Cyclodepsipeptide alveolaride C: Total synthesis and structural assignment

Article abstract of DOI:10.1039/d0sc04478d

First stereoselective total synthesis of naturally occurring bioactive cyclodepsipeptide alveolaride C has been achieved using a convergent approach. This synthetic study enabled us to establish unambiguously the stereochemistry of three unassigned chiral centres embedded in the nonpeptidic segment as well as revised the stereochemistry of the proposed β-phenylalanine counterpart of the molecule. The key strategic features of this synthesis include Sharpless asymmetric dihydroxylation for installing the vicinal diol moiety, Julia-Kocienski olefination for constructing the aliphatic side chain, the Shiina protocol for intermolecular esterification, amide coupling and macrolactamization for the ring formation. This journal is

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Cyclodepsipeptide Alveolaride C: Total Synthesis and Structural
Assignment
Sanu Saha, Debobrata Paul and Rajib Kumar Goswami*
Received 00th January 20xx,
Accepted 00th January 20xx
First stereoselective total synthesis of naturally occurring bioactive cyclodepsipeptide alveolaride C has been
achieved using a convergent approach. This synthetic study enabled us to establish unambiguously the
stereochemistry of three unassigned chiral centres embedded in the nonpeptidic segment as well as revised the
stereochemistry of the proposed β-phenylalanine counterpart of the molecule. The key strategic features of this
synthesis include Sharpless asymmetric dihydroxylation for installing the vicinal diol moiety, Julia-Kocienski
olefination for constructing the aliphatic side chain, Shiina protocol for intermolecular esterification, amide coupling
and macrolactamization for the ring formation.
DOI: 10.1039/x0xx00000x
Introduction
Microorganisms are known as the rich sources of structurally
novel secondary metabolites. Many of them possess a broad
range of biological activities.1 Chemical synthesis of these
metabolites are, thus, crucial for their unambiguous structural
confirmation and ensure adequate supply for exploring their
biological importance.2 During the search for naturally
occurring
environmentally
benign
pesticides
from
microorganisms Dow Agro Sciences, in 2018, first identified and
isolated a family of novel cyclodepsipeptide alveolarides A-C (1-
3, Figure 1) from the culture broth of Microascus alveolaris
strain PF1466.3 Invitro inhibition studies against different
harmful plant pathogens Pyricularia oryzae, Zymoseptoria
tritici, Ustilago maydis, Puccinia triticina, and Phakopsora
pachyrhizi revealed that these cycodepsipeptides exhibited
excellent to moderate activities.3 The structures of these
molecules were determined partially using NMR, mass
spectroscopic analysis and chemical modifications techniques.
Architecturally, alveolarides are 17-membered macrocycles
bearing rarely found 2,3-dihydroxy-4-methyltetradecanoic acid
(DHMTDA) as nonpeptide unit in which the configurations of all
the three stereocentres remained undetermined. DHMTDA
segment of alveolaride B was found slightly different from
alveolarides A and C in which an olefin between C39-C40 is
present. D-β-phenylalanine, L-glutamine and D-serine are the
residues common to all the members of this family of
cyclodepsipeptide. L-glutamic acid derivative bearing two
additional unassigned stereocentres in alveolarides A & B and L-
tryptophan in alveolaride C were observed as the other amino
acid counterparts, respectively.3 The chemical structure of
alveolaride C was proposed based on the similarities in 1H and
Figure1: Chemical Structures of Alveolarides.
School of Chemical Sciences, Indian Association for the Cultivation of
Science, Jadavpur, Kolkata-700032, India. Email: ocrkg@iacs.res.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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13C NMR of alveolarides A and B but no degradation study was precursor
Journal Name
4
which further could be prepared fVrioewmArtsiculeitOanblinlye
and
by amide DcoOuI:p1l0in.1g0.39C/oDm0SpCo0u44n7d8D
by amide coupling with D-
performed due to the scarcity of compound. Our continual protected compounds
interest in natural product synthesis and their structural could be synthesized from acid
assigment4 prompted us to envisage initially the total synthesis serine residue followed by intermolecular esterification with N-
of structurally unique alveolaride C ( ). The establishment of the protected D-β-phenylalanine counterpart
stereochemistry of the unassigned centres in the common There are three stereocentres in DHMTDA counterpart of
5
6
5
7
3
nonpeptide segment of this family of molecules is very crucial alveolaride C which remained unassigned during its discovery.
and essential to synthesize the other members including the Thus, it could be conceived that structure of DHMTDA would
more active alveolaride A. There are three undetermined match with one out of eight possible stereoisomers [
stereocentres in the molecule providing the possibility of eight ent-7 ), Figure 2]. To solve this structural riddle, we initially
configurational isomers among which one could be expected as planned to synthesize four of them ) with an intension to
7(a-d) and
(a-d
7(a-d
the actual structure of alveolaride C. To narrow down these compare their spectroscopic data with the reported data of the
possibilities, we depended on the reported NMR spectral data DHMTDA segment. Initial trial of the isolation group to confirm
of DHMTDA counterpart of alveolaride C.3 Two diastereomers the absolute configurations of these stereocentres using
of purported structure of alveolaride C (3) having the Mosher’s ester method was not successful as the required ester
stereochemistry 29-(R)/30-(S)/31-(R) and 29-(S)/30-(R)/31-(S) did not form.3
were synthesized initially as the specific rotation value of
DHMTDA was not reported.3 Comparison of their NMR data
with the isolated alveolaride C (3) revealed that the later isomer
was in better match with some discrepancies originated from β-
phenylalanine counterpart. Herein, we described a convergent
and flexible route of the first stereoselective total synthesis of
the actual structure of alveolaride C (epi-3b, Figure 1) which
enabled us to assign successfully the undetermined
stereocentres (C-29, C-30, C-31) and also to revise the proposed
configuration of β-phenylalanine (C-3) counterpart of the
molecule.
The retrosynthetic analysis of alveolaride C (3) is delineated
in Scheme 1. There are a few possible sites in the molecule
suitable for macrocyclization. We relied on macrolactamization
approach and planned to synthesize the target molecule from
Figure 2: Possible Stereoisomers of 2,3-Dihydroxy-4-Methyl-
tetradecanoic (DHMTDA) [7(a-d) and ent-7(a-d)].
Results and Discussion
The synthesis of acid 7a commenced with the known epoxide
n
85a (Scheme 2) which was treated with BuLi/Me3Al6 followed
by treatment with NaIO4 to obtain the corresponding 1,3-diol
which further was reacted with PivCl/Et3N to get compound
9.
The secondary hydroxy centre of compound was protected as
9
TBS ether and subsequently treated with DIBAL-H to access
alcohol 10 which was oxidized further using IBX. The resultant
aldehyde was then subjected to Julia-Kochienski olefination7
with sulfone 11, prepared from nonanol in two steps (Scheme
2), in the presence of KHMDS to produce the corresponding
olefin with complete E-selectivity and treated further with 4N
HCl/THF to get triol 12. Next, triol 12 was treated with
PivCl/Et3N followed by 2,2-DMP/CSA and finally with DIBAL-H to
yield compound 13 efficiently. It was then hydrogenated and
subsequently oxidized to acid 14 following a two-step protocol,
DMP oxidation followed by Pinnick oxidation. Many conditions
(HCl/THF, AcOH/H2O, HF/Py, CSA/MeOH, HCl/MeOH) at
different temperature were screened to deprotect the
acetonide of acid 14. CSA/MeOH in 23 h as well as HCl/MeOH in
16 h provided the corresponding acetonide deported product in
satisfactory yield. However, the acid functionality
concomitantly transformed to its corresponding methyl ester
which was later hydrolyzed using LiOH.H2O to result acid 7a
.
Scheme 1: Retrosynthesis of Alveolaride C (3).
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0SC04478D
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Scheme 2: Synthesis of Acids 7a and 7b.
Acid 7b was also synthesized from the known compound 155 Kocienski olefination7 using sulfone 26, prepared from octanol
following exactly the same chemistry of acid 7a [see Scheme S2 in two steps (Scheme 4), to access the corresponding E-olefin
(page-S28) in Supporting Information].
exclusively. The resultant olefin finally was hydrogenated to
The synthesis of acid 7c is described in Scheme 3. The known obtain alcohol 27 which was oxidized further to acid 28 in two
aldehyde 168 was subjected to Crimmins aldol9 using the
thiazolidinethione 179a in the presence of TiCl4/DIPEA to get
compound 18 as a single isomer which further was treated using
TBSOTf/2,6-lutidine followed by NaBH4/EtOH to result alcohol
19. Next, alcohol 19 was oxidized to the corresponding
aldehyde using DMP and subsequently subjected to Julia-
Kocienski olefination7 using sulfone 11 in the presence of
KHMDS to yield the corresponding olefin with complete E-
selectivity. The resultant olefin was hydrogenated further to
provide compound 20 which was then oxidized to the
corresponding acid using DMP following Pinnick oxidations.
Acid was treated further with HCl/MeOH to yield compound 21
which finally was hydrolyzed to get acid 7c in good overall yield.
Initially we planned to introduce the syn C-2 and C-3 hydroxy
centre of acid 7d adopting the same approach as for the
synthesis of acid 7c using auxiliary ent-17 but required isomer
obtained as minor product. Moreover, the use of glycolate aldol
to install the same chiral centres of acid 7d from compound 2210
was also not fruitful. Thus, compound 22 (Scheme 4) was
oxidized using Swern condition and the resultant aldehyde was
subjected to Wittig olefination using Ph3PCHCO2Et to get olefin
23 exclusively. Next, olefin 23 was subjected to Sharpless
asymmetric dihydroxylation11 using AD-mix-
α/MeSO2NH2 to get
the corresponding diol (d:r=9:1) which further was treated with
2,2-DMP followed by LAH to result alcohol 24. It was then
benzylated and treated with TBAF to get alcohol 25 which was
oxidized further. The resultant aldehyde was subjected to Julia-
Scheme 3: Synthesis of Acid 7c.
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Scheme 4: Synthesis of Acids 7d and ent-7d.
steps. Treatment of acid 28 with HCl/MeOH provided methyl Information]. We planned initially to synthesize both the
ester 29 which was hydrolyzed to acid 7d. Comparison of both macrocycles bearing acid 7d and ent-7d as DHMTDA unit to
1H and 13C NMR data [see Tables ST1 to ST4 (page-S3 to S6) in compare their NMR data with the reported data of the isolated
Supporting Information] with the reported data3 revealed that alveolaride C.
acid 7d was the best match among the four isomers
The synthesis of compound 3a is depicted in Scheme 5. N-
synthesized. The optical rotation of DHMTDA unit was not protected L-glutamine was treated with BnBr/K2CO3 followed
reported by the isolation group. Thus, one need to consider the by 30% piperidine to get the corresponding Fmoc deprotected
possibility of its enantiomer ent-7d also as the absolute product that was further coupled with N-protected L-
configurations of those centres were not known. Thus, ent-7d tryptophan in the presence of HATU/HOAt/DIPEA12 to get the
(Scheme 4) was also synthesized from the known compound corresponding amide which was hydrogenated to produce the
ent-2210 following exactly the identical approach of acid 7d [see required dipeptide unit 32. On the other hand, the previously
Scheme S5 (page-S49) in Supporting Information]. Fortunately, synthesized compound 28 was coupled with the known D-
acid ent-7d crystallized and the structure was confirmed serine counterpart 3313 to access compound 34 which was then
unambiguously using X-ray crystallographic analysis [see Figure treated with BiCl3 to yield the corresponding acetonide and TBS
SF1 (page-S7) and Table ST5 (page-S7) in Supporting deprotected triol. The primary hydroxy group of the
Scheme 5: Completion of Total Synthesis of Compound 3a.
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ARTICLE
corresponding triol was protected as TBDPS ether to result diol 15% TFA in CH2Cl2 (entry 8) deprotected only the trityl of
35. Next, different conditions for the selective esterification of compound 37 where the silyl ethers remained unaffected. Thus,
diol 35 with protected D-β-phenylalanine (36)
14 were screened a two-step protocol was adopted for the global deprotection
(Table 1). Yamaguchi condition was not tested because the where compound 37 was first subjected to trityl deprotection
isolation group was unable to get the required Mosher’s ester (entry 8) and subsequently for silyls deprotection (entry 7) to
under this condition.3 EDCI based esterification15a,b was found access compound 3a in good overall yield (68% in two steps).
to be ineffective (entry 1). However, Shiina esterification
protocol15c produced (entry 2) the corresponding C-3 esterified
Table 2: Optimization for Global Deprotection.
product in moderate yield (52%), which was protected further
as TBS ether to obtain compound 5a. Change of solvent polarity
in Shiina protocol did not offer any encouraging result (entry 3
& 4). It was observed that the esterification reaction was highly
sensitive to moisture and impurity. It is noteworthy that we
were unable to detect the formation any C-2 or bis (C-2/C-3)
Entry Conditions
Result
1
2
3
4
5
CSA in MeOH, 0 °C, 2 h
Decomposition
Decomposition
Decomposition
Decomposition
HCl (2N):THF (1:2), 0 °C, 1 h
AcOH:H2O (8:2), 0 °C, 4 h
TBAF in THF, 0 °C, 1 h
Table 1: Optimization for Esterification
.
TBAF:AcOH (1:1), in THF, 0 °C Partial deprotection
to rt, 24 h
Entry Conditions
Yield (%)
of TBDPS and TBS
1
2
EDCI. HCl, CH2Cl2, 0 °C to rt, 6h
MNBA, Et3N, DMAP, CH2Cl2, 0 °C to 52
rt, 30 min
No Reaction
6
HF-Py in THF, 0 °C to rt, 24 h
Partial deprotection
TBDPS and TBS with
some unidentified
spot.
3
4
MNBA, Et3N, DMAP, DMF, 0 °C to unidentified
rt, 30 min
product
7
8
HF-Py:Py (1:2) in THF, 0 °C to Only silyls were
MNBA, Et3N, DMAP, toluene, 0 °C 47
to rt, 30 min
rt, 36 h
deprotected
15% TFA in DCM, 0 °C to rt,
30 min
Only trityl was
deprotected
esterified products during this esterification reaction likely due
to the engagement of C-2 hydroxy group in strong hydrogen
bonding16 with the adjacent amide carbonyl. The formation of
compound 5a was confirmed by detailed 2D NMR analysis [see
Figure SF2 (page-S8), COSY (page-S110) and HSQC (page-S110)
in Supporting Information]. Next, compound 5a was treated
with 30% piperidine/DMF and the resultant compound was
coupled with dipeptide 32 to furnish compound 4a in good
overall yield. Hydrogenation followed by treatment with 30%
piperidine/DMF resulted the corresponding precursor of
macrolactamization from compound 4a in good yield. Quite a
few reaction conditions were screened at this stage for
macrocyclization. EDCI/DIPEA/DMF did not function whereas
Some changes in protection group strategy with respect to
the route of compound 3a were adopted during the synthesis
of compound 3b (Scheme 6) as the global deprotection of
compound 37 was challenging. ent-28 was coupled with
compound 33 to get compound 38 which was then converted
to compound 39 by functional group manipulations. Compound
39 was then esterified with acid 36 following Shiina protocol to
obtain compound 40. Next, the Fmoc group of compound 40
was deprotected and the resultant compound was coupled with
dipeptide 42 to access compound 43. It is noteworthy that
dipeptide 42 was prepared directly from Fmoc protected L-
glutamine (41) [see Scheme S8 (page-S65) in Supporting
Information] to avoid the trityl deprotection step in the final
stage of the synthesis. Next, compound 43 was hydrogenated
and subsequently reacted with piperidine to furnish the
corresponding precursor of macrolactamization. Cyclization
using HATU/HOAt/NMM resulted the corresponding product
which finally was treated with HF-Py/Py (1:2) in THF to get
compound 3b in good overall yield.
PyBOP/DIPEA/DMF,17a
HATU/HOAt/DIPEA/DMF17b
and
HATU/HOAt/NMM/DMF17c provided the cyclized product 37 in
38%, 51% and 61% yield, respectively. Next, a detailed
optimization (Table 2) for the global deprotection was
performed. It was observed that compound 37 decomposed
completely in the presence of CSA/MeOH (entry 1), HCl/THF
(entry 2), AcOH/H2O (entry 3) and TBAF/THF (entry 4).
TBAF/AcOH (1:1) (entry 5), HF-Py (entry 6), HF-Py/Py (1:2) (entry
7) provided only the corresponding desilylated product in
different extent. HF-Py/Py was found as the best desilylation
condition compared to others in our case. It was observed that
The 1H and 13C NMR data of both compounds 3a and 3b were
compared with the reported data of the isolated natural
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Journal Name
14 to
esterified with Fmoc protected L-β-phenylalanineV(iew Article Online
ent-36)
access compound epi-40 which wasDOthI:e10n.10c3o9/uDp0lSeCd044w7i8tDh
dipeptide 42 to get compound epi-43. It was then hydrogenated
and subjected further for Fmoc deprotection. The resultant
compound was then cyclized to get the corresponding
macrocyclic compound. Finally, the TBDPS ether was
deprotected to provide compound epi-3b in good overall yield
(59% over four steps). The 1H and 13C NMR were recorded. We
were quite delighted to observe that the NMR and optical
rotation {observed [α]25D = -15.8 (c 0.21, MeOH); reported [α]25
D
= -10.2 (c 0.12, MeOH)} data of our synthesized compound epi-
3b were in accordance [see comparison Table ST8 (page-S13, S-
14) and Figure SF7 (page-S16) in Supporting Information] with
the reported data of the isolated natural product which clearly
establish the actual structure of alveolaride C. It is noteworthy
that the 13C signals of C-6 and C-8 of phenyl ring of β-phenyl
alanine was reported at δ 126.4 ppm whereas the same carbons
of very similar alveolarides A (1) and B (2) were reported at δ
128.2 ppm by the isolation group. We observed the 13C NMR
signals of those carbons at δ 128.27 ppm for the synthesized
alveolaride C (epi-3b)18.
Scheme 6: Completion of Total Synthesis of Compound 3b.
product [see Tables ST6 (page-S9, S10), ST7 (page-S11, S12),
Figures SF3 (page-S15), SF4 (page-S15), SF5 (page-S16) and SF6
(page-S16) in Supporting Information]. Major mismatches were
observed for compound 3a in both 1H and 13C NMR data
1
whereas the H NMR data of compound 3b seemed promising
even though some anomalies were observed in its 13C NMR
data. However, few noticeable discrepancies in 1H NMR of
compound 3b was observed for the protons near the β-
phenylalanine and DHMTDA counterparts. H-2 of β-
phenylalanine was reported at 2.87 and 3.15 ppm whereas the
same protons for the synthesized compound 3b were observed
at 2.83 ppm. Moreover, anomalies in H-3 and aromatic protons
(H-5, H-6, H-8 and H-9) of phenyl ring of β-phenylalanine were
also observed where the difference in chemical shift was more
than 0.3 ppm. Difference in chemical shift of ~0.2 ppm was also
noted for H-29, H-30 and H-31. These observations clearly
indicated that the stereochemistry either C-3 or C-29 or C-30 or
C-31 or all might not be accurate. However, the stereochemistry
of all the centres (C-29, C-30, C-31) of DHMTDA counterpart was
confirmed by NMR and X-ray crystallographic analysis but the
Scheme 7: Completion of Total Synthesis of the Actual Structure of
Alveolaride C (epi-3b).
absolute stereochemistry of amino acids of alveolaride C (
proposed by comparing the NMR data with alveolaride A (
3) was
Conclusions
1
)
without performing degradation chemistry due to lack of
compound.3 Therefore, we decided to synthesize the C-3
In summary, a flexible and convergent route for the first total
synthesis of structurally attractive alveolaride
C was
epimer of compound 3b
.
accomplished. The target natural product was prepared in 22
linear steps with 6.05% overall yield from the known compound
ent-22. The structural riddle of alveolaride C was solved
successfully. The absolute stereochemistry of three
The completion of total synthesis of actual structure of
alveolaride C (epi-3b) is shown in Scheme 7. The chemistry
adopted was exactly same to compound 3b. Compound 39 was
6 | J. Name., 2012, 00, 1-3
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12 J. Liu, W. Chen, Y. Xu, S. Ren, W. Zhang and Y. Li,VBieiwoAorrtigcl.eMOnelidne.
undetermined centres on DHMTDA segment were established
unambiguously as 29-(S), 30-(R) and 31-(S). The stereochemistry
of β-phenylalanine was revised from S to R. This synthetic study
will be immensely useful for establishing the structure of other
members of alveolaride family. The synthesis of other member
of this family is under progress in our laboratory which will be
reported in due course.
Chem., 2015, 23, 1963-1974
DOI: 10.1039/D0SC04478D
13 L. Zbigniew, Pianowski and N. Winssinger, Chem. Commun.,
2007, 3820–3822.
14 A. Müller, C. Vogt and N. Sewald, SYNTHESIS, 1997, 1997, 837-
841.
15 (a) O. Revu and K. R. Prasad, J. Org. Chem. 2017, 82, 438−460;
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9702−9705; (c) I. Shiina, R. Ibuka and M. A. Kubota, Chem.
Lett. 2002, 286-287.
16 The crystal structure of ent-7d revealed that a possible
hydrogen bonding between the C-2 hydroxy and carbonyl
oxygen of acid moiety.Similar interaction could be expected
between the C-2 hydroxy and carbonyl oxygen of amide of
Conflict of Interest
There are no conflicts to declare.
compound 35
.
17 (a) N. K. Lim, X. Linghu, N. Wong, H. Zhang and C. G. Sowell,
Org. Lett. 2019, 21, 147-151; (b) E. Y. Melikhova, R. D. C. Pullin,
Acknowledgements
C. Winter and T. J. Donohoe, Angew. Chem. Int. Ed. 2016, 55
9753-9757.
,
S.S and D.P thank the Council of Scientific and Industrial
Research, New Delhi for their research fellowship. The financial
support from SERB, Department of Science and Technology
(Project no. CRG/2019/001664) and Council of Scientific and
Industrial Research India (Project no. 02(0294)/17/EMR-II), to
carry out this work is gratefully acknowledged.
18 This anomaly is most likely due to typographic mistakes. No
spectra of alveolaride C were made available by the isolation
group.
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DOI: 10.1039/D0SC04478D
TOC: Cyclodepsipeptide Alveolaride C: Total Synthesis and Structural Assignment
O
NH2
Amide Coupling
O
O
NH2
Amide Coupling
H
N
O
H
N
N
H
*
*
N
H
O
O
HN
O
O
HN
HN
O
Esterification
8
O
O
HN
O
Macrolactamization
O
O
*
HO
N
H
HO
*
N
H
OH
Amide Coupling
8
Julia-Kocienski
Olefination
OH
Sharpless Asymmetric
Dihydroxylation
Reported Structure of Alveolaride C
Assigned Structure of Alveolaride C
First total synthesis of natural cyclodepsipeptide alveolaride C has been accomplished with
unambiguous solution of its structural riddle.