Stereoselective total synthesis of (3 R,5 R)-5-hydroxy-de- O -methyllasiodiplodin via the prins cyclization

Article abstract of DOI:10.1055/s-0030-1258244

A practical stereoselective total synthesis of (3R,5R)-5-hydroxy-de-O- methyllasiodiplodin has been accomplished via Prins cyclization. It exhibits potato microtuber inducing activity. The synthetic sequence involves Prins cyclization, reductive opening o

Full text of DOI:10.1055/s-0030-1258244

PAPER
3657
Stereoselective Total Synthesis of (3R,5R)-5-Hydroxy-de-O-methyllasiodiplo-
din via the Prins Cyclization
Total
S
ynt
h
hesis of (3
R
,
5
R
)
-5-
H
l
ydrox
l
y-de-
O
u
-methyllasiodiplod
Sin . Yadav,* N. Thrimurtulu, Md. Ataur Rahman, J. Satyanarayana Reddy, A. R. Prasad, B. V. Subba Reddy
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 5 July 2010; revised 29 July 2010
O
OH
OH
OH
O
MeO
Abstract: A practical stereoselective total synthesis of (3R,5R)-5-
hydroxy-de-O-methyllasiodiplodin has been accomplished via
Prins cyclization. It exhibits potato microtuber inducing activity.
The synthetic sequence involves Prins cyclization, reductive open-
ing of the pyran ring, esterification, and ring-closing metathesis
(RCM) as the key steps.
OH
O
O
OH
HO
HO
HO
HO
1
2
Key words: Prins cyclization, ring-closing metathesis, esterifica-
tion, reductive ring opening, lactone
O
O
OH
O
O
O
OH
O
HO
HO
The 12-membered lactones (3R,5R)-5-hydroxy-de-O-
methyllasiodiplodin (1), (3R,4S)-4-hydroxylasiodiplodin
(2), and (3R,6R)-6-hydroxy-de-O-methyllasiodiplodin (3)
were isolated1 from mycelium extracts of Lasiodiplodia
theobromae IFO 31059 that exhibit potato microtuber in-
ducing activity (Figure 1).2 Lasiodiplodia theobromae is a
fungus, the culture filtrate of which inhibits the growth of
higher plants and produces various organic metabolites
like jasmonic acid. The structures of 1, 2, and 3 resemble
orsellinic acid3,4 type macrolides such as zearalenone (4),
curvularin (5), and resorcylide (6). Several natural prod-
ucts with oresellinic acid type structural units have been
found to exhibit a wide range of biologically activity.4
Lasiodiplodin and its relatives are known to be very effi-
cient inhibitors of prostaglandin biosynthesis and exhibit
significant anti-leukemic and potato microtuber inducing
activity.4b
3
4
O
OH
O
O
O
O
6
5
Figure 1 Chemical structures of some orsellinic acid type macro-
lides
18 could in turn be obtained via esterification of alcohol
17 with relevant compound 23. It was proposed that the
required 1,3-diol 17 would be obtained from homoallylic
alcohol 7 by Prins cyclization with acetaldehyde.
The synthesis of (3R,5R)-5-hydroxy-de-O-methyllasio-
diplodin (1) is outlined in Scheme 2. Accordingly, the re-
gioselective ring opening5 of (R)-benzyl glycidal ether6
with vinylmagnesium bromide in the presence of copper
In our retrosynthetic analysis (Scheme 1), we envisioned
that the target molecule 1 could be achieved from 19
through ring-closing metathesis (RCM). The compound
O
O
OH
O
OH
O
O
O
OH
OH
OH
HO
BnO
23
+
20
O
O
+
OH
OBn
OBn OH
HO
BnO
HO
OH
1
18
17
7
Scheme 1 Retrosynthesis of (3R,5R)-5-hydroxy-de-O-methyllasiodiplodin (1)
SYNTHESIS 2010, No. 21, pp 3657–3662
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.09.2010
DOI: 10.1055/s-0030-1258244; Art ID: Z17110SS
© Georg Thieme Verlag Stuttgart · New York

3658
J. S. Yadav et al.
PAPER
OH
OH
OBn
a
b
c
HO
OH
HO
TBSO
TBSO
O
O
O
7
8
9
10
OBn
OBn
OBn OH
OBn
O
OMe
f
g
d
e
HO
I
O
O
11
12
13
14
OBn OH
OBn
O
OMe
OBn
O
OMe
h
j
i
HO
15
16
17
O
O
O
OH
OH
OH
k
m
l
O
O
O
OBn
OBn
OH
BnO
BnO
HO
18
19
1
Scheme 2 Reagents and conditions: (a) 1. acetaldehyde, TFA, CH2Cl2, r.t., 3 h, 2. K2CO3, MeOH, r.t., 30 min, 52%; (b) TBSCl, imidazole,
DMAP, CH2Cl2, 0 °C to r.t., 4 h, 87%; (c) NaH, BnBr, anhyd THF, r.t., 2 h, 90%; (d) CSA, MeOH, 0 °C, 10 min; (e) Ph3P, imidazole, I2, THF,
0 °C to r.t., 2 h, 92%; (f) Zn, EtOH, reflux, 1 h, 88%; (g) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 3 h, 90%; (h) 1. Cy2BH, THF, r.t., 3
h, 2. 30% H2O2, NaOH, 0 °C, 4 h, 90%; (i) 1. DMP, CH2Cl2, 2 h, 91%, 2. Ph3MeP+ I–, t-BuOK, THF, r.t., 3 h, 72%; (j) PTSA, MeOH, r.t., 4 h,
90%; (k) NaH, THF–DMF, 23, 0 °C to r.t., 6 h, 81%; (l) Grubbs II catalyst, reflux, 12 h, CH2Cl2, 64%; (m) H2, Pd/C, MeOH, 6 h, 81%.
cyanide gave the homoallylic alcohol 7. The Prins-type in 90% yield. Compound 14 was subjected to dicyclohex-
cyclization of 7 with acetaldehyde in presence of trifluo- ylborane in tetrahydrofuran provided selectively primary
roacetic acid followed by hydrolysis of the resulting tri- alcohol 15 in 90% yield. Oxidation of primary alcohol 15
fluoroacetate afforded the tetrahydropyranol 8 in 52% with Dess–Martin periodinane (DMP) in dichloromethane
yield.7 The configuration of compound 8 was assumed to afforded the aldehyde, which was further treated, without
be (2R,4S,6R) as anticipated, as the stereochemistry of purification, with methylenetriphenylphosphorane to fur-
this reaction has been well examined and established pre- nish olefin 16 in 72%.Thus, deprotection of the MOM
viously.7,8 TBS protection of 8 with tert-butyldimethylsi- ether using 4-toluenesulfonic acid in methanol followed
lyl chloride, 4-(dimethylamino)pyridine, and imidazole by deprotonation of 17 with sodium hydride in tetrahydro-
gave the corresponding TBS ether 9 in 87% yield. The furan–N,N-dimethylformamide (1:1) at 0 °C gave the
secondary hydroxy group of 9 was protected as its benzyl alkoxide anion, which was then esterified10 with the aro-
ether using benzyl bromide in the presence of sodium hy- matic compound 23 to afford diene 18. Treatment of diene
dride in tetrahydrofuran to afford compound 10. Depro- 18 with 5 mol% Grubbs II catalyst under high dilution
tection of the TBS ether using camphor-10-sulfonic acid conditions (0.001 M in CH2Cl2)8j,11 gave the cyclic ester
in methanol gave the pyranylmethanol 11 in 90% yield. 19 in 64% yield. Further treatment of the cyclic ester 19
The primary hydroxy group of 11 was subjected to iodina- with palladium on carbon11 in methanol afforded the tar-
tion using iodine, triphenylphosphine, and imidazole to get molecule, (3R,5R)-5-hydroxy-de-O-methyllasiodiplo-
give iodo compound 12 in 92% yield, which upon reduc- din (1) in 81% yield. The spectral and analytical data (1H
tive opening of the pyran ring using zinc in ethanol fur- and 13C NMR, IR, Rf, and [a]D) for the synthetic com-
nished the homoallyl alcohol 13 in 88%.9 Protection of the pound were identical with those of the natural product.
secondary hydroxy group of 13 as the MOM ether using
The synthesis of fragment 23 was achieved as described in
methoxymethyl chloride in the presence of Hünig’s base
Scheme 3. Accordingly, 2,4,6-trihydroxybenzoic acid
in anhydrous dichloromethane furnished MOM ether 14
(20) was treated with thionyl chloride, 4-(dimethylami-
OH
OH
OH
O
O
O
O
O
O
a
b
c
O
O
O
O
HO
BnO
OTf
BnO
BnO
OH
20
21
22
23
Scheme 3 (a) 1. SOCl2, acetone, DME, 0 °C to r.t., 76%, 2. BnBr, NaH, THF, r.t., 6 h, 98%; (b) Tf2O, pyridine, CH2Cl2, 0 °C to r.t., 81%; (c)
Pd(PPh3)4, allyltributyltin, LiCl, DMF, 60 °C, 8 h, 71%.
Synthesis 2010, No. 21, 3657–3662 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (3R,5R)-5-Hydroxy-de-O-methyllasiodiplodin
3659
no)pyridine, and acetone in 1,2-dimethoxyethane12 fol-
lowed by benzyl protection with benzyl bromide using
sodium hydride to give the corresponding alcohol 21 in
98% yield. Next, the alcohol 21 was treated with triflic
anhydride13 in pyridine to give the triflate 22, which was
further subjected to Stille coupling14 with allyltributyltin
using Pd(PPh3)4 in the presence of lithium chloride in
N,N-dimethylformamide to give the desired product 23 in
71% yield.
(2R,4S,6R)-2-[(tert-Butyldimethylsilyloxy)methyl]-6-methyl-
tetrahydro-2H-pyran-4-ol (9)
To a soln of 8 (3.7 g, 25.34 mmol) in anhyd CH2Cl2 (40 mL) was
added DMAP (15 mg, cat.) and imidazole (3.10 g, 45.6 mmol) in 1
portion followed by TBSCl (3.8 g, 25.3 mmol) in 3 portions at 0 °C.
The resulting mixture was stirred for 4 h and slowly warmed to r.t.
Then the mixture was quenched with H2O (15 mL) and extracted
with CH2Cl2 (3 × 40 mL). The combined organic extracts were
washed with brine (20 mL), dried (anhyd Na2SO4), and concentrat-
ed in vacuo. Purification of the crude product by column chroma-
tography (silica gel, 10% EtOAc–hexane) afforded 9 (5.7 g, 87%)
as a colorless oil; Rf = 0.7 (20% EtOAc–hexane).
[a]D20 –4.5 (c 0.55, CHCl3).
IR (neat): 3379, 2932, 2858, 1464, 1372, 1129, 1033, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.86–3.69 (m, 2 H), 3.54–3.35 (m,
3 H), 2.07–2.01 (dd, J = 3.2, 2.4 Hz, 2 H), 1.96–1.89 (dd, J = 3.7,
2.2 Hz, 2 H), 1.21 (d, J = 6.1 Hz, 3 H), 0.86 (s, 9 H), 0.04 (s, 6 H).
In summary, we have described a simple and concise total
synthesis of (3R,5R)-5-hydroxy-de-O-methyllasiodiplod-
in using the Prins cyclization as a tool for the construction
of the anti-1,3-diol moiety. Further applications of the
Prins cyclization in the synthesis of natural products are in
progress and will be disclosed in due course.
13C NMR (75 MHz, CDCl3): d = 76.1, 71.6, 68.7, 66.3, 42.9, 37.6,
All reactions were carried out under an inert atmosphere, unless
mentioned, following standard syringe septa techniques. Solvents
were dried and purified by conventional methods prior to use. The
progress of all the reactions was monitored by TLC using glass
plates precoated with silica gel-60 F254 (0.5 mm) (Merck). Column
chromatography was performed on silica gel (60–120 mesh) and
neutral alumina using Et2O, EtOAc, and hexane. Optical rotation
values were measured with a Perkin-Elmer P241 polarimeter and
Jasco DIP-360 digital polarimeter at 25 °C and IR spectra were re-
corded with a Perkin-Elmer FT-IR spectrophotometer. 1H and 13C
NMR spectra were recorded with Varian Gemini 200 MHz, Bruker
Avance 300 MHz, Varian Unity 400 MHz, or Varian Inova 500
MHz spectrometer using TMS as an internal standard in CDCl3.
Mass spectra were recorded on Micro mass VG-7070H for EI and
VG Autospec M for FABMS.
25.7, 21.5, 18.2, –3.6, –5.5.
HRMS (ESI): m/z [M + Na]+ calcd for C13H28O3SiNa: 283.1705;
found: 283.1708.
{[(2R,4S,6R)-4-(Benzyloxy)-6-methyl-tetrahydro-2H-pyran-2-
yl]methoxy}(tert-butyl)dimethylsilane (10)
To a stirred soln of 9 (4 g, 15.38 mmol) in THF (40 mL) was added,
at 0 °C, NaH (0.92 g, 38.3 mmol) and the mixture was stirred for 30
min at this temperature. Then BnBr (2.63 mL, 15.38 mmol) was
added and the mixture was stirred for a further 2 h (TLC monitor-
ing). When the reaction was complete, the mixture was quenched
with sat. NH4Cl (40 mL) soln and then extracted with EtOAc (3 ×
40 mL). The combined organic layers were washed with brine (50
mL), dried (anhyd Na2SO4), and concentrated in vacuo. The crude
residue was purified by column chromatography (silica gel, 10%
EtOAc–hexane) to afford 10 (4.84 g, 90%) as a pale yellow syrup;
Rf = 0.8 (10% EtOAc–hexane).
[a]D20 +2 (c 0.5, CHCl3).
IR (neat): 3030, 2931, 2857, 1460, 1253, 1122, 1073, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30–7.21 (m, 5 H), 4.54 (s, 2 H),
3.7–3.65 (m, 1 H), 3.55–3.28 (m, 4 H), 2.1–2.04 (dd, J = 8.3, 2.2
Hz, 2 H), 2.01–1.95 (dd, J = 7.5, 2.2 Hz, 2 H), 1.21 (d, J = 6.1 Hz,
3 H), 0.89 (s, 9 H), 0.05 (s, 6 H).
(2R,4S,6R)-2-(Hydroxymethyl)-6-methyl-tetrahydro-2H-pyr-
an-4-ol (8)
TFA (95 mL) was added slowly to a soln of 7 (5 g, 49.01 mmol) and
acetaldehyde (5.4 g, 122 mmol) in CH2Cl2 (150 mL) at 25 °C under
N2. The mixture was stirred for 3 h and then quenched with sat.
NaHCO3 soln (300 mL) and Et3N was added until pH >7. The mix-
ture was extracted with CH2Cl2 (4 × 100 mL) and the combined or-
ganic layers were concentrated under reduced pressure. The
resulting trifluoroacetate was directly used in the next reaction with-
out purification. The residue was dissolved in MeOH (75 mL) and
treated with K2CO3 (17.9 g) for 30 min. The solvent was removed
under reduced pressure and then diluted with H2O (40 mL) and ex-
tracted with CH2Cl2 (3 × 50 mL). The combined organic layers were
dried (anhyd Na2SO4) and concentrated under reduced pressure. Pu-
rification of the crude product by column chromatography (silica
gel, 60% EtOAc–hexane) gave 8 (3.718 g, 52%) as a colorless liq-
uid; Rf = 0.3 (60% EtOAc–hexane).
13C NMR (75 MHz, CDCl3): d = 138.6, 128.3, 127.5, 76.2, 74.6,
71.7, 69.5, 66.4, 39.4, 34.6, 25.9, 21.7, 18.3, –5.3, –5.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H35O3Si: 351.2277; found:
351.2361.
[(2R,4S,6R)-4-(Benzyloxy)-6-methyl-tetrahydro-2H-pyran-2-
yl]methanol (11)
To a stirred soln of 10 (4.84 g, 13.82 mmol) in MeOH (40 mL) was
added CSA (catalytic amount) at 0 °C and the mixture was stirred
for 10 min at this temperature. When the reaction was complete, the
mixture was quenched with NaHCO3 soln and extracted with
EtOAc (2 × 50 mL). Removal of the solvent followed by purifica-
tion by column chromatography (silica gel, 20% EtOAc–hexane)
gave 11 (2.92 g, 90%) as a colorless oil; Rf = 0.3 (20% EtOAc–hex-
ane).
[a]D20 –13.3 (c 0.5, CHCl3).
IR (neat): 3398, 2925, 2856, 1722, 1452, 1363, 1178, 1030, 976
cm–1.
1H NMR (300 MHz, CDCl3): d = 3.78–3.87 (m, 1 H), 3.45–3.65 (m,
4 H), 1.98–1.92 (dd, J = 3.9, 2.4 Hz, 2 H), 1.87–1.81 (dd, J = 3.7,
2.2 Hz, 2 H), 1.25 (d, J = 6.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 76.0, 71.6, 67.3, 65.8, 42.3, 36.5,
21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C7H14O3Na: 169.0840;
found: 169.0839.
[a]D20 –10.7 (c 0.5, CHCl3).
IR (neat): 3446, 3030, 2934, 2861, 1452, 1365, 1115, 1072, 740
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27–7.18 (m, 5 H), 4.50 (s, 2 H),
3.55–3.35 (m, 5 H), 2.0–1.84 (m, 4 H), 1.24 (d, J = 6.1 Hz, 3 H).
Synthesis 2010, No. 21, 3657–3662 © Thieme Stuttgart · New York

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J. S. Yadav et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 138.5, 128.3, 127.5, 74.3, 71.8,
[a]D25 –18.2 (c 0.9, CHCl3).
IR (neat): 3070, 3030, 2928, 1723, 1640, 1451, 1038 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.33–7.20 (m, 5 H), 5.9–5.74 (m,
1 H), 5.13–5.03 (m, 2 H), 4.64–4.52 (m, 2 H), 4.48–4.41 (m, 2 H),
3.92–3.72 (m, 1 H), 3.71–3.62 (m, 1 H), 3.30 (s, 3 H), 2.38–2.30 (m,
2 H), 1.61–1.53 (m, 1 H), 1.16 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.8, 134.5, 128.3, 127.8, 127.5,
117.3, 96.2, 95.4, 94.6, 75.1, 70.8, 55.2, 42.8, 38.5, 21.4, 20.5.
MS (LCMS): m/z = 287 [M + 23]+.
69.5, 66.0, 39.8, 33.5, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H21O3: 236.1416; found:
237.1489.
(2R,4S,6R)-4-(Benzyloxy)-2-(iodomethyl)-6-methyl-tetrahydro-
2H-pyran (12)
To a stirred soln of 11 (3.5 g, 14.83 mmol) in anhyd THF (35 mL)
was added successively at 0 °C imidazole (2.42 g, 35.5 mmol), Ph3P
(4.66 g, 17.79 mmol), and I2 (4.57 g, 17.796 mmol). The resulting
mixture was stirred at r.t. for 2 h and then quenched with H2O (15
mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic
layers were washed with brine (15 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. Purification of the crude residue by column
chromatography (silica gel, 30% EtOAc–hexane) gave 12 (4.97 g,
92%) as a pale yellow liquid; Rf = 0.7 (30% EtOAc–hexane).
(4R,6R)-4-(Benzyloxy)-6-(methoxymethoxy)heptan-1-ol (15)
To a stirred soln of Cy2BH (6.718 g, 19.53 mmol) in THF (5 mL)
was added, at 25 °C, olefin 14 (1.72 g, 6.51 mmol) in THF (2 mL)
and the mixture was stirred under N2 for 3 h. The mixture was
quenched with 30% H2O2 and 6 M NaOH at 0 °C. The resulting
mixture was allowed to stir for 4 h and then warmed slowly to r.t.
The reaction was quenched with H2O (5 mL) and extracted with
EtOAc (3 × 40 mL). The combined organic extracts were washed
with brine (20 mL), dried (anhyd Na2SO4), and concentrated in vac-
uo. Purification of the crude residue by column chromatography
(silica gel, 10% EtOAc–hexane) afforded 15 (1.64 g, 90%).
[a]D25 –18.2 (c 0.9, CHCl3).
IR (neat): 3423, 2934, 1718, 1452, 1038 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.35–7.21 (m, 5 H), 4.61–4.53 (m,
2 H), 4.48–4.42 (m, 2 H), 3.88–3.80 (m, 1 H), 3.69–3.55 (m, 3 H),
3.32 (s, 3 H), 2.09–1.90 (m, 1 H), 1.71–1.54 (m, 6 H), 1.17 (d,
J = 6.1 Hz, 3 H).
[a]D28 –14.9 (c 0.5, CHCl3).
IR (neat): 3029, 2939, 2856, 1451, 1660, 1362, 1159, 1081, 739
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.3–7.24 (m, 5 H), 4.54 (s, 2 H),
3.57–3.42 (m, 2 H), 3.35–3.28 (m, 1 H), 3.21–3.11 (m, 2 H), 2.29–
2.25 (m, 2 H), 1.98–1.93 (m, 2 H) 1.24 (d, J = 5.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 128.4, 127.5, 75.0, 74.1,
72.1, 69.6, 39.4, 37.5, 21.6, 8.8.
HRMS (ESI): m/z [M + NH4]+ calcd for C14H23INO2: 364.0768;
found: 364.0769.
(2R,4R)-4-(Benzyloxy)hept-6-en-2-ol (13)
13C NMR (75 MHz, CDCl3): d = 128.3, 127.9, 127.6, 96.2, 95.4,
75.4, 70.9, 62.8, 55.3, 42.5, 30.4, 28.0, 21.4.
MS (LCMS): m/z = 305 [M + 23]+.
To a soln of 12 (3 g, 8.287 mmol) in EtOH (80 mL) was added Zn
dust (10.93 g, 165.6 mmol) and the mixture was stirred under reflux
for 1 h. When the reaction was complete (TLC monitoring), the
mixture was quenched with solid NH4Cl (10 g) and diluted with
Et2O (200 mL). The resulting mixture was allowed to stir for 5 min
to give a gray suspension that was filtered through Celite. The fil-
trate was concentrated in vacuo and purified by flash chromatogra-
phy (silica gel, 10% EtOAc–hexane) to give 13 (1.62 g, 88%) as a
pale yellow liquid; Rf = 0.4 (10% EtOAc–hexane).
{[(2R,4R)-2-(Methoxymethoxy)oct-7-en-4-yloxy]methyl}ben-
zene (16)
To a stirred soln of 15 (1.5 g, 5.31 mmol) in CH2Cl2 (4 mL) was
added DMP (1 g, 2.28 mmol) and the mixture was stirred at 25 °C
for 2 h. The reaction was quenched with aq NaHCO3–Na2S2O3 soln
(1:1, 1 mL) and concentrated in vacuo to afford the aldehyde (1.41
g, 95%) as a colorless liquid that was used directly.
A mixture of Ph3MeP+ I– (2.76 g, 6.84 mmol) and t-BuOK (639 mg,
5.69 mmol) in anhyd THF (50 mL) was stirred at r.t. under N2 for 4
h. Stirring ceased and the solid was allowed to settle to the bottom
of the flask. The clear supernatant orange-yellow liquid was cannu-
lated into a soln of aldehyde (650 mg, 2.28 mmol) in anhyd THF (10
mL) at –78 °C. The resulting mixture was allowed to stir at r.t. for
3 h. When the reaction was complete, the reaction was quenched
with sat. NH4Cl soln and extracted with EtOAc (3 × 40 mL). The
combined organic layers were dried (anhyd Na2SO4). Removal of
the solvent under reduced pressure gave the crude product 16 as a
colorless syrup that was purified by column chromatography (silica
gel, hexane–EtOAc, 1.2:1) to furnish pure 16 (1.0 g, 72%) as a
white solid.
[a]D25 –3.2 (c 0.87, CHCl3).
IR (neat): 3069, 3030, 2930, 1640, 1452, 1038 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.37–7.19 (m, 5 H), 5.87–5.72 (m,
1 H), 5.04–4.90 (m, 2 H), 4.62–4.52 (m, 2 H), 4.49–4.39 (m, 3 H),
3.89–3.81 (m, 1 H), 3.66–3.57 (m, 1 H), 3.31 (s, 3 H), 2.17–2.08 (m,
2 H), 1.71–1.51 (m, 4 H), 1.17 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.5, 128.3, 127.7, 127.4, 114.8,
96.2, 95.4, 75.2, 70.9, 55.3, 42.9, 33.3, 29.2, 21.5.
MS (LCMS): m/z 301 [M + 23]+.
[a]D20 –21.8 (c 0.5, CHCl3).
IR (neat): 3427, 3070, 3031, 2967, 2930, 1640, 1453, 1093, 1066,
914, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28–7.17 (m, 5 H), 5.8–5.66 (m,
1 H), 5.06–4.99 (m, 2 H), 4.65–4.36 (m, 2 H), 4.05–3.99 (m, 1 H),
3.71–3.61 (m, 1 H), 2.41–2.20 (m, 2 H), 2.07 (br s, 1 H), 1.56–1.51
(t, J = 5.5 Hz, 2 H), 1.18 (d, J = 6.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.8, 134.4, 128.4, 127.7, 117.4,
76.2, 71.2, 64.5, 41.7, 37.9, 23.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H21O2: 221.1536; found:
221.1525.
{[(4R,6R)-6-(Methoxymethoxy)hept-1-en-4-yloxy]methyl}ben-
zene (14)
To a soln of 13 (1.6 g, 9.13 mmol) in anhyd CH2Cl2 (20 mL) at 0 °C
was added successively DIPEA (6.30 mL, 36.0 mmol), DMAP
(cat.), and MOMCl (1.44 g, 18.0 mmol). The resulting mixture was
stirred at r.t. for 3 h and then quenched with H2O (10 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The organic extracts were washed
with brine (10 mL), dried (anhyd Na2SO4), and concentrated under
reduced pressure. The resulting crude residue was purified by col-
umn chromatography (silica gel, EtOAc–hexane, 5:95) to afford the
pure 14 (1.72 g, 90%) as a liquid; Rf = 0.5 (silica gel, EtOAc–hex-
ane, 5:95).
Synthesis 2010, No. 21, 3657–3662 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (3R,5R)-5-Hydroxy-de-O-methyllasiodiplodin
ESI-MS: m/z = 473 [M + H]+.
3661
(2R,4R)-4-(Benzyloxy)oct-7-en-2-ol (17)
To a stirred soln of 16 (1 g, 3.59 mmol) in MeOH (20 mL) was add-
ed PTSA (0.1 g) at 0 °C and the mixture was then stirred at r.t. for
4 h. The mixture was quenched with sat. NaHCO3 soln (4 mL) and
extracted with EtOAc (2 × 15 mL). The combined organic layers
were washed with brine (50 mL), dried (anhyd Na2SO4), and con-
centrated in vacuo. The crude residue was purified by column chro-
matography (silica gel, 60–120 mesh, EtOAc–hexane, 2:3) to afford
17 (0.75 g, 90%) as a colorless liquid.
5-Allyl-7-(benzyloxy)-2,2-dimethyl-4H-1,3-benzodioxin-4-one
(23)
To a stirred soln of triflate 22 (2.0 g, 4.69 mmol) in anhyd DMF (15
mL) was added successively at 0 °C LiCl (0.288 g, 7.035 mmol),
Pd(PPh3)4 (cat.), and allyltributyltin (2.04 g, 7.035 mmol). The re-
sulting mixture was stirred at r.t. for 4 h and then quenched with
H2O (15 mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with brine (15 mL), dried (anhyd
Na2SO4), and concentrated in vacuo. Purification of the crude resi-
due by column chromatography (silica gel, 30% EtOAc–hexane)
gave 23 (1.08 g, 71%) as a colorless liquid; Rf = 0.6 (10% EtOAc–
hexane).
[a]D25 –18.2 (c 0.9, CHCl3).
IR (neat): 3440, 3072, 2929, 2858, 1738, 1641, 1461, 1253, 1084
cm–1.
1H NMR (200 MHz, CDCl3): d = 7.32–7.22 (m, 5 H), 5.84–5.69 (m,
1 H), 5.03–4.91 (m, 2 H), 4.52 (s, 2 H), 4.12–4.0 (m, 1 H), 3.72–3.63
(m, 1 H), 2.10 (q, J = 6.7 Hz, 2 H), 1.85–1.50 (m, 4 H), 1.15 (d,
J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.2, 128.4, 127.9, 127.7, 114.7,
76.5, 71.1, 64.6, 41.3, 32.6, 29.6, 23.6.
MS (LCMS): m/z = 257 [M + 23]+.
IR (neat): 3398, 2925, 2856, 1722, 1452, 1363, 1178, 1030, 976
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.3–7.18 (m, 5 H), 6.45 (d, J = 2.2
Hz, 1 H), 6.22 (d, J = 2.4 Hz, 1 H), 5.94–5.80 (m, 1 H), 5.0–4.91 (m,
4 H), 3.72 (d, J = 6.7 Hz, 2 H), 1.58 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 199.5, 164.0, 160.0, 159.0, 147.1,
136.6, 135.6, 136.3, 128.6, 128.3, 127.5, 116.2, 112.7, 104.9, 100.3,
70.2, 38.3, 25.6..
(2R,4R)-4-(Benzyloxy)oct-7-en-2-yl 2-Allyl-4-(benzyloxy)-6-hy-
droxybenzoate (18)
MS (LCMS): m/z = 325 [M + H]+.
A soln of 17 (0.6 g, 2.56 mmol) in THF–DMF (1:1, 10 mL) was
added dropwise via cannula to NaH (0.3 g, 13.0 mmol) at 0 °C and
the mixture was stirred for 30 min. Then acetonide 23 (0.83 g, 2.56
mmol) was added and the stirring was continued at r.t. for a further
6 h and then quenched with sat. NH4Cl soln(10 mL) and extracted
with EtOAc (2 × 20 mL). The combined organic layers were washed
with brine soln (50 mL), dried (Na2SO4), and concentrated in vacuo.
The crude residue was purified by column chromatography (silica
gel, 60–120 mesh, EtOAc–hexane, 1:9) to afford 18 (1.03 g, 81%)
as a light yellow syrup.
(3R,5R)-5,12,14-Trihydroxy-3-methyl-3,4,5,6,7,8,9,10-octahy-
dro-1H-2-benzoxacyclododecin-1-one (1)
To a soln of 19 (40 mg, 0.138 mmol) in MeOH (2 mL) was added
10% Pd/C and the mixture was stirred under a H2 atmosphere for 6
h. The mixture was filtered through a small Celite pad and concen-
trated in vacuo. The crude residue thus obtained was purified by col-
umn chromatography (silica gel, 30% EtOAc–hexane) to afford 1
(20.2 mg, 81%) as a white powder; mp 153–155 °C; Rf = 0.15 (30%
EtOAc–hexane).
[a]D25 –18.0 (c 1.1, CHCl3).
[a]D25 +19.1 (c 1.1, MeOH).
IR (neat): 3432, 2926, 2856, 1640, 1459, 1259, 1169, 1024 cm–1.
IR (neat): 3067, 2925, 2855, 1735, 1646, 1612, 1576, 1254, 1164
cm–1.
1H NMR (200 MHz, CDCl3): d = 11.88 (s, 1 H), 7.47–7.08 (m, 10
H), 6.47–6.27 (m, 2 H), 5.97–5.67 (m, 2 H), 5.51–5.28 (m, 1 H),
5.10–4.84 (m, 5 H), 4.56–4.29 (m, 2 H), 3.66–3.40 (m, 2 H), 2.19–
1.98 (m, 2 H), 1.91–1.54 (m, 6 H), 1.36 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.9, 138.3, 137.3, 132.5, 128.3,
128.6, 128.1, 128.0, 127.6, 127.50, 126.8, 115.6, 114.8, 114.7,
111.2, 108.7, 100.6, 100.3, 74.4, 71.4, 71.3, 69.95, 60.3, 41.5, 41.3,
40.3, 33.1, 32.9, 29.6, 28.9, 20.9, 20.8, 18.5, 14.1.
1H NMR (300 MHz, CD3OD): d = 11.82 (s, 1 H), 6.18 (d, J = 2.4
Hz, 1 H), 6.12 (d, J = 2.6 Hz, 1 H), 5.24–5.04 (m, 1 H), 4.05–3.94
(m, 1 H), 3.78–3.60 (m, 2 H), 2.31–2.18 (m, 1 H), 2.12–1.95 (m, 4
H), 1.85–1.44 (m, 7 H) 1.35 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.1, 166.6, 163.8, 150.1, 112.2,
105.0, 101.9, 73.3, 70.7, 62.2, 41.9, 35.7, 35.1, 33.0, 29.1, 21.7,
19.5.
MS (LCMS): m/z = 295 [M + 1]+.
MS (LCMS): m/z 523 [M + 23]+.
Acknowledgement
(Z)-5,12-Bis(benzyloxy)-14-hydroxy-3-methyl-4,5,6,7-tetra-
hydro-3H-benzo[c][1]oxacyclododecen-(10H)-one (19)
Grubbs II catalyst (0.275 g, 5 mol%) was dissolved in CH2Cl2 (10
mL) and was added dropwise to a solution of the ester 18 (0.3 g, 0.6
mmol) in CH2Cl2 (40 mL). The reaction mixture was heated at re-
flux for 12 h, by which time all of the starting material was con-
sumed (TLC). The solvent was removed under vacuum and the
crude product was purified by silica gel column chromatography
(EtOAc–hexane, 1:49) to obtain 19 (0.181 g, 64%) as a colorless oil;
Rf = 0.3 (20% EtOAc–hexane).
J.S.R. and N.T. thank CSIR, New Delhi for the award of fel-
lowships.
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Synthesis 2010, No. 21, 3657–3662 © Thieme Stuttgart · New York