Novel protoilludane lead structure for veterinary antibiotics: Total synthesis of pasteurestins A and B and assignment of their configurations

FULL PAPER

DOI: 10.1002/ejoc.200800074

Novel Protoilludane Lead Structure for Veterinary Antibiotics: Total Synthesis

of Pasteurestins A and B and Assignment of Their Configurations

Marion Kögl,^[a]Lothar Brecker,^[a]Ralf Warrass,^[b]and Johann Mulzer*^[a]

Dedicated to Professor Udo H. Brinker on the occasion of his 65th birthday

Keywords: Total synthesis / Cyclotrimerization / Antibiotics / Reformatsky reaction / Configurational assignment

Two novel protoilludane sesquiterpenoids, named pasteures-

tins A and B (1 and 2), were disclosed in a recent patent.

These compounds were reported to exhibit strong and selec-

tive activity against some Mannheimia haemolytica strains,

pathogen causatives for bovine respiratory disease. These

properties qualified 1 and 2 as potential lead structures for

new veterinary antibiotics; however, neither the absolute nor

the relative configurations had been determined, nor were

the compounds available any longer. We thus developed to-

tal syntheses of 1 and 2 and clarified their structures and

their biological profiles. Key steps were two [2+2+2]

CpCo(CO)₂-mediated Vollhardt cycloadditions in both syn-

theses, and a tin-mediated asymmetric Reformatsky-type

condensation in the synthesis of 2 with a temperature-de-

pendent product distribution.

Germany, 2008)

structures of the two pasteurestins are each characterized

by a highly strained hydrocyclobutaindane nucleus and an

α,β-unsaturated γ-hydroxy moiety on the six-membered

ring. Pasteurestin B (2) contains five contiguous stereocen-

ters, pasteurestin A (1) four contiguous and one isolated

quarternary stereogenic center. For both compounds, the

relative configurations at C-4a, C-7a, and C-7b were as-

sumed to be the same as in other protoilludanes,^[3]of which

illudol (3; Figure 1)^[4]is representative. The stereocenters at

C-4 and C-6 in 1 and C-4 and C-7 in 2, together with the

absolute configurations, had to be established by total syn-

thesis, which appeared feasible as sufficient spectroscopic

data (¹H and ¹³C NMR, IR, and MS) and the optical rota-

tions were given in the patent. Additionally, this was the

only way to obtain 1 and 2, and also their derivatives, for

biological testing, as discussed in our previous communica-

tion.^[5]

Introduction

The total synthesis of a specific natural product may have

different underlying motives: application of a specific meth-

odology, procurement of biologically interesting material

unavailable in sufficient quantities from the natural source,

or the elucidation of structure and configuration. It is sel-

dom that all these motivations should coincide in one target

structure, and so we were particularly intrigued when we

came across a recent Japanese patent in which two protoil-

ludane sesquiterpenoid metabolites from the basidiomycete

Agrocybe cylindracea Maire K-3793 (Agrocybe aegeritta)

were described.^[1]These two compounds, named pasteures-

tin A and B (1 and 2; Figure 1) were reported to show

strong and selective activity against some Mannheimia hae-

molytica strains, pathogen causatives for bovine respiratory

disease (BRD).^[2]These properties made them interesting as

potential antibiotics in veterinary applications, provided

that the required biological tests could be performed. How-

ever, no material was available any longer; moreover, al-

though the basic carbon skeleton common to 1 and 2 had

been described, neither the relative nor the absolute config-

urations of these compounds had been determined. The

[a] University of Vienna, Institute of Organic Chemistry

Währingerstrasse 38, 1090 Wien, Austria

Fax: +43-142779521

Figure 1. Pasteurestin A (1), pasteurestin B (2), and illudol (3).

E-mail: johann.mulzer@univie.ac.at

Results and Discussion

From Vollhardt’s synthesis of racemic 3^[4c]we concluded

that cobalt-mediated [2+2+2] cycloadditions of enediynes 4

[b] Intervet Innovation GmbH

Zur Propstei, 55270 Schwabenheim, Germany

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org/ or from the author.

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Total Synthesis of Pasteurestin A and B and Assignment of Configurations

and 5 should lead to the tricyclic intermediates 6 and 7,

containing the characteristic carbon skeleton common to 1

and 2 (Scheme 1),^[6]which might be convertible into the

fully functionalized target molecules. From the methodo-

logy point of view, it was interesting to investigate how the

pre-existing stereogenic centers in 4 and 5 would influence

the stereochemical outcomes of the cycloadditions.

Scheme 1. Synthetic plan for pasteurestins A (1) and B (2). TBDPS

= tert-butyldiphenylsilyl; TBS = tert-butyldimethylsilyl.

For the construction of enediyne 4, a substrate-con-

trolled α-alkylation of butyrolactone 8 with bromide 9

(Scheme 2) was envisaged, whereas for enediyne 5 a dia-

stereoselective “Reformatsky-type” aldol addition of bro-

mooxazolidinone 10 to aldehyde 11 was considered.

Scheme 3. Synthesis of enediyne 4. Reagents and conditions: (a)

K₂CO₃, (MeO)₂P(O)CN₂C(O)Me, MeOH, 23 °C, 90%; (b) (i)

nBuLi, TMSCl, THF, –78 °C, (ii) HCl 2 , 23 °C, 95%; (c) NaH,

(EtO)₂P(O)CH₂CO₂Et, THF, 72%; (d) DIBAl-H, THF, –78 °C,

90%; (e) CBr₄, PPh₃, CH₂Cl₂, 0 °C, 84%; (f) 8, LDA, HMPA,

THF, –78 °C, then 9, 71%; (g) DIBAl-H, THF, –78 °C, 95%; (h)

TBDPSCl, DMAP, NEt₃, CH₂Cl₂, 23 °C, 90%; (i) Et₂AlCl,

CH₂Cl₂, –78 °C, 87%; (j) Pb(OAc)₄, CH₂Cl₂, 23 °C, 95%; (k)

K₂CO₃, MeOH, (MeO)₂P(O)CN₂C(O)Me, 23 °C, 71%. HMPA =

hexamethyl phosphoramide; LDA = lithium diisopropylamide; DI-

BAl-H = diisobutylaluminium hydride.

ductive opening of the lactone with DIBAl-H furnished diol

16, which was followed by selective TBDPS protection of

the primary alcohol.^[10]

The bulky TBDPS group was chosen as a potentially ste-

reocontrolling element in the [2+2+2] cycloaddition. The

trityl group was selectively removed with Et₂AlCl, and the

resulting diol 17 was cleaved with Pb(OAc)₄. Chain elong-

ation of the resulting aldehyde to provide the desired alkyne

4 was again accomplished with dimethyl (1-diazo-2-oxopro-

pyl)phosphonate.^[8]

Scheme 2. Retrosynthetic analysis for enediynes 4 and 5. Tr = tri-

phenylmethyl; TMS = trimethylsilyl.

Cobalt-mediated [2+2+2] cycloaddition in toluene, fol-

Allylic bromide 9 was obtained from geranyl acetate in lowed by demetallation with the relatively mild CuCl₂, fur-

five steps (Scheme 3). Specifically, selective epoxidation of nished a 4:3 mixture of the diastereomers 6a and 6b

geranyl acetate and oxidative cleavage of the resulting epox- (Scheme 4). Not surprisingly, the stereogenic center in 4 was

ide with HIO₄·2H₂O led to the known aldehyde 12,^[7]which too remote from the olefin for significant stereoinduction.

was transformed into alkyne 13 by means of a Bestmann– Dienes 6a and 6b were extremely apolar, were not separable

Ohira ethynylation^[8]and subsequent TMS protection of the by column chromatography, and proved to be highly air-

resulting triple bond. Alternatively, Horner–Wadsworth– sensitive. Following Vollhardt’s precedent,^[4c]this mixture of

Emmons olefination with methyl ketone 14, obtained in dienes was treated with lithium in liquid ammonia. We ob-

four straightforward steps from pent-4-yn-1-ol and triethyl served a regioselective reduction of the highly strained C-

phosphonoacetate, led to a mixture of (E) and (Z) isomers 2a–C-3 double bond. Additionally, the phenyl groups of the

15a and 15b in a 3.5:1 ratio and 72% yield. After DIBAl-H TBDPS ether were also hydrogenated. Deprotection with

reduction, the corresponding alcohols could be separated. TBAF delivered the primary alcohols 18a and 18b, which

Bromination of 13 under Appel conditions led to bro- were separable by chromatography. It is interesting to note

5

mide 9. Separately, butyrolactone 8 was prepared in two that an uncommon J_H,Hcoupling of 2.5 Hz between pro-

steps from (R)-glycidol.^[9]Alkylation of 8 with 9 proceeded tons attached to C-3 and C-5 can be observed (Scheme 4);

in 71% yield and high diastereoselectivity (96% de). Re- this is caused by an almost planar system in the hydrindane

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M. Kögl, L. Brecker, R. Warrass, J. Mulzer

FULL PAPER

and the ratio of 21a/21b was now increased to 4:1. Selen-

ation at C-3 produced a mixture of diastereomers that was

treated with H₂O₂under weakly acidic conditions to fur-

nish enoates 22a and 22b, which could be separated.

Diastereomer 22a was reduced with CeCl₃·7H₂O and

NaBH₄in MeOH (Scheme 6) to give allylic alcohol 23 as a

single isomer. This was desilylated with HF·pyridine and

hydrolyzed with LiOH in THF/H₂O to give the target com-

pound pasteurestin A (1). The high stereocontrol in the re-

duction step is amazing and must be due to prior complex-

ation of 22a with CeCl₃·7H₂O, since C-4–OH mixtures were

obtained with Red-Al in the synthesis of illudol.^[4]We as-

sume that the cerium complex is formed between the C-4

carbonyl and the C-3 ester groups on the less hindered exo

face, so that the hydride attacks from the more hindered

endo face.

Scheme 4. [2+2+2] Cycloaddition and functionalization of dienes

6a and 6b. Reagents and conditions: (a) CoCp(CO)₂, toluene, re-

flux, then CuCl₂·2H₂O, DME, 23 °C, 46%; (b) Li (excess), NH₃,

tBuOH, THF, –78 °C, 85%; (c) TBAF, THF, 23 °C, 95%; HPLC

separation; (d) TBSCl, imidazole, DMF, 23 °C, 90%. Cp = cyclo-

pentadienyl; DME = 1,2-dimethoxyethane; TBAF = tetrabutylam-

monium fluoride.

nucleus of compound 18. Diastereomer 18a was then pro-

tected to give TBS ether 19, which was subjected to further

functionalization.

Next, an oxygen function at C-4 was introduced by hy-

droboration. All attempts to use bulky reagents for stereo-

selective hydroboration were unsuccessful, resulting in the

total recovery of the starting material. With diborane, after

oxidation with H₂O₂, we obtained two diastereomeric

Scheme 6. Endgame in the synthesis of pasteurestin A (1). Reagents

and conditions: (a) NaBH₄, CeCl₃·7H₂O, MeOH, 87%; (b) (i)

HF·Py, THF, 23 °C; (ii) LiOH, H₂O/THF, 23 °C, 55%. Py = pyr-

idine.

The determination of the relative configuration was ac-

alcohols, which were treated with Dess–Martin periodinane complished by H, ¹³C, and 2D (COSY, NOESY, HMBC,

to give a 2:1 mixture of ketones 20a and 20b in high yield HSQC) NMR spectroscopy, and showed that all data are

(Scheme 5). The next steps required the introduction of the in accord with those reported in the patent. The absolute

carboxy group to form the corresponding β-oxo ester. The configuration and the optical purity were confirmed by

use of methyl cyanoformate (“Mander’s reagent”), deliv- comparison of the optical rotation of our synthetic material

ered – probably because of the sterically demanding cyclo- with the literature value.

1

butane in the β-position – a 1:2 mixture of O- and C-car-

We next turned to the total synthesis of the closely re-

boxylated products.^[11]However, carboxylation of the enol- lated pasteurestin B (2). In order to investigate the stereose-

ate anion with carbon dioxide^[4b,4c][followed by methyl- lectivity of the cobalt-mediated cycloaddition, a racemic

ation with (trimethylsilyl)diazomethane] gave a mixture of enediyne (28) was synthesized as test substrate (Scheme 7).

β-oxo esters 21a and 21b in 55% yield. Unreacted starting For the construction of allylic alcohol 26, we chose a vinyl-

material was recycled, so that the combined yield was in- lithium addition to aldehyde 24.^[12]Vinyl iodide 25 was ob-

creased to 75%. The configuration of bridgehead center C- tained from carboalumination of TBS-protected pent-4-yn-

4a was equilibrated by treatment with 2.5 equiv. of LDA, 1-ol with ZrCpCl₂/Me₃Al/I₂.^[13]Addition of 25 to aldehyde

Scheme 5. Functionalization of the six-membered ring. Reagents and conditions: (a) (i) BH₃, THF, 23 °C, then K₂CO₃, H₂O₂, reflux, (ii)

DMP, CH₂Cl₂, 23 °C, 74%; (b) LDA, HMPA, THF, –78 °C, then CO₂(excess), –58 °C, then 1  HCl, 23 °C, then TMSCHN₂, 0 °C,

55%, 75% (based on recovered starting material); (c) (i) LDA, PhSeCl, THF, –78 °C, (ii) NH₄Cl, H₂O₂, H₂O/CH₂Cl₂, 0 °C, 50%. DMP

= Dess–Martin periodinane.

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Total Synthesis of Pasteurestin A and B and Assignment of Configurations

24 furnished the desired allylic alcohol 26 in 56% yield

(Scheme 7). Further functionalization included MOM pro-

tection, TBS and TMS deprotection with TBAF, and Dess–

Martin periodinane oxidation. Finally, C₁homologation

with dimethyl (1-diazo-2-oxopropyl)phosphonate^[8]gave the

racemic enediyne 28, which was heated at reflux under irra-

diation with CoCp(CO)₂in degassed toluene. The air-sensi-

tive cycloadduct 29 was isolated in diastereomerically pure

form. This result encouraged us to repeat the sequence with

enantiomerically enriched enediyne 5.

Scheme 8. Mukaiyama aldol reaction. Reagents and conditions: (a)

(i) 33, THF, DCM, room temp., (ii) 11, DCM, –78 °C, (iii) 30,

DCM, –78 °C, 89%; (b) (i) 11, 30, DCM, –78 °C, (ii) 33, DCM,

room temp., 75%; (c) (S)-Mosher’s acyl chloride, pyridine, DCM,

0 °C, 70%. Ts = p-toluenesulfonate.

adduct, presumably driven by a Thorpe–Ingold effect.

Interestingly, though, acyclic product 36 was obtained ex-

clusively with SmI₂at –78 °C. We were interested in finding

out whether the rearrangement of 36 into 38 depends on

the metal or can generally be suppressed at low tempera-

tures. Under Sn⁰mediation at –78 °C, again only the de-

sired acyclic product 36 was obtained in good yields. Be-

cause of the efficiency of the reaction and the low cost of

the reagents, these reaction conditions were applied to sub-

strates 10 and 11.

Scheme 7. Cyclotrimerization of test substrate 28. Reagents and

conditions: (a) 25, tBuLi, –78 °C to 0 °C, then 24, –78 °C to room

temp., 56%; (b) (i) MOMCl, DIPEA, CH₂Cl₂, (ii) TBAF, THF,

80%; (c) (i) DMP, CH₂Cl₂, room temp., (ii) K₂CO₃, MeOH, (MeO)

₂P(O)CN₂C(O)Me, 23 °C, 92%; (d) CoCp(CO)₂, toluene, reflux,

then CuCl₂·2H₂O, DME, 23 °C, 43%. MOM = methoxymethyl;

DIPEA = diisopropylethylamine.

Table 1. Reformatsky reaction with test substrates 34/35. Bn = ben-

zyl; M = metal; Ln = ligand.

In our first approach to the optically active form of ene-

diyne 5, we applied the Kiyooka–Mukaiyama aldol reac-

tion (Scheme 8).^[14]Hence, ketene acetal 30 was added to a

mixture of aldehyde 11 and oxazaborolidinone 33, pre-

viously prepared in situ from diborane and N-tosyl--val-

ine. Under these conditions, a ca. 4:1 mixture of (E) and

(Z) isomers 31a and 31b was obtained. In order to avoid

the isomerization of aldehyde 11, reagent 33 was added to

a mixture of 11 and 30, and, indeed, the (E) isomer 31a was

formed exclusively. However, the conversion of alcohol 31a

into its Mosher ester 32 gave an unacceptably low ee of

41%.

We thus switched to Reformatsky-type aldol reactions.

Many versions of this reaction with different metals com-

bined with chiral auxiliaries can be found in the litera-

ture.^[15]The reaction was first tested with (bromoacyl)ox-

azolidinone 34, easily available in one step from the (4R)-

benzyloxazolidinone,^[16]and geranial (35) (Table 1). By

analogy with the literature precedent with Cr^IIas the reduc-

ing metal at ambient temperature, an (S) configuration at

C-3 was expected. However, we did not isolate the desired

acyclic alcohol 36, but only the unwanted 1,3-oxazine-2,6-

dione 38. The same product was also obtained under Sn⁰

mediation at ambient temperature.^[17]The formation of 38

Entry

Metals and solvents

Temperature Product^[a]Yield

1

2

3

4

5

CrCl₂, LiI, THF

CrCl₂, LiI, THF, DMF

SnCl₂, LiAlH₄, THF

SmI₂, THF

23 °C

38

36

25%

70%

85%

75%

30%

23 °C

–78 °C

[a] The configurations at C-3 in 36 and C-6 in 38 were not deter-

might be explained by a rearrangement of the primary aldol mined. All compounds were formed in Ͼ99% de.

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Scheme 9. Reformatsky reaction. Reagents and conditions: (a) (i) SnCl₂, LiAlH₄, THF, 23 °C; (ii) 10, –78 °C; (iii) 11, –78 °C, 78 %.

Aldehyde 11 was obtained by oxidation of the corre- of a Wittig reaction failed (Scheme 11).^[21]This might be

sponding allylic alcohol 13 by the Swern protocol. Re- due to a migration of the silyl moiety to the hydroxy group

duction of 10 with highly active Sn metal generated the Sn^IIat C-1 under basic conditions.

enolate, which was treated with aldehyde 11 at –78 °C

(Scheme 9). The desired (3S) adduct 40 was obtained with

Ͼ99% de and with complete retention of the (E)-alkene ge-

ometry in 78% yield. The stereochemical outcome is the

opposite of that reported for additions at ambient reaction

temperatures.^[17]We think that this discrepancy might be

interpreted by assuming that a fully complexed transition

state 39 (Nerz–Stormes–Thornton model)^[18]is adopted at

low temperature (i.e., in our case), whereas the uncom-

plexed Pridgen-type transition state prevails at ambient

temperature.^[19]Anyway, alcohol 40 was protected as a TBS

ether. Initial attempts to remove the auxiliary with LiBH₄

resulted in a mixture of products: the hydride attacked not

Scheme 11. Pantolactone approach. Reagents and conditions: (a)

(i) isopropenylMgBr, THF, 0 °C; (ii) Ac₂O, NEt₃, DMAP, CH₂Cl₂,

23 °C, 80%; (b) LDA, TMSCl, –78 °C to 23 °C, 69%; (c) DIC,

NEt₃, MeHNOMe·HCl, CH₂Cl₂, 23 °C, 98%. DMAP = 4-(dimeth-

ylamino)pyridine, LDA = lithium diisopropylamide; DIC = N,NЈ-

diisopropylcarbodiimide; PMP = p-methoxyphenyl.

only the amide, but also the oxazolidinone carbonyl group.

This problem could be circumvented by preparing thioester

41 (Scheme 10),^[20]which was reduced to aldehyde 42 with

DIBAl-H in 75% yield.

(R)-Pantolactone was therefore converted into the

known aldehyde 46,^[22]which was treated with isopropen-

ylmagnesium bromide to afford a 4:1 diastereomeric mix-

ture of alcohols. These were subsequently converted into

their acetates 47. Claisen–Ireland rearrangement of this

mixture, followed by conversion of the resulting carboxylic

acid into the Weinreb amide 48 and final reduction, deliv-

ered the corresponding aldehyde (Scheme 12).^[23]A Colvin

reaction gave alkyne 49. After TMS protection of the re-

sulting triple bond, the acetal was removed under acidic

conditions, and the resulting diol was protected as the

bis(TBS) ether 50. The primary TBS ether could be selec-

tively cleaved under the conditions reported by Evans.^[24]

The alcohol was then oxidized to provide the aldehyde 42,

which was identical in all respects to the product obtained

from the Reformatsky approach.

Scheme 10. Synthesis of the enediyne 5. Reagents and conditions:

(a) TBSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 95%; (b) nBuLi, EtSH,

THF, 0 °C, 89%; (c) DIBAl-H, CH₂Cl₂, –78 °C, 75 % (+15 %

alcohol); (d) MeOCH₂PPh₃Cl, nBuLi, 0 °C, then HCl 2 , 23 °C,

60%; (e) K₂CO₃, (MeO)₂P(O)CN₂C(O)Me, MeOH, 23 °C, 94 %.

Tf = trifluoromethanesulfonate.

Enediyne 5 furnished diene 7 as the sole product by the

C₁

homologation

with

(methoxymethylidene)tri- previously described cobalt-mediated [2+2+2] cycload-

phenylphosphane, followed by hydrolysis of the enol ether, dition in toluene. The proximity of the stereogenic center

gave aldehyde 43. Finally, Bestmann–Ohira treatment of 43 not surprisingly led to high asymmetric induction

furnished enediyne 5, ready for [2+2+2] cyclotrimerization. (Scheme 13). Functionalization of the six-membered ring

The absolute configuration of the stereogenic center in was accomplished as described above. Regioselective Birch

enediyne 5 was confirmed by an unambiguous formal syn- reduction delivered olefin 51. Again, the β-face of the al-

thesis from (R)-pantolactone. Initial attempts to prepare kene is less hindered in the hydroboration with diborane;

olefin 45 from the TBS-protected pantolactol 44 by means we thus obtained, after oxidation, an inseparable 2:1 mix-

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Total Synthesis of Pasteurestin A and B and Assignment of Configurations

Scheme 12. Pantolactone approach II. Reagents and conditions: (a) (i) DIBAl-H, THF, –78 °C, 95%; (ii) TMSCHN₂, nBuLi, THF,

–78 °C, 67%; (b) nBuLi, TMSCl, THF, –78 °C, 95%; (c) (i) 80% AcOH, THF, (ii) TBSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 91%; (d) HF·Py,

THF, 23 °C, 65%; (e) DMP, CH₂Cl₂, 23 °C, 92 %.

1

ture of diastereomeric alcohols favoring the syn configura-

The relative configuration of 2 was assigned by H and

tion of the bridgehead protons. We carried on with the dia- ¹³C NMR and 2D NMR analysis (COSY, NOESY, HMBC,

stereomeric mixture, hoping for separation at a later stage HSQC), and our spectroscopic data again match those re-

of the synthesis. Oxidation of the alcohols with Dess–Mar- ported for pasteurestin B (2). The absolute configuration

tin periodinane gave an epimeric mixture of ketones 52a was corroborated by comparison of the optical rotations.

and 52b. Methoxycarbonylation of C-2 with carbon dioxide

Screening against a wide variety of bacteria showed that

followed by methylation with (trimethylsilyl)diazomethane pasteurestin A (1) and pasteurestin B (2) exhibited millimo-

furnished esters 53a and 53b.

lar activity and high selectivity for some versatile patho-

genic Pasteurella multocida strains (for details see Support-

ing Information). ent-Pasteurestin B was also synthesized

by the Reformatsky aldol route starting from (4R)-benzyl-

oxazolidinone. This compound did not show any significant

antibacterial activity under the test conditions.

Conclusions

We have completed the first total synthesis of pasteures-

tin A (1) in 22 steps over the longest linear sequence in

0.43% overall yield and of pasteurestin B (2) in 20 steps

over the longest linear sequence in an overall yield of

0.78%. By doing so, we were able to elucidate the absolute

and relative configurations of both compounds. Thanks to

the functionalization of the six-membered ring at a very

late stage, this versatile and flexible approach towards both

target compounds should allow the preparation of suitable

analogues for further biological testing. They should con-

tribute to the assignment of the mode of action and help in

determining the pharmacophore.

Scheme 13. [2+2+2] cycloaddition and functionalization of diene

7. Reagents and conditions: (a) CoCp(CO)₂, toluene, reflux, then

CuCl₂·2H₂O, DME, 23 °C, 40%; (b) Li (excess), NH₃, tBuOH,

THF, –78 °C, 85%; (c) (i) BH₃, THF, 23 °C, then K₂CO₃, H₂O₂,

THF/H₂O, reflux, (ii) DMP, CH₂Cl₂, 23 °C, 74%; (d) LDA,

HMPA, THF, –78 °C, then CO₂(excess), –58 °C, then 1  HCl,

23 °C, then TMSCHN₂, 0 °C, 45%, 75% (based on recovered start-

ing material); (e) (i) LDA, PhSeCl, THF, –78 °C, (ii) NH₄Cl, H₂O₂,

H₂O/CH₂Cl₂, 0 °C, 45 %.

Selenation with an excess of LDA/HMPA and addition

of phenylselenyl chloride, followed by subjection to H₂O₂

under acidic conditions, was obviously accompanied by epi-

merization at C-4a, and the syn epimer 54 was formed ex-

clusively. Ketone reduction with CeCl₃·7H₂O and NaBH₄

in MeOH delivered alcohol 55 as a single isomer. Desi-

lylation with HF·pyridine and subsequent hydrolysis pro-

vided pasteurestin B (2; Scheme 14).

Experimental Section

General Remarks: ¹H and ¹³C NMR spectra were measured in

CDCl₃at 300 K with Bruker Avance DRX 400 or DRX 600 instru-

ments at 400.13 MHz (100.61 MHz) or 600.13 MHz (150.90 MHz),

respectively. Chemical shifts were referenced to residual CHCl₃(δ_H

= 7.26 ppm) and CDCl₃(δ_C= 77.36 ppm). All chemical shifts are

given in ppm, all coupling constants in Hz. Assignments of proton

resonances were confirmed by two-dimensional homo- and hetero-

nuclear spectroscopy. IR spectra were recorded as thin films on a

silicon disc with a Perkin–Elmer 1600 FT-IR spectrometer. Mass

spectra were measured with a Fisons Instruments Micro mass,

trio 200. High-resolution mass spectra (HRMS) were performed

with a Finnigan MAT 8230 with a resolution of 10000. Optical

rotations were measured at 20 °C with a Perkin–Elmer 351 polari-

meter in a 1 dm cell. Reaction progress was checked on precoated

TLC plates (Merck Kieselgel 60 F₂₅₄). Spots were visualized under

Scheme 14. Endgame in the synthesis of pasteurestin B (2). Rea-

gents and conditions: (a) NaBH₄, CeCl₃·7H₂O, MeOH, 23 °C,

90%; (b) (i) HF·Py, THF, 23 °C, (ii) LiOH, H₂O/THF, 23 °C, 59 %.

Eur. J. Org. Chem. 2008, 2714–2730

www.eurjoc.org

2719

M. Kögl, L. Brecker, R. Warrass, J. Mulzer

FULL PAPER

254 nm UV light and/or by dipping the TLC plate into a solution

of (NH₄)₆Mo₇O₂₄·4H₂O (20 g) and CeSO₄·7H₂O (0.5 g) in H₂SO₄

(10%, 400 mL) followed by heating with a heat gun. Column

chromatography was performed with Merck silica gel 60 (230–

400 mesh). Analytical HPLC was performed with a Jasco System

(PU-980 pump, UV 975 and RI 930) instrument with a Nucleo-

sil 50 column (5 µm, ø 4ϫ241 mm) at ambient temperature. Pre-

parative HPLC was performed with a Dynamix Model SD-1 fitted

with a Model UV-1 absorbance detector with Supersphere (60 Å

pore size, 4 µm particle size, ø 25ϫ250 mm) at ambient tempera-

ture. All solvents were distilled prior to use. THF and Et₂O were

distilled from sodium/benzophenone, toluene from sodium. CH₂Cl₂

was dried with P₂O₅. DMF, NEt₃, iPr₂NH, iPr₂NEt, and 2,6-luti-

dine were distilled from CaH₂. All reactions were performed under

argon with use of oven-dried glassware and standard syringe/septa

techniques.

were removed in vacuo, and the residue with traces of Ph₃PO was

adsorbed on silica gel and purified by flash column chromatog-

raphy (hexane/ethyl acetate, 50:1) to give the desired allylic bromide

1

9 (6.7 g, 26 mmol, 84%). R_f(hexane) = 0.7. H NMR (400 MHz,

CDCl₃): δ = 5.58 (dt, J = 1.2, 8.4 Hz, 1 H), 4.00 (d, J = 8.4 Hz, 2

H), 2.36 (t, J = 6.8 Hz, 2 H), 2.24 (t, J = 6.8 Hz, 2 H), 1.74 (s, 3

H), 0.14 (s, 9 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 141.8

(C), 122.1 (CH), 106.6 (C), 85.6 (C), 38.4 (CH₂), 29.3 (CH₂), 18.9

(CH₂), 16.5 (CH₃) 0.5 (3ϫC) ppm.

(4S)-2-Methyl-4-[(trityloxy)methyl)]-4-butanolide (8a, 8b): nBuLi

(2.5  in hexanes, 108.4 mL, 271 mmol) was added at 0 °C to a

solution of diisopropylamine (27.4 g, 37.9 mL, 271 mmol) in THF

(400 mL). After the mixture had been stirred at 0 °C for 30 min,

propionic acid (130 mmol, 9.7 mL) was slowly added. After the

mixture had been stirred at 0 °C for 30 min and subsequently at

room temp. for 1 h, a white precipitate had formed. The mixture

was then cooled to –78 °C, and a solution of (S)-(trityloxymethyl)

oxirane (24.0 g, 65 mmol) in THF (100 mL) was added. The reac-

tion mixture was stirred at –78 °C for 3 h and was then allowed to

warm to room temp. overnight. The reaction mixture was diluted

with Et₂O and poured into satd. aq. NaHCO₃. The phases were

separated, and the organic layer was washed extensively with four

70 mL portions of NaHCO₃. The combined aqueous layers were

carefully acidified to pH ≈ 3 with HCl (2 ), and the cloudy aque-

ous phase was then washed with three portions of CH₂Cl₂(50 mL).

The combined organic phases were washed with brine, dried with

MgSO₄, filtered, and concentrated under reduced pressure. The res-

idue was then dissolved in toluene and heated to reflux in a Dean–

Stark trap for 2 h. After removal of the solvents, purification by

flash column chromatography (hexane/ethyl acetate, 6:1) delivered

a diastereomeric mixture of lactones 8a and 8b (dr = 1:1, 5.7 g,

50.7 mmol, 78%) as white crystals. M.p. 133–135 °C. IR (thin film):

(2E)-3-Methyl-7-trimethylsilylhept-2-en-6-yn-1-ol (13): Dimethyl (1-

diazo-2-oxopropyl)phosphonate (11.2 g, 58.6 mmol) was added at

0 °C to a solution of aldehyde 12 (10.0 g, 58.6 mmol) and K₂CO₃

(16.2 g, 117 mmol) in MeOH (500 mL). After the reaction mixture

had been allowed to warm to room temp., stirring at the same

temperature was continued for 8 h. At this point, aq. NaHCO₃

(5%, 150 mL) was added to the reaction mixture, and MeOH was

removed under reduced pressure. After addition of Et₂O (300 mL),

the phases were separated and the aqueous phase was extracted

twice with Et₂O (50 mL). The combined organic phases were

washed with brine and dried with MgSO₄, and after filtration and

evaporation of the volatiles, a yellow oil was obtained. Purification

by flash column chromatography, with elution with hexane/ethyl

acetate (6:1), delivered the desired alcohol as a colorless oil (6.5 g,

52.7 mmol, 90%). R_f(hexane/ethyl acetate, 2:1) = 0.2. ¹H NMR

(400 MHz, CDCl₃): δ = 5.46 (dt, J = 6.5, 1.2 Hz, 1 H), 4.15 (t, J

= 6.5 Hz, 2 H), 2.29 (m, 4 H), 1.92 (t, J = 2.6 Hz, 1 H), 1.69 (d, J ν = 1772, 1490, 1449, 1172, 1034, 707 cm^–1. HRMS: calcd. for

˜

= 0.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 138.3 (C), [M]⁺372.1725; found 372.1710. Diastereomer 8a: R_f(hexane/ethyl

1

124.9 (CH), 85.4 (C), 70.3 (CH), 59.6 (CH₂), 38.7 (CH₂), 19.2

(CH ), 16.5 (CH ) ppm. IR (thin film): ν = 3350 (br.), 3290, 3030,

acetate, 4:1) = 0.2. H NMR (400 MHz, CDCl₃): δ = 7.36 (m, 15

H), 4.60 (m, 1 H), 3.28 (m, 2 H), 2.68 (m, 1 H), 2.38 (m, 1 H), 1.70

(m, 1 H), 1.29 (d, J = 7.36 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 179.8 (C), 143.9 (3ϫC), 129.1 (3ϫCH), 128.4

(6ϫCH), 127.6 (6ϫCH), 87.2 (C), 77.5 (CH), 65.7 (CH₂), 35.7

(CH), 33.5 (CH₂), 16.7 (CH₃) ppm. Diastereomer 8b: R_f(hexane/

ethyl acetate, 4:1) = 0.3. ¹H NMR (400 MHz, CDCl₃): δ = 7.36 (m,

15 H), 4.52 (m, 1 H), 3.43, 3.13 (AB system, J = 10.4, 4.1 Hz, 2 H,

dd), 2.90 (m, 1 H), 2.29 (m, 1 H), 1.93 (m, 1 H), 1.29 (d, J =

7.36 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 179.8 (C),

143.9 (3ϫC), 129.0 (3ϫCH), 128.3 (6ϫCH), 127.6 (6ϫCH), 87.2

(C), 77.0 (CH), 65.4 (CH₂), 34.5 (CH), 32.9 (CH₂), 15.7 (CH₃)

ppm.

˜

2

3

2920, 2110, 1665, 1440, 1000 cm^–1. nBuLi (2.5  in hexanes, 58 mL,

145.1 mmol) was added dropwise to a solution of the alcohol ob-

tained above (8.2 g, 66.1 mmol) in THF (100 mL), followed after

stirring for 30 min by TMSCl (15.7 g, 145.0 mmol). After comple-

tion of the reaction, HCl (2 , 50 mL) was added, and the reaction

mixture was stirred for 30 min. Et₂O (50 mL) was then added, the

phases were separated, and the aqueous phase was washed three

times with Et₂O (20 mL). The combined organic phases were

washed with satd. aq. NaHCO₃and brine, dried with MgSO₄, and

filtered. After removal of the solvents, the yellow liquid was puri-

fied by flash column chromatography (hexane/ethyl acetate, 6:1),

and the desired alcohol 13 (12.2 g, 62.7 mmol, 95%) was obtained

as a colorless liquid. R_f(hexane/ethyl acetate 2:1) = 0.24. ¹H NMR

(400 MHz, CDCl₃): δ = 5.46 (t, J = 6.5 Hz, 1 H), 4.15 (t, J =

6.5 Hz, 2 H), 2.36 (t, J = 6.8 Hz, 2 H), 2.24 (t, J = 6.8 Hz, 2 H),

1.69 (s, 3 H), 0.14 (s, 9 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 138.3 (C), 124.9 (CH), 107.1 (C), 85.4 (C), 59.6 (CH₂), 38.7

(2R,4S)-2-Methyl-2-[(2E)-3-methyl-7-(trimethylsilyl)hept-2-en-6-

ynyl]-5-(trityloxy)pentane-1,4-diol (16): nBuLi (2.5 , 10 , 25 mmol)

was added at 0 °C to a solution of iPr₂NH (3.5 mL, 25 mmol) in

THF (60 mL). After the mixture had been stirred for 30 min,

HMPA (4.4 mL, 25 mmol) was added, and the mixture was cooled

to –78 °C. A solution of lactones 8a and 8b (9.5 g, 25 mmol) in

THF (20 mL) was added dropwise over 30 min, and the mixture

was stirred at –78 °C for 2 h. Allylic bromide 9 (5.0 g, 25 mmol) in

THF (10 mL) was then added slowly at the same temperature, and

(CH ), 19.2 (CH ), 16.5 (CH ) 0.5 (3ϫC) ppm. IR (thin film): ν =

˜

2

3

3340 (br.), 2940, 2160, 1245, 1030, 1000 cm^–1.

(2E)-1-Bromo-3-methyl-7-(trimethylsilyl)hept-2-en-6-yne (9):

A

solution of CBr₄(11.2 g, 34 mmol) in CH₂Cl₂(30 mL) was added the mixture was stirred at –78 °C for 4 h. The reaction was

dropwise at 0 °C to a solution of triphenylphosphane (17.7 g,

67 mmol) in CH₂Cl₂(100 mL). After the mixture had been stirred

for 10 min, 13 (6.0 g, 31 mmol) in CH₂Cl₂(30 mL) was added, and

the solution was allowed to warm to room temp. After the mixture

had been stirred for 1 h, the phosphonium salts were precipitated

with pentane (150 mL) and filtered off through Celite. The solvents

quenched with satd. aq. NH₄Cl, and the mixture was diluted with

Et₂O (100 mL). The aqueous phase was extracted three times with

Et₂O (50 mL). The combined organic phases were washed with

satd. aq. NaCl, dried with MgSO₄, and concentrated under reduced

pressure. Purification by flash column chromatography (hexane/

ethyl acetate, 10:1) gave the desired product (9.80 g, 17.8 mmol,

2720

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Eur. J. Org. Chem. 2008, 2714–2730

Total Synthesis of Pasteurestin A and B and Assignment of Configurations

71%) as a colorless oil. R_f(hexane/ethyl acetate, 4:1) = 0.47. [α]²_D⁰

2857, 2172, 1491, 1472, 1450, 1428, 1249, 1113, 1077, 998, 908, 842,

1

= +2.1 (c = 2.8, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 7.46 760, 740 cm^–1. HRMS: calcd. for [M]⁺793.2338; found 793.2328.

(m, 5 H), 7.28 (series of m, 10 H), 5.21 (dd~t, J = 6.3 Hz, 1 H), Et₂AlCl (1.8  in toluene, 13.4 mL, 24.2 mmol) was added drop-

4.51 (m, 1 H), 3.29 (dd, J = 10.4 Hz, 3.7 Hz, 1 H), 3.20 (dd, J =

wise at –78 °C to a solution of the alcohol obtained above (9.6 g,

10.4 Hz, 5.1 Hz, 1 H), 2.31 (m, 3 H), 2.23 (m, 3 H), 2.15 (dd, J = 12.1 mmol) in CH₂Cl₂(300 mL). After 4 h at –78 °C, the reaction

13.0 Hz, 7.12 Hz, 1 H), 1.83 (dd, J = 13.0 Hz, 9.2 Hz, 1 H), 1.69

(s, 3 H), 1.26 (s, 3 H), 0.13 (s, 9 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 181.4 (C), 143.5 (3ϫC), 138.1 (C), 128.6 (6ϫCH),

127.9 (6ϫCH), 127.2 (3ϫCH), 119.3 (CH), 106.8 (C), 86.8 (C),

was quenched by the addition of satd. aq. NaHCO₃, warmed up,

and stirred for 15 min. After addition of potassium sodium tartrate

solution (100 mL), the mixture was vigorously stirred overnight.

The layers were then separated, and the aqueous phase was ex-

84.9 (C), 75.9 (CH), 65.1 (CH₂), 44.1 (C), 38.67 (CH₂), 36.1 (CH₂), tracted four times with CH₂Cl₂(25 mL). The combined organic

35.9 (CH₂), 23.6 (CH₃), 19.1 (CH₂), 16.2 (CH₃), 0.1 (3ϫCH₃) ppm. layers were washed with brine, dried with magnesium sulfate, and

IR (thin film): ν = 3058, 2961, 2872, 2172, 1773, 1490, 1449, 1249,

filtered. After concentration under reduced pressure, the crude

product was purified by flash column chromatography (hexane/

ethyl acetate, 10:1 Ǟ 1:1) to yield 17 (5.8 g, 10.5 mmol, 87%) as a

colorless oil. R_f(hexane/ethyl acetate, 1:1) = 0.15. [α]²_D⁰= –6.1 (c =

2.4, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (m, 6 H), 7.43

(m, 4 H), 5.03 (dd~t, J = 7.0 Hz, 1 H), 3.87 (m, 1 H), 3.53 (dd, J

= 10.8, 3.6 Hz, 1 H), 3.48 (s, 2 H), 3.43 (dd, J = 10.8, 7.6 Hz, 1

H), 2.20 (m, 2 H), 2.11 (m, 3 H), 1.84 (dd, J = 14.3, 7.2 Hz, 1 H),

1.55 (s, 3 H), 1.45 (m, 2 H), 1.09 (s, 9 H), 0.74 (s, 3 H), 0.10 (s, 9

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 136.3 (4ϫCH), 136.2

(C), 133.1 (C), 133.0 (C), 130.3 (2ϫCH), 128.2 (4ϫCH), 121.2

(CH), 107.6 (C), 84.9 (C), 71.8 (CH₂), 68.6 (CH), 68.1 (CH₂), 42.3

(CH₂), 39.2 (CH₂), 38.9 (C), 34.1 (CH₂), 27.4 (3 ϫ CH₃), 24.2

(CH₃), 19.6 (CH₂), 19.5 (C), 16.5 (CH₃), 0.5 (3ϫCH₃) ppm. IR

˜

1185, 1157, 1103, 1053, 1002, 982, 912 cm^–1. HRMS: calcd for

[M]⁺550.2903; found 550.2912. DIBAl-H (1.5  in toluene,

28.9 mL, 43 mmol) was added at –78 °C to a solution of the lactone

obtained above (9.5 g, 17 mmol) in THF (100 mL), and the reac-

tion mixture was warmed to 0 °C. After 4 h, TLC monitoring

showed complete conversion to the diol, the reaction was quenched

with satd. aq. sodium potassium tartrate solution (30 mL), and the

mixture was vigorously stirred overnight. After dilution with Et₂O

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

tracted four times with Et₂O (25 mL). The combined organic layers

were washed with brine, dried with magnesium sulfate, and filtered.

After concentration under reduced pressure, the crude product was

purified by column chromatography (hexane/ethyl acetate, 4:1) to

yield the desired diol 16 (8.9 g, 16.1 mmol, 95%). R_f(hexane/ethyl

acetate, 4:1) = 0.58. [α]²_D⁰= +4.7 (c = 2.8, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 7.46 (m, 5 H), 7.28 (series of m, 10 H),

5.18 (dd~t, J = 7.4 Hz, 1 H), 3.94 (m, 1 H), 3.46 (d, J = 11.4 Hz,

1 H), 3.30 (d, J = 11.4 Hz, 1 H), 3.05 (m, 2 H), 2.28 (m, 2 H), 2.19

(m, 2 H), 2.05 (dd, J = 14.3, 9.2 Hz, 1 H), 1.94 (dd, J = 14.3 Hz,

7.2 Hz, 1 H), 1.57 (s, 3 H), 1.25 (m, 2 H), 0.81 (s, 3 H), 0.13 (s, 9

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 144.0 (3ϫC), 135.8

(C), 129.0 (6ϫCH), 128.3 (6ϫCH), 127.5 (3ϫCH), 121.5 (CH),

107.5 (C), 87.2 (C), 84.9 (C), 70.7 (CH₂), 68.6 (CH₂), 67.8 (CH),

41.2 (CH₂), 39.2 (CH₂), 39.0 (C), 33.7 (CH₂), 24.8 (CH₃), 19.5

(thin film): ν = 3401 (br.), 3070, 2958, 2930, 2857, 1654, 1473, 1428,

˜

1249, 1113, 842, 760, 740 cm^–1. HRMS: calcd. for [M]⁺550.3299;

found 550.3311.

tert-Butyl[(2R,4E)-2,5-dimethyl-2-(prop-2-ynyl)non-4-en-8-ynyloxy]-

diphenylsilane (4): Pb(OAc)₄(5.8 g, 12.9 mmol) was added portion-

wise at 0 °C to a solution of the diol 17 (5.1 g, 9.3 mmol) obtained

above in CH₂Cl₂(100 mL). After TLC analysis showed complete

consumption of the starting material, the reaction was quenched

by addition of satd. aq. NaHCO₃. The organic phase was extracted

four times with CH₂Cl₂(30 mL), and the combined organic phases

were washed with brine, dried with MgSO₄, filtered, and concen-

trated under reduced pressure. Purification by column chromatog-

raphy (hexane/ethyl acetate, 20:1) delivered the desired aldehyde

(4.6 g, 8.8 mmol, 95%) as a colorless oil. R_f(hexane/ethyl acetate,

20:1) = 0.38. [α]²_D⁰= –0.65 (c = 7.5, CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ = 9.84 (t, J = 3.0 Hz, 1 H), 7.64 (m, 4 H), 7.41 (m, 6

H), 5.16 (dd~t, J = 7.0 Hz, 1 H), 3.47, 3.42 (AB system, J = 9.9 Hz,

2 H), 2.39 (dd, J = 15.0, 2.8 Hz, 1 H), 2.33 (dd, J = 15.0, 3.1 Hz,

1 H), 2.27 (m, 2 H), 2.19 (m, 3 H), 2.05 (dd, J = 14.2, 7.3 Hz, 1

H), 1.56 (s, 3 H), 1.09 (s, 9 H), 0.74 (s, 3 H), 0.10 (s, 9 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 203.4 (CH), 137.0 (C), 136.0

(4 ϫ CH), 133.6 (2 ϫ C), 130.1 (2 ϫ CH), 128.1 (4 ϫ CH), 120.8

(CH), 107.5 (C), 85.0 (C), 70.9 (CH₂), 51.2 (CH₂), 40.5 (C), 39.1

(CH₂), 35.7 (CH₂), 27.3 (3 ϫ CH₃), 22.3 (CH₃), 19.7 (C), 19.5

(CH ), 16.3 (CH ), 0.5 (3ϫCH ) ppm. IR (thin film): ν = 3341

˜

2

3

(br.), 2924, 2173, 1449, 1249, 1074, 1034, 900, 841, 761 cm^–1

.

HRMS (ESI): calcd. for [M + Na] 577.3114; found 577.3123.

(2S,4R,6E)-4-{[(2,2-Dimethyl-1,1-diphenylpropyl)silyloxy]methyl}-

4,7-dimethyl-11-(trimethylsilyl)undec-6-en-10-yne-1,2-diol (17): The

diol 16 (11 g, 19.8 mmol) was dissolved in CH₂Cl₂(80 mL), and

then TBDPSCl (7.64 g, 27.8 mmol), NEt₃(3.9 mL, 27.8 mmol),

and catalytic amounts of DMAP (0.1 g, 0.8 mmol) were added. Af-

ter 18 h, the reaction was quenched by the addition of satd. aq.

NaHCO₃. After phase separation, the aqueous layer was extracted

three times with CH₂Cl₂. The combined organic layers were dried

with MgSO₄, filtered, and then concentrated under reduced pres-

sure. Purification by column chromatography (hexane/ethyl acetate,

10:1) delivered the monoprotected product (14.1 g, 17.8 mmol, (CH ), 16.5 (CH ), 0.5 (3ϫCH ) ppm. IR (thin film): ν = 3070,

˜

2

3

90%). R_f(hexane/ethyl acetate, 2:1) = 0.38. [α]²_D⁰= –4.1 (c = 3.7,

2958, 2930, 2857, 2174, 1719, 1473, 1428, 1390, 1362, 1249, 1113,

CH₂Cl₂). ¹H NMR (600 MHz, CDCl₃): δ = 7.60 (m, 4 H), 7.32

1007, 998, 842 cm^–1. HRMS: calcd. for [M – Me]⁺503.2802; found

(series of m, 21 H), 5.10 (dd~t, J = 7.3 Hz, 1 H), 3.90 (m, 1 H), 503.2796. Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.48 g,

3.39 (s, 2 H), 3.09 (dd, J = 9.0, 2.2 Hz, 1 H), 3.03 (s, 1 H), 3.0 (dd,

J = 9.0, 4.7 Hz, 1 H), 2.2 (m, 2 H), 2.11 (m, 3 H), 1.94 (dd, J =

14.3, 7.2 Hz, 1 H, 1.51 (s, 3 H), 1.45 (m, 2 H), 1.03 (s, 9 H), 0.77

(s, 3 H), 0.10 (s, 9 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ =

144.1 (3 ϫ C), 135.8 (4 ϫ CH), 135.8 (C), 135.5 (2 ϫ C), 129.7

(2ϫCH), 129.0 (6ϫCH), 128.3 (6ϫCH), 127.7 (4ϫCH), 127.5

(3ϫCH), 121.5 (CH), 107.5 (C), 87.2 (C), 84.9 (C), 70.7 (CH₂),

68.6 (CH₂), 67.8 (CH), 41.2 (CH₂), 39.2 (CH₂), 39.0 (C), 33.7

(CH₂), 27.0 (3ϫCH₃) 24.8 (CH₃), 19.5 (CH₂), 19.6 (C), 16.3 (CH₃),

2.3 mmol) in MeOH (5 mL) was added at 0 °C to a solution of the

aldehyde obtained above (0.96 g, 1.9 mmol) and K₂CO₃in MeOH

(30 mL). After warming to room temp., stirring was continued for

8 h. The reaction mixture was diluted with Et₂O (50 mL), washed

with aq. NaHCO₃(10%), and dried with MgSO₄. The solvents

were evaporated under reduced pressure, and the remaining residue

was purified by flash column chromatography (hexane/ethyl ace-

tate, 20:1) to give 4 (1.35 mmol, 0.60 g, 71%) as a colorless liquid.

R_f(hexane/ethyl acetate, 20:1) = 0.49. [α]²_D⁰= –5.5 (c = 1.5,

0.5 (3ϫCH ) ppm. IR (thin film): ν = 3422 (br.), 3070, 2958, 2930, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.68 (m, 4 H), 7.41 (m,

˜

3

Eur. J. Org. Chem. 2008, 2714–2730

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2721

M. Kögl, L. Brecker, R. Warrass, J. Mulzer

FULL PAPER

6 H), 5.16 (dd~t, J = 7.0 Hz, 1 H), 3.44 (s, 2 H), 2.19 (series of m,

7 H), 2.06 (dd, J = 14.0, 7.6 Hz, 1 H), 1.93 (t, J = 2.6 Hz, 1 H),

dry THF (5 mL) was introduced by syringe over 1 min. The reac-

tion was quenched after 1 h by treatment with portions of NH₄Cl

1.86 (t, J = 2.6 Hz, 1 H), 1.59 (s, 3 H), 1.07 (s, 9 H), 0.94 (s, 3 H) (0.5 g, excess), and the NH₃was allowed to evaporate overnight.

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 136.1 (4ϫCH), 135.8 (C),

134.0 (2ϫC), 129.9 (2ϫCH), 127.9 (4ϫCH), 121.7 (CH), 84.6 (C),

Hexane was added, and the solids were removed by filtration. The

filtrate was concentrated in vacuo to afford a solid-containing oil,

82.8 (C), 70.3 (CH), 69.4 (CH₂), 68.9 (CH), 40.0 (C), 39.0 (CH₂), which was purified by column chromatography (hexane/ethyl ace-

34.6 (CH₂), 27.2 (3ϫCH₃), 26.7 (CH₂), 21.5 (CH₃), 19.7 (C), 17.9 tate, 50:1) to give a mixture of the regioselectively reduced olefins

(CH ), 16.3 (CH ) ppm. IR (thin film): ν = 3308, 2959, 2930, 2857, (0.73 g, 1.65 mmol, 85%) as a colorless oil. R_f(hexane) = 0.9. Iso-

˜

2

3

1472, 1428, 1113, 1008, 826, 740, 702 cm^–1. HRMS: calcd. for [M – mer a: H NMR (600 MHz, CDCl₃): δ = 5.52 (m, 8 H), 5.46 (m, 1

1

tBu]⁺385.1988; found 385.1995.

H), 3.54 (AB system, J = 9.8 Hz, 1 H), 3.48 (AB system, J = 9.8 Hz,

1 H), 2.75 (m, 2 H), 2.72 (m, 4 H), 2.52 (m, 1 H), 2.28 (m, 1 H),

2.27 (m, 1 H), 2.05 (m, 1 H), 2.04 (m, 1 H), 1.91 (m, 1 H), 1.80

(m, 1 H), 1.73 (m, 2 H), 1.67 (m, 1 H), 1.59 (m, 1 H), 1.19 (m, 1

H), 1.08 (s, 3 H), 1.03 (s, 9 H), 0.83 (s, 3 H) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 145.4 (C), 126.0 (2ϫCH), 125.9 (2ϫCH),

121.8 (2ϫCH), 121.7 (2ϫCH), 116.7 (CH), 70.2 (CH₂), 45.3 (CH),

44.1 (C), 41.6 (CH₂), 40.5 (C), 40.4 (CH), 35.5 (CH₂), 33.1 (CH₂),

29.9 (CH₂), 29.4 (CH₂), 29.1 (2 ϫ CH), 27.7 (3 ϫ CH₃), 26.1

(2ϫCH₂), 24.7 (CH₃), 24.6 (CH₃), 22.0 (C) ppm. Isomer b: ¹H

NMR (600 MHz, CDCl₃): δ = 5.80 (m, 4 H), 5.52 (m, 4 H), 5.50

(m, 1 H), 3.63 (s, 2 H), 2.75 (m, 2 H), 2.72 (m, 4 H), 2.62 (m, 1

H), 2.28 (m, 1 H), 2.27 (m, 1 H), 2.04 (m, 2 H), 1.98 (m, 1 H), 1.73

(m, 2 H), 1.67 (m, 1 H), 1.59 (m, 1 H), 1.55 (m, 1 H), 1.35 (m, 1

H), 1.04 (s, 9 H), 0.96 (s, 3 H), 0.84 (s, 3 H) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 145.2 (C), 126.2 (4ϫCH), 121.7 (4ϫCH),

117.0 (CH), 71.9 (CH₂), 44.8 (CH), 44.0 (C), 41.3 (CH₂), 40.6 (C),

40.5 (CH), 35.2 (CH₂), 33.2 (CH₂), 29.5 (CH₂), 29.2 (2ϫCH), 27.7

(3ϫCH₃), 26.1 (2ϫCH₂), 24.9 (CH₂), 24.6 (CH₃), 23.1 (CH₃), 22.0

(C) ppm. TBAF (1  in THF, 3.3 mmol, 3.3 mL) was added at

room temp to a solution of the monoolefins obtained above (0.73 g,

1.7 mmol) in THF (10 mL). When TLC analysis showed full con-

sumption of the starting material, the reaction was quenched with

satd. aq. NH₄Cl, the mixture was diluted with Et₂O (10 mL), and

the phases were separated. The aqueous phase was extracted four

times with Et₂O (5 mL), and the combined organic phases were

washed with brine, dried with MgSO₄, filtered, and concentrated

under reduced pressure. Purification by column chromatography

(hexane/ethyl acetate, 4:1) delivered a mixture of diastereomers 18a

and 18b (0.32 g, 1.6 mmol, 95%), which could be separated by pre-

parative HPLC [analytical HPLC data: hexane/ethyl acetate, 9:1;

flow: 1 mLmin^–1; t_r(18a) = 2.4 min, t_r(18b) = 3.0 min]. Isomer 18a:

R_f(hexane/ethyl acetate, 4:1) = 0.60. [α]²_D⁰= +20.5 (c = 3.0,

tert-Butyl[{(6R,7aS,7bR)-6,7b-dimethyl-2,5,6,7,7a,7b-hexahydro-

1H-cyclobuta[e]inden-6-yl}methoxy]diphenylsilane and tert-

Butyl[{(6R,7aR,7bS)-6,7b-dimethyl-2,5,6,7,7a,7b-hexahydro-1H-cy-

clobuta[e]inden-6-yl}methoxy]diphenylsilane (6a and 6b): CpCo-

(CO)₂(0.5 g, 2.9 mmol) in predried, degassed toluene (5 mL) and

protected from light was added by syringe (syringe pump) over a

period of 6 h to a solution of enediyne 4 (1.0 g, 2.2 mmol) in tolu-

ene at reflux and under irradiation with a halogen reflector lamp

(visible light, max. 500 W). After completion of the addition, the

solution was irradiated at reflux for another 2 h. When TLC analy-

sis showed the complete disappearance of the enediyne, the crude

reaction mixture was cooled to room temp., and the volatiles were

removed by vacuum transfer. The brown residue was dissolved in

dried, degassed DME (10 mL), and CuCl₂·2H₂O (1.0 g, 5.5 mmol)

was added. The solution was stirred at room temp. for 3 h, the

mixture was then partitioned between H₂O (30 mL) and hexane

(50 mL), and the layers were separated. The aqueous layer was ex-

tracted four times with hexane (10 mL), and the combined organic

phases were dried with MgSO₄and concentrated in vacuo to fur-

nish a very air-sensitive yellow oil. This material was eluted through

a degassed silica gel column with degassed hexane to give an oily

mixture of diastereomers 6a and 6b in a 4:3 ratio (0.45 g, 1.0 mmol,

46%). R (hexane) = 0.71. IR (thin film): ν = 3370 (br.), 2953, 2930,

˜

f

2857, 1428, 1113, 822, 741, 701 cm^–1. HRMS: calcd. for

[M]⁺442.2692; found 442.2685. Diastereomer 6a: ¹H NMR

(600 MHz, CDCl₃): δ = 7.81 (m, 4 H), 7.27 (m, 4 H), 7.26 (m, 2

H), 5.89 (br. s, 1 H), 5.76 (br. s, 1 H), 3.60 (AB system, J = 9.7 Hz,

2 H), 2.90 (m, 2 H), 2.47 (d, J = 16.3 Hz, 1 H), 2.12 (d, J = 16.3 Hz,

1 H), 1.76 (m, 3 H), 1.62 (ddd, J = 14.5, 8.0 Hz, 1 H), 1.36 (dd, J

= 11.5, 7.7 Hz, 1 H), 1.24 (s, 3 H), 1.23 (s, 9 H), 0.97 (s, 3 H)

ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 144.7 (C), 144.4 (C), 136.1

(4 ϫ CH), 134.3 (2 ϫ C), 129.9 (4 ϫ CH), 128.3 (2 ϫ CH), 116.5

(CH), 113.6 (CH), 71.8 (CH₂), 48.3 (CH), 43.3 (C), 41.3 (C), 40.8

(CH₂), 34.8 (CH₂), 33.1 (CH₂), 28.5 (CH₂), 27.1 (3ϫCH₃), 23.1

(CH₃), 19.6, (C), 15.4 (CH₃) ppm. Diastereomer 6b: ¹H NMR

(600 MHz, CDCl₃): δ = 7.81 (m, 4 H), 7.27 (m, 4 H), 7.26 (m, 2

H), 5.78 (br. s, 1 H), 5.70 (br. s, 1 H), 3.49 (AB system, J = 9.7 Hz,

2 H), 2.90 (m, 1 H), 2.76 (m, 1 H), 2.43 (d, J = 18.0 Hz, 1 H), 2.00

(d, J = 18.0 Hz, 1 H), 1.84 (dd, J = 12.7, 8.5 Hz, 1 H), 1.70 (m, 2

H), 1.58 (ddd, J = 14.4, 8.0 Hz, 1 H), 1.29 (dd, J = 12.7, 12.4 Hz,

1 H), 1.23 (s, 9 H), 1.08 (s, 3 H), 1.03 (s, 3 H) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 144.8 (C), 144.7 (C), 136.1 (4ϫCH), 134.3

(2ϫC), 129.9 (4ϫCH), 128.3 (2ϫCH), 116.1 (CH), 113.5 (CH),

70.1 (CH₂), 48.7 (CH), 41.2 (CH₂), 43.6 (C), 41.1 (C), 34.9 (CH₂),

33.1 (CH₂), 28.5 (CH₂), 27.1 (3ϫCH₃), 25.0 (CH₃), 19.6 (C), 15.3

(CH₃) ppm.

1

CH₂Cl₂). H NMR (600 MHz, CDCl₃): δ = 5.52 (m, 1 H), 3.48 (s,

2 H), 2.63 (ddd, J = 9.1, 7.6, 2.9 Hz, 1 H), 2.28 (m, 1 H), 2.08 (m,

4 H), 1.75 (m, 3 H), 1.61 (m, 1 H), 1.54 (br. s, OH), 1.47 (ddd, J

= 11.6, 8.0, 2.4 Hz, 1 H), 1.40 (dd, J = 11.6, 11.6 Hz, 1 H), 1.0 (s,

3 H), 0.83 (s 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 144.4

(C), 117.4 (CH), 72.2 (CH₂), 44.7 (CH), 43.7 (C), 41.6 (CH₂), 40.5

(C), 40.4 (CH), 35.7 (CH₂), 33.1 (CH₂), 29.4 (CH₂), 24.9 (CH₂),

24.7 (CH ), 22.8 (CH ) ppm. IR (thin film): ν = 3351 (br.), 2930,

˜

3

2864, 2831, 1653, 1457, 1374, 1029, 872, 810 cm^–1. HRMS: calcd.

for [M]⁺206.1671; found 206.1668.

tert-Butyl[{(2aS,6R,7aS,7bS)-6,7b-dimethyl-2,2a,3,5,6,7,7a,7b-octa-

hydro-1H-cyclobuta[e]inden-6-yl}methoxy]dimethylsilane (19):

TBSCl (176 mg, 1.5 mmol) was added in small portions to a solu-

tion of alcohol 18a (150 mg, 0.73 mmol) and imidazole (124 mg,

{(2aS,6R,7aS,7bS)-6,7b-Dimethyl-2,2a,3,5,6,7,7a,7b-octahydro-1H- 1.8 mmol) in anhydrous DMF (5 mL), and the mixture was stirred

cyclobuta[e]inden-6-yl}methanol (18a): Li (0.02 g, excess) was added

at –78 °C to a stirred solution of liquid NH₃(ca. 40 mL), dry THF

(15 mL), and dry 2-methylpropan-2-ol (10 mL) contained in a

100 mL three-necked round-bottomed flask fitted with a dry ice/

for 10 h. Water (5 mL) and Et₂O (15 mL) were added, the phases

were separated, and the aqueous phase was extracted five times

with Et₂O (5 mL). The combined organic layers were washed four

times with portions (5 mL) of water and then brine, and were dried

acetone condenser and septa. Upon formation of a persistent deep with MgSO₄. After concentration in vacuo, the crude product was

blue color, a solution of dienes 6a and 6b (0.86 g, 1.94 mmol) in purified by flash column chromatography (hexane/ethyl acetate,

2722

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2714–2730

Total Synthesis of Pasteurestin A and B and Assignment of Configurations

20:1) to give protected 19 (210 mg, 0.66 mmol, 90%) as a colorless

39.5 (C), 39.4 (CH₂), 30.9 (CH₂), 26.5 (CH₃), 26.0 (3ϫCH₃), 22.8

(CH₂), 21.3 (CH₃), 18.1 (C), –5.5 (2ϫCH₃) ppm.

1

oil. R_f(hexane) = 0.95. [α]²_D⁰= +15.0 (c = 2.8, CH₂Cl₂). H NMR

(400 MHz, CDCl₃): δ = 5.52 (m, 1 H), 3.41 (s, 2 H), 2.63 (ddd, J

= 9.12, 7.6, 2.9 Hz, 1 H), 2.26 (m, 2 H), 2.08 (m, 2 H), 1.97 (d, J

= 15.8 Hz, 1 H), 1.74 (m, 3 H), 1.65 (m, 1 H), 1.53 (dd, J = 11.7,

9.4 Hz, 1 H), 1.36 (ddd, J = 11.9, 7.8, 1.3 Hz, 1 H), 1.00 (s, 3 H),

0.89 (s, 9 H), 0.83 (s 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 145.8 (C), 117.2 (CH), 71.2 (CH₂),

45.2 (CH), 44.3 (C), 41.7 (CH₂), 41.0 (C), 40.9 (CH), 35.5 (CH₂),

33.4 (CH₂), 29.8 (CH₂), 26.3 (3ϫCH₃), 25.0 (CH₂), 23.5 (CH₃),

23.5 (CH₃), 18.6 (C), –2.6 (CH₃), –5.1 (CH₃) ppm. IR (thin film):

Methyl (2aS,4aR,6R,7aS,7bR)-6-[(tert-Butyldimethylsilyloxy)-

methyl]-6,7b-dimethyl-4-oxodecahydrocyclobuta[e]indene-3-carb-

oxylate (21a, syn): nBuLi (2.5  in THF, 0.42 mL, 1.05 mmol) was

added at 0 °C to a solution of diisopropylamine (107 mg,

1.05 mmol) in THF (5 mL), and the mixture was stirred at this

temperature for 30 min. After the system had been cooled to

–78 °C, HMPA (194 mg, 0.18 mL, 1.05 mmol) and a solution of

epimeric ketones 20a and 20b (140 mg, 0.42 mmol) were slowly

added, and the mixture was stirred at –78 °C for 2 h. Dry carbon

dioxide (generated from dry ice and passed through concentrated

sulfuric acid) was then bubbled into the mixture at –58 °C for 1 h.

After addition of aq. HCl (1 , 0.5 mL), the mixture was quickly

warmed to 0 °C with an ice bath. (Trimethylsilyl)diazomethane (2 

in diethyl ether, 0.35 mL, 0.70 mmol) was added slowly to the reac-

tion mixture. When TLC showed the acid no longer to be present,

the excess of (trimethylsilyl)diazomethane was quenched with ad-

ditional HCl (1 ), Et₂O was added, and the phases were separated.

The aqueous phase was extracted several times with Et₂O, the com-

bined organic phases were washed with satd. aq. NaHCO₃and

dried, and the volatiles were evaporated under reduced pressure.

Purification by column chromatography delivered a mixture of dia-

stereomers 21a and 21b in a 4:1 ratio (0.23 mmol, 91 mg, 55%). R_f

ν = 2955, 2942, 2929, 2856, 1256, 1091, 837, 774 cm^–1. HRMS:

˜

calcd. for [M]⁺320.2535; found 320.2541.

(2aS,4aR,6R,7aS,7bS)-6-[(tert-Butyldimethylsilyloxy)methyl]-6,7b-

dimethyldecahydro-cyclobuta[e]inden-4-one (20a, syn) and (2aS,4aS,

6R,7aS,7bS)-6-[(tert-Butyldimethylsilyloxy)methyl]-6,7b-dimethyl-

decahydrocyclobuta[e]inden-4-one (20b, anti): B₂H₆·THF (1  in

THF, 1.9 mL, 1.9 mmol) was added at 0 °C to a solution of olefin

19 (200 mg, 0.6 mmol) in dry THF (8 mL). After 5 h at room temp.,

TLC analysis of the reaction mixture indicated no remaining olefin.

Aq. K₂CO₃(1 , 2.5 mL, 2.5 mmol) and H₂O₂(30 % by wt.,

1.1 mL, 10.0 mmol) were added sequentially at 0 °C to the vigor-

ously stirred solution, the flask was then fitted with a reflux con-

denser, and the biphasic mixture was stirred for 3 h while heated

to 60–65 °C in an oil bath. The cooled solution was then diluted

with hexane (30 mL), the layers were separated, and the aqueous

phase was extracted three times with hexane (10 mL); the combined

organic phases were washed with satd. aq. Na₂S₂O₃and then brine,

dried with MgSO₄and filtered, after which the volatiles were evap-

orated under reduced pressure to afford a colorless oil which was

used without further purification. The crude mixture was dissolved

in CH₂Cl₂(5 mL), and Dess–Martin periodinane (419 mg,

1.00 mmol) was added. After the mixture had been stirred at room

temp. for 2 h, TLC monitoring showed complete consumption of

the starting material. A mixture (1:1) of satd. aq. NaHCO₃and aq.

Na₂S₂O₃(1 , 5 mL) was added, and the reaction mixture was

stirred until the biphasic mixture became clear. The phases were

then separated, and the aqueous phase was extracted three times

with CH₂Cl₂(3 mL). The combined organic phases were washed

with brine, dried, and filtered. The solvent was removed in vacuo

and purified by column chromatography (hexane/ethyl acetate,

10:1) to give an epimeric mixture of ketones 20a and 20b as a clear

oil (155 mg, 0.46 mmol, 74% over two steps). R_f(hexane/ethyl ace-

(hexane/ethyl acetate, 9:1) = 0.8. IR (thin film): ν = 2953, 2857,

˜

1653, 1611, 1440, 1361, 1292, 1255, 1236, 1094, 837, 775, 668 cm^–1.

HRMS: calcd. for [M]⁺394.2539; found 394.2547. Diastereomer

21a: ¹H NMR (600 MHz, CDCl₃): δ = 12.40 (s, 1 H), 3.72 (s, 3 H),

3.19, 3.17 (AB system, J = 9.4 Hz, 2 H), 2.91 (t, J = 7.8 Hz, 1 H),

2.58 (m, 1 H), 2.43 (m, 1 H), 2.30 (dd, J = 13.9, 1.9 Hz, 1 H), 2.03

(m, 1 H), 1.93 (dd, J = 20.0, 10.1 Hz, 1 H), 1.53 (dd, J = 13.9,

8.8 Hz, 1 H), 1.43 (m, 1 H), 1.36 (m, 1 H), 1.25 (m, 4 H), 1.14 (t,

J = 12.7 Hz, 1 H), 0.98 (s, 3 H), 0.85 (s, 9 H), –0.02, (s, 3 H), –0.03

(s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 173.6 (C), 172.8

(C), 100.9 (C), 71.9 (CH₂), 51.7 (CH₃), 46.2 (CH), 43.5 (C), 42.0

(CH), 38.3 (CH₂), 37.4 (CH₂), 37.3 (C), 36.2 (CH), 30.0 (CH₂),

26.8 (CH₃), 26.7 (CH₂), 26.2 (3ϫCH₃), 21.0 (CH₃), 18.6 (C), –5.2

(2ϫCH₃) ppm.

Methyl (4aR,6R,7aS,7bR)-6-[(tert-Butyldimethylsilyloxy)methyl]-

6,7b-dimethyl-4-oxo-2,4,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]-

indene-3-carboxylate (22a): A solution of β-oxo esters 21a and 21b

(90 mg, 0.23 mmol) in THF (2 mL) was added slowly at –78 °C

to a stirred solution of lithium diisopropylamide (0.25  in THF,

0.27 mmol, 1.09 mL), and the mixture was allowed to warm to

0 °C. After the solution had been stirred for 45 min, a solution of

phenylselenyl chloride (52 mg, 0.27 mmol) in THF (0.5 mL) was

tate, 9:1) = 0.5. IR (thin film): ν = 2953, 1713, 1472, 1255, 1095,

˜

837, 802, 776, 727 cm^–1. HRMS: calcd. for [M]⁺336.2485; found

336.2485. Epimer 20a: ¹H NMR (600 MHz, CDCl₃): δ = 3.25, 3.21

(AB system, J = 9.5 Hz, 2 H), 2.87 (m, 1 H), 2.82 (dd, J = 14.6, added, and the mixture was stirred for another 20 min. It was then

7.2 Hz, 1 H), 2.45 (m, 1 H), 2.21 (m, 1 H), 2.18 (m, 1 H), 2.09 (dm, quenched by addition of satd. aq. NH₄Cl and diluted with Et₂O,

J = 14.6 Hz, 1 H), 1.95 (dd, J = 14.8, 9.8 Hz, 1 H), 1.87 (ddd, J =

3 ϫ 9.5 Hz, 1 H), 1.83 (m, 1 H), 1.61 (m, 1 H), 1.57 (dd, J =

and the aqueous phase was extracted three times with Et₂O. The

combined organic phases were washed with brine and dried with

14.8 Hz, 5.5 Hz, 1 H), 1.42 (m, 1 H), 1.32 (m, 1 H), 1.17 (s, 3 H), MgSO₄. After concentration of the crude product in vacuo, the

0.98 (s, 3 H), 0.87 (s, 9 H), 0.006 (s, 6 H) ppm. ¹³C NMR product was filtered through a pad of silica gel to deliver the de-

(150 MHz, CDCl₃): δ = 216.8 (C), 70.0 (CH₂), 50.5 (CH), 50.2 sired epimeric mixture (0.13 mmol, 79 mg, 55%) as a yellow oil.

(CH), 41.7 (CH₂), 40.1 (CH), 39.8 (CH₂), 39.4 (CH₂), 37.1 (C),

The two undesired diastereomers with opposite configuration at C-

37.3 (C), 30.8 (CH₂), 27.1 (CH₃), 26.0 (3ϫCH₃), 25.8 (CH₃), 21.3 3 were also obtained (26 mg, 0.042 mmol, 18%) but could be re-

(CH₂), 18.1 (C), –5.5 (2 ϫ CH₃) ppm. Epimer 20b: (600 MHz,

CDCl₃): δ = 3.28, 3.25 (AB system, J = 9.5 Hz, 2 H), 2.63 (m, 1

moved chromatographically. The epimers with the phenylselenide

anti to the cyclobutane (60 mg, 0.11 mmol) were dissolved in

H), 2.51 (dddd, J = 8.5, 8.5, 8.5, 2.5 Hz, 1 H), 2.37 (m, 1 H), 2.35 CH₂Cl₂(5 mL), and satd. aq. NH₄Cl (0.5 mL) and aq. H₂O₂(30%

(m, 1 H), 2.07 (m, 1 H), 1.95 (m, 1 H), 1.87 (m, 1 H), 1.81 (m, 1

H), 1.74 (m, 1 H), 1.67 (m, 1 H), 1.63 (m, 1 H), 1.36 (m, 1 H), 1.17

by wt., 2.5 mL) were added at 0 °C. The biphasic mixture was

stirred vigorously at the same temperature for 2 h. After dilution

(m, 1 H), 1.11 (s, 3 H), 0.98 (s, 3 H), 0.87 (s, 9 H), 0.001 (s, 6 H) with H₂O (1 mL) and CH₂Cl₂(5 mL), the phases were separated,

ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 213.6 (C), 71.4 (CH₂),

49.5 (CH), 51.2 (CH), 44.0 (CH), 43.3 (CH₂), 42.1 (CH₂), 39.7 (C),

the aqueous phase was extracted twice with CH₂Cl₂, and the com-

bined organic phases were washed with aq. Na₂S₂O₃(10%) and

Eur. J. Org. Chem. 2008, 2714–2730

www.eurjoc.org

2723

M. Kögl, L. Brecker, R. Warrass, J. Mulzer

FULL PAPER

brine, dried with MgSO₄, and concentrated in vacuo. The semisolid

product was purified by column chromatography (hexane/ethyl ace-

tate, 10:1) to provide a 72% yield (31 mg, 0.08 mmol) of the desired

α,β-unsaturated β-oxo ester 22a, which could be separated from

22b. R_f(hexane/ethyl acetate, 4:1) = 0.35. [α]²_D⁰= –43.5 (c = 0.55,

ethyl acetate) delivered 1 (3.0 mg, 0.011 mmol, 55%) as a colorless

oil. R_f(ethyl acetate) = 0.13. [α]²_D⁰= –60 (c = 0.13, MeOH). ¹H

NMR (600 MHz, CD₃OD): δ = 4.24 (ddd, J = 8.3, 3.0, 2.5 Hz, 1

H, CHOH), 3.43 (AB system, J = 11 Hz, 2 H, HOCH₂C), 3.15

(dddd, J = 18.0, 9.2, 9.2, 3.5 Hz, 1 H, CCCHH), 3.06 (dddd, J =

18.0, 8.4, 4.4, 2.5 Hz, 1 H, CCCHH), 2.46 (ddd, J = 11.9, 10.5,

8.0 Hz, 1 H, CH₂CHCCH₃), 2.41 (dddd, J = 11.9, 10.4, 8.3, 8.0 Hz,

1

CH₂Cl₂). H NMR (600 MHz, CDCl₃): δ = 3.75 (s, 3 H), 3.39 (s,

2 H), 3.30 (ddd, J = 18.9, 8.8, 1.3 Hz, 1 H), 3.18 (dd, J = 8.8,

4.1 Hz, 1 H), 3.13 (m, 1 H), 2.83 (ddd, J = 11.5, 8.8, 7.8 Hz, 1 H), 1 H, CH₂CHCHOH), 1.97 (m, 2 H, CCCH₂CH₂), 1.74 (ddd, J =

2.01 (m, 2 H), 1.79 (dd, J = 13.4, 7.8 Hz, 1 H), 1.65 (m, 2 H), 1.36

(ddd, J = 13.4, 9.1, 1.1 Hz, 1 H), 1.20 (s, 3 H), 0.92 (s, 3 H), 0.87

(s, 9 H), 0.02 (s, 6 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ =

197.9 (C), 185.5 (C), 163.7 (C), 125.7 (C), 70.6 (CH₂), 52.8 (CH),

12.5, 8.0, 1.8 Hz, 1 H, CHHCHCHOH), 1.56 (dd, J = 12.9,

10.5 Hz, 1 H, CHHCHCCH₃), 1.39 (ddd, J = 12.9, 8.0, 1.8 Hz, 1

H, CH HCHCCH₃) , 1 . 3 3 ( dd , J = 1 2 . 5 , 1 0 . 4 H z , 1 H,

CHHCHCHOH), 1.18 (s, 3 H, CHCCH₃), 1.03 (s, 3 H,

51.9 (CH₃), 47.3 (C), 45.5 (C), 44.7 (CH), 37.3 (CH₂), 34.7 (CH₂), HOCH₂CCH₃) ppm. ¹³C NMR (150 MHz, CD₃OD): δ = 175.4

34.5 (CH₂), 31.0 (CH₂), 26.4 (3ϫCH₃), 24.0 (CH₃), 23.1 (CH₃),

18.8 (C), –5.2 (2ϫCH ) ppm. IR (thin film): ν = 2955, 2368, 2345,

(C), 165.1 (C), 126.2 (C), 73.9 (CH), 72.9 (CH₂), 51.5 (CH), 49.2

(C), 47.1 (C), 46.9 (CH), 43.2 (CH₂), 37.7 (CH₂), 37.6 (CH₂), 30.8

˜

3

1735, 1718, 1700, 1696, 1685, 1437, 1319, 1257, 1093, 856, (CH ), 23.9 (CH ), 21.3 (CH ) ppm. IR (thin film): ν = 3369 (br.),

˜

2

3

836 cm^–1. HRMS: calcd. for [M]⁺392.2383; found 392.2391.

2930, 2854, 1687, 1651, 1463, 1248, 1036, 895, 862 cm^–1. HRMS:

calcd. for [M]⁺280.1675; found 280.1672 (methyl ester).

Methyl (4S,4aR,6R,7aS,7bR)-6-[(tert-Butyldimethylsilyloxy)-

methyl]-4-hydroxy-6,7b-dimethyl-2,4,4a,5,6,7,7a,7b-octahydro-1H- (4R)-4-Benzyl-3-[(3S,4E)-3-hydroxy-2,2,5-trimethyl-9-(trimethylsi-

cyclobuta[e]indene-3-carboxylate (23): A solution of the β-oxo ester

22a (15 mg, 0.04 mmol) in MeOH (2 mL), together with

CeCl₃·7H₂O (134 mg, 0.38 mmol), was stirred at 0 °C for 30 min.

Sodium borohydride (3 mg, 0.077 mmol) was then added, and the

reaction mixture was stirred at 0 °C for another 15 min. At this

point, the reaction was quenched with water, MeOH was evapo-

rated, and the remaining aqueous phase was diluted with CH₂Cl₂

(5 mL). The phases were separated, and the aqueous phase was

extracted three times with CH₂Cl₂(3 mL). The combined organic

extracts were washed with brine, dried with MgSO₄, and concen-

trated under reduced pressure. The crude product was purified by

flash column chromatography (hexane/ethyl acetate, 10:1) to yield

the alcohol 23 (13 mg, 0.03 mmol, 87%). R_f(hexane/ethyl acetate,

4:1) = 0.64. [α]²_D⁰= –35.7 (c = 0.65, CH₂Cl₂). ¹H NMR (600 MHz,

CDCl₃): δ = 5.26 (d, J = 1.4 Hz, 1 H), 4.23 (m, 1 H), 3.75 (s, 3 H),

3.39 (s, 2 H), 3.04 (ddd, J = 19.0, 8.0, 3.9 Hz, 1 H), 2.98 (m, 1 H),

2.36 (m, 2 H), 1.90 (m, 2 H), 1.70 (m, 1 H), 1.56 (dd, J = 13.2,

lyl)non-4-en-8-ynoyl]oxazolidin-2-one (40): Lithium aluminium hy-

dride (1  in THF, 23 mL, 23 mmol) was added portionwise at 0 °C

to a THF solution (80 mL) of anhydrous stannous chloride (8.78 g,

46 mmol), which was previously dried by heating in vacuo at 120 °C

for 1 h. Spontaneous exothermic reaction occurred, and a dark

gray material deposited. The mixture was stirred at room temp. for

20 min. Subsequently, bromide 10 (7.50 g, 23 mmol) in THF

(20 mL) was added to this mixture, which was stirred for another

2 h. The reaction mixture was then cooled to –78 °C, and aldehyde

11 (4.5 g, 23 mmol), dissolved in THF (20 mL), was added over a

period of 30 min. The reaction mixture was stirred at –78 °C for

8 h. The reaction was quenched with water (50 mL), and the mix-

ture was diluted with Et₂O (50 mL). After phase separation, the

aqueous phase was extracted four times with portions of Et₂O

(50 mL), and the combined organic extracts were stirred with satd.

aq. KF (50 mL) and water (50 mL) for 30 min. The phases were

again separated, and the organic extracts were dried with MgSO₄,

9.5 Hz, 1 H), 1.37 (dd, J = 12.4, 10.0 Hz, 1 H), 1.25 (m, 1 H), 1.08 filtered, and concentrated under reduced pressure to give a yellow

(s, 3 H), 0.91 (s, 9 H), 0.87 (s, 3 H), 0.01 (s, 6 H) ppm. ¹³C NMR oil, which was purified by flash column chromatography (hexane/

(150 MHz, CDCl₃): δ = 169.5 (C), 168.3 (C), 121.5 (C), 71.5 (CH), ethyl acetate, 9:1) to yield alcohol 40 (7.92 g, 18 mmol, 78%). R_f

70.7 (CH₂), 51.3 (CH₃), 48.7 (CH), 47.3 (C), 45.1 (C), 44.1 (CH), (hexane/ethyl acetate, 4:1) = 0.2. [α]²_D⁰= +2.4 (c = 2.8, CH₂Cl₂). ¹H

41.1 (CH₂), 35.4 (CH₂), 35.1 (CH₂), 29.3 (CH₂), 25.9 (3ϫCH₃),

NMR (400 MHz, CDCl₃): δ = 7.30 (m, 5 H), 5.33 (d, J = 9.1 Hz,

22.9 (CH₃), 20.2 (CH₃), 18.3 (C), –5.5 (2ϫCH₃) ppm. IR (thin 1 H), 5.21 (d, J = 9.1 Hz, 1 H), 4.74 (m, 1 H), 4.16 (m, 2 H), 3.30

film): ν = 2927, 2787, 1694, 1560, 1113, 887, 876, 612 cm^–1. HRMS: (dd, J = 13.4, 2.4 Hz, 1 H), 2.78 (dd, J = 13.4, 9.8 Hz, 1 H), 2.39

˜

calcd. for [M]⁺337.1835; found 337.1840.

(m, 2 H), 2.26 (m, 3 H), 1.79 (s, 3 H), 1.38 (s, 6 H), 0.14 (s, 9 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 178.1 (C), 152.8 (C), 139.8

(C), 136.0 (C), 129.8 (2ϫCH), 129.2 (2ϫCH), 127.8 (CH), 124.4

(CH), 107.0 (C), 85.3 (C), 71.9 (CH), 66.8 (CH₂), 58.1 (CH), 51.0

(C), 38.9 (CH₂), 38.1 (CH₂), 20.5 (CH₃), 19.1 (CH₃), 18.9 (CH₂),

Pasteurestin A (1): The α,β-unsaturated ester 23 (8.0 mg,

0.020 mmol) was dissolved in THF (2 mL) in a polyethylene vessel,

and the solution was cooled to 0 °C. HF·pyridine (70%, 0.14 mL,

1.0 mmol) was added, and the reaction mixture was stirred at room

temp. overnight. It was quenched by addition of satd. aq. NaHCO₃

(2 mL) and diluted with CH₂Cl₂(5 mL). The aqueous phase was

extracted three times with CH₂Cl₂(2 mL), and the combined or-

ganic extracts were washed with HCl (2 , 2 mL) and subsequently

with satd. aq. NaHCO₃. The organic phase was then dried with

MgSO₄and concentrated under reduced pressure. The crude prod-

uct was dissolved in THF (1.4 mL), and H₂O (0.6 mL) was added.

After the addition of LiOH·H₂O (1.6 mg, 0.038 mmol), the reac-

tion mixture was stirred overnight. When TLC analysis showed the

hydrolysis to be complete, HCl (2 , 0.5 mL) was added. The reac-

tion mixture was again diluted with CH₂Cl₂(5 mL), and after

phase separation the aqueous phase was extracted three times with

CH₂Cl₂(2 mL). The organic phases were washed with satd. aq.

NaHCO₃, dried with MgSO₄, and concentrated in vacuo. Purifica-

tion by flash column chromatography (hexane/ethyl acetate, 1:1 Ǟ

17.3 (CH ), 0.47 (3ϫCH ) ppm. IR (thin film): ν = 3530 (br.),

˜

3

2958, 2173, 1781, 1685, 1477, 1471, 1453, 1417, 1388, 1371, 1348,

1316, 1251, 1229, 1193, 1153, 1140, 1125, 1104, 1066, 1031,

991 cm^–1. HRMS: calcd. for [M]⁺441.2335; found 441.2327.

S-Ethyl (3S,4E)-3-(tert-Butyldimethylsilyloxy)-2,2,5-trimethyl-9-

(trimethylsilyl)non-4-en-8-ynethioate (41): TBSOTf (8.1 g, 7.1 mL,

31 mmol) was added dropwise at 0 °C to a solution of alcohol 40

(9.0 g, 20 mmol) and 2,6-lutidine (8.7 g, 9.5 mL, 82 mmol) in

CH₂Cl₂(50 mL), and the reaction mixture was stirred at 0 °C for

30 min. After TLC analysis showed full consumption of the start-

ing material, the reaction was quenched by the addition of satd.

aq. NaHCO₃. The phases were separated, the organic phase was

washed twice with CH₂Cl₂(10 mL), and the combined organic

phases were washed with HCl (2 ) and then with satd. aq.

NaHCO₃and dried with MgSO₄. Filtration and concentration in

2724

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Eur. J. Org. Chem. 2008, 2714–2730

Total Synthesis of Pasteurestin A and B and Assignment of Configurations

vacuo, together with purification by column chromatography, deliv-

ered the TBS-protected alcohol (10.6 g, 19 mmol, 95%) as a clear

oil. R_f(hexane/ethyl acetate, 4:1) = 0.6. [α]²_D⁰= –19.9 (c = 1.8,

nium chloride (4.9 g, 14.2 mmol) was suspended in THF (30 mL)

and cooled with an ice/salt bath to –10 °C. nBuLi (2.5  in hexane,

5.7 mL, 14.2 mmol) was added slowly, and the bright red mixture

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.31 (m, 5 H), 5.73 (d, was then stirred at room temp. for 1 h. Aldehyde 42 (2.7 g,

J = 9.2 Hz, 1 H), 5.21 (d, J = 9.2 Hz, 1 H), 4.60 (m, 1 H), 4.13 (m, 7.1 mmol) was dissolved in THF (15 mL) and added dropwise to

2 H), 3.45 (dd, J = 13.0, 2.3 Hz, 1 H), 2.64 (dd, J = 13.0, 10.9 Hz,

1 H), 2.37 (t, J = 7.3 Hz, 2 H), 2.24 (t, J = 7.3 Hz, 2 H), 1.79 (s, 3

the resulting solution by syringe at 0 °C. After stirring at room

temp. for 30 min, the reaction mixture was quenched by the ad-

H), 1.35 (s, 3 H), 1.25, (s, 3 H), 0.85 (s, 9 H), 0.14 (s, 9 H), 0.03 (s, dition of H₂O (10 mL), followed by ethyl acetate (80 mL). After

3 H), –0.02 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.13 phase separation, the aqueous phase was extracted three times with

(C), 153.2 (C), 137.5 (C), 136.4 (C), 129.7 (2ϫCH), 129.6 (2ϫCH), ethyl acetate (50 mL), and the combined organic phases were

127.5 (CH), 126.2 (CH), 107.2 (C), 85.1 (C), 70.1 (CH), 66.7 (CH₂), washed with brine and dried with MgSO₄. After removal of the

58.9 (CH), 52.6 (C), 38.9 (CH₂), 38.6 (CH₂), 26.1 (3ϫCH₃), 20.7

(CH₃), 20.0 (CH₃), 19.3 (CH₂), 18.9 (C), 17.3 (CH₃), 0.45

solvents in vacuo, a crude (E)/(Z) mixture of enol ethers was ob-

tained. The crude product was stirred in HCl (1 , 9 mL) and THF

(6 mL) for 8 h and was then diluted with Et₂O (50 mL) and brine

(10 mL). The phases were separated, the aqueous phase was

washed three times with Et₂O (15 mL), and the combined organic

phases were washed with satd. aq. NaHCO₃and brine and dried

with MgSO₄. Removal of the volatiles in vacuo and purification of

the C₁-homologated aldehyde delivered compound 43 (1.7 g,

4.3 mmol, 60%). R_f(hexane/ethyl acetate, 10:1) = 0.6. [α]²_D⁰= –6.7

(3ϫCH ), –3.4 (CH ), –4.2 (CH ) ppm. IR (thin film): ν = 2955,

˜

3

2942, 2929, 2856, 1781, 1692, 1473, 1387, 1346, 1250, 1190, 1144,

1102, 834, 733, 701 cm^–1. HRMS: calcd. for [M⁺– tBu] 498.2496;

found 489.2505. nBuLi (2.5 , 17 mL, 42.5 mmol) was added drop-

wise at 0 °C to a solution of EtSH (2.7 g, 3.2 mL, 43 mmol) in THF

(50 mL), and the mixture was stirred for 1 h. The mixture was then

cooled to –78 °C, and the TBS ether obtained above (6.0 g,

10.8 mmol) was added. The solution was gradually warmed to 0 °C

and stirred for 2 h, and was then was quenched with satd. aq.

NH₄Cl and extracted with ethyl acetate. The combined organic

phases were washed with brine, dried with MgSO₄, and concen-

trated in vacuo. The residue was chromatographed on silica gel.

Elution with hexane/ethyl acetate (10:1) delivered thioester 41

(4.2 g, 9.6 mmol, 89%) as a yellow oil. R_f(hexane/ethyl acetate,

1

(c = 0.55, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 9.85 (t, J =

1.6 Hz, 1 H), 5.20 (d, J = 9.4 Hz, 1 H), 4.07 (d, J = 9.4 Hz, 1 H),

2.38 (m, 3 H), 2.22 (m, 2 H), 2.16 (dd, J = 14.6, 2.8 Hz, 1 H), 1.65

(s, 3 H), 1.08 (s, 3 H), 0.97 (s, 3 H), 0.87 (s, 9 H), 0.13 (s, 9 H),

0.00 (s, 3 H), –0.05 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 203.7 (CH), 136.3 (C), 126.7 (CH), 107.1 (C), 85.2 (C), 76.4

(CH), 52.4 (CH₂), 40.6 (C), 38.9 (CH₂), 26.2 (3ϫCH₃), 24.7 (CH₃),

24.4 (CH₃), 19.2 (CH₂), 18.4 (C), 17.3 (CH₃), 0.47 (3ϫCH₃), –3.6

1

10:1) = 0.9. [α]²_D⁰= –12.8 (c = 2.8, CH₂Cl₂). H NMR (400 MHz,

CDCl₃): δ = 5.15 (dd, J = 9.5, 1 Hz, 1 H), 4.61 (d, J = 9.2 Hz, 1 (CH ), –4.7 (CH ) ppm. IR (thin film): ν = 2957, 2367, 2174, 1844,

˜

3

H), 2.80 (dq, J = 7.4, 1.7 Hz, 2 H), 2.33 (t, J = 7.2 Hz, 2 H), 2.21

(t, J = 7.2 Hz, 2 H), 1.73 (s, 3 H), 1.22 (m, 6 H), 1.04 (s, 3 H), 0.82

(s, 9 H), 0.13 (s, 9 H), 0.024 (s, 3 H), –0.069 (s, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 206.4 (C), 136.8 (C), 125.9 (CH),

107.2 (C), 85.1 (C), 73.7 (CH), 56.0 (C), 38.9 (CH₂), 26.1 (3ϫCH₃),

23.4 (CH₂), 22.6 (CH₃), 19.3 (CH₂), 19.0 (CH₃), 18.4 (C), 17.4

(CH₃), 14.8 (CH₃), 0.45 (3ϫCH₃), –3.4 (CH₃), –4.9 (CH₃) ppm.

1720, 1560, 1472, 1307, 1250, 1202, 1063, 963, 839, 804, 776 cm^–1.

HRMS: calcd. for [M – Me]⁺379.2488; found 379.2484.

tert-Butyl[(1S,2E)-1-(1,1-dimethylbut-3-ynyl)-3-methylhept-2-en-6-

ynyloxy]dimethylsilane (5): Dimethyl (1-diazo-2-oxopropyl)phos-

phonate (0.48 g, 2.3 mmol) in MeOH (5 mL) was added at 0 °C to

a solution of the aldehyde 43 (0.75 g, 1.9 mmol) and K₂CO₃in

MeOH (30 mL). After warming to room temp., stirring was contin-

ued for 8 h. The reaction mixture was diluted with Et₂O (50 mL),

washed with aq. NaHCO₃(10%), and dried with MgSO₄. After

filtration, the solvents were evaporated under reduced pressure and

the residue purified by flash column chromatography (hexane/ethyl

acetate, 20:1) to give 5 (0.70 g, 1.8 mmol, 94%) as a colorless oil.

IR (thin film): ν = 2958, 2175 2176, 1672, 1472, 1249, 1069, 945,

˜

839, 776 cm^–1. HRMS: calcd. for [M – Me]⁺425.2366; found

425.2363.

(3S,4E)-3-(tert-Butyldiphenylsilyloxy)-2,2,5-trimethyl-9-(trimethyl-

silyl)non-4-en-8-ynal (42): A solution of the thioester 41 (5.0 g,

11.4 mmol) in CH₂Cl₂(100 mL) was cooled to –78 °C, and DIBAl- R_f(hexane/ethyl acetate, 20:1) = 0.79. [α]²_D⁰= –21.4 (c = 2.5,

1

H (13.7 mL) in hexane (1 , 13.7 mmol) was slowly added. After

3 h, the reaction was quenched with satd. aq. NH₄Cl, and the mix-

ture was extracted three times with CH₂Cl₂. The combined extracts

were washed with brine, dried with MgSO₄, and concentrated in

vacuo to give a yellow oil, which was purified by flash column

chromatography (hexane/ethyl acetate, 20:1) to yield aldehyde 42

(3.3 g, 8.5 mmol, 75 %) and its corresponding alcohol (0.7 g,

CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 5.17 (d, J = 9.4 Hz, 1

H), 4.19 (dd, J = 9.4, 2.0 Hz, 1 H), 2.27 (m, 5 H), 2.08 (dt, J =

16.5, 2.5 Hz, 1 H), 1.95 (m, 2 H), 1.67 (s, 3 H), 0.92 (s, 3 H), 0.90

(s, 3 H), 0.87, (s, 9 H), 0.024 (s, 3 H), –0.04 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 135.1 (C), 127.4 (CH), 85.5 (CH), 83.4 (C),

74.6 (CH), 70.1 (C), 69.1 (CH), 39.7 (C), 38.9 (CH₂), 28.8 (CH₂),

26.2 (3ϫCH₃), 23.1 (CH₃), 22.3 (CH₃), 18.5 (C), 17.7 (CH₂), 17.1

1.7 mmol, 15%). R_f(hexane/ethyl acetate, 10:1) = 0.81. [α]²_D⁰

=

(CH ), –3.6 (CH ), –4.7 (CH ) ppm. IR (thin film): ν = 3312, 2957,

˜

3

1

–12.8 (c = 2.8, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 9.64 (s,

1 H), 5.26 (dd, J = 9.5, 1 Hz, 1 H), 4.53 (d, J = 9.2 Hz, 1 H), 2.43

(m, 2 H), 2.30 (t, J = 7.1 Hz, 2 H), 1.76 (s, 3 H), 1.12 (s, 3 H), 1.02

(s, 3 H), 0.90 (s, 9 H), 0.20 (s, 9 H), 0.079 (s, 3 H), 0.033 (s, 3 H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 206.8 (CH), 137.2 (C),

125.9 (CH), 106.2 (C), 85.1 (C), 73.7 (CH), 51.5 (C), 39.5 (CH₂),

26.6 (3ϫCH₃), 18.9 (CH₃), 18.8 (CH₂), 17.9 (C), 16.8 (CH₃), 15.9

(CH₃), –0.28 (3 ϫ CH₃), –3.9 (CH₃), –5.1 (CH₃) ppm. IR (thin

2943, 2929, 2871, 1472, 1384, 1362, 1255, 1113, 1064, 1006, 939,

856, 847, 836 cm^–1. HRMS: calcd. for [M – tBu]⁺261.1675; found

261.1679.

1-[(2R,4R)-2-(4-Methoxyphenyl)-5,5-dimethyl-1,3-dioxan-4-yl]-2-

methylallyl Acetate (47): Isopropenylmagnesium bromide (0.5  in

THF, 48.2 mL, 24.1 mmol) was added at 0 °C to a solution of alde-

hyde 46 (5.5 g, 21.9 mmol) in Et₂O (70 mL). The reaction mixture

was allowed to warm to room temp. and stirred at this temperature

for 1 h. TLC analysis showed full consumption of the starting ma-

terial, and the reaction was quenched by the addition of satd. aq.

NH₄Cl. The aqueous phase was extracted four times with Et₂O

film): ν = 2958, 2871, 2858, 2176, 1733, 1472, 1362, 1250, 1067,

˜

840, 776 cm^–1. HRMS: calcd. for [M – Me]⁺365.2328; found

365.2332.

(4S,5E)-4-(tert-Butyldimethylsilyloxy)-3,3,6-trimethyl-10-(trimeth- (30 mL), and the combined organic phases were washed with brine

ylsilyl)dec-5-en-9-ynal (43): (Methoxymethyl)triphenylphospho- and dried with MgSO₄. After filtration and concentration, the

Eur. J. Org. Chem. 2008, 2714–2730

www.eurjoc.org

2725

M. Kögl, L. Brecker, R. Warrass, J. Mulzer

FULL PAPER

crude reaction mixture was purified by column chromatography to

give a mixture of diastereomers in a ratio of 4:1. The crude reaction

mixture was dissolved in CH₂Cl₂(50 mL) and cooled to 0 °C. NEt₃

(12.2 mL, 8.8 mmol) and acetic anhydride (6.1 mL, 6.6 mmol) were

added, and the mixture was stirred for 1 h. It was quenched with

satd. aq. NaHCO₃, and the aqueous phase was extracted four times

with CH₂Cl₂(20 mL). The combined organic phases were washed

with brine and dried with MgSO₄. After filtration, the volatiles

were evaporated under reduced pressure to give a diastereomeric

mixture of acetates 47a and 47b (5.9 g, 17.5 mmol, 80%). IR (thin

CH₂Cl₂(30 mL), and the phases were separated. The aqueous

phase was extracted three times with CH₂Cl₂, and the combined

organic phases were washed with brine and dried with MgSO₄.

After filtration and concentration in vacuo, purification by column

chromatography delivered Weinreb amide 48 (1.9 g, 5.0 mmol,

98%). [α]²_D⁰= –44.8 (c = 0.25, CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ = 7.43 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H),

5.49 (s, 1 H), 5.27 (dd, J = 8.8, 1.2 Hz, 1 H), 4.28 (d, J = 8.8 Hz,

1 H), 3.79 (s, 3 H), 3.76, 3.65 (AB system, J = 11.2 Hz, 2 H), 3.69

(s, 3 H), 3.17 (s, 3 H), 2.58 (m, 2 H), 2.38 (t, J = 7.7 Hz, 2 H), 1.76

(d, J = 1.2 Hz, 3 H), 1.17 (s, 3 H), 0.71 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 175.5 (C), 160.3 (C), 139.9 (C), 131.6 (C),

127.9 (2 ϫ CH), 121.6 (CH), 114.0 (2 ϫ CH), 102.3 (CH), 82.0

film): ν = 3674 (br.), 2956, 2838, 1734, 1651, 1394, 1369, 1302,

˜

1240, 1171, 1125, 1101, 1081, 1032, 981, 910 cm^–1. HRMS: calcd.

for [M]⁺334.1780; found 334.1772. Major Isomer 47a: R_f(hexane/

1

ethyl acetate, 4:1) = 0.36. H NMR (400 MHz, CDCl₃): δ = 7.40 (CH), 79.3 (CH₂), 61.6 (CH₃), 55.6 (CH₃), 34.7 (CH₂), 34.3 (C),

(d, J = 8.8 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2 H), 5.48 (d, J = 4.7 Hz,

1 H), 5.42 (s, 1 H), 5.10 (m, 1 H), 4.98 (t, J = 4.6 Hz, 1 H), 3.80

(s, 3 H), 3.69 (d, J = 4.8 Hz, 1 H), 3.63, 3.57 (AB system, J =

32.7 (CH₃), 30.7 (CH₂), 21.8 (CH₃), 19.2 (CH₃), 17.9 (CH₃) ppm.

IR (thin film): ν = 2928, 2854, 1653, 1616, 1517, 1465, 1387, 1248,

˜

1171, 1091, 1032, 985 cm^–1. HRMS: calcd. for [M]⁺377.2202;

10.9 Hz, 2 H), 2.06 (s, 3 H), 1.81 (dd, J = 1.2, 0.8 Hz, 3 H), 1.20 found 377.2192.

(s, 3 H), 0.87 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

(2R,4S)-2-(4-Methoxyphenyl)-5,5-dimethyl-4-[(1E)-2-methylhex-1-

170.5 (C), 160.2 (C), 142.4 (C), 128.0 (2ϫCH), 115.7 (C), 115.5

(CH₂), 114.2 (2ϫCH), 102.1 (CH), 84.4 (CH), 80.2 (CH₂), 75.2

(CH) 55.6 (CH₃), 33.4 (C), 21.9 (CH₃), 21.7 (CH₃), 19.6 (CH₃),

19.2 (CH₃) ppm. Minor Isomer 47b: R_f(hexane/ethyl acetate, 4:1)

= 0.36. ¹H NMR (400 MHz, CDCl₃): δ = 7.36 (d, J = 8.8 Hz, 2

H), 6.89 (d, J = 8.8 Hz, 2 H), 5.39 (s, 1 H), 5.32 (d, J = 8.6 Hz, 1

H), 5.07 (m, 1 H), 4.97 (t, J = 4.6 Hz, 1 H), 3.79 (s, 3 H), 3.74 (d,

J = 4.8 Hz, 1 H), 3.60 (m, 2 H), 2.06 (s, 3 H), 1.79 (m, 3 H), 1.19

(s, 3 H), 0.86 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

170.5 (C), 160.2 (C), 142.7 (C), 127.6 (2ϫCH), 115.9 (C), 115.7

(CH₂), 114.2 (2ϫCH), 101.8 (CH), 84.1 (CH), 79.3 (CH₂), 76.1

(CH), 55.6 (CH₃), 33.0 (C), 21.6 (CH₃), 19.4 (CH₃), 19.3 (CH₃),

19.0 (CH₃) ppm.

en-5-ynyl)-1,3-dioxane (49): DIBAl-H (1.5  in toluene, 4.7 mL,

7.1 mmol) was added dropwise at –78 °C to a solution of Weinreb

amide 48 (1.3 g, 3.5 mmol) in THF (30 mL). The reaction mixture

was stirred for 20 min. When TLC analysis indicated full consump-

tion of the starting material, the reaction was quenched by addition

of satd. aq. NaHCO₃and potassium sodium tartrate, and the mix-

ture was stirred at room temp. for 3 h. It was then diluted with

Et₂O (30 mL), and the phases were separated. The aqueous phase

was extracted four times with Et₂O (20 mL), and the combined

organic phases were washed with brine and dried with MgSO₄.

The solvents were removed from the reaction mixture in vacuo.

TMSCHN₂(2  in Et₂O, 2.0 mL, 4.0 mmol) in THF (20 mL) was

cooled to –78 °C, and nBuLi (2.5 , 2.0 mL, 4.9 mmol) was added.

After the reaction mixture had been stirred for 1 h, the crude alde-

hyde obtained above, dissolved in THF (5 mL), was added, and the

mixture was stirred at –78 °C for 4 h and allowed to warm to room

temp. overnight. After the addition of satd. aq. NH₄Cl (30 mL),

the reaction mixture was diluted with Et₂O (30 mL), and the phases

were separated. The aqueous phase was extracted with three por-

tions of Et₂O (20 mL) and the combined organic solvents were

washed with brine. After drying with MgSO₄, filtration, and re-

moval of the volatiles in vacuo, the crude product was purified by

column chromatography (hexane/ethyl acetate, 20:1) to give 49 as

a clear oil (2.3 mmol, 0.72 g, 67%). R_f(hexane/ethyl acetate, 20:1)

= 0.6. [α]²_D⁰= –49.4 (c = 0.30, CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ = 7.44 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H),

5.50 (s, 1 H), 5.32 (dd, J = 8.9, 1.1 Hz, 1 H), 4.29 (d, J = 8.8 Hz,

1 H), 3.79 (s, 3 H), 3.78, 3.66 (AB system, J = 11.1 Hz, 2 H), 2.35

(m, 2 H), 2.37 (m, 2 H), 1.95 (t, J = 2.6 Hz, 1 H), 1.74 (d, J =

1.28 Hz, 3 H), 1.20 (s, 3 H), 0.73 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 160.3 (C), 138.7 (C), 131.6 (C), 128.0

(2ϫCH), 125.9 (CH), 122.9 (2ϫCH), 102.3 (CH), 84.3 (C), 82.0

(CH), 79.3 (CH₂), 69.2 (CH), 55.7 (CH₃), 38.9 (CH₂), 34.3 (C), 21.8

(4E)-N-Methoxy-N-methyl-5-[(2R,4S)-2-(4-Methoxyphenyl)-5,5-di-

methyl-1,3-dioxan-4-yl]-4-methylpent-4-enamide (48): A solution of

acetates 47a and 47b (1.0 g, 3.0 mmol) in THF (15 mL) was added

slowly at –78 °C to a solution of lithium diisopropylamide (0.25 ,

35.6 mL, 8.9 mmol). After the mixture had been stirred for 2 h,

TMSCl (1.15 mL, 8.9 mmol) was added, and the reaction mixture

was allowed to warm slowly to room temp. The reaction was

quenched by the addition of satd. aq. NH₄Cl. After phase separa-

tion, the aqueous phase was extracted four times with ethyl acetate,

and the combined organic phases were washed with brine, dried

with MgSO₄, and concentrated in vacuo to give a colorless semi-

solid product, which was purified by flash column chromatography

(hexane/ethyl acetate, 4:1Ǟ1:1) to yield the desired acid (2.10 g,

6.1 mmol, 69%). R_f(hexane/ethyl acetate, 2:1) = 0.20. [α]²_D⁰= –30.0

1

(c = 0.20, CH₂Cl₂). H NMR (600 MHz, CDCl₃): δ = 7.43 (d, J =

9.5 Hz, 2 H), 6.87 (d, J = 9.5 Hz, 2 H), 5.49 (s, 1 H), 5.29 (dd, J =

8.8, 1.2 Hz, 1 H), 4.27 (d, J = 8.8 Hz, 1 H), 3.79 (s, 3 H), 3.77, 3.65

(AB system, J = 11.2 Hz, 2 H), 2.51 (m, 2 H), 2.39 (m, 2 H), 1.75

(d, J = 1.2 Hz, 3 H), 1.17 (s, 3 H), 0.69 (s, 3 H) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 178.0 (C), 160.1 (C), 138.9 (C), 131.5 (C),

128.0 (2 ϫ CH), 122.4 (CH), 114.0 (2 ϫ CH), 102.3 (CH), 81.9

(CH), 79.3 (CH₂), 55.7 (CH₃), 34.9 (CH₂), 34.2 (C), 32.7 (CH₂),

(CH ), 19.3 (CH ), 17.6 (CH ), 17.4 (CH ) ppm. IR (thin film): ν

˜

3

2

= 2924, 1614, 1517, 1388, 1245, 1091, 1029, 868, 828 cm^–1. HRMS:

calcd. for [M]⁺314.1882; found 314.1875.

21.8 (CH ), 19.3 (CH ), 17.6 (CH ) ppm. IR (thin film): ν = 2924,

˜

3

2853, 1717, 1699, 1695, 1683, 1652, 1615, 1517, 1456, 1248, 1092,

1035 cm^–1. HRMS: calcd. for [M]⁺334.1780; found 334.1175. Di-

isopropyl carbodiimide (0.87 mL, 56.0 mmol) was added at 0 °C

to a solution of the acid obtained above (1.7 g, 5.1 mmol), NEt₃

(0.85 mL, 61.0 mmol), MeHNOMe·HCl (0.59 g, 61.0 mmol), and

DMAP (cat.) in CH₂Cl₂(30 mL). The reaction mixture was al-

lowed to warm to room temp. and stirred overnight. It was

quenched by the addition of satd. aq. NH₄Cl and diluted with

(5E,7S)-7,9-Bis(tert-butyldimethylsilyloxy)-5,8,8-trimethyl-1-(tri-

methylsilyl)non-5-en-1-yne (50): Acetal 49 (200 mg, 0.64 mmol) in

THF (2 mL) was added slowly at –78 °C to a solution of lithium

diisopropylamide (1 , 1.91 mL, 1.91 mmol). After the mixture had

been stirred for 1 h, TMSCl (0.24 mL, 1.91 mmol) was added, and

the mixture was allowed to warm to room temp. over 16 h. It was

quenched by the addition of satd. aq. NH₄Cl and diluted with

EtOAc (10 mL), and the phases were subsequently separated. The

2726

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2714–2730

Total Synthesis of Pasteurestin A and B and Assignment of Configurations

aqueous phase was extracted five times with EtOAc (5 mL), and

the combined organic phases were washed with brine and dried

with MgSO₄. After filtration and removal of the organic solvents

volatiles were removed from the reaction mixture, and the crude

product was purified by column chromatography (hexane/ethyl ace-

tate, 10:1) to give the mono(TBS)-protected alcohol (32 mg,

in vacuo, the product was purified by column chromatography 0.08 mmol, 65%). R_f= 0.4 (hexane/ethyl acetate, 10:1). [α]²_D⁰= –2.0

1

(hexane/ethyl acetate, 20:1) to give the TMS-protected acetylene

(0.53 g, 1.65 mmol, 95%) as a colorless oil. R_f(hexane/ethyl acetate,

20:1) = 0.7. [α]²_D⁰= –27.8 (c = 0.65, CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ = 7.44 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H),

5.50 (s, 1 H), 5.32 (dd, J = 8.9, 1.1 Hz, 1 H), 4.29 (d, J = 8.8 Hz,

1 H), 3.79 (s, 3 H), 3.78, 3.66 (AB system, J = 11.1 Hz, 2 H), 2.35

(m, 2 H), 2.37 (m, 2 H), 1.74 (d, J = 1.3 Hz, 3 H), 1.20 (s, 3 H),

0.73 (s, 3 H), 0.13 (s, 9 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 160.3 (C), 138.7 (C), 131.6 (C), 128.0 (2ϫCH), 125.9 (CH), 122.9

(2ϫCH), 107.0 (C), 102.3 (CH), 84.3 (C), 82.0 (CH), 79.3 (CH₂),

55.7 (CH₃), 38.9 (CH₂), 34.3 (C), 21.8 (CH₃), 19.3 (CH₃), 17.6

(c = 0.25, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 5.30 (dd, J

= 9.5, 1.2 Hz, 1 H), 4.22 (d, J = 9.5 Hz, 1 H), 3.67 (dd, J = 10.7,

3.8 Hz, 1 H), 3.28 (dd, J = 10.7, 6.8 Hz, 1 H), 3.06 (dd, J = 6.8,

3.8 Hz, 1 H), 2.36 (m, 2 H), 2.24 (m, 2 H), 1.50 (d, J = 1.3 Hz, 3

H), 0.98 (s, 3 H), 0.87 (s, 9 H), 0.77 (s, 3 H), 0.13 (s, 9 H), 0.05 (s,

3 H), 0.00 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 136.0

(C), 126.8 (CH), 107.0 (C), 85.2 (C), 71.3 (CH₂), 72.1 (CH), 40.3

(C), 38.9 (CH₂), 26.1 (3 ϫ CH₃), 22.9 (CH₃), 20.9 (CH₃), 19.2

(CH₂), 18.6 (C), 17.3 (CH₃), 0.47 (3ϫCH₃), –3.62 (CH₃), –4.80

(CH ) ppm. IR (thin film): ν = 3465 (br.), 2957, 2857, 2175, 1472,

˜

3

1249, 1056, 840, 775, 760 cm^–1. HRMS: calcd. for [M⁺– tBu]

325.2019; found 325.2012. Dess–Martin periodinane (220 mg,

0.52 mmol) was added in one portion to a solution of the alcohol

obtained above (100 mg, 0.26 mmol) in CH₂Cl₂(5 mL). The solu-

tion was stirred for 2 h, a mixture of satd. aq. Na₂S₂O₃and

NaHCO₃(1:1, 3 mL) was added, and the mixture was stirred until

the the organic phase became clear. After phase separation, the

aqueous phase was washed three times with CH₂Cl₂. The combined

organic phases were washed with brine, dried with MgSO₄, and

concentrated in vacuo to give a yellow oil, which was purified by

flash column chromatography (hexane/ethyl acetate, 10:1), to yield

aldehyde 42 (88 mg, 0.24 mmol, 92%). The analytical data obtained

for this compound are identical in all respects to those for 42 from

the Reformatsky approach described above.

(CH ), 17.4 (CH ), 0.5 (3ϫCH ) ppm. IR (thin film): ν = 2957,

˜

3

2

3

1682, 1615, 1519, 1249, 1091, 1040, 841 cm^–1. HRMS: calcd. for

[M]⁺386.2277; found 386.2285. The product obtained above

(0.53 g, 1.7 mmol) was dissolved in THF/CH₃CN (1:1, 6 mL) and

cooled to 0 °C. Acetic acid (80%, 9 mL) was then added, and the

ice bath was removed. After the mixture had been stirred at room

temp. for 24 h, TLC analysis showed full consumption of the start-

ing material. The reaction was quenched by the addition of satd.

aq. NaHCO₃, and THF was removed in vacuo. After addition of

CH₂Cl₂(20 mL) and H₂O (5 mL), the reaction mixture was filtered

through a pad of Celite, the phases were separated, and the aque-

ous phase was extracted four times with CH₂Cl₂(6 mL). The com-

bined organic phases were washed with brine, dried with MgSO₄,

and filtered. The removal of the organic solvents from the reaction

mixture in vacuo delivered a yellow oil, which was used without

further purification. TBSOTf (0.66 g, 0.57 mL, 2.5 mmol) was

added dropwise at 0 °C to the crude product obtained above and

2,6-lutidine (0.54 g, 0.59 mL, 5.0 mmol) in CH₂Cl₂(50 mL), and

the reaction mixture was stirred at 0 °C for 30 min. The reaction

was quenched by the addition of satd. aq. NaHCO₃. The phases

were separated, the organic phase was washed twice with CH₂Cl₂

(10 mL), and the combined organic phases were washed with HCl

(2 ) and then with NaHCO₃and dried with MgSO₄. Filtration

and concentration in vacuo, together with purification by column

chromatography, delivered bis(TBS)-protected alcohol 50 (0.74 g,

1.6 mmol, 91%) as a clear oil. R_f(hexane/ethyl acetate, 50:1) = 0.8.

tert-Butyldimethyl{(7S,7aS,7bR)-6,6,7b-trimethyl-2,5,6,7,7a,7b-hexa-

hydro-1H-cyclobuta[e]inden-7-yloxy}silane (7): CpCo(CO)₂(0.48 g,

2.7 mmol) in predried, degassed toluene (5 mL) and protected from

light was added by syringe (syringe pump) over a period of 6 h to

a solution of enediyne 5 (0.80 g, 2.1 mmol) in toluene at reflux

under irradiation with a halogen reflector lamp (visible light, max.

500 W). After completion of the addition, the solution was irradi-

ated at reflux for another 2 h. When TLC analysis showed the com-

plete disappearance of the enediyne, the crude reaction mixture was

cooled to room temp., and the volatiles were removed by vacuum

transfer. The brown residue was dissolved in dried, degassed DME

(10 mL), and CuCl₂·2 H₂O (1.00 g, 5.5 mmol) was added. The

black solution was stirred at room temp. for 3 h, the mixture was

then partitioned between H₂O (30 mL) and hexane (50 mL), and

the layers were separated. The aqueous layer was extracted four

times with hexane (10 mL), and the combined organic phases were

dried with MgSO₄, filtered, and concentrated in vacuo to furnish

a very air-sensitive yellow oil. This material was eluted through a

degassed silica gel column with degassed hexane to give 7 (0.40 g,

0.9 mmol, 40%). R_f(hexane) = 0.7. [α]²_D⁰= –47.3 (c = 2.3, CH₂Cl₂).

¹H NMR (600 MHz, CDCl₃): δ = 5.68 (s, 1 H), 5.54 (s, 1 H), 3.66

(d, J = 9.6 Hz, 1 H), 2.90 (ddd, J = 19.3, 10.0, 2.0 Hz, 1 H), 2.68

(dm, J = 9.6 Hz, 1 H), 2.61 (ddd, J = 19.3, 8.3, 3.2 Hz, 1 H), 2.16

(d, J = 17.4 Hz, 1 H), 1.95 (d, J = 17.4 Hz, 1 H), 1.89 (m, 1 H),

1.86 (m, 1 H), 1.01 (s, 3 H), 1.00 (s, 3 H), 0.83 (s, 3 H), 0.88 (s, 9

H), 0.02 (s, 3 H), 0.07 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃):

δ = 145.4 (C), 139.5 (C), 116.4 (CH), 112.6 (CH), 80.1 (CH), 54.9

(CH), 43.5 (CH₂), 40.0 (C), 39.6 (C), 33.0 (CH₃), 28.4 (CH₂), 27.2

(CH₂), 26.0 (3 ϫ CH₃), 20.7 (CH₃), 17.9 (C), 15.1 (CH₃), –3.9

1

[α]²_D⁰= –13.6 (c = 0.85, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ

= 5.19 (d, J = 9.6 Hz, 1 H), 4.30 (d, J = 9.6 Hz, 1 H), 3.43, 3.21

(AB system, J = 9.3 Hz, 2 H), 2.38 (m, 2 H), 2.16 (t, J = 7.4 Hz, 2

H), 1.64 (d, J = 0.9 Hz, 3 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.80 (s,

3 H), 0.74 (s, 3 H), 0.14 (s, 9 H), 0.02 (s, 6 H), 0.00 (s, 3 H), –0.06

(s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 134.6 (C), 127.5

(CH), 107.5 (C), 84.9 (C), 72.1 (CH), 69.4 (CH₂), 41.5 (C), 39.0

(CH₂), 26.3 (6ϫCH₃), 21.1 (CH₃), 19.6 (CH₃), 19.3 (CH₂), 18.6

(C), 17.2 (CH₃), 17.4 (CH₂), 0.5 (3ϫCH₃), –3.5 (CH₃), –4.7 (CH₃),

–5.0 (CH ), –5.1 (CH ) ppm. IR (thin film): ν = 2957, 2930, 2857,

˜

3

1652, 1471, 1464, 1456, 1360, 1250, 1060, 840 cm^–1. HRMS: calcd.

for [M⁺– tBu] 439.2884; found 439.2880.

(3S,4E)-3-(tert-Butyldimethylsilyloxy)-2,2,5-trimethyl-9-(trimethyl-

silyl)non-4-en-8-ynal (42): HF·pyridine (70 % HF in pyridine,

0.92 mL, 6.50 mmol) was added to a solution of bis(TBS) ether 50

(65 mg, 0.13 mmol) in THF (3 mL), and the solution was stirred at

room temp. for 48 h. When TLC analysis showed consumption of

the starting material, satd. aq. NaHCO₃was added, the mixture

was diluted with Et₂O (10 mL), and the aqueous phase was further

extracted four times with Et₂O (5 mL). The combined organic ex-

tracts were washed with HCl (2 , 5 mL), then with NaHCO₃

(10 mL), and were finally dried with MgSO₄. After filtration, the

(CH ), –3.8 (CH ) ppm. IR (thin film): ν = 2956, 2942, 2929, 2876,

˜

3

2858, 1468, 1462, 1366, 1257, 1254, 1129, 1113, 1098, 863,

836 cm^–1. HRMS: calcd. for [M]⁺318.2379; found 318.2374.

tert-Butyldimethyl{(2aS,7S,7aS,7bS)-6,6,7b-trimethyl-

2,2a,3,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]inden-7-yloxy}silane

Eur. J. Org. Chem. 2008, 2714–2730

www.eurjoc.org

2727

M. Kögl, L. Brecker, R. Warrass, J. Mulzer

FULL PAPER

(51): Li (0.02 g, excess) was added at –78 °C to a stirred solution

of liquid ammonia (ca. 40 mL), dry THF (15 mL), and dry 2-meth-

ylpropan-2-ol (10 mL) contained in a 100 mL three-necked round-

bottomed flask fitted with a dry ice/acetone condenser and septa.

Upon formation of a persistent deep blue color, a solution of diene

7 (0.62 g, 1.94 mmol) in dry THF (5 mL) was introduced by syringe

over 1 min. The reaction was quenched after 1 h by treatment with

portions of NH₄Cl (0.5 g, excess), the NH₃was allowed to evapo-

rate overnight, hexane was added, and the solids were removed by

filtration. The filtrate was concentrated in vacuo to afford a solid-

containing oil, which was purified by column chromatography

(hexane/ethyl acetate, 50:1) to give olefin 51 (0.53 g, 1.65 mmol,

85%) as a colorless oil. R_f(hexane) = 0.9. [α]²_D⁰= +10.5 (c = 2.2,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 5.46 (m, 1 H), 3.69 (d,

J = 9.1 Hz, 1 H), 2.48 (m, 1 H), 2.25 (m, 1 H), 2.02 (m, 5 H), 1.82

(m, 1 H), 1.66 (m, 2 H), 1.01 (s, 3 H), 0.96 (s, 3 H), 0.91 (s, 9 H),

0.90, (s, 3 H), 0.09 (s, 3 H), 0.04 (s, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 140.7 (C), 118.3 (CH), 81.8 (CH), 52.1 (CH), 44.3 (C),

44.4 (CH₂), 41.6 (CH), 41.7 (CH₂), 41.0 (C), 33.9 (CH₂), 29.6

(CH₂), 27.5 (CH₃), 26.3 (3 ϫ CH₃), 25.2 (CH₃), 21.1 (C), 23.5

(CH₃), 26.7 (3 ϫ CH₃), 26.4 (CH₃), 24.3 (CH₂), 23.3 (C), –2.0

(CH₃), –3.5 (CH₃) ppm.

Methyl (2aR,4aR,7S,7aS,7bS)-7-(tert-Butyldimethylsilyloxy)-4-hy-

droxy-6,6,7b-trimethyl-2,2a,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta-

[e]indene-3-carboxylate (53a, syn): nBuLi (2.5  in THF, 0.18 mL,

0.46 mmol) was added at 0 °C to a solution of diisopropylamine

(47 mg, 0.46 mmol) in THF (5 mL), and the mixture was stirred at

this temperature for 30 min. After it had then been cooled to

–78 °C, HMPA (82 mg, 0.46 mmol) and a solution of epimeric

ketones 52a and 52b (140 mg, 0.42 mmol) in THF (2 mL) were

slowly added, and the mixture was stirred at –78 °C for 2 h. Dry

carbon dioxide (generated from dry ice and passed through concen-

trated sulfuric acid) was then bubbled into the mixture at –58 °C

for 1 h. After addition of aq. HCl (1 , 0.5 mL), the mixture was

quickly warmed to 0 °C with an ice bath. (Trimethylsilyl)diazo-

methane (2  in Et₂O, 0.35 mL, 0.7 mmol) was slowly added to the

reaction mixture. When TLC showed the acid no longer to be pres-

ent, the excess of (trimethylsilyl)diazomethane was quenched with

additional HCl (1 ), Et₂O was added, and the phases were sepa-

rated. The aqueous phase was extracted several times with Et₂O,

the combined organic phases were washed with satd. aq. NaHCO₃

and dried, and the volatiles were evaporated under reduced pres-

sure. Purification by column chromatography delivered an insepa-

rable mixture of β-oxo esters 53a and 53b (0.19 mmol, 75 mg,

(CH ), –2.6 (CH ), –5.1 (CH ) ppm. IR (thin film): ν = 2958, 2871,

˜

3

2857, 1472, 1463, 1257, 1254, 1250, 1121, 875, 835, 773 cm^–1

.

HRMS: calcd. for [M]⁺320.2535; found 320.2529.

(2aS,4aR,7S,7aS,7bS)-7-(tert-Butyldimethylsilyloxy)-6,6,7b-tri-

methyldecahydro-cyclobuta[e]inden-4-one (52a, syn): B₂H₆·THF

(1  in THF, 1.9 mL, 1.9 mmol) was added at 0 °C to a solution of

olefin 51 (202 mg, 0.6 mmol) in dry THF (8 mL). After 5 h at room

temp., TLC analysis of the reaction mixture indicated no remaining

olefin. Aq. K₂CO₃(1 , 2.5 mL, 2.5 mmol) and H₂O₂(30% by wt.,

1.1 mL, 10.0 mmol) were added sequentially at 0 °C to the vigor-

ously stirred solution, the flask was then fitted with a reflux con-

denser, and the biphasic mixture was stirred with heating to 60–

65 °C in an oil bath for 3 h. The cooled solution was then diluted

with hexane (30 mL), the layers were separated, the aqueous phase

was extracted three times with hexane (10 mL), and the combined

organic phases were washed with satd. aq. Na₂S₂O₃and then with

brine, dried with MgSO₄, and filtered, after which the volatiles were

evaporated under reduced pressure. The crude product was filtered

through a short pad of silica gel, to afford a mixture of inseparable

diastereomers as a colorless oil. The product obtained above

(166 mg, 0.49 mmol) was dissolved in CH₂Cl₂(5 mL), and Dess–

Martin periodinane (510 mg, 1.20 mmol) was added. After the mix-

ture had been stirred at room temp. for 2 h, TLC reaction monitor-

ing showed complete consumption of the starting material. A mix-

ture of satd. aq. NaHCO₃and Na₂S₂O₃(1:1, 5 mL) was added to

the reaction mixture, which was stirred until the biphasic mixture

became clear. The phases were then separated, and the aqueous

phase was extracted three times with CH₂Cl₂(3 mL). The com-

bined organic phases were washed with brine, dried, and filtered.

The solvent was removed in vacuo, and the product was purified

by column chromatography (hexane/ethyl acetate, 10:1) to give an

epimeric mixture of ketones 52a and 52b (2:1) as a clear oil

(156 mg, 0.47 mmol, 74%). R_f(hexane/ethyl acetate, 9:1) = 0.7. IR

45%). IR (thin film): ν = 2953, 2930, 2858, 1653, 1648, 1617, 1457,

˜

1437, 1291, 1249, 1223, 1112, 863 837, 773, 668 cm^–1. HRMS:

calcd. for [M]⁺394.2539; found 394.2542. Isomer 53a: ¹H NMR

(400 MHz, CDCl₃): δ = 12.29 (s, 1 H), 3.74 (s, 3 H), 3.61 (d, J =

7.4 Hz, 1 H), 2.92 (dd, J = 14.0, 8.2 Hz, 1 H), 2.65 (m, 1 H), 2.37

(dd, J = 10.9, 7.9 Hz, 1 H), 2.26 (m, 1 H), 2.07 (dd, J = 8.5, 7.5 Hz,

1 H), 1.88 (m, 1 H), 1.82 (m, 1 H), 1.49 (m, 1 H), 1.41 (m, 1 H),

1.33 (s, 3 H), 0.96 (s, 3 H), 0.91 (s, 3 H), 0.89 (s, 9 H), –0.073 (s, 3

H), –0.064 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.7

(C), 173.4 (C), 100.6 (C), 82.3 (CH), 53.6 (CH₃), 51.7 (CH), 43.1

(CH), 42.6 (CH₂), 41.1 (C), 38.4 (C), 34.7 (CH), 32.7 (CH₂), 29.3

(CH₃), 27.3 (CH₂), 27.1 (CH₃), 26.9 (CH₃), 26.8 (3ϫCH₃), 18.7

(C), –1.6 (CH₃), –3.0 (CH₃) ppm.

Methyl (4aR,7S,7aS,7bR)-7-(tert-Butyldimethylsilyloxy)-6,6,7b-tri-

methyl-4-oxo-2,4,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]indene-3-

carboxylate (54): A solution of β-oxo esters 53a and 53b (90 mg,

0.23 mmol) in THF (2 mL) was slowly added at –78 °C to a stirred

solution of lithium diisopropylamide (0.25  in THF, 0.57 mmol,

2.28 mL), and the mixture was allowed to warm to 0 °C. After the

solution had been stirred for 45 min, a solution of phenylselenyl

chloride (0.25 mmol, 48 mg) in THF (0.5 mL) was added, and the

mixture was stirred for another 20 min. Addition of satd. aq.

NH₄Cl quenched the mixture, which was diluted with Et₂O, and

the aqueous phase was extracted three times with Et₂O. The com-

bined organic phases were washed with brine and dried with

MgSO₄. After concentration of the crude product in vacuo and

filtration through a short pad of silica gel in order to separate the

selenides from the excess of phenylselenyl chloride, a mixture of

epimers (80 mg, 0.14 mmol, 63%) was obtained as yellow oil and

(thin film): ν = 2953, 1713, 1472, 1255, 1095, 837, 802, 776, used without further purification. Satd. aq. NH₄Cl (0.25 mL) and

˜

727 cm^–1. HRMS: calcd. for [M]⁺336.2485; found 336.2475. Epi-

mer 52a: H NMR (400 MHz, CDCl₃): δ = 3.83 (d, J = 7.6 Hz, 1 mixture obtained above (20 mg, 0.036 mmol) in CH₂Cl₂(2 mL).

H), 2.99 (m, 1 H), 2.67 (dd, J = 11.6, 7.6 Hz, 1 H), 2.65 (dd, J = The biphasic mixture was stirred vigorously for 2 h at the same

aq. H₂O₂(30% by wt., 1.5 mL) were added at 0 °C to the crude

1

12.8, 8.8 Hz, 1 H), 2.46 (m, 1 H), 2.26 (m, 1 H), 2.18 (ddd, J =

12.8, 4.8, 1.3 Hz, 1 H), 1.94 (m, 1 H), 1.71 (m, 2 H), 1.62 (m, 1 H),

1.40 (m, 1 H), 1.15 (s, 3 H), 1.05 (s, 3 H), 0.92 (s, 3 H), 0.90 (s, 9 H),

–0.11 (s, 3 H), –0.072 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

temperature. After dilution with H₂O (1 mL) and CH₂Cl₂(2 mL),

the phases were separated, the aqueous phase was extracted twice

with CH₂Cl₂, and the combined organic phases were washed with

aq. Na₂S₂O₃(10%) and brine, dried with MgSO₄, and concentrated

= 215.9 (C), 83.5 (CH), 55.7 (CH), 47.7 (CH), 44.4 (CH), 43.44 in vacuo. The semisolid product was purified by column

(C), 42.6 (CH₂), 42.5 (C), 41.1 (CH₂), 32.8 (CH₂), 27.9 (CH₃), 27.3 chromatography (hexane/ethyl acetate 10:1) to provide only the de-

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Eur. J. Org. Chem. 2008, 2714–2730

Total Synthesis of Pasteurestin A and B and Assignment of Configurations

sired α,β-unsaturated β-keto ester 54 in 72 % yield (31 mg,

0.079 mmol). R_f(hexane/ethyl acetate 4:1) = 0.27. [α]²_D⁰= –12.0 (c

2 (2.5 mg, 0.009 mmol, 59%) as a semisolid colorless oil. R_f= 0.10

(ethyl acetate). [α]²_D⁰= –42 (c = 0.10, MeOH). ¹H NMR (600 MHz,

= 0.20, CH₂Cl₂). ¹H NMR (600 MHz, CDCl₃): δ = 3.79 (d, J = CD₃OD): δ = 4.17 (ddd, J = 9.0, 3.2, 2.0 Hz, 1 H, (CO₂H)

7.0 Hz, 1 H), 3.74 (s, 3 H) 3.32 (ddd~dt, J = 18.8, 9.2 Hz, 1 H), CCHOH), 3.65 (d, J = 9.7 Hz, 1 H, C(CH₃)CHCHOH), 3.17

3.19 (ddd, J = 18.9, 8.4, 4.0 Hz, 1 H), 3.08 (ddd~dt, J = 12.6,

(dddd, J = 17.3, 8.3, 3.9, 2.0 Hz, 1 H, C(CO₂H)CCHH), 3.04 (ddd,

7.4 Hz, 1 H), 2.66 (dd, J = 12.6, 7.0 Hz, 1 H), 2.20 (m, 1 H), 2.12 J = 17.3, 9.4, 3.6 Hz, 1 H, C(CO₂H)CCHH), 2.29 (dddd, J = 12.6,

(ddd~dt, J = 10.4, 4.0 Hz, 1 H), 1.82 (dd, J = 13.0, 7.4 Hz, 1 H),

1.41 (t, J = 13.0 Hz, 1 H), 1.26 (s, 3 H), 1.03 (s, 3 H), 0.90 (s, 3 H),

10.2, 9.0, 7.7 Hz, 1 H, C(CO₂H)CH(OH)CH), 2.21 (dd, J = 12.6,

9.7 Hz, 1 H, CH(OH)CHCH), 2.07 (ddd, J = 19.4, 8.3, 3.6 Hz, 1

0.89 (s, 9 H), –0.09 (s, 3 H), –0.04 (s, 3 H) ppm. ¹³C NMR H, CCH₃CHHCH₂), 2.05 (ddd, J = 19.4, 9.4, 3.9 Hz, 1 H,

(150 MHz, CDCl₃): δ = 197.3 (C), 184.6 (C), 163.4 (C), 123.9 (C),

CCH₃CHHCH₂), 1.87 (dd, J = 12.8, 7.7 Hz, 1 H, CH(OH)

81.2 (CH), 52.7 (CH), 51.9 (CH₃), 49.4 (CH), 45.6 (C), 43.1 (C), CHCHH), 1.31 (s, 3 H, CHCCH₃), 1.20 (dd, J = 12.8, 10.2 Hz,

40.3 (CH₂), 35.1 (CH₂), 30.6 (CH₂), 27.4 (CH₃), 26.2 (3ϫCH₃),

23.7 (CH₃), 20.8 (CH₃), 18.4 (C), –3.4 (CH₃), –3.7 (CH₃) ppm. IR

1 H, CH(OH)CHCHH), 1.06 (s, 3 H, CCH₃CH₃), 0.95 (s, 3 H,

CCH₃CH₃) ppm. ¹³C NMR (150 MHz, CD₃OD): δ = 171.8 (C),

(thin film): ν = 2927, 2363, 1734, 1561, 1256, 898 cm^–1. HRMS: 170.3 (C), 123.7 (C), 82.5 (CH), 73.9 (CH), 52.6 (CH), 47.8 (C),

˜

calcd. for [M]⁺392.2383; found 392.2395.

47.3 (CH), 45.2 (CH₂), 43.3 (C), 38.3 (CH₂), 31.2 (CH₂), 28.1

(CH ), 21.4 (CH ), 21.0 (CH ) ppm. IR (thin film): ν = 3369 (br.),

˜

3

Methyl (4S,4aR,7S,7aS,7bR)-7-(tert-Butyldimethylsilyloxy)-4-hy-

droxy-6,6,7b-trimethyl-2,4,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta-

[e]indene-3-carboxylate (55): A solution of β-oxo ester 54 (10 mg,

0.025 mmol) in MeOH (2 mL), together with CeCl₃·7H₂O (93 mg,

0.25 mmol), was stirred at 0 °C for 30 min. Sodium borohydride

(2.8 mg, 0.075 mmol) was then added, and the reaction mixture

was stirred at 0 °C for another 15 min. At this point, the reaction

was quenched with water and diluted with ethyl acetate. The phases

were separated, and the aqueous phase was extracted three times

with ethyl acetate. The combined organic extracts were washed with

brine, dried with MgSO₄, and concentrated under reduced pressure.

The crude product was purified by flash column chromatography,

with elution with hexane/ethyl acetate (4:1), to yield alcohol 55

(8.9 mg, 0.023 mmol, 90%). R_f= 0.50 (hexane/ethyl acetate, 4:1).

2930, 2854, 1687, 1651, 1463, 1248, 1036, 895, 862 cm^–1. HRMS:

calcd. for [M]⁺280.1675; found 280.1679 (methyl ester).

Supporting Information (see footnote on the first page of this arti-

cle): MIC data for pasteurestin A, pasteurestin B, and ent-pasteure-

stin B, NMR data for compounds 1, 2, 4, 5, 6a, 6b, 7, 22a, 23, 40,

54, and 55.

Acknowledgments

M. K. gratefully acknowledges financial support from Intervet In-

novation GmbH. We thank S. Felsinger for NMR spectra, M.

Zinke for HPLC analysis, and Dr. C. Wilhelm for MIC determi-

nation.

[α]²_D⁰= –29.0 (c = 0.10, CH₂Cl₂). H NMR (600 MHz, CDCl₃): δ

1

= 5.28 (d, J = 1.4 Hz, 1 H), 4.19 (d, J = 8.7 Hz, 1 H), 3.74 (s, 3

H), 3.70 (d, J = 8.3 Hz, 1 H), 3.07 (m, 1 H), 2.98 (m, 1 H), 2.33

(m, 1 H), 2.22 (dd, J = 13.1, 8.2 Hz, 1 H), 2.03 (dd, J = 9.4, 3.0 Hz,

2 H), 1.92 (dd, J = 12.4, 7.4 Hz, 1 H), 1.20 (s, 3 H), 1.14 (t, J =

12.4 Hz, 1 H), 1.01 (s, 3 H), 0.91 (s, 3 H), 0.88 (s, 9 H), 0.09 (s, 3

H), 0.04 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 169.6

(C), 168.4 (C), 121.8 (C), 82.1 (CH), 71.8 (CH), 52.4 (CH), 51.7

(CH₃), 46.2 (C), 45.5 (CH), 44.6 (CH₂), 42.5 (C), 36.3 (CH₂), 29.6

(CH₂), 27.7 (CH₃), 26.3 (3ϫCH₃), 20.8 (CH₃), 20.4 (CH₃), 18.6

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˜

3

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Received: January 22, 2008

Published Online: April 15, 2008

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Article Doi

Novel protoilludane lead structure for veterinary antibiotics: Total synthesis of pasteurestins A and B and assignment of their configurations

DOI: 10.1002/ejoc.200800074

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