Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki-Hiyama-Kishi Macrocyclization Reaction

Article abstract of DOI:10.1021/jo5024602

The natural products cochliomycin A (1) and cochliomycin B (2), two resorcylic acid lactones obtained from marine sources, have been prepared in a concise and stereocontrolled manner from the readily accessible building blocks 4-6. Olefin cross-metathesis

Full text of DOI:10.1021/jo5024602

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Article
Modular Total Syntheses of the Marine-Derived Resorcylic
Acid Lactones Cochliomycins A and B Using a Late-
Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction
Benoit Bolte, Jose A. Basutto, Christopher S. Bryan, Mary
J. Garson, Martin Gerhardt Banwell, and Jas S. Ward
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5024602 • Publication Date (Web): 18 Nov 2014
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Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B
Using a Late-Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction
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Benoit Bolte,† Jose A. Basutto,† Christopher S. Bryan,† Mary J. Garson,‡
Martin G. Banwell,*,† and Jas S. Ward†
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†Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra ACT 2601, Australia
‡School of Chemistry and Molecular Biosciences,
University of Queensland, Brisbane QLD 4072, Australia
Martin.Banwell@anu.edu.au
Abstract
nucleophilic ring-opening of
4H-benzo[d][1,3]dioxin-4-one
OH
O
OH
O
NHK
macrocyclization
O
O
O
8'
7'
MeO
MeO
OH
OH
O
olefin
cross-metathesis
O
O
Cochliomycin B
Cochliomycin A
The natural products cochliomycin A (1) and cochliomycin B (2), two resorcylic acid lactones obtained
from marine sources, have been prepared in a concise and stereo-controlled manner from the readily
accessible building blocks 4–6. Olefin cross metathesis, trans-esterification and Nozaki–Hiyama–Kishi
(NHK) macrocyclization reactions were employed in the key steps. Hydrolysis of the immediate
precursor to cochliomycin B affords the resorcylic acid lactone zeaenol (24).
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Introduction
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The 14-membered and benzannulated macrolides known as the resorcylic acid lactones (RALs) are
mycotoxins that have been isolated from a range of fungi.1 The first members of what is now a rather
large family of natural products were described more than fifty years ago2 and new ones continue to be
reported on a regular basis.1,3 The extraordinary range of biological properties displayed by the RALs,
which include (amongst other things) antimalarial, antiviral, antifungal, nematocidal and antiparasitic
activities, has attracted significant attention1 although probably not as much as the capacities of some of
them to act as potent and highly selective inhibitors of kinases1 and the chaperone heat shock protein 90
(Hsp90).1,4 As such, certain RALs have come to be regarded as important leads for the development of
new oncolytic agents. Certainly, an impressive range of derivatization and analoguing programs4,5 has
been launched on this basis and such efforts have even led to a number of clinical trials.4
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The biogenesis of the polyketide-derived RALs has become an increasing focus of attention6 not
least because of the potential to modify (reprogram) the pathways involved and so generate, hopefully in
significant quantity, structurally diverse/novel variants that might display enhanced properties. While the
biomimetic construction of certain RALs has also been reported,7 the vast majority of the successful
efforts directed towards the total synthesis of such systems have involved annulation of the requisite
macrolide onto a resorcylic acid derivative.1 Many of these syntheses have been summarized in recent
reviews1 but new ones continue to be reported.8 A good fraction, if not most of these, employ ring closing
metathesis or macrolactonization protocols for assembling the requisite 14-membered heterocycle.9
In 2012, Wang and co-workers reported on the isolation of cochliomycins A, B and C (1–3,
respectively) from the marine fungus Cochliobolus lunatus (M351) associated with the gorgonian
Dichotella gemmacea found in the South China Sea.1e,10 These RALs are unusual for several reasons.
First of all, they contain acetonide residues that cannot be artifacts arising from the isolation process
because acetone was not employed for this purpose.11 Secondly, they have been isolated from marine
rather than terrestrial sources and, thirdly, when evaluated as an antifouling agent (against larval
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settlement of the barnacle Balanus Amphitrite) cochliomycin A (1) proved to be a very active compound
indeed (EC50 of 1.2 µg/mL).12 Compound 1, the only one of the trio obtained in sufficient amount for
extended biological evaluation, was essentially inactive when tested against the A549 and HepG2 tumor
cell lines but exhibited moderate antibacterial activity against Stapylococcus aureus. Interestingly,
cochliomycin B (2) was observed10 to rearrange to congener 1 on standing in CDCl3 and thus hinting a
possible challenge associated with the synthesis of the former natural product. Very recently the Wang
group reported3b on the isolation of three further, non-acetonide-containing cochliomycins (D, E and F)
from a related fungus [C. lunatus (TA26-46)] found associated with a sea anemone Palythoa haddoni that
was also found in the South China Sea. Two of these compounds also displayed potent anti-fouling
properties although neither was as active as congener 1.
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OH
O
OH
O
O
O
O
MeO
MeO
OH
OH
O
O
O
2
1
OH
O
O
MeO
OH
Cl
OH
OH
3
The rather intriguing structures, chemical behaviors and biological properties of the cochliomycins,
when considered together with our earlier studies on the synthesis of the RALs L-783,290 (a MEK
inhibitor)13 and L-783,277,9c prompted us to pursue the total synthesis of natural product 2, the thus far
untested member of the cochliomycin family and an established precursor to congener 1. Herein we
report on the realization of this objective using a highly modular approach and which exploited a late-
stage and highly stereoselective Nozaki–Hiyama–Kishi (NHK) reaction to effect the necessary
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macrocyclization process.9d,14 We also report on the conversion of a derivative of cochliomycin B (2) into
isomer 1 as well as the generation of the corresponding triol, itself a natural product.
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During the course of the work detailed below, Du and co-workers reported syntheses of both
cochliomycins A8c and B8d using macrocyclization and RCM protocols, respectively, for the pivotal
lactone ring-forming step. Nanda and co-workers have also recently detailed total syntheses of
cochliomycin A15 and 5'-epi-cochliomycin C8a using a late-stage RCM protocol in each instance. The
Nanda and Du groups demonstrated, independently, that treatment of compounds 1 and 2, respectively,
with mineral acid in protic solvent or co-solvent results in cleavage of the associated acetonide residues
and thus delivering the corresponding triol, a previously reported RAL known as zeaenol and the
structure of which had been established by single-crystal X-ray analysis.16 By such means the structures
assigned to cochliomycins A and B were substantiated.
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Results and Discussion
Identifying the Required Building Blocks. An inspection of the structure of cochliomycin B (2)
(Figure 1) reveals that disconnections of the macrolide residue could be carried out at the styrenyl double
bond, at the lactone linkage and between the sp3-hybridized carbon bearing the free hydroxyl group and
the adjacent sp2-hybridized carbon of the non-conjugated double bond. In the forward (synthetic)
direction the styrene-type double bond could be established through an olefin cross metathesis (OCM)
reaction of potential building blocks 4 and 5 while treatment of the product of that process with the
conjugate base derived from alcohol 6 would be expected to effect, via a trans-esterification reaction,
ring-cleavage of the associated [1,3]dioxin-4-one moiety and thereby simultaneously establishing the
required ester/lactone linkage and revealing the free phenolic residue associated with the target 2. This
type of process has been successfully applied in a number of settings.5c,8b–d,17 It was thought the third bond,
the formation of which would establish the target macrocycle, could be installed through an
intramolecular NHK reaction in which the participating functionalities would be the E-configured iodo-
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alkene moiety arising from building block 6 and an carbonyl residue obtained by deprotection of the silyl-
protected primary alcohol within the product of the above-mentioned trans-esterification reaction and
oxidation of this to the aldehyde. While NHK reactions have been employed previously in
macrocyclization processes9d,14 including, on one occasion, in the formation of a RAL,9d we are unaware
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' '
of its use in the synthesis of such systems that incorporate a trans-configured Δ7 ,8 -double bond.
nucleophilic ring-opening of
4H-benzo[d][1,3]dioxin-4-one
OH
O
NHK
macrocyclization
O
O
8'
7'
MeO
OH
olefin
cross-metathesis
O
2
O
O
O
HO
OTBS
O
O
MeO
I
4
5
6
Figure 1. Key disconnections associated with cochliomycin B and identification of building blocks 4, 5
and 6.
Synthesis of the 4H-Benzo[d][1,3]dioxin-4-one 4. Building block 4 has been reported
previously.17,18 Thus, following the protocol detailed by Srihari,18b commercially available 2,4,6-
trihydroxybenzoic acid (7, Scheme 1) was converted into the lactone 8 (76% based on recovered starting
material) by treating a solution of the former compound with a mixture of trifluoroacetic acid (TFA) and
the corresponding anhydride (TFAA). Subjection of compound 8 (as the nucleophile) to a Mitsunobu
reaction with methanol and using a combination of Ph3P and diethyl azodicarboxylate (DEAD) resulted in
the completely regioselective O-methylation of the non-hydrogen-bonded phenolic residue within the
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substrate and so generating ether 9 in 81% yield. Conversion of compound 9 into the corresponding
triflate 10 (96%) was readily achieved under standard conditions and this was then engaged in a Stille
cross-coupling reaction with tri-n-butylvinylstannane in the presence of (Ph3P)4Pd, triethylamine and
lithium chloride to afford the target styrene 4 in 82% yield. The spectral data obtained on compound 4
were in complete accord with those reported earlier.18b
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Scheme 1. Synthesis of Building Block 4
O
O
OH OH
acetone
TFAA, TFA
O
O
ca. 22 °C, 20 h
76% (brsm)
HO
OH
HO
OH
7
8
MeOH, Ph3P
DEAD, THF
0 °C, 4 h
81%
O
O
O
O
O
Tf2O, pyridine
O
MeO
OTf
0 °C, 2h
96%
MeO
OH
10
9
O
O
O
H2C=CHSnBu3, Et3N
(Ph3P)4Pd, LiCl, 1,4-dioxane
105 °C, 6 h
82%
MeO
4
Synthesis of Acetonide 5. While building block 5 has been obtained in seven steps from
commercially available isopropylidene-D-erythrono-1,4-lactone,19 a more concise (three-step) synthesis
from D-2-deoxyribose (11) is shown in Scheme 2. Thus, the readily derived acetonide, 12, of compound
11 was subjected, using a protocol defined by Geng and Danishefsky,5a to a Wittig olefination reaction
with in situ generated triphenylphosphonium methylide and thereby affording the previously reported5a
unsaturated alcohol 13 (72% from 11).
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Scheme 2. Synthesis of Building Block 5
6
7
8
9
OH
OH
2,2-DMP, p-TsOH
DMF
O
O
ca. 22 °C, 24 h
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O
HO
O
OH
11
12
H2C=PPh3, THF
0 °C, 12 h
72% (over two steps)
TBSCl, imidazole
CH2Cl2
OH
OTBS
O
O
ca. 22 °C, 2 h
87%
O
O
5
13
Application of a conventional O-silylation procedure using tert-butyldimethylsilyl (TBS) chloride
to the last compound then afforded ether 5 that was obtained in 87% yield. All the spectral data acquired
on compound 5 were in complete accord with the assigned structure and matched those reported
previously.19
Synthesis of Iodoalkene 6. The reaction sequence employed in the synthesis of the final
building block, namely compound 6, is shown in Scheme 3 and started with commercially available
(S)-(+)-4-penten-2-ol (14) that was first converted into the previously reported6a TBS-ether 15 (95%)
under standard conditions. Engagement of compound 15 in an OCM reaction with the commercially
available pinacol ester of vinylboronic acid using the Hoveyda–Grubbs second generation (HGII)
catalyst20 then afforded the expected boronate ester 1621 with the illustrated E-geometry about the
associated double bond being assigned on the basis of the observation of a 17.5 Hz coupling between the
vicinally-related olefinic protons. Treatment of compound 16 with molecular iodine in the presence of
sodium hydroxide, under conditions defined by Grubbs and Morrill,22 resulted in an ipso-deborylation
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reaction that proceeded with retention of configuration of the alkene geometry and so affording the
iodoalkene 17 (70% from 15). Product 17 has been obtained previously by Sellès and Lett23 over four
steps from trimethylsilylacetylene and by using a hydrozirconation/iododezirconation protocol in the key
step.
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Scheme 3. Synthesis of Building Block 6
TBSCl, imidazole
CH2Cl2
HO
TBSO
ca. 22 °C, 2 h
95%
14
15
H2C=CHBPin
HGII catalyst
CH2Cl2
40 °C, 20 h
83%
I2, NaOH
water, THF
TBSO
TBSO
ca. 22 °C, 0.5 h
17
I
16
BPin
TBAF, THF
HO
20 °C, 1 h
70% (over two steps)
I
6
Treatment of compound 17 with tetra-n-butylammonium fluoride (TBAF) then afforded the target
building block 624 (99%) as a clear, colorless oil. The derived spectral data were in complete accord with
the assigned structure and, most notably, the vicinal coupling between the olefinic protons was 15.0 Hz,
as would be expected for an E-configured alkene.
Coupling of Building Blocks 4–6 and the Ring-Closing NHK Reaction Leading to
Cochliomycin B. With the requisite building blocks, viz. compounds 4–6, to hand, the assembly of
them so as to establish a synthesis of cochliomycin B was the remaining task. In the event, and as
foreshadowed in the original analysis (see above) of the target structure, terminal olefins 4 and 5 were
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subjected to an OCM reaction (Scheme 4) using the HGII catalyst20 and by such means the E-configured
styrene 18 was obtained in 86% yield. Accordingly, the stage was now set for the pivotal lactone ring-
opening/trans-esterification reaction. To such ends, NaH was added to a magnetically stirred solution of
alcohol 6 and lactone 18 in THF maintained at ca. 22 °C and thereby generating the ester 19 (83%) that
incorporates a free phenolic group. Even if it was pleasing to have obtained this last compound, all
attempts to oxidize the alcohol resulting from cleavage of the associated TBS ether only led to complex
mixtures of products, probably because of concomitant or competing oxidation of the phenolic moiety.
Accordingly, compound 19 was protected as the corresponding SEM ether 20 (96%) under conventional
conditions and this was then treated with TBAF in THF at 0 °C so as to selectively remove the TBS ether
residue and thus providing the 1°-alcohol 21 in readiness for oxidation to the corresponding aldehyde.
While, because of the propensity for acetonide group migration, compound 21 proved to be a sensitive
one, when it was subjected to oxidation with the Dess–Martin periodinane (DMP) in dichloromethane
that had been buffered with a combination of anhydrous sodium bicarbonate and pyridine then the desired
aldehyde 22 could be obtained in 87% yield. Upon subjection of the last compound to reaction with a
combination of 10 molar equivalents of CrCl2 and catalytic amounts (5 mole %) of NiCl2 in DMF under
high-dilution conditions at ca. 22 °C for 30 h9d then the desired NHK macrocyclization reaction took
place and thus providing SEM-protected cochliomycin B (23) in 77% yield. No evidence could be
obtained for the co-production of the epimeric 2°-alcohol in this remarkably selective macrocyclization
reaction. In the final step of the synthesis, compound 23 was treated with TBAF in THF at 60 °C and thus
effecting cleavage of the SEM ether and so producing cochliomycin B (2) in 73% yield.
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Scheme 4. Assembly of Building Blocks 4–6 and Completion of the Synthesis of Cochliomycin B (2)
3
4
5
6
7
8
OR
O
O
O
O
O
HGII catalyst
CH2Cl2
compound 6
NaH, THF
I
O
O
O
O
O
+
OTBS
O
ca. 22 °C, 3 h
83%
40 °C, 20 h
86%
MeO
O
MeO
MeO
9
OTBS
OTBS
4
5
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O
O
SEMCl, TBAI
Hünig's base, CH2Cl2
ca. 22 °C, 6 h
96%
19 R = H
20 R = SEM
18
TBAF, THF
0 °C, 2 h
97%
DMP, NaHCO3
pyridine
CH2Cl2
OR
O
SEMO
O
SEMO
O
CrCl2, NiCl2
DMF
I
I
O
O
O
O
O
ca. 22 °C, 30 h
77%
ca. 22 °C, 0.25 h
87%
MeO
MeO
MeO
OH
OH
O
O
O
O
O
TBAF, THF
66 °C, 12 h
73%
22
21
23 R = SEM
2 R = H
The spectral data acquired on compound 2 were in complete accord with the assigned structure.
Furthermore, a comparison of the so-derived H and C NMR spectral data with those reported10 for the
natural product (Table 1) revealed a particularly good match. However, the specific rotation of the
synthetically-derived material was of the opposite sign (and of different magnitude) to that reported for
cochliomycin B {[α]D –17.7 (c 0.05, CH3OH) for synthetic material vs [α]D +7.3 (c 0.05, CH3OH) for the
natural product}. This discrepancy is attributed to contamination of the natural product by quantities of
the strongly dextrorotatory isomer cochliomycin A (1). Interestingly, despite suggestions10 that natural
product 2 slowly isomerizes to congener 1 on standing in CDCl3, we have not observed such a process in
this solvent, at least when it had been passed through basic alumina before use.
1
13
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TABLE 1. Comparison of the C and H NMR Data Recorded for Synthetically-Derived
1
Compound 2 with Those Reported for Cochliomycin B
6
7
8
13C NMR (δC)
1H NMR (δH)
9
cochliomycin Ba
170.6
164.8
164.1
142.6
134.5
132.9
130.5
126.3
107.9
107.7
104.6
100.1
79.5
compound 2b
170.5
164.7
164.0
142.5
134.4
132.8
130.4
126.2
107.7
107.7
104.4
100.0
79.4
cochliomycin Bc
11.50, s, 1H
compound 2d
11.50, s, 1H
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7.00, dd, J = 15.6 and 2.4 Hz, 1H
6.40, d, J = 2.4 Hz, 1H
6.39, d, J = 2.4 Hz, 1H
6.07, ddd, J = 15.6, 9.0 and 4.8 Hz, 1H
5.56,e ddd, J = 15.6, 9.0 and 3.6 Hz, 1H
5.46, m, 1H
7.01, dd, J = 15.5 and 2.4 Hz, 1H
6.40, d, J = 2.6 Hz, 1H
6.39, d, J = 2.6 Hz, 1H
6.07, ddd, J = 15.5, 8.8 and 4.9 Hz, 1H
5.65, ddd, J = 15.6, 9.2 and 3.5 Hz, 1H
5.49–5.40, complex m, 2H
–
5.44, m, 1H
4.36, ddd, J = 12.0, 4.8 and 3.6 Hz, 1H
4.12, t, J = 9.0 Hz, 1H
3.85, dd, J = 9.0 and 4.8 Hz, 1H
3.81, s, 3H
4.36, ddd, J = 11.5, 4.8 and 3.0 Hz, 1H
4.12, dd, J = 9.7 and 8.3 Hz, 1H
3.84, dd, J = 9.7 and 4.6 Hz, 1H
3.82, s, 3H
2.76, m, 1H
2.76, dtd, J = 15.7, 3.1 and 2.9 Hz, 1H
2.59, ddd, J = 15.7, 11.0 and 9.3 Hz, 1H
2.50, ddd, J = 15.7, 9.3 and 3.8 Hz, 1H
2.43, dtd, J = 15.5, 5.2 and 2.2 Hz, 1H
1.54, s, 3H
77.4
77.3
2.59, m, 1H
70.6
70.5
2.50, m, 1H
69.7
69.6
2.44, m, 1H
55.5
55.4
1.52, s, 3H
38.3
38.2
1.44, d, J = 6.6 Hz, 3H
1.42, s, 3Hf
1.46, d, J = 6.4 Hz, 3H
31.4
31.3
1.42, s, 3H
28.5
28.4
–
3.03, broadened s, 1H (OH)
–
25.9
25.9
–
18.8
18.8
–
–
aObtained from ref 10 and recorded in CDCl3 at 150 MHz. Recorded in CDCl3 at 100 MHz. Obtained from ref 10 and
b
c
d
e
recorded in CDCl3 at 600 MHz. Recorded in CDCl3 at 400 MHz. We assume this is a transcription error and that the true
value is 5.65. fSignal due to OH group proton not observed.
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Conversion of the SEM-Derivative of Cochliomycin B into Cochliomycin A and the
RAL Zeaenol. In the course of manipulating the precursor 23 to cochliomycin B (2) it was observed that
on treating the former compound with HCl in methanol containing traces of water at room temperature
for 1 h the SEM-ether residue was cleaved and the acetonide moiety migrated (no specific order of events
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1
implied). As a result cochliomycin A (1) was formed in 91% yield (Scheme 5). A comparison of the H
and C NMR spectral data derived from this material with those reported10 for the natural product
13
revealed an excellent match (Table 2). The specific rotation of the synthetically-derived material was of
the same sign as reported for cochliomycin A {[α]D +34.4 (c 1.99, CH3OH) for synthetic material vs [α]D
+10.5 (c 0.43, CH3OH) for the natural product}. The discrepancy in the magnitudes of these values is
attributed to the evident impurities present in the naturally derived material and the small quantities of
this that were isolated from the producing organism.
Scheme 5. Conversion of Compound 23 into
Cochliomycin A (1) and Zeaenol (24)
HCl
CH3OH
SEMO
O
OH O
22 °C, 1 h
O
O
O
MeO
MeO
OH
OH
O
O
O
23
1
OH
O
HCl
CH3OH/water
O
22 °C, 16 h
MeO
OH
OH
OH
24
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TABLE 2. Comparison of the C and H NMR Data Recorded for Synthetically-Derived
1
Compound 1 with Those Reported for Cochliomycin A
4
5
6
13C NMR (δC)
1H NMR (δH)
cochliomycin Aa compound 1b
cochliomycin Ac
11.49, s, 1H
compound 1d
7
8
9
170.7
164.7
163.7
142.0
134.0
132.6
129.5
126.4
108.4
107.1
104.3
100.0
81.4
170.7
164.7
163.9
142.1
134.0
132.7
129.5
126.4
108.5
107.2
104.4
100.1
81.4
11.50, s, 1H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
37
38
39
40
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44
45
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53
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57
58
59
60
7.16, dd, J = 15.6 and 2.4 Hz, 1H
6.46, d, J = 2.4 Hz, 1H
6.39, d, J = 2.4 Hz, 1H
5.99, ddd, J = 15.6, 8.4 and 4.8 Hz, 1H
5.72, ddd, J = 15.0, 10.2 and 3.0 Hz, 1H
5.52, ddt, J = 15.0, 9.6 and 1.2 Hz, 1H
5.44, m, 1H
7.17, dd, J = 15.5 and 2.3 Hz, 1H
6.47, d, J = 2.6 Hz, 1H
6.39, d, J = 2.6 Hz, 1H
6.00, ddd, J = 15.3, 8.1 and 5.2 Hz, 1H
5.73, ddd, J = 15.3, 10.5 and 3.1 Hz, 1H
5.52, ddt, J = 15.4, 8.8 and 1.5 Hz, 1H
5.45, dtd, J = 11.8, 6.4 and 3.7 Hz, 1H
4.57, t, J = 8.3 Hz, 1H
4.21, ddd, J = 12.3, 4.9 and 2.3 Hz, 1H
3.90, dd, J = 7.9 and 2.3 Hz, 1H
3.82, s, 3H
4.56, t, J = 8.4 Hz, 1H
4.20, ddd, J = 12.0, 4.8 and 2.4 Hz, 1H
3.89, dd, J = 8.4 and 2.4 Hz, 1H
3.81, s, 3H
2.75, m, 1H
2.76, ddt, J = 14.9, 5.3 and 2.9 Hz, 1H
2.65–2.45, complex m, 2H
2.43, m, 1H
75.2
75.2
2.50, m, 1H
70.5
70.5
2.42, m, 1H
68.7
68.8
2.25, m, 1H
2.29, m, 1H
55.4
55.4
1.44, d, J = 6.6 Hz, 3H
1.43, s, 3H
1.45, d, J = 6.4 Hz, 3H
1.44, s, 3H
37.8
37.8
36.0
36.0
1.36, s, 3He
1.38, s, 3H
26.9
27.0
–
–
26.9
26.9
–
–
19.2
19.2
–
–
aObtained from ref 10 and recorded in CDCl3 at 150 MHz. Recorded in CDCl3 at 100 MHz. Obtained from ref 10 and
b
c
recorded in CDCl3 at 600 MHz. dRecorded in CDCl3 at 400 MHz. eSignal due to OH group proton not observed.
Exposure of compound 23 to HCl in 9:1 v/v methanol/water at room temperature for 16 h resulted
in cleavage of both the SEM and acetonide moieties and, thereby, the formation of the corresponding triol
24 (84%) that represents the structure of the RAL known as zeaenol16 and which has been isolated from
the plant pathogenic fungus Drechslera portulacae. The structure of the naturally derived zeaenol was
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established by single-crystal X-ray analysis16 as was the synthetic material produced by the pathway just
described. Details of this second analysis are presented in the Experimental Section and the SI. A
5
1
13
comparison of the H and C NMR spectral data derived from this material with those reported16 for the
natural product revealed an excellent match (Table 3). There was also good agreement between the
specific rotations of the synthetic and naturally derived materials {[α]D –93.8 (c 4.80, CH3OH) vs [α]D
−92 (c 0.52, CH3OH)}.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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TABLE 3. Comparison of the C and H NMR Data Recorded for Synthetically-Derived
1
Compound 24 with Those Reported for Zeaenol
13C NMR (δC)
zeaenola
1H NMR (δH)
compound 24b
171.2
165.3
164.0
142.8
133.7
131.5
129.2
128.5
107.6
103.9
100.1
77.2
zeaenolc
11.85, s, 1H
compound 24d
11.87, s, 1H
171.0
165.0
163.9
142.9
133.4
131.3
128.9
128.7
107.5
103.8
99.9
7.12, d, J = 15.5 Hz, 1H
6.44, d, J = 2.7 Hz, 1H
6.39, d, J = 2.7 Hz, 1H
5.98, dt, J = 15.5 and 6.1 Hz, 1H
5.82, ddd, J = 15.5, 10.1 and 4.0 Hz, 1H
5.71, dd, J = 15.5 and 7.4 Hz, 1H
5.32, m, 1H
7.10, d, J = 15.4 Hz, 1H
6.43, d, J = 2.6 Hz, 1H
6.38, d, J = 2.6 Hz, 1H
5.97, dt, J = 15.6 and 6.2 Hz, 1H
5.83, ddd, J = 14.7, 10.2 and 3.9 Hz, 1H
5.69, dd, J = 15.6 and 7.4 Hz, 1H
5.36–5.27, complex m, 1H
4.25, t, J = 7.9 Hz, 1H
3.95, t, J = 7.8 Hz, 1H
3.80, s, 3H
4.26, dd, J = 8.1 and 7.4 Hz, 1H
3.98, ddd, J = 8.1, 2.0 and 1.3 Hz, 1H
3.82, s, 3H
77.2
3.59, dd, J = 8.1 and 2.0 Hz, 1H
–
3.59, broadened d, J = 8.4 Hz, 1H
3.24, broad s, 1H
72.3
73.2
72.3
72.0
2.53, m, 2H
–
71.4
71.5
2.51, m, 1H
2.72–2.34, complex m, 6H
–
55.3
55.4
2.43, m, 1H
37.5
37.8
1.41, d, J = 6.1 Hz, 3He
–
1.45, d, J = 6.2 Hz, 3H
–
35.9
36.0
19.3
19.7
–
–
b
c
aObtained from ref 16 and recorded in CDCl3/CD3OD at 125 MHz. Recorded in CDCl3 at 100 MHz. Obtained from ref 16
and recorded in CDCl3 at 500 MHz. dRecorded in CDCl3 at 400 MHz. eSignal due to OH group proton not observed/reported.
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Conclusion
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The modular nature of the cochliomycin B (2) synthesis reported here has provided this natural
product in just eleven steps (longest linear sequence) and thus delivering sufficient material for an
extended assessment of its biological properties, including its capacity to serve as an anti-fouling agent. A
reaction sequence of the same length has been employed to generate congener 1 (cochliomycin A), a
demonstrably potent anti-fouling agent, while a sequence with the same number of steps leads to the
corresponding triol zeaenol (24), a rather phytotoxic and therefore potentially useful compound.
The use of an OCM process in conjunction with a NHK macrocyclization reaction provides a
capacity to generate other highly functionalized and generally more biologically active RALs. Work
directed towards such ends is now underway in our laboratories and results will be reported in due course,
as will the outcomes of studies of the ecological properties of compounds 1, 2 and 24.
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Experimental Section
General Experimental Procedures. Unless otherwise specified, proton (1H) and carbon (13C)
NMR spectra were recorded at 18 °C in base-filtered CDCl3 on a spectrometer operating at 400 MHz for
1
proton and 100 MHz for carbon nuclei. H NMR data are recorded as follows: chemical shift (δ)
[multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity is defined as: s = singlet; d
= doublet; t = triplet; q = quartet; m = multiplet or combinations of the above. In relevant cases, the signal
due to residual CHCl3 appearing at δH 7.26 and the central resonance of the CDCl3 “triplet” appearing at
δC 77.0 were used to reference 1H and 13C NMR spectra, respectively. Samples were analyzed by infrared
spectroscopy (νmax) as thin films on KBr plates. Low- and high-resolution electron impact (EI) mass
spectra were recorded on a double focusing, triple sector machine. Low- and high-resolution ESI mass
spectra were recorded on a triple-quadrupole mass spectrometer operating in positive ion mode. Melting
points are uncorrected. Analytical thin layer chromatography (TLC) was performed on aluminum-backed
0.2 mm thick silica gel 60 F254 plates. Eluted plates were visualized using a 254 nm UV lamp and/or by
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treatment with a suitable dip followed by heating. These dips included phosphomolybdic acid : ceric
sulfate : sulfuric acid (conc.) : water (37.5 g : 7.5 g : 37.5 g : 720 mL), potassium permanganate :
potassium carbonate : 5% sodium hydroxide aqueous solution : water (3 g : 20 g : 5 mL : 300 mL) and
p-anisaldehyde or vanillin : sulfuric acid (conc.) : ethanol (15 g : 2.5 mL : 250 mL). Flash
chromatographic separations were carried out following protocols defined by Still et al.25 with silica gel
60 (40–63 µm) as the stationary phase and using the AR- or HPLC-grade solvents indicated. Starting
materials, reagents, drying agents and other inorganic salts were generally commercially available and
were used as supplied. Tetrahydrofuran (THF), methanol and dichloromethane were dried using a solvent
purification system that is based upon a technology originally described by Grubbs et al.26 Where
necessary, reactions were performed under an argon atmosphere.
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Compound 8. Trifluoroacetic anhydride (28.5 mL) and acetone (5.00 mL) were added sequentially
to a magnetically stirred suspension of 2,4,6-trihydroxybenzoic acid monohydrate (5.03 g, 26.8 mmol) in
trifluoroacetic acid (38.0 mL) maintained at 0 °C and the ensuing mixture was then left to warm to room
temperature. After 20 h the reaction mixture was concentrated under reduced pressure and the residue
diluted with ethyl acetate (70 mL). The solution thus obtained was washed with NaHCO3 (2 × 50 mL of a
saturated aqueous solution) and then brine (1 × 50 mL). The separated organic phase was dried (Na2SO4),
filtered then concentrated under reduced pressure. The ensuing light-yellow oil was subjected to flash
chromatography (silica, 4:1 v/v hexane/ethyl acetate) to afford compound 818b (3.13 g, 56% or 76% brsm)
1
as a white, crystalline solid, mp 196–198 °C (lit.18b mp 202 °C). H NMR (400 MHz, CDCl3) δ 10.45 (s,
1H), 6.08 (d, J = 2.2 Hz, 1H), 5.95 (d, J = 2.2 Hz, 1H), 5.63 (broad s, 1H), 1.73 (s, 6H); IR (KBr) νmax
3189, 1658, 1639, 1480, 1351, 1272, 1167, 1160, 1094, 813 cm–1; MS (ESI, +ve) m/z 233 (40%), 211
(50), 153 (100); HRMS (ESI) [M + Na]+ calcd for C10H10O5 233.0426, found 233.0426.
The combined aqueous phases obtained from the workup process described above were treated with
an excess of concentrated HCl and the precipitate so formed collected by filtration to give 2,4,6-
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trihydroxybenzoic acid (1.35 g, 27% recovery) as a white, crystalline solid that was identical, in all
respects, with authentic material.
5
6
7
8
9
Compound 9. Diethyl azodicarboxylate (3.30 mL, 20.7 mmol) was added to a magnetically stirred
solution of phenol 8 (3.11 g, 14.8 mmol) and triphenylphosphine (4.27 g, 16.3 mmol) in THF (25 mL)
containing CH3OH (660 µL, 16.3 mmol) and maintained at 0 ºC under a nitrogen atmosphere. After 4 h
the reaction mixture was concentrated under reduced pressure and the residue thus obtained subjected to
flash chromatography (silica, 9:1 → 4:1 v/v 40–60 petroleum spirit/ethyl acetate gradient elution) to
afford, after concentration of the relevant fractions (Rf = 0.45 in 4:1 v/v 40–60 petroleum spirit/ethyl
acetate), the title compound 918b (2.68 g, 81%) as a white, crystalline solid, mp 105–107 °C (lit.18b mp 108
°C). 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 6.15 (d, J = 2.0 Hz, 1H), 6.01 (d, J = 2.0 Hz, 1H), 3.82
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(s, 3H), 1.74 (6H, s); C NMR (100 MHz, CDCl3) δ 167.7, 165.2, 163.1, 156.8, 106.9, 95.7, 94.6, 93.0,
55.8, 25.6; IR (KBr) νmax 1695, 1636, 1581, 1353, 1189, 1156 cm–1; MS (ESI, +ve) m/z 247 (8%), 225
(33), 167 (100); HRMS (ESI) [M + H]+ calcd for C11H12O5 225.0763, found 225.0764.
Compound 10. Trifluoromethanesulfonic anhydride (3.0 mL, 17.7 mmol) was added to a
magnetically stirred mixture of phenol 9 (2.65 g, 11.8 mmol) and pyridine (24 mL) maintained at 0 ºC
under a nitrogen atmosphere. The ensuing mixture was stirred at 0 ºC for 1.5 h then diluted with ethyl
acetate (100 mL) and the resulting solution washed with CuSO4 (3 × 50 mL of a saturated aqueous
solution), water (1 × 50 mL) and brine (1 × 50 mL) before being dried (MgSO4), filtered and concentrated
under reduced pressure. The resulting light-yellow oil was subjected to flash chromatography (silica, 1:0
→ 4:1 v/v hexane/ethyl acetate gradient elution) and so affording, after concentration of the relevant
fractions (Rf = 0.3 in 4:1 v/v 40–60 petroleum spirit/ethyl acetate), the title compound 1018b (4.05 g, 96%)
1
as a white, crystalline solid: mp 68–71 °C (lit.18b mp 58 °C). H NMR (400 MHz, CDCl3) δ 6.54 (d, J =
13
2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 1.75 (s, 6H); C NMR (100 MHz, CDCl3) δ 165.5,
158.7, 157.1, 149.8, 118.7 (q, J = 320 Hz), 106.5, 105.3, 101.0, 100.8, 56.2, 25.4; IR (KBr) νmax 1746,
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1629, 1578, 1429, 1285, 1211, 1149, 1057, 969, 819 cm–1; MS (ESI, +ve) m/z 379 (58%), 357 (100), 299
(45); HRMS (ESI) [M + H]+ calcd for C12H11F3O7S 357.0256, found 357.0255.
5
6
7
8
9
Compound 4. 1,4-Dioxane (40 mL) was added to a Schlenk flask containing triflate 10 (1.40 g, 3.9
mmol), (Ph3P)4Pd (450 mg, 10 mole %) and lithium chloride (1.25 g, 29.4 mmol) and the ensuing mixture
was deoxygenated with argon. Triethylamine (1.47 mL, 10.6 mmol) and tri-n-butylvinyltin (1.27 mL, 4.3
mmol) were then added sequentially and the deoxygenation process repeated. The ensuing mixture was
heated at 105 °C for 5 h while also being stirred magnetically then allowed to cool to room temperature
before ethyl acetate (100 mL) and water (100 mL) were added. The separated aqueous phase was
extracted with ethyl acetate (2 × 50 mL) and the combined organic phases washed with brine (2 × 50 mL)
before being dried (MgSO4), filtered and concentrated under reduced pressure. The resulting light-yellow
oil was subjected to flash chromatography (silica, 4:1 v/v hexane/ethyl acetate elution) and the relevant
fractions (Rf = 0.4) subjected to further flash chromatography (silica, 4:1 → 3:2 v/v 40–60 petroleum
spirit/dichloromethane gradient elution) and so affording, after concentration of the relevant fractions (Rf
10
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1
= 0.33), compound 418b (752 mg, 82%) as a white, crystalline solid, mp 89–91 °C (lit.18b mp 96 °C). H
NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 17.3 and 10.5 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.33 (d, J = 2.2
Hz, 1H), 5.65 (dd, J = 17.3 and 1.5 Hz, 1H), 5.40 (dd, J = 10.5 and 1.5 Hz, 1H), 3.86 (s, 3H), 1.71 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 164.8, 159.9, 158.5, 143.8, 135.4, 117.4, 108.4, 105.0, 103.7, 100.6,
55.5, 25.5; IR (KBr) νmax 2994, 1723, 1606, 1571, 1290, 1276, 1202, 1158, 1038 cm–1; MS (ESI, +ve) m/z
257 (95%), 235 (28), 177 (100); HRMS (ESI) [M + H]+ calcd for C13H14O4 235.0970, found 235.0970.
Compound 12. Calcium sulfate (1.01 g, 7.5 mmol) was added to a magnetically stirred solution of
2-deoxy-D-ribose (11) (2.00 g, 14.9 mmol) in DMF (30 mL) maintained under nitrogen and the ensuing
mixture cooled to –10 ºC. 2,2-Dimethoxypropane (3.7 mL, 29.8 mmol) and p-toluenesulfonic acid (28
mg, 10 mole %) were then added sequentially and the resulting mixture stirred at –10 °C for 24 h, then
filtered through a silica cartridge (30 g) that was eluted with hexane/ethyl acetate (1:1 v/v mixture). The
filtrate was concentrated under reduced pressure and the ensuing clear, colorless oil subjected to flash
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chromatography (silica, 3:1 → 1:1 v/v hexane/ethyl acetate gradient elution) and so affording, after
concentration of the relevant fractions (Rf = 0.5 in ethyl acetate), the title compound 125a (2.59 g, >95%)
5
6
7
1
as a clear, colorless oil comprised of a ca. 3:1 mixture of anomers and containing traces of DMF. H
8
9
NMR (300 MHz, CDCl3) δ (major anomer) 5.26 (dt, J = 7.0 and 4.0 Hz, 1H), 4.48 (dt, J = 6.5 and 4.0
Hz, 1H), 4.24–4.11 (complex m, 1H), 3.95 (dd, J = 12.5 and 3.0 Hz, 1H), 3.69 (dd, J = 12.5 and 3.5 Hz,
1H), 3.14 (d, J = 3.5 Hz, 1H), 2.24 (dt, J =15.0 and 4.0 Hz, 1H), 1.78 (ddd, J = 15.0, 7.0 and 4.0 Hz, 1H),
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1.50 (s, 3H), 1.35 (s, 3H); C NMR (75 MHz, CDCl3) δ 109.3, 108.6, 91.5, 90.7, 71.4, 71.1, 70.6, 70.4,
61.9, 60.7, 32.9, 32.0, 27.9, 27.1, 25.5, 25.2; IR (KBr) νmax 3412, 2984, 2936, 1664, 1456, 1380, 1372,
1244, 1216, 1113, 1061, 1035, 1003, 870, 852 cm–1; MS (ESI, +ve) m/z 197 (100%); HRMS (ESI)
[M + Na]+ calcd for C8H14O4 197.0790, found 197.0789.
Compound 13. n-Butyllithium (22.3 mL of a 2.0 M solution in hexanes, 44.6 mmol) was added
dropwise to a magnetically stirred solution of methyltriphenylphosphonium bromide (16.0 g, 44.7 mmol)
in THF (70 mL) maintained at –78 ºC under a nitrogen atmosphere. The resulting mixture was left to
warm to ca. 22 °C and after 0.5 h at this temperature was re-cooled to –78 ºC and then treated with a
solution of DMF-contaminated lactol 12 (2.60 g, ca. 14.9 mmol) in THF (30 mL). After addition was
complete the reaction mixture was slowly warmed to ca. 22 °C and after 16 h at this temperature it was
treated, successively, with NH4Cl (100 mL of a saturated aqueous solution) then with ethyl acetate (100
mL). The separated organic phase was washed with brine (2 × 50 mL) before being dried (MgSO4),
filtered and concentrated under reduced pressure. Subjection of the resulting light-yellow oil to flash
chromatography (silica, 4:1 v/v hexane/ethyl acetate elution) afforded, after concentration of the relevant
fractions (Rf = 0.2), the title compound 135a (1.85, 72%) as a clear, colorless oil, [α]D +15.5 (c 6.3,
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CHCl3) {lit.5a [α]D +54.8 (c 0.26, CHCl3)}. H NMR (300 MHz, CDCl3) δ 5.85 (m, 1H), 5.28–5.03
(complex m, 2H), 4.37–4.12 (complex m, 2H), 3.66 (d, J = 5.5 Hz, 2H), 2.52–2.36 (complex m, 1H),
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2.36–2.21 (complex m, 1H), 1.87 (broadened s, 1H), 1.50 (s, 3H), 1.38 (s, 3H); C NMR (75 MHz,
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CDCl3) δ 134.1, 117.3, 108.2, 77.7, 76.2, 61.5, 33.6, 28.1, 24.4; IR (KBr) νmax 3412, 2986, 2935, 1642,
1381, 1372, 1252, 1217, 1064 cm–1; MS (ESI, +ve) m/z 195 (100%); HRMS (ESI) [M + Na]+ calcd for
C9H16O3 195.0997, found 195.0997.
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Compound 5. t-Butyldimethylsilyl chloride (770 mg, 4.56 mmol) was added to a magnetically
stirred solution of alcohol 12 (523 mg, 3.04 mmol) and imidazole (414 mg, 6.08 mmol) in
dichloromethane (30 mL) maintained at ca. 22 °C under a nitrogen atmosphere. After 2 h the reaction
mixture was diluted with dichloromethane (50 mL) and the resulting solution washed with HCl (1 × 20
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mL aqueous solution), NaHCO3 (1 × 30 mL of a saturated aqueous solution) and then brine (1 × 20 mL).
The separated organic phase was then dried (MgSO4), filtered and concentrated under reduced pressure.
Subjection of the resulting light-yellow oil to flash chromatography (silica, 19:1 v/v 40–60 petroleum
spirit/diethyl ether elution then 3:7 → 1:1 v/v 40–60 petroleum spirit/dichloromethane gradient elution)
afforded, after concentration of the relevant fractions (Rf = 0.35 in 1:1 v/v 40–60 petroleum
spirit/dichloromethane), the title compound 5 (757 mg, 87%) as a clear, colorless oil, [α]D20 –21.4 (c 5.4,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.90 (m, 1H), 5.05–5.19 (complex m, 2H), 4.21 (m, 1H), 4.12 (m,
1H), 3.70 (m, 1H), 3.64 (m, 1H), 2.27–2.49 (complex m, 2H), 1.44 (s, 3H), 1.35 (s, 3H), 0.90 (s, 9H),
0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 135.2, 116.8, 107.9, 77.7, 77.0, 61.8, 33.8, 28.1, 25.9, 25.5,
18.2, –5.4, –5.5; IR (KBr) νmax 2955, 2931, 2858, 1642, 1472, 1463, 1379, 1368, 1255, 1217, 1100, 913,
837, 776 cm–1; MS (ESI, +ve) m/z 309 (100%); HRMS (ESI) [M + Na]+ calcd for C15H30O3Si 309.1862,
found 309.1862.
Compound 15. t-Butyldimethylsilyl chloride (2.96 g, 17.3 mmol) was added to a magnetically
stirred solution of (S)-4-penten-2-ol (1.41 g, 14.4 mmol) and imidazole (2.68 g, 35.5 mmol) in
dichloromethane (50 mL) maintained at ca. 22 °C under a nitrogen atmosphere. The ensuing mixture was
stirred at this temperature for 16 h before being diluted with dichloromethane (50 mL) and the resulting
solution washed with HCl (1 × 50 mL of 1 M aqueous solution), NaHCO3 (1 × 50 mL of a saturated
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aqueous solution) and then brine (1 × 50 mL). The separated organic phase was then dried (MgSO4),
filtered and concentrated under reduced pressure. Subjection of the resulting light-yellow oil to flash
chromatography (silica, 1:0 → 19:1 v/v hexane/dichloromethane gradient elution) afforded, after
concentration of the relevant fractions (Rf = 0.35 in 19:1 v/v 40–60 petroleum spirit/dichloromethane), the
title compound 156a (3.13 g, 95%) as a clear, colorless oil, [α]D20 +6.2 (c 3.2, CHCl3). 1H NMR (300 MHz,
CDCl3) δ 5.98–5.67 (complex m, 1H), 5.16–4.92 (complex m, 2H), 3.84 (sextet, J = 6.0 Hz, 1H), 2.19
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(m, 2H), 1.13 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); CNMR (75 MHz, CDCl3) δ 135.6, 116.5,
68.4, 44.3, 25.9, 23.4, 18.2, –4.5, –4.7; IR (KBr) νmax 2958, 2930, 2858, 1642, 1472, 1376, 1255, 1129,
1091, 1046, 1004, 913, 835, 774 cm–1; HRMS (ESI, +ve) [M + H]+ calcd for C11H24OSi 201.1675, found
201.1675.
Compound 16. A magnetically stirred mixture of silyl ether 15 (3.13 g, 15.6 mmol) and
vinylboronic acid pinacol ester (4.0 mL, 23.4 mmol) in dichloromethane (80 mL) maintained under argon
was heated at reflux 0.5 h and then cooled to room temperature. The HGII catalyst (245 mg, 2.5 mole %)
was then added to the reaction mixture that was then again heated at reflux. After 16 h the cooled reaction
mixture was concentrated under reduced pressure and the yellow residue thus obtained subjected to flash
chromatography (silica, 1:0 → 1:1 v/v hexane/dichloromethane gradient elution) and so affording, after
concentration of the relevant fractions (Rf = 0.3 in 1:1 v/v 40–60 petroleum spirit/dichloromethane), the
title compound 1621 (4.09 g, 83%) as a clear, colorless oil, containing traces of vinyl boronate, [α]D20 +9.3
(c 1.01, CHCl3) {lit.9d [α]D23 (for ent-16) –8.1 (c 1.12, CH2Cl2)}. 1H NMR (300 MHz, CDCl3) δ 6.60 (dt, J
= 17.5 and 7.0 Hz, 1H), 5.46 (d, J = 17.5 Hz, 1H) 3.89 (m, 1H), 2.43–2.10 (complex m, 2H), 1.27 (s,
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12H), 1.15 (d, J = 6.0 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); C NMR (100 MHz, CDCl3) δ 151.3, 121.2
(broad), 83.0, 66.2, 46.4, 25.9, 24.7, 23.7, 18.2, –4.6, –4.8; IR (KBr) νmax 2978, 2930, 2858, 1641, 1363,
1321, 1255, 1146, 1084, 1003, 835, 811, 774 cm–1; MS (ESI, +ve) m/z 349 (100%); HRMS (ESI) [M +
Na]+ calcd for C17H3511BO3Si 349.2346, found 349.2346.
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Compound 6. NaOH (2.40 mL of a 3 M aqueous solution, 7.9 mmol) was added to a magnetically
stirred solution of boronate 16 (714 mg, 2.19 mmol) in THF (22 mL) maintained under a nitrogen
atmosphere at ca. 22 °C. After 0.25 h a solution of molecular iodine (1.20 g, 5.3 mmol) in THF (5 mL)
was added dropwise and after a further 0.66 h the reaction mixture was diluted with ethyl acetate (50
mL). The separated organic phase was washed with Na2S2O3 (1 × 30 mL of a saturated aqueous solution)
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and brine (1 × 30 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure. The
resulting light-yellow oil (presumed to contain silyl ether 17) was dissolved in THF (22 mL) and the
solution thus obtained treated with TBAF (1.14 g, 4.4 mmol) while being maintained at ca. 22 °C under a
nitrogen atmosphere. After 16 h the reaction mixture was diluted with ethyl acetate (50 mL) and the
resulting solution washed with brine (1 × 50 mL) before being dried (Na2SO4), filtered and concentrated
under reduced pressure. Subjection of the resulting light-yellow oil to flash chromatography (silica, 1:0
→ 4:1 v/v hexane/ethyl acetate gradient elution) afforded, after concentration of the relevant fractions (Rf
= 0.2 in 4:1 v/v 40–60 petroleum spirit/ethyl acetate), compound 6 (325 mg, 70%) as a clear, pale yellow
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oil, [α]D +17.9 (c 1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 6.55 (dt, J =14.4 and 7.5 Hz, 1H), 6.14
(d, J = 14.4 Hz, 1H), 3.87 (m, 1H), 2.31–2.09 (complex m, 2H), 1.54 (broad s, 1H), 1.20 (d, J = 6.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 77.4, 66.5, 45.4, 22.8; IR (KBr) νmax 3352, 2968, 2928, 1606,
1455, 1423, 1374, 1271, 1121, 1074, 948 cm–1; MS (EI, 70 eV) m/z 212 (M+•, 15%), 168 (100); HRMS
(EI) M+• calcd for C5H9127IO 211.9697, found 211.9698.
Compound 18. The HGII catalyst (270 mg, 8 mole %) was added to a magnetically stirred solution
of styrene 4 (3.18 g, 10.4 mmol) and acetonide 5 (1.54 g, 5.4 mmol) in CH2Cl2 (5.4 mL) maintained
under an argon atmosphere. The resulting mixture was heated at 40 °C for 16 h and then (after solvent
loss) at 60 ºC for 72 h. The cooled reaction mixture was concentrated under reduced pressure and the
residue thus obtained was subjected to two flash chromatography (silica, 1:0 → 17:3 v/v hexane/ethyl
acetate then 1:0 → 9:1 v/v dichloromethane/diethyl ether elution) and concentration of the relevant
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fractions (Rf = 0.4 in 17:3 v/v 40–60 petroleum spirit/ethyl acetate and 0.5 in 9:1 v/v
dichloromethane/diethyl ether) afforded compound 18 (2.28 g, 86%) as a clear, colorless oil, [α]D20 –22.2
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(c 0.99, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 16.0 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.35
(d, J = 2.5 Hz, 1H), 6.31 (dt, J = 16.0 and 7.0 Hz, 1H), 4.31 (dt, J = 9.0 and 5.0 Hz, 1H), 4.17 (dt, J = 7.0
and 5.5 Hz, 1H), 3.85 (s, 3H), 3.78–3.60 (complex m, 2H), 2.68–2.49 (complex m, 2H), 1.70 (s, 6H), 1.47
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(s, 3H), 1.37 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H); C NMR (100 MHz, CDCl3) δ 164.7, 160.2, 158.7,
143.8, 131.3, 130.1, 108.2, 108.0, 104.9, 103.7, 100.3, 77.8, 77.1, 61.9, 55.6, 33.2, 28.2, 25.9, 25.7, 25.6,
18.3, –5.4 (four signals obscured or overlapping); IR (neat) νmax 2931, 2857, 1731, 1605, 1574, 1378,
1273, 1205, 1160, 1071, 837 cm–1; MS (ESI, +ve) m/z 515 (100%); HRMS (ESI) [M + Na]+ calcd for
C26H40O7Si 515.2441, found 515.2451.
Compound 19. Sodium hydride (320 mg of a 60% dispersion in mineral oil, 8.0 mmol) was added
to a magnetically stirred solution of alcohol 6 (1.10 g, 5.2 mmol) and acetonide 18 (1.97 g, 4.0 mmol) in
THF (20 mL) maintained at ca. 22 °C under a nitrogen atmosphere. The ensuing mixture was stirred for
1.5 h at this temperature then treated with NaHCO3 (20 mL of a saturated aqueous solution) and ethyl
acetate (40 mL). The separated organic phase was washed with brine (1 × 40 mL) before being dried
(Na2SO4), filtered and concentrated under reduced pressure. Subjection of the ensuing residue to flash
chromatography (silica, 1:0 → 4:1 v/v hexane/ethyl acetate gradient elution) afforded, after concentration
of the relevant fractions (Rf = 0.5 in 4:1 v/v 40–60 petroleum spirit/ethyl acetate), compound 19 (1.93 g,
83%) as a clear, colorless oil, [α]D20 +17.3 (c 1.54, CHCl3). 1H NMR (400 MHz, CDCl3) δ 11.68 (s, 1H),
7.01 (d, J = 16.0 Hz, 1H), 6.54 (m, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 6.19 (d, J =
14.5 Hz, 1H), 5.99 (dt, J = 16.0 and 7.0 Hz, 1H), 5.23 (sextet, J = 6.0 Hz, 1H), 4.27 (dt, J = 9.5 and 5.0
Hz, 1H), 4.15 (dt, J = 7.5 and 5.5 Hz, 1H), 3.83 (s, 3H), 3.75 (dd, J = 10.5 and 8.0 Hz, 1H), 3.67 (dd, J =
10.5 and 5.0 Hz, 1H), 2.64–2.54 (complex m, 1H), 2.54–2.37 (complex m, 3H), 1.45 (s, 3H), 1.37 (d, J =
6.0 Hz, 3H), 1.36 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 170.7, 165.1, 164.1,
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143.3, 140.9, 133.1, 128.9, 108.6, 107.9, 103.8, 99.8, 78.2, 77.8, 77.3, 70.8, 61.9, 55.4, 42.0, 33.1, 28.2,
25.9, 25.6, 19.6, 18.3, –5.3, –5.4; IR (KBr) νmax 2931, 2856, 1648, 1609, 1572, 1317, 1256, 1213, 1160,
836 cm–1; MS (ESI, +ve) m/z 669 (100%); HRMS (ESI) [M + Na]+ calcd for C28H43127IO7Si 669.1721,
found 669.1722.
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Compound 20. SEM-Cl (200 µL, 1.1 mmol) and DIPEA (300 µL, 1.8 mmol) were added
sequentially and dropwise to a magnetically stirred solution of compound 19 (580 mg, 0.9 mmol) and
TBAI (330 mg, 0.1 mmol) in dichloromethane (4 mL) maintained under nitrogen at room temperature at
ca. 22 °C. After 2 h the reaction mixture was quenched with brine (20 mL) and water (20 mL) then
extracted with dichloromethane (3 × 50 mL). The organic layers were combined and washed with brine (1
× 100 mL) before being dried (MgSO4), filtered and concentrated under reduced pressure. The resulting
light-yellow oil was subjected to flash chromatography (silica, 22:3 v/v 40–60 petroleum spirit/diethyl
ether elution) and thus affording, after concentration of the appropriate fractions (Rf = 0.25), compound
20 (668 mg, 96%) as a clear, colorless oil, [α]D20 –7.2 (c 7.9, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.69
(d, J = 2.3 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 6.59 (m, 1H), 6.46 (m, 1H), 6.28 (m, 1H), 5.26–5.16
(complex m, 4H), 4.23 (m, 1H), 4.13 (m, 1H), 3.81 (s, 3H), 3.80–3.65 (complex m, 6H), 2.61–2.32
(complex m, 4H), 1.43 (s, 3H), 1.34 (s, 3H), 0.95 (m, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.00 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 167.3, 161.1, 155.7, 141.5, 137.2, 130.5, 128.3, 116.5, 108.0, 103.4,
100.6, 93.3, 77.7, 77.6, 77.2, 69.9, 66.4, 61.9, 55.5, 42.0, 33.3, 28.2, 25.9, 25.6, 19.6, 18.3, 18.0, –1.4,
−5.3, –5.4; IR (KBr) νmax 2953, 2929, 1726, 1601, 1577, 1258, 1161, 1104, 1050, 836 cm–1; MS (ESI,
+ve) m/z 799 (100%); HRMS (ESI) [M + Na]+ calcd for C34H57127IO8Si2 799.2534, found 799.2555.
Compound 21. TBAF (2.88 mL of a 1.0 M solution in THF, 2.88 mmol) was added to a
magnetically stirred solution of compound 20 (1.12 g, 1.44 mmol) in THF (30 mL) maintained at 0 °C
under a nitrogen atmosphere. The ensuing mixture was stirred for 2 h at this temperature then filtered
through a short pad of TLC-grade silica gel (2.8 g) and the solids thus retained washed with diethyl ether
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(50 mL). The filtrate was concentrated under reduced pressure and the residue thus obtained subjected to
flash chromatography (silica, 4:1 → 1:4 v/v 40–60 petroleum spirit/diethyl ether gradient elution) to
afford, after concentration of the relevant fractions (Rf = 0.2 in 4:1 v/v 40–60 petroleum spirit/diethyl
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ether), compound 21 (931 mg, 96%) as a clear, pale-yellow oil, [α]D –6.2 [c 6.2, (CH3)2CO]. H NMR
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[400 MHz, (CD3)2CO] δ 6.78 (d, J = 2.3 Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.66 (m, 1H), 6.50 (d, J =
15.9 Hz, 1H), 6.40–6.25 (complex m, 2H), 5.29 (ABq, J = 11.1 Hz, 2H), 5.19 (m, 1H), 4.28 (m, 1H),
4.18 (m, 1H), 3.83 (s, 3H), 3.80 (dd, J = 8.4 and 8.0 Hz, 2H), 3.70–3.58 (complex m, 2H), 2.88 (broad s,
1H), 2.61–2.38 (complex m, 4H), 1.39 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.29 (s, 3H), 0.97 (7, J = 8.2 Hz,
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2H), –0.02 (s, 9H); C NMR [100 MHz, (CD3)2CO] δ 167.5, 161.9, 156.4, 143.0, 137.9, 131.4, 128.9,
117.9, 108.3, 103.6, 101.2, 93.8, 78.9, 78.2, 77.5, 70.6, 66.9, 61.6, 55.8, 42.4, 34.2, 28.5, 25.8, 19.9, 18.5,
1.2; IR (KBr) νmax 3482, 2951, 1723, 1601, 1578, 1262, 1162, 1108, 1049, 836 cm–1; MS (ESI, +ve) m/z
685 (100%); HRMS (ESI) [M + Na]+ calcd for C28H43127IO8Si 685.1670, found 685.1672.
Compound 22. DMP (900 mg, 2.11 mmol) was added to a magnetically stirred mixture of alcohol
21 (931 mg, 1.41 mmol), pyridine (50 µL) and NaHCO3 (260 mg, 3.10 mmol) in dichloromethane (140
mL) maintained at ca. 22 °C. After 0.25 h pyridine (140 µL) was added to the reaction mixture that was
then filtered through a pad of TLC-grade silica gel (14 g) with the solids thus retained being washed with
diethyl ether (100 mL). The combined filtrates were concentrated under reduced pressure and the residue
thus obtained subjected to flash chromatography (silica, 6:2.5:0.5 → 6:3:1 v/v/v dichloromethane/40–60
petroleum spirit/ethyl acetate gradient elution) to afford, after concentration of the relevant fractions (Rf =
0.4 in 6:3:1 v/v/v dichloromethane/40–60 petroleum spirit/ethyl acetate), compound 22 (810 mg, 87%) as
a clear, pale-yellow oil, [α]D20 +2.2 [c 4.4, (CH3)2CO]. 1H NMR [400 MHz, (CD3)2CO] δ 9.71 (d, J = 2.8
Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.66 (dt, J = 14.5 and 7.0 Hz, 1H), 6.51
(broadened d, J = 15.8 Hz, 1H), 6.36–6.27 (complex m, 2H), 5.30 (ABq, J = 11.3 Hz, 2H), 5.19 (m, 1H),
4.58 (m, 1H), 4.46 (dd, J = 7.1 and 2.8 Hz, 1H), 3.84 (s, 3H), 3.80 (m, 2H), 2.57 (m, 1H), 2.52–2.38
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(complex m, 3H), 1.55 (s, 3H), 1.39 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 0.97 (m, 2H), –0.01 (s, 9H); C
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103.8, 101.4, 93.8, 82.7, 78.6, 78.2, 70.7, 67.0, 55.8, 42.4, 34.3, 27.8, 25.6, 19.9, 18.5, 1.2; IR (KBr) νmax
2952, 1728, 1601, 1262, 1162, 1108, 1051, 836 cm–1; MS (ESI, +ve) m/z 683 ([M + Na]+, 20%), 661 (38),
242 (88), 117 (100); HRMS (ESI) [M + Na]+ calcd for C28H41127IO8Si 683.1513, found 683.1514.
Compound 23. Whilst being maintained under an atmosphere of nitrogen, anhydrous CrCl2 (1.55 g,
12.3 mmol) then NiCl2 (8 mg, 5 mole %) were added to a magnetically stirred solution of aldehyde 22
(832 mg, 1.23 mmol) in dry DMF (250 mL, freshly distilled from CaH2). The resulting mixture was
flushed with and then deoxygenated using argon for 0.5 h. The reaction vessel was then sealed and the
contents stirred at ca. 22 °C for 30 h before being quenched with water (ca. 750 mL) then extracted with
diethyl ether (3 × 250 mL). The combined organic layers were washed with “half-brine” (2 × 250 mL)
before being dried (MgSO4), filtered and concentrated under reduced pressure. The resulting light-yellow
oil was subjected to flash chromatography (silica, 1:1 → 1:4 v/v 40–60 petroleum spirit/diethyl ether
gradient elution) to afford, after concentration of the appropriate fractions (Rf = 0.25 in 3:2 v/v 40–60
petroleum spirit/ethyl acetate), the title compound 23 (507 mg, 77%) as a pale-yellow oil, [α]D20 +48.3 [c
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6.8, (CH3)2CO]. 1H NMR [400 MHz, (CD3)2CO] δ 6.66 (d, J = 2.3 Hz, 1H), 6.50 (m, 2H), 6.06 (m, 1H),
5.90 (m, 1H), 5.58 (dd, J = 15.9 and 6.1 Hz, 1H), 5.31 (m, 1H), 5.25 (ABq, J = 7.0 Hz, 2H), 4.26 (m,
1H), 4.11 (m, 1H), 3.95 (dd, J = 9.5 and 4.8 Hz, 1H), 3.81 (s, 3H), 3.78 (m, 2H), 3.43 (broadened s, 1H),
2.62 (m, 1H), 2.50–25 (complex m, 3H), 1.43 (s, 3H), 1.34 (d, J = 6.3 Hz, 3H), 1.32 (s, 3H), 0.96 (m,
13
2H), –0.01 (s, 9H); C NMR [100 MHz, (CD3)2CO] δ 167.7, 161.8, 156.5, 137.9, 132.3, 131.0, 130.9,
130.3, 117.5, 107.9, 106.5, 101.1, 93.8, 81.9, 77.3, 70.6, 69.4, 66.9, 55.8, 38.9, 34.4, 28.7, 26.2, 21.2,
18.5, 1.3; IR (KBr) νmax 3517, 2927, 2852, 1724, 1600, 1578, 1250, 1162, 1104, 1055, 971, 836 cm–1; MS
(ESI, +ve) m/z 557 (100%); HRMS (ESI) [M + Na]+ calcd for C28H42O8Si 557.2547, found 557.2548.
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Compound 2 (Cochliomycin B). TBAF (2.0 mL of a 1.0 M solution in THF, 2.0 mmol) was added
to a magnetically stirred solution of compound 23 (107 mg, 0.20 mmol) in THF (2 mL) and the ensuing
mixture was heated at reflux for 24 h while being maintained under nitrogen. The cooled reaction mixture
was filtered through a pad of TLC-grade silica gel (0.5 g) and the solids thus retained washed with diethyl
ether (20 mL). The combined filtrates were concentrated under reduced pressure and the ensuing light-
yellow oil subjected to flash chromatography (silica, 4:1 v/v diethyl ether/40–60 petroleum spirit elution).
Concentration of the relevant fractions (Rf = 0.3) afforded compound 2 (58 mg, 73%) as a white,
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amorphous solid, mp 134–136 °C, [α]D –17.7 (c 1.41, CH3OH). H NMR (400 MHz, CDCl3) δ see
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Table 1; 13C NMR (100 MHz, CDCl3) δ see Table 1; IR (KBr) 3514, 2984, 2935, 1702, 1647, 1609, 1573,
1382, 1370, 1356, 1320, 1260, 1216, 1160, 1118, 1059, 965, 851 cm–1; MS (ESI, +ve) m/z 427 (100%);
HRMS (ESI) [M + Na]+ calcd for C22H28O7 427.1733, found 427.1733.
Compound 1 (Cochliomycin A). Compound 23 (53.4 mg, 0.10 mmol) was treated with HCl (10
mL of a 0.1 M solution in dry CH3OH) and the resulting mixture stirred at ca. 22 °C then, after 1 h,
quenched with anhydrous K2CO3 and filtered through a pad of TLC-grade silica gel (0.2 g). The solids
thus retained were washed with diethyl ether (20 mL) and the combined filtrates concentrated under
reduced pressure. The resulting light-yellow oil was subjected to flash chromatography (silica, diethyl
ether elution) to afford, after concentration of the relevant fractions (Rf = 0.25), compound 1 (36.8 mg,
91%) as a white solid mp 154–155 °C, [α]D20 +34.4 (c 1.99, CH3OH). 1H NMR (400 MHz, CDCl3) δ see
Table 2; 13C NMR (100 MHz, CDCl3) δ see Table 2; IR (KBr) νmax 3479, 2983, 2932, 1647, 1608, 1571,
1317, 1256, 1210, 1159, 1116, 1042, 965 cm–1; MS (ESI, +ve) m/z 427 (100%); HRMS (ESI) [M + Na]+
calcd for C22H28O7 427.1733, found 427.1728.
Compound 24 (Zeaenol). Compound 23 (107 mg, 0.20 mmol) was treated with HCl (20 mL of a 1
M solution in 9:1 v/v CH3OH/water). The resulting mixture was stirred magnetically at ca. 22 °C for 16 h
before being quenched with anhydrous K2CO3 then filtered through a pad of TLC-grade silica gel (0.5 g)
and the solids thus retained washed with dichloromethane/CH3OH (50 mL of a 4:1 v/v mixture). The
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combined filtrates were concentrated under reduced pressure and resulting light-yellow oil subjected to
flash chromatography (silica, 9:1 v/v dichloromethane/CH3OH elution). Concentration of the relevant
fractions (Rf = 0.3) then gave a white solid that upon recrystallization (chloroform/CH3OH) afforded
compound 24 (85.8 mg, 84%) as a white, crystalline solid, mp 176–178 °C, [α]D20 –93.8 (c 4.8, CH3OH).
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1H NMR (400 MHz, CDCl3) δ see Table 3; C NMR (100 MHz, CDCl3) δ see Table 3; IR (KBr) νmax
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3386, 2917, 1644, 1607, 1572, 1315, 1257, 1160, 1052, 964 cm–1; MS (ESI, +ve) m/z 387 ([M + Na]+,
30%), 139 (100); HRMS (ESI) [M + Na]+ calcd for C19H24O7 387.1420, found 387.1449.
Crystallographic Data. Compound 2: C22H28O7, M = 404.46, T = 150 K, monoclinic, space group P21,
Z = 4, a = 8.5036(1), b = 26.1166(3), c = 9.3544(1) Å; β = 94.3007(9)°; V = 2071.62(4) Å3, Dx = 1.297 g
cm–3, 7438 unique data (2θmax = 144.4°), R = 0.033 [for 7084 reflections with I > 2.0σ(I)]; Rw = 0.084 (all
data), S = 1.00.
Compound 24: C19H24O7•H2O, M = 382.41, T = 150 K, monoclinic, space group C2, Z = 4, a =
16.8112(2), b = 4.9796(1), c = 23.1742(3) Å, β = 105.1099(15)°, V = 1872.91(5) Å3, Dx = 1.356 g cm–3,
3061 unique data (2θmax = 144.8°), R = 0.031 [for 2944 reflections with I > 2.0σ(I)]; Rw = 0.077 (all
data), S = 1.00.
Structure Determinations. Images were measured on a CCD diffractometer (CuKα, mirror
monochromator, λ = 1.54184 Å) and data extracted using the CrysAlis package.27 Structure solutions
were by direct methods (SIR92).28 The structures of compounds 2 and 24 were refined using the
CRYSTALS program package.29 Atomic coordinates, bond lengths and angles, and displacement
parameters for compounds 2 and 24 have been deposited at the Cambridge Crystallographic Data Centre
(CCDC nos. 1029428 and 1029429 for compounds 2 and 24, respectively). These data can be obtained
free-of-charge via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgments. We thank the Australian Research Council and the Institute of Advanced
Studies for generous financial support.
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Supporting Information Available: Crystallographic data (CIFs), anisotropic displacement
ellipsoid plots derived from the single-crystal analyses of compounds 2 and 24; 1H and 13C NMR spectra
for compounds 1, 2, 4–6, 8–10, 12, 13, 15, 16 and 18–24. This material is available free-of-charge via the
Internet at http://pubs.acs.org.
References
(1)
For useful points-of-entry into the literature on RALs, see: (a) Winssinger, N.; Barluenga, S.
Chem. Commun. 2007, 22. (b) Barluenga, S.; Dakas, P.-Y.; Boulifa, M.; Moulin, E.; Winssinger,
N. C. R. Chim. 2008, 11, 1306. (c) Hofmann, T.; Altmann, K.-H. C. R. Chim. 2008, 11, 1318. (d)
Bräse, S.; Encinas, A.; Keck, J.; Nising, C. F. Chem. Rev. 2009, 109, 3903. (e) Napolitano, C.;
Murphy, P. V. Resorcylic Acid Lactones. In Natural Lactones and Lactams: Synthesis,
Occurrence and Biological Activity; Janecki, T., Ed.; Wiley-VCH: Weinheim, 2014; Chapter 7, pp
273–319.
(2)
(3)
(a) Delmotte, P.; Delmotte-Palquee, J. Nature 1953, 171, 344. (b) Mirrington, R. N.; Ritchie, E.;
Shoppee, C. W.; Taylor, W. C.; Sternhell, S. Tetrahedron Lett. 1964, 5, 365.
For very recent examples not covered within ref 1, see: (a) Xu, L.-X.; Wu, P.; Wei, H.-H.; Xue,
J.-H.; Hu, X.-P.; Wei, X.-Y. Tetrahedron Lett. 2013, 54, 2648. (b) Liu, Q.-A.; Shao, C.-L.; Gu,
Y.-C.; Blum, M.; Gan, L.-S.; Wang, K.-L.; Chen, M.; Wang, C.-Y. J. Agric. Food Chem. 2014,
62, 3183.
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