 70.0, 69.6, 31.3, 26.3, 20.7, 20.5, 20.2; MS, m=z
(relative intensity, %) 575 (Mþ, <1), 320 (7), 186 (14),
145 (100), 115 (91). Anal. Calcd for C32H30O10: C,
66.89%; H, 5.26%. Found: C, 66.95%; H, 5.09%.
½aꢀ ¼ )37.3 (c 1.0, CH3OH); mp 138–140 °C (lit.18 mp
D
for ( )-5: 139–141 °C). The 1H NMR spectrum was
identical to that of ( )-5.
3.5. (+)-(6S,7R)-1-Iodo-5,6,7,8-tetrahydro-6,7-naphthal-
enediol (+)-5
3.8. (+)-(6S,7R)-1-Acetoxy-6,7-bis[(S)-O-acetylmandel-
oxy]-5,6,7,8-tetrahydronaphthalene (+)-9
The saponification of (+)-6 was carried out as in the
preceding procedure to afford 93% of diol (+)-5 as a
Racemic 8 was treated with (S)-O-acetylmandelic acid25
as in the preceding procedure to afford, after multiple
recrystallizations from methanol, 23% of triester (+)-9
white solid: ½aꢀ ¼ +40.2 (c 0.93, CH3OH); mp 138–
D
1
140 °C (lit.18 mp for ( )-5: 139–141 °C). The H NMR
spectrum was identical to that of ( )-5.
as white needles: ½aꢀ ¼ +94.7 (c 1.0, acetone); mp
D

878
T. G. Back et al. / Tetrahedron: Asymmetry 15 (2004) 873–880
142–144 °C; IR (film) 1745, 1235, 1206, 1053, 1029 cmꢁ1
;
graphy (elution with 55% ethyl acetate–hexanes) to yield
1H NMR (200 MHz) d 7.41–7.30 (m, 10H), 7.19 (t,
J ¼ 8:2 Hz, 1H), 6.98 (d, J ¼ 8:1 Hz, 1H), 6.91 (d,
J ¼ 8:1 Hz, 1H), 5.84 (s, 1H), 5.75 (s, 1H), 5.31 (m, 2H),
3.18 (m, 2H), 2.65 (m, 2H), 2.27 (s, 3H), 2.16 (s, 3H),
1.98 (s, 3H); 13C NMR (50 MHz) d 170.2, 169.9, 168.6,
168.0, 167.8, 149.0, 133.9, 133.5, 133.5, 129.1, 128.8,
128.7, 128.6, 127.5, 127.4, 127.2, 126.5, 124.4, 119.9,
74.5, 70.0, 69.6, 31.3, 26.3, 20.7, 20.5, 20.2; MS, m=z
(relative intensity, %) 575 (Mþ, <1), 145 (100), 115 (67).
Anal. Calcd for C32H30O10: C, 66.89%; H, 5.26%.
Found: C, 66.59%; H, 5.07%.
624 mg (92%) of acetylene ())-11: ½aꢀ ¼ )49.2 (c 0.84,
D
CH3OH); mp 134–137 °C (lit.18 mp for ( )-11: 133–
136 °C). The 1H NMR spectrum was identical to that of
( )-11.18
3.12. (+)-(6S,7R)-1-Ethynyl-5,6,7,8-tetrahydro-6,7-naph-
thalenediol (+)-11
Diol (+)-5 was treated similarly to afford 94% of acet-
ylene (+)-11: ½aꢀ ¼ +47.6 (c 0.72, CH3OH); mp 134–
D
1
136 °C (lit.18 mp for ( )-11: 133–136 °C). The H NMR
spectrum was identical to that of ( )-11.18
3.9. ())-(6R,7S)-5,6,7,8-Tetrahydro-1,6,7-naphthalene-
triol ())-10
3.13. ())-(6R,7S)-6,7-(Isopropylidenedioxy)-5,6,7,8-tetra-
hydro-1-naphthol ())-12
Potassium hydroxide (2.71 g, 48.3 mmol) was added to a
slurry of ester ())-9 (4.89 g, 8.51 mmol) in methanol
(100 mL). The mixture was stirred for 2 h and the
homogeneous solution concentrated in vacuo. The res-
idue was taken up in ethyl acetate and washed several
times with brine, which was back-extracted with ethyl
acetate. The combined organic layers were dried over
Na2SO4, and evaporated in vacuo to give a crude resi-
due that afforded 1.46 g (95%) of white crystals (from
p-Toluenesulfonic acid (41.5 mg, 10 mol %) was added to
a slurry of triol ())-10 (392 mg, 2.18 mmol) and 2,2-di-
methoxypropane (1.61 mL, 13.1 mmol). The mixture
was stirred for 2 h at ambient temperature, at which time
the homogeneous solution was diluted with dichloro-
methane, washed with NaHCO3 solution and brine,
dried over Na2SO4, and evaporated in vacuo to give an
off-white solid. The crude residue was subjected to flash
chromatography (elution with 20% ethyl acetate–hex-
anes) to give 352 mg (73%) of ())-12 as a white solid:
ethanol–water) of triol ())-10: ½aꢀ ¼ )20.2 (c 0.46,
D
acetone); mp 184–186 °C (lit.30 mp for ( )-10: 188–
188.5 °C); 1H NMR (200 MHz) (acetone-d6–D2O) d 6.85
(t, J ¼ 7:8 Hz, 1H), 6.57 (d, J ¼ 7:9 Hz, 1H), 6.51 (d,
J ¼ 7:6 Hz, 1H), 4.06–3.91 (m, 2H), 2.95–2.61 (m, 4H).
1
½aꢀ ¼ )22.8 (c 0.64, CHCl3); mp 112–114 °C; H NMR
D
(200 MHz)
d
7.04 (t, J ¼ 7:7 Hz, 1H), 6.79 (d,
J ¼ 7:4 Hz, 1H), 6.69 (d, J ¼ 8:0 Hz, 1H), 4.63 (m, 2H),
3.17–2.58 (m, 4H), 1.35 (s, 3H), 1.17 (s, 3H); 13C NMR
(50 MHz) d 152.8, 137.2, 126.8, 121.1, 121.0, 113.5,
108.0, 74.1, 73.9, 34.3, 26.3, 26.1, 24.4. The NMR
spectra were identical to those of ( )-12.18
3.10. (+)-(6S,7R)-5,6,7,8-Tetrahydro-1,6,7-naphthalene-
triol (+)-10
The saponification of (+)-9 was carried out as in the
preceding procedure to afford 93% of triol (+)-10 as a
3.14. (+)-(6R,7S)-4-Iodo-6,7-(isopropylidenedioxy)-
5,6,7,8-tetrahydro-1-naphthol (+)-13
white solid: ½aꢀ ¼ +18.9 (c 0.38, acetone); mp 184–
D
186 °C (lit.30 mp for ( )-10: 188–188.5 °C). The 1H
NMR spectrum was identical to that of ())-10.
A slurry of ())-12 (1.75 g, 7.94 mmol), Na2CO3 (8.42 g,
79.4 mmol), and methanol (100 mL) was cooled to 0 °C.
Iodine monochloride (1.35 g, 8.31 mmol) was added over
45 min and the slurry stirred at ambient temperature for
3 h, at which time the reaction was filtered and evapo-
rated in vacuo to give 2.64 g (96%) of (+)-13, which was
used directly in the next step. A portion was subjected to
flash chromatography (elution with 20% ethyl acetate–
3.11. ())-(6R,7S)-1-Ethynyl-5,6,7,8-tetrahydro-6,7-naph-
thalenediol ())-11
Diol ())-5 (1.04 g, 3.60 mmol), dichlorobis(triphenyl-
phosine)palladium(II) (63 mg, 2.5 mol %), and copper(I)
iodide (34 mg, 5 mol %) were placed in an oven dried
flask, which was then purged with argon. Benzene
(105 mL), triethylamine (25 mL), and trimethylsilylacet-
ylene (710 lL, 5.04 mmol) were added via syringe. Stir-
ring was continued overnight and the reaction quenched
with brine and extracted several times with ethyl acetate.
The combined organic layers were dried over MgSO4
and evaporated in vacuo. The residue was taken up in
THF (50 mL), chilled to 0 °C, and treated with tetra-
butylammonium fluoride (4.3 mL of a 1.0 M solution in
THF, 4.3 mmol). The mixture was stirred for 2 h, after
which NH4Cl solution was added, followed by extrac-
tion several times with ethyl acetate. The combined or-
ganic layers were washed with brine, dried over MgSO4,
evaporated in vacuo, and subjected to flash chromato-
hexanes) to afford (+)-13 as a white solid: ½aꢀ ¼ +23.4 (c
D
0.44, CH3OH); mp 173–175 °C (lit.18 mp for ( )-13: 172–
175 °C); 1H NMR (200 MHz) d 7.56 (d, J ¼ 8:5 Hz, 1H),
6.49 (d, J ¼ 8:5 Hz 1H), 4.88 (s, 1H), 4.66–4.55 (m, 2H),
3.26–3.10 (m, 2H), 2.83–2.52 (m, 2H), 1.33 (s, 3H), 1.15
1
(s, 3H). The H NMR spectrum was identical to that of
( )-13.18
3.15. (+)-(6R,7S)-1-tert-Butyldimethylsilyloxy-4-iodo-
6,7-(isopropylidenedioxy)-5,6,7,8-tetrahydronaphthalene
(+)-14
Imidazole (2.26 g, 33.3 mmol), tert-butyldimethylsilyl
chloride (2.52 g, 16.7 mmol), and (+)-13 (2.64 g,

T. G. Back et al. / Tetrahedron: Asymmetry 15 (2004) 873–880
879
7.63 mmol) were stirred overnight in DMF (42 mL). The
mixture was diluted with water and extracted several
times with ethyl acetate. The organic layers were com-
bined, dried over MgSO4, and evaporated in vacuo. The
residue was purified by flash chromatography (elution
with 2% ethyl acetate–hexanes) to give 2.67 g (76%) of
(1.0 mL of a 1.0 M solution in THF, 1.0 mmol). After
2 h, the reaction was quenched with NH4Cl solution and
extracted several times with ethyl acetate. The combined
organic layers were washed with brine, dried over
MgSO4, and evaporated in vacuo to leave a crude resi-
due that was used immediately in the next step. Hence,
TFA (5 mL) was added to a solution of the crude
product in methanol (85 mL). The solution was refluxed
for 2 h, after which the methanol and TFA were
removed in vacuo and flash chromatographed (10%
methanol–ethyl acetate) to afford 238 mg (79%) of the
silyl ether (+)-14: ½aꢀ ¼ +22.3 (c 0.75, acetone); mp 71–
D
73 °C (lit.18 mp for ( )-14: 72–73 °C); 1H NMR
(200 MHz)
d
7.53 (d, J ¼ 8:6 Hz, 1H), 6.49 (d,
J ¼ 8:6 Hz, 1H), 4.59–4.45 (m, 2H); 3.16–2.67 (m, 4H),
1.32 (s, 3H), 1.20 (s, 3H), 1.04 (s, 9 H) 0.21 (s, 6 H). The
1H NMR spectrum was identical to that of ( )-14.18
desired mimetic (+)-2a as a white solid: ½aꢀ ¼ +93.5 (c
D
1
0.20, CH3OH); mp 258–274 °C H NMR (200 MHz) d
7.30 (m, 1H), 7.21 (d, J ¼ 8:2 Hz, 1H), 7.09 (m, 2H),
6.62 (d, J ¼ 8:2 Hz, 1H), 4.14–4.04 (m, 4H), 3.17 (m,
4H), 2.99 (m, 2H), 2.87 (m, 2H); 13C NMR (50 MHz) d
154.9, 136.4, 134.4, 133.2, 130.0, 128.7, 128.0, 125.0,
123.1, 120.5, 113.2, 111.3, 92.7, 89.8, 68.3, 68.2, 68.1,
67.8, 33.7, 32.9, 32.8, 28.2; MS, m=z (relative intensity,
%) 366 (Mþ, 23), 348 (26), 330 (62); HRMS calculated
for C22H22O5: 366.1467. Found: 366.1483. Products ())-
2a, (+)-2b, and ())-2b were prepared similarly from the
corresponding isomers of 11 and 14 in the overall yields
shown in Scheme 4. Their specific rotations and exact
3.16. ())-(6S,7R)-1-tert-Butyldimethylsilyloxy-4-iodo-
6,7-(isopropylidenedioxy)-5,6,7,8-tetrahydronaphthalene
())-14
The same procedure was used to prepare ())-14 from
(+)-10 as was employed for the preparation of (+)-14
from ())-10 with an overall yield of 19%. The interme-
diates and product had the following specific rotations:
(+)-12: ½aꢀ ¼ +25.6 (c 0.59, CHCl3); ())-13: ½aꢀ ¼ )24.8
D
D
(c 0.77, CH3OH); ())-14: ½aꢀ ¼ )20.6 (c 0.95, acetone).
D
The 1H NMR spectra of these products were identical to
those of their enantiomers.
masses were: ())-2a: ½aꢀ ¼ )92.3 (c 0.38, CH3OH),
D
HRMS 366.1448; (+)-2b: ½aꢀ ¼ +4.2 (c 0.10, CH3OH),
D
HRMS 366.1459, and ())-2b: ½aꢀ ¼ )4.3 (c 0.30,
D
CH3OH), HRMS 366.1455.
3.17. (+)-(6S,7R,60S,70R)-1-{1-[4-(tert-Butyldimethylsil-
yloxy)-6,7-(isopropylidenedioxy)-5,6,7,8-tetrahydro-
naphthyl]}-2-[10-(60,70-dihydroxy-50,60,70,80-tetrahydro-
naphthyl)]ethyne (+)-15a
Acknowledgements
Acetylene (+)-11 (219 mg, 1.16 mmol), iodide (+)-14
(562 mg,
We thank the Natural Sciences and Engineering
Research Council of Canada for financial support and
Dr. X. Wen for technical assistance.
1.22 mmol),
dichlorobis(triphenylphos-
phine)palladium(II) (41 mg, 5 mol %), and copper(I)
iodide (22 mg, 10 mol %) were placed in an oven dried
100 mL round bottom flask and purged with argon.
Benzene (46 mL) and triethylamine (11 mL) were added
by syringe. The reaction was stirred overnight, quenched
with brine, and extracted several times with ethyl ace-
tate. The combined organic layers were washed with
brine, dried over MgSO4, evaporated in vacuo, and flash
chromatographed (elution with 50–100% ethyl acetate–
hexanes) to give 430 mg (71%) of acetylene (+)-15a as a
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