Total Enantioselective Synthesis of the Endophytic Fungal Polyketide Phomolide H and Its Structural Revision

Article abstract of DOI:10.1002/ejoc.201601172

A total synthesis of the proposed structure of the natural polyketide-macrolactone phomolide H 2 has been achieved following a bidirectional strategy from l-tartaric acid. The originally assigned structure of phomolide H displayed discordant NMR spectroscopic data in comparison with synthetic 2. The synthetic strategy was extended to prepare diastereomers and epimeric methyl-ethers of the natural product, structural analysis of which revealed a match of the natural product with diastereomer 27. The structural revision of phomolide H from 2 to the methanol solvate of compound 27 is presented.

Full text of DOI:10.1002/ejoc.201601172

A Journal of
Accepted Article
Title: Total Enantioselective Synthesis of the Endophytic Fungal Polyketide Phomo-
lide H and its Structural Revision
Authors: James McNulty; David Mcleod
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601172
Link to VoR: https://doi.org/10.1002/ejoc.201601172
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601172
Total Enantioselective Synthesis of the Endophytic Fungal Polyketide
Phomolide H and its Structural Revision**
James McNulty* and David McLeod
Abstract: A total synthesis of the proposed structure of the natural
polyketide macrolactone phomolide H 2 has been achieved
following a bidirectional strategy from L-tartaric acid. The
originally assigned structure of phomolide H displayed discordant
NMR data in comparison with synthetic 2. The synthetic strategy
developed was extended to prepare diastereomers and epimeric
methyl-ethers of the natural product, structural analysis of which
allowed for a match of the natural product with diastereomer 27.
The structural revision of phomolide H from 2 to the methanol
solvate of compound 27 is presented.
The naturally occurring nonenolides phomolide G 1 and H 2
(Figure 1) were recently isolated from the endophytic fungus
Phomopsis sp. collected from a Chinese mangrove (Kandelia
[
1]
Candel).
The phomolides belong to an expanding class of
Figure 1. A selection of biologically active nonenolides 1-6 isolated from
functionally diverse polyketides that have been isolated over the last
endophytic fungi.
[
2]
few decades mainly from endophytic and entomopathogenic fungi.
The nonenolides possess a central ten-member macrolactone core
having an aliphatic side chain of varying length appended to C9, as
well as a range of polyhydroxyl and olefinic functionalities. As a
class, the nonenolides display an impressive range of biological
highly dependent on a single stereogenic centre, for example the C2-
methyl stereochemistry of cytospolide A is critical for potent
activity against human lung cancer (A-549 cell line). In addition,
[3c]
[
3a]
[3b, 3c]
activities including antimalarial,
anticancer,
and herbicidal
it is important to note that total syntheses of nonenolides have
required a significant number of structural revisions within the class,
generally involving the reassignment of a single stereogenic centre.
We became interested in developing a two-directional approach
towards the nonenolides in view of the important biological
activities described, and recently reported a total synthesis of
phomolide G 1 that required a structural revision at the C3
[
3d, 3e]
activities.
In addition, specific enzyme inhibitory effects have
been reported for nonenolides including calmodulin-dependent
[
3f]
[3g]
cAMP phosphodiesterase activity, in vivo cholesterol lowering
[
3h]
and cytochrome P450-inhibitory activities.
In addition to
phomolides G 1 and H 2, other specific examples include
[
3d, 3e]
herbarumin II 3,
inhibition of phenylalanine ammonia lyase (PAL), the anticancer
adenocarcinoma) agent Cytospolide A 4, seimatopolide A 5 of
interest against type-2 diabetes and the herbicidal agent pinolidoxin
. The nonenolides have increasingly attracted the attention of
synthetic organic chemists with the total synthesis of many now
which exhibits phytotoxicity through
[5c]
secondary alcohol. The discrepancies seen in the NMR spectra
(
[5c]
reported for phomolide G 1 and the original structural assignment
[1]
as the C3-epimer of 1, in conjunction with reports on the total
6
synthesis of phomolide H 2 through O-methylation of late-stage
[5a, 5b]
intermediates en-route to 1,
prompted us to undertake the total
[
5]
being recorded.
synthesis of phomolide H 2 in order to confirm the structure. In this
work we report the total synthesis of the putative structure of
phomolide H 2 (Scheme 1) and its C3 epimer, as well as a revised
constitution and the stereochemistry of natural phomolide H.
The synthesis of nonenolides has served to showcase the
development and application of a wide range of synthetic
methodologies to access the variously decorated cores in an
asymmetric fashion. Biological activities have been shown to be
[]
Dr. J. McNulty,* Mr. David McLeod
Department of Chemistry and Chemical-Biology
McMaster University
1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada
E-mail: jmcnult@mcmaster.ca
http://www.chemistry.mcmaster.ca/mcnulty/index.html
[]
We thank NSERC, OCE-Connect Canada and CYTEC-Solvay
Canada Inc for financial support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
Scheme 1. Retrosynthetic analysis of the proposed structure of phomolide H 2.
TBS = tertbutyldimethylsilyl, PMB = 4-methoxybenzyl.
1
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601172
A retrosynthetic analysis of phomolide H is shown in Scheme 1.
Briefly, we expected that 2 would be available by selective removal
of the TBS-group from 7, methylation of the C3-alcohol and
removal of the acetonide. Intermediate 7 would be obtained from the
unsaturated aldehyde was achieved with FeCl •6H O in acetone to
give α,β–unsaturated aldehyde 9 .
3
2
[
6]
H3C
O
seco-acid 8 via a Mitsunobu macrolactonization with inversion at
CH3
H3C
O
PMBO
[
7]
CH3
O
C9, and that 8 would be derived via a Nagao acetate aldol on
intermediate 9. This alkenal would be accessed by allylation of the
nitrile derived from 10, and that 10 would be available from a C2
PMBO
O
S
a
O
c
N
S
9
RO
(50:1 d.r.)
[
8]
CHO
H3C
aldehyde to alkenal homologation on the known 4-TBS-protected-
,3-acetonide of L-threose, available in 4-steps from L-tartaric acid
CH3
2
R = H 18
b
dimethyl ester 11.
R = TBS 19
CH3
H3C CH3
H3C
H C
3
H C
3
O
CH3
CH3
H3C CH3
OH
O
O
OTBS
HO
O
PMBO
O
O
d
a
b
e
O
O
CO2Me
MeO2C
O
O
O
TBSO
O
OH
CH3
CH3
8
O
20
O
TBSO
CHO
1
1
12
10
O
O
21
OH
OH
H3C CH3
TBSO
TBSO
H3C
O
CH3
O
H3C CH3
H3C CH3
O
O
HO
O
O
h, i, j
f, g
c, d, e
CH3
CH3
O
OH
PMBO
H3C
H3C
O
O
CH3
CH3
NC
O
HO
OCH3
9
CHO
1
6
14
O
O
CH3
O
OH
O
OCH3

9:1 d.r
O
O
H3C CH3
f
g
h
CH3
O
O
H3C CH3
O
S
H3C CH
O
O
Br
3
H3C
H3C
N
22
23
2
O
CH3
S
Pr3P
O
CH3
CH3
(R)-17
1
3
Scheme 3. Reagents and conditions: Yields are of isolated products. a) (R)-17,
TiCl , DIPEA, CH Cl -78 °C, 82% (4:1 d.r.). b) TBSOTf, 2,6-lutidine, CH Cl
3 °C, 90%. c) LiOH∙H O, H , THF/H O (4:1, v/v), r.t., 82%. d) DDQ, CH Cl
23 °C, 84%. e) PPh , DIAD, PhMe, 0 °C to 23 °C, 57%. f) TBAF, THF, 0 °C,
4
2
2
2
2
,
Scheme 2. Reagents and conditions: Yields are of isolated products. a) ref. 10
1% over four steps. b) 13, KOtBu, THF, 0 °C to 23 °C, 82%. c) TBAF, THF,
°C, 93%. d) PPh , I , 1H-imidazole, THF, 0 °C to 23 °C, 87%. e) KCN, TBAI
10 mol%), DMSO, 23 °C, 67%. f) Allylzinc bromide, THF, 23 °C, 81%. g) LiAlH
LiI, Et O, -100 °C, 92% (≥9:1 d.r.). h) (PPh RuCl , H (1 atm), Benzene/EtOH
1:1 v/v), 23 °C, 94%. i) NaH, PMBCl, DMF, 0 °C to 23 °C, 84%. j) FeCl
acetone, 23 °C, 63%. TBAF tetrabutylammonium fluoride, TBAI
tetrabutylammonium iodide, PMB = p-methoxybenzyl.
2
2
O
2 2
2
2
2
,
5
3
0
3
2
2 2
92%. g) MeI, Ag O, DMS, 23 °C, 83% h) TFA, MeCN/H O (4:1, v/v), 23 °C,
(
4
,
82%. DIPEA = N,N-diisopropylethylamine, TBS = tert-butyldimethylsilyl, Tf =
trifluoromethansulphonyl, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
2
)
3 3
2
2
DIAD = diisopropylazodicarboxylate,TBAF = tetrabutylammonium fluoride, DMS
dimethylsulfide, TFA = trifluoroacetic acid.
(
3
•6H
2
O,
=
=
=
[7]
A Nagao acetate aldol reaction of aldehyde 9 (Scheme 3)
employing TiCl and the (R)-thiazolidinethione 17, prepared from
To synthesize the reported structure 2 for phomolide H, L-
dimethyltartrate 11 was first protected as the 2,3-acetonide (Scheme
4
[
15]
D-valine, gave the non-Evans syn-aldol 18 as the major adduct in
67% yield (dr ≥4:1). The aldol product was protected as its TBS-
ether 19 and then the auxiliary was cleaved selectively using basic
peroxide (LiOH, H O ) leading to the corresponding carboxylic acid
2
), both esters were reduced using LiAlH , and the resulting 1,4-diol
4
[9]
monosilylated as its TBS-ether followed by Swern oxidation
leading to aldehyde 12.
[
10]
The protected threose 12 was then
2
2
subjected to a Wittig reaction employing the pinacol-acetaldehyde
phosphonium salt 13, known as DualPhos, which allowed for
stereoselective olefination (E/Z, >5:1) to the latent alkenal 10. With
the latent enal installed, removal of the silyl-protecting group was
carried out with TBAF, the resulting alcohol converted to the iodide
2
0. The protective PMB-ether was then removed oxidatively using
DDQ, providing the seco-acid derivative 8. This compound was
[
6]
subjected to a standard Mitsunobu reaction employing DIAD, to
afford the fully protected macrolactone 21. Removal of the silyl-
group protecting the C3 alcohol was achieved using TBAF to give
22. Methylation of the C3 hydroxyl group proceeded smoothly using
[
11]
via an Appel reaction
and, with suitable conditions, to nitrile
[
12]
derivative 14. Reaction with allylzinc bromide and mild aqueous
acidic hydrolysis provided the ketone 15 which was stable enough
for full characterization but which slowly isomerized to the α,β-
unsaturated ketone if stored at room temperature over several days.
Chelation-assisted reduction of the ketone 15 was achieved using
lithium aluminium hydride in the presence of excess lithium iodide
[
16]
a modified Kuhn methylation to give methyl ether 23, which was
then subjected to acidic hydrolysis of the acetonide using TFA in
wet-acetonitrile to yield macrolactone 2, the putative structure
[
1]
1
assigned to natural Phomolide H. Unfortunately, the H- and, in
1
3
particular, C-NMR spectrum of synthetic 2 strikingly mismatched
[
1]
[
13]
that reported for the natural product. In particular, significant
chemical shift differences were observed for C3 of the synthetic
derivaive 2 in comparison to the natural prduct (See Table 1 and
vide infra).
at low temperature in diethyl ether,
furnishing the 1,3-syn-
diastereomer of the homoallylic alcohol 16 in excellent yield and
with good stereoselectivity (dr ≥9:1). Chemoselective
hydrogenation
tris(triphenylphosphino)ruthenium(II) dichloride (5 mol%)
followed by protection of the C9 alcohol as its p-methoxybenzyl
PMB) ether. The bis-allylic acetal/alcohol 10 displayed exceptional
of
the
terminal
alkene
using
was
[
14]
At this point we suspected a misinterpretation of the ROESY
spectra regarding the configuration of C3 for the natural product,
[
1]
which was reported as S. This led us to next undertake the
synthesis of the C3-epimer of compound 2, a process that could be
readily achieved utilising the antipode auxiliary of 17. The Nagao
acetate aldol reaction of 9 employing (S)-thiazolidinethione 17 now
provided the C3 epimer of 18 as essentially a single diastereomer
(
stability throughout this series of transformations allowing for
synthesis of the alkyl (omega) portion of the polyketide, including
stereoselective installation of the C9 alcohol. Chemoselective
removal of the pinacolacetal group to liberate the sensitive α,β–
(
dr >20:1). The synthetic route proceeded as described above with
2
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601172
NMR, which corresponds to the protons attached to C3 and C9,
located immediately beside one another at ~δ 4.7 ppm. Examination
of the synthetic compounds 2 and 26 revealed that neither
diastereomer exhibited this pattern; in fact, both showed increased
shielding of the C3 proton in comparison to the natural product.
CH3
H3C
H3C
O
O
OH
CH3
PMBO
a-f
O
OH
HO
OCH3
g,h
O
1
3
O
O
Considering similarities, the conformity of the C-NMR data for
O
O
compound 27 in comparison to natural phomolide H, see Table 1,
was startling! The H-NMR data (See supporting information) for
9
25
CHO
26
1
synthetic 27 also proved identical to that of phomolide H, with the
obvious deletion of the signals corresponding the methoxy
substituent at C3. These data immediately drew our attention to the
data reported for the methoxy group in the natural product. These
signals ( C=48.8 ppm and H=3.31 ppm) in fact correspond to the
solvent methanol in deuterated acetone. Natural phomolide H was
Scheme 4. Reagents and conditions: Yields are of isolated products. Reagents
and conditions: Yields are of isolated products. a) (S)-17, TiCl , DIPEA, CH Cl
8 °C, 86% (>20:1 d.r.). b) TBSOTf, 2,6-lutidine, CH Cl , 23 °C, 89%. c)
LiOH∙H O, H , THF/H O (4:1, v/v), 23 °C, 89%. d) DDQ, CH Cl , 23 °C, 81%.
e) PPh , DIAD, PhMe, 0 °C to 23 °C, 59%. f) TBAF, THF, 0 °C, 87%. g) MeI,
Ag O, DMS, 23 °C, 86% h) TFA, MeCN/H O (4:1, v/v), 23 °C, 85%.
4
2
2
-
1
3
1
7
2
2
2
O
2 2
2
2
2
3
isolated over Sephadex LH-20 eluting with methanol followed by
2
2
[1]
column chromatography.
This data and process raised the
possibility that phomolide H may in fact be compound 27 and
methanol contamination. Evidence for this was obtained by spiking
the NMR tube containing 27, in deuterated acetone, with one
similar yields to reach the cyclized alcohol 25 (Scheme 4).
Methylation of the allylic alcohol (MeI, Ag O) and subsequent
2
equivalent of CH OH. The full set of NMR data for 27+MeOH now
3
hydrolysis of the acetonide under acidic conditions (TFA, wet
proved an identical match to that reported for phomolide H. The
signals which were assigned to correspond with the methyl ether in
CH CN) afforded methyl ether 26 (Scheme 4). Unfortunately, once
3
again the spectroscopic data proved to be discordant to the data
reported for the natural product (Table 1).
[1]
the natural product showed no HMBC or NOE correlations
connecting the methoxy signal to the polyketide backbone. Further,
the HR-Q-TOF-MS data reported form the methyl ether 2 (M+Na =
In order to reconcile the similarities and differences seen in the
[
1]
NMR data comparing natural phomolide-H
with the two
2
81.1532) does not match that of the calculated formulae
1
3
diastereomeric methyl ethers 2 and 26, we tabulated the C-data
alongside that of the two C3-diastereomeric alcohols 27 and 1
[1]
(281.1365).
In fact, no definitive data is presented for the
assignment of the methyl ether constitution or connectivity as
(
Table 1). These alcohols were prepared by acetonide hydrolysis on
depicted in 2, it appears that a methanol peak was erroneously
intermediates 23 and 25 respectively, we note also that compound 1
[1]
assigned as a C3-methyl ether.
[
5c]
13
is synthetic phomolide G.
Careful examination of all of the C-
The overall structure and stereochemistry, including absolute
stereochemistry, of synthetic 27 is fully supported by X-ray
crystallographic analysis (see also supporting information) on the
C3 4-bromobenzoate derivative 24 (Scheme 5), thus securing this
structure in relation to natural phomolide H. We also note that
NMR data, including Δδ ppm differences in comparison with the
natural product, revealed key differences (Table 1, see also Figures
1
3
S1-3, supporting information). The C-NMR signals associated
with the C3 carbon of the diastereomeric methyl ethers 2 and 26
were both significantly deshielded (>9.0 ppm) as compared with the
optical rotation data for 27 [α] –20.4° (MeOH, c 0.19), was similar
1
3
D
natural product. Further, the C-NMR signals associated with the
methyl ether C13 in 2 and 26 were themselves at an identical shift in
each diastereomer but located 7.0 ppm higher than the methyl ether
assigned to the natural material.
to that reported for the natural product, –17.5 (MeOH, c = 0.76).
[5a,b]
Two previous reports
exist in the literature claiming the total
synthesis of phomolide H as structure 2. The paper by Meshram and
colleagues concludes that their synthetic data “exhibited identical
1
The natural material exhibits a characteristic set of signals in the H-
Phomolide-H
Position
[1]
Structure 2
Δδ (ppm)
Structure 26 (ppm)
Δδ (ppm) Structure 27 (ppm) Δδ (ppm) Structure 1 (ppm) Δδ (ppm)
δ (ppm)
170.0
43.6
1
2
3
4
5
6
7
8
9
168.6
40.4
75.8
132.3
127.5
78.6
75.9
40.9
72
38.9
18
13.3
55.8
-1.4
-3.2
9.2
-3.1
1.2
-0.2
0.0
-0.2
-0.2
0.0
169.7
42.4
80.2
134.4
131.1
78.0
75.8
41.1
72.7
38.9
18.1
13.2
55.8
-0.3
-1.2
13.6
-1.0
4.8
169.4
43.6
66.7
135.4
126.3
78.8
76.0
41.1
72.2
39.0
18.1
13.3
NA
-0.6
0.0
0.1
0.0
0.0
0.0
0.1
0.0
0.0
0.1
0.1
0.0
NA
169.8
45.2
71.6
136.4
128.1
78.1
76
-0.2
1.6
5.0
1.0
1.8
-0.7
0.1
0.0
0.3
0.1
0.1
-0.1
NA
66.6
135.4
126.3
78.8
75.9
41.1
72.2
38.9
18.0
13.3
-0.8
-0.1
0.0
0.5
0.0
41.1
72.5
39
1
1
1
1
0
1
2
3
0.0
0.0
7.0
0.1
-0.1
7.0
18.1
13.2
NA
48.8
1
3
[1]
Table 1. Comparison of the C-NMR (CD COCD ) data for Natural phomolide H and compounds 2, 26, 27 and 1
3
3
3
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601172
Kumar, Y. Poornachandra, B. Das, Synthesis 2015, 47, 653-658. (c) S.
Lu, T. Kurtan, G. Yang, P. Sun, A. Mandi, K. Krohn, S. Draeger, B.
Schulz, Y. Yi, L. Li, W. Zhang, Eur. J. Org. Chem. 2011, 5452-5459.
(d) A. Cimmino, M. Masi, M. Evidente, S. Superchi, A. Evidente, Nat.
Prod. Rep. 2015, 32, 1629-1653. (e) J. F. Rivero-Cruz, G. Garcia-
Aguirre, C. M. Cerda-Garcia-Rojas, R. Mata, Tetrahedron, 2000, 56,
5
337-5344. (g) J. F. Rivero-Cruz, M. Macias, C. M. Cerda-Garcia—
Rojas, R. Mata, J. Nat. Prod. 2003, 66, 511-514. (f) S. Grabley, E.
Granzer, K. Hutter, D. Ludwig, M. Mayer, R. Thiercke, G. Till, J.
Wink, S. Philipps, A. Zeek, J. Antibiotics 1992, 45, 56-65. (h) K.
Wada, T. Ishida, Chem. Commun. 1976, 340-341.
[
4] (a) S. Lu, T. Kurtan, G. Yang, P. Sun, A. Mandi, K. Krohn, S. Draeger,
B. Schulz, Y. Yi, L. Li, W. Zhang, Eur. J. Org. Chem. 2011, 5452-
5
459. (b) A. Cimmino, A. Andolfi, S. Findevilla, M. A. Abouzeid, D.
Rubiales, A. Evidente, J. Agric. Food Chem. 2012, 60, 5273-5278. (c)
A Evidente, R. Lanzeta, R. Capasso, M. Vurro, A. Bottalico,
Phytochem. 1993, 34, 999-1003.
24
≡
[
5] For a selection of previous total syntheses and approaches to
nonenolides see:. Phomolide G and H: (a) P. Ramesh, B. C. Reddy, H.
M. Meshram, Tetrahedron Lett. 2012, 53, 3735-3738. (b) B. V.
Subba Reddy, P. Sivaramakrishna Reddy, B. Phaneendra Reddy, J. S.
Yadav, Synlett, 2014, 25, 501-504. (c) J. McNulty, D. Mcleod, H. A.
Jenkins, Eur. J. Org. Chem. 2016, 688-692. Seimatopolide A: (d) B.
Schmidt, O. Kunz, M. H. Petersen, J. Org. Chem. 2012, 77, 10897-
Scheme 5. Synthesis of the C3-(4‘-bromobenzoyl)-ester of compound 23 and
the X-ray structural determination (CCDC 1439915) of the benzoate 24,
confirming the structure and absolute stereochemistry as shown.
1
0906. (e) K. R. Prasad, O. Revu, J. Org. Chem. 2014, 79, 1461-1466.
(
f) C. Raji Reddy, N. Narichmha Rao, M. Damoder Reddy, Eur. J.
spectral data to that of the natural product”, although no
Org. Chem. 2012, 4910-4913. Decarestrictine D: (g) M. B. Andrus,
T.-L. Shih J. Org. Chem. 1996, 61, 8780-8785. (h) R. A. Pilli, M. M.
Victor Tetrahedron Lett. 1998, 39, 4421-4424. (i) S. Colle, C.
Taillefumier, Y. Chapleur, R. Liebl, A. Schmidt Bioorg. Med. Chem.
[
5a]
supplementary data is presented.
The paper by Reddy and co-
workers concludes similarly that their synthetic data was “identical
[
5b]
in all respects with the data reported in the literature”.
groups have also claimed total syntheses of phomolide G,
despite the subsequent structural revision that was required for this
Both
1
999, 7, 1049-1057. (j) M. Binanzer, G. Y. Fang, V. K. Aggarwal
[
5a,b]
Angew. Chem. Int. Ed. 2010, 49, 4264-4268. Nonenolide: (k) D. K.
Mohapatra, D. K. Ramesh, M. A. Giardello, M. S. Chorghade, M. K.
Gurjar, R. H. Grubbs, Tertahedron Lett. 2007, 48, 2621-2625.
Cytospolide E: (l) P. M. Vadhadiya, J. K. Rout, C. V. Ramana,
Tetrahedron 2015, 71, 9088-9094. Pinolide: see 2b. Pinolidoxin: (m)
D. Liu, S. A. Kozmin, Org. Lett. 2002, 4, 3005-3007. Harbarumin I
and II: (n) A. Furstner, K. Radkowski, C. Wirtz, R. Goddard, C. W.
Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061-7069.
[
5c]
natural product. We look forward to further information on the
synthesis and full discussion on the structure of these compounds by
these authors.
In conclusion, we report a total synthesis of compound 2, the
structure originally assigned to the natural product phomolide H, the
spectroscopic data of which do not match. Noting the differences
seen at C3 of the natural product and 2, the C3-epimeric methyl
ether 26 was prepared, the data of which also proved a mis-match
with the natural product. The two corresponding C3 epimeric
alcohols 27 and 1 were also prepared and analysis of all data
permitted a match between the natural product and the methanol
solvate of the diastereomer 27. On the basis of the structural mis-
match and the experimental information reported herein, a structural
[
[
6] (a) O. Mitsunobu, Synthesis, 1981, 1, 1-28. (b) D. L. Hughes, Org.
React. 1992, 42, 335-656. (c) S. Fletcher, Org. Chem. Front. 2015, 2,
7
39-752. (d) A. B. Smith III, I. G. Safonov, R. M. Corbett, J. Am.
Chem. Soc. 2002, 124, 11102 (e) J. McNulty, A. Capretta, V.
Laritchev, J. Dyck, A. J. Robertson, Angew. Chem. Int. Ed. 2003, 42,
4
051-4054. (f) X. Liao, Y. Wu, J. K. De Brabander, Angew. Chem.
Int. Ed. 2003, 42, 1648-1652.
7] (a) Y. Nagao, Y. Hagiwara, T. Kumagai, M. Ochirai, J. Org. Chem.
1
986, 51, 2391-2393; (b) González, A.; Aiguadé, J.; Urpí, F.;
Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949; (c) X. Ariza, J. Garcia,
P. Romea, F. Urpf, Synthesis, 2011, 14, 2175-2191; (d) G. L. Khatik,
V. Kumar, V. A. Nair, Org. Lett. 2012, 14, 2442-2445.
[
1]
revision of phomolide H from the (3S)-methyl ether 2 to the (3S)-
alcohol isomer 27 is warranted.
[
[
8] J. McNulty, C. Zepeda-velazquez, D. McLeod, Green Chem. 2013,
1
5, 3146-3149.
9] K. Omura, D. Swern Tetrahedron, 1978, 34, 1651-1660
Received: ((will be filled in by the editorial staff))
[10] A. Kamimura, K. Miyazaki, S. Suzuki, S. Ishikawa, H. Uno, Org.
Biomol. Chem. 2012, 10, 4362-4366.
Published online on ((will be filled in by the editorial staff))
[
[
[
11] R. Appel, Angew. Chem. Int. Ed. 1975, 14, 801-811
12] G. Rousseau, J. M. Conia, Tetrahedron Lett. 1981, 22, 649-652.
13] Y. Mori, M. Kuhara, A. Takeuchi, M. Suzuki, Tetrahedron Lett. 1988,
29, 5419-5422.
Keywords: polyketides • asymmetric synthesis • nonenolides • total
synthesis • macrolactones
[
[
14] P. S. Hallman, B. R. McGarvey, G. Wilkinson, J. Chem. Soc. A 1968,
3
143-3150.
15] (a) E. Galvalez, P. Romea, F. Urpi, Org. Synth. 2009, 86, 70. (b) Y.
Nagao, W.-M. Dai, M. Ochiai, M. Shiro, J. Org. Chem. 1989, 54,
5211-5217.
[1] Y.-Y. Li, M.-Z. Wang, Y.-J. Huang, Y.-M. Shen, Mycology, 2010, 1,
2
54-261.
[16] (a) R. Kuhn, H. Baer, A. Seeliger, Ann. 1958, 236. (b) R. Kuhn, H.
Trischmann, I. Löw, Angew. Chem. 1955, 67, 32.
[
2] This class of macrolactone are interchangeably referred to as
nonenolids or decanolides. For general reviews see: (a) G. Drager, A.
Kirschning, R. Thiericke, M. Zerlin, Nat. Prod. Rep. 1996, 365- 375.
(b) V. B. Riatto, R. A. Pilli, M. M. Victor, Tetrahedron 2008, 64,
2
279-2300.
[
3]
(a) V. Rukachaisirikul, S. Pramjit, C. Pakawatchi, M. Isaka, S.
Supothina, J. Nat. Prod. 2004, 67, 1953-1955. (b) P. Jangili, C. G.
4
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601172
H3C CH3
H3C CH3
CH3
Natural Product Synthesis
Br
O
O
O
OH
OH
+
Pr3P
O CH3
HO
OCH3
TBSO
CHO
HO
OCH3
J. McNulty,* D. McLeod__________
13
O
12
O
Page – Page
O
O
H3C
O
CH3
2
6
PMBO
Phomolide H 2
Originally assigned
structure
Enantioselective total synthesis of the
reported structure of the nonenolide
Phomolide H and structural revision to
the methanol-solvate of 27 are
demonstrated.
O
OH
9
OH
CHO
HO
OH
HO
OH
O
O
O
O
Phomolide G 1
Phomolide H 27
Revised structure
A total synthesis of the proposed structure of the natural polyketide macrolactone
phomolide H 2 has been achieved following a bidirectional strategy from L-tartaric
acid. The originally assigned structure of phomolide H displayed discordant NMR
data in comparison with synthetic 2. The synthetic strategy developed was
extended to prepare diastereomers and epimeric methyl-ethers of the natural
product, structural analysis of which allowed for a match of the natural product with
diastereomer 27. The structural revision of phomolide H from 2 to the methanol
solvate of compound 27 is presented.
5
This article is protected by copyright. All rights reserved