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LETTER
Probing a Biomimetic Approach To Mycaperoxide B: Hydroperoxidation
Studies
Eduarda M. P. Silva, Richard J. Pye, Christine Cardin, Laurence M. Harwood*
Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AH, U.K.
Fax: +44(0)118 378 6121; E-mail: l.m.harwood@reading.ac.uk
Received: The date will be inserted once the manuscript is accepted.
Dedicated to Gerry Pattenden on the occasion of his 70th birthday; an inspiring scientist and a genial companion.
Abstract: Hydroperoxidation studies on a series of alkene substrates demonstrate the introduction of the hydroperoxide functional group into the required position for a biosynthetiycall inspired synthesis of mycaperoxide B 1.
Key words: hydroperoxidation, cobalt catalyst, mycaperoxide,
marine endoperoxide, Michael addition.
Mycaperoxide B 1 is a member of a group of eight structurally related terpene cyclic peroxides isolated from
marine sponges of the genus Mycale. It was found to
exhibit significant cytotoxicity against various cancer
cell lines and antiviral activity.1 The isolation of a hydroperoxide containing norsesterterpene endoperoxide
from a marine sponge of the genus Sigmosceptrella has
prompted Capon to propose a biosynthetic pathway for
the synthesis of these norsesterterpene cyclic peroxides
that invokes an intramolecular hydroperoxide Michael
type cyclisation.2,3 Our synthetic planning to access the
mycaperoxides has been inspired by Capon’s proposal
and is shown in Scheme 1.3
OOH
COOH
O O
Intramolecular
Michael addition
H
Mycaperoxide B 1
H
2
Wittig reaction
Deprotection
O
OH
OOTES
TBDPS
OH
Co(II)-catalysed
peroxidation
H
4
COOMe
OH
OH
Nucleophilic
coupling
OH
Oxidation
H
3
OH
7
O
I
OTBDPS
H
5
proach and establish the scope and limitations of the key
hydroperoxidation step.
The method chosen to introduce the hydroperoxide functionality utilises the methodology developed by Mukaiyama et al.5 The catalyst Co(modp)2 (modp = 1morpholino-5,5-dimethyl-1,2,4-hexanetrione) was selected as the preferred catalyst for these reactions because of its reported high efficiency in the conversion of
olefins into the corresponding triethylsilyl peroxide derivatives.5,6,7
Compound 78 (Scheme 2) was chosen as an initial model
system. The hydroperoxidation of 7, using the reaction
conditions described in the literature,9 led to the formation of two new compounds. Interpretation of the
NMR data of the less polar component isolated led to it
being identified as 9, with the protected peroxide on the
most substituted carbon of the double bond and the primary alcohol also silylated. The 1H NMR spectrum of
the more polar component exhibited a broad singlet at δ
2.00 ppm characteristic of a free hydroxyl and examination of the integration values of the triplet and quartet at
δ 0.99 and 0.68 ppm, respectively, revealed that there
was only one triethylsilyl protecting group present. Additionally, 13C NMR analysis revealed that a signal corresponding to the resonance of a quaternary carbon at δ
82.8 ppm was present leading to the conclusion that
hydroperoxidation had occurred and that the expected
compound 8 had been obtained in 43% yield.
6
Scheme 1
The proposed route would commence with the known
decalone 5 and an organometallic species derived from
6. The key step in this sequence is the intramolecular
Michael addition of the intermediate 2 to afford the cyclic peroxide that could be converted to the desired carboxylic acid 1.
The work described in this communication, following
previous investigations within our group,4 is concerned
with model studies of the Co(II)-catalysed peroxidation
of alkenes related to the side-chain of the putative hydroperoxidation substrate in order to validate this apTemplate for SYNLETT and SYNTHESIS © Thieme Stuttgart · New York
(i)
OOTES
OOTES
OH
8 (43%)
OTES
9 (19%)
(i) Co(modp)2 (0.05 equiv.), O2, Et3SiH, 1,2-DCE, rt.
Scheme 2
The methodology was next tested on compound 17
(Scheme 3). Compound 17 was prepared in 6 steps in an
overall yield of 34%. The free hydroxyl group in 11 was
activated and displaced to form a new carbon-sulfur
bond using a Mitsunobu substitution.10 Oxidation of the
sulfide 12 to the sulfone 13 was achieved using MCPBA
in 90% yield. Sulfone 13 and ketone 15 were subsequently reacted together in a one-pot Julia-Kocienski
olefination reaction to furnish alkene 16 as a 1:1 mixture
of E- and Z- isomers.11 Selective TBAF-mediated silyl
deprotection of 16 allowed the isolation of a 2:1 mixture
of isomeric alcohols 17 in 80% yield.
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LETTER
Following the previously established conditions for the
hydroperoxidation protocol, reaction of unprotected
alcohol 17 furnished a 1:1 mixture of isomeric triethylsilyl protected peroxides 18 in a disappointing 28% yield
(Scheme 3), given its structural similarity to 7, although,
the reaction again proceeded with high Markovnikov
regioselectivity.
starting material 4 and product 20 were stable to the
peroxidation conditions permitting reaction to be run
until complete consumption of the starting material.
O
H
(i)
16 R = OTHP
6 R=I
S
RO
(i)
OH
TBDPSO
10 R = H
11 R = TBDPS
S
OH
N
9
12
(iv) 14 R = H
15 R = THP
+ TBDPSO
13
S
O2
OR
3'
1
5
(iv)
H
S
OR
(iii) 4 R = TBDPS
19 R = H
OOTES
1'
(iii)
O
(ii)
OTBDPS
H
5
(ii)
N
(v)
THPO
20 R = TBDPS, 80%
21 R = H, 30%
OR
(vi) 16 R = TBDPS
17 R = H
OR
OH
R
(i) a. iodine, DIPHOS, CH2Cl2, 0oC; b. stirring, rt, 2h, 75%; (ii) t-BuLi, diethyl ether,
-100oC, 1.5h, 52%; (iii) TBAF, THF, rt, 3h, 91%; (iv) O2, Co(modp)2 (0.05 equiv.),
Et3SiH, 1,2-DCE, rt.
(vii)
THPO
Scheme 4
OOTES
OH
18
(i) a. TBDPSCl, imidazole, DMF, 35C; b. 5h, rt, 84%; (ii) Mercapto-BT, ADDP, imidazole,
P(CH3)3, THF, rt, 24h, 78%; (iii) MCPBA, NaHCO3, CH2Cl2, rt, 24h, 86%; (iv) a. 3,4-DHP,
PTSA monohydrate, CH2Cl2, 0C, 2h; b. NaHCO3, 30 min., 83%; (v) LHMDS, THF, -78C,
1.5h, 91%; (vi) TBAF, THF, rt, 1h, 80%; (vii) Co(modp)2 (0.05 equiv.), O2, Et3SiH, 1,2-DCE,
rt, 2h, 28%.
Scheme 3
The synthetic approach to alkene 4, a substrate closer to
that proposed in the synthetic pathway, relied upon selective delivery of the lithiated species of 6 equatorially
onto the decalone 5 (Scheme 4). Decalone 5 was prepared using a modified version of the 4 step literature
procedure starting from commercially available (-)carvone.12 The synthesis of 1-(tert-butyldiphenylsilyl
oxy)-6-iodo-3-methylhex-3-ene 6 was accomplished
through conversion of the THP protected alcohol 16 to
iodide 6 using iodine and DIPHOS in 75% yield as a 2:1
isomeric mixture (Scheme 4).
The coupling to form 4 was achieved via in situ organolithium generation by direct treatment of a mixture of 5
and 6, at -100C with two equivalents of t-BuLi leading
to the isolation of 4 in 52% yield as a 3:2 mixture of
diastereoisomers (Scheme 4). The 13C NMR data of the
decalin system of the coupled product 4 correlate well
with those described in the literature for mycaperoxide B
1.1 In particular, the resonance of C-1 (observed at 76.9
and 77.1 ppm) for compound 4 compares favourably
with that for the natural product ( 77.0 ppm). Desilylation of 4 with TBAF furnished the primary alcohol 19 in
91% yield (6:1 isomeric ratio).
When compound 19 (Scheme 4) was subjected to hydroperoxidation13 it gave rise to a 30% purified yield of
hydroperoxide 21 as a 1:1 mixture of diastereoisomers
with 12% of unreacted starting material being recovered.
Following literature precedent that the hydroperoxation
may be improved by protection of hydroxyl groups14 we
repeated the reaction on substrate 4 which furnished
compound 20 (R = TBDPS) in an excellent yield of 80%
(Scheme 4). It is worth noting that this reaction took 5.5
hours, longer than with the other substrates, but that
Template for SYNLETT and SYNTHESIS © Thieme Stuttgart · New York
Attempted
selective
deprotection
of the
tbutyldiphenylsilyl protected alcohol in compound 20
with tetrabutylammonium fluoride led to both silyl protecting groups being removed and compound 22 was
isolated in 86% purified yield as a 1:1 mixture of diastereoisomers (Scheme 5). Although this was not the
desired outcome of the deprotection reaction, it was
decided to attempt the oxidation of the primary hydroxyl
of 22 using Dess-Martin periodinane. After work-up and
purification of the complex reaction mixture, the major
component was isolated and proton and carbon NMR
spectroscopic analysis of this compound showed resonances supporting the formation of the hemiacetal 23 by
spontaneous cyclisation of the intermediate hydroperoxy
aldehyde in 38% yield (Scheme 5).15 Diagnostic of 23
were the characteristic hemiacetal proton signal at δ 5.25
ppm and the quaternary carbon signal at δ 93.4 ppm. The
presence in the 13C NMR spectrum of two signals at δ
80.8 and 80.7 ppm revealed that compound 23 was obtained as a mixture of two diastereoisomers in a 1:1 ratio.
OOR
OH
6'
OR1
OH
1'
O O
H
OH
(ii)
H
H
(i) 20 R = TES, R1 = TBDPS
22 R = R1 = H
23a 6'(S)
23b 6'(R)
i) TBAF, THF, 2h, rt, 86%; (ii) Dess-Martin, CH2Cl2, rt, 3h, 38%.
Scheme 5
Guided by the encouraging result obtained with 4
(Scheme 4) and the unsuccessful selective deprotection
of the primary t-butyldiphenylsilyl alcohol 20 (Scheme
5), dioxolane protected aldehyde analogue 29 was prepared in 4 steps in an overall yield of 44% (Scheme 6).
Treatment of 24 with 2-mercaptobenzothiazole 25 in the
presence of sodium hydride, in anhydrous tetrahydrofuran afforded the desired sulfide 26 in 69%. Oxidation of
the sulfide 26 to the sulfone 27 was achieved using
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MCPBA in 90% yield. Sulfone 27 and ketone 15 were
subsequently coupled in a one-pot Julia-Kocienski olefination reaction to furnish alkene 28 as a 2:1 mixture of
E- and Z- isomers, respectively.11 The tetrahydropyran
group in 28 was transformed in one step to the iodide 29
using iodine and DIPHOS in 70% yield as a 2:1 isomeric
mixture. The synthesis of the trityl protected side chain
analogue 30 (Scheme 7) was accomplished in 6 steps
following the same procedure described previously in
Scheme 3 in an overall yield of 38%.
S
O
O
Br
H
S
O
O
(i)
HS
+
S
H
N
25
24
N
26
(ii)
O
O
R
O
O
(iii)
OTHP +
H
15
28 R = OTHP
29 R = I
(iv)
H
S
O
S
O2
27
N
steric hindrance to the approach of the catalyst by the
bulky trityl protecting group.
The deprotection of the acetal was not attempted by
usual aqueous acid hydrolysis17 due to the presence of
the acid labile triethylsilylperoxy group. Tanemura et al.
reported in 1992 the successful hydrolysis of several
acetals to their corresponding aldehydes or ketones using
catalytic amounts of 2,3-dichloro-5,6-dicyano-pbenzoquinone (DDQ) in aqueous acetonitrile under neutral conditions.18 It was decided to attempt the hydrolysis
of the acetal 33 using DDQ (Scheme 8). The reaction of
compound 33 proceeded smoothly at room temperature
in aqueous acetonitrile to give only one product. Analysis of the 1H NMR spectrum revealed that removal of the
triethylsilyl group had occurred and the two singlets at δ
9.28 and 9.10 ppm in a ratio of 1:1 were attributed to the
resonances of the epimeric hydroperoxides, indicating no
stereocontrol in the original hydroperoxidation. After
purification, compound 35 was isolated in 72% yield.
(i) NaH, THF, overnight, rt, 69%; (ii) MCPBA, NaHCO3, CH2Cl2, rt, overnight, 90%; (iii)
LHMDS, THF, -78C, 2h, quant.; (iv) a. iodine, DIPHOS, CH2Cl2, 0C; b. stirring, rt, 5h, 70%.
OH
TESOO
Scheme 6
O
O
OOH O
H
OH
OH
O
6'
H
O O
H
OH
(i)
Both iodide 29 and 30 were reacted with decalone 5
(Scheme 7) and subjected to Barbier lithiation conditions. Intermediate 31 was obtained as a 2:1 mixture of
diasterioisomers in 57% yield while compound 32 was
prepared as a 1:1 mixture of diasterioisomers in 32%
yield.
H
H
33
35
H
23a 6'(S)
23b 6'(R)
(ii)
(i) DDQ, MeCN-H2O (9:1), rt, 3h, 72%.
(ii) BiCl3, MeOH, rt, 40 min., 39% (as a mixture).
Scheme 8
O
OOTES
R
H
5
OH
OH
(ii)
(i)
I
R
R
H
O
H
O
29 R =
31 R =
O
30 R = CH2OTr
O
32 R = CH2OTr, 32%
, 57%
O
, 55%
O
34 R = CH2OTr, 16%
33 R =
(i) t-BuLi, diethyl ether, -100C, 1.5h; (ii) O2, Co(modp)2 (0.05 equiv.), Et3SiH, 1,2-DCE, rt.
Scheme 7
When the peroxidation reaction was performed using
substrate 31 (Scheme 7), analysis of the 1H NMR spectrum of the product enabled the assignment of the structure as 33, isolated in 55% yield as a 1:1 mixture of diastereoisomers. The presence of the triethylsilyl peroxyether was indicated by the loss of the olefin signal and the
presence of a set of complex ethyl group signals, integrating to 9 and 6 protons. Furthermore, in the 13C NMR
spectrum two signals were present at δ 84.4 and 84.3
ppm corresponding to the resonance of the quaternary
carbon connected to the protected peroxide. Subsequently, compound 32 (Scheme 7) was subjected to the same
established peroxidation conditions and gave a 16%
purified yield of peroxide 34 as 1:1 mixture of diastereoisomers with 17% of unreacted starting material being
recovered. It is proposed that this low yield is due to
Template for SYNLETT and SYNTHESIS © Thieme Stuttgart · New York
The deprotection of the acetal 33 was also attempted
with bismuth(III) chloride.19 This reaction led to the
formation of the already known hemiacetal 23 and compound 35, both obtained as a mixture of diastereoisomers
(Scheme 8). Crystallization using a mixture of petroleum
ether (30-40C) and diethyl ether afforded suitable crystals of single diastereoisomer 23a20 and subsequent Xray crystallographic analysis confirmed the cyclic peroxyhemiacetal structure (Figure 1).21 This also allowed
unambiguous determination of the stereochemistry at C1 with the quaternary alcohol being in the correct axial
position as required for the preparation of the natural
product.
Figure 1
In conclusion, we have demonstrated that introduction of
a triethylsilylperoxy substituent into analogues of a potential synthetic precursor to the mycaperoxides is dependent on hydroxyl protection and this has led to the
successful high yielding synthesis of a triethylsilylperox2016-02-12
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LETTER
ide 20. The ease of cyclisation of the free hydroperoxygroup to form a cyclic peroxyhemiacetal lends support
for the biosynthetic proposal and augers well for the
proposed synthetic approach to Mycaperoxide B 1.
Acknowledgment
E.M.P.S. is grateful to the Portuguese Foundation for Science and
Technology (ref SFRH/BD/22683/2005) for a PhD grant. We are
also grateful to EPSRC for funding of the Oxford Gemini S Ultra
Image Plate System.
References
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(2)
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Typical procedure for hydroperoxidation reaction: Into a
flask flushed with oxygen were added 9,10-trans-1-[3’methylhex-3’-en-6’-ol]-2,5,5,9tetramethyldecahydronaphthalen-1-ol 19 (53 mg, 0.16
mmol), bis(5,5-dimethyl-1-morpholino-1,2,4hexanetrionato)cobalt (II) (4 mg, 0.008 mmol) and 1,2dichloroethane (2 mL) and the flask was again charged
with oxygen. Triethylsilane (0.052 mL, 0.32 mmol) and tBuOOH (2 drops) were added via a 1.0 mL gas-tight syringe and the resulting green solution was stirred vigorously under an oxygen atmosphere at room temperature. After
stirring for 2.5 h, the solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography on silica. Elution with hexane-acetone (9:1)
gave pure 21 as a colourless oil (20 mg, 30 %). IR (thin
film) (max) cm-1: 3 390, 2 929, 2 869, 1 461, 1 375, 1 051, 1
017, 801, and 729; 1H NMR (400 MHz, CDCl3) : 3.683.63 (2H, m, H-6’), 1.63-1.25 (20H, m, H 2,3,4,6,7,8,10
Template for SYNLETT and SYNTHESIS © Thieme Stuttgart · New York
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
and H-1’,2’,4’,5’), 1.15 and 1.14 (3H, s, 3’-CH3), 0.97
(9H, t, J 7.4 Hz, SiCH2CH3), 0.93 and 0.92 (3H, s, 9CH3), 0.858 (3H, d, J 6.4 Hz, 2-CH3), 0.860 (3H, s, 5CH3), 0.83 (3H, s, 5β-CH3), 0.67 (6H, q, J 7.4 Hz,
SiCH2CH3); 13C NMR (100 MHz, CDCl3) : 84.6 and 84.5
(COOTES), 77.1 (C-1), 63.3 (C-6’), 46.2 (C-10), 43.5 and
43.4 (C-9), 41.8 and 41.7 (C-6), 36.6 and 36.3 (C-2), 33.8
(5-CH3), 33.3 (C-5), 32.6 (C-1’), 32.55 and 32.46 (C-8),
32.2 and 32.0 (C-4’), 31.5 (C-2’), 27.6 and 27.5 (C-3),
27.21 and 27.17 (C-5’), 22.1 (5β-CH3), 22.0 (3’-CH3), 21.7
(C-4), 18.7 (C-7), 16.6 and 16.43 (2-CH3), 16.36 and 16.2
(9-CH3), 6.8 [Si(CH2CH3)3], 3.9 [Si(CH2CH3)3]; HRMS
(CI) m/z: Calcd C27H54O4Si (M)+ 470.3791, found
470.3800.
X.-X. Xu and H.-Q. Dong, Tetrahedron Lett., 1994, 35,
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6’-(2’’-(1-Hydroxy-9,10-trans-2,5,5,9tetramethyldecahydronaphthalen-1-yl)ethyl)-6’-methyl1’,2’-dioxan-3’-ol 23a: mp litt. 49-50 C, IR (thin film)
ν(max) cm-1: 3 402, 2 930, 2 863, 1 461, 1 451, 1 372, 1 137,
1 088, and 989; 1H NMR (400 MHz, CDCl3) δ: 5.26 (1H,
q, J 4.0 Hz, H-3’), 3.04 (1H, d, J 4 Hz, OH), 2.07-1.17
(20H, m, H-4’,5’,1’’,2’’ and H-2,3,4,6,7,8,10), 1.15 (3H, s,
6’-CH3), 0.87 (3H, d, J 8.0 Hz, 2-CH3), 0.87 (3H, s, 5CH3), 0.83 (3H, s, 5β-CH3); 13C NMR (100 MHz, CDCl3)
δ: 96.4 (C-3’), 80.9 (C-6’), 77.2 (C-1), 46.3 (C-10), 43.4
(C-9), 41.7 (C-6), 36.5 (C-2), 33.8 (5-CH3), 33.3 (C-5),
32.1 (C-4’), 31.9 (C-5’), 31.4 (C-2’’), 27.8 (C-8 and C-3),
25.4 (C-1’’), 22.1 (6’-CH3), 22.03 (5β-CH3), 21.7 (C-4),
18.7 (C-7), 16.5 (2-CH3), 16.3 (9-CH3); HRMS (ESI) m/z:
Calcd for C21H38O4Na (M+Na)+ 377.2662, found
377.2666.
Crystal data for 23a: C21H38O4 M = 354.51, centered monoclinic, C 2, a = 24.384 (3), b = 7.4398 (12), c = 11.0398 Å
, V = 2000.5 (5) Å3, Z = 4, D = 1.177 g cm-3, F(000) = 784.
2586 Independent reflections were collected on an Oxford
Gemini S Ultra Image Plate System. The structures was
solved by direct methods and refined on F2 using
SHELXL97. Final R = 0.0487, weighted R = 0.1345. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif quoting deposition
no. CCDC 750510.
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Probing a Biomimetic Approach To Mycaperoxide B: Hydroperoxidation Studies
O
OOTES
H
OH
t-BuLi
OR
OR
O2, Co(modp)2
52%
I
OH
Et3SiH
H
OTBDPS
TBAF
91%
R = TBDPS
R=H
H
R = TBDPS, 80%
R = H, 30%
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