Studies toward a total synthesis of rhizoxin d: Stereoselective preparation of the C11-C19 fragment

Article abstract of DOI:10.1055/s-0029-1216903

The C11-C19 fragment of rhizoxin D was synthesized efficiently and stereoselectively. Stereoselective induction at C13 was achieved by means of the Crimmins protocol, whereas a substrate-controlled lithium aldol reaction gave the desired selectivity at th

Full text of DOI:10.1055/s-0029-1216903

PAPER
2709
Studies toward a Total Synthesis of Rhizoxin D: Stereoselective Preparation of
the C11–C19 Fragment1
T
he C11–C19
r
Fragme
n
i
t
of
R
n
D
ivas Padakanti, Chetlur Kiran Kumar, Ettam Ashok, Parthasarathi Das*
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, A.P., India
Fax +91(40)23045438; E-mail: parthasarathi@drreddys.com; E-mail: parthads@yahoo.com
Received 15 April 2009
H
Abstract: The C11–C19 fragment of rhizoxin D was synthesized
efficiently and stereoselectively. Stereoselective induction at C13
was achieved by means of the Crimmins protocol, whereas a sub-
strate-controlled lithium aldol reaction gave the desired selectivity
at the C17 position.
O
5
O
8
7
10
O
HO
3
13
O
1
Key words: acyl thiazolidinone, lithium aldol reaction, Crimmins
protocol, rhizoxin D
O
N
15
20
O
O
19
17
OMe
Rhizoxin D (2), a 16-membered anti-tumor macrolide and
biogenetic precursor of rhizoxin (1), was isolated from the
fungus Rhizopus chinensis by Iwasaki and co-workers.2
The biological profile of this molecule is characterized by
a strong cytotoxic activity against human tumor cell
lines.3–5 All the congeners of this family share a common
carbon skeleton, i.e. a 16-membered macrolactone, but
differ in the numbers of epoxy groups present. The inter-
esting biological activity and challenging macrolide struc-
ture have prompted several groups to attempt syntheses of
rhizoxin D, and eight total syntheses of rhizoxin D has
been reported,6 along with syntheses of several fragments
of the molecule.7 Here, we report details of our stereose-
lective synthesis of the C11–C19 fragment.
rhizoxin (1)
H
O
5
O
8
7
11
HO
13
3
1
O
N
15
20
O
O
19
17
OMe
rhizoxin D (2)
Figure 1 Chemical structures of rhizoxin and rhizoxin D
Our synthesis began with the addition of allyl(tributyl)tin8
to the known aldehyde 3 in the presence of tin(IV) chlo-
ride to give alcohol 4 in 92% yield and 36:1 diastereose-
lectivity. Protection of the allyl alcohol followed by
oxidative cleavage of the terminal olefin by using osmium
tetroxide/sodium periodate in the presence of 2,6-dimeth-
ylpyridine gave aldehyde 6. The C13 stereocenter was in-
troduced with the desired stereochemistry by means of the
Crimmins aldol protocol.9 Addition of a titanium enolate
derived from 4-benzyl-3-propionyl-1,3-oxazolidin-2-one
to aldehyde 6 resulted in formation of the syn-aldol prod-
uct 7 in a 85% yield and excellent diasteroselectivity
( 96%). Reductive removal of the chiral auxiliary with
sodium borohydride in tetrahydrofuran10 gave the corre-
sponding alcohol, and subsequent protection of the 1,3-
diol group with 4-methoxybenzaldehyde dimethyl acetal
afforded the acetal 8 in a good yield. Regioselective
cleavage11 of the acetal group of 8 by diisobutylaluminum
hydride in dichloromethane gave alcohol 9 (Scheme 1).
Tosylation of alcohol 9 gave the tosylate 10, which was
converted into the corresponding terminal olefin 11 by
heating with sodium iodide and 1,8-diazabicyc-
lo[5.4.0]undec-7-ene in 1,2-dimethoxyethane.12 The syn-
thesis of compound 11 from compound 9 helped us in
determining the stereochemistry and the anti-relationship
between the C13 and C15 alcohol groups by single-crystal
X-ray diffraction analysis.13
As the stereochemistry at C13 chiral center was correct,
we converted fragment 9 into the C11–C19 fragment as
shown in Scheme 2. Alcohol 9 was silylated to give the
protected derivative 12, which was debenzylated with
Raney nickel under hydrogen to give the corresponding
alcohol 13. This was converted into the aldehyde 14 by
treatment with Dess–Martin periodinane.14 The tert-butyl-
lithium-mediated reaction of aldehyde 14 with 2-bromo-
propene provided the required homologation to give the
protected C11–C19 fragment 15. A lithuim aldol addition
reaction of the anti-substituted aldehyde 14 gave the ex-
pected Felkin diastereomer with a good level of selectivity
(80:20) at the C-17 position.15
SYNTHESIS 2009, No. 16, pp 2709–2714
x
x.
x
x
.
2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1216903; Art ID: P05909SS
© Georg Thieme Verlag Stuttgart · New York

2710
S. Padakanti et al.
PAPER
BnO
OH
a
b
BnO
BnO
CHO
BnO
OTBDPS
OH
5
4
3
O
TBDPSO
O
c
d
O
BnO
N
O
O
O
OTBDPS
6
7
N
O
Bn
MeO
Bn
TBDPSO
OPMB
O
O
TBDPSO
g
BnO
OH
e,f
BnO
8
9
TBDPSO
OPMB
TBDPSO
OPMB
i
h
BnO
BnO
OTs
11
10
Scheme 1 Reagents and conditions: (a) CH2CH=CHSnBu3, SnCl4, CH2Cl2, –90 °C to 0 °C, 1 h, 92%; (b) TBDPSCl, imidazole, DMF, r.t.,
10 h, 95%; (c) OsO4, NaIO4, 2,6-dimethylpyridine, THF–H2O (3:1), r.t., 5 h, 85%; (d) TiCl4, (–)-sparteine, CH2Cl2, –78 °C to 0 °C, 2 h, 90%;
(e) NaBH4, MeOH–THF (>200:1), r.t., 4 h; (f) 4-MeOC6H4CH(OMe)2, CSA, CH2Cl2, r.t., 16 h, 74% (two steps); (g) DIBAL-H, CH2Cl2, 0 °C,
2 h, 90%; (h) TsCl, py, r.t., 3 h, 93%; (i) NaI, DBU, MeO(CH2)2OMe, 85 °C, 2.5 h, 96%.
TBDPSO
OPMB
TBDPSO
OPMB
a
BnO
OTBS
BnO
OH
12
9
TBDPSO
OPMB
TBDPSO
OPMB
c
b
OTBS
O
HO
OTBS
14
13
TBDPSO
OPMB
HO
d
OTBS
15
Scheme 2 Reagents and conditions: (a) TBSCl, imidazole, DMF, r.t., 10 h, 91%; (b) H2, Raney-Ni, EtOH, r.t., 24 h, 81%; (c) Dess–Martin
periodinane, CH2Cl2, r.t., 0.5 h, 89%; (d) 2-bromopropene, t-BuLi, THF, –78 °C to 0 °C, 4 h, 63%.
spectra were recorded on a Schimadzu IR Prestige 21 FT-IR spec-
1
In conclusion, we synthesized the key C11–C19 fragment
of rhizoxin D from the known aldehyde 3. The route in-
volved the Crimmins aldol protocol, a Lewis acid mediat-
ed stereochemical induction, and a substrate-controlled
lithium aldol reaction to introduce the desired stereo-
centers at C13, C15, and C17, respectively. This flexible
approach provides us with a robust route toward a total
synthesis of rhizoxin D and its structural analogues for
biological studies, which are currently underway in our
laboratory.
trometer, and the absorption bands are reported in cm–1. H NMR
spectra were determined on a Varian Mercury Plus spectrometer at
400 MHz, and 13C NMR spectra were determined on a Varian Gem-
ini-2000 spectrometer at 200 MHz; CDCl3 was used as a solvent in
both cases. Proton chemical shifts (d) are reported relative to TMS
(d = 0.00) as internal standard, and expressed in ppm. The spin mul-
tiplicities are given as s (singlet), d (doublet), t (triplet), m (multip-
let), and br s (broad singlet), and the coupling constants (J) are given
in Hz. Coupling constants were rounded to the first place after the
decimal point. ESI-MS spectra were obtained on a Perkin-Elmer
API 3000 spectrometer. Column chromatography was carried out
with silica gel (grade 60-120, 100–200 mesh). Reactions were mon-
itored by TLC on silica gel plates (60 F254), and spots were visual-
ized by UV irradiation or staining with alkaline KMnO4. Unless
Optical rotations were measured on a JASCO DIP-370 digital pola-
rimeter at 25 °C. Concentrations (c) are quoted in g/100 mL. IR
Synthesis 2009, No. 16, 2709–2714 © Thieme Stuttgart · New York

PAPER
The C11–C19 Fragment of Rhizoxin D
2711
stated otherwise, reactions were performed under N2. All other re-
agents were purchased from Aldrich at the highest commercial
quality, and used without further purification.
1H NMR (400 MHz, CDCl3): d = 0.94 (d, J = 6.8 Hz, 3 H), 1.04 (s,
9 H), 2.11 (m, 1 H), 2.44 (dd, J = 6.0, 2.4 Hz, 2 H), 3.24 (dd, J = 9.6,
5.6 Hz, 1 H), 3.30 (dd, J = 9.6, 7.2 Hz, 1 H), 4.31 (m, 2 H), 4.43 (dt,
J = 2.0, 2.0 Hz, 1 H), 7.30 (m, 10 H), 7.64 (m, 5 H), 9.47 (t, J = 2.4
Hz, 1 H).
(2R,3S)-1-Benzyloxy-2-methylhex-5-en-3-ol (4)
A 1.0 M soln of SnCl4 in CH2Cl2 (117.99 mL, 117.99 mmol) was
added rapidly from a syringe to a soln of allyl(tributyl)stannane
(37.7 mL, 117.95 mmol) in CH2Cl2 (200 mL) at –78 °C. When the
addition was complete, the soln was cooled from –78 °C to –90 °C,
a soln of (R)-3 benzyloxy-2-methylpropanal (15.0 g, 84.26 mmol)
in CH2Cl2 (100 mL) was added dropwise, and the mixture was kept
at –90 °C for 0.5 h. Sat. aq NaHCO3 (160 mL) was added, the mix-
ture was warmed to r.t., and the layers were separated. The aqueous
phase was extracted with CH2Cl2 (3 × 150 mL), and the combined
extracts were filtered through a pad of Florisil. The filtrate was con-
centrated, and the residue was purified by column chromatography
[silica gel, EtOAc–hexanes (20:80)] to give a single diastereomer of
alcohol 4 as a colorless liquid; yield: 17 g (91.7%); colorless liquid;
[a]D23 –5.91 (c 2.13, CHCl3).
13C NMR (50 MHz, CDCl3): d = 12.0, 19.3, 26.9, 39.0, 47.1, 70.0,
72.0, 72.7, 127.6, 127.63, 128.2, 129.7, 133.6, 135.9, 135.96, 138.3,
202.0.
HRMS: m/z calcd for C29H36NaO3Si [M + Na]+: 483.2331; found:
483.2326.
(4R)-4-Benzyl-3-[(2R,3S,5S,6R)-7-(benzyloxy)-5-{[tert-bu-
tyl(diphenyl)silyl]oxy}-3-hydroxy-2,6-dimethylheptanoyl]-1,3-
oxazolidin-2-one (7)
TiCl4 (0.102 mL, 0.934 mmol) was added dropwise over 5 min to a
stirred soln of 4-benzyl-3-propionyl-1,3-oxazolidin-2-one (0.207 g,
0.89 mmol) in anhyd CH2Cl2 (5 mL) at 0 °C under argon. (–)-
Sparteine (0.51 mL, 2.22 mmol) was added to the yellow slurry, and
the resulting dark red enolate was stirred for 20 min at 0 °C. Alde-
hyde 6 (0.45 g, 0.97 mmol) in CH2Cl2 (1 mL) was added dropwise,
and the mixture was stirred for 1 h at 0 °C. The reaction was then
quenched with half-sat. aq NH4Cl (5 mL). The layers were separat-
ed and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. The residue was purified by column chromatography [sil-
ica gel, EtOAc–hexane (25:75)] to give compound 7 as a colorless
thick liquid; yield: 0.63 g (93%); [a]D23 –69.2 (c 0.5, CHCl3).
IR (neat): 3457, 2905, 1640, 1454, 1363 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.93 (d, J = 6.8 Hz, 3 H), 1.89 (m,
1 H), 2.18 (m, 1 H), 2.34 (m, 1 H), 3.07 (d, J = 3.6 Hz, 1 H, OH),
3.50 (dd, J = 9.6, 7.2 Hz, 1 H), 3.61 (m, 2 H), 4.52 (s, 2 H), 5.13 (m,
2 H), 5.90 (m, 1 H), 7.32 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 13.8, 37.9, 39.3, 73.4, 74.6, 74.9,
117.1, 127.6, 127.7, 128.4, 135.2, 137.8.
MS (EI, 70 eV): m/z = 221 [M + H+].
IR (neat): 3519, 2932, 1783, 1695, 1385, 1208 cm–1.
{[(2R,3S)-1-(Benzyloxy)-2-methylhex-5-en-3-yl]oxy}(tert-bu-
tyl)diphenylsilane (5)
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 6.8 Hz, 3 H), 1.04 (s,
9 H), 1.10 (d, J = 7.2 Hz, 3 H), 1.59 (m, 2 H), 2.09 (m, 1 H), 2.72
(dd, J = 13.2, 9.2 Hz, 2 H), 3.17 (dd, J = 6.4, 3.6 Hz, 1 H), 3.20 (m,
J = 6.4, 3.2 Hz, 1 H), 3.45 (dd, J = 9.6, 6.8 Hz, 1 H), 3.53 (dd,
J = 7.2, 3.6 Hz, 1 H), 3.93 (d, J = 9.6 Hz, 1 H), 4.05 (m, 3 H), 4.35
(s, 2 H), 4.54 (m, 1 H), 7.30 (m, 15 H), 7.67 (m, 5 H).
Imidazole (0.12 g, 1.80 mmol) and TBDPSCl (0.35 mL, 1.36 mmol)
were added to a soln of alcohol 4 (0.2 g, 0.90 mmol) in DMF (1 mL)
at r.t. After 24 h, the soln was poured into Et2O (6 mL) and washed
with H2O (3 × 3 mL) and brine (2 × 3 mL). The Et2O layer was
dried (MgSO4), filtered, and concentrated in vacuo. The crude prod-
uct was purified by flash column chromatography [silica gel, Et2O–
hexane (3:97)] to give a colorless oil; yield: 0.385 g (92.7%);
[a]D23 +36.0 (c 0.5, CHCl3).
13C NMR (50 MHz, CDCl3): d = 10.2, 10.8, 12.9, 27.1, 38.0, 38.8,
41.8, 42.9, 55.0, 65.9, 68.3, 68.7, 72.3, 72.8, 127.4, 127.5, 128.2,
128.9, 129.4, 129.6, 133.6, 134.4, 135.1, 136.0, 138.4, 152.9, 176.5.
HRMS: m/z calcd for C42H52NO6Si [M + H]+: 694.3563; found:
694.3585.
IR (neat): 2932, 2857, 1427, 1362, 1110 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.94 (d, J = 7.2 Hz, 3 H), 1.04 (s,
9 H), 2.02 (m, 1 H), 2.14 (m, 1 H), 2.20 (m, 1 H), 3.27 (dd, J = 9.6,
6.8 Hz, 1 H), 3.51 (dd, J = 9.6, 6.0 Hz, 1 H), 3.82 (m, 1 H), 4.36 (s,
2 H), 4.86 (m, 2 H), 5.65 (m, 1 H), 7.32 (m, 10 H), 7.66 (m, 5 H).
7-O-Benzyl-5-O-[tert-butyl(diphenyl)silyl]-2,4,6-trideoxy-1,3-
O-(4-methoxybenzylidene)-2,6-dimethyl-D-gluco-heptitol (8)
A 2 M soln of LiBH4 in THF (1.26 mL, 2.52 mmol) was added drop-
wise to a soln of aldol adduct 7 (0.7 g, 1.008 mmol) and anhyd
MeOH (0.1 mL, 2.52 mmol) in anhyd THF (20 mL) at 0 °C. The
mixture was stirred for 2 h at 0 °C, and then the reaction was
quenched with 2 M aq NaOH (70.6 mL). The mixture was stirred
for 18 h at r.t., the volatiles were removed under a vacuum, and the
resulting slurry was extracted with Et2O (5 × 150 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. Without further purification, the diol was dissolved in
CH2Cl2 (5 mL) and treated with 4-MeOC6H4CH(OMe)2 (0.21 mL,
1.26 mmol) and CSA (0.017 g, 0.08 mmol) at r.t., and the mixture
was stirred for a further 12 h. The reaction was quenched with sat.
aq NaHCO3 (10 mL), and the mixture was extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column
chromatography [silica gel, Et2O–hexane (4:96)] to give a colorless
oil; yield: 0.476 g (74%); [a]D23 –18.2 (c 0.5, CHCl3).
13C NMR (50 MHz, CDCl3): d = 13.5, 19.5, 27.1, 38.0, 38.1, 72.3,
72.7, 74.8, 116.6, 127.3, 127.4, 128.2, 129.4, 129.5, 134.5, 135.2,
136.0, 138.7.
HRMS: m/z calcd for C30H38NaO2Si [M + Na]+: 481.2538; found:
481.2543.
5-O-Benzyl-3-O-[tert-butyl(diphenyl)silyl]-2,4-dideoxy-4-meth-
yl-D-erythro-pentose (6)
2,6-Dimethylpyridine (0.12 mL, 1.09 mmol), OsO4 (1% in t-BuOH,
0.0026 g, 0.010 mmol), and NaIO4 (0.45 g, 2.09 mmol) were added
to a soln of compound 5 (0.24 g, 0.53 mmol) in 3:1 dioxane–H2O (2
mL). The mixture was stirred at 25 °C and the reaction was moni-
tored by TLC. When the reaction was complete, H2O (2.5 mL) and
CH2Cl2 (5 mL) were added. The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic layers were washed with brine and dried (Na2SO4).
The solvent was removed, and the product was purified by column
chromatography [silica gel, EtOAc–hexane (5:95)] to give aldehyde
6 as a colorless oil; yield: 0.216 g (89.6%); [a]D23 –0.80 (c 0.5,
CHCl3).
IR (neat): 2968, 2856, 1615, 1517, 1248 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.97 (d, J = 6.8 Hz, 3 H), 1.01 (d,
J = 6.8 Hz, 3 H), 1.06 (s, 9 H), 1.23 (m, 1 H), 1.44 (ddd, J = 11.2,
9.2, 1.6 Hz, 1 H), 1.61(ddd, J = 12.4, 10.4, 2.0 Hz, 1 H), 2.10 (m, 1
H), 3.25 (dd, J = 9.6, 6.8 Hz, 1 H), 3.35 (dd, J = 9.2, 7.2 Hz, 1 H),
IR (neat): 3383, 2956, 2858, 1737, 1588, 1386, 1253 cm–1.
Synthesis 2009, No. 16, 2709–2714 © Thieme Stuttgart · New York

2712
S. Padakanti et al.
PAPER
3.67 (dd, J = 10.8, 2.0 Hz, 1 H), 3.75 (s, 3 H), 3.79 (dd, J = 4.0, 2.8
Hz, 1 H), 3.85 (dt, J = 10.4, 2.0 Hz, 1 H), 4.22 (dt, J = 9.6, 2.8 Hz,
1 H), 4.31 (s, 2 H), 4.76 (s, 1 H), 6.74 (d, J = 8.8 Hz, 2 H), 7.14 (d,
J = 8.8 Hz, 2 H), 7.27 (m, 11 H), 7.65 (dd, J = 3.6, 1.6 Hz, 2 H), 7.67
(dd, J = 3.2, 1.2 Hz, 2 H).
HRMS: m/z calcd for C47H62NO7SiS [M + NH4]+: 812.4016; found:
812.4022.
({(2R,3S,5S)-1-(Benzyloxy)-5-[(4-methoxybenzyl)oxy]-2,6-di-
methylhept-6-en-3-yl}oxy)(tert-butyl)diphenylsilane (11)
A stirred soln of tosylate 10 (0.41 g, 0.51 mmol) in glyme (2 mL)
containing NaI (0.11 g, 0.77 mmol), and DBU (0.15 mL, 1.03
mmol) was refluxed for 3 h, then cooled to r.t., diluted with Et2O (6
mL) and H2O (6 mL), and stirred for 10 min. The layers were sepa-
rated and the aqueous phase was extracted with Et2O (2 × 6 mL).
The combined organic layers were washed with brine (6 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography [silica gel, EtOAc–hexane
(3:97)] to afford product 11 as an off-white solid; yield: 0.256 g
(80%); [a]D23 –11.6 (c 0.85, CHCl3).
13C NMR (50 MHz, CDCl3): d = 11.1, 11.9, 19.5, 27.0, 32.4, 36.5,
39.5, 55.2, 71.3, 72.6, 72.7, 73.5, 75.7, 100.9, 113.2, 127.2, 127.5,
128.1, 129.4, 129.5, 131.5, 133.9, 134.8, 136.0, 138.7, 159.5.
HRMS: m/z calcd for C40H51O5Si [M + H]+: 639.3505; found:
639.3484.
7-O-Benzyl-5-O-[tert-butyl(diphenyl)silyl]-2,4,6-trideoxy-3-O-
(4-methoxybenzyl)-2,6-dimethyl-D-gluco-heptitol (9)
A 1 M soln of DIBAL-H in toluene (2.97 mL, 2.97 mmol) was add-
ed dropwise to a stirred soln of acetal 8 (0.38 g, 0.59 mmol) in
CH2Cl2 (20 mL) at 0 °C, and the mixture was stirred for 2 h at 0 °C.
The reaction was quenched with MeOH (0.54 mL) and a sat. soln of
sodium potassium tartrate (15 mL) was added. The mixture was
stirred vigorously for 6 h and then extracted with CH2Cl2 (4 × 6
mL). The organic layer was washed with brine (6 mL), dried
(Na2SO4), and concentrated in vacuo. The residue that was purified
by column chromatography [silica gel, EtOAc–hexane (25:75)] to
give alcohol 9 as a colorless oil; yield: 0.35 g (91%); [a]D23 –10.5 (c
1.0, CHCl3).
IR (neat): 2956, 2858, 1514, 1245 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 13.2 Hz, 3 H), 1.05 (s,
9 H), 1.50 (s, 3 H), 1.62 (m, 2 H), 2.11 (m, 1 H), 3.22 (dd, J = 19.2,
13.6 Hz, 1 H), 3.37 (dd, J = 19.2, 14.0 Hz, 1 H), 3.56 (d, J = 21.6
Hz, 1 H), 3.73 (s, 3 H), 3.74 (m, 1 H), 4.05 (d, J = 22.4 Hz, 1 H),
4.17 (m, 1 H), 4.33 (s, 2 H), 4.77 (d, J = 22.8 Hz, 2 H), 6.69 (d,
J = 16.8 Hz, 2 H), 6.96 (d, J = 17.2 Hz, 2 H), 7.29 (m, 11 H), 7.67
(m, 4 H).
13C NMR (50 MHz, CDCl3): d = 12.3, 16.8, 19.5, 27.1, 38.2, 39.2,
55.2, 69.3, 72.1, 72.6, 72.7, 80.1, 112.5, 113.4, 127.2, 128.1, 128.8,
129.3, 129.4, 131.0, 134.1, 134.3, 136.0, 138.7, 145.2, 158.6
IR (neat): 3425, 2927, 1612, 1513, 1453, 1248 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.68 (d, J = 8.8 Hz, 3 H), 0.99 (d,
J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.56 (m, 1 H), 1.64 (m, 1 H), 2.01
(m, 1 H), 2.19 (m, 1 H), 2.56 (br s, 1 H), 3.24 (dd, J = 9.6, 6.4 Hz,
1 H), 3.35 (dd, J = 9.6, 7.6 Hz, 1 H), 3.42 (dd, J = 12.4, 3.2 Hz, 1
H), 3.45 (dd, J = 6.4, 3.2 Hz, 1 H), 3.55 (m, 1 H), 3.67 (d, J = 10.8
Hz, 1 H), 3.73 (s, 3 H), 4.11 (d, J = 10.4 Hz, 1 H), 4.14 (dt, J = 8.0,
3.2 Hz, 1 H), 4.33 (s, 2 H), 6.67 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 9.2
Hz, 2 H), 7.29 (m, 11 H), 7.66 (dd, J = 8.0, 1.2 Hz, 2 H), 7.71 (dd,
J = 8.0, 1.6 Hz, 2 H).
HRMS : m/z calcd for C40H54NO4Si [M + NH4]+: 640.3822; found:
640.3808.
7-O-Benzyl-1-O-[tert-butyl(dimethyl)silyl]-5-O-[tert-bu-
tyl(diphenyl)silyl]-2,4,6-trideoxy-3-O-(4-methoxybenzyl)-2,6-
dimethyl-D-gluco-heptitol (12)
TBSCl (0.30 g, 2.03 mmol) and imidazole (0.17 g, 2.54 mmol) were
added to a soln of alcohol 9 (0.65 g, 1.01 mmol) in DMF (5 mL),
and the mixture was stirred at r.t. overnight. It was then treated with
sat. aq NH4Cl (5 mL) and partitioned between Et2O (10 ml) and H2O
(5 mL). The Et2O layer was washed with H2O (2 × 5 mL) and brine
(2 × 5 mL), dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash chromatography [silica gel, EtOAc–hexane
(5:95)] to give compound 12 as a colorless liquid; yield: 0.697 g
(91%); [a]D23 +3.30 (c 1.0, CHCl3).
13C NMR (50 MHz, CDCl3): d = 11.9, 12.2, 19.4, 27.0, 33.3, 36.4,
39.3, 55.2, 65.8, 70.9, 72.3, 72.6, 72.8, 80.1, 113.5, 127.2, 127.3,
128.1, 129.5, 129.6, 130.4, 134.1, 136.0, 136.1, 138.6, 158.9.
HRMS: m/z calcd for C40H53O5Si [M + H]+: 641.3662; found:
641.3667.
7-O-Benzyl-5-O-[tert-butyl(diphenyl)silyl]-2,4,6-trideoxy-3-O-
(4-methoxybenzyl)-2,6-dimethyl-1-O-[(4-methylphenyl)sulfo-
nyl]-D-gluco-heptitol (10)
TsCl (0.15 g, 0.79 mmol) was added to a stirred soln of alcohol 9
(0.34 g, 0.53 mmol) in pyridine (2 mL) at 0 °C, and the mixture was
stirred for 2 h at r.t. H2O (2 mL) and Et2O (5 mL) were added, and
the organic layer was separated. The ethereal layer was washed with
1 M HCl (2 mL), sat. aq NaHCO3 (2 × 2 mL), and brine (2 mL), then
dried (Na2SO4), filtered, and concentrated. The residue was purified
by flash chromatography [silica gel, EtOAc–hexane (5:95)] to give
IR (neat): 2956, 2857, 1513, 1244 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.01 (s, 6 H), 0.69 (d, J = 6.8 Hz,
3 H), 0.86 (s, 9 H), 0.96 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.55 (m,
1 H), 1.62 (m, 2 H), 2.11 (m, 1 H), 3.24 (dd, J = 10.0, 6.8 Hz, 1 H),
3.29 (dd, J = 9.6, 6.8 Hz, 1 H), 3.39 (dd, J = 5.1, 2.4 Hz, 1 H), 3.44
(dd, J = 8.0, 4.0 Hz, 1 H), 3.51 (dt, J = 10.0, 10.0 Hz, 1 H), 3.74 (s,
3 H), 3.80 (d, J = 12.0 Hz, 1 H), 4.02 (ddd, J = 7.2, 4.4, 2.4 Hz, 1
H), 4.09 (d, J = 11.2 Hz, 1 H), 4.34 (d, J = 3.6 Hz, 1 H), 4.35 (d,
J = 3.6 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H),
7.28 (m, 11 H), 7.35 (dd, J = 7.6, 1.6 Hz, 2 H), 7.69 (dd, J = 8.4, 1.6
Hz, 2 H)
23
the pure product 10 as a colorless oil; yield: 0.413 g (98%); [a]D
–4.2 (c 1.0, CHCl3).
IR (neat): 2958, 2857, 1612, 1513, 1363, 1247 cm–1.
13C NMR (50 MHz, CDCl3): d = –5.3, 11.6, 12.8, 19.5, 25.9, 27.1,
35.5, 38.8, 39.0, 55.2, 64.7, 71.1, 72.5, 72.7, 72.9, 76.3, 113.3,
127.1, 127.3, 127.4, 128.1, 128.7, 129.4, 131.4, 134.3, 135.9, 136.1,
158.8.
1H NMR (400 MHz, CDCl3): d = 0.68 (d, J = 14 Hz, 3 H), 0.95 (d,
J = 14.4 Hz, 3 H), 1.03 (s, 9 H), 1.50 (m, 2 H), 1.95 (m, 1 H), 2.09
(m, 1 H), 2.39 (s, 3 H), 3.29 (m, 3 H), 3.61 (m, 1 H), 3.66 (d, J = 10.0
Hz, 1 H), 3.74 (s, 3 H), 3.75 (d, J = 10.0 Hz, 1 H), 3.93 (m, 1 H),
4.01 (m, 1 H), 4.32 (s, 2 H), 6.65 (d, J = 17.2 Hz, 2 H), 6.79 (d,
J = 17.2 Hz, 2 H), 7.27 (m, 13 H), 7.66 (m, 6 H).
HRMS : m/z calcd for C46H67O5Si2 [M + H]+: 755.4527; found:
755.4519.
1-O-[tert-Butyl(dimethyl)silyl]-5-O-[tert-butyl(diphenyl)silyl]-
2,4,6-trideoxy-3-O-(4-methoxybenzyl)-2,6-dimethyl-D-gluco-
heptitol (13)
Raney Ni (2 g) was added to a stirred soln of the protected deriva-
tive 12 (0.65 g, 0.86 mmol) in absolute EtOH (20 mL) and the mix-
13C NMR (50 MHz, CDCl3): d = 11.2, 12.3, 19.4, 21.5, 27.0, 35.1,
36.1, 38.9, 55.2, 71.0, 72.2, 72.4, 72.7, 76.4, 76.5, 113.4, 127.3,
127.4 127.5, 128.7, 128.9, 129.5, 129.7, 130.8, 133.1, 133.9, 134.1,
136.0, 138.6, 144.5, 158.7.
Synthesis 2009, No. 16, 2709–2714 © Thieme Stuttgart · New York

PAPER
The C11–C19 Fragment of Rhizoxin D
2713
ture was stirred at r.t. under H2 (60 psi) for 24 h. The mixture was
then filtered through Celite on top of silica gel, and the filtrate was
concentrated in vacuo. The residue was purified by column chroma-
tography [silica gel, EtOAc–hexane (10:90)] to give 13 as a gummy
mass; yield: 0.463 g (81%); [a]D23 –2.40 (c 0.5, CHCl3).
to give the single diastereomer 15 as a colorless liquid; yield: 0.20
g (63%); [a]D23 +34.0 (c 0.25, CHCl3).
IR (neat): 3492, 2932, 1613, 1514, 1249 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.001 (s, 6 H), 0.36 (d, J = 6.8
Hz, 3 H), 0.83 (s, 9 H), 0.95 (d, J = 7.2 Hz, 3 H), 1.05 (s, 9 H), 1.35
(m, 2 H), 1.53 (s, 3 H), 1.62 (m, 1 H), 1.73 (dd, J = 6.8 Hz, 1 H),
2.07 (m, 1 H), 3.21 (dd, J = 9.6, 6.4 Hz, 1 H), 3.34 (dt, J = 11.6, 4.4
Hz, 1 H), 3.42 (dd, J = 9.6, 7.6 Hz, 1 H), 3.78 (s, 3 H), 3.83 (s, 2 H),
4.14 (d, J = 11.2 Hz, 1 H), 4.23 (d, J = 10.8 Hz, 1 H), 4.86 (d,
J = 1.2 Hz, 1 H), 5.08 (s, 1 H), 6.79 (d, J = 8.4 Hz, 2 H), 7.06 (d,
J = 8.4 Hz, 2 H), 7.38 (m, 6 H), 7.70 (dd, J = 8.0, 1.6 Hz, 4 H).
IR (neat): 3442, 2956, 2857, 1514, 1249 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.008 (s, 3 H), –0.007 (s, 3 H),
0.69 1(d, J = 6.8 Hz, 3 H), 0.86 (s, 9 H), 1.00 (d, J = 7.2 Hz, 3 H),
1.06 (s, 9 H), 1.55 (m, 1 H), 1.75 (m, 2 H), 1.87 (m, 1 H), 2.30 (m,
1 H), 3.24 (m, 1 H), 3.29 (dd, J = 4.6, 2.8 Hz, 1 H), 3.40 (dd, J = 8.2,
5.6 Hz, 1 H), 3.49 (dd, J = 10.0, 6.4 Hz, 1 H), 3.62 (m, 1 H), 3.77
(s, 3 H), 3.83 (d, J = 10.8 Hz, 1 H), 3.91 (dt, J = 8.4, 2.8 Hz, 1 H),
4.20 (d, J = 10.8 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 2 H), 7.00 (d, J = 8.8
Hz, 2 H), 7.40 (m, 6 H), 7.70 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = –5.3, 0.05, 10.3, 10.5, 19.7, 25.9,
27.0, 35.7, 37.4, 38.1, 55.2, 64.7, 71.2, 73.5, 75.9, 83.5, 110.3,
113.5, 127.7, 129.7, 130.8, 132.2, 135.9, 136.0, 154.0, 158.9.
13C NMR (50 MHz, CDCl3): d = –5.3, 11.7, 12.6, 18.2, 19.4, 25.9,
27.0, 35.0, 38.2, 39.5, 55.2, 64.1, 64.8, 71.3, 74.4, 77.9, 113.6,
127.5, 129.2, 129.7, 133.5, 133.9, 136.0, 158.8.
HRMS : m/z calcd for C42H65O5Si2 [M + H]+: 705.4370; found:
705.4380.
MS (EI, 70 eV): m/z = 665 [M +].
Acknowledgment
7-O-[tert-Butyl(dimethyl)silyl]-3-O-[tert-butyl(diphenyl)silyl]-
2,4,6-trideoxy-5-O-(4-methoxybenzyl)-2,6-dimethyl-L-gulo-
heptose (14)
We thank Dr. Reddy’s Laboratories Ltd. for financial support and
encouragement. Help from the analytical department in recording
spectral data is appreciated.
Dess–Martin periodinane (0.46 g, 1.08 mmol) was added to a soln
of alcohol 13 (0.35 g, 0.526 mmol) in anhyd CH2Cl2 (10 mL) at r.t.,
and the mixture was stirred for 30 min. The soln was diluted with
CH2Cl2 (10 mL), a mixture of sat. aq Na2S2O3 (5 mL) and sat. aq
NaHCO3 (5 mL) was added, and the soln was stirred vigorously for
10 min. H2O (10 mL) and CH2Cl2 (10 mL) were added to the mix-
ture, the layers were separated, and the aqueous phase was extracted
with CH2Cl2 (2 × 10 mL). The combined organic extract was
washed with sat. aq NaHCO3 (10 mL) then dried (Na2SO4). The sol-
vent was removed in vacuo, and the residue was purified by chro-
matography [silica gel, EtOAc–hexane (6:94)] to give 14 as a
colorless liquid; yield: 0.31 g (89%); [a]D23 +33.33 (c 0.37, CHCl3).
References
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Tetrahedron Lett. 1992, 33, 3907. (b) Rama Rao, A. V.;
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IR (neat): 2931, 2857, 1725, 1513, 1248 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.017 (s, 6 H), 0.63 (d, J = 7.2
Hz, 3 H), 0.85 (s, 9 H), 1.04 (s, 9 H), 1.09 (d, J = 7.2 Hz, 3 H), 1.57
(m, 1 H), 1.67 (dd, J = 6.0, 4.4 Hz, 2 H), 2.49 (m, 1 H), 3.27 (dd,
J = 9.6, 6.8 Hz, 1 H), 3.42 (m, 1 H), 3.47 (dd, J = 9.6, 6.4 Hz, 1 H),
3.78 (s, 3 H), 3.97 (d, J = 11.2 Hz, 1 H), 4.11 (dt, J = 6.2, 4.4 Hz, 1
H), 4.25 (d, J = 11.2 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 2 H), 7.03 (d,
J = 8.8 Hz, 2 H), 7.38 (m, 6 H), 7.66 (m, 4 H), 9.66 (t, J = 1.6 Hz, 1
H).
13C NMR (50 MHz, CDCl3): d = –5.3, 10.1, 11.5, 19.4, 25.9, 27.0,
29.7, 36.9, 38.4, 51.4, 55.2, 64.3, 71.0, 72.5, 76.3, 113.5, 127.6,
128.8, 129.8, 135.9, 135.9, 158.8, 203.9.
MS (EI, 70 eV): m/z = 680 [M + NH4]+.
(3R,4R,5S,7S,8S)-9-{[tert-Butyl(dimethyl)silyl]oxy}-5-{[tert-bu-
tyl(diphenyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-2,4,8-tri-
methylnon-1-en-3-ol (15)
A 1.7 M soln of t-BuLi in pentane (1.64 mL, 2.80 mmol) was added
dropwise to a THF (5 mL) soln of 2-bromopropene (0.12 mL, 1.40
mmol) at –78 °C, and the mixture was maintained at –78 °C for 0.5
h. A soln of aldehyde 14 (0.3 g, 0.45 mmol) in THF (3 mL) was then
added slowly over 30 min by using a syringe pump. The resulting
soln was maintained at –78 °C for 4 h and then the reaction was
quenched with sat. aq NH4Cl (5 mL). The organic layer was sepa-
rated and the aqueous phase was extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with brine (10 mL),
dried (Na2SO4), and concentrated to give 0.28 g of an almost color-
less oil comprising an 8:2 mixture of epimers (NMR). This mixture
was purified by chromatography [silica gel, EtOAc–hexane (4:96)]
Synthesis 2009, No. 16, 2709–2714 © Thieme Stuttgart · New York

2714
S. Padakanti et al.
PAPER
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(13) Srinivas, P.; Sreekanth, B. R.; Mahendar, V.; Pal, M.;
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(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
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Synthesis 2009, No. 16, 2709–2714 © Thieme Stuttgart · New York