A chemoenzymatic and fully stereocontrolled total synthesis of the antibacterial natural product (-)-platencin

DOI: 10.1002/asia.201403069

Full Paper

Total Synthesis

A Chemoenzymatic and Fully Stereocontrolled Total Synthesis of

the Antibacterial Natural Product (ꢀ)-Platencin

Ee Ling Chang,^[a]Brett D. Schwartz,^[a]Alistair G. Draffan,^[b]Martin G. Banwell,*^[a]and

Anthony C. Willis^[a]

Abstract: The natural product (ꢀ)-platencin is a potent anti-

bacterial agent that exerts its effects through a novel mode

of action. As such, it is an important lead in the develop-

ment of next-generation antibacterials that are urgently

needed because of the rapidly developing resistance to cur-

rent therapies. The work reported here concerns the devel-

opment of a convergent and chemoenzymatic total synthe-

sis of (ꢀ)-platencin by methods that should provide access

to a range of biologically relevant analogues. The key step

involves a thermally promoted and facially selective intramo-

lecular Diels–Alder (IMDA) cycloaddition reaction to give an

adduct that embodies the tricarbocyclic core of (ꢀ)-platen-

cin. This adduct was elaborated over thirteen steps to the

natural product. The substrate for the IMDA reaction was

prepared by Stille cross-coupling of a Z-configured alkenyl-

stannane with an iodinated diene obtained in an enantio-

merically pure form through the whole-cell biotransforma-

tion of iodobenzene.

Introduction

ed that both compounds are potent inhibitors of certain en-

zymes involved in bacterial fatty acid biosynthesis.^[4]Specifical-

ly, platensimycin (1) is a selective inhibitor of fatty acid acyl

carrier protein synthase II (FabF), whereas congener 2 inhibits

both this enzyme and the related one known as FabH. As

a result, both compounds show potent in vitro activities

against, inter alia, methicillin-resistant Staphylococcus aureus

(MRSA), vancomycin-resistant Enterococcus faecalis (VREF), and

extensively drug-resistant Mycobacterium tuberculosis.^[5]Inter-

estingly, they are also thought to represent promising leads for

the development of antidiabetic therapies.^[6]

The increasingly broad resistance of bacterial pathogens to

current frontline antibiotics represents a major public health

issue.^[1]Indeed, the World Health Organization (WHO) has iden-

tified this situation as one of the three most significant threats

to human health at the present time.^[1b]Accordingly, various ef-

forts are being made to identify next-generation antibacterial

agents that possess novel structures and modes of action. In

this regard, and between 2006 and 2007, the Singh group at

Merck reported the isolation of the structurally related and un-

usual natural products platensimycin (1)^[2]and platencin (2)^[3]

from various strains of Streptomyces platensis and demonstrat-

A wide range of studies has been reported in efforts to ad-

dress the less-than-optimal pharmacokinetic properties of pla-

tensimycin (1) and platencin (2).^[2,3,7,8]These have included the

discovery of naturally occurring congeners^[4,9]and pathway en-

gineering/combinatorial biosynthesis approaches^[10]for the

generation of analogues. Of course, chemical synthesis has

also played a significant role in the development of a struc-

ture–activity relationship (SAR) profile for these compounds

and led to the identification of a significant number of active

analogues including some rather accessible ones that possess

comparable antibacterial properties.^[7,11]Much of the recent

work on analogues has been underpinned by the various total

and formal total syntheses of compounds 1 and 2 that began

emerging very soon after their structures were first estab-

lished.^[4,12]Nicolaou and co-workers reported^[13]the original

total synthesis of platencin (2) in 2008, and this involved the

assembly of the cyclohexannulated bicyclo[2.2.2]octane frame-

work 3 as a key substructure. Subsequently, both our group^[14]

and that of Nicolaou^[15]used an intramolecular Diels–Alder

(IMDA) approach to establish this key substructure in an enan-

tioselective manner. Others reported related routes to com-

[a] E. L. Chang, Dr. B. D. Schwartz, Prof. M. G. Banwell, Dr. A. C. Willis

Research School of Chemistry,

Australian National University

Canberra, ACT 2601 (Australia)

E-mail: Martin.Banwell@anu.edu.au

[b] Dr. A. G. Draffan

Biota Scientific Management Pty Ltd

Melbourne, VIC 3168 (Australia)

Supporting information for this article is available on the WWW under

http://dx.doi.org/10.1002/asia.201403069.

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pionic acid side chain (or some equivalent thereof) and the

methyl group at C4 within the target 2 could be introduced

with full stereochemical control. As such, we envisaged that

a compound of the general form 5 (and wherein P represents

an alcohol protecting group) would be an important and rela-

tively late-stage intermediate and might be accessible in a fully

stereocontrolled manner through engagement of the tetraene

6 in a thermally promoted IMDA reaction. It was thought that

compound 6 itself could be obtained through Stille cross-cou-

pling of the alkenylstannane 8 with acetonide 7 (a known de-

rivative of diol 4) followed by oxidation of the alcohol-contain-

ing compound formed in this way. Compound 8 embodies

two stereochemical elements, namely, a quaternary carbon

center (destined to become C4 of platencin) and a Z-config-

ured alkene (which corresponds to the endocyclic CꢀC double

bond within target 2), and thus represents a challenging sub-

target. By seeking to implement the synthetic plan defined

above, the required stereochemistry at C4 in platencin would

be established prior to the assembly of its carbocyclic core and

not afterwards. This new approach is potentially advantageous

because the (otherwise necessary) twofold C-alkylation of com-

pound 3 is not a completely stereoselective process.

pound 3 shortly thereafter.^[12a,i]A pivotal aspect of the work we

reported was the use of the enantiomerically pure cis-1,2-dihy-

drocatechol 4 (which is obtained by the whole-cell biotransfor-

mation of iodobenzene using a genetically engineered form of

E. coli) as the starting material.^[16]

Enone 3 has proven to be a popular synthetic target be-

cause it can be converted, by using stereocontrolled C-alkyla-

tion protocols,^[13,17]into platencin (2). In our hands, however,

this end-game proved difficult to implement with the rather

small quantities of substrate 3 available to us as a result of em-

ploying the synthetic sequence we established.^[14]As such, we

sought to modify our original route to generate, in as highly

controlled a manner as possible, substrates for the pivotal

IMDA reaction that afford, after the cycloaddition event, deriva-

tives of enone 3 that already incorporate a suitably constituted

quaternary carbon center adjacent to the carbonyl residue and

could, therefore, be more readily elaborated to (ꢀ)-platencin.

Herein, we report the successful realization of this approach.

Synthesis of Alkenylstannane 8

The reaction sequence used to prepare sub-target 8 (P=Bn) is

shown in Scheme 2 and exploited, in its early stages, chiral

auxiliary-based chemistry employed by Yamashita and co-

workers^[18]in a related context. Thus, the commercially avail-

able amino-diol 9 was converted into the corresponding 1,3-di-

oxane 10 under the conditions defined by Nordin and

Thomas^[19](89% yield over three steps). Condensation of the

latter compound with aldehyde 11 in the presence of trifluoro-

acetic anhydride gave the imine 12 that was deprotonated

Results and Discussion

Retrosynthetic Analysis

The retrosynthetic analysis employed in the present study is

shown in Scheme 1 and was informed by our earlier work that

led to the tricyclic framework 3 of platencin and which was ob-

tained, as suggested above, through the engagement of a de-

rivative of the enantiomerically pure starting material 4 in an

IMDA reaction.

A key objective of the present study was to establish, at a rel-

atively early stage in the synthesis, means by which the pro-

Scheme 2. Synthesis of alkenylstannane 8 (P=Bn): a) HCO₂H, MeOH, 188C,

3.5 h; b) 2-methoxypropene, p-TsOH·H₂O, 188C, 2 h; c) N₂H₄, 1208C, 2 h, 89%

over three steps; d) (CF₃CO)₂O, C₆H₆, 808C, 5 h; e) Lithium diisopropylamide

(LDA), THF, ꢀ78 to 188C, 16 h; f) 2m aq. HCl, THF, 188C, 5 h; g) HCCMgBr,

THF, ꢀ108C, 0. 5 h, 44% over three steps; h) Bu₂Sn(OTf)H, hexane, 188C,

16 h; and i) nBuLi, Et₂O, 08C, 0.25 h, 54% over two steps.

Scheme 1. Retrosynthetic analysis of (ꢀ)-platencin employed in the present

study.

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with lithium diisopropylamide and the resulting anion alkylat-

ed with the benzyl ether 13^[20]of 3-iodopropan-1-ol. After

acidic workup, the desired a-alkylation product, aldehyde 14

(52%), was obtained along with the chromatographically sepa-

rable (E)-7-(benzyloxy)-2-methylhept-2-enal (9%), the product

of g-alkylation. The selective formation of compound 14 by

these means is presumed to result from preferential metalation

at the a-position (owing to the proximity of coordinating het-

eroatoms) within the anion derived from precursor 12.

To determine the enantiomeric excess (ee) of compound 14

obtained by the pathway described immediately above, this al-

dehyde was treated with (S)-1-amino-2-methoxymethylpyrroli-

dine (SAMP) hydrazine and the ratio of the diastereoisomeric

hydrazones formed in this manner was then determined by

HPLC analysis. For the purposes of obtaining an appropriate

reference material, the racemic modification of compound 14

was synthesized by related means (see the Experimental Sec-

tion for details) and this too was converted into the corre-

sponding mixture of diastereoisomeric SAMP hydrazones. By

such means, and using a Chiracel OD-H column for the separa-

tion of the diastereoisomeric hydrazones, the ee of compound

14 was determined to be approximately 92%. The illustrated

configuration at C2 was initially assigned on the basis of Yama-

shita’s work^[18]but ultimately confirmed (see below) through

a single-crystal X-ray analysis of a derivative that incorporates

a residue of known absolute stereochemistry.

Scheme 3. Synthesis of the IMDA adduct 5 (P=Bn): a) [Pd(PPh₃)₄], CuI, CsF,

dimethylformamide (DMF), 188C, 16 h, 80%; b) DMP, pyridine, CH₂Cl₂, 0 to

188C, 1.5 h, 53%; and c) toluene, 1128C, 16 h, 70%.

matographically less mobile isomer exhibited a positive specif-

ic rotation, whereas the other displayed a negative one.

Neither of the diastereoisomeric forms of compound 16 par-

ticipated in a thermally promoted IMDA reaction upon heating

in toluene. Furthermore, attempts to promote such a process

through the addition of a range of Lewis acids simply led to

rapid decomposition of the substrates. As a result, and given

the observation^[23]that in certain related type 1 IMDA reactions

the nature of the substituents associated with the side chain

can have a dramatic impact on the efficacy of the process,

compound 16 was oxidized to the corresponding ketone 6

(P=Bn) (53%) using the Dess–Martin periodinane (DMP) in the

presence of pyridine (to prevent acid-catalyzed aromatization

of the cis-1,2-dihydrocatechol residue). The positive-ion electro-

spray mass spectrum of this oxidation product displayed the

expected [M+Na]⁺ion at m/z 431 (base peak), whereas the

corresponding infrared spectrum displayed a strong carbonyl-

stretching band at 1683 cm^ꢀ1. Similarly, the ¹³C NMR spectrum

revealed a carbonyl carbon resonance at d=204.4 ppm as well

as an additional 23 higher-field resonances, as would be ex-

The completion of the synthesis of target stannane 8 (P=

Bn; Scheme 2) involved treating compound 14 with ethynyl-

magnesium bromide in THF and thus generating the anticipat-

ed propargyl alcohol 15 (85 or 44% from 12). This was ob-

tained as an approximately 1:1 mixture of diastereoisomers

and no attempts were made to separate these. Sequential

treatment of compound 15 with the readily prepared Lewis

acidic hydrostannane Bu₂Sn(OTf)H^[21]then nBuLi gave, in

a seemingly completely regio- and stereo-controlled process,

the required Z-configured alkene 8 (P=Bn) (54%) and, once

again, as an approximately 1:1 mixture of diastereoisomers. All

the data acquired on this material were in accord with the as-

signed structure, although no attempt was made to record its

mass spectrum because of concerns about contamination of

the spectrometer by tin residues.

1

pected for the assigned structure. The corresponding H NMR

spectrum was also in complete accord with the proposed

structure. Gratifyingly, when a 2.9 mm solution of compound 6

(P=Bn) in toluene was heated at reflux for 16 h, the desired

cycloaddition reaction took place and such that the anticipated

IMDA adduct 5 (P=Bn) could be obtained as a white crystal-

line solid in 70% yield after chromatographic purification.

There was no evidence for the accompanying formation of

a product or products that arise from an electrocyclization re-

action involving the doubly unsaturated ketone moiety em-

bedded within the substrate. The ¹³C NMR spectrum of the

product provided the most convincing early evidence for the

assigned structure. In particular, only nine signals due to sp²-

hybridized carbon atoms were apparent, whereas fifteen were

observed for their sp³-hybridized counterparts. However, defin-

itive assignment of structure 5 (P=Bn) to this adduct followed

from a single-crystal X-ray analysis. The derived ORTEP diagram

is shown in Figure 1, while certain crystal data are provided in

Synthesis of Tetraene 6 (P=Bn) and its Engagement in the

IMDA Reaction: Formation of Compound 5 (P=Bn)

With compound 8 (P=Bn) in hand, an examination of its ca-

pacity to engage in a Stille cross-coupling reaction with the

previously reported^[14]acetonide 7 could be undertaken. Given

the expected fragile nature of the hoped-for product, this pro-

cess was carried out under the mildest possible conditions. In

the event (Scheme 3), treatment of an approximately 1:1 mix-

ture of these substrates with [Pd(PPh₃)₄] in the presence of CuI

and CsF^[22]at 188C resulted in the generation of the target tet-

raene 16 as an approximately 1:1 mixture of diastereoisomers

in 80% combined yield. These diastereoisomers could be sepa-

rated chromatographically, and each was subjected to the

usual range of spectroscopic analyses. Interestingly, the chro-

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Figure 1. ORTEP diagram derived from the single-crystal X-ray analysis of the

IMDA adduct 5 (P=Bn). Anisotropic displacement ellipsoids show 30%

probability levels. Hydrogen atoms are drawn as circles with small radii.

the Experimental Section. Significantly, this analysis unequivo-

cally established the absolute stereochemistry associated with

C4 (platencin numbering) of compound 5 (P=Bn) and that

was constructed using the chiral auxiliary-mediated and diaste-

reoselective alkylation reaction 12+13!14 shown in

Scheme 2. Clearly this configuration at C4 is required for elabo-

ration of the IMDA adduct to (ꢀ)-platencin. The following sec-

tions delineate how this was achieved.

Scheme 4. Synthesis of Yoshimitsu’s intermediate 24: a) H₂(1 atm), 10% Pd

on C, MeOH, 188C, 16 h, 94%; b) 1m aq. HCl, acetone, 0.25 h, 188C; c) PCC,

NaOAc, CH₂Cl₂, 188C, 2 h; d) NaClO₂, NaH₂PO₄, 2-methyl-2-butene, tBuOH/

water, 188C, 1 h, 45% over three steps; e) DOWEX-50 (acidified), MeOH/

water, 658C, 48 h, 24% of 19 and 46% of 20; f) 4-NHAc-TEMPO, p-TsOH·H₂O,

CH₂Cl₂, 0 to 188C, 4 h, 88%; g) BzCl, DMAP, Et₃N, CH₂Cl₂, 0 to 188C, 16 h,

95%; h) SmI₂, THF, ꢀ788C, 0.25 h, 88%; and i) Ph₃P=CH₂, THF, 08C, 0.5 h,

63%.

Synthesis of the Homochiral Form, 24, of Yoshimitsu’s Inter-

mediate from IMDA Adduct 5 (P=Bn)

The reaction sequence used for the purposes of elaborating

compound 5 (P=Bn) to an established (and advanced) precur-

sor to (ꢀ)-platencin is shown in Scheme 4. To such ends, and

with a view to cleaving the benzyl ether residue within this

substrate as well as reducing the associated nonconjugated

carbonꢀcarbon double bond, a solution of compound 5 (P=

Bn) in methanol was exposed to dihydrogen in the presence

of 5% Pd on C. Although the desired transformations were

achieved under these conditions, they were accompanied by

the unwanted reduction of the C=C moiety associated with

the enone residue. In addition, the liberated primary alcohol

cyclized onto the C3 carbonyl moiety and (presumably after

methanolysis of initially produced lactol) the crystalline ketal

17 was obtained in 92% yield. The structure of this compound

followed from a single-crystal X-ray analysis (see Figure 2 and

the Experimental Section), which revealed that the associated

pyran and cyclohexane rings are fused in a cis fashion and

with the angular methoxy group axially oriented as a result of

the operation of the anomeric effect.

Figure 2. ORTEP diagram derived from the single-crystal X-ray analysis of

compound 17. Anisotropic displacement ellipsoids show 30% probability

levels. Hydrogen atoms are drawn as circles with small radii.

ingly, efforts were directed toward “salvaging” matters by elab-

orating ketal 17 to a derivative that incorporated a propionic

acid side chain to which the required polyfunctionalized aro-

matic residue could be attached. To such ends, compound 17

was treated with aqueous HCl in acetone, and the ensuing

Extensive efforts were made to try and avoid the undesired

reduction of the enone C=C bond observed during the course

of the conversion of 5 (P=Bn)!17 but all to no avail. Accord-

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lactol immediately oxidized with pyridinium chlorochromate

(PCC) in the presence of sodium acetate to give the corre-

sponding keto-aldehyde. As a result of its instability, this last

compound was immediately subjected to a Pinnick oxidation

and thus afforded the desired carboxylic acid 18 in 45% yield

over the three steps involved. Cleavage of the acetonide resi-

due within the last compound proved rather difficult but could

ultimately be achieved by treating a solution of the substrate

in methanol/water with acidified Dowex-50 resin at 658C for

48 h. After workup, a chromatographically separable mixture of

esters 19 (24%) and 20 (46%) was obtained. Subjecting the

former product to the reaction conditions again gave addition-

al quantities of the latter (57% at 82% conversion). The diol

residue within compound 20 could be regioselectively mono-

oxidized using the sterically demanding oxammonium salt de-

rived from the acid-catalyzed disproportionation of 4-acetami-

do-TEMPO^[24](TEMPO=(2,2,6,6-tetramethyl-piperidin-1-yl)oxyl)

and thus afforded acyloin 21 in 82% yield. Esterification of the

remaining hydroxyl group within compound 21 using benzoyl

chloride in the presence of 4-(N,N-dimethylamino)pyridine

(DMAP) and triethylamine afforded benzoate 22 (95%) and

this was subjected to a samarium iodide promoted reduc-

tion^[25]and thereby generated the diketo ester 23 (88%). Final-

ly, subjection of compound 23 to a Wittig olefination reaction

using Ph₃P=CH₂gave a chromatographically separable mixture

of the desired alkene 24 (37%) and the corresponding twofold

methylenation product (13%). The yield of the former product

could be increased to 63% if the reaction was carried out at

08C for 0.5 h rather than between 0 and 188C for 16 h.

Table 1. Comparison of the ¹³C NMR spectroscopic data (d_C) [ppm] re-

corded for compound 24 with those reported by Yoshimitsu and co-

workers^[12e]for the corresponding racemate.

Present work^[a]

Yoshimitsu et al.^[b]

Dd

215.9

174.2

150.6

106.3

51.6

50.0

46.3

42.9

35.9

35.4

35.2

32.8

31.3

29.4

28.3

28.2

26.6

20.3

216.0

174.2

150.6

106.3

51.6

50.0

46.3

42.9

36.0

35.4

35.2

32.8

31.3

29.4

28.3

28.2

26.6

20.3

ꢀ0.1

0

ꢀ0.1

0

[a] Data obtained from present work, recorded for samples in CDCl₃at

100 MHz. [b] Data obtained from Ref. [12e], recorded for samples in

CDCl₃at 125 MHz.

The racemic modification of olefin 24 has been described by

Yoshimitsu et al.^[12e]and served as a late-stage intermediate in

their synthesis of (ꢁ)-platencin. As such, we were prompted to

compare the spectral data sets they derived from their sample

of racemic material with those obtained from our homochiral

counterpart. These comparisons proved very favorable as evi-

denced by the closely matching chemical shifts observed in

the relevant ¹³C NMR spectra (Table 1).

Scheme 5. Completion of the synthesis of (ꢀ)-platencin (2): a) TMSCl, LiI,

HMDS, CH₂Cl₂, 188C, 4 h; b) IBX, NMO, DMSO, 608C, 16 h, 53% over two

steps; c) 1m aq. NaOH, THF, 188C, 24 h, 88%; and d) 3-amino-b-resorcylic

acid, DCC, Et₃N, DMAP, MeCN, DMF, 188C, 38 h, 44%.

Completion of the Synthesis of (ꢀ)-Platencin (2)

With the homochiral form, 24, of a late-stage intermediate

used in Yoshimitsu’s synthesis of (ꢁ)-platencin^[12e]in hand, it

seemed most appropriate to deploy his method in establishing

a synthesis of the natural product itself, namely, (ꢀ)-platencin

(2). Accordingly, and as shown in Scheme 5, the first step was

the conversion of ketone 24 into the corresponding silyl enol

ether through treatment of the former compound with a mix-

ture of trimethylsilyl chloride (TMSCl), lithium iodide, and hex-

amethyldisilazane (HMDS). The enol ether formed in this way

was not isolated. Rather, it was immediately treated with 2-io-

doxybenzoic acid (IBX) and 4-methylmorpholine 4-oxide

(NMO)^[26]so as to affect its oxidation to the corresponding

enone 25 (57% over two steps). By such means the carbonyl-

conjugated C=C moiety that had been unavoidably removed

immediately after the IMDA reaction was now reinstated. Sapo-

nification of ester 25 by using aqueous sodium hydroxide in

THF followed by an acid workup afforded the carboxylic acid

26 (97%). As was the case with compound 24, the spectral

data acquired on congeners 25 and 26 were in complete

accord with the assigned structures and matched those data

reported by Yoshimitsu et al.^[12e]for their racemic counterparts.

The final step in the synthesis of (ꢀ)-platencin involved, as

prescribed by Yoshimitsu, coupling of acid 26 with 3-amino-b-

resorcylic acid^[17]in the presence of dicyclohexylcarbodiimide

(DCC), triethylamine, and DMAP. The purification of the (ꢀ)-pla-

tencin [(ꢀ)-2] formed in this way proved problematic because

of the difficulties in separating this material from coproduced

N,N’-dicyclohexylurea. After extensive chromatography, the

target natural product was obtained in essentially pure form

and 44% yield. The derived NMR spectroscopic, IR, and mass

spectral data were in complete accord with the assigned struc-

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ture and the set of ¹³C NMR spectroscopic chemical shifts re-

corded for our material proved to be a good match (Table 2)

with that derived from the material prepared by Mulzer

et al.^[27]This is especially so when one takes account of the ca-

pacity for variations in the chemical shifts of carbon atoms as-

sociated with acidic residues such as phenolic and carboxylate

moieties.

quantities of compound 2 for further studies, it does, as will

be reported elsewhere, allow for the production of small

amounts of a range of analogues. Furthermore, variations to

the structure of compound 8 that participates in the Stille

cross-coupling reaction, and wherein, for example, the BnOCH₂

residue is replaced by a carboxamide group, should allow for

a more convergent approach to biologically relevant systems.

Similarly, variations in the nature of the iodinated cyclohexa-

diene (compound 7 in the present case) that engages in the

Stille cross-coupling reaction could deliver further efficiencies.

Such possibilities are currently under active investigation in

our laboratories.

Table 2. Comparison of the ¹³C NMR data (d_C) [ppm] recorded for com-

pound 2 with those reported by Mulzer et al.^[27]

Present work^[a]

Mulzer et al.^[b]

Dd

205.6

174.1

172.7

155.7

155.6

154.4

148.3

128.2

126.0

114.5

111.4

107.7

103.1

47.7

44.5

39.6

36.3

35.8

32.4

31.1

28.1

26.6

205.9

174.1

172.5

156.0

155.4

154.4

148.3

128.2

126.0

114.4

111.3

107.7

103.3

47.7

44.4

39.4

36.3

35.8

32.3

31.0

28.0

26.5

ꢀ0.3

0

+0.2

ꢀ0.3

+0.2

0

+0.1

0

ꢀ0.2

0

+0.1

+0.2

0

Experimental Section

Specific Synthetic Transformations

Compound 10

Following the procedure of Nordin and Thomas,^[19]a magnetically

stirred solution of aminodiol 9 (10.00 g, 59.8 mmol) in methanol

(50 mL) was treated with methyl formate (4.00 mL, 68.67 mmol)

and sodium methoxide (150 mg, 3 mmol). The ensuing mixture

was stirred at 188C for 3.5 h then concentrated under reduced

pressure to give brown crystals. This material was dissolved in di-

methylformamide (DMF; 280 mL), and the resulting solution was

treated with 2-methoxypropene (14.00 mL, 143 mmol), then p-

TsOH·H₂O (p-TsOH=p-toluenesulfonic acid; 2.30 g, 12.04 mmol).

The mixture thus obtained was stirred at 188C for 2 h before being

quenched with NaHCO₃(500 mL) and extracted with ethyl acetate

(4ꢁ250 mL). The combined organic layers were washed with brine

(1ꢁ50 mL), then dried (Na₂SO₄), filtered, and concentrated under

reduced pressure to give a viscous yellow oil. This was dissolved in

hydrazine hydrate (50 mL of an 50–60% solution in water), and the

ensuing mixture was heated under reflux conditions for 2 h before

being cooled and then extracted with toluene (3ꢁ100 mL). The

combined organic fractions were washed with water (2ꢁ50 mL),

then dried (Na₂SO₄), filtered, and concentrated under reduced pres-

sure to afford compound 10^[18,19](11.37 g, 89% yield) as an orange

oil. ½aꢂ²_D⁵= +37.5 (c=1.0, CHCl₃); ¹H NMR (300 MHz, CDCl₃): d=

7.40–7.19 (complex m, 5H), 5.04 (d, J=1.8 Hz, 1H), 4.23 (dd, J=

12.0, 2.4 Hz, 1H), 3.87 (dd, J=12.0, 1.8 Hz, 1H), 2.75 (m, 1H), 1.80

(brs, 2H), 1.48 ppm (m, 6H); ¹³C NMR (75 MHz, CDCl₃): d=139.4

(C), 128.3 (CH), 127.3 (CH), 125.6 (CH), 99.1 (C), 73.6 (CH), 65.9

(CH₂), 49.5 (CH), 29.7 (CH₃), 18.5 ppm (CH₃); IR (KBr): n˜_max=2990,

2938, 2871, 1605, 1586, 1498, 1450, 1379, 1271, 1238, 1199, 1161,

1051, 944, 865, 739, 700 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 208 (13)

0

+0.1

ꢀ0.1

25.8

21.1

25.7

21.2

[a] Data obtained from present work, recorded for samples in CDCl₃at

200 MHz. [b] Data obtained from Ref. [27], recorded for samples in CDCl₃

at 150 MHz.

The specific rotation ([a]_D) of our material, recorded at 188C,

was ꢀ5.7 (c=0.21, methanol) and this compares with a value

of ꢀ15 (c=0.24, methanol) recorded by Mulzer et al.^[27]at

208C. Two factors might be contributing to these rather dispa-

rate values. First of all, it is clear from Mulzer and co-workers’

studies^[27]that the specific rotation of platencin varies to a rea-

sonable degree as a function of temperature. Secondly, it is

conceivable that variations in specific rotation will occur as

a function of small variations in the pH because of the pres-

ence of acid residues attached to the aromatic core of (ꢀ)-pla-

tencin.

+

C

[M+H] , 192 (29) [Mꢀ CH₃] , 150 (24), 149 (40), 132 (100), 119 (68),

105 (66), 91 (94), 77 (92).

Compound 12

Following the procedure of Yamashita et al.,^[18]a magnetically

stirred solution of aldehyde 11 (405 mL, 4.2 mmol) in benzene

(8.7 mL) maintained under nitrogen in a round-bottomed flask

fitted with a Dean–Stark trap topped with a Liebig condenser was

treated successively with compound 10 (870 mg, 4.2 mmol), then

trifluoroacetic anhydride (15 mL). The ensuing mixture was heated

at reflux for 5 h, then cooled to 188C, diluted with diethyl ether

(15 mL) and dried (Na₂SO₄) before being filtered and concentrated

under reduced pressure to afford compound 12^[18](1.16 g, quant.)

as a light brown solid. ½aꢂ²_D⁵= +70.8 (c=1.0, CHCl₃); ¹H NMR

Conclusion

The present work has provided a new route to (ꢀ)-platencin

(2) and serves to demonstrate the utility of IMDA reactions of

the general form 6!5 as a means for the direct assembly of

the tricarbocyclic framework associated with this important

natural product. Although the reaction sequence reported

here is too lengthy to be of any real value in generating useful

&

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Full Paper

(300 MHz, CDCl₃): d=7.42 (s, 1H), 7.26–7.14 (complex m, 5H), 5.65

(m, 1H), 5.23 (d, J=2.7 Hz, 1H), 4.35 (dd, J=12.0, 2.7 Hz, 1H), 3.87

(dd, J=12.0, 2.4 Hz, 1H), 3.30 (m, 1H), 1.71 (m, 6H), 1.61 (s, 3H),

1.59 ppm (s, 3H); ¹³C NMR (101 MHz, CDCl₃): d=166.1 (CH), 139.2

(C), 137.3 (C), 135.7 (CH), 128.3 (CH), 127.6 (CH), 127.0 (CH), 99.4

(C), 74.3 (CH), 66.5 (CH), 65.2 (CH₂), 28.8 (CH₃), 19.8 (CH₃), 14.1

(CH₃), 11.1 ppm (CH₃); IR (KBr): n˜_max=2990, 2938, 2862, 1648, 1629,

gen in a round-bottomed flask fitted with a Dean–Stark trap

topped with a Liebig condenser was treated with 1,1-dimethylhy-

drazine (1.1 mL, 14.28 mmol) and trifluoroacetic anhydride (5 mL) at

188C. The resulting mixture was stirred under reflux conditions for

5 h, then cooled to room temperature and diluted with diethyl

ether (20 mL) and water (5 mL). The separated organic phase was

dried (Na₂SO₄), filtered, and concentrated under reduced pressure,

and the yellow residue thus obtained was subjected to column

chromatography (silica, 1:19 v/v ethyl acetate/hexane elution). Con-

centration of the relevant fractions (R_f=0.5 in 1:9 v/v ethyl ace-

tate/hexane) afforded (E)-2-methylbut-2-enal N,N-dimethylhydra-

1451, 1378, 1267, 1238, 1196, 1168, 1127, 1097, 849, 745, 698 cm^ꢀ1

;

MS (EI, 70 eV): m/z (%): 273 (1) [M⁺], 258 (7), 109 (100), 108 (53),

C

94 (63), 82 (45); HRMS (EI, 70 eV): m/z calcd for C₁₇H₂₃NO₂:

+

273.1729 [M⁺]; found: 273.1738 [M ].

C

zone^[29](1.00 g, 66% yield) as

a

clear, colorless oil. ¹H NMR

(400 MHz, CDCl₃): d=7.04 (s, 1H), 5.63 (m, 1H), 2.80 (s, 6H), 1.83 (s,

3H), 1.77 ppm (d, J=8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

140.6, 135.2, 127.3, 43.2, 13.8, 11.3 ppm; IR (KBr): n˜_max=3354, 2952,

2918, 2854, 2787, 1590, 1120 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 127 (24)

[M+H⁺], 111 (26), 100 (34), 87 (63), 84 (100), 72 (52); HRMS (EI,

70 eV): m/z calcd for C₇H₁₄N₂: 127.1235 [M+H]⁺; found: 127.1236

[M+H]⁺

Compound 14

In a minor modification of the procedure described by Yamashita

et al.,^[18]

a magnetically stirred solution of diisopropylamine

(24.7 mL, 170 mmol) in THF (87 mL) maintained under nitrogen

was cooled to ꢀ158C, then nBuLi (99.0 mL of a 1.6m solution in

hexane, 159 mmol) was added dropwise. The ensuing mixture was

maintained at ꢀ158C for 0.5 h before being cooled to ꢀ788C, and

a solution of compound 12 (28.96 g, 106 mmol) in THF (87 mL)

was then added. After 2 h, compound 13^[20](43.9 g, 159 mmol) was

also added, and the ensuing mixture was allowed to warm to 188C

over 16 h before being quenched with water (670 mL), then treat-

ed with THF (1100 mL) and HCl (670 mL of a 2m aqueous solution).

After being stirred at 188C for 5 h, the reaction mixture was diluted

with diethyl ether (500 mL) and the separated aqueous phase ex-

tracted with diethyl ether (1ꢁ500 mL). The combined organic

phases were dried (Na₂SO₄), filtered, and concentrated under re-

duced pressure to give a dark brown oil. Subjection of this material

to flash column chromatography (silica, 1:19 v/v ethyl acetate/

hexane elution) and concentration of the appropriate fractions af-

forded three fractions: A, B, and C.

Step 2:

A magnetically stirred solution of diisopropylamine

(570 mL, 4.04 mmol) in THF (8 mL) maintained under a nitrogen at-

mosphere at ꢀ58C was treated with nBuLi (2.5 mL of a 1.6m solu-

tion in hexane, 4.08 mmol), and after another 0.5 h, a solution of

(E)-2-methylbut-2-enal N,N-dimethylhydrazone (500 mg, 3.96 mmol)

in THF (2 mL) was added to the reaction mixture. After another

1 h, iodide 13 (930 mg, 4.08 mmol) was added, and the resulting

mixture was warmed to approximately 188C, then stirred at this

temperature for 20 h before being diluted with diethyl ether

(10 mL) and water (10 mL). The separated organic layer was

washed with brine (1ꢁ10 mL), then dried (Na₂SO₄), filtered, and

concentrated under reduced pressure. The yellow residue obtained

in this way was subjected to flash chromatography (silica, 1:9 v/v

ethyl acetate/hexane elution), and concentration of the relevant

fractions (R_f=0.2) afforded the anticipated C-alkylation product

Concentration of fraction A (R_f=0.4 in 1:9 v/v ethyl acetate/

hexane) afforded the starting iodide 13 (15.0 g, 34% recovery) that

was identical in all respects to an authentic sample.

1

(500 mg, 46%) as clear, colorless oil. H NMR (400 MHz, CDCl₃): d=

7.34–7.27 (complex m, 5H), 6.49 (s, 1H), 5.87 (dd, J=17.2, 10.8 Hz,

1H), 4.96–5.04 (complex m, 2H), 4.49 (s, 2H), 3.45 (m, 2H), 2.71 (s,

6H), 1.59 (m, 4H), 1.16 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

144.9, 143.4, 138.6, 128.3, 127.6, 127.4, 112.2, 72.8, 71.0, 43.3, 35.8,

24.7, 22.3 ppm; IR (KBr): n˜_max=3082, 3029, 2950, 2852, 2783, 1634,

Concentration of fraction B (R_f=0.4 in 1:9 v/v ethyl acetate/

hexane) afforded aldehyde 14 (12.0 g, 53%) as a light yellow oil.

½aꢂ²_D⁵= +20.2 (c=1.0, CHCl₃); H NMR (300 MHz, CDCl₃): d=9.37 (s,

1

1H), 7.35–7.25 (complex m, 5H), 5.76 (dd, J=17.4, 10.8 Hz, 1H),

5.26 (dd, J=10.8, 0.6 Hz, 1H), 5.12 (d, J=17.4, 0.6 Hz, 1H), 4.47 (s,

2H), 3.45 (t, J=6.0 Hz, 2H), 1.60 (m, 2H), 1.53 (m, 2H), 1.16 ppm (s,

3H); ¹³C NMR (75 MHz, CDCl₃): d=202.6, 138.5, 138.4, 128.3, 127.6,

1602, 1495, 1468, 1454, 1410, 1362, 1249, 1204, 1137, 1101 cm^ꢀ1

;

MS (EI, 70 eV): m/z (%): 274 (10) [M⁺], 183 (66), 125 (100), 98 (35),

C

91 (91), 82 (36); HRMS (EI, 70 eV): m/z calcd for C₁₇H₂₆N₂O:

+

274.2045 [M⁺]; found: 274.2042 [M ].

C

127.5, 116.8, 72.8, 70.3, 52.4, 31.8, 24.3, 17.6 ppm; IR (KBr): n˜_max

=

2948, 2858, 1726, 1632, 1454, 1368, 1102, 923, 736, 697 cm^ꢀ1; MS

(ESI⁺): m/z (%): 255 (100) [M+Na]⁺, 125 (81); HRMS (ESI⁺): m/z

calcd for C₁₅H₂₀O₂: 255.1361 [M+Na]⁺; found: 255.1362 [M+Na]⁺.

Step 3: A magnetically stirred solution of CuCl₂(59 mg, 0.40 mmol)

in water (3.65 mL) maintained at 188C was treated with a solution

of the product of step 2 (100 mg, 0.37 mmol) in THF (5.5 mL). The

resulting mixture was stirred at this temperature for 4 h, then

quenched with ammonia (5 mL of an 3m aqueous solution) and

extracted with ethyl acetate (3ꢁ10 mL). The combined organic

phases were dried (Na₂SO₄), filtered, and concentrated under re-

duced pressure. The resulting brown residue was subjected to

flash chromatography (silica, 1:19 v/v ethyl acetate/hexane elution)

to afford, after concentration of the relevant fractions (R_f=0.4 in

1:9 v/v ethyl acetate/hexane), compound (ꢁ)-14 (67 mg, 79%) as

a clear, yellow oil. The spectral data recorded on this material were

identical in all respects to those obtained from compound 14.

Concentration of fraction C (R_f=0.5 in 1:4 v/v ethyl acetate/

hexane) afforded (E)-7-(benzyloxy)-2-methylhept-2-enal^[28](2.32 g,

9%) as a light yellow oil. H NMR (300 MHz, CDCl₃): d=9.39 (s, 1H),

7.36–7.25 (complex m, 5H), 6.48 (m, 1H), 4.51 (s, 2H), 3.50 (m, 2H),

2.37 (m, 2H), 1.73 (s, 3H), 1.65–1.50 ppm (complex m, 4H);

¹³C NMR (75 MHz, CDCl₃): d=195.2, 154.4, 139.4, 138.4, 128.3,

1

127.5, 72.9, 69.7, 29.6, 29.4, 28.7, 25.1, 9.1 ppm; IR (KBr): n˜_max

=

2926, 2854, 1686, 1454, 1102 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 232 (9)

[M⁺], 141 (72), 126 (58), 108 (38), 92 (100), 79 (40), 65 (50); HRMS

C

(EI, 70 eV): m/z calcd for C₁₅H₂₀O₂[M⁺]: 232.1463; found: 232.1467

C

[M⁺].

C

Formation of the SAMP Hydrazones of Compounds 14 and

(ꢁ)-14

Compound (ꢁ)-14

Step 1: A magnetically stirred solution of (E)-2-methylbut-2-enal

A magnetically stirred solution of aldehyde 14 (20 mg, 0.09 mmol)

(1.00 g, 11.90 mmol) in benzene (4.8 mL) maintained under nitro-

in benzene (1 mL) maintained under a nitrogen atmosphere at

Chem. Asian J. 2014, 00, 0 – 0

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7

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188C was treated with SAMP (22 mg, 0.17 mmol) and trifluoroace-

tic acid (2 mL). The ensuing mixture was heated under reflux condi-

tions for 2 h, then cooled to 188C and diluted with diethyl ether

(5 mL) before being dried (Na₂SO₄), filtered, and concentrated

under reduced pressure. The yellow residue thus obtained was

subjected to flash chromatography (silica, 1:20 v/v ethyl acetate/

hexane elution), and concentration of the appropriate fractions

(R_f=0.3 in 1:4 v/v ethyl acetate/hexane) afforded the SAMP hydra-

zone of compound 14 (20 mg, 67% yield) as a light yellow oil in

1638, 1495, 1454, 1414, 1369, 1098 cm^ꢀ1; MS (EI, 70 eV): m/z (%):

258 (5) [M⁺], 225 (10), 203 (68), 185 (45), 157 (28), 143 (53), 129

C

(40), 117 (40), 107 (60), 95 (87), 92 (100), 65 (78); HRMS (EI, 70 eV):

+

m/z calcd for C₁₇H₂₂O₂: 258.1620 [M⁺]; found: 258.1620 [M ].

C

Compound 8 (P=Bn)

A solution of propargyl alcohol 15 (850 mg, 3.3 mmol) in hexane

(15 mL) was poured into a flask that contained Bu₂Sn(OTf)H

(3.40 g, 8.47 mmol) prepared according to the method of Hosomi

et al.^[21]and maintained at 188C. The ensuing mixture was stirred

at 188C for 16 h, then diluted with anhydrous diethyl ether (15 mL)

and cooled to 08C before being treated with nBuLi (2.64 mL of

a 2.5m solution in hexane, 6.6 mmol). After 0.25 h, the reaction

mixture was quenched with a mixture of NH₄Cl (20 mL of a saturat-

ed aqueous solution) and water (20 mL) before being filtered

through Celite and the filtrate extracted with diethyl ether (3ꢁ

20 mL). The combined organic fractions were dried (Na₂SO₄), fil-

tered, and concentrated under reduced pressure to give a clear,

colorless oil that was subjected to flash chromatography (silica,

1:20 v/v ethyl acetate/hexane elution). Concentration of the rele-

vant fractions (R_f=0.6 in 1:9 v/v ethyl acetate/hexane) afforded

compound 8 (P=Bn) (980 mg, 54% yield) as a clear, colorless oil

and very unstable material that was immediately subjected to the

next step of the reaction sequence.

1

92% ee. ½aꢂ²_D⁰=ꢀ63.6 (c=1.0, CHCl₃); H NMR (300 MHz, CDCl₃): d=

7.34–7.26 (complex m, 5H), 6.49 (s, 1H), 5.87 (dd, J=17.4, 10.8 Hz,

1H), 5.04–4.93 (complex m, 2H), 4.49 (s, 2H), 3.59 (dd, J=9.0,

3.6 Hz, 1H), 3.47–3.27 (complex m, 5H), 3.37 (s, 3H), 2.70 (m, 1H),

1.99–1.74 (complex m, 4H), 1.67–1.52 (complex m, 4H), 1.15 ppm

(s, 3H); ¹³C NMR (75 MHz, CDCl₃): d=145.1, 143.0, 138.6, 128.3,

127.6, 127.4, 112.0, 74.6, 72.8, 71.0, 63.4, 59.2, 49.9, 43.4, 35.8, 26.5,

24.7, 22.4, 21.9 ppm; IR (KBr): n˜_max=2925, 2854, 1596, 1453, 1361,

1197, 1114 cm^ꢀ1; MS (ESI⁺): m/z (%): 367 (14) [M+Na]⁺, 345 (100)

[M+H]⁺, 237 (35), 143 (68), 129 (24), 91 (50); HRMS (ESI⁺): m/z

calcd for C₂₁H₃₂N₂O₂: 367.2361 [M+Na]⁺; found: 367.2364 [M+Na]⁺

.

Analogous treatment of the racemic modification (namely (ꢁ)-14)

of aldehyde 14 afforded a light yellow oil on workup. Subjection of

this material to flash chromatography (silica, 1:20 v/v ethyl acetate/

hexane elution) and concentration of the appropriate fractions

(R_f=0.5 in 1:4 v/v ethyl acetate/hexane) afforded a 1:1 mixture of

the diastereoisomeric forms of the SAMP hydrazones of compound

Compound 16

1

(ꢁ)-14 (22 mg, 73% yield) as a pale yellow oil. The H and ¹³C NMR

A magnetically stirred solution of iodide 7 (1.10 g, 3.95 mmol) and

alkenyl stannane 8 (P=Bn) (2.39 g, 4.35 mmol) in DMF (9.6 mL)

maintained at 188C under a nitrogen atmosphere was treated with

cesium fluoride (1.20 g, 7.9 mmol), [Pd(PPh₃)₄] (204 mg, 0.20 mmol),

and CuI (75 mg, 0.40 mmol). The ensuing mixture was stirred at

188C for 16 h, then diluted with water (90 mL) and dichlorome-

thane (225 mL) before being filtered through a pad Celite that was

washed with ethyl acetate/dichloromethane (300 mL of a 1:1 v/v

mixture). The separated organic phase derived from the filtrate

was dried (Na₂SO₄), filtered, and concentrated under reduced pres-

sure, and the resulting dark brown oil was subjected to flash chro-

matography (silica, 1:5 v/v ethyl acetate/hexane elution) to afford

two fractions, A and B.

spectroscopic as well as the IR and mass spectral data recorded on

this mixture were essentially indistinguishable from those obtained

from the SAMP hydrazone of compound 14 as detailed immediate-

ly above.

High-performance liquid chromatography (HPLC) analysis of the

SAMP hydrazone of compound 14 on a Daicel Chiracel OD-H

column eluted isocratically using 1% isopropanol in hexane elution

at a flow rate of 1 mLmin^ꢀ1revealed peaks at 12.4 and 13.3 min in

a 96:4 ratio. The equivalent analysis of the SAMP hydrazones de-

rived from compound (ꢁ)-14 showed the same peaks in a 1:1

ratio.

Concentration of fraction A (R_f=0.4(6) in 3:7 v/v ethyl acetate/

hexane) afforded a single diastereoisomeric form of compound 16

(630 mg, 39%) as light brown oil. ½aꢂ²_D⁵=ꢀ11.1 (c=1.0, CHCl₃);

¹H NMR (500 MHz, CDCl₃): d=7.38–7.26 (complex m, 5H), 6.10–6.07

(complex m, 2H), 5.92–5.89 (complex m, 1H), 5.80 (dd, J=17.5,

10.5 Hz, 2H), 5.66 (dd, J=12.5, 10.5 Hz, 1H), 5.16 (dd, J=11.0,

1.5 Hz, 1H), 5.05 (dd, J=17.5, 1.5 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H),

4.74 (dd, J=9.0, 3.5 Hz, 1H), 4.48 (s, 2H), 4.34 (dd, J=10.0, 5.0 Hz,

1H), 3.44 (m, 2H), 2.70 (d, J=5.0 Hz, 1H), 1.60–1.34 (complex m,

3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.08 (s, 3H), 0.92 ppm (m, 1H);

¹³C NMR (100 MHz, CDCl₃): d=142.5, 138.5, 133.2, 131.2, 131.0,

128.3, 127.6, 127.5, 124.8, 124.7, 124.6, 114.8, 105.5, 73.0, 72.8, 72.7,

Compound 15

A magnetically stirred solution of ethynylmagnesium bromide in

THF (12.5 mL of a 0.5m solution, 6.26 mmol) maintained at ꢀ108C

was treated dropwise with aldehyde 14 (1.21 g, 5.22 mmol). The

ensuing mixture was stirred at ꢀ108C for 1.5 h then quenched

with NH₄Cl (50 mL of a saturated aqueous solution) and extracted

with ethyl acetate (3ꢁ50 mL). The combined organic phases were

washed with brine (2ꢁ10 mL) before being dried (Na₂SO₄), filtered,

and concentrated under reduced pressure. The light brown oil

thus obtained was subjected to flash chromatography (silica,

3:20!5:20 v/v ethyl acetate/hexane gradient elution), and concen-

tration of the relevant fractions (R_f=0.5 in 1:4 v/v ethyl acetate/

hexane) afforded compound 15 (1.31 g, 85%) as a light yellow oil

and an approximately 1:1 mixture of diastereoisomers. ¹H NMR

(300 MHz, CDCl₃): d=7.29–7.20 (complex m, 5H), 5.76 (m, 1H), 5.18

(dd, J=10.5, 1.2 Hz, 1H), 5.05 (ddd, J=17.4, 3.0, 1.2 Hz, 1H), 4.43

(s, 2H), 4.08–4.00 (complex m, 1H), 3.38 (m, 2H), 2.45 (m, 0.5H),

2.04–2.02 (m, 1.5H), 1.51–1.45 (complex m, 4H), 1.03 ppm (s, 3H);

¹³C NMR (100 MHz, CDCl₃): d=142.0, 141.3, 138.4, 128.3, 127.6,

127.5, 116.4, 116.2, 82.8, 82.5, 74.4(2), 74.3(5), 72.8, 70.8, 69.2, 69.1,

44.9(0), 44.8(7), 33.0, 32.7, 24.3, 24.2, 18.2, 17.5 ppm (six signals ob-

scured or overlapping); IR (KBr): n˜_max=3419, 3298, 2947, 2859,

71.3, 71.0, 43.7, 33.2, 26.7, 24.8, 24.3, 18.4 ppm; IR (KBr): n˜_max

=

3481, 2982, 2934, 2870, 1454, 1379, 1370, 1235, 1209, 1159, 1099,

1078, 1051, 1028, 1005, 913, 892, 867, 736, 698 cm^ꢀ1; MS (ESI⁺):

m/z (%): 433 (100) [M+Na]⁺; HRMS (ESI⁺): m/z calcd for C₂₆H₃₄O₄:

433.2355 [M+Na]⁺; found: 433.2359 [M+Na]⁺.

Concentration of fraction B (R_f=0.4(3) in 3:7 v/v ethyl acetate/

hexane) afforded the second diastereoisomeric form of compound

16 (660 g, 41%) as a light brown oil. ½aꢂ²_D⁵= +58.4 (c=1.0, CHCl₃);

¹H NMR (500 MHz, CDCl₃): d=7.40–7.26 (complex m, 5H), 6.21 (d,

J=12.0 Hz, 1H), 6.08–6.01 (complex m, 2H), 5.89–5.81 (complex m,

2H), 5.64 (m, 1H), 5.22 (dd, J=11.0, 1.5 Hz, 1H), 5.08 (dd, J=17.5,

&

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+

C

1.5 Hz, 1H), 4.78 (m, 1H), 4.69 (d, J=8.5 Hz, 1H), 4.48 (s, 2H), 4.40

(brd, J=10.0 Hz, 1H), 3.44 (m, 2H), 1.75–0.09 (complex m, 5H),

1.44 (s, 6H), 0.95 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=143.0,

138.6, 132.7, 132.3, 130.4, 128.3, 127.6, 127.5, 126.2, 124.8, 123.5,

115.5, 105.3, 72.9, 72.2, 72.1, 71.8, 71.0, 44.3, 33.8, 26.8, 25.0, 24.4,

17.1 ppm; IR (KBr): n˜_max=3435, 2981, 2931, 2856, 1454, 1380, 1370,

1235, 1210, 1098, 1050, 1028, 914, 736, 697 cm^ꢀ1; MS (ESI⁺): m/z

(%): 433 (100) [M+Na]⁺; HRMS (ESI⁺): m/z calcd for C₂₆H₃₄O₄:

433.2355 [M+Na]⁺; found: 433.2357 [M+Na]⁺.

(16) [Mꢀ CH₃] , 259 (52), 241 (33), 201 (66), 91 (100); HRMS (EI,

+

C

70 eV): m/z calcd for C₂₆H₃₂O₄: 393.2066 [Mꢀ CH₃] ; found:

+

C

393.2063 [Mꢀ CH₃] .

Compound 17

A magnetically stirred solution of unsaturated ketone 5 (P=Bn)

(640 mg, 1.57 mmol) in methanol was treated with 10% palladium

on carbon (640 mg), and the resulting suspension was stirred at

188C under a hydrogen atmosphere for 16 h. The mixture thus ob-

tained was filtered through a pad of Celite that was washed with

ethyl acetate (150 mL). The combined filtrates were concentrated

under reduced pressure to give the title compound 17 (495 mg,

94% yield) as a white, crystalline solid. M.p. 1068C; ½aꢂ²_D⁵=ꢀ34.0

(c=1.0, CHCl₃) (R_f=0.6 in 3:7 v/v ethyl acetate/hexane); ¹H NMR

(400 MHz, CDCl₃): d=4.13 (dd, J=8.4, 4.0 Hz, 1H), 3.63 (dd, J=8.4,

2.0 Hz, 1H), 3.60–3.57 (complex m, 2H), 3.17 (s, 3H), 1.90–1.51

(complex m, 9H), 1.50–1.35 (complex m, 4H), 1.49 (s, 3H), 1.35 (s,

3H), 1.34–1.21 (complex m, 3H), 1.03 ppm (s, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=108.1, 100.8, 83.8, 76.3, 60.2, 47.1, 39.2,

34.6, 33.5, 30.4, 29.7, 28.9, 25.7, 24.5, 24.3, 24.2, 21.0, 19.7,

19.4, 19.0 ppm; IR (KBr): n˜_max=2980, 2938, 2873, 2823, 1471,

1381, 1368, 1260, 1201, 1164, 1119, 1107, 1093, 1071, 1035, 930,

Compound 6 (P=Bn)

A magnetically stirred solution of tetraene 16 (1.70 g of an 1:1 mix-

ture of diastereoisomers, 4.14 mmol) in dichloromethane (83 mL)

maintained at 08C under a nitrogen atmosphere was treated with

pyridine (2.13 mL, 27.51 mmol), then the Dess–Martin periodinane

(3.16 g, 7.46 mmol). The ensuing mixture was stirred at 08C for

0.75 h and then at 188C for an additional 0.5 h before being dilut-

ed with diethyl ether (80 mL). The mixture thus obtained was fil-

tered through Celite, and the filtrate was concentrated under re-

duced pressure to give a clear, yellow oil. This was subjected to

flash chromatography (silica, 1:5 v/v ethyl acetate/hexane elution)

to afford two fractions, A and B.

901, 878, 819 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 336 (2) [M⁺], 321 (85)

C

Concentration of fraction A (R_f=0.7 in 3:7 v/v ethyl acetate/

hexane) afforded compound 6 (P=Bn) (900 mg, 69% yield at 77%

conversion) as a light yellow oil. ½aꢂ²_D⁵= +91.5 (c=1.0, CHCl₃);

¹H NMR (500 MHz, CDCl₃): d=7.35–7.27 (complex m, 5H), 6.31–6.27

(m, 2H), 6.21 (d, J=13.0 Hz, 1H), 6.11 (dd, J=10.0, 6 Hz, 1H), 6.01

(m, 1H), 5.91 (dd, J=17.5, 10.5 Hz, 1H), 5.21–5.07 (complex m, 3H),

4.65 (dd, J=9.0, 4.5 Hz, 1H), 4.49 (s, 2H), 3.47 (t, J=7.0 Hz, 2H),

1.75 (t, J=8.5 Hz, 2H), 1.58–1.55 (complex m, 2H), 1.34 (s, 3H),

1.30 (s, 3H), 1.27 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=204.4,

141.9, 138.5, 137.7, 134.1, 128.7, 128.3, 127.5(8), 127.5(0), 127.5(6),

126.4, 124.9, 115.1, 105.4, 72.9, 70.9, 70.8, 70.7, 53.4, 33.6, 26.8,

25.0, 24.6, 19.7 ppm; IR (KBr): n˜_max=2982, 2934, 2858, 1683, 1630,

1591, 1454, 1407, 1235, 1207, 1159, 1100, 1056, 1027, 917, 871,

735, 697 cm^ꢀ1; MS (ESI⁺): m/z (%): (100) [M+Na]⁺; HRMS (ESI⁺):

m/z calcd for C₂₆H₃₂O₄: 431.2198 [M+Na]⁺; found: 431.2197

[M+Na]⁺.

+

C

[Mꢀ CH₃] , 304 (100), 289 (58), 231 (58), 202 (39), 127 (36), 85 (51),

69 (59), 55 (70); HRMS (EI, 70 eV): m/z calcd for C₂₀H₃₂O₄: 321.2066

+

C

[Mꢀ CH₃] ; found: 321.2070 [Mꢀ CH₃] .

Compound 18

A magnetically stirred solution of ketal 17 (930 mg, 2.77 mmol) in

acetone (93 mL) was treated with HCl (93 mL of a 1m aqueous so-

lution), and the resulting mixture was stirred at 188C for 0.17 h,

then extracted with ethyl acetate (3ꢁ100 mL). The combined or-

ganic phases were washed with brine (1ꢁ20 mL) before being

dried (MgSO₄), filtered, and concentrated under reduced pressure

to afford a white solid presumed to be the lactol derived from the

starting material. This solid was dissolved in dichloromethane

(40 mL) and the resulting solution was stirred magnetically at

188C, and then treated with 4 ꢂ molecular sieves (200 mg), sodium

acetate (354 mg, 4.26 mmol), and PCC (2.29 g, 10.64 mmol). After

2 h, the reaction mixture was diluted with diethyl ether (100 mL),

then filtered through a pad of Celite, and the solids thus retained

were washed with diethyl ether (2ꢁ100 mL). The combined fil-

trates were concentrated under reduced pressure to afford a pale

yellow oil presumed to contain the aldehydic precursor to acid 18.

A magnetically stirred solution of this oil in tBuOH (19.7 mL) main-

tained at 188C and that contained water (6.02 mL) was treated

with 2-methyl-2-butene (1.50 mL), NaH₂PO₄·H₂O (338 mg,

2.45 mmol), and NaClO₂(177 mg, 1.97 mmol). After 1 h, the reac-

tion mixture was quenched with brine (50 mL) and extracted with

ethyl acetate (4ꢁ50 mL). The combined organic phases were dried

(Na₂SO₄), filtered, and concentrated under reduced pressure to

give a light yellow oil that was subjected to column chromatogra-

phy (60:40:05 v/v ethyl acetate/hexane/acetic acid elution). Con-

centration of the relevant fractions (R_f=0.2 in 2:3 v/v ethyl ace-

tate/hexane) afforded carboxylic acid 18 (440 mg, 47% from 17) as

Concentration of fraction B (R_f=0.5 in 3:7 v/v ethyl acetate/

hexane) afforded an 1:1 mixture of the diastereoisomeric forms of

the starting material 16 (391 mg, 23% recovery) that was identical

in all respects with an authentic sample.

Compound 5 (P=Bn)

A magnetically stirred solution of tetraene 6 (1.03 g, 2.70 mmol) in

toluene (1 L) was stirred under reflux conditions for 16 h then

cooled and concentrated under reduced pressure. The resulting

dark residue was subjected to flash chromatography (silica, 1:5 v/v

ethyl acetate/hexane elution), and concentration of the appropri-

ate fractions (R_f=0.5 in 3:7 v/v ethyl acetate/hexane) afforded

compound 5 (P=Bn) (720 mg, 70%) as a white, crystalline solid.

1

M.p. 548C; ½aꢂ²_D⁵= +61.0 (c=1.0, CHCl₃); H NMR (400 MHz, CDCl₃):

d=7.34–7.27 (complex m, 5H), 7.13 (d, J=10.0 Hz, 1H), 6.21 (m,

1H), 6.02 (d, J=10.0 Hz, 1H), 5.83 (brd, J=8.4 Hz, 1H), 4.48 (s, 2H),

4.26 (dd, J=6.8, 2.8 Hz, 1H), 3.86 (d, J=8.0 Hz, 1H), 3.51–3.36

(complex m, 2H), 2.92 (m, 1H), 1.94 (m, 1H), 1.84 (m, 1H), 1.63–

1.40 (complex m, 3H), 1.35 (s, 3H), 1.27 (s, 3H), 1.26–1.15 (complex

m, 2H), 0.81 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=203.6,

149.5, 138.6, 130.9, 130.7, 128.3, 128.1, 127.6, 127.5, 109.2, 82.5,

78.6, 72.8, 70.8, 47.8, 43.4, 37.4, 35.1, 31.1, 25.4, 25.1, 24.9, 23.8,

23.0 ppm; IR (KBr): n˜_max=2923, 2852, 1683, 1595, 1454, 1371, 1208,

1161, 1098, 1071, 918, 737, 698 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 393

a clear, colorless oil. ½aꢂ_D²⁵=ꢀ1.2 (c=1.0, CHCl₃); H NMR (400 MHz,

1

CDCl₃): d=4.17 (m, 1H), 3.64 (d, J=7.6 Hz, 1H), 2.59 (m, 1H), 2.32

(m, 2H), 2.20 (td, J=14.4, 4.8 Hz, 1H), 1.99–1.50 (complex m, 15H),

1.52 (s, 3H), 1.36 (s, 3H), 1.25 ppm (s, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=215.5, 179.0, 108.7, 82.1, 75.8, 50.2, 40.6, 34.6, 33.9, 33.0,

31.2, 29.3, 29.1, 25.7, 24.2, 24.1, 20.4, 19.8, 19.1 ppm; IR (KBr): n˜_max

2934, 1706, 1471, 1454, 1380, 1281, 1261, 1207, 1163, 1067, 1037,

=

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974 cm^ꢀ1; MS (ESI^ꢀ): m/z (%): 335 (100) [MꢀH⁺]^ꢀ; HRMS (ESI^ꢀ): m/z

calcd for C₁₉H₂₈O₅: 335.1858 [MꢀH⁺]^ꢀ; found: 335.1858 [MꢀH⁺]^ꢀ.

Compound 21

A magnetically stirred mixture of p-TsOH·H₂O (412 mg, 2.215 mmol)

and 4-acetamido-TEMPO (320 mg, 1.03 mmol) in dichloromethane

(21 mL) was maintained at 188C for 0.5 h, and the resulting sus-

pension was added, in portions, to a magnetically stirred solution

of compound 20 (320 mg, 1.032 mmol) in dichloromethane

(21 mL) maintained at 08C. Stirring was continued for a further

2.5 h, then the resulting mixture was quenched with NaHCO₃

(20 mL of a saturated aqueous solution). The separated aqueous

phase was extracted with dichloromethane (3ꢁ100 mL) and the

combined organic fractions washed with water (1ꢁ10 mL) and

brine (1ꢁ10 mL) before being dried (Na₂SO₄), filtered, and concen-

trated under reduced pressure. The resulting light yellow oil was

subjected to flash chromatography (silica, 2:3 v/v ethyl acetate/

hexane elution) to afford, after concentration of the appropriate

fractions (R_f=0.4), acyloin 21 (262 mg, 82%) as a clear, colorless oil.

½aꢂ²_D⁵= +15.1 (c=1, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=3.65 (s,

3H), 3.43 (s, 1H), 2.93 (s, 1H), 2.63 (m, 1H), 2.50 (brs, 1H), 2.36–

2.22 (complex m, 3H), 2.05–1.58 (complex m, 11H), 1.28 ppm (s,

3H); ¹³C NMR (100 MHz, CDCl₃): d=217.5, 214.1, 173.9, 81.0, 51.6,

50.4, 42.2, 41.1, 39.9, 34.7, 31.1, 31.0, 29.4, 26.4, 23.0, 20.3(4),

20.2(7) ppm; IR (KBr): n˜_max=3417, 2951, 2870, 1730, 1706, 1465,

1438, 1384, 1313, 1298, 1195, 1180, 1142, 1100, 1070 cm^ꢀ1; MS (EI,

Compounds 19 and 20

A magnetically stirred solution of carboxylic acid 18 (440 mg,

1.31 mmol) in methanol/water (12.3 mL of a 5:1 v/v mixture) was

treated with DOWEX-50 resin (465 mg, acidified form). The ensuing

mixture was heated at 658C for 48 h, then cooled. The resin was

removed by filtration and washed with methanol (3ꢁ10 mL). The

combined filtrates were concentrated under reduced pressure and

the residue diluted with brine (5 mL), then extracted with ethyl

acetate (3ꢁ25 mL). The combined organic phases were dried

(Na₂SO₄), filtered, and concentrated under reduced pressure and

the light yellow oil thus obtained subjected to column chromatog-

raphy (silica, 30:70 v/v ethyl acetate/hexane!80:20:0.5 v/v ethyl

acetate/hexane/acetic acid gradient elution) to afford three frac-

tions: A, B, and C.

Concentration of fraction A (R_f=0.4 in 3:7 v/v ethyl acetate/

hexane) afforded methyl ester 19 (110 mg, 24%) as a clear, color-

less oil. ½aꢂ²_D⁵=ꢀ1.3 (c=1.0, CHCl₃); H NMR (400 MHz, CDCl₃): d=

1

70 eV): m/z (%): 308 (21) [M⁺], 293 (19), 276 (90), 222 (73), 221

C

4.17 (dd, J=7.6, 3.2 Hz, 1H), 3.65 (s, 3H), 2.61–2.52 (complex m,

1H), 2.26 (t, J=7.6 Hz, 2H), 2.19 (dt, J=15.2, 4.8 Hz, 1H), 1.97–1.90

(complex m, 3H), 1.80–1.54 (complex m, 7H), 1.51 (s, 3H), 1.50–

1.47 (complex m, 3H), 1.35 (s, 3H), 1.23 ppm (s, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=215.3, 174.1, 108.7, 82.0, 76.0, 51.6, 50.2, 40.4,

34.6, 33.9, 32.9, 31.5, 29.5, 29.1, 25.7, 24.2, 24.1, 20.5, 19.9,

19.1 ppm; IR (KBr): n˜_max=2935, 2879, 1738, 1706, 1437, 1380, 1296,

(80), 55 (100); HRMS (EI, 70 eV): m/z calcd for C₁₇H₂₄O₅: 308.1624

[M⁺]; found: 308.1627 [M ].

+

C

Compound 22

A magnetically stirred solution of acyloin 21 (255 mg, 0.828 mmol)

in dichloromethane (11.6 mL) maintained at 188C was treated, in

portions and successively, with triethylamine (230 mL, 1.66 mmol),

benzoyl chloride (370 mL, 3.15 mmol), and DMAP (17 mg, cat.). The

ensuing mixture was stirred at 188C for 16 h, then quenched with

NaHCO₃(20 mL of a saturated aqueous solution). The resulting bi-

phasic system was stirred for 0.5 h at 188C, then diluted with di-

chloromethane (20 mL). The separated aqueous phase was extract-

ed with dichloromethane (3ꢁ20 mL), and the combined organic

fractions were then washed with brine (1ꢁ5 mL) before being

dried (Na₂SO₄), filtered, and concentrated under reduced pressure.

The light yellow oil thus obtained was subjected to flash chroma-

tography (silica, 2:3 v/v ethyl acetate/hexane elution) to afford,

after concentration of the appropriate fractions (R_f=0.7 in 3:2 v/v

ethyl acetate/hexane), compound 22 (323 mg, 95%) as a clear, col-

1261, 1207, 1165, 1067, 1038, 974, 876, 812, 731, 647, 517 cm^ꢀ1; MS

+

(EI, 70 eV): m/z (%): 350 (2) [M⁺], 335 (100) [Mꢀ CH₃] , 303 (23),

C

263 (54), 243 (73), 215 (29), 205 (28), 91 (30), 55 (30); HRMS (EI,

70 eV): m/z calcd for C₂₀H₃₀O₅: 335.1858 [Mꢀ CH₃] ; found:

+

C

+

C

335.1858 [Mꢀ CH₃] .

Concentration of fraction B (R_f=0.4 in 80:20:0.5:1.0:0.5 v/v ethyl

acetate/hexane/water/methanol/acetic acid) afforded compound

20 (198 mg, 49%) as a clear, colorless oil. ½aꢂ²_D⁵=ꢀ0.9 (c=0.6,

1

CHCl₃); H NMR (400 MHz, CDCl₃): d=3.98 (dm, J=8.4 Hz, 1H), 3.66

(s, 3H), 3.47 (brd, J=8.4 Hz, 1H), 2.51 (m, 1H), 2.27–2.20 (complex

m, 2H), 2.00–1.30 (complex m, 15H) 1.21 ppm (s, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=215.7, 174.0, 73.6, 68.1, 51.6, 49.9, 39.5, 35.0,

34.9, 32.3, 31.4, 31.3, 29.4, 24.7, 20.8, 20.8, 19.0 ppm; IR (KBr): n˜_max

=

orless oil. ½aꢂ²_D⁵= +95.5 (c=1.0, CHCl₃); H NMR (400 MHz, CDCl₃):

1

3405, 2931, 2869, 1736, 1705, 1594, 1438, 1381, 1299, 1259, 1199,

1170, 1135, 1107, 1070, 1029, 987 cm^ꢀ1; MS (ESI⁺): m/z (%): 310

d=8.03–8.01 (complex m, 2H), 7.59–7.55 (complex m, 1H), 7.45–

7.42 (complex m, 2H), 5.16 (d, J=1.6 Hz, 1H), 3.64 (s, 3H), 2.62–

2.54 (complex m, 2H), 2.33–1.60 (complex m, 14H), 1.28 ppm (s,

3H); ¹³C NMR (100 MHz, CDCl₃): d=213.4, 210.4, 173.7, 165.7,

133.4, 129.8, 129.1, 128.4, 79.1, 51.6, 50.1, 42.0, 41.0, 39.2, 34.4,

31.1, 30.1, 29.2, 25.0, 23.3, 21.8, 20.5 ppm; IR (KBr): n˜_max=2950,

2874, 1737, 1471, 1451, 1437, 1315, 1270, 1195, 1177, 1111, 1070,

1025, 991, 915, 853, 802, 731, 711 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 412

(<1) [M⁺], 239 (100), 196 (60); HRMS (EI, 70 eV): m/z calcd for

C

+

C₁₇H₂₆O₅: 310.1780 [M⁺]; found: 310.1780 [M ].

C

Concentration of fraction C (R_f=0.1 in 80:20:0.5:1.0:0.5 v/v ethyl

acetate/hexane/water/methanol/acetic acid) afforded the carboxyl-

ic acid derived from the hydrolysis of compound 20 (28 mg, 7%)

as clear, colorless oil. ½aꢂ²_D⁰=ꢀ2.8 (c=1.0, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=3.97 (d, J=6.4 Hz, 1H), 3.47 (d, J=6.4 Hz,

1H), 2.55–2.48 (complex m, 1H), 2.21 (m, 3H), 2.05–1.25 (complex

m, 15H), 1.22 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=216.1,

178.0, 73.6, 68.0, 50.0, 39.6, 35.0, 32.1, 31.4, 31.0, 29.7, 29.3, 24.7,

20.8, 20.7, 19.0 ppm; IR (KBr): n˜_max=3304, 2918, 1705, 1399, 1384,

1070 cm^ꢀ1; MS (ESI⁺): m/z (%): 319 (100) [M+Na]⁺, 302 (17), 276

(24), 190 (11); HRMS (ESI⁺): m/z calcd for C₁₆H₂₄O₅: 319.1521

[M+Na]⁺; found: 319.1526 [M+Na]⁺.

(<1) [M⁺], 174 (33), 146 (26), 105 (100), 77 (18); HRMS (EI, 70 eV):

C

m/z calcd for C₂₄H₂₈O₆: 412.1886 [M⁺]; found: 412.1889 [M ].

+

C

Compound 23

A magnetically stirred solution of benzoate 22 (67 mg, 0.16 mmol)

in THF/methanol (3.6 mL of a 2:1 v/v mixture) was cooled to

ꢀ788C then SmI₂(approximately 3.5 mL of a 0.1m solution in THF)

was added dropwise until a blue color persisted. The ensuing mix-

ture was stirred at ꢀ788C for a further 0.25 h then poured directly

Resubjecting compound 19 to the above-mentioned reaction con-

ditions provided further quantities of compound 20 (57% at 82%

conversion).

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into saturated K₂CO₃(2 mL of a saturated aqueous solution), and

the mixture thus formed was extracted with diethyl ether (4ꢁ

5 mL). The combined organic phases were washed with brine (1ꢁ

5 mL) before being dried (Na₂SO₄), filtered, and concentrated

under reduced pressure. The resulting light yellow oil was subject-

ed to column chromatography (silica, 2:3 v/v ethyl acetate/hexane

elution) to afford, after concentration of the relevant fractions (R_f=

0.3), ketone 23 (42 mg, 88%) as clear, colorless oil. ½aꢂ²_D⁵=ꢀ26.9

Compound 25

Following the procedure of Yoshimitsu et al.,^[12e]a magnetically

stirred solution of compound 24 (36 mg, 0.12 mmol) in dichloro-

methane (12 mL) maintained at 188C was treated with lithium

iodide (164 mg, 1.24 mmol), hexamethyldisilazane (520 mL,

2.48 mmol), and trimethylsilyl chloride (160 mL, 1.24 mmol). The en-

suing mixture was allowed to stir at 188C for 1 h, then treated

with NaHCO₃(5 mL of a saturated aqueous solution) before being

extracted with diethyl ether (3ꢁ10 mL). The combined organic

phases were washed with brine (2ꢁ5 mL) then dried (MgSO₄), fil-

tered, and concentrated under reduced pressure. The ensuing light

yellow oil was treated with freshly prepared IBX-NMO (500 mL of

a 0.4m solution in DMSO, 0.18 mmol), and the reaction mixture

was stirred at 608C for 16 h before being cooled, then treated with

NaHCO₃(4 mL of a saturated aqueous solution) and extracted with

diethyl ether (5ꢁ4 mL). The combined organic phases were

washed with brine (2ꢁ2 mL), then dried (MgSO₄), filtered, and con-

centrated under reduced pressure to give a light yellow oil. Subjec-

tion of this material to flash chromatography (silica, 1:7 v/v ethyl

acetate/hexane elution) afforded two fractions, A and B.

1

(c=0.8, CHCl₃); H NMR (400 MHz, CDCl₃): d=3.65 (s, 3H), 2.66 (m,

1H), 2.43–2.24 (complex m, 4H), 2.37–1.56 (complex m, 12H), 1.42

(m, 1H), 1.25 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=215.3,

214.3, 173.9, 54.5, 51.6, 50.1, 43.0, 42.5, 35.3, 34.9, 31.4, 29.3, 26.9,

25.1, 23.2, 20.0 ppm; IR (KBr): n˜_max=2948, 2871, 1728, 1706, 1438,

1383, 1296, 1261, 1172, 1100 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 292 (5)

[M⁺], 277 (25), 245 (38), 206 (48), 205 (100); HRMS (EI, 70 eV): m/z

C

+

C

calcd for C₁₇H₂₄O₄: 277.1440 [Mꢀ CH₃] ; found: 277.1437

+

C

[Mꢀ CH₃] .

Compound 24

Concentration of fraction A (R_f=0.5(0) in 1:4 v/v ethyl acetate/

hexane) afforded the starting ketone 24 (7 mg, 19% recovery),

which was identical in all respects to an authentic sample.

A magnetically stirred solution of Ph₃PCH₃Br (147 mg, 0.41 mmol)

in THF (1 mL) maintained at 08C was treated with KOtBu (43 mg,

0.38 mmol), and the resulting mixture was allowed to warm to

188C, stirred at this temperature for 1 h, then cooled again to 08C.

A solution of compound 24 (27 mg, 0.09 mmol) in THF (1 mL) was

then added dropwise to the now yellow reaction mixture. After

the addition was complete, the reaction mixture was allowed to

warm to 188C, then kept at this temperature for 16 h before being

quenched with NH₄Cl (5 mL of a saturated aqueous solution) and

extracted with diethyl ether (5ꢁ5 mL). The combined organic

phases were washed with brine (1ꢁ5 mL), then dried (Na₂SO₄), fil-

tered, and concentrated under reduced pressure. The resulting

light yellow oil was subjected to flash chromatography (silica, 1:20

v/v ethyl acetate/hexane!1:10 v/v ethyl acetate/hexane gradient

elution); two fractions, A and B, were obtained.

Concentration of fraction B (R_f=0.4(7) in 1:4 v/v ethyl acetate/

hexane) afforded enone 25^[12e](19 mg, 53% at 81% conversion) as

a clear, colorless oil. ½aꢂ_D²⁵= +9.7 (c=1.0, CHCl₃); H NMR (400 MHz,

1

CDCl₃): d=6.46 (d, J=10.4 Hz, 1H), 5.84 (d, J=10.4 Hz, 1H), 4.64

(m, 1H), 4.68 (m, 1H), 3.65 (s, 3H), 2.42 (m, 1H), 2.31 (dm, J=

16.0 Hz, 1H), 2.26–1.91 (complex m, 6H), 1.75–1.45 (complex m,

6H), 1.16 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=204.0, 174.1,

154.3, 148.8, 126.2, 107.3, 51.6, 47.2, 44.5, 39.5, 36.1, 35.9, 29.8,

29.3, 28.0, 26.6, 25.9, 21.2 ppm; IR (KBr): n˜_max=2924, 2862, 1739,

1674, 1451, 1436, 1383, 1357, 1288, 1262, 1228, 1172, 1122, 1092,

1077, 1019, 884, 826, 802 cm^ꢀ1; MS (ESI⁺): m/z (%): 311 (100)

[M+Na]⁺; HRMS (ESI⁺): m/z calcd for C₁₈H₂₄O₃: 311.1623 [M+Na]⁺;

found: 311.1624 [M+Na]⁺.

Concentration of fraction A (R_f=0.9 in 2:3 v/v ethyl acetate/

hexane) afforded the twofold methylenation product (3.5 mg,

13%) as a clear, colorless oil. ½aꢂ²_D⁵=ꢀ46.0 (c=0.4, CHCl₃); H NMR

1

Compound 26

(400 MHz, CDCl₃): d=4.76 (s, 1H), 4.75 (m, 1H), 4.63 (s, 1H), 4.59

(m, 1H), 3.66 (s, 3H), 2.43–2.15 (complex m, 4H), 2.10–2.04 (com-

plex m, 3H), 1.97–1.80 (complex m 2H), 1.74–1.56 (complex m,

5H), 1.49–1.33 (complex m, 3H), 1.25–1.14 (complex m, 1H),

1.11 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=174.8, 154.1, 152.0,

106.5, 105.2, 51.5, 47.4, 42.6, 42.1, 38.1, 36.4, 33.3, 32.9, 29.9, 29.1,

28.1, 27.0, 23.3 ppm (one signal obscured or overlapping); IR (KBr):

n˜_max=2929, 2865, 1740, 1636, 1462, 1435, 1376, 1287, 1192, 1171,

Following the procedure of Yoshimitsu et al.,^[12e]a magnetically

stirred solution of compound 25 (37 mg, 0.13 mmol) in THF

(1.5 mL) maintained at 188C was treated with sodium hydroxide

(1.5 mL of a 1m aqueous solution). After 48 h, the reaction mixture

was diluted with water (4.0 mL) and brine (2.0 mL), then washed

with diethyl ether (2ꢁ5 mL). The separated aqueous phase was

acidified with HCl (approximately 1.5 mL of a 1.2m aqueous solu-

tion) and extracted with diethyl ether (3ꢁ5 mL). The combined or-

ganic phases were dried (Na₂SO₄), filtered, and concentrated under

reduced pressure to give carboxylic acid 26^[12e](31 mg, 88%) as

877 cm^ꢀ1; MS (EI, 70 eV): m/z (%): 288 (17) [M⁺], 273 (15), 207 (62),

C

201 (100), 173 (36), 145 (45), 13 (42), 91 (48); HRMS (EI, 70 eV): m/z

+

calcd for C₁₉H₂₈O₂: 288.2089 [M⁺]; found: 288.2079 [M ].

C

Concentration of fraction B (R_f=0.7 in 2:3 v/v ethyl acetate/

hexane) afforded compound 24^[12e](10 mg, 37% yield) as a clear,

colorless oil. ½aꢂ²_D⁵=ꢀ17.6 (c=0.3, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=4.82 (brs, 1H), 4.65 (brs, 1H), 3.65 (s, 3H), 2.59 (m, 1H),

2.35 (m, 1H), 2.04–2.26 (complex m, 5H), 1.92 (m, 1H), 1.75–1.47

(complex m, 8H), 1.33–1.23 (complex m, 2H), 1.18 ppm (s, 3H);

¹³C NMR (100 MHz, CDCl₃): see Table 1; IR (KBr): n˜_max=2918, 2867,

1738, 1706, 1649, 1436, 1378, 1292, 1260, 1194, 1172, 912,

732 cm^ꢀ1; MS (ESI⁺): m/z (%): 313 (100) [M+Na]⁺; HRMS (ESI⁺): m/z

calcd for C₁₈H₂₆O₃:, 313.1780 [M+Na]⁺; found: 313.1779 [M+Na]⁺.

a

clear, colorless oil. ½aꢂ²_D⁵= +10.0 (c=0.6, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=6.47 (d, J=10.0 Hz, 1H), 5.84 (d, J=10.0 Hz,

1H), 4.85 (m, 1H), 4.69 (m, 1H), 2.43 (brs, 1H), 2.34–2.24 (complex

m, 3H), 2.15–2.03 (complex m, 3H), 2.00–1.94 (complex m, 2H),

1.75–1.46 (complex m, 6H), 1.17 ppm (s, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=204.2, 178.3, 154.4, 148.7, 126.2, 107.4, 47.2, 44.5, 39.6,

36.1, 35.9, 29.5, 29.0, 28.0, 26.6, 25.8, 21.1 ppm; IR (KBr): n˜_max

=

2932, 2867, 1708, 1674, 1455, 1293, 1181, 1124, 1093, 1078,

872, 827, 733 cm^ꢀ1; MS (ESI⁺): m/z (%): 297 (100) [M+Na]⁺; HRMS

(ESI⁺): m/z calcd for C₁₇H₂₂O₃: 297.1467 [M+Na]⁺; found: 297.1468

[M+Na]⁺.

The yield of compound 24 could be increased to 63% if the reac-

tion was conducted at 08C for 0.5 h rather than between 0 and

188C for 16 h.

This material was used directly in the next step of the reaction se-

quence.

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Full Paper

Compound 2 ((ꢀ)-Platencin)

Acknowledgements

Following the procedure of Yoshimitsu et al.,^[12e]a magnetically

stirred solution of compound 26 (31 mg, 0.11 mmol) in acetonitrile

(1.1 mL) maintained at 188C was treated with triethylamine (47 mL,

0.34 mmol), DMAP (28 mg, 0.23 mmol), and then DCC (150 mL of

a 1.0m solution in dichloromethane, 0.15 mmol). After 7.5 h, a solu-

tion of 3-amino-2,4-dihydroxybenzoic acid (38 mg, 0.23 mmol) in

DMF (0.31 mL) was added to the reaction mixture, and stirring was

then continued for another 70 h. The ensuing mixture was subject-

ed, without concentration or workup, to flash chromatography

(silica, 80:20:1:0.5:0.5 v/v ethyl acetate/hexane/methanol/acetic

acid/water elution) to afford, after concentration of the relevant

fractions (R_f=0.2), platencin (2)^[27](20 mg, 42%) as a white, crystal-

line solid. ½aꢂ_D¹⁸=ꢀ5.7 (c=0.2, CH₃OH) (lit.^[27]½aꢂ²_D⁰=ꢀ15.0 (c=0.2,

We thank the Australian Research Council and the Institute of

Advanced Studies for financial support. E.L.C is the grateful re-

cipient of an Australian Post-graduate (Industry) Award.

Keywords: chirality · cross-coupling · cycloaddition · natural

products · total synthesis

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CH₃OH)); H NMR (400 MHz, CDCl₃): d=11.57 (brs, 1H), 11.24 (brs,

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Structural Determination

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Received: September 11, 2014

Published online on && &&, 0000

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FULL PAPER

Just apply enzymes, metals, and heat:

A reaction sequence that involves enzy-

matic dihydroxylation, auxiliary-con-

trolled alkylation, directed metalation,

then Stille cross-coupling protocols pro-

vides a tetraene that engages in a ther-

mally induced intramolecular Diels–

Alder cycloaddition reaction (see

&

Total Synthesis

Ee Ling Chang, Brett D. Schwartz,

Alistair G. Draffan, Martin G. Banwell,*

Anthony C. Willis

&& – &&

A Chemoenzymatic and Fully

Stereocontrolled Total Synthesis of the

Antibacterial Natural Product (ꢀ)-

Platencin

scheme). The resulting adduct can be

elaborated to the potent antibacterial

agent (ꢀ)-platencin.

&

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Article Doi

A chemoenzymatic and fully stereocontrolled total synthesis of the antibacterial natural product (-)-platencin

DOI: 10.1002/asia.201403069

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