Chemo-enzymatic synthesis of the C15-C23 unit of Leptomycin B

Article abstract of DOI:10.1139/v02-070

The asymmetric synthesis of the C₁₅-C₂₃ unit of Leptomycin B (LMB) is described. All four stereocenters of the C₁₅-C₂₃ unit were prepared from one building block exhibiting only one stereocenter. This building block was synthesized via either an enzymatic transformation or starting from a chiral reagent.

Full text of DOI:10.1139/v02-070

5
71
Chemo-enzymatic synthesis of the C –C
15
23
unit of Leptomycin B
Michael Scheck and Herbert Waldmann
Abstract: The asymmetric synthesis of the C -C unit of Leptomycin B (LMB) is described. All four stereocenters
1
5
23
of the C -C unit were prepared from one building block exhibiting only one stereocenter. This building block was
1
5
23
synthesized via either an enzymatic transformation or starting from a chiral reagent.
Key words: Leptomycin, natural product synthesis, enzymatic transformation, Aldol reaction, Pseudomonas fluorescence
lipase (PFL).
Résumé : On décrit la synthèse asymétrique de l’unité C -C de la leptomycine B. Les quatre stéréocentres de
1
5
23
l’unité C -C ont été préparés à partir d’un seul bloc ne comportant qu’un seul stéréocentre. Ce bloc a été synthétisé
1
5
23
par le biais d’une transformation enzymatique ou à partir d’un ensemble chiral.
Mots clés : leptomycine, synthèse d’un produit naturel, transformation enzymatique, réaction aldolique, lipase Pseudo-
monas fluorescence (PFL).
[
Traduit par la Rédaction] Scheck and Waldmann 576
Introduction
et al. (17) Herein we report the synthesis of the C -C
15 23
fragment employing a substrate-controlled diastereoselective
aldol reaction to assemble two smaller subunits, which are
both derived from monoprotected chiral diol 6.
Leptomycin B (LMB, 1) is an unsaturated branched-chain
polyketide isolated from Streptomyces sp (1, 2), which was
found to induce arrest of the eukaryotic cell cycle at G1 and
G2 phases (3). LMB is a specific inhibitor of proteins con-
taining a nuclear-export signal and has been used as an im-
portant tool in the study of this phenomenon (4). It inhibits
nucleo-cytoplasmic translocation of molecules such as the
HIV-1 Rev protein and Rev-dependent export of mRNA,
thereby inhibiting the propagation of HIV-1 in low nano-
molar concentrations (5, 6). LMB also interacts with the nu-
clear-export signal of Hepatitis B Virus X and causes the
virus to accumulate in the nucleus (7). Other proteins that
are influenced by LMB are actin (8), c-Abl (9), cyclin B1
Results and discussion
The retrosynthetic analysis of LMB (1) described in
Scheme 1 dissects the molecule at the central diene moiety
(C-13 and C-14) using the Stille transformation to provide
two fragments of nearly equal size and structural complex-
ity. The northern half (3) contains a polypropionate unit with
four stereocenters, which can be derived from fragments 4
and 5 by a diastereoselective aldol reaction. In turn, both
fragments can be synthesized from the same building block
(6). Through this sequence all four stereocenters in 3 can be
traced back to a single stereocenter in 6.
Synthesis of the key building block 6 begins from methyl-
malonic acid diethyl ester (7), which was first reduced with
borane and then acetylated to afford diacetate 8 (Scheme 2).
Via an enzymatic resolution with Pseudomonas fluorescens
lipase (PFL), the selective hydrolysis of diacetate 8 to
monoacetate 9 could be achieved with an enantiomeric ex-
cess of 95% (18, 19). Protection of the free hydroxy function
of 9 as a TBS-ether and cleavage of the acetate with potas-
sium carbonate in methanol provided the central building
block 6. (R)-Methyl-3-hydroxy-2-methylpropanoate (10) also
yielded 6 after TBS-protection and reduction with diiso-
butylaluminiumhydride (DIBAH).
(
10), MDM2/p53 (11), IꢀB (12), MPF (13), and PKA (14).
The suggested inhibition mechanism involves the direct
binding of LMB to CRM1 (chromosomal region mainte-
nance), which blocks the binding of CRM1 to proteins con-
taining the nuclear-export signal (6, 15), via the interaction
with a cysteine residue in CRM1 (16).
Due to these outstanding properties, LMB is an interesting
target for total synthesis. The absolute stereochemistry was
proven through the only known total synthesis by Kobayashi
Received 6 December 2001. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 7 May 2002.
Dedicated to Professor J. Bryan Jones on the occasion of his
6
5th birthday.
1
M. Scheck and H. Waldmann. Max-Planck Institut für
molekulare Physiologie, Otto-Hahn-Strasse 11, 44227
Dortmund, Germany; and Institut für Organische Chemie,
Universität Dortmund, Otto-Hahn-Strasse 8, 44227 Dortmund,
Germany.
Swern oxidation of alcohol 6, followed by Grignard addi-
tion of ethylmagnesium bromide to the resulting aldehyde
furnished alcohol 11, which was oxidized with tetrapropy-
lammonium perruthenate (TPAP) and N-methylmorpholine
N-oxide (NMO) to ketone 5 (Scheme 3). The second build-
ing block (4) for the asymmetric aldol reaction was also syn-
thesized from 6. After transformation of the hydroxy
1Corresponding author (e-mail: herbert.waldmann@mpi-
dortmund.mpg.de).
Can. J. Chem. 80: 571–576 (2002)
DOI: 10.1139/V02-070
© 2002 NRC Canada

5
72
Can. J. Chem. Vol. 80, 2002
Scheme 1. Retrosynthetic analysis of Leptomycin B (LMB, 1).
Scheme 2. Reagents and conditions: (a) BH , Et O, rt, 87%;
3
2
(
b) Ac O, pyridine, reflux, 95%; (c) Pseudomonas fluorescence
2
lipase, pH 7, rt, 31%, ee O 95%; (d) TBSCl, imidazole, DMF, rt,
9%; (e) K CO , MeOH, reflux, 69%; ( f ) TBSCl, imidazole,
9
2
3
DMF, rt, quant.; (g) DIBAH, THF, –78°C, 96%.
Scheme 3. Reagents and conditions: (a) (COCl) , DMSO, NEt ,
2
3
DCM, –78°C, 68%; (b) EtMgBr, Et O, reflux, 94%; (c) TPAP,
2
NMO, 4 Å MS, DCM, rt, 78%; (d) I , PPh , imidazole, toluene,
2
3
rt, 100%; (e) 2-propenyl–MgBr, CuI (2.5 mol%), DMPU, THF,
20°C to 0°C, 93%; ( f ) TBAF, HOAc, 4 Å MS, THF, rt, 72%;
g) (COCl) , DMSO, NEt , DCM, –78°C, 75%.
–
(
2
3
function of 6 into an iodide (12) a Cu(I)-catalyzed cross-
coupling with 2-propenylmagnesium bromide led to silyl-
protected alcohol 13 (19). Deprotection of the silyl ether 13
with tetrabutylammonium fluoride buffered with acetic acid
and subsequent Swern oxidation provided aldehyde 4.
Coupling of fragments 4 and 5 was achieved by a diastereo-
selective substrate-controlled Aldol-addition of a Ti(IV)-enolate
Scheme 4. Reagents and conditions: (a) DIPEA, TiCl , THF,
4
–
78°C, 42%, diastereomers: 1.8:1 RS:SR, syn–anti: 10:1;
(
b) HOCH CH OH, TMSCl, rt, 84%; (c) MOMCl, DIPEA,
2
2
DCM, 0°C, 29%.
(Scheme 4) (20). Although this represents a mismatched case
between the influence of the C-20 and the C-16 stereocenters,
Felkin–Anh control by C-20 is slightly favored affording an ap-
proximate 1.8:1 mixture of syn diastereomers, with the desired
diastereomer predominating (21). The desired product could be
readily separated by preparative HPLC. Finally, the keto func-
tion was protected as a 1,3 dioxolane and the hydroxy function
as a methoxymethyl ether (15).
1
methylene chloride over CaH immediately prior to use. H
2
1
3
and C NMR spectra were recorded in CDCl on Bruker
3
AC-250, AM-400, or DRX-500 spectrometers (250, 400,
and 500 MHz, respectively). The enantiomeric excess was
determined with gas chromatography, which was carried out
on a Hewlett Packard 5890 Series II gas chromatograph with
a capillary column Lipodex E (with chiral stationary phase)
from Macherey&Nagel, a mass selective detector Hewlett
Packard MSD 5972 A, and using the racemate as the refer-
ence. All measurements were carried out with helium as car-
Compound 15, which represents the C -C fragment of
1
5
23
LMB, was synthesized in a highly convergent fashion using
. The terminal olefin provides a handle for extension to the
6
desired carboxylic acid, while the TBS protected alcohol
should allow conversion to the desired trisubstituted vinyl
iodide.
rier gas. Optical rotations were measured with
a
PerkinElmer 241 polarimeter at ambient temperature. TLC
was conducted on Merck aluminum slides coated with silica
gel 60 F254. Flash column chromatography was performed
using Baker silica gel 60 (corn size 30–60 ꢁm). HPLC was
carried out with a L-6000A-HPLC from Merck/Hitachi with
diode-array detector L-3000. A EC 250/4 Nucleosil (100–5)
PPN from Macherey&Nagel was used as column. Mass
Experimental
General methods
All reactions were carried out under argon unless water
was used.
Solvents were dried by distillation prior to use. Tetra-
hydrofuran was distilled from sodium–benzophenone and
©
2002 NRC Canada

Scheck and Waldmann
573
spectrometry and high resolution mass spectrometry were
carried out with a Finnigan MAT 90.
added and the aqueous phase was extracted with diethyl
ether (4 × 20 mL). The combined organic layers were
washed with 10 mL of
a
5% aqueous sodium
2
-Methyl-1,3-propanediol
To a solution of 2.17 g (12.5 mmol) of methylmalonic
hydrogencarbonate solution and dried over MgSO4. Column
chromatography (cyclohexane–ethyl acetate 50:1) afforded
0.79 g (3.23 mmol, 100%) of the title compound as a color-
acid diethyl ester (7) in 20 mL of THF was added 12.5 mL
18.8 mmol) of a 1.5 M solution of borane in THF at –78°C.
20
1
(
less oil. [a] +5.0 (c = 0.8, CH Cl ). H NMR (250 MHz,
D
2 2
The mixture was allowed to warm to room temperature and
stirred overnight. A 10% aqueous solution of citric acid was
added until a clear solution was obtained. The solvent was
removed under reduced pressure and the resulting white
solid was dissolved in water. The solution was extracted
with methylene chloride (4 × 50 mL) and the combined or-
CDCl ) d: 0.02 (s, 6H, Si-CH ), 0.87 (s, 9H, Si-C(CH ) ),
3 3 3 3
0.97–1.03 (m, 3H, CH-CH ), 1.90–1.98 (m, 1H, CH), 2.02
3
(s, 3H, CO-CH ), 3.42 (d, J = 6.4 Hz, 2H, CH -O-Si),
3
2
1
3.87–4.02 (m, 2H, CH -O-CO). The H NMR data is in con-
2
cordance with literature (18).
ganic layers were dried over MgSO . Column chromatogra-
phy (cyclohexane–ethyl acetate 1:1) afforded 0.98 g
(2S)-3-([tert-Butyldimethylsilyl]oxy)-2-methyl-1-propanol
(6)
4
(
10.9 mmol, 87%) of the title compound as a colorless oil.
To a solution of 0.75 g (3.04 mmol) of (2R)-acetic acid-3-
([tert-butyldimethylsilyl]oxy)-2-methyl-propyl ester in 5 mL
of methanol was added 5 mL of a 10% aqueous potassium
carbonate solution. The mixture was heated at reflux for 5 h
and the then solvent was removed under reduced pressure.
The resulting white solid was dissolved in 10 mL of water
and extracted with methylene chloride (4 × 20 mL). The
1
H NMR (250 MHz, CDCl ) d: 0.88 (d, J = 7.8 Hz, 3H,
3
CH ), 1.63–1.70 (m, 1H, CH), 3.40–3.63 (m, 4H, CH ), 3.71
(
erature (18).
3
2
1
br s, 2H, OH). The H NMR data is in concordance with lit-
2
-Methyl-1,3-propanediyl diacetate (8)
To a solution of 1.0 g (11.0 mmol) of 2-methyl-1,3-
combined organic layers were dried over MgSO . Column
4
propane diol in 20 mL of THF was added 16.6 g (54.5 mmol)
of acetic acid anhydride and 6.6 mL (82 mmol) of pyridine
and the mixture was stirred at room temperature for 2 days.
The solvent was removed under reduced pressure and the re-
sulting white solid was dissolved in 30 mL of water. The so-
lution was extracted with diethyl ether (3 × 40 mL) and
chromatography (cyclohexane–ethyl acetate 4:1) afforded
0.43 g (2.09 mmol, 69%) of the title compound as a color-
20
1
less oil. [a] +11.0 (c = 1.2, CHCl ). H NMR (250 MHz,
D
3
CDCl ) d: 0.02 (s, 6H, Si-CH ), 0.84 (d, J = 7.8 Hz, 3H,
3
3
CH-CH ), 0.87 (s, 9H, C(CH ) ), 1.89–2.04 (m, 1H, CH),
3
3 3
2.68 (br s, 1H, OH), 3.29–3.74 (m, 4H, CH -O-Si and CH -
2
2
1
dried over MgSO . After solvent removal in vacuo, 1.83 g
OH). The H NMR data is in concordance with literature
(22).
4
(
10.5 mmol, 95%) of the title compound were obtained as a
1
colorless oil H NMR (250 MHz, CDCl ) d: 1.02 (d, J =
3
7
.5 Hz, 3H, CH ), 2.01 (s, 6H, CO-CH ), 2.14–2.21 (m, 1H,
(2R)-3-([tert-Butyldimethylsilyl]oxy)-2-methyl propanoate
To a solution of 1.0 mL (9.02 mmol) of (R)-methyl-3-
hydroxy-2-methyl propanoate (10) in 5 mL of dry N,N-
dimethylformamide were added 1.87 g (27.3 mmol) of
imidazole and 2.30 g (14.7 mmol) of tert-butyldimethyl-
chlorsilane. The mixture was stirred for 3 h at room temper-
ature, then 40 mL of water and 40 mL of diethyl ether were
added and the aqueous phase was extracted with diethyl
ether (4 × 40 mL). The combined organic extracts were
washed with 40 mL of a 5% aqueous sodium hydrogen-
3
3
1
CH), 4.01 (d, J = 4.9 Hz, 4H, CH ). The H NMR data is in
concordance with literature (18).
2
(
2R)-Acetic acid-3-hydroxy-2-methyl-propyl ester (9)
To a suspension of 1.83 g (10.35 mmol) of 2-methyl-1,3-
propane diacetate (8) in 100 mL phosphate buffer (0.1 M,
pH 7) was added 900 mg of Pseudomonas fluorescens lipase
immobilized on Sol-Gel-AK and the mixture was stirred at
3
0°C for 2.5 h. Diethyl ether (100 mL) was added and the
solution was filtered to recover the enzyme. The solution
was extracted with diethyl ether (2 × 100 mL), the organic
carbonate solution and dried over MgSO . Column chroma-
4
tography (cyclohexane–ethyl acetate 5:1) afforded 2.09 g
(9.00 mmol, quantitative) of the title compound as a color-
layers were combined and dried over MgSO . Column chro-
4
2
0
1
matography (cyclohexane–ethyl acetate 1:1) afforded 0.43 g
less oil. [a] +18.1 (c = 4.0, CHCl ). H NMR (250 MHz,
D
3
(
3.26 mmol, 31%) of the title compound as a colorless oil.
CDCl ) d: 0.02 (s, 6H, Si-CH ), 0.87 (s, 9H, C(CH ) ), 1.11
3 3 3 3
20
1
[a] +7.1 (c = 0.9, CHCl ). H NMR (250 MHz, CDCl ) d:
(d, J = 6.8 Hz, 3H, CH-CH ), 2.43–2.54 (m, 1H, CH),
D
3
3
3
1
0
2
.98 (d, J = 8.6 Hz, 3H, CH ), 2.01 (s, 3H, CO-CH ),
3.22–3.46 (m, 2H, CH ), 3.56 (s, 3H, O-CH ). The H NMR
3
3
2
3
.04–2.11 (m, 1H, CH), 2.27 (s, 1H, OH), 3.43–3.54 (m, 2H,
data is in concordance with literature (23).
1
CH -OH), 4.01–4.12 (m, 2H, CH -O-CO). The H NMR
2
2
data is in concordance with literature (18).
(2S)-3-([tert-Butyldimethylsilyl]oxy)-2-methyl-1-propanol
6)
To a solution of 1.94 g (8.40 mmol) of methyl-(2R)-3-
(
(
2R)-Acetic acid-3-([tert-butyldimethylsilyl]oxy)-2-
methyl-propyl ester
([tert-butyldimethylsilyl]oxy)-2-methyl propanoate in 25 mL
of THF was added 18.5 mL of a 1.0 M solution of
diisobutylaluminiumhydride in heptane at –78°C. The solu-
tion was stirred for 2 h at that temperature and additional
15 h at room temperature. The mixture was quenched with
40 mL of methanol and 15 mL of brine at –78°C. After stir-
To a solution of 430 mg (3.26 mmol) of (2R)-acetic acid-
-hydroxy-2-methyl-propyl ester (9) in 1.5 mL of dry N,N-
3
dimethylformamide were added 0.60 g (9.8 mmol) of
imidazole and 0.72 g (4.6 mmol) of tert-butyldimethylsilyl
chloride, and the mixture was stirred at room temperature
for 2 days. Water (2 mL) and diethyl ether (10 mL) were
ring for 1 hour the mixture was dried over MgSO and
4
©
2002 NRC Canada

5
74
Can. J. Chem. Vol. 80, 2002
+
+
filtered through Celite. After solvent removal 1.64 g
8.06 mmol, 96%) of the title compound was obtained as a
[C(CH ) ] , 55 (12.9), 43 (33.5)[C H ] , 42 (49.6), 41
3
3
3
7
(
(36.1). FAB-HRMS: calcd. for C H O Si: 232.4351;
found: 232.4379.
12 28 2
20
1
colorless liquid. [a] +11.0 (c = 2.0, CH Cl ). H NMR
D
2
2
(
250 MHz, CDCl ) d: 0.02 (s, 6H, Si-CH ), 0.84 (d, J =
3
3
7
1
.3 Hz, 3H, CH-CH ), 0.87 (s, 9H, C(CH ) ), 1.89–2.04 (m,
(2R)-1-([tert-Butyldimethylsilyl]oxy)-2-methyl-3-
pentanone (5)
3
3 3
H, CH), 2.68 (br s, 1H, OH), 3.29–3.74 (m, 4H, CH -O-Si
2
1
and CH -OH). The H NMR data is in concordance with lit-
To a mixture of 6.91 g (29.8 mmol) of (2R)-1-([tert-
butyldimethylsilyl]oxy)-2-methyl-3-pentanol (11), 6.11 g
2
erature (22).
(
44.7 mmol) of N-methylmorpholin N-oxide and 14.9 g of
(
2S)-3-([tert-Butyldimethylsilyl]oxy)-2-methyl-1-propanal
To a solution of 0.67 mL (7.8 mmol) of oxalyl chloride in
molecular sieves (4 Å) in 100 mL of methylene chloride was
added 209 mg (0.59 mmol) of tetrapropylammonium
perruthenate. The mixture was stirred for 1 day at room tem-
perature, tetrapropylammonium perruthenate was filtered off,
and the resulting brown solution was consecutively washed
with 100 mL of a saturated solution of ammonium chloride,
sodium chloride, and copper sulfate. The organic layer was
0 mL of methylene chloride was added 0.74 mL
for 20 min, 1.05 g (5.17 mmol) of (2S)-3-([tert-butyl-
dimethylsilyl]oxy)-2-methyl-1-propanol (6) was added and
after 30 min 5.1 mL (36.2 mmol) of triethylamine. After
stirring for additional 5 min at –78°C, the solution was al-
lowed to warm to room temperature and stirred for 1 hour.
After cooling to –78°C water (25 mL) was added, the mix-
ture was allowed to warm to room temperature and the aque-
ous layer was extracted with methylene chloride (4 ×
then dried over MgSO . Column chromatography (cyclohex-
4
ane–ethyl acetate 10:1) afforded 5.36 g (23.2 mmol, 78%) of
2
0
the title compound as a colorless oil. [a] +4.3 (c = 0.2,
D
1
CH Cl ). H NMR (400 MHz, CDCl ) d: 0.01 (s, 6H, Si-
2
2
3
CH ), 0.85 (s, 9H, C(CH ) ), 0.99–1.03 (m, 6H, CH-CH
3
3 3
3
6
0 mL). The organic layers were combined and dried over
and CH -CH ), 2.49 (q, J = 7.1 Hz, 2H, CH -CH ),
2 3 2 3
1
3
MgSO . Column chromatography (cyclohexane–ethyl ace-
2.74–2.79 (m, 1H, CH), 3.56–3.60 (m, 2H, O-CH2).
C
4
tate 10:1) afforded 0.71 g (3.51 mmol, 68%) of the title
NMR (100.6 MHz, CDCl ) d: –5.60 (Si-CH ), 7.43 (CH -
3
3
2
2
0
compound as a colorless oil. [a] +25.5 (c = 2.2, CHCl3).
CH ), 13.06 (CH-CH ), 18.15 (C-(CH ) ), 25.77 (C-(CH ) ),
D
3 3 3 3 3 3
1
H NMR (250 MHz, CDCl ) d: 0.02 (s, 6H, Si-CH ), 0.87
35.95 (CH -CH ), 48.26 (CH-CH ), 65.71 (CH -O), 214.44
2 3 3 2
3
3
+
(
2
1
s, 9H, C(CH ) ), 1.06 (d, J = 5.3 Hz, 3H, CH-CH ),
(C=O). MS (70 eV) m/z (%): 230 (8.0) [M] , 215 (3.1) [M –
3
3
3
+
+
.42–2.48 (m, 1H, CH), 3.41–3.51 (m, 2H, CH ), 9.63 (s,
CH ] , 189 (31.0), 174 (12.6), 173 (100) [M – C(CH ) ] ,
2
3
3
3
1
+
H, COH). The H NMR data is in concordance with litera-
147 (13.3), 143 (16.9) [M – CH – CH – C(CH ) ] , 131
3 3 3 3
(10.0), 115 (34.8) [M – CH – CH – C(CH ) – Si] , 99
4.3) [M – CH – CH – C(CH ) – Si – O] , 75 (63.5)
3 3
HO=Si(CH ) ] , 73 (25.7) [C H O ] , 69 (11.1), 57 (12.9)
+
ture (24).
3 3 3 3
+
(
[
[
3 3
+ +
+
(
(
2R)-1-([tert-Butyldimethylsilyl]oxy)-2-methyl-3-pentanol
11)
To a mixture of 1.6 g (65 mmol) of magnesium fillings in
3 2
4
9
C(CH ) ]. HRMS (FAB): calcd. for C H O Si: 230.4193;
3 3
12 26
2
found: 230.4181.
0 mL of diethyl ether was added approx. 5% of 7.1 g
(2R)-1-(tert-Butyldimethylsilyloxy)-3-iodo-2-
methylpropane (12)
To a solution of 1.11 g (5.50 mmol) of (2S)-3-([tert-
butyldimethylsilyl]oxy)-2-methyl-1-propanol (6) in 30 mL
of toluene were added 2.2 g (8.3 mmol) of triphenyl-
phosphine, 1.1 g (16.5 mmol) of imidazole, and 1.9 g
(7.6 mmol) of iodine. The flask was protected against light
and the mixture was stirred for 1 day at room temperature.
The liquid was decanted and the bronze colored solid was
extracted with ether (3 × 20 mL). The combined organic lay-
ers were washed with 50 mL of a concentrated solution of
sodium hydrogen carbonate, sodium thiosulfate, and sodium
chloride. The organic layer was dried over MgSO4. Column
chromatography (cyclohexane–ethyl acetate 10:1) afforded
1.71 g (5.47 mmol, 100%) of the title compound as a yellow
h. A solution of 6.62 g (32.6 mmol) of (2S)-3-([tert-
4
.14 g (30.7 mmol, 94%) of the title compound as a color-
2
0
1
D
3
3
3
3 3
20
1
.89–0.92 (m, 3H, CH-CH ), 0.93–0.97 (m, 3H, CH -CH ),
oil. [a]D +12.2 (c = 0.6, CH2Cl2). H NMR (250 MHz,
CDCl3) d: 0.02 (s, 6H, Si-CH3), 0.87 (s, 9H, C(CH3)3), 0.96
(d, J = 7.3 Hz, 3H, CH-CH3), 1.47–1.59 (m, 1H, CH),
3.14–3.23 (m, 2H, CH2-I), 3.31–3.53 (m, 2H, CH2-O).
3
2
3
.41–1.52 (m, 2H, CH -CH ), 1.60–1.71 (m, 1H, CH), 2.85
2
3
2
1
3
H, CH-OH). C NMR (100.6 MHz, CDCl ) d: – 0.03 (Si-
3
CH ), 9.90 (CH -CH ), 10.59 (CH-CH ), 13.82 (C-(CH ) ),
3
2
3
3
3 3
2
6.85 (C-(CH ) ), 27.90 (CH -CH ), 39.26 (CH-CH ), 67.13
(2S)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethyl-1-
pentene (13)
To a solution of 0.86 g (2.75 mmol) of (2R)-1-(tert-
butyldimethylsilyloxy)-3-iodo-2-methylpropane (12) in
10 mL of THF were added 60 mg (0.30 mmol) of copper(I)
iodide and 1.33 mL (10.9 mmol) of 1,3-dimethyl-3,4,5,6-
3
3
2
3
3
(
[
(
CH -O), 76.03 (CH-OH). MS (70 eV) m/z (%): 232 (3.1)
M] , 205 (2.1) [M – C H ] , 190 (15.4), 189 (94.8), 147
13.0), 131 (17.8), 117 (7.8) [M – CH – CH – C(CH ) –
2
+
+
2
5
3
3
3 3
+
+
Si] , 89 (15.6), 83 (11.1), 75 (5.3) [HO=Si(CH ) ] , 73
3
2
+
+
(
12.3) [C H O] , 71 (25.5), 59 (100) [C H O] , 57 (47.4)
4 9 3 7
©
2002 NRC Canada

Scheck and Waldmann
575
tetrahydro-2(1H)-pyrimidinone (DMPU). The mixture was
cooled to –20°C and a freshly prepared solution of 2-
propenylmagnesium bromide (6.85 mmol) in THF (7 mL)
was added over 20 min. After stirring for 2 h at –20°C, the
mixture was stirred for 1 h at 0°C and then quenched with
(250 MHz, CDCl ) d: 1.06 (d, J = 8.3 Hz, 3H, CH-CH ),
3
3
1.78 (s, 3H, C-CH ), 2.06–2.33 (m, 2H, C-CH ), 2.43–2.61
3
2
(m, 1H, CH), 4.81 (s, 1H, C=CH ), 4.85 (s, 1H, C=CH ),
2
2
1
9.63 (s, 1H, COH). The H NMR data is in concordance
with literature (25).
1
0 mL of saturated ammonium chloride solution. The layers
were separated and the aqueous phase was extracted with
ether (3 × 20 mL). The combined organic layers were
washed with 20 mL of a concentrated solution of ethylene
diamine tetraacetate and sodium chloride. The organic layer
(
2
2R,4S,5R,6S)-1-([tert-Butyldimethylsilyl]oxy)-5-hydroxy-
,4,6,8-tertamethyl-8-nonen-3-one (14)
To a solution of 1.39 g (6.00 mmol) of (2R)-1-([tert-
butyldimethylsilyl]oxy)-2-methyl-3-pentanone (5) in 70 mL
of methylene chloride was added at –78°C 18 mL (18 mmol)
was dried over MgSO . Column chromatography (cyclohex-
4
ane–ethyl acetate 8:1) afforded 581 mg (2.54 mmol, 93%) of
of a 1.0 M solution of TiCl in methylene chloride. After
4
2
0
the title compound as a colorless oil. [a] –3.4 (c = 0.9,
30 min, 2.21 mL (13.0 mmol) of N-ethyl-diisopropylamine
was added dropwise and after 70 min a solution of 0.60 g
(5.36 mmol) of (2S)-2,4-dimethyl-4-pentenal (4) in 5 mL
methylene chloride was added. After strirring at –78°C for
1 h, the reaction mixture was allowed to warm slowly to
–5°C. Saturated ammonium chloride solution (15 mL) and
D
1
CH Cl ). H NMR (250 MHz, CDCl ) d: 0.02 (s, 6H, Si-
2
2
3
CH ),), 0.83 (d, J = 6.5 Hz, 3H, CH-CH ), 0.87 (s, 9H,
3
3
C(CH ) ), 1.63 (s, 3H, CH =C-CH ), 1.83–1.88 (m, 2H,
3
3
2
3
CH -C=CH ), 2.09–2.15 (m, 1H, CH), 3.35–3.41 (m, 2H,
2
2
CH -O), 4.65 (d, J = 10.5 Hz, 2H, CH =C).
2
2
2
0 mL buffer solution (pH 7) were added, the layers were
(
2S)-2,4-Dimethyl-4-pentenol
separated, and the aqueous layer was extracted with diethyl
ether (3 × 70 mL). The organic layers were combined,
washed with 150 mL of a concentrated solution of sodium
hydrogencarbonate and 150 mL of brine. After drying over
To a solution of 6.57 g (28.8 mmol) of (2S)-5-(tert-
butyldimethylsilyloxy)-2,4-dimethyl-1-pentene (13) in
0 mL of THF were added 85 mL (85 mmol) of a 1.0 M so-
1
lution of tetrabutylammonium fluoride in THF, 11.0 g of
molecular sieves (4 Å), 5 mL of acetic acid, and 5 g of glass
splinters. The mixture was stirred for 2 days at room temper-
ature. The solution was then filtered and 50 mL of water was
added to the filtrate. The layers were separated and the aque-
ous phase was extracted with diethyl ether (3 × 50 mL). The
combined organic layers were washed with 50 mL of a con-
centrated solution of sodium hydrogen carbonate and so-
MgSO , column chromatography (cyclohexane–ethyl acetate
4
10:1) afforded 780 mg (2.28 mmol, 42%) of crude product
as a slightly red oil. The diastereomers were separated by
HPLC, which lead to the desired diastereomer as a slight
yellow oil. The diastereomers were found in a ratio of 1.8:1
2
0
and with a syn–anti ratio of 10:1. [a] +14.1 (c = 1.3,
D
1
CHCl ). H NMR (500 MHz, CDCl ) d: 0.03 (s, 6H, Si-
3
3
CH ), 0.88 (s, 9H, Si-C(CH ) ), 0.91–0.92 (m, 3H, C-CH -
3
3 3
2
dium chloride. The organic layer was dried over MgSO and
CH-CH ), 1.11 (d, J = 6.1 Hz, 3H, O-CH-CH-CH ),
4
3
3
the solvent was removed under reduced pressure. The result-
ing oil was distilled under reduced pressure (p = 3 mbar,
bp = 42°C) to afford 2.36 g (20.7 mmol, 72%) of the title
1.16–1.18 (m, 3H, CH-CH-CO-CH-CH ), 1.73 (s, 3H, C=C-
3
CH ), 2.02–2.04 (m, 3H, C=C-CH ), 2.07 (dd, J = 7.4 and
3
3
14.2 Hz, 1H, C-CH -CH-CH ), 2.66–2.68 (m, 1H, O-CH-
2
3
20
1
compound as a colorless oil. [a] –3.9 (c = 0.7, CHCl ). H
CH-CH ), 2.93–2.99 (m, 1H, CH-CO-CH-CH ), 3.47–3.53
D
3
3
3
NMR (250 MHz, CDCl ) d: 0.90 (d, J = 7.3 Hz, 3H, CH-
(m, 2H, O-CH ), 3.68–3.69 (m, 1H, CH-O), 4.61 (s, 1H,
2
3
1
3
CH ), 1.62 (s, 1H, OH), 1.76 (s, 3H, C-CH ), 1.84–1.96 (m,
C=CH ), 4.69 (s, 1H, C=CH ). C NMR (125.6 MHz,
3
3
2
2
2
H, CH-CH -C), 2.09–2.15 (m, 1H, CH), 3.42–3.53 (m, 2H,
CDCl ) d: –5.56 (Si-CH ), 13.10 (CH-CH-CO-CH-CH ),
3 3 3
2
1
CH -OH), 4.65 (d, J = 11.6 Hz, 2H, CH =C). The H NMR
14.21 (O-CH-CH-CH ), 17.73 (C-CH -CH-CH ), 19.37
2
2
3 2 3
data is in concordance with literature (25).
(C(CH ) ), 22.15 (C=C-CH ), 25.66 (C(CH ) ), 28.30 (C-
3 3 3 3 3
CH -CH-CH ), 41.53 (C-CH -CH-CH ), 42.41 (CH-CO-
2
3
2
3
(
2S)-2,4-Dimethyl-4-pentenal (4)
To a solution of 0.67 mL (7.77 mmol) of oxalyl chloride
CH-CH ), 48.30 (O-CH-CH-CH ), 65.16 (CH -O), 65.73
3 3 2
(CH-OH), 112.24 (CH =C), 142.95 (CH =C), 214.46 (C=O).
2 2
+
+
in 60 mL of methylene chloride was added 0.74 mL
10.4 mmol) of dimethyl sulfoxide at –78°C and the result-
ing solution was stirred for 20 min. Next, 0.59 g
5.17 mmol) of (2S)-2,4-dimethyl-4-penten-1-ol was added
and the solution was stirred for another 30 min. Then
.06 mL (36.2 mmol) of triethylamine was added and the
MS (70 eV) m/z (%): 342 (0.1) [M] , 327 (0.1) [M – CH ] ,
3
+
(
285 (3.7) [M – C(CH ) ] , 271 (14.7), 259 (2.2) [M –
3
3
+
+
C H ] , 227 (1.7) [M – CH – CH – C(CH ) – Si] , 201
6
11
3
3
3 3
+
(
(5.7) [M – C H O] , 185 (60.0), 174 (12.8), 173 (100.0),
9 17
+
169 (0.8) [M – C H O – CH – CH – C(CH ) – Si] , 115
3
6
3
3
3 3
+
+
5
(6.5) [Si(CH ) C(CH ) ] , 113 (22.1) [C H O] , 81 (12.3),
3 2 3 3 7 13
+
mixture was stirred for 5 min at –78°C. The reaction mixture
was allowed to warm to room temperature and stirred for an-
other hour. The solution was cooled to –78°C, water
75 (25.7), 73 (16.4), 57 (9.1) [C(CH ) ] . FAB-HRMS calcd.
3 3
for C H O Si: 342.2590; found: 342.2587.
1
9
38
3
(
25 mL) was added, and the mixture was allowed to warm to
(
2
2R,4S,5R,6S)-1-([tert-Butyldimethylsilyl]oxy)-5-hydroxy-
,4,6,8-tetramethyl-8-nonene-3-[1,3]dioxolane
To a solution of 240 mg (0.70 mmol) of (2R,4S,5R,6S)-1-
room temperature again. The aqueous layer was extracted
with methylene chloride (4 × 60 mL). The organic layers
were combined, washed consecutively with a saturated aque-
ous solutions of ammonium chloride and sodium chloride,
and then dried over MgSO . Removal of the solvent under
reduced pressure afforded 435 mg (3.88 mmol, 75%) of the
([tert-butyldimethylsilyl]oxy)-5-hydroxy-2,4,6,8-tertamethyl-
8
-nonen-3-one (14) in 10 mL of ethylene glycol was added
4
0.89 mL (0.76 g, 7.01 mmol) of chlorotrimethylsilane and
the resulting solution was stirred overnight. A 5% aqueous
sodium hydrogencarbonate solution (15 mL) was then
2
0
1
title compound. [a] +3.3 (c = 0.1, CHCl3). H NMR
D
©
2002 NRC Canada

5
76
Can. J. Chem. Vol. 80, 2002
added, the layers were separated, and the aqueous phase was
extracted with ether (3 × 75 mL). The organic layers were
combined, washed twice with brine, and dried over MgSO4.
Column chromatography (cyclohexane–ethyl acetate 10:1)
afforded 227 mg (0.59 mmol, 84%) of the title compound as
112.61 (CH =C), 113.94 (CH-O-CH -O), 122.89 (C-O-CH -
2
2
2
CH -O), 142.96 (CH =C). FAB-HRMS calcd. for
2
2
C H O Si: 430.6989; found: 430.6987.
23
46
5
20
1
References
a slightly yellow oil. [a] +24.4 (c = 2.59, MeOH). H
D
NMR (400 MHz, CDCl ) d: 0.02 (s, 6H, Si-CH ), 0.88 (s,
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36, 639 (1983).
3
3
9
H, Si-C(CH ) ), 0.91–0.92 (m, 3H, C-CH -CH-CH ), 1.14
3 3 2 3
(
d, J = 6.1 Hz, 3H, O-CH-CH-CH ), 1.16 (d, J = 6.9 Hz, 3H,
2. T. Hammamoto, S. Gunji, H. Tsuji, and T. Beppu. J. Antibiot.
36, 646 (1983).
3
CH-CH-CO-CH-CH ), 1.73 (s, 3H, C=C-CH ), 2.02–2.04
3
3
(
m, 3H, C=C-CH ), 2.07 (dd, J = 7.4 and 14.2 Hz, 1H,
3. M. Yoshida, M. Nishikawa, K. Nishi, K. Abe, S. Horinouchi,
and T. Beppu. T. Exp. Cell. Res. 187, 150 (1990).
3
C-CH -CH-CH ), 2.34–2.42 (m, 1H, O-CH-CH-CH3),
2
3
4
. K.S. Ullman, M.A. Powers, and D.J. Forbes. Cell, 90, 967
1997).
5. B. Wolff, J.-J. Sanglier, and Y. Wang. Chem. & Biol. 4, 139
1997).
2
4
1
.63–2.73 (m, 1H, CH-CO-CH-CH ), 3.62 (t, J = 4.7 Hz,
3
(
H, O-CH -CH ), 3.65–3.69 (m, 2H, O-CH ), 3.88–3.91 (m,
2
2
2
1
3
H, CH-O), 4.67 (s, 1H, C=CH ), 4.74 (s, 1H, C=CH ).
C
2
2
(
NMR (125.6 MHz, CDCl ) d: –5.12 (Si-CH ), 17.04 (CH-
CH-CO-CH-CH ), 17.88 (O-CH-CH-CH ), 18.54 (C-CH -
3
3
6
. K. Nishi, M. Yoshida, D. Fujiwara, M. Nishikawa, S.
Horinouchi, and T. Beppu. J. Biol. Chem. 269, 6320 (1994).
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3
3
2
CH-CH3), 22.32 (C(CH3)3), 25.86 (C=C-CH3), 26.11
C(CH ) ), 33.37 (C-CH -CH-CH ), 37.93 (C-CH -CH-
7
(
3
3
2
3
2
CH ), 42.08 (CH-CO-CH-CH ), 49.18 (O-CH-CH-CH ),
3
3
3
(
2001).
. A. Wada, M. Fukuda, M. Mishima, and E. Nishida. EMBO J.
7, 1635 (1998).
6
3.91 (CH -O), 64.03 (CH-OH), 64.29 and 64.33 (O-CH -
2
2
8
CH -O), 112.55 (CH =C), 122.08 (C-O-CH -CH -O),
1
3
2
2
2
2
1
42.93 (CH =C). FAB-HRMS: calcd. for C H O Si:
2
21 42
4
9. S. Taagepera, D. McDonald, J.E. Loeb, L.L. Whitaker, A.K.
McElroy, J.Y.K. Wang, and T. Hope. J. Proc. Natl. Acad. Sci.
U.S.A. 95, 7457 (1998).
0. J. Yang, E.S.G. Bardes, J.D. Moore, J. Brennan, M.A. Powers,
and S. Kornbluth. Genes Dev. 12, 2131 (1998).
86.6459; found: 386.6461.
(
2R,4S,5R,6S)-1-([tert-Butyldimethylsilyl]oxy)-5-
1
methoxymethoxy-2,4,6,8-tertamethyl-8-nonene-3-
[
1,3]dioxolane (15)
To a solution of 81 mg (0.19 mmol) of (2R,4S,5R,6S)-1-
[tert-butyldimethylsilyl]oxy)-5-hydroxy-2,4,6,8-tetramethyl-
11. D.A. Freedman and A.J. Levine. Mol. Cell. Biol. 18, 7288
(1998).
12. T.T. Huang, N. Kudo, M. Yoshida, and S. Miyamoto. Proc.
Natl. Acad. Sci. U.S.A. 97, 1014 (2000).
(
8
-nonene-3-[1,3]dioxolane in 3 mL of methylene chloride
were added 0.33 mL (1.9 mmol) of N,N-diisopropylamine
and 72 ꢁL (0.95 mmol) of chloromethyl methyl ether, and
the solution was stirred overnight. Saturated aqueous sodium
hydrogencarbonate solution (10 mL) was then added, the
layers were separated, and the aqueous phase was extracted
with ether (3 × 20 mL). The organic layers were combined
13. A. Hagting, C. Karlsson, P. Clute, M. Jackman, and J. Pines.
EMBO J. 17, 4127 (1998).
1
4. W. Wen, A.T. Harootunian, S.R. Adams, J. Feramisco, R.Y.
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2214 (1994).
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Natl. Acad. Sci. U.S.A. 96, 9112 (1999).
1
1
(
and dried over MgSO . Column chromatography (cyclohex-
4
ane–ethyl acetate 10:1) afforded 23 mg (55 ꢁmol, 29%) of
2
0
the title compound as a yellow oil. [a] +21.3 (c = 2.33,
D
1
MeOH). H NMR (400 MHz, CDCl ) d: 0.08 (s, 6H, Si-
3
1
1
7. M. Kobayashi, W. Wang, Y. Tsutsui, M. Sugimoto, and N.
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4, 973 (1993).
CH ), 0.86 (s, 9H, Si-C(CH ) ), 0.92–0.93 (m, 3H, C-CH -
3
3 3
2
CH-CH ), 1.14 (d, J = 6.1 Hz, 3H, O-CH-CH-CH ), 1.16 (d,
3
3
J = 6.9 Hz, 3H, CH-CH-CO-CH-CH ), 1.72 (s, 3H, C=C-
3
CH ), 2.03–2.07 (m, 3H, C=C-CH ), 2.35–2.43 (m, 1H, O-
3
3
19. J. Tamura and A. Kochi. J. Am. Chem. Soc. 93, 1485 (1971).
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Tetrahedron, 48, 3827 (1992).
CH-CH-CH ), 2.61–2.70 (m, 1H, CH-CO-CH-CH ), 2.71
3
3
(
dd, J = 7.4 and 14.3 Hz, 1H, C-CH -CH-CH ), 3.52 (s, 3H,
2 3
O-CH ), 3.62 (t, J = 4.7 Hz, 4H, O-CH -CH -O), 3.64–3.67
3
2
2
(
5
–
m, 2H, O-CH ), 4.71 (s, 1H, C=CH ), 4.76 (s, 1H, C=CH ),
2
2
2
1
3
.47 (s, 2H, O-CH -O). C NMR (125.6 MHz, CDCl ) d:
2
3
5.27 (Si-CH ), 17.32 (CH-CH-CO-CH-CH ), 18.47 (O-CH-
23. E.J. Thomas and J.W.F. Whitehead. J. Chem. Soc. Perkin
Trans. 1, 507 (1989).
3
3
CH-CH ), 18.83 (C-CH -CH-CH ), 22.48 (C(CH ) ), 25.16
3
2
3
3 3
(
3
C=C-CH ), 25.32 (C(CH ) ), 31.46 (C-CH -CH-CH ),
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112, 6348 (1990).
3
3 3
2
3
8.14 (C-CH -CH-CH ), 42.37 (CH-CO-CH-CH ), 45.53
2 3 3
2
5. D.A. Evans, R.P. Polniaszek, K.M. De Vries, M. Keith, D.E.
(
O-CH-CH-CH ), 53.21 (CH-O-CH -O-CH ), 62.71 (CH-
3 2 3
Guinn, and D.J. Mathre. J. Am. Chem. Soc. 113, 7613 (1991).
OH), 63.97 (CH -O), 64.30 and 64.34 (O-CH -CH -O),
2
2
2
©
2002 NRC Canada