Total synthesis of myxovirescin A1

DOI: 10.1002/chem.200700926

Total Synthesis of Myxovirescin A₁

Alois Fürstner,* Melanie Bonnekessel, Jarred T. Blank, Karin Radkowski, Günter Seidel,

Fabrice Lacombe, Barbara Gabor, and Richard Mynott^[a]

Abstract: A convergent total synthesis

of the antibiotic macrolide myxovires-

cin A₁(1) is described that is largely

based on reagent- and catalyst-control-

led transformations. This includes a

highly regioselective Negishi reaction

of dibromo-alkene 48 with an alkynyl-

zinc reagent, and a palladium catalyzed

alkyl-Suzuki coupling of the resulting

enyne derivative 12 with the 9-BBN-

adduct derived from alkene 61. The

latter was obtained via an asymmetric

hydrogenation of the chlorinated b-ke-

toester 49 and an anti-selective oxyally-

lation of the functionalized aldehyde

53 as the key steps. The preparation of

the bis-borylated allyl-donor 57 used in

the oxyallylation step, however, re-

quired careful optimization and led to

important insights into the nature of

the classical hydroborating agent “di-

(isopinocampheyl)borane (Ipc₂BH)”. It

was unambiguously shown by X-ray

crystallography that in the solid state

this compound is dimeric, but it is

prone to undergo an essentially quanti-

tative mono-deborylation when dis-

solved in CH₂Cl₂or benzene; its com-

position in ethereal solvents is even

more complex as evident from

¹¹B NMR data. Product 71 derived

from 12 and 61 was elaborated into the

enyne–yne derivative 75, which served

as the substrate for an exquisitely se-

lective ring closing alkyne metathesis

reaction (RCAM) catalyzed by the mo-

lybdenum tris-amido complex 20 acti-

vated in situ with CH₂Cl₂. The resulting

cyclic enyne 76 was subjected to a

ruthenium catalyzed trans-hydrosilyla-

tion/proto-desilylation tandem. Al-

though [Cp*RuACTHRE(UNG MeCN)₃]PF₆had pre-

viously been recommended as catalyst

of choice for trans-hydrosilylation reac-

tions of internal alkynes, this complex

failed to afford the desired product,

whereas its sterically less hindered con-

gener [CpRuCAHTER(UNG MeCN)₃]PF₆permitted

the reaction to be performed in appre-

ciable yield, but at the expense of a

lower stereoselectivity. AgF-mediated

proto-desilylation of the isomeric si-

lanes 79 and 80 followed by cleavage

of the remaining acetal protecting

groups afforded myxovirescin A₁and

its hitherto unknown 14Z-isomer 81,

respectively.

Keywords: alkynes · antibiotics ·

macrocyclization · metathesis · nat-

ural products

Introduction

agents of various origins remains a valid strategy in the

quest for ever more effective drugs to combat bacterial in-

fections.^[1]

Antibacterial chemotherapy has benefited enormously from

natural products, which have found either direct use as ther-

apeutic agents, serve as elaborate building blocks for the

preparation of semisynthetic drugs, or play an important

role as leads for further optimization. Although challenged

by alternative paradigms of contemporary medicinal chemis-

try, the (re)evaluation of naturally occurring antimicrobial

In this context, the myxovirescins represent an interesting

class of compounds. Isolated as early as 1982 from Myxo-

coccus virescens (strain v 48), more than 30 members of this

family of macrocyclic lactone/lactam derivatives are known

to date.^[2–5]Although a few ring-expanded as well as ring-

contracted representatives are on this list,^[3]most myxovires-

cins differ solely in the substitution-, oxygenation- and ste-

reochemical pattern of a highly conserved 28-membered

macrocyclic frame.^[2,3]It is interesting to note that they are

usually produced in form of either epimer at C-25, with

myxovirescin A₁(1) and A₂(2) being a typical pair.^[3]The

obvious capacity of the operative biosynthetic machinery

therefore holds great promise for metabolic engineering in

order to obtain “non-natural” natural products with im-

proved application profiles.^[6,7]

[a] Prof. A. Fürstner, Dr. M. Bonnekessel, Dr. J. T. Blank,

K. Radkowski, Ing. G. Seidel, Dr. F. Lacombe, B. Gabor,

Dr. R. Mynott

Max-Planck-Institut für Kohlenforschung

45470 Mülheim/Ruhr (Germany)

Fax : (+49)208-306-2994

E-mail: fuerstner@mpi-muelheim.mpg.de

8762

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

FULL PAPER

difficult to separate and hence of limited synthetic utility

(Scheme 1).^[17,18]Moreover, as the stereochemical outcome

of RCM-based macrocyclizations cannot yet be rigorously

Scheme 1. Possible product spectrum arising from RCM reactions of

diene–ene substrates.

predetermined, the number of possible isomers may increase

even further. Finally, one has to keep in mind that polar

substituents in the substrate that are able to chelate the in-

cipient metal carbene intermediates can strongly impact the

effectiveness of RCM-based macrocyclizations.^[19,20]Because

these issues, collectively, discourage an RCM approach to

1,^[8]we envisaged the formation of its 28-membered ring at

C-14/C-15 by an a priori less ambiguous ring closing alkyne

metathesis (RCAM) reaction.^[21,22]

However, this strategic decision also bore considerable

risk. The metathesis of alkynes in general is much less ex-

plored, although a rapidly growing number of applications

in the total synthesis arena^[23–25]highlight the favorable ap-

plication profile of the available catalysts.^[26–28]Yet, success-

ful cases of RCAM reactions of conjugated enynes, as re-

quired in the present context, remain extremely scarce.^[29]

This may be due to the fact that the catalyst must be able to

rigorously distinguish between their conjugated double and

triple bonds. Moreover, the catalytically competent high

valent metal alkylidyne species are inherently Lewis acidic

and hence responsive to donor sites within a given substrate.

Therefore, it was by no means clear at the outset of this

project if an enyne flanked by a methyl ether, as present in

the cyclization precursor B, would be amenable to produc-

tive enyne–yne metathesis by any of the available systems

(Scheme 2).^[26–28]

Provided that this challenge could be met, the subsequent

reduction of the produced cyclic enyne A to an (E,Z)-con-

figured 1,3-diene also constitutes a non-trivial task. Al-

though ruthenium catalyzed trans-hydrosilylation of the

alkyne followed by proto-desilylation of the resulting vinyl-

silane may be viable (Scheme 3),^[30,31]previous studies indi-

cate that 1,3-enynes are at the edge of this emerging meth-

odology, requiring not only fairly high catalyst loadings but

also the reactions to be performed in neat silane in order to

be effective.^[31a]None of the few examples reported in the

literature is anywhere close in complexity to the projected

case. Therefore a model study was undertaken to assess the

risk of this strategy prior to launching the actual total syn-

thesis campaign.

The myxovirescins are broad spectrum antibiotics with

considerable activity against Gram-negative bacteria.^[3]They

are believed to interfere with bacterial cell wall synthesis,

most probably by inhibiting the translocation rather than

the cross linking steps. Moreover, they are exceptionally ad-

hesive to various surfaces, including dental tissue, which po-

tentially qualifies them for the treatment of plaque and gin-

givitis in humans.^[2–7]Preliminary investigations indicate con-

siderable scope for structural modifications while maintain-

ing appreciable antibacterial activity.^[3,8]

In addition to the emerging mutasynthetic approaches,^[7]

“diverted total synthesis” represents another way for sys-

tematic structural editing once the natural leads have been

conquered.^[9]This latter challenge has been met by the

groups of Williams and Seebach, who reported concise total

syntheses of myxovirescin A₁, B and M₂.^[10,11]The complex

structures of these targets, however, provide ample opportu-

nity for complementary studies, with the primary aim of cut-

ting back on the number of steps, particularly those in the

longest linear sequence.^[12,13]Moreover, the published syn-

theses rely on chiral building blocks from nature as well as

on macrolactonization or -lactamization strategies. Hence,

we became interested in developing a largely reagent- and

catalyst-controlled alternative route to myxovirescin A₁(1)

as the most potent antibiotic of this series.^[14]The results of

our “first-generation” approach are summarized below.

Results and Discussion

Strategic considerations: Despite the tremendous success of

ring closing metathesis (RCM) for the formation of macro-

cyclic skeletons,^[15,16]the preparation of cyclic 1,3-dienes re-

mains a difficult task. Conjugated dienes can react with the

standard metathesis catalysts either at the terminal or the

internal double bond, thereby leading to mixtures that are

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8763

A. Fürstner et al.

Scheme 4. a) PDC, CH₂Cl₂, 59%; b) Mg, THF, reflux, then aldehyde 7,

RT, 73%; c) conc. HCl, MeOH, quant.; d) i) Dess-Martin periodinane,

CH₂Cl₂; ii) NaClO₂, H₂NSO₃H, THF/H₂O (1:1), 78% (over both steps);

e) 9-H-9-BBN, THF, 08C ! RT; then bromide 12, Cs₂CO₃, [(dppf)PdCl₂]

(7 mol%), Ph₃As (15 mol%), aq. DMF, 90%; f) TBAF, THF, 90%;

g) EDC, DMAP, CH₂Cl₂, 90%.

Scheme 2. Retrosynthetic analysis of 1 based on ring closing alkyne meta-

thesis (RCAM) as the key transformation.

generated in situ from complex 20 and CH₂Cl₂as previously

described by our group,^[27]smoothly converted compound 15

into the desired cyclic enyne 16 (Scheme 5). From this result

Scheme 3. Strategy for the conversion of enynes into 1,3-dienes by a

ruthenium catalyzed trans-hydrosilylation and subsequent proto-desilyla-

tion.

Model studies: The chosen model 15 was prepared as shown

in Scheme 4. To this end, commercial 8-bromooctanol was

MOM-protected and the resulting product 4 transformed

into the corresponding Grignard reagent 5. Addition of 5 to

aldehyde 7, cleavage of the MOM-acetal in 8, and oxidation

of the resulting diol 9 gave keto-acid 10 in good overall

yield.

This compound was esterified with alcohol 14, which was

accessible by an alkyl-Suzuki reaction^[32]of bromide 12 (see

below) with the organoborane derived from 11 and 9-H-9-

BBN. Although this transformation required optimization, it

could be effected in high yield with catalytic amounts of

[(dppf)PdCl₂] in the presence of Ph₃As and Cs₂CO₃. Gratify-

ingly, the molybdenum-based alkyne metathesis catalyst

Scheme 5. a) Complex 20 (10 mol%), toluene, CH₂Cl₂, 808C, 80%;

b) complex 21 (50 mol%), toluene, 808C, 40% (16)

+ 24% (17);

c) (EtO)₃SiH, complex 3 (30 mol%); d) AgF, aq. THF/MeOH, 50%

(over both steps).

8764

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

it must be concluded that the ether flanking the reacting

alkyne does not interfere with productive RCAM, thus fur-

ther attesting to the remarkable functional group tolerance

of the chosen catalyst system.^[27]For comparison, the now

commercially available Schrock alkylidyne complex

[26]

ꢀ

[(tBuO)₃W CCMe₃] (21) has also been tested, yet found

to be significantly less productive. In this case, substantial

amounts of the alkyne cross metathesis product 17 were also

formed, indicating that the reaction likely initiates at the

alkyne- rather than the enyne site of the substrate.

The subsequent trans-hydrosilylation of 16 in neat

(EtO)₃SiH required

ACHTREUNG

a fairly high loading of [Cp*Ru-

(MeCN)₃]PF₆(3, 30 mol%)^[33]as precatalyst of choice. The

resulting mixture of regioisomeric vinylsilanes was proto-de-

silylated with the aid of AgF in aqueous THF/MeOH as pre-

viously described,^[31]affording the (E,Z)-configured diene 19

in 50% unoptimized yield over both steps.

Scheme 6. a) I₂, PPh₃, imidazole, CH₂Cl₂, 97%; b) LDA, LiCl, THF, 08C,

85% (> 99% de); c) LDA, then BH₃·NH₃, THF, 08C ! RT, 81%; d) I₂,

PPh₃, imidazole, CH₂Cl₂, 99%; e) ent-22, LDA, LiCl, THF, 08C, 70%

(99% de); f) LDA, then BH₃·NH₃, THF, 08C ! RT, 86 %; g) p-methoxy-

phenol, PPh₃, DEAD, THF, 808C; h) TBAF, THF, 90% (over both

steps); i) PDC, DMF, 74%; j) carbonyldiimidazole (CDI), Et₃N, NH-

Preparation of the building blocks—The Western fragment:

Encouraged by this model study, the development of effi-

cient fragment syntheses became the next immediate goal.

Access to the required acid segment was based on an itera-

tive use of the excellent asymmetric alkylation methodology

developed by Myers and co-workers (Scheme 6).^[34]Specifi-

cally, reaction of the pseudo-ephedrine derived propion-

AHCTRE(UNG OMe)(Me)·HCl, CH₂Cl₂, 08C, 87%.

son of the NMR spectra of these isomers allowed for an un-

ambiguous assignment of their double bond configuration.

ACHTREUNGamide 22 with iodide 24 mediated by LDA in the presence

of LiCl afforded 25 in high yield and diastereoselectivity (de

>99%) on a multigram scale. This product was converted

into iodide 27, which then served as electrophilic component

in the next alkylation step with ent-22. The outcome of this

reaction was equally rewarding, since the diastereomeric

purity of the resulting product 28 was again close to the

limits of detection (99% de). Routine oxidation state- and

protecting group management readily afforded acid 31,

which was converted into the corresponding Weinreb

amide^[35]32 under standard conditions.

The second fragment was equally well accessible upon al-

kylation of butyramide 33 with iodide 35 (Scheme 7). Subse-

quent conversion into aldehyde 38 followed by an alkylative

Corey–Fuchs reaction^[36]smoothly installed the end-capped

alkyne 40. Cleavage of the residual silyl ether and transfor-

mation of the resulting alcohol 41 into bromide 42 was

straightforward. Addition of the Grignard reagent 43 to

Weinreb amide 32 delivered ketone 44,^[37]which was readily

elaborated into the western domain of myxovirescin A₁by

cleavage of the terminal p-methoxyphenyl ether^[38]followed

by oxidation of the released alcohol 45 to the corresponding

carboxylic acid 46.

In the presence of catalytic amounts of [PdACHTRE(NUG PPh₃)₄], 48 re-

acted with propynylzinc chloride regioselectively at its steri-

cally less hindered site to give enyne 12 (Scheme 8), con-

serving the internal bromine function. The excellent repro-

ducibility and scalability of this Negishi coupling^[40,41]were

prerequisites for the success of the total synthesis campaign.

Preparation of the triol subunit: While the approaches to

the polar segment of 1 pursued in the previous total synthe-

ses relied on chiral building blocks derived from nature (d-

ribose, d-mannose),^[10,11]we developed a largely reagent-

and catalyst-controlled entry. Advantage was taken from the

practicality of a slightly modified Noyori hydrogenation for

the production of large quantities of 50 (> 50 g per run)

with high optical purity (96% ee).^[42]Substitution of the

chloride by azide and protection of the secondary alcohol in

51 (Scheme 9) as MOM-acetal using MOM-Br generated in

situ^[43]were also high yielding. The resulting ester 52 was

then reduced to the corresponding aldehyde 53 with the aid

of DIBAl-H in CH₂Cl₂at ꢁ788C; it is noteworthy that the

azide group remains intact under these conditions. Although

53 is somewhat sensitive, it can be stored in pure form at

ꢁ208C under Argon for several weeks without noticeable

decomposition.

An anti-selective oxyallylation was envisaged to open

access to compound 61 featuring the correct oxygenation

pattern and a terminal double bond. The latter provides a

convenient handle for subsequent fragment coupling via an

alkyl-Suzuki reaction^[11,32]with bromide 12. Of the different

oxyallylation methods known in the literature,^[44]the proto-

col pioneered by Brown was deemed most convenient.^[45,46]

Preparation of the enyne linchpin: A very satisfactory route

to the required alkenyl bromide 12 was gleaned by an essen-

tially quantitative and exquisitely trans-selective dibromina-

tion of commercial methyl propargyl ether 47 with pyridini-

um perbromide.^[39]However, it is essential to perform the

reaction in the dark, as exposure of the produced dibromide

48 to daylight induces isomerization to the thermodynami-

cally more stable (Z)-isomer. Careful analysis and compari-

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8765

A. Fürstner et al.

tently high, the isolated yields were variable and mostly un-

satisfactory; even more seriously, these problems increased

further upon attempted up-scaling. During these initial

trials, however, it was noticed that significant amounts of al-

cohol 62 were produced as a by-product, indicating that a

reducing species must be present in the mixture that com-

petes with allylborane 57 for the aldehyde substrate.^[48]Sus-

pecting that this competing nucleophile might either be un-

reacted “Ipc₂BH” or a borane derived thereof, we took a

closer look at this classical and seemingly well established

reagent.

In fact, “Ipc₂BH” in THF solution consists of an equili-

brating mixture of several boron-containing components

(see below). Because of this complex composition, a careful

empirical optimization of the conditions and the stoichiome-

try of the hydroboration reaction converting 56 into the re-

quired allylborane 57 was carried out. Only after this exer-

cise (cf. Experimental Section) could the required oxyallyl-

AHCTREaUNG tion product 58 be obtained in well reproducible 88% iso-

Scheme 7. a) I₂, PPh₃, imidazole, CH₂Cl₂, 96%; b) LDA, LiCl, THF, 08C,

85% (> 97% de); c) LDA, then BH₃·NH₃, THF, 08C ! RT, 88 %; d)

TMAP (5 mol%), NMO·H₂O, MS 4 , CH₂Cl₂, 86%; e) CBr₄, PPh₃,

Et₃N, CH₂Cl₂, 08C, then 38, ꢁ788C; f) nBuLi, MeI, THF, ꢁ788C!

ꢁ168C, 98%; g) TBAF, THF, 95%; h) CBr₄, PPh₃, CH₂Cl₂, 77%; i) Mg,

1,2-dibromoethane cat., THF, 408C; j) amide 32, THF, 08C, 77%;

k) CAN, MeCN/H₂O, 0 8C, 81%; l) i) 4-methoxy-TEMPO, KBr, NaOCl,

NaHCO₃, H₂O/CH₂Cl₂, 08C; ii) NaClO₂, tBuOH, 2-methylbutene,

NaH₂PO₄, H₂O/CH₂Cl₂, 90% (> 99% de).

lated yield and diastereomeric purities in excess of 92% de,

whereas the amount of alcohol 62 was consistently lower

than 10% in all runs. Conversion of the diol unit of 58 into

the corresponding isopropylidene acetal 59, reduction of the

azide and protection of the resulting amine 60 as phthal-

AHCTREiUNG mide 61 completed the preparation of the polar building

block E in suitably protected form.

Interlude on “di(isopinocampheyl)borane”: Di(isopinocam-

pheyl)borane is a highly useful reagent for the preparation

of a large variety of chiral products.^[49]It is common practice

in the literature to refer to it as the simple mononuclear

boron derivative “Ipc₂BH”, even though in the initial re-

ports it was suggested that it probably exists as a dimer,

sym-tetra(isopinocampheyl)diborane 63 (Scheme 11).^[50]

Surprisingly many optimized procedures for its prepara-

tion have been reported over the years.^[50,51]A common fea-

ture is that in the hydroboration step an excess a-pinene is

used, which does not have to be optically pure but becomes

enriched upon incorporation into “Ipc₂BH” (thus, (+)-a-

pinene of only 84% ee delivers (ꢁ)-“Ipc₂BH” of >98%

ee).^[51]At the same time, the excess of the olefin is thought

to minimize the dissociation of sym-tetra(isopinocampheyl)-

diborane (63) into tri(isopinocampheyl)diborane (64) and a-

pinene (Scheme 12).

Scheme 8. a) Pyridine·HBr₃, CH₂Cl₂, quant.; b) 1-propynylmagnesium

bromide, ZnCl₂, [PdACHTREUNG(PPh₃)₄] (5 mol%), THF/Et₂O, 0 8C, 62%.

Thus, addition of the substituted allylborane 57, generated

from allenylboronate 56 and “Ipc₂BH”, should deliver the

correct stereoisomer upon oxidative work up (Scheme 10).

Despite considerable experience with the use of chiral al-

lylboron reagents,^[47]we encountered significant difficulties

with this particular transformation. Although the diastereo-

selectivities observed in our preliminary assays were consis-

Despite this knowledge, numerous synthetic procedures

described in the literature using “Ipc₂BH” completely disre-

gard the possibility of serious interference from a deboryla-

tion reaction. Because we suspected that this could be re-

sponsible for the reduction of 53 to 62 and the other difficul-

ties encountered in the preparation and use of the function-

alized allylborane 57, it was decided to have a closer look

into the actual composition of this classical reagent.

In line with the suggestions made in the early literature,^[50]

hydroboration of excess a-pinene with BH₃·SMe₂in THF

generates a mixture of compounds, from which only one

component crystallizes upon standing. This crystalline frac-

tion consists of pure sym-tetra(isopinocampheyl)diborane

Scheme 9. a) [((R)-binap)RuCl₂] (0.03 mol%); H₂(100 bar), EtOH/ace-

tone (1:1), 1008C, 96% (96% ee); b) NaN₃, DMF, 1008C, 77%;

c) pTsOH·H₂O, LiBr, dimethoxymethane, 70%; d) DIBAl-H, CH₂Cl₂,

ꢁ788C, 89%.

8766

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

Scheme 12. Deborylation upon dissolution of crystalline [Ipc₂BH]₂(63),

as evident by comparison of the ¹¹B NMR data with those of authentic

tetraorganodiborane derivatives.

Scheme 10. a) i) Mg, cat. HgCl₂, Et₂O, reflux; ii) B

A

08C, then aq. HCl; b) 1,3-propanediol, 41% (over three steps); c) crystal-

line [(l-Ipc)₂BH]₂(63), Et₂O, 0 8C; d) i) aldehyde 53, ꢁ788C; ii) MeOH,

aq. H₂O₂(30% w/w), aq. NaOH (3m), 08C ! RT, 88 % (58); e) 2,2-di-

methoxypropane, pTsOH·H₂O, 90%; f) LiAlH₄, Et₂O, 0 8C ! RT, 91%;

g) phthalic anhydride, toluene, MS 4 , 808C, 88%.

Figure 1. Molecular structure of 63 in the solid state. The molecule is situ-

ated on a crystallographic 2-fold axis. Anisotropic displacement parame-

ter ellipsoids are shown at 50% probability, hydrogen atoms except for

the B-H-B bridge have been omitted for clarity. Disordered solvent is

not shown.

Scheme 11. Dimeric constitution of “di(isopinocampheyl)borane” in the

solid state.

(63) as unequivocally proven by single crystal X-ray diffrac-

tion (Figure 1). To exclude the unlikely scenario that the

chosen crystal may not be representative for the bulk of the

material, powdered samples were analyzed by FT-IR in atte-

nuated total reflectance (ATR) mode, which showed only

the band characteristic for bridging B-H-B entities (n˜ =

1517 cm^ꢁ1). When recorded in hexane solution, however, the

rived thereof. Rather, two major resonances at d_B=

19.4 ppm and d_B=38.3 ppm were observed. These chemical

shifts together with the recorded integral (ꢂ1:1) are highly

indicative of a triorganodiborane,^[52]and are hence ascribed

to tri(isopinocampheyl)diborane 64, which obviously consti-

tutes the only (or at least predominant) boron-containing

species in the equilibrated solution. Hence, dimeric di(isopi-

nocampheyl)borane (63) must have undergone an essential-

ly quantitative mono-deborylation in CDCl₃(Scheme 12).

The clearly discernable olefinic proton in the corresponding

¹H NMR spectrum (d_H=5.20 ppm) corroborates this view.

Exactly the same observations were made when C₆D₆(d_B=

18.7, 38.3; ꢂ1:1) rather than CDCl₃was chosen as the sol-

vent.

IR spectrum is strikingly different, clearly featuring an addi-

ꢁ1

ꢁ

tional band for a terminal B H bond (n˜ =2494 cm ).

Therefore, samples of analytically pure, crystalline 63

were dissolved in various solvents and inspected by

¹¹B NMR. To our surprise, the spectra recorded in CDCl₃

were totally inconsistent with the presence of any apprecia-

ble amount of 63 (for which a boron resonance in the 25–

30 ppm range is expected), or any monomeric “Ipc₂BH” de-

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8767

A. Fürstner et al.

Despite the good literature precedence for the assign-

ments of the observed ¹¹B shifts,^[52]further independent con-

firmation was sought. To this end, we prepared tetracyclo-

hexyldiborane (65),^[53]confirmed its dimeric nature by X-ray

crystallography (Figure 2), and recorded the corresponding

¹¹B NMR spectrum in CDCl₃for comparison. 65, which is

not prone to undergo deborylation, shows the characteristic

chemical shift of a tetraorganodiborane in CDCl₃solution

(d_B=30.5 ppm), as does the well known 9-H-9-BBN dimer

66 (d_B=27.0 ppm).

These results support the notion that tetraorganodibor-

anes and triorganodiboranes are easily distinguished by

¹¹B NMR spectroscopy. Therefore we must conclude that an

equilibrated solution of “di(isopinocampheyl)borane” in

CDCl₃or C₆D₆contains neither 63 nor the elusive “Ipc₂BH”

frequently invoked in the literature, but rather consists of a

1:1 mixture of Ipc₂BH and IpcBH₂associated in form of the

hetero-dimer 64. Even more complex is the composition of

this reagent in ethereal solvents. While the dissolution of 63

in Et₂O is rather slow and the composition therefore varia-

ble with time,^[54]clear solutions of analytically pure, recrys-

tallized 63 in THF show four discernable peaks of similar in-

tensity in ¹¹B NMR (d_B=12.4, 20.3, 40.0, 43.3 ppm); while

two of them again appear to correspond to 64, the constitu-

tion of the other boron containing component(s) in this mix-

ture cannot be assigned with certainty at this point.

In summary, this study shows that the famous “di(isopino-

campheyl)borane” is dimeric in the solid state, but a com-

plex reagent in solution as vir-

Figure 2. Molecular structure of 65 as found in the crystal. The molecule

is situated on a crystallographic inversion centre. Anisotropic displace-

ment parameter ellipsoids are shown at 50% probability, hydrogen atoms

except for the B-H-B bridge have been omitted for clarity.

bustness of the method. A good example for this is the opti-

mized procedure for the preparation of the valuable reagent

Ipc₂BOMe derived from 63 by methanolysis.^[55]

Fragment coupling and ring closing alkyne metathesis: With

the access to the required building blocks now secured, the

stage was set for the coupling of these fragments

(Scheme 13). To this end, alkene 61 was reacted with 9-H-9-

BBN dimer to give the corresponding alkylborane, which

tually quantitative deborylation

and/or equilibration phenom-

ena occur upon standing. Its

successful use as a chiral re-

agent for hydroboration, as ex-

emplified by the preparation of

the functionalized allylborane

57 described above, therefore

hinges critically upon the

chosen stoichiometry, solvent,

concentration,

temperature,

order and time of addition, and

presence or absence of any ad-

ditives able to coordinate to

boron etc. We recommend that,

when this reagent is used, the

utmost attention is paid to an

empirical optimization of these

and other relevant parameters

to ensure an appropriate degree

of reproducibility. In certain

cases, it may be beneficial to

add excess pinene to a reaction

mixture as this will retard or

(partly) suppress the formation

of 64 and hence have a positive

effect on the chemical and/or

optical yield as well as the ro-

Scheme 13. a) NaNO₂, H₂SO₄, H₂O, 0 8C ! RT, 80%; b) BnBr, (nBu)₄NI, K₂CO₃, acetone, 408C, 69%;

c) TBDPSCl, imidazole, CH₂Cl₂, 98%; d) Pd/C (10% w/w), EtOAc/EtOH (1:1), 63%; e) 61, 9-H-9-BBN, THF,

08C, then 12, Cs₂CO₃, [(dppf)PdCl₂] (7 mol%), Ph₃As (15 mol%), aq. THF, 81%; f) H₂N-NH₂·H₂O, EtOH,

608C; g) acid 70, 1-HOBt, EDC·HCl, (iPr)₂NEt, CH₂Cl₂, 77% (over both steps); h) TBAF, THF, 90%; i) acid

46, EDC·HCl, 1-HOBt, Et₃N, DMAP, 65–75%; j) Complex 20 (40–50 mol% in 3 portions), toluene, CH₂Cl₂,

808C, 79%.

8768

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

underwent a high yielding cross coupling reaction with al-

kenyl bromide 12 under the conditions successfully em-

ployed in the model study. In practical terms, it was advan-

tageous that the by-products derived from the minor diaste-

reomer formed in the oxyallylation step could be conven-

iently removed at this stage. Hydrazinolysis of the phthal-

Semi-reduction and completion of the total synthesis: Whilst

the semi-reduction of acetylenes to (Z)-alkenes is well es-

tablished and opens a reliable entry into (Z)-cycloalkenes

when combined with RCAM,^[21–25]the stereo-complementary

reduction to the corresponding (E)-isomers is considerably

more challenging. Whereas the few classical solutions to this

problem are hardly attractive, the recent discovery of Trost

ACHTREUNGimide in 71 and condensation of the resulting crude amine

72 with the TBDPS-protected 2-hydroxypentanoic acid 70,

which is readily available from l-norvaline 67 as shown in

Scheme 13,^[56]afforded amide 73 without incident.^[57]The

structure of acid 70 in the solid state is depicted in Figure 3.

that [Cp*RuACHTRE(UNG MeCN)₃]PF₆(3) catalyzes a trans-hydrosilyla-

tion of terminal as well as internal alkynes opens a poten-

tially much more rewarding alternative. Proto-desilylation of

the vinylsilanes primarily formed delivers the corresponding

(E)-alkenes in good yields in many cases.^[30]

We have previously combined this methodology with

RCAM to produce (E)-cycloalkenes of various ring sizes

with high stereochemical integrity.^[31]Thereby, the use of

AgF in aq. THF/MeOH turned out to be particularly effec-

tive in the proto-desilylation step. The method is applicable

to conjugated enyne substrates, since the catalyzed hydrosi-

lylation occurs selectively at the triple bond and leaves the

pre-existing olefin intact (Scheme 3). However, the reactivi-

ty of enynes was found to be significantly lower than that of

ordinary alkynes, a fact that can be partly compensated by

conducting the hydrosilylation in neat silane and using a

higher catalyst loading.^[31]

Since this methodology had worked reasonably well in

the model study summarized in Scheme 5, we were confi-

dent that it would equally apply to the actual total synthesis

of myxovirescin A₁. Despite considerable experimentation,

however, attempted hydrosilylation of the cyclic enyne 76

with (EtO)₃SiH as the silane of choice and [Cp*Ru-

Figure 3. Molecular structure of 70 in the solid state. The proton of the

carboxylic acid is disordered over atom positions O2 and O3. In the crys-

tal, hydrogen bonded carboxylic acid dimers are formed incorporating a

crystallographic 2-fold axis. Anisotropic displacement parameter ellip-

soids are shown at 50% probability, hydrogen atoms have been omitted

for clarity.

AHCTRE(UNG MeCN)₃]PF₆(3) did not work well at all, remaining incom-

While the deprotection of the TBDPS-ether in 73 with

TBAF posed no problem, the esterification of the released

alcohol 74 with the western domain 46 proceeded in reason-

able yields of up to 75% only when effected by EDC (N-(3-

dimethylaminopropyl)-N’-ethylcarbodiimide) and HOBt (1-

hydroxy-7-azabenzotriazole), while the use of DCC or re-

course to the Yamaguchi protocol were largely unsuccessful.

The highly functionalized enyne–yne derivative 75 could

be cyclized to the corresponding 28-membered cycloalkyne

76 in well reproducible 79% yield with the aid of the molyb-

denum catalyst generated in situ from 20 and CH₂Cl₂as pre-

viously described.^[27]However, a fairly high catalyst loading

was necessary to ensure complete conversion (40–50%,

added in three portions). Whether this is due to the inher-

ently lower intrinsic reactivity of conjugated enynes and/or

the presence of a secondary amide linkage has not been ad-

dressed in detail.^[58]In line with the results of the model

study, however, the molybdenum based catalyst system was

much more efficacious than the tungsten alkylidyne 21,^[26]

which had previously been found equipotent in less demand-

ing cases. Moreover, this particular RCAM reaction high-

lights again the truly remarkable capacity of the catalyst to

distinguish between triple- and double bonds even if they

are conjugated, which makes alkyne metathesis orthogonal

to the more commonly practiced metathesis of alkenes in

conceptual terms.

plete even when very high catalyst loadings were chosen, ir-

respective of whether the reaction was performed neat or in

the presence of suitable co-solvents.

Puzzled by this unexpected failure, various other rutheni-

um catalysts were screened, amongst which the sterically

less demanding analogue [CpRuACHTRE(UNG MeCN)₃]PF₆(3b) per-

formed best (Scheme 14). With its aid, 76 could be convert-

ed into three isomeric vinylsilanes that were isolated in a

combined yield of 66% in two fractions (77 and 78). This

outcome was surprising, as it implied that the course of the

reaction had not been rigorously trans-selective; appreciable

amounts of a cis-isomer also must have formed. In fact, sub-

sequent proto-desilylation with AgF in aqueous THF/

MeOH^[31]furnished the desired (E,Z)-configured product 79

and the (Z,Z)-configured isomer 80 that were readily sepa-

rable and could therefore be assigned with certainty. Depro-

tection of the acetal groups in 79 and 80 following the pro-

cedures established in the previous total syntheses^[10,11]then

afforded myxovirescin A₁(1) and its hitherto unknown 14Z-

configured analogue 81, respectively. The spectroscopic and

analytical data of the synthetic samples of 1 were in full

accord with those of the natural product reported in the lit-

erature.^[3,11]Although this synthetic endeavor was ultimately

successful and the new route to myxovirescin A₁is competi-

tive in terms of the usual empirical indices (17 steps and

ꢂ2% overall yield over the longest linear sequence, 46

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8769

A. Fürstner et al.

late-stage ruthenium catalyzed trans-hydrosilylation that

posed the most significant problems. Although this method

did allow to covert cycloalkyne 76 produced by RCAM into

the required E,Z-configured 1,3-diene, the observed selec-

tivity and the isolated yield need further improvement.

Hence, this study illustrates the notion that the total synthe-

sis of complex target molecules remains the ultimate test for

the performance, scope and limitations of any newly devel-

oped methodology.

Experimental Section

General: All reactions were carried out in flame-dried glassware under

Ar. The solvents were purified by distillation over the drying agents indi-

cated and were transferred under Ar: THF, Et₂O, DME (Mg/anthra-

cene), DMSO, CH₂Cl₂, MeCN, Et₃N, (CaH₂), MeOH (Mg), DMF (Des-

modur, dibutyltin dilaurate), hexanes, pentanes, toluene (Na/K). Flash

chromatography: Merck silica gel 60 (230–400 mesh). NMR: Spectra

were recorded on Bruker DPX 300, AV 400, or DMX 600 spectrometers

in the solvents indicated; chemical shifts (d) are given in ppm relative to

TMS, coupling constants (J) in Hz. The solvent signals were used as ref-

ꢀ

erences and the chemical shifts converted to the TMS scale (CDCl₃: d_C

ꢀ

77.0 ppm; residual CHCl₃in CDCl₃: d_H

7.26 ppm; CD₂Cl₂: d_C

53.8 ppm; residual CH₂Cl₂in CD₂Cl₂: d_H5.32 ppm). ¹¹B NMR chemical

shifts are given relative to external BF₃·Et₂O ( 0 ppm). Where indicated,

the signal assignments are unambiguous; the numbering Scheme is arbi-

trary and is shown in the inserts. The assignments are based upon 1D and

2D spectra recorded using the following pulse sequences from the

Bruker standard pulse program library: DEPT; COSY (cosygs and co-

ꢀ

sydqtp); HSQC (invietgssi) optimized for ¹J

ACHTREUNG

(inv4gslplrnd) for correlations via ⁿJ

AHCTREUNG

using an MLEV17 mixing time of 120 ms. IR: Nicolet FT-7199 spectrom-

eter, wavenumbers (n˜) in cm^ꢁ1. MS (EI): Finnigan MAT 8200 (70 eV),

ESI-MS: Finnigan MAT 95, accurate mass determinations: Bruker

APEX III FT-MS (7 T magnet). Melting points: Büchi melting point ap-

paratus B-540 (corrected). Elemental analyses: H. Kolbe, Mülheim/Ruhr.

All commercially available compounds (Fluka, Lancaster, Aldrich) were

used as received.

Scheme 14. a) (EtO)₃SiH, toluene, [CpRuACTHRE(UNG MeCN)₃]PF₆(3b, 30 mol%),

78 (53%) + 77 (13%); b) AgF, aq. THF/MeOH, 94% (79); c) AgF, aq.

THF/MeOH, 25% (79) + 23% (80); d) HClO₄, aq. THF, MeOH, 38–

52%.

Model studies

steps overall),^[12]it also revealed that the methodology for

the formal trans-reduction of alkynes requires further inves-

tigation.

1-Bromo-8-methoxymethoxy-octane (4): Dimethoxymethane (30 mL)

and 8-bromo-1-octanol (840 mg, 4.02 mmol) were added to a suspension

of phosphorus pentoxide (3 g, 21.1 mmol) in CH₂Cl₂(40 mL). The mix-

ture was stirred for 30 min before the solution was decanted and diluted

with aq. sat. NaHCO₃(50 mL). The aqueous phase was extracted with

CH₂Cl₂(330 mL), the combined organic layers were dried over Na₂SO₄

and evaporated, and the residue purified by flash chromatography (pen-

tanes/Et₂O 95:5) to give product 4 as a colorless oil (840 mg, 83%).

¹H NMR (400 MHz, CDCl₃): d=4.55 (s, 2H), 3.45 (t, J=6.6 Hz, 2H),

3.34 (t, J=6.8 Hz, 2H), 3.29 (s, 3H), 1.79 (m, 2H), 1.52 (m, 2H), 1.22–

1.41 ppm (m, 8H); ¹³C NMR (75 MHz): d=96.4, 67.8, 55.1, 33.9, 32.8,

29.7, 29.2, 28.7, 28.1, 26.1 ppm; IR (KBr): n˜ =2988, 2931, 2856, 1465,

1215, 1145, 1112, 1048, 919, 645, 563 cm^ꢁ1; MS (EI): m/z (%): 253 [M⁺]

(0.7), 204 (3), 190 (3), 148 (3), 109 (6), 75 (15), 69 (14), 55 (12), 45 (100),

41(12); HRMS (ESI +): m/z: calcd for C₁₀H₂₁BrO₂: 253.08033; found:

253.08002.

Conclusion

The complex macrolide antibiotic myxovirescin A₁(1)

served as template for the development of a convergent

total synthesis that is flexible enough to accommodate sys-

tematic structural variations at a later stage. The chosen

route is largely based on reagent- and catalyst-controlled

transformations, of which the venerable Suzuki reaction and

the more recent ring closing alkyne metathesis performed

exceptionally well. Moreover, it was possible to improve the

reliability of Brownꢁs anti-oxyallylation methodology after

studying the true nature of the classical “di(isopinocam-

pheyl)borane (Ipc₂BH)” used for the preparation of the re-

quired allylborane reagent 57. We believe that this investiga-

tion on “Ipc₂BH” will also positively impact many other

transformations employing this classical hydroborating

agent. Of the key steps employed en route to 1, it was the

Oct-6-ynal (7): Oct-8-yn-1-ol (6, 1.22 g, 9.6 mmol) was slowly added to a

suspension of pyridinium dichromate (5.44 g, 14.5 mmol) in CH₂Cl₂

(25 mL). The solution was stirred overnight before it was filtered through

a pad of silica which was carefully rinsed with CH₂Cl₂. The combined fil-

trates were evaporated and the residue was purified by Kugelrohr distil-

lation (100–1158C, 1mbar) to afford aldehyde 7 (707 mg, 59%) as a col-

orless oil. 7 easily oxidized in air to form the corresponding carboxylic

acid and should therefore be kept in a refrigerator under inert atmos-

phere. ¹H NMR (300 MHz, CDCl₃): d=9.76 (t, J=1.7 Hz, 1H), 2.43 (dt,

J=7.3 Hz, 1.7 Hz, 2H), 2.14 (m, 2H), 1.76 (t, J=2.6 Hz, 3H), 1.72 (m,

8770

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

2H), 1.50 ppm (m, 2H); ¹³C NMR (75 MHz): d=202.4, 78.5, 76.0, 43.4,

28.4, 21.2, 18.5, 3.4 ppm; IR (KBr): n˜ =2940, 2921, 2722, 1724, 1437, 1334,

1077 cm^ꢁ1; MS (EI): m/z (%): 124 [M⁺] (2), 123 (8), 109 (32), 95 (57), 91

(38), 79 (89), 67 (99), 53 (91), 41 (100), 27 (64). HRMS (ESI+): m/z:

calcd for C₈H₁₃O+H: 125.09664; found: 125.09658.

4H), 2.27 (t, J=7.5 Hz, 2H), 2.05 (m, 2H), 1.69 (t, J=2.5 Hz, 3H), 1.15–

1.64 ppm (m, 14H); ¹³C NMR (100 MHz): d=211.2, 179.7, 78.7, 75.7,

42.7, 42.2, 33.9, 29.0 (2 C), 28.8, 28.5, 24.5, 23.7, 23.0, 18.5, 3.4 ppm; IR

(KBr): n˜ =2934, 2924, 2908, 2862, 2849, 1701, 1419, 1305, 738 cm^ꢁ1; MS

(EI): m/z (%): 266 [M⁺] (1), 248 (6), 186 (12), 171 (50), 138 (55), 123

(70), 110 (20), 95 (81), 81 (41), 67 (58), 55 (100), 41 (48); HRMS (ESI+):

m/z: calcd for C₁₆H₂₆O₃+Na: 289.17796; found: 289.17804; elemental

analysis calcd (%) for C₁₆H₂₆O₃: C 72.14, H 9.84, found C 72.12, H 9.84.

16-Methoxymethoxy-hexadec-2-yn-8-ol (8): Magnesium turnings (150 mg,

6.2 mmol) were activated by stirring under reduced pressure with gentle

heating; they were allowed to reach ambient temperature before being

suspended in freshly distilled THF (15 mL). 1 mL of a solution of bro-

mide 4 (647 mg, 2.56 mmol) in THF (9 mL) was added to the mixture at

room temperature. Once the reaction had started, the remaining solution

of 4 was added at such a rate as to maintain gentle reflux. Once the addi-

tion was complete, the mixture was refluxed for 2 h before it was cooled

to room temperature. The solution of aldehyde 7 (220 mg, 1.77 mmol) in

THF (7 mL) was introduced and the reaction mixture stirred overnight

before being quenched with water. The aqueous layer was extracted with

CH₂Cl₂(330 mL), the combined organic phases were dried over

Na₂SO₄and evaporated, and the residue purified by flash chromatogra-

AHCTRE(GNU 11Z)-11-Methoxymethylpentadec-11-en-13-ynyl-1-oxy(tert-butyl-dimeth-

yl)-silane (13): 9-H-9-BBN (45 mg, 0.37 mmol) was added to a solution of

alkene 11 (38 mg, 0.20 mmol) in THF (3 mL) at 08C. The mixture was al-

lowed to warm to ambient temperature and was stirred overnight. In a

second Schlenk flask, vinyl bromide 12 (38 mg, 0.2 mmol), cesium car-

bonate (123 mg, 0.38 mmol), Ph₃As (9 mg, 0.03 mmol) and [PdCl₂-

AHCTRE(UNG dppf)·CH₂Cl₂] (12 mg, 0.015 mmol) were dissolved in DMF (3 mL).

Before the solution of the alkylborane was transferred to this flask, water

(100 mL) was added to quench excess 9-BBN. The resulting solution was

stirred for 30 min before it was quenched with sat. aq. NH₄Cl (5 mL). A

standard extractive work up followed by flash chromatography afforded

phy to give alcohol

8 (389 mg, 73%) as a

colorless oil. ¹H NMR

(400 MHz, CDCl₃): d=4.54 (s, 2H), 3.52 (m, 1H), 3.44 (t, J=6.6 Hz,

2H), 3.29 (s, 3H), 2.06 (m, 2H), 1.70 (t, J=2.5 Hz, 3H), 1.15–1.55 ppm

(m, 21H); ¹³C NMR (100 MHz): d=96.4, 79.1, 75.5, 71.8, 67.9, 55.0, 37.5,

37.0, 29.7, 29.6, 29.5, 29.3, 29.1, 26.2, 25.6, 24.9, 18.7, 3.4 ppm; IR (KBr):

n˜ =3435, 2929, 2856, 1463, 1214, 1146, 1112, 1044, 919 cm^ꢁ1; MS (EI): m/z

(%): 304 [M⁺] (0.4), 235 (2), 203 (2), 171 (20), 135 (8), 123 (16), 109 (12),

95 (24), 81 (41), 67 (36), 55 (39), 45 (100); HRMS: m/z: calcd for

C₁₈H₃₄O₃+Na: 321.24056; found: 321.24062.

the desired product 13 (69 mg, 90%) as

(400 MHz, CDCl₃): d=5.41(m, 1H), 4.41 (s, 2H), 3.59 (t,

a

colorless oil. ¹H NMR

J=6.6 Hz,

2H), 3.30 (s, 3H), 2.12 (m, 2H), 1.93 (d, J=2.3 Hz, 3H), 1.22–1.52 (m,

16H), 0.89 (s, 9H), 0.04 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=

149.9, 108.1, 89.4, 76.3, 71.3, 63.3, 57.8, 33.5, 32.9, 29.6, 29.5, 29.43, 29.40,

29.3, 27.6, 26.0 (3C), 25.8, 18.3, 4.3, ꢁ5.3 ppm (2C); IR (KBr): n˜ =2928,

2855, 2221, 1630, 1471, 1463, 1255, 1098, 836, 755, 662 cm^ꢁ1; MS (EI): m/z

(%): 380 [M⁺] (3), 365 (3), 350 (1), 323 (38), 308 (53), 217 (21), 161 (20),

147 (22), 109 (52), 93 (100), 75 (82), 55 (35), 41 (23); HRMS (ESI+):

m/z: calcd for C₂₃H₄₄O₂Si: 380.31106, found: 380.31066.

Hexadec-14-yne-1,9-diol (9): HCl (12m, 1 00mL) was added to a solution

of compound 8 (386 mg, 1.21 mmol) in MeOH (10 mL), the resulting so-

lution was heated under reflux for 3 h and then stirred overnight at room

temperature. The reaction was quenched with aq. sat. NaHCO₃(5 mL)

and the aqueous layer was extracted with CH₂Cl₂(315 mL). The com-

bined organic phases were dried over Na₂SO₄and evaporated to afford

the desired diol 9 (307 mg, quant.) as a colorless oil, which was used in

the next step without further purification. ¹H NMR (400 MHz, CDCl₃):

d=3.54 (t, J=6.6 Hz, 2H), 3.52 (m, 1H), 2.05 (m, 2H), 1.69 (t, J=

2.5 Hz, 3H), 1.62 (brs, 2H), 1.16–1.53 ppm (m, 20H); ¹³C NMR

(100 MHz, CDCl₃): d=79.1, 75.5, 71.8, 62.9, 37.4, 36.9, 32.7, 29.6, 28.5,

29.3, 29.0, 25.7, 25.6, 24.9, 18.7, 3.4 ppm; IR (KBr): n˜ =3326, 2924, 2851,

1464, 1118, 1072, 858, 663 cm^ꢁ1; MS (EI): m/z (%): 254 [M⁺] (0.1), 207

(2), 159 (23), 135 (16), 125 (32), 123 (30), 107 (32), 95 (30), 81 (98), 67

(87), 55 (100), 43 (82), 29 (21); HRMS (ESI+): m/z: calcd for

C₁₆H₃₀O₂+Na: 277.21435, found: 277.21450.

AHCTRE(GNU 11Z)-11-Methoxymethyl-pentadec-11-en-13-yn-1-ol (14): TBAF (1m in

THF, 160 mL, 0.16 mmol) was added to a solution of compound 13

(60 mg, 0.16 mmol) in THF (2 mL). After stirring for 1 h, the reaction

was quenched with aq. sat. NaHCO₃(5 mL), the aqueous layer was ex-

tracted with tert-butyl methyl ether, the combined organic phases were

dried over Na₂SO₄and evaporated, and the residue purified by flash

chromatography (hexanes/EtOAc 2:1) to give alcohol 14 (38 mg, 90%)

as a colorless oil. ¹H NMR (300 MHz, CDCl₃): d=5.41(m, 1H), 4.15 (s,

2H), 3.63 (t, J=6.6 Hz, 2H), 3.30 (s, 3H), 2.12 (m, 2H), 1.97 (d, J=

2.3 Hz, 3H), 1.56 (m, 2H), 1.22–1.48 ppm (m, 13H); ¹³C NMR (75 MHz,

CDCl₃): d=149.9, 108.1, 89.5, 76.3, 71.3, 63.1, 57.8, 33.5, 32.8, 29.5, 29.5,

29.4 (2C), 29.3, 27.6, 25.7, 4.4 ppm; IR (KBr): n˜ =3372, 2926, 2854, 2220,

1628, 1465, 1375, 1087, 722 cm^ꢁ1; MS (EI): m/z (%): 266 [M⁺] (8), 251

(5), 165 (2), 151 (5), 123 (18), 109 (100), 91 (10), 77 (7), 55 (6), 45 (7);

HRMS (ESI+): m/z: calcd for C₁₇H₂₈O₂: 266.22458; found: 266.22423.

9-Oxo-hexadec-14-ynoic acid (10): Dess–Martin periodinane (1.50 g,

3.54 mmol) was added to a solution of diol 9 (300 mg, 1.18 mmol) in

CH₂Cl₂(5 mL). The mixture was stirred for 5 h before the reaction was

quenched with aq. sat. NaOH (1m, 3 mL). The organic phase was washed

with aq. sat. Na₂S₂O₅(5 mL), the aqueous layer was extracted with

CH₂Cl₂(35 mL), the combined organic phases were dried over Na₂SO₄

and evaporated to afford the corresponding aldehyde as a white solid,

which was used in the next step without further purification. Characteris-

tic data of this keto-aldehyde: ¹H NMR (300 MHz, CDCl₃): d=9.68 (t,

J=1.9 Hz, 1H), 2.32 (m, 6H), 2.05 (m, 2H), 1.69 (t, J=2.5 Hz, 3H),

1.31–1.64 (m, 8H), 1.15–1.30 ppm (m, 6H); ¹³C NMR (75 MHz): d=

211.0, 202.7, 78.7, 75.7, 43.8, 42.6, 42.2, 29.1, 29.0, 28.9, 28.5, 23.7, 23.0,

21.9, 18.5, 3.4 ppm; IR (KBr): n˜ =2924, 2863, 2849, 1711, 1701, 1419,

1092, 718 cm^ꢁ1; MS (EI): m/z (%): 250 [M⁺] (0.4), 235 (2), 175 (2), 155

(20), 138 (14), 123 (48), 109 (53), 95 (76), 81 (45), 67 (100), 55 (93), 41

(67).

AHCTRE(GNU 11Z)-11-Methoxymethyl-pentadec-11-en-13-ynyl-9-oxo-hexadec-14-

ynoate (15): Carboxylic acid 10 (72 mg, 0.27 mmol) was added to a solu-

tion of alcohol 14 (65 mg, 0.24 mmol), EDC (94 mg, 0.49 mmol) and

DMAP (59 mg, 0.49 mmol) in CH₂Cl₂(15 mL). The resulting mixture

was stirred for 6 h before the reaction was quenched with aq. HCl (1m).

A standard extractive work up followed by flash chromatography (hex-

anes/EtOAc 4:1) afforded product 15 (117 mg, 90%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): d=5.40 (m, 1H), 4.13 (s, 2H), 4.03 (t, J=

6.7 Hz, 2H), 3.28 (s, 3H), 2.37 (m, 4H), 2.26 (t, J=7.5 Hz, 2H), 2.11 (m,

4H), 1.95 (d, J=2.3 Hz, 3H), 1.75 (t, J=2.6 Hz, 3H), 1.17–1.72 ppm (m,

30H); ¹³C NMR (75 MHz, CDCl₃): d=211.0, 173.8, 149.9, 108.1, 89.4,

78.7, 76.3, 75.7, 71.3, 64.4, 57.8, 42.7, 42.2, 34.3, 33.5, 29.4 (2C), 29.3, 29.2,

29.1, 29.0 (2C), 28.9, 28.6, 28.5, 27.6, 25.9, 24.9, 23.7, 23.0, 18.5, 4.3,

3.4 ppm; IR (KBr): n˜ =2920, 2850, 2215, 1726, 1726, 1703, 1377, 1176,

1107, 719 cm^ꢁ1; MS (EI): m/z (%): 514 [M⁺] (30), 499 (20), 482 (10), 402

(4), 249 (5), 133 (17), 123 (4), 109 (100), 105 (17), 81 (30), 55 (34), 43

(15); HRMS (ESI+): m/z: calcd for C₃₃H₅₄O₄: 514.40221; found:

514.40245; elemental analysis calcd (%) for C₃₃H₅₄O₄: C 76.99, H 10.57;

found: C 76.81, H 10.65.

H₂NSO₃H (140 mg, 1.44 mmol) and

a solution of NaClO₂(163 mg,

1.44 mmol) in H₂O (6 mL) were added to a solution of the crude alde-

hyde (300 mg, 1.2 mmol) in THF (6 mL), causing an immediate color

change to yellow. After stirring for 1h, the mixture was diluted with tert-

butyl methyl ether (10 mL) and water, the aqueous layer was extracted

with tert-butyl methyl ether, the combined organic phases were dried

over Na₂SO₄and evaporated, and the residue was purified by flash chro-

matography (hexanes/EtOAc 2:1) to give acid 10 (249 mg, 78% over

both steps) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): d=2.32 (m,

AHCTRE(GNU 17Z)-18-Methoxymethyl-oxa-cyclooctacos-17-en-15-yne-2,10-dione (16):

[59]

Complex 20 (7.5 mg, 0.016 mmol)^[20]

,

and CH₂Cl₂(120 mL, 1.87 mmol)

were successively added to a solution of diyne 15 (60 mg, 0.12 mmol) in

toluene (85 mL) and the resulting mixture was stirred at 808C for 15 h.

For work up, the reaction was quenched with MeOH (5 mL), all volatile

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8771

A. Fürstner et al.

materials were evaporated and the residue was purified by flash chroma-

tography (hexanes/EtOAc 9:1) to afford macrocycle 16 (43 mg, 80%) as

a colorless oil. ¹H NMR (400 MHz, CDCl₃): d=5.44 (m, 1H), 4.14 (s,

2H), 4.07 (t, J=6.2 Hz, 2H), 3.30 (s, 3H), 2.32–2.47 (m, 6H), 2.28 (t, J=

7.3 Hz, 2H), 2.15 (t, J=6.9 Hz, 2H), 1.19–1.81 ppm (m, 30H); ¹³C NMR

(100 MHz, CDCl₃): d=211.3, 173.9, 149.7, 108.3, 93.5, 77.8, 71.3, 64.3,

57.8, 42.4, 42.3, 34.4, 33.2, 29.1, 29.0, 28.9 (3C), 28.8, 28.7, 28.5, 28.4, 28.0,

27.0, 25.7, 24.9, 23.7, 23.2, 19.2ppm; IR (KBr): n˜ =2927, 2855, 2213, 1734,

1714, 1175, 1107, 1089 cm^ꢁ1; MS (EI): m/z (%): 460 [M⁺] (98), 445 (14),

428 (100), 410 (25), 259 (10), 131 (62), 91 (68), 55 (98), 41 (43); HRMS

(ESI+): m/z: calcd for C₂₉H₄₈O₄: 483.34503; found: 483.34506.

Compound 17: ¹H NMR (400 MHz, CDCl₃): d=5.41(m, 1H), 4.15 (s,

2H), 4.05 (t, J=6.7 Hz, 2H), 3.30 (s, 3H), 2.39 (m, 4H), 2.28 (t, J=

7.5 Hz, 2H), 2.13 (m, 4H), 1.97 (d, J=2.3 Hz, 3H), 1.22–1.72 (m, 30H),

1.19 ppm (s, 9H); MS (EI): m/z (%): 556 [M⁺] (54), 541 (16), 509 (17),

499 (30), 467 (19), 291 (11), 233 (7), 151 (24), 137 (29), 123 (32), 109

(100), 55 (46), 43 (25), 41 (20), 29 (6).

analysis calcd (%) for C₁₄H₃₁IOSi: C 45.40, H 8.44; found: C 45.32, H

8.41.

tert-Butyl(3-iodopropoxy)dimethylsilane (35): Prepared analogously from

alcohol 34 (13.3 g, 69.9 mmol), imidazole (7.10 g, 104 mmol), I₂(24 g,

95 mmol) and PPh₃(22 g, 84 mmol). Flash chromatographic purification

of the crude material (hexanes) afforded iodide 35 as a yellow liquid

(20.2 g, 96%). The analytical data are in good agreement with those re-

ported in the literature.^{[61] 1}H NMR (400 MHz, CDCl₃): d=3.67 (t, J=

5.7 Hz, 2H), 3.28 (t, J=6.7 Hz, 2H), 1.99 (m, 2H), 0.90 (s, 9H), 0.07 ppm

(s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=63.9, 33.6, 26.2, 14.8, 7.2,

ꢁ5.3 ppm; IR (film): n˜ =2954, 2929, 2895, 2857, 2738, 1471, 1425, 1386,

1361, 1256, 1182, 1138, 1102, 1053, 1006, 931, 835, 813, 777, 715, 663,

606 cm^ꢁ1; MS (EI): m/z (%): 244 (11), 243 (100), 215 (52), 186 (5), 185

(65), 115 (40), 101 (5), 75 (10), 73 (13), 58 (6), 57 (6), 45 (8), 41 (13), 29

(5); HRMS (CI): m/z: calcd for C₉H₂₂IOSi: 301.0485; found: 301.0488

[M⁺+H].

(2R)-7-((tert-ButylCAHTRE(UNG dimethyl)silyl)oxy)-N-((1S,2S)-2-hydroxy-1-methyl-2-

ACHTREUNG(15E,17Z)-18-Methoxymethyl-oxa-cyclooctacosa-15,17-diene-2,10-dione

phenylethyl)-N,2-dimethylheptanamide (25): nBuLi (1.6m in hexane,

13.1 mL, 21.0 mmol) was slowly added to a suspension of LiCl (2.54 g,

59.9 mmol) and (iPr)₂NH (3.16 mL, 22.5 mmol) in THF (12 mL) at

ꢁ788C before the resulting mixture was allowed to reach ambient tem-

perature. After stirring for 10 min, the mixture was cooled to ꢁ788C

before a pre-cooled (08C) solution of amide 22 (2.21g, 9.99 mmol) ^[34]in

THF (33 mL) was introduced. After stirring for 1h at that temperature

and for an additional 20 min at 08C, a solution of iodide 24 (4.92 g,

15.0 mmol) in THF (63 mL) was added dropwise at 08C over a period of

1h and stirring continued until TLC showed complete conversion. The

reaction was quenched with aq. sat. NH₄Cl (80 mL), the aqueous layer

was extracted with EtOAc (3100 mL), the combined organic phases

were dried over MgSO₄and evaporated, and the residue was purified by

flash chromatography (hexanes/EtOAc 10:1 ! 2:1) to give product 25 as

a pale yellow liquid (3.59 g, 85%). [a]²_D⁰=+548 (c=1.3, CHCl₃); de >

(18): A mixture of enyne 16 (27 mg, 0.059 mmol), (EtO)₃SiH (50 mL,

0.36 mmol) and complex 3 (9 mg, 0.018 mmol) was vigorously stirred for

5 h before it was filtered through a short pad of silica which was carefully

rinsed with Et₂O. The combined filtrates were evaporated and the resi-

due was dissolved in THF (3 mL), MeOH (0.5 mL) and water (25 mL).

AgF (10.3 mg, 0.081 mmol) was added and the resulting mixture was

stirred in the dark for 5 h. Insoluble residues were filtered off through a

plug of silica which was carefully rinsed with Et₂O, the combined filtrates

were evaporated and the residue purified by flash chromatography (hex-

anes/Et₂O 10:1) to give the title compound as a colorless oil (13 mg, 50%

over both steps). ¹H NMR (400 MHz, CDCl₃): d=6.34 (dd, J=11.0,

14.9 Hz, 1H), 5.97 (d, J=11.0 Hz, 1H), 5.62 (dt, J=7.1, 14.9 Hz, 1H),

4.07 (t, J=6.4 Hz, 2H), 4.01(s, 2H), 3.29 (s, 3H), 2.38 (m, 4H), 2.29 (t,

J=7.3 Hz, 2H), 2.12 (m, 4H), 1.20–1.66 ppm (m, 30H); ¹³C NMR

(100 MHz, CDCl₃): d=211.5, 173.9, 136.0, 134.2, 129.0, 126.2, 69.8, 64.4,

57.8, 42.7, 42.5, 35.0, 34.4, 32.4, 29.2, 29.1, 29.0, 28.9 (2 C), 28.83 (2 C),

28.75, 28.6, 28.5, 27.4, 25.8, 24.8, 23.7, 23.3 ppm; IR (KBr): n˜ =3027, 2928,

2855, 1734, 1713, 1655, 1617, 1187, 969 cm^ꢁ1; MS (EI): m/z (%): 463 (3),

462 [M⁺] (8), 431 (32), 430 (100), 412 (7), 262 (3), 171 (7), 120 (30), 105

(21), 81 (18), 55 (31), 41 (14); HRMS (ESI+): m/z: calcd for C₂₉H₅₀O₄+

Na: 485.36068; found: 485.36098.

99% (HPLC: column: 125 mm Purospher C18e (5 mm),

1 3.0 mm;

MeOH/water 75:25, 0.5 mLmin^ꢁ1; T=308 K; 17.8MPa; t_R=32.03 min);

¹H NMR (400 MHz, CDCl₃, major rotamer): d=7.34 (m, 5H), 4.60 (m,

2H), 4.41(brs, 1H), 3.54 (t, J=6.5 Hz, 2H), 2.84 (s, 3H), 2.58 (m, 1H),

1.64–0.98 (m, 8H), 1.14 (d, J=7.0 Hz, 3H), 1.07 (d, J=6.7 Hz, 3H), 0.89

(s, 9H), 0.04 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl_3,major rotamer):

d=179.1, 142.6, 128.2, 127.5, 126.3, 76.4, 63.1, 57.8, 36.5, 34.0, 32.7, 27.2,

26.0, 25.9 (2 C), 18.3, 17.3, 14.4, ꢁ5.3 ppm; IR (film): n˜ =3386, 3086,

3063, 3029, 2954, 2931, 2896, 2857, 2737, 1621, 1471, 1463, 1408, 1388,

1375, 1360, 1304, 1255, 1199, 1100, 1052, 1028, 1006, 988, 835, 775,

701cm ^ꢁ1; MS (EI): m/z (%): 406 (3), 366 (4), 365 (15), 364 (57), 315 (10),

314 (24), 258 (5), 257 (7), 230 (3), 148 (17), 115 (4), 101 (3), 97 (9), 89

(4), 75 (17), 73 (14), 59 (6), 58 (100), 55 (16); HRMS (ESI+): m/z: calcd

for C₂₄H₄₃NO₃Si+Na: 444.2905; found: 444.2905 [M⁺+Na]; elemental

analysis calcd (%) for C₂₄H₄₃NO₃Si: C 68.36, H 10.28, N 3.32; found: C

68.28, H 10.22, N 3.26.

Western segment

tert-Butyl((5-iodopentyl)oxy)dimethylsilane (24): Imidazole (3.30 g,

49 mmol) and I₂(11.1 g, 43.7 mmol) were successively added to a vigo-

rously stirred solution of PPh₃(10.2 g, 38.9 mmol) in CH₂Cl₂(100 mL). A

solution of alcohol 23 (7.10 g, 32.5 mmol)^[60]in CH₂Cl₂(40 mL) was

slowly added and the mixture stirred for 4 h before all volatile materials

were evaporated and the residue purified by flash chromatography (hex-

anes/EtOAc 1:0 ! 4:1) to give product 24 as a yellow liquid (10.36 g,

97%). ¹H NMR (400 MHz, CDCl₃): d=3.61(t, J=6.2 Hz, 2H), 3.19 (t,

J=7.1Hz, 2H), 1.85 (quint, J=7.2 Hz, 2H), 1.57–1.41 (m, 4H), 0.90 (s,

9H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=62.9, 33.4, 31.7,

27.0, 26.0, 18.4, 6.9, ꢁ5.3 ppm; IR (film): n˜ =2954, 2930, 2886, 2857, 2737,

1471, 1462, 1255, 1213, 1103, 836, 812, 775 cm^ꢁ1; MS (EI): m/z (%): 271

(24), 215 (19), 185 (16), 143 (6), 101 (4), 75 (19), 70 (6), 69 (100), 45 (4),

ACHRTE(UGN 2S,4R)-9-((tert-ButylACHTRE(UGN dimethyl)silyl)oxy)-N-((1R,2R)-2-hydroxy-1-

methyl-2-phenylethyl)-N,2,4-trimethylnonanoic acid amide (28): Prepared

analogously from ent-22 (1.37 g, 6.19 mmol) and iodide 27 (3.44 g,

9.29 mmol) using LiCl (1.58 g, 37.3 mmol), (iPr)₂NH (1.96 mL,

13.9 mmol) and nBuLi (1.6m in hexane, 8.06 mL, 12.9 mmol). Flash chro-

matography (hexanes/EtOAc 10:1 ! 4:1) afforded product 28 as a color-

less liquid (2.00 g, 70%). [a]=ꢁ578 (c=0.9, CHCl₃); de=99% (HPLC:

41(81); HRMS (CI):

m/z: calcd for C₁₁H₂₆IOSi: 329.0798; found:

329.0801[ M⁺+H].

column: 125 mm Purospher C18e (5 mm),

1 3.0 mm; MeOH/water

tert-Butyl(((6R)-7-iodo-6-methylheptyl)oxy)dimethylsilane (27): Pre-

pared analogously from alcohol 26 (8.34 g, 32 mmol), imidazole (3.28 g,

48.2 mmol), I₂(11.1 g, 43.7 mmol) and PPh₃(10.11 g, 38.6 mmol). Flash

chromatography (hexanes/EtOAc 10:1) provides product 27 as a yellow

liquid (11.86 g, 99%). [a]_D²⁰=ꢁ18 (c=1.1, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=3.60 (t, J=6.5 Hz, 2H), 3.19 (ddd, J=5.3, 9.6, 15.5 Hz, 2H),

1.54–1.17 (m, 9H), 0.97 (d, J=6.5 Hz, 3H), 0.89 (s, 9H), 0.05 ppm (s,

6H); ¹³C NMR (100 MHz, CDCl₃): d=63.2, 36.4, 34.7, 32.8, 26.7, 26.0,

25.9, 20.6, 18.4, 17.9, ꢁ5.3 ppm; IR (film): n˜ =2955, 2929, 2856, 2739,

1471, 1462, 1388, 1361, 1255, 1194, 1101, 835, 775 cm^ꢁ1; MS (EI): m/z

(%): 313 (13), 215 (6), 185 (7), 111 (42), 83 (5), 75 (23), 73 (10), 70 (6),

69 (100), 59 (5), 57 (5), 55 (29), 43 (6), 41 (11); HRMS (ESI+): m/z:

calcd for C₁₄H₃₁INaOSi: 393.1081; found: 393.1081 [M⁺+Na]; elemental

85:15; 0.5 mLmin^ꢁ1; T=308 K; 14.4MPa; t_R=13.97 min (major diaste-

reomer), 24.95 min (minor diastereomer)); ¹H NMR (400 MHz, CDCl₃):

d=7.34–7.07 (m, 5H), 5.05 (brs, 1H), 4.56 (m, 1H), 4.22 (m, 1H), 3.57

(t, J=6.4 Hz, 2H), 2.42 (m, 1H), 2.34 (s, 3H), 1.59–0.98 (m, 17H), 0.99

(s, 9H), 0.78 (d, J=6.4 Hz, 3H), 0.08 ppm (s, 6H); ¹³C NMR (100 MHz,

C₆D₆): d=178.5, 143.9, 128.3, 127.3, 126.8, 74.5, 63.3, 58.3, 41.6, 37.6, 34.4,

33.3, 30.9, 27.1, 26.7, 26.2 (2 C), 19.8, 18.5, 17.4, 14.4, ꢁ5.1ppm; IR

(film): n˜ =3383, 3087, 3063, 3029, 2955, 2930, 2857, 2737, 1622, 1471,

1463, 1408, 1377, 1360, 1255, 1100, 1052, 1028, 836, 775, 701 cm^ꢁ1; MS

(EI): m/z (%): 408 (7), 407 (24), 406 (79), 357 (13), 356 (33), 299 (6), 148

(20), 115 (5), 97 (6), 83 (12), 75 (15), 73 (9), 69 (9), 59 (6), 58 (100), 55

(10); HRMS (ESI+): m/z: calcd for C₂₇H₄₉NNaO₃Si: 486.3374; found:

8772

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

486.3378 [M⁺+Na]; elemental analysis calcd (%) for C₂₇H₄₉NO₃Si: C

69.92, H 10.65; found: C 70.06, H 10.61.

afforded the title compound as a yellow liquid (265 mg, 88%). [a]_D²⁰

=

1

+28 (c=0.9, CHCl₃); H NMR (400 MHz, CDCl₃): d=3.61(t, J=6.5 Hz,

2H), 3.55 (brs, 2H), 1.58–1.51 (m, 2H), 1.47–1.29 (m, 6H), 0.90 (t, J=

7.4 Hz, 3H), 0.89 (s, 9H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz,

CDCl₃): d=65.3, 63.5, 41.8, 29.9, 26.5, 26.0, 23.5, 18.4, 11.1, ꢁ5.3 ppm; IR

(film): n˜ =3349, 2957, 2930, 2858, 2738, 1472, 1463, 1387, 1361, 1255,

1099, 1039, 1006, 969, 939, 836, 813, 775, 712, 662 cm^ꢁ1; MS (EI): m/z

(%): 105 (15), 101 (5), 97 (60), 89 (5), 75 (44), 73 (14), 69 (16), 59 (5), 56

(5), 55 (100), 43 (6), 29 (5); HRMS (ESI+): m/z: calcd for

C₁₃H₃₀NaO₂Si: 269.1908; found: 269.1904 [M⁺+Na]; elemental analysis

calcd (%) for C₁₃H₃₀O₂Si: C 63.35, H 12.27; found: C 63.39, H 12.24.

(2R)-5-((tert-ButylACHTREUNG(dimethyl)silyl)oxy)-2-ethyl-N-((1S,2S)-2-hydroxy-1-

methyl-2-phenyl-ethyl)-N-methylpentanamide (36): Prepared analogously

from 33 (2.35 g, 9.99 mmol) and iodide 35 (4.50 g, 15 mmol) using LiCl

(2.54 g, 59.9 mmol), (iPr)₂NH (3.16 mL, 22.5 mmol) and nBuLi (1.6m in

hexane, 13.1 mL, 21.0 mmol). Flash chromatography (hexanes/EtOAc

10:1 ! 2:1) afforded product 36 as a yellow liquid (3.45 g, 85%). [a]_D²⁰

=

+718 (c=1.2, CHCl₃); de > 97% (¹³C NMR); ¹H NMR (400 MHz, C₆D₆,

major rotamer): d=7.34–7.06 (m, 5H), 5.17 (br s, 1H), 4.54 (m, 1H),

4.32 (m, 1H), 3.44 (m, 2H), 2.36 (s, 3H), 2.23 (m, 1H), 1.77–1.00 (m,

9H), 0.96 (s, 9H), 0.80 (t, J=7.4 Hz, 3H), 0.04 ppm (s, 6H); ¹³C NMR

(100 MHz, C₆D₆, major rotamer): d=177.6, 143.9, 128.3, 127.3, 126.8,

76.2, 63.3, 58.2, 43.6, 30.9, 29.4, 26.4, 26.3, 26.2, 18.5, 14.5, 12.0, ꢁ5.2 ppm;

IR (film): n˜ =3382, 3087, 3063, 3029, 2957, 2930, 2857, 2738, 1618, 1472,

1462, 1409, 1386, 1361, 1305, 1255, 1195, 1143, 1098, 1051, 1006, 973, 939,

836, 775, 701, 662 cm^ꢁ1; MS (EI): m/z (%): 351 (13), 350 (50), 300 (14),

244 (21), 243 (100), 75 (12), 73 (22), 58 (32), 55 (10); HRMS (ESI+):

m/z: calcd for C₂₃H₄₁NNaO₃Si: 430.2748; found: 430.2744 [M⁺+Na].

tert-ButylACHTRE(UGN ((6R,8S)-9-(4-methoxyphenoxy)-6,8-dimethylnonyl)-oxy)dime-

thylsilane (30): A solution of alcohol 29 (500 mg, 1.65 mmol), para-me-

thoxyphenol (622 mg, 5.01mmol), PPh ₃(569 mg, 2.17 mmol) and diethyl

azodicarboxylate (0.34 mL, 2.16 mmol) in THF (6.3 mL) was stirred in a

sealed tube at 808C for 30 min. The reaction was quenched with water

(5 mL), the aqueous layer was extracted with tert-butyl methyl ether (3

10 mL), and the combined organic phases were dried (MgSO₄) and

evaporated. The crude product was used in the next step without further

purification. Analytically pure samples obtained by flash chromatography

(hexanes/EtOAc 10:1) analyzed as follows: [a]²_D⁰=ꢁ58 (c=1.3, CHCl₃);

(2R)-7-((tert-ButylACHTREUNG(dimethyl)silyl)oxy)-2-methyl-1-heptanol (26): nBuLi

(1.6m in hexane, 76.3 mL, 122 mmol) was slowly added to a solution of

(iPr)₂NH (18.5 mL, 132 mmol) in THF (130 mL) at ꢁ788C. The mixture

was stirred at that temperature for 10 min and at 08C for another 10 min

before BH₃·NH₃(4.29 g, 90%, 125 mmol) was introduced and stirring

continued at ambient temperature for 30 min. The mixture was cooled to

08C before a solution of compound 25 (13.2 g, 31.3 mmol) in THF

(220 mL) was added and stirring continued at ambient temperature for

2 h. For work up, the reaction was quenched by slow addition of aq. sat.

NH₄Cl (150 mL). The mixture was stirred for 30 min before the aqueous

layer was extracted with tert-butyl methyl ether (3200 mL). The com-

bined organic phases were washed with brine before they were dried

over MgSO₄and evaporated. Flash chromatography of the residue (hex-

anes/EtOAc 10:1) afforded product 26 as a pale yellow liquid (6.57 g,

81%). ¹H NMR (400 MHz, CDCl₃): d=3.60 (t, J=6.6 Hz, 2H), 3.46 (m,

2H), 1.65–1.25 (m, 9H), 1.09 (m, 1H), 0.92 (d, J=6.8 Hz, 3H), 0.89 (s,

9H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=68.4, 63.3, 35.8,

33.1, 32.8, 26.8, 26.1, 26.0, 18.4, 16.6, ꢁ5.3 ppm; IR (film): n˜ =3348, 2953,

2930, 2857, 2737, 1472, 1463, 1387, 1361, 1255, 1101, 1034, 1006, 836, 813,

775 cm^ꢁ1; MS (EI): m/z (%): 203 (2), 157 (2), 115 (4), 112 (2), 111 (21),

105 (11), 101 (3), 93 (5), 89 (3), 77 (2), 76 (3), 75 (37), 73 (12), 70 (6), 69

(100), 67 (3), 61 (2), 59 (4), 57 (5), 56 (2), 55 (36), 45 (2), 43 (6), 41 (11),

31(3), 29 (4); HRMS (ESI +): m/z: calcd for C₁₄H₃₂NaO₂Si: 283.2064;

found: 283.2064 [M⁺+Na]; elemental analysis calcd (%) for C₁₄H₃₂O₂Si:

C 64.55, H 12.38; found: C 64.50, H 12.46.

de

>

99% (HPLC: column: 125 mm YMC ProC18, 120 A, 5 mm, 1

ꢁ1

2.1mm; MeCN/water 90:10; 0.2 mLmin

; T=308 K; 2.8MPa; t_R=

31.58 min); ¹H NMR (400 MHz, CDCl₃): d=6.83 (s, 4H), 3.77 (s, 3H),

3.69 (ddd, J=6.3, 8.9, 15.8 Hz, 2H), 3.60 (t, J=6.6 Hz, 2H), 1.99 (m,

1H), 1.53 (m, 3H), 1.40–1.13 (m, 8H), 0.98 (d, J=6.6 Hz, 3H), 0.90 (s,

9H), 0.86 (d, J=6.6 Hz, 3H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz,

CDCl₃): d=153.6, 153.5, 115.4, 114.6, 74.6, 63.3, 55.8, 41.0, 37.9, 32.9,

30.8, 29.9, 26.9, 26.2, 26.0, 19.4, 18.4, 16.9, ꢁ5.3 ppm; IR (film): n˜ =2954,

2929, 2856, 1592, 1509, 1469, 1442, 1388, 1361, 1288, 1232, 1181, 1102,

1045, 1006, 992, 939, 905, 835, 775, 748, 712, 662 cm^ꢁ1; MS (EI): m/z (%):

409 (6), 408 ([M⁺], 20), 211 (8), 199 (9), 181 (16), 125 (8), 124 (100), 123

(5), 111 (13), 109 (13), 98 (5), 97 (59), 95 (7), 89 (5), 83 (42), 75 (36), 73

(18), 71 (12), 69 (34), 59 (6), 57 (15), 55 (41), 43 (12), 41 (11); HRMS

(ESI+): m/z: calcd for C₂₄H₄₄NaO₃Si: 431.2952; found: 431.2954 [M⁺

+Na]; elemental analysis calcd (%) for C₂₄H₄₄O₃Si: C 70.53, H 10.85;

found: C 70.61, H 10.77.

AHCTRE(GNU 6R,8S)-9-(4-Methoxyphenoxy)-6,8-dimethylnonanoic acid (31): TBAF

(1m in THF, 1.82 mL, 1.82 mmol) was added to a solution of crude com-

pound 30 (1.65 mmol) in THF (8.3 mL) and the resulting mixture was

stirred for 18 h before it was adsorped on silica. Eluation with hexanes/

EtOAc 10:1 ! 4:1afforded (6 R,8S)-9-(4-methoxyphenoxy)-6,8-dimethyl-

1-nonanol as a pale yellow liquid (436 mg, 90% over two steps) which

analyzed as follows: [a]²_D⁰=ꢁ38 (c=1.1, CHCl₃); de

> 99% (HPLC:

column: 125 mm YMC ProC18, 120 A, 5 mm, 1 2.1mm; eluent: MeOH/

water 70:30; 0.2 mLmin^ꢁ1; T=308 K; 8.8MPa; t_R=28.30 min); ¹H NMR

(400 MHz, CDCl₃): d=6.83 (s, 4H), 3.77 (s, 3H), 3.69 (ddd, J=6.3, 9.0,

15.8 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.00 (m, 1H), 1.56 (m, 3H), 1.41–

1.13 (m, 9H), 0.98 (d, J=6.7 Hz, 3H), 0.86 ppm (d, J=6.6 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): d=153.6, 153.5, 115.4, 114.6, 74.6, 63.1,

55.8, 41.0, 37.8, 32.8, 30.7, 29.9, 26.8, 26.0, 19.4, 16.9 ppm; IR (film): n˜ =

A

G

(29):

Prepared analogously from substrate 28 (2.44 g, 5.26 mmol), using nBuLi

(1.6m in hexane, 12.8 mL, 20.5 mmol), (iPr)₂NH (3.1mL, 22 mmol) and

BH₃·NH₃(722 mg, 90%, 21.0 mmol). Flash chromatography (hexanes/

EtOAc 10:1) afforded the title compound as a colorless liquid (1.37 g,

86%). [a]²_D⁰=ꢁ148 (c=1.5, CHCl₃); de > 99% (HPLC: column: 125 mm

Nucleodur 100–5-C18ce, 1 4.0 mm; MeOH/water 80:20; 0.8 mLmin^ꢁ1

;

3337, 3047, 2929, 2857, 1614, 1591, 1509, 1466, 1231, 1043, 824, 748 cm^ꢁ1

;

1

T=308 K; 8.6MPa; t_R=17.74 min); H NMR (400 MHz, CDCl₃): d=3.60

(t, J=6.6 Hz, 2H), 3.44 (ddd, J=6.2, 10.4, 17.1 Hz, 2H), 1.71 (m, 1H),

1.54–1.03 (m, 12H), 0.89 (s, 9H), 0.88 (d, J=5.7 Hz, 3H), 0.84 (d, J=

6.6 Hz, 3H), 0.04 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=69.1,

63.3, 40.6, 38.0, 33.2, 32.9, 29.9, 26.8, 26.1, 26.0, 19.4, 18.4, 16.3, ꢁ5.3 ppm;

IR (film): n˜ =3346, 2954, 2929, 2857, 2737, 1471, 1463, 1385, 1255, 1102,

1038, 1006, 836, 813, 775 cm^ꢁ1; MS (EI): m/z (%): 245 (3), 129 (3), 115

(5), 111 (18), 109 (3), 105 (16), 101 (5), 98 (8), 97 (100), 95 (7), 93 (7), 89

(6), 85 (7), 84 (5), 83 (72), 81(5), 75 (55), 73 (20), 71(19), 70 (5), 69 (74),

59 (7), 57 (24), 56 (5), 55 (87), 43 (21), 41 (15), 29 (5); HRMS (ESI+):

m/z: calcd for C₁₇H₃₈NaO₂Si: 325.2533; found: 325.2531[ M⁺+Na]; ele-

mental analysis calcd (%) for C₁₇H₃₈O₂Si: C 67.48, H 12.66; found: C

67.43, H 12.64.

MS (EI): m/z (%): 294 (14) [M⁺], 125 (9), 124 (100), 109 (9), 69 (5), 55

(13), 43 (5), 41 (7); HRMS (ESI+): m/z: calcd for C₁₈H₃₀NaO₃:

317.2087; found: 317.2088 [M⁺+Na]; elemental analysis calcd (%) for

C₁₈H₃₀O₃: C 73.43, H 10.27; found: C 73.50, H 10.32.

A

mixture of this alcohol (100 mg, 0.340 mmol) and PDC (1.28 g,

3.40 mmol) in DMF (3.5 mL) was stirred for 15 h before it was quenched

with water (10 mL) and extracted with Et₂O (55 mL). The combined

organic layers were dried over MgSO₄and evaporated, and the residue

was purified by flash chromatography with hexanes/EtOAc 10:1 ! 4:1to

give acid 31 as a yellow liquid (78 mg, 74%). [a]²_D⁰=ꢁ98 (c=1.5, CHCl₃);

de

> 99% (HPLC: column: 125 mm Purospher RP-18e (5 mm), 1

3.0 mm; eluent: MeOH/0.1% TFA 75:25; 0.5 mLmin^ꢁ1

; T=308 K;

(2R)-5-((tert-Butyl

A

13.1MPa; t_R=11.52 min); ¹H NMR (400 MHz, CDCl₃): d=10.79 (br s,

1H), 6.83 (s, 4H), 3.77 (s, 3H), 3.69 (ddd, J=6.3, 8.9, 15.7 Hz, 2H), 2.36

(t, J=7.5 Hz, 2H), 2.01 (m, 1H), 1.67–1.51 (m, 3H), 1.45–1.13 (m, 6H),

0.98 (d, J=6.6 Hz, 3H), 0.86 ppm (d, J=6.6 Hz, 3H); ¹³C NMR

analogously from substrate 36 (0.50 g, 1.2 mmol), using nBuLi (1.6m in

hexane, 3.0 mL, 4.8 mmol), (iPr)₂NH (0.72 mL, 5.1mmol) and BH ₃·NH₃

(168 mg, 90%, 4.9 mmol). Flash chromatography (hexanes/EtOAc 10:1)

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8773

A. Fürstner et al.

(100 MHz, CDCl₃): d=179.7, 153.6, 153.5, 115.4, 114.6, 74.6, 55.7, 40.9,

37.4, 34.0, 30.7, 29.8, 26.5, 24.9, 19.3, 16.8 ppm; IR (film): n˜ =3044, 2955,

2927, 2871, 2676, 2058, 1709, 1591, 1509, 1466, 1412, 1389, 1379, 1288,

1232, 1181, 1107, 1043, 948, 824, 748 cm^ꢁ1; MS (EI): m/z (%): 308 (9)

[M⁺], 125 (8), 124 (100), 123 (3), 109 (10), 83 (3), 69 (5), 55 (9), 43 (5),

41(7); HRMS (ESI +): m/z: calcd for C₁₈H₂₈NaO₄: 331.1880; found:

331.1880 [M⁺+Na]; elemental analysis calcd (%) for C₁₈H₂₈O₄: C 70.10,

H 9.15; found: C 70.14, H 9.12.

108 (28), 107 (100), 93 (14), 91 (19), 83 (19), 81 (11), 79 (71), 75 (44), 73

(40), 67 (15), 65 (15), 59 (17), 57 (10), 55 (35), 41 (20), 29 (15); HRMS

(ESI+): m/z: calcd for C₁₄H₂₈Br₂NaOSi: 421.0169; found: 421.0165 [M⁺

+Na]; elemental analysis calcd (%) for C₁₄H₂₈Br₂OSi: C 42.01, H 7.05;

found: C 41.87, H 7.02.

tert-Butyl(((4R)-4-ethyl-5-heptynyl)oxy)dimethylsilane (40): nBuLi (1.6m

in hexane, 2.67 mL, 4.27 mmol) was added over a period of 30 min to a

solution of compound 39 (855 mg, 2.14 mmol) in THF (22 mL) at ꢁ788C.

Once the addition was complete, the mixture was allowed to stir at

ꢁ168C for 30 min before MeI (0.67 mL, 11 mmol) was introduced and

stirring continued at that temperature for 60 min. An aqueous extractive

work up followed by flash chromatography (hexanes) provided alkyne 40

ACHTREUNG(6R,8S)-N-Methoxy-9-(4-methoxyphenoxy)-N,6,8-trimethylnonanoic acid

amide (32): 1 ,1’-Carbonyldiimidazole (35 mg, 0.21mmol) was added to a

solution of acid 31 (50 mg, 0.16 mmol) in CH₂Cl₂(1mL) at 0 8C and the

resulting mixture was stirred at ambient temperature for 1h. The solu-

tion was then cooled to 08C before Et₃N (73 mL, 0.52 mmol) and N,O-di-

methylhydroxylamine hydrochloride (26 mg, 0.26 mmol) were successive-

ly introduced. After stirring for 14 h, the reaction was quenched with aq.

HCl (3m, 1mL), the aqueous phase was extracted with CH ₂Cl₂(3

5 mL), the combined organic layers were washed with aq. sat. NaHCO₃

and dried over MgSO₄. Evaporation of the solvent followed by flash

chromatography of the residue (hexanes/EtOAc 10:1 ! 4:1) furnished

product 32 as a yellow liquid (50 mg, 87%). [a]²_D⁰=ꢁ88 (c=1.1, CHCl₃);

as

a

colorless liquid (532 mg, 98%). [a]²_D⁰=ꢁ78 (c=0.8, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=3.62 (t, J=6.5 Hz, 2H), 2.20 (m, 1H),

1.80 (d, J=2.4 Hz, 3H), 1.76–1.32 (m, 6H), 0.97 (t, J=7.4 Hz, 3H), 0.90

(s, 9H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=82.4, 76.6,

63.2, 33.2, 31.3, 30.7, 28.4, 26.0, 18.4, 11.8, 3.5, ꢁ5.3 ppm; IR (film): n˜ =

2957, 2929, 2858, 2738, 1472, 1463, 1387, 1361, 1347, 1255, 1188, 1101,

1047, 1006, 968, 939, 836, 775, 662 cm^ꢁ1; MS (EI): m/z (%): 198 (7), 197

(41), 121 (13), 101 (8), 97 (7), 93 (5), 89 (5), 76 (7), 75 (100), 73 (17), 59

(7), 55 (9); HRMS (ESI+): m/z: calcd for C₁₅H₃₀NaOSi: 277.1958;

found: 277.1961 [M⁺+Na]; elemental analysis calcd (%) for C₁₅H₃₀OSi:

C 70.79, H 11.88; found: C 70.86, H 11.81.

de

> 99% (HPLC: column: 125 mm YMC ProC18, 120 A, 5 mm, 1

2.1mm; eluent: MeOH/water 70:30; 0.2 mLmin ^ꢁ1; T=308 K; 8.8MPa;

t_R=29.45 min); ¹H NMR (300 MHz, CDCl₃): d=6.82 (s, 4H), 3.76 (s,

3H), 3.74–3.61(m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.42 (t, J=7.5 Hz,

2H), 2.00 (m, 1H), 1.67–1.12 (m, 9H), 0.97 (d, J=6.7 Hz, 3H), 0.86 ppm

(d, J=6.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=174.7, 153.5, 153.4,

115.4, 114.5, 74.5, 61.1, 55.6, 40.9, 37.6, 32.1, 31.8, 30.7, 29.8, 26.8, 24.8,

19.3, 16.7 ppm; IR (film): n˜ =2956, 2930, 2870, 1667, 1591, 1509, 1466,

1442, 1414, 1384, 1289, 1232, 1180, 1106, 1042, 995, 824, 799, 748, 639,

523 cm^ꢁ1; MS (EI): m/z (%): 352 (5), 351(24) [ M⁺], 228 (20), 124 (100),

83 (12), 69 (10), 55 (24), 41 (12); HRMS (ESI+): m/z: calcd for

C₂₀H₃₄NO₄: 352.2482; found: 352.2484 [M⁺+H]; elemental analysis calcd

(%) for C₂₀H₃₃NO₄: C 68.34, H 9.46, N 3.99; found: C 68.27, H 9.38, N

4.06.

(4R)-4-Ethyl-5-heptyn-1-ol (41): TBAF (1m in THF, 2.3 mL, 2.3 mmol)

was added to a solution of compound 40 (532 mg, 2.09 mmol) in THF

(10 mL) and the resulting mixture was stirred for 14 h. A standard extrac-

tive work up followed by flash chromatographic purification of the crude

material (hexanes/EtOAc 4:1) furnished product 41 as a yellow liquid

1

(278 mg, 95%). [a]²_D⁰=ꢁ68 (c=0.9, CHCl₃); H NMR (400 MHz, CDCl₃):

d=3.67 (t, J=6.5 Hz, 2H), 2.22 (m, 1H), 1.80 (d, J=2.4 Hz, 3H), 1.78–

1.34 (m, 6H), 0.98 ppm (t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃):

d=82.2, 76.9, 62.9, 33.3, 31.2, 30.7, 28.5, 11.8, 3.5 ppm; IR (film): n˜ =

3337, 2960, 2934, 2872, 2738, 1455, 1379, 1348, 1229, 1059, 1031, 925 cm^ꢁ1

;

MS (EI): m/z (%): 111 (7), 97 (9), 96 (66), 91 (29), 84 (10), 81 (100), 79

(62), 77 (48), 67 (33), 65 (15), 55 (40), 53 (39), 43 (27), 41 (48), 39 (25),

27 (17); HRMS (CI): m/z: calcd: 141.1279; found: 141.1281 [M⁺+H]; ele-

AHCTREmUNG ental analysis calcd (%) for C₉H₁₆O: C 77.09, H 11.50; found: C 77.14,

H 11.46.

tert-Butyl(((4R)-6,6-dibromo-4-ethyl-5-hexenyl)oxy)dimethyl-silane (39):

A solution of N-methylmorpholin-N-oxide monohydrate (97%, 588 mg,

4.87 mmol) and powdered molecular sieves (4 , 1.62 g) in CH₂Cl₂

(5 mL) was stirred for 10 min before a solution of alcohol 37 (800 mg,

3.25 mmol) in CH₂Cl₂(5 mL) and tetra-N-propylammonium perruthenate

(57 mg, 0.16 mmol, 5 mol%) were successively added. The resulting mix-

ture was stirred for 30 min before it was passed through a short pad of

Celite which was carefully rinsed with CH₂Cl₂. The combined filtrates

were evaporated and the resulting crude aldehyde 38 (685 mg,

2.80 mmol, 86%) immediately used in the next step without further pu-

rification.

(4R)-7-Bromo-4-ethyl-2-heptyne (42): PPh₃(2.27 g, 8.66 mmol) was

added in portions to a solution of alcohol 41 (1.10 g, 7.86 mmol) and

CBr₄(2.87 g, 8.65 mmol) in CH₂Cl₂(40 mL) and the resulting mixture

was stirred for 5 h at ambient temperature. For work up, the solvents

were carefully evaporated and the residue was purified by flash chroma-

tography (hexanes/EtOAc 1:0 ! 30:1) to give product 42 as a colorless

liquid (1.23 g, 77%). [a]_D²⁰=ꢁ178 (c=0.8, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=3.44 (t, J=6.8 Hz, 2H), 2.22 (m, 1H), 2.13–1.89 (m, 2H),

1.80 (d, J=2.4 Hz, 3H), 1.63–1.55 (m, 1H), 1.51–1.35 (3H), 0.98 ppm (t,

J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=81.7, 77.2, 33.9, 33.5,

32.8, 30.8, 28.4, 11.8, 3.5 ppm; IR (film): n˜ =2962, 2922, 2873, 2858, 1459,

1380, 1348, 1293, 1251, 1206, 649, 561 cm^ꢁ1; MS (GC-EI): m/z (%): 174

(7), 107 (6), 97 (5), 96 (68), 95 (20), 94 (11), 93 (16), 91 (18), 82 (7), 81

(100), 79 (57), 77 (33), 67 (31), 66 (9), 65 (17), 55 (23), 53 (46), 41 (40),

39 (28), 27 (20); HRMS (CI): m/z: calcd for C₉H₁₆Br: 203.0436; found:

203.0433 [M⁺+H]; elemental analysis calcd (%) for C₉H₁₅Br: C 53.22, H

7.44; found: C 53.31, H 7.52.

PPh₃(3.41g, 13.0 mmol) was added in portions over a period of 20 min

to a solution of CBr₄(2.15 g, 6.48 mmol) in CH₂Cl₂(22 mL) at 08C. After

stirring for 10 min, the resulting clear orange-red solution was cooled to

ꢁ788C before a solution of the crude aldehyde in CH₂Cl₂(11 mL) was

added dropwise. The resulting mixture was stirred for 40 min before it

was transferred under stirring into a mixture of hexanes (460 mL) and

Et₃N (2.28 mL, 16.22 mmol). The precipitates formed were filtered off

over basic alumina, which was carefully rinsed with hexanes/EtOAc 1:1.

The combined filtrates were evaporated and the crude product dissolved

in CH₂Cl₂(16.5 mL). To remove residual PPh₃, MeI (0.81mL, 13 mmol)

was added. After stirring for 1h, the reaction was quenched with aq. sat.

NH₄Cl (10 mL), the aqueous layer was extracted with tert-butyl methyl

ether (315 mL), the combined organic phases were dried over MgSO₄

and evaporated, and the residue was purified by flash chromatography

(hexanes) to give the title compound 39 as a colorless liquid (965 mg,

74% over both steps). [a]_D²⁰=ꢁ18 (c=1.1, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=6.12 (d, J=9.8 Hz, 1H), 3.60 (t, J=6.2 Hz, 2H), 2.31(m,

1H), 1.54–1.42 (m, 4H), 1.37–1.26 (m, 2H), 0.91–0.88 (m, 3H), 0.90 (s,

9H), 0.05 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=143.3, 88.1, 63.0,

45.1, 30.3, 30.2, 27.4, 26.0, 18.4, 11.5, ꢁ5.3 ppm; IR (film): n˜ =2957, 2928,

2895, 2857, 2738, 1617, 1471, 1462, 1386, 1361, 1255, 1188, 1101, 1006,

983, 939, 900, 835, 813, 775, 714, 661, 567 cm^ꢁ1; MS (EI): m/z (%): 345

(17), 343 (32), 341 (16), 169 (12), 167 (12), 147 (10), 139 (22), 137 (20),

Compound 44: A solution of bromide 42 (168 mg, 0.827 mmol) in THF

(3 mL) was added to

a suspension of magnesium turnings (40 mg,

1.7 mmol, pre-activated with catalytic amounts of 1,2-dibromoethane) in

THF (5 mL) and the mixture stirred at 408C for 100 min. The solution of

the resulting Grignard reagent 43 was then transferred via canula under

Ar to a solution of compound 32 (223 mg, 0.635 mmol) in THF (2 mL) at

08C. After stirring for 17 h at ambient temperature, the reaction was

quenched with sat. aq. NH₄Cl (5 mL). A standard extractive work up fol-

lowed by flash chromatography of the crude material (hexanes/EtOAc

30:1) provided product 44 as a colorless liquid (202 mg, 77%). [a]_D²⁰

ꢁ118 (c=0.5, CHCl₃); H NMR (300 MHz, CDCl₃): d=6.82 (s, 4H), 3.77

(s, 3H), 3.69 (m, 2H), 2.39 (m, 4H), 2.20 (m, 1H), 1.99 (m, 1H), 1.79 (d,

J=2.3 Hz, 3H), 1.77–1.10 (m, 15H), 0.98 (d, J=6.6 Hz, 3H), 0.97 (t, J=

=

1

8774

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

7.4 Hz, 3H), 0.86 ppm (d, J=6.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃):

d=211.3, 153.7, 153.5, 115.5, 114.6, 82.1, 76.8, 74.6, 55.8, 42.8, 42.7, 41.0,

37.7, 34.5, 33.3, 30.8, 29.9, 28.3, 26.7, 24.2, 21.9, 19.4, 16.9, 11.8, 3.5 ppm;

IR (film): n˜ =3045, 2957, 2927, 2858, 2058, 1713, 1616, 1591, 1509, 1464,

1411, 1377, 1288, 1232, 1181, 1106, 1043, 992, 824, 748 cm^ꢁ1; MS (EI): m/z

(%): 415 (5), 414 ([M⁺], 17), 125 (8), 124 (100), 109 (9), 81 (4), 69 (4), 55

(9), 43 (5), 41(5); HRMS (ESI +): m/z: calcd for C₂₇H₄₂NaO₃: 437.3026;

found: 437.3029 [M⁺+Na]; elemental analysis calcd (%) for C₂₇H₄₂O₃: C

78.21, H 10.21; found: C 78.28, H 10.21.

The enyne linchpin

(1E)-1,2-Dibromo-3-methoxy-1-propene (48): Ether 47 (4.00 g,

55.4 mmol) was added to a solution of pyridinium perbromide (95% w/w,

26.2 g, 77.8 mmol) in CH₂Cl₂(80 mL) and the resulting mixture was

stirred at ambient temperature in the dark for 91h. Pentane (60 mL) was

then added and the precipitates were filtered off through a short pad of

Kieselgur which was carefully rinsed with pentanes. The combined fil-

trates were evaporated to give dibromide 48 as a yellow oil which was

pure enough for use in the next step without further purification (12.73 g,

quant.). ¹H NMR (400 MHz, CDCl₃): d=6.69 (s, 1H), 4.30 (s, 2H),

3.35 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=122.7, 106.5, 72.1,

57.6 ppm; IR (film): n˜ =3081, 2991, 2928, 2823, 1702, 1604, 1449, 1191,

1102, 1035, 912, 794, 706 cm^ꢁ1; MS (EI): m/z (%): 230 (13), 228 (7) [M⁺],

199 (12), 151 (68), 149 (70), 121 (23), 119 (35), 117 (12), 107 (9), 105 (10),

95 (33), 93 (28), 69 (12), 55 (51), 45 (100), 41 (53), 39 (100), 37 (13), 29

(39), 27 (20), 26 (11); HRMS (EI): m/z: calcd for C₄H₆Br₂O: 227.8786;

found: 227.8785; elemental analysis calcd (%) for C₄H₆Br₂O: C 20.90, H

2.63, Br 69.51; found: C 20.86, H 2.40, Br 69.36.

Compound 45: A solution of CAN (80 mg, 0.15 mmol) in water (0.7 mL)

was added to a solution of compound 44 (20 mg, 0.05 mmol) in MeCN

(0.5 mL) at 08C and the resulting mixture was stirred at that temperature

for 45 min. For work up, the solution was diluted with water (5 mL) and

extracted with EtOAc (55 mL), the combined organic phases were suc-

cessively washed with aq. sat. NaHCO₃, aq. sat. Na₂SO₃and brine before

they were dried over MgSO₄and evaporated. Purification of the crude

product by flash chromatography (hexanes/EtOAc 10:1 ! 4:1) furnished

product 45 as a yellow liquid (12 mg, 81%). [a]²_D⁰=ꢁ198 (c=0.8, CHCl₃);

de > 99% (HPLC: column: 125 mm Nucleodur 5-100-C18ec, 1 4.0 mm;

eluent: MeOH/0.1% TFA 70:30; 0.8 mLmin^ꢁ1; T=308 K; 8.1MPa; t_R=

22.79 min); ¹H NMR (400 MHz, CDCl₃): d=3.43 (ddd, J=13.7, 10.4,

6.2 Hz, 2H), 2.40 (m, 4H), 2.18 (m, 1H), 1.79 (d, J=2.3 Hz, 3H), 1.74–

1.02 (m, 16H), 0.96 (t, J=7.4 Hz, 3H), 0.88 (d, J=6.7 Hz, 3H), 0.83 ppm

(d, J=6.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): d=211.4, 82.1, 76.8,

69.1, 42.8, 42.6, 40.6, 37.7, 34.5, 33.3, 33.2, 29.8, 28.3, 26.7, 24.1, 21.8, 19.3,

16.3, 11.8, 3.5 ppm; IR (film): n˜ =3422, 2957, 2925, 2871, 2736, 1712,

1461, 1410, 1378, 1290, 1129, 1038, 987 cm^ꢁ1; MS (EI): m/z (%): 308 (3)

[M⁺], 167 (17), 166 (27), 151 (31), 149 (16), 137 (77), 124 (24), 123 (53),

110 (16), 109 (54), 108 (42), 107 (24), 95 (31), 93 (57), 83 (50), 82 (16), 81

(54), 79 (36), 71 (16), 69 (48), 67 (33), 57 (30), 55 (100), 53 (17), 43 (57),

(2E)-2-Bromo-1-methoxy-2-hexen-4-yne (12): A solution of propynyl-

magnesium bromide (0.5m in THF, 144 mL, 72.0 mmol) was slowly added

to a solution of ZnCl₂(1.0m in Et₂O, 72 mL, 72 mmol) at 08C. After stir-

ring for 45 min at that temperature, (PPh₃)₄Pd (3.20 g, 2.77 mmol, 5

mol%) was added to the white suspension, followed by bromide 48

(12.8 g, 55.7 mmol). After stirring for 15 h at 08C, the mixture was fil-

tered through a pad of Kieselgur which was rinsed with Et₂O. The com-

bined filtrates were carefully reduced (T ꢂ308C; p=450 mbar) to about

¹= of the original volume and the precipitated salts were again removed

2

by filtration through Kieselgur. The filtrate was then evaporated and the

residue purified by distillation to give product 12 as a pale yellow liquid

(41–438C, 10^ꢁ3mbar) (6.85 g, ꢃ95% (GC/MS), 62%). ¹H NMR

(400 MHz, CDCl₃): d=6.12 (appq, J=2.5 Hz, 1H), 4.34 (s, 2H), 3.36 (s,

3H), 1.96 ppm (d, J=2.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

134.3, 116.8, 92.8, 75.1, 72.8, 57.5, 4.5 ppm; IR (film): n˜ =2916, 2821, 224,

1726, 1449, 1375, 1282, 1190, 1099, 913, 859 cm^ꢁ1; MS (EI): m/z (%): 190

(14), 188 (15) [M⁺], 109 (100), 78 (18), 77 (18), 66 (13), 65 (15), 53 (27),

51 (20), 45 (10), 39 (19); HRMS (EI): m/z: calcd for C₇H₉BrO: 187.9837;

found: 187.9839; elemental analysis calcd (%) for C₇H₉BrO: C 44.47, H

4.80, Br 42.27; found: C 44.42, H 4.86, Br 42.34. The stereochemistry was

confirmed by comparison with the data of the (Z)-configured isomer

formed upon isomerization. The following ¹³C NMR data are most char-

acteristic, see graphic:

41(59), 31(12), 29 (18); HRMS (ESI

+): m/z: calcd for C₂₀H₃₆NaO₂:

331.2608; found: 331.2609 [M⁺+Na]; elemental analysis calcd (%) for

C₂₀H₃₆O₂: C 77.87, H 11.76; found: C 77.83, H 11.68.

Acid 46: 4-Methoxy-TEMPO (4.3 mg, 23 mmol) was added to a vigorous-

ly stirred solution of alcohol 45 (35 mg, 0.11 mmol) and KBr (2.7 mg,

23 mmol) in CH₂Cl₂(2.5 mL) and aq. sat. NaHCO₃(5 mL) at 08C. A solu-

tion of NaOCl (0.25m, 0.60 mL, 0.15 mmol) was then introduced and the

mixture stirred at 08C for 7 h. For work up, the reaction was quenched

with aq. sat. Na₂S₂O₃(2.5 mL) and aq. sat. NaHCO₃(50 mL), the aque-

ous layer was extracted with EtOAc (320 mL), the combined organic

phases were dried over MgSO₄and evaporated, and the resulting crude

aldehyde was immediately used in the next step without further purifica-

tion.

A solution of NaClO₂(72 mg, 80%) and NaH₂PO₄(38 mg) in water

(1.4 mL) was added to a solution of tBuOH (3.35 mL) and 2-methylbu-

tene (1.34 mL) and the resulting mixture was vigorously stirred for

10 min. An aliquot of this mixture (1.5 mL) was then added dropwise to

a solution of the crude aldehyde in CH₂Cl₂(0.5 mL). After stirring for

13 h, the mixture was diluted with water (10 mL) and extracted with

EtOAc (310 mL). The combined organic phases were dried over

MgSO₄and evaporated, and the residue was purified by flash chromatog-

raphy (hexanes/EtOAc 10:1 ! 4:1) to give acid 46 as a yellow liquid

(32.9 mg, 90% over both steps). [a]²_D⁰=ꢁ18 (c=1.0, CHCl₃); de > 99%

(HPLC: column: 125 mm Nucleodur 100-5-C18ec, 1 4.0 mm; eluent:

MeOH/0.1% TFA 70:30; 0.8 mLmin^ꢁ1

; T=308 K; 8.3MPa; t_R=

19.34 min); ¹H NMR (400 MHz, CDCl₃): d=10.40 (brs, 1H), 2.52 (m,

1H), 2.39 (m, 4H), 2.18 (m, 1H), 1.79 (d, J=2.3 Hz, 3H), 1.77–1.18 (m,

15H), 1.14 (d, J=6.9 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H), 0.85 ppm (d, J=

6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=211.4, 183.1, 82.0, 76.8,

42.7, 42.6, 40.7, 37.0, 36.7, 34.5, 33.3, 30.3, 28.3, 26.5, 24.0, 21.8, 19.2, 16.8,

11.7, 3.5 ppm; IR (film): n˜ =3096, 2958, 2931, 2859, 2670, 1737, 1707,

1462, 1413, 1378, 1291, 1181, 949 cm^ꢁ1; MS (EI): m/z (%): 322 (1) [M⁺],

266 (8), 241 (8), 171 (15), 166 (27), 153 (43), 151 (30), 141 (21), 137 (77),

123 (53), 109 (46), 108 (43), 107 (27), 97 (20), 95 (31), 93 (57), 83 (31), 81

(59), 79 (41), 69 (57), 67 (38), 57 (32), 55 (100), 53 (20), 45 (21), 43 (60),

41(66), 29 (22); HRMS (ESI +): m/z: calcd for C₂₀H₃₄NaO₃: 345.2400;

found: 345.2400 [M⁺+Na]; elemental analysis calcd (%) for C₂₀H₃₄O₃: C

74.49, H 10.63; found: C 74.42, H 10.57.

The hydroxylated sector

Ethyl (3S)-4-azido-3-hydroxybutanoate (51): A mixture of chloride 50

(21.3 g, 128 mmol^[42]) and NaN₃(17.9 g, 275 mmol) in DMF (300 mL) was

stirred at 1008C for 48 h. After reaching ambient temperature, the mix-

ture was diluted with tert-butyl methyl ether (300 mL) and extracted with

aq. sat. NH₄Cl (3200 mL). The aqueous layers were extracted with tert-

butyl methyl ether, the combined organic phases were dried over Na₂SO₄

and evaporated, residual DMF was removed in high vacuum (408C, 2

10^ꢁ2mbar), and the crude product purified by flash chromatography

(hexane/EtOAc 7:3) to give product 51 as a colorless oil (17.1 g, 77%).

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8775

A. Fürstner et al.

[a]²_D⁰=ꢁ128 (c=1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=4.16 (m,

3H), 3.35 (m, 2H), 3.14 (br s, 1H), 2.55 (m, 2H), 1.28 ppm (t, J=7.1Hz,

3H); ¹³C NMR (100 MHz, CDCl₃): d=171.9, 67.3, 60.9, 55.6, 38.5,

14.0 ppm; IR (film): n˜ =3452, 2983, 2933, 2097, 1717, 1374, 1270, 1164,

1094, 1024, 925 cm^ꢁ1; MS (EI): m/z (%): 128 (21), 117 (77), 89 (27), 75

(13), 71 (100), 56 (10), 47 (12), 45 (15), 44 (14), 43 (50), 30 (14), 29 (63),

27 (16); HRMS (CI): m/z: calcd for C₆H₁₂N₃O₃: 174.0879; found:

174.0881 [M⁺+H]; elemental analysis calcd (%) for C₆H₁₁N₃O₃: C 41.61,

H 6.40, N 24.27; found: C 41.37, H 6.44, N 24.34.

1043, 1001, 939, 920, 911, 807, 761 cm^ꢁ1; MS (EI): m/z (%): 145 (4), 113

(22), 84 (3), 71 (4), 70 (4), 69 (14), 58 (3), 57 (10), 46 (3), 45 (100), 43 (3),

42 (4), 41(14), 31(4), 30 (4), 29 (10), 27 (4); HRMS (CI):

m/z: calcd for

C₉H₁₈N₃O₄: 232.1297; found: 232.1295 [M⁺+H]; elemental analysis calcd

(%) for C₉H₁₇N₃O₄: C 46.74, H 7.41, N 18.17; found: C 46.85, H 7.48, N

18.23.

1-Azido-1,3,6,7-tetradeoxy-2-O-(methoxymethyl)-4,5-O-(1-methylethyl-

AHCTREiUNG dene)-d-arabino-hept-6-enitol (59): A solution of diol 58 (0.39 g,

1.69 mmol) and pTsOH·H₂O (5 mg, 26 mmol, 1.5 mol%) in 2,2-dimethox-

ypropane (5 mL) was stirred for 30 min. For work up, the solution was di-

luted with EtOAc (3 mL) and hexane (7 mL) before it was passed

through a pad of silica that was carefully rinsed with the same solvents.

The combined filtrates were evaporated to give product 59 as a colorless

oil, which was pure enough for immediate use in the next step (0.414 g,

90%). [a]²_D⁰=+128 (c=1.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

5.77 (m, 1H), 5.28 (m, 2H), 4.72 (s, 2H), 4.52 (t, J=6.9 Hz, 1H), 4.32

(ddd, J=10.6, 6.3, 2.6 Hz, 1H), 3.89 (dt, J=8.9, 4.2 Hz, 1H), 3.52 (dd, J=

12.8, 4.1 Hz, 1H), 3.41 (s, 3H), 3.27 (dd, J=12.8, 4.9 Hz, 1H), 1.60 (m,

2H), 1.46 (s, 3H), 1.34 ppm (s, 3H); ¹³C NMR (75 MHz, CDCl₃): d=

134.0, 118.4, 108.4, 96.6, 79.4, 74.4 ( 2), 55.8, 55.1, 34.0, 28.1, 25.6 ppm;

IR (film): n˜ =2935, 2098, 1371, 1214, 1102, 1033, 919 cm^ꢁ1; MS (EI): m/z

(%): 157 (7), 125 (5), 98 (36), 95 (25), 83 (11), 69 (11), 67 (5), 57 (5), 55

(7), 45 (100), 43 (27), 41 (16), 39 (5), 29 (6); HRMS (ESI+): m/z: calcd

for C₁₂H₂₁N₃NaO₄: 294.1424; found: 294.1422 [M⁺+Na]; elemental anal-

ysis calcd (%) for C₁₂H₂₁N₃O₄: C 53.12, H 7.80, N 15.49; found: C 53.15,

H 7.84, N 15.62.

Ethyl (3S)-4-azido-3-(methoxymethoxy)butanoate (52): LiBr (2.43 g,

28 mmol) and pTsOH·H₂O (2.5 g, 13 mmol) were added to a solution of

compound 51 (19.4 g, 112 mmol) in dimethoxymethane (350 mL) and the

resulting mixture was stirred for 116 h. The reaction was quenched with

water (200 mL), the aqueous phase was extracted with tert-butyl methyl

ether (3100 mL), the combined organic phases were washed with brine

and dried over MgSO₄, the solvent was evaporated and the residue puri-

fied by flash chromatography (hexanes/EtOAc 10:1) to give product 52

(16.96 g, 70%) as a colorless oil and a second fraction of recovered start-

ing material (5.04 g, 21%). [a]²_D⁰=+38 (c=1.1, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=4.71(q, J=7.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H),

4.13 (m, 1H), 3.43 (dq, J=12.8, 5.0 Hz, 2H), 3.39 (s, 3H), 2.60 (dq, J=

16.0, 6.4 Hz, 2H), 1.26 ppm (t, J=7.2 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=170.5, 96.5, 73.6, 60,7, 55.7, 54.3, 37.8, 14.1 ppm; IR (film):

n˜ =2939, 2099, 1731, 1377, 1284, 1149, 1024, 918 cm^ꢁ1; MS (EI): m/z (%):

161 (11), 117 (2), 84 (4), 71 (2), 56 (3), 46 (2), 45 (100), 43 (3), 41 (3), 31

(2), 29 (11), 27 (3); HRMS (ESI+): m/z: calcd for C₈H₁₅N₃NaO₄:

240.0955; found: 240.0955 [M⁺+Na]; elemental analysis calcd (%) for

C₈H₁₅N₃O₄: C 44.23, H 6.96, N 19.34; found: C 44.26, H 6.97, N 19.42.

1-Amino-1,3,6,7-tetradeoxy-2-O-(methoxymethyl)-4,5-O-(1-methylethyl-

AHCTREiUNG dene)-D-arabino-hept-6-enitol (60): A solution of azide 59 (414 mg,

1.53 mmol) in Et₂O (10 mL) was slowly added to a suspension of LiAlH₄

(200 mg, 5.27 mmol) in Et₂O (10 mL) at 08C. The mixture was allowed to

stir at ambient temperature for 2 h before the reaction was carefully

quenched with water (9 mL) and NaOH (3m, 7.5 mL). After stirring until

a clear separation of the phases was reached, the aqueous layer was ex-

tracted with Et₂O (320 mL), and the combined organic phases were

dried over Na₂SO₄and evaporated to give amine 60 as a yellow liquid

which was used in the next step without further purification (339 mg,

91%). [a]²_D⁰=+28 (c=1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=5.78

(3S)-4-Azido-3-(methoxymethoxy)butanal (53): DIBAl-H (1.0m in

CH₂Cl₂, 8.9 mL, 8.9 mmol) was slowly added to a solution of compound

52 (1.62 g, 7.46 mmol) in CH₂Cl₂(15 mL) at ꢁ788C and the resulting

mixture was stirred at that temperature of 1h. For work up, the reaction

was quenched with EtOAc (5 mL) and sat. aq. potassium sodium tartrate,

and the resulting mixture was stirred at ambient temperature for 30 min

until a clear separation of the phases was reached. The aqueous layer

was extracted with EtOAc (315 mL), the combined organic layers were

dried over MgSO₄and evaporated, and the residue adsorbed on Florisil

and purified by flash chromatography (hexanes/EtOAc 10:1 ! 4:1) to

give product 53 as a yellow liquid (1.15 g, 89%). The aldehyde is sensi-

tive and must be kept under Ar at ꢁ208C. [a]²_D⁰=ꢁ128 (c=1.1, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=9.75 (m, 1H), 4.69 (s, 2H), 4.20 (m,

1H), 3.39 (m, 2H), 3.35 (s, 3H), 2.72 ppm (m, 2H); ¹³C NMR (100 MHz,

CDCl₃): d=199.5, 96.4, 71.9, 55.7, 54.1, 46.5 ppm; IR (film): n˜ =2897,

2097, 1721, 1444, 1369, 1287, 1151, 1102, 1024, 916 cm^ꢁ1; MS (EI): m/z

(%): 117 (16), 45 (100), 41 (4), 31 (4), 29 (10), 27 (3); HRMS (CI): m/z:

calcd for C₆H₁₂N₃O₃: 174.0879; found: 174.0880 [M⁺+H].

(ddd, J=17.2, 10.4, 7.6 Hz, 1H), 5.27 (m, 2H), 4.71 (s, 2H), 4.51ACHTREUNG(m, 1H),

4.32 (ddd, J=9.6, 6.3, 3.5 Hz, 1H), 3.71 (quint, J=4.5 Hz, 1H), 3.40 (s,

3H), 2.88 (d, J=3.4 Hz, 1H), 2.70 (br s, 1H), 1.84–1.50 (m, 4H), 1.47 (s,

3H), 1.35 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=134.3, 118.2,

108.2, 96.5, 79.6, 77.6, 74.6, 55.6, 46.1, 33.7, 28.2, 25.6 ppm; IR (film): n˜ =

2985, 2933, 1597, 1455, 1370, 1239, 1214, 1150, 1098, 1031, 917, 874 cm^ꢁ1

;

MS (EI): m/z (%): 230 (11), 156 (6), 113 (11), 108 (10), 98 (17), 96 (5), 95

(16), 85 (5), 83 (9), 70 (5), 69 (13), 68 (7), 67 (8), 59 (12), 56 (10), 55 (6),

45 (100), 43 (17), 41 (14), 30 (53), 29 (5); HRMS (ESI+): m/z: calcd for

C₁₂H₂₃NNaO₄: 268.1519; found: 268.1520 [M⁺+Na]; elemental analysis

calcd (%) for C₁₂H₂₃NO₄: C 58.75, H 9.45, N 5.71; found: C 58.67, H

9.45, N 5.79.

Compound 58: Allenylboronate 56 (587 mg, 4.74 mmol)^[45a]was added to

a

suspension of crystalline [Ipc₂BH]₂(1.45 g, 2.53 mmol) in Et₂O

(9.5 mL) at 08C and the resulting mixture was stirred at that temperature

for 1h until a clear solution had formed. After cooling to ꢁ788C, a solu-

tion of aldehyde 53 (410 mg, 2.37 mmol) in Et₂O (2.4 mL) was added via

syringe pump over a period of 20 min and stirring was continued for 2.5 h

once the addition was complete. MeOH (0.88 mL, 20.9 mmol) was intro-

duced at ꢁ788C and the mixture was then stirred at 08C for 15 min

before H₂O₂(30% w/w, 1.8 mL) and aq. NaOH (3m, 3.3 mL, 9.9 mmol)

were successively added. The resulting mixture was stirred at ambient

temperature for 90 min. For work up, the aqueous layer was extracted

with CH₂Cl₂(710 mL), the combined organic phases were dried over

Na₂SO₄and evaporated, and the residue was purified by flash chromatog-

1,3,6,7-Tetradeoxy-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-O-(meth-

oxymethyl)-4,5-O-(1-methylethylidene)-D-arabino-hept-6-enitol

(61):

Phthalic anhydride (330 mg, 2.20 mmol) was added to a suspension of

amine 60 (650 mg, 2.65 mmol) and molecular sieves (4 , 1.1 g) in tolu-

ene (4.4 mL) and the resulting mixture was stirred at 808C for 48 h. For

work up, the molecular sieves were filtered off, the filtrate was evaporat-

ed and the residue purified by flash chromatography (hexanes/EtOAc 4:1

! 2:1) to give product 61 as a pale yellow liquid (732 mg, 88%).

¹H NMR (600 MHz, CDCl₃): d=7.86

(m, 2H, H-22), 7.72 (m, 2H, H-23),

5.77 (ddd, J=17.1, 10.3, 7.8 Hz, 1H,

raphy (pentanes/Et₂O 2:1) to give product 58 as

a colorless liquid

H-8), 5.30 (ddd, J=17.1, 1.6, 1.1 Hz,

(484 mg, 88%). [a]²_D⁰=ꢁ408 (c=1.2, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=5.90 (ddd, J=17.0, 10.6, 6.3 Hz, 1H), 5.28 (m, 2H), 4.74 (q,

J=6.4 Hz, 2H), 4.15 (m, 1H), 3.95 (m, 1H), 3.90 (m, 1H), 3.42 (s, 3H),

3.42 (dd, J=12.5, 4.2 Hz, 1H), 3.32 (dd, J=12.7, 5.9 Hz, 1H), 2.91 (br s,

1H), 2.46 (br s, 1H), 1.68 (ddd, J=14.5, 9.1, 2.5 Hz, 1H), 1.56 ppm (ddd,

J=14.4, 10.5, 3.56 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=136.1,

117.5, 97.4, 75.9, 74.9, 70.1, 55.9, 55.3, 34.3 ppm; IR (film): n˜ =3247, 2955,

2892, 2827, 2150, 2101, 1438, 1377, 1348, 1293, 1231, 1150, 1107, 1069,

1H, H-9Z), 5.17 (ddd, J=10.3, 1.6,

0.9 Hz, 1H, H-9E), 4.60 (d, J=7.0 Hz,

1H, H-13a), 4.57 (d, J=7.0 Hz, 1H,

H-13b), 4.55 (ddt, J=7.7, 6.2, 1.8 Hz,

1H, H-4), 4.46 (ddd, J=8.4, 6.1,

5.1Hz, 1H, H-5), 4.06 (dq, J=6.2,

4.4 Hz, 1H, H-11), 3.91 (dd, J=14.3,

6.5 Hz, 1H, H-16a), 3.76 (dd, J=14.3,

8776

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

4.4 Hz, 1H, H-16b), 3.22 (s, 3H), 1.80 (ddd, J=14.4, 8.4, 6.1 Hz, 1H, H-

10a), 1.71 (ddd, J=14.3, 5.9, 5.1 Hz, 1H, H-10b), 1.48 (s, 3H, H-6),

1.37 ppm (s, 3H, H-7); ¹³C NMR (150 MHz, CDCl₃): d=168.5 (C-18),

134.3 (C-8), 134.0 (C-23), 132.1 (C-19), 123.2 (C-22), 118.6 (C-9), 108.4

(C-2), 95.9 (C-13), 79.8 (C-4), 74.4 (C-5), 73.0 (C-11), 55.7 (C-15), 41.0

(C-16), 33.9 (C-10), 28.2 (C-6), 25.7 ppm (C-7); IR (film): n˜ =3082, 2986,

2936, 2897, 2824, 1775, 1715, 1645, 1615, 1468, 1430, 1396, 1381, 1325,

1239, 1216, 1191, 1155, 1134, 1102, 1038, 920, 867, 725, 714, 530 cm^ꢁ1; MS

(EI): m/z (%): 360 (22), 256 (11), 206 (7), 205 (37), 188 (11), 186 (10),

175 (6), 174 (11), 173 (75), 161 (13), 160 (97), 157 (13), 153 (12), 133 (5),

125 (9), 121 (7), 113 (6), 109 (7), 104 (6), 99 (7), 98 (91), 95 (33), 85 (7),

83 (17), 77 (8), 70 (6), 69 (22), 67 (5), 59 (9), 58 (7), 55 (8), 45 (100), 43

(22), 41(12); HRMS (ESI +): m/z: calcd for C₂₀H₂₅NNaO₆: 398.1574;

found: 398.1576 [M⁺+Na]; elemental analysis calcd (%) for C₂₀H₂₅NO₆:

C 63.99, H 6.71, N 3.73; found: C 64.11, H 6.67, N 3.71.

1H), 1.13 (s, 9H), 0.82 ppm (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=176.9, 135.8, 135.7, 132.9, 132.3, 130.1, 127.8, 72.5, 36.7, 26.9,

19.3, 17.3, 13.8 ppm; IR (film): n˜ =3072, 3019, 2963, 2932, 2859, 2688,

2579, 1712, 1589, 1473, 1464, 1430, 1273, 1230, 1145, 1112, 1090, 1039,

892, 824, 816, 745, 708, 686, 611, 505, 487 cm^ꢁ1; MS (EI): m/z (%): 300

(11), 299 (46), 271 (10), 200 (18), 199 (100), 139 (44); HRMS (ESI+):

m/z: calcd for C₂₁H₂₈NaO₃Si: 379.1700; found: 379.1695 [M⁺+Na]; ele-

mental analysis calcd (%) for C₂₁H₂₈NaO₃Si: C 70.74, H 7.92, Si 7.88;

found: C 70.66, H 7.85, Si 7.78.

Fragment couplings and completion of the total synthesis

Compound 71: 9-H-9-BBN dimer (330 mg, 0.7 mmol of dimer) was

added to

a solution of compound 61 (676 mg, 1.80 mmol) in THF

The a-hydroxyacid segment

Benzyl (2S)-2-hydroxypentanoate: nBu₄NI (1.28 g, 0.347 mmol) and

benzyl bromide (4.75 mL, 39.9 mmol) were added to a suspension of acid

68 (4.10 g, 34.7 mmol)^[56]and K₂CO₃(5.50 g, 39.9 mmol) in acetone

(175 mL) and the resulting mixture was stirred under reflux for 24 h.

After reaching ambient temperature, all insoluble materials were filtered

off through a pad of Celite which was carefully rinsed with acetone, the

combined filtrates were evaporated, and the residue was purified by flash

chromatography (hexanes/EtOAc 20:1 ! 10:1) to give the title com-

pound as a colorless liquid (5.0 g, 69%). [a]²_D⁰=ꢁ58 (c=1.0, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=7.40–7.34 (m, 5H), 5.21(s, 2H), 4.23

(dd, J=7.6, 4.2 Hz, 1H), 2.7 (br s, 1H), 1.81–1.73 (m, 1H), 1.69–1.59 (m,

1H), 1.50–1.38 (m, 2H), 0.93 ppm (t, J=4.05 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=175.3, 135.2, 128.6, 128.5, 128.3, 70.3, 67.2, 36.4,

18.0, 13.7 ppm; IR (film): n˜ =3464, 2960, 2874, 1731, 1456, 1262, 1195,

1128, 1073, 736, 696 cm^ꢁ1; MS (EI): m/z (%): 208 (8) [M⁺], 108 (3), 107

(3), 92 (24), 91 (100), 79 (4), 77 (5), 73 (54), 65 (12), 56 (3), 55 (72), 51

(3), 43 (24), 41(5), 39 (6), 31(10), 29 (6), 27 (5); HRMS (EI): m/z: calcd

for C₁₂H₁₆O₃: 208.1100; found: 208.1097; elemental analysis calcd (%) for

C₁₂H₁₆O₃: C 69.21, H 7.74; found: C 69.09, H 7.65.

(2.6 mL) at 08C and the resulting mixture was stirred at ambient temper-

ature for 2 h. Excess 9-H-9-BBN was quenched with water (0.4 mL) and

the resulting solution was transferred via canula into a mixture of bro-

mide 12 (511 mg, 2.70 mmol), Cs₂CO₃(1.09 g, 3.35 mmol), Ph₃As (97%,

85 mg, 0.27 mmol) and [PdCl₂ACHTER(UNG dppf)]·CH₂Cl₂(103 mg, 0.126 mmol) in

THF (15 mL) and water (0.5 mL). The mixture was stirred at ambient

temperature for 17 h before the solvent was evaporated and the residue

purified by flash chromatography (hexanes/EtOAc 50:1 ! 4:1) to give

product 71 as a pale yellow liquid (696 mg, 81%). [a]²_D⁰=ꢁ18 (c=0.8,

CHCl₃); de > 99% (HPLC: column: 125 mm Nucleodur 100-5-C18ec, 1

4.0 mm; eluent: MeCN/H₂O 45:55; 0.8 mLmin^ꢁ1; T=308 K; 5.5MPa;

t_R=38.23 min); ¹H NMR (600 MHz, CD₂Cl₂): d=7.84 (m, 2H, H-30),

7.73 (m, 2H, H-31), 5.43 (m, 1H, H-20), 4.65 (d, J=6.9 Hz, 1H, H-17a),

4.60 (d, J=6.9 Hz, 1H, H-17b), 4.21 (ddd, J=10.8, 5.7, 2.7 Hz, 1H, H-5),

4.14 (d, J=12.0 Hz, 1H, H-11a), 4.12 (d, J=12.0 Hz, 1H, H-11b), 4.09

(dddd, J=9.7, 7.0, 4.9, 3.2 Hz, 1H, H-15), 4.02 (ddd, J=9.4, 5.7, 4.3 Hz,

1H, H-4), 3.82 (dd, J=14.1, 7.0 Hz, 1H, H-24a), 3.72 (dd, J=14.1,

5.0 Hz, 1H, H-24b), 3.28 (s, 3H, H-13), 3.15 (s, 3H, H-19), 2.32 (ddd, J=

15.0, 10.0, 5.0 Hz, 1H, H-9a), 2.12 (ddd, J=15.0, 10.0, 6.0 Hz, 1H, H-9b),

1.97 (d, J=2.4 Hz, 3H, H-23), 1.65 (ddd, J=14.1, 10.8, 3.2 Hz, 1H, H-

14a), 1.58 (m, 1H, H-8a), 1.54 (ddd, J=14.1, 9.8, 2.6 Hz, 1H, H-14b),

1.51 (m, 1H, H-8b), 1.34 (s, 3H, H-6), 1.28 ppm (s, 3H, H-7); ¹³C NMR

(150 MHz, CD₂Cl₂): d=168.7 (C-26), 149.7 (C-10), 134.3 (C-31), 132.6

(C-27), 123.4 (C-30), 108.7 (C-20), 108.0 (C-2), 97.2 (C-17), 90.3 (C-22),

77.6 (C-4), 76.3 (C-21), 74.4 (C-5), 73.9 (C-15), 71.6 (C-11), 58.1 (C-13),

56.0 (C-19), 42.5 (C-24), 34.4 (C-14), 30.6 (C-9), 28.6 (C-6), 28.5 (C-8),

26.1(C-7), 4.4 ppm (C-23); IR (film): n˜ =2984, 2932, 2824, 2220, 1774,

1716, 1615, 1467, 1432, 1396, 1324, 1243, 1218, 1191, 1155, 1134, 1100,

1072, 1036, 964, 918, 866, 794, 725, 714, 530 cm^ꢁ1; MS (ESI+): 508 [M⁺

+Na]; HRMS (ESI+): m/z: calcd for C₂₇H₃₅NNaO₇: 508.2306; found:

508.2308 [M⁺+Na]; elemental analysis calcd (%) for C₂₇H₃₅NO₇: C 66.79,

H 7.27, N 2.88; found: C 66.84, H 7.23, N 2.88.

Benzyl (2S)-2-((tert-butylACTHRE(UNG diphenyl)silyl)oxy)pentanoate (69): A solution

of benzyl (2S)-2-hydroxypentanoate (2 g, 96 mmol), imidazole (0.85 g,

13 mmol), and TBDPSCl (2.8 mL, 11 mmol) in CH₂Cl₂(50 mL) was

stirred for 5 h before it was adsorbed on silica. The product was isolated

by flash chromatography (hexanes/EtOAc 20:1) in form of a colorless

liquid (4.2 g, 98%). [a]_D²⁰=ꢁ378 (c=1.1, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=7.66–7.61(m, 4H), 7.43–7.29 (m, 9H), 7.20–7.18 (m, 2H),

4.93 (d, J=12.3 Hz, 1H), 4.89 (d, J=12.3 Hz, 1H), 4.28 (t, J=5.7 Hz,

1H), 1.78–1.62 (m, 2H), 1.47–1.26 (m, 2H), 1.08 (s, 9H), 0.83 ppm (t, J=

7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=173.1, 136.0, 135.8, 135.7,

133.5, 133.3, 129.7, 129.7, 128.4, 128.2, 128.1, 127.6, 127.5, 72.6, 66.1, 37.3,

26.9, 19.4, 17.8, 13.9 ppm; IR (film): n˜ =3070, 3048, 3034, 2998, 2959,

2932, 2893, 2858, 1754, 1734, 1589, 1498, 1487, 1472, 1457, 1428, 1390,

1362, 1313, 1268, 1213, 1185, 1136, 1113, 1043, 999, 939, 895, 822, 741,

701, 613, 508, 488 cm^ꢁ1; MS (EI): m/z (%): 390 (5), 389 (16), 361 (12),

221 (11), 199 (6), 183 (6), 135 (7), 92 (8), 91 (100); HRMS (ESI+): m/z:

calcd for C₂₈H₃₄NaO₃Si: 469.2169; found: 469.2169 [M⁺+Na]; elemental

analysis calcd (%) for C₂₈H₃₄O₃Si: C 75.29, H 7.67; found: C 75.38, H

7.65.

(2S)-2-((tert-ButylACHTREUNG(diphenyl)silyl)oxy)pentanoic acid (70): A mixture

containing compound 69 (9.17 g, 20.5 mmol) and palladium on charcoal

(10% w/w, 1.31 g) in EtOAc (100 mL) and EtOH (100 mL) was stirred

for 30 h under an atmosphere of H₂. For work up, the catalyst was fil-

tered off through a short pad of Celite which was carefully rinsed with

EtOH, the combined filtrates were evaporated, and the residue was puri-

fied by flash chromatography (hexanes/EtOAc 10:1 ! 4:1) to give prod-

uct 70 as colorless crystals (4.58 g, 63%). Crystals suitable for X-ray anal-

ysis were obtained by recrystallization from hexane. M.p. 96–978C;

[a]²_D⁰=ꢁ148 (c=0.7, CHCl₃); de > 99% (HPLC: column: 250 mm Chir-

Compound 73: Hydrazine monohydrate (16 mL, 0.32 mmol) was added to

a solution of compound 71 (52.2 mg, 108 mmol) in EtOH (1.1 mL) and

the mixture was stirred for 2.5 h at 608C. The precipitate formed was fil-

tered off and the filtrate was evaporated to give crude amine 72 which

was immediately used in the next step without further purification.

A solution of this crude amine, EDC·HCl (57.7 mg, 0.301mmol), 1-

HOBt (42 mg, 0.31mmol), ( iPr)₂NEt (71 mL, 0.43 mmol) and acid 70

(77 mg, 0.22 mmol) in CH₂Cl₂(0.5 mL) was stirred for 8 h at ambient

temperature. The mixture was adsorbed on silica and the product was pu-

rified by flash chromatography (hexanes/EtOAc 7:1 ! 4:1) to give com-

alpak AD,

1 4.6 mm; eluent: n-heptane/2-propanol/TFA 99:1:0.1;

0.5 mLmin^ꢁ1; T=298 K; 1.6MPa; t_R=34.40 min); ¹H NMR (400 MHz,

CDCl₃): d=9.60 (brs, 1H), 7.69–7.64 (m, 4H), 7.48–7.36 (m, 6H), 4.30 (t,

J=5.2 Hz, 1H), 1.75–1.66 (m, 1H), 1.63–1.41 (m, 2H), 1.37–1.23 (m,

pound 73 as a colorless liquid (57.6 mg, 77% over both steps). [a]_D²⁰

=

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8777

A. Fürstner et al.

1H, H-30b), 1.56 (m, 2H, H-14), 1.53 (m, 1H, H-8), 1.44 (m, 2H, H-31),

1.39 (s, 3H, H-6), 1.30 (s, 3H, H-7), 0.94 ppm (t, J=7.4 Hz, 3H, H-32);

¹³C NMR (150 MHz, CD₂Cl₂): d=174.2 (C-26), 149.5 (C-10), 108.9 (C-

20), 108.0 (C-2), 97.4 (C-17), 90.4 (C-22), 77.6 (C-4), 76.3 (C-21), 76.2 (C-

15), 74.4 (C-5), 72.1 (C-28), 71.6 (C-11), 58.0 (C-13), 55.9 (C-19), 43.7 (C-

24), 37.5 (C-30), 34.0 (C-14), 30.5 (C-9), 28.7 (C-6), 28.6 (C-8), 26.1 (C-7),

18.7 (C-31), 14.0 (C-32), 4.4 ppm (C-23); IR (film): n˜ =3398, 2982, 2957,

2931, 2874, 2822, 2220, 1715, 1654, 1534, 1454, 1379, 1369, 1246, 1218,

1154, 1101, 1059, 1034, 917, 868 cm^ꢁ1; MS (EI): m/z (%): 456 (5), 455

(18) [M⁺], 199 (15), 187 (16), 186 (24), 175 (25), 143 (24), 135 (19), 133

(21), 131 (17), 130 (20), 119 (15), 109 (19), 105 (22), 101 (18), 93 (18), 91

(25), 55 (29), 45 (100), 43 (25), 30 (54); HRMS (EI): m/z: calcd for

C₂₄H₄₁NO₇: 455.2883; found: 455.2882; elemental analysis calcd (%) for

C₂₄H₄₁NO₇: C 63.27, H 9.07, N 3.07; found: C 63.18, H 8.92, N 3.02.

ꢁ248 (c=0.5, CHCl₃); ¹H NMR (600 MHz, CD₂Cl₂): d=7.67 (m, 2H, H-

37), 7.61(m, 2H, H-43), 7.46 (m, 1H, H-39), 7.45 (m, 1H, H-45), 7.39

(m, 2H, H-38), 7.38 (m, 2H, H-44), 7.12 (t, J=6.0 Hz, 1H, H-25), 5.38

(m, J=2.4 Hz, 1H, H-20), 4.70 (d, J=6.7 Hz, 1H, H-17a), 4.67 (d, J=

6.7 Hz, 1H, H-17b), 4.23 (dd, J=5.3, 4.1Hz, 1H, H-28), 4.20 (dt, J=7.5,

5.9 Hz, 1H, H-5), 4.11 (d, J=12.0 Hz, 1H, H-11a), 4.09 (d, J=12.0 Hz,

1H, H-11b), 3.99 (ddd, J=10.0, 5.8, 3.6 Hz, 1H, H-4), 3.83 (m, 1H, H-

15), 3.55 (ddd, J=13.9, 6.1, 4.2 Hz, 1H, H-24a), 3.37 (s, 3H, H-19), 3.27

(s, 3H, H-13), 3.21 (ddd, J=13.9, 6.0, 4.8 Hz, 1H, H-24b), 2.32 (ddd, J=

15.0, 10.0, 5.0 Hz, 1H, H-9a), 2.11 (ddd, J=15.0, 10.0, 6.0 Hz, 1H, H-9b),

1.96 (d, J=2.4 Hz, 3H, H-23), 1.62 (m, 1H, H-30a), 1.54 (m, 2H, H-14),

1.52 (m, 1H), 1.43 (m, 1H, H-8), 1.39 (s, 3H, H-6), 1.38 (m, 1H, H-31a),

1.37 (m, 1H, H-30b), 1.30 (s, 3H, H-7), 1.17 (m, 1H, H-31b), 1.11 (s, 9H,

H-35), 0.74 ppm (t, J=7.3 Hz, 3H, H-32); ¹³C NMR (150 MHz, CD₂Cl₂):

d=173.2 (C-26), 149.7 (C-10), 136.2 (C-37), 136.1 (C-43), 133.6 (C-36),

133.2 (C-42), 130.4 (2 C, C-39, C-45), 128.2 (C-44), 128.1 (C-38), 108.7

(C-20), 108.0 (C-2), 96.9 (C-17), 90.3 (C-22), 77.6 (C-4), 76.4 (C-21), 75.1

(C-15), 74.7 (C-28), 74.5 (C-5), 71.6 (C-11), 58.1 (C-13), 55.9 (C-19), 43.2

(C-24), 37.2 (C-30), 33.9 (C-14), 30.5 (C-9), 28.7 (C-6), 28.5 (C-8), 27.2

(C-35), 26.1 (C-7), 19.5 (C-34), 17.2 (C-31), 14.1 (C-32), 4.4 ppm (C-23);

IR (film): n˜ =3432, 3072, 3049, 2958, 2931, 2859, 2821, 2220, 1720, 681,

1589, 1518, 1488, 1463, 1428, 1379, 1368, 1346, 1246, 1218, 1153, 1111,

1036, 919, 895, 863, 822, 742, 703, 612, 506 cm^ꢁ1; MS (EI): m/z (%): 694

(5), 693 (9) [M⁺], 638 (15), 637 (45), 636 (100), 604 (13), 578 (13), 546

(22), 338 (11), 298 (13), 213 (11), 199 (45), 197 (19), 183 (14), 139 (14),

135 (50), 91 (11), 45 (31); HRMS (ESI+): m/z: calcd for

C₄₀H₅₉NNaO₇Si: 716.3953; found: 716.3945 [M⁺+Na]; elemental analysis

calcd (%) for C₄₀H₅₉NO₇Si: C 69.23, H 8.57, N 2.02; found: C 69.17, H

8.48, N 1.88.

Compound 75: A solution containing compound 74 (24.4 mg, 53.6 mmol),

acid 70 (13.3 mg, 41.2 mmol), Et₃N (11.6 mL, 82.4 mmol), DMAP (10.1 mg,

82.4 mmol), EDC·HCl (15.8 mg, 82.4 mmol) and 1-HOBt (11.4 mg,

82.4 mmol) in CH₂Cl₂(0.2 mL) was stirred for 1h before additional

EDC·HCl (11.8 mg, 61.6 mmol) and DMAP (15.2 mg, 124.4 mmol) were

introduced and stirring continued for 18 h. The mixture was then ad-

sorbed on silica and the product purified by flash chromatography (hex-

anes/EtOAc 10:1 ! 4:1) to give compound 75 as a colorless liquid

(20.3 mg, 65%). [a]²_D⁰=ꢁ58 (c=0.1, CHCl₃); ¹H NMR (600 MHz,

CD₂Cl₂): d=6.62 (t, J=5.6 Hz, 1H), 5.44 (m, 1H), 5.07 (dd, J=6.1Hz,

1H), 4.70 (d, J=6.6 Hz, 1H), 4.66 (d, J=6.6 Hz, 1H), 4.18 (m, 1H), 4.15

(d, J=12.0 Hz, 1H), 4.12 (d, J=12.0 Hz, 1H), 4.02 (ddd, J=9.7, 5.7,

4.3 Hz, 1H), 3.78 (m, 1H), 3.54 (ddd, J=14.0, 6.2, 3.6 Hz, 1H), 3.38 (s,

3H), 3.28 (s, 3H), 3.18 (dt, J=14.0, 5.7 Hz, 1H), 2.58 (m, 1H), 2.36 (m,

5H), 2.16 (m, 2H), 1.96 (d, J=2.3 Hz, 3H), 1.78 (d, J=2.4 Hz, 3H),

1.82–1.23 (m, 23H), 1.39 (s, 3H), 1.30 (s, 3H), 1.17 (d, J=7.0 Hz, 3H),

0.96 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.85 ppm (d, J=6.2 Hz,

3H); ¹³C NMR (150 MHz, CD₂Cl₂): d=210.8, 175.8, 170.0, 149.4, 108.4,

107.7, 97.0, 90.0, 82.1, 77.3, 76.7, 76.0, 75.8, 74.1, 73.8, 71.4, 57.8, 55.5,

43.4, 42.7, 42.6, 40.6, 37.4, 37.1, 34.6, 34.1, 33.6, 33.4, 30.4, 30.3, 28.4 (2 C),

28.2, 26.6, 25.8, 24.1, 21.9, 19.0, 18.3, 16.8, 13.6, 11.6, 4.1, 3.1 ppm; IR

(film): n˜ =3446, 3349, 2957, 2925, 2873, 2856, 2823, 2220, 1739, 1713,

1688, 1527, 1459, 1409, 1378, 1245, 1218, 1153, 1106, 1061, 1034, 964, 918,

865 cm^ꢁ1; MS (ESI+): 782 [M⁺+Na]; HRMS (ESI+): m/z: calcd for

C₄₄H₇₃NNaO₉: 782.5178; found: 782.5186 [M⁺+Na]; elemental analysis

calcd (%) for C₄₄H₇₃NO₉: C 69.53, H 9.68, N 1.84; found: C 69.70, H

9.57, N 1.77.

Compound 76: A solution of complex 20 (12.7 mg, 20.3 mmol) in toluene

(6 mL) and CH₂Cl₂(78 mL, 1.2 mmol) was added to a solution of sub-

strate 75 (31mg, 41 mmol) in toluene (35 mL) and the resulting mixture

was stirred at 808C for 14 h. A standard extractive work up followed by

flash chromatography (hexanes/EtOAc 4:1 ! 3:1) gave product 76 as a

Compound 74: A solution of compound 73 (57.7 mg, 83.1 mmol) and

TBAF (1.0m in THF, 108 mL, 108 mmol) in THF (0.5 mL) was stirred for

14 h. Evaporation of the solvent followed by flash chromatography of the

crude material (hexanes/EtOAc 1:1 ! 1:2) gave product 74 as a colorless

liquid (34.3 mg, 90%). [a]_D²⁰=ꢁ178 (c=0.9, CHCl₃); ¹H NMR (600 MHz,

CD₂Cl₂): d=6.95 (m, 1H, H-25), 5.44 (m, 1H, H-20), 4.71 (d, J=6.7 Hz,

1H, H-17a), 4.67 (d, J=6.7 Hz, 1H, H-17b), 4.20 (ddd, J=9.3, 5.8,

4.3 Hz, 1H, H-5), 4.15 (d, J=12.0 Hz, 1H), 4.13 (d, J=12.0 Hz, 1H, H-

11), 4.06 (ddd, J=8.0, 5.1, 3.8 Hz, 1H, H-28), 4.04 (ddd, J=9.2, 5.7,

4.6 Hz, 1H, H-4), 3.80 (m, 1H, H-15), 3.52 (ddd, J=14.0, 6.2, 3.7 Hz, 1H,

H-24a), 3.39 (s, 3H, H-19), 3.28 (s, 3H, H-13), 3.23 (ddd, J=14.0, 6.2,

5.3 Hz, 1H, H-24b), 2.78 (d, J=5.2 Hz, 1H, H-29), 2.31 (ddd, J=15.0,

10.0, 5.0 Hz, 1H, H-9a), 2.11 (ddd, J=15.0, 10.0, 6.0 Hz, 1H, H-9b), 1.96

(d, J=2.4 Hz, 3H, H-23), 1.75 (m, 1H, H-30a), 1.58 (m, 1H), 1.57 (m,

1

pale yellow liquid (22.6 mg, 79%). [a]²_D⁰=ꢁ98 (c=0.9, toluene); H NMR

(600 MHz, C₆D₆): d=6.17 (br dd, J=6.4, 4.4 Hz, 1H, H-25), 5.66 (m, 1H,

H-20), 5.24 (dd, J=7.7, 5.0 Hz, 1H, H-28), 4.55 (d, J=6.7 Hz, 1H, H-

17a), 4.53 (d, J=6.7 Hz, 1H, H-17b), 4.37 (d, J=11.9 Hz, 1H, H-11a),

4.34 (d, J=11.9 Hz, 1H, H-11b), 4.18 (m, 1H, H-5), 3.97 (m, 1H, H-4),

3.88 (m, 1H, H-15), 3.55 (ddd, J=14.0, 7.2, 3.2 Hz, 1H, H-24a), 3.41 (dt,

J=13.9, 4.5 Hz, 1H, H-24b), 3.26 (s, 3H, H-13), 3.17 (s, 3H, H-19), 2.58

(m, 1H, H-36), 2.52 (m, 1H, H-9a), 2.30 (m, 1H, H-9b), 2.25 (m, 1H, H-

23), 2.22 (m, 1H, H-47a), 2.18 (m, 1H, H-44a), 2.15 (m, 1H, H-44b), 2.09

(m, 1H, H-47b), 1.85 (m, 3H, H-30, H-48a), 1.73–1.52 (m, 8H, H-8, H-

8778

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

14, H-38a, H-43, H-48b), 1.49 (m, 1H, H-39), 1.44–1.21 (m, 10H, H-31,

H-38b, H-41a, H-42, H-49, H-50), 1.41 (s, 3H, H-6), 1.27 (s, 3H, H-7),

1.13 (d, J=6.9 Hz, 3H, H-37), 1.08 (m, 1H, H-41b), 0.98 (t, J=7.4 Hz,

3H, H-51), 0.83 (d, J=6.9 Hz, 3H, H-40), 0.81ppm (t, J=7.4 Hz, 3H, H-

32); ¹³C NMR (150 MHz, C₆D₆): d=209.0 (C-45), 175.7 (C-34), 169.8 (C-

26), 149.9 (C-10), 109.0 (C-20), 107.7 (C-2), 97.4 (C-22), 96.5 (C-17), 79.7

(C-21), 77.2 (C-4), 74.8 (C-15), 74.5 (C-5), 74.3 (C-28), 71.9 (C-11), 57.9

(C-13), 55.4 (C-19), 42.8 (C-47), 42.6 (C-24), 41.9 (C-44), 41.2 (C-38),

37.7, 36.9 (C-41), 34.6 (C-23, C-49), 34.3 (C-30), 33.3 (C-14), 30.7 (C-9, C-

36), 30.5 (C-39), 28.8 (C-6, C-50), 28.4 (C-8), 26.7 (C-42), 26.1(C-7), 24.2

(C-43), 23.0 (C-48), 19.9 (C-40), 18.7 (C-31), 17.2 (C-37), 13.8 (C-32),

12.1 ppm (C-51); IR (film): n˜ =3445, 3342, 2960, 2930, 2874, 2822, 2209,

1739, 1710, 1691, 1525, 1459, 1406, 1378, 1218, 1153, 1099, 1034, 918,

863 cm^ꢁ1; MS (ESI+): 728 [M⁺+Na]; HRMS (ESI+): m/z: calcd for

C₄₀H₆₈NO₉: 706.4889; found: 706.4891[ M⁺+H].

4.6 Hz, 1H), 4.65 (d, J=6.2 Hz, 1H), 4.63 (d, J=6.2 Hz, 1H), 4.33 (m,

1H), 4.23 (ddd, J=9.6, 5.8, 4.0 Hz, 1H), 4.16 (d, J=11.3 Hz, 1H), 4.11

(d, J=11.2 Hz, 1H), 3.97 (m, 1H), 3.90 (q, J=7.0 Hz, 6H), 3.77 (ddd, J=

14.0, 6.5, 3.2 Hz, 1H), 3.30 (ddd, J=14.0, 7.0, 5.0 Hz, 1H), 3.26 (s, 3H),

3.19 (s, 3H), 2.64 (m, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.45 (m, 1H),

2.11 (m, 2H), 2.07 (m, 2H), 1.95 (m, 1H), 1.87 (m, 1H), 1.86 (m, 1H),

1.78 (m, 1H), 1.76 (m, 1H), 1.64 (m, 2H), 1.60 (m, 2H), 1.57 (m, 2H),

1.52 (m, 1H), 1.43 (s, 3H), 1.42–1.35 (m, 4H), 1.34 (s, 3H), 1.27 (m, 1H),

1.26 (m, 1H), 1.22 (t, J=7.0 Hz, 9H), 1.22 (m, 2H), 1.16 (m, 1H), 1.15

(m, 1H), 1.11 (d, J=6.9 Hz, 3H), 0.99 (m, 1H), 0.93 (t, J=7.4 Hz, 3H),

0.85 (d, J=6.6 Hz, 3H), 0.80 ppm (t, J=7.4 Hz, 3H); ¹³C NMR

(150 MHz, C₆D₆): d=208.7, 175.6, 169.6, 151.5, 137.7, 133.0, 126.6, 107.8,

97.6, 77.2, 76.8, 74.4, 74.2, 71.5, 58.9, 58.2, 55.2, 43.8, 42.7, 42.6, 41.8, 41.2,

37.2, 36.5, 34.5 (2 C), 34.2, 31.2, 30.7, 28.8, 28.6, 28.0, 27.2, 26.2, 24.0, 22.2,

20.2, 18.8, 18.5, 17.9, 13.8, 12.0 ppm.

Hydrosilylation: A mixture of substrate 76 (9.3 mg, 13 mmol), (EtO)₃SiH

(95%, 5.1 mL, 26 mmol), [CpRuACTHRE(UNG MeCN)₃]PF₆(3b) (1.7 mg, 3.9 mmol,

Compounds 79 and 80: A suspension of AgF (1.8 mg, 14 mmol) in MeOH

(14 mL) and water (0.7 mL) was sonicated in an ultrasound laboratory

cleaning bath for 15 min. A solution of compounds 78 (isomeric mixture,

6.0 mg, 6.9 mmol) in THF (35 mL) and MeOH (10 mL) was added and the

resulting mixture was stirred for 75 min in the dark at ambient tempera-

ture. For work up, the mixture was passed through a short pad of silica

which was carefully rinsed with Et₂O (3 mL) and EtOAc (2 mL), the

combined filtrates were evaporated and the products purified by prepara-

tive TLC (hexanes/EtOAc 1.5:1) to give product 79 (1.2 mg, 25%) and

product 80 (1.1 mg, 23%) as a pale yellow liquid each. If performed with

pure isomer 77, the analogous proto-desilylation reaction delivered prod-

uct 79 in 94% yield as a pale yellow liquid.

30 mol%) in toluene (65 mL) was vigorously stirred for 75 min. For work

up, tris(hydroxymethyl)phosphine (1mg, 8 mmol) was introduced and stir-

ring continued for 30 min before the mixture was filtered through a short

pad of silica which was carefully rinsed with EtOAc (3 mL). Evaporation

of the solvent, removal of residual silane in high vacuum, and purification

of the residue by preparative TLC (hexanes/EtOAc 1.5:1) gave two prod-

uct containing fractions. The faster moving fraction consisted of two iso-

meric products (78, 6.0 mg, 53%), whereas the slower moving fraction

contained isomer 77 in pure form (1.5 mg, 13%).

Isomer 77: ¹H NMR (600 MHz, C₆D₆): d=7.19 (d, J=11.8 Hz, 1H, H-

21), 7.01 (d, J=11.7 Hz, 1H, H-20), 6.22 (dd, J=6.6, 5.0 Hz, 1H, H-25),

Product 79: ¹H NMR (600 MHz, C₆D₆): d=6.43 (dd, J=15.0, 10.8 Hz,

5.24 (dd, J=7.5, 5.1Hz, 1H, H-28), 4.56 (d, J=6.6 Hz, 1H, H-17a), 4.55

(d, J=6.6 Hz, 1H, H-17b), 4.21 (m, 1H, H-5), 4.16 (dd, J=12.0, 0.6 Hz,

1H, H-11a), 4.12 (d, J=12.0 Hz, 1H, H-11b), 4.02 (ddd, J=9.7, 5.9,

3.9 Hz, 1H, H-4), 3.91 (m, 1H, H-15), 3.91 (q, J=7.0 Hz, 6H, H-52), 3.53

(ddd, J=14.1, 6.9, 3.5 Hz, 1H, H-24a), 3.45 (ddd, J=13.9, 4.5, 4.4 Hz,

1H, H-24b), 3.22 (s, 3H, H-13), 3.17 (s, 3H, H-19), 2.59 (m, 1H, H-9a),

2.58 (m, 1H, H-36), 2.39 (m, 1H, H-9b), 2.38 (m, 1H, H-23), 2.25 (m,

1H, H-47a), 2.14 (m, 2H, H-44), 2.13 (m, 1H, H-47b), 1.86 (m, 2H, H-

30), 1.77 (m, 2H, H-48a, H-50a), 1.75 (m, 1H, H-8a), 1.74 (m, 1H, H-

49a), 1.67 (m, 1H, H-8b), 1.65 (m, 1H, H-38a), 1.62 (m, 2H, H-14), 1.57

(m, 1H, H-48b), 1.56 (m, 1H, H-50b), 1.54 (m, 2H, H-43), 1.50 (m, 1H,

H-39), 1.49 (m, 1H, H-49b), 1.45 (s, 3H, H-6), 1.39 (m, 2H, H-31), 1.36

(m, 1H, H-38b), 1.30 (s, 3H, H-7), 1.29 (m, 1H), 1.26 (t, J=7.0 Hz, 9H,

H-53), 1.21 (m, 2H, H-42), 1.12 (d, J=6.9 Hz, 3H, H-37), 1.06 (m, 1H,

H-41), 1.00 (t, J=7.4 Hz, 3H, H-51), 0.82 (d, J=6.6 Hz, 3H, H-40),

0.81ppm (t, J=7.4 Hz, 3H, H-32); ¹³C NMR (150 MHz, C₆D₆): d=209.3

(C-45), 175.7 (C-34), 169.8 (C-26), 140.0 (C-10), 139.8 (C-22), 139.6 (C-

21), 128.9 (C-20), 107.7 (C-2), 96.5 (C-17), 77.4 (C-4), 74.9 (C-15), 74.6

(C-5), 74.2 (C-28), 69.7 (C-11), 58.6 (C-52), 57.8 (C-13), 55.3 (C-19), 48.8

(C-23), 43.4 (C-47), 42.7 (C-24), 41.9 (C-44), 41.2 (C-38), 37.6 (C-36),

36.9 (C-41), 34.4 (C-49), 34.3 (C-30), 33.4 (C-14), 33.2 (C-9), 30.4 (C-39),

29.5 (C-8), 29.1(C-50), 28.9 (C-6), 26.7 (C-42), 26.2 (C-7), 24.1(C-43),

23.1 (C-48), 19.8 (C-40), 18.7 (C-31), 18.6 (C-53), 17.1 (C-37), 13.8 (C-

32), 12.6 ppm (C-51).

1H, H-21), 6.21 (br s, 1H, H-25), 6.16 (d, J=10.8 Hz, 1H, H-20), 5.38

(dd, J=15.0, 9.1 Hz, 1H, H-22), 5.20 (dd, J=6.9, 5.7 Hz, 1H, H-28), 4.56

(s, 2H, H-17), 4.18 (m, 1H, H-5), 4.05 (d, J=11.8 Hz, 1H, H-11a), 4.02

(d, J=11.8 Hz, 1H, H-11b), 3.99 (m, 1H, H-4), 3.90 (m, 1H, H-15), 3.52

(ddd, J=14.1, 6.9, 3.7 Hz, 1H, H-24a), 3.44 (ddd, J=14.0, 4.6, 4.3 Hz,

1H, H-24b), 3.17 (s, 3H, H-19), 3.15 (s, 3H, H-13), 2.60 (m, 1H, H-36),

2.50 (ddd, J=14.5, 10.6, 5.2 Hz, 1H, H-9a), 2.31 (ddd, J=14.5, 10.2,

5.7 Hz, 1H, H-9b), 2.10 (m, 1H, H-47a), 2.08 (m, 1H, H-44a), 2.01 (m,

2H, H-44b, H-47b), 1.86 (m, 2H, H-30), 1.82 (m, 1H, H-23), 1.73–1.00

(m, 21H, H-8, H-14, H-31, H-38, H-39, H-41, H-42, H-43, H-48, H-49, H-

50), 1.44 (s, 3H, H-6), 1.29 (s, 3H, H-7), 1.13 (d, J=6.9 Hz, 3H, H-37),

0.86 (t, J=7.4 Hz, 3H, H-51), 0.82 (d, J=6.2 Hz, 3H, H-40), 0.82 ppm (d,

J=7.4 Hz, 3H, H-32); ¹³C NMR (150 MHz, C₆D₆): d=209.1(C-45), 175.8

(C-34), 169.7 (C-26), 138.9 (C-22), 136.5 (C-10), 128.9 (C-20), 126.6 (C-

21), 107.7 (C-2), 96.6 (C-17), 77.8 (C-4), 75.0 (C-15), 74.6 (C-5), 74.2 (C-

28), 70.4 (C-11), 57.6 (C-13), 55.3 (C-19), 45.3 (C-23), 43.1 (C-47), 42.8

(C-24), 41.8 (C-44), 41.3 (C-38), 37.6 (C-36), 36.7 (C-41), 34.9 (C-49),

34.3 (C-30), 33.5 (C-14), 32.1 (C-9), 30.4 (C-39), 29.5 (C-8), 28.8 (C-6),

28.7 (C-50), 26.7 (C-42), 26.1(C-7), 24.0 (C-43), 22.8 (C-48), 20.0 (C-40),

18.7 (C-31), 17.3 (C-37), 13.8 (C-32), 12.0 ppm (C-51); MS (ESI+): 730

[M⁺+Na]; HRMS (ESI+): m/z: calcd for C₄₀H₆₉NNaO₉: 730.4865;

found: 730.4867 [M⁺+Na].

Compound 80: ¹H NMR (600 MHz, C₆D₆): d=6.60 (t, J=5.6 Hz, 1H),

6.49 (A-part of ABMX system, J=11.6, 1.5 Hz (extracted by simulation),

1H, H-20a), 6.46 (B-part of ABMX-system, J=11.6, ꢁ11.4 Hz (extracted

by simulation), 1H, H-20b), 5.47 (dd, J=8.0, 4.6 Hz, 1H, H-28), 5.03 (X-

Isomeric compounds 78: ¹H NMR (600 MHz, C₆D₆): d=6.77 (dd, J=6.1,

5.2 Hz, 1H), 6.12 (dd, J=9.5, 1.9 Hz, 1H), 6.11 (s, 1H), 5.49 (dd, J=8.1,

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8779

A. Fürstner et al.

6.49 (appdd, J=11.7, 9.8 Hz, 1H, H-21), 5.49 (dd, J=7.9, 4.5 Hz, 1H, H-

28), 5.04 (appt, J=9.9 Hz, 1H, H-22), 4.04 (brs, 1H, H-15), 3.97 (d, J=

11.6 Hz, 1H, H-11a), 3.94 (brs, 1H, H-5), 3.92 (brs, 1H, 15-OH), 3.91 (d,

J=11.5 Hz, 1H, H-11b), 3.68 (m, 1H, H-4), 3.63 (ddd, J=13.5, 6.7,

3.2 Hz, 1H, H-24a), 3.25 (ddd, J=13.6, 7.4, 4.7 Hz, 1H, H-24b), 3.10 (s,

3H, H-13), 3.08 (brs, 1H, 5-OH), 2.75 (brs, 1H, 4-OH), 2.56 (m, 2H, H-

9a, H-36), 2.50 (ddd, J=13.6, 10.0, 5.6 Hz, 1H, H-9b), 2.39 (m, 1H, H-

23), 1.94 (m, 1H), 1.92 (m, 1H, H-44a), 1.87 (m, 1H, H-30), 1.84 (m, 2H,

H-47), 1.83 (m, 2H, H-38a, H-44b), 1.70 (m, 1H, H-8a), 1.67 (m, 2H, H-

14), 1.66 (m, 1H, H-8b), 1.56–1.08 (m, 14H), 1.08 (d, J=6.9 Hz, 3H, H-

37), 0.94 (m, 1H, H-41), 0.90 (m, 1H, H-49a), 0.89 (t, J=7.4 Hz, 3H, H-

51), 0.84 (d, J=6.6 Hz, 3H, H-40), 0.81ppm (t, J=7.4 Hz, 3H, H-32);

¹³C NMR (150 MHz, C₆D₆): d=212.8 (C-45), 175.7 (C-34), 170.5 (C-26),

138.4 (C-10), 136.0 (C-22), 125.7 (C-20), 125.3 (C-21), 74.1 (C-28), 73.2

(C-4), 72.6 (C-5), 70.0 (C-11), 69.2 (C-15), 57.9 (C-13), 45.5 (C-24), 43.1

(C-47), 42.5 (C-44), 41.8 (C-38), 39.4 (C-23), 37.0 (C-36), 36.5 (C-41),

36.3 (C-14), 35.6 (C-49), 34.5 (C-30), 32.2 (C-9), 30.6 (C-39), 29.9 (C-8),

29.4 (C-50), 26.9 (C-42), 23.9 (C-43), 21.9 (C-48), 20.0 (C-40), 18.7 (C-

31), 18.1 (C-37), 13.8 (C-32), 12.2 ppm (C-51); MS (ESI+): 646 [M⁺

+Na]; HRMS (ESI+): m/z: calcd for C₃₅H₆₁NNaO₈: 646.4289; found:

646.4287 [M⁺+Na].

part of ABMX-system, t, J=10.0 Hz (measured), J=ꢁ11.4, 1.5 Hz (ex-

tracted by simulation), 1H, H-22), 4.62 (d, J=6.5 Hz, 1H, H-17a), 4.60

(d, J=6.5 Hz, 1H, H-17b), 4.37 (ddd, J=10.4, 5.7, 2.9 Hz, 1H, H-5), 4.13

(ddd, J=10.5, 5.8, 3.5 Hz, 1H, H-4), 3.99 (m, 1H, H-15), 3.98 (d, J=

11.4 Hz, 1H, H-11a), 3.92 (d, J=11.5 Hz, 1H, H-11b), 3.56 (ddd, J=13.8,

5.0, 3.6 Hz, 1H, H-24a), 3.53 (ddd, J=13.8, 6.4, 4.6 Hz, 1H, H-24b), 3.20

(s, 3H, H-19), 3.16 (s, 3H, H-13), 2.58 (m, 1H, H-36), 2.45 (M-part of

ABMX-system, m, 1H, H-23), 2.37 (dt, J=14.0, 8.2 Hz, 1H, H-9), 2.22–

1.04 (m, 27H), 1.43 (s, 3H, H-6), 1.35 (s, 3H, H-7), 1.08 (d, J=6.9 Hz,

3H, H-37), 0.84 (t, J=7.4 Hz, 3H, H-51), 0.83 (d, J=6.6 Hz, 3H, H-40),

0.79 ppm (t, J=7.4 Hz, 3H, H-32); ¹³C NMR (150 MHz, C₆D₆): d=212.4

(C-45), 175.7 (C-34), 169.7 (C-26), 138.4 (C-10), 136.3 (C-22), 125.1 (C-

20), 125.0 (C-21), 107.8 (C-2), 96.9 (C-17), 77.0 (C-4), 75.7 (C-15), 74.3

(C-5), 74.1 (C-28), 70.0 (C-11), 57.9 (C-13), 55.3 (C-19), 43.1 (C-24), 42.9

(C-47), 42.1(C-44), 4.14 (C-38), 38.8 (C-23), 37.0 (C-36), 36.8 (C-41),

35.3 (C-49), 34.5 (C-30), 33.5 (C-14), 32.6 (C-9), 30.4 (C-39), 29.2 (C-50),

28.9 (C-6, C-8), 27.2 (C-42), 26.3 (C-7), 24.1(C-43), 22.5 (C-48), 20.0 (C-

40), 18.7 (C-31), 17.2 (C-37), 13.8 (C-32), 12.1 ppm (C-51); MS (ESI+):

730 [M⁺+Na]; HRMS (ESI+): m/z: calcd for C₄₀H₆₉NNaO₉: 730.4865;

found: 730.4868 [M⁺+Na].

X-ray crystallographic study: Diffraction data for the compounds were

collected using a Nonius KappaCCD diffractometer employing CCD

scans. The structures were solved by direct methods using SHELXS-97;

atomic positions and displacement parameters were refined using full

matrix least-squares based on F²using SHELXL-97.^[62]

Selected X-ray crystallographic data for compound 63: C₄₆H₈₄B₂, M=

658.75 gmol^ꢁ1, colorless, crystal dimensions 0.200.160.04 mm, mono-

clinic C2 (no. 5), at 100 K a=21.4010(8), b=7.8170(3), c=12.6936(5) ,

b=107.790(2),

V=2021.99(13) ³,

Z=2,

1=1.082 Mgm^ꢁ3

,

m=

0.059 mm^ꢁ1, l=0.71073 . Data completeness to q_max=27.158 98.6%, in-

tegration of raw data yielded a total of 14502 reflections, merged into

4423 unique reflections with R_int=0.036. Refinement of 218 parameters

using all reflections converged at R=0.076, wR=0.204, highest residual

electron density peak 0.3 ³.

Myxovirescin A₁(1): HClO₄(70%, 32 mL) was added to a solution of

compound 79 (7.50 mg, 10.6 mmol) in THF (1.1 mL), water (150 mL) and

MeOH (32 mL) and the resulting mixture was stirred at 408C for 22 h

before the reaction was carefully quenched with aq. sat. NaHCO₃. Ex-

traction of the product with CH₂Cl₂(5 mL), drying (MgSO₄) and evapo-

ration of the organic phase, followed by purification of the residue by

preparative TLC (EtOAc) afforded myxovirescin A₁as a colorless solid

(2.5 mg, 38%). The spectroscopic data were in full agreement with those

published in the literature.^[3,1^{1] 1}H NMR (600 MHz, C₆D₆): d=6.44 (brs,

1H), 6.35 (dd, J=14.9, 10.9 Hz, 1H), 6.12 (d, J=10.9 Hz, 1H), 5.30 (m,

2H), 4.02 (d, J=11.3 Hz, 1H), 4.00 (brm, 1H), 3.84 (brm, 1H), 3.79 (br

s, 1H), 3.74 (d, J=11.3 Hz, 1H), 3.58 (brm, 1H), 3.52 (ddd, J=13.6, 6.6,

3.8 Hz, 1H), 3.27 (dt, J=13.6, 5.6 Hz, 1H), 3.04 (s, 3H), 3.01 (brs, 1H),

2.80 (brs, 1H), 2.57 (m, 1H), 2.37 (m, 1H), 2.29 (m, 1H), 2.12–0.98 (m,

28H), 1.09 (d, J=6.9 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H), 0.83 (d, J=6.6 Hz,

3H), 0.82 ppm (t, J=7.4 Hz, 3H); ¹³C NMR (150 MHz, C₆D₆): d=210.2,

175.9, 170.8, 139.2, 135.9, 130.0, 126.6, 74.1, 73.8, 72.2, 71.1, 69.3, 57.9,

45.7, 45.6, 42.9, 42.3, 41.4, 37.4, 36.7 (2), 35.0, 34.3, 31.2, 31.1, 30.6, 28.8,

26.8, 24.0, 22.4, 19.9, 18.6, 17.6, 13.8, 12.1 ppm; MS (ESI+): 646 [M⁺

+Na]; HRMS (ESI+): m/z: calcd for C₃₅H₆₁NNaO₈: 646.4289; found:

646.4290 [M⁺+Na].

Selected X-ray crystallographic data for compound 65: C₂₄H₄₆B₂, M=

356.23 gmol^ꢁ1, colorless, crystal dimensions 0.420.120.10 mm, mono-

clinic C2/c (no. 15), at 100 K a=20.1816(4), b=6.31770(10), c=

17.8640(3) , b=95.6790(10), V=2266.50(7) ³, Z=4, 1=1.044 Mgm^ꢁ3

,

m=0.056 mm^ꢁ1, l=0.71073 . Data completeness to q_max=36.358 99.5%,

integration of raw data yielded a total of 42637 reflections, merged into

5496 unique reflections with R_int=0.048. Refinement of 122 parameters

using all reflections converged at R=0.037, wR=0.109, highest residual

electron density peak 0.4 ³.

Selected X-ray crystallographic data for compound 70: C₂₁H₂₈O₃Si, M=

356.52 gmol^ꢁ1, colorless, crystal dimensions 0.180.130.04 mm, mono-

clinic C2 (no. 5), at 100 K a=16.7363(7), b=8.2671(4), c=14.5748(6) ,

b=100.540(2),

V=1982.55(15) ³,

Z=4,

1=1.194 Mgm^ꢁ3

,

m=

0.134 mm^ꢁ1, l=0.71073 . Data completeness to q_max=31.428 99.4%, in-

tegration of raw data yielded a total of 21530 reflections, merged into

6514 unique reflections with R_int=0.034. Refinement of 230 parameters

using all reflections converged at R=0.037, wR=0.088, highest residual

electron density peak 0.3 ³.

CCDC-649747, -649748, and -650025 contain the supplementary crystal-

lographic data for this paper. These data can be obtained free of charge

from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-

c.uk/data_request/cif.

Compound 81: Prepared analogously from compound 80 (3.9 mg,

5.5 mmol); colorless solid (1.3 mg, 38%). ¹H NMR (600 MHz, C₆D₆): d=

6.66 (dd, ꢀJ=11.3 Hz, 1H, H-25), 6.51 (app d, J=11.7 Hz, 1H, H-20),

Acknowledgement

Generous financial support by the Max-Planck-Gesellschaft, the

Alexander-von-Humboldt Foundation (fellowship to J.T.B.) and the

Fonds der Chemischen Industrie (fellowship to M.B.) is gratefully ac-

knowledged. We sincerely thank Dr. C. W. Lehmann for performing the

X-ray structure analyses.

8780

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

Chem. Int. Ed. 2003 , 42 , 459 2 –4 633; d) M. Schuster, S. Blechert,

Angew. Chem. 1997 , 109 , 212 4 –2 144; Angew. Chem. Int. Ed. Engl.

1997 , 36 , 203 6 –2 056; e) A. Fürstner, Top. Catal. 1997 , 4 , 28 5 –2 99;

f) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005 , 117 ,

456 4 –4 601; Angew. Chem. Int. Ed. 2005 , 44 , 449 0 –4 527; g) A. Dei-

ters, S. F. Martin, Chem. Rev. 2004 , 104 , 219 9 –2 238.

[1] For an excellent overview, see: F. von Nussbaum, M. Brands, B.

Hinzen, S. Weigand, D. Häbich, Angew. Chem. 2006 , 118 , 519 4 –

5254; Angew. Chem. Int. Ed. 2006 , 45 , 507 2 –5 129, and references

therein.

[2] a) W. Trowitzsch, V. Wray, K. Gerth, G. Hçfle, J. Chem. Soc. Chem.

Commun. 1982 , 134 0 –1 341; b) K. Gerth, H. Irschik, H. Reichen-

bach, W. Trowitzsch, J. Antibiot. 1982, 35, 1454–1459.

[3] a) W. Trowitzsch, K. Borgschulte, V. Wray, D. Schomburg, G. Hçfle,

Liebigs Ann. Chem. 1985, 1629–1652; b) W. Trowitzsch-Kienast, K.

Schober, V. Wray, K. Gerth, H. Reichenbach, G. Hçfle, Liebigs

Ann. Chem. 1989, 345–355.

[4] Two other families of natural products have been described that ex-

hibit the same constitution as the myxovirescins. Designated “mego-

valicins” and “antibiotic TA”, respectively, the stereochemical de-

tails of the individual members are largely unknown. However, the

identity of myxovirescin A₁(1) and megovalicin C has been firmly

established (cf. ref. [3]), and the identity of 1 and antibiotic TA has

also been made highly likely. For references on the isolation of

these families, see: a) S. Miyashiro, S. Yamanaka, S. Takayama, H.

Shibai, J. Antibiot. 1988, 41, 433–438; b) S. Takayama, S. Yamanaka,

S. Miyashiro, Y. Yokokawa, H. Shibai, J. Antibiot. 1988, 41, 439–

445; c) E. Rosenberg, B. Vaks, A. Zuckerberg, Antimicrob. Agents

Chemother. 1973, 4, 507–513; d) E. Rosenberg, S. Fytlovitch, S. Car-

meli, Y. Kashman, J. Antibiot. 1982, 35, 788–793; e) D. Zafriri, E.

Rosenberg, D. Mirelman, Antimicrob. Agents Chemother. 1981, 19,

349–351.

[5] For a general review on secondary metabolites from myxobacteria,

see: H. Reichenbach, G. Hçfle in Drug Discovery from Nature

(Eds.: S. Grabley, R. Thiericke), Springer, Berlin, 1999, pp. 149–179.

[6] W. Trowitzsch, K. Gerth, V. Wray, G. Hçfle, J. Chem. Soc. Chem.

Commun. 1983 , 117 4 –1 175.

[7] a) V. Simunovic, J. Zapp, S. Rachid, D. Krug, P. Meiser, R. Müller,

ChemBioChem 2006 , 7 , 120 6 –1 220; b) K. Gerth, S. Pradella, O. Per-

lova, S. Beyer, R. Müller, J. Biotechnol. 2003 , 106 , 23 3 –2 53; c) V. Si-

munovic, R. Müller, ChemBioChem 2007 , 8 , 49 7 –5 00; d) review:

H. B. Bode, R. Müller, Angew. Chem. 2005 , 117 , 698 8 –7 007; Angew.

Chem. Int. Ed. 2005 , 44 , 682 8 –6 846.

[8] For a (non-stereoselective) RCM approach to myxovirescin ana-

logues that retain significant antibacterial activity, see: S. Content,

C. J. Dutton, L. Roberts, Bioorg. Med. Chem. Lett. 2003 , 13 , 321–

325.

[9] For an interesting reference discussing the concept of “diverted total

synthesis”, see: R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2006 ,

71 , 832 9 –8 351.

[10] a) D. R. Williams, J. M. McGill, J. Org. Chem. 1990 , 55 , 345 7 –3 459;

b) D. R. Williams, J. Li, Tetrahedron Lett. 1994 , 35 , 511 3 –5 116.

[11] a) D. Seebach, M. A. Maestro, M. Sefkow, A. Neidlein, F. Sternfeld,

G. Adam, T. Sommerfeld, Helv. Chim. Acta 1991 , 74 , 211 2 –2 118;

b) D. Seebach, M. A. Maestro, M. Sefkow, G. Adam, S. Hintermann,

A. Neidlein, Liebigs Ann. Chem. 1994, 701–717; c) M. Sefkow, A.

Neidlein, T. Sommerfeld, F. Sternfeld, M. A. Maestro, D. Seebach,

Liebigs Ann. Chem. 1994, 719–729; d) M. A. Maestro, M. Sefkow,

D. Seebach, Liebigs Ann. Chem. 1994, 731–738.

[16] For a few selected applications from this laboratory, see: a) A.

Fürstner, T. Nagano, J. Am. Chem. Soc. 2007, 129, 1906–1907; b) A.

Fürstner, F. Jeanjean, P. Razon, C. Wirtz, R. Mynott, Chem. Eur. J.

2003 , 9 , 32 0 –3 26; c) A. Fürstner, K. Radkowski, C. Wirtz, R. God-

dard, C. W. Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124,

7061–7069; d) A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda,

Chem. Eur. J. 2001 , 7 , 528 6 –5 298; e) A. Fürstner, T. Müller, J. Am.

Chem. Soc. 1999, 121, 7814–7821; f) B. Scheiper, F. Glorius, A. Leit-

ner, A. Fürstner, Proc. Natl. Acad. Sci. USA 2004 , 101 , 1196 0 –

11965; g) A. Fürstner, N. Kindler, Tetrahedron Lett. 1996 , 37 , 700 5 –

7008; h) A. Fürstner, C. Müller, Chem. Commun. 2005 , 558 3 –5 585;

i) A. Fürstner, B. Fasching, G. W. OꢁNeil, M. D. B. Fenster, C. Godb-

out, J. Ceccon, Chem. Commun. 2007 , 304 5 –3 047.

[17] For leading references on the synthesis of cyclic 1,3-dienes by RCM

strategies and illustrations of the daunting selectivity issues related

to 1,3-diene substrates in cyclization reactions see: a) R. Sedrani, J.

Kallen, L. M. Martin Cabrejas, C. D. Papageorgiou, F. Senia, S.

Rohrbach, D. Wagner, B. Thai, A.-M. Jutzi Eme, J. France, L.

Oberer, G. Rihs, G. Zenke, J. Wagner, J. Am. Chem. Soc. 2003 , 125 ,

384 9 –3 859; b) L. A. Paquette, K. Basu, J. C. Eppich, J. E. Hoffer-

berth, Helv. Chim. Acta 2002 , 85 , 303 3 –3 051; c) R. M. Garbaccio,

S. J. Stachel, D. K. Baeschlin, S. J. Danishefsky, J. Am. Chem. Soc.

2001 , 123 , 1090 3 –1 0908; d) Z.-Q. Yang, X. Geng, D. Solit, C. A. Pra-

tilas, N. Rosen, S. J. Danishefsky, J. Am. Chem. Soc. 2004 , 126 ,

7881 –7 889; e) K. Biswas, H. Lin, J. T. Njardarson, M. D. Chappell,

T.-C. Chou, Y. Guan, W. P. Tong, L. He, S. B. Horwitz, S. J. Dani-

shefsky, J. Am. Chem. Soc. 2002 , 124 , 982 5 –9 832; f) C. A. Dvorak,

W. D. Schmitz, D. J. Poon, D. C. Pryde, J. P. Lawson, R. A. Amos,

A. I. Meyers, Angew. Chem. 2000 , 112 , 173 0 –1 732; Angew. Chem.

Int. Ed. 2000 , 39 , 166 4 –1 666; g) T. Bach, A. Lemarchand, Synlett

2002 , 130 2 –1 304; h) K. Lu, M. Huang, Z. Xiang, Y. Liu, J. Chen, Z.

Yang, Org. Lett. 2006 , 8 , 1193; i) X. Wang, J. A. Porco, Jr., Angew.

Chem. 2005 , 117 , 312 7 –3 131; Angew. Chem. Int. Ed. 2005 , 44 , 306 7 –

3071; corrigendum: X. Wang, J. A. Porco, Jr., Angew. Chem. 2006 ,

118 , 6759; Angew. Chem. Int. Ed. 2006 , 45 , 6607; j) A. Rivkin, F.

Yoshimura, A. E. Gabarda, Y. S. Cho, T.-C. Chou, H. Dong, S. J.

Danishefsky, J. Am. Chem. Soc. 2004 , 126 , 10913; k) S. Barluenga, P.

Lopez, E. Moulin, N. Winssinger, Angew. Chem. 2004 , 116 , 354 9 –

3552; Angew. Chem. Int. Ed. 2004 , 43 , 346 7 –3 470; l) X. Wang, E. J.

Bowman, B. J. Bowman, J. A. Porco, Jr., Angew. Chem. 2004 , 116 ,

368 5 –3 689; Angew. Chem. Int. Ed. 2004 , 43 , 3601 –3 605; m) S. Basu,

H. Waldmann, J. Org. Chem. 2006 , 71 , 397 7 –3 979; n) G. Evano, J. V.

Schaus, J. S. Panek, Org. Lett. 2004 , 6 , 52 5 –5 28; o) X. Wang, J. A.

Porco, Jr., J. Am. Chem. Soc. 2003 , 125 , 604 0 –6 041; p) A. K. Ghosh,

G. Gong, J. Org. Chem. 2006 , 71 , 108 5 –1 093.

[18] For a successful example from our group for the formation of a

highly unsaturated macrocycle at a 1,3-diene unit, see: a) A. Fürst-

´

ner, C. Nevado, M. Tremblay, C. Chevrier, F. Teply, C. Aïssa, M.

[12] Step counting is inherently difficult and potentially controversial.

However, Seebach himself analyzed his synthesis of 1 as comprising

25 steps in the longest linear sequence (overall yield ꢂ0.8%) and 66

steps overall, cf. ref. [11]. The synthesis reported by Williams is of

similar length and efficiency (@40 steps).

[13] For a discussion concerning the “economy of steps”, see: A. Fürst-

ner, Synlett 1999 , 152 3 –1 533.

[14] For a recent catalysis-based synthesis of another antimicrobial agent

from this laboratory, see: A. Fürstner, E. K. Heilmann, P. W. Davies,

Angew. Chem. 2007 , 119 , 484 4 –4 847; Angew. Chem. Int. Ed. 2007 ,

46 , 476 0 –4 763.

Waser, Angew. Chem. 2006 , 118 , 596 9 –5 974; Angew. Chem. Int. Ed.

2006 , 45 , 583 7 –5 842; b) A. Fürstner, C. Nevado, M. Waser, M.

´

Tremblay, C. Chevrier, F. Teply, C. Aïssa, E. Moulin, O. Müller, J.

Am. Chem. Soc. 2007, 129, 9150–9161.

[19] a) A. Fürstner, K. Langemann, J. Org. Chem. 1996, 61, 3942–3943;

b) A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130–

9136; c) A. Fürstner, K. Langemann, Synthesis 1997 , 79 2 –8 03; d) A.

Fürstner, T. Gastner, H. Weintritt, J. Org. Chem. 1999, 64, 2361–

2366; e) A. Fürstner, O. R. Thiel, N. Kindler, B. Bartkowska, J. Org.

Chem. 2000, 65, 7990–7995; f) A. Fürstner, O. R. Thiel, G. Blanda,

Org. Lett. 2000, 2, 3731–3734.

[15] Selected reviews: a) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res.

2001 , 34 , 1 8 –2 9; b) A. Fürstner, Angew. Chem. 2000 , 112 , 314 0 –

3172; Angew. Chem. Int. Ed. 2000 , 39 , 301 2 –3 043; c) R. R. Schrock,

A. H. Hoveyda, Angew. Chem. 2003 , 115 , 474 0 –4 782; Angew.

[20] A. Fürstner, O. R. Thiel, C. W. Lehmann, Organometallics 2002, 21,

331–335.

[21] a) A. Fürstner, G. Seidel, Angew. Chem. 1998 , 110 , 175 8 –1 760;

Angew. Chem. Int. Ed. 1998 , 37 , 173 4 –1 736; b) A. Fürstner, O.

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8781

A. Fürstner et al.

Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108–

11113.

[22] Review: A. Fürstner, P. W. Davies, Chem. Commun. 2005 , 230 7 –

2320.

4568; b) for early examples from our group see: A. Fürstner, I. Ko-

netzki, J. Org. Chem. 1998, 63, 3072–3080; c) A. Fürstner, G. Seidel,

J. Org. Chem. 1997, 62, 2332–2336; d) A. Fürstner, I. Konetzki, Tet-

rahedron 1996 , 52 , 1507 1 –1 5078.

[23] a) A. Fürstner, O. Larionov, S. Flügge, Angew. Chem. 2007 , 119 ,

5641 –5 644; Angew. Chem. Int. Ed. 2007 , 46 , 554 5 –5 548; b) A.

Fürstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc.

2000, 122, 11799–11805; c) A. Fürstner, K. Radkowski, J. Grabow-

ski, C. Wirtz, R. Mynott, J. Org. Chem. 2000, 65, 8758–8762; d) A.

Fürstner, A. Rumbo, J. Org. Chem. 2000, 65, 2608–2611; e) A.

Fürstner, G. Seidel, J. Organomet. Chem. 2000 , 606 , 7 5 –7 8; f) A.

Fürstner, A.-S. Castanet, K. Radkowski, C. W. Lehmann, J. Org.

Chem. 2003, 68, 1521–1528; g) A. Fürstner, C. Mathes, K. Grela,

Chem. Commun. 2001 , 105 7 –1 059; h) A. Fürstner, F. Stelzer, A.

Rumbo, H. Krause, Chem. Eur. J. 2002 , 8 , 185 6 –1 871; i) A. Fürstner,

K. Grela, Angew. Chem. 2000 , 112 , 129 2 –1 294; Angew. Chem. Int.

Ed. 2000 , 39 , 123 4 –1 236; j) D. Song, G. Blond, A. Fürstner, Tetrahe-

dron 2003 , 59 , 689 9 –6 904; k) A. Fürstner, T. Dierkes, Org. Lett.

2000, 2, 2463–2465; l) A. Fürstner, C. Mathes, Org. Lett. 2001, 3,

221–223.

[24] a) A. Fürstner, D. Kirk, M. D. B. Fenster, C. Aïssa, D. De Souza, O.

Müller, Proc. Natl. Acad. Sci. USA 2005, 102, 8103–8108; b) A.

Fürstner, D. De Souza, L. Parra-Rapado, J. T. Jensen, Angew. Chem.

2003 , 115 , 551 6 –5 518; Angew. Chem. Int. Ed. 2003 , 42 , 535 8 –5 360;

c) A. Fürstner, D. Kirk, M. D. B. Fenster, C. Aïssa, D. De Souza, C.

Nevado, C. T. T. Tuttle, W. Thiel, O. Müller, Chem. Eur. J. 2007 , 13 ,

13 5 –1 49.

[25] a) V. V. Vintonyak, M. E. Maier, Angew. Chem. 2007 , 119 , 5301–

5303; Angew. Chem. Int. Ed. 2007 , 46 , 520 9 –5 211; b) V. V. Vinto-

nyak, M. E. Maier, Org. Lett. 2007 , 9 , 65 5 –6 58; c) M. IJsselstijn, B.

Aguilera, G. A. van der Marel, J. H. van Boom, F. L. van Delft,

H. E. Schoemaker, H. S. Overkleeft, F. P. J. T. Rutjes, M. Overhand,

Tetrahedron Lett. 2004 , 45 , 437 9 –4 382; d) M. I. IJsselstijn, J. Kaiser,

F. L. van Delft, H. E. Schoemaker, F. P. J. T. Rutjes, Amino Acids

2003 , 24 , 26 3 –2 66; e) J. Chan, T. F. Jamison, J. Am. Chem. Soc.

2004 , 126 , 1068 2 –1 0691; f) N. Ghalit, A. J. Poot, A. Fürstner, D. T. S.

Rijkers, R. M. J. Liskamp, Org. Lett. 2005 , 7 , 2961 –2 964; g) B. Agui-

lera, L. B. Wolf, P. Nieczypor, F. P. J. T. Rutjes, H. S. Overkleeft,

J. C. M. van Hest, H. E. Schoemaker, B. Wang, J. C. Mol, A. Fürst-

ner, M. Overhand, G. A. van der Marel, J. H. van Boom, J. Org.

Chem. 2001 , 66 , 358 4 –3 589.

[26] a) R. R. Schrock, D. N. Clark, J. Sancho, J. H. Wengrovius, S. M.

Rocklage, S. F. Pedersen, Organometallics 1982 , 1 , 164 5 –1 651;

b) J. H. Freudenberger, R. R. Schrock, M. R. Churchill, A. L. Rhein-

gold, J. W. Ziller, Organometallics 1984 , 3 , 156 3 –1 573; c) M. L. Lis-

temann, R. R. Schrock, Organometallics 1985 , 4 , 7 4 –8 3; d) R. R.

Schrock, C. Czekelius, Adv. Synth. Catal. 2007 , 349 , 5 5 –7 7; e) J.

Zhu, G. Jia, Z. Lin, Organometallics 2006 , 25 , 181 2 –1 819.

[27] a) A. Fürstner, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 1999,

121, 9453–9454; b) A. Fürstner, C. Mathes, C. W. Lehmann, Chem.

Eur. J. 2001 , 7 , 529 9 –5 317.

[33] The catalyst is commercially available; for convenient preparations

see: a) T. P. Gill, K. R. Mann, Organometallics 1982 , 1 , 48 5 –4 88;

b) B. Steinmetz, W. A. Schenk, Organometallics 1999 , 18 , 94 3 –9 46.

[34] a) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky,

J. L. Gleason, J. Am. Chem. Soc. 1997 , 119 , 649 6 –6 511; b) A. G.

Myers, B. H. Yang, H. Chen, J. L. Gleason, J. Am. Chem. Soc. 1994 ,

116 , 9361 –9 362; c) A. G. Myers, B. H. Yang, Org. Synth. 2000, 77,

22–28.

[35] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981 , 22 , 381 5 –3 818.

[36] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972 , 13 , 376 9 –3 772.

[37] Not unexpectedly, the yields of the Grignard addition were consis-

tently higher when the reaction was performed on somewhat larger

scales.

[38] A para-methoxyphenyl ether (PMP) group was preferred over the

more common para-methoxybenzyl ether (PMB) because of its

much higher yielding and more practical introduction via a Mitsuno-

bu reaction.

[39] For precedence see: A. G. Myers, M. M. Alauddin, M. A. M. Fuhry,

P. S. Dragovich, N. S. Finney, P. M. Harrington, Tetrahedron Lett.

1989 , 30 , 699 7 –7 000.

[40] Review: E. Negishi, Bull. Chem. Soc. Jpn. 2007 , 80 , 23 3 –2 57.

[41] For related selective coupling reactions of dibromoacrylates and for

the stereochemical complementarity of Negishi and Sonogashira re-

actions of substrates of this type, see: a) R. Rossi, F. Bellina, A. Car-

pita, R. Gori, Gazz. Chim. Ital. 1995, 125, 381–392; b) M. Biagetti,

F. Bellina, A. Carpita, P. Stabile, R. Rossi, Tetrahedron 2002 , 58 ,

502 3 –5 038.

[42] a) Review: T. Ohkuma, M. Kitamura, R. Noyori, in Catalytic Asym-

metric Synthesis (Ed.: I. Ojima), Wiley, New York, 2nd ed., 2000,

pp. 1–110; b) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H. Ku-

mobayashi, S. Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am.

Chem. Soc. 1988 , 110 , 62 9 –6 31; c) B. M. Trost, P. R. Hanson, Tetra-

hedron Lett. 1994 , 35 , 811 9 –8 122; d) for an application from our

group in another total synthesis program, see: A. Fürstner, M.

Albert, J. Mlynarski, M. Matheu, E. DeClercq, J. Am. Chem. Soc.

2003, 125, 13132–13142.

[43] K. Hirose, A. Fujiwara, K. Matsunaga, N. Aoki, Y. Tobe, Tetrahe-

dron: Asymmetry 2003 , 14 , 55 5 –5 66.

[44] For other conceivable methods for anti-oxyallylation see the follow-

ing and references therein: a) M. Lombardo, K. Gianotti, S. Licciul-

li, C. Trombini, Tetrahedron 2004 , 60 , 1172 5 –1 1732; b) J. A. Hunt,

W. R. Roush, J. Org. Chem. 1997 , 62 , 111 2 –1 124.

[45] a) H. C. Brown, G. Narla, J. Org. Chem. 1995 , 60 , 468 6 –4 687; b) G.

Narla, H. C. Brown, Tetrahedron Lett. 1997 , 38 , 21 9 –2 22.

[46] For an interesting alternative use of reagents of type 57 for the

preparation of 1,5-diols, see: a) E. M. Flamme, W. R. Roush, J. Am.

Chem. Soc. 2002 , 124 , 1364 4 –1 3645; b) R. M. Owen, W. R. Roush,

Org. Lett. 2005 , 7 , 3941 –3 944; c) J. D. Hicks, E. M. Flamme, W. R.

Roush, Org. Lett. 2005 , 7 , 550 9 –5 512. In the present context, it is in-

teresting to note that a limited efficiency of the hydroboration step

leading to 57 was considered by the authors as the determinant for

the moderate chemical efficiency of the 1,5-anti-diol syntheses based

upon its use, cf. ref. [46a].

[47] For recent large-scale applications of Brown-allylation and Brown-

crotylation reactions from this laboratory, see: a) C. Aïssa, R. Riv-

eiros, J. Ragot, A. Fürstner, J. Am. Chem. Soc. 2003, 125, 1 551 2–

15520; b) A. Fürstner, C. Aïssa, R. Riveiros, J. Ragot, Angew.

Chem. 2002 , 114 , 495 8 –4 960; Angew. Chem. Int. Ed. 2002 , 41 , 476 3 –

4766; c) A. Fürstner, M. D. B. Fenster, B. Fasching, C. Godbout, K.

Radkowski, Angew. Chem. 2006 , 118 , 563 2 –5 636; Angew. Chem.

Int. Ed. 2006 , 45 , 550 6 –5 510; d) A. Fürstner, M. D. B. Fenster, B.

Fasching, C. Godbout, K. Radkowski, Angew. Chem. 2006 , 118 ,

563 6 –5 641; Angew. Chem. Int. Ed. 2006 , 45 , 551 0 –5 515.

[28] a) W. Zhang, S. Kraft, J. S. Moore, J. Am. Chem. Soc. 2004 , 126 ,

32 9 –3 35; b) J. M. Blackwell, J. S. Figueroa, F. H. Stephens, C. C.

Cummins, Organometallics 2003 , 22 , 3351 –3 353; c) W. Zhang, J. S.

Moore, Adv. Synth. Catal. 2007 , 349 , 9 3 –1 20.

[29] a) A. Fürstner, L. Turet, Angew. Chem. 2005 , 117 , 352 8 –3 532;

Angew. Chem. Int. Ed. 2005 , 44 , 346 2 –3 466; b) A. Fürstner, D.

De Souza, L. Turet, M. D. B. Fenster, L. Parra-Rapado, C. Wirtz, R.

Mynott, C. W. Lehmann, Chem. Eur. J. 2007 , 13 , 11 5 –1 34.

[30] a) B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2005 , 127 , 1764 4 –

17655; b) B. M. Trost, Z. T. Ball, T. Jçge, J. Am. Chem. Soc. 2002 ,

124 , 792 2 –7 923; c) B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2003 ,

125 , 3 0 –3 1; d) B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2001 , 123 ,

1272 6 –1 2727.

[31] a) F. Lacombe, K. Radkowski, G. Seidel, A. Fürstner, Tetrahedron

2004 , 60 , 731 5 –7 324; b) A. Fürstner, K. Radkowski, Chem.

Commun. 2002 , 218 2 –2 183.

[32] a) Review: S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew.

Chem. 2001 , 113 , 467 6 –4 701; Angew. Chem. Int. Ed. 2001 , 40 , 454 4 –

[48] In this context, it is noteworthy that similar problems with the re-

duction of the aldehyde substrate were encountered by Roush et al.,

8782

www.chemeurj.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 8762 – 8783

Total Synthesis of Myxovirescin A₁

FULL PAPER

but no attempts were made to investigate the origins of this undesir-

able side reaction, cf. ref. [46a], Supporting Information.

[49] H. C. Brown, P. K. Jadhav, A. K. Mandal, Tetrahedron 1981 , 37 ,

354 7 –3 587.

[50] a) H. C. Brown, N. R. Ayyangar, G. Zweifel, J. Am. Chem. Soc.

1964 , 86 , 39 7 –4 03; b) H. C. Brown, G. Zweifel, J. Am. Chem. Soc.

1961, 83, 486–487; c) H. C. Brown, G. J. Klender, Inorg. Chem.

1962 , 1 , 20 4 –2 14.

[51] a) H. C. Brown, M. J. Desai, P. K. Jadhav, J. Org. Chem. 1982 , 47 ,

506 5 –5 069; b) H. C. Brown, B. Singaram, J. Org. Chem. 1984 , 49 ,

94 5 –9 47; c) H. C. Brown, N. N. Joshi, J. Org. Chem. 1988 , 53 , 405 9 –

4062; d) U. S. Racherla, H. C. Brown, J. Org. Chem. 1991 , 56 , 401–

404.

[52] Compare, for example, the reported shifts of triethyldiborane (d_B=

34.3, 17.2 ppm) or tri(isopropyl)diborane (d_B=36.6, 16.4 ppm): B.

Wrackmeyer, J. Organomet. Chem. 1976 , 117 , 31 3 –3 20.

[53] H. C. Brown, Boranes in Organic Chemistry, Cornell University

Press, Ithaca, 1972.

[56] a) P. Raddatz, K.-O. Minck, F. Rippmann, C.-J. Schmitges, J. Med.

Chem. 1994 , 37 , 48 6 –4 97; b) K. Mori, H. Takaishi, Tetrahedron

1989 , 45 , 163 9 –1 646; c) T. Storz, P. Dittmar, P. F. Fauquex, P. Mars-

chal, W. U. Lottenbach, H. Steiner, Org. Process Res. Dev. 2003 , 7 ,

55 9 –5 70.

[57] However, the phasing of events is critical. Attempted Suzuki cou-

pling reactions of bromide 12 with boranes derived from olefins of

type 61 carrying a 2-hydroxypentanoic acid amide rather than a

phthalimide were invariably low yielding.

[58] For an incompatibility of an unprotected amide with 20, see

ref. [27].

[59] For the preparation of 20 see the following references: a) C. C.

Cummins, Chem. Commun. 1998 , 177 7 –1 786; b) C. E. Laplaza,

A. L. Odom, W. M. Davis, C. C. Cummins, J. D. Protasiewicz, J. Am.

Chem. Soc. 1995 , 117 , 499 9 –5 000.

[60] K. Takahashi, H. Nakamura, S. Furumoto, K. Yamamoto, H.

Fukuda, A. Matsumura, Y. Yamamoto, Bioorg. Med. Chem. 2005 ,

13 , 73 5 –7 43.

[61] X. Gu, M. Sun, B. Gugiu, S. Hazen, J. W. Crabb, R. G. Salomon, J.

Org. Chem. 2003 , 68 , 374 9 –3 761.

[62] G. M. Sheldrick, SHELXS-97 and SHELXL-97, Programs for the

determination and refinement of crystal structures, University of

Gçttingen, Germany, 1997.

[54] Therefore, it is difficult to say with certainty at which point exactly

one equivalent of active “Ipc₂BH” is in the mixture and which and

how many other B-H containing species accompany this reagent at

a given point in time.

[55] M. Lautens, M. L. Maddess, E. L. O. Sauer, S. G. Ouellet, Org. Lett.

2002 , 4 , 8 3 –8 6 (cf. Supporting Information available).

Received: June 18, 2007

Published online: September 4, 2007

Chem. Eur. J. 2007, 13, 8762 – 8783

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

8783

Article Doi

Total synthesis of myxovirescin A1

DOI: 10.1002/chem.200700926

Source and publish data:

Authors:

Article abstract of DOI:10.1002/chem.200700926

Full text of DOI:10.1002/chem.200700926

Products guided by the article

R&D Labs maybe for 157733-19-2

Relevant to this article

Hot Product