Total Synthesis of Mycinolide IV and Path-Scouting for Aldgamycin N

Article abstract of DOI:10.1002/anie.202016475

Proof-of-concept is provided that a large estate of 16-membered macrolide antibiotics can be reached by a “unified” approach. The key building block was formed on scale by an asymmetric vinylogous Mukaiyama aldol reaction; its alkene terminus was then converted either into the corresponding methyl ketone by Wacker oxidation or into a chain-extended aldehyde by catalyst-controlled branch-selective asymmetric hydroformylation. These transformations ultimately opened access to two structurally distinct series of macrolide targets. Notable late-stage maneuvers comprise a rare example of a ruthenium-catalyzed redox isomerization of an 1,3-enyne-5-ol into a 1,3-diene-5-one derivative, as well as the elaboration of a tertiary propargylic alcohol into an acyloin by trans-hydrostannation/Chan-Lam-type coupling. Moreover, this case study illustrates the underutilized possibility of forging complex macrolactone rings by transesterification under essentially neutral conditions.

Full text of DOI:10.1002/anie.202016475

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7893–7899
International Edition: doi.org/10.1002/anie.202016475
German Edition: doi.org/10.1002/ange.202016475
Total Synthesis
Total Synthesis of Mycinolide IV and Path-Scouting for Aldgamycin N
+
+
Bart HerlØ , Georg Späth , Lucas Schreyer, and Alois Fürstner*
th
Dedicated to Professor Siegfried Hünig on the occasion of his 100 birthday
Abstract: Proof-of-concept is provided that a large estate of
6-membered macrolide antibiotics can be reached by a “uni-
subtle alterations in the glycosidation pattern at C5: specif-
1
ically, all aldgamycins carry the eponymous aldgarose at this
site, a highly unusual octopyranose, which may or may not
feature a cyclic carbonate at the branching point; the other
families have different sugars appended to this secondary
hydroxy group or may not be glycosylated at all. Another
modification in constitutional terms lies in the substituent
branching off C15, in that the mycinolide/mycinamicin
derivatives have a one-carbon longer chain ending in an ethyl
rather than the usual methyl group. Within a given family, the
individual members differ from each other in the level of
unsaturation/epoxidation of the “western sector” of the
highly conserved 16-membered macrolide core. An additional
fied” approach. The key building block was formed on scale by
an asymmetric vinylogous Mukaiyama aldol reaction; its
alkene terminus was then converted either into the correspond-
ing methyl ketone by Wacker oxidation or into a chain-
extended aldehyde by catalyst-controlled branch-selective
asymmetric hydroformylation. These transformations ulti-
mately opened access to two structurally distinct series of
macrolide targets. Notable late-stage maneuvers comprise
a rare example of a ruthenium-catalyzed redox isomerization
of an 1,3-enyne-5-ol into a 1,3-diene-5-one derivative, as well as
the elaboration of a tertiary propargylic alcohol into an acyloin
by trans-hydrostannation/Chan-Lam-type coupling. More-
over, this case study illustrates the underutilized possibility of
forging complex macrolactone rings by transesterification
under essentially neutral conditions.
Introduction
Actinobacteria in general and the genus Streptomyces sp.
in particular rank amongst the most prolific sources of
[
1–3]
antibiotics that found their way into clinical use.
It has
been noticed, however, that the rate of discovery of new
antimicrobial agents from these sources is declining, thus
making it necessary to explore strains collected at more
remote places or in the (deep) sea, which have been studied
[1,4,5]
less systematically in the past.
In this context, the
isolation of several novel aldgamycin macrolides from the
aquatic Streptomycetes strain HK-2006-1 is noteworthy, which
exhibit significant and selective activity against Staphylococ-
[6–8]
cus aureus 209P.
The aldgamycins are closely related to the macrolides of
[
9,10]
[11]
the mycinolide/mycinamicin,
tianchimycin, swalpamy-
[
12]
[13]
cin,
and chalcomycin
series, all of which contain D-
mycinose whenever the primary C20-OH group is glycosy-
lated (Figure 1). The individual families are distinguished by
[
+]
[+]
[
*] Dr. B. HerlØ, G. Späth, Dr. L. Schreyer, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
4
5470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016475.
ꢀ
2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Figure 1. Selected members of the aldgamycin, mycinamicin, swalpa-
mycin and chalcomycin macrolide antibiotics.
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variation concerns the substitution pattern at C8, which can
either be a tertiary alcohol or a simple methyl branch adjacent
to the invariant carbonyl group at C9. Overall, this particular
estate of macrocycles is an excellent example for how nature
institutes diversity upon a conserved ichnography. Therefore
it should potentially lend itself to an “integral synthesis”
endeavor: provided one can formulate a modular assembly
process, a fairly small number of building blocks should
suffice to reach a significant subset of antibiotics of this type
thought to open entry into the “A-series”, since the triple
bond in A can be seen as a carbonyl surrogate. Equally
straightforward was the projected route to the “B-series”,
which capitalizes on a branch-selective hydroformylation of
[23–26]
the terminal alkene in G.
However, the literature knows
of surprisingly little precedent for (late-stage) applications of
[27–29]
this transformation in target-oriented synthesis.
Provided
this challenging step can be accomplished with the necessary
level of regio- and stereoselectivity, alkynylation of the
resulting aldehyde E with the conjugated 1,3-enyne F
followed by cyclization and redox-isomerization of B might
open the doorway, even though the exact order of events
remains to be determined. In any case, the modular and
divergent character of the overall synthesis plan and the need
for a single building block G representing the eastern
hemisphere of both series reduces the synthetic exertion
and makes the approach potentially practical and scalable.
[14]
as well as non-natural analogues for biological evaluation.
Over this enticing outlook, however, one must not forget
the lessons learnt from previous studies in this field. Members
[15–19]
of the mycinamicin family were targeted in the past.
This
precedent shows the delicacy of these compounds and
illustrates the numerous challenges to be met en route to
this sensitive chemotype. These issues notwithstanding, it was
hoped that a “collective” rather than “individual” approach is
[
20,21]
[6]
feasible.
For proof-of-concept, aldgamycin N (1) and
[9]
mycinolide IV (2) were chosen as initial targets, because
they (i) stand for the two subsets characterized by the Results and Discussion
different oxygenation pattern at C8, (ii) feature different
levels of unsaturation within the macrolide ring, and (iii)
represent the families with either a C15-Me or a C15-Et
branch. If these particular compounds can be made, permu-
tations of the modules needed for their synthesis should bring
many of their siblings into reach.
A vinylogous asymmetric Mukaiyama aldol reaction was
deemed the ideal entry point into the preparation of the
[30,31]
common eastern fragment (Scheme 2).
Rather than
pursuing an auxiliary-based approach for the preparation of
the required aldehyde 6, we opted for kinetic resolution. To
this end, cheap 3 was reduced and the resulting alcohol
reacted with vinyl acetate in the presence of Pseudomonas
fluorescens lipase to give the corresponding acetate 4 with
To this end, the blueprint shown in Scheme 1 was pursued,
which traces both series back to the very same unsaturated
[
22]
synthon G: Tsuji/Wacker oxidation
followed by alkyny-
[32]
lation of the resulting ketone D with the skipped enyne C was
94% ee on > 20 g scale (40% yield of possible 50%).
Because of the volatility of the derived alcohol 5, the
deacetylation was best performed with MeLi in Et O, as the
2
lithium salts are easy to remove by aqueous work-up and the
ethereal solvent can be evaporated without undue loss of
material. Subsequent Swern oxidation furnished aldehyde 6
without noticeable isomerization; the crude product was used
in the subsequent vinylogous Mukaiyama aldol reaction to set
Scheme 2. a) LiAlH , THF, 91%; b) vinyl acetate, Amano lipase (Pseu-
4
domonas fluorescens), THF, À208C, 40%, 94% ee; c) MeLi, Et O, 75%,
2
À308C ! RT; d) (COCl) , DMSO, Et N, CH Cl , À788C ! RT; e) 9,
2
3
2
2
1
1 (50 mol%), iPrOH, CH Cl , À788C, 69% (over two steps,
2
2
dr=89:11, C6-epimers) [10 g scale]; f) 10, TfOH cat., CH Cl , À208C
2
2
!
RT, 68%; g) O , PdCl (20 mol%), CuCl, THF, H O, 88%; PMB=p-
2 2 2
Scheme 1. Layout of a potentially “collective” synthesis of the aldgamy-
methoxybenzyl; TBS=tert-butyldimethylsilyl; Tf=trifluoromethanesul-
cin/mycinamicin macrolides.
fonyl.
7
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the syn/anti-configured stereotriade. At the outset we faced
massive reproducibility issues, which could ultimately be
traced back to the catalyst preparation. Gratifyingly, it was
found that samples of complex 11 prepared in a separate step
by condensation of diphenylprolinol and phenylboronic
cleavage of the TES-ether. Subsequent Sonogashira cou-
[39]
pling
of 15b with trimethylsilylacetylene followed by
selective cleavage of the CÀSi bond gave the 1,3-enyne 16
as required for the assembly of the “B-series”. Equally facile
was the elaboration of 15a into 17 by a copper-mediated
[33]
[30]
[40]
acid (rather than from PhBCl2) in a Dean–Stark trap
followed by activation of the resulting oxazaborolidine with
TfOH at low temperature led to good results, consistently
furnishing compound 7 in 69% yield (over two steps, dr=
coupling with lithiated trimethylsilylpropyne; importantly,
no trace of allene was observed in the crude mixture under
these conditions nor after desilylation with K CO /MeOH.
2
3
The skipped enyne 17 was deprotonated with nBuLi and
the resulting lithio-acetylide added to ketone 8 in the
[34,35]
8
9:11, C6-epimers, > 10 g scale).
With access to decagram quantities of this key building
presence of LaCl ·2LiCl to reduce the basicity of the reagent
3
[41,42]
block in only five operations, a solid basis was reached from
which the project could branch out toward the two different
product series. To this end, 7 was PMB-protected; only the
(Scheme 4).
Unsurprisingly perhaps, the remote stereo-
centers in 8 (drꢀ 90:10) had no significant impact on the
stereochemical course of the reaction. Because the two
[36]
[43]
quinolone ether 10 worked well, whereas more traditional
isomers were separable at this stage, no effort was made
[44]
methods gave complex mixtures. The subsequent Tsuji/
to impose better control over the addition process; rather,
we were pressing forward to check the feasibility of the
subsequent key steps en route to aldgamycin N (1) and its
cousins of the “A-series”. Whereas the selective deprotection
of the TES-ether of adduct 18 proceeded smoothly in acidic
medium under carefully controlled conditions without dam-
aging the acid-sensitive tertiary alcohol, all attempts to cleave
the methyl ester of 19 and release the seco-acid in readiness
for macrolactonization were met with poor yields or even
Wacker oxidation with catalytic PdCl , CuCl as co-catalyst,
2
and oxygen as the terminal oxidant furnished the required
[22]
methyl ketone 8 in high yield.
The necessary alkyne modules of type C and F could also
be accessed by a uniform strategy (Scheme 3). Thus, Sharpless
epoxidation of the homologous Z-alkenes 12a,b followed by
opening of the resulting oxirane derivatives 13a,b with
lithium acetylide ethylenediamine complex proved practi-
[37]
[45]
cal: although the attack of the nucleophile is not overly
regioselective, the undesired isomer—which is a 1,2- rather
than 1,3-diol—is readily discarded by an oxidative work-up
complete failure. Rather than opting for a re-launch of the
project with a more orthogonal ester, we explored the
possibility of forging the large ring by transesterification.
Gratifyingly, stannoxane 25a proved adequate in that it
allowed lactone 20 to be formed in 68% yield on a decent
[
37]
with NaIO4. After appropriate differential protection, the
terminal alkyne was subjected to hydrozirconation/iodina-
[
38]
[46]
tion; the procedure had to be modified in that 2,6-lutidine
was introduced prior to the addition of iodine to avoid
scale (> 400 mg, single largest batch). The isomeric addi-
tion product 8-epi-18 was processed analogously to the
corresponding epimeric lactone (see the SI); it was at this
stage that the configuration of the C8-stereocenter could be
tentatively assigned, which was later confirmed by the total
[
47]
synthesis of aldgamycin N. In the end, this transesterifica-
tion saved a step in the longest linear sequence as it rendered
the formation of the seco-acid obsolete. It is also notable that
this example seems to be only the second successful applica-
tion of this methodology to the synthesis of a macrolide
[48–51]
natural product.
With the macrocyclic frame closed, we faced the challenge
of transforming the propargylic entity of 20 into the acyloin
motif characteristic of aldgamycin N (1) by regioselective
hydration of the triple bond at the more hindered site. This
goal was reached by resorting to a method previously
[52]
developed in our laboratory, which was slightly modified
and further improved for this particular application. Specif-
ically, 20 was subjected to a ruthenium catalyzed trans-
hydrostannation, because this reaction faithfully delivers the
Scheme 3. a) Cumene hydroperoxide, Ti(OiPr) , L-diisopropyl tartrate,
4
CH Cl , À208C, 54% (13a, 92% ee), 73% (13b, 87% ee); b) (i)
2
2
[
2
HCꢁCLi]·eda, THF, 08C ! RT; (ii) NaIO , CH Cl /H O, 42% (14a),
4
2
2
2
-
SnBu moiety to the position proximal to the -OH substitu-
3
9% (14b, 97% ee after recrystallization); c) TBDPSCl, imidazole,
[53,54]
ent.
This regioselective outcome is rooted in a highly
CH Cl , 83% (R=H); d) TESOTf, 2,6-lutidine, CH Cl , 08C ! RT, 96%
2
2
2
2
ordered transition state, in which the polarized [RuÀCl] unit
(
R=H), 91% (R=Me, over both steps); e) (i) Cp ZrCl , Dibal-H, THF,
2 2
0
8C ! RT; (ii) I , 2,6-lutidine, THF, À788C, 65% (15a), 74% (15b);
of the catalyst [Cp*RuCl] locks the substrate in place by
2
f) 15b, TMSCꢁCH, [(PPh ) PdCl ] (2.5 mol%), CuI, Et N; g) K CO ,
3
2
2
3
2
3
interligand hydrogen bonding; at the same time, the chloride
MeOH, THF, 96% (over two steps); h) TMSCꢁCMe, nBuLi, THF,
À788C, then 15a, CuI, DMAP, 08C ! RT; i) K CO , MeOH, THF, 84%
[54,55]
ligand steers the incoming stannane as shown in H.
As
2
3
expected, this directing effect was also operative in the
present case in that alkenylstannane 21 was formed in good
yield as a single regio- and stereoisomer. This compound was
then subjected to a Chan-Lam-type coupling: rather than
(
over two steps); Cp=cyclopentadienyl; Dibal-H=diisobutylaluminum
hydride; DMAP=4-dimethylamino-pyridine; eda=ethylene-
,2-diamine; TBDPS=tert-butyldiphenylsilyl; TES=triethylsilyl;
1
TMS=trimethylsilyl.
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Scheme 4. a) 17, nBuLi, LaCl ·2LiCl, THF, À788C, 83% (dr ꢀ1:1); b) PPTS, EtOH, 08C, 89%; c) 25a, toluene, reflux, 68%; d) [Cp*RuCl]
3
4
(
12 mol%), Bu SnH, CH Cl , 72%; e) [Cu(tfa) ]·H O, DMAP (40 mol%), DMSO, 458C, 83%; f) DDQ, CH Cl , H O, see Text; Cp*=pentamethyl-
3
2
2
2
2
2
2
2
cyclopentadienyl; DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; PPTS=pyridinium p-toluenesulfonate; tfa=trifluoroacetate.
[52]
using Cu(OAc) in DMSO/Et N as previously described,
linear sequence; the accompanying paper describes how this
2
3
we resorted to Cu(tfa) in DMSO in the presence of catalytic
challenge has been met and an efficient synthesis of 1 been
accomplished.
2
[47]
amounts of DMAP. Under these conditions, the reaction
proceeded under milder conditions and delivered the unpro-
tected acyloin 22 right away instead of the corresponding
From a purely strategic perspective, however, it was
deemed essential to first validate the projected route to the
“B-series”, which constitutes an equally integral part of the
proposed “unified” approach shown in Scheme 1. It was
arguably most important to check whether the common
building block 7 is amenable to a catalyst-controlled branch-
selective asymmetric hydroformylation or not. Although the
C5-OH group of this substrate suggested that recourse should
be taken to a covalently bound directing group, which is
acetate derivative that is generated when Cu(OAc) is used as
2
[52]
the reagent.
At this stage, the completion of the total synthesis of
aldgamycin N seemed just a matter of routine protecting
group manipulations and appropriate glycosidation reactions.
This optimistic assessment, however, was premature: al-
though cleavage of the PMB-group per se worked well, the
released C5-OH group invariably engaged the ketone at C9 in
transannular lactol formation; on top, the resulting hemiketal
[23]
a well-established tactic for this purpose,
the need to
introduce and later remove such an auxiliary in separate
operations was deemed far from ideal. In the end, it turned
out to be unnecessary to resort to such a maneuver because
the MOM-derivative 26 (dr= 87:13) succumbed to the
desired transformation in the presence of a catalyst that had
to be pre-formed from [Rh(acac)(CO) ] and (R ,R,R)-
2
3b proved sensitive, resulting in partial decomposition.
Although the reasons for this instability were not investigated
in any great detail, we noticed in parallel attempts using
globally deprotected samples of the aglycone the formation of
appreciable amounts ( ꢀ 20%) of the ring-contracted diolide
2
ax
2
4 (R = H), likely formed by spontaneous oxidative diol
BOBPhos (32) prior to addition of the substrate
[26,57]
cleavage. This process is presumably also one of the ways by
which 23b degrades to compounds of type 24 (R = TBDPS)
and further downstream products. Attempted elaboration of
(Scheme 5).
Further optimization of the reaction showed
that strictest temperature control during the actual hydro-
[58]
formylation step was quintessential for success:
when
[56]
this mixture into the target compound 1 was to no avail.
performed at 30 Æ 18C in hexafluorobenzene as the preferred
solvent, gram scale experiments furnished the desired alde-
hyde 27 in respectable 60% yield with an isomer ratio of 83:17
(sum of all undesired isomers). When assessing this result, one
has to consider that the chosen substrate 7 had not been
isomerically pure but had a dr of 89:11, as set by the
Mukaiyama aldol reaction; the methyl-branched chiral center
itself was hence formed under the aegis of the catalyst with
a dr= 96:4. Control experiments using the enantiomeric
BOBPhos ligand proved that the induction results from
Although this unforeseen transannular interference
stopped this initial foray towards aldgamycin N, the obtained
results clearly proved the viability of all key transformations
meant to provide access to the “A-series”. The only significant
modification to be implemented concerns the timing of the
events: the aldgarose unit must be introduced at an earlier
stage rather than in the penultimate step, as originally
planned. The price to pay is the need to carry this precious
monosaccharide through a number of steps along the longest
7
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[63]
our laboratory, even though a high catalyst loading was
[43]
indeed necessary. In contrast to the original literature on
[62,64,65]
ruthenium-catalyzed cycloisomerization,
it proved ben-
eficial to leave any acid co-catalyst out; rather, addition of
PhPCy to the [CpRu(MeCN) ]BF complex ensured that the
2
3
4
reaction proceeded cleanly and in well reproducible
[66,67]
yield.
Cleavage of the protecting groups with aq. HCl in
MeOH also worked well to give mycinolide IV (2) as
a colorless solid material. The analytical and spectral data
of our samples matched those of the authentic compound
[9,17a]
reported in the literature in every regard.
Conclusion
Needless to say that the two orthogonal protecting groups
in 31 ensure that this compound can also be elaborated into
the glycosylated siblings of 2; this aspect is subject to ongoing
work in our laboratory. At this point, however, the key
strategic goal of this endeavor had essentially been attained in
that a “unified” approach to the mycinamicin and the
aldgamycin series was shown to be feasible. While the
conquest of mycinolide IV (2) in only 12 steps (longest linear
sequence) leaves no doubt that various natural and non-
natural compounds of the “B-series” can be formed analo-
gously in a “serial” manner, one might object that a rigorous
proof for the complementary “A-series” is yet missing.
Although the newly scouted pathway envisaging an early
glycosylation event seems perfectly viable, only the crossing
of the finish line is what ultimately counts. The accompanying
paper describes how this second task has been reached.
Scheme 5. a) CH (OMe) , P O , CH Cl , 87%; b) [Rh(acac)(CO) ]
2
2
4
10
2
2
2
(
(
6
3.4 mol%), 32 (4.2 mol%), H /CO (1:1, 15 bar), C F , 30Æ18C, 60%
2
6 6
dr=83: 17 (S of all other isomers)); c) 16, nBuLi, THF, À788C, 56–
5% (dr=1.4:1); d) camphor-10-sulfonic acid (5 mol%), MeOH,
CH Cl , À208C, 86%; e) 25b, chlorobenzene, reflux, 32–37%; f) [CpRu-
2
2
(
MeCN) ]BF (50 mol%), PhPCy (50 mol%), THF, reflux, 65%; g) aq.
3
4
2
HCl (3 M), MeOH, 408C, 74%; acac=acetylacetonato.
catalyst- rather than substrate-control; the absolute config-
uration of the newly formed stereocenter was proven by
transformation of 27 into the literature-known derivative
[15a]
3
3
and careful comparison of the NMR data (see the
Supporting Information).
Acknowledgements
Addition of the lithiated enyne 16 to freshly prepared
[59]
aldehyde 27 gave alcohol 28 as an inconsequential mixture
of isomers, which were treated with camphorsulfonic acid in
MeOH/CH Cl at À208C to deprotect the TES ether selec-
Generous financial support by the Fonds der Chemischen
Industrie (KekulØ stipend to G.S.) and the Max-Planck-
Gesellschaft is gratefully acknowledged. We thank Dr.
M. Fernandez Bieber for exploratory studies, and the Ana-
lytical Departments of our Institute for excellent support,
especially C. Wirtz and Dr. M. Leutzsch as well as S.
Kestermann for help with several NMR and HPLC analyses,
respectively. Open access funding enabled and organized by
Projekt DEAL.
2
2
tively. Once again, attempted formation of the seco-acid by
cleavage of the methyl ester in 29 via chemical or enzymatic
means was to no avail, but macrolactonization by transesteri-
fication with the aid of stannoxane 25b proved again viable,
although the reaction was very slow even in refluxing
chlorobenzene (rather than toluene) and the yield of 30
[60,61]
significantly lower than in case of 20.
The difference is
ascribed to the higher rigidity imposed onto the incipient ring
by the conjugated E-configured enyne relative to the skipped Conflict of interest
enyne subunit in 30 that contains a rotatable bond in between
the stiff substructures.
The authors declare no conflict of interest.
At this stage, the only remaining key step to be
accomplished was the reorganization of the p-system of the
propargylic alcohol 30 to the corresponding dienone. Ruthe-
nium-catalyzed redox isomerizations of 1,3-enyn-5-ol deriv-
Keywords: antibiotics · asymmetric hydroformylation ·
macrolides · redox-isomerization · ruthenium ·
trans-hydrostannation
[62]
atives, however, are extremely scarce;
moreover, the
conjugated p-systems present in the enyne substrate and the
resulting diene product might disfavor or even impede the
reaction as they are able to bind tightly to the active [CpRu]
[
[
1] Antibiotics: Challenges, Mechanisms, Opportunities, 2nd ed.
Eds.: C. Walsh, T. Wencewicz), Wiley, Hoboken, 2016.
(
[
54]
fragment. Despite these concerns, the conversion of 30 into
2] S. Omura, Macrolide Antibiotics. Chemistry, Biology and Prac-
nd
3
1 proceeded well under conditions previously optimized in
tice, 2 ed, Academic Press, New York, 2002.
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[
[
3] F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Häbich,
Angew. Chem. Int. Ed. 2006, 45, 5072 – 5129; Angew. Chem.
[21] For examples of total synthesis projects from this laboratory
which were not targeting a single individual compound but were
a priori more integral, see: a) S. Schulthoff, J. Y. Hamilton, M.
Heinrich, Y. Kwon, C. Wirtz, A. Fürstner, Angew. Chem. Int. Ed.
2021, 60, 446 – 454; Angew. Chem. 2021, 133, 450 – 458; b) M.
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[
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898 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 7893 – 7899

Angewandte
Research Articles
Chemie
[
35] a) The relative and absolute stereochemistry of this key
[54] a) S. M. Rummelt, K. Radkowski, D.-A. Rosca, A. Fürstner, J.
compound was proven by Mosher-ester analysis and conversion
into a six-membered lactone, see the SI; b) the assignment that
the isomers are epimeric at C6 is based on a control experiment
using rac-6 as the substrate, cf. the Supporting Information. Since
aldehyde 6 formed by Swern oxidation was isomerically pure
Am. Chem. Soc. 2015, 137, 5506 – 5519; b) D.-A. Ro s¸ ca, K.
Radkowski, L. M. Wolf, M. Wagh, R. Goddard, W. Thiel, A.
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(
GC) and was freshly used, some isomerization must occur
[55] A. Fürstner, J. Am. Chem. Soc. 2019, 141, 11 – 24.
[56] Similar problems of transannular interference are known for
several other 16-membered macrolide antibiotics, including
erythromycin B; for representative cases, see ref. [17b] and the
following: a) T. J. Perun, J. Org. Chem. 1967, 32, 2324 – 2330;
b) V. Velvadapu, T. Paul, B. Wagh, I. Glassford, C. DeBrosse,
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during the vinylogous Mukaiyama reaction itself to explain the
observed dr of 89:11.
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screened but found inadequate.
[
[
[
[58] Even at slightly higher temperatures, reversible isomerization of
the terminal alkene to various internal positions (“chain walk”)
becomes a serious issue, leading to the formation of regio- and
stereoisomers (scrambling of the C6 stereocenter); at lower
temperatures, the reaction rates are unacceptably slow.
[59] As the aldehyde gets partly oxidized on storage, it was used in
the next step without delay.
1
397.
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42] For a recent application in natural product synthesis from this
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43] Diastereomeric impurities derived from the minor isomer of the
substrate could also be removed at this stage.
[47]
[
[60] In the accompanying study,
it was found that reactions at
higher concentration resulted in low yields, whereas further
dilution did not lead to significant improvements. Small amounts
of the corresponding seco-acid were usually observed as side
product, which was present even when utmost care was taken to
ensure that all reagents and the glassware were thoroughly dried.
[61] An alternative method for transesterification using La-
(NO ) ·H O was unsuccessful; it led to the formation of an
[
[
44] Y.-L. Liu, X.-T. Lin, Adv. Synth. Catal. 2019, 361, 876 – 918.
45] The major issue seems to be the exceptional sensitivity of
substrate and product towards basic conditions (LiOH in aq.
MeOH/THF; Ba(OH) ·8H O in MeOH) leading to intra- and/or
2
2
intermolecular addition of the tert-OH group to the enoate as
well as partial or total cleavage of the TBDPS-ether; even the
3
3
2
use of Me SnOH in 1,2-dichloroethane furnished a complex
undesired tetrahydropyran, see the Supporting Information: M.
Hatano, S. Kamiya, K. Ishihara, Chem. Commun. 2012, 48,
9465 – 9467.
3
mixture. Demethylation by S 2 reaction with LiI (in pyridine,
N
lutidine or DMF) gave small but variable amounts of the seco-
acid (ꢂ 45%) together with several unidentified side products.
46] a) J. Otera, T. Yano, Y. Himeno, H. Nozaki, Tetrahedron Lett.
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47] Since acceptance of this manuscript, a related study was
published: G. Späth, A. Fürstner, Angew. Chem. Int. Ed. 2021,
https://doi.org/10.1002/anie.202016477; Angew. Chem. 2021,
https://doi.org/10.1002/ange.202016477.
48] For the formation of a 13-membered lactone en route to (Æ)-
jasmine ketolactone, see: I. Shimizu, H. Nakagawa, Tetrahedron
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[65] K. Gebauer, A. Fürstner, Angew. Chem. Int. Ed. 2014, 53, 6393 –
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[
[
[
[66] Although the exact role of the phosphine additive has not yet
+
been elucidated, complexes of type [CpRu(R P)] exhibit only
3
49] For the synthesis of natural-product-like macrodiolides, see: Q.
Su, A. B. Beeler, E. Lobkovsky, J. A. Porco, J. S. Panek, Org.
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P failed; a medium-sized lactone was formed instead, cf: B. M.
Trost, J. P. N. Papillon, T. Nussbaumer, J. Am. Chem. Soc. 2005,
two coordination sites, as necessary for the cycloisomerization to
proceed; this defined situation seems to be particularly favorable
in reactions of (poly)functionalized substrates carrying poten-
tially chelating substituents. Electronic effects of the phosphine
ligand, however, may also play a role, see ref. [63] and the
following: K. Gebauer, Dissertation, TU Dortmund, 2016.
[67] The reverse order of events, that is redox isomerization prior to
macrolactonization, was lower yielding.
1
27, 17921 – 17937.
[
51] For the formation of six-membered lactones, see ref. 28 and the
following: a) B. M. Trost, H. Yang, O. R. Thiel, A. J. Frontier,
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52] H. Sommer, J. Y. Hamilton, A. Fürstner, Angew. Chem. Int. Ed.
[
[
Manuscript received: December 11, 2020
Revised manuscript received: January 13, 2021
Accepted manuscript online: January 15, 2021
Version of record online: February 26, 2021
2
017, 56, 6161 – 6165; Angew. Chem. 2017, 129, 6257 – 6261.
53] S. M. Rummelt, A. Fürstner, Angew. Chem. Int. Ed. 2014, 53,
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3
Angew. Chem. Int. Ed. 2021, 60, 7893 – 7899
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH www.angewandte.org 7899