Stereostructure Clarifying Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone B. A Highly Acid-Labile N-Protecting Group for Amides ?

Christian Drescher and Reinhard Bruckner*

Letter

Stereostructure Clarifying Total Synthesis of the (Polyenoyl)tetramic

Acid Militarinone B. A Highly Acid-Labile N‑Protecting Group for

†

Amides

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sı Supporting Information

ABSTRACT: The 5S, 8′R, and 10′R conﬁgurations of milita-

rinone B (3), which is a natural product from Paecilomyces militaris,

should equal those in its biosynthetic precursor, militarinone C.

The conﬁguration at C-1′ emerged from syntheses of the

militarinone B candidates 1′′S- and 1′′R-(5S,8′R,10′R)-3 from

the building blocks 9, 11, 14, and 15a while introducing TMB as a

more acid-labile N-protecting group for β-ketoamides than DMB.

Comparisons of 1′′S- and 1′′R-(5S,8′R,10′R)-3 with natural

militarinone B (3; reisolated from Nature) revealed identity versus

distinctness.

even natural products are named after the fungus

(1′′R,5S,8′R,10′R)-conﬁguredbegan by the installment of

protecting groups (Figure 2). We needed not only O-

protecting groups, but also an N-protecting group. Without

(such) an N-substituent, the desired tetramic-acid forming

Paecilomyces militaris, namely, the (−)-militarinones A

2,3

3 3 2 2

(

6), B (3), C (1), D (5), E (4), and F (2) plus (−)-N-

4−7

deoxymilitarinone A

polyenoyl)tetramic acids, and ﬁve are (polyenoyl)-

hydroxypyridones. Earlier total syntheses in this class of

compounds led to the militarinones C (1

(7; Figure 1). Two of them (B, C) are

(

step, i.e., Lacey′s variant of a Dieckmann cyclization, would

fail. The substrates of this step would be made by Stille

10,11

12,6,13

) and D (5

)

couplings between a “Western” building block (S,S)- or

and to N-deoxymilitarinone A (7 ). The present study

(

R,S)-10 and an “Eastern” building block 9. The former

describes stereoselective total syntheses of the naturally

compounds should be reached from the completely enolized β-

occurring (polyenoyl)tetramic acid militarinone B (3) and

ketothioester 11 (which we introduced

and used

its unnatural diastereomer epi-3 (formulas are shown in Figure

previously) and appropriately protected β-hydroxytyrosin

ester diastereomers (S,S)- or (R,S)-12 through aminolyses.

Considering the last-mentioned esters (S,S)- or (R,S)-12 as

aldol adducts, we noticed their similarity to the “azaenolate

aldol adducts” (S,S,R)- or (R,S,R)-13b (Figure 2). Those had

The conﬁgurations of compounds 1−7 were mostly

,3,4

unknown when ﬁrst reported.

An exception are the syn-

conﬁgurations of the methylated stereocenters (C-8′, C-10′)

deducible from δ₈

− δ = 2.0−2.2 ppm (Figure 1).

10′‑CH

′‑CH

been prepared by Boger et al. and Schobert et al. by

21,22

Their (R)-conﬁgurations in 1, 5, and 7 emerged from total

applying Scho

llkopf′s methodology:

They lithiated the

0−12,6,13

syntheses

and in 1 and 6 from reisolations,

bis(lactim methyl ether) (R)-15b and added the resulting

azaenolate to the (benzyloxy)benzaldehyde 14. They found

great induced diastereoselectivities but almost no simple

diastereoselectivity. This was because they obtained an almost

equimolar mixture of the (hydroxybenzyl)bis(lactim methyl

Lemieux−Johnson cleavage/NaBH reduction tandems, and

the identity of the resulting alcohol 8 with authentic (R,R)-8

(

ref 11 and the present work, respectively). The heterocyclic

stereocenter of militarinone C (1), C-5, is (S)-conﬁgured,

10,11

according to synthesis.

to be biosynthesized from militarinone C (1) it should be

5S)-conﬁgured, too. The (S)-conﬁguration of the fourth

Since militarinone B (3) is believed

3,2

Received: May 17, 2021

(

stereocenter of militarinone B (3), C-1′′, became evident after

we synthesized the remaining militarinone B candidates,

namely 3 and epi-3 (Figure 2), as disclosed below.

Our retrosynthetic analysis of these compounds3, being

(

1′′S,5S,8′R,10′R)-conﬁgured and epi-3, being

XXXX The Authors. Published by

American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Figure 1. Militarinone family 1−7 of natural products. Full

0,11

conﬁgurational assignments by experiment [1,

3 (this work),

12,6,13

6 (this work), 7 ] or extrapolation (2, 4).

19,20

ether) diastereomers (S,S,R)- and (R,S,R)-13b;

i.e., the

newly formed stereocenter in the heterocycle was solely (S)-

conﬁgured, whereas the oxygen-bearing stereocenter was as

much (S)-conﬁgured as (R)-conﬁgured. The two diaster-

19,20

eomers were readily separable by column chromatography.

We adopted this strategy but followed its originator′s

recommendations for the less-expensive and faster-forming

bis(lactim ethyl ether) (R)-15a.

Figure 2. Retrosynthetic analysis of the hitherto conceivable

candidates 3 and epi-3 for the structure of natural militarinone B.

Emergence of precursors that we had encountered earlier (9, 11) or

were the ethyl analogues [(S,S,R)- and (R,S,R)-13a] of previously

reported methyl esters [(S,S,R)- and (R,S,R)-13b] and should be

accessible analogously.

Our envisaged route to the militarinone B candidates 3 and

epi-3 (Figure 2) required us to choose an N-protecting group

“PG” in compounds 12 and 10). This is because the benzylic

(

C−OH bond in either target appeared to be poised to break in

the presence of too strong or too much acid. Such bond

breaking could destroy the stereochemical integrity at C-1′′ or

lead to a dehydration and/or initiate a ring-enlarging

semipinacol rearrangement. We opted for benzylic N-

protecting groups and studied the (polyenoyl)tetramic acid

models TBDMS-16a−16c and 16d and 16e of Scheme 1,

which we equipped therewith. Two benzyl group variations (in

TBDMS-16a and TBDMS-16c) promised cleavability without

an acid. Two other variations (in 16d and 16e) were acid-

labile. Our N-protecting groups of the ﬁrst type were para-

nitrobenzyl (in TBDMS-16a), which would be reduced to

para-aminobenzyl (in TBDMS-16b) for becoming cleavable by

dimethoxybenzyl (in 16d) and 2,4,6-trimethoxybenzyl (in

16e), but the grading of lability remained to be determined. N-

2,4,6-trimethoxybenzylated amides of various types are known

but they were deprotected−if at all−mainly by hydrogenolysis,

secondly by a Birch reduction, and only rarely by acidolysis.

The origins of the less appropriately protected model N-

benzyl (polyenoyl)tetramic acids TBDMS-16a and TBDMS-

16c are speciﬁed in the Supporting Information ; those of the

more appropriately protected analogues 16d and 16e in

Scheme 1. We proceeded in accordance with the strategy of

Figure 2, the N-protections and aminolyses in the lower part of

Scheme 2, and the transformations of Scheme 3. A cornerstone

of our model syntheses of Scheme 1 was using the β-ketoester

oxidants, and dimethoxy(ortho-nitrobenzyl) (in TBDMS-

6c), which is photolabile at longer wavelengths than ortho-

nitrobenzyl. Our acid-labile N-protecting groups were 2,4-

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 1. (Polyenoyl)tetramic Acids Debenzylated Acid-

Free (TBDMS-16a,c) or with Dilute Triﬂuoroacetic Acid

Scheme 2. Synthesis of the N-TMB-Protected

Hydroxytyrosines (S,S)- and (R,S)-12e and Their

Conversion into the “Western” Building Blocks (S,S)- and

(

16e > 16d)

(

R,S)-10e (500 MHz H-NMR Data in CDCl )

suﬃced for de(trimethoxybenzylating) compound 16e (→17;

rt, 4.5 h; 93%). The cleanness and mildness of the last

deprotection convinced us of choosing trimethoxybenzyl as the

N-protecting group in our total syntheses of militarinone B (3)

and its isomer epi-3 (see Schemes 2 and 3).

as a conjunctive reagent for combining the protected

amino acids 18d or 18e with trans-(tributylstannyl)styrene

prepared from phenylacetylene after hydrozirconation and

iodinolysis ) to the β-ketoamides 22d and 22e. Their Lacey−

Dieckmann cyclizations delivered the respective (polyenoyl)-

tetramic acids 16d and 16e.

Debenzylating compound TBDMS-16a by reduction (→

TBDMS-16b) and treatment with DDQ produced <20% of

the tetramic acid TBDMS-17 (Scheme 1). Irradiating

compound TBDMS-16c gave twice as much TBDMS-17 yet

as an isomeric mixture. F CCO H/CH Cl = 1:4 was needed

We started by an aldol addition of the bis(lactim ethyl ether)

(R)-15a to the (benzyloxy)benzaldehyde 14 (Scheme 2). After

(

separation by ﬂash chromatography, this delivered 47%

amounts of the aldols (S,S,R)- and (R,S,R)-13a. Their

heterocycles were 2,5-trans-disubstituted, not 2,5-cis-disubsti-

tuted. The diethyl ether (S,S,R)-13a eluted ﬁrst and its

diastereomer (R,S,R)-13a second. This was the same order as

for the analogous dimethyl ethers (S,S,R)- vs (R,S,R)-13b. In

CDCl the C-bound protons in the β-aminoalcohol moieties of

(S,S,R)-13a vs (R,S,R)-13a were similarly deshielded (Δδ =

0.22 and 0.14 ppm, respectively) as in their dimethyl

counterparts (S,S,R)-13b vs (R,S,R)-13b (Δδ = 0.24 and

for the de(dimethoxybenzylation) of compound 16d at 25 °C

→ 17; rt, 1 h; 80%). In contrast F CCO H/CH Cl = 1:99

(

3 2 2 2

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 3. In-Situ Conversion of the Enyne 25 into the

ketothioester 11 and AgO CCF let aminolyses occur. They

2 3

“

Eastern” Building Block (R,R)-9. Its Couplings with the

Western” Building Blocks (S,S)- and (R,S)-10e and the

provided the corresponding β-ketoamidesor “Western”

“

building blocks(S,S)- and (R,S)-10e.

Final Steps Leading to Militarinone B [(S,S,R,R)-3] and Its

Epimer (R,S,R,R)-3

We continued with a Pd-catalyzed hydrostannylation of the

enyne 25 [step (a ), Scheme 3]; it was derived from (2R,4R)-

,4-dimethylhexanol (7-step synthesis: see ref 35) in three

steps (11% yield over the 10 steps ). The resulting

dienylstannane 9or “Eastern” building blockwas so labile

that we coupled it without puriﬁcation with either of the

“

Western” building blocks (S,S)- and (R,S)-10e [step (a )].

This furnished the chain-extended hydroxytyrosine ethyl esters

S,S,R,R)- and (R,S,R,R)-26 in 60% and 62% yield,

(

respectively. Their, Lacey-Dieckmann cyclizations were

eﬀected with NaOMe in MeOH [step (b)]. This took longer

(

1.5 h) than the analogous cyclization of a related methyl ester

15 min ). The (tetraenoyl)tetramic acids (S,S,R,R)- and

R,S,R,R)-27 resulted in 61% and 63% yield, respectively, after

puriﬁcation by ﬂash chromatography on reversed-phase silica

gel. Gratifyingly both compounds released their N-bound

trimethoxybenzyl protecting groups under as mildly acidic

conditions as established for the model de(trimethoxybenzyl-

ation) 16e → 17 (Scheme 1). This delivered the (tetraenoyl)-

tetramic acid bis(silyl ethers) (S,S,R,R)- and (R,S,R,R)-28 in

yields of 70% and 68%, respectively [step (c) in Scheme 3].

Our syntheses were completed by desilylating the tetramic

acid bis(silyl ethers) (S,S,R,R)- and (R,S,R,R)-28 with HOAc

and Bu NF (Scheme 3). Exposure of (S,S,R,R)-28 to 16 and

2 equiv of these reagents, as suggested by a literature

analogy, gave 74% silicon-free material. It was a 70:30

mixture of the desired tetramic acid (S,S,R,R)-3, which

contains a “syn“-conﬁgured “Western” moiety, and an “anti”-

epimer thereof. Doubling the amount of HOAc and working

up earlier converted the same substrate into 35% of the

tetramic acid (S,S,R,R)-3 (now almost epimer-free: “syn“:”anti”

98:2) and 30% of the tetramic acid (S,S,R,R)-29 [step (d)].

The latter, HOAc, and Bu NF [step (e)] gave a second crop of

(

S,S,R,R)-3 (25%, “syn“:”anti“ = 98:2), its combined yield

totaling 43%.

Under the conditions of step (d), the epimeric bis(silyl

ether) (R,S,R,R)-28 did not react with HOAc and Bu NF.

Increasing the temperature by 15 °C let the substrate subside

[

step (f)] yet preponderantly by a monodesilylation; it

rendered the silicon-containing tetramic acid (R,S,R,R)-29 in

54% yield. Didesilylation occurred to a much lesser extent; it

delivered the silicon-free tetramic acid (R,S,R,R)-3 with the

“anti”-conﬁgured “Western” moiety in only 3% yield and,

Compound (S,S,R,R)-3 is drawn such that its heteroatom-

substituted stereocenters are syn-conﬁgured, and compound

(

R,S,R,R)-3 such that they are anti-conﬁgured. “dr” speciﬁes the

syn:anti ratios in reisolated natural militarinone B (3) or synthetic

worse, jointly with 2% of a “syn”-epimer.

(

S,S,R,R)-3 but the anti:syn ratio in synthetic (R,S,R,R)-3.− NMR

The following ﬁndings establish that natural militarinone B

(3) equals (S,S,R,R)-3 (bottom part of Scheme 3): ① their

speciﬁc rotations are the same; ② 3 was retained as much as

(S,S,R,R)-3 in an HPLC comparison but less than (R,S,R,R)-3;

data: 500 MHz, CDCl .

9,20

.08 ppm, respectively

). The vicinal couplings between

these protons was somewhat larger in (S,S,R)-13 than in

R,S,R)-13, regardless of whether they were diethylated or

dimethylated: 13a, ΔJ = 1.0 Hz; 13b, ΔJ = 0.8 Hz.

ethyl esters (S,S)- and (R,S)-23 obtained by hydrolyses of the

bislactimethers (S,S,R)- and (R,S,R)-13a, respectively,

displayed analogous NMR diﬀerences (they are shared by

the identically conﬁgured methyl esters ). O-Debenzylation

step (c) in Scheme 2], O,O,N-trisilylation [step (d)], and

transforming the N-silyl into an N-trimethoxybenzyl moiety

under reductive amination conditions [step (e)] furnished the

fully protected hydroxytyrosine diastereomers (S,S)-12e and

③ the H NMR subspectra of the O−C ′′(−H)-C ′(−H)−N

motifs are identical in 3 and (S,S,R,R)-3 but not in (R,S,R,R)-3.

In conclusion, we accomplished the ﬁrst total synthesis of

the (polyenoyl)tetramic acid natural product (−)-militarinone

B (3). This revealed that its stereostructure is (S,S,R,R)-3. The

center parts of militarinone B and of the diﬀerentially

protected model compounds TBDMS-16a−16c and 17d and

(

19,20

The

[

17e originated from our group′s β-ketothioester 11. We

highlighted 2,4,6-trimethoxybenzyl as an N-protecting group

for β-ketoamides including β-ketolactames; it was removable at

room temperature with as little acid as 1% F CCO H in

(R,S)-12e, respectively. Exposure of these compounds to the β-

CH Cl . Finally, we proved the absolute conﬁguration of the

2 2

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

(6) Ding, F.; William, R.; Leow, M. L.; Chai, H.; Fong, J. Z. M.; Liu,

Letter

(

polyenoyl)hydroxypyridone natural product (−)-militarinone

(5) Natural N-deoxymilitarinone A (7) was reported to be

dextorotatory ([α] = +33.3 ). In contrast, totally synthetic (R,R)-

A (6) following a Lemieux-Johnson cleavage and corrected the

sense of rotation of the natural product N-deoxymilitarinone A

was levorotatory ([α] = − 19.3 ). For reisolated natural N-

deoxymilitarinone A (7) we determined [α] = − 22.7. Accordingly,

(

7). Now all members of the militarinone family can be drawn

compound 7 should be considered as levorotatory.

with fact-founded stereoformulas.

X.-W. Directed Orthometalation and the Asymmetric Total Synthesis

of N -Deoxymilitarinone A and Torrubiellone B. Org. Lett. 2014, 16,

26−29.

ASSOCIATED CONTENT

sı Supporting Information

■

(

7) Drescher, C. Ph.D. Thesis; Universitat

71.

8) For most recent reviews, see: (a) Yoda, H.; Takahashi, M.;

Freiburg 2021; pp 155,

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.1c01652.

(

Experimental procedures and characterizations including

NMR spectra (PDF)

Sengoku, T. Developments in the Synthesis of 3-Acyltetramic Acid

Natural Products. In Studies in Natural Product Chemistry, Vol. 46;

Atta-ur-Rahman, Ed.; Elsevier, 2015; pp 99 −131. (b) Bai, W.-J.; Lu,

C.; Wang, X. Recent Advances in the Total Synthesis of Tetramic

Acid-Containing Natural Products. J. Chem. 2016, 8510278.

(9) For a review, see: Jessen, H. J.; Gademann, K. 4-Hydroxy-2-

pyridone alkaloids: Structures and synthetic approaches. Nat. Prod.

Rep. 2010, 27, 1168−1185.

AUTHOR INFORMATION

Corresponding Author

■

Reinhard Bruckner − Institut fur Organische Chemie, Albert-

Ludwigs-Universit ä t, D-79104 Freiburg, Germany;

orcid.org/0000-0002-9028-8436 ;

Email: reinhard.brueckner@organik.chemie.uni-

freiburg.de

10) Bruckner, S.; Weise, M.; Schobert, R. Synthesis of the

Entomopathogenic Fungus Metabolites Militarinone C and Fumosor-

inone A. J. Org. Chem. 2018, 83, 10805−10812.

(11) Drescher, C.; Keller, M.; Potterat, O.; Hamburger, M.;

Bru

ckner, R. Structure-Elucidating Total Synthesis of the

Author

(12) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.; Gademann,

Polyenoyl)tetramic Acid Militarinone C. Org. Lett. 2020, 22,

Christian Drescher − Institut fu

r Organische Chemie, Albert-

Ludwigs-Universität, D-79104 Freiburg, Germany

2559−2563.

K. A Unified Approach for the Stereoselective Total Synthesis of

Pyridone Alkaloids and Their Neuritogenic Activity. Angew. Chem.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c01652

011, 123, 4308−4312; Angew. Chem., Int. Ed. 2011 , 50 , 4222 −4226.

13) Dash, U.; Sengupta, S.; Sim, T. A Concise and Efficient Total

Synthesis of Militarinone D. Eur. J. Org. Chem. 2015, 2015, 3963−

970.

14) These diﬀerences were about twice as large as the

U.; Frenking, G.; Hoffmann, R. W. Assignment of Relative

Author Contributions

(

All synthetic work was performed by C.D. under the guidance

of R.B. The manuscript was composed by C.D. and R.B.

corresponding diﬀerence in an anti-isomer. (a) Stahl, M.; Schopfer,

Configuration to Acyclic Compounds Based on C NMR Shifts. A

Density Functional and Molecular Mechanics Study. J. Org. Chem.

Notes

The authors declare no competing ﬁnancial interest.

996 , 61 , 8083 −8088. (b) Clark, A. J.; Ellard, J. M. Synthesis of the

ACKNOWLEDGMENTS

We are indebted to the Deutsche Forschungsgemeinschaft for

supporting this work (Project No. BR 881/10). We are grateful

to Tamara Ley (Institut fur Organische Chemie, Albert-

Ludwigs-Universität) for skilled technical assistance. The

fungal strain was kindly provided by Prof. Matthias Hamburger

■

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(

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28) (a) In 36 acyltetramic acid syntheses using N-benzyl groups of

any kind, according to a SciFinder search, 31 employed DMB; in 30

28b

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see: (b) Lovmo, K.; Dutz, S.; Harras, M.; Haase, R. G.; Milius, W.;

Schobert, R. A short synthesis of 3-enoyltetramic acids employing a

new acyl ylide conjugate of Meldrum ′s acid. Tetrahedron Lett. 2017,

29) Johnson, T.; Quibell, M.; Sheppard, R. C. N ,O -bisFmoc

8, 4796−4798.

derivatives of N -(2-hydroxy-4-methoxybenzyl)amino acids: Useful

intermediates in peptide synthesis. J. Pept. Sci. 1995, 1 , 11 −25.

(30) Method adopted from: Huang, Z.; Negishi, E. A Convenient

and Genuine Equivalent to HZrCp Cl Generated in Situ from

ZrCp Cl −DIBAL-H. Org. Lett. 2006, 8, 3675 −3678.

(31) Still, W. C.; Kahn, M.; Mitra, A. Rapid chromatographic

technique for preparative separations with moderate resolution. J. Org.

Chem. 1978, 43, 2923−2925.

(

32) Eluting the compounds with CH Cl /acetone = 97:3, we

2 2

realized R

improvement

− R

F,(S,S,R)‑13b

= 0.34. This topped an earlier

= 0.24 (CH Cl /acetone =

F,(S,S,R)‑13a

F,(R,S,R)‑13a

− R

F,(R,S,R)‑13b

8:2) of the original separation (R_F_,₍_S_,_S_,_R₎_‑₁₃_b− R_F_,₍_R_,_S_,_R₎_‑₁₃_b= 0.05;

CHCl /MeOH ≥ 98:2) of the dimethyl ethers.

(

33) The long-range couplings J in two related 2-isopropyl-5-(α-

2,5

hydroxyalkyl)bislactim ethers were 3.7 Hz if trans-conﬁgured

[

(S,S,R)-13b: 3.7 Hz; vs. (R,S,R)-13b: 3.6 Hz] but 6.0 Hz if cis -

con ﬁ gured: Ruiz, M.; Ojea, V.; Quintela, J. M. Amino acid based

diastereoselective synthesis of fucosamines. Tetrahedron: Asymmetry

(

002, 13, 1535−1549.

34) Procedure adopted from the literature cited in ref 33.

(35) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,

D. J.; Gleason, J. L. Pseudoephedrine as a Practical Chiral Auxiliary

for the Synthesis of Highly Enantiomerically Enriched Carboxylic

Acids, Alcohols, Aldehydes, and Ketones. J. Am. Chem. Soc. 1997, 119,

(

496−6511.

36) N-Protected N-unprotected tetramic acids form chelates with

Ca , Mg , or Fe cations, which are common impurities of silica gel

used for standard puriﬁcations by ﬂash chromatography. In order to

avoid the line broadening in their H NMR spectra caused thereby, all

tetramic acids of Scheme 3 were chromatographed exclusively with

reversed-phase silica gel. See: Barnickel, B.; Schobert, R. Toward the

Macrocidins: Macrocyclization via Williamson Etherification of a

Phenolate. J. Org. Chem. 2010, 75, 6716−6719.

(37) Syn- and anti-conﬁgured “Western” moieties of compounds of

constitution 3 can be told apart by the chemical shifts of the C-bound

protons in the heterocycle and the benzylic position (see Table part of

Scheme 3, columns 4−5). However, this does not reveal whether

(

S,S,R,R)-3 epimerized to (R,S,R,R)- or (S,R,R,R)-3 or whether

R,S,R,R)-3 epimerized to (S,S,R,R)- or (R,R,R,R)-3.