Highly stereoselective total synthesis of (+)-9-epi-Dictyostatin and (-)-12,13-Bis-epi-dictyostatin

FULL PAPER

DOI: 10.1002/ejoc.201100244

Highly Stereoselective Total Synthesis of (+)-9-epi-Dictyostatin and

(–)-12,13-Bis-epi-dictyostatin

Chiara Zanato,^[a]Luca Pignataro,^[a]Andrea Ambrosi,^[a]Zhongyan Hao,^[a]Chiara Trigili,^[b]

José Fernando Díaz,^[b]Isabel Barasoain,^[b]and Cesare Gennari*^[a]

Keywords: Medicinal chemistry / Natural products / Total synthesis / Asymmetric synthesis / Antitumor agents /

Macrocycles

The total syntheses of (+)-9-epi-dictyostatin (1a) and (–)-

12,13-bis-epi-dictyostatin (1b), diastereomers of the antimi-

totic marine sponge-derived macrolide (–)-dictyostatin (1),

were achieved by creating 11 stereogenic centers and 4

stereogenic double bonds with a high level of stereocontrol.

The yield for the 29-step longest linear sequence from Roche

ester was 1.53 and 1.52%, respectively. The final key steps

to these unnatural products were the addition of vinylzinc-

ates C10-C26 to aldehyde C1–C9 (leading surprisingly to

complete stereoselectivity for the 9R-configuration in 28a

and for the 9S-configuration in 12,13-bis-epimeric 28b), fol-

lowed by Yamaguchi macrolactonization and global depro-

tection. (–)-12,13-Bis-epi-dictyostatin (1b) displayed a dra-

matic decrease of cytotoxicity and of the affinity toward the

paclitaxel binding site of microtubules.

esting opportunities for structural simplification whilst

maintaining biological potency, and for better understand-

ing the structure-activity-relationships of this class of anti-

tumor agents. Although much work has been carried out in

this area, syntheses of dictyostatin analogs modified at C12

and/or C13 were never reported. In this full paper, we de-

scribe a highly stereoselective total synthesis of two non-

natural analogs of (–)-dictyostatin: (+)-9-epi-dictyostatin

(1a) and (–)-12,13-bis-epi-dictyostatin (1b), building on our

previous work in this field.^[5j,7j–7k]Our retrosynthetic ap-

proach, shown in Scheme 1 and common to the two target

molecules, disconnects the macrolide ring into two key in-

termediates: C1–C9 aldehyde 2, prepared from the corre-

sponding alcohol,^[7k]and C10–C26 vinyl iodides 3a and 3b,

prepared by taking advantage of a synthetic route partially

described in two communications from our group.^[5j,7j]

Introduction

The sponge-derived macrolide (–)-dictyostatin (1,

Scheme 1) has been reported to be a potent, paclitaxel-like

inducer of tubulin polymerization and to inhibit human

cancer cell proliferation at low nanomolar concentrations,

with activity somewhat superior to the already very active

discodermolide.^[1]With the recent withdrawal of discod-

ermolide from clinical development^[2]the importance of

dictyostatin further increases. Moreover, (–)-dictyostatin is

also extremely potent against paclitaxel-resistant human

cancer cell lines over-expressing the P-glycoprotein efflux

pump.^[1]The structure of (–)-dictyostatin (1) with full ste-

reochemical assignments was established by Paterson and

coworkers in 2004,^[3]and four total syntheses were com-

pleted in the period 2004–2007.^[4]A growing number of re-

search groups have recently been involved in targeting this

interesting natural product, and the syntheses of several an-

alogs (e.g., desmethyldictyostatins, epi-dictyostatins, bis-epi-

dictyostatins, hydrodictyostatins, methoxy-dictyostatins),^[5]

discodermolide/dictyostatin hybrids,^[6]and various frag-

ments and synthetic intermediates^[7]have been described.

The development of dictyostatin analogs is an appealing

goal from a pharmaceutical perspective, and provides inter-

Results and Discussion

The synthesis of fragments C10-C26 is based on the dis-

connection of the target compounds into four key interme-

diates, as shown in Scheme 2.

The synthesis of alkyne 4 (Scheme 3) started from com-

mercially available (S)-3-hydroxy-2-methylpropionate [(S)-

Roche ester, 8] which was converted into its PMB ether 9

[PMBOC(=NH)CCl₃, PPTS, DCM/Cy, 92%]. LiAlH₄re-

duction (10, 87%)^[8]followed by iodination (I₂, PPh₃, imid-

azole) provided compound 11 in high yield (95%). Myers’

alkylation^[9]gave amide 12 in 92% yield and with a Ͼ 98:2

diastereomeric ratio (dr) in favor of the desired dia-

stereomer. Reduction with the borane–ammonia complex

[a] Università degli Studi di Milano, Dipartimento di Chimica

Organica e Industriale, Centro Interdipartimentale C.I.S.I.,

Via G. Venezian 21, 20133 Milan, Italy

Fax: +39-02-50314072

E-mail: cesare.gennari@unimi.it

[b] Centro de Investigaciones Biológicas, Departamento de

Biología Físico-Química,

C/ Ramiro de Maeztu 9, 28040 Madrid, Spain

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201100244.

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Scheme 2. Retrosynthetic approach to C10-C26 fragments 3a and

3b (dictyostatin numbering).

afforded alcohol 13 in 95% yield. Benzyl protection (NaH,

BnBr, nBu₄NI, 83%), followed by selective removal of the

PMB group over the benzyl group [ceric ammonium nitrate

(CAN), CH₃CN/H₂O (4:1)], delivered alcohol 14 in 93%

yield. Dess–Martin oxidation furnished aldehyde 15, which

was not isolated, but directly homologated to alkyne 4.

For the latter step, different methods were investigated

with the twofold aim of obtaining a high yield and avoiding

epimerization at the α-stereocenter (Table 1). Shioiri’s lithio-

diazomethane protocol, which takes advantage of the Col-

vin rearrangement [Table 1, entry 1; Me₃SiCHN₂, LDA,

THF],^[10]provided the desired alkyne 4 in good yield (61%)

as a single diastereomer.^[7j]Unfortunately, the yield could

Scheme 1. Retrosynthetic approach to (+)-9-epi-dictyostatin (1a)

and 12,13-bis-epi-dictyostatin (1b), with key reactions involved and

associated diastereomeric ratios.

Scheme 3. Synthesis of alkyne 4 (dictyostatin numbering).

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Highly Stereoselective Total Synthesis of Dictyostatins

not be reproduced during the scale-up (from 0.1 to 1.0 gram stereomeric ratio. Acetal 17 was cleaved with DIBAL-H to

scale). Corey–Fuchs dibromo-olefination (Table 1, entry 2; generate diol 18 in 75% yield. Hydrogenation (under 4 bar

CBr₄, PPh₃, Zn, DCM), followed by nBuLi-promoted elimi- H₂pressure) of the propargylic alcohol 18, in the presence

nation,^[11]caused no epimerization but the yield could not of 10 mol-% Wilkinson’s catalyst, afforded the desired satu-

be improved above a modest 35%. The Seiferth-Gilbert rated compound 19 (70%), which was then silylated to give

procedure [Table 1, entry 3; HC(N₂)PO(OMe)₂, tBuOK, the fully protected tetraol 20 in 97% yield. Selective re-

THF]^[12]gave a reasonable yield (59%) accompanied by moval of the benzyl group over the PMB group (H₂, Raney-

10% epimerization. Finally, the Ohira-Bestmann protocol Ni, EtOH)^[17]furnished primary alcohol 21 in 81% yield,

was explored: under the original conditions [Table 1, entry which was oxidized (TPAP/NMO)^[18]to the corresponding

4; CH₃COC(N₂)PO(OMe)₂, K₂CO₃, MeOH, room aldehyde. Subsequent Marshall–Tamaru palladium-cata-

temp.]^[13]a good yield (88%) was obtained, but with exten- lyzed allenylzinc addition^[19]with the mesylate of (R)-3-but-

sive epimerization of the α stereocenter (dr = 75:25). After yn-2-ol (6a) gave alcohol 22a (82% over two steps) with a

a thorough investigation, we found that the epimerization high level of diastereoselectivity (dr Ͼ 98:2) in favor of the

could be suppressed by avoiding the protic solvent and desired anti,syn adduct. Using the enantiomeric mesylate

decreasing the temperature. Eventually, optimal conditions 6b, derived from (S)-3-butyn-2-ol, the diastereomeric

[Table 1, entry 5; CH₃COC(N₂)PO(OMe)₂(4 equiv.), alcohol 22b was prepared (84% over two steps) with a Ն

MeONa (4 equiv.), THF, –78 °C to room temp.]^[14]were 95:5 anti,anti/anti,syn ratio, which was used to access 12,13-

identified which allowed the synthesis of alkyne 4 in excel- bis-epi-dictyostatin. From this point, we carried forward

lent yield (91%) and diastereomeric ratio (dr Ͼ 97:3).

two parallel syntheses, denoted a [C12(S), C13(R)] and b

[C12(R), C13(S)] (dictyostatin numbering).

TBS protection of alcohols 22a–b afforded alkynes 23a–

b, which were then lithiated with nBuLi and converted into

the corresponding alkynyl iodides 24a–b in quantitative

yield (Scheme 5). Reduction of compounds 24 with di-

imide^[5d,20]provided (Z)-vinyl iodides 25a–b as single dia-

stereoisomers (Z/E Ͼ 100:1) in excellent yield (92–100%).

The primary tert-butyldimethylsilyl ether of 25a–b was se-

lectively cleaved (HF·Py, THF/Py, 80%) to give compounds

26a–b, which were converted into aldehydes 27a–b by oxi-

dation with Dess–Martin periodinane. The latter com-

pounds were treated with (1-bromoallyl)trimethylsilane 7

Table 1. Different methodologies for the alkynylation of aldehyde

15.

under

Nozaki–Hiyama–Kishi

coupling

conditions

(CrCl₂),^[21]followed by Peterson elimination (KOH,

MeOH) to give the C10-C26 fragments 3a and 3b in good

yield and excellent diastereoselectivity (Z/E Ͼ 100:1).^[22]

Following Ramachandran’s lead,^[4d]lithiation of (Z)-

vinyl iodides 3a and 3b (tBuLi) and subsequent treatment

with dimethylzinc provided the corresponding lithium (Z)-

vinylzincates,^[23]which were added to β-silyloxy aldehyde 2

to give the coupling products 28a and 28b in moderate yield

(40%) and excellent diastereomeric ratio (Ͼ 95:5)

(Scheme 6).

On the basis of the structural assignment of the final

product 1a (vide infra) the stereochemistry of the newly cre-

ated stereogenic center in compound 28a turned out to be

The second key intermediate, Weinreb amide 5, was pre- 9R. We found this outcome quite surprising, as the addition

pared according to Smith III and co-workers.^[8]In our first of the same (Z)-vinylzincate to a very similar aldehyde (2

approach,^[7j]Weinreb amide 5 was reduced to the corre- with the ethyl ester instead of the methyl ester) was reported

sponding aldehyde, which was then coupled to alkyne 4 via to give an excellent ratio in favor of the 9S stereoisomer.^[4d]

the Carreira asymmetric alkynylation protocol [(–)-(1R,2S)- Unexpectedly, however, the addition of the 3b-derived lith-

N-methylephedrine, Zn(OTf)₂, Et₃N, toluene, 67%]^[15]to ium (Z)-vinylzincate to aldehyde 2 gave the desired 9S iso-

give alcohol 17. However, this reaction proved capricious mer 28b. The C9 configuration for compound 28b was as-

and poorly reproducible during the scale-up. We thus opted signed according to the Rychnovsky’s NMR method.^[24]For

for the direct addition of alkyne 4 to Weinreb amide 5 this purpose, a small amount of 28b was totally deprotected

(Scheme 4; nBuLi, THF, 70%) to form ynone 16, which was (HF·Py, THF, 76%) and quantitatively converted into the

then subjected to a Noyori asymmetric transfer hydrogena- corresponding 7,9-acetonide (28b-acetonide) using 2,2-di-

tion [(S,S)-Noyori catalyst, iPrOH]^[16]to give the desired methoxypropane and PPTS (Scheme 7). Following the

alcohol 17 in excellent yield (98%) with a Ͼ 100:1 dia- Rychnovsky’s rule, the stereochemistry of 1,3-diol aceton-

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Scheme 4. Synthesis of C10-C23 fragments 23a and 23b (dictyostatin numbering).

Scheme 5. Synthesis of C10-C26 fragments 3a and 3b (dictyostatin numbering).

ides can be assigned on the basis of the relevant ¹³C NMR observed at δ = 24.4 and 25.2ppm (Figure 1), clearly

chemical shifts: the quaternary C atom of the acetonide was pointing to an anti-1,3-diol relationship and therefore to 9S

observed at δ = 100.7 ppm, and the methyl-C signals were stereochemistry.

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Highly Stereoselective Total Synthesis of Dictyostatins

Scheme 6. (Z)-vinylzincate coupling reactions.

Scheme 7. Synthesis of 7,9-acetonide 28b-acetonide.

dictyostatin (1a, 70%) and 32b into (–)-12,13-bis-epi-

dictyostatin (1b, 72%).

Our synthetic compound 1a produced analytical data

(¹H NMR in CD₃OD, [α]_D) in disagreement with those re-

corded from an authentic sample of (–)-dictyostatin (1)

kindly provided by Prof. Ian Paterson (University of Cam-

bridge, UK), but proved to be identical (¹H NMR and ¹³C

NMR in [D₆]benzene, [α]_D, HRMS, IR, R_f) to the com-

pounds described by Paterson^[5c]and Curran^[5i]as (+)-9-

epi-dictyostatin. In principle, compound 28a could be easily

conveyed into the total synthesis of (–)-dictyostatin (1) by

oxidation of the 9R-allylic alcohol to the corresponding 9-

ketone, completion of the synthetic sequence (as outlined

in Scheme 8) and reduction of the enone to the 9S-allylic

alcohol (NaBH₄, CeCl₃·7H₂O, EtOH, –30 °C)^[4a]immedi-

ately before final deprotection. The synthetic compound 1b

is a novel (–)-dictyostatin analog and was fully charac-

terized (¹H NMR and ¹³C NMR in [D₆]benzene, [α]_D,

HRMS, IR, R_f) by us for the first time.

Figure 1. Relevant peaks in the ¹³C NMR spectrum of 28b-acet-

onide.

The secondary alcohol of compounds 28a–b was sub-

sequently silylated with TBSOTf to give the fully protected

intermediates 29a–b (100%, Scheme 8). Selective PMB re-

moval with DDQ provided compounds 30a–b (85–90%),

In order to find a rationale for the observed stereochemi-

which were then saponified under basic conditions (KOH) cal outcome of the lithium (Z)-vinylzincate coupling reac-

to provide seco-acids 31a–b (100%). Yamaguchi macrolac- tions (Scheme 6), we searched for literature precedents. Ac-

tonization^[25]of seco-acids 31 gave macrolides 32a–b in cording to the 1,3-asymmetric induction models thoroughly

good yield (76–80%), together with a small amount (5– investigated by Evans,^[26]steric interactions in the aldehyde

10%) of the (2E,4E)-dienoates (J_H2-H3= 15.2 Hz for the a conformations are minimized when the β-alkyl substituent

series and J_H2-H3= 15.3 Hz for the b series), probably (Rβ) is oriented anti to the Cα-C=O bond as in structures

formed via a reversible Michael addition of DMAP to the A and B shown in Scheme 9. Usually, β-OTBS substituted

(2Z,4E)-dienoates,^[4e]which could be separated by flash aldehydes afford preferentially the 1,3-anti diastereomer via

chromatography. Global deprotection of the TBS groups of the polar model A, where dipoles are opposed.^[26]When

32a with 3 n HCl/MeOH in THF (2.2:1 volume ratio)^[4d]aluminum Lewis acids (Me₂AlCl or MeAlCl₂) are used, ex-

caused extensive degradation of the product, while the use ceptional chelation control reinforces the 1,3-anti stereo-

of HF·Py in THF^[4c,4e]cleanly converted 32a into (+)-9-epi- chemical outcome (model C, axial attack).^[27]In the case of

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Scheme 8. Completion of the total syntheses.

α-OTBS substituted aldehydes, addition reactions of (Z)- these addition reactions. In summary, it appears that for

disubstituted vinylzinc reagents, in the presence of added this particular type of (Z)-vinylmetal addition reactions the

RZnX (1.5 equiv.), have been shown to proceed via a Cram- 1,3-asymmetric induction models have no predictive value,

chelation mechanism.^[28]Recently, Curran and co-workers as the stereochemical outcome is mainly dependent on the

studied the addition of a (Z)-vinyllithium compound to al- induction of the chiral (Z)-vinylmetal reagent rather than

dehyde 2, and reported a ca. 2:1 1,3-anti/1,3-syn dia- on the preference of the β-OTBS substituted aldehyde. In-

stereomeric ratio.^[5i]Addition of other (Z)-vinyllithium deed, using the same β-OTBS substituted aldehyde 2 and

compounds to similar aldehydes gave 1,3-anti/1,3-syn ratios the two bis-epimeric lithium (Z)-dimethylalkenylzincates

ranging from 1.5:1 to 1:1.9.^[5d,5i,29]These results suggest derived from 3a and 3b, we observed the opposite stereo-

that also models B and/or C (equatorial attack), leading to chemical outcome at C9: 9R in 28a (1,3-syn) and 9S in 28b

the 1,3-syn diastereomer, can make a substantial impact in (1,3-anti).

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Highly Stereoselective Total Synthesis of Dictyostatins

dictyostatin [(R)/(S) = 0.95 vs. 1.12, see Table 2]. The 12,13-

bis-epi diastereomer (1b) displayed a total loss of activity

(IC₅₀Ͼ 20 μm).

Both compounds were evaluated for their ability to in-

hibit the binding of the fluorescent taxoid Flutax-2 to the

paclitaxel binding site of microtubules.^[30]The binding con-

stants were calculated from the Flutax-2 displacement iso-

therms at 35 °C (see the Supporting Information).^[30]

Dictyostatin (1, K_app= 16.7 ϫ 10⁷m^–1) is roughly 4 times

more powerful than docetaxel (K_app= 3.9ϫ10⁷m^–1), 9-epi-

dictyostatin (1a, K_app= 2.6ϫ10⁶m^–1) is more than 10 times

less powerful and 12,13-bis-epi-dictyostatin (1b, K_app

Ͻ

10⁵m^–1) is at least 400 times less powerful. Therefore, while

dictyostatin (1) strongly inhibits Flutax-2 as described, (+)-

9-epi-dictyostatin (1a) is a weaker inhibitor and 12,13-bis-

epi-dictyostatin (1b) fails to significantly displace the fluo-

rescent taxane from its binding site, indicating that the lack

of cytotoxicity arises from the reduced affinity for the pacli-

taxel binding site of microtubules. The above data indicate

that stereocenters in 12,13 are very relevant for the bio-

logical activity. This can be either due to a local steric effect

Table 2. Cytotoxicity of (–)-dictyostatin (1), (+)-9-epi-dictyostatin

(1a) and (–)-12,13-bis-epi-dictyostatin (1b) in ovarian carcinoma

cell lines sensitive to chemotherapy (A2780) and resistant to che-

motherapy by P-glycoprotein overexpression (A2780AD).^[a]

Scheme 9. 1,3-Asymmetric induction models.

Compound

IC₅₀/nm^[b]

A2780 A2780AD

R/S^[c]

Biological Evaluation

The cell growth inhibitory activity of (+)-9-epi-dictyosta-

tin (1a) and (–)-12,13-bis-epi-dictyostatin (1b), as compared

to that of (–)-dictyostatin (1), were determined against two

ovarian carcinoma cell lines (Table 2). As already reported

with other cell lines,^[5c,5i]the 9-epi diastereomer (1a) showed

an IC₅₀a hundred times higher than that of dictyostatin (1)

both in cells sensitive to chemotherapy and in cells resistant

to chemotherapy by P-glycoprotein overexpression, main-

(–)-Dictyostatin (1)

2.86Ϯ0.9 3.2Ϯ0.6

1.12

0.95

–

(+)-9-epi-Dictyostatin (1a)

241Ϯ93

228Ϯ53

Ͼ20000

(–)-12,13-Bis-epi-dictyostatin (1b) Ͼ 20000

[a] IC₅₀(50% inhibition of cell proliferation) of the compounds in

ovarian carcinomas determined with the MTT assay modified as

referenced in the Exp. Section (Biological assays). [b] IC₅₀values

[nM] are the mean Ϯ standard error values for three independent

experiments. [c] The relative resistance of A2780AD cell line, ob-

tained dividing the IC₅₀of the resistant cell line by the IC₅₀of the

taining approximately the same relative resistance ratio of parental A2780 cell line.

Figure 2. Qualitative structure-activity relationships in dictyostatins.

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lamp and/or staining with a ceric ammonium molybdate or

KMnO₄solution. Flash chromatography was performed on silica

gel (60 Å, particle size 0.040–0.062 mm) according to the procedure

of Still and co-workers.^[31]Yields refer to chromatographically and

spectroscopically pure compounds, unless stated otherwise.

or to a global effect altering the entire macrocyclic confor-

mation. In fact, a NOESY experiment in CD₃OD showed

a substantially different pattern of NOE correlations com-

pared to dictyostatin (see the Supporting Information),^[3]

witnessing a different macrocyclic conformation induced by

the inversion of the C12,C13 stereocenters.

Methyl (2Z,4E,6R,7S)-7-(tert-Butyldimethylsilyloxy)-6-methyl-9-

oxonona-2,4-dienoate (2): A solution of methyl (2Z,4E,6R,7S)-7-

(tert-butyldimethylsilyloxy)-9-hydroxy-6-methylnona-2,4-

dienoate^[7k](140 mg, 0.42 mmol, 1 equiv.) in DCM (2.5 mL) was

treated at 0 °C with pyridine (86 μL, 1.04 mmol, 2.5 equiv.) and

DMP (214 mg, 0.50 mmol, 1.2 equiv.). The reaction mixture was

warmed to room temperature and stirred for 1 h. After completion

of the reaction, satd. aq. NaHCO₃(7 mL) and Na₂S₂O₃(760 mg,

3.06 mmol) were added. The mixture was stirred for 30 min, then

the phases were separated and the aqueous phase was extracted

with Et₂O (3 ϫ 10 mL). The combined organic extracts were

washed with brine (2ϫ10 mL), dried with Na₂SO₄and evaporated

under reduced pressure. The crude product was purified by flash

chromatography (8:2 hexane/EtOAc) to give aldehyde 2 (135 mg,

100% yield) as a yellow oil; R_f= = 0.37 (8:2 hexane/EtOAc). ¹H

NMR (400 MHz, CDCl₃): δ = 0.07 (s, 3 H), 0.11 (s, 3 H), 0.90 (s,

9 H), 1.12 (d, J = 6.8 Hz, 3 H), 2.45–2.61 (m, 3 H), 3.75 (s, 3 H),

4.24 (m, 1 H), 5.65 (d, J = 11.3 Hz, 1 H), 6.00 (dd, J = 7.9, 15.5 Hz,

1 H), 6.58 (t, J = 11.3 Hz, 1 H), 7.40 (dd, J = 11.2, 15.4 Hz, 1 H),

9.80 (dd, J = 1.9, 2.3 Hz, 1 H) ppm.

Conclusions

A highly stereoselective total synthesis of (+)-9-epi-

dictyostatin (1a) was carried out in 1.53% overall yield (cal-

culated over 29 steps, longest linear sequence from the Ro-

che ester). Unfortunately, unnatural configuration at C9 is

known to cause a substantial drop in cytotoxicity relative

to dictyostatin (1).^[5c,5i]However, the new synthetic route is

flexible enough to allow for inversion at C9 by oxidation–

reduction,^[4a,4e]thus providing potential access to the natu-

ral product. Through a simple adjustment in the synthetic

sequence, i.e. by using the mesylate of (S)-3-butyn-2-ol in

the Marshall–Tamaru palladium-catalyzed allenylzinc ad-

dition, we also synthesized (–)-12,13-bis-epi-dictyostatin

(1b) in 1.52% overall yield. This novel non-natural analog

of dictyostatin displayed a dramatic decrease of cytotoxicity

and of affinity for the paclitaxel binding site of microtu-

bules, due to a different macrocyclic conformation induced

by the inversion of the C12,C13 stereocenters.

(R)-But-3-yn-2-yl Methanesulfonate (6a) and (S)-But-3-yn-2-yl

Methanesulfonate (6b): TEA (5.31 mL, 38.1 mmol, 4 equiv.) and

methanesulfonyl chloride (2.21 mL, 28.6 mmol, 3 equiv.) were

added to a solution of (R)-but-3-yn-2-ol or (S)-but-3-yn-2-ol

(0.75 mL, 9.52 mmol, 1 equiv.) in DCM (7.5 mL) at –78 °C. The

reaction mixture was stirred for 40 min and then quenched with

satd. aq. NaHCO₃(8 mL). Phases were separated and the aqueous

layer was washed with DCM (2ϫ10 mL). The combined organic

extracts were washed with brine, dried and concentrated under re-

duced pressure (800 mbar). The residue was purified by flash col-

umn chromatography (6:3 pentane/Et₂O) to afford the desired

product 6a or 6b (1.39 g, 100% yield) as a colorless liquid; R_f=

0.65 (8:2 DCM/EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 1.58 (d,

J = 6.8 Hz, 3 H), 2.74 (d, J = 2.4 Hz, 1 H) 3.06 (s, 3 H), 5.20 (m,

1 H) ppm.

These biological results add a piece of information to the

structure-activity relationships based on dictyostatin ana-

logs developed by the Paterson and Curran research groups

(Figure 2).

Experimental Section

General: ¹H (400.13 MHz) and ¹³C (100.58 MHz) NMR spectra

were recorded on a Bruker Avance-400 spectrometer. ¹H NMR

chemical shifts are reported relative to TMS, and the solvent reso-

nance was employed as the internal standard (CDCl₃, δ = 7.26;

C₆D₆, δ = 7.16 ppm). The following abbreviations are used to de-

scribe spin multiplicity: s singlet, d doublet, t triplet, q quartet, m

multiplet, dd doublet-doublet, td triplet-doublet, dt doublet-triplet,

br. broad signal. ¹³C NMR spectra were recorded with complete

proton decoupling, and the chemical shifts are reported relative to

TMS with the solvent resonance as the internal standard (CDCl₃,

δ = 77.0; C₆D₆, δ = 128.06 ppm). Infrared spectra were recorded

on a standard FT/IR spectrophotometer. Optical rotation values

were measured on an automatic polarimeter with a 1-dm cell at the

sodium D line. High resolution mass spectra (HRMS) were per-

formed on a Fourier Transform Ion Cyclotron Resonance (FT-

ICR) Mass Spectrometer APEX II & Xmass software (Bruker Dal-

tonics) – 4.7 T Magnet (Magnex) equipped with ESI source, avail-

able at C.I.G.A. (Centro Interdipartimentale Grandi Apparecchiat-

ure dell’Università degli Studi di Milano). All reactions were car-

ried out in oven- or flame-dried glassware under nitrogen atmo-

sphere, unless stated otherwise. All commercially available reagents

were used as received. All solvents were dried by standard pro-

cedures before use. Organic extracts were dried with anhydrous

Na₂SO₄. Reactions were magnetically stirred and monitored by

TLC on silica gel (60 F254 pre-coated glass plates, 0.25 mm thick-

ness). Visualization was accomplished by irradiation with a UV

(1-Bromoallyl)trimethylsilane (7): nBuLi (1.6 m in hexane, 15 mL,

24 mmol, 1.2 equiv.) was added to a stirred solution of iPr₂NH

(3.64 mL, 26 mmol, 1.3 equiv.) in THF (6 mL) at –78 °C. After stir-

ring at 0 °C for 30 min, the solution was added to a flask contain-

ing allyl bromide (2.08 mL, 24 mmol, 1.2 equiv.) and chlorotri-

methylsilane (2.52 mL, 20 mmol, 1 equiv.) in THF (5 mL) at

–78 °C. After stirring for 1 h, the reaction was quenched by adding

satd. aq. NH₄Cl (12 mL). Phases were separated and the aqueous

phase was extracted with pentane (3ϫ10 mL). The combined or-

ganic extracts were dried and concentrated under reduced pressure.

The residue was purified by flash chromatography (9:1 pentane/

Et₂O) to give the desired product 7 (2.83 g, 73% yield) as a color-

less liquid; R_f= 0.77 (95:5 hexane/EtOAc). ¹H NMR (400 MHz,

CDCl₃): δ = 0.16 (s, 9 H), 3.82 (d, J = 9.6 Hz, 1 H), 5.06 (d, J =

10.0 Hz, 1 H), 5.19 (d, J = 16.8 Hz, 1 H), 5.95 (m, 1 H) ppm.

({[(2S,4R)-2,4-Dimethylhex-5-yn-1-yl]oxy}methyl)benzene (4).

Shioiri Alkynylation: A solution of nBuLi in hexane (1.6 m,

1.17 mL, 1.87 mmol, 1.4 equiv.) was added to a solution of DIPA

(262 μL, 1.87 mmol, 1.4 equiv.) in THF (10 mL) at 0 °C. After

30 min at 0 °C, the mixture was cooled to –78 °C, and trimethyl-

silyldiazomethane in Et₂O (2.0 m, 935 μL, 1.87 mmol, 1.4 equiv.)

was added. After 30 min, a solution of aldehyde 15^[7j](295 mg,

2650

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Eur. J. Org. Chem. 2011, 2643–2661

Highly Stereoselective Total Synthesis of Dictyostatins

1.34 mmol, 1 equiv.) in THF (3.5 mL) was slowly added, and the

mixture was stirred for 1 h at –78 °C. Temperature was raised to

room temperature, and stirring was maintained overnight. The mix-

ture was then poured into ice-cooled water, and extracted with

Et₂O. The combined organic extracts were dried and concentrated

under reduced pressure. The residue was purified by flash

chromatography (10:1 hexane/EtOAc) to afford the alkyne 4 as a

yellow oil (176.9 mg, 61% yield over two steps).

Noyori catalyst (156 mg, 0.246 mmol, 0.2 equiv.)^[16]was added to a

solution of ynone 16 (588 mg, 1.23 mmol, 1 equiv.) in iPrOH

(12 mL). After stirring for 5 h at room temperature, the solvent was

removed under vacuum and the residue purified by flash column

chromatography (9:1 hexane/EtOAc), affording the propargylic

alcohol 17 (580 mg, 98% yield) as a colorless oil; R_f= 0.37 (8:2

hexane/EtOAc). [α]²_D⁰= +35.9 (c = 1.03, CHCl₃). ¹H NMR

(400 MHz, C₆D₆): δ = 0.45 (d, J = 6.8 Hz, 3 H), 1.07 (d, J = 6.8 Hz,

3 H), 1.12–1.22 (m, 1 H), 1.25 (d, J = 6.8 Hz, 3 H), 1.38 (d, J =

6.8 Hz, 3 H), 1.77–1.84 (m, 1 H), 1.97–2.05 (m, 2 H), 2.25 (br. s, 1

H), 2.38–2.43 (m, 1 H), 2.62–2.69 (m, 1 H), 3.16–3.31 (m, 2 H),

3.34 (s, 3 H), 3.34–3.43 (m, 1 H), 3.87 (dd, J = 2.0, 10.0 Hz, 1 H),

4.02 (dd, J = 4.8, 11.2 Hz, 1 H), 4.46 (s, 2 H), 4.75 (d, J = 5.6 Hz,

1 H), 5.61 (s, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.18–7.43 (m, 5 H),

7.68 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, C₆D₆): δ =

9.2 (CH₃), 12.1 (CH₃), 17.1 (CH₃), 22.6 (CH₃), 24.5 (CH), 31.2

(CH), 32.8 (CH), 41.7 (CH), 41.8 (CH₂), 55.2 (CH₃), 67.0 (CH),

73.6 (CH₂), 76.7 (CH₂), 76.8 (CH₂), 82.7 (C₀), 85.8 (CH), 89.7 (C₀),

102.0 (CH), 114.3 (CH), 129.0 (CH), 132.4 (C₀), 136.7 (C₀), 161.2

Bestmann–Ohira Alkynylation: A solution of dimethyl (1-diazo-2-

oxopropyl)phosphonate (3.73 g, 19.4 mmol, 4 equiv.) in THF

(37 mL) was slowly added to a cooled (–78 °C) solution of MeONa

(1.05 g, 19.4 mmol, 4 equiv.) in THF (84 mL). After 15 min, a solu-

tion of aldehyde 15^[7j](1.07 g, 4.85 mmol, 1 equiv.) in THF (25 mL)

was added. The resulting mixture was stirred at –78 °C for 30 min,

allowed to reach room temperature over 1.5 h, quenched with satd.

aq. NH₄Cl (15 mL) and diluted with water (40 mL). Phases were

separated and the aqueous layer extracted with Et₂O (3ϫ40 mL).

The combined organic extracts were washed with brine, dried

(Na₂SO₄) and concentrated. The residue was purified by flash col-

umn chromatography (100:1 hexane/EtOAc) to afford product 4

(0.95 g, 91% yield over two steps) as a yellow oil; R_f= 0.87 (10:1

hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (d, J =

6.8 Hz, 3 H), 1.17–1.22 (m, 1 H), 1.23 (d, J = 6.8 Hz, 3 H), 1.58–

1.68 (m, 1 H), 2.05 (d, J = 2.4 Hz, 1 H), 2.08–2.20 (m, 1 H), 2.50–

2.62 (m, 1 H), 3.30–3.39 (m, 2 H), 4.50 (s, 2 H), 7.26–7.37 (m, 5

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.9 (CH₃), 22.0 (CH₃),

23.8 (CH), 32.0 (CH), 41.2 (CH₂), 68.8 (CH), 73.3 (CH₂), 76.5

(CH₂), 89.4 (C₀), 127.8 (CH), 127.9 (CH), 128.7 (CH), 139.2 (C₀)

ppm. HRMS (ESI): calcd. for C₁₅H₂₀NaO: 239.14064 [M + Na]⁺;

found 239.14059.

(C ) ppm. IR (neat): ν = 1462, 1518, 1615, 1732, 2851, 2874, 2933,

˜

0

2969, 3024, 3040, 3501 cm^–1. HRMS (ESI): calcd. for C₃₀H₄₀O₅Na:

503.27680 [M + Na]⁺; found 503.27575.

(3S,4R,5S,7S,10R,11R,12S,13S)-10,14-Bis(tert-butyldimethylsilan-

yloxy)-12-(4-methoxybenzyloxy)-3,5,7,11,13-pentamethyltetradec-1-

yn-4-ol (22a): Triphenylphosphane (recrystallized from ethanol

prior to use, 4.6 mg, 0.0175 mmol, 0.05 equiv.), the crude aldehyde

obtained from alcohol 21^[7j](220 mg, 0.35 mmol, 1 equiv.) and (R)-

mesylbutynol 6a (78 mg, 0.53 mmol, 1.5 equiv.) were sequentially

added to a cooled (–78 °C) solution of Pd(OAc)₂(3.9 mg,

0.0175 mmol, 0.05 equiv.) in THF (3.5 mL). Diethylzinc (1.0 m in

hexane, 1.05 mL, 1.05 mmol, 3 equiv.) was added over 15 min. Af-

ter 10 min, the temperature was raised to –20 °C, and the reaction

mixture was stirred overnight at –20 °C. The mixture was quenched

with satd. aq. NH₄Cl and extracted with Et₂O. The Et₂O layer

was washed with brine, dried and concentrated under vacuum. The

residue was purified by flash column chromatography (95:5 hexane/

EtOAc) to afford product 22a (196 mg, 82% yield over two steps)

as a yellow oil with very high diastereoselectivity (dr Ͼ 98:2); R_f=

0.49 (8:2 hexane/EtOAc). [α]²_D²= –4.5 (c = 0.61, CHCl₃). ¹H NMR

(400 MHz, C₆D₆): δ = 0.20 (s, 6 H), 0.27 (s, 6 H), 1.04 (d, J =

6.8 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.13 (s, 9 H), 1.17 (d, J =

6.8 Hz, 3 H), 1.18 (s, 9 H), 1.22 (d, J = 6.9 Hz, 3 H), 1.31 (d, J =

6.9 Hz, 3 H), 1.62–1.95 (m, 9 H), 2.11–2.19 (m, 2 H), 2.62–2.67 (m,

1 H), 3.28 (dd, J = 6.0, 10.8 Hz, 1 H), 3.43 (s, 3 H), 3.80–3.87 (m,

2 H), 3.92–4.00 (m, 2 H), 4.77 (d, J_AB= 10.8 Hz, 1 H, upfield part

of an AB system), 4.83 (d, J_AB= 10.8 Hz, 1 H, downfield part of

an AB system), 6.97 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H)

ppm. ¹³C NMR (100 MHz, C₆D₆): δ = –4.7 (CH₃), –3.6 (CH₃),

–3.4 (CH₃), 11.1 (CH₃), 14.5 (CH₃), 16.0 (CH₃), 18.0 (CH₃), 18.9

(C₀), 21.2 (CH₃), 26.7 (CH₃), 26.8 (CH₃), 31.0 (CH), 31.7 (CH),

32.1 (CH₂), 32.7 (CH₂), 33.6 (CH), 39.9 (CH), 40.7 (CH), 42.1

(CH₂), 55.2 (CH₃), 65.5 (CH₂), 71.7 (CH), 74.6 (CH₂), 75.5 (CH),

77.5 (CH), 81.4 (CH), 86.6 (C₀), 114.5 (CH), 129.5 (CH), 132.6

(2R,6R,8S)-9-(Benzyloxy)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-

methyl-1,3-dioxan-4-yl]-6,8-dimethylnon-4-yn-3-one (16): Alkyne 4

(969 mg, 4.48 mmol, 1 equiv.) was dissolved in THF (45 mL), co-

oled to –78 °C and treated with nBuLi (1.6 m in hexane, 2.8 mL,

1 equiv.). After 5 min, the mixture was warmed to 0 °C and stirred

for 30 min. The solution was then recooled to –78 °C and Weinreb

amide 5^[8](1.64 g, 5.06 mmol, 1.1 equiv.) in THF (2.8 mL) was

added slowly. After 5 min the solution was warmed to 0 °C and

stirred for 1 h. The reaction was quenched with a satd. aq. NH₄Cl

(2.8 mL). The aqueous phase was extracted with Et₂O and the com-

bined organic extracts were washed with brine and dried with

Na₂SO₄. Filtration and concentration under reduced pressure, fol-

lowed by flash chromatography (9:1 hexane/EtOAc) afforded the

ynone 16 (1.5 g, 70% yield) as a pale yellow oil; R_f= 0.53 (8:2

hexane/EtOAc). [α]²_D²= +46.4 (c = 1.00, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 0.81 (d, J = 6.7 Hz, 3 H), 0.97 (d, J =

6.7 Hz, 3 H), 1.26–1.29 (m, 1 H), 1.27 (d, J = 6.6 Hz, 3 H), 1.27

(d, J = 7.2 Hz, 3 H), 1.74 (ddd, J = 4.2, 10.5, 14.4 Hz, 1 H), 2.00–

2.11 (m, 2 H), 2.76 (m, 2 H), 3.31 (d, J = 6.2 Hz, 2 H) 3.55 (t, J =

11.1 Hz, 1 H), 3.80 (s, 3 H), 4.15 (dd, J = 6.4, 13.3 Hz, 1 H), 4.23

(dd, J = 2.8, 10.1 Hz, 1 H), 4.50 (s, 2 H), 5.48 (s, 1 H), 6.86 (d, J

= 8.7 Hz, 2 H), 7.33 (m, 7 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 8.3 (CH₃), 11.8 (CH₃), 16.5 (CH₃), 20.8 (CH₃), 24.0 (CH), 30.9

(CH), 32.0 (CH), 40.2 (CH₂), 49.4 (CH), 55.1 (CH₃), 72.8 (CH₂),

72.9 (CH₂), 75.8 (CH₂), 80.4 (C₀), 82.8 (CH), 98.1 (C₀), 100.9 (CH),

113.3 (CH), 127.3 (CH), 127.4 (CH), 128.3 (CH), 131.2 (C₀), 138.8

(C ), 160.0 (C ) ppm. IR (neat): ν = 1255, 1301, 1386, 1462, 1470,

˜

0

1514, 1613, 1727, 2655, 2663, 2857, 2882, 2930, 2956, 3306 cm^–1.

HRMS (ESI): calcd. for C₃₉H₇₂O₅Si₂Na: 699.48105 [M + Na]⁺;

found 699.48154.

(C ), 159.8 (C ), 188.7 (C ) ppm. IR (neat): ν = 699, 737, 829, 1034,

˜

0

(5R,6S,8S,11R,12R,13S,14S)-5-[(S)-But-3-yn-2-yl]-11-[(tert-butyldi-

methylsilyl)oxy]-13-[(4-methoxybenzyl)oxy]-2,2,3,3,6,8,12,14,

17,17,18,18-dodecamethyl-4,16-dioxa-3,17-disilanonadecane (23a):

Freshly distilled 2,6-lutidine (0.13 mL, 1.16 mmol, 4 equiv.) and

TBSOTf (0.1 mL, 0.43 mmol, 1.5 equiv.) were added to a stirred

1078, 1127, 1249, 1303, 1372, 1392, 1456, 1518, 1615, 1678, 1737,

2207, 2850, 2874, 2933, 2968 cm^–1. HRMS (ESI): calcd. for

C₃₀H₃₈O₅Na: 501.26115 [M + Na]⁺; found 501,26102.

(2S,3S,6R,8S)-9-(Benzyloxy)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-

methyl-1,3-dioxan-4-yl]-6,8-dimethylnon-4-yn-3-ol (17): (S,S)- solution of compound 22a (196 mg, 0.29 mmol, 1 equiv.) in DCM

Eur. J. Org. Chem. 2011, 2643–2661

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2651

C. Gennari et al.

FULL PAPER

(7 mL) at –20 °C. On completion of the reaction (approximately

2 h), the mixture was quenched with satd. aq. NH₄Cl (3 mL). The

organic phase was separated and the aqueous layer extracted with

DCM. The combined organic extracts were washed with brine,

dried with Na₂SO₄and the solvents evaporated. Purification of the

crude product by flash chromatography (7:3 hexane/EtOAc) af-

(5R,6S,8S,11R,12R,13S,14S)-11-(tert-Butyldimethylsilyloxy)-5-

[(S,Z)-4-iodobut-3-en-2-yl]-13-(4-methoxybenzyloxy)-2,2,3,3,6,8,

12,14,17,17,18,18-dodecamethyl-4,16-dioxa-3,17-disilanonadecane

(25a): A solution of iodoalkyne 24a (266 mg, 0.29 mmol, 1 equiv.)

in THF (0.7 mL) and iPrOH (0.7 mL) at room temperature was

treated with TEA (53 μL, 0.377 mmol, 1.3 equiv.) and NBSH

(74.0 mg, 0.34 mmol, 1.1 equiv.). After 12 h, additional TEA

(24 μL, 0.174 mmol, 0.6 equiv.) and NBSH (33.0 mg, 0.15 mmol,

0.5 equiv.) were added, and the mixture was stirred for 12 h. The

reaction was quenched by adding water (1.7 mL) and the mixture

was extracted with EtOAc (3ϫ3 mL). The combined organic layers

forded compound 23a (229 mg, 100% yield) as a colorless oil; R_f

22

= 0.80 (8:2 hexane/EtOAc). [α]

= –3.1 (c = 0.51, CHCl₃). ¹H

D

NMR (400 MHz, C₆D₆): δ = 0.21 (s, 6 H), 0.25 (s, 3 H), 0.26 (s, 3

H), 0.27 (s, 3 H), 0.28 (s, 3 H), 1.10 (d, J = 7.2 Hz, 3 H), 1.12 (d,

J = 6.8 Hz, 3 H), 1.13 (s, 9 H), 1.16 (s, 9 H), 1.19 (s, 9 H), 1.23 (d,

J = 7.2 Hz, 3 H), 1.30 (d, J = 6.8 Hz, 3 H), 1.31 (d, J = 6.4 Hz, 3 were washed with brine (2ϫ3 mL), dried with Na₂SO₄and concen-

H), 1.32–1.13 (m, 2 H), 1.81–1.64 (m, 4 H), 2.01–1.96 (m, 1 H),

2.02 (d, J = 2.4 Hz, 1 H), 2.17–2.13 (m, 3 H), 2.79–2.71 (m, 1 H),

3.43 (s, 3 H), 4.01–3.69 (m, 5 H), 4.77 (d, J_AB= 10.8 Hz, 1 H,

upfield part of an AB system), 4.83 (d, J_AB= 10.8 Hz, 1 H, down-

field part of an AB system), 6.97 (d, J = 8.4 Hz, 2 H), 7.49 (d, J =

8.4 Hz, 2 H) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = –4.7 (CH₃),

–3.6 (CH₃), –3.3 (CH₃), –3.2 (CH₃), –3.1 (CH₃), 11.0 (CH₃), 15.9

(CH₃), 16.0 (CH₃), 18.0 (CH₃), 18.9 (C₀), 19.1 (C₀) 20.9 (CH₃),

trated in vacuo. The crude product was purified by flash

chromatography (9.5:0.5 hexane/EtOAc) to give the desired product

25a (245 mg, 92% yield) as a colorless oil; R_f= 0.85 (8:2 hexane/

EtOAc). [α]²_D³= +2.9 (c = 0.5, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 0.07 (s, 6 H), 0.08 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 6 H),

0.86 (d, J = 7.2 Hz, 3 H), 0.90 (d, J = 8.0 Hz, 3 H), 0.93 (s, 30 H),

0.99 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 7.0 Hz, 3 H), 1.28–1.47 (m,

6 H), 1.60–1.71 (m, 2 H), 1.80 (m, 1 H), 1.90 (m, 1 H), 2.71 (m, 1

26.6 (CH₃), 26.7 (CH₃), 26.8 (CH₃), 31.4 (CH), 32.4 (CH₂), 32.7 H), 3.48 (m, 2 H), 3.68 (m, 3 H), 3.82 (s, 3 H), 4.49 (d, J_AB

(CH₂), 32.9 (CH), 34.1 (CH), 39.9 (CH), 40.7 (CH), 43.7 (CH₂), 10.9 Hz, 1 H, upfield part of an AB system), 4.57 (d, J_AB

=

55.2 (CH₃), 65.6 (CH₂), 71.2 (CH), 74.7 (CH₂), 75.4 (CH), 78.5

10.9 Hz, 1 H, downfield part of an AB system), 6.14 (d, J = 7.3 Hz,

(CH), 81.5 (CH), 87.9 (C₀), 114.5 (CH), 129.5 (CH), 132.6 (C₀), 1 H), 6.29 (dd, J = 7.3, 8.8 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 2 H),

160.0 (C ) ppm. IR (neat): ν = 1256, 1471, 1514, 1587, 1614, 2856,

7.28 (d, J = 8.7 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

–5.3 (CH₃), –5.2 (CH₃), –4.3 (CH₃), –4.0 (CH₃), –3.7 (CH₃), –3.6

(CH₃), 10.1 (CH₃), 15.2 (CH₃), 15.8 (CH₃), 17.7 (CH₃), 18.1 (C₀),

18.3 (C₀), 18.4 (C₀), 20.5 (CH₃), 26.0 (CH₃), 26.1 (CH₃), 26.2

(CH₃), 29.7 (CH₂), 30.8 (CH), 31.1 (CH₂), 31.6 (CH₂), 35.3 (CH),

38.9 (CH), 39.6 (CH), 41.5 (CH₂), 43.5 (CH), 55.2 (CH₃), 64.6

(CH₂), 74.0 (CH₂), 74.2 (CH), 79.1 (CH), 81.1 (CH), 81.2 (CH),

113.7 (CH), 128.9 (CH), 131.6 (C₀), 144.2 (CH), 158.9 (C₀) ppm.

˜

0

2884, 2904, 2929, 2957, 3312 cm^–1. HRMS (ESI): calcd. for

C₄₅H₈₆O₅Si₃Na: 813.56753 [M + Na]⁺; found 813.56718.

(5R,6S,8S,11R,12R,13S,14S)-11-(tert-Butyldimethylsilyloxy)-5-

[(S)-4-iodobut-3-yn-2-yl]-13-(4-methoxybenzyloxy)-2,2,3,3,6,8,

12,14,17,17,18,18-dodecamethyl-4,16-dioxa-3,17-disilanonadecane

(24a): A 1.6 m solution of nBuLi in hexane (0.22 mL, 0.35 mmol,

1.2 equiv.) was added dropwise over 5 min to a solution of alkyne

23a (229 mg, 0.29 mmol, 1 equiv.) in THF (1.5 mL) at –50 °C. After

1 h, a solution of iodine (125 mg, 0.50 mmol, 1.7 equiv.) in THF

(0.10 mL) was added. The mixture was stirred at –50 °C for 30 min,

then warmed to a room temperature over 30 min. After quenching

by the addition of satd. aq. Na₂S₂O₃solution (0.8 mL) and brine

(0.8 mL), the mixture was extracted with EtOAc (3ϫ3 mL) and

the combined organic layers were washed with brine (2ϫ4 mL).

The organic phase was dried with Na₂SO₄and concentrated in

vacuo. The crude product was purified by flash chromatography

(9.5:0.5 hexane/EtOAc) to give the desired product 24a (266 mg,

100% yield) as a colorless oil; R_f= 0.40 (9.5:0.5 hexane/EtOAc).

IR (neat): ν = 773, 805, 835, 1079, 1256, 1377, 1462, 1514, 1611,

˜

2855, 2927, 2956 cm^–1. HRMS (ESI): calcd. for C₄₅H₈₇IO₅Si₃Na:

941.47982 [M + Na]⁺; found 941.47749.

(2S,3S,4R,5R,8S,10S,11R,12S,Z)-5,11-Bis(tert-butyldimethyl-

silyloxy)-14-iodo-3-(4-methoxybenzyloxy)-2,4,8,10,12-pentamethyl-

tetradec-13-en-1-ol (26a): A solution of compound 25a (680 mg,

0.74 mmol, 1 equiv.) in THF (3.8 mL) at 0 °C was treated with a

solution of HF·Py in THF/pyridine [16.5 mL, prepared by slow

addition of commercially available 70% HF in pyridine (1.3 mL) to

a mixture of pyridine (5.0 mL) and THF (10.2 mL)]. The reaction

mixture was warmed to room temperature and stirred for 3 h. After

quenching the reaction by the addition of satd. aq. NaHCO₃

(30 mL), the mixture was extracted with EtOAc (4ϫ20 mL). The

combined organic extracts were washed with satd. aq. CuSO₄

1

[α]¹_D⁹= –24.0 (c = 0.4, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

0.07 (s, 9 H), 0.10 (s, 6 H), 0.11 (s, 3 H), 0.85 (d, J = 6.7 Hz, 3 H),

0.88 (d, J = 6.5 Hz, 3 H), 0.93 (s, 9 H), 0.93 (s, 9 H), 0.94 (s, 9 H),

0.94 (d, J = 6.7 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.98–1.05 (m, (3ϫ15 mL) and brine (2ϫ40 mL), dried with Na₂SO₄and concen-

2 H), 1.18 (d, J = 7.1 Hz, 3 H), 1.27–1.50 (m, 4 H), 1.63 (m, 1 H),

1.81 (m, 2 H), 1.91 (m, 1 H), 2.76 (m, 1 H), 3.48 (dd, J = 4.3,

trated in vacuo. The crude product was purified by flash

chromatography (9:1 hexane/EtOAc) to give the desired product

6.7 Hz, 1 H), 3.52 (dd, J = 2.5, 5.7 Hz, 1 H), 3.69 (m, 3 H), 3.83 26a (477 mg, 80% yield) as a colorless oil; R_f= 0.29 (8:2 hexane/

(s, 3 H), 4.50 (d, J_AB= 10.9 Hz, 1 H, upfield part of an AB system),

4.57 (d, J_AB= 10.9 Hz, 1 H, downfield part of an AB system), 6.89

(d, J = 8.6 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR

EtOAc). [α]¹_D⁶= +9.6 (c = 0.9, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 0.07 (s, 3 H), 0.08 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 3 H),

0.88 (d, J = 6.5 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.86–0.91 (m,

(100 MHz, CDCl₃): δ = –3.7 (CH₃), –3.6 (CH₃), –3.3 (CH₃), –3.2 2 H), 0.94 (s, 18 H), 1.01 (d, J = 7.0 Hz, 3 H), 1.02 (d, J = 6.8 Hz,

(CH₃), –3.1 (CH₃), 10.8 (CH₃), 15.4 (CH₃), 16.0 (CH₃), 18.0 (CH₃), 3 H), 1.13 (d, J = 7.1 Hz, 3 H), 1.28–1.47 (m, 4 H), 1.60–1.71 (m,

18.9 (C₀), 19.0 (C₀), 19.6 (C₀), 20.7 (CH₃), 26.7 (CH₃), 26.8 (CH₃), 2 H), 1.90 (m, 1 H), 1.96 (m, 1 H), 2.71 (m, 1 H), 2.87 (br. s, 1 H),

30.4 (CH₂), 31.1 (CH), 32.3 (CH₂), 32.5 (CH₂), 33.7 (CH), 35.1

(CH), 39.5 (CH), 40.3 (CH), 43.5 (CH₂), 56.0 (CH₃), 65.3 (CH₂), 2 H), 6.13 (d, J = 7.3 Hz, 1 H), 6.30 (t, J = 7.3 Hz, 1 H), 6.89 (d,

74.7 (CH₂), 74.9 (CH), 78.3 (CH), 81.7 (CH), 114.4 (CH), 129.6

J = 8.6 Hz, 2 H), 7.28 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR

(CH), 132.4 (C ), 159.6 (C ) ppm. IR (neat): ν = 670, 773, 835, (100 MHz, CDCl₃): δ = –3.7 (CH₃), –3.1 (CH₃), –2.9 (CH₃), 10.7

3.48 (m, 2 H), 3.61 (m, 2 H), 3.83 (s, 3 H), 3.84 (m, 1 H), 4.55 (s,

˜

0

939, 1078, 1171, 1250, 1301, 1361, 1387, 1462, 1514, 1613, 2856,

2928 cm^–1. HRMS (ESI): calcd. for C₄₅H₈₅IO₅Si₃Na: 939.46417 [M

+ Na]⁺; found 939.46033.

(CH₃), 16.5 (CH₃), 16.7 (CH₃), 18.5 (CH₃), 18.8 (C₀), 19.1 (C₀),

21.2 (CH₃), 26.7 (CH₃), 26.9 (CH₃), 31.5 (CH), 32.3 (CH₂), 32.8

(CH₂), 36.2 (CH), 37.6 (CH), 41.2 (CH), 42.1 (CH₂), 44.0 (CH),

2652

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Eur. J. Org. Chem. 2011, 2643–2661

Highly Stereoselective Total Synthesis of Dictyostatins

56.0 (CH₃), 65.9 (CH₂), 74.3 (CH), 76.0 (CH₂), 79.8 (CH), 81.9

(CH), 86.7 (CH), 114.6 (CH), 130.0 (CH), 131.2 (C₀), 144.8 (CH),

1735, 2855, 2927 cm^–1. HRMS (ESI): calcd. for C₄₂H₇₅IO₄Si₂Na:

849.41408 [M + Na]⁺; found 849.41248.

159.9 (C ) ppm. IR (neat): ν = 773, 805, 1028, 1255, 1377, 1461,

˜

0

Methyl (2Z,4E,6R,7S,9R,10Z,12S,13R,14S,16S,19R,20R,

21S,22S,23Z)-7,13,19-Tris(tert-butyldimethylsilyloxy)-9-hydroxy-

21-(4-methoxybenzyloxy)-6,12,14,16,20,22-hexamethylhexacosa-

2,4,10,23,25-pentaenoate (28a): To a solution of tBuLi (1.7 m in

1514, 1614, 2067, 2959, 3448 cm^–1. HRMS (ESI): calcd. for

C₃₉H₇₃IO₅Si₂Na [M + Na]⁺: 827.39334; found 827.39126.

(2R,3R,4R,5R,8S,10S,11R,12S,Z)-5,11-Bis(tert-butyldimethyl-

silyloxy)-14-iodo-3-(4-methoxybenzyloxy)-2,4,8,10,12-pentamethyl- pentane, 0.17 mL, 0.29 mmol, 2.2 equiv.) in Et₂O (0.2 mL) kept at

tetradec-13-enal (27a): A solution of alcohol 26a (394 mg,

0.49 mmol 1 equiv.) in DCM (3.1 mL) was treated at 0 °C with pyr-

idine (0.10 mL, 1.2 mmol, 2.5 equiv.) and DMP (250 mg,

0.59 mmol, 1.2 equiv.). The reaction mixture was warmed to room

temperature and stirred for 1 h. After completion of the reaction,

satd. aq. NaHCO₃(8.0 mL) and Na₂S₂O₃(888 mg, 3.6 mmol) were

added. The resulting mixture was stirred for 30 min, then the

phases were separated and the aqueous phase was extracted with

–78 °C under argon atmosphere, a solution of vinyl iodide 3a

(110 mg, 0.13 mmol, 1 equiv.) in Et₂O (0.4 mL) was added. After

stirring for 30 min, dimethylzinc (2.0 m in toluene, 0.11 mL,

0.21 mmol, 1.6 equiv.) was added dropwise and the reaction mix-

ture was further stirred at –78 °C for 15 min. A solution of alde-

hyde 2 (64 mg, 0.20 mmol, 1.5 eq, azeotropically dried with tolu-

ene), in Et₂O (0.6 mL) was added dropwise, and the mixture was

stirred for 1 h at –78 °C. The reaction was quenched with water

Et₂O (3ϫ5 mL). The combined organic extracts were washed with (2.2 mL), warmed to room temperature and diluted with Et₂O

brine (2ϫ10 mL), dried (Na₂SO₄) and evaporated under reduced

pressure, providing the crude aldehyde 27a, which was used without

further purification; R_f= 0.60 (8:2 hexane/EtOAc). ¹H NMR

(400 MHz, CDCl₃): δ = 0.07 (s, 3 H), 0.08 (s, 3 H), 0.09 (s, 3 H),

(3.6 mL). Phases were separated and the aqueous layer was ex-

tracted with Et₂O (3ϫ5 mL). The combined organic extracts were

washed with brine (2ϫ5 mL), dried with Na₂SO₄and concentrated

in vacuo. The crude product was purified by flash chromatography

0.10 (s, 3 H), 0.84–0.94 (m, 2 H), 0.88 (d, J = 6.3 Hz, 3 H), 0.89 (10:0.5 hexane/EtOAc) and the following compounds were isolated

(d, J = 6.7 Hz, 3 H), 0.93 (s, 9 H), 0.94 (s, 9 H), 1.01 (d, J = 6.4 Hz,

3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H), 1.28–

(the reported R_fvalues were obtained using 8:2 hexane/EtOAc as

the eluent): (i) de-iodinated alkene C10-C26 (R_f= = 0.67, 49 mg);

1.49 (m, 4 H), 1.58–1.73 (m, 2 H), 1.90 (m, 1 H), 2.71 (m, 1 H), (ii) 9R addition product 28a (R_f= 0.55, 53 mg, 40% yield, light

2.80 (m, 1 H), 3.49 (m, 1 H), 3.68 (m, 2 H), 3.83 (s, 3 H), 4.52 (s,

2 H), 6.13 (d, J = 7.3 Hz, 1 H), 6.30 (t, J = 7.3 Hz, 1 H), 6.89 (d,

yellow oil); (iii) unknown product lacking C23-C26 diene portion

(R_f= 0.50, Ͻ5% compared to the 9R addition product, MS-ESI⁺

J = 8.6 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H), 9.83 (d, J = 2.2 Hz, 1 782.5); (iv) unreacted aldehyde C1-C9 2 (R_f= 0.37, 32 mg); (v)

H) ppm.

mixture of unreacted aldehyde and unknown product – possibly,

the 9S addition product (R_f= 0.31, Ͻ 5% compared to the 9R

addition product); R_f= 0.55 (8:2 hexane/EtOAc). [α]¹_D⁹= +2.6 (c =

(5R,6S,8S,11R)-5-[(S,Z)-4-Iodobut-3-en-2-yl]-11-[(2R,3S,4S,Z)-3-

(4-methoxybenzyloxy)-4-methylocta-5,7-dien-2-yl]-2,2,3,3,6,8,

13,13,14,14-decamethyl-4,12-dioxa-3,13-disilapentadecane (3a): To

a slurry of CrCl₂(301 mg, 2.45 mmol, 5 equiv.) in THF (4.9 mL),

obtained by sonication and cooled to 0 °C, freshly prepared alde-

hyde 27a (394 mg, 0.49 mmol, 1 equiv.) in THF (1.7 mL) and (1-

bromoallyl)trimethylsilane (7, 530 mg, 2.74 mmol, 5.6 equiv.) were

added. The resulting mixture was stirred for 3 h at room tempera-

ture before being re-cooled to 0 °C and quenched by the addition

of MeOH (2.1 mL) and 6 n aqueous KOH (4.2 mL). After stirring

for 20 h at room temperature, the phases were separated and the

aqueous layer was extracted with DCM (4ϫ5 mL). The combined

organic extracts were washed with brine (2ϫ15 mL), dried with

Na₂SO₄and concentrated in vacuo. The crude product was purified

by flash chromatography (100:0.5 hexane/EtOAc) to give the de-

sired product 3a (308 mg, 76% yield over two steps) as a colorless

oil; R_f= 0.45 (10:0.5 hexane/EtOAc). [α]²_D²= +22.4 (c = 0.2,

CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.04–0.11 (m, 12 H),

0.77–1.01 (m, 14 H), 0.94 (s, 9 H), 0.95 (s, 9 H), 1.12 (d, J = 6.9 Hz,

3 H), 1.25–1.38 (m, 4 H), 1.59–1.70 (m, 3 H), 2.70 (m, 1 H), 3.00

(m, 1 H), 3.35 (dd, J = 2.9, 7.9 Hz, 1 H), 3.47 (m, 1 H), 3.63 (m,

1 H), 3.83 (s, 3 H), 4.56 (d, J_AB= 10.6 Hz, 1 H, upfield part of an

AB system), 4.52 (d, J_AB= 10.5 Hz, 1 H, downfield part of an AB

system), 5.12 (d, J = 10.1 Hz, 1 H), 5.20 (d, J = 16.8 Hz, 1 H), 5.60

(t, J = 10.6 Hz, 1 H), 6.03 (t, J = 11.1 Hz, 1 H), 6.13 (d, J = 7.3 Hz,

1 H), 6.28 (t, J = 7.4 Hz, 1 H), 6.60 (ddd, J = 10.7, 10.7, 16.9 Hz,

1 H), 6.89 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –3.8 (CH₃), –3.2 (CH₃), –3.0 (CH₃),

–2.9 (CH₃), 9.9 (CH₃), 16.5 (CH₃), 18.4 (CH₃), 18.9 (C₀), 19.1 (C₀),

1

1.4, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 0.05 (s, 3 H), 0.06

(s, 3 H), 0.10 (s, 3 H), 0.11 (s, 9 H), 0.80–0.82 (m, 1 H), 0.83 (d, J

= 6.5 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 7.0 Hz, 3

H), 0.92 (s, 9 H), 0.93 (s, 9 H), 0.95 (s, 9 H), 0.97 (d, J = 6.8 Hz,

3 H), 1.06–1.07 (m, 1 H), 1.12 (d, J = 6.8 Hz, 6 H), 1.17–1.42 (m,

4 H), 1.44–1.62 (m, 2 H), 1.65–1.79 (m, 3 H), 2.38 (br. s, 1 H), 2.63

(m, 1 H), 2.71 (m, 1 H), 3.01 (m, 1 H), 3.34 (m, 2 H), 3.64 (m, 1

H), 3.74 (s, 3 H), 3.82 (s, 3 H), 3.88 (m, 1 H), 4.49 (m, 1 H), 4.51

(d, J_AB= 10.6 Hz, 1 H, upfield part of an AB system), 4.58 (d, J_AB

= 10.6 Hz, 1 H, downfield part of an AB system), 5.12 (d, J =

10.2 Hz, 1 H), 5.20 (dd, J = 1.8, 16.8 Hz, 1 H), 5.40 (m, 2 H), 5.61

(t, J = 11.4 Hz, 1 H), 5.62 (d, J = 11.4 Hz, 1 H), 6.00–6.09 (m, 2

H), 6.58 (t, J = 11.3 Hz, 1 H), 6.62 (t, J = 10.7 Hz, 1 H), 6.89 (d,

J = 8.6 Hz, 2 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.41 (dd, J = 11.3,

15.4 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.4 (CH₃),

–4.4 (CH₃), –4.3 (CH₃), –3.8 (CH₃), –3.5 (CH₃), –2.7 (CH₃), 9.2

(CH₃), 14.7 (CH₃), 15.4 (CH₃), 18.1 (C₀), 18.2 (C₀), 18.6 (C₀), 18.8

(CH₃), 19.0 (CH₃), 20.2 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 26.4 (CH₃),

30.3 (CH), 31.5 (CH₂), 32.4 (CH₂), 34.0 (CH), 35.2 (CH), 36.8

(CH), 40.5 (CH), 41.4 (CH₂), 42.4 (CH₂), 42.5 (CH), 51.1 (CH₃),

55.3 (CH₃), 65.3 (CH), 72.8 (CH), 73.6 (CH), 75.1 (CH₂), 79.6

(CH), 84.4 (CH), 113.7 (CH), 115.6 (CH), 117.2 (CH₂), 127.1 (CH),

128.9 (CH), 129.1 (CH), 131.4 (C₀), 132.4 (CH), 132.6 (CH), 134.6

(CH), 136.2 (CH), 145.5 (CH), 147.0 (CH), 159.0 (C₀), 166.8 (C₀)

ppm. IR (neat): ν = 773, 836, 1075, 1174, 1251, 1377, 1462, 1514,

˜

1613, 1637, 1720, 2855, 2926, 3503 cm^–1. HRMS (ESI): calcd. for

C₅₉H₁₀₆O₈Si₃Na: 1049.70877 [M + Na]⁺; found 1049.70940.

19.5 (CH₃), 21.1 (CH₃), 26.7 (CH₃), 26.9 (CH₃), 31.3 (CH), 31.9 Methyl (2Z,4E,6R,7S,9R,10Z,12S,13R,14S,16S,19R,20R,

(CH₂), 33.1 (CH₂), 35.9 (CH), 36.0 (CH), 41.2 (CH), 42.1 (CH₂), 21S,22S,23Z)-7,9,13,19-Tetrakis(tert-butyldimethylsilyloxy)-21-(4-

44.0 (CH), 56.0 (CH₃), 73.4 (CH), 75.8 (CH₂), 79.9 (CH), 81.9 methoxybenzyloxy)-6,12,14,16,20,22-hexamethylhexacosa-

(CH), 85.2 (CH), 114.4 (CH), 117.9 (CH₂), 129.6 (CH), 129.8 (CH), 2,4,10,23,25-pentaenoate (29a): 2,6-Lutidine (18 μL, 0.156 mmol,

132.1 (C₀), 133.0 (CH), 135.3 (CH), 144.9 (CH), 159.7 (C₀) ppm. 4 equiv.) and TBSOTf (18 μL, 0.078 mmol, 2 equiv.) were added

IR (neat): ν = 772, 835, 1039, 1172, 1251, 1376, 1462, 1514, 1613,

dropwise to a stirred solution of 28a (40 mg, 0.039 mmol, 1 equiv.)

˜

Eur. J. Org. Chem. 2011, 2643–2661

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2653

C. Gennari et al.

FULL PAPER

in DCM (0.3 mL) cooled to –78 °C. After stirring at –78 °C for 1 h,

the reaction was quenched by adding satd. aq. NaHCO₃(1.7 mL)

dropwise, then it was warmed to room temperature. The mixture

H); 6.12 (t, J = 11.0 Hz, 1 H); 6.20 (dd, J = 8.9, 15.5 Hz, 1 H),

6.60 (t, J = 11.3 Hz, 1 H), 6.62–6.71 (m, 1 H), 7.43 (dd, J = 11.3,

15.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.8 (CH₃),

was diluted with DCM (11 mL), layers were separated and the –4.7 (CH₃), –4.4 (CH₃), –4.1 (CH₃), –3.9 (CH₃), –3.8 (CH₃), –3.7

aqueous phase was extracted with DCM (3ϫ10 mL). The com-

bined organic extracts were washed with brine (2ϫ5 mL), dried

with Na₂SO₄and evaporated under reduced pressure. The crude

product was purified by flash chromatography (10:0.5 hexane/

(CH₃), –3.5 (CH₃), 6.8 (CH₃), 15.7 (CH₃), 17.8 (CH₃), 18.0 (C₀),

18.1 (C₀), 18.1 (C₀), 18.5 (CH₃), 20.2 (CH₃), 20.6 (CH₃), 25.8

(CH₃), 25.9 (CH₃), 25.9 (CH₃), 26.2 (CH₃), 30.7 (CH), 31.7 (CH₂),

32.4 (CH₂), 35.5 (CH), 36.1 (CH), 36.5 (CH), 37.7 (CH), 40.9 (CH),

EtOAc) to give the desired product 29a (45 mg, 100% yield) as a 41.6 (CH₂), 44.8 (CH₂), 50.9 (CH₃), 66.5 (CH), 72.4 (CH), 76.8

pale yellow oil; R_f= 0.80 (8:2 hexane/EtOAc). [α]²_D⁴= +7.3 (c =

0.4, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 0.05 (s, 3 H), 0.06 129.9 (CH), 131.4 (CH), 132.3 (CH), 132.7 (CH), 135.4 (CH), 145.9

(CH), 77.8 (CH), 79.2 (CH), 115.0 (CH), 117.2 (CH₂), 127.3 (CH),

1

(s, 3 H), 0.06 (s, 3 H), 0.08 (s, 3 H), 0.10 (s, 9 H), 0.10 (s, 3 H),

(CH), 147.1 (CH), 166.6 (C ) ppm. IR (neat): ν = 799, 1020, 1093,

˜

0

0.80–0.82 (m, 1 H), 0.82 (d, J = 6.1 Hz, 3 H), 0.83 (d, J = 6.9 Hz, 1260, 1412, 1461, 1601, 1637, 1720, 2855, 2927, 2961, 3447 cm^–1.

3 H), 0.86 (d, J = 6.8 Hz, 3 H), 0.91 (s, 9 H), 0.92 (s, 9 H), 0.92 (s,

9 H), 0.94 (s, 9 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.01 (m, 1 H), 1.12

(d, J = 6.8 Hz, 3 H), 1.12 (d, J = 6.8 Hz, 3 H), 1.27–1.42 (m, 4 H),

1.46 (m, 1 H), 1.62–1.72 (m, 4 H), 2.49 (m, 1 H), 2.59 (m, 1 H),

3.00 (m, 1 H), 3.34 (dd, J = 3.1, 8.0 Hz, 1 H), 3.41 (m, 1 H), 3.64

(m, 1 H), 3.72 (s, 3 H), 3.82 (s, 3 H), 3.93 (m, 1 H), 4.43 (br. t, J

= 8.4 Hz, 1 H), 4.52 (d, J_AB= 10.6 Hz, 1 H, upfield part of an AB

system), 4.57 (d, J_AB= 10.6 Hz, 1 H, downfield part of an AB

system), 5.11 (d, J = 10.2 Hz, 1 H), 5.20 (dd, J = 1.7, 16.9 Hz, 1

H), 5.25 (dd, J = 8.2, 11.4 Hz, 1 H), 5.47 (t, J = 10.5 Hz, 1 H),

5.58–5.63 (m, 2 H), 6.02 (t, J = 11.0 Hz, 1 H), 6.20 (dd, J = 8.9,

15.5 Hz, 1 H), 6.55–6.65 (m, 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 7.30

(d, J = 8.7 Hz, 2 H), 7.43 (dd, J = 11.2, 15.5 Hz, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –4.8 (CH₃), –4.7 (CH₃), –4.3 (CH₃),

–4.5 (CH₃), –4.1 (CH₃), –3.8 (CH₃), –3.5 (CH₃), 9.1 (CH₃), 14.1

(CH₃), 15.6 (CH₃), 18.0 (C₀), 18.1 (C₀), 18.2 (C₀), 18.5 (CH₃), 18.9

(CH₃), 20.5 (CH₃), 25.8 (CH₃), 26.0 (CH₃), 26.0 (CH₃), 26.2 (CH₃),

30.5 (CH), 31.7 (CH₂), 32.6 (CH₂), 35.1 (CH), 35.2 (CH), 36.5

(CH), 40.4 (CH), 40.9 (CH), 41.5 (CH₂), 44.8 (CH₂), 50.9 (CH₃),

55.3 (CH₃), 66.4 (CH), 72.4 (CH), 72.6 (CH), 75.1 (CH₂), 79.1

(CH), 84.5 (CH), 113.7 (CH), 115.0 (CH), 117.2 (CH₂), 127.4 (CH),

128.9 (CH), 129.1 (CH), 131.4 (C₀), 131.6 (CH), 132.4 (CH), 132.6

(CH), 134.6 (CH), 146.0 (CH), 147.2 (CH), 159.0 (C₀), 166.8 (C₀)

HRMS (ESI): calcd. for C₅₇H₁₁₂O₇Si₄Na: 1043.73773 [M + Na]⁺;

found 1043.73670.

(2Z,4E,6R,7S,9R,10Z,12S,13R,14S,16S,19R,20R,21S,22S,23Z)-

7,9,13,19-Tetrakis(tert-butyldimethylsilyloxy)-21-hydroxy-

6,12,14,16,20,22-hexamethylhexacosa-2,4,10,23,25-pentaenoic Acid

(31a): To a stirred solution of the ester 30a (35.0 mg, 0.034 mmol,

1 equiv.) in THF (1.8 mL) and EtOH (4.1 mL), KOH (1 n solution

in water, 0.33 mL) was added, and the reaction was refluxed (bath

temperature: 52 °C) for 5 h. The solvent was removed in vacuo. The

residue was diluted with Et₂O (26 mL) and satd. aq. NH₄Cl solu-

tion (8 mL); layers were separated and the aqueous layer was ex-

tracted with Et₂O (3ϫ15 mL). The combined organic extracts were

dried with Na₂SO₄and evaporated under reduced pressure. The

product was purified by flash chromatography (9:1 hexane/EtOAc)

to afford the seco-acid 31a (34.3 mg, 100% yield) as a colorless oil;

R_f= 0.26 (8:2 hexane/EtOAc). [α]³_D²= +3.4 (c = 0.2, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 0.03 (s, 6 H), 0.04 (s, 3 H), 0.05 (s,

3 H), 0.06 (s, 3 H), 0.07 (s, 6 H), 0.08 (s, 3 H), 0.82 (d, J = 7.0 Hz,

3 H), 0.85 (d, J = 6.9 Hz, 3 H), 0.86 (d, J = 6.2 Hz, 3 H), 0.88 (s,

9 H), 0.89 (s, 9 H), 0.89–0.92 (m, 1 H), 0.90 (s, 18 H), 0.92 (d, J =

7.1 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.99–1.05 (m, 1 H), 1.09

(d, J = 6.7 Hz, 3 H), 1.22–1.46 (m, 5 H), 1.60–1.66 (m, 3 H), 1.73–

1.76 (m, 1 H), 2.43 (m, 1 H), 2.56 (m, 1 H), 2.78 (m, 1 H), 3.41

(m, 1 H), 3.53 (dd, J = 2.7, 7.6 Hz, 1 H), 3.75 (m, 1 H), 3.91 (m,

1 H), 4.40 (br. t, J = 8.6 Hz, 1 H), 5.11 (d, J = 10.2 Hz, 1 H), 5.19–

5.27 (m, 2 H), 5.38–5.48 (m, 2 H), 5.57 (d, J = 11.4 Hz, 1 H), 6.10

(t, J = 11.0 Hz, 1 H), 6.22 (dd, J = 9.0, 15.5 Hz, 1 H), 6.58–6.67

(m, 2 H), 7.36 (dd, J = 11.4, 15.5 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = –4.8 (CH₃), –4.7 (CH₃), –4.4 (CH₃), –4.1

(CH₃), –3.8 (CH₃), –3.7 (CH₃), –3.5 (CH₃), 7.4 (CH₃), 15.6 (CH₃),

17.7 (CH₃), 18.0 (C₀), 18.1 (C₀), 18.5 (C₀), 18.7 (CH₃), 20.3 (CH₃),

20.5 (CH₃), 25.8 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 26.2 (CH₃), 30.7

(CH), 31.9 (CH₂), 32.0 (CH₂), 35.5 (CH), 36.2 (CH), 37.1 (CH),

38.1 (CH), 41.0 (CH), 42.3 (CH₂), 45.0 (CH₂), 66.5 (CH), 72.4

(CH), 76.5 (CH), 77.3 (CH), 79.3 (CH), 114.6 (CH), 117.8 (CH₂),

127.4 (CH), 130.1 (CH), 131.5 (CH), 132.2 (CH), 132.7 (CH), 135.1

ppm. IR (neat): ν = 669, 802, 865, 1078, 1257, 1361, 1412, 1461,

˜

1514, 1637, (a719), 2856, 2928, 2961 cm^–1. HRMS (ESI): calcd. for

C₆₅H₁₂₀O₈Si₄Na: 1163.79525 [M + Na]⁺; found 1163.79601.

Methyl (2Z,4E,6R,7S,9R,10Z,12S,13R,14S,16S,19R,20R,

21S,22S,23Z)-7,9,13,19-Tetrakis(tert-butyldimethylsilyloxy)-21-

hydroxy-6,12,14,16,20,22-hexamethylhexacosa-2,4,10,23,25-

pentaenoate (30a): DDQ (11.6 mg, 0.051 mmol, 1.3 equiv.) was

added to a solution of the PMB ether 29a (44.0 mg, 0.039 mmol,

1 equiv.) in DCM (1.2 mL) stirred at 0 °C in the presence of

0.12 mL of a KH₂PO₄/K₂HPO₄buffer solution (pH = 7). The reac-

tion was stirred at 0 °C for 1 h before being quenched by dropwise

addition of satd. aq. NaHCO₃(19 mL). After diluting with DCM

(37 mL), layers were separated and the aqueous phase was ex-

tracted with DCM (3 ϫ30 mL). The combined organic extracts

were washed with brine (2ϫ30 mL), dried with Na₂SO₄and con-

centrated under reduced pressure. The crude product was purified

by flash chromatography (95:5 hexane/EtOAc) to give the desired

product 30a (35.9 mg, 90% yield) as a colorless oil; R_f= 0.35 (9:1

hexane/EtOAc). [α]¹_D⁸= –4.1 (c = 0.2, CHCl₃). ¹H NMR (400 MHz,

(CH), 147.3 (CH), 147.9 (CH), 169.2 (C ) ppm. IR (neat): ν = 774,

˜

0

836, 1005, 1027, 1081, 1255, 1377, 1461, 1600, 1636, 1686, 2855,

2927, 2955, 3417 cm^–1. HRMS (ESI): calcd. for C₅₆H₁₀₉O₇Si₄:

1005.72559 [M – H]^–; found 1005.72635.

(3Z,5E,7R,8S,10R,11Z,13S,14R,15S,17S,20R,21R,22S)-8,10,14,20-

Tetrakis(tert-butyldimethylsilyloxy)-22-[(S,Z)-hexa-3,5-dien-2-yl]-

CDCl₃): δ = 0.07 (s, 3 H), 0.07 (s, 3 H), 0.08 (s, 3 H), 0.10 (s, 12 7,13,15,17,21-pentamethyloxacyclodocosa-3,5,11-trien-2-one (32a):

H), 0.11 (s, 3 H), 0.85 (d, J = 6.9 Hz, 3 H), 0.89–0.90 (m, 6 H), To a solution of the seco-acid 31a (18.0 mg, 0.018 mmol, 1 equiv.)

0.90 (m, 1 H), 0.92–0.95 (m, 39 H), 0.99 (d, J = 6.9 Hz, 3 H), 1.01– in THF (2.2 mL) cooled to 0 °C, Et₃N (15 μL, 0.108 mmol,

1.08 (m, 1 H), 1.13 (d, J = 6.8 Hz, 3 H), 1.18–1.50 (m, 5 H), 1.58– 6 equiv.) and 2,4,6-trichlorobenzoyl chloride (14 μL, 0.09 mmol,

1.79 (m, 4 H), 2.51 (m, 1 H), 2.59 (m, 1 H), 2.83 (m, 1 H), 3.44 5 equiv.) were added. The reaction was stirred at 0 °C for 1 h and

(m, 1 H), 3.50 (dd, J = 2.1, 7.3 Hz, 1 H), 3.73 (s, 3 H), 3.78 (m, 1 monitored by TLC (90:10 hexane/EtOAc; R_f(anhydride) = 0.4) be-

H), 3.95 (m, 1 H), 4.45 (t, J = 8.4 Hz, 1 H), 5.14 (d, J = 10.3 Hz, fore being added to a 4-DMAP (22.0 mg, 0.18 mmol, 10 equiv.)

1 H), 5.21–5.29 (m, 2 H), 5.48 (m, 2 H), 5.60 (d, J = 11.3 Hz, 1 solution in toluene (8.9 mL) at room temperature. The mixture was

2654

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Eur. J. Org. Chem. 2011, 2643–2661

Highly Stereoselective Total Synthesis of Dictyostatins

stirred at room temperature for 24 h (TLC: 97:3 hexane/EtOAc;

R_f(macrolactone) = 0.31) and the solvent was removed in vacuo.

The residue was diluted with Et₂O (22 mL) and water (16 mL),

layers were separated and the aqueous layer was extracted with

Et₂O (3ϫ15 mL). The combined organic extracts were washed

with brine (2ϫ15 mL), dried with Na₂SO₄and evaporated under

reduced pressure. The crude product was purified by flash

chromatography (9:1 hexane/DCM; R_f(macrolactone) = 0.13) to

give macrolactone 32a (14.0 mg, 80% yield) as a pale yellow oil; R_f

= 0.31 (97:3 hexane/EtOAc). [α]²_D¹= –19.6 (c = 0.1, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 0.04 (s, 6 H), 0.05 (s, 3 H), 0.06 (s,

9 H), 0.07 (s, 6 H), 0.84–0.85 (m, 6 H), 0.86–0.89 (m, 6 H), 0.89–

0.90 (br. s, 27 H), 0.92 (s, 9 H), 1.01 (d, J = 6.8 Hz, 3 H), 1.10 (d,

J = 7.0 Hz, 3 H), 1.11 (m, 2 H), 1.15–1.32 (m, 4 H), 1.38–1.55 (m,

3 H), 1.62 (m, 1 H), 1.78–1.86 (m, 1 H), 2.41–2.47 (m, 1 H), 2.47–

2.54 (m, 1 H), 3.05 (m, 1 H), 3.41 (d, J = 2.8 Hz, 1 H), 3.56 (m, 1

H), 3.94 (m, 1 H), 4.41 (t, J = 8.8 Hz, 1 H), 5.12–5.28 (m, 4 H),

5.43 (t, J = 10.4 Hz, 1 H), 5.50–5.54 (m, 2 H), 6.05 (t, J = 11.0 Hz,

1 H), 6.16 (dd, J = 9.1, 15.5 Hz, 1 H), 6.53 (t, J = 11.5 Hz, 1 H),

6.61 (dt, J = 10.6, 16.8 Hz, 1 H), 7.17 (dd, J = 11.2, J = 15.5 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –5.0 (CH₃), –4.8

(CH₃), –4.4 (CH₃), –4.1 (CH₃), –3.8 (CH₃), –3.7 (CH₃), –3.3 (CH₃),

10.7 (CH₃), 14.1 (CH₃), 14.3 (CH₃), 18.0 (C₀), 18.1 (CH₃), 18.1

(C₀), 18.7 (C₀), 18.7 (CH₃), 21.2 (CH₃), 25.8 (CH₃), 25.9 (CH₃),

26.3 (CH₃), 29.5 (CH₂), 29.7 (CH₂), 30.2 (CH), 34.5 (CH), 37.9

(CH), 39.3 (CH), 40.0 (CH), 41.1 (CH), 43.8 (CH₂), 44.8 (CH₂),

66.5 (CH), 72.4 (CH), 73.1 (CH), 77.3 (CH), 81.8 (CH), 116.7

(CH), 118.1 (CH₂), 127.6 (CH), 130.0 (CH), 131.5 (CH), 132.1

(CH), 132.4 (CH), 133.4 (CH), 143.7 (CH), 146.2 (CH), 166.4 (C₀)

(CH), 167.2 (C ) ppm. IR (neat): ν = 665, 740, 804, 1019, 1380,

˜

0

1415, 1460, 1602, 1637, 1685, 1709, 2927, 2961, 3380 cm^–1. HRMS

(ESI): calcd. for C₃₂H₅₂O₆Na: 555.36561 [M + Na]⁺; found

555.36537.

(3R,4S,5S,7S,10R,11R,12S,13S)-10,14-Bis(tert-butyldimethyl-

silanyloxy)-12-(4-methoxy-benzyloxy)-3,5,7,11,13-pentamethyltetra-

dec-1-yn-4-ol (22b): Triphenylphosphane (recrystallized from etha-

nol prior to use, 5.8 mg, 22 μmol, 0.05 equiv.), the crude aldehyde

obtained from alcohol 21^[7j](276 mg, 0.44 mmol, 1 equiv.) and (S)-

mesylbutynol 6b (98 mg, 0.66 mmol, 1.5 equiv.) were sequentially

added to a cooled (–78 °C) solution of Pd(OAc)₂(5 mg, 22 μmol,

0.05 equiv.) in THF (4.5 mL). Diethylzinc (1.0 m in hexane,

1.35 mL, 1.35 mmol, 3 equiv.) was added over 15 min. After

10 min, the temperature was raised to –20 °C and the reaction mix-

ture was stirred overnight. The mixture was then quenched with

satd. aq. NH₄Cl/Et₂O, 1:1. The Et₂O layer was washed with brine,

dried and concentrated in vacuo. The residue was purified by flash

column chromatography (95:5 hexane/EtOAc) to afford the prod-

uct 22b (252 mg, 84% over two steps) as a yellow oil with high

diastereoselectivity (dr Ͼ 95:5); R_f= 0.39 (8:2 hexane/EtOAc).

[α]²_D³= –4.6 (c = 0.51, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ =

0.20 (s, 6 H), 0.26 (s, 6 H), 1.00 (d, J = 6.4 Hz, 3 H), 1.10 (d, J =

6.8 Hz, 3 H), 1.03–1.15 (m, 1 H), 1.13 (s, 9 H), 1.18 (s, 9 H), 1.22

(d, J = 6.8 Hz, 3 H), 1.26 (d, J = 6.8 Hz, 3 H), 1.30 (d, J = 7.2 Hz,

3 H), 1.46–1.95 (m, 7 H), 2.06–2.20 (m, 3 H), 2.68 (m, 1 H), 3.05

(m, 1 H), 3.43 (s, 3 H), 3.79–4.00 (m, 4 H), 4.76 (d, J_AB= 11.2 Hz,

1 H, upfield part of an AB system), 4.82 (d, J_AB= 11.2 Hz, 1 H,

downfield part of an AB system), 6.96 (d, J = 8.4 Hz, 2 H), 7.48

(d, J = 8.4 Hz, 2 H) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = –4.7

(CH₃), –3.6 (CH₃), –3.4 (CH₃), 11.1 (CH₃), 16.0 (CH₃), 17.3 (CH₃),

18.8 (CH₃), 18.9 (C₀), 19.0 (C₀), 21.9 (CH₃), 26.3 (CH₃), 26.4

(CH₃), 31.0 (CH), 31.5 (CH), 32.0 (CH₂), 35.7 (CH), 39.9 (CH),

40.6 (CH₂), 40.8 (CH), 55.2 (CH₃), 65.6 (CH₂), 71.8 (CH), 74.6

(CH₂), 75.6 (CH), 79.6 (CH), 81.4 (CH), 114.5 (CH), 129.5 (CH),

ppm. IR (neat): ν = 662, 743, 799, 1020, 1260, 1413, 1462, 1637,

˜

1709, 2854, 2927, 2961 cm^–1. HRMS (ESI): calcd. for C₅₆H₁₀₈O₆-

Si₄Na: 1011.71152 [M + Na]⁺; found 1011.71340.

(3Z,5E,7R,8S,10R,11Z,13S,14R,15S,17S,20R,21S,22S)-22-[(S,Z)-

Hexa-3,5-dien-2-yl]-8,10,14,20-tetrahydroxy-7,13,15,17,21-penta-

methyloxacyclodocosa-3,5,11-trien-2-one (1a): To a solution of

macrolactone 32a (10.0 mg, 10.2 μmol, 1 equiv.) in THF (1.34 mL)

kept at 0 °C in a plastic vial, HF·Py (0.34 mL) was added dropwise

over 2 min, and the solution was allowed to slowly warm to room

temperature. The reaction was stirred for 20 h, then it was cooled

to 0 °C, diluted with EtOAc (7.0 mL) and quenched with a satd.

aq. NaHCO₃solution (7.0 mL). The layers were separated and the

aqueous layer was extracted with EtOAc (3ϫ10 mL). The com-

bined organic extracts were dried with Na₂SO₄and evaporated un-

der reduced pressure. The crude product was purified by flash

chromatography (3:7 hexane/EtOAc) to give (+)-9-epi-dictyostatin

132.6 (C ), 160.0 (C ) ppm. IR (neat): ν = 3309, 2960, 2933, 2850,

˜

0

2663, 2655, 1727, 1613, 1514, 1470, 1462, 1386, 1360, 1301, 1255

cm^–1. HRMS (ESI): calcd. for C₃₉H₇₂O₅Si₂Na: 699.48105 [M +

Na]⁺; found 699.47937.

(5S,6S,8S,11R,12R,13S,14S)-5-[(R)-But-3-yn-2-yl]-11-[(tert-butyldi-

methylsilyl)oxy]-13-[(4-methoxybenzyl)oxy]-2,2,3,3,6,8,12,

14,17,17,18,18-dodecamethyl-4,16-dioxa-3,17-disilanonadecane

(23b): 2,6-Lutidine (0.22 mL, 1.85 mmol, 5 equiv.) and TBSOTf

(0.26 mL, 1.11 mmol, 3 equiv.) were added dropwise to a stirred

solution of 22b (252 mg, 0.37 mmol, 1 equiv.) in DCM (9.3 mL)

cooled to 0 °C. After stirring at 0 °C for 1.5 h, the reaction was

(1a) (3.8 mg, 70 % yield) as a white powder; R_f= 0.54 (100 % quenched by adding satd. aq. NH₄Cl (3.5 mL) dropwise, then it

EtOAc). [α]³_D¹= +43.4 (c = 0.17, CHCl₃). ¹H NMR (400 MHz,

C₆D₆): δ = 0.85 (d, J = 6.7 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3 H),

was warmed to room temperature. Layers were separated and the

aqueous phase was extracted with DCM (3ϫ15 mL). The com-

0.93 (d, J = 6.5 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 6 H), 1.03 (d, J = bined organic extracts were washed with brine (10 mL), dried with

7.0 Hz, 3 H), 1.24–1.58 (m, 7 H), 1.69–1.84 (m, 3 H), 1.83–1.94 (m, Na₂SO₄and evaporated under reduced pressure. The crude product

2 H), 2.19–2.28 (m, 1 H), 2.81–2.96 (m, 2 H), 3.18–3.22 (m, 1 H),

3.26–3.35 (m, 1 H), 3.41–3.53 (m, 2 H), 3.90–3.96 (m, 1 H), 4.21

was purified by flash chromatography (98:2 hexane/EtOAc) to give

the desired product 23b (234 mg, 80% yield) as a colorless oil; R_f

(br. s, 1 H), 4.60 (br. s, 1 H), 4.98–5.02 (m, 2 H), 5.09 (t, J = = 0.62 (85:15 hexane/EtOAc). [α]²_D²= –4.8 (c = 0.3, CHCl₃). ¹H

16.7 Hz, 1 H), 5.27–5.38 (m, 2 H), 5.44 (dd, J = 4.4, 11.6 Hz, 1 H), NMR (400 MHz, C₆D₆): δ = 0.09 (s, 6 H), 0.11 (s, 3 H), 0.12 (s, 3

5.56 (d, J = 11.3 Hz, 1 H), 5.74 (dd, J = 6.2, 15.8 Hz, 1 H), 5.98

(t, J = 11.0 Hz, 1 H), 6.25 (t, J = 11.3 Hz, 1 H), 6.58 (dt, J = 10.6,

H), 0.14 (s, 3 H), 0.15 (s, 3 H),0.99 (d, J = 6.1 Hz, 3 H), 1.01 (s, 9

H), 1.05 (s, 9 H), 1.06 (s, 9 H), 1.11 (d, J = 7.1 Hz, 3 H), 1.13 (d,

16.7 Hz, 1 H), 7.89 (dd, J = 11.3, 15.7 Hz, 1 H) ppm. ¹³C NMR J = 7.1 Hz, 3 H), 1.19 (d, J = 6.9 Hz, 3 H), 1.23 (d, J = 7.1 Hz, 3

(100 MHz, C₆D₆): δ = 9.4 (CH₃), 14.9 (CH₃), 16.7 (CH₃), 17.6 H), 1.28–1.35 (m, 2 H), 1.50–1.58 (m, 2 H), 1.59–1.70 (m, 2 H),

(CH₃), 18.5 (CH₃), 21.9 (CH₃), 30.3 (CH), 32.9 (CH₂), 33.5 (CH₂), 1.79–1.86 (m, 1 H), 1.90 (d, J = 2.5 Hz, 1 H), 2.02 (m, 3 H), 2.65

33.6 (CH), 35.1 (CH), 35.9 (CH), 40.7 (CH), 41.6 (CH₂), 41.7

(CH₂), 42.2 (CH), 71.1 (CH), 73.8 (CH), 74.2 (CH), 76.6 (CH), = 3.9, 6.9 Hz, 1 H), 3.73 (dd, J = 3.4, 9.7 Hz, 1 H), 3.81 (m, 1 H),

77.7 (CH), 116.3 (CH), 118.0 (CH₂), 127.5 (CH), 130.5 (CH), 132.5 3.87 (m, 1 H), 4.64 (d, J_AB= 11.1 Hz, 1 H, upfield part of an AB

(CH), 133.1 (CH), 133.8 (CH), 133.9 (CH), 146.2 (CH), 146.9 system), 4.71 (d, J_AB= 11.1 Hz, 1 H, downfield part of an AB

(m, 1 H), 3.31 (s, 3 H), 3.42 (dd, J = 3.9, 4.9 Hz, 1 H), 3.69 (dd, J

Eur. J. Org. Chem. 2011, 2643–2661

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C. Gennari et al.

FULL PAPER

system), 6.84 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 8.6 Hz, 2 H) ppm. 25b (147 mg, 100% yield) as a colorless oil; R_f= 0.85 (8:2 hexane/

¹³C NMR (100 MHz, CDCl₃): δ = –5.3 (CH₃), –5.2 (CH₃), –4.3 EtOAc). [α]²_D⁴= –14.3 (c = 0.2, CHCl₃). ¹H NMR (400 MHz,

(CH₃), –4.1 (CH₃), –4.0 (CH₃), –3.9 (CH₃), 10.1 (CH₃), 15.3 (CH₃), CDCl₃): δ = 0.04 (s, 6 H), 0.05 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H),

16.7 (CH₃), 18.1 (C₀), 18.2 (CH₃), 18.3 (C₀), 18.4 (C₀), 20.9 (CH₃), 0.08 (s, 3 H), 0.81 (d, J = 6.9 Hz, 3 H), 0.90 (d, J = 7.1 Hz, 3 H),

25.9 (CH₃), 26.0 (CH₃), 26.1 (CH₃), 30.2 (CH), 30.5 (CH), 31.0

(CH₂), 31.4 (CH₂), 35.1 (CH), 38.8 (CH), 39.7 (CH), 40.3 (CH₂), H), 0.98 (d, J = 6.8 Hz, 3 H), 0.99–1.02 (m, 1 H), 1.22–1.32 (m, 2

55.3 (CH₃), 64.6 (CH₂), 69.9 (CH), 73.9 (CH₂), 74.3 (CH), 78.8 H), 1.36–1.49 (m, 3 H), 1.58–1.62 (m, 1 H), 1.66–1.73 (m, 1 H),

(CH), 80.9 (CH), 87.3 (C₀), 113.7 (CH), 128.9 (CH), 131.6 (C₀), 1.78 (m, 1 H), 1.88 (m, 1 H), 2.68 (m, 1 H), 3.46 (dd, J = 4.1,

0.91 (s, 12 H), 0.92 (s, 9 H), 0.93 (s, 9 H), 0.97 (d, J = 6.8 Hz, 3

158.9 (C ) ppm. IR (neat): ν = 625, 669, 774, 836, 939, 1040, 1079,

6.9 Hz, 1 H), 3.49 (dd, J = 1.8, 5.1 Hz, 1 H), 3.62–3.69 (m, 3 H),

3.80 (s, 3 H), 4.47 (d, J_AB= 10.9 Hz, 1 H, upfield part of an AB

˜

0

1172, 1251, 1302, 1361, 1387, 1463, 1514, 1614, 2856, 2929 cm^–1.

HRMS (ESI): calcd. for C₄₅H₈₆O₅Si₃Na: 813.56753 [M + Na]⁺; system), 4.55 (d, J_AB= 10.9 Hz, 1 H, downfield part of an AB

found 813.56975.

system), 6.06 (d, J = 7.3 Hz, 1 H), 6.38 (dd, J = 7.3, 8.8 Hz, 1 H),

6.86 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = –5.3 (CH₃), –5.2 (CH₃), –4.2 (CH₃), –3.9

(CH₃), –3.7 (CH₃), 10.2 (CH₃), 15.3 (CH₃), 15.5 (CH₃), 18.2 (C₀),

18.3 (C₀), 18.8 (CH₃), 20.6 (CH₃), 26.8 (CH₃), 29.7 (CH₂), 30.5

(CH), 31.5 (CH₂), 36.5 (CH), 39.0 (CH), 39.8 (CH), 41.2 (CH₂),

41.6 (CH), 55.3 (CH₃), 64.7 (CH₂), 74.0 (CH₂), 74.3 (CH), 79.0

(CH), 80.4 (CH), 81.0 (CH), 113.7 (CH), 128.9 (CH), 131.7 (C₀),

(5S,6S,8S,11R,12R,13S,14S)-11-[(tert-Butyldimethylsilyl)oxy]-5-

[(R)-4-iodobut-3-yn-2-yl]-13-[(4-methoxybenzyl)oxy]-2,2,3,3,6,8,

12,14,17,17,18,18-dodecamethyl-4,16-dioxa-3,17-disilanonadecane

(24b): A 1.6 m solution of nBuLi in hexane (0.22 mL, 0.35 mmol,

1.2 equiv.) was added dropwise over 5 min to a solution of alkyne

23b (231 mg, 0.29 mmol, 1 equiv.) in THF (1.5 mL) at –50 °C. After

1 h, a solution of iodine (125 mg, 0.50 mmol, 1.7 equiv.) in THF

(0.1 mL) was added. The mixture was stirred at –50 °C for 30 min,

then warmed to room temperature over 30 min. After quenching

by the addition of a satd. aq. Na₂S₂O₃solution (0.8 mL) and brine

(0.8 mL), the mixture was extracted with EtOAc (3ϫ3 mL) and

the combined organic layers were washed with brine (2ϫ4 mL).

The organic phase was dried with Na₂SO₄and concentrated in

vacuo. The crude product was purified by flash chromatography

(95:5 hexane/EtOAc) to give the desired product 24b (268 mg,

100% yield) as a colorless oil; R_f= 0.41 (95:5 hexane/EtOAc). [α]

144.2 (CH), 159.0 (C ) ppm. IR (neat): ν = 773, 836, 1038, 1078,

˜

0

1171, 1249, 1301, 1360, 1387, 1461, 1514, 1614, 1677, 2855, 2928,

2954 cm^–1. HRMS (ESI): calcd. for C₄₅H₈₇IO₅Si₃Na: 941.47982 [M

+ Na]⁺; found 941.47890.

(2S,3S,4R,5R,8S,10S,11S,12R,Z)-5,11-Bis[(tert-butyldimethylsilyl)-

oxy]-14-iodo-3-[(4-methoxybenzyl)oxy]-2,4,8,10,12-pentamethyl-

tetradec-13-en-1-ol (26b): A solution of compound 25b (147 mg,

0.16 mmol, 1 equiv.) in THF (0.8 mL) at 0 °C was treated with a

solution of HF·Py in THF/pyridine [3.6 mL, prepared by slow ad-

dition of commercially available 70% HF in pyridine (0.31 mL) to

a mixture of pyridine (1.1 mL) and THF (2.2 mL)]. The reaction

mixture was warmed to room temperature and stirred for 4 h. After

28

1

= –0.9 (c = 0.3, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 0.05

D

(s, 9 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89 (d, J =

7.0 Hz, 3 H), 0.92 (s, 9 H), 0.92 (s, 9 H), 0.93 (s, 9 H), 0.94 (d, J =

7.0 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H), quenching the reaction by the addition of satd. aq. NaHCO₃

1.17 (d, J = 7.1 Hz, 3 H), 1.28–1.33 (m, 3 H), 1.35–1.44 (m, 3 H), (6 mL), the mixture was extracted with EtOAc (4ϫ10 mL). The

1.58–1.62 (m, 1 H), 1.73–1.82 (m, 2 H), 1.89 (m, 1 H), 2.76 (m, 1 combined organic extracts were washed with satd. aq. CuSO₄

H), 3.40 (t, J = 4.4 Hz, 1 H), 3.48 (dd, J = 4.2, 6.9 Hz, 1 H), 3.61–

3.70 (m, 3 H), 3.80 (s, 3 H), 4.48 (d, J_AB= 10.9 Hz, 1 H, upfield

part of an AB system), 4.56 (d, J_AB= 10.9 Hz, 1 H, downfield part

of an AB system), 6.87 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.6 Hz, 2

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –5.4 (CH₃), –5.3 (C₀),

–5.2 (CH₃), –4.2 (CH₃), –4.1 (CH₃), –4.0 (CH₃), –3.9 (CH₃), 10.1

(3ϫ10 mL) and brine (2ϫ10 mL), dried with Na₂SO₄and concen-

trated in vacuo. The crude product was purified by flash

chromatography (9:1 hexane/EtOAc) to give the desired product

26b (102 mg, 80% yield) as a colorless oil; R_f= 0.29 (8:2 hexane/

EtOAc). [α]²_D⁵= –9.0 (c = 0.2, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.08 (s, 3 H),

(CH₃), 15.3 (CH₃), 16.7 (CH₃), 18.1 (C₀), 18.2 (CH₃), 18.3 (C₀), 0.82 (d, J = 6.9 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.91 (s, 9 H),

18.3 (C₀), 20.8 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 26.1 (CH₃), 30.5 0.92 (s, 9 H), 0.98 (d, J = 7.1 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H),

(CH), 31.1 (CH₂), 31.4 (CH₂), 32.5 (CH), 35.0 (CH), 38.9 (CH), 1.11 (d, J = 7.0 Hz, 3 H), 1.20–1.70 (m, 8 H), 1.88 (m, 1 H), 1.95

39.7 (CH), 39.9 (CH₂), 55.3 (CH₃), 64.7 (CH₂), 73.9 (CH₂), 74.4 (m, 1 H), 2.68 (m, 1 H), 3.44–3.49 (m, 2 H), 3.56–3.64 (m, 2 H),

(CH), 79.0 (CH), 80.9 (CH), 97.6 (C₀), 113.7 (CH), 128.9 (CH),

131.7 (C ), 158.9 (C ) ppm. IR (neat): ν = 670, 773, 836, 1038,

1078, 1172, 1250, 1302, 1361, 1387, 1462, 1514, 1614, 1677, 2208,

2855, 2928, 2954 cm^–1. HRMS (ESI): calcd. for C₄₅H₈₅IO₅Si₃Na:

939.46417 [M + Na]⁺; found 939.46313.

3.78–3.82 (m, 1 H), 3.80 (s, 3 H), 4.53 (s, 2 H), 6.06 (d, J = 7.3 Hz,

1 H), 6.38 (dd, J = 7.4, 8.8 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 2 H),

7.26 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

–4.4 (CH₃), –4.2 (CH₃), –3.8 (CH₃), –3.7 (CH₃), 10.1 (CH₃), 15.5

(CH₃), 15.8 (CH₃), 18.2 (C₀), 18.3 (C₀), 18.8 (CH₃), 20.5 (CH₃),

26.0 (CH₃), 26.1 (CH₃), 30.5 (CH), 31.8 (CH₂), 31.9 (CH₂), 36.6

(CH), 37.0 (CH), 40.7 (CH), 41.1 (CH₂), 41.6 (CH), 55.3 (CH₃),

65.2 (CH₂), 73.8 (CH), 75.2 (CH₂), 79.0 (CH), 80.4 (CH), 85.9

(CH), 113.9 (CH), 129.3 (CH), 130.6 (C₀), 144.2 (CH), 159.3 (C₀)

˜

0

(5S,6S,8S,11R,12R,13S,14S)-11-[(tert-Butyldimethylsilyl)oxy]-5-

[(R,Z)-4-iodobut-3-en-2-yl]-13-[(4-methoxybenzyl)oxy]-2,2,3,3,6,8,

12,14,17,17,18,18-dodecamethyl-4,16-dioxa-3,17-disilanonadecane

(25b): A solution of iodoalkyne 24b (147 mg, 0.16 mmol, 1 equiv.)

in THF (0.4 mL) and iPrOH (0.4 mL) at room temperature was

treated with TEA (30 μL, 0.21 mmol, 1.3 equiv.) and NBSH

(38.0 mg, 0.18 mmol, 1.1 equiv.). After 12 h, additional TEA

(10 μL, 0.10 mmol, 0.6 equiv.) and NBSH (17.0 mg, 0.08 mmol,

0.5 equiv.) were added, and the mixture was stirred for 12 h. The

reaction was quenched by adding water (1.0 mL) and the mixture

ppm. IR (neat): ν = 772, 806, 835, 1037, 1077, 1251, 1302, 1378,

˜

1462, 1514, 1612, 2852, 2925, 2955, 3447 cm^–1. HRMS (ESI): calcd.

for C₃₉H₇₃IO₅Si₂Na [M + Na]⁺: 827.39334; found 827.39306.

(2R,3R,4R,5R,8S,10S,11S,12R,Z)-5,11-Bis[(tert-butyldimethylsil-

yl)oxy]-14-iodo-3-[(4-methoxybenzyl)oxy]-2,4,8,10,12-pentamethyl-

tetradec-13-enal (27b): A solution of alcohol 26b (91 mg, 0.11 mmol

was extracted with EtOAc (3ϫ3 mL). The combined organic layers 1 equiv.) in DCM (0.6 mL) was treated at 0 °C with pyridine

were washed with brine (2ϫ3 mL), dried with Na₂SO₄and concen-

trated in vacuo. The crude product was purified by flash

chromatography (95:5 hexane/EtOAc) to give the desired product

(23 μL, 0.28 mmol, 2.5 equiv.) and DMP (58 mg, 0.14 mmol,

1.2 equiv.). The reaction mixture was warmed to room temperature

and stirred for 1 h. After completion of the reaction, satd. aq.

2656

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Eur. J. Org. Chem. 2011, 2643–2661

Highly Stereoselective Total Synthesis of Dictyostatins

NaHCO₃(2.0 mL) and Na₂S₂O₃(205 mg, 0.82 mmol) were added.

The resulting mixture was stirred for 30 min, then the phases were

separated and the aqueous phase was extracted with Et₂O

stirring for 30 min, dimethylzinc (2.0 m in toluene, 0.08 mL,

0.17 mmol, 1.6 equiv.) was added dropwise and the reaction mix-

ture was further stirred at –78 °C for 15 min. A solution of alde-

(3ϫ4 mL). The combined organic extracts were washed with brine hyde 2 (51 mg, 0.16 mmol, 1.5 eq, azeotropically dried with tolu-

(2ϫ5 mL), dried (Na₂SO₄) and evaporated under reduced pressure,

providing the crude aldehyde 27b, which was used without further

purification; R_f= 0.60 (8:2 hexane/EtOAc). H NMR (400 MHz,

ene) in Et₂O (0.5 mL) was added dropwise, and the mixture was

stirred for 1 h at –78 °C. The reaction was quenched with water

(2.0 mL), warmed to room temperature and diluted with Et₂O

1

CDCl₃): δ = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), (3.0 mL). Phases were separated and the aqueous layer was ex-

0.82 (d, J = 6.9 Hz, 3 H), 0.88 (d, J = 6.4 Hz, 3 H), 0.90 (s, 9 H),

0.92 (s, 9 H), 0.98 (d, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.9 Hz, 3 H),

1.15 (d, J = 7.0 Hz, 3 H), 1.27–1.36 (m, 3 H), 1.38–1.43 (m, 2 H),

tracted with Et₂O (3ϫ5 mL). The combined organic extracts were

washed with brine (2ϫ5 mL), dried with Na₂SO₄and concentrated

in vacuo. The crude product was purified by flash chromatography

1.53–1.69 (m, 3 H), 1.87 (m, 1 H), 2.67 (m, 1 H), 2.78 (m, 1 H), (10:0.3 hexane/EtOAc) and the following compounds were isolated

3.48 (dd, J = 1.9, 5.1 Hz 1 H), 3.67 (m, 2 H), 3.80 (s, 3 H), 4.49 (s, (the reported R_fvalues were obtained using 8:2 hexane/EtOAc as

2 H), 6.06 (d, J = 7.3 Hz, 1 H), 6.37 (dd, J = 7.3, 8.8 Hz, 1 H), the eluent): (i) de-iodinated alkene C10-C26 (R_f= 0.67, 36 mg); (ii)

6.86 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H), 9.80 (d, J = mixture of unknown products (R_f= 0.45–0.48, Ͻ5% compared to

2.3 Hz, 1 H) ppm.

the 9S addition product); (iii) 9S addition product 28b (R_f= 0.41,

42 mg, 40% yield, light yellow oil); (iv) unreacted aldehyde C1-C9

2 (R_f= 0.37, 29 mg); (v) unknown product (R_f= 0.29, Ͻ 5% com-

pared to the 9S addition product); R_f= 0.41 (8:2 hexane/EtOAc).

(5S,6S,8S,11R)-5-[(R,Z)-4-Iodobut-3-en-2-yl]-11-{(2R,3S,4S,Z)-3-

[(4-methoxybenzyl)oxy]-4-methylocta-5,7-dien-2-yl}-2,2,3,3,6,8,

13,13,14,14-decamethyl-4,12-dioxa-3,13-disilapentadecane (3b): To

a slurry of CrCl₂(69 mg, 0.57 mmol, 5 equiv.) in THF (1.1 mL),

obtained by sonication and cooled to 0 °C, freshly prepared alde-

hyde 27b (0.11 mmol, 1 equiv.) in THF (0.4 mL) and (1-bromo-

allyl)trimethylsilane (7, 122 mg, 0.63 mmol, 5.6 equiv.) were added.

The resulting mixture was stirred for 3 h at room temperature be-

fore being re-cooled to 0 °C and quenched by the addition of

MeOH (0.5 mL) and 6 n aqueous KOH (1.0 mL). After stirring for

20 h at room temperature, the phases were separated and the aque-

ous layer was extracted with DCM (4ϫ5 mL). The combined or-

ganic extracts were washed with brine (2 ϫ 10 mL), dried with

Na₂SO₄and concentrated in vacuo. The crude product was purified

by flash chromatography (100:0.5 hexane/EtOAc) to give the de-

sired product 3b (86 mg, 92% yield over two steps) as a colorless

oil; R_f= 0.50 (95:5 hexane/EtOAc). [α]²_D²= –0.6 (c = 0.3, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.07

(s, 3 H), 0.08 (s, 3 H), 0.79 (d, J = 6.9 Hz, 3 H), 0.84 (d, J = 6.3 Hz,

3 H), 0.85–0.97 (m, 2 H), 0.92 (s, 9 H), 0.93 (s, 9 H), 0.95 (d, J =

7.4 Hz, 3 H), 0.97 (d, J = 7.3 Hz, 3 H), 1.10 (d, J = 6.9 Hz, 3 H),

1.18–1.37 (m, 4 H), 1.48–1.54 (m, 1 H), 1.57–1.67 (m, 2 H), 2.67

(m, 1 H), 2.98 (m, 1 H), 3.33 (dd, J = 3.3, 7.8 Hz, 1 H), 3.46 (dd,

1

[α]²_D⁹= –10.6 (c = 0.2, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

0.04 (s, 6 H), 0.07 (s, 3 H), 0.08 (s, 6 H), 0.13 (s, 3 H), 0.72–0.78

(m, 1 H), 0.83 (d, J = 6.4 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3 H), 0.88–

0.91 (m, 5 H), 0.90 (s, 9 H), 0.91 (s, 9 H), 0.92 (s, 9 H), 0.95 (d, J

= 6.8 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H), 1.10 (d, J = 6.9 Hz, 3

H), 1.17–1.41 (m, 6 H), 1.45–1.55 (m, 1 H), 1.61–1.68 (m, 1 H),

2.01 (br. s, 1 H), 2.55 (m, 1 H), 2.69 (m, 1 H), 2.98 (m, 1 H), 3.30–

3.34 (m, 2 H), 3.61 (m, 1 H), 3.72 (s, 3 H), 3.80 (s, 3 H), 3.95 (m,

1 H), 4.49 (d, J_AB= 10.6 Hz, 1 H, upfield part of an AB system),

4.54–4.59 (m, 1 H), 4.55 (d, J_AB= 10.8 Hz, 1 H, downfield part of

an AB system), 5.09 (d, J = 10.1 Hz, 1 H), 5.17 (dd, J = 1.7,

16.8 Hz, 1 H), 5.33 (dd, J = 8.8, 10.8 Hz, 1 H), 5.51–5.58 (m, 2 H),

5.59 (d, J = 11.5 Hz, 1 H), 5.96–6.06 (m, 2 H), 6.53–6.62 (m, 2 H),

6.86 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.37 (dd, J =

11.3, 15.4 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.5

(CH₃), –4.4 (CH₃), –4.3 (CH₃), –3.7 (CH₃), –3.6 (CH₃), –3.5 (CH₃),

9.3 (CH₃), 14.5 (CH₃), 16.0 (CH₃), 18.1 (C₀), 18.2 (C₀), 18.4 (C₀),

18.8 (CH₃), 20.1 (CH₃), 20.8 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 26.2

(CH₃), 30.3 (CH), 31.0 (CH₂), 32.2 (CH₂), 35.0 (CH), 35.2 (CH),

35.7 (CH), 40.4 (CH₂), 40.6 (CH), 41.0 (CH₂), 43.1 (CH), 51.0

(CH₃), 55.3 (CH₃), 64.2 (CH), 72.3 (CH), 72.8 (CH), 75.0 (CH₂),

80.5 (CH), 84.4 (CH), 113.7 (CH), 115.6 (CH), 117.2 (CH₂), 126.8

(CH), 128.9 (CH), 129.1 (CH), 131.4 (CH), 131.4 (C₀), 132.4 (CH),

134.6 (CH), 135.0 (CH), 145.5 (CH), 147.2 (CH), 159.0 (C₀), 166.9

J = 1.9, 5.1 Hz, 1 H), 3.61 (m, 1 H), 3.80 (s, 3 H), 4.49 (d, J_AB

10.6 Hz, 1 H, upfield part of an AB system), 4.56 (d, J_AB

=

10.6 Hz, 1 H, downfield part of an AB system), 5.10 (d, J =

10.1 Hz, 1 H), 5.18 (dd, J = 1.8, 16.8 Hz, 1 H), 5.58 (t, J = 10.6 Hz,

1 H), 6.01 (t, J = 11.1 Hz, 1 H), 6.06 (d, J = 7.3 Hz, 1 H), 6.37

(dd, J = 7.3, 8.8 Hz, 1 H), 6.58 (td, J = 10.7, 16.8 Hz, 1 H), 6.87

(d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.7 Hz, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = –4.4 (CH₃), –4.2 (CH₃), –3.7 (CH₃), –3.5

(CH₃), 9.3 (CH₃), 15.5 (CH₃), 18.2 (C₀), 18.3 (C₀), 18.7 (CH₃), 18.8

(CH₃), 20.5 (CH₃), 26.0 (CH₃), 26.1 (CH₃), 30.2 (CH), 31.6 (CH₂),

32.2 (CH₂), 35.3 (CH), 36.4 (CH), 40.6 (CH), 41.1 (CH2), 41.6

(CH), 55.3 (CH₃), 72.8 (CH), 75.0 (CH₂), 79.1 (CH), 80.4 (CH),

84.4 (CH), 113.7 (CH), 117.2 (CH₂), 128.9 (CH), 129.1 (CH), 131.4

(C₀), 132.4 (CH), 134.6 (CH), 144.2 (CH), 159.0 (C₀) ppm. IR

(C ) ppm. IR (neat): ν = 773, 806, 836, 1039, 1080, 1174, 1252,

˜

0

1377, 1462, 1514, 1602, 1638, 1721, 2855, 2926, 2955, 3427 cm^–1.

HRMS (ESI): calcd. for C₅₉H₁₀₆O₈Si₃Na: 1049.70877 [M + Na]⁺;

found 1049.70714.

Methyl (2Z,4E,6R,7S,9S,10Z,12R,13S,14S,16S,19R,20S,

21S,22S,23Z)-7,9,13,19-Tetrahydroxy-21-[(4-methoxybenzyl)oxy]-

6,12,14,16,20,22-hexamethylhexacosa-2,4,10,23,25-pentaenoate

(28b-acetonide precursor): To a solution of 28b (12.0 mg, 11.6 μmol,

1 equiv.) in THF (1.5 mL) kept at 0 °C in a plastic vial, HF·Py

(0.35 mL) was added dropwise over 2 min, and the solution was

allowed to slowly warm to room temperature. The reaction mixture

was stirred for 24 h, then it was cooled to 0 °C, diluted with EtOAc

(8 mL) and quenched with a satd. aq. NaHCO₃solution (8 mL).

(neat): ν = 772, 804, 835, 868, 1039, 1179, 1257, 1361, 1377, 1462,

˜

1514, 1613, 2854, 2925, 2956 cm^–1. HRMS (ESI): calcd. for

C₄₂H₇₅IO₄Si₂Na: 849.41408 [M + Na]⁺; found 849.41270.

Methyl (2Z,4E,6R,7S,9S,10Z,12R,13S,14S,16S,19R,20R, The layers were separated and the aqueous layer was extracted with

21S,22S,23Z)-7,13,19-Tris[(tert-butyldimethylsilyl)oxy]-9-hydroxy- EtOAc (3ϫ10 mL). The combined organic extracts were dried with

21-[(4-methoxybenzyl)oxy]-6,12,14,16,20,22-hexamethylhexacosa-

2,4,10,23,25-pentaenoate (28b): To a solution of tBuLi (1.7 m in

pentane, 0.15 mL, 0.23 mmol, 2.2 equiv.) in Et₂O (0.2 mL) kept at

–78 °C under argon atmosphere, a solution of vinyl iodide 3b

(86 mg, 0.104 mmol, 1 equiv.) in Et₂O (0.4 mL) was added. After

Na₂SO₄and evaporated under reduced pressure. The crude product

was purified by flash chromatography (1:1 hexane/EtOAc) to give

the desired de-silylated product (6.0 mg, 76% yield) as a white pow-

der; R_f= 0.15 (1:1 hexane/EtOAc). H NMR (400 MHz, C₆D₆): δ

= 0.84 (d, J = 5.4 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 0.97 (d, J =

1

Eur. J. Org. Chem. 2011, 2643–2661

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2657

C. Gennari et al.

FULL PAPER

7.7 Hz, 3 H), 0.99 (d, J = 7.5 Hz, 3 H), 1.04 (d, J = 6.8 Hz, 3 H), NMR (400 MHz, CDCl₃): δ = 0.02 (s, 3 H), 0.04 (s, 6 H), 0.07 (s,

1.07 (d, J = 6.5 Hz, 3 H), 1.24–1.36 (m, 4 H), 1.52–1.71 (m, 7 H), 6 H), 0.08 (s, 6 H), 0.10 (s, 3 H), 0.83 (d, J = 6.8 Hz, 6 H), 0.82–

2.24 (m, 1 H), 2.82–2.89 (m, 2 H), 3.06 (m, 1 H), 3.30 (s, 3 H), 3.31 0.95 (m, 8 H), 0.84 (s, 9 H), 0.90 (s, 9 H), 0.91 (s, 9 H), 0.92 (s, 9

(m, 1 H), 3.38 (s, 3 H), 3.75 (s, 1 H), 3.93 (m, 1 H), 4.34 (d, J_AB

10.2 Hz, 1 H, upfield part of an AB system), 4.60 (d, J_AB

10.2 Hz, 1 H, downfield part of an AB system), 4.83 (m, 1 H), 5.08

(d, J = 10.0 Hz, 1 H), 5.14–5.24 (m, 2 H), 5.49 (t, J = 10.2 Hz, 1

H), 5.60 (d, J = 11.3 Hz, 1 H), 5.67 (t, J = 9.3 Hz, 1 H), 6.02–6.13

=

H), 1.04 (d, J = 6.8 Hz, 3 H), 1.10 (d, J = 6.9 Hz, 3 H), 1.20–1.39

(m, 5 H), 1.47–1.55 (m, 2 H), 1.59–1.67 (m, 2 H), 2.53 (m, 1 H),

2.62 (m, 1 H), 2.97 (m, 1 H), 3.31–3.35 (m, 2 H), 3.61 (m, 1 H),

3.72 (s, 3 H), 3.80 (s, 3 H), 3.92 (m, 1 H), 4.49–4.57 (m, 1 H), 4.50

(d, J_AB= 10.6 Hz, 1 H, upfield part of an AB system), 4.54 (d, J_AB

(m, 2 H), 6.31 (t, J = 11.2 Hz, 1 H), 6.71 (dt, J = 10.6, 16.8 Hz, 1 = 10.6 Hz, 1 H, downfield part of an AB system), 5.09 (d, J =

H), 6.81 (d, J = 7.7 Hz, 2 H), 7.29 (d, J = 7.7 Hz, 2 H), 7.84 (m, 1

H) ppm. HRMS (ESI): calcd. for C₄₁H₆₄O₈Na: 707.44934 [M +

Na]⁺; found 707.44853.

10.6 Hz, 1 H), 5.17 (d, J = 16.8 Hz, 1 H), 5.26 (dd, J = 9.3, 10.9 Hz,

1 H), 5.55–5.62 (m, 2 H), 5.59 (d, J = 11.1 Hz, 1 H), 5.97–6.02 (m,

2 H), 6.52–6.62 (m, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.27 (d, J =

8.8 Hz, 2 H), 7.36 (dd, J = 11.3, 15.5 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = –4.5 (CH₃), –4.3 (CH₃), –4.2 (CH₃), –4.1

(CH₃), –4.0 (CH₃), –3.7 (CH₃), –3.5 (CH₃), –2.9 (CH₃), 9.2 (CH₃),

13.5 (CH₃), 16.7 (CH₃), 18.1 (C₀), 18.2 (C₀), 18.4 (C₀), 18.9 (CH₃),

20.9 (CH₃), 20.6 (CH₃), 25.8 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 26.2

(CH₃), 29.7 (CH₂), 30.1 (CH), 31.6 (CH₂), 34.3 (CH), 35.1 (CH),

36.1 (CH), 40.5 (CH), 41.0 (CH₂), 43.4 (CH₂), 43.5 (CH), 51.0

(CH₃), 55.3 (CH₃), 66.7 (CH), 72.2 (CH), 72.7 (CH), 75.1 (CH₂),

80.3 (CH), 84.4 (CH), 113.6 (CH), 115.4 (CH), 117.2 (CH₂), 126.8

(CH), 128.9 (CH), 129.0 (CH), 131.3 (CH), 131.4 (C₀), 132.3 (CH),

132.4 (CH), 134.5 (CH), 145.6 (CH), 147.3 (CH), 158.9 (C₀), 166.9

(R,2Z,4E)-Methyl 6-((4S,6S)-6-{(1Z,3R,4S,5S,7S,10R,11S,12S,

13S,14Z)-4,10-Dihydroxy-12-[(4-methoxybenzyl)oxy]-3,5,7,11,13-

pentamethylheptadeca-1,14,16-trien-1-yl}-2,2-dimethyl-1,3-dioxan-

4-yl)hepta-2,4-dienoate (28b-acetonide): A small crystal of PPTS

was added to a solution of 28b-acetonide precursor (6.0 mg,

8.8 μmol) in 2,2-dimethoxypropane (0.45 mL) and DCM (0.1 mL).

The reaction mixture was stirred at room temperature for 2 h, then

quenched with satd. aq. NaHCO₃(5 mL). Phases were separated

and the aqueous layer was extracted with DCM (3ϫ5 mL). The

combined organic extracts were dried with Na₂SO₄and concen-

trated in vacuo. The crude product was purified by flash

chromatography (8:2 hexane/EtOAc) to give 28b-acetonide (6.3 mg,

100% yield) as a colorless oil; R_f= 0.59 (1:1 hexane/EtOAc). ¹H

NMR (400 MHz, CDCl₃): δ = 0.87–0.91 (m, 7 H), 0.94 (d, J =

6.8 Hz, 3 H), 0.96 (d, J = 7.0 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3 H),

1.08 (d, J = 6.9 Hz, 3 H), 1.11–1.15 (m, 1 H), 1.24–1.29 (m, 2 H),

1.33 (s, 3 H), 1.38 (s, 3 H), 1.42–1.50 (m, 3 H), 1.64–1.77 (m, 4 H),

2.63 (dd, J = 7.4 Hz, 16.3, 1 H), 2.70 (br. s, 1 H), 3.04–3.10 (m, 2

H), 3.41 (m, 1 H), 3.65–3.76 (m, 2 H), 3.72 (s, 3 H), 3.79 (s, 3 H),

4.41 (d, J_AB= 10.3 Hz, 1 H, upfield part of an AB system), 4.54

(dd, J = 6.5, 15.6, Hz, 1 H), 4.68 (d, J_AB= 10.3 Hz, 1 H, downfield

part of an AB system), 5.13 (d, J = 10.2 Hz, 1 H), 5.22 (d, J =

16.8 Hz, 1 H), 5.35 (m, 1 H), 5.46 (m, 2 H), 5.61 (d, J = 11.3 Hz,

1 H), 6.08 (m, 2 H), 6.58 (t, J = 11.3 Hz, 1 H), 6.66 (m, 1 H), 6.84

(d, J = 8.6 Hz, 2 H), 7.24 (m, 2 H), 7.39 (m, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 6.7 (CH₃), 14.1 (CH₃), 15.6 (CH₃), 17.3

(CH₃), 18.2 (CH₃), 21.2 (CH₃), 24.4 (CH₃), 25.2 (CH₃), 30.2 (CH),

31.7 (CH₂), 32.4 (CH₂), 32.5 (CH), 35.5 (CH), 35.9 (CH), 36.6

(CH₂), 37.6 (CH₂), 39.0 (CH), 41.6 (CH), 51.1 (CH₃), 55.3 (CH₃),

63.0 (CH), 69.7 (CH), 74.1 (CH₂), 75.2 (CH), 79.1 (CH), 87.6 (CH),

100.7 (C₀), 113.8 (CH), 115.7 (CH), 117.8 (CH₂), 120.3 (CH), 127.0

(CH), 129.5 (CH), 130.3 (CH), 130.9 (C₀), 132.4 (CH), 135.3 (CH),

136.6 (CH), 145.5 (CH), 146.9 (CH), 159.3 (C₀), 166.9 (C₀) ppm.

HRMS (ESI): calcd. for C₄₄H₆₈O₈Na: 747.48064 [M + Na]⁺; found

747.48058.

(C ) ppm. IR (neat): ν = 773, 802, 836, 1005, 1040, 1082, 1174,

˜

0

1251, 1462, 1514, 1602, 1638, 1721, 2855, 2927, 2955 cm^–1. HRMS

(ESI): calcd. for C₆₅H₁₂₀O₈Si₄Na: 1163.79525 [M + Na]⁺; found

1163.79475.

Methyl (2Z,4E,6R,7S,9S,10Z,12R,13S,14S,16S,19R,20R,

21S,22S,23Z)-7,9,13,19-Tetrakis[(tert-butyldimethylsilyl)oxy]-21-hy-

droxy-6,12,14,16,20,22-hexamethylhexacosa-2,4,10,23,25-penta-

enoate (30b): DDQ (5.7 mg, 25 μmol, 1.3 equiv.) was added to a

solution of the PMB ether 29b (22.2 mg, 19.5 μmol, 1 equiv.) in

DCM (0.6 mL) stirred at 0 °C in the presence of 7 μL of a KH₂PO₄/

K₂HPO₄buffer solution (pH = 7). The reaction was stirred at 0 °C

for 1 h before being quenched by dropwise addition of satd. aq.

NaHCO₃(8 mL). After diluting with DCM (18 mL), layers were

separated and the aqueous phase was extracted with DCM

(3 ϫ 10 mL). The combined organic extracts were washed with

brine (2ϫ10 mL), dried with Na₂SO₄and concentrated under re-

duced pressure. The crude product was purified by flash

chromatography (6:4 hexane/DCM) to give the desired product 30b

(17.0 mg, 85% yield) as a colorless oil; R_f= 0.38 (95:5 hexane/

1

EtOAc). H NMR (400 MHz, CDCl₃): δ = 0.02 (s, 3 H), 0.05 (s, 9

H), 0.07 (s, 3 H), 0.09 (s, 6 H), 0.11 (s, 3 H), 0.87–0.94 (m, 11 H),

0.89 (s, 9 H), 0.90 (s, 9 H), 0.91 (s, 9 H), 0.92 (s, 9 H), 0.95 (d, J =

6.7 Hz, 6 H), 1.04 (d, J = 6.8 Hz, 3 H), 1.25–1.34 (m, 3 H), 1.38–

1.44 (m, 2 H), 1.50–1.71 (m, 4 H), 2.35 (br. s, 1 H), 2.53 (m, 1 H),

Methyl (2Z,4E,6R,7S,9S,10Z,12R,13S,14S,16S,19R,20R, 2.63 (m, 1 H), 2.80 (m, 1 H), 3.35 (m, 1 H), 3.48 (dd, J = 2.2,

21S,22S,23Z)-7,9,13,19-Tetrakis[(tert-butyldimethylsilyl)oxy]-21-

7.6 Hz, 1 H), 3.73 (s, 3 H), 3.74–3.78 (m, 1 H), 3.93 (m, 1 H), 4.54

[(4-methoxybenzyl)oxy]-6,12,14,16,20,22-hexamethylhexacosa-

(t, J = 8.8 Hz, 1 H), 5.12 (d, J = 10.3 Hz, 1 H), 5.21 (d, J = 16.9 Hz,

2,4,10,23,25-pentaenoate (29b): 2,6-Lutidine (9 μL, 78 μmol, 1 H), 5.22–5.28 (m, 1 H), 5.42 (t, J = 10.5 Hz, 1 H), 5.56–5.63 (m,

4 equiv.) and TBSOTf (9 μL, 39 μmol, 2 equiv.) were added drop-

wise to a stirred solution of 28b (20.0 mg, 19.5 μmol, 1 equiv.) in

DCM (0.2 mL) cooled to –78 °C. After stirring at –78 °C for 2 h,

the reaction was quenched by adding satd. aq. NaHCO₃(1.5 mL)

dropwise, then it was warmed to room temperature. The mixture

was diluted with DCM (5 mL), layers were separated and the aque-

ous phase was extracted with DCM (3ϫ5 mL). The combined or-

ganic extracts were washed with brine (2 ϫ 5 mL), dried with

Na₂SO₄and evaporated under reduced pressure. The crude product

was purified by flash chromatography (95:5 hexane/EtOAc) to give

1 H), 5.59 (d, J = 11.0 Hz, 1 H), 5.99 (dd, J = 7.1, 15.5 Hz, 1 H),

6.09 (t, J = 11.1 Hz, 1 H), 6.55 (t, J = 11.4 Hz, 1 H), 6.63 (td, J =

10.8, 17.1 Hz, 1 H), 7.36 (dd, J = 11.3, 15.4 Hz, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –4.4 (CH₃), –4.3 (CH₃), –4.2 (CH₃),

–4.1 (CH₃), –4.0 (CH₃), –3.8 (CH₃), –3.7 (CH₃), –2.9 (CH₃), 6.7

(CH₃), 14.1 (CH₃), 15.6 (CH₃), 17.7 (CH₃), 18.0 (C₀), 18.1 (C₀),

18.4 (C₀), 20.7 (CH₃), 21.0 (CH₃), 25.8 (CH₃), 25.9 (CH₃), 26.0

(CH₃), 26.1 (CH₃), 30.9 (CH), 31.0 (CH₂), 31.6 (CH₂), 34.2 (CH),

36.0 (CH), 36.2 (CH), 37.5 (CH), 41.1 (CH₂), 43.4 (CH₂), 43.5

(CH), 51.1 (CH₃), 66.7 (CH), 72.2 (CH), 77.3 (CH), 77.9 (CH),

the desired product 29b (22.2 mg, 100% yield) as a pale yellow oil; 80.2 (CH), 115.4 (CH), 117.7 (CH₂), 126.8 (CH), 129.8 (CH), 131.2

1

R_f= 0.80 (8:2 hexane/EtOAc). [α]²_D⁹= –14.7 (c = 0.4, CHCl₃). H

(CH), 132.3 (CH), 132.5 (CH), 135.4 (CH), 145.6 (CH), 147.3

2658

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Eur. J. Org. Chem. 2011, 2643–2661

Highly Stereoselective Total Synthesis of Dictyostatins

(CH), 166.9 (C₀) ppm. HRMS (ESI): calcd. for C₅₇H₁₁₂O₇Si₄Na: ¹³C NMR (100 MHz, CDCl₃): δ = –4.7 (CH₃), –4.5 (CH₃), –4.0

1043.73773 [M + Na]⁺; found 1043.73677.

(CH₃), –3.9 (CH₃), –3.8 (CH₃), –3.5 (CH₃), –3.2 (CH₃), 9.5 (CH₃),

14.1 (CH₃), 18.0 (C₀), 18.1 (C₀), 18.3 (CH₃), 19.5 (CH₃), 19.8

(CH₃), 20.6 (CH₃), 25.9 (CH₃), 26.2 (CH₃), 31.8 (CH₂), 32.8 (CH),

33.5 (CH), 34.8 (CH), 35.0 (CH), 37.4 (CH₂), 39.0 (CH), 41.2

(CH₂), 42.4 (CH), 45.4 (CH₂), 65.0 (CH), 70.9 (CH), 72.5 (CH),

79.4 (CH), 79.7 (CH), 117.5 (CH), 118.1 (CH₂), 128.9 (CH), 129.6

(CH), 130.0 (CH), 132.0 (CH), 132.1 (CH), 135.6 (CH), 143.1

(CH), 144.7 (CH), 166.5 (C₀) ppm. HRMS (ESI): calcd. for

C₅₆H₁₀₈O₆Si₄Na: 1011.71152 [M + Na]⁺; found 1011.71116.

(2Z,4E,6R,7S,9S,10Z,12R,13S,14S,16S,19R,20R,21S,22S,23Z)-

7,9,13,19-Tetrakis[(tert-butyldimethylsilyl)oxy]-21-hydroxy-

6,12,14,16,20,22-hexamethylhexacosa-2,4,10,23,25-pentaenoic Acid

(31b): To a stirred solution of the ester 30b (17.0 mg, 16.6 μmol,

1 equiv.) in THF (0.8 mL) and EtOH (2.1 mL), KOH (1 n solution

in water, 0.17 mL) was added, and the reaction was refluxed (bath

temperature: 52 °C) for 24 h. The mixture was diluted with Et₂O

(8 mL) and satd. aq. NH₄Cl (3.5 mL); layers were separated and

the aqueous layer was extracted with Et₂O (3ϫ10 mL). The com-

bined organic extracts were dried with Na₂SO₄and evaporated un-

der reduced pressure. The product was purified by flash chromatog-

raphy (9:1 hexane/EtOAc) to afford the seco-acid 31b (16.7 mg,

100% yield) as a colorless oil; R_f= 0.22 (8:2 hexane/EtOAc). ¹H

(3Z,5E,7R,8S,10S,11Z,13S,14R,15S,17S,20R,21S,22S)-22-[(S,Z)-

Hexa-3,5-dien-2-yl]-8,10,14,20-tetrahydroxy-7,13,15,17,21-penta-

methyloxacyclodocosa-3,5,11-trien-2-one (1b): To a solution of

macrolactone 32b (12.5 mg, 12.7 μmol, 1 equiv.) in THF (1.7 mL)

kept at 0 °C in a plastic vial, HF·Py (0.43 mL) was added dropwise

NMR (400 MHz, CDCl₃): δ = 0.02 (s, 3 H), 0.04 (s, 3 H), 0.05 (s, over 2 min, and the solution was allowed to slowly warm to room

3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.09 (s, 6 H), 0.11 (s, 3 H), 0.86

(s, 9 H), 0.86–0.92 (m, 11 H), 0.89 (s, 9 H), 0.91 (s, 9 H), 0.92 (s, 9

temperature. The reaction mixture was stirred for 24 h, then it was

cooled to 0 °C, diluted with EtOAc (9 mL) and quenched with a

H), 0.95 (d, J = 6.7 Hz, 6 H), 1.04 (d, J = 6.8 Hz, 3 H), 1.28–1.44 satd. aq. NaHCO₃solution (9 mL). The layers were separated and

(m, 4 H), 1.51–1.61 (m, 2 H), 1.63–1.72 (m, 3 H), 2.53 (m, 1 H), the aqueous layer was extracted with EtOAc (3ϫ10 mL). The com-

2.63 (m, 1 H), 2.80 (m, 1 H), 3.35 (m, 1 H), 3.48 (dd, J = 2.6 Hz,

7.5, 1 H), 3.76 (m, 1 H), 3.90 (m, 1 H), 4.53 (t, J = 8.9 Hz, 1 H),

5.12 (d, J = 10.3 Hz, 1 H), 5.21 (d, J = 16.8 Hz, 1 H), 5.27 (m, 1

bined organic extracts were dried with Na₂SO₄and evaporated un-

der reduced pressure. The crude product was purified by flash

chromatography (2:8 hexane/EtOAc) to give 1b (4.8 mg, 72% yield)

H), 5.42 (t, J = 10.4 Hz, 1 H), 5.60 (m, 2 H), 6.02–6.11 (m, 2 H), as a white powder; R_f= 0.30 (100% EtOAc). [α]¹_D⁵= –8.4 (c = 0.08,

6.58–6.68 (m, 2 H), 7.34 (dd, J = 11.4 Hz, 15.3, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –4.4 (CH₃), –4.3 (CH₃), –4.2 (CH₃), 0.94 (d, J = 6.8 Hz, 3 H), 0.93–0.97 (m, 1 H), 0.95 (d, J = 6.2 Hz,

–4.0 (CH₃), –3.8 (CH₃), –3.7 (CH₃), –3.0 (CH₃), 6.8 (CH₃), 14.0

3 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.9 Hz, 3 H), 1.09 (t,

(CH₃), 15.8 (CH₃), 17.7 (CH₃), 18.1 (C₀), 18.4 (C₀), 20.6 (CH₃), J = 8.1 Hz, 3 H), 1.13–1.18 (m, 2 H), 1.38–1.49 (m, 3 H), 1.53–

20.9 (CH₃), 25.8 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 26.1 (CH₃), 30.3

1.60 (m, 1 H), 1.63–1.66 (m, 1 H), 1.71–1.85 (m, 3 H), 2.10 (br. s,

CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 0.84 (d, J = 6.5 Hz, 3 H),

(CH), 31.0 (CH₂), 31.6 (CH₂), 34.2 (CH), 36.1 (CH), 36.2 (CH), 1 H), 2.24 (m, 1 H), 2.38 (br. s, 1 H), 2.78 (m, 1 H), 2.96 (dd, J =

37.7 (CH), 41.1 (CH₂), 43.5 (CH), 43.7 (CH₂), 66.7 (CH), 72.3 1.7, 9.0 Hz, 1 H), 3.13 (dt, J = 6.4, 17.2 Hz, 1 H), 3.51–3.55 (m, 1

(CH), 76.8 (CH), 77.8 (CH), 80.1 (CH), 114.8 (CH), 117.7 (CH₂), H), 3.65–3.70 (m, 1 H), 4.79 (dd, J = 11.5, 7.2 Hz, 1 H), 5.00 (d, J

127.0 (CH), 130.0 (CH), 131.4 (CH), 132.3 (CH), 132.4 (CH), 135.3 = 10.4 Hz, 1 H), 5.08 (d, J = 16.8 Hz, 1 H), 5.16 (t, J = 10.5 Hz,

(CH), 147.4 (CH), 148.2 (CH), 169.9 (C₀) ppm. HRMS (ESI): 1 H), 5.38 (t, J = 5.7 Hz, 1 H), 5.49–5.69 (m, 4 H), 5.99 (t, J =

calcd. for C₅₆H₁₀₉O₇Si₄: 1005.72559 [M – H]^–; found 1005.72430.

11.0 Hz, 1 H), 6.23 (t, J = 11.3 Hz, 1 H), 6.61 (dt, J = 10.6, 16.8 Hz,

1 H), 7.45 (dd, J = 11.0, 15.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

C₆D₆): δ = 9.0 (CH₃), 16.4 (CH₃), 17.8 (CH₃), 17.9 (CH₃), 20.1

(CH₃), 20.9 (CH₃), 31.7 (CH₂), 31.9 (CH), 33.0 (CH₂), 33.3 (CH),

34.4 (CH), 36.1 (CH), 36.8 (CH₂), 40.1 (CH), 41.4 (CH₂), 43.6

(CH), 65.6 (CH), 71.4 (CH), 72.3 (CH), 78.7 (CH), 79.7 (CH),

117.8 (CH₂), 118.2 (CH), 128.7 (CH), 130.1 (CH), 132.3 (CH),

133.7 (CH), 134.5 (CH), 134.6 (CH), 142.6 (CH), 145.0 (CH), 166.4

(3Z,5E,7R,8S,10S,11Z,13S,14R,15S,17S,20R,21R,22S)-8,10,14,20-

Tetrakis(tert-butyldimethylsilyloxy)-22-[(S,Z)-hexa-3,5-dien-2-yl]-

7,13,15,17,21-pentamethyloxacyclodocosa-3,5,11-trien-2-one (32b):

To a solution of the seco-acid 31b (16.7 mg, 16.6 μmol, 1 equiv.) in

THF (2 mL) cooled to 0 °C, Et₃N (1 μL, 0.099 mmol, 6 equiv.) and

2,4,6-trichlorobenzoyl chloride (13 μL, 0.083 mmol, 5 equiv.) were

added. The reaction was stirred at 0 °C for 1 h and monitored by

TLC (9:1 hexane/EtOAc; R_f(anhydride) = 0.33) before adding a 4-

DMAP (18.5 mg, 0.165 mmol, 10 equiv.) solution in toluene (8 mL)

at room temperature. The mixture was stirred at room temperature

for 24 h (TLC: 97:3 hexane/EtOAc; R_f(macrolactone) = 0.31) and

the solvent was removed in vacuo. The residue was diluted with

Et₂O (20 mL) and water (14 mL), layers were separated and the

aqueous layer was extracted with Et₂O (3ϫ15 mL). The combined

organic extracts were washed with brine (2ϫ15 mL), dried with

Na₂SO₄and evaporated under reduced pressure. The crude product

was purified by flash chromatography (9:1 hexane/DCM;

R_f(macrolactone) = 0.13) to give macrolactone 32b (12.5 mg, 76%

(C ) ppm. IR (neat): ν = 665, 741, 807, 1018, 1380, 1415, 1461,

˜

0

1600, 1637, 1685, 1709, 2926, 2961, 3380 cm^–1. HRMS (ESI): calcd.

for C₃₂H₅₂O₆Na: 555.36561 [M + Na]⁺; found 555.36660.

Biological Assays: The binding of the ligands to the Paclitaxel bind-

ing site was measured as described previously.^[32]Binding constants

for compounds reversibly displacing Flutax-2 were calculated using

Equigra v5.^[33]Ovarian carcinoma cells A2780 and P-glycoprotein-

overexpressing ovarian carcinoma cells A2780AD were cultured as

described previously.^[34]Cytotoxicity experiments were performed

with the MTT assay modified as described previously.^[35]

Supporting Information (see footnote on the first page of this arti-

cle): Copies of the NMR spectra (¹H, ¹³C) for all new compounds

described in this paper; NOESY experiment on (–)-12,13-bis-epi-

dictyostatin (1b); competition experiments between Flutax-2 and

several ligands for the paclitaxel binding site.

1

yield) as a colorless oil; R_f= 0.31 (97:3 hexane/EtOAc). H NMR

(400 MHz, CDCl₃): δ = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.05 (s, 3 H),

0.07 (s, 3 H), 0.08 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 3 H), 0.12 (s, 3

H), 0.82–0.88 (m, 10 H), 0.90 (s, 9 H), 0.91 (s, 18 H), 0.92 (s, 9 H),

0.97 (d, J = 6.7 Hz, 6 H), 1.02–1.06 (m, 1 H), 1.05 (d, J = 6.9 Hz,

3 H), 1.17–1.43 (m, 4 H), 1.49–1.61 (m, 2 H), 1.68–1-72 (m, 2 H),

1.81 (m, 1 H), 2.31 (m, 1 H), 2.57 (dt, J = 7.0 Hz, 10.8, 1 H), 3.14

(m, 1 H), 3.41–3.47 (m, 2 H), 3.80 (m, 1 H), 4.33 (br. t, 1 H), 5.14–

5.24 (m, 4 H), 5.51–5.59 (m, 3 H), 6.03 (t, J = 11.0 Hz, 1 H), 6.17

(dd, J = 9.5 Hz, 15.4, 1 H), 6.58–6.68 (m, 2 H), 7.26 (m, 1 H) ppm.

Acknowledgments

We thank the Ministero dell’Università e della Ricerca (MIUR)

for financial support (PRIN prot. 2008J4YNJY) and for a PhD

Eur. J. Org. Chem. 2011, 2643–2661

www.eurjoc.org

2659

C. Gennari et al.

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Published Online: March 29, 2011

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2661

Article Doi

Highly stereoselective total synthesis of (+)-9-epi-Dictyostatin and (-)-12,13-Bis-epi-dictyostatin

DOI: 10.1002/ejoc.201100244

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