Structure-Elucidating Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone C §

Article abstract of DOI:10.1021/acs.orglett.0c00431

The (polyenoyl)tetramic acid militarinone C (1) heads a family of seven members. Before our work, the configuration of C-5 was unknown whereas the configurations of C-8′ and C-10′ were either (R,R) or (S,S). We synthesized the four stereoisomers of constitution 1, which conform with these insights. This included cross-coupling both enantiomers of the western building block (8) with both enantiomers of the eastern building block (9). The specific rotations of the resulting 1 isomers suggested that natural 1 is configured like the coupling partners (S)-8 and (R,R)-9. This conclusion was corroborated by degrading natural 1 to alcohol 35 and by proving its configurational identity with synthetic (R,R)-35.

Full text of DOI:10.1021/acs.orglett.0c00431

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Letter
Structure-Elucidating Total Synthesis of the (Polyenoyl)tetramic
Acid Militarinone C§
̈
Christian Drescher, Morris Keller, Olivier Potterat, Matthias Hamburger,* and Reinhard Bruckner*
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ABSTRACT: The (polyenoyl)tetramic acid militarinone C (1)
heads a family of seven members. Before our work, the
configuration of C-5 was unknown whereas the configurations of
C-8′ and C-10′ were either (R,R) or (S,S). We synthesized the four
stereoisomers of constitution 1, which conform with these insights.
This included cross-coupling both enantiomers of the western
building block (8) with both enantiomers of the eastern building
block (9). The specific rotations of the resulting 1 isomers
suggested that natural 1 is configured like the coupling partners
(S)-8 and (R,R)-9. This conclusion was corroborated by degrading
natural 1 to alcohol 35 and by proving its configurational identity
with synthetic (R,R)-35.
even natural products are named after the fungus
in all compounds depicted in Figure 1 because their structures
are viewed3,1 as biogenetically related.
S
Paecilomyces militaris, (−)-militarinones A1,2 (5), B3,1 (2),
C3 (1), D3 (3), E1 (6), and F1 (7) and (+)-N-deoxymilitarinone
A4 [4 (Figure 1)].5 Two of them (B and C) are (polyenoyl)-
For the same reason, the (R,R)-configuration of totally
synthetic (−)-militarinone D (1), proven in 2011,11 would have
indicated the generality of such (R,R)-configurations in the
series, had there not been a conflicting observation in the sequel.
(R,R)-configured N-deoxymilitarinone A (4) from total syn-
thesis12 turned out to be levorotatory ([α]2D0 = −19.312) as
opposed to N-deoxymilitarinone A (4) from nature, which was
dextrorotatory ([α]D20 = +33.34). With the conclusion,
accordingly, that natural 4 is (S,S)-configured, the postulate3,1
of biogenetic configurational homogeneity of all militarinone
side chains is breached.
We took the incertitude about militarinone side-chain
configurations beyond the reported cases of (−)-militarinone
D (1)11 and N-deoxymilitarinone A (4)12 into account when
pursuing the first total syntheses of all four militarinone C
candidates: (5S,8′R,10′R)-1, naturally configured 1, as it turned
out eventually; (5S,8′S,10′S)-1, 5-epimer of the unnatural
enantiomer of 1; (5R,8′R,10′R)-1, 5-epimer of naturally
configured 1; (5R,8′S,10′S)-1, unnatural enantiomer of 1. In
parallel with our effort, the Schobert group took on a total
synthesis of the same target militarinone C (1). They addressed
Figure 1. Militarinone family of natural products.
tetramic acids,6 and five are (polyenoyl)pyridones.7 Our study
describes stereoselective total syntheses of the (polyenoyl)-
tetramic acid militarinone C3 (1) and three of its diastereomers,
and it establishes the (5S,8′R,10′R)-configuration of natural 18
unambiguously. This attribution was not possible originally,3
although the stereogenic C−CH3 bonds were recognized as syn-
oriented,3,9,10 i.e., (R,R)- or (S,S)-configured. The (R,R)-
configuration now proven in militarinone C (1) should occur
Received: February 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00431
© XXXX American Chemical Society
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just the (natural) (5S,8′R,10′R)-configuration and disclosed the
respective first total synthesis in mid-2018.13
Scheme 1. Synthesis of the N,O-Protected Tyrosine (S)-
13
a
20
,
In 2014, Hofferberth from our group achieved total syntheses
of the (polyenoyl)tetramic acid natural products α-lipomycin
and its aglycon, β-lipomycin.14 His route was very convergent,
not in the least because of the use of the newly developed δ-
bromo-β-ketothioester 1114 and the previously developed all-
trans-hexatriene-1,6-bis(tributylstannane)15 as conjuctive re-
agents.
Conceiving a related retrosynthetic analysis of the four
militarinone C (1) candidates, we identified the δ-bromo-β-
ketothioester 1114 as a conjunctive building block once more
(Figure 2). The western building block (8) was traced back to
a
Reagents and conditions: (a) SOCl2, MeOH, 25 °C, 12 h, 95% (ref
17, 99%); (b) tBuMe2SiCl, imidazole, CH2Cl2, 25 °C, 16 h, 84% (ref
18, 86%); (c) 22, HOAc or NaOAc, MeOH, 25 °C, t1; NaBH3CN or
NaBH(OAc)3, 25 °C, t2. DMB = 2,4-dimethoxybenzyl.
Methyl N-DMB-O-TBS tyrosinate [(S)-13], according to
Figure 2 the source of the tyrosine motif of the naturally
configured target 1, was obtained from L-tyrosine [(S)-16] in
three steps (Scheme 1): esterification [→95% (S)-2017], O-
silylation [→84% (S)-2118], and reductive amination of 2,4-
dimethoxybenzaldehyde (22). Although the last transformation
[→(S)-13] had precedent (e.g., ref 19), it eroded the ee
significantly (table in Figure 2, entries 2−9) or entirely (entry 1;
for conditions, see ref 19). Employing less HOAc (3 to 0.3 vol %)
and shortening the delay between the additions of aldehyde 22
and NaBH3CN (from 120 min to 10 s), we increased the ee of
(S)-13 to 99.5% (entries 2 and 5−9).
Our route to western building block (S)-8 began with three
known steps (Scheme 2): trans-hydrobromination of propiolic
a
20
,
Scheme 2. Synthesis of Western Building Block (S)-8
Figure 2. Our retrosynthetic analysis of militarinone C (1). It engages
thioester 11 from our lipomycin work14 anew.
diprotected tyrosine esters (R)- or (S)-13 and the eastern
building block [(R,R)- or (S,S)-9] to α-chiral aldehyde (R,R)- or
(S,S)-12. As a late step, we envisaged a Stille coupling of building
blocks (R)- or (S)-8 and (R,R)- or (S,S)-9. Thereupon, a Lacey−
Dieckmann cyclization16 should establish the heterocycle.
Removal of the protecting groups would render the target(s).
The four syntheses based on the retrosynthesis of Figure 2 are
exemplified in Schemes 1−4 by our access to the isomer
(5S,8′R,10′R)-1, which equalsnaturallyconfigured 1. Ourroutes
to the unnatural enantiomer of 1, (5R,8′S,10′S)-1, and to
enantiomers (5S,8′S,10′S)- and (5R,8′R,10′R)-1 of a diaster-
eomer of 1 were strictly analogous; their description is available
in the Supporting Information.
a
Reagents and conditions: (a) HBr (concentrated), 100 °C, 1.5 h,
75% (ref 21, 85%); (b) Me(MeO)NH, N-methylmorpholine, T3P,
CH2Cl2, 0 °C, 30 min, 85% (ref 14, 86%); (c) LiHMDS, 24, THF,
−78 °C, 1 h; MgBr2·OEt2, 1 h; 23, 2 h; 75% (ref 14, 83%); (d)
thioester 11, 4 Å molecular sieves (powdered), THF, 25 °C, 30 min;
AgO2CCF3, 25 °C, 24 h;22 65%.
B
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acid (17)21 (→75% 18), Weinreb amide formation14 (→85%
23), and a crossed Claisen condensation with the Mg enolate of
tert-butyl thioacetate.14 In step 4, the resulting enol 11 (75%
yield) of the desired δ-bromo-β-ketothioester was aminolyzed in
the presence of AgO2CCF3 and powdered molecular sieves22 (to
prevent any competing hydrolysis) by tyrosinate (S)-13 from
Scheme 1 [→65% (S)-8].
Scheme 4. Finishing Eastern Building Block (R,R)-9 and
Reaching Militarinone C [(5S,8′R,10′R)-1] and Three
Diastereomers Thereof [(S,S,S)-1, (R,R,R)-1, and
a
37
,
(5R,8′S,10′S)-1]
The stereogenic C−CH3 bonds of eastern building block
(R,R)-9 were established by asymmetric Myers alkylations23 of
the Li enolate of the amide (S,S)-18, prepared from
pseudoephedrin [(S,S)-26] and propionic anhydride23 (Scheme
3). Ethylation of its enolate24 [→94% (S,S,R)-26], reduction
Scheme 3. Establishing the syn-Configured C−Methyl
a
20,36
,
Bonds
a
Reagents and conditions: (a) NEt3, propionic anhydride, CH2Cl2, 25
°C, 30 min, 92% (ref 23, 95%); (b) iPr2NH, LiCl, nBuLi, THF, −78
to 0 °C, 5 min; (S,S)-18, −78 °C, 1 h; 0 °C, 15 min; 25 °C, 5 min;
EtI, 25 °C, 15 h; 94% (ref 24, 88%); (c) iPr2NH, nBuLi, THF, −78
°C, 10 min; 0 °C, 10 min; BH3·NH3, 0 °C, 15 min; 25 °C, 15 min;
(S,S,R)-26, 25 °C, 2 h; 76% (ref 24, 85%); (d) TsCl, pyridine, 0 °C,
12 h, 83% (ref 25, 99%); (e) NaI, DMF, 60 °C, 1.5 h, 58% (ref 26,
89%); (f) iPr2NH, LiCl, nBuLi, THF, −78 to 0 °C, 5 min; (S,S)-18,
−78 °C, 1 h; 0 °C, 15 min; 25 °C, 5 min; (R)-28, 25 °C, 24 h; 88%
(ref 23 for the enantiomer, 94%; ref 24, 95%); (g) iPr2NH, nBuLi,
THF, −78 °C, 10 min; 0 °C, 10 min; BH3·NH3, 0 °C, 15 min; 25 °C,
15 min; (S,S,R,R)-15, 25 °C, 2 h; 74% (ref 24, 88%); (h) NMO, 4 Å
molecular sieves, CH2Cl2, 25 °C, 15 min; TPAP (5 mol %), 25 °C, 1
h; 77% (ref 24, 98%); (i) (COCl)2, DMSO, THF, −78 °C, 2 min; 0
°C, 3 min; alcohol (R,R)-29, −78 °C, 2 min; 0 °C, 15 min; NEt3, 0 to
25 °C; 76%. TPAP = Pr4NRuO4.
a
Reagents and conditions: (a) 30, sBuLi, THF, −78 °C, 30 min;
(R,R)-12, −20 °C, 2.5 h; isolation of the imine; CF3CO2H, THF, 0
°C, 1 h; H2O, 0 °C, 14 h; 86%;29 (b) 31, KOtBu, THF, −78 °C, 15
min; (R,R)-10, −78 °C, 5 min; −30 °C, 1.5 h; NH4Cl, −30 °C, 15
min; −30 to 25 °C; 83%;30 (c) PdCl2(PPh3)2 (catalyst), Bu3SnH,
THF, 25 °C, 30 min;30 (S)-8, Pd2(dba)3 (catalyst), AsPh3 (catalyst),
25 °C, 24 h; 52%; (d) TBAF, THF, 25 °C, 1 h, 61%;22 (e) PhSMe,
CH2Cl2/F3CCO2H, 25 °C, 1 h, 75%.33
with LiBH2·NH3 [→76% alcohol (R)-1924], tosylation [→
23
83% (R)-2725], and a Finkelstein reaction [→58% (R)-2826]
provided an iodide of 99% ee. It was combined with another
equivalent of the Li enolate of the amide (S,S)-18 to amide
(S,S,R,R)-1524,27 (88% yield). Reduction with LiBH2·NH323 [→
74% alcohol (R,R)-2924] and oxidation either with TPAP24 or by
the Ireland modification28 of Swern’s method accomplished the
desired aldehyde (R,R)-12 (76−77% yield, 98:2 dr).
presence of Pd2(dba)3 and AsPh3.31 The polyenoyl amide
(S,R,R)-33 resulted in a 51% yield over the two steps. Treatment
with 3.5 equiv of TBAF22 led to a Lacey−Dieckmann cyclization
and desilylation. Purification by flash chromatography on
reversed-phase silica gel32 furnished the DMB-protected
tetramic acid (S,R,R)-34 (61%). Exposure to 50 equiv of
thioanisole as a cation scavenger in a F3CCO2H/CH2Cl2
mixture (1:4) removed the DMB group.33 The crude product
was dissolved in MeOH to separate it from insoluble
impurities.34 Prepurification by reversed-phase flash chromatog-
raphy32 and purification by reversed-phase HPLC32 delivered
target (S,R,R)-1 in 75% yield. Whether it equates to natural
militarinone C (1) could have emerged from the respective
specific rotations had they not differed by as much as
[α]2D0synthetic (S,R,R)‑1 = −31735 and [α]2D0natural 1 = −430.2.3
Aldehyde (R,R)-12 of Scheme 3 and the azaenolate of α-
silylimine 30 were subjected to a condensation/hydrolysis
sequence,29 providing 86% of the unsaturated aldehyde (R,R)-
10 E-selectively (Scheme 4). Alkyne formation by a Seyferth−
Gilbert reaction30 [→81% (R,R)-32] followed by a
PdCl2(PPh3)2-catalyzed cis-hydrostannylation30 completed
eastern building block (R,R)-9 in situ. It Stille-coupled with 0.7
equiv of western building block (S)-8 (Scheme 2) in the
C
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We continued our study by synthesizing another levorotatory
reproducibly. The “larger”-scale reactions of synthetic 1 isomers
allowed us to record meaningful 1H NMR spectra of 35 even if it
typically contained some residual solvent. The “large”-scale
route to 35, from natural 1, even allowed us to determine the
yield [20% (reaction a of Scheme 5)]. Regardless of the scale, the
configuration of 35 could be identified unambiguously by chiral
GLC. This became clear after we obtained both the (R,R)-
enantiomer and the (S,S)-enantiomer of the same alcohol 35
selectively from LiAlH4 reductions of the aldehydes (R,R)-10
(Scheme 4) and (S,S)-10 (SI), respectively [79−80% yield
(reactions b of Scheme 5)]. The retention time of the synthetic
alcohol (S,S)-35 was 23.4 min, and that of synthetic (R,R)-35
was 24.8 min. The latter value equaled the retention time of the
alcohol 35 prepared from natural 1. This equality proves that the
methylated stereocenters of militarinone C (1) are R,R-
configured.
In conclusion, militarinone C (1) was synthesized first by
Schobert et al.13 and now by us. Our synthesis was slightly
shorter (21 steps vs ∼2213 steps altogether). Our longest linear
sequence comprised 13 steps (vs 18 steps13) and totaled 2.8%
yield (vs 2.5%13). Besides naturally configured militarinone C
(5S,8′R,10′R)-1, we synthesized its enantiomer (5R,8′S,10′S)-1
and the diastereomers (S,S,S)-1 and (R,R,R)-1 analogously (for
details, see the Supporting Information). Moreover, we re-
isolated natural militarinone C (1) and degraded it to an alcohol
that was identical with synthetic (R,R)-35. These supplements to
our total synthesis proved that natural militarinone C (1) is
(5S,8′R,10′R)-configured. If all members of the militarinone
family interrelate biosynthetically (Figure 1),1,3 our configura-
tional assignment of 1 corroborates Gademann’s conclusion11
about the ubiquity of an R,R-configuration in all side chains.
Independent of such inferences, we suggest that pure (R,R)-N-
deoxymilitarinone A (4) is dextrorotatory like the natural
product4 and not levorotatory as reported for a synthetic
specimen12 (see the second paragraph). This is because a 50:50
mixture of militarinone C diastereomers synthesized from rac-8
and (R,R)-(sic!)-9 was dextrorotatory {[α]2D0 = +19 (Scheme
4)}.
diastereomer {(S,S,S)-1: [α]2D0 = −350} and two dextrorotatory
isomers {(5R,8′S,10′S)-1): [α]2D0 = +319; (R,R,R)-1: [α]2D0
=
+353}. Altogether, our specific rotations prove that natural 1 is
(5S)-configured. This is so because the “partial specific rotation”
(absolute value) due to the heterocycle of type 1 compounds
exceeds the “partial specific rotation” (absolute value) of their
side chains by 20-fold. On average, the heterocycle contributes
(−317 + −350)/2 and (319 + 353)/2 to [α]2D0, i.e., 335, and
the side chain only (−317 − −350)/2 and (319 − 353)/2, i.e.,
17.38 Or, natural 1 is levorotatory because C-5 is (S)-
configured and despite C-8′ and C-10′ being (R)-configured.
At this stage, we felt obliged to re-isolate militarinone C (1)
from P. militaris39 to elucidate its side-chain configurations
unambiguously: by degrading 1 to a syn-dimethylated entity and
by comparing it, by chiral GLC, with synthetic reference
compounds of known absolute configurations. We cultivated P.
militaris in 8.4 L of nutrient broth for 32 days. The mycelium was
dried and extracted with MeOH (3 × 1 L, 3 × 24 h). After the
solvent had been evaporated, a red solid (25.9 g) resulted. It was
triturated with H2O (500 mL). Centrifugation gave a precipitate.
After the supernatant was decanted off, this precipitate was
triturated with MeOH. The insoluble fraction was precipated by
centrifugation. The solution was decanted off and evaporated.
This left a red solid (3.52 g). A solution thereof was separated on
a Sephadex LH-20 column to afford three militarinone-
containing fractions (A−C). They were purified by reverse-
phase HPLC. Altogether, this furnished N-deoxymilitarinone A
(4 , 11.5 mg; from fraction A), militarinone A (5, 177.0 mg; from
fraction A), militarinone C (1, 63.2 mg; from fraction B),
militarinone B (2, 45.0 mg; from fraction B), and militarinone D
(3, 2.4 mg; from fraction C).
We trained the degradation of 12 mg of natural militarinone C
(1) into an alcohol of constitution 35 (Scheme 5) by subjecting
solutions (aqueous THF) of 3−8 mg slots of synthetic (S,S,S)-1,
(R,R,R)-1, (5S,8′R,10′R)-1, and (5R,8′S,10′S)-1 to a one-pot
room-temperature Lemieux−Johnson cleavage/NaBH4 reduc-
tion. The use of 75 mol % K2OsO4·2H2O, >30 equiv of NaIO4,
and 120 equiv of NaBH4 gave the respective alcohol 35
ASSOCIATED CONTENT
* Supporting Information
■
sı
Scheme 5. Degrading Natural Militarinone C and Converting
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00431.
Our Synthetic Intermediates (S,S)- and (R,R)-10 to syn-
a
Dimethylated Allyl Alcohols of Constitution 35
Experimental procedures, characterizations, and NMR
spectra of the synthetic natural product [(5S,8′R,10′R)-1]
and its synthetic diastereomers (S,S,S)-1, (5R,8′S,10′S)-1,
and (R,R,R)-1 (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Reinhard Bruckner − Institut fur Organische Chemie, Albert-
̈
̈
̈
Ludwigs-Universitat, D-79104 Freiburg, Germany;
orcid.org/0000-0002-9028-8436;
Email: reinhard.brueckner@organik.chemie.unifreiburg.de
̈
Matthias Hamburger − Pharmazeutische Biologie, Universitat
Basel, 4056 Basel, Switzerland; orcid.org/0000-0001-9331-
273X; Email: matthias.hamburger@unibas.ch
a
Reagents and conditions: (a) K2OsO4·2H2O (35 mol %), NaIO4 (14
equiv), 1:1 H2O/THF, 25 °C, 1.5 h; K2OsO4·2H2O (20 mol %),
NaIO4 (10 equiv), 25 °C, 1 h; K2OsO4·2H2O (20 mol %), NaIO4 (10
equiv), 25 °C, 1 h; NaBH4 (120 equiv), 25 °C, 1.5 h; 20%; (b)
LiAlH4, Et2O, 25 °C, 1.5 h; 80% for (S,S)-35, 79% for (R,R)-35.
Authors
Christian Drescher − Institut fu
̈
r Organische Chemie, Albert-
Ludwigs-Universitat, D-79104 Freiburg, Germany
̈
D
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pubs.acs.org/OrgLett
Letter
(12) Ding, F.; William, R.; Leow, M. L.; Chai, H.; Fong, J. Z. M.; Liu,
X.-W. Org. Lett. 2014, 16, 26−29.
̈
Morris Keller − Pharmazeutische Biologie, Universitat Basel,
4056 Basel, Switzerland
(13) Bruckner, S.; Weise, M.; Schobert, R. J. Org. Chem. 2018, 83,
10805−10812.
̈
Olivier Potterat − Pharmazeutische Biologie, Universitat Basel,
4056 Basel, Switzerland; orcid.org/0000-0001-5962-6516
(14) (a) Hofferberth, M. L.; Bruckner, R. Angew. Chem., Int. Ed. 2014,
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00431
53, 7328−7334; Angew. Chem. 2014, 126, 7456−7462. (b) Hofferberth,
M. L.; Bruckner, R. In Strategies and Tactics in Organic Synthesis;
̈
Harmata, M., Ed.; Elsevier/Academic Press: Amsterdam, 2017; pp 37−
93.
Author Contributions
(15) Sorg, A.; Bruckner, R. Angew. Chem., Int. Ed. 2004, 43, 4523−
̈
All synthetic work was performed by C.D. under the guidance of
R.B., and all isolation work by C.D. under the guidance of M.K.,
M.H., and O.P. The manuscript was composed by C.D. and R.B.
4526; Angew. Chem. 2004, 116, 4623−4626.
(16) Lacey, R. N. J. Chem. Soc. 1954, 0, 850−854.
(17) Liu, R.; Sogawa, H.; Shiotsuki, M.; Masuda, T.; Sanda, F. Polymer
2010, 51, 2255−2263.
Notes
(18) Raffier, L.; Piva, O. Beilstein J. Org. Chem. 2011, 7, 151−155.
(19) Riache, N.; Bailly, C.; Deville, A.; Dubost, L.; Nay, B. Eur. J. Org.
Chem. 2010, 2010, 5402−5408.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(20) The enantiomorphous compound was also synthesized; it is
described in the Supporting Information.
■
The authors are indebted to the Deutsche Forschungsgemein-
schaft for supporting this work (Project BR 881/10). The
̈
authors are grateful to Tamara Ley (Institut fur Organische
Chemie, Albert-Ludwigs-Universitat) for skilled technical
assistance. The fungal strain was provided by M.H.
(21) Luo, Y.; Roy, I. D.; Madec, A.G. E.; Lam, H. W. Angew. Chem., Int.
Ed. 2014, 53, 4186−4190.
(22) Experimental details adopted from: Ley, S. V.; Smith, S. C.;
Woodward, P. R. Tetrahedron 1992, 48, 1145−1174.
(23) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496−6511.
(24) Bellotta, F.; D’Auria, M. V.; Sepe, V.; Zampella, A. Tetrahedron
2009, 65, 3659−3663.
̈
DEDICATION
■
§Dedicated to Professor Siegfried Hu
̈
nig (Julius-Maximilians-
Universitat Wurzburg) on the occasion of his 99th birthday.
(25) Mori, K.; Kamada, A.; Kido, M. Liebigs Ann. Chem. 1991, 1991,
775−781.
̈
̈
(26) Akasaka, K.; Tamogami, S.; Beeman, R. W.; Mori, K. Tetrahedron
2011, 67, 201−209.
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■
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̈
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Ca2+, Mg2+, or Fe2+ cations, which are common impurities of silica gel
used for standard purifications by flash chromatography; as a
consequence, their 1H NMR spectra suffer from line broadening:
Barnickel, B.; Schobert, R. J. Org. Chem. 2010, 75, 6716−6719.
(33) Experimental details adopted from: Yoshimura, H.; Takahashi,
K.; Ishihara, J.; Hatakeyama, S. Chem. Commun. 2015, 51, 17004−
17007.
(4) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li, Z.;
Hamburger, M. J. Nat. Prod. 2006, 69, 436−438.
(5) (−)-Fumosorinone is an N-hydroxy(polyenoyl)pyridone ana-
logueof militarinone D3: Liu, L.;Zhang, J.; Chen, C.; Teng, J.; Wang, C.;
Luo, C. Fungal Genet. Biol. 2015, 81, 191−200.
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(34) Moore, M. C.; Cox, R. J.; Duffin, G. R.; O’Hagan, D. Tetrahedron
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(35) Schobert et al. found [α]2D0synthetic (S,R,R)‑1 = −310, which matches
3 = −430.2 slightly less, yet they held these compounds to be
1168−1185.
20
[α]
D natural 1
(8) This configuration was first inferred in ref 13 by comparing the
(correct) specific rotation of totally synthetic 1 to the (somewhat faulty)
specific rotation of natural 1 reported in ref 3.
identical.13
(36) The enantiomorphous compound (S)-19 is commercially
available.
(9) This is because the chemical shifts of the respective 13CH3 groups
differed by 2.2 ppm,3 which is ∼2 times the value expected for an anti-
isomer: (a) Stahl, M.; Schopfer, U.; Frenking, G.; Hoffmann, R. W. J.
Org. Chem. 1996, 61, 8083−8088. (b) Clark, A. J.; Ellard, J. M.
Tetrahedron Lett. 1998, 39, 6033−6036.
(37) The pair of enantiomers of a diastereomer of this compound were
synthesized, too, as described in the Supporting Information.
(38) In accordance with the last number, the (S,S)-configured side
chain in a 1:1 mixture of (5S,8′S,10′S)- and (5R,8′S,10′S)-1 led to [α]D20
= −14; similarly, the (R,R)-configured side chain in a 1:1 mixture of
(5S,8′R,10′R)- and (5R,8′R,10′R)-1 caused [α]2D0 = +17 (details in
(10) The same syn-attribution follows from the observation that the
chemical shifts of the protons in the CH2 group between the stereogenic
C−CH3 bonds of militarinone C (1) differ by 0.16 ppm3, which is more
than expected for an anti-isomer: Schmidt, Y.; Breit, B. Org. Lett. 2010,
12, 2218−2221.
(11) (a) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.; Gademann,
K. Angew. Chem., Int. Ed. 2011, 50, 4222−4226; Angew. Chem. 2011,
123, 4308−4312. More recent syntheses: (b) See ref 12. (c) Dash, U.;
Sengupta, S.; Sim, T. Eur. J. Org. Chem. 2015, 2015, 3963−3970.
Scheme 4).
20
(39) Eventually, this allowed us to redetermine [α]
=
D reisolated natural 1
−310 (Scheme 4). This value matches [α]2D0synthetic (S,R,R)‑1 = −317 better
than [α]2D0synthetic (S,S,S)‑1 = −350 (Scheme 4), which, if true, supports the
finding that natural 1 is 8′R- and 10′R-configured.
E
https://dx.doi.org/10.1021/acs.orglett.0c00431
Org. Lett. XXXX, XXX, XXX−XXX