Synthesis of the 8-hydroxy acid of jasplakinolide

Article abstract of DOI:10.1002/adsc.200404004

The protected ω-hydroxy acid 4b contained in the depsipeptide jasplakinolide (1) was prepared in a sequence of 13 steps from the silylated 3-hydroxy ester 6. By chain extension 6 was converted to the allyl alcohol 10. A subsequent asymmetric cyclopropanat

Full text of DOI:10.1002/adsc.200404004

FULL PAPERS
Synthesis of the 8-Hydroxy Acid of Jasplakinolide
Saengchai Wattanasereekul, Martin E. Maier*
Institut f¸r Organische Chemie, Universit‰t T¸bingen, Auf der Morgenstelle 18, 72076 T¸bingen, Germany
Fax: (þ49)-7071-295-137; e-mail: martin.e.maier@uni-tuebingen.de
Received: January 8, 2004; Accepted: April 5, 2004
Dedicated to Joe P. Richmond on the occasion of his 60th birthday.
Abstract: The protected w-hydroxy acid 4b contained ring cleavage of the (iodomethyl)cyclopropane 14.
in the depsipeptide jasplakinolide (1) was prepared in The alkene 15 was used for a cross alkene metathesis
a sequence of 13 steps from the silylated 3-hydroxy reaction with 2-methylacrylate 20 providing the
ester 6. By chain extension 6 was converted to the all- enoate 19. The derived allylic iodide 24 served as an
yl alcohol 10. Asubsequent asymmetric cyclopropa-
electrophile in the final Evans alkylation step to
nation of the allylic alcohol 10 using the Charette give the w-hydroxy acid derivative 26.
method provided the hydroxymethylcyclopropane 12
with excellent diastereoselectivity. This cyclopropana-
tion was used to establish the methyl-bearing stereo- Keywords: alkenes; alkylation; asymmetric synthesis;
center at C-6 of the hydroxy acid 4 by reductive cyclopropanes; metathesis; natural products
Introduction
The key structural feature of cyclic depsipeptides is the
replacement of an amide bond by an ester bond. Besides
the presence of hydroxy acids, depsipeptides often con-
tain unusual amino acids. The most common modifica-
tions include N-methylation or extension of the carbon
chain. Aromatic amino acids such as tyrosine or trypto-
phan sometimes contain ring substituents like halides.
While b-hydroxy acids can be traced back to the corre-
sponding a-amino acids, w-hydroxy acids present in cy-
clic depsipeptides are made by the polyketide machi-
nery. Thus, these natural products are made by the com-
bination of building blocks from different biosynthetic
pathways. An illustrative example is the cyclodepsipep-
tide jasplakinolide (1) which was isolated from the ma-
rine sponge Jaspis sp.[1] Jasplakinolide shows potent an-
tifungal, insecticidal and antitumor activity. It is also
used as a tool in cytoskeletal research since it stabilizes
F-actin which includes the reorganization of actin fila-
ments into a layer adjacent to the plasma membrane.[2]
Figure 1. Structures of jasplakinolide (1) and geodiamolide
(2).
Related compounds are the marine cyclodepsipeptides
geodiamolide Aand B which are reported to have
weak antifungal activity.[3] These depsipeptides share
the same 11-carbon polypropionate unit, the 8-hy-
The two depsipeptides differ in the tripeptide frag-
droxy-2,4,6-trimethyl-4-nonenoic acid (4a). The retro- ment. Due to the presence of the b-amino acid in jaspla-
synthesis which is typical for several total syntheses dis- kinolide they also have different ring sizes (19 vs. 18). It
sects the macrolide 1 into a tripeptide fragment 3 and a is not clear what the role of the individual building
hydroxy-protected carboxylic acid 4b. This strategy blocks is. The tripeptide fragment might mimic a peptide
should allow for an easy variation of the tripeptide frag- or protein ligand. The 8-hydroxy acid could function as a
ment.
conformational control element, being involved in bind-
Adv. Synth. Catal. 2004, 346, 855 861
DOI: 10.1002/adsc.200404004
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
855

Saengchai Wattanasereekul, Martin E. Maier
FULL PAPERS
ing or not. Thus, akin to the immunosuppressives FK506 hol 10.[15] In order to introduce a methyl group at posi-
and rapamycin,[4] jasplakinolide could be a dual domain tion 6 of the target hydroxy acid we used the reductive
molecule. Irrespective of that, the w-hydroxy acid is of opening of an (iodomethyl)cyclopropane. Accordingly,
interest from the viewpoint of conformational control. the allylic alcohol was converted to the hydroxymethyl-
The hydroxy acid 4a contains four methyl groups in a cyclopropane 12 using the combination of diiodome-
1,3-distance. One can identify two syn-pentane interac- thane, diethylzinc and the chiral dioxaborolane 11
tions and one 1,3-allylic interaction. The consequence of (Charette method).[16] Since a direct conversion of the
the methyl groups is that the functional groups (carboxyl primary alcohol to the corresponding iodide (I2, imida-
and hydroxy) at both ends of the chain point in one di- zole, PPh3, CH3CN) was not a clean reaction, the path-
rection and allow bridging with a peptide fragment. way via the mesylate 13 was followed. Treatment of
Based on the work of Hoffmann et al.[5] one can assume the mesylate 13, obtained from the alcohol 12 with mesyl
that the conformation of the chain is largely determined chloride and triethylamine, with NaI in acetone gave an
by the central double bond and the three other methyl excellent yield of the iodide 14. The reductive ring open-
groups. While definitely several low energy conforma- ing[17,18] of 14 was achieved with n-butyllithium in THF
tions are possible, an arrangement such as the one de- between À78 and À308C providing the alkene 15 in
picted in Figure 2 should be accessible and still allow 73% yield. According to the 13C NMR spectrum, this
for an easy bridging.[6] The conformation of the central compound is diastereomerically pure (>98%).
part is governed by 1,3-allylic strain. The dihedral angles
For the extension of the alkene to the enoate we ini-
of the single bonds next to the allylic system are gaucheþ tially used the sequence of ozonolysis and Wittig reac-
(608) and gaucheÀ (3008), respectively. Since the hy- tion of the resulting aldehyde with the stabilized ylide
droxy acid 4a is of great interest as a controlling element 18. However, the ozonide 16 proved to be rather stable
for the orientation of bridging peptide fragments we de- and its reductive cleavage with dimethyl sulfide (2 mL/
veloped a novel synthesis for this compound.
mmol of 15) in CH2Cl2 required stirring for 1 week.
Also the one-pot cleavage and Wittig reaction did not
work.[19] Therefore we opted for the direct conversion
of the alkene 15 to the enoate 19 by alkene cross-meta-
thesis[20] with methyl 2-methylacrylate (20). Using an ex-
Results and Discussion
In most of the published syntheses[7 9] of 4, the aldehyde cess of 20 (10 equivs.) and 5 mol % of the Grubbs cata-
17 (cf. Scheme 2) serves as a key building block. Exten- lyst 21 gave a good yield of the desired enoate 19. The
sion is done either by reaction with 2-propenylmagnesi- original Grubbs catalyst provided the enoate 19 only
um bromide followed by Claisen rearrangement or by
the tactical sequence Wittig reaction, conversion to al-
lylic halide and asymmetric alkylation. Our synthesis
started with the chiral 3-hydroxy ester 5 which is availa-
ble by yeast reduction of acetoacetate.[10] Alternatively a
Noyori reduction might be used.[11] The latter option is
of particular interest for the synthesis of other ana-
logues. Asubsequent silylation of the hydroxy ester
with tert-butyldimethylsilyl chloride in the presence of
imidazole gave the known compound 6.[12] Reduction
with diisobutylaluminium hydride (DIBAL-H) provid-
ed the aldehyde[12a,13] 7 that was converted to the
enoate[14] 9 by reaction with the stabilized Wittig reagent
¼
(Ph)3P CHCO2Me (8). Reaction of the enoate 9 with
2.2 equivalents of DIBAL-H furnished the allylic alco-
Scheme 1. Synthesis of the key building block 15 by a stereo-
selective Charette cyclopropanation followed by reductive
cyclopropane opening of the iodomethylcyclopropane 14.
Reaction conditions: a) TBDMSCl, imidazole, CH2Cl2,
238C, 21 h, 100%; b) DIBAL-H, CH2Cl2, À78 to À308C,
¼
0.5 h, 100%; c) Ph3PC CHCO2Me (8), benzene, 808C, 16 h,
97%; d) DIBAL-H, CH2Cl2, À78 to À308C, 1.5 h, 96%; e)
Et2Zn, CH2Cl2, CH3OCH2CH2OCH3, À108C, CH2I2,
10 min, then add 11, À10 to 238C, 15.5 h, 96%; f) NEt3,
CH3SO2Cl, CH2Cl2; g) NaI, acetone, 0 to 238C, 3 h, 96%
Figure 2. Possible conformation of the 8-hydroxy acid 4a due
to the avoidance of CH3 CH3 steric interactions.
(from 12); h) TMEDA, MS 4 ä, n-BuLi, À78 to À308C,
À
2.5 h, 73%.
856
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 855 861

Synthesis of the 8-Hydroxy Acid of Jasplakinolide
FULL PAPERS
in traces. The remaining steps to the desired acid were of the allylic alcohol 10, a reductive ring opening of
performed more or less according to the literature. the (iodomethyl)-cyclopropane 14 and an alkene meta-
Thus, reduction of ester 19 to the alcohol 22, followed thesis to extend the alkene 15 to the enoate 19. Since 3-
by conversion to the allylic mesylate 23 and substitution hydroxy esters such as 5 are easily available by Noyori
of the mesylate with iodide delivered the iodide[7b,9c] 24 reduction, and the Evans alkylation can be done with
in good overall yield for the three steps. Besides the me- different ester derivatives, analogues of the hydroxy
sylate 23, the corresponding allylic chloride is also acid 4 should be easily accessible by the route described
formed in less than 10%. For analytical purposes, the in this paper.
mesylate and chloride were separated. However, the
mixture can be used as such for the next step. The iodide
24 was then used as the electrophile in an Evans alkyla-
Experimental Section
tion[21] with the propionyloxazolidinone 25. The latter
was prepared from d-phenylalanine.[22] Afinal hydroly-
sis of the alkylation product 26 provided the TBDMS-
protected hydroxy acid 4b.[7,8,9]
General
1H and 13C NMR: Bruker Avance 400, spectra were recorded in
CDCl3;chemical shifts are calibrated to the residual protonand
carbon resonance of the solvent: CDCl3 (dH ¼7.25 ppm, dC ¼
77.00 ppm). Melting points: B¸chi Melting Point B-540, uncor-
rected. Polarimeter: JASCO Polarimeter P-1020. IR: Jasco FT/
IR-430. EI-MS: Finnigan Triple-Stage-Quadrupole (TSQ-70).
HR-MS (EI): modified AMD Intectra MAT 711 A. HPLC-
MS (API-ES): Agilent 1100 Series LC/MSD. HR-MS (FT-
ICR): Bruker Daltonic APEX 2 with electrospray ionization
(ESI). Flash chromatography: J. T. Baker silica gel 43
60 mm. Thin layer chromatography Machery-Nagel Polygram
Sil G/UV254. Solvents were distilled prior to use; petroleum
ether with a boiling range of 40 608C was used.
Conclusion
The whole sequence involves 13 steps from the ester 6.
Key reactions include the Charette cyclopropanation
Ethyl (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}butanoate
(6)
To a stirred solution of alcohol 5 (38.3 g, 0.29 mol) in CH2Cl2
(500 mL) was added imidazole (39.5 g, 0.58 mol) at 08C and
the mixture stirred for 5 min resulting in a homogeneous solu-
tion. Subsequently, tert-butyldimethylsilyl chloride (52.6 g,
0.348 mol) was added and the whole mixture stirred for 0.5 h
at 08C and then at room temperature for 21 h. The reaction
mixture was diluted with H2O, the layers were separated and
the aqueous layer extracted with CH2Cl2 (4ꢀ75 mL). The
combined organic layers were washed with brine, dried
(MgSO4), filtrated, and concentrated to give 6 as colorless
oil; yield: 71.4 g (100%). TLC (petroleum ether/ethyl acetate,
19:1): Rf ¼0.44; [a]2D6: þ22.0 (c 0.97, CHCl3) {Ref.[12a] [a]2D3:
À1
˜
þ28 (c 1.5, CHCl3)}. IR (neat): n¼1739, 1255, 1183 cm
;
1H NMR (400 MHz, CDCl3): d¼0.01, 0.03 (2 s, 3H each),
0.83 [s, 9H, SiC(CH3)3], 1.17 (d, J¼6.1 Hz, 3H, H-4), 1.23 (t,
J¼7.1 Hz, 3H, CH3), 2.33 (dd, J¼14.5, 5.3 Hz, 1H, H-2), 2.44
(dd, J¼14.5, 7.6 Hz, 1H, H-2), 4.04 4.13 (m, 2H, CH2),
4.21 4.29 (m, 1H, H-3); 13C NMR (100 MHz, CDCl3): d¼
À5.1, À4.6, 14.2, 17.9, 23.9, 25.7, 44.9, 60.2, 65.8, 171.6.
Scheme 2. Conversion of the alkene 15 to the enoate 19 by a
cross alkene metathesis reaction with the 2-methylacrylate 20
followed by chain extension via an Evans alkylation to yield
compound 26. Reaction conditions: a) O3, CH2Cl2, À788C; b)
¼
Me2S, CH2Cl2, 238C, 7 d, 97%; c) Ph3PC C(Me)CO2Me (18),
(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}butanal (7)
¼
benzene, 808C, 16 h, E/Z¼3:1, 82%; d) CH2 C(Me)CO2Me
(20), complex 21 (5 mol %), CH2Cl2, 408C, 20 h, 73%; e) DI-
BAL-H, CH2Cl2, À78 to À308C, 1.5 h, 100%; f) CH3SO2Cl,
NEt3, CH2Cl2, 08C, 30 min; g) NaI, acetone, 0 to 238C, 3 h,
95% (from 22); h) oxazolidinone 25, NaN(SiMe3)2, THF, À
788C, 2 h, add iodide 24, À788C, 15 h, 61%; i) LiOH,
H2O2, THF/H2O, 0 8C, 1.5 h, 100%.
To a solution of ester 6 (123 mg, 0.5 mmol) in CH2Cl2 (5 mL)
was added DIBAL-H (1.0 M in hexane, 0.55 mL, 0.55 mmol)
dropwise at À788C. After being stirred for 0.5 h at À788C,
the temperature was raised to À308C, methanol (0.5 mL)
was then added, the cooling bath removed, and the mixture
warmed to 08C. Asaturated solution of potassium sodium tar-
Adv. Synth. Catal. 2004, 346, 855 861
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857

Saengchai Wattanasereekul, Martin E. Maier
FULL PAPERS
tarte was added and the mixture was extracted with Et2O (3ꢀ
5 mL). The combined organic layers were washed with brine,
dried (MgSO4), filtered and concentrated. The residue was pu-
rified by flash chromatography (petroleum ether/Et2O, 1:8) to
afford aldehyde 7 as a colorless oil; yield: 101 mg (100%); TLC
(petroleum ether/ethyl acetate, 6:1): Rf ¼0.47; [a]2D7: þ14 (c
[(1S,2R)-2-((2R)-2-{[tert-Butyl(dimethyl)silyl]-
oxy}propyl)cyclopropyl]methanol (12)
To a mixture of CH2Cl2 (300 mL) and 1,2-dimethoxyethane
(DME) (10.4 mL, 100 mmol) was added a solution of diethyl-
zinc (1 M in hexane, 100 mL, 100 mmol) at À108C followed
by the dropwise addition of CH2I2 (16.1 mL, 200 mmol) over
15 20 min while maintaining the internal temperature be-
tween À8 and À12 8C. After complete addition, the resulting
clear solution was stirred for 10 min at À108C before a solu-
tion of dioxaborolane ligand 11 (16.21 g, 60 mmol) in CH2Cl2
(50 mL, 1.2 M) was added via a cannula over a 15 20 min pe-
riod while maintaining the internal temperature below À58C.
This was followed by the dropwise addition of alcohol 10
(11.5 g, 50.0 mmol), dissolved in CH2Cl2 (50 mL) while main-
taining the internal temperature below À58C. After being stir-
red for 0.5 h at À108C, the mixture was allowed to reach room
temperature and stirred for 15 h. The reaction was quenched
with saturated NH4Cl solution (50 mL) and 10% HCl
(200 mL) and the mixture was extracted with Et2O (3ꢀ
100 mL). The combined organic layers were added to a mixture
of 2 N NaOH (300 mL) and H2O2 (30%, 50 mL). The biphasic
solution was stirred for 5 min and then the layers were separat-
ed. The organic phase was washed with 10% HCl (250 mL),
Na2SO3 (250 mL), NaHCO3 (250 mL), and brine (250 mL). Af-
ter drying (MgSO4), filtration and concentration of the organic
layer under reduced pressure, the crude product was purified
by flash chromatography (petroleum ether/Et2O, 5:1) to afford
12 as colorless oil; yield:11.73 g (96%, the diastereomeric ratio
was determined in the next step); TLC (petroleum ether/ethyl
acetate, 4:1): Rf ¼0.47; [a]2D6: þ22.2 (c 0.97, CH2Cl2); IR (neat):
1.0, CHCl3) {Ref.[13] [a]D : þ19 (c 2.0, CHCl3)}; IR (neat): n¼
23
˜
2930, 1715, 1256 cmÀ1
;
1H NMR (400 MHz, CDCl3): d¼
À0.02, 0.00 (2 s, 3H each, SiCH3), 0.79 [s, 9H, SiC(CH3)3],
1.16 (d, J¼6.2 Hz, 3H, H-4), 2.33 (dd, J¼15.9, 3.4 Hz, 1H,
H-2), 2.47 (dd, J¼15.7, 2.5 Hz, 1H, H-2), 4.26 4.30 (m, H-3),
9.72 (s, 1H, H-1); 13C NMR (100 MHz, CDCl3): d¼ À4.6, À
4.0, 18.3, 24.6, 26.1, 53.4, 64.9, 202.7.
Methyl (2E,5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2-
hexenoate (9)
Amixture of the aldehyde 7 (51 mg, 0.25 mmol) and methoxy-
carbonylmethylenetriphenylphosphorane
(8)
(92 mg,
0.28 mmol) in benzene (2 mL) was refluxed overnight (80 8C,
16 h). The resulting precipitate was removed by filtration and
washed with Et2O. The filtrate was concentrated and the resi-
due purified by chromatography (petroleum ether/Et2O,
15:1) to afford the enoate 9 as colorless oil; yield: 67 mg
(97%; trans/cis¼33:1 as determined by relative peak heights
1
in the H NMR spectrum); TLC (petroleum ether/ethyl ace-
tate, 16:1): Rf ¼0.45; [a]2D6: þ7.8 (c 0.98, CHCl3) {Ref.[14c]
18
˜
[a]D : þ8.94 (c 1.01, CHCl3)}; IR (neat): n¼2954 , 2930, 1729,
n¼3348 (br), 2956, 2929, 2857, 1255 cmÀ1; 1H NMR (400 MHz,
1258 cmÀ1; H NMR (400 MHz, CDCl3): d¼0.01, 0.02 (2 s,
1
˜
CDCl3): d¼0.04, 0.05 (2 s, 3H each, SiCH3), 0.29 0.39 (m, 2H,
cyclopropane CH2), 0.63 0.72 (m, 1H, H-2’), 0.83 0.90 (m,
2H, H-1’), 0.88 [s, 9H, SiC(CH3)3], 1.12 1.19 (m, 1H, H-1’’),
1.15 (d, J¼6.1 Hz, 3H, CH3), 1.53 1.60 (m, 1H, H-1’’), 3.37
3.52 (m, 2H, CH2OH), 3.85 (q, J¼6.1 Hz, 1H, CHOR);
13C NMR (100 MHz, CDCl3): d¼ À4.7, À4.5, 9.9, 13.8, 18.1,
21.1, 23.6, 25.9, 43.5, 67.1, 68.7. HRMS: calcd. for C13H28O2
SiNa: 267.17508; found: 267.17513.
3H each, SiCH3), 0.85 [s, 9H, SiC(CH3)3], 1.13 (d, J¼6.1 Hz,
3H, H-6), 2.27 2.31 (m, 2H, H-4), 3.70 (s, 3H, OCH3), 3.86
3.94 (m, 1H, H-5), 5.81 (d, J¼15.7 Hz, 1H, H-2), 6.93 (dt, J¼
15.7, 7.7 Hz, 1H, H-3); 13C NMR (100 MHz, CDCl3): d¼
À4.9, À4.6, 18.0, 23.7, 25.8, 42.4, 51.3, 67.6, 122.8, 146.3, 166.8.
(2E,5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2-hexen-1-
ol (10)
[(1S,2R)-2-((2S)-2-{[tert-
To a solution of ester 9 (17.6 g, 68 mmol) in CH2Cl2 (150 mL)
was added DIBAL-H (1.0 M in hexane, 150 mL, 150 mmol)
dropwise at À788C. After being stirred for 1.5 h at À788C,
the temperature was raised to À308C, methanol (2 mL) was
added, and the mixture allowed to reach 08C. Then a saturated
solution of potassium sodium tartarte (100 mL) was added and
the mixture extracted with Et2O (3ꢀ25 mL). The combined
organic layers were washed with brine, dried (MgSO4), filtered
and concentrated. The crude product was purified by flash
chromatography (petroleum ether/Et2O, 4:1) to afford alcohol
10 as a colorless oil; yield: 15.0 g (96%); TLC (petroleum ether/
ethyl acetate, 4:1): Rf ¼0.49; [a]2D6: þ6.04 (c 0.98, CHCl3); IR
˜
(400 MHz, CDCl3): d¼0.02, 0.02 (2 s, 3H, SiCH3), 0.86 [s,
9H, SiC(CH3)3], 1.11 (d, J¼6.1 Hz, 3H, H-6), 1.62 (s, br, 1H,
OH), 2.09 2.21 (m, 2H, H-4), 3.77 3.85 (m, 1H, H-5), 4.07
(d, J¼4.0 Hz, 1H, H-1), 5.63 5.67 (m, 2H, H-3, H-2);
13C NMR (100 MHz, CDCl3): d¼ À4.6, À4.6, 18.1, 23.4,
25.8, 42.5, 63.7, 68.4, 129.6, 131.2.
Butyl(dimethyl)silyl]oxy}propyl)cyclopropyl]methyl
Methanesulfonate (13)
Triethylamine (6.3 mL, 45 mmol) and methanesulfonyl chlor-
ide (1.75 mL, 22.5 mmol) were added to a cooled (0 8C) solu-
tion of the alcohol 12 (3.67 g, 15 mmol) in dry CH2Cl2
(100 mL) under a nitrogen atmosphere. After being stirred
for 30 min at 0 8C, the mixture was diluted with ether, washed
with H2O and brine. The organic layer was dried (MgSO4), fil-
tered, and concentrated to give 13 as colorless oil; yield: 4.84 g.
The residue was used for the next reaction without further
purification. TLC (petroleum ether/ethyl acetate, 4:1): Rf ¼
(neat): n¼3343 (br), 2956, 2929, 1255 cmÀ1
;
1H NMR
0.40; [a]D : þ7.89 (c 0.93, CHCl3); IR (neat): n¼2956, 2930,
23
˜
2858, 1255 cmÀ1; H NMR (400 MHz, CDCl3): d¼0.03, 0.04
1
(2 s, 3H each, SiCH3), 0.45 0.56 (m, 2H, cyclopropane CH2),
0.87 [s, 9H, SiC(CH3)3], 0.95 1.02 (m, 1H, H-2’), 1.14 (d, J¼
6.0 Hz, 3H, CH3), 1.15 1.19 (m, 1H, CH2), 1.24 (s, br, 1H, H-
1’), 1.56 1.62 (m, 1H, CH2), 2.99 (s, 3H, Ms CH3), 3.85 (q,
J¼6.1 Hz, 1H, CHOR), 4.01 4.14 (m, 2H, CH2OMs);
858
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of the 8-Hydroxy Acid of Jasplakinolide
FULL PAPERS
13C NMR (100 MHz, CDCl3): d¼ À4.7, À4.5, 11.0, 14.9, 17.4,
18.1, 23.6, 25.9, 37.9, 43.2, 68.3, 74.7; HRMS: calcd. for C14H30O4
SSiNa [MþNa]þ: 345.15263; found: 345.15299.
3-[(1R,3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-1-
methylbutyl]-1,2,4-trioxolane (16)
Ozone was passed through the solution of 15 (6.85 g,
30.0 mmol) in 100 mL of CH2Cl2 (0.3 M) at À788C until a
deep blue color appeared (2 h). The solution was kept at
À788C before nitrogen gas was passed through it until the col-
or faded (2 h). The solution was used for the next reaction with-
out further purification. For analytical purposes, a sample was
carefully concentrated under vacuum. TLC (petroleum ether/
(1R,2R)-1-[(2S)-2-[tert-Butyl(dimethyl)silyl]oxy]-2-
(iodomethyl)cyclopropane (14)
˜
ethyl acetate, 4:1): Rf ¼0.40; IR (neat): n¼2957, 2930, 2886,
Asolution of the crude sulfonate 13 (4.84 g, 15 mmol) in dry
acetone (100 mL) was treated with sodium iodide (4.84 g,
135 mmol) at 08C. After being stirred for 3 h at room temper-
ature, the mixture was diluted with petroleum ether (50 mL)
and washed with H2O (50 mL). The aqueous phase was extract-
ed with Et2O (3ꢀ30 mL). The combined organic layers were
washed with brine, dried (MgSO4), filtered and concentrated.
The residue was purified by flash chromatography (petroleum
ether/Et2O, 8:1) to afford the iodide 14 as a pale yellow oil
which is used immediately for the next step; yield: 5.11 g
(96% from 12); TLC (petroleum ether/ethyl acetate, 60:1):
2858, 1463, 1255, 1084 cmÀ1
;
1H NMR (400 MHz, CDCl3):
d¼0.04 (s, 6H, SiCH3), 0.05 (s, 6H, SiCH3), 0.87 [s, 9H,
SiC(CH3)3], 0.97 (dd, J¼6.8, 2.3 Hz, 3H, CH3), 1.14 (d, J¼
6.1 Hz, 3H, H-4’), 1.32 1.71 (m, 1H, H-2’), 2.04 2.12 (m, 1H,
H-2’), 3.86 3.96 (m, 1H, H-1’), 4.93 4.96 (m, 1H, H-3), 5.00
(d, J¼3.8 Hz, 1H, H-5), 5.20 (d, J¼2.0 Hz, 1H, H-5);
13C NMR (100 MHz, CDCl3): d¼ À4.9, À4.1, 13.5, 13.7,
18.2, 24.4, 25.8, 31.3, 31.6, 41.2, 41.4, 65.6, 94.2, 94.3, 106.8;
HRMS: calcd. for C13H28O4SiNa [MþNa]þ: 299.16491; found:
299.16494.
À1
Rf ¼0.44; IR (neat): n¼2956, 2928, 2857 cm
;
1H NMR
˜
(400 MHz, CDCl3): d¼0.04, 0.04 (2 s, 3H each, SiCH3),
0.42 0.46 (m, 1H, cyclopropane CH2), 0.59 0.63 (m, 1H, cy-
clopropane CH2), 0.68 0.76 (m, 1H, cyclopropane CH), 0.87
[s, 9 H, SiC(CH3)3], 1.03 1.10 (m, 1H, CH2), 1.15 (d, J¼
6.0 Hz, 3H, CH3), 1.24 (s, br, 1H, cyclopropane CH), 1.47
1.53 (m, 1H, CH2), 3.09 3.19 (m, 2H, CH2I), 3.85 (q, J¼
6.1 Hz, 1H, CHOR); 13C NMR (100 MHz, CDCl3): d¼ À4.7,
À4.5, 13.7, 17.9, 18.1, 22.1, 23.3, 23.6, 25.9, 43.8, 68.4; HRMS:
calcd. for C13H27OISiNa [MþNa]þ: 377.07681; found:
377.07665.
(2R,4S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-
methylpentanal (17)
The ozonide 16 was reduced to aldehyde by the addition of di-
methyl sulfide (60 mL, 2 mL/mmol). The solution was allowed
to warm to room temperature and stirred for 7 days, then wash-
ed with H2O (2ꢀ50 mL) and brine (2ꢀ50 mL), respectively.
The organic layer was dried (MgSO4), filtered and concentrat-
ed. The residue was purified by flash chromatography (petrole-
um ether/Et2O, 15:1) to afford aldehyde 17 as a colorless oil;
yield: 6.71 g (97%, over 2 steps from alkene 15); TLC (petrole-
um ether/ethyl acetate, 16:1): Rf ¼0.47; [a]2D4: þ6.20 (c 0.89,
CHCl3) {Ref.[9b] [a]D : þ23.2 (c 0.06, CHCl3)}; IR (neat): n¼
25
˜
2957, 2930, 2858, 1728, 1255 cmÀ1
;
1H NMR (400 MHz,
(3R,5S)-5-[tert-Butyl(dimethyl)silyl]oxy-3-methylhex-
1-ene (15)
CDCl3): d¼0.04 (s, 6H, SiCH3), 0.05 (s, 6H, SiCH3), 0.87 [s,
9H, SiC(CH3)3], 1.09 (d, J¼6.0 Hz, 3H, CH3), 1.16 (d, J¼
6.1 Hz, 3H, H-5), 1.47 1.54 (m, 1H, H-3), 1.80 1.87 (m, 1H,
H-3), 2.47 2.57 (m, 1H, H-4), 3.83 3.96 (m, 1H, H-4), 9.61
(s, 1H, H-1); 13C NMR (100 MHz, CDCl3): d¼ À4.8, À4.1,
13.4, 18.0, 24.3, 25.8, 40.4, 43.5, 66.1, 205.2.
Asolution of the iodide 15 (15.6 g, 44.0 mmol) in dry Et2O
(250 mL) containing 4 ä molecular sieves (7.7 g) and TMEDA
(13.2 mL, 88 mmol) was treated with n-BuLi (2.5 M in hexane,
35.2 mL, 88 mmol) at À788C. The resulting mixture was stir-
red at À788C for 1 h, then the temperature was raised to
À308C over 2 h. The reaction was quenched with H2O
(100 mL), the layers were separated and the aqueous layer ex-
tracted with Et2O (3ꢀ75 mL). The combined organic layers
were successively washed with 10% HCl (100 mL), saturated
NaHCO3 solution (100 mL), H2O and brine, respectively.
The organic layer was dried (MgSO4), filtered, and concentrat-
ed. The crude product was purified by flash chromatography
(petroleum ether) to give the alkene 15 as a colorless oil; yield:
Methyl (2E,4R,6S)-6-{[tert-Butyl(dimethyl)silyl]oxy}-
2,4-dimethylhept-2-enoate (19)
Methyl methacrylate (20) (222 mL 2.0 mmol) and alkene 15
(46 mg 0.2 mmol) were added to a solution of Grubbs catalyst
21 (8 mg, 10À2 mmol, 5 mol %) in CH2Cl2 (1 mL). The mixture
was refluxed at 408C under nitrogen for 20 h. The reaction mix-
ture was then concentrated to about 0.5 mL and purified di-
rectly by flash chromatography (petroleum ether/Et2O, 20:1)
to afford the enoate 19 as a colorless oil; yield: 42 mg (73%,
only trans was detected by 1H NMR spectroscopy); TLC (pe-
troleum ether/ethyl acetate, 20:1): Rf ¼0.52; [a]2D6: À6.98 (c
7.33 g (73%,>98% de); TLC (petroleum ether): Rf ¼0.44;
26
˜
[a]D : þ3.91 (c 0.98, CH2Cl2); IR (neat): n¼2957, 2927,
1463 cmÀ1
;
1H NMR (400 MHz, CDCl3): d¼0.04 (s, 6H,
SiCH3), 0.87 [s, 9H, SiC(CH3)3], 0.98 (d, J¼6.7 Hz, 3H, CH3),
1.12 (d, J¼6.0 Hz, 3H, H-6), 1.24 1.29 (m, 1H, H-4), 1.49
1.56 (m, 1H, H-4), 2.23 (m, 1H, H-3), 3.78 3.85 (m, 1H, H-
5), 4.90 (d, J¼10.3 Hz, 1H, H-1), 4.93 (d, J¼17.2 Hz, 1H, H-
1), 5.65 5.74 (m, 1H, H-2); 13C NMR (100 MHz, CDCl3): d¼
À4.7, À4.3, 18.1, 20.1, 23.7, 25.9, 34.4, 46.7, 66.5, 112.2 144.8;
HRMS: calcd. for C13H28O2Si [M 1]þ: 227.183116; found:
227.183745.
À1
˜
1.0, CH2Cl2); IR (neat): n¼2956, 2929, 2857, 1719, 1256 cm
;
1H NMR (400 MHz, CDCl3): d¼0.04 (s, 6H, SiCH3), 0.87
[s, 9H, SiC(CH3)3], 0.98 (d, J¼6.6 Hz, 3H, CH3), 1.10 (d, J¼
6.0 Hz, 3H, H-7), 1.32 1.38 (m, 1H, H-5), 1.46 1.53 (m, 1H,
H-5), 1.83 (s, 3H, CH3), 2.58 2.69 (m, 1H, H-4), 3.72 (s, 3H,
OCH3), 3.75 3.79 (m, 1H, H-6), 6.57 (d, J¼9.9 Hz, 1H, H-3);
Adv. Synth. Catal. 2004, 346, 855 861
asc.wiley-vch.de
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
859

Saengchai Wattanasereekul, Martin E. Maier
FULL PAPERS
13C NMR (100 MHz, CDCl3): d¼ À4.8, À4.2, 12.4, 18.0, 19.5,
24.0, 25.8, 29.7, 46.5, 51.7, 66.2, 125.7, 148.2, 168.9; HRMS:
calcd. for C16H32O3SiNa: 323.20129; found: 323.20125.
with Et2O (3ꢀ5 mL). The combined organic layers were wash-
ed with brine, dried (MgSO4), filtered and concentrated. The
crude product was purified by short flash chromatography (pe-
troleum ether/Et2O, 1:1) to yield the iodide 24 as pale yellow
oil; yield: 292 mg (94% from 22); TLC (petroleum ether/ethyl
˜
acetate, 100:1): Rf ¼0.40; IR (neat): n¼2957, 2928, 2857, 1361,
(2E,4R,6S)-6-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-
dimethylhept-2-en-1-ol (22)
1256 cmÀ1
;
1H NMR (400 MHz, CDCl3): d¼0.04 (s, 6H,
SiCH3), 0.88 [s, 9H, SiC(CH3)3], 0.90 (d, J¼4.0 Hz, 3H, H-
4a), 1.10 (d, J¼6.1 Hz, 3H, H-7), 1.26 1.33 (m, 1H, H-5),
1.39 1.46 (m, 1H, H-5), 1.76 (s, 3H, H-2a), 2.37 2.46 (m, 1H,
H-4), 3.71 3.77 (m, 1H, H-6), 3.92 (s, 2H, H-1), 5.44 (d, J¼
9.6 Hz, 1H, H-3); 13C NMR (100 MHz, CDCl3): d¼ À4.8, À
4.3, 15.5, 17.0, 18.1, 19.8, 23.8, 25.9, 29.6, 47.0, 66.3, 131.3,
136.2; HRMS: calcd. for C15H31OISiNa: 405.10867; found:
405.10812.
Asolution of ester 19 (990 mg, 3.3 mmol) in CH2Cl2 (100 mL)
was treated with DIBAL-H (1.0 M in hexane, 7.3 mL,
7.3 mmol) in a dropwise fashion at À788C. After stirring for
1.5 h at À788C, the temperature was raised to À308C, metha-
nol (0.5 mL) was added, and the mixture warmed up to 08C.
The other work-up manipulations were carried out as describ-
ed for the synthesis of 10. The crude product was used without
further purification; yield: 898 mg (100%), colorless oil; TLC
(petroleum ether/ethyl acetate, 6:1): Rf ¼0.50; [a]2D5: À1.94
(c 0.25, CHCl3) {Ref.[9c] [a]D24: À1.6 (c 0.91, CHCl3)}; IR
(4R)-4-Benzyl-3-((2S,4E,6R,8S)-8-{[tert-
butyl(dimethyl)silyl]oxy}-2,4,6-trimethylnon-4-enoyl)-
1,3-oxazolidin-2-one (26)
1
(neat): n¼3336 (br), 2957, 2928, 2857, 1255 cmÀ1; H NMR
˜
(400 MHz, CDCl3): d¼0.04 (s, 6H, SiCH3), 0.88 [s, 9H,
SiC(CH3)3], 0.93 (d, J¼6.6 Hz, 3H, CH3), 1.10 (d, J¼6.0 Hz,
3H, CH3), 1.26 (s, br, 1H, OH), 1.26 1.32 (m, 1H, H-5),
1.41 1.48 (m, 1H, H-5), 1.66 (s, 3H, CH3), 2.47 2.54 (m, 1 H,
H-4), 3.73 3.81 (m, 1H, H-6), 3.97 (s, 2H, CH2OH), 6.57 (d,
J¼9.9 Hz, 1H, H-3); 13C NMR (100 MHz, CDCl3): d¼ À4.7,
À4.2, 13.7, 18.1, 20.5, 24.0, 25.9, 28.6, 47.5, 66.5, 69.0, 132.8,
133.0.
To a solution of propionyl-1,3-oxazolidin-2-one 25 (173 mg,
0.74 mmol) in THF (20 mL) was added sodium hexamethyldi-
silazide (0.4 mL, 2 M in THF, 0.8 mmol) at À788C. The solu-
tion was then stirred at À788C for 2 h before a solution of io-
dide 24 (264 mg, 0.64 mmol) in THF (3 mL) was added. The re-
action was allowed to proceed at À788C for 15 h, then the mix-
ture was allowed to reach 08C. Thereafter, the mixture was par-
titioned between saturated NH4Cl (10 mL) and Et2O (10 mL).
The layers were separated and the aqueous layer was extracted
with Et2O (2ꢀ50 mL). The combined organic extracts were
dried (MgSO4), filtered, and concentrated to yield a white
amorphous solid. The crude product was purified by flash chro-
matography (petroleum ether/Et2O, 6:1) to afford the alkyla-
tion product 26 as a sticky colorless oil (yield: 190 mg, 61%)
and recovered iodide 24 (24%). TLC petroleum ether/ethyl
(2E,4R,6S)-6-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-
dimethylhept-2-enyl Methanesulfonate (23)
Triethylamine (340 mL, 1.25 mmol) and methanesulfonyl
chloride (97 mL, 1.25 mmol) were added to a cooled (08C) sol-
ution of the alcohol 22 (221 mg, 0.81 mmol) in dry CH2Cl2
(5 mL) under a nitrogen atmosphere. After being stirred for
30 min at 08C, the mixture was diluted with Et2O (10 mL),
washed with H2O, brine, dried (MgSO4), filtered and concen-
trated under vacuum providing the crude mesylate 23 as a col-
orless oil; yield: 275 mg (97%). The crude product, containing
around 10% of the corresponding chloride was used for the
next step without further purification. TLC (petroleum ether/
ethyl acetate, 8:1): Rf ¼0.54; [a]2D4: À1.04 (c 1.00, CHCl3); IR
acetate, 6:1): Rf ¼0.54; [a]2D5: À30.0 (c 0.94, CHCl3) {Ref.[9c]
24
˜
[a]D : À35.2 (c 0.94, CHCl3)}; IR (neat): n¼2956, 2929, 1783,
1387 cmÀ1
;
1H NMR (400 MHz, CDCl3): d¼0.06 (s, 6H,
SiCH3), 0.89 (d, J¼6.6 Hz, 3H, CH3), 0.90 [s, 9H, SiC(CH3)3],
1.11 (d, J¼5.8 Hz, 3H, H-9’), 1.12 (d, J¼6.8 Hz, 3H, CH3),
1.27 1.34 (m, 1H, H-7’), 1.43 1.50 (m, 1H, H-7’), 1.68 (s, 3H,
CH3), 1.97 2.03 (m, 1H, H-3’), 2.46 2.50 (m, 1H, H-6’), 2.52
(m, 1H, H-3’), 2.69 2.75 (m, 1H, benzylic H), 3.26 3.30 (m,
1H, benzylic H), 3.75 3.82 (m, 1H, H-8’), 3.92 4.01 (m, 1H,
H-2’), 4.13 4.20 (m, 2H, H-5), 4.66 4.72 (m, 1H, H-4), 5.03
(d, J¼9.4 Hz, 1H, H-5’), 7.21 7.35 (m, 5H, aromatic H);
13C NMR (100 MHz, CDCl3): d¼ À4.9, À4.5, 15.4, 16.0,
18.0, 20.8, 23.6, 25.8, 29.0, 35.4, 38.0, 43.9, 47.5, 55.2, 68.5,
66.6, 127.2, 128.8, 129.3, 130.1, 134.4, 135.3, 153.0, 177.0.
(neat): n¼2956, 2930, 1353, 1175; 1H NMR (400 MHz,
˜
CDCl3): d¼0.05 (s, 6H, SiCH3), 0.89 [s, 9H, SiC(CH3)3], 0.98
(d, J¼6.8 Hz, 3H, H-4a), 1.39 (d, J¼6.3 Hz, 3H, H-7), 1.50
1.55 (m, 1H, H-5), 1.59 (s, 3H, H-2a), 1.71 1.78 (m, 1H, H-
5), 2.46 2.54 (m, 1H, H-4), 2.97 (s, 3H, Ms CH3), 3.98 (s, 2H,
H-1), 4.73 4.78 (m, 1H, H-6), 5.18 (dd, J¼9.6, 2.6 Hz, 1H,
H-3); 13C NMR (100 MHz, CDCl3): d¼ À5.3, 13.5, 18.4, 20.8,
21.3, 25.9, 28.6, 38.6, 44.2, 68.3, 78.8, 129.0, 134.1; HRMS: calcd.
for C16H34O4SSiNa [MþNa]þ: 373.18393; found: 373.18381.
(2S,4E,6R,8S)-8-{[tert-Butyl(dimethyl)silyl]oxy}-2,4,6-
trimethylnon-4-enoic Acid (4b)
(2E,4R,6S)-6-{[tert-Butyl(dimethyl)silyl]oxy}-1-iodo-
Acooled (0 8C) solution of the oxazolidinone 26 (73 mg,
0.15 mmol) in THF (2.5 mL) was treated with H2O2 (35% by
weight, 68 mL, 0.60 mmol), then with a solution of LiOH¥H2O
(13 mg, 0.30 mmol) in H2O (1 mL). The solution was stirred at
08C for 1.5 h. After TLC indicated completion of the hydroly-
sis, a mixture of saturated Na2SO3 (2 mL) and saturated
NaHCO3 (2 mL) was added at 08C. The mixture was partially
2,4-dimethylhept-2-ene (24)
Asolution of the crude mesylate 23 (274 mg, 0.78 mmol) in dry
acetone (5 mL) was treated with sodium iodide (1.05 g,
7.0 mmol) at 08C. After being stirred for 3 h at room tempera-
ture, the mixture was diluted with petroleum ether (10 mL) and
washed with H2O (5 mL). The aqueous phase was extracted
860
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 855 861

Synthesis of the 8-Hydroxy Acid of Jasplakinolide
FULL PAPERS
concentrated and then diluted with H2O (2 mL). The aqueous
solution was extracted with CH2Cl2 (3ꢀ5 mL). The combined
organic extracts were dried (MgSO4), filtered and concentrat-
ed. The crude product was purified by flash chromatography
(petroleum ether/Et2O, 6:1) to afford the acid 4b as a colorless
oil; yield: 49 mg (100%); TLC (petroleum ether/ethyl acetate,
6:1): Rf ¼0.57; [a]2D2: À9.0 (c 0.23, CH2Cl2) {Ref.[9c] [a]2D4:5: À
c) A. V. Rama Rao, M. K. Gurjar, B. R. Nallaganchu,
A. Bhandari, Tetrahedron Lett. 1993, 34, 7081 7084.
[8] For total syntheses of jasplakinolide (1), see: a) P. A.
Grieco, Y. S. Hon, A. Perez-Medrano, J. Am. Chem.
Soc. 1988, 110, 1630 1631; b) K. S. Chu, G. R. Negrete,
J. P. Konopelski, J. Org. Chem. 1991, 56, 5196 5201;
c) A. V. Rama Rao, M. K. Gurjar, B. R. Nallaganchu,
A. Bhandari, Tetrahedron Lett. 1993, 34, 7085 7088;
d) Y. Hirai, K. Yokota, T. Momose, Heterocycles 1994,
39, 603 612; e) P. Ashworth, B. Broadbelt, P. Jankowski,
P. Kocienski, A. Pimm, R. Bell, Synthesis 1995, 199 206.
[9] For total syntheses of geodiamolide (2), see: a) P. A.
Grieco, A. Perez-Medrano, Tetrahedron Lett. 1988, 29,
4225 4228; b) Y. Hirai, K. Yokota, T. Yamazaki, T. Mo-
mose, Heterocycles 1990, 30, 1101 1119; c) T. Shioiri, T.
Imaeda, Y. Hamada, Heterocycles 1997, 46, 421 442.
[10] D. Seebach, M. A. Sutter, R. H. Weber, M. F. Z¸ger,
Org. Synth., Coll. Vol. 1990, 7, 215 220.
˜
9.2 (c 1.1, CHCl3)}; IR (neat): n¼2957, 2929, 2857, 1709,
1255 cmÀ1
;
1H NMR (400 MHz, CDCl3): d¼0.03 (s, 6H, SiCH3), 0.87 (s,
3H, CH3), 0.87 [s, 9H, SiC(CH3)3], 1.08 (d, J¼6.3 Hz, 3H,
CH3), 1.10 (d, J¼7.3 Hz, 3H, CH3), 1.25 1.31 (m, 1H, H-7),
1.39 1.45 (m, 1H, H-7), 1.59 (s, 3H, CH3), 1.98 2.04 (m, 1H,
H-3), 2.35 2.41 (m, 1H, H-3), 2.38 2.46 (m, 1H, H-6), 2.56
2.65 (m, 1H, H-2), 3.70 3.78 (m, 1H, H-8), 4.96 (d, J¼
9.5 Hz, 1H, H-5), 11.43 (s, br, 1H, COOH); 13C NMR
(100 MHz, CDCl3): d¼ À4.8, À4.4, 15.6, 16.1, 18.3, 20.9,
23.6, 25.9, 29.1, 37.8, 43.8, 47.5, 66.7, 129.9, 134.3, 183.0.
[11] M. Kitamura, M. Tokunaga, T. Ohkuma, R. Noyori, Org.
Synth. 1992, 71, 1 13.
Acknowledgements
[12] a) K. Mori, Z.-H. Qian, Bull. Soc. Chim. Fr. 1993, 130,
382 387; b) D. Romo, R. M. Rzasa, H. A. Shea, K.
Park, J. M. Langenhan, L. Sun, A. Akhiezer, J. O. Liu,
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Financial support by the Deutsche Forschungsgemeinschaft
(grant Ma 1012/13 1) and the Fonds der Chemischen Industrie
is gratefully acknowledged.
¬
[13] G. Solladie, F. Somny, F. Colobert, Tetrahedron: Asym-
metry 1997, 8, 801 810.
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[6] Aconformational search (Macromodel) on a derivative
of 4a (methyl ester, 8-O-acetyl) revealed 6 low energy
conformations (within 1 kcal of the minimum). In 4 of
these, the conformation corresponds to the one depicted
in Figure 2.
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[22] a) J. R. Gage, D. A. Evans, Org. Synth. 1989, 68, 77 82;
b) J. R. Gage, D. A. Evans, Org. Synth. 1989, 68, 83 91.
[7] For syntheses of the acid 4, see: a) U. Schmidt, W. Siegel,
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b) S.-K. Kang, D.-H. Lee, Synlett 1991, 175 176;
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