Total synthesis of (-)-platensimycin by advancing oxocarbenium- and iminium-mediated catalytic methods

DOI: 10.1002/chem.201400131

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Organocatalysis

Total Synthesis of (ꢀ)-Platensimycin by Advancing Oxocarbenium-

and Iminium-Mediated Catalytic Methods

Stanley T.-C. Eey^[a]and Martin J. Lear*^{[a, b]}

Dedicated to Professor Emeritus Masahiro Hirama for his mentorship and lasting contributions to complex and applied total synthesis

Abstract: (ꢀ)-Platensimycin is a potent inhibitor of fatty acid

synthase that holds promise in the treatment of metabolic

disorders (e.g., diabetes and “fatty liver”) and pathogenic in-

fections (e.g., those caused by drug-resistant bacteria).

Herein, we describe its total synthesis through a four-step

preparation of the aromatic amine fragment and an im-

proved stereocontrolled assembly of the ketolide fragment,

(ꢀ)-platensic acid. Key synthetic advances include 1) a modi-

fied Lieben haloform reaction to directly convert an aryl

methyl ketone into its methyl ester within 30 seconds, 2) an

experimentally improved dialkylation protocol to form pla-

tensic acid, 3) a sterically controlled chemo- and diastereose-

lective organocatalytic conjugate reduction of a spiro-cy-

clized cyclohexadienone by using the trifluoroacetic acid salt

of a-amino di-tert-butyl malonate, 4) a tetrabutylammonium

fluoride promoted spiro-alkylative para dearomatization of

a free phenol to assemble the cagelike ketolide core with

the moderate leaving-group ability of an early tosylate inter-

mediate, and 5) a bismuth(III)-catalyzed Friedel–Crafts cycli-

zation of a free lactol, with LiClO₄as an additive to liberate

a more active oxocarbenium perchlorate species and sup-

press the Lewis basicity of the sulfonyloxy group. The lon-

gest linear sequence is 21 steps with an overall yield of

3.8% from commercially available eugenol.

Introduction

In 2006, Merck researchers reported the discovery of a new

and potent antibiotic, (ꢀ)-platensimycin (1, Figure 1), isolated

from Streptomyces platensis strain MA7327, which originated

from South Africa.^[3]A collection of 250000 natural product ex-

As bacterial strains have evolved mechanisms according to

Darwinian selection principles to foil drug treatments, the ef-

fectiveness of antibiotics has diminished steadily.^[1]Hospitals

worldwide have been plagued with the continual emergence

of drug resistance, and multiple-drug-resistant strains of patho-

genic Gram-positive bacteria are becoming more prevalent in

the clinic. These include the potent strains of methicillin-resist-

ant Staphylococcus aureus (MRSA) and vancomycin-resistant

enterococci (VRE).^[2]Most antibiotics used in clinics today gen-

erally work on limited biochemical processes, such as blocking

the synthesis of the bacterial cell wall, deformation of the cell

membrane, or inhibition of bacterial protein production.

Henceforth, new classes of antibiotics will be continually

needed in this enduring battle against the increasing drug re-

sistance of microbes.

Figure 1. Structure of (ꢀ)-platensimycin (1) and common synthetic targets 2

and 3.

tracts was screened by using an antisense/RNA-based differen-

tial sensitivity assay in a search for new antibacterial agents

targeting the fatty acid synthesis (FAS) pathway.^[4]In vitro stud-

ies and in vivo assays with mice models showed that platensi-

mycin possessed strong and broad-spectrum Gram-positive an-

tibacterial activity.^[3]Owing to its unique mode of action, pla-

tensimycin demonstrated no cross-resistance to an array of

major antibiotic-resistant microbes. In view of its architectural

complexity, platensimycin swiftly generated tremendous efforts

in the chemical synthesis community; for example, the first

total synthesis, in racemic form, was achieved by Nicolaou and

co-workers just four months after the discovery of platensimy-

cin was reported in 2006.^[5–7]Despite unfavorable pharmacoki-

netics hindering the clinical progress of platensimycin in the

[a] Dr. S. T.-C. Eey, Prof. Dr. M. J. Lear

Department of Chemistry

National University of Singapore

3 Science Drive 3, Singapore 117543 (Singapore)

[b] Prof. Dr. M. J. Lear

Department of Chemistry, Graduate School of Science

Tohoku University

Aza Aramaki, Aoba-ku, Sendai 980-8578 (Japan)

Fax: (+81)22-795-6566

E-mail: martin.lear@m.tohoku.ac.jp

Supporting information for this article is available on the WWW under

http://dx.doi.org/10.1002/chem.201400131.

Chem. Eur. J. 2014, 20, 1 – 19

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antibiotics pipeline hitherto, the highly selective mammalian

FAS activity of this natural product continues to be of interest

against metabolic disorders like diabetes and “fatty liver” stea-

tosis,^[8]and the structural complexity has resulted in numerous

synthetic analogues of platensimycin.^[9]

Synthetically, the development of a stereocontrolled route

with convenient access to the cis-C8/C9 ring junction of the

key tetracyclic ketolide, that is, the Nicolaou group’s intermedi-

ate (ꢀ)-2, has been nontrivial.^[7,9]The intermolecular Diels–

Alder strategy has been successfully applied in the highly ste-

reoselective assembly of the (ꢁ)-cis-decalin of the tetracyclic

core,^[6n,q,r]whereas high diastereoselectivity has been achieved

under high-pressure asymmetric hydrogenation conditions.^[6b,f]

We have previously reported a high-yielding, enantioselective

synthesis of 2 by developing a new Bi^III-catalyzed Friedel–Crafts

cyclization to assemble the cagelike core, and we realized a ste-

reocontrolled organocatalytic conjugate reduction to install

the desired C8/C9 stereochemical configuration.^[7h]Herein, we

report a detailed account of our studies that led to the devel-

opment of these key transformations to construct the intricate

tetracyclic core 2, as well as the development of a highly prac-

tical route to the tetrasubstituted aniline fragment 3 and com-

pletion of the total synthesis of (ꢀ)-1 after further improve-

ments in synthetic methods and practical matters.

Results and Discussion

Our strategic disconnection (Scheme 1) of (ꢀ)-platensimycin

(1) commenced at the amide bond to provide the aniline ester

3 and platensic acid (6). Ester 3 would be derived from the

protected acetophenone 4 by a newly modified Lieben halo-

form reaction, which we developed during these synthetic

studies and subsequently applied to the rapid oxidative

esterification of aromatic methyl ketones.^[10]Intermediate 4

would, in turn, be traced back through a double benzylation

and a Friedel–Crafts acylation to commercially available 2-nitro-

resorcinol (5). A double disconnection of the propionate and

methyl side arms of platensic acid (6) revealed the key tetracy-

clic enone 2 or the 6-methoxy version 7 as the primary syn-

thetic subtarget. The inherent structural bias of the cagelike in-

termediate 2 (or 7) would clearly provide the necessary a-facial

stereocontrol in constructing the all-carbon, quaternary C4 ste-

reocenter. The 6-methoxy group of the logical dienone precur-

sor 8 was anticipated to provide a possible means to achieve

the needed electronic and steric control in securing the de-

sired cis-C8/C9-ring juncture in 7 reductively (see below). It

should be noted, however, that the exact chemo- and diaste-

reoselective conjugate conditions required for this reduction

step were not obvious to us during our early retrosynthetic

planning stages. Disconnection of the C9/C10 bond in 8 by

way of a retro Friedel–Crafts cyclization^[11]traced our synthesis

back to lactol 9. We were thus attracted to Marson type oxo-

carbenium chemistry as a straightforward approach to con-

struct the oxabicyclo[3.2.1]octane motif and install the C10 ste-

reocenter.^[12]The para-directing 6-methoxy group in 9 was

again expected to generate the desired C9/C10 regiocontrol.

Additionally, a Masamune-inspired intramolecular spiro-alkyla-

Scheme 1. Retrosynthetic analysis of (ꢀ)-platensimycin (1). Bn: benzyl; Ts:

toluene-4-sulfonyl.

tive dearomatization strategy^[13]would complete the cagelike

core of 8 from 9. Lactol 9 could, in turn, be derived from the

readily available monotosylated 1,2-diol 10 through a series of

standard functional-group interconversions.

As reported previously in our initial communication, 10 was

prepared from natural eugenol in a high overall yield of 75%

over 7 steps and 91% ee through catalytic Sharpless epoxida-

tion.^[7h]Compound 10 was converted into bromohydrin 12

through epoxide-ring closure with K₂CO₃in MeOH and subse-

quent regioselective reopening with LiBr (Scheme 2).^[14]Two

equivalents of AcOH were found to be necessary to realize the

latter transformation in good, reliable yields. Oxidative double-

bond cleavage with concomitant cyclization then furnished the

cis-bromolactol 9 in 91% yield over 2 steps. Efforts to cyclize 9

into the benzotetrahydrofuran 13 were nontrivial. The initial

conditions to drive the Marson cyclization with stoichiometric

or excess amounts of Lewis acids, such as BF₃·Et₂O^[12b,c,15]and

TMSOTf (TMS: trimethylsilyl; Tf: trifluoromethanesulfonyl), or

a Brønsted acid, for example, TfOH, were either sluggish or re-

sulted in complex mixtures. Significant decomposition of 13

into the original lactol 9 (major product) and the benzobromo-

hydrin 16 (minor product) were always observed when the re-

action was quenched with conventional aqueous protocols.

The situation did not improve when the reaction mixture was

treated with either an organic base or silica gel. After consider-

able experimentation, exposure to 5 equivalents of SnCl₄at

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Table 1. Lewis acid promoted Friedel–Crafts arylation of bromolactol 9.^[a]

Entry Lewis acid

mol% t [h] 13 [%] 15^[b][%] 16 [%] 9 [%]

1

2

3

4

5

6

7

8

Al(OTf)₃

Sc(OTf)₃

La(OTf)₃

Bi(OTf)₃

FeCl₃

InCl₃

AuCl₃

GaCl₃

50

25

50

25

50

100

12

1.25 94

1.5 78

3

2

1

–

30

54

67

59

33

–

4

–

trace

–

85

82

–

[c]

–

9

10

Ph₃PAuCl/AgOTf 50/50 12

–

59

22

62

72

–

34

–

22

10

–

ZnCl₂

100

40

25^[f]

10

2

12

2

11^[d,e]HNTf₂

12^[d,e]HOTf

13

14

15^[g]

Bi(OTf)₃

1.5 88

62

1.5 92

trace

–

2

4

31

–

5

[a] Conditions: 9 (20–30 mg), Lewis acid, 4 ꢁ molecular sieves, CH₂Cl₂,

room temperature; yields after isolation are shown. [b] Compound 15

could be converted into 13 with 10 mol% Bi(OTf)₃in 80% yield. [c] A

complex mixture was obtained. [d] Reaction was carried out at 08C.

[e] TLC streaking and blotting of unidentified baseline material was ob-

served. [f] One equivalent of HOTf liberated a complex mixture. [g] Reac-

tion with compound 9 at the 540 mg scale.

Scheme 2. Preparation of the tetracyclic dienone 8. NMO: 4-methylmorpho-

line N-oxide; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

ꢀ788C, coupled with quenching with a half-saturated Rochelle

salt solution, provided 13 reliably in good yields at practical

scales.^[16]Excellent regio- and stereocontrol toward C9/C10

bond formation were achieved through the chiral center at the

C12 atom by virtue of the para-directing 6-methoxy group.

The alternative C7/C10 regioisomer and, notably, the C8/C10

ipso isomer were not detected.

Debenzylation of 13 with ammonium formate in refluxing

acetone^[6e]resulted in an undesirable 1:1 mixture of the bro-

mophenol 14 and its debromo derivative. A switch to 1,4-cy-

clohexadiene as the hydrogen source furnished 14 cleanly and

quantitatively. This phenol was directly subjected to intramo-

lecular alkylative dearomatization conditions without further

purification. Treatment of 14 with strongly anionic bases, such

as NaH and NaOtBu, was unsuccessful in promoting the classi-

cal Winstein Ar-3’ spiro-cyclization,^[17]and hydrolysis of the

alkyl bromide was observed instead. Exposure of 14 to the

conditions described by Boger et al. (DBU in refluxing

CH₃CN)^[13b,c]were also explored and successfully drove the alky-

lative dearomatization to afford the tetracyclic 6-methoxydie-

none 8 in 84% yield over 2 steps.

A practical limitation of this strategy was the excessive re-

quirement for highly toxic and ecologically harmful SnCl₄to

drive the Friedel–Crafts arylation; thus, we were keen to devel-

op a direct catalytic Friedel–Crafts method to form the tricyclic

system 13. Initially, 9 was treated with various oxophilic Lewis

acids at 25–100 mol% loadings in the presence of 4 ꢁ molecu-

lar sieves (Table 1, entries 1–10). The results collectively sug-

gested that the Lewis acid activated transformation of the free

lactol to its oxocarbenium species occurred readily, but the en-

suing alkylative cyclization onto the aromatic ring appeared to

be subtly encumbered. Competitive formation of the dimeric

ether 15 was observed, with the Lewis acids showing little or

none of the desired catalytic activity, including Al(OTf)₃,

Sc(OTf)₃, Au^I/Ag^I, and ZnCl₂(Table 1, entries 1, 2, 9, 10). Further

experimentation revealed Bi(OTf)₃, FeCl₃, InCl₃, and AuCl₃to be

more effective than SnCl₄in promoting the cyclization at sub-

stoichoimetric amounts (Table 1, entries 4–7). Triflimide,

a strong Brønsted acid, also furnished 13 in a modest yield of

59% (Table 1, entry 11). Bi(OTf)₃was found to be the most su-

perior in reactivity and afforded 13 in 94% yield within 1.25 h

(Table 1, entry 4). The increasing use of bismuth(III) salts as ox-

ophilic Lewis acids in organic reactions is attributed to their

ecofriendliness, tolerance to air and moisture, and inexpensive-

ness.^[18]The contrastingly poor results obtained with one

equivalent or substoichiometric amounts of triflic acid (Table 1,

entry 12) supported our hypothesis that the Bi^IIILewis acid was

primarily responsible for catalyzing the Friedel–Crafts process.

Furthermore, in the absence of 4 ꢁ molecular sieves, cycliza-

tion with Bi(OTf)₃generated several byproducts, which sug-

gested that the presence of HOTf (likely generated in situ in

the reaction mixture) was undesirable.

Next, the catalyst loading was reduced and the efficiency of

the reaction was examined (Table 1, entries 13–15). This dem-

onstrated that 5 mol% Bi(OTf)₃was sufficient to drive the cycli-

zation of 9 efficiently. Lower catalyst loadings (for example,

2 mol%; Table 1, entry 14) were not optimal and, in turn, led to

the sluggish formation of 13 and undesired dimerization into

15. Dimer 15 could, in turn, be conveniently transformed into

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13 by simply adding more Bi(OTf)₃(Table 1, footnote [b]). A

secondary limitation with Bi(OTf)₃as the catalyst was the unde-

sired, ready formation of the relatively stable bromohydrin–

olefin 16 upon quenching with saturated aqueous NH₄Cl. Alter-

native quenching with Rochelle salt solutions generated even

more of the furan-opened olefin 16. This unwanted benzylic

ether cleavage of the tetrahydrofuran system in 13 could be

minimized with reduced catalyst loadings.

Friedel–Crafts transformation. As such, we rationalized that the

sulfonate group likely retarded the reactivity of the Lewis acid.

Accordingly, a Lewis acid cocatalyst was sought to circumvent

the poor catalytic activity experienced with tosylate 17.

Inspired by Bartoli, Sambri, and co-workers,^[19]we eventually

turned to LiClO₄as a cocatalyst to Bi(OTf)₃to help drive the

Friedel–Crafts cyclization of 17. Although lower equivalencies

were not productive, 1 equivalent of LiClO₄and 25 mol%

Bi(OTf)₃gave a better conversion into 18 after stirring over-

night (16 h) at room temperature (Table 2, entry 3). The best

catalytic combination of 5 mol% Bi(OTf)₃with 3 equivalents of

LiClO₄eventually furnished 18 in 94% yield within 3.5 h

(Table 2, entries 4–6). In a control experiment, LiClO₄alone was

incapable of promoting the cyclization, but the subsequent ad-

dition of a catalytic amount of Bi(OTf)₃provided 18 in 74%

yield (Table 2, entry 7). We rationalized that the combination of

Bi(OTf)₃and LiClO₄possibly resembled Mukaiyama’s catalyst

system, SbCl₅/LiClO₄, which is speculated to form a highly reac-

tive oxocarbenium perchlorate species, reported to promote

the Friedel–Crafts acylation of aromatic compounds with acid

anhydrides.^[20]Likewise, a more active cationic species “Bi(OTf)₂-

(ClO₄)”^[21]could have been generated to strongly interact with

17 and favor the formation of more reactive oxocarbenium

ions, which, in turn, can promote nucleophilic ring closure. Ad-

ditionally, in comparison with the Friedel–Crafts conditions be-

tween 9 and 17, we also reasoned that Li⁺ions could compete

and coordinatively saturate the Lewis basic sulfonyloxyl group,

which would release any trapped Bi^IIIcatalyst and thereby

allow a catalytic cycle to persist.

In efforts to expand the substrate scope of our catalytic ary-

lation protocol and to employ earlier intermediates of our syn-

thesis, we investigated the Lewis acid mediated cyclization of

the cis-tosyl lactol 17, which could be accessed directly by oxi-

dative cyclization of 10 (Scheme 3). Treatment of 17 under the

Scheme 3. Synthesis of the tosylbenzotetrahydrofuran 18.

Although the Bi(OTf)₃-catalyzed Friedel–Crafts cyclization of

electron-rich aromatics 9 and 17 could be reproduced on prac-

tical scales, the cyclization of their 6-demethoxy counterparts

could not be achieved, either at high catalyst loadings or with

excess catalyst, at various temperatures.^[22]No other Lewis or

Brønsted acid combinations, such as SnCl₄, TfOH, and InCl₃,

were found to cyclize the free lactol in the absence of the

para-methoxy group. Furthermore, the activation of the less re-

active lactol in the form of an activated furanosyl donor (in-

cluding the use of O-acetates, trichloroacetimidates, or halides)

has provided little success in promoting the desired aryl C-gly-

cosylation reaction with different Lewis acid treatments. The

results from these feasibility studies on Friedel–Crafts ring clo-

sure onto the meta position of monoactivated aryl systems

support our choice of employing a para-methoxy group to

impart the needed electronic control for realizing the Marson

type cyclization. Neither ortho-cyclized C10/C7 products nor

ipso-cyclized C10/C8 products were observed from 9 or 17, as

expected because of the steric constraints enforced by the

C12/C13 stereochemistry of the tetrahydrofuranyl moiety.

After reliable catalytic Friedel–Crafts cyclization conditions

had been secured, the benzyl deprotection of 18 and alkylative

dearomatization were investigated (Scheme 4). Although de-

benzylation proceeded quantitatively over catalytic Pd/C, the

resulting tosylphenol 19 cyclized in only 21% yield when treat-

ed with excess DBU under CH₃CN reflux (Table 3, entry 1). This

result was in contrast to the efficient cyclization observed for

the bromophenol 13 under the same conditions (Scheme 2).

optimized conditions (Table 1, entry 13) gave the tosyl benzo-

tetrahydrofuran 18 in 16% yield, even after 12 h (Table 2,

entry 1). At stoichiometric quantities of Bi(OTf)₃, only a modest

yield of 52% of 18 was observed after 12 h (Table 2, entry 2).

In both situations, the initial lactol 17 was recovered and none

of the dimeric ether was observed. This suggested that tosy-

late 17 was not as reactive as the bromo analogue 9 toward

Bi(OTf)₃-catalyzed oxocarbenium formation. In additional stoi-

chiometric studies, the treatment of 17 with SnCl₄required an

even greater excess (8–10 equiv) to achieve a high-yielding

Table 2. Bi(OTf)₃-promoted Friedel–Crafts arylation of tosyllactol 17.^[a]

Entry

Lewis acid

Amount

t [h]

18 [%]

17 [%]

1

2

3

4

5^[b]

6

Bi(OTf)₃

5 mol%

1 equiv

12

16

3

3.5

6

16

52

83

96

94

82

67

38

–

Bi(OTf)₃/LiClO₄

LiClO₄

25 mol%/1 equiv

25 mol%/3 equiv

5 mol%/3 equiv

2.5 mol%/3 equiv

3 equiv

trace

7

5

no reaction^[c]

[a] Conditions: 17 (30–50 mg), Lewis acid, 4 ꢁ molecular sieves, CH₂Cl₂,

room temperature; yields after isolation are shown. [b] Reaction was per-

formed at the 50 and 760 mg scales with comparable yields. [c] Without

isolation of 17, 10 mol% Bi(OTf)₃was added into the same pot and 18

was afforded in 74% yield after 3 h.

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of the electron-deficient C4–C9 olefin in 8 was anticipated to

be challenging to achieve in a practically convenient manner

under pure substrate control (Table 4). In our initial investiga-

tions, for example, atmospheric hydrogenation of 8 over cata-

lytic Pd/C afforded a 1:3 d.r. at the C9 atom in favor of the un-

desired trans-C8/C9 decalin, 22, over the desired cis-C8/C9 dec-

alin, 21 (Table 4, entry 1). Double hydrogenation with Crab-

tree’s Ir catalyst^[7c]only led to recovery of the initial dienone

(Table 4, entry 2). The substrate also proved to be resilient to-

wards various nonchiral hydride 1,4-reduction methods, be-

cause efforts to selectively furnish 6-methoxyenone 7 were

futile (Table 4, entries 3–6). 1,4-Hydrosilylation with Wilkinson’s

catalyst, likewise, only afforded an inseparable 1:1 diastereo-

meric mixture of 7 and the C9 epimer 20 in 9% yield (Table 4,

entry 7).^[7e]A practical point to note here is that, although the

stereocenter at the C6 position is inconsequential to the final

synthesis, it nevertheless complicated these optimization stud-

ies.

Scheme 4. Synthesis of the dienone 8.

Table 3. Alkylative cyclodearomatization of tosylphenol 19.^[a]

Entry

Scale [mg]

Base^[b](equiv)

Solvent

T [8C]

t [h]

8 [%]

1

2

3

4

5

6

7

30

19

28

20

23

14

54

790

320

DBU (15)

DIPEA (20)

TBAF (20)

TBAF (5)

MeCN

EtNO₂

PrCN

MeCN

PrCN

xylene

85

20

12

36

12

4

21

–

120

130

100

130

47

10

70

80

82

86

90

1,4-Reduction of 8 with a bisphosphine copper hydride spe-

cies was investigated under the conditions of Buchwald and

co-workers,^[24]and rac-BINAP was used as the ligand to initially

examine the substrate reactivity. Although smooth 1,4-reduc-

tion of the C4–C9 olefin occurred, over-reduction of the car-

bonyl group also occurred in the same pot. Reoxidation of the

resulting 6-methoxycyclohexenol with Dess–Martin periodi-

nane provided undesired 20 in preference over the desired

diastereomer 7 in a 1:7.6 d.r., although a better yield of 59%

over 2 steps was achieved (Table 4, entry 8). The procedure

was repeated with an in situ prepared (R)-p-tol-BINAP-stabi-

lized CuH complex, which also afforded a 1:4 d.r. mixture in

favor of 20 over 7 (Table 4, entry 9). Alternative CuH conditions

that utilized copper(II)acetate as the air-stable copper source

over the air-sensitive copper(I)chloride^[25]were, however, found

to be less powerful in the conjugate reduction of 8. In the

presence of either (R)-BINAP (Table 4, entry 10) or (R)-p-tol-

BINAP (Table 4, entry 11), the initial dienone was mainly recov-

ered, whereas with (S)-BINAP the formation of undesired 20

was favored exclusively (Table 4, entry 12).

8^[c]

9^[d]

4

[a] Mixture of isomers. [b] DIPEA: N,N-diisopropylethylamine; TBAF:tetra-

butylammonium fluoride. [c] 19, crude, obtained from quantitative de-

benzylation of 18. [d] Cyclodearomatization of the bromophenol 14.

At the higher refluxing temperature of nitroethane, a complex

mixture resulted, presumably due to solvent participation

(Table 3, entry 2). A switch to butyronitrile and heating to

reflux at above 1308C gave a significant improvement in yield,

but byproduct formation remained significant (Table 3,

entry 3). Next, the strongly basic DBU was replaced with the

less basic Hꢂnig’s base, DIPEA (Table 3, entry 4), in an attempt

to reduce the competing side reactions, but the conversion

only furnished 8 in 10% yield at best. Further screening led to

heating of phenol 19 with excess TBAF as a relatively mild

base^[23]in butyronitrile. This gave the desired 8 in a 70% yield

after isolation (Table 3, entry 5). Xylene was explored as a more

practical solvent to sequester the residual water in TBAF and

increase the basicity of the fluoride anion (Table 3, entry 6).

Eventually, the dienone cagelike core was achieved reliably in

82–86% yield (Table 3, entries 7 and 8) with the use of 5 equiv-

alents of TBAF. This protocol importantly circumvented the

need to resort to stronger leaving groups (than OTs) or phenol

silyl ether activation methods.^[6b,e,13b,d]The same conditions

could be successfully applied to the alkylative dearomatization

of bromophenol 14 in excellent yield (Table 3, entry 9). We ra-

tionalized that the success in employing TBAF at 1308C to

effect the cyclodearomatization may be due to the mild basici-

ty of both the fluoride anion and the possible in situ generata-

tion of tributylamine, which can occur through Hofmann elimi-

nation of TBAF.

Collectively, these results suggested a subtle but over-riding

substrate-controlled steric effect that enforces b-facial attack

onto dienone 8 and leads to preferential formation of 20 and

the doubly reduced ketone 22. These results are also consis-

tent with Tiefenbacher and Mulzer’s first investigation into

nonchiral catalytic hydrogenation methods, which only fur-

nished a 1.3:1 cis/trans-C8/C9 decalin mixture, at best, from

a 6-demethoxy analogue of 8 under atmospheric Crabtree’s

conditions.^[7c]To circumvent substrate bias, only high pressures

of hydrogen with highly optimized chiral reagents, including

Corey’s 600 psi Rh^I/2,3-alkylidene-2,3-dihydroxy-1,4-bis(diphe-

nylphosphino)butane-catalyzed hydrogenation^[6b]and the Ir^I/

P,N-ligand-catalyzed hydrogenation procedure at 50 bar of

pressure used by Mulzer, Pfaltz, and co-workers,^[6f]have deliv-

ered the desired stereocontrolled reduction. Nevertheless, we

conceived that high diastereoselectivity of the C8/C9 ring junc-

tion could still be achieved by applying amine-based organo-

catalytic mechanistic rationales to relay steric information

under substrate control. By blocking the more accessible

With dienone 8 in hand, the stage was set for installing the

cis-C8/C9 ring junction. With neither specialized apparatus nor

reagents, a chemo- and stereocontrolled conjugate reduction

Chem. Eur. J. 2014, 20, 1 – 19

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(Table 4, entry 14), tert-butyl d-valinate TFA salt (ꢀ)-

25^[7h]with Hantzsch ethyl ester 27, as described by

Martin and List,^[33]afforded a promising 3.5:1 d.r. in

favor of desired 7 over 20, albeit in only 30% yield

(Table 4, entry 15). Gratifyingly, when more equiva-

lents of 27 were used with substoichiometric

amounts of (ꢀ)-25, the reduction yield was improved

to 62% over 2 steps (Table 5, entries 1–3). Although

elevated temperatures helped to promote the reac-

tion, the drawback was an accompanying drop in

diastereoselectivity. More hours of heating also led to

over-reduction of the C6–C7 olefin of the resulting

enones 7/20 to further afford minor amounts of the

tetrahydrogenated ketones 21/22 (Table 5, entry 3). It

is otherwise noteworthy that this organocatalytic 1,4-

specific reductive procedure displayed high chemose-

lectivity for the more electron-deficient C4–C9 olefin,

as expected by electronic moderation through the 6-

methoxy group.

Table 4. Conjugate reduction study of tetracyclic dienone (ꢀ)-8.^[a]

Entry Conditions (a) or (b)^[b]

Yield d.r.^[c]

[%]

1

2

3

4

5

6

7

8

(b) cat. Pd/C, H₂, EtOAc/ethanolic KOH, 2 h

(b) cat. [Ir(cod)Py(PCy₃)]PF₆, H₂, CH₂Cl₂, 12 h

70

1:3

–

NR^[d]

UCM^[e]

(a) Na₂S₂O₄, NaHCO₃, 1,4-dioxane/H₂O, 508C, 6 h^[26]

(a) Me₂PhSiH, tBuOOtBu, nBu₃SnH, toluene, 1208C, 24 h^[27]

(a) 27,^[28]silica gel, benzene, reflux, 24 h^[29]

trace ND^[f]

NR^[d]

9

–

1:1

1:7.6

The application of Martin and List’s optimal antipo-

dal catalyst combination, the (S)-3,3’-bis(2,4,6-triiso-

propylphenyl)-1,1’-binaphthyl-2,2’-diyl-hydrogenphos-

phate ((S)-TRIP) salt of d-valine tert-butyl ester, 28,

however, gave only poor conversion and a diastereo-

selectivity of 1.2:1 d.r. (7/20), which suggested the

likely presence of competing, although still unclear,

steric effects (Table 5, entry 4). Higher catalytic activi-

ty and selectivity were eventually achieved with the

unreported TFA salt of the tert-butyl ester of d-phe-

nylalanine, (ꢀ)-29;^[7h]however, further reduction of 7/

20 into 21/22 could not be avoided (Table 5, en-

tries 5–7). The use of fewer equivalents of 27 (with

ꢂ98% purity) was possible with little adverse affect

on the reactivity and further aided the purification.

Other etheral solvents were also examined and

proved unfavorable for the conjugate reduction of 8

(Table 5, entries 8 and 9). The best selectivity was,

thus, furnished with 20 mol% (ꢀ)-29 in 1,4-dioxane

at 608C under Ar. This afforded an inseparable mix-

ture of 7 and 20 in 61% yield and 8:1 d.r. (Table 5,

entry 7). A marginally separable mixture of 21 and 22

(4:1 d.r. at the C9 position) could be isolated in 73%

yield over 2 steps by further subjecting the 7/20 mix-

ture to Pd/C-mediated hydrogenation.

(a) cat. Cp₂TiCl₂, Zn dust, collidine·HCl, THF, 10 h^[30]

(a) cat. RhCl(PPh₃)₃, Me₂PhSiH, toluene, 608C, 24 h

(a) 1. cat. CuCl/NaOtBu/rac-BINAP, PMHS, toluene, 48 h; 2. DMP, 59

CH₂Cl₂, 7 h

9

(a) 1. cat. CuCl/NaOtBu/ (R)-tol-BINAP, PMHS, toluene, 5 d;

2. DMP, CH₂Cl₂, 7 h

56

1:4

10

11

12

(a) cat. (R)-BINAP/Cu(OAc)₂·H₂O, PMHS, tBuOH/THF, 36 h

(a) cat. (R)-tol-BINAP/Cu(OAc)₂·H₂O, PMHS, tBuOH/THF, 36 h

(a) cat. (S)-BINAP/Cu(OAc)₂·H₂O, PMHS, tBuOH/THF, 36 h

trace ND^[f]

8

17

2:3

20

only

–

13

14

15

(a) cat. 23, EtOH, 48 h^[31]

(a) cat. 24, 26; 1. THF, 08C, 24 h; 2. 1,4-dioxane, 858C, 48 h

(a) (ꢀ)-25, 27, 1,4-dioxane, 608C, 48 h

NR^[d]

30^[g]

3.5:1

[a] Reactions were performed on 10–20 mg scales. TCA: trichloroacetic acid; TFA: tri-

fluoroacetic acid. [b] cod:cycloocta-1,5-diene; Py: pyridine; Cy: cyclohexyl; tol: tolyl;

Cp: cyclopentyl; BINAP: 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl; PHMS: polyme-

thylhydrosiloxane; DMP: Dess–Martin Periodinane. [c] The d.r. at the C9 position was

calculated based on a ¹H NMR comparison of yields after isolation for 7/20 (insepara-

ble mixture) or for 21/22 (separable mixture). [d] NR: no reaction. [e] UCM: Unresolved

complex mixture. [f] ND: not determined. [g] 95% based on recovered 8.

We rationalized that the observed p-facial selectivi-

ty in the Hantzsch ester hydride delivery to 8 could

have occurred via the d-phenylalanine-derived trans-

iminium intermediate 31 (Figure 2). Conceivably, the

sterically more congested a-face would preferentially

relay the benzyl group (compared with the smaller

b face selectively through bulky groups on the organocatalyst, isopropyl group in (ꢀ)-25) and the tert-butyl ester group to

the facial preference of 8 towards 1,4-hydride delivery could the opposite (b) face and thereby make the bottom (a) face

be conceivably reversed via a 6-methoxy group directed, puta- comparatively more accessible to incoming Hantzsch hydride

tive trans-iminium species 30 (Figure 2).

donors. Such iminium intermediates are also suggested to be

Although treatment with imidazolidinone catalyst 24 and stabilized by an additional trifluoroacetate counteranion hydro-

tert-butyl Hantzsch hydride donor 26, in accordance with the gen-bonding network.^[33]Although we were unable to provide

work of MacMillan and co-workers,^[32]gave no reaction experimental evidence for intermediate 31 or such mecha-

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The speculated mechanistic model (Figure 2) also formulates

an equally feasible 6-methoxy-directed trans-iminium inter-

mediate 32 with the other enantiomer (+)-29 to provide the

desired stereocontrol necessary for the conjugate reduction of

the C4–C9 olefin. Gratifyingly, the Martin and List inspired or-

ganocatalytic reduction^[33a]of 8 occurred under similar chemo-

and diastereoselectivity to afford comparable yields, irrespec-

tive of the use of the (ꢀ), (+), or even (ꢁ) forms of the phenyl-

alanine tert-butyl ester 29 (Table 6, entries 1 and 2). Some TFA

salts of achiral and racemic primary amines were also explored

as possible catalysts, through the speculated intermediate 30,

for the modified conjugate reduction process. Treatment with

1,3-diphenylacetone-derived amine catalyst 33, through reduc-

tive amination, and its structural isomer (ꢁ)-34 (Table 6, en-

tries 3 and 4) showed that the tert-butyl ester group was criti-

cal for both suitable activity and selectivity. The TFA salt of

tert-butyl glycinate, 35, however, exhibited poor reactivity with

Figure 2. Putative trans-iminium 30 species derived from 8 and the amine

catalyst 29.^[33]

Table 5. Organocatalytic conjugate reduction of

8 based on amino

acids.^[a]

Entry

Cat. (mol%)

27^[b][equiv]

T [8C]

t [h]

Yield [%]

d.r.^[c]

1

2

3

4^[f]

5

(ꢀ)-25 (100)

(ꢀ)-25 (25)

28 (25)

(ꢀ)-29 (20)

2.4

5

1.8

5

60

80

85

60

48

80

30^[d]

46^[d]

62^[e]

10

53^[d]

70^[e]

61

73^[e]

26

3.5:1

3.1:1

1.2:1

5:1^[g]

3.9:1

8:1^[h]

4:1

Table 6. Organocatalytic conjugate reduction of 8 with nonchiral primary

amine catalysts.^[a]

130

120

80

130

Entry

Catalyst

Yield [%]

d.r.^[b]

6

7

7/20

21/22

7:20

21:22

3.2

8^[f]

9^[i]

(ꢀ)-29 (20)

3.2

60

130

80

2.8:1

2.5:1

1

–

68^[c]

–

4.2:1

20

[a] Reactions were performed on 30–40 mg scales in 0.05–0.1m 1,4-diox-

ane and sealed under Ar. [b] 27 with ꢂ98% purity gave better yields.

2

3

4

–

8

70^[c]

–

4:1

1

[c] The d.r. at the C9 position was calculated based on a H NMR compari-

son for 7/20 (inseparable mixture) or yields after isolation for 21/22 (sep-

arable mixture) in entries 3, 6, and 7(ii). [d] 90% (entry 1), 91% (entry 2),

and 88% (entry 5) yields based on recovered 8. [e] Yield after isolation of

a separable mixture of 21/22 after hydrogenation of an inseparable mix-

ture of 7/20 over cat. Pd/C in EtOAc/ethanolic KOH for 1 h (yield after

two steps). [f] The reaction was carried out in 0.05m nBu₂O. [g] Com-

pounds 21/22 were also isolated in <5% yield (ꢃ2:1). [h] Compounds

21/22 were also isolated in 17% yield (ꢃ1:1). [i] The reaction was carried

out in 0.05m THF.

trace

2.9:1

ND^[d]

5

–

8

2.2:1

1.3:1

–

5

6

18

1:1

74

–

6

5:1

–

5:1

70^[c]

7

8

39

10

3.2:1

2.5:1

ND^[d]

22

trace

2.5:1

nisms, this steric-reversal reasoning could account for the low

reactivity and diastereoselectivity observed with Martin and

List’s TRIP catalyst;^[33a]thus, the large TRIP counteranion proba-

bly engenders severe steric clashes with both faces of 31

through the putative hydrogen-bonding network (Figure 2). In

addition, we reason that (ꢀ)-29 is more acidic than (ꢀ)-25 (the

pK_avalue of Phe is lower than that of Val), which favors trans-

iminium formation and thus further activates Hantzsch hydride

reduction.^[33b]

[a] Reactions were performed on 30–40 mg scales with the TFA salt of the

amine catalyst (20 mol%) and 27 (3.2 equiv) in 0.08m 1,4-dioxane, sealed

under Ar at 608C for 120–130 h. [b] The d.r. at the C9 position was calcu-

lated based on a ¹H NMR comparison for 7/20 (inseparable mixture) or

yields after isolation for 21/22 (separable mixture). [c] Yield after isolation

of a separable mixture of 21/22 after hydrogenation of an inseparable

mixture of 7/20 over cat. Pd/C in EtOAc/ethanolic KOH for 1 h (yield after

two steps). [d] ND: not determined.

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almost no selectivity (Table 6, entry 5). This suggested the im-

portance of a sec-alkyl amine for good stereocontrol.

On the basis of these results, the TFA salt of a-amino di-tert-

butyl malonate, 36, was investigated, which was prepared

from the malonate ester 39 in 47% yield over 4 steps

(Scheme 5). Regitz diazo transfer with p-ABSA installed the

requisite diazo group on 39, and subsequent Rh(II)-catalyzed

Scheme 5. Preparation of the TFA salt of a-amino di-tert-butyl malonate 36.

p-ABSA: para-acetamidobenzenesulfonyl amide.

NH insertion^[34]with benzyl carbamide furnished the benzylox-

ycarbonyl-protected amino malonate 40. Deprotection of the

benzyloxy carbamate revealed the free amine, and TFA treat-

ment furnished the amine salt 36. Amine 36 was found to pos-

sess catalytic activity noticeably superior to that of 29 at

20 mol% (Table 6, entry 6). Greater chemoselectivity for the

C4–C9 olefin was also exhibited, because over-reduction to the

6-methoxyketones 21/22 was lower. A higher diastereoselectiv-

ity in preference of the desired 21 over 22 with 5:1 d.r. at the

C9 position was achievable via the sequential Hantzsch-based

and Pd/C-mediated reduction of 8 in a good, reliable yield of

70% over 2 steps. Subsequent examination of the catalytic ac-

tivities of homologated analogues of 36, including dl-aspar-

tate-derived (ꢁ)-37 (Table 6, entry 7) and dl-glutamate-derived

(ꢁ)-38 (Table 6, entry 8) were found to catalyze the conjugate

reduction with inferior resultant yields and stereoselectivities.

With the cis-C8/C9 ring junction secured, we went on to ex-

plore different approaches to furnish the doubly alkylated tet-

racyclic enone core. The first strategy was to methylate the in-

separable mixture 7/20 (8:1) under the conditions reported by

Nicolaou et al.,^[6d]which afforded an inseparable C9-epimeric

mixture of the methylated caged intermediates 41/42, along

with their inconsequential 4-methyl epimers, in 62% yield

(Scheme 6). The second alkylation through 1,4-addition to tert-

butyl acrylate provided a separable C9-epimeric mixture of the

tert-butyl 6-methoxyplatensinoates 43/44. In this case, the re-

action favored the formation of 43 and its inseparable C4

epimer in only 23% yield and 4:1 d.r. Unlike the 6-demethoxy

analogue, compound 7 demonstrated reduced reactivity and

poor substrate control toward the Michael addition reaction.

Additionally, the reductive cleavage of the methyl enol ether

and installation of the conjugated C6–C7 double bond pro-

ceeded with limited success.

Scheme 6. Attempted synthesis of the tert-butyl-6,7-dihydroplatensinoate

45. KHMDS: potassium hexamethyldisilazanide; HMPA: hexamethylphos-

phoramide.

A model study with enantiomerically pure 7 showed that

radical reduction of the conjugated olefin, followed by

a second electron-transfer a-demethoxylation, was achievable

with SmI₂and tBuOH as the proton source. However, nonselec-

tive 1,2-reduction occurred, and reoxidation with Dess–Martin

periodinane was necessary to furnish the late-stage intermedi-

ate, the tetrahydroketone 46, as reported by Lalic and Corey^[6b]

and by Tiefenbacher and Mulzer.^[7c]The anticipated reduction

of 43 into the desired tetracyclic ketone 45 under these Sm^II

conditions was, nevertheless, unsuccessful, and the starting

material was recovered quantitatively. The search for alterna-

tive methods to selectively generate the unprotected enol in

43 for a palladium-catalyzed reductive detriflation sequence to

platensinoate 45 turned out to be unsuccessful. The electroni-

cally stable methyl enol ether proved to be highly robust to-

wards a large variety of conditions, including transition-metal-

catalyzed hydrolysis^[35]and oxidation with ceric ammonium ni-

trate,^[36]Hg(OAc)₂,^[37]meta-chloroperoxybenzoic acid, or the

conditions of Inoue and co-workers,^[38]as well as Brønsted and

Lewis acidic treatments. With little success in this initial ap-

proach, we next decided to target the known tetracyclic enone

2 from (6R)-21 and then follow the dialkylation sequence of

Nicolaou et al.^[6d]to synthesize platensinoate 45 (Scheme 7).

In our earlier communication, we demonstrated that the tet-

racyclic enone 2 could be obtained from the 6-methoxyketone

(6R)-21 through a three-step sequence: 1) Lewis acid promoted

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Scheme 8. High-yielding synthesis of the aniline ester 3. PPA: polyphosphor-

ic acid; TBAI: tetrabutylammonium iodide.

Scheme 7. Synthesis of platensic acid (6) via tetracyclic enone 2.

sodium methoxide solution.^[10]The high-yielding reaction was

complete in less than a minute. This is in contrast to the con-

ventional and less efficient two-step synthesis via an acid inter-

mediate. Catalytic hydrogenation of 50 subsequently led to

a global reduction of the nitro group and hydrogenolysis of

the bis-Bn ethers to give the aniline unit 3 in 92% yield. No

further purification was required, and 3 was immediately car-

ried forward to the next step because it was found to be un-

stable.

demethylation, 2) mesylation of the resulting acyloin, and 3) a-

dehydrohalogenation of the mesylate to generate the conju-

1

gated double bond.^[7h]The H and ¹³C NMR spectra of 2 were

found to be identical to those reported by Nicolaou et al.^[6d]

and others. Methylation of 2 with KHMDS in THF/HMPA (5:1)

then afforded the methylated caged intermediate 47 in 80%

yield with almost complete stereoselectivity. Relative to the re-

action with the 6-methoxy analogue 7, it is noteworthy that

the alkylation of 2 improved in reactivity and diastereoselectiv-

ity in the absence of the methoxy functionality. The subse-

quent 1,4-addition with alkyl acrylates to install the propionate

side chain under the reported conditions from Yeung and

Corey,^[9g]Nicolaou et al.,^[6d]and Tiefenbacher and Mulzer^[39]was

nontrivial. In our hands, the reaction was consistently plagued

by inefficient conversion due to significant byproduct forma-

tion, even though 47 was completely consumed. After consid-

erable experimentation, the alkylation with tert-butyl acrylate

was found to proceed optimally with 1m KOtBu (0.8 equiv) in

tBuOH to furnish the tert-butyl platensinoate 48 in 62% yield

and a 10:1 d.r. at the C4 position. Fewer byproducts were ob-

served under these improved conditions. The tert-butyl ester

cleavage under TFA treatment proceeded uneventfully and fur-

nished platensic acid (6) in quantitative yield.

The end-game amide coupling between platensic acid (6)

and the aniline unit 3 was carried out by treatment with N-[(di-

methylamino)-1H-1,2,3-triazole[4,5-b]-pyridin-1-ylmethylene]-N-

methylmethanaminium hexafluorophosphate (HATU) and Et₃N

to provide the desired amide 51, gratifyingly, as a single diaste-

reomer in 71% yield after preparative TLC (Scheme 9). The C4

epimer of 51 was not detected by any means. Unexpectedly,

the final deprotection step, hydrolysis of the methyl benzoate

ester, was found to be problematic. Basic hydrolysis with aque-

ous LiOH/THF and aqueous NaOH/MeOH only afforded 30–

40% yields (at best) of platensimycin, due to poor conversions.

In this case, we suspected the methyl ester was deactivated by

the strongly electron-donating ortho- and para-phenolic

groups, which may account for its poorer reactivity, relative to

During our total synthesis efforts, two unique syntheses of

the aromatic fragment of platensimycin 1 were reported. The

aniline precursor 3 has been prepared by Heretsch and Giannis

in two steps from methyl 2,4-dihydoxybenzoate in 28%

yield.^[40]Our synthesis of 3 proceeded in 4 practical steps from

2-nitroresorcinol (5) with an overall yield of 57% (Scheme 8). In

contrast to the other synthesis by Nicolaou et al.,^[5]we ach-

ieved the carboxylation of 5 without the need for an additional

aniline protection–deprotection sequence. Thus, our synthesis

commenced with an early Friedel–Crafts acylation of 5 with

AcOH in hot PPA to afford the acetophenone 49 in 69%

yield.^[41]Bisbenzylation of both phenolic groups then occurred

uneventfully under classical conditions with BnBr, K₂CO₃, and

a catalytic amount of TBAI. With the resulting bis-Bn acetophe-

none 4 in hand, our new direct oxidative esterification to the

methyl benzoate 50 could be realized in excellent yield upon

treatment of 4 with tert-butyl hypochlorite in methanolic

Scheme 9. Completion of the synthesis of (ꢀ)-platensimycin (1).

Chem. Eur. J. 2014, 20, 1 – 19

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Merck precoated silica gel plates (60F-254) by using UV light at

254 nm as the visualizing agent, with ceric ammonium molybdate,

KMnO₄, or ninhydrin as developing stains. Flash column chroma-

tography was performed on silica gel 60 (0.040–0.063 mm), and

preparative TLC was performed on 1 mm thickness Merck precoat-

the hydrolysis of the known methoxymethyl-protected ana-

logue.^[5]Eventually, ester hydrolysis of 51 was significantly im-

proved by treatment with 2m aqueous KOH in a 1,4-dioxane/

MeOH mixture at 358C to furnish (ꢀ)-platensimycin (1) in 60%

1

yield. The H and ¹³C NMR spectra of (ꢀ)-1 were found to be

1

ed silica gel plates (60F-254). H NMR and ¹³C NMR spectra were re-

identical to those reported by Nicolaou et al.^[6d]

corded on either Bruker AMX500 or Bruker ACF300 NMR spectrom-

eters in deuterated solvents as indicated. Chemical shifts (d) are re-

ported in ppm, and the residual solvent peak was used as an inter-

nal reference (CDCl₃: dH=7.26 ppm, dC=77.0 ppm; CD₃OD: dH=

Conclusion

1

3.33 ppm, dC=49.05 ppm). H NMR coupling constants (J) are re-

In summary, we have achieved a unique and stereoselective

route to (ꢀ)-platensimycin (1) from commercially available eu-

genol that is competitive in practice with the diverse synthetic

approaches continually appearing in the literature for this

highly intriguing ketolide natural product. The synthesis fea-

tures the tactical employment of a 6-methoxy group to impart

needed electronic and steric controls to help advance three

key transformations toward platensic acid (6). These key steps

are 1) a direct and efficient para-arylation of an oxocarbenium

species in a novel Bi(OTf)₃-catalyzed Marson type Friedel–Crafts

cyclization of the free lactols 9 and 17, 2) a superior TBAF-

mediated alkylative cyclodearomatization of the free phenol

19 without undue silyl preactivation or use of more powerful

leaving groups than OTs, and 3) a chemo- and diastereoselec-

tive conjugate reduction of the 6-methoxydienone 8 mediated

by the TFA salt of di-tert-butyl a-amino malonate, 36, to re-

verse the strongly intrinsic, unfavorable p-facial selectivity of

the substrate with readily available laboratory resources and

techniques.

ported in Hertz (Hz), and multiplicities are represented as follows:

s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd

(doublet of doublet), ddd (doublet of doublet of doublet), dt (dou-

blet of triplet), td (triplet of doublet), and br (broad). Low-resolu-

tion mass spectra were obtained on a Finnigan/MAT LCQ spec-

trometer in ESI mode. High-resolution ESI mass spectra were ob-

tained on a Shimadzu LCMS-IT-TOF spectrometer, and high-resolu-

tion EI mass spectra were obtained on a Micromass VG7035

double-focusing mass spectrometer. Samples for infrared measure-

ments were prepared as thin films, either neat or in CH₂Cl₂solu-

tion, spread on NaCl cells, and the spectra were recorded on a BIO-

RAD FTS 165 FTIR spectrometer. Optical rotations were recorded

on a Jasco DIP-1000 polarimeter with an Na lamp of 589 nm wave-

length.

Compound syntheses

Synthesis of bromohydrin 12: K₂CO₃(0.415 g, 3.00 mmol) was

added to a solution of monotosylated diol 10 (0.766 g, 1.50 mmol)

in MeOH (AR grade, 20 mL) at room temperature. The resulting

mixture was stirred at room temperature for 1 h before it was con-

centrated in vacuo. The resulting white precipitate was redissolved

in sat. aq. NH₄Cl and extracted with Et₂O (3ꢃ). The combined or-

ganic extracts were washed with brine, dried over Na₂SO₄, filtered,

and concentrated in vacuo. Dried LiBr·H₂O (0.95 g, 9.06 mmol) and

glacial AcOH (0.17 mL, 3.00 mmol) were added to the crude epox-

ide 11 in THF (23 mL) at room temperature. The LiBr·H₂O was pre-

dried in vacuo for 3 h at 1258C. The resulting mixture was heated

to reflux at 908C for 5 h, before it was cooled to room temperature

and brine was added. The organic layer was separated, and the

aqueous layer was extracted with EtOAc (3ꢃ). The combined or-

ganic layers were dried over Na₂SO₄, filtered, and concentrated in

vacuo. Flash column chromatography of the crude product over

silica gel (5% EtOAc/hexane ! 20% EtOAc/hexane) afforded bro-

mohydrin 12 (0.573 g, 91% over two steps) as a colorless oil. R_f=

0.29 (silica, 20% EtOAc in hexanes); [a]²_D⁵= +25.2 (c=0.57, CHCl₃);

IR (thin film): n_max=3512, 2938, 1594, 1512, 1453, 1385, 1263, 1229,

Demethoxylation of the 6-methoxyenone 7 was necessary

before final elaboration to (ꢀ)-1. This was achieved either

through radical reduction with SmI₂and tBuOH or through the

utilization of our previously established demethylation–dehy-

drohalogenation sequence.^[7h]The total synthesis of (ꢀ)-1 was

further progressed to completion by virtue of practical efforts

in optimizing a substrate-controlled double alkylation se-

quence from the enone 6 and the development of an efficient

four-step synthesis of the aromatic domain, which showcases

a key oxidative esterification methodology under study in our

laboratory.^[10]Application of this total synthesis and the meth-

ods developed en route for fatty acid synthase probe studies

will be the subject of future bioorganic investigations.^[43]

1

1138, 1144, 1028, 816, 737 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=7.44

Experimental Section

(d, J=7.6 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H),

6.81 (d, J=7.6 Hz, 1H), 6.77 (d, J=1.3 Hz, 1H), 6.69 (dd, J=1.9,

8.2 Hz, 1H), 5.79–5.70 (m, 1H), 5.12 (s, 2H), 5.01–4.96 (m, 2H), 3.88

(s, 3H), 3.62 (d, J=10.7 Hz, 1H), 3.56 (d, J=10.1 Hz, 1H), 3.02 (dd,

J=3.8, 14.5 Hz, 1H), 2.44–2.39 (m, 1H), 2.17–2.05 (m, 3H),

1.32 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=149.7, 146.6, 137.4,

137.4, 134.6, 128.4, 127.7, 127.3, 121.2, 116.1, 114.5, 113.2, 73.9,

71.3, 56.1, 47.6, 45.6, 34.9, 34.4, 22.4 ppm; HRMS (EI): m/z calcd for

C₂₂H₂₇O₃⁷⁹Br⁺[M]⁺: 418.1144; found: 418.1139; m/z calcd for

C₂₂H₂₇O₃⁸¹Br⁺[M]⁺: 420.1123; found: 420.1119 (intensity ratio 1:1).

General information

All moisture-sensitive reactions were performed in flame-dried

round-bottom flasks under an inert Ar atmosphere with freshly dis-

tilled dry solvents: THF from Na/benzophenone; Et₂O from Na

wire; CH₂Cl₂and 1,4-dioxane from CaH₂; MeOH from Mg. Dry

CH₃CN and toluene were directly obtained from Glass Contour’s

solvent dispensing system. Commercial reagents were used as re-

ceived without further purification. (S)-TRIP was kindly donated by

Professor Benjamin List from the Max-Planck-Institut fꢂr Kohlenfor-

schung. Molecular sieves (4 ꢁ) were activated by heating in a fur-

nace at 3008C for 20 h before storing in a dry dessicator. Yields

refer to chromatographically and spectroscopically homogeneous

materials. Reaction progress was monitored by TLC with 0.25 mm

Synthesis of cis-bromolactol 9: A solution of NMO (50% w/w in

H₂O, 0.524 g, 2.24 mmol) in H₂O (6 mL) and OsO₄(2 mol%) were

added to a solution of 12 (0.782 g, 1.87 mmol) in tBuOH (30 mL)

and THF (12 mL) at room temperature. The resulting mixture was

stirred at room temperature for 12 h, before it was cooled to 08C

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Full Paper

and quenched with NaHSO₃(1.4 g, 3m in H₂O). The mixture was

warmed to room temperature and stirred for 45 min. The organic

layer was separated and concentrated in vacuo, and EtOAc was

added to redissolve the residue that formed. The aqueous layer

was extracted with EtOAc (3ꢃ), and the combined organic layers

were washed with H₂O (1ꢃ) followed by brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. NaIO₄(1.0 g, 4.68 mmol) was

added to this crude diol in THF (30 mL) and H₂O (15 mL) at room

temperature, and the mixture was stirred for 2 h. The resulting mix-

ture was carefully concentrated to less than half its volume by re-

moving THF under vacuum. The mixture was diluted with water

and extracted with EtOAc (3ꢃ). The combined organic extracts

were washed with brine, dried over Na₂SO₄, filtered, and concen-

trated in vacuo. Flash column chromatography of the crude prod-

uct over silica gel (10% EtOAc/hexane ! 45% EtOAc/hexane) af-

forded cis-bromolactol 9 (0.713 g, 91% over 2 steps) as a white

solid. R_f=0.39 (silica, 50% EtOAc/hexane); m.p. 52.8–56.18C;

[a]²_D⁵= +15.7 (c=0.71, CHCl₃); IR (thin film): n_max=3421, 2936,

C₂₁H₂₃O₃⁷⁹Br⁺[M]⁺: 402.0831; found: 402.0827; m/z calcd for

C₂₁H₂₃O₃⁸¹Br⁺[M]⁺: 404.0810; found: 404.0813 (intensity ratio 1:1).

Synthesis of bromophenol 14: 10% Pd on carbon (20% wt/wt,

55.2 mg), followed by 1,4-cyclohexadiene (1.6 mL, 17.1 mmol) was

added to a solution of 13 (0.276 g, 0.684 mmol) in absolute EtOH

(6 mL) at room temperature under an atmosphere of N₂. The re-

sulting mixture was stirred at room temperature for 3 h, before it

was filtered through a pad of Celite, eluted with EtOAc, and con-

centrated in vacuo. Flash column chromatography of the crude

product over silica gel (10% EtOAc/hexane ! 40% EtOAc/hexane)

afforded bromophenol 14 (0.213 g, 99%) as a colorless viscous oil.

R_f=0.29 (silica, 30% EtOAc/hexane); [a]²_D⁶= +26.2 (c=0.27, CHCl₃);

IR (thin film): n_max=2924, 2853, 1652, 1510, 1452, 1348, 1275, 1218,

1170, 1107, 968, 814 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃): d=6.65 (s,

;

1H), 6.62 (s, 1H), 5.45 (s, 1H), 4.76 (d, J=5.5 Hz, 1H), 3.87 (s, 3H),

3.30 (d, J=10.0 Hz, 1H), 3.22–3.18 (m, 2H), 3.00 (dd, J=4.4,

17.6 Hz, 1H), 2.56–2.49 (m, 2H), 2.00 (d, J=10.7 Hz, 1H), 1.45 ppm

(s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=146.6, 143.4, 133.4, 125.4,

113.3, 111.0, 84.1, 78.0, 56.0, 41.4, 38.5, 35.3, 31.8, 26.2 ppm; ESI-

1591, 1512, 1456, 1419, 1379, 1263, 1229, 1140, 1020, 737 cm^ꢀ1

;

¹H NMR (500 MHz, CDCl₃): d=7.43 (d, J=7.6 Hz, 2H), 7.36 (t, J=

7.6 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 6.81 + 6.80 (d each, J=8.2 Hz,

1H), 6.71 + 6.69 (d each, J=1.9 Hz, 1H), 6.66–6.63 (m, 1H), 5.52–

5.50 (m, 1H), 5.13 (s, 2H), 3.89 + 3.88 (s each, 3H), 3.81 + 3.44 (d₁,

J₁=10.1 Hz + d₂, J₂=10.7 Hz, 1H), 3.49 + 3.37 (d₁, J₁=10.1 Hz +

d₂, J₂=10.7 Hz, 1H), 3.09 + 2.81–2.71 (m each, 2H), 2.56 (dd, J=

10.8, 13.3 Hz, 1H), 2.41–2.27 (m, 1H), 2.00–1.92 + 1.81–1.76 (m

each, 1H), 1.46 + 1.36 ppm (s each, 3H); ¹³C NMR (125 MHz,

CDCl₃): d=149.8, 149.7, 146.80, 146.8, 137.2, 133.1, 133.0, 128.5,

127.8, 127.3, 127.3, 120.6, 120.5, 114.4, 112.4, 97.8, 97.2, 83.6, 83.1,

71.2, 56.1, 56.0, 50.8, 47.9, 39.8, 39.5, 39.4, 39.3, 35.4, 34.8, 27.4,

25.0 ppm; HRMS (EI): m/z calcd for C₂₁H₂₅O₄⁷⁹Br⁺[M]⁺: 420.0936;

found: 420.0929; m/z calcd for C₂₁H₂₅O₄⁸¹Br⁺[M]⁺: 422.0916;

found: 422.0922 (intensity ratio 25:22).

MS: m/z calcd for C₁₄H₁₆⁷⁹BrO₃[MꢀH]^ꢀ: 311.0; found: 311.3.

ꢀ

General procedure for the Lewis acid catalyzed Marson type

Friedel–Crafts cyclization of 9: Activated 4 ꢁ molecular sieves

(1.0 gmmol^ꢀ1) were added to 9 (20–30 mg) under an atmosphere

of Ar, followed by CH₂Cl₂(0.01–0.02m) to make a suspension. The

Lewis acid was weighed, either in the open or in an N₂-filled Al-

drich AtmosBag glove bag, and transferred to the solution of 9 at

room temperature under Ar. The resulting mixture was stirred at

room temperature until TLC indicated the complete consumption

of 9. At higher catalyst loadings of Bi(OTf)₃, the colorless solution

turns a persistent pink color, which indicates completion of the re-

action. The reaction mixture was poured into ice-cooled sat. aq.

NH₄Cl with vigorous stirring, before the organic layer was separat-

ed. The aqueous layer was extracted with CH₂Cl₂(2ꢃ). The com-

bined organic layers were washed with brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (5% EtOAc/hexane ! 18%

EtOAc/hexane) afforded bromobenzotetrahydrofuran 13 as a color-

less oil. Further elution at 22% EtOAc/hexane gave the bromolactol

dimeric ether 15 as a colorless viscous oil and benzobromohydrin

16 was obtained as a yellow oil with 30% EtOAc/hexane.

Synthesis of bromobenzotetrahydrofuran 13 (through SnCl₄-

mediated Friedel–Crafts cyclization): SnCl₄(0.96 mL, 8.20 mmol)

was quickly added to a solution of 9 (0.685 g, 1.63 mmol) in CH₂Cl₂

(20 mL) at ꢀ788C. The solution gave a strong orange color after

10–15 min of stirring at ꢀ788C. The solution was stirred at ꢀ788C

for 75 min, before it was quenched with half-saturated Rochelle

salt aq. solution. The half-saturated Rochelle salt (90 g in 200 mL

H₂O) was cooled to 08C with vigorous stirring. The reaction mix-

ture was lifted above the ꢀ788C dry ice/acetone bath, and its con-

tents were immediately poured into the half-saturated Rochelle

salt upon removing the rubber septum. After the transfer was

complete and the resulting organic layer became colorless in less

than 1 min, the mixture was diluted with some H₂O, and the or-

ganic layer was separated. The aqueous layer was extracted with

CH₂Cl₂(2ꢃ). The combined organic layers were washed with brine,

dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash

column chromatography of the crude product over silica gel (5%

EtOAc/hexane ! 18% EtOAc/hexane) afforded bromobenzotetra-

hydrofuran 13 (0.578 g, 88%) as a colorless oil. R_f=0.63 (silica,

30% EtOAc/hexanes); [a]²_D⁵= +106.7 (c=0.67, CHCl₃); IR (thin film):

n_max=2943, 1607, 1510, 1452, 1325, 1267, 1223, 1119, 1049, 972,

Compound 15: R_f=0.47 (silica, 30% EtOAc/hexane); [a]²_D⁶=ꢀ61.4

(c=0.48, CHCl₃); IR (thin film): n_max=3059, 2924, 2853, 1589, 1512,

1452, 1377, 1263, 1231, 1140, 1011, 961, 735 cm^ꢀ1

;

¹H NMR

(500 MHz, CDCl₃): d=7.44 (d, J=7.6 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H),

7.30 (t, J=8.2 Hz, 1H), 6.82–6.80 (m, 1H), 6.69 (d, J=1.9 Hz, 1H),

6.67–6.63 (m, 1H), 5.56–5.54 + 5.45–5.44 (m each, 1H), 5.13 + 5.12

(s each, 2H), 3.89 + 3.88 (s each, 3H), 3.73 + 3.41–3.35 (d₁, J₁=

10.1 Hz + m₂, 2H), 2.81–2.73 (m, 1H), 2.58–2.32 + 2.02–1.96 (m

each, 3H), 1.86–1.82 + 1.77–1.72 (m each, 1H), 1.33 ppm (s, 3H);

¹³C NMR (125 MHz, CDCl₃): d=149.8, 149.7, 146.8, 146.8, 137.3,

133.4, 133.1, 128.5, 127.8, 127.3, 120.7, 120.5, 114.4, 114.3, 112.7,

112.4, 99.8, 98.7, 83.3, 82.9, 71.2, 56.1, 56.1, 50.4, 48.2, 39.7, 39.0,

38.8, 35.6, 34.9, 29.7, 27.4, 24.5 ppm; HRMS (EI): m/z calcd for

C₄₂H₄₈O₇⁷⁹Br₂[M]⁺: 822.1767; found: 822.1796; m/z calcd for

+

C₂₁H₂₅O₄⁷⁹Br⁸¹Br⁺[M]⁺: 824.1746; found: 824.1783; m/z calcd for

C₂₁H₂₅O₄⁸¹Br⁸¹Br⁺[M]⁺: 826.1726; found: 826.1788 (intensity ratio

1:2:1).

866, 739 cm^{ꢀ1 1}H NMR (500 MHz, CDCl₃): d=7.43 (d, J=7.0 Hz,

;

2H), 7.36 (t, J=7.6 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 6.67 (s, 1H), 6.64

(s, 1H), 5.12 (d, J=12.0 Hz, 1H), 5.07 (d, J=12.0 Hz, 1H), 4.72 (d,

J=5.1 Hz, 1H), 3.86 (s, 3H), 3.30 (d, J=10.1 Hz, 1H), 3.21 (d, J=

10.1 Hz, 1H), 3.19 (d, J=5.0 Hz, 1H), 3.01 (dd, J=4.4, 17.7 Hz, 1H),

2.56 (brs, 1H), 2.52–2.48 (d, J=5.4 Hz, 1H), 2.00 (d, J=11.4 Hz, 1H),

1.45 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=149.7, 146.2, 137.2,

132.8, 128.5, 127.8, 127.3, 126.8, 113.1, 112.2, 84.1, 78.1, 71.3, 56.1,

41.4, 38.5, 35.3, 31.8, 26.2 ppm; HRMS (EI): m/z calcd for

Compound 16: R_f=0.35 (silica, 30% EtOAc/hexane); [a]²_D⁶=ꢀ157.3

(c=0.15, CHCl₃); IR (thin film): n_max=2955, 2922, 2853, 1510, 1454,

1379, 1260, 1227, 1119, 1022, 854, 739 cm^ꢀ^{1 1}H NMR (500 MHz,

;

CDCl₃): d=7.43 (d, J=6.9 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.30 (t,

J=7.6 Hz, 1H), 6.70 (s, 1H), 6.62 (s, 1H), 6.42 (dd, J=1.9, 10.1 Hz,

1H), 5.74 (dd, J=4.4, 10.1 Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H), 3.61 (d,

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J=10.7 Hz, 1H), 3.47 (d, J=10.1 Hz, 1H), 2.94 (d, J=2.5 Hz, 2H),

2.78–2.77 (m, 1H), 2.02 (s, 1H), 1.20 ppm (s, 3H); ¹³C NMR

(125 MHz, CDCl₃): d=149.2, 146.6, 137.3, 129.3, 128.5, 128.0, 127.8,

127.3, 125.9, 124.7, 113.1, 112.0, 73.7, 71.5, 56.1, 44.6, 41.6, 28.0,

22.3 ppm; HRMS (EI): m/z calcd for C₂₁H₂₃O₃⁷⁹Br⁺[M]⁺: 402.0831;

found: 402.0815; m/z calcd for C₂₁H₂₃O₃⁸¹Br⁺[M]⁺: 404.0810;

found: 404.0816 (intensity ratio 1:1).

133.1, 133.1, 132.8, 132.7, 129.9, 129.9, 128.5, 128.0, 127.9, 127.8,

127.8, 127.3, 120.5, 120.5, 114.4, 112.5, 112.5, 98.1, 97.4, 83.5, 82.4,

72.8, 72.5, 71.2, 60.4, 56.1, 50.1, 47.2, 40.4, 40.2, 34.8, 34.4, 25.2,

23.5, 21.6 ppm; HRMS (IT-TOF): m/z calcd for C₂₈H₃₂O₇SNa⁺

[M+Na]⁺: 535.1766; found: 535.1772.

Synthesis of tosylbenzotetrahydrofuran 18 (through SnCl₄-medi-

ated Friedel–Crafts cyclization): SnCl₄(0.68 mL, 5.81 mmol) was

quickly added to

a solution of cis-tosyllactol 17 (0.392 g,

Synthesis of 6-methoxydienone

8 from 14: DBU (1.5 mL,

0.765 mmol) in CH₂Cl₂(38 mL) at ꢀ788C. The solution gave

a bright yellow color after 65 min of stirring at ꢀ788C. After stirring

at ꢀ788C for 75 min, the reaction vessel was lifted above the dry

ice/acetone bath and, upon removal of the rubber septum, its con-

tents were immediately poured into precooled (08C) half-saturated

Rochelle salt solution (80 g in 150 mL H₂O) with vigorous stirring.

After the transfer was complete and the resulting organic layer

became colorless, typically within 1 min, the mixture was diluted

with some H₂O, and the organic layer was separated. The aqueous

layer was extracted with CH₂Cl₂(2ꢃ). The combined organic layers

were washed with brine, dried over Na₂SO₄, filtered, and concen-

trated in vacuo. Flash column chromatography of the crude prod-

uct over silica gel (5% EtOAc/hexane ! 22% EtOAc/hexane) af-

forded tosylbenzotetrahydrofuran 18 (0.325 g, 86%) as a colorless

oil.

10.2 mmol) was added to a stirred solution of 14 (0.213 g,

0.68 mmol) in CH₃CN (35 mL) at room temperature, and the mix-

ture was heated at 70–758C for 10 h. The resulting mixture was

concentrated in vacuo to half its volume and added 10% aq. citric

acid to adjust the pH value of the solution to approximately pH 3.

The organic layer was separated, and the aqueous layer was ex-

tracted with EtOAc (3ꢃ). The combined organic layers were

washed with water (2ꢃ), followed by brine, dried over Na₂SO₄, fil-

tered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (20% EtOAc/hexane ! 65%

EtOAc/hexane) afforded 6-methoxydienone 8 (0.134 g, 85%) as

a pale yellowish-white solid. R_f=0.25 (silica, 60% EtOAc/hexane);

m.p. 76.1–78.48C; [a]²_D⁶= +44.7 (c=0.68, CHCl₃); IR (thin film):

n_max=2957, 2916, 1668, 1659, 1616, 1475, 1213, 1171, 1140, 1113,

1

1084, 1016 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=6.16 (s, 1H), 5.55 (s,

1H), 4.72 (d, J=4.5 Hz, 1H), 3.67 (s, 3H), 2.56 (t, J=6.3 Hz, 1H),

2.24–2.16 (m, 2H), 1.99 (d, J=11.4 Hz, 1H), 1.93 (dd, J=3.2,

11.3 Hz, 1H), 1.75 (d, J=11.4 Hz, 1H), 1.52 (d, J=3.2 Hz, 1H),

1.50 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=182.0, 160.6, 152.2,

121.4, 117.9, 86.7, 79.6, 55.9, 54.9, 49.7, 44.1, 42.5, 22.2 ppm; HRMS

(IT-TOF): m/z calcd for C₁₄H₁₆O₃Na⁺[M+Na]⁺: 255.0997; found:

255.0999.

Synthesis of tosylbenzotetrahydrofuran 18 (through Bi(OTf)₃/

LiClO₄-catalyzed Friedel–Crafts cyclization): Activated 4 ꢁ molec-

ular sieves (1.0 gmmol^ꢀ1) were added to cis-tosyllactol 17 (0.518 g,

1.01 mmol) under an atmosphere of Ar, followed by CH₂Cl₂

(50 mL). LiClO₄(0.326 g, 3.06 mmol) was added to 17 at room tem-

perature under Ar, and the mixture was stirred for 45 min before

Bi(OTf)₃(5 mol%, 35 mg) was added to the reaction at the same

temperature under Ar. The resulting mixture was stirred at room

temperature for 3.5 h, before it was poured into an ice-cooled sat.

aq. NH₄Cl with vigorous stirring. The organic layer was separated,

and the aqueous layer was extracted with CH₂Cl₂(2ꢃ). The com-

bined organic layers were washed with brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (5% EtOAc/hexane ! 22%

EtOAc/hexane) afforded tosylbenzotetrahydrofuran 18 (0.469 g,

Synthesis of cis-tosyllactol 17: A solution of NMO (50% w/w in

H₂O, 2.10 g, 8.96 mmol) in H₂O (10 mL) and OsO₄(2 mol%) were

added to a solution of monotosylated diol 10 (3.80 g, 7.44 mmol)

in tBuOH (50 mL) and THF (20 mL) at room temperature. The re-

sulting mixture was stirred at room temperature for 12 h before it

was cooled to 08C and quenched with NaHSO₃(5.6 g, 3m in H₂O).

The mixture was warmed to room temperature and stirred for

45 min. The organic layer was separated and concentrated in

vacuo, and EtOAc was added to redissolve the residue that

formed. The aqueous layer was extracted with EtOAc (3ꢃ), and the

combined organic layers were washed with H₂O (1ꢃ), followed by

brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. NaIO₄

(4.10 g, 19.2 mmol) was added to this crude diol in THF (100 mL)

and H₂O (50 mL) at room temperature, and the mixture was stirred

for 2 h. The resulting mixture was carefully concentrated to less

than half its volume by removing THF in vacuo. The mixture was

diluted with water and extracted with EtOAc (3ꢃ). The combined

organic extracts were washed with brine, dried over Na₂SO₄, fil-

tered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (10% EtOAc/hexane ! 60%

EtOAc/hexane) afforded cis-tosyllactol 17 (3.24 g, 85% over two

steps) as a white solid foam. R_f=0.29 (silica, 50% EtOAc/hexane);

m.p. 64.4–65.98C; [a]²_D⁵= +21.1 (c=0.51, CHCl₃); IR (thin film):

n_max=3524, 3061, 2938, 1595, 1512, 1456, 1360, 1265, 1229, 1177,

94%) as a colorless oil. R_f=0.46 (silica, 30% EtOAc/hexane); [a]_D²⁵

=

+45.5 (c=0.47, CHCl₃); IR (thin film): n_max=3034, 2951, 1607, 1510,

1452, 1358, 1329, 1269, 1177, 1130, 1111, 1045, 970, 862, 829,

735 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃): d=7.72 (d, J=8.2 Hz, 2H),

;

7.42 (d, J=7.6 Hz, 2H), 7.36 (t, J=7.3 Hz, 2H), 7.31–7.28 (m, 3H),

6.56 (s, 1H), 6.46 (s, 1H), 5.09 (d, J=12.0 Hz, 1H), 5.04 (d, J=

12.6 Hz, 1H), 4.63 (d, J=5.1 Hz, 1H), 3.83 (s, 3H), 3.77 (d, J=8.9 Hz,

1H), 3.70 (d, J=8.9 Hz, 1H), 2.93 (dd, J=4.4, 17.7 Hz, 1H), 2.83 (d,

J=17.7 Hz, 1H), 2.47 (brs, 1H), 2.45 (s, 3H), 2.40–2.36 (m, 1H), 1.92

(d, J=11.4 Hz, 1H), 1.21 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃):

d=149.7, 146.3, 144.8, 137.2, 132.5, 132.4, 129.8, 128.5, 128.1,

127.8, 127.3, 126.3, 113.0, 112.3, 81.9, 77.9, 73.3, 71.2, 56.1, 41.2,

34.8, 31.6, 25.4, 21.6 ppm; HRMS (IT-TOF): m/z calcd for

C₂₈H₃₀O₆SNa⁺[M+Na]⁺: 517.1661; found: 517.1661.

Synthesis of tosylphenol 19: 10% Pd on carbon (10% wt/wt,

0.11 g) was added to a solution of 18 (1.06 g, 2.14 mmol) in THF

(45 mL) at room temperature. The resulting mixture was stirred

under a hydrogen atmosphere (balloon) for 2.5 h, before it was fil-

tered through a pad of Celite, eluted with EtOAc, and concentrated

in vacuo. Flash column chromatography of the crude product over

silica gel (50% EtOAc/hexane) afforded tosylphenol 19 (0.867 g,

100%), which was recrystallized from CH₂Cl₂/EtOAc as white crys-

tals.^[7h]R_f=0.19 (silica, 30% EtOAc/hexane); [a]²_D⁵= +20.3 (c=0.27,

CHCl₃); IR (thin film): n_max=3462, 2924, 2853, 1653, 1510, 1458,

1

1096, 1022, 972, 839, 814, 737 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=

7.83 + 7.80 (d each, J=8.2 Hz, 2H), 7.43 (d, J=7.0 Hz, 2H), 7.36 (t,

J=6.9 Hz, 4H), 7.29 (t, J=7.3 Hz, 1H), 6.80–6.77 (m, 1H), 6.70 +

6.66 (d each, J=1.9 Hz, 1H), 6.60–6.57 (m, 1H), 5.39 + 5.34 (m

each, 1H), 5.11 (s, 2H), 4.13–4.10 + 3.94 (m₁+ d₂, J₂=10.1 Hz, 1H),

4.05 + 3.86–3.85 (d₁, J₁=10.1 Hz + m₂, 1H), 3.87 (s, 3H), 2.73–2.70

+ 2.62–2.48 (m each, 3H), 2.45 (s, 3H), 2.26–2.24 + 1.93–1.84 (m

each, 2H), 1.70–1.67 (m, 1H), 1.20 + 1.17 ppm (s each, 3H);

¹³C NMR (125 MHz, CDCl₃): d=149.7, 146.7, 144.9, 137.3, 137.2,

1368, 1348, 1275, 1175, 1108, 968, 833, 812 cm^ꢀ1

;

¹H NMR

&

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(500 MHz, CDCl₃): d=7.71 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz,

2H), 6.55 (s, 1H), 6.46 (s, 1H), 5.46 (s, 1H), 4.65 (d, J=5.1 Hz, 1H),

3.84 (s, 3H), 3.83 (d, J=8.9 Hz, 1H), 3.68 (d, J=9.5 Hz, 1H), 2.93

(dd, J=3.8, 17.7 Hz, 1H), 2.85 (d, J=17.7 Hz, 1H), 2.47 (brs, 1H),

2.43 (s, 3H), 2.41–2.37 (m, 1H), 1.93 (d, J=11.4 Hz, 1H), 1.20 ppm

(s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=146.5, 144.7, 143.4, 133.2,

132.4, 129.7, 128.1, 124.9, 113.1, 110.9, 81.8, 77.7, 73.4, 56.0, 41.3,

34.8, 31.6, 25.3, 21.6 ppm; HRMS (IT-TOF): m/z calcd for

C₂₁H₂₄O₆SNa⁺[M+Na]⁺: 427.1191; found: 427.1196.

perature for 3 h, before it was filtered, repeatedly washed with

hexane, and dried in vacuo to afford the TFA salt of glycine tert-

butyl ester 35 (62.9 mg, 78% over two steps) as a white solid. M.p.

120.8–122.68C; ¹H NMR (300 MHz, CDCl₃): d=3.79 (s, 2H),

1.38 ppm (s, 9H); ESI-MS: m/z c_ꢀalcd for C₆H₁₄O₂N⁺[M]⁺: 132.1;

found: 132.3; m/z calcd for C₂F₃O₂[M]^ꢀ: 113.0; found: 113.0.

Preparation of the TFA salt of dl-aspartate di-tert-butyl ester

(ꢁ)-37: 1) Synthesis of Cbz-protected di-tert-butyl dl-aspartate:

1,4-Dioxane (12 mL) and H₂O (12 mL) were added to a mixture of

dl-aspartic acid (500 mg, 3.76 mmol) and Na₂CO₃(1.59 g,

15.0 mmol) at room temperature. The resulting mixture was cooled

to 08C, before CbzCl (1.15 mL, 7.52 mmol) was added, and the re-

action was stirred at room temperature for 16 h. Water was added,

and the aqueous mixture was extracted with Et₂O (2ꢃ). The aque-

ous layer was acidified with 1n HCl to pH 1–2, before it was ex-

tracted with EtOAc (3ꢃ). The combined EtOAc extracts were

washed with water (1ꢃ), followed by brine, dried over Na₂SO₄, fil-

tered, and concentrated in vacuo to give crude Cbz-protected dl-

aspartic acid (1.121 g) as a colorless oil. Concentrated H₂SO₄

(0.54 mL, 9.72 mmol) was added to a suspension of anhydrous

MgSO₄(2.65 g, 22.0 mmol) in CH₂Cl₂(6 mL) at room temperature

and stirred under Ar for 15 min. A solution of crude Cbz-protected

dl-aspartate (0.587 g, 2.20 mmol) in CH₂Cl₂(6 mL) was added to

this mixture, before anhydrous tBuOH (2.5 mL, 26.1 mmol) was

added at the same temperature. The resulting mixture was tightly

stoppered and stirred at room temperature for 40 h, before it was

carefully quenched with sat. aq. NaHCO₃to dissolve the MgSO₄,

and the solution was basified. After dilution with water, the organic

layer was separated, and the aqueous layer was extracted with

Et₂O (3ꢃ). The combined organic layers were washed with brine,

dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash

column chromatography of the crude product over silica gel (10%

EtOAc/hexane) afforded the Cbz-protected di-tert-butyl dl-aspar-

tate (76.2 mg, 11% over two steps) as a colorless oil. IR (thin film):

n_max=3317, 2976, 2938, 1726, 1708, 1552, 1464, 1334, 1228, 1155,

Synthesis of 6-methoxydienone 8 from 19: TBAF (1m in THF,

10.8 mL, 10.8 mmol) was added to a solution of 19 in xylene

(98 mL) at room temperature, and the mixture was heated at

1308C for 4 h in a sealed tube. The resulting mixture was concen-

trated in vacuo to half its volume, and 10% aq. citric acid was

added to adjust the pH value of the solution to approximately

pH 3. The organic layer was separated, and the aqueous layer was

extracted with EtOAc (3ꢃ). The combined organic layers were

washed with water (1ꢃ), followed by brine, dried over Na₂SO₄, fil-

tered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (20% EtOAc/hexane ! 65%

EtOAc/hexane) afforded 6-methoxydienone 8 (0.428 g, 86% over

two steps) as a pale yellowish-white solid.

Preparation of the TFA salt of 1,3-diphenylisopropylamine 33:

NH₄OAc (0.147 g, 1.91 mmol) and NaBH₃CN (0.179 g, 2.85 mmol)

were added to

a solution of 1,3-diphenylacetone (100 mg,

0.476 mmol) in MeOH (5 mL) at room temperature. The resulting

mixture was stirred at room temperature for 40 h, before it was

concentrated in vacuo, and the residue was partitioned between

1m HCl and Et₂O. The organic layer was separated, and the aque-

ous layer was extracted with Et₂O (2ꢃ). The aqueous layer was ba-

sified with 2m NaOH to pH 10–11, before it was extracted with

EtOAc (3ꢃ). The combined organic extracts were washed with

brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. TFA

(36 mL, 0.485 mmol) was added to this crude amine in a mixture of

hexane (AR, 2 mL) and CH₂Cl₂(AR, 2 mL) at 08C. The resulting mix-

ture was stirred at room temperature for 3 h before it was concen-

trated in vacuo. The crude product was repeatedly washed with

hexane, filtered, and dried in vacuo to obtain the TFA salt of 1,3-di-

phenylisopropylamine 33 (43.3 mg, 28% over two steps) as

1055, 828, 743 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃): d=7.35–7.29 (m,

;

5H), 5.75 (d, J=8.2 Hz, 1H), 5.11 (s, 2H), 4.47–4.44 (m, 1H), 2.86

(dd, J=4.4, 16.4 Hz, 1H), 2.71 (dd, J=4.4, 17.0 Hz, 1H), 1.44 +

1.42 ppm (s each, 18H); ¹³C NMR (125 MHz, CDCl₃): d=170.0, 169.7,

156.0, 136.4, 128.4, 128.0, 127.9, 82.1, 81.4, 66.8, 51.0, 37.8, 28.0,

27.8 ppm; ESI-MS: m/z calcd for C₂₀H₃₀O₆N⁺[M+H]⁺: 380.2; found:

380.2.

a

white solid. M.p.: decomposed at 132.3–134.48C; ¹H NMR

(500 MHz, CDCl₃): d=7.79 (br, 2H), 7.33–7.19 (m, 10H), 3.62–3.56

(m, 1H), 3.02–2.92 ppm (m, 4H); ESI-MS: m/z_ꢀcalcd for C₁₅H₁₈N⁺

[M]⁺: 212.1; found: 212.3; m/z calcd for C₂F₃O₂[M]^ꢀ113.0; found:

113.0.

2) Synthesis of (ꢁ)-37: 10% Pd on carbon (10 mg) was added to

a solution of the Cbz-protected di-tert-butyl dl-aspartate (76.2 mg,

0.236 mmol) in THF (freshly distilled over Na/benzophenone,

10 mL) at room temperature. The resulting mixture was stirred

under a hydrogen atmosphere (balloon) for 4 h, before it was fil-

tered through a pad of Celite, eluted with CH₂Cl₂, and concentrat-

ed in vacuo at 288C. TFA (18 mL, 0.242 mmol) was added to this

crude amine in hexane (AR, 10 mL) at 08C. A white precipitate was

immediately observed upon addition of the TFA. The resulting mix-

ture was stirred at room temperature for 3 h before it was filtered,

repeatedly washed with hexane, and dried in vacuo to afford the

TFA salt of dl-aspartate di-tert-butyl ester (ꢁ)-37 (60.7 mg, 85%

over two steps) as a white solid. M.p. 157.0–158.48C; ¹H NMR

(500 MHz, CDCl₃): d=4.14–4.12 (m, 1H), 3.06–2.96 (m, 2H), 1.48 +

1.46 ppm (s each, 18H); ESI-MS: m/z calcd_ꢀfor C₁₂H₂₄O₄N⁺[M]⁺:

246.2; found: 246.3; m/z calcd for C₂F₃O₂[M]^ꢀ: 113.0; found:

113.0.

Preparation of the TFA salt of 1,1-diphenylisopropylamine (ꢁ)-

34: The same procedure as that used for the preparation of 33

was repeated with 1,1-diphenylacetone (50 mg, 0.238 mmol) to

afford the TFA salt of 1,1-diphenylisopropylamine (ꢁ)-34 (14.7 mg,

1

19% over two steps) as a white solid. M.p. 148.1–148.98C; H NMR

(500 MHz, CDCl₃): d=7.78 (br, 2H), 7.38–7.20 (m, 10H), 4.08–3.99

(m, 1H), 1.28 ppm (d, J=5.7 Hz, 3H); ESI-MS: m/z calcd for

C₁₅H₁₈N⁺[M]⁺: 212.1; found: 212.3; m/z calcd for C₂F₃O₂[M]^ꢀ:

ꢀ

113.0; found: 113.0.

Synthesis of the TFA salt of glycine tert-butyl ester 35: 10% Pd

on carbon (10% wt/wt, 10 mg) was added to a solution of Cbz-

protected glycine tert-butyl ester (87.2 mg, 0.329 mmol) in THF

(freshly distilled over Na/benzophenone, 3.5 mL) at room tempera-

ture. The resulting mixture was stirred under a hydrogen atmos-

phere (balloon) for 3 h, before it was filtered through a pad of

Celite, eluted with CH₂Cl₂, and concentrated in vacuo at 288C. TFA

(25 mL, 0.335 mmol) was added to this crude amine in hexane (AR,

5 mL) at 08C. A white precipitate was immediately observed upon

addition of the TFA. The resulting mixture was stirred at room tem-

Preparation of the TFA salt of dl-glutamate di-tert-butyl ester

(ꢁ)-38: 1) Synthesis of Cbz-protected di-tert-butyl dl-glutamate:

The same procedures as those used for the preparation of Cbz-pro-

tected di-tert-butyl dl-aspartate were repeated with dl-glutamic

Chem. Eur. J. 2014, 20, 1 – 19

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acid (500 mg, 3.40 mmol). The crude Cbz-protected dl-glutamic

acid (0.635 g, 2.26 mmol) was used to furnish the Cbz-protected di-

tert-butyl dl-glutamate (67.2 mg, 9% over two steps) as a colorless

oil under the previously used conditions. IR (thin film): n_max=3337,

2978, 2936, 1730, 1710, 1563, 1456, 1368, 1274, 1231, 1155, 1055,

TOF): m/z calcd for C₁₁H₂₂O₄N⁺[M]⁺: 232.1543; found: 232.1548;

m/z calcd for C₂F₃O₂^ꢀ[M]^ꢀ: 112.9856; found: 112.9852.

General procedure for the preparation of 6-methoxyketone 21:

1) Amine-based organocatalytic reduction of 6-methoxydienone 8:

The TFA salt of the amine catalyst (0.0268 mmol, 20 mol%) and

Hantzsch ethyl ester 27 (105 mg, 0.414 mmol) were added to a so-

lution of 8 (30 mg, 0.129 mmol) in 1,4-dioxane (1.6 mL) at room

temperature. The resulting mixture was tightly sealed under an

argon atmosphere and stirred at 608C for 130 h, before it was di-

luted with EtOAc and treated with 2n aq.NaOH solution. The or-

ganic layer was separated, and the aqueous layer was extracted

with EtOAc (1ꢃ). The combined organic layers were washed with

water (1ꢃ), followed by brine, dried over Na₂SO₄, filtered, and con-

centrated in vacuo. Flash column chromatography of the crude

product over Et₃N-deactivated silica gel [0.05% Et₃N v/v (30%

EtOAc/hexane ! 45% EtOAc/hexane)] under N₂afforded an insep-

arable mixture of 6-methoxyenones 7/20 and the separable mix-

ture of 6-methoxyketones 21/22, separated, as yellow-white solids.

Mixture of 7 (major) + 20* (minor): R_f=0.34 (silica, 60% EtOAc/

hexane); m.p. 76.1–78.48C; [a]²_D⁵=ꢀ68.1 (c=0.16, CHCl₃); IR (thin

film): n_max=2955, 2872, 1690, 1620, 1454, 1371, 1277, 1202, 1161,

845, 743 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃): d=7.35–7.27 (m, 5H),

;

5.40 (d, J=6.9 Hz, 1H), 5.09 (s, 2H), 4.26–4.25 (m, 1H), 2.36–2.22

(m, 2H), 2.15–2.11 (m, 1H), 1.93–1.85 (m, 1H), 1.45 + 1.43 ppm (s

each, 18H); ¹³C NMR (125 MHz, CDCl₃): d=172.0, 171.0, 155.9,

136.3, 128.4, 128.0, 128.0, 82.2, 80.6, 66.8, 53.9, 31.4, 28.0,

27.9 ppm; ESI-MS: m/z calcd for C₂₁H₃₂O₆N⁺[M+H]⁺: 394.2; found:

394.2.

2) Synthesis of (ꢁ)-38: The same procedure as that used for the

synthesis of (ꢁ)-37 was repeated with the Cbz-protected di-tert-

butyl dl-glutamate (67.2 mg, 0.199 mmol) to afford the TFA salt of

dl-aspartate di-tert-butyl ester (ꢁ)-38 (49.9 mg, 79% over two

steps) as a white solid. M.p. 136.8–138.18C; ¹H NMR (500 MHz,

CDCl₃): d=4.04–4.02 (m, 1H), 2.52–2.49 (m, 2H), 2.23–2.16 (m, 2H),

1.49 + 1.44 ppm (s each, 18H); ESI-MS: m/z calcd for C₁₃H₂₆O₄N⁺

[M]⁺: 260.2; found: 260.3; m/z calcd for C₂F₃O₂[M]^ꢀ: 113.0; found:

ꢀ

113.0.

1

1080, 1042, 949, 864, 824 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=5.46*

Synthesis of Cbz-protected amino malonate 40: p-ABSA (0.566 g,

2.36 mmol) and Et₃N (0.37 mL, 2.65 mmol) were added to a solution

of di-tert-butyl malonate 39 (0.35 mL, 1.56 mmol) in CH₃CN (10 mL)

at room temperature, and the mixture was stirred for 72 h. Flash

column chromatography of the crude product over silica gel (10%

EtOAc/hexane) afforded the di-tert-butyl diazomalonate (0.302 g,

80%) as a pale yellow oil. R_f=0.29 (silica, 10% EtOAc/hexane); IR

(s), 5.45 (s, 1H), 4.12 (brs, 1H), 4.06* (d, J=4.4 Hz), 3.56 (s, 3H),

2.81* (dd, J=15.2, 17.7 Hz), 2.44–2.37 (m, 3H), 2.36–2.34* (m), 2.26

(t, J=6.3 Hz, 1H), 2.03–1.95* (m), 1.92–1.89 (m, 2H), 1.82 (d, J=

11.4 Hz, 1H), 1.76–1.70 (m, 2H), 1.61 (d, J=11.4 Hz, 1H), 1.53–1.47*

(m), 1.40 (s, 3H), 1.38* ppm (s); ¹³C NMR (125 MHz, CDCl₃): d=

193.3, 150.9, 121.4, 120.7*, 86.5, 86.0*, 78.9*, 78.6, 54.8, 52.4, 48.2*,

47.6*, 45.4, 45.2*, 44.6*, 44.1, 43.0, 42.6, 41.9*, 41.6*, 39.4*, 38.0,

37.2, 37.1*, 27.8*, 23.1, 22.8* ppm; HRMS (EI): m/z calcd for

(thin film): n_max=2093, 1688 cm^{ꢀ1 1}H NMR (300 MHz, CDCl₃): d=

;

1.50 (major) + 1.47 ppm (minor) (s each, 18H); ¹³C NMR (75 MHz,

CDCl₃): d=160.3, 82.7, 28.3 (major) + 27.9 ppm (minor); ESI-MS:

m/z calcd for C₁₁H₁₈O₄N₂Na⁺[M+Na]⁺: 265.1; found: 266.0.

C₁₄H₁₈O₃[M]⁺: 234.1256; found: 234.1254.

+

2) Hydrogenation over Pd/C to form 21: 10% Pd on carbon (20%

wt/wt, 5 mg) was added to a mixture of 7/20 and, optionally sepa-

rated, 6-methoxyketones 21/22 in EtOAc (6 mL) and 0.3n KOH in

EtOH (3 mL) at room temperature. The resulting mixture was

stirred under a hydrogen atmosphere (balloon) for 1.5 h, before it

was quickly filtered through a pad of Celite, eluted with EtOAc,

and concentrated in vacuo. Flash column chromatography of the

crude product over Et₃N-deactivated silica gel [0.05% Et₃N v/v

(10% EtOAc/hexane ! 32% EtOAc/hexane)] under N₂afforded 6-

methoxyketones 21 and 22, separated, as white solids.

A solution of the di-tert-butyl diazomalonate (40 mg, 0.165 mmol)

in CH₂Cl₂(3 mL) was slowly added to a stirred solution of benzyl

carbamide (30 mg, 0.198 mmol) and Rh₂(OAc)₄(3 mg, 6.79 mmol) in

CH₂Cl₂(5 mL) with heating at gentle reflux over a period of 5–

10 min. The resulting mixture was heated at a gentle reflux at

508C for 16 h, before it was concentrated in vacuo. Flash column

chromatography of the crude product over silica gel (hexane !

8% EtOAc/hexane) afforded Cbz-protected aminomalonate 40

(41.5 mg, 69%) as a colorless oil. R_f=0.24 (silica, 10% EtOAc/

hexane); IR (thin film): n_max=3375, 2982, 2936, 1760, 1742, 1721,

(6R)-21: R_f=0.37 (silica, 60% EtOAc/hexane); m.p. 50.2–51.88C;

1

[a]²_D⁵=ꢀ35.1 (c=0.31, CHCl₃); H NMR (500 MHz, CDCl₃): d=4.11 (t,

1503, 1366, 1325, 1175, 1065, 1022, 868 cm^ꢀ^{1 1}H NMR (500 MHz,

;

J=3.5 Hz, 1H), 3.82 (dd, J=6.3, 12.6 Hz, 1H), 3.44 (s, 3H), 2.32–2.30

(m, 3H), 2.07 (t, J=9.5 Hz, 1H), 2.02 (dd, J=3.5, 12.0 Hz, 1H), 1.93

(dd, J=6.3, 12.6 Hz, 1H), 1.86 (m, 2H), 1.78–1.71 (m, 2H), 1.55 (d,

J=11.4 Hz, 2H), 1.41 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=

207.9, 85.6, 82.0, 78.9, 58.1, 52.7, 45.9, 45.3, 44.9, 42.5, 41.1, 40.9,

CDCl₃): d=7.33–7.29 (m, 5H), 5.73 (d, J=7.0 Hz, 1H), 5.12 (s, 2H),

4.79 (d, J=7.5 Hz, 1H), 1.51 + 1.49 ppm (s each, 18H); ¹³C NMR

(125 MHz, CDCl₃): d=167.8, 165.5, 155.4, 136.1, 128.6, 128.1, 128.1,

83.2, 83.2, 67.1, 59.1, 27.8, 27.3 ppm; ESI-MS: m/z calcd for

C₁₉H₂₈O₆N⁺[M+H]⁺: 366.1917; found: 366.1923.

37.2, 23.0 ppm; HRMS (EI): m/z calcd for C₁₄H₂₀O₃[M]⁺: 236.1412;

+

found: 236.1409.

Synthesis of TFA salt of amino di-tert-butyl malonate 36: 10%

Pd on carbon (10 mg) was added to a solution of 40 (41.5 mg,

0.114 mmol) in THF (freshly distilled over Na/benzophenone,

10 mL) at room temperature. The resulting mixture was stirred

under a hydrogen atmosphere (balloon) for 4 h, before it was fil-

tered through a pad of Celite, eluted with CH₂Cl₂, and concentrat-

ed in vacuo at 288C. TFA (8.8 mL, 0.118 mmol) was added to this

crude amine in hexane (AR, 10 mL) at 08C. A white precipitate was

immediately observed upon addition of the TFA. The resulting mix-

ture was stirred at room temperature for 3 h, before it was filtered,

repeatedly washed with hexane, and dried in vacuo to obtain the

TFA salt of amino di-tert-butyl malonate 36 (33.3 mg, 85% over

two steps) as a white fluffy solid. M.p. 141.0–143.28C; ¹H NMR

(500 MHz, CD₃OD): d=4.68 (s, 1H), 1.55 ppm (s, 18H); HRMS (IT-

(6S)-21: R_f=0.67 (silica, 30% EtOAc/hexane); m.p. 49.8–51.68C;

[a]²_D⁵= +42.6 (c=0.23, CHCl₃); ¹H NMR (500 MHz, CDCl₃): d=4.09

(brs, 1H), 3.48 (brs, 1H), 3.27 (s, 3H), 2.75 (dd, J=12.6, 13.9 Hz,

1H), 2.30 (dd, J=3.8, 12.6 Hz, 1H), 2.25 (t, J=6.3 Hz, 1H), 2.10–2.03

(m, 2H), 1.88–1.83 (m, 4H), 1.63 (dd, J=3.2, 11.4 Hz, 1H), 1.52 (d,

J=11.4 Hz, 2H), 1.39 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=

210.7, 85.3, 83.6, 79.4, 57.3, 53.4, 46.3, 45.6, 43.3, 42.9, 40.9, 38.1,

37.4, 23.0 ppm.

(6R)-22: R_f=0.38 (silica, 60% EtOAc/hexane); [a]²_D⁵= +38.7 (c=

1

0.32, CHCl₃); H NMR (500 MHz, CDCl₃): d=4.01 (d, J=4.5 Hz, 1H),

3.78 (dd, J=6.3, 12.6 Hz, 1H), 3.45 (s, 3H), 2.79 (t, J=13.9 Hz, 1H),

2.31–2.27 (m, 3H), 2.01–1.99 (m, 1H), 1.93 (dd, J=6.3, 12.6 Hz, 1H),

1.77–1.70 (m, 4H), 1.48–1.43 (m, 1H), 1.42 (s, 3H), 1.34 ppm (d, J=

&

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11.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): d=207.8, 85.5, 82.0, 78.9,

58.1, 52.6, 45.8, 44.8, 42.5, 41.1, 40.8, 37.2, 23.0 ppm.

vent level in the sonicator and sonicated for 5 min to trigger the

reaction.^[42]The resulting deep blue solution of SmI₂was stirred at

room temperature for 12 h before it was directly used in the sub-

sequent step.

Synthesis of methylated 6-methoxyenones 41/42: 0.5m KHMDS

in toluene (0.4 mL, 0.200 mmol) was added to a solution of the in-

separable mixture of 6-methoxyenones 7/20 (31 mg, 0.132 mmol)

in THF (2 mL) at ꢀ788C. The bright yellow solution was stirred at

the same temperature for 30 min before the addition of HMPA

(0.4 mL) and MeI (70 mL, 1.12 mmol). The resulting mixture was

stirred at ꢀ788C and gradually warmed to ꢀ108C over 4 h, before

it was quenched with saturated aq. NaHCO₃and briefly stirred at

room temperature. The mixture was diluted with water and ex-

tracted with EtOAc (3ꢃ). The combined organic extracts were

washed with water (1ꢃ), followed by brine, dried over Na₂SO₄, fil-

tered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (5% EtOAc/hexane ! 20%

EtOAc/hexane ! 40% EtOAc/hexane) afforded an inseparable C4-

diastereomeric mixture of methylated 6-methoxyenones 41/42

(20.3 mg, 62%) as a white solid. R_f=0.30 (silica, 30% EtOAc/

hexane); m.p. 76.2–80.48C; IR (thin film): n_max=2956, 2875, 1694,

2) Preparation of 46: Anhydrous tBuOH (15 mL, 0.157 mmol) was

added to a solution of 6-methoxyenone 7 (major isomer; 3.6 mg,

0.0154 mmol) in THF (1 mL) at room temperature. The solution was

cooled to 08C, before 0.1m SmI₂in THF (2 mL) was added through

a gas-tight syringe. The resulting mixture was stirred at 08C !

room temperature over 5 h, before the reaction was quenched

with water. The mixture was extracted with EtOAc (3ꢃ), and the

combined organic extracts were washed with brine, dried over

Na₂SO₄, filtered, and concentrated in vacuo. The crude product

was briefly purified through flash column chromatography over

silica gel, eluted with EtOAc, before it was used in the subsequent

step. NaHCO₃(10.4 mg, 0.124 mmol) and Dess–Martin periodinane

(21.5 mg, 0.0507 mmol) were added to a solution of this tetrahy-

droalcohol (2.8 mg) in CH₂Cl₂(1 mL) at room temperature. The re-

sulting mixture was stirred at room temperature for 7 h, before it

was quenched with saturated aq. NaHCO₃and saturated aq.

Na₂S₂O₃solutions (1:1) and stirred at room temperature to obtain

a clear solution. The mixture was diluted with water and extracted

with EtOAc (3ꢃ). The combined organic extracts were washed with

brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Prep-

arative TLC of the crude product (35% EtOAc/hexane ꢃ 03 elution)

spread over a 16ꢃ10 cm glass plate afforded tetrahydroketone 46

(1.7 mg, 52% over two steps) as a white solid. R_f=0.26 (silica, 30%

1608, 1554, 1474, 1327, 1250, 1181, 1080, 1022, 949, 864, 821 cm^ꢀ1

;

¹H NMR (500 MHz, CDCl₃): d=5.38 + 5.41 (s each, 1H), 4.33 + 4.41

(brs each, 1H), 3.58 + 3.56 (s each, 3H), 2.45–2.41 (m, 1H), 2.34–

2.28 (m, 1H), 2.06–2.04 (m, 1H), 1.96–1.67 (m, 4H), 1.63–1.58 (m,

1H), 1.42–1.40 (m, 3H), 1.22–1.21 + 1.15–1.13 ppm (m each, 3H);

¹³C NMR (125 MHz, CDCl₃): d=195.8, 150.4, 120.5, 86.6, 77.6, 54.9,

52.7, 48.4, 45.1, 44.3, 43.4, 41.4, 37.0, 23.2, 11.7 ppm; EI-MS: m/z

calcd for C₁₅H₂₁O₃[M+H]⁺: 249.1; found: 249.3.

+

EtOAc/hexane); [a]_D²⁷=ꢀ58.9 (c=0.05, CHCl₃); IR (thin film): n_max

=

Synthesis of tert-butyl 6-methoxyplatensinoates 43: 1m KOtBu

in tBuOH (0.17 mL) was added to a solution of 41/42 (21 mg,

0.0846 mmol) in THF (1.2 mL) at 08C. The resulting bright yellow

solution was stirred at 08C for 20 min before the addition of tert-

butyl acrylate (50 mL, 0.341 mmol). The resulting mixture was

stirred at 08C for a further 3 h, before it was quenched with satu-

rated aq. NH₄Cl and briefly stirred at room temperature. The mix-

ture was diluted with water and extracted with EtOAc (3ꢃ). The

combined organic extracts were washed with brine, dried over

Na₂SO₄, filtered, and concentrated in vacuo. Flash column chroma-

tography of the crude product over silica gel (10% EtOAc/hexane

! 36% EtOAc/hexane) afforded an inseparable C4-diastereomeric

mixture of tert-butyl 6-methoxyplatensinoate 43 (7.4 mg, 23%),

with a 4:1 d.r. at the C4 position, as a pale yellow oil. R_f=0.26

(silica, 30% EtOAc/hexane); IR (thin film): n_max=2975, 2880, 1686,

2972, 2854, 1710, 1538, 1424, 1326, 1277, 1211, 1150, 1072, 956,

1

831 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=4.08 (s, 1H), 2.39–2.21 (m,

5H), 2.09–2.02 (m, 2H), 1.91–1.77 (m, 3H), 1.70 (dd, J=3.1, 11.3 Hz,

1H), 1.65–1.60 (m, 1H), 1.52 (overlapped by impurity, 1H), 1.42–

1.39 ppm (m, 4H); ¹³C NMR (125 MHz, CDCl₃): d=210.6, 86.1, 79.3,

52.8, 45.2, 45.0, 44.4, 41.6, 40.0, 39.2, 37.1, 35.1, 23.1 ppm; HRMS

(EI): m/z calcd for C₁₃H₁₈O₂[M]⁺: 206.1307; found: 206.1302.

+

Synthesis of methylated tetracyclic enone 47: 0.5m KHMDS in

toluene (0.22 mL, 0.110 mmol) was added to a solution of tetracy-

clic enone (ꢀ)-2 (14 mg, 0.0685 mmol) in THF (1.2 mL) and HMPA

(0.24 mL) at ꢀ788C. The bright yellow solution was stirred at the

same temperature for 20 min before the addition of MeI (35 mL,

0.562 mmol). The resulting mixture was stirred at ꢀ788C and grad-

ually warmed to ꢀ108C over 3 h, before it was quenched with sa-

turated aq. NaHCO₃and briefly stirred at room temperature. The

mixture was diluted with water and extracted with EtOAc (3ꢃ). The

combined organic extracts were washed with water (1ꢃ), followed

by brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the crude product over silica gel

(5% EtOAc/hexane ! 20% EtOAc/hexane) afforded methylated

tetracyclic enone 47 (11.9 mg, 80%), with almost complete C4 dia-

stereoselectivity, as a white solid. R_f=0.30 (silica, 20% EtOAc/

hexane); m.p. 79.1–81.08C; [a]²_D⁵=ꢀ42.2 (c=0.26, CHCl₃); IR (thin

film): n_max=2966, 2855, 1734, 1674, 1602, 1568, 1454, 1379, 1282,

1441, 1378, 1276, 1218, 1153, 1104, 1042, 989, 864, 832 cm^ꢀ1

;

¹H NMR (500 MHz, CDCl₃): d=5.34 (s, 1H), 4.37 (brs, 1H), 3.58 (s,

3H), 2.39–2.36 (m, 1H), 2.33 (s, 1H), 2.26–2.22 (m, 2H), 2.17–2.10

(m, 1H), 2.05–1.97 (m, 3H), 1.84 (dd, J=3.8, 10.7 Hz, 1H), 1.75–1.67

(m, 2H), 1.58 (d, J=11.3 Hz, 1H), 1.43 (s, 3H), 1.41 (s, 9H),

1.25 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=197.9, 172.5, 149.1,

120.2, 86.8, 80.2, 76.5, 56.1, 55.0, 46.9, 45.7, 44.6, 44.4, 44.2, 40.4,

+

31.1, 30.3, 28.1, 24.9, 23.1 ppm; EI-MS: m/z calcd for C₂₂H₃₂O₅

[M]⁺: 376.2; found: 376.5. tert-Butyl 6-methoxyplatensinoate 44

was observed in trace amounts contaminated with unknown by-

products.

1181, 1080, 1040, 946, 854, 813 cm^{ꢀ1 1}H NMR (300 MHz, CDCl₃):

;

d=6.53 (d, J=10.0 Hz, 1H), 5.92 (d, J=9.9 Hz, 1H), 4.35 (brs, 1H),

2.40–2.31 (m, 2H), 2.09–2.05 (m, 1H), 1.97–1.73 (m, 5H), 1.61 (d,

J=11.1 Hz, 1H), 1.43 (s, 3H), 1.13 ppm (d, J=6.7 Hz, 3H); ¹³C NMR

(75 MHz, CDCl₃): d=201.2, 154.1, 128.1, 77.6, 51.8, 48.5, 46.7, 44.4,

42.5, 41.2, 37.1, 23.0, 10.9 ppm; HRMS (IT-TOF): m/z calcd for

C₁₄H₁₈O₂Na⁺[M+Na]⁺: 241.1204; found: 241.1210.

Synthesis of tetrahydroketone 46: 1) Preparation of 0.1m solution

of SmI₂in THF: Sm powder (ꢃ40 mesh, 50 mg, 0.33 mmol) was

added to a flame-dried round-bottom flask, followed by addition

of diiodoethane (85 mg, 0.3 mmol). The round-bottom flask was

placed on the vacuum line to evacuate the air and was refilled

with Ar. This procedure was repeated twice before the flask was

immediately sealed and an Ar balloon was attached. THF (3 mL)

was added to the stirring mixture at room temperature, the Ar bal-

loon was removed, and the reaction flask was tightly sealed. The

resulting mixture in the flask was partially submerged to the sol-

Synthesis of tert-butyl platensinoate 48: 1m KOtBu in tBuOH

(48 mL) was added to a solution of 47 (12 mg, 0.0550 mmol) in THF

(1 mL) at ꢀ108C. The resulting bright yellow solution was stirred at

ꢀ108C for 10 min, before the addition of tert-butyl acrylate (23 mL,

Chem. Eur. J. 2014, 20, 1 – 19

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15

ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

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Full Paper

0.154 mmol). The resulting mixture was stirred at ꢀ108C ! 08C

for a further 2 h, before it was quenched with saturated aq.

NaHCO₃and briefly stirred at room temperature. The mixture was

diluted with water and extracted with EtOAc (4ꢃ). The combined

organic extracts were washed with brine, dried over Na₂SO₄, fil-

tered, and concentrated in vacuo. Flash column chromatography

of the crude product over silica gel (10% EtOAc/hexane ! 25%

EtOAc/hexane) afforded an inseparable C4-diastereomeric mixture

of tert-butyl platensinoate 48 (11.9 mg, 62%), with a 10:1 d.r. at

the C4 position, as a colorless oil. R_f=0.21 (silica, 20% EtOAc/

hexane); [a]²_D⁵=ꢀ31.6 (c=0.18, CHCl₃); IR (thin film): n_max=2967,

2870, 1690, 1623, 1456, 1395, 1378, 1266, 1208, 1161, 1101, 1080,

lowed by brine, dried over Na₂SO₄, filtered, and concentrated in

vacuo. Flash column chromatography of the crude product over

silica gel (5% EtOAc/hexane ! 25% EtOAc/hexane) afforded bis-

benzylacetophenone 4 (0.647 g, 95%) as a pale yellow oil. R_f=0.34

(silica, 30% EtOAc/hexane); IR (thin film): n_max=2987, 2949, 1685,

1

1601, 1536, 1461, 1376, 1266, 1094, 1001, 924, 814 cm^ꢀ1; H NMR

(500 MHz, CDCl₃): d=7.76 (d, J=9.4 Hz, 1H), 7.39–7.35 (m, 10H),

6.89 (d, J=9.5 Hz, 1H), 5.25 (s, 2H), 5.03 (s, 2H), 2.54 ppm (s, 3H);

¹³C NMR (125 MHz, CDCl₃): d=196.8, 153.6, 151.0, 135.0, 134.7,

132.5, 128.9, 128.9, 128.7, 128.6, 128.6, 127.1, 126.9, 109.3, 79.5,

71.4, 30.1 ppm; HRMS (IT-TOF): m/z calcd for C₂₂H₁₉O₅NNa⁺

[M+Na]⁺: 400.1161; found: 400.1168.

1

1024, 948, 844, 832 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=6.45 (d, J=

Synthesis of methyl benzoate 50: 1) Preparation of tert-butylhy-

pochlorite: The reaction was carried out with minimal exposure to

light. A solution of tBuOH (5 mL) and glacial AcOH (3 mL) was

added in a single portion to a vigorously stirring 14% NaOCl solu-

tion placed in a conical flask wrapped in aluminum foil and im-

mersed in an ice bath at 08C. The resulting mixture was stirred for

3–4 min, before it was transferred to a separatory funnel, and the

aqueous layer was separated. The yellow organic layer was washed

with saturated aq. NaHCO₃(1ꢃ), followed by water, dried over

Na₂SO₄, filtered, and used in the following reaction immediately.

10.1 Hz, 1H), 5.87 (d, J=10.1 Hz, 1H), 4.39 (brs, 1H), 2.41–2.38 (m,

1H), 2.34 (s, 1H), 2.24–2.21 (m, 2H), 2.14–2.06 (m, 2H), 2.03–1.99

(m, 2H), 1.84 (dd, J=3.1, 10.7 Hz, 1H), 1.77–1.73 (m, 1H), 1.69–1.64

(m, 1H), 1.61–1.59 (m, 3H), 1.44 (s, 3H), 1.42 (s, 9H), 1.22 ppm (s,

3H); ¹³C NMR (125 MHz, CDCl₃): d=203.3, 172.6, 153.4, 127.3, 87.0,

80.2, 76.5, 55.0, 46.2, 46.0, 46.0, 44.7, 43.2, 40.6, 30.8, 30.3, 28.1,

24.6, 23.0 ppm; HRMS (IT-TOF): m/z calcd for C₂₁H₃₁O₄[M+H]⁺:

+

347.2222; found: 347.2226.

Synthesis of platensic acid 6: TFA (0.6 mL) was added to a solution

of 48 (6 mg, 0.0173 mmol) in CH₂Cl₂(0.6 mL) at 08C. The resulting

mixture was stirred at 08C for 12 h before it was concentrated in

vacuo. The crude platensic acid 6 was placed under high vacuum

pull for 12 h to afford a white solid (5 mg, 100%), which was used

in the subsequent step without further purification. R_f=0.14 (silica,

60% EtOAc/hexane); [a]²_D⁶=ꢀ35.1 (c=0.16, MeOH); IR (thin film):

n_max=2972, 2932, 1712, 1646, 1471, 1444, 1390, 1248, 1202, 1121,

2) Preparation of 50: 25% NaOMe in MeOH (0.6 mL) was added to

a stirred solution of 4 (0.166 g, 0.440 mmol) in MeOH (HPLC grade,

14 mL), followed by dropwise addition of tBuOCl (0.6 mL), at 58C

with minimal exposure to light. The resulting mixture was stirred

at room temperature for 1 h, before acetone was added to decom-

pose the excess tBuOCl. The resulting mixture was concentrated in

vacuo, and the residue was partitioned between 1m HCl and

EtOAc. The organic layer was separated, and the aqueous layer

was extracted with EtOAc (2ꢃ). The combined organic layers were

washed with brine, dried over Na₂SO₄, filtered, and concentrated in

vacuo. Flash column chromatography of the crude product over

silica gel (5% EtOAc/hexane ! 25% EtOAc/hexane) afforded

methyl benzoate 50 (0.164 g, 95%) as a white crystalline solid. R_f=

0.29 (silica, 30% EtOAc/hexane); m.p. 101.2–102.68C; IR (thin film):

n_max=3099, 2960, 2844, 1720, 1609, 1536, 1436, 1381, 1268, 1189,

1090, 1048, 968, 840 cm^{ꢀ1 1}H NMR (500 MHz, CDCl₃): d=6.47 (d,

;

J=10.1 Hz, 1H), 5.89 (d, J=10.1 Hz, 1H), 4.41 (brs, 1H), 2.42–2.40

(t, 1H), 2.36–2.24 (m, 4H), 2.13–1.99 (m, 3H), 1.87 (dd, J=3.1,

11.3 Hz, 1H), 1.79–1.75 (m, 2H), 1.61 (d, J=10.7 Hz, 1H), 1.44 (s,

+

3H), 1.24 ppm (s, 3H); HRMS (IT-TOF): m/z calcd for C₁₇H₂₃O₄

[M+H]⁺: 291.1596; found: 291.1591.

Synthesis of acetophenone 49: PPA (11 g per 100 mg of 5) was

heated at 508C until it became less viscous, and then glacial AcOH

(0.51 mL, 8.86 mmol) and 2-nitroresorcinol (5; 0.55 g, 3.58 mmol)

were added at the same temperature. The temperature was raised

to 75–808C, and the resulting mixture was stirred for 2 h, before it

was cooled to room temperature and quenched with cold water

(180 mL). The resulting mixture was extracted with EtOAc (4ꢃ), and

the combined organic layers were washed with H₂O (1ꢃ), followed

by brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.

Flash column chromatography of the crude product over silica gel

(CH₂Cl₂, then 5% MeOH/CH₂Cl₂to eventually flush out the tailing)

afforded acetophenone 49 (0.482 g, 69%) as a yellow crystalline

solid. R_f=0.23 (silica, 2% MeOH/CH₂Cl₂); m.p. 123.4–125.88C; IR

(thin film): n_max=1629, 1535, 1370, 1286, 1163, 1061, 981, 887,

1102, 992, 818 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃): d=8.00 (d, J=

;

9.0 Hz, 1H), 7.48–7.33 (m, 10H), 6.87 (d, J=8.9 Hz, 1H), 5.21 (s, 2H),

5.15 (s, 2H), 3.88 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=164.2,

153.7, 151.9, 138.2, 135.8, 134.7, 134.2, 128.7, 128.4, 128.4, 127.0,

117.8, 108.9, 78.7, 71.2, 52.2 ppm; HRMS (IT-TOF): m/z calcd for

C₂₂H₁₉O₆NNa⁺[M+Na]⁺: 416.1110; found: 416.1114.

Synthesis of aniline presursor 3: 10% Pd on carbon (10 mg) was

added to a solution of 50 (22.4 mg, 56.8 mmol) in MeOH (5 mL) at

room temperature. The resulting mixture was stirred under a hydro-

gen atmosphere (balloon) for 16 h, before it was filtered through

a pad of Celite, eluted with 5% MeOH/EtOAc, and concentrated in

vacuo to afford the aniline precursor 3 (9.5 mg, 92%) as a white

crystalline solid. No further purification was required, and the

crude aniline 3 was carried forward to the next step. ¹H NMR

(500 MHz, CD₃OD): d=7.19 (d, J=8.8 Hz, 1H), 6.35 (d, J=8.8 Hz,

1H), 3.87 ppm (s, 3H); ESI-MS: m/z calcd for C₈H₈O₄N^ꢀ[MꢀH]^ꢀ:

182.0; found: 182.1; m/z calcd for C₈H₁₀O₄N^ꢀ[M+H]⁺: 184.1;

found: 184.0.

1

742 cm^ꢀ1; H NMR (300 MHz, CDCl₃): d=14.84 (s, 1H), 11.34 (s, 1H),

7.90 (d, J=9.0 Hz, 1H), 6.64 (d, J=9.0 Hz, 1H), 2.62 ppm (s, 3H);

¹³C NMR (75 MHz, CDCl₃): d=202.9, 161.9, 161.4, 137.6, 125.1,

113.5, 108.9, 26.6 ppm; HRMS (IT-TOF): m/z calcd for C₈H₅O₅N^2ꢀ

[Mꢀ2H]^2ꢀ: 195.0179; found: 195.0168.

Synthesis of bisbenzylacetophenone 4: Anhydrous K₂CO₃(1.50 g,

10.8 mmol), TBAI (0.133 g, 0.361 mmol), and BnBr (644 mL,

5.42 mmol) were added to a solution of 49 (0.356 g, 1.81 mmol) in

anhydrous DMF (12 mL) at room temperature. The resulting mix-

ture was warmed to 558C and stirred for 12 h, before it was cooled

to room temperature and quenched with cold water. Vigorous stir-

ring was maintained for 5–10 min until a homogenous layer was

obtained, and the reaction mixture was extracted with Et₂O (3ꢃ).

The combined organic extracts were washed with water (1ꢃ), fol-

Synthesis of amide 51: Et₃N (14.5 mL, 0.104 mmol) and HATU

(26.3 mg, 69.2 mmol) were added to a solution of platensic acid (6;

5 mg, 17.3 mmol) in anhydrous DMF (1 mL) at room temperature.

The resulting mixture was stirred at room temperature for 10–

15 min before the addition of a solution of 3 (9.5 mg, 51.9 mmol) in

anhydrous DMF (1 mL). The resulting mixture was stirred at room

temperature for 25 h, before it was poured into brine and extract-

ed with EtOAc (4ꢃ). The combined organic extracts were back-

&

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Full Paper

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trated in vacuo. Flash column chromatography of the crude prod-

uct over silica gel (5% acetone/hexane ! 24% acetone/hexane !

100% acetone), followed by preparative TLC (25% acetone/hexane

ꢃ 02 elution) spread over a 20ꢃ10 cm glass plate afforded amide

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sis) as a pale yellow viscous oil. R_f=0.21 (silica, 40% acetone/

hexane); [a]²_D⁴=ꢀ39.3 (c=0.21, CHCl₃); IR (thin film): n_max=3225,

2965, 2872, 1668, 1654, 1610, 1530, 1424, 1381, 1270, 1206, 1181,

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1

1086, 1025, 950, 884, 814 cm^ꢀ1; H NMR (500 MHz, CDCl₃): d=11.64

(s, 1H), 11.07 (brs, 1H), 8.10 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 6.52–

6.50 (m, 2H), 5.93 (d, J=10.0 Hz, 1H), 4.44 (brs, 1H), 3.92 (s, 3H),

2.56–2.49 (m, 1H), 2.44–2.36 (m, 4H), 2.12–2.00 (m, 3H), 1.93–1.86

(m, 2H), 1.81–1.77 (m, 1H), 1.63 (d, J=11.3 Hz, 1H), 1.45 (s, 3H),

1.27 ppm (s, 3H); ¹³C NMR (125 MHz, CDCl₃): d=203.6, 173.6, 170.7,

154.9, 153.9, 153.8, 127.4, 127.2, 114.4, 111.3, 104.1, 87.0, 76.4, 54.9,

52.2, 46.7, 46.2, 46.1, 44.7, 43.1, 40.6, 32.1, 31.6, 29.7, 24.2,

23.0 ppm; HRMS (EI): m/z calcd for C₂₅H₂₉O₇N⁺[M]⁺: 455.1944;

found: 455.1946.

Synthesis of (ꢀ)-platensimycin (1): 2m aq. KOH (0.2 mL) was

added to a solution of 51 (3.7 mg, 8.12 mmol) in 1,4-dioxane

(0.2 mL) and MeOH (0.1 mL) at room temperature. The resulting

mixture was tightly sealed and stirred at 358C for 16 h, before the

solvents were concentrated in vacuo. The residue was then parti-

tioned between water and CH₂Cl₂. The organic layer was separated,

and the aqueous layer was extracted with CH₂Cl₂(2ꢃ). The aque-

ous layer was acidified with 1m HCl to pH 1–2 and extracted with

EtOAc (5ꢃ). The combined EtOAc extracts were washed with brine,

dried over Na₂SO₄, filtered, and concentrated in vacuo. Preparative

TLC of the crude product (60% EtOAc/hexane + 1% AcOH ꢃ 02

elution) spread over a 16ꢃ10 cm glass plate, followed by flash

column chromatography over silica gel (10% acetone/hexane !

40% acetone/hexane ! 70% acetone/hexane + 0.5% AcOH) af-

forded (ꢀ)-platensimycin (1; 2.5 mg, 60%) as a white solid. R_f=

0.12 (silica, 60% acetone/hexane); [a]²_D³=ꢀ48.2 (c=0.11, MeOH); IR

(thin film): n_max=3321, 2962, 2928, 2879, 1665, 1652, 1605, 1542,

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1438, 1392, 1278, 1212, 1150, 1090, 1001, 912, 820 cm^ꢀ^{1 1}H NMR

;

(500 MHz, C₅D₅N): d=10.5 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 6.87 (d,

J=8.8 Hz, 1H), 6.36 (d, J=10.0 Hz, 1H), 5.93 (d, J=9.4 Hz, 1H),

4.48 (brs, 1H), 2.86–2.65 (m, 3H), 2.44 (s, 1H), 2.20–2.18 (m, 1H),

2.07–2.00 (m, 1H), 1.91–1.89 (m, 1H), 1.80 (d, J=11.9 Hz, 1H), 1.72

(d, J=10.0 Hz, 1H), 1.58–1.54 (m, 1H), 1.47 (d, J=10.7 Hz, 1H), 1.39

(s, 3H), 1.14 ppm (s, 3H); ¹³C NMR (125 MHz, C₅D₅N): d=203.2,

174.7, 158.2, 153.9, 129.4, 127.2, 115.3, 110.0, 107.1, 86.8, 76.4, 54.9,

46.7, 46.6, 46.1, 45.0, 43.0, 40.8, 32.1, 31.8, 30.5, 24.4, 23.2 ppm;

HRMS (EI): m/z calcd for C₂₄H₂₇O₇N⁺[M]⁺: 441.1788; found:

441.1784.

Acknowledgements

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This work was financially supported by a National University of

Singapore Graduate Scholarship (to S.T.-C.E.) and by the Na-

tional Research Foundation Competitive Research Program of

Singapore (NRF-G-CRP 2007–04). We are grateful to Benjamin

List and co-workers for the generous gift of (S)-TRIP and advice

on the preparation of the (S)-TRIP salt of the d-valine tert-butyl

ester.

Keywords: bismuth · conjugate reduction · Friedel–Crafts

reactions · organocatalysis · total synthesis

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Published online on && &&, 0000

&

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ÝÝ These are not the final page numbers!

Full Paper

FULL PAPER

&

Organocatalysis

S. T.-C. Eey, M. J. Lear*

&& – &&

Total Synthesis of (ꢀ)-Platensimycin

by Advancing Oxocarbenium- and

Iminium-Mediated Catalytic Methods

Relay tactics: The stereocontrolled as-

sembly of the potent antibiotic (ꢀ)-pla-

tensimycin in 21 steps and 3.8% yield

from eugenol is described (see scheme;

TBAF: tetrabutylammonium fluoride; Ts:

toluene-4-sulfonyl). Highlights are 1)

a rapid oxidative esterification of an acyl

aromatic, 2) a reliable dialkylation proto-

col to form platensic acid, 3) a p-facial

conjugate reduction of a dienone, 4)

a TBAF-promoted alkylative dearomati-

zation of a free phenol, and 5) a Frie-

del–Crafts closure of a free lactol.

Chem. Eur. J. 2014, 20, 1 – 19

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19

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These are not the final page numbers! ÞÞ

Article Doi

Total synthesis of (-)-platensimycin by advancing oxocarbenium- and iminium-mediated catalytic methods

DOI: 10.1002/chem.201400131

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Article abstract of DOI:10.1002/chem.201400131

Full text of DOI:10.1002/chem.201400131

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