The evolution of a stereoselective synthesis of the C1-C16 fragment of bryostatins

Article abstract of DOI:10.1039/c6ob01804a

The development of a synthesis of the C1-C16 fragment of bryostatins in which the key step is a stereoselective oxy-Michael reaction used to assemble the cis-2,6-disubstituted tetrahydropyran with the exocyclic alkene already installed, is described. Foll

Full text of DOI:10.1039/c6ob01804a

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DOI: 10.1039/C6OB01804A
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ARTICLE
The evolution of a stereoselective synthesis of the C1-C16
fragment of bryostatins
Received 00th January 20xx,
Accepted 00th January 20xx
Matthew Ball,a Anne Baron,a Ben Bradshaw,a Raphaël Dumeunier,a Matthew O’Briena and Eric J.
Thomasa*
DOI: 10.1039/x0xx00000x
The development of a synthesis of the C1-C16 fragment of bryostatins in which the key step is a stereoselective oxy-
Michael reaction used to assemble the cis-2,6-disubstituted tetrahydropyran with the exocyclic alkene already installed, is
described. Following early work using Stille reactions to prepare precursors for oxy-Michael reactions, a more efficient
route was devised based on a ketophosphonate-aldehyde condensation to prepare the key dienone. Synthesis of the
www.rsc.org/
aldehyde required for the ketophosphonate condensation involved the highly stereoselective addition of
a
diorganocuprate derived from allylmagnesium bromide and copper(i) iodide to the methyl 5-hydroxyhex-2-ynoate
prepared by ring-opening of a protected glycidol using lithiated methyl propiolate. Ester reduction, selective alcohol
protection and oxidative cleavage of the terminal double bond gave the required aldehyde. The ketophosphonate was
prepared in 13 steps from (R)-pantolactone using a synthesis based on a chelation controlled aldol condensation and an
anti-selective reduction of a 3-hydroxyketone. Following the ketophosphonate – aldehyde reaction, selective deprotection
followed by treatment with base effected the oxy-Michael reaction that gave the cis-2,6-disubstituted tetrahydropyran via
thermodynamic control. Subsequent functional group manipulation led to the synthesis of a hydroxy ester that
corresponded to the C1-C16 fragment of the bryostatins in 23 steps from (R)-pantolactone. The synthesis was repeated
using slightly different protecting groups for a study of a ring-closing metathesis approach to the bryostatins.
Introduction
Me
Me
Me
Me
Me
H
O
Me
Me
HO
H
O
HO
The bryostatins as exemplified by bryostatin 1 (1) and 10 (2)
(Fig. 1) are a group of marine macrolides isolated from the
filter feeder Bugula neritina.1 They have attracted a substantial
amount of interest because they exhibit anticancer activity
along with other, possibly useful, clinical behaviour, due in part
to their activation of conventional and novel protein kinase C
isoforms by binding to the regulatory C1 domains.2 However,
isolation of bryostatins from natural sources has proved to be
very difficult and has restricted the amount of material that is
available for biological studies.3 The synthesis of these
compounds has therefore been widely studied and has led to
the completion of several total syntheses with examples
reported recently involving fewer than thirty linear steps.4
These syntheses exemplify the recent development of total
synthesis and are outstanding contributions to the field. In
addition analogues have been prepared, mainly with modified
C1-C16 fragments. Some of these have been found to have
potent biological effects with tumour promoting phorbol-like
activity or tumour suppressing bryostatin-like activity.5.6
O
O
Me
O
MeO2C
MeO2C
H
H
H
H
H
H
O
O
1
O
O
1
OH
OH
16
17
OH
O
16
Me
Me
OH
Me
Me
O
O
O
O
20
27
Me
20
27
Me
OH
O
OH
nPr
O
CO2Me
CO2Me
2
1
Figure 1 Representative bryostatins
Many years ago we set ourselves the target of developing a
synthesis of a bryostatin that would be of the order of thirty
steps along its longest linear route. We also identified the 20-
deoxybryostatins, e.g. bryostatin 10 (2),7 as a subset of
bryostatins that had received less attention from synthetic
chemists. In early syntheses of bryostatins, Julia reactions
were used to assemble the C16-C17 double-bond with a
subsequent lactonisation being used to close the
macrocycle.4a-c However, the basic and reductive reaction
conditions that were necessary for the Julia reactions meant
that many steps had to be deferred until late in these
syntheses. Alternative procedures for the convergent assembly
of bryostatins from C1 – C16 and C17 – C27 fragments were
therefore of interest. In particular, with the onset of efficient
a. The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
*
Corresponding
author;
tel:
+44
(0)161
275
4613;
e-mail:
e.j.thomas@manchester.ac.uk
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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methods for ring-closing metathesis,8 it was of interest to see
whether the bryostatins could be synthesized using a late-
stage ring-closing metathesis that forms the C16-C17 alkene to
assemble the macrolide.
Such studies would require syntheses of alkenes
corresponding to the C1-C16 and C17-C27 fragments. Our first
target was therefore to prepare an alkene analogous to the
C1-C16 fragment, e.g. acid 3, Fig. 2. In our early studies
towards the synthesis of this fragment,9 it was shown that an
oxy-Michael reaction could be used to assemble 2,6-cis-
disubstituted 4-methylenetetrahydropyrans. Thus treatment
Me Me
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DOI: 10.1039/C6OB01804A
TBSO
O
OBn
O
O
OBn
OTBS
OTBS
Me
Me
8
Y
Me Me
TBSO
OTBS
OTBS
Y
+
X
OBn
O
O
OBn
Me
Me
9 X = I
10 X = Br
12 Y = Br, X = O
13 Y = SnBu3, X = H,OH
of
the
enone
4
with
acid
gave
the
4-
11 X = SnBu3
methylenetetrahydropyran 5 after acetalisation, and the
exocyclic alkene was converted into the unsaturated ester 6 by
condensation of the corresponding ketone with the chiral
phosphonate 7, see Fig. 2.9
Figure 3 Disconnections of the dienyl ketone 8
Me
Me
Results and discussion
Preliminary studies of Stille and Wadsworth-Emmons-Horner
based strategies
H
O
MeO
OP
MeO2C
H
H
O
OP
O
The reaction of the racemic epoxide 14 with lithiated methyl
propiolate was more efficient in the presence of the boron
trifluoride-tetrahydrofuran complex and gave the hydroxy-
ester 15 in an excellent yield.13 Following O-silylation, the
OH
(P = protecting groups)
3
Me Me
MeO
SiMe3
Me Me
H
OBn
o
H
H
copper(I) catalysed addition of tributyltin lithium at −78 C
O
O
HF then
O
OBn
O
O
OBn
OTBS
OTBS
using the Piers procedure using copper(I) bromide.dimethyl
sulfide to form the cuprate,14 provided the (E)-vinylstannane
17. Reduction using DIBAL-H gave the alcohol 18 that was
silylated to give the required vinylic stannane 11. Treatment of
this stannane with N-iodo- or N-bromo-succinimide gave the
vinylic iodide and bromide 9 and 10, respectively. In all cases,
only the (E)-isomer of these vinylic products was observed
consistent with literature precedent,14 see Scheme 1.
Me
Me
HC(OMe)3
PPTS
OH
OH
OBn
5
4
O-silyl., oxid.
then 7-NaHMDS
Me Me
MeO
H
O
O
O
O
P
OBn
MeO2C
H
H
O
CO2Me
(E) : (Z) = 72 : 28
CO2Me
OTBS
SnBu3
MeO2C
O
OTBS OBn
7
6
i
iii
OTBS
OTBS
OR
Figure 2 An oxy-Michael approach to the C1-C16 fragment9
OTBS
14
17
OTBS
Although this work had established the viability of the oxy-Michael
reaction for the synthesis of the 2,6-disubstituted tetrahydropyran
present in bryostatins, the introduction of the exocyclic
methoxycarbonylmethylene group after the assembly of the
tetrahydropyran was not ideal in that the (Z):(E)-stereoselectivity
was only 72:28. We now describe the development of an
alternative synthesis of the C1-C16 fragment of bryostatins in which
the trisubstituted exocyclic methylene group is introduced before
the oxy-Michael cyclisation.10,11
The dienyl ketone 8 was identified as a suitable oxy-
Michael precursor, see Figure 3, cf. enone 4. This already
possesses the trisubstituted double-bond that was to become
the exocyclic methylene group. Stille reactions12 were
identified as possible approaches to this enone and so the
halides 9 and 10 and the corresponding stannane 11 were
intentified as useful vinylic intermediates to be coupled with
the allylic bromide 12 or stannane 13.
15 R = H
16 R = TBS
ii
iv
SnBu3
X
vi or vii
PO
OTBS
TBSO
OTBS
OTBS
OTBS
18 P = H
11 P = TBS
9 X = I
10 X = Br
v
Scheme 1 Synthesis of vinylic intermediates for Stille couplings
n
Reagents and conditions: i, methyl propiolate, BuLi, THF, −87
oC, 30 min., BF3.THF, 30 min., add 14, −78 C 3 h (92%); ii,
o
TBSOTf, 2,6-lut., DCM, 0 oC to rt, 2 h (97%); iii, (Bu3Sn)2, nBuLi,
o
o
THF, 0 C, 25 min then added to CuBr.DMS, THF, −50 C, 16
added, −78 oC, 4 h (87%); iv, DIBAL-H, THF, −78 oC, 2 h (96%); v,
TBSCl, imid., DCM, rt, 2 h (93%); vi, NIS, DCM, rt, 1 h (97%); vii,
NBS, DCM, rt, 2 h (87%).
2 | J. Name., 2012, 00, 1-3
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The other components for the Stille reactions, bromide 12 and 27 using the Corey-Fuchs procedure19 gave a mVixietwuArreticloefOntlhinee
DOI: 10.1039/C6OB01804A
stannane 13, were to be prepared from the aldehyde 19 that alkyne 27 and the isomeric allene, but the use of dimethyl
was available in 11 steps from (R)-pantolactone.9 Addition of diazomethylphosphonate20 was more successful and gave the
lithiated propargylic alcohol15 to the aldehyde 19 gave the alkyne 27 exclusively. The alkyne 27 was taken through to the
alkyne 20 that was reduced to the (E)-alkene 21.16 However, (E)-vinylstannane 28 by addition of tributyltin hydride under
conversion to the bromide by treatment of the corresponding free-radical conditions.21 Addition of the lithiated alkyne 27 to
mesylate with lithium bromide was capricious and although the aldehyde 19 gave the alcohol 29 as a mixture of
the bromoketone 12 was prepared it was difficult to bring diastereoisomers that was oxidised to the ketone 30, still a
material through on a sufficient scale to continue with the mixture of epimers, for characterisation. However, attempts to
synthesis. Addition of prop-2-enyl(phenyl)sulfone to the reduce the hydroxyalkyne to the corresponding (E)-alkene
aldehyde 19 gave the isomeric alcohols 2317 and reaction with using Red-Al or lithium aluminium hydride gave mixtures of
tributyltin hydride provided the hydroxyalkenylstannanes 13 products including trienes formed by dehydration. This
(Scheme 2).18 However, the intermediate sulfone 23 and the problem was avoided by transmetalation of the stannane 28
stannane 13 were mixtures of diastereoisomers and were and addition of the vinyllithium reagent so obtained to the
difficult to characterise. Moreover, preliminary studies of the aldehyde 19. Oxidation of the resulting alcohols 31 gave the
Stille reaction between the iodide 9 and the stannane 13 gave oxy-Michael precursor 8 (Scheme 3).
only traces of the required product. An alternative approach to
the enone 8 from the aldehyde 19 was therefore required.
The structures shown for the products in Scheme 3 were
assigned on the basis of spectroscopic data and literature
It was decided to use a Stille reaction between prop-2- precedent. Early attempts to prepare the alkyne 27 directly
enyl(tributyl)stannane and the vinyl iodide 9 to prepare from the stannane 9 had been complicated by competing
compounds that already had the required trisubstituted allene formation. This work had achieved a synthesis of the
double bond in place. The addition of these intermediates to required ketone 8, albeit as a mixture of epimers because
the aldehyde 19 would then be studied, see Scheme 3.
racemic epoxide 14 was used in this exploratory work.
The Stille coupling of the vinylic iodide 9 with prop-2- However, it was difficult to prepare the enone 8 on a
enyl(tributyl)stannane gave the diene 24 in an excellent yield. multigram scale using this synthesis because the preparation
Selective dihydroxylation of the less hindered terminal double- of the stannane 28 is somewhat protracted (eleven steps from
bond of diene 24 was carried out using osmium tetroxide to the epoxide 14). An alternative synthesis of the enone 8 from
give a moderate yield, 53%, of the diol 25 as a mixture of the aldehyde 26 using a keto-phosphonate condensation was
diastereoisomers. Cleavage of the diol using sodium periodate therefore investigated (Scheme 4).
gave the aldehyde 26 that was used immediately without
OH
i
iii
purification. Attempts to convert this aldehyde into the alkyne
ii
OH
CHO
9
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
Me Me
Me Me
HO
OHC
i
24
OTBS
25
26
OBn
O
O
OBn
OH
20
OBn
O
O
OBn
iv
Me Me
Me
Me
Me
Me
19
vi
TBSO
OTBS
ii
Me Me
v
OTBS
X
OBn
O
O
OBn
OTBS
OTBS
PhO2S
Me Me
OTBS
Me
Me
X
29 X = H,OH
30 X = O
vii
27
OH
OBn
O
O
OBn
OH
OBn
O
O
OBn
v
Me
Me
Me
Me
Me Me
23
21 X = OH
22 X = Br
iii
SnBu3
viii
vi
TBSO
OTBS X
OTBS
OBn
O
O
OBn
iv
OTBS
OTBS
OTBS
Me
Me
Me Me
Me Me
31 X = H,OH
8 X = O
vii
Bu3Sn
Br
28
OH
OBn
O
O
OBn
O
OBn
O
O
OBn
Scheme 3 Synthesis of the oxy-Michael precursor 8 Reagents
and conditions: i, Pd(Ph3P)4, CH2=CHCH2SnBu3, THF, reflux, 4 h
(92%); ii, OsO4 (cat.), Me3NO.2H2O, DCM, rt, 16 h (53%); iii,
Me
Me
Me
Me
12
13
Scheme 2 Synthesis of allylic Stille precursors from aldehyde
n
o
19 Reagents and conditions: i, HCCCH2OH, BuLi, THF, −20 C,
20 min, add 19, −78 oC, 1 h, rt, 1 h (81%); ii, RED-Al, THF, 0 oC
to rt, 2 h (76%); iii, MsCl, Et3N, DCM, 0 oC, 10 min, LiBr,
acetone, 0 oC, 90 min (typically 35%); iv, Dess-Martin
NaIO4, THF, MeOH, H2O, rt,
1
h
(ca. 100%); iv,
(MeO)2P(O)CHN2, KOtBu, THF, −78 oC, 5 min., add 26, THF, −78
oC, 24 h (70%); v, Bu3SnH, AIBN (cat.), benzene, reflux, 1 h
n
o
(90%); vi, BuLi, 27, THF, −78 C, 30 min., 19 added, THF, −78
oC, 30 min., rt, 1 h (70%); vii, Dess-Martin periodinane, DCM, 1
h (30, 89%; 8, ca. 100%); viii, nBuLi, 28, THF, −50 oC, 30 min., 19
THF, −78 oC to rt, 2 h (60%).
n
periodinane, DCM, rt, 1 h (74%); v, CH2=CHCH2S(O)2Ph, BuLi,
THF, −78 oC, 15 min., 19, THF, −78 oC, 2 h, rt (81%); vi, Bu3SnH,
AIBN (cat.), benzene, reflux, 3 h (91%).
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solvent, to the hydroxyhexynoate 15 also proVcieewedAreticdle Ownilitnhe
excellent stereoselectivity to give the diene 42 that cyclised
Me Me
DOI: 10.1039/C6OB01804A
i
(MeO)2P
19
under acidic conditions to the lactone 43. The selective
dihydroxylation of the terminal double bond of this lactone
using osmium tetroxide gave modest yields of the diol 44 but
preliminary studies of the oxidative cleavage of this diol gave a
complex mixture of products.
O
OH
OBn
O
O
OBn
Me
Me
32
ii
Me Me
iii
Diene 42 was a promising intermediate for an improved
synthesis of the aldehyde 26, but at this stage it was decided
to modify the protecting group strategy to provide more
flexibility later in the synthesis. The formation of the syn-
addition products from the addition of organocuprates to 5-
hydroxyhex-2-ynoates22 is consistent with rapid in situ
protonation of the initially formed cuprate syn-addition
product.14 The formation of the anti-addition product 34 from
the silyl ether 16 is consistent with rapid isomerisation of the
initially formed syn-diorganocuprate addition product to an
allenoate before the protonation on work-up.14
(MeO)2P
8
O
O
OBn
O
O
OBn
Me
Me
33
Scheme 4 The keto-phosphonate approach to ketone 8
Reagents and conditions: i, (MeO)2P(O)Me, nBuLi, THF, −78 oC,
45 min., add 19, THF, −78 oC, 5 h (69%); ii, Dess-Martin
periodinane, DCM, rt, 2 h (66%); iii, KOtBu, 33, THF, −78 oC, 45
min., 26 in THF, added, −78 oC to rt, 16 h (60%).
The addition of lithiated dimethyl methylphosphonate to the
aldehyde 19 gave the epimeric alcohols 32 that were oxidised
to the ketophosphonate 33. This reacted with the aldehyde 26
to give the ketone 8 directly with a yield of 60%. This second
synthesis of enone 8 is 14 linear steps long from (R)-
pantolactone.9 However, the synthesis of the aldehyde 26
from epoxide 14 via the iodide 9 prepared for the original Stille
based investigations, still required nine steps.
HO
MeO2C
nOe
i
ii
16
OTBS
OTBS
OTBS
OTBS
35
34
It had been reported that the addition of diorganocuprates
to 5-hydroxyhex-2-ynoates analogous to ester 15 gives syn-
addition products.22 As applied to the ester 15 this would
provide an alkene with the required geometry if the group
derived from the cuprate could be modified to provide
aldehyde 26. The addition of the diethenylcuprate prepared
from ethenylmagnesium bromide and copper(I) iodide to the
bis-tert-butyldimethylsilyl ether 16 was carried out first to
check the role of the free hydroxyl group in additions to these
alkynoate esters. This gave an 80:20 mixture of two isomeric
dienes in which the (Z)-isomer 34 was the major component.
Reduction of the ester 34 with di-isobutylaluminium hydride
gave the alcohol 35 that was assigned the configuration shown
from nOe effects (Scheme 5). In contrast the addition of the
same diethenylcuprate to the hydroxyhexynoate 15 gave the
(E)-isomer 36 with excellent stereoselectivity.22 The
configuration of this diene was initially assigned by silylation to
the bis-tert-butyldimethylsilyl ether 37 that was the minor
component in the mixture of products obtained from the
reaction of the cuprate with the bis-silyated hydroxyester 16.
This stereochemical assignment was confirmed by cyclisation
of the hydroxyester 36 to the lactone 38 by treatment with
acid. Reduction of the ester 37 gave the alcohol 39 that was
protected as the tris-tert-butyldimethylsilyl ether 40.
Preliminary investigations of the selective monohydroboration
of this diene to prepare the primary alcohol 41 gave only low
yields and although the alcohol could be oxidised to the
aldehyde 26 that was identical to the sample prepared earlier,
see Scheme 3, this route seemed unlikely to provide a useful
synthesis of this aldehyde. The addition of the allyl cuprate
prepared from prop-2-enylmagnesium bromide and copper(I)
iodide, in this case in the presence of dimethyl sulfide as a co-
MeO2C
ii
iii
15
OP
OP
OTBS
OTBS
viii
OTBS
39 P = H
36 P = H
iv
iv
40 P = TBS
37 P = TBS
MeO2C
vi
v
OH
O
OH
OTBS
42
O
OTBS
OTBS
OTBS
v
OTBS
41
vii
38
O
O
OH
ix
CHO
O
O
OH
OTBS
OTBS
OTBS
OTBS
OTBS
26
43
44
Scheme 5 Studies of conjugate addition reactions of alkynyl
esters Reagents and conditions: i, CuI, THF, CH2=CHMgBr, −30
o
o
oC, 30 min, cool to −78 C, 30 min, 16, −78 C, 1.5 h [75%,
(E):(Z) = 80:20]; ii, DIBAL-H, hexane, THF, −78 oC to rt (35, 72%;
39, 71%); iii, CuI, THF, −78 oC, CH2=CHMgBr, 10 min, −30 oC, 1
o
h, cool to −78 C, 15, 2 h (90%); iv, TBSOTf, DCM, rt, 10 min
(37, 60%; 40, 88%); v, TsOH (cat.), THF, 3 Å sieves, rt, (38, 56%;
43, ca. 100%); vi, BH3.THF, 2-methylbut-2-ene, THF, rt, 2 h, add
to 40, rt, 18 h, NaOH, aq. H2O2, rt, 3 h (18%); vii, PDC, DCM, rt,
o
18 h (60%); viii, CuI, THF, DMS, −78 C, CH2=CHCH2MgBr, −78
oC, 30 min, add 15, −78 oC, 1 h (86%); ix, OsO4 (cat.),
Me3NO.H2O, DCM, rt, 4 h (41%).
4 | J. Name., 2012, 00, 1-3
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Development of the keto-phosphonate and oxy-Michael
reactions
View Article Online
(3E)-6-tert-butyldimethylsilyloxy-5,5-dimDeOthI:y1l0h.e10x3a9-/1C,36O-dBi0e1n8e04A
resulting from elimination of benzyl alcohol. Following
The (S)-enantiomer 45 of 4-methoxybenzyl protected glycidol desilylation of the alkene 53, oxidation of the resulting alcohol
was converted into the alkynyl ester 4623 by the improved 54 gave the aldehyde 55 that was taken through to the
procedure using the BF3.THF complex.13b The required (Z)- ketophosphonate 57 by addition of lithiated dimethyl
alkene 47 was now obtained in essentially a quantitative yield methylphosphonate and oxidation of the intermediate alcohol
on a multigram scale using an excess of allylmagnesium 56. The condensation of the ketophosphonate 57 with the
bromide in the presence of copper(I) iodide and lithium aldehyde 51 was best carried out using lithium chloride and di-
chloride at temperatures between −60 oC and −78 oC, see isopropylethylamine under Masumune-Roush conditions24 and
Scheme 6. Dimethyl sulfide was not necessary for this syn- gave the (E)-enone 58 in a 73% yield, see Scheme 7.
addition reaction, the in situ protonation of the initial adduct
The desilylation and oxy-Michael reaction of the enone 4
by the 5-hydroxyl group being sufficient.14 No reaction was had been carried out using hydrogen fluoride in acetonitrile,
observed in the absence of the lithium chloride or in the conditions which were known to lead to the selective
presence of lithium bromide at these temperatures. The formation of 2,6-cis-disubstituted tetrahydropyrans via
configuration of the (Z)-alkene 47 was established by nOe thermodynamic control.9,25 For the enone 58 milder conditions
studies. The ester was then reduced to the diol 48 that was using HF.pyridine complex were investigated in order to see
protected as its bis-tert-butyldimethylsilyl ether 49. Selective wthether the p-methoxybenzyl ether could be retained during
dihydroxylation of the terminal double-bond in the diene 49 the oxy-Michael cyclisation. However, under these conditions
was best effected using AD-mix β with the slow addition of a although the removal of the tert-butyldimethylsilyl group from
catalytic amount of osmium tetroxide during the oxidation to the primary allylic alcohol was fast, cleavage of the tert-
regenerate the catalyst. This procedure gave the diol 50, as a butyldimethylsilyl ether of the secondary alcohol was very
mixture of epimers, in yield of 70%, better than had been slow. In contrast, 5% aqueous hydrogen chloride in methanol
obtained in the earlier dihydroxylation of the diene 24. at room temperature led to the cleavage of both tert-
Cleavage of the mixture of epimeric diols 50 with sodium butyldimethylsilyl ethers and gave an 80 : 20 mixture of the
periodate gave the aldehyde 51 in essentially a quantitative 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans 59. This
yield (Scheme 6). This six-step sequence to the aldehyde 51 80 : 20 mixture of epimers is probably due to thermodynamic
o
from the epoxide 45 had an overall yield of ca. 60% with control since the reaction at 40 C gave the same ratio of the
several of the steps not requiring chromatography.
products albeit in a shorter reaction time of 15 minutes and
It was decided at this point to incorporate the aldehyde 51 with a slightly better overall yield (84%).
into a slightly truncated enone to check conditions for the oxy-
The epimers of the tetrahydropyran 59 were difficult to
Michael reaction, see Scheme 7. The aldehyde 52 is available separate by chromatography but, following protection of the
from (R)-pantolactone in six steps.9 The Wittig homologation free alcohol as its tert-butyldiphenylsilyl ether, the major 2,6-
of this aldehyde using potassium tert-butoxide as base gave cis-epimer 60 could be isolated. Treatment of a mixture of silyl
the alkene 53 (58%) and a side product (23%) identified as
ethers, but not of the alcohols 5925b enriched in the minor 2,6-
trans-isomer with potassium tert-butoxide in tetrahydrofuran
led to equilibration, presumably via a reverse oxy-Michael
reaction, and provided more of the required 2,6-cis-epimer 60.
Overall this sequence provide a 75% yield of the required 2,6-
cis-epimer 60 from the oxy-Michael precursor 58 (Scheme 6).
The structures of the products in Scheme 7 were consistent
with spectroscopic data including a significant nOe between
the 2-H and 6-H in the tetrahydropyran ring for the protected
product 60. The chemistry outlined in Schemes 6 and 7 had
provided an acceptable synthesis of oxy-Michael precursors
with the requisite trisubstituted double bond. It had also been
shown that these skipped dienes would undergo the oxy-
Michael cyclisation without any significant side reaction such
as double-bond migration or elimination.
Preliminary attempts were made to cleave the
monosubstituted terminal double-bond of the diene 60.
However, AD-mix β and osmium tetroxide either returned
unchanged starting material or gave mixtures of products. It
was therefore decided to progress this work by studying the
synthesis of enones that had the full C1-C16 carbon framework
assembled before the oxy-Michael addition, cf. enone 8.
CO2Me
O
MeO2C
i
ii
OH
H
OPMB
OH
OPMB
45
46
47
OPMB
iii
OH
CHO
OH
v
vi
OTBS
OTBS
OP
OP
OTBS
OTBS
OPMB
OPMB
OPMB
50
48 P = H
49 P = TBS
51
iv
Scheme 6 Synthesis of the βγ-unsaturated aldehyde 51
n
Reagents and conditions: i, methyl propiolate, BuLi, THF, −90
o
o
oC, 30 min, BF3.THF added, −90 C, 40 min., 45, −78 C, 3 h
(94%); ii, LiCl, CuI, THF, rt to −78 oC, CH2=CHCH2MgBr, THF, −78
oC to −60 oC, 30 min, −78 oC, 46, 30 min. (ca. 100%); iii, DIBAL-
H, THF, −78 oC, 1 h, rt, 1 h (ca. 100%); iv, TBSOTf, 2,6-lut., 0 oC
t
o
to rt, 1 h (91%); v, AD-mix β, BuOH, H2O, 0 C, OsO4 (5%)
added via a syringe pump over 8 h, 0 oC, 10 h (70%); vi, NaIO4,
MeOH, THF, H2O, rt, 1 h (ca. 100%).
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 6 of 31
ARTICLE
Journal Name
traces of the syn-epimer being detected in the crude reaction
mixture. The anti-configuration was assigned to the product 68
View Article Online
DOI: 10.1039/C6OB01804A
Me
PO
Me
Me
Me
Me
Me
i
iii
CHO
OHC
on the basis of precedent and by comparision of the relative
chemical shifts of the (R)- and (S)-O-acetylmandelates 69 and
70.27 Reduction of the ketone 68 using lithium tri-tert-
butoxyaluminium hydride gave the anti-diol 71 that was
protected as its acetonide 72. The methyl groups of the
acetonide were observed at δ25.7 and 25.9 in its 13C NMR
spectrum consistent with the anti-configuration of the 1,3-diol
OBn
TBSO
OBn
OBn
53 P = TBS
54 P = H
52
55
ii
iv
Me
Me
Me
X
Me
MeO
MeO
vi
P
OTBS
OTBS
O
OBn
O
OBn
OPMB
Me
PO
Me
Me
Me
Me
Me
56 X = H,OH
57 X = O
v
58
vii
ii
iii
CHO
OBn
PMBO
OBn OH
PMBO
OBn
61 P = H
63
Me
O
Me
64
H
Me
O
Me
i
H
O
62 P = PMB
+
viii
H
H
TBDPSO
O
Me
OBn
Me
OH
v
OBn
Me
iv
O
OTBDPS
OH
OTBDPS
66
OH
OH
OPMB
OPMB
67
65
59
60
vi
Scheme
7
Synthesis
of
the
cis-2,6-disubstituted
Me
Me
Me
Me
viii
tetrahydropyran 60 Reagents and conditions: i, Ph3PCH3Br,
o
KOtBu, THF, rt, 50 min, 52, 0 C to rt, 45 min. (58%); ii, TBAF,
PMBO
OBn OH
OH
OTBDPS
PMBO
OBn OP
O
OTBDPS
o
THF, rt, 19 h (ca. 100%); iii, (COCl)2, DCM, DMSO, −78 C, 20
68 P = H
71
o
min., 54, −78 C, 25 min., Et3N, 20 min; iv, (MeO)2P(O)Me,
69 P = (R)-PhCH(OAc)C(O)-
70 P = (S)-PhCH(OAc)C(O)-
vii
ix
nBuLi, THF, −78 C, 1 h, 55 added, −78 C, 90 min.; v, Dess-
o
o
Me
PO
Me
Me
Me
Martin periodinane, DCM, rt, 1 h (83% from 54); vi, LiCl, MeCN,
i
xi
OHC
57, Pr2NEt, rt, 30min., 51 added, rt, 21 h (73%); vii, conc. aq.
HCl, MeOH, 40 oC, 15 min.; viii, (a) TBDPSCl, imid., DCM, 0 oC to
rt, 30 min. (b) KOtBu, THF, 60 and its epimer, 10 : 90, rt, 10
min. (60, 75% from 58).
OBn
O
O
OTBDPS
OBn
xii
O
O
OTBDPS
Me
Me
Me
Me
74
72 P = PMB
73 P = H
x
Synthesis of the intact C1-C16 fragment of bryostatins
Me
X
Me
MeO
P
MeO
Different protecting groups were to be incorporated into the
oxy-Michael precursor relative to those in the original target 8
to provide better flexibility later in the synthesis. The
ketophosphonate 76 with the primary hydroxyl group
protected as its more stable tert-butyldiphenylsilyl ether was
the primary target. In our synthesis of this ketophosphonate,
see Scheme 8, the three-step conversion of the aldehyde 64
into the acetonide 72 was taken from the work of De
Brabander and Vandewalle.26
O
OBn
O
O
OTBDPS
Me
Me
75 X = H,OH
76 X = O
xiii
Scheme 8 Synthesis of the ketophosphonate 76 Reagents and
o
o
conditions; i, NaH, DMF, 0 C to rt, 30 min, PMBCl, 0 C to rt,
TBAI, 3 h, MeOH, 0 oC, 10 min (88%); ii, BH3.THF, −25 C to rt,
o
18 h, NaOH, aq, H2O2, rt, 1.5 h, 60 oC, 40 min (72%); iii, (COCl)2,
DMSO, DCM, −78 oC, 20 min., 63, −78 oC, 20 min., Et3N, −78 oC
to rt, 20 min. (92%); iv, TBDPSCl, imid., DCM, 0 oC, 2 h (92%); v,
The alcohol 61 is available in three steps from (R)-
pantolactone9 and was protected as its p-methoxybenzyl ether
o
o
(COCl)2, DMSO, DCM, −78 C, 30 min., 66, −78 C, 30 min.,
Et3N, −78 oC to rt, 30 min. (88%); vi, iPr2NH, THF, −30 oC, nBuLi,
rt, 5 min, 67, −78 oC added over 75 min., −78 oC, 2 h, 64, THF,
62 using sodium hydride and
a small excess of p-
methoxybenzyl chloride with methanol added before the
work-up to remove any unreacted p-methoxybenzyl chloride.
Hydroboration using borane in THF followed by oxidation gave
the primary alcohol 63 that was oxidised to the aldehyde 64.
4-tert-Butyldiphenylsilyloxybutan-2-one 67 was better
prepared from butane-1,3-diol 65 by protection and oxidation
to avoid taking side-products from the protection step into the
subsequent aldol reaction. The chelation controlled aldol
reaction between the ketone 67 and the aldehyde 64 was
more selective if the deprotonation step was carried out over a
period of 2 h at −78 oC and gave the anti-product 68 with only
o
−78 C, 5 min, (76%); vii, (R)- or (S)-O-acetylmandelic acid,
o
DMAP (cat.), THF, DCC, 0 C, THF, rt, 16 h (69, 88%; 70, 91%);
viii, Li(OtBu)3AlH, LiI, DCM, Et2O, −78 C, 4 h; ix, Me2C(OMe)2,
o
TsOH, rt, 2 h (91% from 68); x, DDQ, DCM, pH 7 buffer, rt, 20
o
min. (63%); xi, (COCl)2, DMSO, DCM, −78 C, 20 min., 73, −78
oC, 20 min., Et3N, −78 C to rt, 20 min; xii, (MeO)2P(O)Me,
o
o
o
nBuLi, THF, −78 C, 1 h, 74, −78 C, 1.5 h; xiii, Dess-Martin
periodinane, DCM, py., rt, 50 min. (80% from 73).
6 | J. Name., 2012, 00, 1-3
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Page 7 of 31
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
71.28 The oxidative removal of the p-methoxybenzyl ether complex in pyridine to remove the labile trimethylsilyl group
View Article Online
DOI: 10.1039/C6OB01804A
from 72 was complicated by a small amount of competing gave the alcohol 83 with retention of all the other protecting
oxidation of the benzyl ether, but with a short reaction time groups in 65% yield based on the ketophosphonate. On a
this could be minimised and the alcohol 73 isolated in an larger scale, using Masamune-Roush conditions for the
acceptable yield. Oxidation then gave the aldehyde 74 that ketophosphonate coupling, a 47% yield was obtained over the
was taken through to the ketophosphonate 76 by addition of two steps. Alcohol 83 was cyclised to give the tetrahydropyran
lithiated dimethyl methylphosphonate and oxidation of the 84 by treatment with potassium tert-butoxide in THF at room
resulting epimeric alcohols 75 (Scheme 8).
temperature for 5 min. Under these conditions only the cis-
The synthesis of ketophosphonate 76 outlined in Scheme 8 2,6-disubstituted tetrahydropyran 84 was obtained and so
was thirteen steps long starting from (R)-pantolactone and both the ring closure and subsequent equilibration had taken
provided the ketophosphonate on a multigram scale. Indeed place, see Scheme 10. Shorter reaction times gave mixtures of
the material prepared in this way from two early runs the 11,15-cis,trans-isomers.
supported all our later work on bryostatin synthesis.
Next, it was necessary to effect removal of the acetonide
The studies of the oxy-Michael conversion of the bis-tert- and formation of an acetal corresponding to the A-ring of the
butyldimethylsilyl ether 58 had shown that the primary allylic bryostatins. This was carried out as before by reaction of the
alcohol was deprotected much faster than the secondary acetonide 84 with trimethyl orthoformate and pyridinium
alcohol required for the cyclisation. The diol 48 was therefore toluene p-sulfonate (PPTS) in methanol and gave the required
protected as its mono tert-butyldiphenylsilyl ether 77 (Scheme acetal 85 in which both of the tert-butyldiphenylsilyl groups
9). The secondary alcohol was then protected as its tert- had been retained, see Scheme 10.
butyldimethylsilyl ether 78 but later in the synthesis, the
Me
Me
reactivity difference between the tert-butyldiphenylsilyl ether
on the primary alcohol and the tert-butyldimethylsilyl ether on
the secondary alcohol remained small and so a more labile
protecting group was required for the secondary alcohol. The
alcohol was therefore protected as its trimethylsilyl ether 79.
Following dihydroxylation using AD-mix β, oxidative cleavage
of the diol 80 so obtained using sodium periodate was
complicated by loss of the trimethylsilyl group and led to the
formation of a hemiacetal that could not be used efficiently in
the ketophosphonate step. The diol 80 was therefore cleaved
using lead tetraacetate and the aldehyde 81 was isolated in a
quantitative yield with no loss of the trimethylsilyl group.
Coupling the ketophosphonate 76 and the aldehyde 81
using barium hydroxide as base29 followed by immediate
treatment of the enone 82 with the hydrogen fluoride pyridine
CHO
i
O
OBn
O
O
OTBDPS
TBDPSO
OTMS
TBDPSO
OP
Me
Me
OPMB
OPMB
82 P = TMS
83 P = H
81
ii
iii
Me
MeO
Me
H
Me
O
Me
H
O
OBn
iv
TBDPSO
H
H
H
O
TBDPSO
O
OBn
O
O
OTBDPS
Me
Me
OPMB
OPMB
OP
Me
OTBDPS
85 P = H
86 P = SEM
84
v
vi
Me
MeO
Me
Me
H
O
H
O
MeO
OBn
OBn
vii
H
H
H
H
O
TBDPSO
O
TBDPSO
CHO
OH
SEMO
OTBDPS
SEMO
OTBDPS
88
87
i
ii or iii
TBDPSO
OP
48
TBDPSO
OH
viii
H
Me
Me
Me
Me
H
O
H
O
MeO
MeO
x
OBn
OBn
OPMB
OPMB
MeO2C
H
H
H
78 P = TBS
77
O
PO
O
79 P = TMS
iv
SEMO
OP
SEMO
OH
89 P = TBDPS
90 P = H
91
ix
OH
CHO
OH
v
TBDPSO
OTMS
TBDPSO
OTMS
Scheme 10 Completion of a synthesis of the ester 91 that
corresponds to the C1-C16 fragment of bryostatins Reagents
and conditions: i, 76, Ba(OH)2.H2O, THF, rt, 30 min., 81, rt, 18
OPMB
OPMB
80
81
o
h; ii, HF.py., py., 0 C, 0.5 min. (65% from 76); iii, KOtBu, THF,
rt, 5 min.; iv, HC(OMe)3, PPTS, MeOH, rt, 17 h (60% from 83); v,
Scheme 9 Preparation of the unsaturated aldehyde 81
Reagents and conditions: i, TBDPSCl, imid., 0 C, 30 min. (86%
i
o
o
SEMCl, Pr2NEt, DCM, 0 C, DMAP (cat.), rt, 18 h (85%); vi, (a)
pH 7 buffer, DCM, DDQ, rt, 45 min. (b) HC(OMe)3, PPTS, MeOH,
rt, 4 h (71%); vii, Dess-Martin, py., rt, 1 h; viii, Ph3PCH3Br,
from 47); ii, TBSOTf, 2,6-lut., DCM. (96%); iii, Et3N, Me3SiCl,
o
t
DCM, 0 C, rt, 40 min. (91%); iv, AD-mix β, BuOH, H2O, rt, 10
o
KOtBu, THF, rt, 20 min, 88, 0 C to rt, 1 h (71% from 87); ix,
t
o
t
min., 79, BuOH, acetone, 0 C, OsO4, BuOH, acetone added
over 10 h, 0 C to rt, 18 h (70%); v, Pb(OAc)4, py., DCM, rt, 45
o
o
TBAF, THF, rt, 2 h; x, MnO2, DCM, rt, 1 h, 0 C, KCN, MeOH,
AcOH, 0 oC, 1 h (34% from 89).
min (ca. 100%).
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
To complete a synthesis of the C1-C16 fragment of the However, attempts to mono-silylate the dihydroxyalkene 90
View Article Online
DOI: 10.1039/C6OB01804A
bryostatins ready for studies of ring-closing metathesis it was regioselectively on the allylic alcohol to provide the C1 alcohol
necessary to to introduce methoxycarbonylmethylene 94 were unreliable and difficult to reproduce. Rather than try
functionality and a double-bond at C16. The alcohol 85 was to optimise this reaction it was decided to tweak the overall
therefore protected as its (2-trimethylsilylethoxy)methyl (SEM) synthesis to access intermediates for metathesis studies that
ether 86 and the p-methoxybenzyl ether removed using retained the protected allylic alcohol functionality at C13, see
dichlorodicyanoquinone. Even though this deprotection was Scheme 12. These additional studies were useful in that they
carried out under buffered conditions, some hydrolysis of the tested the reliabilty of the overall approach and provided
acetal was observed and so the crude reaction mixture was intermediates with a different set of protecting groups for
treated with trimethyl orthoformate and PPTS in methanol to investigations into different assembly strategies.
reinstate it. Under these conditions the alcohol 87 was
(S)-Glycidol 95 was protected as its triethylsilyl ether 9630
obtained in a yield of ca. 60%. Other reaction conditions, e.g. that was converted into the alkynoate 97 using lithiated
using ceric ammonium nitrate were no better. A Dess-Martin methyl propioloate as before. Addition of the cuprate derived
oxidation then gave the aldehyde 88 that was immediately from allylmagnesium bromide and copper(I) iodide/lithium
homologated using a Wittig reaction to give the alkene 89. The chloride gave the (Z)-alkene 98 that was reduced to the diol
diol 90 prepared by desilylation of the alkene 89 appeared to 99. Selective protection gave firstly the tert-butyldimethylsilyl
be unstable to chromatography and so was not purified but ether 100 and then the trimethylsilyl ether 101. This was taken
was immediately oxidised using manganese dioxide. Potassium though to the aldehyde 102 by oxidative cleavage of the diol
cyanide in methanol was added to the reaction mixture to prepared by selective dihydroxylation of the terminal alkene,
complete the conversion into the ester 91, see Scheme 10.
and the aldehyde was immediately condensed with the
The structures of the products in Scheme 10 were assigned ketophosphonate 76 to provide the dienone 103. Desilylation
from spectroscopic data. The configuration of of the acetal 85 using the hydrogen fluoride – pyridine complex for 12 min at rt
at C9 was allocated on the basis of the anomeric effect. The removed both the trimethylsilyl and the triethylsilyl groups
conversion of the diol 90 into the ester 91 was accompanied and gave the diol 104 and treatment of this with potassium
by ca. 20% (Z)- to (E)-isomerisation, see experimental, but this tert-butoxide initiated selective cyclisation to give the 2,6-cis-
was avoided in later work by using a two-step procedure.
disubstituted tetrahydropyran 105 in an overall yield of 45%
The hydroxy ester 91 corresponds to the fully based on the phosphonate 76. Shorter reaction times gave
functionalised C(1)-C(16) fragment of a bryostatin. However, mixtures of products but the tetrahydropyran 105 was the
before investigating the incorporation of this intermediate into only product isolated under the optimised conditions
the assembly of a bryostatin it was decided to see whether presumably due to thermodynamic control. Oxidation of the
analogous intermediates could be prepared that retained the alcohol 105 gave the corresponding aldehyde that was
protected allylic alcohol at C13. These could provide more immediately converted into the alkene 106 using a Wittig
options during studies of the ring-closing metathesis. reaction. This two-step sequence was difficult to scale up but
Desilyation of the bis-tert-butyldiphenylsilyl ether 86 gave yields of 60% were obtained on smallish scales and provided
the diol 92 that was efficiently protected as its bis-tert- sufficient material to continue with the synthesis. Removal of
butyldimethylsilyl ether 93 (Scheme 11).
the acetonide under the usual conditions using pyridium
toluene p-sulphonate and trimethyl orthoformate in methanol
was accompanied by acetal formation and loss of the relatively
labile tert-butyldimethylsilyl group to give the diol 107. This
was converted into its bis-(2-trimethylsilylethoxymethyl) ether
108 that was desilylated to give the primary alcohol 109
(Scheme 12).
The structures shown were assigned to the intermediates
in Scheme 12 on the basis of spectroscopic data and by
comparison with the results of the previous work. The
configuration at C9 was assigned on the basis of the anomeric
effect as observed before for bryostatin intermediates.
The alcohol 109 corresponds to a protected C1-C16
fragment of a bryostatin albeit the C13 substituent is at the
alcohol oxidation level. The formation of tetrahydropyran 105
rather than the corresponding oxepane on cyclisation of the
diol 104 is of interest since this facilitated the introduction of
the double-bond required for metathesis studies earlier in the
synthesis.
Me
Me
MeO
Me
Me
H
MeO
H
OBn
OBn
ii
H
H
H
H
O
TBSO
O
O
PO
O
OPMB
93
OPMB
SEMO
OTBS
SEMO
OP
86 P = TBDPS
92 P = H
i
Me
Me
Me
MeO
Me
H
MeO
H
O
OBn
OBn
ii
H
H
H
H
O
HO
O
O
TBSO
SEMO
OH
SEMO
OH
90
94
Scheme 11 Preliminary studies of selective deprotection
Reagents and conditions: i, TBAF, THF, rt, 1 h; ii, TBSCl, imid.,
DCM, rt (93, 89% from 86; 94, unreliable).
8 | J. Name., 2012, 00, 1-3
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Page 9 of 31
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
CO2Me
O
View Article Online
CHO
DOI: 10.1039/C6OB01804A
MeO2C
iv
vii
ii
iii
vi
H
OP
OH
OTBS
OTMS
OH
OTBS
OTMS
OTES
OP
OH
OTES
OTES
OTES
OTES
99 P = H
100 P = TBS
95 P = H
96 P = TES
97
98
v
102
101
i
viii
Me
Me
Me
Me
Me
H
Me
H
xi
x
H
OP1
H
O
OBn
O
O
OTBDPS
OTBS
O
OBn
O
O
OTBDPS
OTBS
O
O
OBn
O
O
OTBDPS
OTBS
O
Me
Me
Me
Me
Me
Me
OP2
ix
OH
103 P1 = TMS, P2 = TES
104 P1 = P2 = H
105
106
xii
Me
Me
Me
Me
Me
Me
H
O
MeO
H
O
H
O
MeO
O
MeO
OBn
OBn
OBn
9
xiii
xiv
H
H
H
H
H
H
O
OSEM
O
OH
OSEM
SEMO
OH
OH
OTBDPS
SEMO
OTBDPS
108
107
109
Scheme 12 Synthesis of the C1-C17 alkenol 109 Reagents and conditions: i, TESCl, imid., DCM, 0 oC to rt, 1 h (94%); ii, methyl propiolate,
nBuLi, −90 oC, 1 h, BF3.THF, 40 min, 96, −78 oC, 3 h (77%); iii, LiCl, CuI, THF, −78 oC, CH2=CHCH2MgBr, ether, −78 to −60 oC, 1 h, 97, −78 oC,
30 min (98%); iv, DIBAL-H, THF, −78 oC, 1 h, −60 oC, 3 h (96% from 97); v, TBSCl, imid., DCM, 0 oC to rt, 3 h (81%); vi, TMSCl, Et3N, DCM, 0 oC
to rt, 40 min (99%); vii, (a) AD-mix β, tBuOH, H2O, 101, 0 oC, tBuOH, acetone, OsO4 (cat.), 40 h (73%) (b) Pb(OAc)4, DCM, py., 45 min; viii,
76, Ba(OH)2.H2O, THF, rt, 30 min, 102, wet THF, rt, 19 h (80% from 76); ix, HF.py., 0 oC, 12 min; x, KOtBu, THF, rt, 15 min (45% from 76); xi,
(a) Dess-Martin, DCM, py., rt, 17 h (b) Ph3PCH3Br, KOtBu, THF, rt, 20 min, add aldehyde, THF, −10 oC, 1 h (63%); xii, HC(OMe)3, PPTS (cat.),
methanol, rt, 21 h (58%); xiii, SEMCl, iPr2NEt, DCM, 0 oC to rt, 18 h (79%); xiv, TBAF, THF, rt, 140 min (84%).
Summary and conclusions
Experimental
The ester 91 and alcohol 109 have been prepared in 20-23 General experimental details
steps from (R)-pantolactone and correspond to the intact C1-
C16 fragment of the bryostatins. The next steps in a synthesis Flash column chromatography was performed using Merck silica gel
of a bryostatin by a ring-closing metathesis would involve (60H; 40-60m, 230-240 mesh). Petrol refers to light petroleum
oxidation of these alcohols at C1 followed by esterification of which was redistilled before use and refers to the fraction boiling
the acid so formed using an alcohol corresponding to the C17- between 40 and 60 °C. Tetrahydrofuran was dried over sodium-
C27 fragment. Full details of our studies of the syntheses of benzophenone and was distilled under nitrogen prior to use.
the C17-C27 fragment and preliminary investigations into ring- Dichloromethane was dried over CaH2 and was distilled before use.
closing metathesis as an approach to bryostatins using the Ether refers to diethyl ether. Reactions under non-aqueous
alcohol 109 and simpler analogues will be outlined in the conditions were carried out under an atmosphere of nitrogen or
following paper in this series.31 A second metathesis-based argon.
approach to the synthesis of bryostatins has been described
but, as in our work,31 was only successful for the preparation ionisation using ammonia (CI+), electrospray ionisation in the
of analogues of the bryostatins.32 positive mode (ES+) and atmospheric pressure chemical ionisation
Mass spectra used electron impact ionisation (EI+), chemical
Of interest in the present work is the efficient in the positive or negative mode (APCI+ or APCI-). Low and high
stereoselective conjugate addition of the cuprate derived from resolution mass spectra were recorded using a Micromass Trio 200
allylmagnesium bromide and copper(I) iodide-lithium chloride and a Kratos Concept IS spectrometer, respectively. Infra-red
to hydroxyalkynyl esters, the development of mild conditions spectra were measured using a Genesis FTIR spectrometer on NaBr
for the oxy-Michael reactions to give cis-2,6-disubstituted plates, either neat or as evaporated films unless otherwise stated.
tetrahydropyrans with excellent stereoselectivity as illustrated Nuclear magnetic resonance spectra were recorded in deuteriated
by the synthesis of tetrahydropyrans 84 and 105, and the chloroform unless otherwise indicated using Varian Unity 500 (500
overall selective functional group transformations in these MHz), Varian INOVA 400 (400 MHz) and Varian Unity 300 (300 MHz)
sensitive systems leading to syntheses of the advanced spectrometers. Coupling constants (J) are given in Hertz (Hz) and
intermediates 91 and 109. As an aside, the ketophosphonate chemical shifts are relative to tetramethylsilane. Residual non-
76 was prepared on a multigram scale and this material was deuteriated solvent was used as the internal standard.
used in all of our later work.33,34
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Organic & Biomolecular Chemistry
Page 10 of 31
ARTICLE
Journal Name
Methyl 6-tert-butyldimethylsilyloxy-5-hydroxyhex-2-ynoate mixture stirred at −78 oC for 4 h. Methanol (33 mVLi)ewwAartsiclaedOdnleinde
DOI: 10.1039/C6OB01804A
and the mixture allowed to warm to rt then stirred for 1 h.
(15)
n-Butyllithium (1.6 M in hexanes, 2.49 mL, 3.98 mmol) was Water (50 mL) and ether (50 mL) were added and the mixture
added to methyl propiolate (0.36 mL, 3.98 mmol) in THF (6 mL) filtered through Celite. The aqueous phase was extracted with
at −87 oC and the solution stirred for 30 min. Boron trifluoride ether (3 × 50 mL) and the organic extracts washed with brine
(1.1 M in THF, 0.44 mL, 3.98 mmol) was added and the (100 mL), then dried (MgSO4), and concentrated under
solution stirred for 30 min. The epoxide 14 (0.5 g, 2.66 mmol) reduced pressure. Chromatography of the residue (light
in THF (2 mL) was added and the reaction mixture allowed to petroleum:ether 99:1 to light petroleum:ether: triethylamine
warm to −78 oC then stirred for 3 h. Saturated aqueous 97:2:1) gave the title compound 17 (3.6 g, 87%), as a colourless
ammonium chloride (5 mL) was added and the mixture oil (Found: M+ + H, 679.3592. C31H67O4Si2Sn requires M,
allowed to warm to rt. Ether was added and the aqueous 679.3599); νmax/cm-1 2955, 2929, 2857, 1723, 1463, 1253,
phase extracted with ether (3 × 15 mL). The organic extracts 1168, 1125, 1098, 836 and 777; δH (300 MHz, CDCl3) 0.00 (6 H,
were washed with saturated aqueous sodium bicarbonate (2 × s, 2 × SiCH3), 0.01 and 0.02 (each 3 H, s, SiCH3), 0.85-1.02 [33
50 mL), dried (MgSO4), and concentrated under reduced H, m, 2 × SiC(CH3)3, 3 x CH2CH3], 1.25 (6 H, m, 3 × CH2), 1.42 (6
pressure.
Chromatography
of
the
residue
(light H, m, 3 × SnCH2), 3.00-3.15 (2 H, m, 4-H2), 3.38 (1 H, dd, J 10.5,
petroleum:ether 4:1) gave the title compound 15 (622 mg, 5.1, 6-H), 3.46 (1 H, dd, J 10.5, 6.3, 6-Hʹ), 3.64 (3 H, s, OCH3),
92%), as a colourless oil (Found: M+ + NH4, 290.1781. 3.75 (1 H, m, 5-H) and 5.99 (1 H, s, 2-H; JSn 60.0); δC (75 MHz,
C13H28O4SiN requires M, 290.1787); νmax/cm-1 3429, 2953, CDCl3) −5.5, −5.4, −4.5, −4.2, 10.4, 13.6, 18.0, 18.3, 25.8, 25.9,
2930, 2859, 2240, 1714, 1471, 1464, 1436, 1259, 1121, 1078, 27.3, 28.9, 40.1, 50.7, 67.7, 73.3, 129.5, 164.5 and 169.5; m/z
839 and 779; δH (300 MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.80 (ES+) 696 (M+ + 18, 100%) and 679 (40).
[9 H, s, SiC(CH3)3], 2.45 (1 H, br. s, OH), 2.46 (2 H, d, J 6.3, 4-H2),
3.53 (1 H, dd, J 10.2, 5.5, 6-H), 3.62 (1 H, dd, J 10.2, 4.4, 6-Hʹ), (E)-5,6-Bis-(tert-butyldimethylsilyloxy)-3-tri-n-
3.67 (3 H, s, OCH3) and 3.79 (1 H, m, 5-H); δC (75 MHz, CDCl3) butylstannylhex-2-en-1-ol (18)
−5.6(2), 18.1, 23.3, 25.7, 52.5, 65.3, 69.4, 74.2, 85.7 and 153.8; Di-isobutylaluminium hydride (1 M in toluene, 40.16 mL, 40.16
m/z (CI+) 290 (M+ + 18, 100%).
mmol) was added to the ester 17 (10.88 g, 16.06 mmol) in THF
(90 mL) at −78 C. The mixture was stirred at −78 C for 2 h
o
o
Methyl 5,6-bis-tert-butyldimethylsilyloxyhex-2-ynoate (16)
and then allowed to warm to rt. Water (17 mL) was added
tert-Butyldimethylsilyl trifluoromethanesulfonate (11.02 mL, followed by saturated aqueous sodium potasium tartrate (100
48.61 mmol) was added to the alcohol 15 (8.82 g, 32.41 mmol) mL). The mixture was stirred until it separated into two distinct
o
and 2,6-lutidine (23.06 mL, 0.19 mol) in DCM (335 mL) at 0 C layers. The aqueous phase was extracted with ether (3 × 100
and the mixture allowed to warm to room temperature then mL) and the organic extracts washed with brine then dried
stirred for 2 h. Water (150 mL) was added and the aqueous (MgSO4) and concentrated under reduced pressure.
phase extracted with DCM (3 × 100 mL). The organic extracts Chromatography of the residue (light petroleum:ether:
were dried (MgSO4) and concentrated under reduced triethylamine 95:4:1) gave the title compound 18 (9.78 g, 96%),
pressure.
Chromatography
of
the
residue
(light as a colourless oil; νmax/cm-1 3401, 2955, 2928, 2857, 1463,
petroleum:ether 95:5) gave the title compound 16 (12.22 g, 1254, 1100, 1078, 836 and 777; δH (300 MHz, CDCl3) 0.01 (6 H,
97%), as a colourless oil (Found: M+ + NH4, 404.2642. br. s, 2 × SiCH3), 0.01 and 0.03 (each 3 H, s, SiCH3), 0.70-1.00
C19H42O4Si2N requires M, 404.2652); νmax/cm-1 2955, 2930, [33 H, m, 2 × SiC(CH3)3, 3 x CH2CH3], 1.27 (6 H, m, 3 × CH2),
2887, 2859, 2241, 1721, 1472, 1464, 1435, 1257, 1116, 1079, 1.43 (6 H, m, 3 × SnCH2), 2.35 (1 H, t J 5.7, OH), 2.48 (1 H, dd, J
838 and 778; δH (300 MHz, CDCl3) 0.01 (6 H, s, 2 × SiCH3), 0.03 13.3, 7.7, 4-H), 2.55 (1 H, dd, J 13.7, 4.9, 4-Hʹ), 3.35 (1 H, dd, J
and 0.07 (each 3 H, s, SiCH3), 0.84 [18 H, s, 2 × SiC(CH3)3], 2.38 9.9, 6.2, 6-H), 3.51 (1 H, dd, J 9.9, 4.7, 6-Hʹ), 3.61 (1 H, m, 5-H),
(1 H, dd, J 17.0, 6.5, 4-H), 2.60 (1 H, dd, J 17.0, 4.8, 4-Hʹ), 3.42 4.11 (2 H, m, 1-H2) and 5.91 (1 H, t, J 6.2, 2-H); δC (75 MHz,
(1 H, dd, J 10.0, 6.9, 6-H), 3.54 (1 H, dd, J 10.0, 4.9, 6-Hʹ), 3.70 CDCl3) −5.4(2), −4.6, −4.1, 9.2, 9.6, 13.6, 18.1, 18.3, 25.9, 27.4,
(3 H, s, OCH3) and 3.38 (1 H, m, 5-H); δC (75 MHz, CDCl3) 29.0, 38.4, 58.8, 67.1, 72.9, 141.8 and 144.7; m/z (ES+) 1301
−5.5(2), −4.9, −4.7, 17.9, 18.2, 24.6, 25.6, 25.8, 52.4, 66.3, (12%), 860 (45), 839 (32), 650 (M+, 100) and 400 (20).
71.1, 73.9, 87.3 and 154.0; m/z (CI+) 404 (M+ + 18, 100%) and
329 (30).
(E)-1,5,6-Tris-(tert-butyldimethylsilyloxy)-3-tri-n-
butylstannylhex-2-ene (11)
Methyl
(E)-5,6-bis-(tert-butyldimethylsilyloxy)-3-tri-n- tert-Butyldimethylsilyl chloride (2.22 g, 14.7 mmol) was added
butylstannylhex-2-enoate (17)
to the alcohol 18 (7.77 g, 12.3 mmol) and imidazole (1.67 g,
n-Butyllithium (1.6 M in hexanes, 11.67 mL, 18.33 mmol) was 24.5 mmol) in DCM (77 mL) at rt and the mixture stirred for 2
added to bis-tributyltin (9.26 mL, 18.33 mmol) in THF (14.1 mL) h. Water (50 mL) was added and the aqueous phase was
o
at 0 C. The solution was stirred for 25 min then added to a extracted with DCM (3 × 50 mL). The organic extracts were
suspension of copper(I) bromide dimethylsulfide complex dried (MgSO4) and concentrated under reduced pressure.
(3.77 g, 18.33 mmol) in THF (29 mL) at −50 oC. The mixture was Chromatography of the residue (light petroleum:ether:
o
o
stirred at −50 C for 30 min and cooled to −78 C. The alkyne triethylamine 98:1:1) gave the title compound 11 (8.66 g, 93%),
16 (2.36 g, 6.11 mmol) in THF (11.8 mL) was added and the as
a
colourless oil (Found: M+
−
C4H9, 707.3728.
10 | J. Name., 2012, 00, 1-3
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Page 11 of 31
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
C32H71O3Si3118Sn requires M, 707.3732); νmax/cm-1 2955, 2928, n-Butyllithium (2.5 M in hexanes, 0.99 mL, 2.47 mmol) was
View Article Online
DOI: 10.1039/C6OB01804A
2857, 1463, 1361, 1254, 1083, 1005, 979, 836 and 776; δH (300 added to propargyl alcohol (70 mg, 1.24 mmol) in THF (3 mL)
o
MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.01 (3 H, s, SiCH3), 0.02 (6 at −20 C and the solution stirred for 20 min then cooled to
o
H, s, 2 × SiCH3), 0.03 (3 H, s, SiCH3), 0.70-1.01 [42 H, m, 3 × −78 C. The aldehyde 19 (468 mg, 1.03 mmol) in THF (7 mL)
SiC(CH3)3, 3 × CH2CH3], 1.28 (6 H, m, 3 × CH2), 1.44 (6 H, m, 3 × was added and the solution stirred for 1 h before being
SnCH2), 2.29 and 2.45 (each 1 H, dd, J 13.4, 6.6, 4-H), 3.38 (2 H, allowed to warm to 0 oC. After stirring for 1 h, saturated
d, J 5.4, 6-H2), 3.59 (1 H, m, 5-H), 4.22 (1 H, dd J 13.6, 5.0, 1-H), aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL)
4.29 (1 H, dd J 13.6, 6.0, 1-Hʹ) and 5.69 (1 H, t, J 5.4, 2-H); δC were added and the aqueous phase was extracted with ethyl
(75 MHz, CDCl3) −5.5, −5.4, −5.1(2), −4.4(2), 9.6, 13.6, 18.1, acetate (3 × 10 mL). The organic extracts were dried (MgSO4)
18.3, 25.9, 27.4, 29.0, 39.1, 60.5, 67.3, 73.5, 140.4 and 143.4; and concentrated under reduced pressure. Chromatography of
m/z (CI+) 707 (M+ − 57, 3%), 462 (6), 443 (7), 334 (8), 308 (62), the residue (light petroleum:ethyl acetate 4:1 to 3:2) gave the
174 (61) and 90 (100).
title compound 20 (427 mg, 81%), as a colourless oil, a 50:50
mixture of diastereoisomers (1H NMR); νmax/cm-1 3424, 2983,
(E)-1,5,6-Tris-(tert-butyldimethylsilyloxy)-3-iodohex-2-ene (9) 2934, 2871, 1453, 1380, 1223, 1097, 1027 and 735; δH (300
The stannane 11 (8.66 g, 11.33 mmol) in DCM (130 mL) was MHz, CDCl3) 0.99, 1.02, 1.13 and 1.15 (each 1.5 H, s, 5-CH3),
added to N-iodosuccinimide (3.31 g, 14.72 mmol) in DCM (86 1.36 (3 H, s, CCH3), 1.38 and 1.39 (each 1.5 H, s, CCH3), 1.64-
mL) at rt and the solution stirred for 1 h before being 1.82 (6 H, m, 7-H2, 9-H2, 11-H2), 2.18 (1 H, br. s, OH), 3.55-3.62
concentrated under reduced presure. Chromatography of the (3 H, m, 6-H, 12-H2), 3.73 (0.5 H, br. s, OH), 3.85 (0.5 H, dd J
residue (light petroleum:ether: triethylamine 98:1:1) gave the 8.9, 2.3, OH), 4.00-4.11 (2 H, m, 8-H, 10-H), 4.29-4.36 (2 H, m,
title compound 9 (6.58 g, 97%), as a colourless oil (Found: M+ + 1-H2), 4.44 (1 H, m, 4-H), 4.53 (2 H, s, PhCH2), 4.64 and 4.69
NH4, 618.2699. C24H57INO3Si3 requires M, 618.2693); νmax/cm-1 (each 0.5 H, d, J 11.4, PhHCH), 4.73 (1 H, s, PhCH2) and 7.36 (10
2954, 2930, 2887, 2858, 1471, 1362, 1256, 1098, 1005, 983, H, m, ArH); δC (75 MHz, CDCl3) 18.7, 19.5, 20.4, 20.5, 20.7,
837 and 776; δH (300 MHz, CDCl3) 0.00 (12 H, br. s, 4 × SiCH3), 22.5, 24.8, 25.0, 25.1, 25.3, 29.0, 30.3, 35.8, 35.9, 38.2, 38.3,
0.03 and 0.04 (each 3 H, s, SiCH3), 0.82, 0.84 and 0.85 [each 9 38.7, 38.8, 42.2, 43.4, 51.0, 63.6, 63.7, 65.5, 65.7, 66.0, 66.4,
H, s, SiC(CH3)3], 2.50 (1 H, dd, J 14.3, 7.8, 4-H), 2.59 (1 H, dd, J 68.8, 69.2, 73.0, 73.8, 74.5, 81.6, 82.1, 84.1, 84.2, 85.0, 85.3,
14.3, 4.0, 4-Hʹ), 3.39 (1 H, dd, J 10.3, 6.2, 6-H), 3.50 (1 H, dd, J 100.3, 100.5, 127.3, 127.4, 127.5, 127.6, 127.7, 128.3, 128.4,
10.3, 4.7, 6-Hʹ), 3.82 (1 H, m, 5-H), 4.04 (1 H, dd J 13.2, 5.4, 1- 138.1, 138.3, 138.4 and 138.5; m/z (ES+) 1038 (2M+ + 18, 30%),
H), 4.17 (1 H, dd J 13.2, 7.1, 1-Hʹ) and 6.31 (1 H, dd J 7.1, 5.4, 2- 554 (50), 528 (M+ + 18, 100) and 453 (80).
H); δC (75 MHz, CDCl3) −5.4, −5.3(2), −4.5, −4.4, 17.9, 18.2,
25.8, 25.9, 44.4, 61.2, 66.3, 71.9, 100.8 and 143.2; m/z (CI+) (2E,4RS,6S,8R,10S)-6,12-Dibenzyloxy-8,10-di-O-
618 (M+ + 18, 5%), 469 (5), 337 (7), 240 (10) and 174 (100).
isopropylidene-5,5-dimethyldodeca-2-ene-1,4-diol (21)
Red-Al (0.97 mL, 3.28 mmol) was added dropwise to the
o
(E)-1,5,6-Tris-(tert-butyldimethylsilyloxy)-3-bromohex-2-ene
alkyne 20 (421 mg, 0.82 mmol) in THF (5 mL) at 0 C and the
(10)
reaction mixture slowly warmed to rt then stirred for 2 h.
The stannane 11 (200 mg, 0.26 mmol) in DCM (3 mL) was Water (5 mL) and ethyl acetate (10 mL) were added and the
added to N-bromosuccinimide (61 mg, 0.34 mmol) in DCM (2 aqueous phase extracted with ethyl acetate (3 × 10 mL). The
mL) at rt and the solution stirred for 2 h. Saturated aqueous organic extracts were dried (MgSO4) and concentrated under
sosium sulfite (5 mL) was added and the aqueous phase was reduced pressure. Chromatography of the residue (light
extracted with DCM (3 × 10 mL). The organic extracts were petroleum:ethyl acetate 1:1) gave the title compound 21 (319
dried (MgSO4) and concentrated under reduced presure. mg, 76%), as a colourless oil, a 55:45 mixture of epimers (1H
Chromatography of the residue (light petroleum:ether: NMR); νmax/cm-1 3425, 2982, 2934, 2897, 2869, 1453, 1368,
triethylamine 98:1:1) gave the title compound 10 (125 mg, 1223, 1169, 1094, 1027 and 735; δH (300 MHz, CDCl3) 0.86 (3
87%), as a colourless oil (Found: M+ + NH4, 570.2838. H, s, 5-CH3), 1.01 (1.4 H, s, 5-CH3ʹ), 1.09 (1.6 H, s, 5-CH3ʹ), 1.37
C24H5779BrNO3Si3 requires M, 570.2830); νmax/cm-1 2954, 2930, (6 H, s, 2 × CCH3), 1.61-1.84 (6 H, m, 7-H2, 9-H2, 11-H2), 3.57-
2857, 1655, 1472, 1255, 1093, 836 and 776; δH (300 MHz, 3.67 (3 H, m, 6-H, 12-H2), 3.99-4.12 (3 H, m, 4-H, 8-H, 10-H),
CDCl3) 0.01 (18 H, br. s, 6 × SiCH3), 0.81, 0.82 and 0.83 [each 9 4.15-4.25 (2 H, m, 1-H2), 4.53 (2 H, s, PhCH2), 4.64 and 4.70
H, s, SiC(CH3)3], 2.53 (1 H, dd, J 14.3, 7.9, 4-H), 2.59 (1 H, dd, J (each 0.45 H, d, J 11.4, PhHCH), 4.71 and 4.73 (each 0.55 H, d, J
14.3, 4.2, 4-Hʹ), 3.38 (1 H, dd, J 10.2, 6.2, 6-H), 3.50 (1 H, dd, J 11.1, PhHCH), 5.72-5.98 (2 H, m, 2-H, 3-H) and 7.37 (10 H, m,
10.2, 4.7, 6-Hʹ), 3.89 (1 H, m, 5-H), 4.06 (1 H, dd J 13.0, 5.8, 1- ArH); δC (75 MHz, CDCl3) 17.7, 19.7, 20.0, 22.5, 24.8, 25.0, 25.1,
H), 4.14 (1 H, dd J 13.0, 7.5, 1-Hʹ) and 6.01 (1 H, t, J 6.7, 2-H); δC 25.3, 30.2, 35.8, 38.0, 38.1, 38.8, 41.4, 42.6, 63.1, 63.2, 63.5,
(75 MHz, CDCl3) −5.4, −5.3, −4.7, 17.9, 18.2, 25.8, 41.4, 60.5, 63.6, 65.7, 66.4, 66.5, 73.0, 73.8, 75.2, 76.3, 82.5, 84.9, 100.2,
66.6, 71.1, 124.2 and 134.3; m/z (CI+) 572 (M+ + 18, 9%), 570 100.5, 127.1, 127.3, 127.5(2), 127.6, 127.8, 128.3(2), 128.4,
(M+ + 18, 9), 423 (50), 421 (45) and 174 (100).
130.5, 131.2, 131.6, 138.0, 138.4 and 138.6; m/z (ES+) 1042
(2M+ + 18, 35%), 535 (M+ + 23, 100), 530 (M+ + 18, 97) and 455
(85).
(4RS,6S,8R,10S)-6,12-Dibenzyloxy-8,10-di-O-isopropylidene-
5,5-dimethyldodeca-2-yne-1,4-diol (20)
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 12 of 31
ARTICLE
Journal Name
(2E,6S,8R,10S)-1-Bromo-6,12-dibenzyloxy-8,10-di-O-
isopropylidene-5,5-dimethyldodeca-2-en-4-one (12)
Tributyltin hydride (0.465 mL, 1.728 mmol) and AIBN (20
mg) were added to the sulfone 23 (550 mg, 0.864 mmol) in
View Article Online
DOI: 10.1039/C6OB01804A
Methane sulfonyl chloride (0.024 mL, 0.31 mmoL) was added degassed benzene (16 mL) and the mixture heated under
to the diol 21 (103 mg, 0.20 mmol) and triethylamine (0.043 reflux for 3 h. After concentration under reduced pressure,
o
mL, 0.60 mmol) in DCM (1 mL) at 0 C and the mixture stirred chromatography of the residue (light petroleum:ether:
for 10 min before the addition of lithium bromide (88 mg, 1.05 triethylamine 90:9:1) gave the title compound 13 (616 mg,
mmol) in acetone (1 mL). The yellow solution was stirred at 0 91%), as a colourless oil, a mixture of epimers (1H NMR);
oC for 90 min, then filtered through Celite and concentrated νmax/cm-1 3475, 2956, 2926, 2896, 2858, 1650, 1457, 1378,
under reduced pressure. Chromatography of the residue (light 1224, 1099, 1029 and 734; δH (300 MHz, CDCl3) 0.75-1.02 (27
petroleum:ethyl acetate 3:2) gave the bromododecenol 22 (45 H, m, 3 × CH2CH3, 2 × 5-CH3, 2 × CCH3), 1.20-1.77 (20 H, m, 3 ×
mg, 37%); νmax/cm-1 3450, 3030, 2934, 1379, 1223, 1097 and CH2, 3 × SnCH2, 1-H2, 7-H2, 9-H2, 11-H2), 3.40-3.70 (3 H, m, 6-H,
736; δH (300 MHz, CDCl3) 0.77, 0.79m 0.90 and 0.98 (each 1.5 12-H2), 3.90-4.10 (3 H, m, 4-H, 8-H, 10-H), 4.48 (2 H, s, PhCH2),
H, s, 5-CH3), 1.25 (1.5 H, s, CCH3), 1.26 (3 H, s, CCH3), 1.27 (1.5 4.60-4.80 (2 H, m, PhCH2), 5.29 (1 H, m, 3-H), 5.73 (1 H, m, 2-H)
H, s, CCH3), 1.40-1.82 (6 H, m, 7-H2, 9-H2, 11-H2), 3.38-3.58 (3 and 7.32 (10 H, m, ArH).
H, m), 3.80-4.15 (5 H, m), 4.42 (2 H, s, PhCH2), 4.54 and 4.59
(each 0.5 H, d, J 11.4, PhHCH), 4.61 (1 H, s, PhCH2), 5.65-6.00 (2 (Z)-6,7-Bis-(tert-butyldimethylsilyloxy)-4-(2-tert-
H, m, 2-H, 3-H) and 7.18-7.25 (10 H, m, ArH).
butyldimethylsilyloxyethylidene)hept-1-ene (24)
Dess-Martin periodinane (93 mg, 0.22 mmol) was added to The iodide 9 (6.58 g, 10.97 mmol) in THF (159 mL) was added
the alcohol 22 (42 mg, 0.074 mmol) in DCM (3 mL) at rt and to tetrakis(triphenylphosphine)palladium (635 mg, 0.55 mmol)
the solution stirred for 1 h. Saturated aqueous sodium in THF (113 mL) followed by tributyl(prop-2-enyl)stannane
bicarbonate (7 mL), saturated aqueous sodium sulfite (5 mL) (10.2 mL, 32.9 mmol) and the mixture was heated under reflux
were added and ether were added and the aqueous phase under nitrogen for 4 h. After concentration under reduced
extracted with ether (3 × 10 mL). The organic extracts were presure,
dried (MgSO4) and concentrated under reduced pressure. petroleum:triethylamine
chromatography
of
99:1
the
residue
to
(light
light
Chromatography of the residue (light petroleum:ether 4:1 to petroleum:ether:triethylamine 95:4:1) gave the title compound
7:3) gave the title compound 12 (31 mg, 74%), as a colourless 24 (5.16 g, 92%), as a colourless oil (Found: M+ + NH4,
oil; νmax/cm-1 2920, 2851, 1726, 1688, 1624, 1465, 1378, 1260, 532.4050. C27H62O3Si3N requires M, 532.4037); νmax/cm-1 3079,
1098, 1027, 780 and 738; δH (300 MHz, CDCl3) 1.20 and 1.25 2950, 2930, 2887, 1638, 1472, 1256, 1105, 836 and 768; δH
(each 3 H, s, 5-CH3), 1.38 and 1.40 (each 3 H, s, CCH3), 1.38- (400 MHz, CDCl3) 0.02, 0.04, 0.04(5) and 0.05 (each 3 H, s,
1.68 (4 H, m, 9-H2, 11-H2), 1.75-1.78 (2 H, m, 7-H2), 3.48-3.65 (2 SiCH3), 0.06 (6 H, s, SiCH3), 0.87 [9 H, s, SiC(CH3)3], 0.88 [18 H, s,
H, m, 12-H2), 3.89-4.10 (5 H, m, 1-H2, 6-H, 8-H, 10-H), 4.53 (2 H, 2 × SiC(CH3)3], 2.10 (1 H, dd, J 10.2, 6.0, 5-H), 2.33 (1 H, dd, J
s, PhCH2), 4.60 and 4.66 (each 1 H, d, J 11.1, PhHCH), 6.81 (1 H, 10.2, 3.6, 5-Hʹ), 2.79 (2 H, dd, J 5.1, 0.6, 3-H2), 3.36 (1 H, dd, J
d, J 15.1, 3-H), 6.93 (1 H, m, 2-H) and 7.37 (10 H, m, ArH); δC 7.5, 4.8, 7-H), 3.49 (1 H, dd, J 7.5, 3.9, 7-Hʹ), 3.71 (1 H, m, 6-H),
(75 MHz, CDCl3) 20.4, 21.0, 25.1, 25.3, 30.0, 35.9, 38.7, 38.9, 4.18 (1 H, dd J 9.9, 4.5, 2ʹ-H), 4.26 (1 H, dd J 9.9, 5.1, 2ʹ-Hʹ),
51.6, 63.3, 63.5, 66.5, 73.0, 74.8, 80.6, 100.2, 127.0, 127.2, 5.00-5.08 (2 H, m, 1-H2), 5.40 (1 H, t, J 6.2, 1ʹ-H) and 5.78 (1 H,
127.3, 127.4, 127.5, 127.6, 128.2, 128.3, 138.4, 139.2 and m, 2-H); δC (75 MHz, CDCl3) −5.4(2), −5.1, −4.6, 18.0, 18.1,
202.7.
25.8, 25.9(2), 35.6, 42.1, 60.3, 67.2, 72.3, 116.2, 128.1, 136.1
and 136.4; m/z (CI+) 532 (M+ + 18, 10%), 251 (100), 174 (48)
and 119 (80).
(2E,4RS,6S,8R,10S)-6,12-Dibenzyloxy-8,10-di-O-
isopropylidene-5,5-dimethyl-1-tributylstannyldodeca-2-en-4-
ol (13)
(Z)-6,7-Bis-(tert-butyldimethylsilyloxy)-4-(2-tert-
n-Butyllithium (1.5 M in hexanes, 0.81 mL, 1.21 mmol) was butyldimethylsilyloxyethylidene)heptane-1,2-diol (25)
added to phenyl(prop-2-enyl)sulfone (220 mg, 1.21 mmol) in Osmium tetroxide (15 mg) was added to the alkene 24 (1.2 g,
THF (2.5 mL) at −78 oC and the mixture stirred for 15 min. The 2.33 mmol) and trimethylamine-N-oxide dihydrate (311 mg,
aldehyde 19 (500 mg, 1.1 mmol) in THF (2.5 mL) was added 2.79 mmol) in DCM (28 mL) at rt and the reaction mixture
o
and the mixture stirred at −78 C for 2 h, allowed to warm to stirred for 16 h. After concentration under reduced presure,
rt, then cooled back to −78 oC. Saturated aqueous ammonium chromatography of the residue (light petroleum:ether 7:3)
chloride (10mL) was added and the mixture allowed to attain gave the title compound 25 (676 mg, 53%), as a brown oil, a
rt. Ether (15 mL) was added and the aqueous phase extracted mixture of epimers (1H NMR) (Found: M+ + NH4, 566.4088.
with ether. The organic extracts were dried (MgSO4) and C27H64IO5Si3N requires M, 566.4091); νmax/cm-1 3400, 2953,
concentrated under reduced pressure. Chromatography of the 2930, 2894, 2857, 1471, 1388, 1361, 1255, 1102, 1079, 836
residue (light petroleum:ether 3:2) gave the sulfone 23 (565 and 776; δH (300 MHz, CDCl3) 0.04 (18 H, overlapping s, 6 ×
mg, 81%), as a colourless oil, a mixture of epimers (Found: M+ SiCH3), 0.86 [9 H, s, SiC(CH3)3], 0.88 [18 H, s, 2 × SiC(CH3)3],
− C3H5O, 579.2748. C34H43O6S requires M, 579.2780); νmax/cm-1 2.00-2.35 (3 H, m, 3-H2, 5-H), 2.47 (1 H, dd, J 13.9, 4.0, 5-Hʹ),
3508, 3031, 2939, 2857, 1451, 1378, 1305, 1223, 1143, 1086 3.30-3.55 (3 H, m, 1-H2, 7-H), 3.60-3.75 (2 H, m, 2-H, 7-Hʹ), 3.82
and 777; m/z (CI+) 654 (M+ + 18, 2%), 579 (M+ − 57, 20) and (1 H, m, 6-H), 4.10-4.35 (2 H, m, 2ʹ-H2) and 5.49 (1 H, m, 1ʹ-H);
200 (100).
δC (75 MHz, CDCl3) −5.4, −5.2, −4.7, 17.9, 18.2, 25.8, 25.9, 35.1,
12 | J. Name., 2012, 00, 1-3
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ARTICLE
35.4, 41.2, 42.0, 60.0, 66.4, 66.9, 67.2, 69.6, 69.9, 72.3, 73.9, 4.3, 5-Hʹ), 3.03 (2 H, br. s, 3-H2), 3.37 (1 H, dd, J 9.8, 6.7, 7-H),
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130.3, 130.9, 134.1and 134.6; m/z (CI+) 566 (M+ + 18, 30%), 3.52 (1 H, dd, J 9.8, 4.9, 7-Hʹ), 3.76 (1 H, DmO,I:61-0H.1)0,349./2C36OanB0d1840.340A
516 (50), 174 (60) and 90 (100).
(each 1 H, dd, J 12.0, 6.0, 2ʹ-H) and 5.78 (1 H, t, J 6.0, 1ʹ-H); δC
(75 MHz, CDCl3) −5.4, −5.2, −4.8, −4.7, 17.9, 18.2, 18.3, 25.9,
27.3, 35.4, 60.1, 67.0, 70.8, 72.4, 81.5, 128.6 and 132.0; m/z
(CI+) 398 (M+ - 114, 10%), 381 (40), 174 (22) and 90 (100).
(E)-5,6-Bis-(tert-butyldimethylsilyloxy)-3-(2-tert-
butyldimethylsilyloxyethylidene)hexanal (26)
Sodium periodate (633 mg, 2.96 mmol) was added to a
suspension of the diol 25 (326 mg, 0.59 mmol) in a mixture of (Z)-6,7-Bis-(tert-butyldimethylsilyloxy)-4-(2-tert-
THF (3.2 mL), methanol (3.2 mL) and water (4 mL) and the butyldimethylsilyloxyethylidene)-1-tributylstannylhept-1-ene
mixture was stirred at rt for 1 h. Saturated aqueous sodium (28)
sulfite (5 mL) and ether (15 mL) were added and the aqueous Tributyltin hydride (0.11 mL, 0.43 mmol) was added to the
layer extracted with ether (3 × 15 mL). The organic extracts alkyne 27 (183 mg, 0.357 mmol) and AIBN (20 mg) in degassed
were washed with brine (59 mL), dried (MgSO4) and benzene (5 mL). The mixture was heated under reflux for 1 h
concentrated under reduced pressure to give the title then concentrated under reduced pressure. Chromatography
compound 26 (321 mg, ca. 100%), as a colourless oil; δH (300 of the residue (light petroleum:triethylamine 99:1 to light
MHz, CDCl3) 0.05 (3 H, s, SiCH3), 0.08 (9 H, s, 3 × SiCH3), 0.10 (6 petroleum:ether:triethylamine 98:1:1) gave the title compound
H, s, 2 × SiCH3), 0.90 [9 H, s, SiC(CH3)3], 0.93 [18 H, s, 2 × 28 (257 mg, 90%), as a colourless oil; νmax/cm-1 2955, 2928,
SiC(CH3)3], 2.24 (1 H, dd, J 13.7, 7.7, 4-H), 2.40 (1 H, dd, J 13.7, 2857, 1593, 1463, 1361, 1254, 1104, 1076, 1005, 836 and 776;
4.2, 4-Hʹ), 3.17 (2 H, br. s, 2-H2), 3.39 ( 1 H, dd, J 9.9, 6.8, 6-H), δH (300 MHz, CDCl3) 0.04 (3 H, s, SiCH3), 0.07 (9 H, s, 3 × SiCH3),
3.53 (1 H, dd, J 9.9, 4.7, 6-Hʹ), 3.75 (1 H, m, 5-H), 4.27 (1 H, dd, 0.09 (6 H, s, 2 × SiCH3), 0.88-0.94 [42 H, m, 3 × SiC(CH3)3, 3 ×
J 13.2, 5.7, 2ʹ-H), 4.33 (1 H, dd, J 13.2, 6.6, 2ʹ-Hʹ), 5.58 (1 H, t, J CH2CH3], 1.24-1.40 (6 H, m, 3 × CH2), 1.44-1.58 (6 H, m, 3 ×
6.1, 1ʹ-H) and 9.67 (1 H, t, J 2.3, 1-H); δC (75 MHz, CDCl3) −5.4, SnCH2), 2.11 (1 H, dd, J 13.4, 7.8, 5-H), 2.33 (1 H, dd, J 13.4, 5.0,
−5.2, −4.7, −4.6, 17.9, 18.2(2), 25.9, 36.1, 52.4, 60.0, 66.8, 5-Hʹ), 2.89 (2 H, br. s, 3-H2), 3.41 (1 H, dd, J 10.0, 6.0, 7-H), 3.45
72.3, 129.1, 133.0 and 200.1.
(1 H, dd, J 10.0, 5.1, 7-Hʹ), 3.74 (1 H, m, 6-H), 4.15-4.35 (2 H, m,
Pyridinium dichromate (32 mg, 0.085 mmol) was added to the 2ʹ-H2), 5.43 (1 H, t, J 5.9, 1ʹ-H) and 5.94 (2 H, narrow m, 1-H, 2-
alcohol 41 (40 mg, 0.077 mmol) in DCM (2 mL) and the mixture H); δC (75 MHz, CDCl3) −5.0, −4.7, −4.3, −4.2, 9.7, 14.0, 18.3,
stirred at rt for 18 h. More pyridinium dichromate (16 mg) was 18.6, 26.2, 26.3, 27.5, 29.4, 35.8, 46.6, 60.7, 67.6, 72.7, 128.4,
added and the stirring continued for 10 h. The mixture was filtered 130.2, 136.5 and 146.9; m/z (ES+) 827 (M+ + 23, 20%), 537
through a bed of silica and then concentrated under reduced (100) and 214 (65).
pressure to give the title compound 26 (24 mg, 60 %) as a colourless
oil, Rf = 0.4 (light petroleum:ethyl acetate 9:1) (Found: M+, (2RS,8RS,10S,12R,14S)-10,16-dibenzyl-1,2-bis-(tert-
516.3484. C26H56O4Si3 requires M, 516.3486); νmax/cm-1 2954, 2930, butyldimethylsilyloxy)-4-[(Z)-2-tert-
2857, 1728, 1471, 1361, 1255, 1105, 1081, 1006, 836 and 776; m/z butyldimethylsiloxyethylidene]-12,14-di-O-isopropylidene-
1
(CI+) 534 (M+ + 18, 35%), 517 (28), 385 (50) and 253 (100) with H 9,9-dimethylhexadec-6-yn-8-ol (29)
and 13C NMR spectra identical to those of a sample prepared from n-Butyllithium (1.6 M in hexanes, 0.22 mL, 0.373 mmol) was
the diol 25.
added to the alkyne 27 (191 mg, 0.373 mmol) in THF at −78 oC
and the solution stirred for 30 min before the addition of the
aldehyde 19 (169 mg, 0.373 mmol) in THF (1.4 mL). After being
stirred at −78 oC for 30 min, the solution was allowed to warm
(Z)-6,7-Bis-(tert-butyldimethylsilyloxy)-4-(2-tert-
butyldimethylsilyloxyethylidene)hept-1-yne (27)
Dimethyl diazomethylphosphonate (115 mg, 0.76 mmol) in to rt and was stirred for 1 h. Saturated aqueous ammonium
THF (9.4 mL) was added to a slurry of potassium tert-butoxide chloride (5 mL) and ether (10 mL) were added and the aqueous
(86 mg, 0.86 mmol) in THF (4.7 mL) at −78 oC and the mixture phase extracted with ether (3 × 25 mL). The organic extracts
stirred for 5 min before the adition of the aldehyde 26 (263 were dried (MgSO4) and concentrated under reduced
mg, 0.52 mmol) in THF (7.2 mL). The mixture was stirred at −78 pressure.
Chromatography
of
the
residue
(light
oC for 24 h. Water (5 mL) was added and the mixture allowed petroleum:ether 9:1 to 4:1) gave the title compound 29 (173
to warm to room temperature. Ether (10 mL) was added and mg, 70%), as a colourless oil, a mixture of diastereoisomers
the aqueous phase extracted with ether (3 × 25 mL). The only two being distinguished, 3:1 (1H NMR); νmax/cm-1 3446,
organic extracts were washed with brine (50 mL), dried 2953, 2928, 2857, 1472, 1463, 1380, 1362, 1256, 1224, 1100,
(MgSO4) and concentrated under reduced pressure. 836 and 777; δH (300 MHz, CDCl3) 0.06 and 0.08 (each 3 H, s,
Chromatography of the residue (light petroleum:ether 98:2) SiCH3), 0.09 and 0.10 (each 6 H, s, 2 × SiCH3), 0.91 [9 H, s,
gave the title compound 27 (183 mg, 70%), as a colourless oil SiC(CH3)3], 0.93 [18 H, s, 2 × SiC(CH3)3], 0.98-1.00 (3 H, 2 × s, 9-
(Found: MH+ − Si(CH3)2C(CH3)3, 398.2676. C21H42O3Si2 requires CH3), 1.14-1.16 (3 H, 2 × s, 9-CH3ʹ),1.36-1.40 (6 H, 3 × s, 2 ×
M, 398.2672); νmax/cm-1 3315, 2955, 2930, 2887, 2858, 1472, CCH3), 1.60-1.82 (6 H, m, 11-H2, 13-H2, 15-H2), 2.18 (1 H, dd, J
1361, 1258, 1105, 836, 809 and 776; δH (300 MHz, CDCl3) 0.05, 13.7, 7.0, 3-H), 2.43 (1 H, dd, J 13.7, 4.0, 3-Hʹ), 3.08 (2 H, br. s,
0.07, 0.07(5) and 0.08 (each 3 H, s, SiCH3), 0.09 (6 H, s, 2 × 5-H2), 3.29 (1 H, t, J 4.9, 10-H), 3.39 (1 H, dd, J 10.0, 6.7, 1-H),
SiCH3), 0.90, 0.92 and 0.93 [each 9 H, s, SiC(CH3)3], 2.14 (1 H, t, 3.56 (3 H, m, 1-Hʹ, 16-H2), 3.75 (1 H, m, 2-H), 3.95-4.15 (2 H, m,
J 2.6, 1-H), 2.17 (1 H, dd, J 13.8, 8.0, 5-H), 2.49 (1 H, dd, J 13.9, 12-H, 14-H), 4.27 (2 H, m, 2ʹ-H2), 4.49 (1 H, m, 8-H), 4.53 (2 H,
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Organic & Biomolecular Chemistry
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s, PhCH2), 4.70 and 4.75 (each 1 H, d, J 11.0, PhHCH), 5.78 (1 the mixture stirred for 1 h. Saturated aqueous sodium
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H, t, J 6.3, 1ʹ-H) and 6.74 (10 H, m, ArH); m/z (ES+) 984 (M+ + bicarbonate (2 mL) and saturated aqueous sodium sulfite (2
DOI: 10.1039/C6OB01804A
18, 100%), 777 (20), 533 (33) and 503 (52).
mL) were added followed by ether (5 mL). The aqueous phase
Dess-Martin periodinane (ca. 20 mg) was added to the extracted with ether (3 × 5 mL) and the organic extracts were
alcohol 29 (18 mg, 0.019 mmol) in DCM (1 mL) at rt and the dried (MgSO4) and concentrated under reduced pressure.
solution stirred for 1 h. Saturated aqueous sodium bicarbonate Chromatography of the residue (light petroleum:ethyl acetate
(2 mL) and saturated aqueous sodium sulfite (2 mL) were 9:1 to 4:1) gave the title compound 8 (46 mg, ca. 100%), as a
added followed by ether (5 mL). The aqueous phase was colourless oil; νmax/cm-1 2952, 2932, 2858, 1669, 1621, 1466,
extracted with ether (3 × 5 mL) and the organic extracts were 1381, 1254, 1105, 837 and 777; δH (300 MHz, CDCl3) 0.05 (3 H,
dried (MgSO4) and concentrated under reduced pressure. s, SiCH3), 0.07 (15 H, s, 5 × SiCH3), 0.92, 0.95 and 0.96 [each 9
Chromatography of the residue (light petroleum:ethyl acetate H, s, SiC(CH3)3], 1.15 and 1.18 (each 1.5 H, s, 9-CH3), 1.21 (3 H,
9:1) gave the ketone 30 (16 mg, 89%), as a colourless oil, a s, 9-CH3ʹ), 1.38 and 1.40 (each 3 H, s, CCH3), 1.50-1.65 (4 H, m,
mixture of epimers; νmax/cm-1 2929, 2857, 2209, 1672, 1472, 15-H2, 13-H2), 1.70-1.90 (2 H, m, 11-H2), 2.13 and 2.38 (each 1
1380, 1253, 1102, 836 and 776; δH (300 MHz, CDCl3) 0.06 (3 H, H, m, 3-H), 2.97 (2 H, br. d, J 5.2, 5-H2), 3.39 (1 H, m, 1-H), 3.50-
s, SiCH3), 0.09 (15 H, s, 5 × SiCH3), 0.91, 0.92 and 0.93 [each 9 3.65 (3 H, m, 1-Hʹ, 16-H2), 3.72 (1 H, m, 2-H), 3.90-4.10 (3 H, m,
H, s, SiC(CH3)3), 1.20 and 1.31 (each 3 H, s, 9-CH3), 1.37 and 10-H, 12-H, 14-H), 4.10-4.30 (2 H, m, 2ʹ-H2), 4.49 (2 H, s,
1.39 (each 3 H, m, CCH3), 1.50-1.70 (4 H, m, 11-H2, 13-H2), PhCH2), 4.61 (2 H, m, PhCH2), 5.42 (1 H, t, J 6.3, 1ʹ-H), 6.62 (1 H,
1.76-1.84 (2 H, m, 15-H2), 2.21 (1 H, m, 3-H), 2.47 (1 H, dd, J d, J 15.0, 7-H), 6.91 (1 H, m, 6-H) and 7.28 (10 H, m, ArH); m/z
13.8, 4.1, 3-Hʹ), 3.26 (2 H, br. s, 5-H2), 3.37 (1 H, dd, J 10.0, 7.0, (ES+) 989 (M+ + 23, 100%) and 984 (M+ + 18, 75).
1-H), 3.50-3.64 (3 H, m, 1-Hʹ, 16-H2), 3.74 (1 H, m, 2-H), 3.98-
Potassium tert-butoxide (12 mg, 0.11 mmol) was added to
4.17 (3 H, m, 10-H, 12-H, 14-H), 4.20-4.34 (2 H, m, 2ʹ-H2), 4.53 the phosphonate 33 (62 mg, 0.11 mmol) in THF (1 mL) at −78
and 4.65 (each 2 H, s, PhCH2), 5.78 (1 H, t, J 6.3, 1ʹ-H) and 7.33 oC and the resulting suspension stirred for 45 min. The
(10 H, m, ArH); δC (75 MHz, CDCl3) −5.2(2), −5.0, −4.9, −4.5(2), aldehyde 26 (50 mg, 0.097 mmol) in THF (1 mL) was added and
18.1, 18.4(2), 19.9, 21.3, 25.2, 25.5, 26.0, 26.1, 28.3, 29.8, the reaction mixture allowed to warm to rt then stirred for 16
35.6, 36.0, 38.6, 38.9, 53.0, 60.0, 63.5, 63.6, 66.6, 66.9, 72.8, h. Saturated aqueous ammonium chloride (2 mL) and ether (5
73.1, 74.6, 79.8, 81.8, 93.1, 100.2, 127.2, 127.3, 127.5, 127.6, mL) were added and the aqueous phase extracted with ether
128.2, 128.3, 129.5, 131.0, 138.4, 138.6 and 193.0.
(3 × 5 mL). The organic extracts were dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue (light petroleum:ether 9:1 to 4:1) gave the ketone 8
(56 mg, 60%) as a colourless oil with spectroscopic data
identical to those of the sample prepared earlier.
(2RS,10S,12R,14S)-10,16-dibenzyl-1,2-bis-(tert-
butyldimethylsilyloxy)-4-[(Z)-2-tert-
butyldimethylsiloxyethylidene]-12,14-di-O-isopropylidene-
9,9-dimethylhexadec-6-en-8-one (8)
n-Butyllithium (1.6 M in hexanes, 0.2 mL, 0.32 mmol) was Dimethyl (4S,6R,8S)-4,10-dibenzyl-6,8-di-O-isopropylidene-
added to the stannane 28 (257 mg, 0.32 mmol) in THF (4 mL) 3,3-dimethyl-2-oxodecan-1-ylphosphonate (33)
o
at −50 C and the solution stirred for 30 min then cooled to n-Butyllithium (1.6 M in hexanes, 0.81 mL, 1.27 mol) was
o
−78 C. The aldehyde 19 (146 mg, 0.32 mmol) in THF (2.6 mL) added to dimethyl methylphosphonate (0.14 mL, 1.29 mmol)
o
was added and the yellow solution allowed to warm to rt in THF (4.4 mL) at −78 C and the solution stirred for 45 min
before being stirred for 2 h. Saturated aqueous ammmonium before the aldehyde 19 (293 mg, 0.65 mmol) in THF (1.5 mL)
chloride (5 mL) and ether (10 mL) were added and the aqueous was added. The solution was stirred at −78 oC for 5 h and then
layer extracted with ether (3 × 15 ml). The organic extracts saturated aqueous ammonium chloride (5 mL) was added. The
were washed with brine (40 mL), dried (MgSO4) and mixture was allowed to attain rt and ether (10 mL) was added.
concentrated under reduced pressure. Chromatography of the The aqueous phase was extracted with ether (3 × 10 mL) and
residue (light petroleum:ether 4:1 to 7:3) gave the alcohol 31 the organic extracts were dried (MgSO4) and concentrated
(188 mg, 60%), as
a
colourless oil,
a
mixture of under reduced pressure. Chromatography of the residue
diastereoisomers; νmax/cm-1 3476, 2953, 2931, 2887, 2857, (ether to ethyl acetate) gave the hydroxydecylphosphonate 32
1466, 1381, 1253, 1223, 1102, 836 and 776; δH (300 MHz, (257 mg, 69%), as a colourless oil, a mixture of epimers (1H
CDCl3) 0.00 (3 H, s, SiCH3), 0.03 (15 H, s, 5 × SiCH3), 0.79 (3 H, NMR); νmax/cm-1 3441, 2951, 2855, 1454, 1380, 1226, 1033,
m, 9-CH3), 0.97 [27 H, br. s, 3 × SiC(CH3)3), 1.04 (3 H, s, 9-CH3ʹ), 849, 828 and 736; δH (300 MHz, CDCl3) 0.92, 0.93, 1.12 and
1.32 (6 H, m, 2 × CCH3), 1.56-1.77 (6 H, m, 11-H2, 13-H2, 15-H2), 1.13 (each 1.5 H, s, 3-CH3), 1.37 and 1.38 (each 3 H, s, 2 ×
2.08 and 2.29 (each 1 H, m, 3-H), 2.79 (2 H, br. d, J 5.3, 5-H2), CCH3), 1.60-1.90 (6 H, m, 5-H2, 7-H2, 9-H2), 3.40-3.60 (3 H, m, 4-
3.36 (1 H, m, 1-H), 3.43-3.53 (5 H, m, 1-H, 2-H, 10-H, 16-H2), H, 10-H2), 3.70-3.90 (8 H, m, 2 x OCH3, 6-H, 8-H), 3.90-4.10 (2
3.90-4.10 (2 H, m, 12-H, 14-H), 4.10-4.25 (3 H, m, 8-H, 2ʹ-H2), H, m, 1-H2), 4.18 (1 H, m, 2-H), 4.54 (2 H, s PhCH2), 4.68 (2 H,
4.48 (2 H, s, PhCH2), 4.66 (2 H, 2 × d, J 11.0, PhHCH), 5.37 (1 H, m, PhCH2) and 7.18 (10 H, m, ArH).
m, 1ʹ-H), 5.45-5.68 (2 H, m, 6-H, 7-H) and 7.30 (10 H, m, ArH);
The Dess-Martin periodinane (533 mg, 1.25 mmol) was
added to the hydroxydecanylphosphonate 32 (242 mg, 0.42
m/z (ES+) 991 (M+ + 23, 70%), 533 (40), 512 (50) and 437 (55).
Dess-Martin periodinane (66 mg, 0.155 mmol) was added mmol) in DCM (10 mL) at rt and the mixture stirred for 2 h.
to the alcohol 31 (50 mg, 0.051 mmol) in DCM (2 mL) at rt and Saturated aqueous sodium bicarbonate (5 mL) and saturated
14 | J. Name., 2012, 00, 1-3
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ARTICLE
aqueous sodium sulfite (5 mL) were added. The aqueous phase 8.5, 4-H), 2.76 (1 H, dd, 13.5, 3.0, 4-H’), 3.51 (1 H, dd,VJiew10A.r0tic,le7.O5n,lin6e-
DOI: 10.1039/C6OB01804A
extracted with DCM (3 × 10 mL) and the organic extracts were H), 3.55 (1 H, dd, J 10.0, 4.5, 6-H’), 3.77 (1 H, m, 5-H), 4.27 (1 H, dd, J
dried (MgSO4) and concentrated under reduced pressure. 13.0, 6.5, 1-H), 4.35 (1 H, dd, J 13.0, 7.5, 1-H’), 5.19 (1 H, d, J 11.0,
Chromatography of the residue (ether to ethyl acetate) gave 2’-H), 5.35 (1 H, d, J 17.5, 2’-H’), 5.63 (1 H, t, J 7.0, 2-H) and 6.62 (1
the title compound 33 (159 mg, 66%), as a colourless oil; H, dd, 17.5, 11.0, 1’-H); δC (50 MHz, CDCl3) −4.9, −4.8, −4.1, −4.0,
νmax/cm-1 2950, 28578 1704, 1455, 1378, 1258, 1225, 1173 18.6, 18.8, 26.4, 26.4, 39.4, 59.2, 67.7, 72.4, 116.4, 131.4, 132.7 and
1100, 1033 and 739; δH (300 MHz, CDCl3) 1.221 and 1.25 (each 136.9; m/z (CI+) 404 (M+ + 18, 21) and 174 (100 %).
3 H, s, 3-CH3), 1.37 and 1.40 (each 3 H, s, CCH3), 1.52-1.81 (6 H,
m, 5-H2, 7-H2, 9-H2), 3.15-3.40 (2 H, m, 1-H2), 3.50-3.64 (2 H, m, Methyl (E)-6-tert-butyldimethylsilyloxy-3-ethenyl-5-hydroxyhex-2-
10-H2), 3.76 (3 H, d, J 3.7, OCH3), 3.79 (1 H, m, 4-H), 3.81 (3 H, enoate (36)
d, J 3.7, OCH3), 3.95-4.12 (2 H, m, 6-H, 8-H), 4.51 (2 H, s Ethenylmagnesium bromide (0.9 M in THF, 16 mL, 14.1 mmol) was
PhCH2), 4.60 and 4.68 (each 1 H, d, J 11.6, PhHCH) and 7.34 (10 added dropwise to copper(I) iodide (1.57 g, 8.27 mmol) suspended
o
o
H, m, ArH).
in THF (30 mL) at –78 C. The mixture was stirred at −78 C for 10
min then warmed to –30 oC and stirred for 1 h to give a dark green
(Z)-5,6-bis-(tert-butyldimethylsilyloxy)-3-ethenylhex-2- suspension. This mixture was cooled to –78 C, the hexynoate 15
o
Methyl
enoate (34)
(500 mg, 1.84 mmol) in THF (10 mL) was added and the mixture
Ethenylmagnesium bromide (0.9 M in THF, 3.02 mL, 2.72 mmol) stirred at –78 oC for 2 h. Saturated aqueous ammonium chloride (20
was added dropwise to a stirred suspension of copper(I) iodide (271 mL) was added and the mixture and allowed to warm to rt then
mg, 1.43 mmol) in THF (7 mL) at –30 oC and the mixture stirred for extracted with ethyl acetate (3 × 10 mL). The organic extracts were
30 min then cooled to –78 oC. After 30 min, the hexynoate 16 (130 washed with brine, dried (MgSO4) and concentrated reduced
mg, 0.34 mmol) in THF (2 mL) was added slowly and the reaction pressure. Chromatography of the residue (light petroleum to light
mixture stirred at for 1.5 h. Saturated aqueous ammonium chloride petroleum:ethyl acetate 1:1) gave the title compound 36 (495 mg,
(2 mL) was added and the mixture was allowed to warm to rt and 90 %) as a colourless oil, Rf = 0.3 (light petroleum:ethyl acetate 9:1)
extracted with ethyl acetate (3 × 5 mL). The organic extracts were (Found: M+ + H+, 301.1836. C15H29O4Si requires M, 301.1835);
washed with brine, dried (MgSO4) and concentrated under reduced νmax/cm-1 3467, 2953, 2930, 2857, 1714, 1697, 1624, 1602, 1462,
pressure. Chromatography of the residue (light petroleum to light 1435, 1376, 1257, 1194, 1177, 1158, 1117, 1066, 921 and 838; δH
petroleum:ethyl acetate 9:1) gave the title compound 34 (106 mg, (300 MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.83 [9 H, s, SiC(CH3)3],
75 %) as a colourless oil, an 80:20 mixture of (Z):(E)-isomers (1H 2.79 (1 H, dd, J 13.2, 3.7, 4-H), 2.95 (1 H, dd, J 13.2, 8.8, 4-H’), 3.29
NMR), Rf = 0.5 (light petroleum:ethyl acetate 9:1) (Found: M+ + H+, (1 H, d, J 5.9, OH), 3.48 (1 H, dd, J 9.8, 6.2, 6-H), 3.58 (1 H, dd, J 9.8,
415.2693. C21H43O4Si2 requires M, 415.2700); νmax/cm-1 2952, 2930, 5.2, 6-H’), 3.64 (3 H, s, CO2CH3), 3.69 (1 H, m, 5-H), 5.34 (1 H, d, J
2858, 1720, 1637, 1589, 1470, 1435, 1362, 1253, 1160, 1110, 1082, 10.7, 2’-H), 5.64 (1 H, d, J 17.4, 2’-H’), 5.86 (1 H, s, 2-H) and 6.31 (1
837 and 777; δH (300 MHz, CDCl3) major (Z)-isomer 34 0.01 and 0.07 H, dd, J 17.4, 10.7, 1’-H); δC (75 MHz, CDCl3) −5.5, 18.2, 25.8, 31.2,
(each 3 H, s, SiCH3), 0.14 (6 H, 2 × SiCH3), 0.92 and 0.98 [each 9 H, s, 51.4, 67.3, 72.1, 120.2, 120.9, 138.8, 153.6 and 168.3; m/z (CI+) 301
SiC(CH3)3], 2.17 (1 H, dd, J 13.3, 8.8, 4-H), 3.04 (1 H, dd, J 13.3, 2.7, (M+ + 1, 100 %) and 269 (52).
4-H’), 3.42 (1 H, dd, J 9.5, 8.2, 6-H), 3.66 (1 H, dd, J 9.8, 4.5, 6-H’),
3.78 (3 H, s, CO2CH3), 3.84 (1 H, m, 5-H), 5.53 (1 H, d, J 11.1, 2’-H), Methyl
5.73 (1 H, d, J 17.7, 2’-H’), 5.84 (1 H, s, 2-H) and 7.81 (1 H, dd, J 17.7, enoate (37)
(E)-5,6-bis-(tert-butyldimethylsilyloxy)-3-ethenylhex-2-
11.1, 1’-H); δC (75 MHz, CDCl3) −5.5, −5.5, −4.8, −4.7, 17.9, 18.2, tert-Butyldimethylsilyl trifluoromethanesulfonate (436 µL, 1.9
25.7, 25.8, 39.1, 50.9, 67.2, 72.2, 119.4, 120.6, 133.1, 151.8 and mmol) was added to the hydroxyester 36 (500 mg, 1.72 mmol) in
166.3; m/z (CI+) 415 (M+ + H, 100 %) and 174 (43).
DCM (8 mL) at –15 oC and the mixture stirred 10 min. Water (5 mL)
was added and the mixture was extracted with ether (3 × 10 mL).
(Z)-5,6-Bis-(tert-butyldimethylsilyloxy)-3-ethenylhex-2-en-1-ol (35) The organic extracts were washed with water (5 mL) and brine (5
Di-isobutylaluminium hydride (1 M in hexanes, 12.3 mL, 12.3 mmol) mL) then dried (MgSO4) and concentrated under reduced pressure.
was added to the ester 34 (1.7 g, 4.1 mmol) in THF (16 mL) at –78 oC Chromatography of the residue (light petroleum to light
and the mixture was allowed to warm to rt. Water (5 mL), saturated petroleum:ether 9:1) gave the title compound 37 (420 mg, 60 %) as
aqueous sodium potassium tartrate (40 mL) and ether (30 mL) were a colourless oil, Rf = 0.7 (light petroleum:ethyl acetate 9:1) (Found:
added and the suspension was stirred overnight at rt to produce M+ + H+, 415.2692. C21H43O4Si2 requires M, 415.2700); νmax/cm-1
two clear layers. The mixture was extracted with ether (3 × 30 mL) 2952, 2930, 2894, 2857, 1721, 1625, 1601, 1471, 1463, 1434, 1362,
and the organic extracts were washed with brine (10 mL), dried 1256, 1194, 1158, 1112, 1083, 987, 836 and 776; δH (300 MHz,
(MgSO4)
and
concentrated
under
reduced
pressure. CDCl3) 0.00, 0.01, 0.13 and 0.14 (each 3 H, s, SiCH3), 0.89 and 0.98
Chromatography of the residue (light petroleum to ethyl acetate) [each 9 H, s, SiC(CH3)3], 3.03 (1 H, dd, J 12.7, 3.8, 4-H), 3.28 (1 H, dd,
gave the title compound 35 (1.39 g, 72 %) as a colourless oil, Rf = 0.2 J 12.8, 8.9, 4-H’), 3.53 (1 H, dd, J 9.9, 6.6, 6-H), 3.66 (1 H, dd, J 9.8,
+
(light petroleum:ethyl acetate 9:1) (Found: M+ + NH4 , 404.3007. 5.0, 6-H’), 3.77 (3 H, s, CO2CH3), 3.95 (1 H, m, 5-H), 5.46 (1 H, d, J
C20H46NO3Si2 requires M, 404.3015); νmax/cm-1 3336, 2954, 2930, 10.9, 2’-H), 5.71 (1 H, d, J 17.4, 2’-H’), 5.92 (1 H, s, 2-H) and 6.41 (1
2858, 1596, 1471, 1388, 1361, 1255, 1117, 1097, 1005, 836 and H, dd, J 17.4, 10.8, 1’-H); δC (75 MHz, CDCl3) −5.5(2), −4.8, −4.6,
776; δH (300 MHz, CDCl3) –0.05, 0.00, 0.05 and 0.06 (each 3 H, s, 17.9, 18.3, 25.8, 25.9, 31.9, 50.9, 67.8, 72.9, 119.9, 120.7, 139.4,
SiCH3), 0.86 and 0.90 [each 9 H, s, SiC(CH3)3], 2.05 (1 H, dd, J 13.5,
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
153.8 and 166.8; m/z (CI+) 432 (M+ + 18, 85%) and 415 (M+ + H+, petroleum:ether 9:1) gave the title compound 40 (2.41 g, 88 %) as a
View Article Online
DOI: 10.1039/C6OB01804A
100).
colourless oil, Rf = 0.8 (light petroleum:ethyl acetate 9:1) (Found:
M+ + H+, 501.3606. C26H57O3Si3 requires M, 501.3615); νmax/cm-1
2954, 2930, 2857, 1607, 1472, 1388, 1361, 1255, 1107, 1079, 1005,
939, 901, 836 and 776; δH (300 MHz, CDCl3) 0.00, 0.05, 0.10 and
6-tert-Butyldimethylsilyloxymethyl-4-ethenyl-5,6-dihydropyran-2-
one (38)
Toluene p-sulfonic acid hydrate (2.5 mg) and molecular sieves (3 Å, 0.11 (each 3 H, s, SiCH3), 0.90, 0.95 and 0.96 [each 9 H, s, SiC(CH3)3],
10 mg) were added to the hydroxyester 36 (50 mg, 0.17 mmol) in 2.27 (1 H, dd, J 13.7, 8.8, 4-H), 2.66 (1 H, dd, J 13.9, 3.6, 4-H’), 3.41
THF (2.5 mL) and the mixture was stirred at rt for 72 h. Saturated (1 H, dd, J 9.8, 7.1, 6-H), 3.59 (1 H, dd, J 9.8, 4.8, 6-H’), 3.78 (1 H, m,
aqueous sodium bicarbonate (10 mL) was added and the mixture 5-H), 4.33 (1 H, dd, J 13.9, 5.4, 2’-H), 4.44 (1 H, dd, J 13.9, 7.1, 2’-H’),
extracted with ethyl acetate (3 × 5 mL). The organic extracts were 5.05 (1 H, d, J 10.9, 1-H), 5.27 (1 H, d, J 17.6, 1-H’), 5.71 (1 H, t, J 5.8,
washed with water (5 mL) and brine (5 mL) then dried (MgSO4) and 1’-H) and 6.34 (1 H, dd, J 17.6, 10.9, 2-H); δC (75 MHz, CDCl3) −5.4,
concentrated under reduced pressure to yield the title compound −5.2, −4.8, −4.6, 17.9, 18.2, 18.3, 25.9, 31.9, 60.4, 67.5, 72.2, 112.5,
38 (25 mg, 56 %) as white crystals, Rf = 0.6 (light petroleum:ethyl 134.42, 135.5 and 140.0; m/z (CI+) 391 (38%), 369 (57), 237 (80) and
acetate 1:1) (Found: M+ + H+, 269.1568. C14H25O3Si requires M, 174 (100).
269.1573); νmax/cm-1 2949, 2928, 2856, 1702, 1397, 1250, 1044,
990, 835 and 776; δH (300 MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.80 (Z)-5,6-Bis-(tert-butyldimethylsilyloxy)-3-(2-tert-
[9 H, s, SiC(CH3)3], 2.40-2.50 (2 H, m, 5-H2), 3.70-3.82 (2 H, m, 6- butyldimethylsilyloxyethylidene)hexan-1-ol (41)
CH2), 4.37 (1 H, m, 6-H), 5.47 (1 H, d, J 10.6, 2’-H), 5.59 (1 H, d, J Borane (1.0 M in THF, 1.1 mL, 1.1 mmol) was added to 2-methylbut-
17.5, 2’-H’), 5.79 (1 H, s, 3-H), 6.43 (1 H, dd, J 17.5, 10.7, 1’-H); δC 2-ene (2.0 M in THF, 1.2 mL, 2.3 mmol) at rt and the mixture was
(75 MHz, CDCl3) −5.5, 18.2, 24.8, 25.8, 64.2, 77.2, 117.7, 121.7, stirred for 2 h then added to the diene 40 (500 mg, 1.0 mmol). After
135.4, 152.2 and 165.0; m/z (CI+) 286 (M+ + 18, 50%), 269 (M+ + 1, being stirred at rt for 18 h, aqueous sodium hydroxide (3 M, 3 mL)
100) and 286 (50).
and aqueous hydrogen peroxide (30 %, 3 mL) were added and the
mixture was stirred at rt for 3 h. The mixture was extracted with
(E)-5,6-Bis-(tert-butyldimethylsilyloxy)-3-ethenylhex-2-en-1-ol (39) ether (4 × 3 mL) and the organic extracts were washed with brine,
Di-isobutylaluminium hydride (1.0 M in THF, 18 mL, 18 mmol) was dried (MgSO4) and concentrated under reduced pressure.
added to the ester 37 (3.2 g, 7.7 mmol) in THF (35 mL) at –78 oC and Chromatography of the residue (light petroleum to ether) gave the
the mixture was allowed to warm to rt when water (10 mL), title compound 41 (93 mg, 18 %) as a colourless oil, Rf = 0.3 (light
+
saturated aqueous sodium potassium tartrate (20 mL) and ether (20 petroleum:ethyl acetate 9:1) (Found: M+
+
NH4 , 536.4005.
mL) were added. After stirring for 1 h, the mixture was extracted C26H62NO4Si3 requires M, 536.3986); νmax/cm-1 3408, 2954, 2929,
with ethyl acetate (3 × 20 mL), and the organic extracts were 2857, 1662, 1471, 1389, 1361, 1255, 1108, 1079, 836 and 776; δH
washed with brine (10 mL), dried over (MgSO4) and concentrated (300 MHz, CDCl3) 0.00, 0.02(5), 0.03 and 0.03(5) (each 3 H, s, SiCH3),
under reduced pressure. Chromatography of the residue (light 0.04 (6 H, s, 2 × SiCH3) 0.85 [9 H, s, SiC(CH3)3], 0.88 (18 H, s, 2 ×
petroleum to light petroleum:ethyl acetate 1:1) gave the title SiC(CH3)3], 1.60 (1 H, s, OH), 2.11 (1 H, dd, J 13.6, 7.8, 4-H), 2.24-
compound 39 (2.19 g, 71 %) as a colourless oil, Rf = 0.2 (light 2.39 (3 H, m, 4-H’, 2-H2), 3.35 (1 H, dd, J 9.9, 6.7, 6-H), 3.51 (1 H, dd,
petroleum:ethyl acetate 9:1) (Found: M+ + H+, 387.2751. C20H43O3Si2 J 9.9, 4.8, 6-H’), 3.64-3.74 (3 H, m, 1-H2, 5-H), 4.17 (1 H, dd, J 13.0,
requires M, 387.2750); νmax/cm-1 3240, 2952, 2931, 2857, 1601, 5.8, 2’-H), 4.26 (1 H, dd, J 12.9, 6.7, 2’-H’) and 5.45 (1 H, t, J 6.2, 1’-
1463, 1361, 1255, 1112, 1077, 1004, 983, 902, 837 and 774; δH (300 H); δC (300 MHz, CDCl3) −5.4, −5.2, −4.7, −4.6, 17.9, 18.2, 18.3, 25.8,
MHz, CDCl3) 0.00, 0.04, 0.08 and 0.09 (each 3 H, s, SiCH3), 0.87 and 25.9, 35.2, 40.6, 60.0, 60.4, 67.1, 72.6, 130.0 and 134.2; m/z (ES+)
0.92 [each 9 H, s, SiC(CH3)3], 2.43 (1 H, s, OH), 2.44 (1 H, dd, J 14.0, 541 (M+ + 23, 45%), 536 (M+ + 18, 75), 387 (85) and 255 (100).
9.6, 4-H), 2.44 (1 H, dd, J 13.9, 3.4, 4-H’), 3.41 (1 H, dd, J 9.9, 7.7, 6-
H), 3.64 (1 H, dd, J 9.9, 4.4, 6-H’), 3.84 (1 H, m, 5-H), 4.15-4.30 (2 H, Methyl
(Z)-6-tert-butyldimethylsilyloxy-5-hydroxy-3-prop-2-
m, 1-H2), 5.08 (1 H, d, J 10.9, 2’-H), 5.27 (1 H, d, J 17.7, 2’-H’), 5.91 (1 enylhexa-2-enoate (42)
H, t, J 7.0, 2-H) and 6.32 (1 H, dd, J 17.6, 10.9, 1’-H); δC (75 MHz, Dimethyl sulfide (8 mL) was added to a suspension of copper(I)
CDCl3) −5.5, −4.9, −4.4, 18.0, 18.2, 25.8, 31.5, 58.7, 67.4, 71.5, iodide (3.85 g, 20.2 mmol) in THF (80 mL) to obtain a clear solution
o
113.2, 132.9, 138.4 and 139.6; m/z (CI+) 369 (M+ − 17, 14) and 174 that was cooled to –78 C. Prop-2-enylmagnesium bromide (1.0 M
(100 %).
in THF, 37 mL, 37 mmol)) was added dropwise and the mixture
stirred for a 30 min. The hexynoate 15 (1.0 g, 3.7 mmol) in THF (40
mL) was added dropwise to the resulting slurry and the reaction
(E)-5,6-Bis-(tert-butyldimethylsilyloxy)-3-(2-tert-
butyldimethylsilyloxyethylidene)hex-1-ene (40)
o
mixture stirred at –78 C for 1 h. Saturated aqueous ammonium
Triethylamine (1.44 mL, 11 mmol) was added to the alcohol 39 (2.1 chloride (100 mL) was added and the mixture allowed to warm to rt
g, 5.4 mmol) in DCM (30 mL) and the solution cooled to −15 oC. tert- then extracted with ether (3 × 100 mL). The organic extracts were
Butyldimethylsilyl trifluoromethanesulfonate (1.50 mL, 6.5 mmol) washed with water (50 mL) and brine (50 mL) then dried (MgSO4)
was added and the reaction mixture was stirred for 15 min. Water and concentrated under reduced pressure. Chromatography of the
(10 mL) was added and the mixture was extracted with ether (3 × residue (light petroleum to ether) gave the title compound 42 (1 g,
30 mL). The organic extracts were washed with water (10 mL) and 86 %) as a colourless oil, Rf (light petroleum:ethyl acetate 1:1)
brine (10 mL) then dried (MgSO4) and concentrated under reduced (Found: M+ + H+, 315.1988. C16H31O4Si requires M, 315.1992);
pressure. Chromatography of the residue (light petroleum to light νmax/cm-1 3460, 2953, 2929, 2858, 1719, 1644, 1463, 1435, 1374,
16 | J. Name., 2012, 00, 1-3
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ARTICLE
1254, 1177, 1136, 1118, 837 and 778; δH (300 MHz, CDCl3) 0.00 (6 stirred for 3 h before saturated aqueous ammoniumVciehwloArrtiidclee O(n1l5in0e
DOI: 10.1039/C6OB01804A
H, s, 2 × SiCH3), 0.91 [9 H, s, SiC(CH3)3], 2.61 (1 H, dd, J 13.3, 3.3, 4- mL) was added. After warming to room temperature, ether (200
H), 2.74 (1 H, dd, J 13.3, 9.3, 4-H’), 2.92 (2 H, dd, J 6.7, 1.2, 1’-H2), mL) was added and the aqueous phase extracted with ether (3 ×
3.19 (1 H, d, J 5.5, OH), 3.52 (2 H, d, J 5.6, 6-H2), 3.62 (3 H, s, 200 mL). The organic extracts were washed with saturated aqueous
CO2CH3), 3.74 (1 H, m, 5-H), 4.93-5.12 (2 H, m, 3’-H2), 5.71 (1 H, m, sodium bicarbonate (150 mL), dried (MgSO4) and concentrated
2’-H) and 5.76 (1 H, s, 2-H); δC (50 MHz, CDCl3) −4.9, 18.7, 26.4, under reduced pressure. Chromatography (light petroleum:ether
36.5, 43.7, 51.7, 67.9, 72.2, 118.3, 118.7, 134.6, 160.1 and 168.5; 3:3 to 1:1,) gave the hexynoate 4624 (13.48g, 94%), as a pale yellow
m/z (CI+) 315 (M+ + H+, 8%), 300 (30) and 283 (100).
oil, Rf = 0.1 (light petroleum:ether 1:1); νmax/cm-1 3427, 2238, 1712,
1611, 1513, 1252, 1077 and 819; m/z (CI+) 296 (M+ + 18, 100%).
6-tert-Butyldimethylsilyloxymethyl-4-prop-2-enyl-5,6-
dihydropyran-2-one (43)
Methyl
(2Z,5R)-5-hydroxy-6-(4-methoxybenzyloxy)-3-prop-2-
Molecular sieves (3Å, 100 mg) and toluene p-sulfonic acid (10 mg) enylhex-2-enoate (47)
were added to the hydroxyester 42 (1 g, 3.15 mmol) in THF (35 mL) Lithium chloride (7.67 g, 0.181 mol) and copper(I) iodide (34.47 g,
and the mixture was stirred at rt for 18 h. After filtering and 0.181 mol) were suspended in THF (900 mL) and the mixture stirred
washing the molecular sieves with ether (2 × 5 mL), saturated until a clear solution was obtained. After cooling to −78 °C, prop-2-
aqueous sodium bicarbonate (10 mL) was added to the filtrate that enylmagnesium bromide (1 M in Et2O, 329 mL, 0.329 mol), cooled
was extracted with ethyl acetate (3 × 5 mL). The organic extracts to −78 °C, was added dropwise. The mixture was warmed to −60 °C
were washed with water (20 mL), dried (MgSO4) and concentrated over 30 min, stirred for 30 min, then cooled to −78 °C over 30 min.
under reduced pressure to give the title compound 43 (898 mg, 100 The alkyne 46 (22.9 g, 0.082 mol) in THF (450 mL) was added
%) as a colourless paste, Rf = 0.6 (light petroleum:ethyl acetate 9:1) dropwise over 15 min and the mixture stirred for 30 min before the
(Found: M+ + H, 283.1733. C15H27O3Si requires M, 283.1729); dropwise addition of saturated aqueous ammonium chloride (100
νmax/cm-1 2954, 2930, 2857, 1725, 1639, 1474, 1388, 1252, 1123, mL). After warming to room temperature, ether (1000 mL) was
1043, 995, 921, 838 and 780; δH (300 MHz, CDCl3) 0.00 (6 H, s, 2 × added, and the aqueous phase extracted with ether (3 × 1000 mL).
SiCH3), 0.91 [9 H, s, SiC(CH3)3], 2.22 (1 H, dd, J 17.8, 4.3, 5-H), 2.43 (1 The organic extracts were dried (MgSO4) and concentrated under
H, dd, J 17.7, 11.0, 5-H’), 2.92 (2 H, d, J 6.9, 1’-H2), 3.70-3.78 (2 H, m, reduced pressure to give the title compound 47 (08.54 g, ca. 100%)
6-CH2), 4.34 (1 H, m, 6-H), 5.04-5.20 (2 H, m, 3’-H2), 5.72 (1 H, m, 2’- as a yellow oil that was used without purification. Chromatography
H) and 5.75 (1 H, s, 2-H); δC (75 MHz, CDCl3) −5.4, 18.2, 25.8, 29.4, of a sample (light petroleum:ether 20:1 to 4:1) gave the title
40.7, 64.1, 76.9, 116.0, 119.1, 132.1, 158.4 and 164.6; m/z (CI+) 300 compound 47 as a pale yellow oil, Rf = 0.44 (light petroleum:ether
(M+ + 18, 32%) and 283 (M+ + 1, 100).
1:2), [α]D −6.6 (c 1.7, CHCl3) (Found: M+ + H, 321.1697. C18H25O5
requires M, 321.1697); νmax/cm-1 3465, 2949, 2907, 1714, 1644,
1613, 1513, 1435, 1248, 1177, 1034 and 820; δH (300 MHz, CDCl3)
2.72 (1 H, dd, J 12.5, 3.5, 4-H), 2.89 (1 H, dd, J 12.0, 9.5, 4-H’), 3.02
20
6-tert-Butyldimethylsilyloxymethyl-4-(2,3-dihydroxypropyl)-5,6-
dihydropyran-2-one (44)
Osmium tetroxide (1 crystal) was added to the alkene 43 (500 mg, (2 H, dq, J 6.9, 1.2, 1ʹ-H2), 3.35 (1 H, d, J 5.4, OH), 3.49 (1 H, dd, J 7.5,
1.77 mmol) and trimethylamine N-oxide hydrate (216 mg, 1.95 3.8, 6-H), 3.52 (1 H, dd, J 7.5, 2.6, 6-Hʹ), 3.82 and 3.86 (each 3 H, s,
mmol) in DCM (20 mL) and the mixture stirred at rt for 4 h. After OCH3), 4.02 (1 H, m, 5-H), 4.53 (2 H, s, ArCH2), 5.15-5.20 (2 H, m, 3ʹ-
concentration under reduced pressure, chromatography of the H2), 5.80 (1 H, m, 2ʹ-H), 5.86 (1 H, s, 2-H) and 6.92 and 7.30 (each 2
residue (ight petroleum to light petroleum:ether 1:1) gave the title H, m, ArH); δC (75 MHz, CDCl3) 36.6, 43.4, 51.5, 55.5, 70.4, 73.3,
compound 44 (230 mg, 41 %) as a colourless oil, Rf = 0.3 (ethyl 74.7, 114.1, 118.2, 118.5, 129.6, 130.5, 134.4, 159.5, 159.6 and
acetate) (Found: M+ + H+, 317.1784. C15H29O5Si requires M, 168.2; m/z (CI+) 338 (M+ + 18, 20%) and 306 (100).
317.1784); νmax/cm-1 3386, 2953, 2930, 2858, 1694, 1640, 1257,
1125, 838 and 758; δH (300 MHz, CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.90 (Z,6R)-4-(2-Hydroxyethylidene)-7-(4-methoxybenzyloxy)hept-1-en-
[9 H, s, SiC(CH3)3], 2.20-2.40 (3 H, m, 5-H, 1’-H2), 2.50 (1 H, m, 5-H’), 6-ol (48)
3.43 (1 H, dd, J 10.7, 6.9, 3’-H), 3.61 (1 H, dd, J 10.8, 3.0, 3’-H’), 3.73 Di-isobutylaluminium hydride (1 M in THF, 316 mL, 0.316 mol) was
(2 H, d, J 5.0, 6-CH2), 3.88 (1 H, m, 2’-H), 4.37 (1 H, m, 6-H) and 5.71 added to the methyl ester 47 (25.32 g, 0.079 mol) in THF (500 mL)
(1 H, dd, J 5.8, 1.0, 2-H); δC (75 MHz, CDCl3) −5.5, −5.4, 18.2, 25.8, at −78 °C and the solution stirred for 1 h, warmed to room
29.9, 30.0, 40.1, 40.1, 64.2, 64.2, 66.2, 66.3, 69.4, 69.7, 77.7, 77.3, temperature, and stirred for 1 h. The reaction mixture was added to
117.4, 157.3, 157.3 and 164.6; m/z (CI+) 317 (M+ + 1, 41%) and 257 ether (600 mL) and saturated aqueous sodium potassium tartrate
(100).
(300 mL) and stirred for 1 h. The aqueous phase was extracted with
ether (3 × 600 mL) and the organic extracts were concentrated
Methyl
(46)24
(5R)-5-hydroxy-6-(4-methoxybenzyloxy)hex-2-ynoate under reduced pressure to a volume of ca. 500 mL, washed with
brine (200 mL), dried (MgSO4) and concentrated under reduced
n-Butyllithium (1.6 M in hexanes, 56.35 mL, 0.090 mol) was added pressure to give the title compound 48 (25.0 g, ca. 100%) as a
to methyl propiolate (7.58 g, 0.090 mol) in THF (140 mL) at −90 °C yellow oil that was used without purification. Chromatography
over 30 min and the stirred for 30 min. Boron trifluoride in THF (ether) of a sample gave the title compound 48 as a pale yellow oil,
+
20
(9.95 mL, 0.090 mol) was added and the mixture stirred for 40 min Rf = 0.36 (ether), [α]D −18.0 (c 1.5, CHCl3) (Found: M , 292.1677.
before the slow addition of the epoxide 45 (10.0 g, 0.052 mol) in C17H24O4 requires M, 292.1674); νmax/cm-1 3409, 2909, 1611, 1513,
THF (60 mL). The mixture was allowed to warm to –78 °C and was 1247, 1174, 1099, 1033, 998, 915 and 818; δH (300 MHz, CDCl3) 2.10
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(1 H, dd, J 13.6, J 5.0, 5-H), 2.44 (1 H, dd, J 13.6, J 8.1, 5-H’), 2.75- OCH3), 3.94 (1 H, m, 6-H), 4.15-4.38 (2 H, m, 2’-H2), 4.47 (2 H, s,
View Article Online
DOI: 10.1039/C6OB01804A
2.90 (2 H, m, 3-H2), 3.39 (1 H, dd, J 9.4, 8.1, 7-H), 3.49 (1 H, dd, J 9.5, ArCH2), 5.54 (1 H, m, 1’-H) and 6.90 and 7.24 (each 2 H, m, ArH); δC
3.4, 7-H’), 3.78 (1 H, m, OH), 3.84 (3 H, s, OCH3), 3.90 (1 H, m, 6-H), (75 MHz, CDCl3) −4.8, −4.4, −4.3, 18.3, 18.6, 26.1, 26.2, 35.9, 36.3,
3.97 (1 H, dd, J 11.9, 6.9, 2’-H), 4.19 (1 H, dd, J 11.9, 8.4, 2’-H’), 4.46 41.5, 41.9, 55.5, 60.3(2), 66.8, 70.0, 70.4, 70.8, 71.3, 73.3, 74.3,
(2 H, s, ArCH2), 5.05-5.15 (2 H, m, 1-H2), 5.73-5.89 (2 H, m, 2-H, 1’-H) 74.4, 114.0, 129.5, 130.5, 130.7, 131.3, 134.2, 134.7 and 159.4; m/z
and 6.92 and 7.30 (each 2 H, m, ArH); δC (75 MHz, CDCl3) 33.9, 41.9, (ES+) 578 (M+ + 23, 100%).
55.6, 58.0, 67.9, 73.4, 74.5, 114.2, 117.0, 128.0, 129.8, 130.1, 136.3,
139.5 and 159.6; m/z (CI+) 310 (M+ + 18, 20%), 138 (60) and 121 (E,5R)-5-tert-Butyldimethylsilyloxy-3-(2-tert-
(100).
butyldimethylsilyloxyethylidene)-6-(4-methoxybenzyloxy)hexanal
(51)
(Z,6R)-6-tert-Butyldimethylsilyloxy-4-(2-tert-
butyldimethylsilyloxyethylidene)-7-(4-methoxybenzyloxy)hept-1-
ene (49)
Sodium periodate (1.28 g, 6.0 mmol) was added to the diol 50 (666
mg, 1.20 mmol) in a mixture of THF (16 mL), methanol (16 mL) and
water (20 mL). After 1 h, saturated aqueous sodium sulphite (20
2,6-Lutidine (13.0 mL, 0.112 mmol) was added to the diol 48 (4.0 g, mL) and (50 mL) ether were added. The aqueous phase was
o
0.014 mol) in DCM (350 mL) and the solution cooled to 0 C. tert- extracted with ether (2 × 50 mL) and the organic extracts were
Butyldimethylsilyl trifluoromethanesulfonate (9.73 mL, 0.041 mol) washed with brine (50 mL), dried (MgSO4) and concentrated under
was added and the solution was stirred for 1 h at rt before water reduced pressure to afford the aldehyde 51 (625 mg, ca. 100%), as a
(250 mL) was added. The aqueous phase was extracted with DCM (2 colourless oil used immediately without purification; νmax/cm-1
× 250 mL) and the organic extracts dried (MgSO4) and concentrated 2953, 2931, 2857, 1725, 1663, 1613, 1513, 1466, 1251, 1102, 1082
under reduced pressure. Chromatography (light petroleum:ether and 836; δH (300 MHz, CDCl3) 0.03(5) and 0.05 (each 3 H, s, SiCH3),
9:1) gave the title compound 49 (6.66 g, 91%) as a clear oil, Rf = 0.51 0.07 (6 H, s, 2 × SiCH3), 0.88 and 0.92 [each 9 H, s, SiC(CH3)3], 2.31 (1
20
(light petroleum:ether 9:1), [α]D −2.6 (c 1.4, CHCl3); νmax/cm-1 H, dd, J 13.9, 7.2, 4-H), 2.36 (1 H, dd, J 13.9, 4.8, 4-H’), 3.12-3.17 (2
2953, 2929, 2856, 1613, 1514, 1471, 1250, 1098 and 836; δH (300 H, m, 2-H2), 3.31 (1 H, dd, J 9.5, 5.9, 6-H), 3.37 (1 H, dd, J 9.6, 5.1, 6-
MHz, CDCl3) 0.03 and 0.05 (each 3 H, s, SiCH3), 0.07 (6 H, s, 2 × H’), 3.83 (3 H, s, OCH3), 3.91 (1 H, m, 5-H), 4.24 (1 H, dd, J 13.0, 5.7,
SiCH3), 0.93 and 0.96 [each 9 H, s, SiC(CH3)3], 2.20 (1 H, dd, J 13.5, 2’-H), 4.30 (1 H, dd, J 13.0, 6.6, 2’-H’), 4.46 (2 H, s, ArCH2), 5.54 (1 H,
7.5, 5-H), 2.32 (1 H, dd, J 13.5, 5.5, 5-H’), 2.80 (2 H, d, J 6.7, 3-H2), t, J 6.2, 1’-H), 6.90 and 7.26 (each 2 H, m, ArH) and 9.65 (1 H, t J 2.5,
3.28-3.39 (2 H, m, 7-H2), 3.82 (3 H, s, OCH3), 3.90 (1 H, m, 6-H), 4.14- 1-H); δC (75 MHz, CDCl3) −4.8, −4.4, −4.3, 18.3, 18.6, 26.1, 26.2,
4.30 (2 H, m, 2’-H2), 4.43 (2 H, s, ArCH2), 5.00-5.10 (2 H, m, 1-H2), 36.8, 52.6, 55.5, 60.3, 70.8, 73.3, 74.1, 114.0, 129.2, 129.5, 130.5,
5.42 (1 H, t, J 6.0, 1’-H), 5.80 (1 H, m, 2-H) and 6.90 and 7.23 (each 2 133.6, 159.4 and 200.4; m/z (APCI+) 523 (M+ + 1, 42%), 385(28) and
H, m, ArH); δC (75 MHz, CDCl3) -4.9, −4.5, −4.4, 18.3, 18.6, 26.1, 121 (100).
26.2, 36.2, 42.2, 55.4, 60.5, 70.8, 73.1, 74.5, 113.9, 116.6, 128.5,
129.3, 130.7, 136.0, 136.5 and 159.3; m/z (ES+) 543 (M+ + 23, 100%). (3S)-3-Benzyloxy-1-tert-butyldimethylsilyloxy-2,2-dimethylhex-5-
ene (53)
(Z,2RS,6R)-6-tert-Butyldimethylsilyloxy-4-(2-tert-
butyldimethylsilyloxyethylidene)-7-(4-
methoxybenzyloxy)heptane-1,2-diol (50).
Potassium tert-butoxide (5.41 g, 48.21 mmol) was added to
methyltriphenylphosphonium bromide (18.44 g, 51.62 mmol) and
the mixture stirred rapidly for 30 min to grind it into a fine powder.
AD-mix β (7.95 g, 9.46 mmol) was added portionwise to a stirred Tetrahydrofuran (300 mL) was added and the resulting bright
mixture of tert-butanol (25 mL) and H2O (25 mL). After 10 min, the yellow suspension was stirred at room temperature for 50 min
o
mixture was cooled to 0 °C and the alkene 49 (4.93 g, 9.46 mol) in before cooling to 0 C. The aldehyde 52 (12.05 g, 34.41 mmol) in
tert-butanol (7 mL) was added portionwise. Osmium tetroxide (120 THF (35 mL) was added and the yellow suspension was warmed to
mg, 0.473 mmol) dissolved in tert-butanol (5 mL) and H2O (15 mL) rt and stirred for 45 min before the addition of saturated aqueous
was added dropwise by syringe pump over 8 h and then the mixture ammonium chloride (300 mL) and water (300 mL). The aqueous
was stirred for 10 h. The reaction mixture was allowed to warm to phase was extracted with ether (3 × 200 mL) and the organic
rt, aqueous sodium sulfite (30 g in 150 mL) was added, and the extracts were dried (MgSO4) then concentrated under reduced
mixture was stirred for 30 min. Ethyl acetate (250 mL) was added pressure. The residue was filtered through a plug of silica (light
and the aqueous phase was extracted with ethyl acetate (3 × 250 petroleum to light petroleum:ether 1:1). Further chromatography
mL). The organic extracts were dried (MgSO4) and concentrated (light petroleum to light petroleum:ether 30:1) gave (3E)-6-tert-
under reduced pressure. Chromatography of the residue (light butyldimethylsilyloxy-5,5-dimethylhexa-1,3-diene (1.9 g, 23%) as a
petroleum:ether:triethylamine 51:49:1 then ether:triethylamine colourless oil, Rf = 0.74 (light petroleum); νmax/cm-1 2956, 2930,
99:1) gave unchanged alkene 49 (0.434 g) followed by the title 2857, 1649, 1603, 1470, 1389, 1361, 1254, 1100, 1004, 897, 838
compound 50 (3.30 g, 70%), a clear oil, as a mixture of epimers, ca. and 774; δH (300 MHz, CDCl3) 0.06 (6 H, s, 2 × SiCH3), 0.93 [9 H, s,
2:1 (13C NMR), Rf = 0.46 (ether) (Found: M+ + H, 555.3532. SiC(CH3)3], 1.05 (6 H, s, 2 × 5-CH3), 3.35 (2 H, s, 6-H2), 5.03 and 5.17
C29H55O6Si2 requires M, 555.3537); νmax/cm-1 3432, 2952, 2929, (each 1 H, m, 1-H), 5.77 (1 H, d, J 15.6, 4-H), 6.08 (1 H, dd, J 15.6,
2856, 1612, 1513, 1464, 1361, 1250, 1081, 1039 and 842; δH (300 10.3, 3-H) and 6.36 (1 H, dt, J 15.5, 10.3, 2-H); δC (75 MHz, CDCl3) –
MHz, CDCl3) 0.05 and 0.07 (each 3 H, s, SiCH3), 0.10 (6 H, s, 2 × 5.19, 18.6, 24.2, 26.2, 38.7, 72.0, 115.3, 128.2, 138.1 and 142.9. The
SiCH3), 0.90 and 0.95 [each 9 H, s, SiC(CH3)3], 2.10-2.80 (6 H, m, 3- second fraction was the title compound 53 (7.0 g, 58%) as a pale
21
H2, 5-H2, 2 × OH), 3.30-3.65 (5 H, m, 1-H2, 2-H, 7-H2), 3.83 (3 H, s, yellow oil, Rf = 0.14 (light petroleum), [α]D +4.6 (c 2.7, CHCl3)
18 | J. Name., 2012, 00, 1-3
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ARTICLE
(Found: M+ + 1, 349.2568. C21H37O2Si requires M, 349.2563);
n-Butyllithium (1.6 M in hexanes, 14.1 mL, 22.56 mmol) was
View Article Online
DOI: 10.1039/C6OB01804A
νmax/cm-1 3067, 3029, 2955, 2930, 2857, 1640, 1471, 1391, 1360, added dropwise to dimethyl methylphosphonate (2.5 mL, 23.07
1254, 1094, 910, 852 and 838; δH (300 MHz, CDCl3) 0.07 and 0.08 mmol) in THF (50 mL) at –78 oC and the solution stirred for 1 h at –
(each 3 H, s, SiCH3), 0.92 and 0.93 (each 3 H, s, 2-CH3), 0.95 [9 H, s, 78 C. The aldehyde 55 in THF (22 mL) was added and the mixture
o
SiC(CH3)3], 2.25-2.50 (2 H, m, 4-H2), 3.30 (1 H, d, J 9.5, 1-H), 3.49 (1 was stirred for 1.25 h at –78 oC. Saturated aqueous ammonium
H, dd, J 8.5, 3.6, 3-H), 3.58 (1 H, d, J 9.5, 1-H’), 4.57 and 4.68 (each 1 chloride (90 mL) was added and the mixture allowed to warm to rt.
H, d, J 11.3, ArHCH), 5.06 and 5.16 (each 1 H, m, 6-H), 6.02 (1 H, m, Ethyl acetate (200 mL) and water (100 mL) were added and the
5-H) and 7.35 (5 H, m, ArH); δC (75 MHz, CDCl3) –5.2, −5.1, 18.6, aqueous phase extracted with ethyl acetate (4 × 100 mL). The
20.4, 21.9, 26.2, 35.8, 41.0, 70.0, 74.5, 83.3, 116.3, 127.5, 127.8, organic extracts were dried (MgSO4) and concentration under
128.5, 137.8 and 139.7; m/z (CI+) 349 (M+ + 1, 100%), 261 (97), 203 reduced pressure afforded the hydroxyheptenylphosphonate 56, Rf
(75), 132 (95), 106 (96) and 72 (87).
= 0.22 (ether), a 60:40 mixture of epimers, that was used without
purification (Found: M+ + NH4, 374.2091. C18H33NO2P requires M,
374.2096); νmax/cm-1 3381, 3068, 3030, 2954, 1640, 1455, 1233,
(3S)-3-Benzyloxy-2,2-dimethylhex-5-en-1-ol (54)
tetra-n-Butylammonium fluoride (1.0 M in THF, 16.40 mL, 16.40 1035, 912, 850, 828, 735 and 698; δH (300 MHz, CDCl3) 0.86 (1.8 H,
mmol) was added to the silyl ether 53 (3.04 g, 8.73 mmol) in THF s, 3-CH3), 0.88 (1.2 H, s, 3-CH3), 0.98 (1.8 H, s, 3-CH3’), 1.02 (1.2 H, s,
(60 mL) at rt and the solution stirred for 19 h. Ether (150 mL) and 3-CH3’), 1.80-2.14 (2 H, m, 5-H2), 2.33 (1 H, m, 1-H), 2.40-2.57 (2 H,
water (150 mL) were added and the aqueous phase was extracted m, 1-H’, OH), 3.51 (1 H, m, 4-H), 3.76 (3.6 H, d, J 10.8, 2 × OCH3),
with ether (3 × 100 mL).The organic extracts were washed with 3.78 (2.4 H, d, J 10.8, 2 × OCH3), 4.00 (1 H, m, 2-H), 4.49 and 4.55
brine (200 mL), dried (MgSO4) and concentrated under reduced (each 0.5 H, d, J 11.3, PhHCH), 4.71 (1 H, d, J 11.3, PhHCH), 5.02-
pressure. Chromatography of the residue (light petroleum:ether 5:1 5.24 (2 H, m, 7-H2), 5.99 (1 H, m, 6-H) and 7.15-7.43 (5 H, m, ArH);
to 3:1) afforded the title compound 54 (2.04 g, ca. 100%), as a m/z (CI+) 374 (M+ + 18, 50%) and 357 (M+ + 1, 100).
21
colourless oil, Rf = 0.60 (light petroleum:ether 1:1), [α]D +11.3 (c
The Dess-Martin periodinane (5.44 g, 12.84 mmol) was added
2.8, CHCl3) (Found: M+ + 1, 235.1697. C15H23O2 requires M, to the alcohol 56 in DCM (70 mL) at room temperature and the
235.1698); νmax/cm-1 3440, 3067, 3029, 2961, 2874, 1640, 1603, solution stirred for 1 h. Saturated aqueous sodium bicarbonate (150
1472, 1455, 1432, 1397, 1345, 1210, 1072, 1054, 911 and 735; δH mL), saturated aqueous sodium thiosulfate (150 mL) and water (300
(300 MHz, CDCl3) 0.91 and 1.01 (each 3 H, s, 2-CH3), 2.34-2.54 (2 H, mL) were added and the aqueous phase extracted with ethyl
m, 4-H2), 2.64 (1 H, dd, J 6.2, 5.3, OH), 3.34 (1 H, dd, J 10.8, 6.2, 1- acetate (4 × 200 mL). The organic extracts were dried (MgSO4) and
H), 3.40 (1 H, dd, J 7.5, 4.0, 3-H), 3.61 (1 H, dd, J 10.8, 5.3, 1-H’), 4.50 concentrated under reduced pressure. Chromatography of the
and 4.71 (each 1 H, d, J 11.1, ArCH2), 5.09 and 5.17 (each 1 H, m, 6- residue (ether to ethyl acetate) afforded the title compound 57
H), 5.99 (1 H, m, 5-H) and 7.34 (5 H, m, ArH); δC (75 MHz, CDCl3) (3.43 g, 83% from alcohol 54), as a pale yellow oil, Rf = 0.58 (ethyl
20
20.8, 23.3, 35.9, 40.1, 70.9, 74.2, 86.7, 117.0, 128.0, 128.1, 128.7, acetate), [α]D +12.4 (c 2.1, CHCl3) (Found: M+ + 1, 355.1678.
136.9 and 138.6; m/z (CI+) 252 (M+ + 18, 100%), 235 (M+ + 1, 53), C18H28O5P requires M, 355.1674); νmax/cm-1 3469, 3066, 3030, 2954,
214 (25) and 162 (25).
1704, 1640, 1497, 1469, 1455, 1388, 1365, 1258, 1185, 1031, 916,
870, 805 and 737; δH (300 MHz, CDCl3) 1.20 and 1.25 (each 3 H, s, 3
Dimethyl
ylphosphonate (57)
(4S)-4-Benzyloxy-3,3-dimethyl-2-oxohept-6-en-1- × CH3), 2.20-2.40 (2 H, m, 5-H2), 3.22 (2 H, dd, J 21.1, 1.3, 1-H2), 3.67
(1 H, dd, J 7.2, 4.5, 4-H), 3.78 (6 H, d, J 11.1, 2 × OCH3), 4.45 and
Dimethyl sulfoxide (1.82 mL, 25.67 mmol) in DCM (14 mL) was 4.69 (each 1 H, d, J 11.1, PhCH2), 5.08 and 5.16 (each 1 H, m, 7-H),
added to oxalyl chloride (1.12 mL, 12.84 mmol) in DCM (14 mL) at – 5.93 (1 H, m, 6-H) and 7.32 (5 H, m, ArH); δC (75 MHz, CDCl3) 20.5,
78 oC over 20 min and the solution stirred for 20 min at −78 oC. The 21.5, 36.1, 36.4, 38.2, 53.0, 53.6, 74.0, 84.4, 117.3, 127.7, 128.4,
alcohol 54 (2.73 g, 11.67 mmol) in DCM (8.5 mL) was added over 25 136.0, 138.4 and 207.1; m/z (CI+) 372 (M+ + 18, 100%), 355 (M+ + 1,
min and the solution stirred for 25 min at –78 oC. Triethylamine (8.1 25), 245 (25) and 102 (33).
mL, 58.35 mmol) was added over 10 min and the solution stirred for
o
a further 20 min at –78 C before being allowed to warm to room (4S,7E,12R)-4-Benzyloxy-12-tert-butyldimethylsilyloxy-10-[(Z)-2-
temperature. Saturated aqueous ammonium chloride (300 mL) and tert-butyldimethylsilyloxyethylidene]-13-(4-methoxybenzyloxy)-
ether (300 mL) were added and the aqueous phase was extracted 5,5-dimethyltrideca-1,7-dien-6-one (58)
with ether (3 × 200 mL). The organic extracts were washed with The ketophosphonate 57 (2.13 g, 5.99 mmol) in dry acetonitrile (35
brine (300 mL) and concentrated under reduced pressure to afford mL) was added dropwise to a suspension of lithium chloride (586
the aldehyde 55 as a colourless oil, Rf = 0.85 (light petroleum:ether mg, 13.82 mmol) in dry acetonitrile (35 mL) at room temperature
1:1) that was used without purification (Found: M+, 232.1467. followed by di-isopropylethylamine (0.96 mL, 5.51 mmol) and the
C15H20O2 requires M, 232.1463); νmax/cm-1 3068, 3031, 2976, 2937, mixture stirred for 30 min. The aldehyde 51 (4.43 mmol) in dry
2872, 2707, 1727, 1640, 1465, 1397, 1343, 1093, 913 and 737; δH acetonitrile (16 mL) was added dropwise before stirring the mixture
(300 MHz, CDCl3) 1.10 and 1.16 (each 3 H, s, 2-CH3), 2.34-2.48 (2 H, for 21 h, partitioning between saturated aqueous ammonium
m, 4-H2), 3.65 (1 H, dd, J 6.6, 5.0, 3-H), 4.51 and 4.70 (each 1 H, d, J chloride (100 mL) and ether (100 mL), extraction of the aqueous
11.3, PhHCH), 5.07-5.24 (2 H, m, 6-H2), 5.93 (1 H, m, 5-H), 7.28-7.40 with ether (3 × 100 mL), washing the organic extracts with brine
(5 H, m, ArH) and 9.62 (1 H, s, 1-H); δC (75 MHz, CDCl3) 18.1, 19.6, (250 mL) and drying (MgSO4). After concentration under reduced
35.7, 51.3, 73.8, 83.0, 117.7, 127.9, 128.6, 135.8, 138.5 and 206.0; pressure, chromatography of the residue (light petroleum:ether
m/z (CI+) 250 (M+ + 18, 100%).
10:1) afforded the title compound 58 (2.42 g, 73%) as a colourless
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oil, Rf = 0.65 (light petroleum:ether 4:1), [α]D +8.6 (c 2.1, CHCl3)
Potassium tert-butoxide (4.3 mg, 0.038 mmol) was added to the
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(Found: M+ + NH4, 768.5050. C44H74NO6Si2 requires M, 768.5049); mixture of epimeric tetrahydropyrans (cis:trDaOnsI: =101.100:3990/Cb6yOBH01N8M04RA,
νmax/cm-1 2953, 2930, 2856, 1688, 1618, 1513, 1467, 1386, 1361, 289 mg) in THF (2.8 mL) at 0 oC and the solution stirred for 10 min.
1301, 1251, 1173, 1095, 915, 836 and 777; δH (300 MHz, CDCl3) 0.05 Saturated aqueous ammonium chloride (2.0 mL) was added and the
and 0.06 (each 3 H, s, SiCH3), 0.08 (6 H, s, 2 × SiCH3), 0.91 and 0.93 mixture allowed to warm to rt. Following addition of ether (25 mL)
[each 9 H, s, 2 × SiC(CH3)3], 1.18 and 1.24 (each 3 H, s, 5-CH3), 2.0- and saturated aqueous ammonium chloride (25 mL), the aqueous
2.45 (4 H, m, 3-H2, 11-H2), 2.95 (2 H, d, J 6.4, 9-H2), 3.32 (1 H, dd, J phase was extracted with ether (2 × 15 mL). The organic extracts
18.8, 5.6, 13-H), 3.37 (1 H, dd, J 18.8, 5.1, 13-H’), 3.77 (1 H, dd, J 7.3, were washed with brine (15 mL), dried (MgSO4) and concentrated
4.4, 4-H), 3.84 (3 H, s, OCH3), 3.90 (1 H, m, 12-H), 4.18 (1 H, dd, J under reduced pressure to give a ca. 60:40 mixture of cis- and
13.0, 6.0, 2’-H), 4.27 (1 H, dd, J 13.0, 7.0, 2’-H’), 4.47 (2 H, s, ArCH2), trans-2,6-disubstituted tetrahydropyrans that was subjected to
1
4.50 and 4.68 (each 1 H, d, J 11.3, ArHCH), 5.05-5.25 (2 H, m, 1-H2), more
potassium
tert-butoxide
catalysed
equilibration.
5.49 (1 H, t, J 6.5, 1’-H), 5.95 (1 H, m, 2-H), 6.57 (1 H, d, J 15.2, 7-H), Chromatography (light petroleum:ether 5:1) gave the 2,6-cis-
6.92 (3 H, m, 8-H, 2 × ArH) and 7.30 (7 H, m, ArH); δC (75 MHz, disubstituted tetrahydropyran 60 (131 mg; 915 mg in total, 75%
CDCl3) −4.7, −4.3(2) 18.4, 18.7, 20.8, 21.3, 26.2, 26.3, 36.4, 36.7, yield from the enone 58).
40.8, 51.9, 55.5, 60.4, 71.1, 73.3, 74.4, 74.5, 84.1, 114.0, 117.2,
127.0, 127.7, 127.8, 128.5, 129.5, 130.1, 130.7, 134.8, 136.6, 138.9, (3S)-3-Benzyloxy-2,2-dimethyl-1-(4-methoxbenzyloxy)pent-4-ene
144.9, 159.4 and 203.2; m/z (APCI-) 785 (M+ + 35, 100 %).
(62)
The alcohol 61 (13.23 g, 60 mmol) in dry DMF (20 mL) was added to
a suspension of sodium hydride (60% in mineral oil, 4.81 g, 120
(2S,6R)-2-[(S)-4-Benzyloxy-3,3-dimethyl-2-oxohept-6-en-1-yl]-4-
[(Z)-2-tert-butyldiphenylsilyloxyethylidene]-6-(4-
methoxybenzyloxymethyl)tetrahydropyran (60)
o
mmol) in DMF (65 mL) at 0 C and the mixture stirred at rt for 30
o
min. After cooling to 0 C, 4-methoxybenzyl chloride (8.96 mL, 66
Concentrated aqueous hydrogen chloride (0.49 mL) was added to mmol) was added and the mixture warmed to room temperature
o
the enone 58 (1.23 g, 1.64 mmol) in methanol (9.8 mL) at 40 C. before the addition of tetra-n-butylammonium iodide (cat.). The
o
After heating for 15 min and cooling for 2 min, saturated aqueous mixture was stirred for 2 h 45 min, cooled to 0 C, and methanol
sodium bicarbonate (125 mL) and ether (150 mL) were added. (2.51 mL, 60 mmol) was added dropwise. The mixture was warmed
Following extraction of the aqueous phase with ether (3 × 100 mL), to room temperature, stirred for 10 min, cooled to 0 oC, and water
the organic extracts were dried (MgSO4) and concentrated under (20 mL) was added carefully. After warming to room temperature,
reduced pressure to give the tetrahydropyran 59, Rf = 0.68 (ether); ether (400 mL) and water (400 mL) were added, and the aqueous
m/z (AP-) 557 (M+ + 35, 100 %).
phase was extracted with ether (3 × 250 mL). The organic extracts
tert-Butyldiphenylsilyl chloride (0.85 mL, 3.28 mmol) and were washed with brine (400 mL), dried (MgSO4) and concentrated
imidazole (257 mg, 3.77 mmol) were added to the 4- under reduced pressure. Chromatography of the residue (light
(hydroxyethylidene)tetrahydropyran 59 in DCM (2.5 mL) at 0 oC and petroleum:ether 30:1 containing 1% triethylamine) gave the title
the solution stirred at rt for 30 min. Water (150 mL) and ether (150 compound 62 (18.09 g, 88%) as a colourless oil, Rf = 0.46 (light
20
mL) were added and the aqueous phase extracted with ether (3 × petroleum:ether 10:1), [α]D +14.4 (c 3.0, CHCl3) (Found: M+ + H,
50 mL). The organic extracts were washed with brine, dried (MgSO4) 341.2120. C22H29O3 requires M, 341.2117); νmax/cm-1 3066, 3030,
and concentrated under reduced pressure. Chromatography of the 2961, 2933, 2867, 1612, 1586, 1513, 1457, 1301, 1247, 1174, 1092,
residue (light petroleum:ether 8:1 to 1:1) gave the title compound 1037, 998, 928, 822 and 738; δH (300 MHz, CDCl3) 0.97 and 1.02
60 (784 mg, 63%), Rf = 0.31 (light petroleum:ether 4:1), [α]D21 +10.1 (each 3 H, s, 2-CH3), 3.23 and 3.45 (each 1 H, d, J 8.6, 1-H), 3.80 (1 H,
(c 1.9, CHCl3) (Found: M+ + NH4, 778.4498. C48H64NO6Si requires M, d, J 8.1, 3-H), 3.85 (3 H, s, OCH3), 4.35 (1 H, d, J 11.9, PhHCH), 4.46
778.4497); νmax/cm-1 3069, 3031, 2955, 2891, 2858, 1704, 1638, (2 H, s, ArCH2), 4.63 (1 H, d, J 11.9, PhHCH), 5.25-5.45 (2 H, m, 5-H2),
1612, 1588, 1513, 1467, 1428, 1386, 1362, 1248, 1173, 1108, 1068, 5.86 (1 H, ddd, J 17.3, 10.5, 8.1, 4-H), 6.92 and 7.29 (each 2 H, m,
1038, 1005, 822 and 740; δH (300 MHz, CDCl3) 1.10 [9 H, s, ArH) and 7.37 (5 H, m, ArH); δC (75 MHz, CDCl3) 20.7, 22.0, 39.2,
SiC(CH3)3], 1.16 and 1.28 (each 3 H, s, 3’-CH3), 1.69 (1 H, br. m, 5- 55.5, 70.8, 73.1, 76.9, 84.8, 113.9, 119.0, 127.5, 127.8, 128.4, 129.3,
Hax), 1.87 (1 H, br. m, 3-Hax), 2.20-2.36 (4 H, m, 3-Heq, 5-Heq, 5’-H2), 131.4, 135.9, 139.6 and 159.2; m/z (CI+) 341 (M+ + 1, 5%), 138 (28)
2.60 (1 H, dd, J 17.5, 6.8, 1’-H), 3.01 (1 H, dd, J 17.5, 5.6, 1’-H’), 3.35- and 121 (100).
3.45 (3 H, m, 6-H, 6-CH2), 3.84 (2 H, m, 2-H, 4’-H), 3.85 (3 H, s,
OCH3), 4.26 (2 H, d, J 6.4, 2’’-H2), 4.48 (1 H, d, J 11.3, PhHCH), 4.49 (3S)-3-Benzyloxy-4,4-dimethyl-5-(4-methoxybenzyloxy)pentan-1-
(2 H, s, ArCH2), 4.72 (1 H, d, J 11.3, PhHCH), 5.05-5.25 (2 H, m, 7’- ol (63)
H2), 5.52 (1 H, t, J 6.4, 1’’-H), 5.98 (1 H, m, 6’-H), 6.90 and 7.26 (each Borane (1.0 M in THF, 74.0 mL, 74.0 mmol) was added to the alkene
2 H, d, J 8.7, ArH), 7.30-7.55 (11 H, m, ArH) and 7.74 (4 H, m, ArH); 62 (22.8 g, 66.8 mmol) in THF (230 mL) at –25 oC over a period of 15
δC (75 MHz, CDCl3) 19.5, 20.8, 21.2, 27.2, 31.5, 36.5, 41.7, 45.5, min before allowing the solution to warm to rt (1 h). The reaction
52.9, 55.6, 60.3, 73.0, 73.2, 74.3, 74.8, 76.9, 84.3, 110.0, 114.1, mixture was stirred at rt for 18 h before aqueous sodium hydroxide
117.2, 124.1, 127.8(2), 128.0, 128.6, 129.7, 129.9, 130.0, 130.6, (3 M, 480 mL) and aqueous hydrogen peroxide (30% v/v, 480 mL)
134.1, 134.2, 135.7, 135.9(2), 136.6, 139.0, 159.5 and 213.2; m/z were added with stirring for 1.5 h before heating the mixture to 60
(APCI-) 759 (M+ - 1, 20%), 579 (35), 504 (100) and 323 (21). The oC for 40 min. Ether (800 mL) and water (400 mL) were added and
second fraction was a mixture of 59 and its 2,6-trans-epimer (302 the aqueous phase was extracted with ether (3 × 400 mL). The
mg).
organic extracts were washed with brine (400 mL), dried (MgSO4)
20 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
and concentrated under reduced pressure. Chromatography of the DCM (315 mL) at −78 °C dropwise via a cannula. After 30 min, the
View Article Online
DOI: 10.1039/C6OB01804A
residue (light petroleum:ether 3:1 + 1% triethylamine to ether +1% alcohol 66 (44.2 g, 0.148 mol) in DCM (315 mL) was added and after
triethylamine) gave the title compound 63 (17.23 g, 72%) as a a further 30 min, Et3N (82.25 g, 113.28 mL, 0.812 mol) was added.
21
colourless oil, Rf = 0.22 (light petroleum:ether 1:1), [α]D +4.3 (c The mixture stirred for 30 min then allowed to warm to room
2.3, CHCl3) (Found: M+ + H, 359.2219. C22H31O4 requires M, temperature. Saturated aqueous ammonium chloride (400 mL) was
359.2222); νmax/cm-1 3431, 2959, 2873, 1611, 1513, 1457, 1360, added and the aqueous phase extracted with DCM (3 × 200 mL).
1301, 1247, 1175, 1092, 1036, 822 and 738; δH (300 MHz, CDCl3) The organic extracts were dried (MgSO4) and concentrated under
1.00 and 1.02 (each 3 H, s, 4-CH3), 1.70-1.90 (2 H, m, 2-H2), 2.03 (1 reduced pressure. Chromatography of the residue (light
H, br. m, OH), 3.18 and 3.45 (each 1 H, d, J 8.8, 5-H), 3.65-3.85 (3 H, petroleum:ether 9:1) gave the title compound 6726 (38.89 g, 88%)
m, 1-H2, 3-H), 3.85 (3 H, s, OCH3), 4.47 and 4.66 (each 2 H, s, ArCH2), as a waxy white solid; δH (300 MHz, CDCl3) 1.07 [9 H, s, SiC(CH3)3],
6.93 and 7.31 (each 2 H, d, J 8.6, ArH) and 7.38 (5 H, m, ArH); δC 2.26 (3 H, s, 1-H3), 2.68 (2 H, t, J 6.3, 3-H2), 3.98 (2 H, t, J 6.3, 4-H2),
(300 MHz, CDCl3) 20.9, 22.3, 33.5, 40.2, 55.6, 61.4, 73.2, 74.9, 77.0, 7.39-7.50 (6 H, m, ArH) and 7.70 (4 H, m, ArH).
81.5, 114.0, 127.8, 128.0, 128.7, 129.5, 131.0, 139.2 and 159.4; m/z
(CI+) 376 (M+ + 18, 14%), 359 (M+ + 1, 16), 136 (42) and 121 (100).
(5S,7S)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-8,8-dimethyl-5-
hydroxy-9-(4-methoxybenzyloxy)nonan-3-one (68)26
(3S)-3-Benzyloxy-4,4-dimethyl-5-(4-methoxybenzyloxy)pentanal
n-Butyllithium (1.60 M in hexanes, 38.00 mL, 60.8 mmol) was added
(64)
dropwise to di-isopropylamine (8.60 mL, 60.85 mmol) in THF (90
o
Dimethyl sulfoxide (9.70 mL, 136.41 mmol) in DCM (100 mL) was mL) at –30 C. The resulting pale yellow solution was warmed to rt
added to oxalyl chloride (6.00 mL, 68.21 mmol) in DCM (100 mL) at and stirred for 5 min before cooling to −78 oC. A cooled solution of
–78 oC over 20 min. After stirring for a further 20 min at −78 oC, the the ketone 67 (19.78 g, 60.7 mmol) in THF (60 mL) was added over
alcohol 63 (16.30 g, 45.47 mmol) in DCM (100 mL) was added over 1 h 15 min via narrow gauge cannula and stirring continued at –78
20 min. After stirring for 20 min at –78 oC, triethylamine (38.00 mL, oC for 2 h. The aldehyde 64 (13.86 g, 38.88 mmol) in THF (50 mL)
272.82 mmol) was added over 20 min and, after a final 20 min at – was added over 5 min and after a further 5 min at −78 oC, a cooled
78 oC, the reaction mixture was warmed to room temperature. solution of acetic acid (10% v/v in dry ether, 100 mL,) was added
Saturated aqueous ammonium chloride (300 mL) and ether (300 rapidly. The resulting mixture was allowed to warm to rt then
mL) were added and the aqueous phase was extracted with ether (3 carefully added to saturated aqueous sodium bicarbonate (500 mL).
× 200 mL). The organic extracts were washed with brine (300 mL), Ethyl acetate (300 mL) was added and the aqueous phase extracted
dried (MgSO4), and concentrated under reduced pressure. with ethyl acetate (3 x 200 mL). The organic extracts were dried
Chromatography of the residue (light petroleum:ether 50:1 to 2:1) (MgSO4)
and
concentrated
under
reduced
pressure.
gave the title compound 64 (14.92 g, 92%) as a colourless oil, Rf = Chromatography of the residue (light petroleum:ether 5:1 to 3:1)
21
0.75 (light petroleum:ether !:1), [α]D + 4.8 (c 6.5 , CHCl3) (Found: gave the title compound 6826 (20.18 g, 76%) as a highly viscous
21
M+, 356.1984. C22H28O4 requires M, 356.1982); νmax/cm-1 3053, colourless gum, Rf = 0.36 (light petroleum:ether 1:1), [α]D +2.7 (c
2961, 2872, 1627, 1586, 1493, 1446, 1425, 1370, 1335, 1250, 1211, 1.9, CHCl3) (Found: M+ + H, 683.3764. C42H55O6SI requires M,
1181, 1162, 1135, 1083, 1050, 1030, 839, 815 and 764; δH (300 683.3762); νmax/cm-1 3508, 2957, 2932, 2857, 1707, 1611, 1513,
MHz, CDCl3) 0.98 and 1.01 (each 3 H, s, 4-CH3), 2.68 (2 H, dd, J 5.9, 1467, 1427, 1389, 1361, 1302, 1247, 1175, 1108, 1092, 1035, 822
2.1, 2-H2), 3.17 and 3.39 (each 1 H, d, J 8.8, 5-H), 3.84 (3 H, s, OCH3), and 738; δH (300 MHz, CDCl3) 0.99 and 1.00 (each 3 H, s, 8-CH3),
4.08 (1 H, t, J 5.9, 3-H), 4.43 (2 H, s, ArCH2), 4.54 and 4.63 (each 1 H, 1.08 [9 H, s, SiC(CH3)3], 1.51 and 1.65 (each 1 H, m, 6-H), 2.57-2.67
d, J 11.3, ArHCH), 6.92 (2 H, m, ArH), 7.28 (7 H, m, ArH) and 9.83 (1 (4 H, m, 2-H2, 4-H2), 3.19 (1 H, d, J 8.7, 9-H), 3.21 (1 H, br. m, OH),
H, t, J 2.1); δC (75 MHz, CDCl3) 21.2, 22.0, 39.9, 45.9, 55.5, 73.1, 3.43 (1 H, d, J 8.7, 9-H’), 3.82 (3 H, s, OCH3), 3.83 (1 H, m, 7-H), 3.97
73.8, 76.7, 78.5, 114.0, 127.8(2), 128.6, 129.5, 130.8, 138.9, 159.4 (2 H, t, J 6.2, 1-H2), 4.29 (1 H, m, 5-H), 4.47 (2 H, s, ArCH2), 4.67 and
and 202.2; m/z (EI+) 356 (M+, 2%), 248 (12), 235 (30), 137 (35) and 4.74 (each 1 H, d, J 11.4, ArHCH), 6.90 (2 H, d, J 8.8, ArH), 7.26-7.52
121 (100).
(13 H, m, ArH) and 7.65 (4 H, m, ArH); δC (75 MHz, CDCl3) 19.4, 20.9,
22.5, 27.1, 37.7, 40.0, 46.3, 51.0, 55.5, 59.7, 65.0, 73.1, 75.1, 77.4,
79.6, 114.0, 127.6, 127.8, 127.9, 128.0, 128.1, 128.6, 129.4, 129.5,
4-tert-Butyldiphenylsilyloxybutan-2-one (67)26
tert-Butyldiphenylsilyl chloride (10.57 g, 10.0 mL, 0.038 mol) was 130.1, 131.1, 133.6, 135.8 139.6, 159.3 and 211.3; m/z (APCI-) 717
added to the butane-1,3-diol 65 (6.85 g, 0.076 mol) and imidazole (M+ + 35], 100%).
(5.17 g, 0.076 mol) in DCM (250 mL) at 0 °C dropwise and the
mixture stirred for 2 h. Water (250 mL) was added and the aqueous (5S,7S)-5-[(R)-2-acetoxy-2-phenylacetoxy]-7-Benzyloxy-1-tert-
phase extracted with DCM (3 × 250 mL). The organic extracts were butyldiphenylsilyloxy-8,8-dimethyl-9-(4-
dried (MgSO4) and concentrated under reduced pressure. methoxybenzyloxy)nonan-3-one (69)
Chromatography of the residue (light petroleum:ether 20:1 to 4:1) (R)-O-Acetylmandelic acid (34 mg, 0.175 mmol) and DMAP (cat.)
gave the silyl ether 66 (11.48 g, 92%) as a colourless oil; δH (300 were added to the alcohol 68 (59 mg, 0.086 mmol) in THF (0.6 mL)
o
MHz, CDCl3) 1.13 [9 H, s, SiC(CH3)3], 1.27 (3 H, d, J 7.5, 1-H3), 1.60- and the solution cooled to 0 C. Dicyclohexylcarbodi-imide (45 mg,
1.90 (2 H, m, 3-H2), 3.32 (1 H, d, J 3.8, OH), 3.84-3.95 (2 H, m, 4-H2), 0.218 mmol) in THF (0.5 mL) was added and the mixture warmed to
4.15 (1 H, m, 2-H), 7.35-7.52 (6 H, m, ArH) and 7.73 (4 H, m, ArH).
rt. After stirring for 16 h, ether (15 mL) was added, and the mixture
Dimethyl sulfoxide (31.75 g, 28.83 mL, 0.406 mol) in DCM (315 filtered and concentrated under reduced pressure. Chromatography
mL) was added to oxalyl chloride (25.79 g, 17.73 mL, 0.203 mol) in of the residue (light petroleum:ether 2:1) gave the title compound
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69 (65 mg, 88%), as a colourless oil, Rf = 0.50 (light petroleum:ether 7.70 (4 H, m, ArH); δC (75 MHz, CDCl3) 19.3, 21.0, 22.3, 27.1, 38.4,
View Article Online
1:1), [α]D21 −32.6 (c 5.7, CHCl3) (Found: M+ + H, 859.4268. C52H63O9Si 40.0, 43.6, 55.4, 63.6, 66.5, 70.0, 73.0, 74.9, 80.2, 113.9, 127.5,
DOI: 10.1039/C6OB01804A
requires M, 859.4236); νmax/cm-1 2958, 2932, 2857, 1746, 1717, 127.8, 128.0, 128.5, 129.4, 130.1, 131.0, 133.1, 133.2, 135.7, 135.8,
1611, 1513, 1465, 1427, 1372, 1236, 1176, 1106, 1091, 823 and 139.6 and 159.2; m/z (ES+) 708 (70%).
738; δH (300 MHz, CDCl3) 0.82 and 0.86 (each 3 H, s, 8-CH3), 1.08 [9
Toluene p-sulfonic acid monohydrate (129 mg, 0.68 mmol) was
H, s, SiC(CH3)3], 1.55-1.90 (2 H, m, 6-H2), 2.23 (3 H, s, CH3CO), 2.60- added to the diol 71 in 2,2-dimethoxypropane (200 mL) at rt and
2.73 (2 H, m, 2-H2), 2.80 (1 H, dd, J 16.2, 7.0, 4-H), 2.91 (1 H, dd, J the mixture stirred for 2 h. Saturated aqueous sodium bicarbonate
16.2, 5.0, 4-H’), 3.02 (1 H, dd, J 9.1, 1.2, 7-H), 3.08 and 3.24 (each 1 (400 mL) and ether (400 mL) were added and the aqueous phase
H, d, J 8.8, 9-H), 3.86 (3 H, s, OCH3), 3.90-4.02 (4 H, m, 1-H2, ArCH2), extracted with ether (3 × 200 mL). The organic extracts were dried
4.40 and 4.46 (each 1 H, d, J 11.8, ArHCH), 5.38 (1 H, m, 5-H), 5.90 (MgSO4)
and
concentrated
under
reduced
pressure.
(1 H, s, 2’-H), 6.96 (2 H, d, J 8.5, ArH), 7.20-7.38 (10 H, m, ArH), 7.40- Chromatography of the residue (light petroleum:ether 4:1 + 1%
7.54 (8 H, m, ArH) and 7.70 (4 H, m, ArH); δC (75 MHz, CDCl3) 19.4, triethylamine) afforded the title compound 72 (8.82 g, 91%) as a
20
20.9, 21.1, 21.9, 27.1, 35.9, 39.9, 46.1, 48.7, 55.5, 59.8, 70.3, 73.1, colourless oil, Rf = 0.75 (light petroleum:ether 2:1), [α]D +0.6 (c
74.8, 75.0, 77.1, 79.7, 114.0, 127.4, 127.7, 127.9, 128.0, 128.4, 2.0, CHCl3) (Found: M+ + NH4, 742.4498. C45H64NO6Si requires M,
128.5, 129.2, 129.4, 129.5, 130.0, 131.1, 133.7, 133.9, 135.8, 139.3, 742.4497); νmax/cm-1 3070, 3031, 2933, 2857, 1612, 1588, 1514,
159.4, 168.8, 170.6 and 206.2; m/z (APCI-) 845 (20%) 680 (18) and 1472, 1428, 1378, 1363, 1302, 1248, 1224, 1173, 1112, 1038, 960,
509 (100).
823, 736 and 702; δH (300 MHz, CDCl3) 1.02 and 1.04 (each 3 H, s, 8-
CH3)2), 1.14 [9 H, s, SiC(CH3)3], 1.45 (6 H, s, 2 × CCH3), 1.55-1.90 (6 H,
m, 2-H2, 4-H2, 6-H2), 3.22 and 3.46 (each 1 H, d, J 8.7, 9-H), 3.70-
3.83 (2 H, m, 1-H2), 3.86 (3 H, s, OCH3), 3.87 (1 H, m, 7-H), 4.06-4.24
(2 H, m, 3-H, 5-H), 4.48 and 4.54 (each 1 H, d, J 11.9, ArCH2), 4.66
(5S,7S)-5-[(S)-2-acetoxy-2-phenylacetoxy]-7-Benzyloxy-1-tert-
butyldiphenylsilyloxy-8,8-dimethyl-9-(4-
methoxybenzyloxy)nonan-3-one (70)
Following the procedure outlined for the preparation of ester 69, and 4.74 (each 1 H, d, J 11.4, ArHCH), 6.94 (2 H, d, J 8.8, ArH), 7.30-
the alcohol 68 (34 mg, 0.05 mmol) and (S)-mandelic acid gave the 7.50 (13 H, m, ArH) and 7.74 (4 H, m, ArH); δC (75 MHz, CDCl3) 19.5,
title compound 70 (39 mg, 91%) as a colourless oil, Rf = 0.50 (light 21.0, 22.5, 25.7, 25.9, 27.2, 38.4, 39.2, 39.4, 40.2, 55.5, 60.4, 63.6,
20
petroleum:ether 1:1), [α]D +17.0 (c 2.1, CHCl3) (Found: M+ + H, 64.0, 73.1, 74.9, 77.4, 79.9, 100.5, 114.0, 127.5, 127.6, 127.9, 128.6,
859.4224. C52H63O9Si requires M, 859.4236); νmax/cm-1 2958, 2932, 129.4, 129.9, 131.2, 134.2, 134.3, 135.9, 139.7 and 159.4; m/z (AP+)
2857, 1744, 1719, 1611, 1513, 1467, 1427, 1372, 1233, 1176, 1107, 725 (M+ + 1, 5%), 685 (20), 667 (12), 492 (10), 279 (50) and 1PCI2
1091, 823 and 738; δH (300 MHz, CDCl3) 0.96 and 0.97 (each 3 H, s, (100).
8-CH3), 1.05 [9 H, s, SiC(CH3)3], 1.66 and 1.94 (each 1 H, m, 6-H),
2.22 (3 H, s, CH3CO), 2.32-2.50 (2 H, m, 2-H2), 2.63 (1 H, dd, J 16.1, (3S,5R,7R)-3-Benzyloxy-9-tert-butyldiphenylsilyloxy-5,7-O-
6.0, 4-H), 2.69 (1 H, dd, J 16.1, 6.2, 4-H’), 3.17 and 3.36 (each 1 H, d, isopropylidene-2,2-dimethylnonan-1-ol (73)
J 8.8, 9-H), 3.51 (1 H, dd, J 10.1, 1.6, 7-H), 3.78 (2 H, t, J 6.4, 1-H2), Dichlorodicyanoquinone (2.82 g, 12.42 mmol) was added to the
3.84 (3 H, s, OCH3), 4.40 (1 H, d, J 11.7, ArHCH), 4.45 (2 H, s, ArCH2), PMB-ether 72 (8.83 g, 12.18 mmol) in DCM (67 mL) and pH 7 buffer
4.50 (1 H, d, J 11.7, ArHCH), 5.47 (1 H, m, 5-H), 5.88 (1 H, s, 2’-H), (3.3 mL). After 20 min, saturated aqueous sodium bicarbonate (250
6.89 (2 H, d, J 8.5, ArH), 7.24-7.37 (8 H, m, ArH), 7.38-7.51 (10 H, m, mL) and ether (250 mL) were added and the aqueous phase was
ArH) and 7.67 (4 H, m, ArH); δC (75 MHz, CDCl3) 19.4, 21.0, 21.1, extracted with ether (3 × 100 mL). The organic extracts were
22.2, 27.0, 35.9, 40.1, 45.9, 48.2, 55.5, 59.6, 70.5, 73.1, 75.0, 75.1, washed with aqueous sodium bicarbonate (30 mL), dried (MgSO4)
77.1, 80.1, 113.9, 127.5, 127.8, 128.0, 128.5, 129.0, 129.1, 129.4, and concentrated under reduced pressure. Chromatography of the
129.5, 130.0, 131.1, 133.7, 133.8, 135.8, 139.5, 159.3, 168.6, 170.5 residue (light petroleum:ether 9:1 to 2:1 containing 0.5%
and 205.8; m/z (APCI-) 846 (40%), 680 (38) and 511 (100).
triethylamine) gave recovered starting material 72 (1.08 g, 12%)
followed by the title compound 73 (4.66 g, 63%) as a colourless,
22
(3S,5R,7S)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-3,5-O-
isopropylidene-9-(4-methoxybenzyloxy)-8,8-dimethylnonane
(72)26
highly viscous oil, Rf 0.16 (light petroleum:ether 3:1), [α]D –4.0 (c
1.9, CHCl3) (Found: M+ + NH4, 622.3922. C37H56NO5Si requires M,
622.3922); νmax /cm-1 3473, 2954, 2933, 2859, 1471, 1428, 1380,
Lithium tris-(tert-butoxy)aluminium hydride (1 M in THF, 68 mL, 68 1223, 1169, 1110, 959, 823 and 736; δH (300 MHz, CDCl3) 0.96 and
mmol) was added dropwise to the keto-alcohol 68 (9.3 g, 13.6 1.02 (each 3 H, s, 2-CH3), 0.07 [9 H, s, SiC(CH3)3, 1.36 and 1.37 (each
mmol) and lithium iodide (9.11 g, 68 mmol) in DCM (80 mL) and dry 3 H, s, CCH3), 1.50-1.90 (6 H, m, 4-H2, 6-H2, 8-H2), 2.85 (1 H, t, J 5.9,
ether (400 mL) at −78 °C. The mixture was stirred for 4 h before OH), 3.41 (1 H, dd, J 11.3, 5.9, 1-H), 3.52-3.65 (2 H, m, 1-H’, 3-H),
aqueous hydrogen chloride (1%) was added. The aqueous phase 3.71 and 3.81 (each 1 H, m, 9-H), 4.00-4.20 (2 H, m, 5-H, 7-H), 4.63
was extracted with DCM (6 × 500mL), and the organic extracts dried and 4.69 (each 1 H, d, J 11.3, PhHCH), 7.25-7.55 (11 H, m, ArH) and
(MgSO4) and concentrated under reduced pressure to provided the 7.69 (4 H, m, ArH); δC (75 MHz, CDCl3) 19.5, 21.9, 22.1, 25.4, 25.6,
diol 7126 (9.86 g, ca. 100%); δH (300 MHz, CDCl3) 0.99 (6 H, s, 2 × 8- 27.1, 38.5, 39.1, 39.2, 40.1, 60.3, 63.6, 64.9, 70.7, 74.7, 83.1, 100.6,
CH3), 1.19 [9 H, s, SiC(CH3)3], 1.45-1.95 (6 H, m, 2-H2, 4-H2, 6-H2), 127.6, 127.9, 128.7, 129.9, 134.1, 134.2, 135.8 and 138.8; m/z
3.19 (1 H, d, J 8.7, 9-H), 3.29 (1 H, m, 7-H), 3.44 (1 H, d, J 8.7, 9-H’), (APCI+) 627 (M+ + 23, 45%), 547 (78), 469 (100), 391 (64) and 361
3.78 (3 H, s, OCH3), 3.78-3.95 (2 H, m, 1-H2), 4.15 and 4.25 (each 1 (22).
H, m, 3-H, 5-H), 4.45 (2 H, s, ArCH2), 4.66 and 4.75 (each 1 H, d, J
11.4, ArHCH), 6.88 (2 H, d, J 9.0, ArH), 7.20-7.50 (13 H, m, ArH) and Dimethyl (4S,6R,8S)-4-Benzyloxy-10-tert-butyldiphenylsilyloxy-6,8-
22 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Journal Name
O-isopropylidene-3,3-dimethyl-2-oxododec-1-yl phosphonate (76)
ARTICLE
the aqueous phase was extracted with DCM (2 × 200 mL). The
View Article Online
DOI: 10.1039/C6OB01804A
Dimethyl sulfoxide (3.20 mL, 44.19 mmol) in DCM (32 mL) was organic extracts were dried (MgSO4) and concentrated under
added to oxalyl chloride (2.20 ml, 25.04 mmol) in DCM (32 mL) at – reduced pressure. Chromatography of the residue (light
78 oC over a period of 20 min. After stirring for 20 min at −78 oC, the petroleum:ether 9:1 to 3:2) afforded the title compound 77 (32.3 g,
alcohol 73 (8.91 g, 14.73 mmol) in DCM (34 mL) was added over 20 86% from the alkyne 46), as a clear oil, Rf = 0.41 (light
min. After a further 20 min at –78 oC, triethylamine (12.30 mL, petroleum:ether 9:1), [α]D +2.7 (c 1.7, CHCl3); νmax/cm-1 3460,
20
88.38 mmol) was added (15 min), and after a final 20 min at –78 oC, 3071, 2931, 2857, 1612, 1513, 1428, 1248, 1110, 1038, 915, 823
the reaction mixture was allowed to warm to rt. Saturated aqueous and 740; δH (300 MHz, CDCl3) 1.60 [9 H, s, SiC(CH3)3], 2.15 (1 H, dd, J
ammonium chloride (250 mL) and ether (250 mL) were added and 13.6, 5.2, 3-H), 2.26 (1 H, dd, J 13.6, 8.3, 3-H’), 2.64 (1 H, d, J 3.8,
the aqueous phase extracted with ether (3 × 100 mL). The organic OH), 2.84 (2 H, d, J 5-H2), 3.36 (1 H, dd, J 9.5, 6.6, 1-H), 3.44 (1 H, dd,
extracts were washed with brine (200 mL) and concentrated under J 9.5, 4.0, 1-H’), 3.86 (3 H, s, OCH3), 3.88 (1 H, m, 2-H), 4.25 and 4.33
reduced pressure to afford the aldehyde 74, Rf = 0.48 (light (each 1 H, dd, J 12.5, 6.7, 2’-H), 4.46 (2 H, s, ArCH2), 5.08-5.18 (2 H,
petroleum:ether 3:1) as a pale yellow oil that was used without m, 7-H2), 5.66 (1 H, t, J 6.7, 1’-H), 5.84 (1 H, m, 6-H), 6.93 and 7.30
further purification.
(each 2 H, m, ArH), 7.40-7.55 (6 H, m, ArH) and 7.78 (4 H, m,
n-Butyllithium (1.60 M in hexanes, 17.4 mL, 27.84 mmol) was ArH); δC (75 MHz, CDCl3) 19.5, 27.1, 34.9, 42.0, 55.6, 60.7, 68.9,
added dropwise to dimethyl methylphosphonate (3.20 mL, 29.53 73.3, 74.1, 114.1, 116.9, 128.0(2), 128.2, 129.7, 130.0, 130.4,
mmol) in THF (60 mL) at –78 oC followed, after 1 h at –78 oC, by the 134.0(2), 136.0, 136.4, 137.5 and 159.6; m/z (ES+) 553 (M+ + 23,
aldehyde 74 in THF (40 mL). The mixture was stirred for 1.5 h at –78 100).
oC before the addition of saturated aqueous ammonium chloride
(120 mL). After warming to room temperature, saturated aqueous (2R)-4-[(Z)-2-tert-Butyldiphenylsilyloxyethylidene]-2-
ammonium chloride (300 mL) and ethyl acetate (300 mL) were trimethylsilyloxy-1-(4-methoxybenzyloxy)hept-6-ene (79)
added, and the aqueous phase extracted with ethyl acetate (4 × 200 Triethylamine (7.89 mL, 56.58 mmol) was added to the alcohol 77
mL). The organic extracts were dried (MgSO4) and concentrated (10.00 g, 18.86 mmol) in DCM (70 mL) and the solution cooled to 0
under reduced pressure afforded the phosphonate 75 as a mixture oC. Trimethylsilyl chloride (3.07 mL, 28.29 mmol) was added
of epimers, Rf = 0.29 (ether), that was used without further dropwise and the mixture warmed to room temperature and stirred
purification.
for 40 min. Saturated aqueous sodium bicarbonate (130 mL) was
Pyridine (16.6 mL, 205.45 mmol) was added to a suspension of added dropwise and ether (500 mL) and water (150 mL) were
the Dess-Martin periodinane (9.40 g, 22.17 mmol) in DCM (100 mL) added. The aqueous phase was extracted with ether (2 × 250 mL)
at rt followed by the phosphonate 75 in DCM (40 mL). After 50 min, and the organic extracts washed with saturated aqueous sodium
saturated aqueous sodium bicarbonate (500 mL) and ethyl acetate bicarbonate (250 mL), dried (MgSO4) and concentrated under
(500 mL) were added and the organic phase washed with saturated reduced pressure. Filtration of the residue through a silica plug
aqueous sodium thiosulfate (200 mL). The aqueous phases were (light petroleum:ether 10:1 + 1% triethylamine) afforded the title
extracted with ethyl acetate (3 × 200 mL) and the organic extracts compound 79 (10.33 g, 91%), as a colourless oil, Rf = 0.75 (light
20
were washed with brine (30 mL), dried (MgSO4) and concentrated petroleum:ether 1:1), [α]D +3.0 (c 0.8, CHCl3) (Found: M+ + NH4,
under reduced pressure. Chromatography of the residue gave the 620.3592. C36H54NO4Si2 requires M, 620.3586); νmax/cm-1 3071,
title compound 76 (8.58 g, 80% yield from the alcohol 73), as a 2955, 2931, 2857, 1613, 1587, 1513, 1466, 1428, 1362, 1301, 1249,
highly viscous, colourless gum, Rf 0.48 (ethyl acetate), [α]D21 –2.1 (c 1174, 1109, 1058, 1040, 1001, 913, 842 and 741; δH (300 MHz,
4.4, CHCl3) (Found: M+ + H, 725.3634. C40H58O8PSi requires M, CDCl3) 0.00 (9 H, s, 3 × SiCH3), 1.07 [9 H, s, SiC(CH3)3], 1.98 (1 H, dd, J
725.3633); νmax/cm-1 3068, 2952, 2935, 2857, 1704, 1468, 1428, 13.6, 8.0, 3-H), 2.12 (1 H, dd, J 13.6, 5.1, 3-H’), 2.77 (2 H, br. d, J 6.8,
1381, 1258, 1224, 1174, 1109, 1071, 1033 and 738; δH 1.06 [9 H, s, 5-H2), 3.24 (2 H, d, J 5.5, 1-H2), 3.78 (1 H, m, 2-H), 3.82 (3 H, s,
SiC(CH3)3], 1.20 and 1.25 (each 3 H, s, 3-CH3), 1.35 (6 H, s, 2 × CCH3), OCH3), 4.23-4.39 (2 H, m, 2’-H2), 4.36 and 4.41 (each 1 H, d, J 11.7,
1.50-1.80 (6 H, m, 5-H2, 7-H2, 9-H2), 3.24 and 3.30 (each 1 H, dd, J ArHCH), 5.03-5.13 (2 H, m, 7-H2), 5.52 (1 H, t, J 6.2, 1’-H), 5.79 (1 H,
28.6, 15.9, 1-H), 3.70-3.90 (3 H, m, 4-H, 10-H2), 3.81 and 3.82 (each m, 6-H), 6.86 and 7.21 (each 2 H, m, ArH), 7.37-7.50 (6 H, m, ArH)
3 H, d, J 11.2, OCH3), 4.00-4.20 (2 H, m, 6-H, 8-H), 4.59 and 4.70 and 7.70 (4 H, m, ArH); δC (75 MHz, CDCl3) 0.51, 19.5, 21.1, 35.9,
(each 1 H, d, J 11.3, PhHCH), 7.25-7.50 (11 H, m, ArH) and 7.68 (4 H, 42.4, 55.5, 61.4, 70.9, 73.1, 74.4, 113.9, 116.6, 127.9, 128.4, 129.4,
m, ArH); δC (75 MHz, CDCl3) 19.5, 21.0, 21.4, 25.4, 25.7, 27.1, 36.5, 129.8, 130.7, 134.3, 135.9, 136.2, 136.7 and 159.3; m/z (APCI+) 620
38.3, 39.1, 39.2, 53.0, 53.1, 53.2, 54.0, 60.3, 63.5, 63.7, 75.1, 81.4, (M+ + 18, 17%), 603 (M+ + 1, 10%), 391 (14), 347 (12), 317 (14), 277
100.5, 127.5, 127.9(3), 128.7, 129.9, 134.2, 135.8, 138.7, 207.3 and (20), 196 (15) and 157 (100).
207.4; m/z (APCI-) 723 (M- - H, 100%) and 633 (14).
(6R,2RS)-4-[(Z)-2-tert-Butyldiphenylsilyloxyethylidene]-6-
(2R)-4-[(Z)-2-tert-Butyldiphenylsilyloxyethylidene]-1-(4-
trimethylsilyloxy-7-(4-methoxybenzyloxy)heptane-1,2-diol (80).
methoxybenzyloxy)hept-6-en-2-ol (77)
AD-mix β (15.73 g, 16.86 mmol) was added in portions to a stirred
tert-Butyldiphenylsilyl choride (19.54 g, 0.071 mol) was added mixture of tert-butanol (62 mL) and water (62 mL). After 10 min,
dropwise to the diol 48 (23.09 g) and imidazole (8.07 g, 0.119 mol) the mixture was cooled to 0 °C, and the alkene 79 (10.15 g, 16.86
in DCM (400 mL) at 0 °C and the solution stirred for 30 min. The mol) in tert-butanol (19 mL) and acetone (10 mL) was added in
reaction mixture was allowed to warm to rt and was stirred for 1 h. portions. Osmium tetroxide (214 mg, 0.843 mmol) dissolved in tert-
Saturated aqueous ammonium chloride (200 mL) was added and butanol (3 mL) and water (17 mL) was added dropwise by a syringe
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Organic & Biomolecular Chemistry
Page 24 of 31
ARTICLE
Journal Name
pump over 10 h. After a further 18 h, the reaction mixture was phase washed with DCM (2 × 150 mL). The organic VeiexwtrAarctictsle Ownelirnee
allowed to warm to rt, and aqueous sodium sulfite (60 g in 300 mL) washed with brine (100 mL), dried (MgSO4) DanOdI: c10o.n10ce39n/tCra6tOeBd0u18n0d4eAr
was added. The mixture was stirred for 1 h, ethyl acetate (300 mL) reduced pressure to afford the enone 82 (6.1 g) as a yellow oil, Rf =
was added and the aqueous phase was extracted with ethyl acetate 0.48 (ethyl acetate).
(3 × 300 mL). The organic extracts were dried (MgSO4) and
The trimethylsilyl ether 82 in THF (91.2 mL) was divided into
concentrated under reduced pressure. Chromatography of the approximately two equal portions in polypropylene bottles. To each
residue (light petroleum:ether 1:1 + 1% triethylamine to ether + 1% of these was added pyridine (4.56 mL). After cooling to 0 oC,
triethylamine) afforded the title compound 80 (7.51 g, 70%) as a hydrogen fluoride-pyridine complex (2.28 mL) was added rapidly to
clear oil, a 60:40 mixture of diastereoisomers, Rf = 0.33 (ether); one of the flasks in one portion via a plastic syringe before stirring
νmax/cm-1 3432, 2953, 2932, 2857, 1612, 1513, 1463, 1428, 1362, for 30 s. The reaction mixture was then immediately poured into a
1301, 1249, 1110, 1038 and 842; δH (300 MHz, CDCl3) 0.04 (5.5 H, s, 2-L conical flask containing saturated aqueous sodium bicarbonate
3 × SiCH3), 0.06 (3.5 H, s, 3 × SiCH3), 1.05 [9 H, s, SiC(CH3)3], 2.00- (250 mL) and the flask rinsed immediately with more saturated
2.30 (6 H, m, 3-H2, 5-H2, 2 × OH), 3.20-3.35 (2 H, m, 1-H2), 3.47 (1 H, aqueous sodium hydrogen carbonate and ether. The aqueous phase
dd, J 8.5, 6.5, 7-H), 3.66 (1 H, dd, J 8.5, 3.5, 7-H’), 3.75-3.85 (2 H, m, was extracted with ether (3 × 250 mL) and the organic extracts
2-H, 6-H), 3.86 (3 H, s, OCH3), 4.30-4.38 (2 H, m, 2’-H2), 4.40 (2 H, s, washed with more saturated aqueous sodium bicarbonate. This
ArCH2), 5.60 (0.4 H, t, J 6.2, 1’-H), 5.63 (0.6 H, t, J 6.2, 1’-H), 6.90 and process was repeated for the second batch of material and the
7.22 (each 2 H, m, ArH), 7.35-7.50 (6 H, m, ArH) and 7.72 (4 H, m, combined organic extracts from the two reactions were dried
ArH); δC (75 MHz, CDCl3) 0.46, 19.4, 27.1, 35.6, 35.8, 41.7, 42.4, 5.5, (MgSO4)
and
concentrated
under
reduced
pressure.
61.0, 61.1, 66.7, 66.8, 69.9, 70.5, 70.9, 71.5, 73.2(2), 74.2(2), 114.0, Chromatography (light petroleum:ether 3:1 to 1:1) afforded the
114.1, 128.0, 128.6, 129.5(2), 129.7, 129.9, 130.5, 130.7, 131.3, title compound 83 (3.08 g, 65% from the ketophosphonate 76), as a
134.1(2), 134.9, 135.9 and 159.4; m/z (ES+) 660 (M+ + 24, 100%).
highly viscous colourless oil, Rf = 0.31 (light petroleum:ether 1:1),
21
[α]D +6.9 (c 2.6, CHCl3); νmax/cm-1 3505, 3069, 2932, 2857, 1686,
(5R)-3-[(E)-2-tert-Butyldiphenylsilyloxyethylidene]-6-(4-
1616, 1588, 1513, 1467, 1428, 1383, 1302, 1249, 1224, 1173, 1109,
methoxybenzyloxy)-5-trimethylsilyloxyhexanal (81)
1037, 910, 823 and 737; δH (300 MHz, CDCl3) 1.06 and 1.08 [each 9
Lead tetra-acetate in DCM (80 mL) was added to the diol 80 (3.81 g, H, s, 2 × SiC(CH3)3], 1.18 and 1.24 (each 3 H, s, 9-CH3), 1.38 [6 H, s,
6.00 mmol) in DCM (40 mL) and pyridine (3.81 mL) and the mixture C(CH3)2], 1.48-1.80 (6 H, m, 11-H2, 13-H2, 15-H2), 2.04 (1 H, dd, J
stirred for 45 min. DCM (150 mL) was added followed by saturated 13.8, 4.8, 3-H), 2.15 (1 H, dd, J 13.8, 8.4, 3-H’), 2.57 (1 H, br. m, OH),
aqueous sodium bicarbonate (150 mL). The mixture was filtered 2.95 (2 H, d, J 7.2, 5-H2), 3.26 (1 H, dd, J 9.4, 6.5, 1-H), 3.35 (1 H, dd,
through a pad of celite and the aqueous phase extracted with DCM J 9.4, 4.0, 1-H’), 3.65-3.76 (2 H, m, 16-H2), 3.80 (1 H, m, 2-H), 3.82 (3
(2 × 150 mL). The organic extracts were washed with brine (150 H, s, OCH3), 3.95 (1 H, dd, J 8.2, 6.0, 10-H), 4.00-4.12 (2 H, m, 12-H,
mL), dried (MgSO4), and concentrated under reduced pressure to 14-H), 4.15 (1 H, dd, J 12.7, 6.9, 2’-H), 4.22 (1 H, dd, J 12.7, 6.7, 2’-
afforded the title compound 81 (3.5 g, ca. 100%) as a colourless oil, H’), 4.43 (2 H, s, ArCH2), 4.58 and 4.64 (each 1 H, d, J 11.1, ArHCH),
Rf 0.49 (light petroleum:ether 1:1); νmax/cm-1 2955, 2932, 2894, 5.59 (1 H, dd, J 6.6, 6.3, 1’-H), 6.64 (1 H, d, J 15.1, 7-H), 6.84-6.94 (3
2857, 1725, 1612, 1513, 1428, 1249, 1110 and 842; δH (300 MHz, H, m, 6-H, 2 × ArH), 7.22 (2 H, d, J 8.6, ArH), 7.28-7.48 (17 H, m,
CDCl3) 0.05 (9 H, s, 3 × SiCH3), 1.10 [9 H, s, SiC(CH3)3], 2.08 (1 H, dd, J ArH) and 7.69 (8 H, m, ArH); δC (75 MHz, CDCl3) 19.4, 19.5, 20.8,
11.5, 7.0, 4-H), 2.15 (1 H, dd, J 11.5, 2.8, 4-H’), 3.12 (2 H, m, 2-H2), 21.5, 25.5, 25.7, 27.1(2), 30.0, 34.8, 39.0, 39.1, 40.4, 51.6, 55.5,
3.20-3.30 (2 H, m, 6-H2), 3.78 (1 H, m, 5-H), 3.83 (3 H, s, OCH3), 60.3, 60.5, 63.5, 63.6, 69.0, 73.3, 74.0, 75.0, 80.8, 100.5, 114.1,
4.27-4.40 (2 H, m, 2’-H2), 4.39 (2 H, s, ArCH2), 5.67 (1 H, t, J 6.2, 1’- 127.5, 127.6, 127.7, 127.9(2), 128.0, 128.6, 129.4, 129.6, 129.8,
H), 6.88 and 7.22 (each 2 H, m, ArH), 7.25-7.50 (6 H, m, ArH), 7.72 (4 130.0, 130.3, 133.8, 134.1, 134.2, 135.8, 135.9, 136.0, 138.9, 144.4,
H, m, ArH) and 9.59 (1 H, t, J 2.0, 1-H); δC (75 MHz, CDCl3) 0.43, 19.4, 159.5 and 203.6.
27.1, 36.5, 52.7, 55.6, 61.1, 70.8, 73.2, 74.0, 114.0, 128.0, 129.5,
129.9, 130.5, 133.2, 134.0, 135.9, 159.4 and 200.6.
(4S,6R,8S)-4-Benzyloxy-10-tert-butyldiphenylsilyloxy-1-{(2S,6R)-4-
[(Z)-2-tert-butyldiphenylsilyloxyethylidene]-6-(4-
(2R,6E,10S,12R,14S)-10-Benzyloxy-16-tert-butyldiphenylsilyloxy-4- methoxybenzyloxymethyl)tetrahydropyran-2-yl}-6,8-O-
[(Z)-2-tert-butyldiphenylsilyloxyethylidene]-2-hydroxy-1-(4- isopropylidene-3,3-dimethyldecan-2-one (84)
methoxybenzyloxy)-9,9-dimethyl-12,14-O-isopropylidenehexadec- Potassium tert-butoxide (0.092 M in THF, 1.0 mL, 0.092 mmol) was
6-en-8-one (83) added rapidly to the alcohol 83 (414 mg, 0.366 mmol) in THF (2.1
The ketophosphonate 76 (3.04 g, 4.19 mmol) in THF (40 mL) was mL) at rt and the solution stirred for 5 min. Saturated aqueous
added via a canula to oven-dried barium hydroxide monohydrate ammonium chloride (30 mL) and ether (30 mL) were added and the
(1.72 g, 5.45 mmol) suspended in THF (23 mL). The mixture was aqueous phase was extracted with ether (2 × 20 mL). The organic
stirred for 30 min before the dropwise addition of the aldehyde 81 extracts were dried (MgSO4) and concentrated under reduced
(3.3 g, 5.5 mmol) in wet THF (40:1 THF:water, 65 mL) over ca. 30 pressure to afford the title compound 84 (409 mg) that was used
min. After stirring for 18 h, the mixture was diluted with DCM (150 without further purification. Chromatography of a small sample
mL) and filtered through a pad of celite. The reaction flask was gave the title compound 84 as a colourless oil, Rf = 0.43 (light
21
rinsed with DCM (2 × 150 mL), the resulting solvent being used to petroleum:ether 2:1), [α]D +5.0 (c 1.6, CHCl3) (Found: M+ + Na,
wash the filter cake. The organic extracts were washed with 1153.6027. C70H90O9NaSi2 requires M, 1153.6016); νmax/cm-1 2932,
saturated aqueous sodium bicarbonate (200 mL) and the aqueous 2890, 2857, 1704, 1611, 1587, 1513, 1468, 1427, 1381, 1363, 1247,
24 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
1224, 1172, 1108, 822 and 738; δH (300 MHz, CDCl3) 1.06 and 1.07 trimethylsilylethoxymethyl chloride (1.057 mL, 5.97 mmol) were
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o
[each 9 H, s, SiC(CH3)3], 1.10 and 1.11 (each 3 H, s, 3-CH3), 1.37 and added to the alcohol 85 (1.1 g, 0.995 mmol)DiOnID: 1C0M.10(359./0Cm6OLB) 0a1t8004AC
1.38 (each 3 H, s, CCH3), 1.46 to 1.78 (7 H, br. m, 5’-Hax, 5-H2, 7-H2, and the solution warmed to rt. DMAP (cat.) was added and the
9-H2), 1.87 (1 H, m, 3’-Hax), 2.21 (2 H, d, J 13.2, 3’-Heq, 5’-Heq), 2.60 mixture stirred for 18 h. Saturated aqueous sodium bicarbonate (20
(1 H, dd, J 17.7, 6.6, 1-H), 3.03 (1 H, dd, J 17.7, 5.5, 1-H’), 3.25-3.43 mL) and DCM (20 mL) were added with stirring for 30 min before
(3 H, m, 6’-H, 6’-CH2), 3.69 and 3.72 (each 1 H, m, 10-H), 3.81 (3 H, s, the addition of saturated aqueous sodium bicarbonate (100 mL)
OCH3), 3.84 (1 H, m, 2’-H), 3.92-4.14 (3 H, m, 4-H, 6-H, 8-H), 4.22 (2 and DCM (100 mL). The aqueous phase was extracted with DCM (2
H, d, J 6.3, 2’’-H2), 4.45 (2 H, s, ArCH2), 4.60 and 4.69 (each 1 H, d, J × 100 mL) and the organic extracts were washed with saturated
11.3, ArHCH), 5.48 (1 H, t, J 6.3, 1’’-H), 6.87 and 7.22 (each 2 H, d, J aqueous sodium bicarbonate (20 mL), then dried (MgSO4) and
8.6, ArH), 7.26-7.48 (16 H, m, ArH) and 7.62-7.78 (9 H, m, ArH); δC concentrated under reduced pressure. Chromatography of the
(75 MHz, CDCl3) 15.6, 19.5(2), 20.8, 21.1, 25.5, 25.7, 26.9, 27.2, residue (light petroleum:ether 20:1 to 4:1 + 1% triethylamine) gave
31.6, 39.2, 39.3, 41.7, 45.3, 53.1, 55.6, 60.3, 63.6, 63.8, 68.3, 73.0, the title compound 86 (1.05 mg, 85%) as a colourless oil, Rf = 0.67
73.2, 74.7, 75.2, 76.9, 80.8, 100.6, 114.1, 124.1, 127.4, 127.8, 128.0, (light petroleum:ether 4:1), [α]D20 +23.8 (c 4.1, CHCl3) (Found: M+ +
128.7, 129.7, 129.9, 130.6, 134.2, 135.2, 135.7, 135.9(3), 139.1, NH4, 1252.7109. C74H106NO10Si3 requires M, 1252.7119); νmax/cm-1
159.5 and 213.0; m/z (APCI-) 1165 (M- + 35, 22%), 1130 (M+, 5), 937 3069, 2951, 2932, 2891, 2857, 1611, 1588, 1513, 1467, 1427, 1385,
(31), 909 (40) and 874 (100).
1362, 1301, 1249, 1107, 1060, 1035, 938, 858, 824 and 739; δH (300
MHz, C6D6) 0.01 (9 H, s, 3 × SiCH3), 0.98 (2 H, m, SiCH2), 1.20 and
1.21 [each 9 H, s, SiC(CH3)3], 1.30 and 1.38 (each 3 H, s, 8-CH3), 1.50
(1 H, m, 12-H), 1.70 (1 H, m, 14-H), 1.75-1.85 (3 H, m, 2-H2, 12-H’),
1.92 (1 H, m, 14-H’), 1.95-2.15 (4 H, m, 4-H2, 6-H, 10-H), 2.25-2.40 (2
H, m, 6-H’, 10-H’), 3.32 and 3.36 (each 3 H, s, 2 × OCH3), 3.40-3.55
(3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-
13-[(Z)-2-tert-butyldiphenylsilyloxyethylidene]-5,9-epoxy-11,15-
epoxy-8,8-dimethyl-9-methoxy-16-(4-
methoxybenzyloxy)hexadecan-3-ol (85)
Anhydrous methanol (10.5 mL) and trimethyl orthoformate (1.6 mL) (2 H, m, 15-H, 16-H), 3.59 (1 H, m, 16-H’), 3.70 (2 H, m, OCH2CH2Si),
were added to the acetonide 84 (from 530 mg of alcohol 83, 0.47 3.80 (1 H, m, 11-H), 3.84-4.08 (4 H, m, 1-H2, 5-H, 7-H), 4.20 (1 H, m,
mmol) followed by oven dried pyridinium toluene p-sulfonate (40 3-H), 4.33 (1 H, d, J 12.0, ArHCH), 4.36 (2 H, d, J 6.6, 2’-H2), 4.42 and
mg, 0.162 mmol) and the mixture was stirred for 17 h. More 4.43 (each 1 H, d, J 11.5, ArHCH), 4.52 (1 H, d, J 12.0, ArHCH), 4.77
pyridinium toluene p-sulfonate (11 mg, 0.044 mmol) was added and (2 H, s, OCH2O), 5.66 (1 H, t, J 6.6, 1’-H), 6.82 (2 H, d, J 8.8, ArH),
the mixture stirred for 2 h. Saturated aqueous sodium bicarbonate 7.10-7.40 (19 H, m, ArH) and 7.75-7.90 (8 H, m, ArH); δC (75 MHz,
(50 mL) and ether (50 mL) were added and the aqueous phase was C6D6) −1.3, 1.3, 17.2, 18.2, 19.4(2), 21.3, 27.0, 27.1, 31.7, 33.5, 39.0,
extracted with ether (2 × 20 mL). The organic extracts were washed 40.0, 42.6, 43.6, 43.8, 48.5, 54.7, 60.4, 60.8, 65.4, 65.8, 71.6, 73.1,
with saturated aqueous sodium bicarbonate (2 × 20 mL), dried 73.4, 73.9, 75.3, 77.1, 79.2, 95.0, 104.4, 114.0, 123.5, 127.4, 127.5,
(MgSO4)
and
concentrated
under
reduced
pressure. 127.6, 127.7, 127.8, 127.9, 128.0, 128.3(2), 129.3, 129.9, 131.2,
Chromatography of the residue (light petroleum:ether 3:1 + 1% 134.2, 134.3, 135.9, 136.0(3), 137.0, 139.9 and 159.6; m/z (APCI+)
triethylamine) afforded the title compound 85 (309 mg, 60% from 1258 (100%), 1001 (37) and 490 (30).
the alcohol 83), as a colourless oil, Rf = 0.58 (light petroleum:ether
1:1), [α]D +27.3 (c 3.5, CHCl3) (Found: M+ + Na, 1127.5851. (3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-13-
20
C68H88O9NaSi2 requires M, 1127.5859); νmax/cm-1 3509, 3046, 2932, [(Z)-2-tert-butyldiphenylsilyloxyethylidene]-5,9-epoxy-11,15-
2857, 1611, 1588, 1513, 1467, 1428, 1385, 1362, 1302, 1248, 1174, epoxy-8,8-dimethyl-9-methoxy-3-(2-
1108, 822 and 738; δH (300 MHz, C6D6) 1.17 [18 H, s, 2 × SiC(CH3)3], trimethylsilylethoxy)methoxyhexadecan-16-ol (87)
1.28 and 1.30 (each 3 H, s, 2 × 8-CH3), 1.50 to 1.80 (8 H, br. m, 2-H2, A pH 7 buffer (0.4 ml) was added to the 4-methoxybenzyl ether 86
4-H2, 6-H2, 10-H2), 1.96 (1 H, m, 12-Hax), 2.14-2.42 (3 H, m, 12-Heq, (1.49 g, 1.21 mmol) in DCM (8 mL) at rt followed, with rapid stirring,
14-H2), 3.21 (3 H, s, 9-OCH3), 3.24 (1 H, m), 3.30 (3 H, s, OCH3), 3.34- by dichlorodicyanoquinone (357 mg, 1.57 mmol), and the mixture
3.60 (3 H, m, 3-H, 16-H2), 3.70-3.89 (3 H, m), 3.96 (2 H, t, J 5.9, 1- stirred for 45 min. DCM (100 mL) was added and the mixture
H2), 4.29 (1 H, d, J 11.9, ArHCHCH), 4.35 (2 H, d, J 6.4, 2’-H2), 4.39 (2 filtered through celite. Saturated aqueous sodium bicarbonate (100
H, s, ArCH2), 4.47 (1 H, d, J 11.9, ArHCH), 5.62 (1 H, t, J 6.0, 1’-H), mL) was added and the aqueous phase extracted with DCM (3 × 100
6.80 (2 H, d, J 8.5, ArH), 7.10-7.40 (17 H, m, ArH) and 7.75-7.90 (10 mL). The organic extracts were washed with saturated aqueous
H, m, ArH); δC (75 MHz, C6D6) 17.2, 19.3, 19.4, 21.1, 27.0, 31.8, 32.5, sodium bicarbonate (100 mL), dried (MgSO4) and concentrated
39.9, 40.3, 43.1, 43.4, 43.5, 48.3, 54.7, 60.4, 62.9, 66.2, 66.6, 71.5, under reduced pressure. The residue was azeotroped with benzene
73.1, 73.3, 75.1, 76.9, 79.0, 104.2, 113.9, 123.4, 127.4, 127.5, 127.6, before the addition of anhydrous methanol (15 mL), trimethyl
127.7, 127.8, 127.9, 128.0, 128.1, 128.3, 128.5, 129.3, 129.9, orthoformate (2.5 mL) and oven-dried pyridinium toluene p-
130.0(2), 131.3, 133.8, 133.9, 134.2, 135.9(2), 136.0, 137.0, 139.9 sulfonate (34 mg, 0.134 mmol). After stirring for 4 h, saturated
and 159.5; m/z (APCI+) 1127 (M+ + 23, 100%), 870 (42) and 491 (52).
aqueous sodium bicarbonate (100 mL) and DCM (100 mL) were
added and the aqueous phase was extracted with DCM (2 × 100
mL). After drying (MgSO4) and concentration under reduced
pressure, chromatography of the residue (light petroleum:ether 3:1
to 2:1 + 1% triethylamine) gave the title compound 87 (854 mg,
(3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-
13-[(Z)-2-tert-butyldiphenylsilyloxyethylidene]-5,9-epoxy-11,15-
epoxy-8,8-dimethyl-9-methoxy-16-(4-methoxybenzyloxy)-3-(2-
trimethylsilylethoxy)methoxyhexadecane (86)
20
71%) as a colourless oil, Rf = 0.50 (light petroleum:ether 1:1), [α]D
Di-isopropylethylamine (2.08 mL, 11.94 mmol) and 2- +23.4 (c 4.5, CHCl3) (Found: M+ + Na, 1137.6090. C66H94O9NaSi3
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J. Name., 2013, 00, 1-3 | 25
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Organic & Biomolecular Chemistry
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ARTICLE
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requires M, 1137.6098); νmax/cm-1 3492, 3069, 2951, 2931, 2890, (17 H, m, ArH) and 7.80-7.88 (8 H, m, ArH); δC (75 MHz, C6D6) −1.3,
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2858, 1589, 1470, 1428, 1386, 1362, 1250, 1190, 1108, 1061, 938, 1.3, 17.2, 18.2, 19.3, 21.2, 27.0, 27.1, 30.1D, O3I3:.150,.13043.99/,C36O9.B00,13890.49A,
859, 825 and 739; δH (300 MHz, C6D6) 0.00 (9 H, s, 3 × SiCH3), 0.98 (2 42.7, 43.5, 48.4, 60.4, 60.8, 65.4, 65.8, 71.6, 73.8, 75.1, 77.7, 79.2,
H, t, J 8.2, SiCH2), 1.18 and 1.20 [each 9 H, s, SiC(CH3)3], 1.21 and 95.0, 104.4, 114.1, 123.5, 127.4, 127.5, 127.6, 128.0(2), 128.3,
1.23 (each 3 H, s, 8-CH3), 1.30-1.50 (2 H, m, 12-H, 14-H), 1.70-1.95 129.9, 134.2, 135.9, 136.0(3), 136.9, 139.3 and 139.9; m/z (APCI+)
(6 H, m, 2-H2, 6-H, 10-H, 12-H’, 14-H’), 2.00-2.25 (5 H, m, 4-H2, 6-H’, 1133 (M+ + 23, 100%) and 491 (63).
10-H’, OH), 3.13 (1 H, m, 15-H), 3.26 (3 H, s, OCH3), 3.36 (2 H, d, J
4.4, 16-H2), 3.60-3.80 (3 H, m, 11-H, OCH2CH2Si), 3.80-4.05 (4 H, m, (3S,5R,7S,9S,11S,15R)-7-Benzyloxy-13-[(Z)-
1-H2, 5-H, 7-H), 4.18 (1 H, m, 3-H), 4.25-4.35 (3 H, m, ArHCH, 2’-H2), methoxycarbonylethylidene]-5,9-epoxy-11,15-epoxy-8,8-
4.50 (1 H, d, J 11.6, ArHCH), 4.76 (2 H, s, OCH2O), 5.62 (1 H, t, J 6.3, dimethyl-9-methoxy-3-(2-trimethylsilylethoxy)methoxyheptadec-
1’-H), 7.05-7.40 (17 H, m, ArH) and 7.75-7.90 (8 H, m, ArH); δC (75 16-en-1-ol (91)
MHz, C6D6) −1.3, 1.3, 17.3, 18.2, 19.4, 21.3, 27.0, 27.1, 30.4, 33.4, Tetra-n-butylammonium fluoride (1.0 M in THF, 0.16 mL, 0.16
38.9, 39.5, 42.6, 43.2, 43.3, 48.3, 60.4, 60.9, 65.5, 65.7, 66.0, 71.6, mmol) was added to the bis-tert-butyldiphenylsilyl ether 89 (30 mg,
73.7, 75.0, 77.8, 79.2, 94.9, 104.3, 124.0, 127.1, 127.4, 127.5, 127.6, 0.027 mmol) in THF (1 mL) and the mixture stirred for 2 h. The
128.0(2), 128.3, 129.9, 130.0(2), 134.2(3), 135.9, 136.0(2) and mixture was then poured into a mixture of saturated aqueous
139.9; m/z (APCI+) 1137 (M+ + 23, 100%) and 490 (30).
sodium bicarbonate (10 mL) and DCM (20 mL). The aqueous phase
was extracted with DCM (3 × 20 mL) and the organic extracts were
(3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-13- dried (MgSO4) then concentrated under reduced pressure to afford
[(Z)-2-tert-butyldiphenylsilyloxyethylidene]-5,9-epoxy-11,15-
epoxy-8,8-dimethyl-9-methoxy-3-(2-
trimethylsilylethoxy)methoxyheptadec-16-ene (89)
the diol 90 that was used without purification; δH (300 MHz, C6D6)
0.00 (9 H, s, 3 × SiCH3), 0.99 (2 H, m, SiCH2), 1.28 and 1.31 (each 3 H,
s, 8-CH3), 1.44 (1 H, q, J 12.2, 6-Hax), 1.62-1.94 (8 H, m, 2-H2, 4-H2, 6-
Pyridine (1.83 mL, 21.9 mmol) and then, after 5 min, the alcohol 87 Heq, 10-H, 12-H, 14-H), 2.02 (1 H, br. t, J 12.2, 12-Hax), 2.14 (1 H, br.
(814 mg, 0.73 mmol) in DCM (5.4 mL), were added to a stirred s, OH), 2.36 (1 H, dd, J 15.9, 4.4, 10-H’), 2.45 (1 H, br. t, J 12.1, 14-
suspension of the Dess-Martin periodinane (928 mg, 2.19 mmol) in Hax), 2.88 (1 H, br. s, OH), 3.18 (3 H, s, OCH3), 3.60 (2 H, m,
DCM (6.9 mL) and the mixture stirred for 1 h. Saturated aqueous OCH2CH2Si), 3.70-3.90 (6 H, m, 1-H2, 3-H, 5-H, 7-H, 11-H), 4.02 (1 H,
sodium bicarbonate (50 mL) and ether (100 mL) were added and dd, J 12.3, 6.3, 2’-H), 4.08-4.18 (2 H, m, 2’-H’, 15-H), 4.30 and 4.47
the aqueous phase extracted with ether (3 × 25 mL). The organic (each 1 H, d, J 12.0, PhHCH), 4.71 and 4.78 (each 1 H, d, J 6.9,
extracts were washed with saturated aqueous sodium thiosulfate OHCHO), 5.04 (1 H, dt, J 10.7, 1.8, 17-H), 5.32 (1 H, dt, J 17.3, 1.8,
(50 mL), dried (MgSO4) and concentrated under reduced pressure 17-H’), 5.61 (1 H, t, J 6.3, 1’-H), 5.90 (1 H, ddd, J 17.3, 10.7, 4.8, 16-
to afford the aldehyde 88. After azeotropic removal of traces of H) and 7.01-7.24 (5 H, m, ArH).
water, the aldehyde was used without further purification.
Manganese dioxide (82 mg, 0.945 mmol) was added to the diol
Tetrahydrofuran (5.1 mL) was added to a rapidly stirred mixture 90 in DCM (1 mL) and the mixture stirred at rt for 1 h. After cooling
of methyl(triphenyl)phosphonium bromide (1.56 g, 4.38 mmol) and to 0 oC, methanol (1 mL), crushed potassium cyanide (17.5 mg, 0.27
potassium tert-butoxide (459 mg, 4.09 mmol) and the resulting mmol) and acetic acid (0.0077 mL, 0.135 mmol) were added and the
o
bright yellow solution was stirred for 20 min before cooling to 0 oC. mixture was stirred at 0 C for 1 h and then at rt for 90 h. After
The aldehyde 88 (from 814 mg of the alcohol 87, 0.730 mmol) in adding DCM (20 mL), the mixture was filtered through Celite before
THF (6.0 mL) was added and the mixture warmed to rt. After 1 h, the addition of saturated aqueous sodium bicarbonate (10 mL). The
saturated aqueous sodium bicarbonate (20 mL) and ether (50 mL) aqueous phase was extracted with DCM (2 × 20 mL) and the organic
were added and the aqueous phase extracted with ether (3 × 25 extracts were dried (MgSO4) then concentrated under reduced
mL). The organic extracts were dried (MgSO4) and concentrated pressure. Chromatography of the residue (light petroleum:ether 2:1
under reduced pressure. Chromatography of the residue (light + 1% triethylamine to light petroleum:ether 1:1 + 1% triethylamine)
petroleum:ether 10:1 + 1% triethylamine) afforded the title gave the title compound 91 (6 mg, 34%) as a colourless oil, a 4:1
20
compound 89 (575 mg, 71% yield from alcohol 87) as a colourless mixture of (Z)- and (E)-isomers, Rf = 0.60 (ether), [α]D +27.1 (c
20
oil, Rf = 0.75 (light petroleum:ether 2:1), [α]D +22.0 (c 3.2, CHCl3) 2.78, CHCl3) (Found: M+ + Na, 685.3743. C36H58O9NaSi requires M,
(Found: M+ + Na, 1133.6142. C67H94O8NaSi3 requires M, 1133.6149); 685.3742); νmax/cm-1 3485, 2950, 2895, 1719, 1650, 1436, 1374,
νmax/cm-1 3069, 2953, 2930, 2892, 2857, 1589, 1469, 1427, 1386, 1363, 1248, 1152, 1098, 1058, 1027, 925, 859 and 836; δH (300
1362, 1258, 1108, 1060, 1030, 859, 824, 800 and 738; δH (300 MHz, MHz, C6D6) 0.00 (9 H, s, 3 × SiCH3), 0.66 (1 H, br. s, OH), 0.93-1.03 (2
C6D6) 0.00 (9 H, s, 3 × SiCH3), 0.97 (2 H, m, SiCH2), 1.18 and 1.21 H, m, SiCH2) 1.08-2.40 (17 H, m, 2-H2, 4-H2, 6-H2, 10-H2, 12-H2, 14-H,
[each 9 H, s, SiC(CH3)3], 1.27 and 1.35 (each 3 H, s, 8-CH3), 1.48 (1 H, 2 × 8-CH3), 3.17 (2.4 H, s, OCH3) 3.25 (0.6 H, s, OCH3), 3.42 (2.4 H, s,
m, 6-H), 1.64 (1 H, m, 12-H), 1.72-1.85 (3 H, m, 2-H2, 6-H’), 1.90 (1 CO2CH3), 3.44 (0.6 H, s, CO2CH3), 3.52-3.94 (8 H, m, 1-H2, 3-H, 5-H,
H, dd, J 16.0, 4.5, 14-H), 1.92-2.12 (3 H, m, 4-H2, 10-H), 2.20-2.40 (3 11-H, 15-H, SiCH2CH2O), 4.07 (1 H, m, 7-H), 4.24 (1H, m, 4-Heq), 4.30
H, m, 10-H’, 12-H’, 14-H’), 3.34 (3 H, s, OCH3), 3.62 (1 H, m, 15-H), and 4.48 (each 1 H, d, J 12.0, PhHCH), 4.67 (0.8 H, d, J 6.9, OHCHO),
3.68 (2 H, m, OCH2CH2Si), 3.78 (1 H, m, 11-H), 3.83-4.05 (4 H, m, 1- 4.72 (0.2 H, d, J 6.9, OHCHO), 4.73 (0.8 H, d, J 6.9, OHCHO), 4.80 (0.2
H2, 5-H, 7-H), 4.18 (1 H, m, 3-H), 4.32 (1 H, d, J 12.0, ArHCH), 4.34 (2 H, d, J 6.9, OHCHO), 4.99 (1 H, dt, J 10.5, 1.6, 17-H), 5.27 (0.2 H, m,
H, d, J 6.4, 2’-H2), 4.50 (1 H, d, J 12.0, ArHCH), 4.76 (2 H, s, OCH2O), 17-H’), 5.33 (0.8 H, dt, J 17.3, 1.6, 17-H’), 5.64 (0.2 H, m, 1’-H), 5.74
5.00 (1 H, dt, J 10.7, 1.8, 17-H), 5.30 (1 H, dt, J 17.3, 1.8, 17-H’), 5.65 (0.2 H, ddd, J 17.3, 10.7, 4.8, 16-H), 5.84 (0.8 H, J 17.3, 10.7, 6.8, 16-
(1 H, t, J 6.4, 1’-H), 5.75 (1 H, ddd, J 17.3, 10.7, 4.8, 16-H), 7.10-7.36 H), 5.90 (0.8 H, m, 1’-H) and 7.04-7.36 (5 H, m, ArH); δC (75 MHz,
26 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Journal Name
C6D6) −1.4, 16.8, 18.2, 21.2, 33.5, 36.0, 37.3, 38.7, 39.3, 42.3, 42.6, enoate (98)
ARTICLE
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43.6, 44.4, 48.2, 50.6(2), 59.3, 59.5, 65.7, 65.9, 71.6, 74.4, 74.5, The procedure outlined for the synthesis DoOfI:h1e0x.1e0n3o9a/Cte6O4B701u8s0i4nAg
74.6, 75.1, 78.1, 78.8, 79.0, 95.0, 104.4, 114.6, 114.7, 127.4, 127.5, lithium chloride (2.19 g, 48 mmol), copper(I) iodide (9.77 g, 51.2
128.4, 138.7, 138.9, 139.8, 157.7 and 166.6; m/z (APCI+) 686 (100%) mmol), THF (250 mL), prop-2-enylmagnesium bromide (1 M in Et2O,
and 685 (M+ + 23, 80).
93 mL, 93 mmol) and alkyne 97 (6.35 g, 23.3 mmol) in THF (125 mL)
gave the title compound 98 (7.18 g, 98%) as a yellow oil used
20
(3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-
13-[(Z)-2-tert-butyldimethylsilyloxyethylidene]-5,9-epoxy-11,15-
epoxy-8,8-dimethyl-9-methoxy-16-(4-methoxybenzyloxy)-3-(2-
trimethylsilylethoxy)methoxyhexadecane (93)
without purification, [α]D +5.5 (c 0.02, CHCl3) (Found: M+ + H,
315.1992. C16H31O4Si requires M, 315.1986); νmax/cm-1 3468, 2954,
2913, 2877, 1718, 1644, 1459, 1435, 1413, 1374, 1287, 1239, 1193,
1177, 1139, 1075, 1015, 919, 797 and 743; δH (300 MHz, CDCl3) 0.65
Tetra-n-butylammonium fluoride (1.0 M in THF, 2.43 mL, 2.43 (6 H, q, J 7.9, 3 × SiCH2), 0.95 (9 H, t, J 8.2, 3 × SiCH2CH3), 2.72 (1 H,
mmol) was added to the bis-tert-butyldiphenylsilyl ether 86 (500 dd, J 13.5, 4.0, 4-H), 2.83 (1 H, dd, J 13.5, 8.1, 4-Hʹ), 3.05 (2 H, m, 1ʹ-
mg, 0.405 mmol) in THF (5 mL) and the solution stirred for 1 h at rt. H2), 3.30 (1 H, br. s, OH), 3.62 (2 H, d, J 7.1, 6-H2), 3.72 (3 H, s,
It was then poured into a mixture of saturated aqueous sodium OCH3), 3.90 (1 H, m, 5-H), 5.05-5.20 (2 H, m, 3ʹ-H2), 5.82 (1 H, m, 2ʹ-
bicarbonate (20 mL) and DCM (40 mL) and the aqueous extracted H) and 5.87 (1 H, s, 2-H); δC (75 MHz, CDCl3) 4.6, 7.0, 36.3, 43.4,
with DCM (3 × 40 mL). The organic extracts were dried (MgSO4) and 51.5, 67.4, 72.0, 118.1, 118.5, 134.4, 159.9 and 168.2; m/z (CI+) 315
concentrated under reduced pressure to afford the diol 92 that was (M+ + 1, 100%).
used without further purification. Imidazole (110 mg, 1.62 mmol)
and tert-butyldimethylsilyl chloride (183 mg, 1.21 mmol) were (Z,6R)-4-(2-Hydroxyethylidene)-7-triethylsilyloxyhept-1-en-6-ol
added to this diol in DCM (10 mL) and, after stirring for 16 h, the (99)
reaction mixture was poured into brine (25 mL) and ether (50 mL). The procedure outlined to prepare diol 48 using di-
The aqueous phase was extracted with ether (3 × 50 mL) and the isobutylaluminium hydride (1 M in THF, 93 mL, 93 mmol), the
organic extracts were dried (MgSO4) and concentrated under methyl ester 98 (7.33 g, 23 mmol) in THF (160 mL), after stirring for
reduced pressure. Chromatography of the residue (light 3 h at −60 °C, gave the title compound 99 (6.42 g, 96% from
petroleum:ether 10:1 + 1% triethylamine) gave the title compound alkynoate 97) as a yellow oil that was used without purification
93 (354 mg, 89%) as a colourless oil, Rf = 0.50 (light petroleum:ether (Found: M+ + NH4, 304.2304. C15H34O3NSi requires M, 304.2302);
20
2:1), [α]D +15.8 (c 2.8, CHCl3); νmax/cm-1 2952, 2928, 2884, 2856, νmax/cm-1 3445, 2954, 2912, 2877, 1638, 1459, 1414, 1239, 1118,
1612, 1513, 1470, 1360, 1250, 1098, 1065, 1057, 858, 835 and 777; 1005, 913, 812 and 743; δH (300 MHz, CDCl3) 0.65 (6 H, q, J 7.9, 3 ×
δH (300 MHz, C6D6) 0.02 (9 H, s, 3 × SiCH3), 0.11 and 0.13 (each 6 H, SiCH2), 0.95 (9 H, t, J 8.2, 3 × SiCH2CH3), 2.05 (1 H, dd, J 13.6, 2.9, 5-
s, 2 × SiCH3), 0.92-1.05 (2 H, m, SiCH2), 1.01 and 1.02 [each 9 H, s, H), 2.42 (1 H, dd, J 13.5, J 9.6, 5-H’), 2.80-2.95 (2 H, m, 3-H2), 3.10 (2
SiC(CH3)3], 1.29 and 1.34 (each 3 H, s, 8-CH3), 1.32-1.40 (2 H, m), H, br. s, 2 × OH), 3.48 (1 H, dd, J 9.8, 7.8, 7-H), 3.62 (1 H, dd, J 9.8,
1.50 (1 H, q, J 12.2, 6-Hax), 1.74-2.10 (6 H, m), 2.28-2.46 (2 H, m, 12- 2.9, 7-H’), 3.75 (1 H, m, 6-H), 3.80 (1 H, dd, J 11.9, 6.9, 2’-H), 4.20 (1
H, 14-H’), 2.64 (1 H, d, J 13.6, 12-H’), 3.31 (6 H, s, 9-OCH3, OCH3), H, dd, J 12.0, 8.4, 2’-H’), 5.05-5.15 (2 H, m, 1-H2) and 5.75-5.90 (2 H,
3.40-4.26 (13 H, m, 1-H2, 3-H, 5-H, 7-H, 11-H, 15-H, 16-H2, 2’-H2, m, 2-H, 1’-H); δC (75 MHz, CDCl3) 4.6, 7.0, 33.5, 42.0, 58.0, 67.2,
OCH2CH2Si), 4.31 (1 H, d, J 11.8, ArHCH), 4.43 and 4.45 (each 1 H, d, 69.4, 117.0, 127.9, 136.3 and 139.7; m/z (CI+) 304 (M+ + 18, 20%),
J 11.7, PhHCH), 4.50 (1 H, d, J 11.8, ArHCH), 4.78 and 4.79 (each 1 H, 287 (M+ + 1, 30), 269 (80) and 132 (100).
J 7.0, OHCHO), 5.58 (1 H, t, J 6.5, 1’-H), 6.82 (2 H, d, J 8.6, ArH) and
7.09-7.35 (7 H, m, ArH); m/z (ES+) 1009 (M+ + 23, 100%).
(Z,6R)-4-(2-tert-Butyldimethylsilyloxyethylidene)-7-
triethylsilyloxyhept-1-en-6-ol (100)
Methyl (R)-5-hydroxy-6-triethylsilyloxyhex-2-ynoate (97)
tert-Butyldimethylsilyl chloride (100 mg, 0.83 mmol) was added to
The procedure outlined for the synthesis of the alkynoate 15 the diol 99 (200 mg, 0.69 mmol) and imidazole (152 mg, 2.24 mmol)
o
using n-butyllithium (1.6 M in THF, 33.5 mL, 53.6 mmol), in DCM (4 mL) at 0 C and the mixture stirred for 3 h during which
methyl propiolate (4.51 g, 53.6 mmol) in THF (6 mL), boron time it was allowed to warm to rt. Saturated aqueous sodium
trifluoride.THF (5.8 mL, 53.6 mmol) and (R)-epoxide 96 (5.75 g, hydrogen carbonate (10 mL) was added and the aqueous phase was
30.6 mmol) in THF (2 mL), after chromatography of the residue extracted with DCM (3 × 10 mL). The organic extracts were dried
(light petroleum:ether = 6:1), gave the title compound 97 (6.4 (MgSO4)
and
concentrated
under
reduced
pressure.
g, 77%), as a pale yellow oil (Found: M+ + NH4, 290.1783. Chromatography of the residue (light petroleum:ether 9:1 with 1%
C13H28O4SiN requires M, 290.1782); νmax/cm-1 3422, 2955, triethylamine) gave the title compound 100 (227 mg, 81%) as a clear
2913, 2877, 2240, 1718, 1459, 1454, 1415, 1259, 1118, 1077, oil, [α]D +4.0 (c 0.021, CHCl3) (Found: M+ + H, 401.2907.
20
1014, 799 and 747; δH (300 MHz, CDCl3) 0.61 (6 H, q, J 7.9, 3 × C21H45O3Si2 requires M, 401.2902); νmax/cm-1 3465, 2954, 2932,
SiCH2), 0.95 (9 H, t, J 8.2, 3 × SiCH2CH3), 2.56 (2 H, d, J 6.3, 4- 2878, 1638, 1462, 1413, 1383, 1361, 1254, 1101, 1069, 1006, 914,
H2), 2.65 (1 H, d, J 6.0, OH), 3.59 (1 H, dd, J 10.6, 5.5, 6-H), 3.69 836, 776 and 743; δH (300 MHz, CDCl3) 0.05 (6 H, s, 2 × SiCH3), 0.65
(1 H, dd, J 10.4, 4.1, 6-Hʹ), 3.75 (3 H, s, OCH3) and 3.79 (1 H, m, (6 H, q, J 7.7, 3 × SiCH2), 0.93 [9 H, s SiC(CH3)3], 0.95 (9 H, t, J 7.7, 3 ×
5-H); δC (75 MHz, CDCl3) 4.5, 6.9, 23.6, 52.9, 65.3, 69.8, 74.6, SiCH2CH3), 2.12 (1 H, dd, J 13.6, 4.8, 5-H), 2.27 (1 H, dd, J 13.6, J 8.4,
86.0 and 154.2; m/z (CI+) 290 (M+ + 18, 100%).
5-H’), 2.82 (2 H, d, J 6.9, 3-H2), 2.85 (1 H, d, J 3.8, OH), 3.55-3.57 (2
H, m, 7-H2), 3.80 (1 H, m, 6-H), 4.15 and 4.25 (each 1 H, dd, J 12.4,
Methyl (2Z,5R)-5-hydroxy-3-prop-2-enyl-6-triethylsilyloxyhex-2- 6.9, 2’-H), 5.05-5.13 (2 H, m, 1-H2), 5.60 (1 H, t, J 6.9, 1’-H) and 5.85
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 28 of 31
ARTICLE
Journal Name
(1 H, m, 2-H); δC (75 MHz, CDCl3) −4.9(2), 4.6, 7.0, 18.6, 26.2, 34.7, dried barium hydroxide monohydrate (0.31 g, Vie0w.9A3rticlme Omnloinle)
42.0, 59.7, 67.0, 70.2, 116.9, 128.0, 136.4 and 138.1; m/z (CI+) 401 suspended in THF (4 mL) and the aldehyde 102 (470 mg) in wet THF
DOI: 10.1039/C6OB01804A
(M+ + 1, 10%), 269 (70) and 132 (100).
(40:1 THF:water, 11.2 mL), after concentration under reduced
pressure, gave the enone 103 (0.67 g, ca. 80% based on
phosphonate 76) as a yellow oil, that was used directly in the next
step; νmax/cm-1 2955, 2858, 1690, 1622, 1472, 1428, 1380, 1251,
(Z,6R)-4-(2-tert-Butyldimethylsilyloxyethylidene)-7-
triethylsilyloxy-6-trimethylsilyloxyhept-1-ene (101)
Following the procedure outlined for the preparation of the TMS- 1225, 1111, 839, 737 and 702; δH (300 MHz, CDCl3) 0.08 (6 H, s, 2 ×
ether 79, triethylamine (7.3 mL, 52.5 mmol), the alcohol 100 (7.01 SiCH3), 0.12 (9 H, s, 3 × SiCH3), 0.58-0.70 (6 H, m, 3 × SiCH2), 0.83 [9
g, 17.5 mmol) in DCM (87 mL) and trimethylsilyl chloride (3.3 mL, H, s, SiC(CH3)3], 0.96 (3 H, s, 9-CH3), 1.00 (9 H, t, J 7.5, 3 × SiCH2CH3),
26.2 mmol), after filtration through
a
silica plug (light 1.08 [9 H, s, SiC(CH3)3], 1.18 (3 H, s, 9-CH3’), 1.38 (6 H, s, 2 × CCH3),
petroleum:ether 10:1 + 1% triethylamine) afforded the title 1.50-1.84 (6 H, m, 11-H2, 13-H2, 15-H2), 2.10 (1 H, dd, J 13.2, 8.6, 3-
compound 101 (8.2 g, 99%), as a colourless oil, [α]D20 -7.2 (c 0.019, H), 2.34 (1 H, dd, J 13.2, 4.0, 3-H’), 2.97 (2 H, br. d, J 6.9, 5-H2), 3.42
CHCl3); νmax/cm-1 3078, 2955, 2878, 1638, 1462, 1433, 1413, 1384, (1 H, dd, J 9.9, 6.0, 1-H), 3.52 (1 H, m, 1-H’), 3.66-3.87 (4 H, m), 4.02-
1361, 1251, 1104, 1077, 1005, 913, 838, 776 and 745; δH (300 MHz, 4.14 (2 H, m), 4.20 and 4.28 (each 1 H, dd, J 13.0, 6.3, 2’-H), 4.60
CDCl3) 0.09 (6 H, s, 2 × SiCH3), 0.11 (9 H, s, 3 × SiCH3), 0.63 (6 H, q, J and 4.63 (each 1 H, d, J 11.0, PhHCH), 5.44 (1 H, t, J 6.3, 1’-H), 6.63
7.9, 3 × SiCH2), 0.93 [9 H, s, SiC(CH3)3], 0.95 (9 H, t, J 8.2, 3 × (1 H, d, J 15.2, 7-H), 6.97 (1 H, dt, J 15.2, 7.5, 6-H), 7.25-7.48 (11 H,
SiCH2CH3), 2.11 (1 H, dd, J 13.5, 8.3, 5-H), 2.35 (1 H, dd, J 13.6, 4.3, m, ArH) and 7.66-7.74 (4 H, m, ArH).
5-H’), 2.82 (2 H, br. d, J 7.0, 3-H2), 3.43 (1 H, dd, J 10.1, 6.1, 7-H),
3.51 (1 H, dd, J 10.1, 5.6, 7-H’), 3.75 (1 H, m, 6-H), 4.17 (1 H, dd, J (4S,6R,8S)-4-Benzyloxy-10-tert-butyldiphenylsilyloxy-1-{(2S,6R)-4-
13.0, 5.7, 2’-H), 4.31 (1 H, dd, J 13.2, 6.9, 2’-H’), 5.05-5.13 (2 H, m, 1- [(Z)-2-tert-butyldimethylsilyloxyethylidene]-6-
H2), 5.45 (1 H, t, J 5.9, 1’-H), 5.82 (1 H, m, 2-H); δC (75 MHz, CDCl3) hydroxymethyltetrahydropyran-2-yl}-6,8-O-isopropylidene-3,3-
−4.8, 0.5, 4.7, 7.1, 18.7, 26.3, 35.7, 42.5, 60.7, 67.3, 72.8, 116.6, dimethyldecan-2-one (105)
128.6, 136.1 and 136.6; m/z (CI+) 490 (M+ + 18, 3%) and 132 (100).
The trimethylsilyl ether 103 (6.7 g) in THF (260 mL) was divided into
approximately two equal portions in polypropylene bottles. To each
of these was added pyridine (7.2 mL). After cooling to 0 oC,
hydrogen fluoride-pyridine complex (3.5 mL) was added rapidly in
one portion to each fraction via a plastic syringe before stirring for
12 min. The reaction mixtures were then immediately poured into
(2R,6E,10S,12R,14S)-10-Benzyloxy-16-tert-butyldiphenylsilyloxy-4-
[(Z)-2-tert-butyldimethylsilyloxyethylidene]-1-triethylsilyloxy-9,9-
dimethyl-2-trimethylsilyloxy-12,14-O-isopropylidenehexadec-6-
en-8-one (103)
AD-mix β (1.31 g) was added portionwise to a stirred mixture of saturated aqueous sodium bicarbonate (800 mL) and ether. The
tert-butanol (5 mL) and water (5 mL). After 10 min, the mixture was aqueous phase was extracted with ether (3 × 600 mL) and the
cooled to 0 °C, and the alkene 101 (630 mg, 1.33 mmol) in tert- organic extracts were dried (MgSO4) and concentrated under
butanol (1.5 mL) and acetone (0.75 mL) was added portionwise. reduced pressure to give the diol 104; δH (300 MHz, CDCl3) 0.13 (6
Osmium tetroxide (17 mg) dissolved in tert-butanol (0.25 mL) and H, s, 2 × SiCH3), 0.94 and 1.09 [each 9 H, s, 2 × SiC(CH3)3], 1.20 and
water (1.34 mL) followed by osmium tetroxide (4 mg) dissolved in 1.26 (each 3 H, s, 9-CH3), 1.39 [6 H, s, C(CH3)2], 1.50-1.85 (6 H, m,
tert-butanol (0.25 mL) and water (1.34 mL) were added dropwise by 11-H2, 13-H2, 15-H2), 2.17 (1 H, m, 3-H), 2.36-2.48 (2 H, m, 3-H’, OH),
a syringe pump over a total of 20 h. After a further 20 h, the 2.98 (2 H, d, J 6.9, 5-H2), 3.18 (1 H, br. s, OH), 3.42-4.30 (10 H, m, 1-
reaction mixture was allowed to warm to rt, and aqueous sodium H2, 2-H, 10-H, 12-H, 14-H, 16-H2, 2’-H2), 4.59 and 4.65 (each 1 H, d, J
sulfite (4 g in 20 mL) was added. The mixture was stirred for 30 min, 11.1, PhHCH), 5.65 (1 H, t, J 7.2, 1’-H), 6.67 (1 H, d, J 15.2, 7-H), 6.90
ethyl acetate (50 mL) was added and the aqueous phase was (1 H, dt, J 15.2, 7.5, 6-H), 7.22-7.50 (11 H, m, ArH) and 7.65-7.75 (4
extracted with ethyl acetate (3 × 50 mL). The organic extracts were H, m, ArH); δC (75 MHz, CDCl3) −4.9, 18.6, 19.5, 20.9, 21.8, 25.5,
dried (MgSO4) and concentrated under reduced pressure. 25.7, 26.2, 27.1, 34.8, 39.0, 40.2, 51.7, 59.0, 60.3, 63.5, 63.6, 66.7,
Chromatography of the residue (light petroleum:ether 25:1 to 3:1 + 69.5, 75.0, 80.9, 100.5, 127.5, 127.8, 127.9, 128.5, 128.6, 129.8,
1% triethylamine) afforded unchanged diene 101 (45 mg) and then 134.2, 135.8, 138.5, 138.9, 143.8 and 203.5.
the corresponding terminal vicinal diol (0.5 g, 73%) as a clear oil, a
Potassium tert-butoxide (0.1 M in THF, 16.0 mL, 0.16 mmol) was
mixture of diastereoisomers; νmax/cm-1 3432, 2955, 2878, 1463, added rapidly to the diol 104 in THF (40 mL) at rt and the solution
1413, 1387, 1361, 1251, 1077, 1006 and 838; δH (300 MHz, CDCl3) stirred for 5 min. Saturated aqueous ammonium chloride (300 mL)
0.09 (6 H, s, 2 × SiCH3), 0.11 (9 H, s, 3 × SiCH3), 0.63 (6 H, q, J 7.9, 3 × and ether (300 mL) were added and the aqueous phase was
SiCH2), 0.93 [9 H, s, SiC(CH3)3], 0.95 (9 H, t, J 8.2, 3 × SiCH2CH3), extracted with ether (3 × 200 mL). The organic extracts were dried
2.00-2.75 (6 H, m, 3-H2, 5-H2, 2 × OH), 3.40-3.90 (6 H, m, 1-H2, 2-H, (MgSO4)
and
concentrated
under
reduced
pressure.
6-H, 7-H2), 4.15 and 4.25 (each 1 H, m, 2’-H) and 5.45 (1 H, m, 1’-H); Chromatography of the residue gave the title compound 105 (2.6 g,
21
m/z (CI+) 375 (100%).
45% from phosphonate 76) as a colourless oil, [α]D +1.3 (c 0.015,
Following the procedure outlined for the preparation of the CHCl3); νmax/cm-1 3435, 2931, 2857, 1702, 1471, 1428, 1380, 1252,
aldehyde 81, the vicinol diol (470 mg, 0.93 mmol) in DCM (6 mL) 1223, 1170, 1106, 836, 776, 736 and 701; δH (300 MHz, CDCl3) 0.11
was treated with lead(IV) acetate to afford the aldehyde 102 (ca. and 0.12 (each 3 H, s, SiCH3), 0.94 and 1.10 [each 9 H, s SiC(CH3)3],
470 mg, ca. 100%) as a colourless oil.
1.16 and 1.26 (each 3 H, s, 3-CH3), 1.38 and 1.39 (each 3 H, s, CCH3),
Following the procedure outlined for the synthesis of enone 82, 1.44 to 1.78 (6 H, m, 5-H2, 7-H2, 9-H2), 1.84 and 1.94 (each 1 H, br. t,
the ketophosphonate 76 (0.55 g, 0.77 mmol) in THF (7.5 mL), oven- J 12.6, 3’-Hax, 5’-Hax), 2.20 and 2.41 (each 1 H, d, J 13.5, 3’-Heq, 5’-
28 | J. Name., 2012, 00, 1-3
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Page 29 of 31
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
Heq), 2.58 (1 H, dd, J 17.7, 5.4, 1-H), 3.02 (1 H, dd, J 17.6, 6.6, 1-H’), was stirred for 17 h. More pyridinium toluene p-sulVfoienwaAtreticl(e5Omnlinge)
DOI: 10.1039/C6OB01804A
3.40-4.22 (10 H, m, 4-H, 6-H, 8-H, 10-H2, 2’-H, 6’-H, 6’-CH2, OH), 4.24 was added and the mixture stirred for 4 h. Saturated aqueous
(2 H, d, J 6.4, 2’’-H2), 4.65 and 4.72 (each 1 H, d, J 11.4, PhHCH), 5.43 sodium bicarbonate (30 mL) and ether (30 mL) were added and the
(1 H, t, J 6.4, 1’’-H), 7.25-7.50 (11 H, m, ArH) and 7.66-7.75 (4 H, m, aqueous phase was extracted with ether (2 × 20 mL). The organic
ArH); δC (75 MHz, CDCl3) −4.8, 1.3, 18.7, 19.5, 20.7, 21.3, 25.4, 25.6, extracts were washed with saturated aqueous sodium bicarbonate
26.3, 27.1, 30.0, 30.6, 30.7, 39.1, 39.3, 41.7, 45.2, 53.1, 59.4, 60.3, (2 × 20 mL), dried (MgSO4) and concentrated under reduced
63.5, 63.8, 66.2, 74.4, 75.2, 78.0, 81.0, 100.6, 124.7, 127.3, 127.8, pressure. Chromatography of the residue (light petroleum:ether 1:2
127.9, 128.6, 129.8, 134.1, 135.2, 135.8, 139.0 and 212.7.
+ 1% triethylamine) afforded the title compound 107 (122 mg, 58%),
as a colourless oil, Rf = 0.2 (light petroleum:ether 2:1); νmax/cm-1
3414, 3071, 2931, 2857, 1705, 1472, 1428, 1379, 1362, 1253, 1224,
1179, 1106, 836, 777, 736 and 702; δH (300 MHz, C6D6) 1.17 [9 H, s,
SiC(CH3)3], 1.19 and 1.22 (each 3 H, s, 2 × 8-CH3), 1.45-1.80 (8 H, br.
m, 2-H2, 4-H2, 6-H2, 12-Hax, OH), 1.84 (1 H, dd, J 15.0, 7.7, 10-H),
(4S,6R,8S)-4-Benzyloxy-10-tert-butyldiphenylsilyloxy-1-{(2S,6R)-4-
[(Z)-2-tert-butyldimethylsilyloxyethylidene]-6-
ethenyltetrahydropyran-2-yl}-6,8-O-isopropylidene-3,3-
dimethyldecan-2-one (106)
Pyridine (0.2 mL) and the alcohol 105 (99 mg, 0.113 mmol) in DCM 1.98 (1 H, br. t, J 12.0, 14-Hax), 2.25 (1 H, br. d, J 12.2, 12-Heq), 2.34
(6.2 mL) were added to the Dess-Martin periodinane (191 mg, 0.45 (1 H, dd, J 15.0, 6.2, 10-H’), 2.44 (1 H, br. d, J 12.2, 14-Heq), 3.26 (3
mmol) in DCM (3.7 mL) and the solution stirred at rt for 17 h. H, s, 9-OCH3), 3.66-4.08 (8 H, m, 1-H2, 3-H, 5-H, 7-H, 11-H, 2’-H2),
Saturated aqueous sodium hydrogen carbonate (30 mL) and ether 4.30 (1 H, d, J 11.3, PhHCH), 4.35 (1 H, m, 15-H), 4.49 (1 H, d, J 11.3,
(40 mL) were added and the aqueous phase extracted with ether (3 PhHCH), 5.16 (1 H, dt, J 10.5, 1.5, 17-H), 5.32 (1 H, dt, J 17.3, 1.5, 17-
x 20 mL). The organic extracts were washed with saturated sodium H’), 5.43 (1 H, br. t, J 6.4, 1’-H), 5.94 (1 H, ddd, J 17.3, 10.4, 5.4, 16-
thiosulfate (30 mL), dried (MgSO4) and concentrated under reduced H), 7.00-7.45 (11 H, m, ArH) and 7.70-7.90 (4 H, m, ArH); δC (75
pressure to give the corresponding aldehyde used without further MHz, C6D6) 17.1, 19.3, 21.1, 27.0, 30.4, 32.7, 34.8, 39.7, 40.2, 43.4,
purification.
Tetrahydrofuran
43.6, 48.2, 58.2, 62.9, 66.0, 66.9, 71.5, 75.1, 77.9, 79.0, 104.3,
to 114.3, 123.7, 130.0, 130.2, 133.7, 133.8, 133.9, 135.9(2), 136.1,
(3.7
mL)
was
added
methyl(triphenyl)phosphonium bromide (242 mg, 0.68 mmol) and 137.7, 139.4, 139.9 and 140.0.
potassium tert-butoxide (71 mg, 0.63 mmol) and the yellow
solution stirred for 20 min then cooled to −10 oC. The aldehyde (3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-13-
prepared from alcohol 105 in THF (3.7 mL) was added and the [(Z)-2-(2-trimethylsilylethoxymethoxy)ethylidene]-5,9-epoxy-
mixture stirred for 1 h. Saturated aqueous sodium bicarbonate (30 11,15-epoxy-8,8-dimethyl-9-methoxy-3-(2-
mL) and ether (30 mL) were added and the aqueous phase trimethylsilylethoxymethoxy)heptadec-16-ene (108)
extracted with ether (4 × 20 mL). The organic extracts were dried Di-isopropylethylamine (0.8 mL) and 2-trimethylsilylethoxymethyl
(MgSO4) and concentrated under reduced pressure to leave a chloride (0.42 mL) were added to the diol 107 (283 mg, 0.381
residue that was dissolved in minimum amount of DCM. mmol) in DCM (2 mL) at 0 oC. The mixture was allowed to warm to
Chromatography (light petroleum:ether 6:1 with 1% triethylamine) rt, DMAP (cat.) was added and the solution stirred for 18 h.
gave the title compound 106 (63 mg, 63% from the alcohol 105) as a Saturated aqueous sodium hydrogen carbonate (10 mL) and DCM
colourless oil; νmax/cm-1 3420, 3071, 2932, 2857, 1705, 1647, 1472, (10 mL) were added and the mixture stirred for 30 min before more
1428, 1380, 1362, 1252, 1224, 1106, 836, 776, 736 and 702; δH (300 saturated aqueous sodium hydrogen carbonate (15 mL) and DCM
MHz, CDCl3) 0.12 and 0.13 (each 3 H, s, SiCH3), 0.95 and 1.09 [each (15 mL) were added. The aqueous phase was extracted with DCM (2
9 H, s SiC(CH3)3], 1.15 and 1.29 (each 3 H, s, 3-CH3), 1.39 [6 H, s, × 15 mL) and the organic extracts were washed with saturated
C(CH3)2], 1.44 to 1.80 (6 H, m, 5-H2, 7-H2, 9-H2), 1.84 and 1.96 (each aqueous sodium hydrogen carbonate (5 mL), dried (MgSO4) and
1 H, br. t, J 12.2, 3’-Hax, 5’-Hax), 2.24 (1 H, d, J 13.5, 3’-Heq or 5’-Heq), then concentrated under reduced pressure. The residue was
2.54-2.65 (2 H, m, 5’-Heq or 3’-Heq, 1-H), 3.07 (1 H, dd, J 17.4, 6.2, 1- dissolved in the minimum amount of light petroleum and DCM (2:1)
H’), 3.67-4.17 (7 H, m, 4-H, 6-H, 8-H, 10-H2, 2’-H, 6’-H), 4.26 (2 H, br. and chromatographed (light petroleum:ether 20:1 with 1%
d, J 6.6, 2’’-H2), 4.63 and 4.70 (each 1 H, d, J 11.4, PhHCH), 5.15 (1 H, triethylamine) to give the title compound 108 (303 mg, 79%) as a
20
dt, J 10.5, 1.5, 2’’’-H), 5.27 (1 H, dt, J 17.3, 1.5, 2’’’-H’), 5.45 (1 H, br. colourless oil, Rf = 0.55 (light petroleum:ether 4:1), [α]D +13.6 (c
t, J 6.4, 1’’-H), 5.89 (1 H, ddd, J, 17.3, 10.4, 5.4, 1’’’-H), 7.25-7.50 (11 0.014, CHCl3); νmax/cm-1 2952, 2893, 1649, 1472, 1428, 1362, 1249,
H, m, ArH) and 7.66-7.76 (4 H, m, ArH); δC (75 MHz, CDCl3) −4.7, 1106, 1057, 1029, 937, 860, 835 and 737; δH (300 MHz, C6D6) 0.00
15.6, 18.7, 19.5, 20.7, 21.1, 25.4, 25.6, 26.3, 27.1, 34.9, 39.1, 41.6, and 0.01 [each 9 H, s, Si(CH3)3], 0.91-1.02 (4 H, m, 2 × SiCH2), 1.20 [9
45.3, 53.1, 59.4, 60.3, 63.5, 63.8, 66.2, 74.5, 75.1, 78.3, 80.8, 100.5, H, s, SiC(CH3)3], 1.26 and 1.33 (each 3 H, s, 8-CH3), 1.46 (1 H, q, J
115.5, 124.4, 127.4, 127.7, 127.9, 128.6, 129.9, 134.2, 135.6, 135.8, 11.9, 6-Hax), 1.71-2.10 (8 H, m, 2-H2, 4-H2, 6-Heq, 10-H, 12-H, 14-H),
138.9, 139.0 and 212.9.
2.29-2.42 (2 H, m, 10-H’, 12-H’), 2.62 (1 H, br. d, J 12.2, 14-Heq), 3.31
(3 H, s, OCH3), 3.62-3.73 (4 H, m, 2 × CH2CH2Si), 3.73-4.01 (7 H, m, 1-
(3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-13- H2, 3-H, 5-H, 7-H, 11-H, 15-H), 4.10-4.23 (2 H, m, 2’-H2), 4.30 and
[(Z)-2-hydroxyethylidene]-5,9-epoxy-11,15-epoxy-8,8-dimethyl-9-
methoxyheptadec-16-en-3-ol (107)
4.49 (each 1 H, d, J 11.9, PhHCH), 4.67 and 4.69 (each 1 H, d, J 6.7,
OHCHO), 4.73 (2 H, s, OCH2O), 5.05 (1 H, dt, J 10.5, 1.6, 17-H), 5.39
Anhydrous methanol (6.2 mL) and trimethyl orthoformate (0.95 mL) (1 H, dt, J 17.3, 1.6, 17-H’), 5.58 (1 H, br. t, J 6.9, 1’-H), 5.90 (1 H,
were added to the acetonide 106 (252 mg, 0.29 mmol) followed by ddd, J 17.3, 10.4, 5.4, 16-H), 7.10-7.38 (11 H, m, ArH) and 7.75-7.90
oven-dried pyridinium toluene p-sulfonate (25 mg) and the mixture (4 H, m, ArH); δC (75 MHz, C6D6) −1.3, 17.1, 18.2(2), 19.4, 21.2, 27.1,
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