Stereocontrolled synthesis of a Cn-Cn+7 building block ("eastern moiety") for the unnatural enantiomers of important polyol,polyene antibiotics based on a ring-closing metathesis and an aldol addition of a lactone enolate

FULL PAPER

DOI: 10.1002/ejoc.201300183

Stereocontrolled Synthesis of a Cⁿ–Cⁿ⁺⁷Building Block (“Eastern Moiety”)

for the Unnatural Enantiomers of Important Polyol,Polyene Antibiotics Based

on a Ring-Closing Metathesis and an Aldol Addition of a Lactone Enolate

Sonja B. Kamptmann^[a]and Reinhard Brückner*^[a]

Keywords: Aldol reactions / Asymmetric allylation / Enantioselectivity / Metathesis / Lactones / Tamao–Fleming oxidation

A stereocontrolled synthesis of epoxide 6, which represents

the Cⁿ–Cⁿ⁺⁷or “eastern moiety” building block for the title

compounds, has been realized in 19 steps. Our synthesis

started from tetrabromoacetone 26 and afforded dibromotri-

ene 33b in six steps. The latter was subjected to a ring-clos-

ing metathesis, which gave the dibromovinyl-substituted lac-

tone 34 in high yield. A highly stereoselective conjugate ad-

dition/enolate aldolization sequence established the ad-

ditional stereocenters with perfect selectivity. Epoxide 47b

was reached in another eight steps, which included a

C–SiMe₂PhǞC–OH oxidation in the presence of an acetal

group. The final structure 6 was completed by hydrostan-

nylation/brominolysis.

aglycons of amphotericin B^[2](aglycon = ent-1) and nystatin

Introduction

[3]

A₁(aglycon = ent-2) as well as of candidin^[4](aglycon =

The polyol,polyene macrolides are a family of several hun- ent-3), pimaricin^[5,6](aglycon = ent-4), and rimocodin^[7](ag-

dred secondary metabolites produced by bacterial patho- lycon = ent-5). The accompanying papers^[8]provide a sum-

gens of the genus Streptomyces.^[1]Several of these macro- mary of their structure–activity relationships and give a ra-

lides are used as antifungal agents.^[1]Scheme 1 illustrates tionale for our interest in developing synthetic routes to

the typical structural features of such polyol,polyene macro- both the aglycons 1–5^[9]of the naturally occurring polyol,-

lides through a display of the unnatural enantiomers of the polyene macrolides and of their unnatural counterparts ent-

Scheme 1. Unnatural enantiomers ent-1–5 of the naturally occurring polyol/polyene macrolides amphotericin B (= aminoglycoside of 1),

nystatin A₁(= aminoglycoside of 2), candidin (= aminoglycoside of 3), pimaricin (= aminoglycoside of 4), and rimocidin (= aminoglycos-

ide of 5). Compounds ent-1–5 have a tetrahydropyrancarboxylic acid/allyl alcohol motif (~ “eastern moiety”; grey backgrounds) in

common.

[a] Institut für Organische Chemie, Albert-Ludwigs-Universität,

1–5.^[10]The synthesis of the “eastern moiety” of the natural

Albertstr. 21, 79104 Freiburg, Germany

enantiomers is described in ref.^[8a], while syntheses of the

E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de

http://ww w .chemie.uni-freiburg.de/orgbio/brueck/w3br/

“eastern moiety” of the unnatural enantiomers (Scheme 1)

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300183.

6584

are described in ref.^[8b]and in the following.

Eur. J. Org. Chem. 2013, 6584–6600

Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

Our building blocks for the “eastern moieties” of 1–5 cross-coupling at that end of the derived C¹–Cⁿ⁺⁷building

and ent-1–5, which are described in the accompanying arti- block with the M–Cⁿ⁺⁸=Cⁿ⁺⁹end of a polyene building

cles,^[8a,8b]comprise a Cⁿ–Cⁿ⁺⁶subunit of the respective tar- block, for example, by a Stille coupling reaction^[13](if M =

get structure. Therein, Cⁿis part of an epoxide and Cⁿ⁺⁶is Bu₃Sn).

part of a latent aldehyde group. These functionalities are

expected to allow C^n–1–Cⁿbond formation by nucleophilic

attack on the C¹–C^n–1building block (which introduces the

Results and Discussion

polyol moiety) and Cⁿ⁺⁶=Cⁿ⁺⁷bond formation by a trans-

selective olefination (which introduces the polyene moiety).

Scheme 2 shows that the desired “eastern moiety” build-

In the present study the “eastern moieties” of the target ing block 6 is traced back retrosynthetically to the 1,2,4-

structures ent-1–5 are traced back to a homologous subunit, triol 11 (which should lead to 6 by tosylation of the primary

namely to the Cⁿ–Cⁿ⁺⁷building block 6 (see Scheme 2). As OH group and subsequent epoxide formation^[14]). Triol 11

before, Cⁿis part of an epoxide, which, as before, will be was envisioned to arise from intermediate 10, which is a

involved in C^n–1–Cⁿbond formation by nucleophilic attack silane-containing monoprotected glycol, by Tamao–Flem-

on the C¹–C^n–1building block (which introduces the polyol ing^[15,16]oxidation of the Cⁿ⁺³–Si bond.^[17,18]The intermedi-

moiety). In addition, building block 6 contains a trans-con- ate 10 should be derived from the α,β-unsaturated δ-lactone

figured Cⁿ⁺⁶=Cⁿ⁺⁷–Br unit. The latter is introduced in re- 9. This seemed likely because unpublished work from our

cognition of the usefulness of Pd⁰-catalyzed C_sp₂–C_sp₂cross- group^[19,20]on related α,β-unsaturated δ-lactones had estab-

coupling reactions in synthesis^[11]and of the cornucopia of lished that the stereocenters present in 10 but not yet pres-

applications of diene-, triene-, and polyene-containing natu- ent in 9 should be established if 9 behaved as its predeces-

ral products.^[12]Accordingly, the presence of the sors under the following conditions: 1) 1,4-addition of the

C

ⁿ⁺⁶=Cⁿ⁺⁷–Br moiety in our “eastern moiety” 6 anticipates silyl-containing mixed cyanocuprate 7 to 9 and 2) conver-

sion of the resulting lactone into a boron enolate and aldol

addition to an aldehyde 8. We then hypothesized that the

α,β-unsaturated δ-lactone 9 would be obtained by a regiose-

lective ring-closing metathesis^[21]of crotonate 12, which is

a triene. This crotonate would stem from an esterification

of the underlying dienol (formula not shown in Scheme 2),

which was expected to arise from trans-bromoprop-2-enal

(13^[22]) by an asymmetric allyl addition, for example, by a

Brown^[23,24]or Soderquist allylation.^[25,26]trans-Bromo-

prop-2-enal (13^[22]

) was synthesized from propargylic

alcohol (15) as depicted in the bottom line of Scheme 2.

Bromoalkyne formation followed by reduction with LiAlH₄

yielded trans-bromopropenol (14) in 70% overall yield.^[27]

Subsequent oxidation afforded trans-bromoprop-2-enal (13)

[22]

as a concentrated solution in CH₂Cl₂(72% yield), mak-

ing a concession to its high volatility.

trans-3-Bromoprop-2-enal (13) then became the object of

asymmetric allyl addition reactions following typical

Brown^[23,24]and Soderquist^[25,26]procedures (Table 1,

step a). The first method afforded the bromohexadienol 16

in moderate yield (64%) and with moderate ee (78%),

whereas the second method furnished the same bromohexa-

dienol in 80% yield and with Ͼ99% ee. The latter and cro-

tonic acid were condensed in the presence of DCC/DMAP

to give triene 12 in 78% yield (Table 1, step b). This triene

seemed to be an appropriate substrate for a ring-closing me-

tathesis reaction, delivering the α,β-unsaturated δ-lactone 9.

Indeed, a large number of both ring-closing^[28]and acyclic

cross-metathesis reactions^[29]in the presence of C=C–Br

groups have been reported, especially propelled by the

Grubbs I^[30]and II catalysts.^[31]Accordingly, we noted with

considerable surprise that our first metathesis experiments

(with 100 mm solutions of the triene 12 in CH₂Cl₂or tolu-

ene) in the presence of the Grubbs II catalyst^[32]afforded at

best traces (Ͻ5%) of the expected lactone 9 (Table 1, en-

tries 1–4). Instead, we isolated another olefin metathesis

Scheme 2. Retrosynthetic analysis of the Cⁿ–Cⁿ⁺⁷building block 6

and synthesis of the known aldehyde 13^[22]from propargylic

alcohol (15). Reagents and conditions: a) KOH (2.9 equiv.), Br₂

(1.0 equiv.), H₂O, –5 °C; addition to 15 (1.1 equiv.), H₂O, –10 °C,

within 3 h; –10 °C, 1 h; in the course of 1 h Ǟ+10 °C; no purifica-

tion; b) LiAlH₄(1.8-fold molar amount), AlCl₃(1.3 equiv.), Et₂O,

–10 °C; addition of 3-bromoprop-2-yn-1-ol, reflux, 4 h; 70% over

the two steps (ref.^[27]79%); c) activated MnO₂(30 equiv.), CH₂Cl₂,

room temp., 3 h; filtration; 72%.^{[a] [a]}13 was obtained as a solution

in CH₂Cl₂. PG = protecting group.

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S. B. Kamptmann, R. Brückner

FULL PAPER

Table 1. Synthesis of the monobromotriene 12 and ring-closing me- urated δ-lactone 9 was directed towards the synthesis of en-

tathesis giving the bromovinyl-substituted lactone 9.

ynyl acrylate 23a or crotonate 23b, as “benign” metathesis

substrates (Scheme 3). However, this seemingly minor

change entailed two complications. First, there have only

been scattered reports of asymmetric allyl additions to

propargylic aldehydes.^[35,36]If studied at all, enantiocontrol

was mostly moderate,^[37]or, if it was, as an exception,

good,^[35d,35h]it involved allyltin reagents, yet it was feared

that use of the latter could thwart the subsequent metathe-

sis reaction.^[38]A second complication concerned the feasi-

bility of the ring-closing of the dienynes 23, even in the

absence of tin-containing contaminants: A CϵC bond,

which is not genuinely internal^[39]but terminal or sil-

ylated,^[40]seems to lower the yield. It has been suggested

that this arises from bonding of the triple bond to the metal

of the ruthenium carbene complex.^[40e]

[a] Reagents and conditions: Variant 1: [(–)-Ipc]₂BH [(–)-18,

1.0 equiv.], MeOH (2.0 equiv.), THF, 0 °CǞroom temp., removal

of solvent; allylMgBr (1.0 equiv.), Et₂O, –78 °C, 15 min; Ǟroom

temp.; 13 (in CH₂Cl₂), Et₂O, –78 °C, 2 h; Ǟroom temp.; NaOH/

H₂O₂; 64%, 78% ee (determined by chiral HPLC of O-benzoyl-

16); variant 2: (10S)-19 (1.0 equiv.), allylMgBr (1.0 equiv.), Et₂O,

–78 °CǞroom temp., 1 h; 13 (in CH₂Cl₂), Et₂O, –78 °CǞroom

temp., 3 h; (1R,2R)-pseudo-ephedrine (1.0 equiv.), CH₃CN, reflux,

2 h; 80% 16, 99% ee (determined by chiral HPLC of O-benzoyl-

16) + 71% reisolated (10S)-19. [b] Reagents and conditions: Cro-

tonic acid (1.5 equiv.), DCC (1.5 equiv.), DMAP (20 mol-%),

CH₂Cl₂, 0 °CǞroom temp., 20 h; 78%. [c] CH₂Cl₂for entry 1, tol-

uene for entries 2–6. Grubbs II catalyst = [1,3-bis(2,4,6-trimeth-

Scheme 3. Syntheses of dienynes 23a,b and ring-closing metathesis

to give the ethynyl-substituted lactone 24. Reagents and conditions:

a) IBX (1.4 equiv.), acetone, reflux, 4 h; 64% (ref.^[43]70%); b) vari-

ant 1: (10S)-19 (1.0 equiv.), allylMgBr (1.0 equiv.), Et₂O,

–78 °CǞroom temp., 1 h; 21, Et₂O, –78 °CǞroom temp., 14 h;

(1R,2R)-pseudo-ephedrine (1.0 equiv.), CH₃CN, reflux, 2 h; 76%

21, 77% ee^[a]+ 63% reisolated (10S)-19; variant 2: (R,R)-25

(1.3 equiv.), allylMgBr (1.1 equiv.), THF, 0 °C, 2 h; 21, –78 °C, 3 h;

62% 21, 85% ee^[a]+ 70% reisolated TADDOL; c) acryloyl chloride

(1.2 equiv.), NEt₃(1.7 equiv.), CH₂Cl₂, 0 °CǞroom temp., 14 h;

87%; d) crotonic acid (1.05 equiv.), DCC (1.10 equiv.), DMAP

(20.0 mol-%), CH₂Cl₂, 0 °CǞroom temp., 20 h; 79%; e) Grubbs II

catalyst (10 mol-%), toluene (5 mm), 80 °C, 2 h; 0% for R = H,

21% for R = Me (contaminated). ^[a]Determined by chiral HPLC

ylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricy-

clohexylphosphane)ruthenium; DCC = N,NЈ-dicyclohexylcarbodii-

mide; DMAP = 4-(dimethylamino)pyridine.

product, namely the cross-metathesis product 17 (21–49%

yield, 73:27 E/Z mixture^[33]). In addition, we reisolated the

unreacted triene 12 in yields of 42–77%. In certain ring-

closing metathesis reactions, high dilution appears to be a

sine qua non for success.^[34]Even under such conditions

(starting from a 5 mm solution of the triene 12 in toluene),

while trying to make up for the concomitant decrease in

reactivity by using 10 mol-% Grubbs II catalyst (Table 1,

entries 5 and 6; as opposed to 2 mol-% in the experiments

of entries 1–4), we isolated no more than 34% lactone 9

(entry 6).

of O-benzoyl-22. IBX

=

1-hydroxy-1-oxo-1H-1λ⁵-benzo[d][1,2]

iodoxol-3-one; DCC=N,NЈ-dicyclohexylcarbodiimide; DMAP = 4-

(dimethylamino)pyridine; Grubbs II catalyst = [1,3-bis(2,4,6-tri-

methylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylen-

e)(tricyclohexylphosphane)ruthenium; TADDOL = (4R,5R)-2,2-

dimethyl-α,α,αЈ,αЈ-tetraphenyl-1,3-dioxolane-4,5-methanol.

We interpreted the (near-)failure of the ring-closing me-

tatheses of Table 1 as resulting from a deactivation if not

destruction of the Grubbs II catalyst by the bromovinyl

Aware of the aforementioned considerations we synthe-

moiety of substrate 12. As a consequence, we considered sized the dienynes 23a and 23b from the C-silylated propar-

introducing that moiety at a later stage. Accordingly, we gyl alcohol 20^[41]in three steps (Scheme 3). Oxidation with

started our next approach towards the α,β-unsaturated δ- IBX^[42]afforded the aldehyde 21 in 64% yield.^[43]An asym-

lactone 9, or a synthetic equivalent, by employing a (tri- metric allyl addition of the Soderquist reagent^[25]gave en-

methylsilyl)ethynyl rather than bromovinyl moiety in the ynol 22 in 76% yield and with 77% ee. Addition of the

metathesis step. Our second attempt towards the α,β-unsat- Duthaler–Haffner allylation reagent^[44]derived from Ti^IV–

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Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

TADDOLate (R,R)-25 afforded the same enynol 22 less ef- Table 2. Synthesis and asymmetric allylation of dibromoprop-2-

enal (28), a precursor of the dibromotrienes 33a,b of Table 3.

ficiently (62% yield) but with 85% ee. Esterification of the

latter with acryloyl chloride or crotonic acid/DCC/DMAP

furnished the dienynes 23a (87%) and 23b (79%), respec-

tively. Unfortunately, 5 mm solutions of dienynes 23a or 23b

in toluene and 10 mol-% Grubbs II catalyst at 80 °C deliv-

ered none of the α,β-unsaturated δ-lactone 24 or only 24%

thereof, respectively.^[45]

We adjusted to this difficulty by resolving to anticipate

the trans-configured C=C–Br moiety of our “eastern”

building block 6 (formula: Scheme 2) as a C=CBr₂unit (ul-

timately in the α,β-unsaturated δ-lactone 34) rather than as

a C=C–Br group (cf. discussion of Table 1) or CϵC–SiMe₃

moiety (cf. discussion of Scheme 3). We felt that a C=CBr₂

group, for steric reasons, would be inclined to a lesser extent

than C=C–Br or CϵC–SiMe₃groups to interfere with the

intermediates formed from the target dibromotrienes 33a or

33b (see Table 3) and a Ru-based metathesis catalyst. Once

we had reached the α,β-unsaturated δ-lactone 34, the

C=CBr₂moiety was likely to be convertible into a CϵC–H

moiety by step 2 of the Corey–Fuchs sequence.^[46]The

CϵC–H group, in turn, was intended to provide the trans-

C=C–Br group either by hydrozirconation followed by bro-

minolysis^[47]or by hydrostannylation followed by bromino-

[a] Reagents and conditions: NaHCO₃(10 equiv.), room temp., 2 d;

62% (ref.^[50]63%). [b] Reagents and conditions: H₂SO₄(10 mol-

lysis.^[48]

%), MeOH, reflux, 12 h; 96% (ref.^[51]83%). [c] Reagents and condi-

We prepared the dibromotrienes 33a and 33b from the

tions: DIBAH (2.1 equiv.) within 3 h, CH₂Cl₂, –78 °C, 1 h; in the

tetrabromoacetone 26^[49]in 49% overall yield (Table 2). A

Favorskii rearrangement afforded β,β-dibromoacrylic

acid.^[50]Esterification with methanol,^[51]reduction to the

corresponding allylic alcohol,^[51]and oxidation of the latter

with IBX gave aldehyde 28.^[52]We attempted asymmetric

course of 14 h Ǟroom temp.; 94% (ref.^[51]83%). [d] Reagents and

conditions: IBX (1.4 equiv.), acetone, reflux, 4 h; 83%.^[52]DIBAH

= diisobutylaluminium hydride; IBX = 1-hydroxy-1-oxo-1H-1λ⁵-

benzo[d][1,2]iodoxol-3-one. [e] Determined by chiral HPLC of O-

benzoyl-27. [f] 66% (10S)-19 was reisolated. [g] 63% TADDOL was

reisolated. TADDOL

=

(4R,5R)-2,2-dimethyl-α,α,αЈ,αЈ-tet-

allyl addition reactions to this aldehyde by Soderquist allyl- raphenyl-1,3-dioxolan-4,5-methanol.

ation (entry 1),^[25]Duthaler–Haffner allylation (entry 2),^[44]

Roush allylation (entry 3),^[53]Leighton allylation (en- of the Grubbs II catalyst furnished the dibromovinyl-substi-

try 4),^[54]and Carreira allylation (entry 5).^[55]As in the case tuted lactone 34 in near-quantitative yield (97%, entry 8).

of the monobromprop-2-enal 13 (cf. Table 1), the highest ee This is remarkable because so far only sparse examples of

of dibromprop-2-enal 28 (Table 2) was achieved by Soder- metathesis reactions tolerating a C=CBr₂group have been

quistЈs method,^[25]although the ee did not surpass 88%. reported; none of them proceeded in such a high yield.^[56]

However, it was likely that if it was used for the preparation In the cases in hand (33a,bǞ34, Table 2), we never detected

of α,β-unsaturated δ-lactone 34, the latter might crystallize a cross-metathesis product akin to compound 17 from the

and thereby allow its enantiopurity to be increased. This less efficient ring-closure 12Ǟ9 (Table 1). Increasing the

hope stemmed from the previously observed crystallinity of amount of crotonate 33b in the ring-closing metathesis reac-

“debromo-34” (that is, 9).

tion from 0.1 to 8 mmol, degassing the reaction mixture

Table 3 illustrates how we proceeded to the desired lac- prior to the addition of the catalyst, and passing a slow

tone 34. First, we esterified the allylic alcohol (S)-29 (88% stream of nitrogen through the apparatus during the reac-

ee) to obtain acrylate 33a and crotonate 33b (76 and 88% tion enabled us to lower the amount of catalyst and simulta-

yields, respectively). These were the dibromotriene sub- neously improve the isolated yield. Such an optimized me-

strates used for a series of ring-closing metathesis experi- tathesis of 33b in the presence of 6 mol-% freshly prepared

ments performed in toluene (Ǟ34) in which we varied both Grubbs II catalyst^[32]gave the lactone 34 in 100% yield (not

the substrate concentration and the amount of Grubbs II shown in Table 3).

catalyst.^[32]Starting from the acrylate 33a we isolated 34 in

As we had hoped, 34 was formed as a solid (with 88%

moderate yields of 45–60% (entries 1–3). In addition, unre- ee) and was transformed into an enantiopure material

acted 33a was reisolated. Fortunately, the crotonate 33b af- (Ͼ99% ee) by two consecutive crystallizations (69% yield

forded 34 in substantially better yields (70–97%, entries 4– from the scalemic material). In this manner we had found

8). As noted in the metathesis 12Ǟ9 (Table 1), the lower an appropriate starting point for continuing our synthesis

the substrate concentration and the greater the amount of by a strategy similar to that depicted in Scheme 2.

catalyst, the better the isolated yield of the ring-closing me-

Next we converted the enantiomerically pure dibromo-

tathesis product: Ring-closure with 5 mm 33 and 10 mol-% vinyl-substituted lactone 34 into the mixed acetal 36

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S. B. Kamptmann, R. Brückner

FULL PAPER

Table 3. Synthesis of the dibromotrienes 33a,b and their ring-clos-

ing metatheses (Grubbs II catalyst, toluene, 80 °C, 2 h, scale: 0.10–

0.13 mmol) to the dibromovinyl-substituted lactone 34.

Scheme 4. Reaction of dibromovinyl-substituted lactone 34 by 1,4-

addition/enolate aldolization and transformation of the resulting

lactone 37 into the mixed acetal 36. Reagents and conditions: a) Li

(30 equiv.), PhMe₂SiCl (4.0 equiv.), THF, –25 °C, 40 h; addition to

CuCN (2.0 equiv.), THF, –25 °C; Ǟ–78 °C, Me₃SiCl (2.2 equiv.);

34, THF, –78 °C, 3 h; 78%; b) iPr₂NEt (1.6 equiv.), nBu₂BOTf

(1.5 equiv.), CH₂Cl₂, room temp.Ǟ–78 °C; 35, CH₂Cl₂, –78 °C,

2 h; PMBOCH₂CHO (2.0 equiv.), –78 °C, 3 h; aq. H₂O₂(30%),

MeOH, room temp., 14 h; 71%; c) DIBAH (2.5 equiv.), toluene,

–78 °C, 30 min; in the course of 14 h Ǟroom temp.; d) CSA

(1 mol-%), MeOH, room temp., 10 h; 81% over two steps. DIBAH

= diisobutylaluminium hydride; CSA = camphorsulfonic acid.

[a] Reagents and conditions: Acryloyl chloride (1.2 equiv.), NEt₃

(1.7 equiv.), CH₂Cl₂, 0 °CǞroom temp., 14 h; 76%. [b] Reagents

and conditions: Crotonic acid (1.05 equiv.), DCC (1.10 equiv.),

DMAP (20.0 mol-%), CH₂Cl₂, 0 °CǞroom temp., 20 h; 88%.

DMAP = 4-(dimethylamino)pyridine. [c] Grubbs II catalyst = [1,3-

bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phen-

ylmethylene)(tricyclohexylphosphane)ruthenium. [d] n.d.: not de-

termined. [e] On a larger scale the yield of scalemic 34 was 100%

(see preceding page).

C–SiMe₂PhǞC–H had occurred (as known for C–Si-

Me₂Ph groups in the presence of Bu₄N⁺F^{– [63]}).

The lessons from these experiments were that 1) we

(Scheme 4). The key steps for accomplishing this were 1) the would have to engage a Tamao rather than Fleming oxi-

Me₃SiCl-promoted diastereoselective 1,4-addition of the dation of the C–SiMe₂Ph group and 2) we could not keep

mixed silylcyanocuprate 7 (formula in Scheme 2) to 34 and the C=CBr₂group but would have to integrate its seemingly

2) conversion of the resulting lactone 35 (78% yield) via its unavoidable conversion into a CϵCH group into a modi-

dibutylboron enolate and PMBOCH₂CHO^[57]with perfect fied procedure. We improved the corresponding transfor-

diastereoselectivity (cf. ref.^[19,20]) into the hydroxyalkylated mation 36Ǟ38 from 71% yield [under the unexpected con-

lactone 37 (71% yield). The absolute and relative configura- ditions b)] to 85% [by treatment with MeLi;^[46]according

tion(s) of this compound were elucidated by X-ray analysis to conditions a)]. We were concerned about the risk of los-

(Bijvoet method^[58]). Subsequently, lactone 37 was reduced ing the C–SiMe₂Ph group of the hydroxysilane 38 by a pro-

to the corresponding lactol (not shown in Scheme 4), which todesilylation reaction (cf. 36Ǟ39). To limit this risk we

was subjected to condensation with methanol in the pres- employed KF rather than Bu₄N⁺F^–as the fluoride source

ence of camphorsulfonic acid to give the mixed acetal 36 because the latter is notorious for containing water, which

(81% yield over the two steps).^[59]

is not easily removable.^[64]Under these conditions we ob-

We tried to generate the C–OH unit of alcohol 40 by tained 41 in 65% yield.^[65]Tamao oxidations are known to

oxidizing the C–SiMe₂Ph moiety of the mixed acetal 36 un- proceed with retention of configuration.^[66]Thus, we were

der the conditions of Peng and Woerpel,^[61]that is, by expo- confident that the newly established C–OH bond of 41

sure in N-methylpyrrolidinone solution first to KH would be oriented as drawn in Table 4, that is, “up”. In

(6 equiv.) and tBuOOH (6 or 1.1 equiv.) and then to retrospect this was confirmed by an X-ray analysis of the

Bu₄N⁺F^–(2.1 equiv.; Table 4, upper part). Although our follow-up product 47b (which resulted from the sequence

substrate reacted, it did so in an unforeseen manner, with- 41Ǟ44bǞ45bǞ46bǞ47b as depicted in Table 4 and

out forming the desired alcohol. By employing 6 equiv. of Scheme 6). It should be mentioned that we tried to realize

tBuOOH we isolated compound 38 (71%), in which the di- the oxidation C–SiMe₂PhǞC–OH at several later points of

bromovinyl substituent had been transformed into an al- our synthesis, instead of effecting it in 55% overall yield

kyne^[62]but the C–SiMe₂Ph group had survived. When we during the conversion of 36 via 38 into 41, as shown in

employed 1.1 equiv. of tBuOOH we isolated compound 39 Table 4. However, these attempts were futile.^[67]

(44%), in which the dibromovinyl substituent had also been

Our next objective related to step 6⇒11 of our retrosyn-

converted into an alkyne.^[62]In addition, protodesilylation thetic analysis (Scheme 2). It consisted of transforming the

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Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

Table 4. Vain attempts to oxidize the C–SiMe₂Ph group in the was not successful,^[68]we turned to the alternative (Table 4,

mixed acetal 36 to the C–OH group of alcohol 40 without affecting

Scheme 5, and Scheme 6). Accordingly, diol 41 was pro-

the C=CBr₂unit (upper part). Differentiation of the secondary OH

tected by using two different chlorosilanes RMe₂SiCl (R =

groups in the Tamao oxidation product 41 by substoichiometric

tBu, tHex; Table 4). The silyl groups were introduced at

50 °C in DMF (14 h). This furnished the Cⁿ⁺³–O-monopro-

tected silyl ethers 44a (entry 1) and 44b (entry 2) as the

main products (62% yield for R = tBu and 55% yield for

R = tHex, respectively) and the silyl ethers 42a,b (Cⁿ⁺¹–O-/

amounts of trialkylsilyl chlorides (lower part and Table section).^[60]

C

ⁿ⁺³–O-disilyl ether; 11% yield for R = tBu; 21% yield for

R = tHex) and 43a,b (Cⁿ⁺¹–O-silyl ether; 13% yield for R

= tBu; 19% yield for R = tHex) as the minor products. In

addition, all the silylations left some diol 41 unchanged,

which we reisolated in yields of 4–13%. Fortunately, each

of the undesired silyl ethers 42a,b and 43a,b could be sepa-

rated from the

C

ⁿ⁺³–O-silyl ethers 44a,b by flash

chromatography.^[69]This allowed the regeneration of the

diol 41 and its resubmission to silylation. This ensured

minimal loss of material.

The tert-butyldimethylsilyl ether 44a was more efficiently

accessible than the corresponding tert-hexyldimethylsilyl

ether 44b. Therefore we continued our synthesis with 44a

(Scheme 5). PMB deprotection with CAN (Ǟ45a), tosyl-

ation (Ǟ46a), and formation of the epoxide 47a gave just

17% overall yield. We held the following factors responsi-

ble: 1) The separation of 45a from p-methoxybenzaldehyde,

which resulted from the reaction of 44a and CAN, was diffi-

cult and caused losses of yield, 2) the corresponding silyl

ether and acetal moieties made compounds 45a, 46a, and

[a] Reagents and conditions: MeLi (4.0 equiv.), Et₂O, 0 °C Ǟroom

temp., 1 h; 85%. [b] KH (6.1 equiv.), tBuOOH (6.1 equiv.), NMP,

0 °CǞroom temp.; 36, NMP, room temp., 30 min; nBu₄N⁺F^–

(2.1 equiv.), 50 °C, 30 min; 71% 38. [c] KH (6.1 equiv.), tBuOOH

(1.1 equiv.), NMP, 0 °CǞroom temp.; 36, NMP, room temp.,

30 min; nBu₄N⁺F^–(2.1 equiv.), 70 °C, 3 h; 44% 39. [d] KH

(8.1 equiv.), tBuOOH (20 equiv.), NMP, 0 °CǞroom temp.; ad-

dition of 38, NMP, room temp., 15 min; KF (4.1 equiv.), 70 °C, 3 h;

65% 41. [e] nBu₄N⁺F^–·3H₂O (2.0 equiv.), THF, 0 °CǞroom temp.;

for 42a (R = tBu): 2 h, 100%, for 42b (R = tHex): 4 h, 100%. [f]

nBu₄N⁺F^–·3H₂O (1.0 equiv.), THF, 0 °CǞroom temp.; for 43a (R

= tBu): 2 h, 100%, for 43b (R = tHex): 4 h, 98%. NMP = N-meth-

ylpyrrolidinone; DMF = dimethylformamide.

Scheme 5. Efforts at synthesizing equivalents of the Cⁿ–Cⁿ⁺⁷build-

ing block 6 from the tert-butyldimethylsilylated alkyne 44a, namely

via epoxide 47a (an alkyne) or the epoxide precursors 48 (a vinyl-

stannane) or 49 (a vinyl iodide). Reagents and conditions:

a) Ce(NH₄)₂(NO₃)₆(3.0 equiv.), CH₃CN/H₂O (9:1), room temp.,

2 h; b) pTsCl (1.5 equiv.), NEt₃(3.0 equiv.), DMAP (20 mol-%),

CH₂Cl₂, room temp., 16 h; c) K₂CO₃(cat.), MeOH; 17% over the

three steps; d) CuCN (2.0 equiv.), nBuLi (4.2 equiv.), THF, –78Ǟ

–20 °C within 1 h; Ǟ–78 °C, Bu₃SnH (4.2 equiv.), THF, –78 °C,

30 min; addition of 44a; Ǟ–20 °C, 16 h; 75%; e) Ce(NH₄)₂(NO₃)₆

(3.0 equiv.), CH₃CN/H₂O (9:1), room temp., decomposition; f) I₂

PMB-protected glycol moiety of diol 41 into an epoxide. At

some point this would require the protection of the OH

group, which emerged from the Tamao oxidation. The over-

all process involved first removing the PMB group and then

protecting the last-mentioned OH group or effecting the

two changes in the reverse order. Because the first approach (1.2 equiv.), Et₂O, 0 °C, 30 min; 100%; g) same as for (e).

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6589

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FULL PAPER

47a acid-sensitive in the flash chromatography column,^[69]of the resulting C_sp₂–Sn bond with NBS delivered the

and 3) compounds 45a and 47a were very volatile. We tried (trans-bromovinylated) epoxide 6 (J_trans= 13.7 Hz) in 90%

to exclude the last-mentioned problem by increasing the yield over the two steps.

molecular weight of silyl ether 44a by advancing to the alk-

enylstannane 48 (75% yield)^[70]and converting the latter

into the alkenyl iodide 49 (100% yield).^[71]However, both

of these derivatives decomposed when we tried to cleave

the PMB group with CAN (even though such cleavages are

known in the presence of alkenyl iodides^[72]).

Conclusions

We have synthesized the Cⁿ–Cⁿ⁺⁷“eastern moiety” 6 (PG

= tHexMe₂Si) common to the unnatural enantiomers 1–

5 of the macrolides amphotericin (ent-1), candidin (ent-2),

nystatin (ent-3), pimaricin (ent-4), and rimocidin (ent-5; cf.

Scheme 1). Starting from the tetrabromoacetone 26 this

synthesis comprised 19 steps in the longest linear sequence

and rendered an overall yield of 1.9%. The Br₂C=CH-sub-

stituted lactone 34 was established by a ring-closing metath-

esis reaction of dibromotriene 33b, which itself was ob-

tained from 26 in six steps. Conjugate addition, aldol for-

mation, lactone reduction, and acetalization resulted in the

intermediate 36, in which all the stereocenters were in-

stalled. Another six steps, one of which was a Tamao oxi-

We solved the suspected volatility problem of our epox-

ide synthesis 44aǞ45aǞ46aǞ47a in the tert-butyldi-

methylsilyl ether series (Scheme 5) by realizing the analo-

gous transformations for the tert-hexyldimethylsilyl ethers,

as outlined in Scheme 6. The silyl ether 44b was PMB-de-

protected with CAN to give diol 45b. Selective tosylation of

the primary OH group (Ǟ46b) and epoxide formation un-

der slightly basic conditions (Ǟ47b) followed; good yields

were obtained for each step (93, 87, and 94%). The epoxide

47b was obtained as a crystalline solid and hence the abso-

lute and relative configuration(s) of its stereocenters could

be proven by Bijvoet-type X-ray analysis.^[58]

dation of a C–SiMe₂Ph group, which introduced the Cⁿ⁺³

–

OH group, led to the CϵC-containing epoxide 47b. Its ab-

solute configuration was elucidated by an X-ray analysis.

Steps 18 and 19, a radical hydrostannylation and bromino-

lysis, respectively, gave the desired “eastern” building block

6 (PG = tHexMe₂Si).

Compared with our previous syntheses of “eastern moie-

ties” for the polyol,polyene targets 1–5^[8a,76]and ent-1-ent-

5,^[8b]the synthesis disclosed in this publication required

more steps but it provided a Cⁿ–Cⁿ⁺⁷rather than a Cⁿ–Cⁿ⁺⁶

building block. The former contains a trans-configured

C=C bond, whereas the latter do not.

Experimental Section

General: Reactions were performed under N₂in glassware dried

with a heat gun under vacuum. THF was freshly distilled from

potassium, Et₂O was freshly distilled from Na/K, toluene was

freshly distilled from Na, and CH₂Cl₂and NMP were freshly dis-

tilled from CaH₂.

Products were purified by flash chromatography^[69]on Merck silica

gel 60 (0.040–0.063 mm). Filling height, column diameter, fraction

size, eluent, and the number of fractions that contained the product

are given in parentheses, yields refer to analytically pure samples.

¹H NMR [CHCl₃(δ = 7.26 ppm) as internal standard in CDCl₃,

CHD₅(δ = 7.16 ppm) as internal standard in C₆D₆]: Bruker DRX

250, Varian Mercury VX 300, Bruker Avance II 400, and Bruker

DRX 500. The coupling constants are given in hertz (Hz). ¹³C

NMR [CDCl₃(δ = 77. 10 ppm) as internal standard in CDCl₃,

C₆D₆(δ = 128.00 ppm) as internal standard in C₆D₆]: Bruker Av-

ance II 400 and Bruker DRX 500. ²⁹Si NMR (no internal standard,

calibration was carried out according to ref.^[77]): Bruker DRX 500.

Assignments of the ¹H and ¹³C NMR resonances are in accord

with IUPAC nomenclature except within substituents (for which

primed numbers are used) or where explicitly indicated otherwise.

Heteronuclear couplings: The ratio between the coupling constants

Scheme 6. Completion of the Cⁿ–Cⁿ⁺⁷building block 6 (PG =

tHexMe₂Si) from the tert-hexyldimethylsiloxylated alkyne 44b and

elucidation of the absolute configuration of all stereocenters by an

X-ray analysis^[a]of crystals of the siloxylated alkyne 47b. Reagents

and conditions: a) Ce(NH)₄(NO₃)₆(3.0 equiv.), CH₃CN/H₂O (9:1),

room temp., 1 h; 93%; b) pTsCl (1.4 equiv.), NEt₃(3.0 equiv.),

DMAP (20 mol-%), CH₂Cl₂, room temp., 16 h; 87%; c) K₂CO₃

(cat.), MeOH, room temp., 22 h; 94%; d) Bu₃SnH (4.0 equiv.), tolu-

ene, 80 °C; addition of AIBN (0.25 equiv.); Ǟ90 °C, 1 h; e) NBS

(1.2 equiv.), CH₂Cl₂, 0 °C, 1 h; 90% over the two steps. [a] For a

projection of the X-ray structure, which reveals the configuration

of the epoxide ring, see the Supporting Information. AIBN = azo-

bisisobutyronitrile; NBS = N-bromosuccinimide.

Finally, the synthetic design of Scheme 2 called for the

conversion of the CϵC-containing epoxide 47b^[73]into the

trans-Br–C=C-containing analogue 6 (PG = tHexMe₂Si) to

yield the “eastern” building block. We managed to obtain

this compound by an AIBN-induced addition of tributyl-

119

117

ⁿJ¹

_Snand ⁿJ¹

_Snacross n interspersed bonds must equal the

H,

quotient of the gyromagnetic ratios of ¹¹⁹Sn (–9.9708ϫ

10⁷radT^–1s^–1[78]) and ¹¹⁷Sn (–9.5301ϫ 10⁷radT^–1s^–1[79]), that is,

stannane to the alkyne 47b^[74,75](Scheme 6). Brominolysis 1.046. The same is true for the ratio between the coupling constants

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Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

119

n

117

ⁿJ¹³

and J¹³

_Sn. In alkenylstannanes, the limits of spec-

1 H, 2Ј-H¹), 2.82 (dd, J_{2Ј-H2,2Ј-H1}= 4.9, J_2Ј-H2,1Ј= 3.9 Hz, 1 H, 2Ј-

H²), 2.94 (ddd, J_1Ј,3= 8.3, J_1Ј,2Ј-H2= 4.0, J_1Ј,2Ј-H1= 2.8 Hz, 1 H,

C,

Sn

C,

tral resolution and the occurrence of line-splitting through H,H

coupling allow ¹H,Sn and ¹³C,Sn coupling constants to be deter-

mined for ¹¹⁹Sn and ¹¹⁷Sn separately only for large J values; small

J values are usually isotope-averaged.^[79]NMR measurements: Dr.

M. Keller, F. Reinbold, M. Schonhard, Institut für Organische

Chemie und Biochemie, University of Freiburg. MS measurements:

Dr. J. Wörth, C. Warth, Institut für Organische Chemie und Bio-

chemie, University of Freiburg. Combustion analyses: F. Tönnies,

A. Siegel, Institut für Organische Chemie und Biochemie, Univer-

sity of Freiburg. IR spectra: Perkin–Elmer Paragon 1000. Optical

rotations were measured with a Perkin–Elmer polarimeter 341 at

589 nm and 20 °C and were calculated by the Drude equation

1Ј-H), 3.32 (s, 3 H, 2-OCH₃), 3.95 (ddd, J_4,3= J_4,5A= J_4,5B

=

4.1 Hz, 1 H, 4-H), 4.59 (dddd, J_6,5B= 10.2, J_6,7= 5.6, J_6,5A= 3.8,

J_6,8= 1.4 Hz, 1 H, 6-H), 4.75 (d, J_2,3= 2.2 Hz, 1 H, 2-H), 6.24

(dd, J_7,8= 13.6, J_7,6= 5.7 Hz, 1 H, 7-H), 6.38 (dd, J_8,7= 13.7, J_8,6

= 1.4 Hz, 1 H, 8-H) ppm. ¹³C NMR (125.6 MHz, CDCl₃): δ =

–2.90 and –2.85 [Si(CH₃)₂], 18.61 [2ϫ C(CH₃)-2ЈЈ], 20.26 [2ϫ

C(CH₃)-1ЈЈ], 24.87 (C-1ЈЈ), 34.38 (C-2ЈЈ), 36.95 (C-5), 46.83 (C-2Ј),

48.14 (C-3), 51.19 (C-1Ј), 55.14 (2-OCH₃), 64.80 (C-6), 65.72 (C-

4), 100.12 (C-2), 107.35 (C-8), 137.92 (C-7) ppm. IR (film): ν =

˜

2955, 1625, 1465, 1415, 1360, 1300, 1250, 1190, 1140, 1105, 1070,

1030, 970, 935, 895, 875, 830, 810, 775, 740, 665 cm^–1.

{[α]_D= (100α_exp)/(cd)}; rotational values are the average of five C₁₈H₃₃BrO₄Si (421.45): calcd. C 51.30, H 7.89; found C 51.49, H

measurements of α_expin a given solution of the respective sample.

Melting points were measured with a Dr. Tottoli apparatus (Büchi).

The ee values were determined by chiral HPLC by G. Fehrenbach

or A. Schuschkowski, Institut für Organische Chemie and Bioche-

mie, University of Freiburg. The concentration of allylMgBr was

determined by titration according to Love and Jones,^[80]the con-

centration of nBuLi was determined by titration according to Suf-

fert,^[81]the concentration of DIBAH was determined by titration

according to Hoye et al.,^[82]and the concentration of tBuOOH was

determined by NMR analysis.^[83]

7.75.

3,3-Dibromoprop-2-enal (28):^[84]

At room temp., a solution of 3,3-dibromoprop-2-en-1-ol (62;^[51]

10.4 g, 48.0 mmol) in acetone (24 mL) was added to a suspension

of IBX (18.8 g, 67.2 mmol, 1.4 equiv.) in acetone (48 mL). The re-

action mixture was stirred at reflux for 4 h and afterwards cooled

to room temp. The suspension was filtered through a pad of Celite

and the solvent was removed in vacuo. Purification of the residue

by distillation (50 mbar) afforded 28 (8.48 g, 83%) as a colorless to

slightly yellowish oil. It was stored at –32 °C under nitrogen to

protect it from decomposition; b.p. 83–85 °C/50 mbar. ¹H NMR

(300.1 MHz, CDCl₃): δ = 7.00 (d, J_2,1= 6.4 Hz, 1 H, 2-H), 9.71

(J_1,2= 6.3 Hz, 1 H, 1-H) ppm. C₃H₂Br₂O (213.86): calcd. C 16.85,

H 0.94; found C 17.18, H 0.93.

(2S,3S,4R,6S)-6-[(E)-2-Bromovinyl]-2-methoxy-3-[(S)-oxiran-2-yl]-

4-[dimethyl-(1,1,2-trimethylpropyl)siloxy]-3,4,5,6-tetrahydro-2H-pyr-

an (6):

1,1-Dibromohexa-1,5-dien-3-ol (29)

A solution of 47b (51 mg, 0.15 mmol) in toluene (12 mL) was

treated with a solution of Bu₃SnH (0.16 mL, 0.18 g, 0.60 mmol,

4.0 equiv.) in toluene (1.0 mL) and heated to 80 °C. At 80 °C,

AIBN (6.2 mg, 38 μmol, 25 mol-%) was added in one portion. Af-

ter stirring for 1 h at 90 °C, the solvent was evaporated under re-

duced pressure, and the residue was purified by flash chromatog-

raphy^[69](2.0ϫ 18 cm, 8.0 mL, cyclohexane + 1 vol-% NEt₃, from

fraction 10, cyclohexane/AcOEt, 50:1 + 1 vol-% NEt₃) to yield the

corresponding vinylstannane (fractions 31–36, 93 mg) as a colorless

oil. At 0 °C, NBS (32 mg, 0.18 mmol, 1.2 equiv.) was added to a

solution of the vinylstannane (93 mg, 0.15 mmol) in CH₂Cl₂

(15 mL) in one portion. After stirring for 1 h at this temperature,

the reaction was quenched by the addition of saturated aqueous

Na₂S₂O₃(5.0 mL). The phases were separated and the aqueous

phase was extracted with CH₂Cl₂(3ϫ 8.0 mL). The combined or-

ganic phases were washed with brine (5.0 mL), dried with Na₂SO₄,

and concentrated in vacuo. The residue was purified by flash

chromatography^[69](2.0ϫ 20 cm, 8.0 mL, cyclohexane/AcOEt,

Variant 1: At –78 °C, allylmagnesium bromide (0.60 m in Et₂O,

83.3 mL, 50.0 mmol, 1.0 equiv.) was added dropwise to a suspen-

sion of (10S)-19 (18.6 g, 50.0 mmol, 1.0 equiv.) in Et₂O (500 mL).

After stirring the solution for 1 h at room temp., the reaction mix-

ture was cooled to –78 °C. A solution of aldehyde 28 (10.7 g,

50.0 mmol) in Et₂O (100 mL) was added over 1 h. After complete

addition, the reaction mixture was stirred at –78 °C for 3 h and

then warmed to room temp. overnight (14 h). The solvent was evap-

orated under reduced pressure and the residue was suspended in

pentane (300 mL) and filtered through a pad of Celite. The filtrate

was concentrated in vacuo. CH₃CN (100 mL) and (1R,2R)-pseudo-

20:1) to afford vinyl bromide 6 (fractions 20–36, 57 mg, 90% over ephedrine (8.26 g, 50 mmol) were added and the mixture was

the two steps) as a colorless oil. [α]²_D⁰= +23.7 (c = 0.97, CHCl₃,

heated at reflux for 2 h. The mixture was allowed to cool to room

10 cm). ¹H NMR (499.5 MHz, CDCl₃): δ = 0.06 [s, 6 H, temp. The crystals, which had formed, were separated, washed with

Si(CH₃)₂], 0.82 and 0.83 (2 s, 6 H, 2ϫ 1ЈЈ-CH₃), 0.878 [d, J_{2ЈЈ-CH3,2ЈЈ}

pentane (3ϫ 50 mL), and dried to yield regenerated (10S)-19

(12.2 g, 66%). The combined filtrates were concentrated under re-

= 6.9 Hz, 3 H, (2ЈЈ-CH₃)¹], overlapped by 0.882 [d, J_{2ЈЈ-CH3,2ЈЈ}

=

6.6 Hz, 3 H, (2ЈЈ-CH₃)²], 1.41 (m_c, 1 H, 3-H), 1.58–1.65 (m, 1 H, duced pressure and the residue was purified by flash chromatog-

2ЈЈ-H), overlapped by AB signal (δ_A= 1.65, δ_B= 1.73, J_AB

=

raphy^[69](10ϫ 20 cm, 100 mL, cyclohexane/AcOEt, 10:1) to afford

allylic alcohol (S)-29 (fractions 19–49, 10.0 g, 78%; 88% ee*) as a

colorless oil. [α]²_D⁰= –16.9 (c = 0.98, CHCl₃, 10 cm).

13.7 Hz, additionally split by J_5A,4= J_5A,6= 3.9, J_5B,6= 10.1, J_5B,4

= 3.6 Hz, 2 H, 5-H₂), 2.55 (dd, J_{2Ј-H1,2Ј-H2}= 4.9, J_2Ј-H1,1Ј= 2.7 Hz,

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6591

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FULL PAPER

Variant 2: At 0 °C, allylmagnesium bromide (0.84 m in Et₂O, H, OH), 2.29–2.42 (m, 2 H, 4-H₂), 4.40 (m_c, 1 H, 3-H), 5.15–5.19

2.62 mL, 2.20 mmol, 1.1 equiv.) was added dropwise to a solution

(m, 2 H, 6-H^E, 6-H^Z), 5.81 (dddd, J_{5,6 -HZ = 17.3, J5,6-HE}= 10.0,

of (R,R)-25 (1.60 g, 2.60 mmol, 1.3 equiv.) in Et₂O (30 mL). After J_5,4-H1= 7.2, J_5,4-H2= 7.1 Hz, 1 H, 5-H), 6.47 (d, J_2,3= 8.1 Hz, 1

2 h at 0 °C, the reaction mixture was cooled to –78 °C, treated with

a solution of aldehyde 28 (428 mg, 2.00 mmol) in Et₂O (5.0 mL),

and stirred for 3 h at –78 °C. The reaction was quenched by ad-

dition of NH₄F (45%, 10 mL). After warming to room temp. over-

night (16 h), the reaction mixture was filtered through a pad of

Celite. The filtrate was extracted with Et₂O (3ϫ 25 mL). The com-

bined organic extracts were washed with brine (20 mL), dried with

MgSO₄, and concentrated in vacuo. The residue was treated with

pentane (25 mL), stirred for 10 min at room temp., and filtered.

TADDOL (764 mg, 63%) was recovered as a colorless solid. The

filtrate was concentrated in vacuo and the residue was purified by

flash chromatography^[69](5.0ϫ 20 cm, 60 mL, cyclohexane/AcOEt,

10:1). Compound (S)-29 (fractions 26–42, 298 mg, 58%, 85% ee*)

was obtained as a colorless oil.

H, 2-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 40.24 (C-4),

71.66 (C-3), 91.22 (C-1), 119.26 (C-6), 132.85 (C-5), 140.17 (C-

2) ppm. IR (film): ν = 3340, 3080, 3010, 2980, 2935, 2845, 1845,

˜

1640, 1620, 1430, 1315, 1235, 1125, 1035, 990, 920, 840, 790, 715,

640 cm^–1. C₆H₈Br₂O (255.94): calcd. C 28.16, H 3.15; found C

28.17, H 2.96.

*The enantiomeric excess was determined by chiral HPLC of O-

benzoyl-29.

(S)-1,1-Dibromohexa-1,5-dien-3-yl (E)-But-2-enoate (33b):

Variant 3: At –78 °C, a solution of aldehyde 28 (2.18 g, 10.2 mmol)

in CH₂Cl₂(20 mL) was added to a solution of (S,S)-30 (3.45 g,

12.2 mmol, 1.2 equiv.) in CH₂Cl₂(30 mL) over 1 h. After complete

addition the reaction mixture was stirred at –78 °C for 1 h. The

reaction was quenched by slow addition of H₂O (15 mL). The reac-

tion mixture was warmed to room temp. and poured into tBuOMe

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

extracted with tBuOMe (3ϫ 50 mL). The combined organic phases

were washed with aqueous KOH (1%, 40 mL) and brine (40 mL),

and then dried with Na₂SO₄. After evaporation of the solvent un-

der reduced pressure the residue was purified by flash chromatog-

raphy^[69](5.0ϫ 16 cm, 60 mL, cyclohexane/AcOEt, 10:1) to yield

(S)-29 (fractions 13–30, 2.48 g, 95%, 49% ee*) as a colorless oil.

At 0 °C, DCC (6.81 g, 33.0 mmol, 1.10 equiv.), crotonic acid

(2.71 g, 31.5 mmol, 1.05 equiv.), and finally DMAP (733 mg,

6.00 mmol, 20.0 mol-%) were added to a solution of alcohol (S)-29

(6.78 g, 30.0 mmol) in CH₂Cl₂(150 mL). After stirring the reaction

mixture for 24 h at room temp., the solvent was removed under

reduced pressure. The residue was purified by flash chromatog-

raphy^[69](10ϫ 15 cm, 100 mL, cyclohexane/AcOEt, 100:1, from

fraction 18, cyclohexane/AcOEt, 50:1) to yield crotonate 33b (frac-

tions 21–35, 8.54 g, 88%) as a colorless oil. [α]²_D⁰= +23.1 (c = 0.86,

CHCl₃, 10 cm). ¹H NMR (400.1 MHz, CDCl₃): δ = 1.88 (dd, J_4Ј,3Ј

= 6.9, J_4Ј,2Ј= 1.8 Hz, 3 H, 4Ј-CH₃), 2.42–2.47 (m, 2 H, 4-H₂), 5.10–

Variant 4: At –10 °C,

a solution of aldehyde 28 (214 mg,

5.16 (m, 2 H, 6-H^E, 6-H^Z), 5.49 (ddd, J_3,2= 8.3, J_3,4-H1= J_3,4-H2

=

1.00 mmol) in toluene (1.0 mL) was added dropwise to a solution

of (R,R)-31 (402 mg, 1.50 mmol, 1.5 equiv.) in toluene (4.0 mL).

The reaction mixture was stirred at –10 °C for 2 h, treated with

aqueous HCl (1 m, 4.0 mL) and AcOEt (4.0 mL), and then stirred

at room temp. for 15 min. The phases were separated and the aque-

ous phase was extracted with AcOEt (3ϫ 5.0 mL). The combined

organic extracts were washed with brine (5.0 mL), dried with

MgSO₄, and concentrated in vacuo. The residue was purified by

flash chromatography^[69](3.0ϫ 18 cm, 20 mL, cyclohexane/AcOEt,

10:1) to furnish (S)-29 (fractions 23–37, 180 mg, 70%, 67% ee*) as

a colorless oil.

Z

E

6.3 Hz, 1 H, 3-H), 5.75 (dddd, J_5,6-H= 17.1, J_5,6-H= 10.2,

J_5,4-H1= J_5,4-H2= 7.0 Hz, 1 H, 5-H), 5.82 (dq, J_2Ј,3Ј= 15.5, J_2Ј,4Ј

=

1.7 Hz, 1 H, 2Ј-H), 6.44 (d, J_2,3= 8.3 Hz, 1 H, 2-H), 6.90 (dq, J_3Ј,2Ј

= 15.5, J_3Ј,4Ј= 6.9 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR (100.6 MHz,

CDCl₃): δ = 18.10 (C-4Ј), 37.80 (C-4), 73.09 (C-3), 93.09 (C-1),

118.95 (C-6), 122.26 (C-2Ј), 131.97 (C-5), 136.52 (C-2), 145.62 (C-

3Ј), 165.30 (C-1) ppm. IR (film): ν = 3080, 2980, 2940, 2915, 1725,

˜

1655, 1440, 1375, 1335, 1295, 1255, 1175, 1100, 1000, 970, 920,

835, 795, 740, 685 cm^–1. C₁₀H₁₂Br₂O₂(324.01): calcd. C 37.07, H

3.73; found C 36.93, H 3.52.

(S)-6-(2,2-Dibromovinyl)-5,6-dihydro-2H-pyran-2-one (34)

Variant 5: A solution of TiF₄(13 mg, 0.10 mmol, 10 mol-%) in

CH₃CN (0.5 mL) was added to a solution of (R)-BINOL [(R)-32;

57 mg, 0.20 mmol, 20 mol-%) in CH₃CN (0.5 mL). The deeply red

solution was stirred for 10 min. Afterwards, the solvent was re-

moved in vacuo. The residue was suspended in CH₂Cl₂(0.5 mL),

cooled to 0 °C, and treated with allyltrimethylsilane (0.24 mL,

0.17 g, 1.5 mmol, 1.5 equiv.) dropwise. After 1.5 h at 0 °C, a solu-

tion of aldehyde 28 (0.21 g, 1.0 mmol) in CH₂Cl₂(1.0 mL) was

added, and the reaction mixture was stirred for 4 h at constant

temperature. The reaction mixture was diluted with Et₂O/pentane

(2:1, 10 mL) and the resulting suspension was filtered through a

pad of Celite. The filtrate was concentrated in vacuo and the resi-

due was dissolved in THF (5.0 mL), treated with nBu₄⁺NF^–(1.0 m

in THF, 1.0 mL), and stirred at room temp. overnight (18 h). Et₂O

(50 mL) and H₂O (20 mL) were added and the phases were sepa-

rated. The organic phase was washed with brine (20 mL), dried

with Na₂SO₄, and concentrated under reduced pressure. The resi-

From 33a: At room temp., Grubbs II catalyst (5.1 mg, 6.0 μmol,

5 mol-%) was added to a solution of 33a (37 mg, 0.12 mmol) in

toluene (12 mL), and the reaction mixture was stirred at 80 °C for

2 h. After cooling to room temp., the solvent was removed under

reduced pressure and the residue was purified by flash chromatog-

raphy^[69](2.0ϫ 25 cm, 10 mL, cyclohexane/AcOEt, 3:1). Com-

pound 34 (fractions 27–34, 20 mg, 60%) was obtained as a slightly

brown solid.

From 33b: A solution of crotonate 33b (2.59 g, 8.00 mmol) in tolu-

due was purified by flash chromatography^[69](3.0ϫ 16 cm, 20 mL, ene (1600 mL) was evacuated repeatedly and ventilated with nitro-

cyclohexane/AcOEt, 10:1) to afford (R)-29 (fractions 13–35, 49 mg,

19%, 48% ee*). H NMR (400.1 MHz, CDCl₃): δ = 2.08 (br. s, 1

gen. Grubbs II catalyst (408 mg, 480 μmol, 6.0 mol-%) was added

in one portion under vigorous stirring. The reaction mixture was

1

6592

www.eurjoc.org

Eur. J. Org. Chem. 2013, 6584–6600

Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

immediately heated to 80 °C and stirred for 2 h while passing a low

990, 960, 900, 835, 815, 775, 735, 700, 665, 625 cm^{– 1}

.

stream of nitrogen through the apparatus. Afterwards, the solvent C₁₅H₁₈Br₂O₂Si (418.20): calcd. C 43.08, H 4.34; found C 43.62, H

was evaporated under reduced pressure and the residue was puri-

4.16 (in spite of several attempts no better analysis was obtained).

fied by flash chromatography^[69](5.0ϫ 20 cm, 60 mL, cyclohexane/

HRMS (CI, NH₃): calcd. for C₁₅H₁₉O₆Si⁷⁹Br₂[M + H]⁺416.95211;

AcOEt, 3:1) to afford α,β-unsaturated lactone 34 (fractions 20–30, found 416.95200 (Δ = –0.3 ppm).

2.25 g, 100%, 88% ee*) as a slightly brown solid. Two consecutive

(S)-1-[(2S,3R,4R,6S)-6-(2,2-Dibromovinyl)-4-(dimethylphenylsilyl)-

2-methoxy-3,4,5,6-tetrahydro-2H-pyran-3-yl]-2-(4-methoxybenzyl-

oxy)ethan-1-ol (36):

crystallizations from Et₂0 (3.0 mL) gave enantiomerically pure 34

(1.56 g, 69%, Ͼ99% ee*) as a colorless crystalline solid, m.p. 47 °C.

[α]²_D⁰= –30.0 (c = 1.1, CHCl₃, 10 cm). ¹H NMR (400.1 MHz,

CDCl₃): δ = 2.38–2.45 (m, 1 H, 5-H¹), 2.52–2.58 (m, 1 H, 5-H²),

5.07–5.13 (m, 1 H, 6-H), 6.03–6.08 (m, 1 H, 3-H), 6.64–6.66 (m, 1

H, 7-H), 6.89 (dddd, J_4,3= 9.9, J_4,5-H1= 5.6, J_4,5-H2= J_4,6= 2.8 Hz,

1 H, 4-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 27.84 (C-5),

77.45 (C-6), 94.68 (C-8), 121.64 (C-3), 135.02 (C-7), 144.32 (C-4),

162.75 (C-2) ppm. IR (film): ν = 3440, 3035, 2940, 2250, 1720,

˜

1635, 1605, 1420, 1380, 1345, 1300, 1240, 1185, 1150, 1135, 1100,

1060, 1025, 1000, 975, 960, 915, 875, 825, 745, 715, 665 cm^–1.

C₇H₆Br₂O₂(281.93): calcd. C 29.82, H 2.15; found C 29.99, H 2.04.

*The enantiomeric excess was determined by chiral HPLC: Chi-

ralcel OD-H column, heptane/2-propanol (90:10), 0.8 mL/min,

20 °C isothermal, λ_detector= 220 nm; t_r(S)-34= 17.0 min, t_r(R)-34

=

21.2 min.

(4R,6S)-6-(2,2-Dibromovinyl)-4-(dimethylphenylsilyl)-3,4,5,6-tetra-

hydro-2H-pyran-2-one (35):

At –78 °C, DIBAH (1.0 m in hexane, 1.8 mL, 2.5 equiv.) was added

to a solution of lactone 37 (0.42 g, 0.70 mmol) in toluene (25 mL)

over 30 min. The reaction mixture was warmed to room temp. over-

night (14 h) and quenched by the addition of saturated aqueous

Na/K tartrate (6.0 mL). Afterwards, the reaction mixture was di-

luted with H₂O (15 mL) and extracted with AcOEt (6ϫ 75 mL).

The combined extracts were dried with MgSO₄, filtered through a

pad of Celite, and concentrated in vacuo. The residue was purified

by flash chromatography^[69](3.0ϫ 15 cm, cyclohexane/AcOEt, 3:1).

The resulting lactol (fractions 11–23, 0.39 g) was dissolved in

MeOH (15 mL) at room temp. and treated with camphorsulfonic

acid (1.6 mg, 7.0 μmol, 1 mol-%). The solution was stirred at room

temp. for 10 h. The solvent was removed under reduced pressure at

room temp. The residue was purified by flash chromatography^[69]

(3.0ϫ 18 cm, 20 mL, cyclohexane/AcOEt, 5:1) to afford acetal 36

(fractions 24–40, 0.35 g, 81%) as a colorless oil. [α]²_D⁰= +22.1 (c =

0.93, CHCl₃, 10 cm). ¹H NMR (400.1 MHz, CDCl₃): δ = 0.37 and

0.43 [2 s, 6 H, Si(CH₃)₂], 1.14 (m_c, 1 H, 4-H), 1.61–1.67 (m, 2 H,

5-H₂), 1.75 (ddd, J_3,1Ј= 8.7, J_3,4= 2.2, J_3,2= 2.1 Hz, 1 H, 3-H),

2.37 (d, J_1Ј-OH,1Ј= 4.9 Hz, 1 H, 1Ј-OH), 3.36 (s, 3 H, 2-OCH₃),

overlapped by AB signal (δ_A= 3.35, δ_B= 3.52, J_AB= 9.7 Hz, ad-

ditionally split by J_2ЈA,1Ј= 6.6, J_2ЈB,1Ј= 3.0 Hz, 2 H, 2Ј-H₂), 3.82

(s, 3 H, Ar-OCH₃), 3.94–3.99 (m, 1 H, 1Ј-H), 4.37–4.42 (m, 1 H,

6-H), overlapped by AB signal (δ_A= 4.43, δ_B= 4.47, J_AB= 11.4 Hz,

At –25 °C, PhMe₂SiCl (3.31 mL, 3.41 g, 20.0 mmol, 4.0 equiv.) was

added dropwise to a suspension of small pieces of Li (1.04 g,

150 mmol, 30 equiv.) in THF (40 mL). After stirring for 40 h, the

deep-red solution was transferred to a suspension of CuCN

(896 mg, 10.0 mmol, 2.0 equiv.) in THF (40 mL) at –30 °C. After

complete addition the reaction mixture was cooled to –78 °C. Si-

Me₃Cl (1.39 mL, 1.20 g, 11.0 mmol, 2.2 equiv.) and a solution of

34 (1.41 g, 5.00 mmol) in THF (10 mL) were then added dropwise.

The reaction mixture was stirred at –78 °C for 3 h and then

quenched by the addition of saturated aqueous NH₄Cl (75 mL)

and warmed to room temp. overnight (14 h) under vigorous stir-

ring. The phases were separated and the aqueous phase extracted

with CH₂Cl₂(5 ϫ 75 mL). The combined organic extracts were

washed with aqueous NH₄Cl/NH₃(95:5, 2 ϫ 75 mL) and brine

(75 mL), and dried with MgSO₄. The solvent was removed under

reduced pressure and the residue was purified by flash chromatog-

raphy^[69](5.0ϫ 22 cm, 50 mL, cyclohexane/AcOEt, 10:1) to yield

35 (fractions 22–38, 1.63 g, 78%) as a colorless to yellowish oil.

[α]²_D⁰= +46.7 (c = 4.0, CHCl₃, 10 cm). ¹H NMR (400.1 MHz,

CDCl₃): δ = 0.369 and 0.372 [2 s, 6 H, Si(CH₃)₂], 1.47 (m_c, 1 H, 4-

H), 1.80–1.93 (m, 2 H, 5-H₂), AB signal (δ_A= 2.30, δ_B= 2.48, J_AB

2 H, benzyl-H₂), 4.93 (d, J_2,3= 1.6 Hz, 1 H, 2-H), 6.43 (d, J_7,6

=

7.8 Hz, 1 H, 7-H), AAЈBBЈ signal centered at δ = 6.88 and 7.23 (4

H, 2ЈЈЈ-H, 3ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H), 7.31–7.33 (m, 3 H, 3ЈЈ-H, 4ЈЈ-H,

5ЈЈ-H), 7.47–7.48 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = –2.96 and –2.89 [Si(CH₃)₂], 19.12 (C-4),

25.96 (C-5), 40.24 (C-3), 54.49 (2-OCH₃), 55.36 (OCH₃-Ar), 67.92

(C-6), 69.82 (C-1Ј), 72.32 (C-2Ј), 73.21 (C-benzyl), 91.24 (C-8),

98.75 (C-2), 113.95 (C-3ЈЈЈ, C-5ЈЈЈ), 127.81 (C-3ЈЈ, C-5ЈЈ), 128.93

(C-4ЈЈ), 129.51 (C-2ЈЈЈ, C-6ЈЈЈ), 129.92 (C-1ЈЈЈ), 133.94 (C-2ЈЈ, C-

= 16.3 Hz, additionally split by J_3A,4= 13.2, J_3B,4= 5.5, J_3B,5-H1

=

0.4 Hz, 2 H, 3-H₂), 4.81 (ddd, J_6,5-H1= J_6,7= 8.1, J_6,5-H2= 4.8 Hz,

1 H, 6-H), 6.55 (d, J_7,6= 7.8 Hz, 1 H, 7-H), 7.37–7.42 (m, 3 H, 3Ј-

H, 4Ј-H, 5Ј-H), 7.43–7.50 (m, 2 H, 2Ј-H, 6Ј-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = –5.36 and –5.34 [Si(CH₃)₂], 15.37 (C-4),

27.23 (C-5), 30.13 (C-3), 78.23 (C-6), 93.21 (C-8), 128.31 (C-3Ј, C-

6ЈЈ), 139.34 (C-7), 139.44 (C-1ЈЈ), 159.45 (C-4ЈЈЈ) ppm. IR (film): ν

˜

= 3455, 1935, 2360, 1610, 1515, 1425, 1300, 1250, 1220, 1175, 1110,

1035, 940, 905, 810, 775, 705 cm^–1. C₂₆H₃₄Br₂O₅Si (614.45): calcd.

C 50.82, H 5.58; found C 51.09, H 5.37.

5Ј), 129.93 (C-4Ј), 133.95 (C-2Ј, C-6Ј), 135.21 (C-1Ј), 135.79 (C-7), (4R,6S)-6-(2,2-Dibromovinyl)-4-(dimethylphenylsilyl)-3-[(S)-1-hy-

171.68 (C-2) ppm. IR (film): ν = 3475, 3070, 3045, 2955, 2360,

droxy-2-(4-methoxybenzyloxy)ethyl]-3,4,5,6-tetrahydro-2H-pyran-2-

˜

1750, 1625, 1490, 1425, 1360, 1285, 1250, 1220, 1115, 1050, 1010,

one (37):

Eur. J. Org. Chem. 2013, 6584–6600

www.eurjoc.org

6593

S. B. Kamptmann, R. Brückner

FULL PAPER

Variant 1: At 0 °C, tBuOOH (3.15 m in toluene, 223 μL, 702 μmol,

6.1 equiv.) was added dropwise to a suspension of KH (28.1 mg,

702 μmol, 6.1 equiv.) in NMP (1.0 mL). The reaction mixture was

then warmed to room temp. A solution of 36 (70.7 mg, 115 μmol)

in NMP (1.0 mL) was added. After stirring for 30 min at room

temp., the reaction mixture was treated with nBu₄N⁺F^–(63.3 mg,

242 μmol, 2.1 equiv.) and heated at 50 °C for 30 min. The reaction

was quenched by addition of Na₂S₂O₃·5H₂O (240 mg) and H₂O

(5.0 mL), and diluted with tBuOMe (5.0 mL). The phases were sep-

arated and the aqueous phase extracted with tBuOMe (5ϫ 10 mL).

The combined organic phases were washed consecutively with H₂O

(2ϫ 5.0 mL), aqueous NaOH (2 m, 5.0 mL), and brine (5.0 mL),

dried with MgSO₄, and concentrated in vacuo. The residue was

purified by flash chromatography^[69](2.0ϫ 18 cm, 8.0 mL, cyclo-

hexane/AcOEt, 3:1) to afford alkyne 38 (fractions 16–26, 36.9 mg,

71%) as a colorless oil.

A solution of iPr₂NEt (1.36 mL, 1.03 g, 8.00 mmol, 1.6 equiv.) in

CH₂Cl₂(40 mL) was cooled to –5 °C. Freshly distilled nBu₂BOTf

(1.82 mL, 2.06 g, 7.50 mmol, 1.5 equiv.) was added dropwise while

cooling the reaction mixture slowly to –78 °C. At –78 °C, a solution

of 35 (2.09 g, 5.00 mmol) in CH₂Cl₂(25 mL) was added over

30 min. The reaction mixture was stirred at –78 °C for 2 h, treated

with a solution of PMBOCH₂CHO (64;^[57]1.80 g, 10.0 mmol,

2.0 equiv.), and stirred for a further 3 h at this temperature. After-

wards, the reaction was quenched by the addition of pH 7 buffer

(25 mL). After warming to room temp., the phases were separated

and the aqueous phase was extracted with AcOEt (5ϫ 100 mL).

The combined organic phases were washed with brine (100 mL),

dried with Na₂SO₄, and concentrated in vacuo. The residue was

solved in MeOH (50 mL), cooled to 0 °C, and treated with H₂O₂

(30%, 14 mL). The reaction mixture was warmed to room temp.

overnight (14 h) and diluted with H₂O (50 mL) and AcOEt

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

extracted with AcOEt (5ϫ 120 mL). The combined organic phases

were washed consecutively with saturated aqueous Na₂S₂O₃(5ϫ

100 mL), saturated aqueous NaHCO₃(100 mL), and brine

(100 mL), and then dried with MgSO₄. The solvent was removed

under reduced pressure and the residue was purified by flash

chromatography^[69](9.0ϫ 20 cm, 100 mL, CH/AcOEt, 3:1). The

impure product (fractions 15–27) was purified by flash chromatog-

raphy^[69](9.0ϫ 20 cm, 100 mL, CH/AcOEt, 3:1) to afford 37 (frac-

Variant 2: At 0 °C, MeLi (1.60 m in Et₂O, 4.50 mL, 7.20 mmol,

4.00 equiv.) was added to a solution of dibromo olefin 36 (1.11 g,

1.80 mmol) in Et₂O (90 mL). The reaction mixture was warmed to

room temp. over 1 h and then quenched by the addition of satu-

rated aqueous NH₄Cl (40 mL). The phases were separated and the

aqueous phase extracted with tBuOMe (4ϫ 100 mL). The com-

bined organic phases were washed with brine (40 mL) and dried

with Na₂SO₄. After evaporation of the solvent the residue was puri-

fied by flash chromatography^[69](5.0ϫ 22 cm, 60 mL, cyclohexane/

AcOEt, 3:1) to yield alkyne 38 (fractions 16–29, 699 mg, 85%) as

tions 16–24, 2.13 g, 71%) as a colorless solid, m.p. 81 °C. [α]²_D⁰

=

1

+6.93 (c = 0.88, CHCl₃, 10 cm). H NMR (400.1 MHz, CDCl₃): δ

= 0.40 and 0.42 [2 s, 6 H, Si(CH₃)₂], 1.72–78 (m, 1 H, 4-H), 1.86–

1.98 (m, 2 H, 5-H₂), 2.75 (dd, J_3,1Ј= 9.2, J_3,4= 1.8 Hz, 1 H, 3-H),

2.82 (d, J_OH,1Ј= 6.8 Hz, 1 H, OH), AB signal (δ_A= 3.51, δ_B= 3.68,

J_AB= 9.3 Hz, additionally split by J_2ЈA,1Ј= 5.8, J_2ЈB,1Ј= 7.1 Hz, 2

H, 2Ј-H₂), 3.73–3.78 (m, 1 H, 1Ј-H), 3.81 (s, 3 H, Ar-OCH₃), AB

signal (δ_A= 4.37, δ_B= 4.43, J_AB= 11.4 Hz, 2 H, benzyl-H₂), 4.81

a colorless oil. [α]²_D⁰= +21.5 (c = 0.69, CHCl₃, 10 cm). H NMR

1

(400.1 MHz, CDCl₃, sample contained 7% tBuOMe with s at δ =

1.19 ppm and s at δ = 3.21 ppm): δ = 0.34 und 0.37 [2 s, 6 H,

Si(CH₃)₂], 1.44 (ddd, J_4,3= J_4,5A= J_4,5B= 6.1 Hz, 1 H, 4-H), 1.63

(ddd, J_3,4= J_3,1Ј= 6.0, J_3,2= 3.9 Hz, 1 H, 3-H), AB signal (δ_A

=

1.78, δ_B= 1.86, J_AB= 13.8 Hz, additionally split by J_5A,4= 6.6,

J_5A,6= 4.4, J_5B,6= 8.0, J_5B,4= 5.9 Hz, 2 H, 5-H₂), 2.25 (d, J_1Ј-OH,2

= 4.2 Hz, 1 H, 1Ј-OH), 2.43 (d, J_8,6= 2.1 Hz, 1 H, 8-H), 3.35 (s, 3

H, 2-OCH₃), 3.42–3.44 (m, 2 H, 2Ј-H₂), 3.81 (s, 3 H, Ar-OCH₃),

3.98 (ddd, J_1Ј,2ЈA= 10.4*, J_1Ј,3= 6.1, J_1Ј,2ЈB= 4.4 Hz*, 1 H, 1Ј-H),

AB signal (δ_A= 4.39, δ_B= 4.42, J_AB= 11.5 Hz, 2 H, benzyl-H₂),

4.49 (ddd, J_6,5B= 8.0, J_6,5A= 4.3, J_6,8= 2.2 Hz, 1 H, 6-H), 4.94

(d, J_2,3= 3.9 Hz, 1 H, 2-H), AAЈBBЈ signal centered at 6.88 and

7.21 (4 H, 2ЈЈЈ-H, 3ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H), 7.31–7.34 (m, 3 H, 3ЈЈ-

H, 4ЈЈ-H, 5ЈЈ-H), 7.47–7.49 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = –3.09 and –3.01 [Si(CH₃)₂], 19.11 (C-4),

29.83 (C-5), 41.61 (C-3), 54.95 (2-OCH₃), 55.34 (OCH₃-Ar), 59.81

(C-6), 70.34 (C-1Ј), 72.92 (C-2Ј)**, 72.94 (C-8)**, 73.27 (C-benzyl),

83.01 (C-7), 99.05 (C-2), 113.90 (C-3ЈЈЈ, C-5ЈЈЈ), 127.84 (C-3ЈЈ, C-

5ЈЈ), 129.05 (C-4ЈЈ), 129.42 (C-2ЈЈЈ, C-6ЈЈЈ), 130.13 (C-1ЈЈЈ), 133.86

(dd, J_6,7= J_6,5A= 7.8, J_6,5B= 4.4 Hz, 1 H, 6-H), 6.71 (d, J_7,6

=

7.8 Hz, 1 H, 1ЈЈ-H), AAЈBBЈ signal centered at δ = 6.89 and 7.21

(4 H, 2ЈЈЈ-H, 3ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H), 7.32–7.41 (m, 3 H, 3ЈЈ-H, 4ЈЈ-

H, 5ЈЈ-H), 7.48–7.50 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = –4.00 and –3.72 [Si(CH₃)₂], 19.66 (C-4),

28.18 (C-5), 42.21 (C-3), 55.37 (OCH₃-Ar), 72.28 (C-2Ј), 72.30 (C-

1Ј), 73.00 (C-benzyl), 78.77 (C-6), 92.90 (C-8), 113.91 (C-3ЈЈЈ, C-

5ЈЈЈ), 128.34 (C-3ЈЈ, C-5ЈЈ), 129.43 (C-2ЈЈЈ, C-6ЈЈЈ), 129.88 (C-4ЈЈ),

130.12 (C-1ЈЈЈ), 134.05 (C-2ЈЈ, C-6ЈЈ), 135.82 (C-1ЈЈ), 136.14 (C-7),

159.38 (C-4ЈЈЈ), 172.00 (C-2) ppm. IR (film): ν = 3450, 3035, 2955,

˜

2360, 2340, 1725, 1615, 1515, 1425, 1360, 1300, 1250, 1095, 1035,

915, 815, 775, 740, 705 cm^–1. C₂₅H₃₀Br₂O₅Si (598.40): calcd. C

50.18, H 5.05; found C 50.17, H 4.94. For the crystallographic data

of this compound, see ref.^[85]

(C-2ЈЈ, C-6ЈЈ), 138.79 (C-1ЈЈ), 159.37 (C-4ЈЈЈ) ppm. IR (film): ν =

˜

(S)-1-[(2S,3R,4R,6S)-4-(Dimethylphenylsilyl)-6-ethynyl-2-methoxy-

3470, 3285, 3070, 2930, 2360, 1615, 1585, 1515, 1465, 1425, 1360,

3,4,5,6-tetrahydro-2H-pyran-3-yl]-2-(4-methoxybenzyloxy)ethan-1- 1300, 1250, 1220, 1175, 1110, 1070, 1035, 990, 935, 900, 815, 770,

ol (38)

740, 705, 645 cm^–1. C₂₆H₃₄O₅Si (454.64): calcd. C 68.69, H 7.54;

6594

www.eurjoc.org

Eur. J. Org. Chem. 2013, 6584–6600

Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

found C 68.60, H 7.83. *Assignment of coupling constants inter-

changeable. **Assignment interchangeable.

chromatography^[69](1.0ϫ 20 cm, 6.0 mL, cyclohexane/AcOEt, 1:1)

to yield 41 (fractions 9–16, 11 mg, 100%) as a colorless oil.

From 43b: At 0 °C, a solution of silyl ether 43b (62.2 mg,

0.130 mmol) in THF (10 mL) was treated with nBu₄N⁺F^–·3H₂O

(41.0 mg, 0.130 mmol, 1.0 equiv.) in one portion. The reaction mix-

ture was warmed to room temp. over 4 h. Afterwards, brine

(15 mL) was added. The phases were separated and the aqueous

phase was extracted with tBuOMe (3ϫ 20 mL). The combined or-

ganic phases were washed with brine (15 mL) and dried with

Na₂SO₄. After evaporation of the solvent the residue was purified

by flash chromatography^[69](2.5ϫ 15 cm, cyclohexane/AcOEt, 1:1)

to afford diol 41 (fractions 11–24, 42.9 mg, 98%) as a colorless oil.

[α]²_D⁰= +29.6 (c = 1.0, CHCl₃, 10 cm). ¹H NMR (499.5 MHz,

(2S,3R,4R,6S)-6-Ethynyl-3-[(S)-1-hydroxy-2-(4-methoxybenzyloxy)-

ethyl]-2-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-ol (41)

CDCl₃): δ = 1.83–1.90 (m, 2 H, 3-H, 5-H¹), 1.96 (ddd, J_5-H1,5-H2

=

13.7, J_5-H2,6= 8.4, J_5-H2,4= 3.6 Hz, 1 H, 5-H²), 2.47 (d, J_8,6

2.3 Hz, 8-H), 2.74 (d, J_1Ј-OH,1Ј= 4.2 Hz, 1Ј-OH), 3.45 (s, 2-OCH₃),

AB signal (δ_A= 3.49, δ_B= 3.55, J_AB= 9.7 Hz, additionally split

by J_2ЈA,1Ј= 7.0, J_2ЈB,1Ј= 3.6 Hz, 2 H, 2Ј-H₂), 3.79–3.83 (m, 1 H, 4-

OH), overlapped by 3.81 (s, 3 H, Ar-OCH₃), 3.93–4.03 (m, 2 H, 4-

H, 1Ј-H), AB signal (δ_A= 4.49, δ_B= 4.51, J_AB= 11.4 Hz, 2 H,

benzyl-H₂), 4.79 (ddd, J_6,5-H2= 8.3, J_6,5-H1= 3.9, J_6,8= 2.3 Hz, 1

H, 6-H), 4.99 (d, J_2,3= 3.7, 1 H, 2-H), AAЈBBЈ signal centered at

δ = 6.89 and 7.25 (4 H, 2ЈЈ-H, 3ЈЈ-H, 5ЈЈ-H, 6ЈЈ-H) ppm. ¹³C NMR

(125.6 MHz, CDCl₃): δ = 36.72 (C-5), 47.84 (C-3), 55.37 (2-OCH₃),

56.24 (OCH₃-Ar), 57.14 (C-1), 65.00 (C-4), 68.70 (C-6), 71.88 (C-

benzyl), 73.28 (C-2Ј), 73.94 (C-8), 82.04 (C-7), 100.01 (C-2), 114.02

(C-3ЈЈ, C-5ЈЈ), 129.56 (C-2ЈЈ, C-6ЈЈ), 129.67 (C-1ЈЈ), 159.53 (C-

From 38: At 0 °C, tBuOOH (3.15 m in toluene, 4.32 mL,

13.6 mmol, 20.0 equiv.) was added dropwise to a suspension of KH

(221 mg, 5.51 mmol, 8.10 equiv.) in NMP (7.0 mL) over 30 min.

After warming to room temp., a solution of 38 (309 mg,

0.680 mmol) in NMP (2.5 mL) was added. The reaction mixture

was stirred at room temp. for 30 min, treated with KF (162 mg,

2.79 mmol, 4.10 equiv.), and heated at 70 °C for 3 h. The reaction

was quenched at room temp. by addition of Na₂S₂O₃·5H₂O (1.40 g,

pulverized) and H₂O (20 mL), and was diluted with tBuOMe

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

extracted with tBuOMe (8ϫ 20 mL). The combined organic phases

were washed consecutively with H₂O (2ϫ 10 mL), aqueous NaOH

(2 m, 10 mL), and brine (10 mL). After evaporation of the solvent

the residue was purified by flash chromatography^[69](3.0ϫ 20 cm,

20 mL, cyclohexane/AcOEt, 1:1) to yield diol 41 (fractions 24–40,

149 mg, 65%) as a colorless oil.

4ЈЈ) ppm. IR (film): ν = 3430, 3285, 2935, 1615, 1585, 1515, 1455,

˜

1370, 1305, 1250, 1175, 1030, 975, 820, 745 cm^–1. C₁₈H₂₄O₆

(336.38): calcd. C 64.27, H 7.19; found C 63.70, H 7.32; (in spite of

several attempts no better analysis was obtained). HRMS (APCI,

MeOH/NH₄Cl): calcd. for C₂₈H₅₀NO₆Si [M + NH₄]⁺354.19166;

found 354.19220 (Δ = +1.5 ppm).

From 42a: At 0 °C, nBu₄N⁺F^–·3H₂O (48 mg, 0.15 mmol, 2.0 equiv.)

was added to a solution of 42a (43 mg, 76 μmol) in THF (5.0 mL)

in one portion. The reaction mixture was warmed to room temp.

over 2 h. Afterwards, brine (6.0 mL) and tBuOMe (15 mL) were

added under vigorous stirring. The phases were separated and the

aqueous phase was extracted with tBuOMe (3ϫ 15 mL). The com-

bined organic phases were washed with brine (15 mL), dried with

Na₂SO₄, and concentrated in vacuo. The residue was purified by

flash chromatography^[69](1.5ϫ 15 cm, 8.0 mL, cyclohexane/Ac-

OEt, 1:1) to afford 43 (fractions 13–20, 26 mg, 100%) as a colorless

oil.

(S)-1-{(2S,3S,4R,6S)-4-[Dimethyl(1,1,2-trimethylpropyl)siloxy]-6-

ethynyl-2-methoxy-3,4,5,6-tetrahydro-2H-pyran-3-yl}-2-(4-methoxy-

benzyloxy)ethan-1-ol (44b):^[a]

From 42b: At 0 °C, nBu₄N⁺F^–·3H₂O (18.9 mg, 60.0 μmol,

2.0 equiv.) was added to a solution of 42b (18.6 mg, 30.0 μmol) in

THF (5.0 mL). After stirring at room temp. for 4 h, the reaction

mixture was treated with brine (5.0 mL) and tBuOMe (5.0 mL),

and the phases were separated. The aqueous phase was extracted

with tBuOMe (3ϫ 15 mL) and the combined organic phases were

washed with brine (15 mL), dried with Na₂SO₄, and concentrated

in vacuo. The residue was purified by flash chromatography^[69]

(1.0ϫ 25 cm, 8.0 mL, cyclohexane/AcOEt, 1:1) to afford 41 (frac-

tions 12–22, 10.1 mg, 100%) as a colorless oil.

Compound 41 (135 mg, 0.400 mmol) was dissolved in DMF

(1.3 mL) and treated with a solution of tHexMe₂SiCl (103 μL,

93.0 mg, 0.520 mmol, 1.3 equiv.) in DMF (0.6 mL) and imidazole

(54.5 mg, 0.800 mmol, 2.0 equiv.). The reaction mixture was heated

at 50 °C for 14 h, cooled to room temp., and diluted with H₂O

(8.0 mL). After extraction with tBuOMe (5ϫ 15 mL), the com-

bined organic phases were washed with brine (10 mL), dried with

Na₂SO₄, and concentrated in vacuo. Purification of the residue by

flash chromatography^[69](3.0ϫ 20 cm, 20 mL, cyclohexane/AcOEt,

8:1, from fraction 10, cyclohexane/AcOEt, 6:1, from fraction 24,

cyclohexane/AcOEt, 3:1, from fraction 36, cyclohexane/AcOEt,

1:1) gave 44b (fractions 23–35, 106 mg, 55%) as the main product

as a colorless oil. In addition, 42b (fractions 4–14, 52.1 mg, 21%),

43b (fractions 39–55, 37.2 mg, 19 %), and 41 (fractions 62–67,

From 43a: A solution of 43a (15 mg, 33 μmol) in THF (4.0 mL)

was cooled to 0 °C. The reaction mixture was treated with

nBu₄N⁺F^–·3H₂O (10 mg, 33 μmol, 1.0 equiv.) and was afterwards

warmed to room temp. over 2 h. Brine (3.0 mL) and tBuOMe

(5.0 mL) were added, the phases were separated and the aqueous

phase was extracted with tBuOMe (3ϫ 5.0 mL). The combined

organic phases were washed with brine (15 mL), dried with Na₂SO₄

and concentrated in vacuo. The residue was purified by flash

Eur. J. Org. Chem. 2013, 6584–6600

www.eurjoc.org

6595

S. B. Kamptmann, R. Brückner

FULL PAPER

5.4 mg, 4%) were isolated. [α]²_D⁰= +11.6 (c = 1.7, CHCl₃, 10 cm).

[α]²_D⁰= +5.86 (c = 1.0, CHCl₃, 10 cm). ¹H NMR (400.1 MHz,

¹H NMR (499.5 MHz, CDCl₃): δ = 0.12 and 0.13 [2 s, 6 H, C₆D₆): δ = 0.11 and 0.21 [2 s, 6 H, Si(CH₃)₂], 0.87 and 0.89 [2 s, 6

Si(CH₃)₂], 0.828 and 0.834 (2 s, 6 H, 2 ϫ 1ЈЈЈ-CH₃), 0.87 (d,

J_{2ЈЈЈ-CH3,2ЈЈЈ}= 6.9 Hz, 3 H, 2ЈЈЈ-CH₃), 1.45 (ddd, J_3,4= 9.1, J_3,2

H, 2ϫ 1ЈЈ-CH₃], 0.93 (d, J_{2ЈЈ-CH3,2ЈЈ}= 6.9 Hz, 6 H, 2ϫ 2ЈЈ-CH₃),

=

1.60–1.69 (m, 3 H, 3-H, 5-H¹, 2ЈЈ-H), 1.90 (ddd, J_5-H2,5-H1= 12.7,

7.1, J_3,1Ј= 2.7 Hz, 1 H, 3-H), 1.58–1.66 (m, 1 H, 2ЈЈЈ-H), 1.76 (ddd, J_5-H2,4= 4.5, J_5-H2,6= 4.3 Hz, 1 H, 5-H²), 2.11 (d, J_8,6= 2.4 Hz, 1

J_5-H1,5-H2= 12.9, J_5-H1,4= 9.8, J_5-H1,6= 5.4 Hz, 1 H, 5-H¹), 2.00 H, 8-H), 2.45 (br. s, 1 H, 2Ј-OH), 2.79 (br. s, 1 H, 1Ј-OH), 3.29 (s,

(ddd, J_5-H2,5-H1= 12.9, J_5-H2,4= J_5-H2,6= 4.3 Hz, 1 H, 5-H²), 2.50

(d, J_8,6= 2.2 Hz, 1 H, 8-H), 3.41 (s, 3 H, 2-OCH₃), overlapped by

3 H, 2-OCH₃), 3.57 (dd, J_{2Ј-H1,2Ј-H2}= 11.1, J_2Ј-H1,1Ј= 3.3 Hz, 1 H,

2Ј-H¹), 3.71 (dd, J_{2Ј-H2,2Ј-H1}= 11.2, J_2Ј-H2,1Ј= 7.3 Hz, 1 H, 2Ј-H²),

3.43 (dd, J_{2Ј-H1,2Ј-H2}= 10.2, J_2Ј-H1,1Ј= 3.3 Hz, 1 H, 2Ј-H¹), 3.66 4.16–4.17 (m, 1 H, 1Ј-H), 4.35 (ddd, J_4,3= J_4,5-H1= 9.3, J_4,5-H2

=

(dd, J_{2Ј-H2,2Ј-H1}= 9.9, J_2Ј-H2,1Ј= 9.0 Hz, 1 H, 2Ј-H²), 3.81 (s, 3 H, 4.7 Hz, 1 H, 4-H), 4.69 (m_c, 1 H, 6-H), 5.10 (d, J_2,3= 7.2 Hz, 1

Ar-OCH₃), 4.20 (ddd, J_1Ј,2Ј-H2= 8.7, J_1Ј,2Ј-H1= J_1Ј,3= 2.8 Hz, 1 H, H, 2-H) ppm. ¹³C NMR (100.6 MHz, C₆D₆): δ = –2.73 and –2.29

1Ј-H), overlapped by 4.23 (ddd, J_4,3= J_4,5-H1= 9.5, J_4,5-H2= 4.1 Hz,

1 H, 4-H), 4.48 (s, 2 H, benzyl-H₂), 4.77–4.80 (m, 1 H, 6-H), 4.90 CH₃-1ЈЈ), 25.10 (C-1ЈЈ), 34.52 (C-2ЈЈ), 39.54 (C-5), 51.34 (C-3),

(d, J_2,3= 7.6 Hz, 1 H, 2-H), AAЈBBЈ signal centered at δ = 6.88 and 55.67 (2-OCH₃), 60.25 (C-6), 66.06 (C-4), 66.56 (C-2Ј), 69.47 (C-

7.26 (4 H, 2ЈЈ-H, 3ЈЈ-H, 5ЈЈ-H, 6ЈЈ-H) ppm. ¹³C NMR (125.6 MHz, 1Ј), 74.76 (C-8), 82.07 (C-7), 99.01 (C-2) ppm. IR (film): ν = 3435,

[Si(CH₃)₂], 18.80 and 18.83 (2ϫ CH₃-2ЈЈ), 20.48 and 20.52 (2ϫ

˜

CDCl₃): δ = –2.81 and –2.20 [2ϫ Si(CH₃)₂], 18.62, 18.67, 20.28

and 20.34 (2ϫ CH₃-1ЈЈЈ, 2ϫ CH₃-2ЈЈЈ), 24.85 (C-1ЈЈЈ), 34.15 (C-

2ЈЈЈ), 39.25 (C-5), 50.76 (C-3), 55.35 (OCH₃-Ar), 56.16 (2-OCH₃),

3310, 2955, 2870, 1635, 1465, 1380, 1255, 1185, 1085, 1070, 980,

940, 920, 865, 830, 775, 720, 665 cm^–1. C₁₈H₃₄O₅Si (358.55): calcd.

C 60.30, H 9.56; found C 60.70, H 9.86. HRMS (APCI, MeOH):

60.23 (C-6), 65.63 (C-4), 67.63 (C-1Ј), 72.75 (C-benzyl), 73.95 (C- calcd. for C₁₈H₃₂O₅³⁵ClSi [M + Cl]^–393.18641; found 393.18610

2Ј), 74.65 (C-8), 81.71 (C-7), 98.94 (C-2), 113.87 (C-3ЈЈ, C-5ЈЈ),

(Δ = –0.8 ppm).

129.44 (C-2ЈЈ, C-6ЈЈ), 130.38 (C-1ЈЈ), 159.30 (C-4ЈЈ) ppm. ²⁹Si NMR

(S)-2-{(2S,3S,4R,6S)-4-[Dimethyl(1,1,2-trimethylpropyl)siloxy]-6-eth-

ynyl-2-methoxy-3,4,5,6-tetrahydro-2H-pyran-3-yl}-2-hydroxyethyl

p-Toluenesulfonate (46b):

(99.2 MHz, CDCl ): δ = 19.59 (4-OSi) ppm. IR (film): ν = 3480,

˜

3

3305, 2955, 1610, 1515, 1465, 1365, 1300, 1250, 1175, 1080, 1035,

980, 865, 830, 775 cm^–1. C₂₆H₄₂O₆Si (478.70): calcd. C 65.24, H

8.84; found C 64.99, H 8.61. ^[a]The position of the silyl group was

distinguished by a ²⁹Si HMBC analysis (“long-range Si,H COSY

spectrum”, 99.2 MHz/499.5 MHz) by the following cross-peak [δ_Si

1

↔ δ_H]: δ = 19.59 (4-OSi) ↔ 4.23 (ddd, J_4,3= J_4,5-H= 9.5, J_4,5-H2

= 4.1 Hz, 1 H, 4-H). The protons 4-H and 1Ј-H had previously

been assigned unequivocally in a DQF COSY spectrum (“H,H

COSY spectrum”, 499.5 MHz, CDCl₃) by the following cross-

peaks [δ_H(¹H) ↔ δ_H(¹H)]: δ = 4.20 (ddd, J_1Ј,2Ј-H2= 8.7, J_1Ј,2Ј-H

J_1Ј,3= 2.8 Hz, 1Ј-H) ↔ δ = 1.45 (ddd, J_3,4= 9.1, J_3,2= 7.1, J_3,1Ј

=

1

2.7 Hz, 3-H), δ = 3.43 (dd, J_{2Ј-H1,2Ј-H2}= 10.2, J_2Ј-H1,1Ј= 3.3 Hz, 2Ј-

H¹), δ = 3.66 (dd, J_{2Ј-H2,2Ј-H1}= 9.9, J_2Ј-H2,1Ј= 9.0 Hz, 2Ј-H²), δ =

4.23 (ddd, J_4,3= J_4,5-H1= 9.5, J_4,5-H2= 4.1 Hz, 4-H) ↔ δ = 2.00

(ddd, J_5-H2,5-H1= 12.9, J_5-H2,4= J_5-H2,6= 4.3 Hz, 5-H²) ppm.

At 0 °C, a solution of diol 45b (108 mg, 0.300 mmol) in CH₂Cl₂

(55 mL) was treated with a solution of NEt₃(125 μL, 91.1 mg,

0.900 mmol, 3.0 equiv.) in CH₂Cl₂(1.0 mL), pTsCl (80.1 mg,

0.420 mmol, 1.4 equiv.), and DMAP (3.7 mg, 30 μmol, 10 mol-%).

The reaction mixture was warmed to room temp. overnight (16 h).

H₂O (30 mL) was added, and the phases were separated. The aque-

ous phase was extracted with CH₂Cl₂(3ϫ 30 mL). The combined

organic phases were washed with brine (25 mL), dried with

Na₂SO₄, and concentrated in vacuo. The residue was purified by

flash chromatography^[69](3.0ϫ 18 cm, 20 mL, cyclohexane/AcOEt,

4:1, from fraction 10, cyclohexane/AcOEt, 3:1) to afford tosylate

46b (fractions 17–29, 134 mg, 87%) as a colorless solid. [α]²_D⁰= +5.3

(c = 1.2, CHCl₃, 10 cm). ¹H NMR (400.1 MHz, CDCl₃): δ = 0.117

and 0.122 [2 s, 6 H, Si(CH₃)₂], 0.81 (s, 6 H, 2ϫ 1ЈЈ-CH₃), 0.84 [d,

J_{2ЈЈ-CH3,2ЈЈ}= 6.8 Hz, 3 H, (2ЈЈ-CH₃)¹], overlapped by 0.85 [d, J_2ЈЈ-

(S)-1-{(2S,3S,4R,6S)-4-[Dimethyl(1,1,2-trimethylpropyl)siloxy]-6-

ethynyl-2-methoxy-3,4,5,6-tetrahydro-2H-pyran-3-yl}ethane-1,2-

diol (45b):

= 6.9 Hz, 3 H, (2ЈЈ-CH₃)²], 1.34 (ddd, J_3,4= 10.0, J_3,2= 8.5,

CH3,2ЈЈ

At 0 °C, to a solution of 44b (168 mg, 0.350 mmol) in CH₃CN/

H₂O (9:1, 35 mL) was added Ce(NH₄)₂(NO₃)₆(576 mg, 1.05 mmol,

3.0 equiv.) in three portions. The reaction mixture was stirred at

room temp. until TLC control indicated nearly complete conversion

(1 h). The reaction mixture was diluted with CH₂Cl₂(15 mL) and

quenched by the addition of saturated aqueous NaHCO₃(15 mL).

The phases were separated and the aqueous phase was extracted

with CH₂Cl₂(5 ϫ 20 mL). The combined organic phases were

washed with brine (10 mL) and dried with Na₂SO₄. The solvent

was evaporated under reduced pressure and the residue was puri-

J_3,1Ј= 1.5 Hz, 1 H, 3-H), 1.55–1.65 (m, 1 H, 2ЈЈ-H), 1.74 (ddd, J_5-

= 12.8, J_5-H1,4= 10.7, J_5-H1,6= 5.6 Hz, 1 H, 5-H¹), 1.99

H1,5-H2

(ddd, J_5-H2,5-H1= 12.8, J_5-H2,4= 4.7, J_5-H2,6= 2.4 Hz, 1 H, 5-H²),

2.13 (br. s, 1 H, 1Ј-OH), 2.45 (s, 3 H, 4ЈЈЈ-CH₃), 2.52 (d, J_8,6

=

2.4 Hz, 1 H, 8-H), 3.38 (s, 3 H, 2-OCH₃), 3.97 (m_c, approximately

interpretable as dd, J_{2Ј-H1,2Ј-H2}= 16.3, J_2Ј-H1,1Ј= 8.2 Hz, 1 H, 2Ј-

H¹), 4.23 (ddd, J_4,3= J_4,5-H1= 10.4, J_4,5-H2= 4.7 Hz, 1 H, 4-H),

4.30 (dd, J_1Ј,2Ј-H2= 8.0, J_1Ј,2Ј-H1= 7.3 Hz, 1 H, 1Ј-H), 4.31 (dd, J_2Ј-

= 17.0, J_2Ј-H2,1Ј= 8.9 Hz, 1 H, 2Ј-H²), 4.76 (ddd, J_6,5-H1

5.3, J_6,5-H2= 2.6 Hz*, J_6,8= 2.5 Hz*, 1 H, 6-H), 4.84 (d, J_2,3

=

H2,2Ј-H1

fied by flash chromatography^[69](3.0ϫ 20 cm, 20 mL, cyclohexane/ 8.5 Hz, 1 H, 2-H), AAЈBBЈ signal centered at δ = 7.35 and 7.80

AcOEt, 2:1). Diol 45b (fractions 29–49, 117 mg, 93%) was obtained (4 H, 2ЈЈЈ-H, 3ЈЈЈ-H, 4ЈЈЈ-H, 5ЈЈЈ-H) ppm. ¹³C NMR (100.6 MHz,

as a colorless oil, which crystallized on storage to a colorless solid.

CDCl₃): δ = –2.88 and –2.14 [2 s, Si(CH₃)₂], 18.55 and 18.66 [2ϫ

6596

www.eurjoc.org

Eur. J. Org. Chem. 2013, 6584–6600

Cⁿ–Cⁿ⁺⁷Building Block for Polyol,Polyene Antibiotics

CH₃-2ЈЈ], 20.20 and 20.34 [2ϫ CH₃-1ЈЈ], 21.71 (CH₃-4ЈЈЈ), 24.85

(C-1ЈЈ), 34.10 (C-2ЈЈ), 39.36 (C-5), 51.56 (C-3), 56.33 (2-OCH₃),

61.25 (C-6), 65.34 (C-4), 66.93 (C-1Ј), 75.30 (C-2Ј)**, 75.34 (C-

8)**, 80.98 (C-7), 98.19 (C-2), 128.07 (C-2ЈЈЈ, C-6ЈЈЈ), 129.96 (C-

Dr. Manfred Keller, Institut für Organische Chemie, University of

Freiburg, for the X-ray diffraction analyses and for numerous

NMR experiments.

3ЈЈЈ, C-5ЈЈЈ), 132.87 (C-1ЈЈЈ), 144.99 (C-4ЈЈЈ) ppm. IR (film): ν =

˜

3535, 3285, 2960, 2870, 2115, 1920, 1600, 1495, 1465, 1450, 1360,

1310, 1290, 1255, 1210, 1190, 1175, 1120, 1095, 1070, 1020, 965,

865, 830, 780, 735, 705, 680, 665 cm^–1. C₂₅H₄₀O₇SSi (512.74): calcd.

C 58.56, H 7.86, S 6.25; found C 58.37, H 7.79, S 6.43. *Assign-

ment of coupling constants interchangeable. **Assignment inter-

changeable.

[1]

For reviews of polyol,polyene macrolides, see: a) J. M. T. Ham-

ilton-Miller, Bacteriol. Rev. 1973, 37, 166–196; b) J.-M. Beau,

G. Lukacs, in: Recent Progress in the Chemical Syntheses of

Antibiotics (Ed.: M. Ohno), Springer, Berlin, 1990, p. 137–179;

c) S. Omura, H. Tanaka, Macrolide Antibiotics: Chemistry, Bio-

chemistry and Practice (Ed: S. Omura), Academic Press, New

York, 1984, p. 351–404; d) S. D. Rychnovsky, Chem. Rev. 1995,

95, 2021–2040; e) S. B. Zotchev, Curr. Med. Chem. 2003, 10,

211–223.

[Dimethyl(1,1,2-trimethylpropyl)]{(2S,3S,4R,6S)-6-ethynyl-2-meth-

oxy-3-[(S)-oxiran-2-yl]-3,4,5,6-tetrahydro-2H-pyran-4-

yloxy}dimethylsilane (47b):

[2] a) For the isolation from Streptomyces nodosus, see: J. Vander-

putte, J. L. Wachtel, E. T. Stiller, Antibiot. Ann. 1956, 587–591;

for connectivity and configuration, see: b) W. Mechlinski, C. P.

Schaffner, P. Ganis, G. Avitabile, Tetrahedron Lett. 1970, 11,

3873–3876; c) P. Ganis, G. Avitabile, W. Mechlinski, C. P.

Schaffner, J. Am. Chem. Soc. 1971, 93, 4560–4564.

[3] For the isolation from Streptomyces noursei, see: a) E. L.

Hazen, R. Brown, Science 1950, 112, 423–430; b) E. L. Hazen,

R. Brown, Proc. Soc. Exp. Biol. Med. 1951, 76, 93–98; for con-

nectivity, see: c) C. N. Chong, R. W. Rickards, Tetrahedron

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[8] a) L. Nachbauer, R. Brückner, Eur. J. Org. Chem. 2013, DOI:

10.1002/ejoc.201300181 (prepreceding article in this issue); b)

R. Kramer, R. Brückner, Eur. J. Org. Chem. 2013, DOI:

10.1002/ejoc.201300182 (preceding article in this issue).

[9] L. Nachbauer, Ph.D. Dissertation, University of Freiburg, Frei-

burg, 2012.

A catalytic amount of K₂CO₃was added to a solution of tosylate

46b (128 mg, 0.250 mmol) in MeOH (15 mL). After stirring for

12 h at room temp., the reaction mixture was diluted with H₂O

(15 mL) and tBuOMe (15 mL). The phases were separated and the

aqueous phase was extracted with tBuOMe (3ϫ 15 mL). The com-

bined organic phases were washed with brine (10 mL), dried with

Na₂SO₄, and concentrated in vacuo. Flash chromatography^[69]

(2.0ϫ 15 cm, 10 mL, cyclohexane/AcOEt, 8:1, from fraction 15,

cyclohexane/AcOEt, 6:1) of the residue delivered epoxide 47b (frac-

tions 13–23, 80.3 mg, 94%) as a colorless solid, m.p. 86 °C. [α]²_D⁰

=

1

+34.2 (c = 0.72, CHCl₃, 10 cm). H NMR (499.5 MHz, CDCl₃): δ

= 0.10 and 0.11 [2 s, 6 H, Si(CH₃)₂], 0.830 and 0.834 (2 s, 6 H, 2ϫ

1ЈЈ-CH₃), 0.88 (d, J_{2ЈЈ-CH3,2ЈЈ}= 6.9 Hz, 6 H, 2 ϫ 2ЈЈ-CH₃), 1.41

(ddd, J_3,1Ј= J_3,4= 7.1, J_3,2= 6.5 Hz, 1 H, 3-H), 1.58–1.66 (m, 1 H,

2ЈЈ-H), 1.81 (ddd, J_5-H1,5-H2= 13.2, J_5-H1,4= 8.4, J_5-H1,6= 4.7 Hz, 1

H, 5-H¹), 2.00 (ddd, J_5-H2,5-H1= 13.2, J_5-H2,4= J_5-H2,6= 4.7 Hz, 1

H, 5-H²), 2.51 (d, J_8,6= 2.2 Hz, 1 H, 8-H), 2.68 (dd, J_{2Ј-H1,2Ј-H2}

=

5.0, J_2Ј-H1,1Ј= 2.8 Hz, 1 H, 2Ј-H¹), 2.80 (dd, J_{2Ј-H2,2Ј-H1}= 5.0, J_2Ј-

= 4.1 Hz, 1 H, 2Ј-H²), 2.98 (ddd, J_1Ј,3= 6.9, J_1Ј,2Ј-H2= 4.1,

H2,1Ј

J_1Ј,2Ј-H1= 2.8 Hz, 1 H, 1Ј-H), 3.45 (s, 3 H, 2-OCH₃), 4.07 (ddd,

J_4,5-H1= J_4,3= 8.1, J_4,5-H2= 4.2 Hz, 1 H, 4-H), 4.73 (d, J_2,3

=

6.0 Hz, 1 H, 2-H), 4.84 (ddd, J_6,5-H1= J_6,5-H2= 4.9, J_6,8= 2.4 Hz,

1 H, 6-H) ppm. ¹³C NMR (125.6 MHz, CDCl₃): δ = –2.81 and

–2.52 [Si(CH₃)₂], 18.58 and 18.66 [2ϫ 2ЈЈ-C(CH₃)], 20.18 and 20.30

[2ϫ 1ЈЈ-C(CH₃)], 24.84 (C-1ЈЈ), 34.20 (C-2ЈЈ), 38.66 (C-5), 46.65

(C-2Ј), 50.08 (C-3), 50.85 (C-1Ј), 56.06 (2-OCH₃), 59.24 (C-6),

66.15 (C-4), 74.47 (C-8), 81.78 (C-7), 99.94 (C-2) ppm. IR (film): ν

˜

= 3280, 2960, 2915, 1560, 1360, 1300, 1250, 1190, 1140, 1105, 1070,

1025, 940, 895, 840, 775, 700 cm^–1. C₁₈H₃₂O₄Si (340.53): calcd. C

63.49, H 9.47; found C 63.46, H 9.39. For the crystallographic data

of this compound, see ref.^[85]

Supporting Information (see footnote on the first page of this arti-

cle): bution): Experimental procedures and characterization data

1

for all synthesized compounds not described in the Exp. Sect., H,

¹³C, and ²⁹Si NMR spectra of all the synthesized compounds, and

X-ray crystallographic data of compounds 37 and 47b.

Acknowledgments

[10] a) R. Kramer, Ph.D. Dissertation, University of Freiburg, Ger-

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Freiburg, Germany, 2013.

The authors thank Grazian Lehmann, Institut für Organische

Chemie, University of Freiburg, for skilful technical assistance and

Eur. J. Org. Chem. 2013, 6584–6600

www.eurjoc.org

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S. B. Kamptmann, R. Brückner

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Article Doi

Stereocontrolled synthesis of a Cn-Cn+7 building block ("eastern moiety") for the unnatural enantiomers of important polyol,polyene antibiotics based on a ring-closing metathesis and an aldol addition of a lactone enolate

DOI: 10.1002/ejoc.201300183

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