Syntheses of C17-C27 fragments of 20-deoxybryostatins for assembly using Julia and metathesis reactions

Article abstract of DOI:10.1039/c7ob00076f

Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tri

Full text of DOI:10.1039/c7ob00076f

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DOI: 10.1039/C7OB00076F
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Syntheses of C17-C27 fragments of 20-deoxybryostatins for
assembly using Julia and metathesis reactions
Matthew Ball,a Thomas Gregson,a Hiroki Omori,a and Eric J. Thomasa*
Received 00th January 20xx,
Accepted 00th January 20xx
Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are
described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol
acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless
asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins.
Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate
followed by tributyltin – bromine exchange gave the required vinylic bromides. The palladium(0) catalysed couplings
worked very well for enol esters containing thioether substituents and gave products with retention of the position and
geometry of the trisubstituted double bond derived from the vinylic bromide. These were taken through to compounds
corresponding to fully developed C17-C27 fragments ready for assembly of the 16,17-double-bond of bryostatins by Julia
reactions. This chemistry was also applied to prepare intermediates suitable for incorporation into bryostatins by ring-
closing metathesis but, in this case, the coupling reaction gave mixtures of products including both the required βγ-
unsaturated ketone and a conjugated diene formed by a competing Heck reaction. To avoid this problem, a second
approach to compounds suitable for incorporation into a metathesis-based assembly of 20-deoxybryostatins was
developed. In this organotin-free synthesis, the key step was the conjugate addition of an organic cuprate generated from
allylmagnesium bromide to an alkynoate that gave the required (Z)-trisubstituted alkene with excellent stereoselectivity.
This was converted into metathesis precursors in a few steps.
DOI: 10.1039/x0xx00000x
www.rsc.org/
The 20-deoxybryostatins, e.g. bryostatin 10 (2),7 have received
less attention from synthetic chemists than their more
oxygenated analogues, such as bryostatin 1 (1), that have an
acyloxy group at C20. We therefore selected 20-
deoxybryostatins as the initial targets for our synthetic work in
this area. Convergent syntheses of bryostatins can be
Introduction
The bryostatins1 as exemplified by bryostatin 1 (1) and 10 (2),
see Figure 1, have attracted a substantial amount of interest
because of their significant biological activities.2 As the
isolation of bryostatins from natural sources is problematic,
their synthesis has been widely studied and has led to the
completion of several outstanding total syntheses.3,4 Synthetic
analogues with modified C1-C16 fragments have also been
found to have potent biological effects, some with tumour
suppressing bryostatin-like activity.5,6
envisaged based on
a late stage assembly from two
intermediates corresponding to the C1-C16 and C17-C27
fragments, see Figure 2. Indeed some of the earlier syntheses
followed this strategy using Julia reactions to introduce the
C16-C17 double-bond followed by macrolactonisation. One
difficulty with these syntheses, however, is that because of the
conditions required for the conventional Julia reaction, several
functional group interconversions had to be deferred until
after the assembly steps so undermining the convergency of
the overall synthesis. An alternative would be to use a ring-
closing metathesis8 to assemble the macrocycle since this
chemistry should be compatible with more of the functionality
present in the bryostatins.
Me
Me
Me
Me
Me
H
H
Me
Me
HO
HO
O
Me
O
MeO2C
MeO2C
H
H
H
H
H
H
O
O
O
O
O
O
OH
OH
O
O
OH
OH
Me
Me
O
O
O
O
Me
Me
20
20
O
Me
CO2Me
OH
Me
CO2Me
OH
nPr
O
2
1
In the preceding paper in this series,9 we described a
scaleable synthesis of intermediates 3 that corresponded to
the C1-C16 fragments of bryostatins We here describe
syntheses of intermediates that are equivalent to the C17-C27
fragments 4 [Y = H, PhS(O)2 or Y = CH2] of 20-deoxybryostatins.
These could be incorporated into either Julia or metathesis-
based approaches to bryostatins, see Figure 2.
Figure 1 Representative bryostatins
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Journal Name
Me
Me
H
O
X
MeO
View Article Online
OP
The vinylic bromide 24 was prepared forDfOuIr:t1h0e.1r03s9tu/Cd7iOesB0o0f0t7h6eF
MeO2C
Me
Me
Me
H
H
H
O
Me
Me
HO
O
O
Migita coupling. Sharpless asymmetric hydroxylation of the
silylated (E)-pent-3-enol 12 gave the diol 13 that was taken
through to the alcohol 15 (e.e. > 80% - Mosher’s derivatives13)
by acetonide formation and desilylation. Following oxidation,
addition of allenylzinc bromide to the resulting aldehyde 16
gave a mixture of the alcohols 17 and 19, ratio ca. 75 : 25, the
major alcohol 17 being assigned the configuration shown from
literature precedent for chelation controlled reactions and
comparison of the 1H NMR spectra of its O-acetyl
mandelates.14 Methoxycarbonylation of the 4-methoxybenzyl
ether 18 of this alcohol gave the ester 20 and addition of tri-n-
butyltin hydride following the Piers’ procedure15 gave the (E)-
vinyl stannane 21. Reduction gave the alcohol 22 and, after O-
silylation, reaction with N-bromosuccinimide gave the required
(E)-bromide 24, see Scheme 1; the (E)-configuration was
assigned by analogy with the literature.3a,11,15
MeO2C
OP
H
H
H
1
O
16
O
O
1
3
OH
OH
16
17
OH
O
+
17
Y
Me
Me
O
O
OP
H
Me
O
OH
20
27
Me
Me
OH
27
Me
OP
CO2Me
CO2Me
2
(X = O, Y = H, PhS(O)2, Julia;
X = Y = CH2, metathesis
P = protecting groups)
4
Figure 2 Disconnections of 20-deoxybryostatins
Results and discussion
Use of Migita coupling for the synthesis of C17-C27 fragments
for Julia reactions
OH
PO
O
TBSO
iii
ii
CH3
CH3
PO
i
CH3
At the planning stage of this work, it was not clear whether
cyclic acetals 4 or their open-chain equivalents 5 would be
more convenient intermediates. The open-chain compounds
were recognised as βγ-unsaturated ketones. A variation of the
Stille reaction developed by Migita10 was identified as an
attractive option for the synthesis of these compounds since it
CH3
O
OH
13
CH3
11 P = OH
14 P = TBS
15 P = H
iv
12 P = OTBS
v
PO
HO
O
O
O
O
CH3
CH3
CH3
CH3
OHC
CH3
CH3
+
vi
provided
a direct and stereospecific synthesis of βγ-
O
CH3
O
CH3
CH3
unsaturated ketones with control of the geometry of the
double-bond. As applied to the synthesis of the unsaturated
ketones 5, this reaction would involve the palladium(0)
catalysed coupling of a tin enolate generated from the enol
acetate 6 with a suitably protected vinylic bromide 7, see
Figure 3. Indeed in early preliminary studies,11 treatment of
the enol acetate 8 with tributyltin methoxide in the presence
of the (E)-vinylic bromide 9 and a palladium(0) catalyst gave an
excellent yield of the βγ-unsaturated ketone 10 that had the
correct alkene geometry for incorporation into a synthesis of
bryostatins. It was now necessary to extend this chemistry to
prepare fully functionalised C17-C27 fragments for
19
16
17 P = H
vii
18 P = PMB
viii
PMBO
O
O
PMBO
ix
O
CH3
CH3
CH3
CH3
Bu3Sn
CH3
O
CH3
MeO2C
CO2Me
21
20
x
PMBO
Br
PMBO
Bu3Sn
O
O
O
CH3
CH3
CH3
CH3
xii
O
CH3
CH3
OP
incorporation into Julia and metathesis based assemblies 12
.
OTBDPS
Y
24
22 P = H
23 P = TBDPS
xi
O
PO
OP
OP
Me
Y
PO
OP
OP
Me
Me
Br
+
OAc
Me
Me
Me
Scheme 1 Synthesis of the (E)-vinylic bromide 24 Reagents and
o
CO2Me
conditions: i, TBSCl, imid., DCM, 0 C to rt, 16 h (ca. 100%); ii, AD-
OP
5
6
7
mix-β, tBuOH, MeS(O)2NH2, −2 oC, 20
h
(88%); iii, 2,2-
dimethoxypropane, PPTS, rt, 19 h (95%); iv, TBAF, THF, rt, 80 min
PhS
Me
PMBO
Br
PhS
o
o
(86%); v, (COCl)2, DCM, DMSO, −78 C, 20 min, add 15, −78 C, 45
OPMB
O
Me
Me
OMEM
+
OAc
o
nBu3SnOMe,
Me
min, Et3N, 20 min; vi, propargyl bromide, Zn, tol., THF, −15 C, 30
OMEM
min, 16, −78 oC, 4.25 h (43% from 15; 17:19 = 75:25); vii, NaH, THF,
0 oC – rt, 1 h, TBAI, PMBCl, 0 oC – rt, 20 h (76%); viii, nBuLi, THF, −78
PdCl2[P(o-tolyl)3]2,
tol., 100 oC, 14 h
OTBDPS
o
n
n
oC, 45 min, add MeOC(O)Cl, −78 C, 3 h (90%); ix, BuLi, Bu6Sn2,
81%
OTBDPS
9
8
10
o
o
THF, 0 C, 20 min, add to CuBr.DMS, THF, −50 C, 25 min, add 20,
−78 oC, 4 h (91%); x, DIBAL-H, hexanes, THF, −78 oC, 2.3 h; xi,
o
TBDPSCl, imid., DMF, 0 C to rt, 15 h (82% from 21); xii, NBS, DCM,
Figure 3 Strategy for assembly of the C17-C27 fragment 5:
preliminary results leading to ketone 10
rt, 1 h (94%).
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trimethylsilylethoxy)methyl (SEM) ether 34 that was converted into
the Weinreb amide 35. O-Silylation using tert-butyldimethylsilyl
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DOI: 10.1039/C7OB00076F
OTMS
CH3
O
OAc
ii
i
CH3
PhS
CH3
PhS
chloride gave the silyl ether 36 that was reduced using di-
isobutylaluminium hydride to give the aldehyde 37. Addition of
allenylzinc to this aldehyde was expected to proceed by chelation
control directed by the SEM-ether18 to give the (S)-alcohol 38 but
this was not the case and a ca. 50:50 mixture of the epimeric
alcohols 38 and 39 was obtained, see Scheme 3. However, these
alcohols could be separated and the less polar epimer was
CH3 CH3
CH3 CH3
CH3
25
26
8
iii
PhS(O)2
Me
PhS
Me
OPMB
Me
OPMB
Me
O
O
O
O
O
CH3
CH3
CH3
Me
Me
iv
CH3
O
1
identified as the required (S)-isomer 38 by comparison of the H
NMR spectra of its (R)- and (S)-O-acetylmandelates.14
OTBDPS
OTBDPS
28
27
The chelation-controlled stereoselectivity of reactions of the
aldehyde 37 with other achiral C-nucleophiles was also
disappointing. For example, with allyltributylstannane in the
presence of magnesium bromide,18 the (S)-isomer 40 was only the
minor product, 40:42 = 21:79. A similar product ratio was also
obtained using allylmagnesium bromide. Only with the allyl(di-
isopinocampheyl)borane from (+)-α-pinene19 was the (S)-epimer 40
the major product, but even then the stereoselectivity was less than
hoped for being only ca. 70:30.
v
PhS(O)2
Me
PhS(O)2
Me
OP
OMe
O
H
O
O
O
O
O
CH3
CH3
CH3
CH3
Me
Me
Me
Me
OTBDPS
OTBDPS
29 P = H
31
vi
30 P = TBS
The (4S)-configuration was initially assigned to the major
Scheme 2 Initial studies of Migita coupling reactions Reagents and product 40 from the reaction with the allylborane by comparison of
conditions: i, ClCH2SPh, TiCl4, DCM, −25 oC, ca. 3 h (85%); ii, the 1H NMR spectra of its O-acetyl mandelates. The epimers 40 and
isopropentyl acetate, TsOH.H2O, reflux, 48 h (57%); iii, 23, PdCl2(o- 42 were also converted into their tert-butyldimethylsilyl ethers 41
tolyl3P)2, tol., nBuSnOMe, reflux, 1 h (82%); iv, mCPBA, NaHCO3, and 43, see Scheme 3, for comparison with a sample of the (S)-
DCM, rt, 4 h (72%); v, DDQ, pH 7 buffer, DCM, rt, 30 min (91%); vi, isomer 41 that was also prepared by a different route.
TBSOTF, 2,6-lut., DCM, rt, 15 min (60%).
O
Me
N
OSEM
OH
iii
O
i
MeO
MeO2C
HO
CH3
The enol acetate 8 was prepared from 3-methylbutan-2-one by
titanium(IV) chloride mediated alkylation of its trimethylsilyl enol
ether 25 using chloromethyl phenyl sulphide16 and conversion of
the resulting ketone 26 into the enol acetate 8 using isopropenyl
acetate and tosic acid.11 The palladium(0) catalysed coupling of the
tin enolate generated from the enol acetate 8 and tributyltin
methoxide in situ with the vinylic bromide 24 was carried out in
toluene heated under reflux for one hour and gave an 82% yield of
alkene 27. Under these conditions, the (E)-alkene 27 was the only
product isolated although some migration of the double-bond into
conjugation with the ketone was observed with longer reaction
times. Oxidation of the sulfide 27 using meta-chloroperoxybenzoic
acid gave the sulfone 28 but it was now necessary to protect the
ketone so that the sulfone could be deprotonated for Julia
reactions. Removal of the p-methoxybenzyl group gave the
O
PO
CH3
CH3
35
iv
32
33 P = H
ii
OSEM
34 P = SEM
Me
N
CH3
OTBS
OSEM
OSEM
OSEM
OTBS
OHC
CH3
MeO
38
+
vi
v
x, xi
O
CH3
OTBS
HO
37
vii
36
CH3
OTBS
PO
39
PO
OSEM
OSEM
+
CH3
OTBS
CH3
OTBS
40 P = H
42 P = H
43 P = TBS
ix
viii
41 P = TBS
hydroxyketone 29 together with a little hemiacetal, that was not Scheme 3 Synthesis and reactions of the aldehyde 37 Reagents and
t
o
i
isolated pure. Attempts to prepare acetal 31 were unsuccessful conditions: i, AD-mix β, BuOH, H2O, 10 C, 18 h (59%); ii, Pr2NEt,
with either unchanged ketone 29 or mixtures of products being SEMCl, DCM, DMAP (cat.), rt, 3 d (95%); iii, NHMe.OMe.HCl, DCM,
isolated, see experimental, although the hydroxyketone was Me3Al, hexanes, rt, 50 min, add 34, rt, 2h; iv, TBSCl, imid., DCM, 0 oC
converted into its tert-butyldimethylsilyl ether 30.
to rt, DMAP (cat.), DBAI (cat.), rt, 14 h (66% from 34); v, DIBAL-H,
This work had shown that the Migita coupling could be used for DCM, hexanes, −78 oC, 1 h (87%); vi, propargyl bromide, Zn,
o
o
o
an efficient synthesis of ketosulfones corresponding to the C17-C27 toluene, THF, −15 C to −78 C, add 37, −78 C, 4 h (38, 45%; 39,
fragment of 20-deoxybryostatins. However, it was necessary to 45%); vii, (a) allylSnBu3, MgBr2.Et2O, −78 oC to −20 oC (80%; 40:42 =
o
o
develop the protecting group strategy to prepare intermediates 21:79) or (b) allylmagnesium bromide, THF, −78 C to 0 C (69%,
that could be used in Julia reactions.
40:42 = 25:75) or (c) [(+)-Ipc]2BCH2CH=CH2, −78 oC, 1.5 h, rt, aq.
Sharpless hydroxylation of methyl (E)-pent-3-enoate 32 using NaOH, 30% H2O2, reflux 1 h (40, 55%; 42, 25%); viii, TBSCl, imid.,
AD-mix-β with in situ cyclisation gave the lactone 3317 shown to DCM, DMAP (cat.), rt, 18 h (77%); ix, TBSOTf, 2,6-lut., DCM, 0 oC, 1 h
have an ee of ca. 91% by chiral GLC of its tert-butyldimethylsilyl (89%); x, Ph3P, THF, Cl2CHCO2H, THF, 0 oC, DIAD, rt, 18 h (61% with
ether. For the synthesis, the lactone 33 was protected as its (2- 22% elimination); xi, NaOH, MeOH, 0 oC to rt, 3.5 h (85%).
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An Evans aldol reaction of the aldehyde 37 was investigated to see At this point the (E)-geometry of the trisubstituteVdiewalAkreticnleeOwnlianes
whether a more stereoselective route could be developed to the confirmed by selective deprotection oDfOIb: 1o0t.h1039th/Ce7OtBr0is0-0te7r6tF-
alkenol 40. The chiral oxazolidinone 4420 reacted highly butyldimethylsilyl ether 58 and the triethylsilyl ether 59 using
stereoselectively with aldehyde 37 and gave the syn-adduct 45 as HF.pyridine complex to give the alcohol 60. The geometry of the
the dominant product. After reductive removal of the thio-ether, O- double-bond in this alkenol was confirmed by the significant nOe
silylation of the oxazolidinone 46 gave the bis-tert-butyldimethylsiyl observed between the vinylic hydrogen and the methylene group
ether 47 esentially as a single diastereoisomer. Reductive cleavage next to the ketone. The ketone 58 was now reduced using lithium
of the oxazolidinone gave the alcohol 48 and this was converted triethylborohydride to give a mixture of the epimeric alcohols 61,
into the alkene 41 via the aldehyde 49, see Scheme 4. Although this ratio ca. 55:45. These were not separated but were converted into
route was highly stereoselective in favour of the required their p-methoxybenzyl ethers 62 and oxidation gave a mixture of
diastereoisomer 41, it required six steps to prepare the alkene from the epimeric sulfones 63 ready for a Julia assembly reaction, see
the aldehyde 37 and was considered too long. However, it did Scheme 5.
confirm the configurations assigned to the alkenes 40 and 42.
At this point, conversion of the unwanted alkynol 39 into the
PO
OSEM
OTBS
TBSO
OSEM
OTBS
required isomer 38 via a Mitsunobu reaction was investigated.
Better results with less elimination were observed using
dichloroacetic rather than 4-nitrobenzoic acid and saponification
gave the required epimer 38. Overall, the alkynol 38 was now
available in a 70% yield from the aldehyde 37, see Scheme 3, and
was taken further in the synthesis.
Following silylation of the alkynol 38, reaction of the resulting
alkyne 50 with methyl chloroformate gave the alkynyl ester 51 and
Piers addition of tri-butyltin lithium in the presence of methanol
gave the (E)-unsaturated ester 52.15 The alcohol 53 was prepared by
reduction of this ester and was protected as both its tert-
butyldimethylsilyl- and triethylsilyl ethers 54 and 55. These were
converted ino the corresponding vinylic bromides 56 and 57 using
N-bromosuccinimide and both bromides were efficiently coupled
with the enol acetate 8 to give the (E)-βγ-unsaturated ketones 58
and 59 with excellent stereospecificity, see Scheme 5.
ii
CH3
CH3
MeO2C
38 P = H
51
i
50 P = TBS
iii
TBSO
Bu3Sn
OSEM
OTBS
TBSO
Bu3Sn
OSEM
iv
CH3
CH3
OTBS
CO2Me
OP
52
53 P = H
54 P = TBS
55 P = TES
v or vi
PhS
Me
vii
OTBS
TBSO
Br
OSEM
O
OSEM
viii
Me
CH3
OP
OTBS
CH3
OTBS
HO
OSEM
O
O
OSEM
OP
i
OHC
CH3
SMe
O
X
CH3
+
N
O
OTBS
58 P = TBS
59 P = TES
60 P = H
56 P = TBS
57 P = TES
ix
O
OTBS
N
Me
CH3
O
CH3
Me
x
37
44
PhS(O)2
Me
PhS
Me
45 X = SMe
46 X = H
ii
OPMBOTBS
CH3
OTBS
OP
OSEM
OTBS
OSEM
OTBS
Me
Me
iii
xii
CH3
TBSO
O
OSEM
OTBS
TBSO
HO
OSEM
OTBS
iv
OTBS
CH3
OTBS
61 P = H
CH3
48
O
N
63
CH3
CH3
xi
62 P = PMB
O
v
Scheme 5 Synthesis of the C17-C27 fragment for Julia assembly
47
Reagents and conditions i, TBSOTf, 2,6-lut., DCM, 0 oC 1 h (94%); ii,
TBSO
OSEM
TBSO
OSEM
OTBS
nBuLi, hexanes, THF, −78 C, 45 min, add MeCO2Cl, −78 C, 3.5 h
(92%); iii, nBu3Sn2, nBuLi, hexanes, THF, 0 oC, 25 min, add to
CuBr.Me2S, THF, −50 oC, 25 min, add 51, −78 oC, 4 h (88%); iv,
o
o
vi
CH3
OTBS
OHC CH3
41
49
o
DIBAL-H, hexanes, THF, −78 C, 1 h, rt, 3 h (83%); v, TBSCl, imid.,
DCM, 0 oC to rt, TBAI (cat.), DMAP (cat.), 16 h (97%); vi, TESCl, imid.,
DMF, 0 oC to rt, TBAI (cat.), DMAP (cat.), 16 h (97%); vii, NBS,
NaHCO3 for 55, DCM, rt (56, 96%; 57, 92%); viii, 8, nBu3SnOMe,
PdCl2[(o-tolyl)3P]2, tol., reflux, 1 h (58, 80%; 59, 80%); ix, HF.py.,
Scheme 4 A stereoselective aldol reaction of aldehyde 37 Reagents
and conditions i, 44, nBu2BOTf, DCM, iPr2NEt, 0 oC, 30 min, add 37 at
o
n
−78 C, rt, 24 h (62%); ii, Bu3SnH, AIBN (cat.), benzene, reflux, 40
min (80%); iii, TBSOTf, 2,6-lut., DCM, 0 oC, 1 h (80%); iv, LiBH4, THF,
o
THF, rt, 20 h (52% from 58; 78% from 59); x, LiBEt3H, THF, 0 C, rt,
16 h (70%); xi, NaH, DMF, 0 C to rt, 20 min, PMCl, 0 C to rt, TBAI
(cat.), 2 h (55%); xii, mCPBA, NaHCO3, DCM, rt, 25 min (77%).
o
MeOH, 0 C, 5 h (70%); v, Dess-Martin periodinane, DCM, rt, 2.5 h
o
o
o
(97%); vi, Ph3PMeBr, THF, nBuLi, hexanes, −78 C to rt, 30 min, add
49, −78 oC, rt, 16 h (69%).
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ARTICLE
To check that the protecting groups in the sufide 62 and sulfone 63
could be manipulated selectively, the p-methoxybenzyl ether of the
sulfide 62 was cleaved using buffered DDQ to give the alcohol 61.
This was oxidised to give the ketone 58. The SEM-ether was then
removed selectively using butanethiol and magnesium bromide
diethyletherate21 under buffered conditions to give the
hydroxyketone 64, see Scheme 6. This work showed that the ketone
at C21 could be regenerated and that the hydroxyl group at C25
(both bryostatin numbering) could be deprotected selectively.
TBSO
Bu3Sn
OSEM
OTBS
TBSO
Br
OSEM
View Article Online
OAc
DOI: 10.1039/C7OB00076F
ii
+
CH3
OP
CH3
OTBS
Me
Me
67
OTBDPS
53 P = H
66
i
65 P = TBDPS
iii
Me
Me
O
OTBS
CH3
Me
Me
OTBS
CH3
O
OSEM
OSEM
+
Me
OTBS
PhS
Me
PhS
Me
OTBS
OPMBOTBS
CH3
OTBS
CH3
OSEM
OTBS
O
OH
OTBDPS
i
Me
iii
Me
ii
OTBDPS
61
58
69
68
OTBS
OTBS
OTBS
62
64
Scheme 7 Synthesis of the C17-C27 fragment for ring closing
metathesis Reagents and conditions i, TBDPSCl, imid., DCM, 0 oC to
n
Scheme 6 Selective deprotections Reagents and conditions i, DDQ,
pH 7 buffer, DCM, rt, 35 min (ca. 100%); ii, Dess-Martin
periodinane, DCM, rt, 25 min (90%); iii, K2CO3, MgBr2.Et2O, BuSH,
rt, 3 h (ca. 100%); ii, NBS, DCM, rt, 2 h (97%); iii, 67, Bu3SnOMe,
PdCl2dppe (cat.), tol., reflux, 5 h [68, (E):(Z) = 8:1, 40%; 69, 38%).
n
Me
OSEM
ether, rt, 10 min (70%).
OHC
CH3
71
N
OSEM
ii
MeO
OTBDPS
O
Syntheses of C17-C27 fragments for a metathesis-based assembly
CH3
OP
35 P = H
70 P = TBDPS
The alcohol 53 was protected as its tert-butyldiphenylsilyl ether 65.
Reaction with N-bromosuccinimide then gave the bromide 66 for
coupling with the enol acetate 67 that was available from the
corresponding methyl ketone. However, in this case, the Migita
coupling was less efficient, see Scheme 7. Under the usual
conditions with PdCl2[(o-tolyl)3P]2 as the catalyst, the (E)-alkene 68
was isolated as the major product but was contaminated by a side
product that was not obtained pure but which may have been the
corresponding (Z)-alkene. In the presence of thioanisole, less side
product was detected but the yield of the required (E)-alkene 68
was only 35% because 30% of the Heck product 69 was also
isolated. With PdCl2(Ph2PCH2CH2PPh2) as the catalyst, the yield of
the (E)-alkene 68, improved slightly to 40%, but the Heck product
69 was still obtained in a yield of about 38%. As the alkene 68 and
the Heck product 69 could be separated, these conditions enabled
sufficient alkene 68 to be prepared for metathesis studies and so
these conditions for the Migita coupling were accepted and not
optimised any further, see Scheme 7.
An alternative synthesis of C17-C27 fragments of 20-
deoxybryostatins required for metathesis studies was also
investigated based on the conjugate addition of organocuprates to
alkynoates. This chemistry had proved to be very useful for the
stereoselective synthesis of trisubstituted alkenes corresponding to
the C11-C16 fragment of the bryostatins.9
For this work, the hydroxy Weinreb amide 35 was protected as
its tert-butyldiphenylsilyl ether 70. Following reduction to the
aldehyde 71, addition of allenylzinc gave a mixture of the required
alcohol 72 and its epimer 73. The unwanted isomer 73 was
converted into the required epimer 72 by saponification of the
inverted dichloroacetate 74 prepared by a Mitsunobu reaction as
shown in Scheme 8.
i
iii
HO
OSEM
HO
OSEM
+
CH3
OTBDPS
CH3
73
OTBDPS
72
iv
Cl2CHC(O)O
OSEM
v
72
CH3
OTBDPS
74
Scheme 8 Synthesis of the alkynol 72 Reagents and conditions i,
o
TBDPSCl, imid., DCM, 0 C, DMAP (cat.), TBAI (cat.), rt, 18 h
o
(72% from 34); ii, DIBAL-H, hexanes, THF, -78 C, 1.5 h (99%);
iii, propargyl bromide, Zn, THF, 0 oC, 20 min, 71, -78 oC, 5 h (72,
44%, 73, 37%); iv, Ph3P, DIAD, Cl2CHCO2H, 0 oC to rt, 18 h (74,
71%; 25% elimination); v, NaH, MeOH, 0 oC to rt, 2 h (82%).
The alcohol 72 was protected as its triethylsilyl ether 75 that was
taken through to the alkynoate 76 by lithiation and reaction with
methyl chloroformate, see Scheme 9. Perhaps a little surprisingly,
the conjugate addition of the organocuprate prepared from
allylmagnesium bromide, lithium chloride and copper(I) iodide at
−78 oC to the alkynoate 76 proceeded with excellent
stereoselectivity in favour of the required (Z)-isomer 77.9 The
configuration of the trisubstituted double-bond in this ester was
established by nOe studies of the alcohol 78 prepared by reduction
of the ester 77 by DIBAL-H that confirmed the (Z)-configuration as
shown. The terminal double-bond of the ester 77 was now
dihydroxylated using osmium tetroxide and the resulting diol 79
cleaved using sodium periodate to give the aldehyde 80. Reaction
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
View Article Online
OTES
OH
DOOTIE: S10.1039/C7OB00076F
OSEM
TESO
OSEM
OH
OSEM
TESO
OSEM
ii
ii
i
CH3
OTBDPS
72
CH3
OTBDPS
CH3
OTBDPS
CH3
OTBDPS
MeO2C
OP
76
75
OTBDPS
iii
78 P = H
84
i
OTES
CH3
OH
83 P = TBDPS
iii
OTES
OSEM
OSEM
iv
OTES
X
OTES
CH3
OTBDPS
Me
Me
OSEM
OSEM
CH3
OTBDPS
OHC
CO2Me
iv
CH3
OTBDPS
OTBDPS
78
77
v
OTBDPS
86 X = H,OH
87 X = O
OTBDPS
85
v
OTES
CH3
OTES
OH
OSEM
OSEM
OHC
HO
vi
OTBDPS
CH3
OTBDPS
Scheme 10 Synthesis of the ketone 87 for metathesis studies
o
Reagents and conditions i, TBDPSCl, imid., DCM, 0 C to rt, 16 h
CO2Me
CO2Me
(81% from 77); ii, AD-mix β, tBuOH, water, OsO4 (cat.), rt, 30 h (78 h
(78%); iii, NaIO4, pH 7 buffer, THF, rt, 30 min (75%); iv, dimethylallyl
bromide, Zn, THF, rt, 1.5 h (88%); v, Dess-Martin periodinane, py.,
DCM, rt, 1 h (80%).
80
79
vii
OTES
O
OTES
Me
Me
OSEM
Me
Me
OH
OSEM
viii
CH3
OTBDPS
CH3
OTBDPS
Ketone 87 is also functionalised for incorporation into a metathesis
based assembly of the 20-deoxybryostatins albeit that the
methoxycarbonyl group present in ester 82 has been replaced by a
protected allylic alcohol. This should more stable for future
transformations.
CO2Me
CO2Me
81
82
Scheme 9 Synthesis of the C17-C27 ketone 82 for metathesis
Reagents and conditions; i, TESCl, imid., DCM, 0 C to rt, 16 h
o
As an aside, the use of the relatively labile triethylsilyl group
provided an opportunity to deprotect selectively the hydroxyl group
in the ketone 87 that corresponds to the 25-hydroxyl of the
bryostatins, see Scheme 11. This would allow for an investigation of
protection of the ketone as a methoxyacetal formation, cf. the
attempted conversion of the hydroxyketone 29 into the
methoxyacetal 31, see Scheme 2. In the event, the only product
that was isolated from these reactions, albeit in a very modest
unoptimised yield, was the enol ether 88 (22%), see Scheme 11. It
appeared that dehydration often competes with acetal formation in
precursors of the 20-deoxybryostatins and this conclusion, that was
only tentative at this stage, was supported by later observations
during the course of our work. For this reason no attempts were
made to prepare cyclic acetals from intermediates presented in
n
o
o
(93%); ii, BuLi, THF, −78 C, 45 min, MeOC(O)Cl, −78 C, 3 h
(97%); iii, LiCl, CuI, THF, rt, CH2=CHCH2MgBr, −78 oC to −60 oC,
30 min, add 76, −78 oC (70%); iv, DIBAL-H, THF, −78 oC, 1 h; v,
OsO4 (cat.), NMO, acetone, water, 5.5 h (69%); vi, NaIO4, THF,
pH 7 buffer, rt, 30 min (96%); vii, dimethylallyl bromide, Zn,
THF, rt, 1.5 h (55%); viii, Dess-Martin periodinane, DCM, rt, 1.5
h (53%).
with the organozinc reagent prepared from dimethylallyl bromide
gave the alcohol 81 as a mixture of epimers and oxidation gave the
(E)-unsaturated ketoester 82, see Scheme 9.
The aldehyde 80 and the ketoester 82 both correspond to
skipped unsaturated dicarbonyl compounds and as such were
expected to be unstable. The aldehyde 80 was not purified although
the crude product appeared relatively clean and could be fully
characterised. The ketoester 82 could be chromatographed and was
identified as the keto tautomer shown by NMR with significant
quantities of its enol not being evident. However, perhaps not
surprisingly, it started to decompose on storage and was not
thought to be sufficiently stable to take further in the synthesis
although it does correspond to the C19-C21-fragment of the 20-
deoxybryostatins. For this reason, the allylic alcohol 78 was
protected as its tert-butyldiphenylsilyl ether 83. Oxidative cleavage
of the terminal double-bond gave the aldehyde 85 and addition of
the dimethylallyl fragment gave the alcohol 86 as a mixture of
epimers. This was oxidised to the ketone 87, see Scheme 10.
Scheme
5
and our subsequent work4 towards the 20-
deoxybryostatins used intermediates in which the 20-ketone was
OTES
CH3
H
Me
Me
O
OSEM
Me
Me
O
OSEM
i
OTBDPS
CH3
OTBDPS
OTBDPS
OTBDPS
87
88
Scheme 11 Enol ether formation Reagents and conditions i,
HC(OMe)3, PPTS, MeOH, rt, 1 h (22%).
6 | J. Name., 2012, 00, 1-3
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OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
disguised as a protected alcohol, cf. sulfone 63. However, this was chloroform unless otherwise indicated using Varian Unity 500 (500
View Article Online
DOI: 10.1039/C7OB00076F
not the case in our work concerned with the synthesis of MHz), Varian INOVA 400 (400 MHz) and Varian Unity 300 (300 MHz)
bryostatins with an oxygenated substituent at C20.22
spectrometers. Spectra are at 300 Mz (1H), at 75 Mz (13C) and at 282
Mz (19F) in CDCl3 unless otherwise stated. Coupling constants (J) are
given in Hertz (Hz) and chemical shifts are relative to
tetramethylsilane. Residual non-deuteriated solvent was used as
the internal standard.
Summary and conclusions
This work has delivered several compounds that correspond to the
C17-C27 fragment of the 20-deoxybryostatins including sulfones, 1-tert-Butyldimethylsiloxypent-3-ene (12). The alcohol 11 (5.00 g,
e.g. the sulfone 63, that are suitable for use in the assembly of 58.05 mmol) in DCM (65 mL) was added to tert-butyldimethylsilyl
bryostatins via a Julia reaction, and terminal alkenes that could be chloride (8.75 g, 58.10 mmol) and imidazole (7.91 g, 116.2 mmol) in
o
used in ring-closing metathesis, see for example the dienes 68, 82 DCM (65 mL) at 0 C and the mixture allowed to warm to rt. After
and 87. The palladium(0) mediated coupling of tin enolates stirring for 16 h the mixture was filtered and the filtrate was
generated in situ from enol acetates with vinylic bromides provides washed with brine (150 mL). The aqueous layer was extracted with
a highly regio- and stereo-selective synthesis of βγ-unsaturated DCM (50 mL) and the organic extracts were dried (MgSO4) and
ketones with the required alkene geometry for the Julia precursors concentrated under reduced pressure. Chromatography of the
but competing Heck reactions were observed during the residue (1:30 to 1:8 ether:light petroleum) afforded the title
preparation of the unsaturated ketones required for the metathesis compound 12 as a colourless oil (11.63 g, ca. 100%), Rf = 0.89 (1:1
programme. For this reason, an alternative synthesis of the C17-C27 ether:light petroleum) (Found: M+ + H, 201.1671. C11H25OSi requires
metathesis precursors was developed based on the stereoselective M, 201.1674); νmax/cm-1 2955, 2930, 2896, 2858, 1472, 1255, 1101,
conjugate addition of a cuprate derived from allylmagnesium 1054, 966, 837 and 775; δH 0.06 [6 H, s, Si(CH3)2], 0.90 [9 H, s,
bromide to an alkynoate.
SiC(CH3)3], 1.66 (3 H, d, J 4.9, 5-H3), 2.21 (2 H, q, J 7.0, 2-H2), 3.62 (2
Of interest in this work is the application of the tin enolate – H, t, J 7.0, 1-H2) and 5.35-5.55 (2 H, m, 3-H, 4-H); δC –5.3, 17.9, 18.3,
vinylic bromide coupling reaction in such complicated systems as 25.9, 36.2, 63.3, 126.8 and 127.5; m/z (CI+) 201 (M+ + 1, 100%).
those reported in this paper. Thioether substituents in the tin (2R,3R)-5-tert-Butyldimethylsilyloxypentane-2,3-diol
(13).
A
enolate appeared to faciitate these reactions but the origin of this mechanically stirred three-necked flask was charged with t-butanol
effect was not studied any further. The (Z)-selective addition of the (300 mL), water (300 mL), AD-mix β (83.83 g, 1.4 g per mmol olefin)
cuprate reagent to the fully silylated alkynoate 76 is also of interest. and methanesulfonamide (5.70 g, 59.92 mmol) before gentle
o
It must be that in this system, the cuprate syn-adduct is stable with heating to 22 C produced a clear orange biphasic system. The
respect to isomerisation before the reaction is quenched.
mixture was cooled to –2 oC and the alkene 12 (12.0 g, 59.88 mmol)
The next phase of our work in this area was concerned with was added. Stirring was continued at –2 oC for 19.5 h before sodium
studies of ring-closing metathesis for the synthesis of sulfite (89.82 g, 0.71 mmol, 1.5 g per mmol olefin) was added. After
bryostatins23,24 and this work together with additional studies, will warming to rt, the aqueous phase was extracted with ethyl acetate
be described in detail in the following paper in this series.
(3 × 200 mL). The organic extracts were washed with brine, dried
(MgSO4) and concentrated under reduced pressure.
Chromatography (2:1 to 10:1 ether:light petroleum) afforded the
Experimental
General experimental details
title compound 13 as a pale yellow oil (12.40 g, 88%), Rf = 0.35 (8:2
20
ether:light petroleum), [α]D –5.3 (c 1.6, CH2Cl2) (Found: M+,
234.1654. C11H26O3Si require M, 234.1650); νmax/cm-1 3409, 3382,
Flash column chromatography was performed using Merck silica gel 2955, 2930, 2886, 1468, 1388, 1255, 1096, 938, 836 and 777; δH
(60H; 40-60µ, 230-240 mesh). Light petroleum was redistilled 0.10 [6 H, s, Si(CH3)2], 0.92 [9 H, s, SiC(CH3)3], 1.19 (3 H, d, J 6.0, 1-
before use and refers to the fraction boiling between 40 and 60 °C. H3), 1.65-1.80 (2 H, m, 4-H2), 3.55-3.75 (2 H, m, 2-H, 3-H) and 3.80-
Tetrahydrofuran was dried over sodium-benzophenone and was 3.95 (2 H, m, 5-H2); δC −5.7, –5.6, 18.0, 18.9, 25.7, 35.0, 61.4, 70.4
distilled under nitrogen prior to use. Dichloromethane was dried and 75.0; m/z (CI+) 235 (M+ + 1, 100%).
over CaH2 and was distilled before use. Ether refers to diethyl ether. (3R,4R)-3,4-Di-O-isopropylidene-1-tert-
Reactions under non-aqueous conditions were carried out under an butyldimethylsilyloxypentane (14). Pyridinium toluene p-sulfonate
atmosphere of nitrogen or argon.
(0.55 g, 2.19 mmol) was added to the diol 13 (5.13 g, 21.88 mmol)
Mass spectra used electron impact ionisation (EI+), chemical in 2,2-dimethoxypropane (105 mL) and the mixture was stirred at rt
ionisation using ammonia (CI+), electrospray ionisation in the for 19 h before being filtered and concentrated under reduced
positive mode (ES+) and atmospheric pressure chemical ionisation pressure. The residue was dissolved in ether (150 mL), and the
in the positive or negative mode (APCI+ or APCI-). Low and high solution washed with saturated aqueous sodium bicarbonate (150
resolution mass spectra were recorded using a Micromass Trio 200 mL) and brine (150 mL), dried (Na2SO4) and concentrated under
and a Kratos Concept IS spectrometer, respectively. For organotin reduced pressure to afford the title compound 14 as a colourless
20
compounds, peaks corresponding to 120Sn are given. Infra-red mobile oil (5.73 g, 95%), Rf = 0.73 (3:2 ether:light petroleum), [α]D
spectra were measured using a Genesis FTIR spectrometer on NaBr +27.2 (c 1.0, CH2Cl2) (Found: M+ − CH3, 259.1723. C13H27O3Si
plates, either neat or as evaporated films unless otherwise stated. requires M, 259.1729); νmax/cm-1 2954, 2932, 2882, 1472, 1378,
Nuclear magnetic resonance spectra were recorded in deuteriated 1251, 1225, 1175, 1096, 1006, 838 and 776; δH 0.07 [6 H, s,
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Si(CH3)2], 0.90 [9 H, s, SiC(CH3)3], 1.26 (3 H, d, J 6.1, 5-H3), 1.39 [6 H, DCM (2 × 60 mL). The organic extracts were washed with equal
View Article Online
DOI: 10.1039/C7OB00076F
s, C(CH3)2], 1.65-1.80 (2 H, m, 2-H2), 3.65 (1 H, dt, J 8.0, 4.0, 3-H) and volumes of saturated aqueous ammonium chloride, water and
3.64-3.80 (3 H, m, 1-H2, 4-H); δC –5.5(2), 17.2, 18.2, 25.8, 27.1, 27.2, brine before drying (Na2SO4). Concentration under reduced
35.3, 59.8, 77.3, 79.2 and 107.6; m/z (CI+) 275 (M+ + 1, 100%) and pressure afforded the title compound 16 (6.25 g) used without
217 (83).
further purification, Rf = 0.50 (1:9 ethyl acetate:DCM); νmax/cm-1
(3R,4R)-3,4-Di-O-isopropylidenepentan-1-ol
(15).
Tetra-n- 1729; δH 1.22 (3 H, d, J 6.0, 5-H3), 1.32 and 1.35 (each 3 H, s, CCH3),
butylammonium fluoride (1 M in THF, 43.7 mL, 43.7 mmol) was 2.50-2.60 (2 H, m, 2-H2), 3.74 (1 H, dq, J 8.4, 6.0, 4-H), 3.93 (1 H, m,
added to the silyl ether 14 (7.99 g, 29.11 mmol) in THF (235 mL) at 3-H) and 9.76 (1 H, t, J 2.1, 1-H).
rt and the mixture was stirred for 80 min before the addition of (4S,6R,7R)- and (4R,6R,7R)-6,7-Di-O-isopropylideneoct-1-yn-4-ol
water (150 mL) and extraction with ether (4 × 100 mL). The organic (17) and (19). Propargyl bromide (80% by wt in toluene, 1.6 mL,
extracts were washed with brine (400 mL), dried (MgSO4) and 17.9 mmol) was added dropwise to activated zinc (4.69 g, 71.77
concentrated under reduced pressure. Chromatography of the mmol) in THF (19 mL) and the mixture cooled to –15 oC. More
residue (9:1 to 20:1 ether:light petroleum) afforded the title propargyl bromide (80% by wt in toluene, 6.4 mL, 71.82 mmol) was
o
compound 15 as a colourless oil (3.99 g, 86%), Rf = 0.44 (9:1 added and the mixture stirred at −15 C for 30 min before being
20
o
ether:light petroleum), [α]D +10.0 (c 0.8, CH2Cl2) (Found: M+ + H, cooled to –78 C. The aldehyde 16 (from 4.36 g, 27.19 mmol of
161.1180. C8H17O3 requires M, 161.1178); νmax/cm-1 3431, 2984, alcohol 15) in THF (20 mL) was added and stirring at −78 oC
2935, 2878, 1455, 1378, 1241, 1173, 1051, 1002 and 858; δH 1.30 (3 continued for 4.25 h. Saturated aqueous ammonium chloride (19
H, d, J 5.9, 5-H3), 1.43 and 1.44 (each 3 H, s, CCH3), 1.71-1.90 (2 H, mL) was added, and the mixture warmed to rt and partitioned
m, 2-H2), 2.40 (1 H, t, J 5.5, OH), 3.72 (1 H, td, J 3.3, 8.5, 3-H) and between ether (150 mL) and water (150 mL). Following extraction
3.78-3.90 (3 H, m, 4-H, 1-H2); δC 16.9, 27.0, 27.1, 34.1, 60.2, 76.6, of the aqueous phase with ether (3 × 125 mL), the organic extracts
80.8 and 108.0; m/z (CI+) 161 (M+ + 1, 100%).
were washed with brine (450 mL), dried (MgSO4) and concentrated
(R)-2-Methoxy-2-phenyl-3,3,3-trifluoropropanoic acid (33 mg, under reduced pressure. Chromatography of the residue (91:9
0.128 mmol) and DMAP (cat.) were added to the alcohol 15 (17 mg, DCM:ethyl acetate) afforded the (4R)-epimer of the title compound
o
20
0.106 mmol) in THF (0.5 mL) at 0 C. Dicyclohexylcarbodiimide (44 19 (0.85 g, 16%), Rf = 0.30 (9:1 DCM:ethyl acetate), [α]D –2.7 (c
mg, 0.213 mmol) in THF (0.5 mL) was added and the mixture was 0.6, CHCl3); νmax/cm-1 3461, 3291, 2984, 2934, 1455, 1425, 1380,
allowed to warm to rt and stirred for 21 h. After dilution with ether 1242, 1172, 1088, 997, 872 and 848; δH 1.30 (3 H, d, J 5.9, 8-H3),
(20 mL), concentration under reduced pressure and 1.41 and 1.43 (each 3 H, s, CCH3), 1.64 (1 H, dt, J 14.1, 4.3, 5-H), 1.96
chromatography of the residue afforded the (R)-Mosher’s (1 H, dt, J 14.1, 2.0, 5-Hʹ), 2.07 (1 H, t, J 2.6, 1-H), 2.40 (1 H, ddd, J
derivative, a colourless oil (38 mg, 95%), Rf = 0.54 - 0.60 (2:3 16.8, 6.8, 2.7, 3-H), 2.51 (1 H, ddd, J 16.8, 5.4, 2.6, 3-Hʹ), 3.41 (1 H,
21
ether:light petroleum), [α]D +43.9 (c 2.7, CHCl3) (Found: M+, br. s, OH), 3.69 (1 H, m, 6-H), 3.79 (1 H, m, 7-H) and 4.02 (1 H, m, 4-
376.1496. C18H23F3O5 requires M, 376.1497); νmax/cm-1 2984, 2932, H); δC 16.9, 26.9, 27.0, 27.2, 37.6, 69.5, 70.5, 76.5, 80.6, 81.8 and
2855, 1751, 1715, 1666, 1498, 1452, 1378, 1245, 1172, 1121, 1099, 108.6; m/z (CI+) 216 (M+ + 18, 17%) and 199 (M+ + 1, 100). The more
1024, 859 and 718; δF –68.05 (90%) and −68.03 (10%); δH 1.19 (3 H, polar product was the (4S)-epimer of the title compound 17 (2.33 g,
20
d, J 6.0, 5-H3), 1.40 [6 H, s, C(CH3)2], 1.80-2.00 (2 H, m, 2-H2), 3.52 (1 43%), Rf = 0.19 (9:1 DCM:ethyl acetate), [α]D +29.1 (c 1.1, CHCl3);
H, td, J 8.4, 3.3, 3-H), 3.55 (2.7 H, s, OCH3), 3.56 (0.3 H, s, OCH3), νmax/cm-1 3446, 3295, 2984, 2935, 1455, 1426, 1379, 1242, 1171,
3.71 (1 H, dq, J 8.4, 6.0, 4-H), 4.45-4.55 (2 H, m, 1-H2), 7.42 (3 H, m, 1091, 1058, 1033, 998, 869 and 835; δH 1.28 (3 H, d, J 5.8, 8-H3),
ArH) and 7.53 (2 H, m, ArH); m/z (CI+) 377 (M+ + 1, 100%).
1.39 and 1.41 (each 3 H, s, CCH3) 1.72 (1 H, m, 5-H), 1.85 (1 H, m, 5-
Using (S)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoic acid Hʹ), 2.07 (1 H, t, J 2.6, 1-H), 2.42-2.48 (2 H, m, 3-H2), 2.86 (1 H, br. s,
acid, the alcohol 15 (17 mg, 0.106 mmol) afforded the (S)-Mosher’s OH), 3.74-3.84 (2 H, m, 6-H, 7-H) and 4.07 (1 H, m, 4-H); δC 16.9,
derivative, a colourless oil (39 mg, 98%), Rf = 0.54 - 0.60 (2:3 27.1, 27.2, 27.3, 37.1, 67.3, 70.7, 76.4, 79.2, 80.6 and 108.1; m/z
21
ether:light petroleum), [α]D –19.6 (c 2.2, CHCl3) (Found: M+, (CI+) 216 (M+ + 18, 12%) and 199 (M+ + 1, 100).
376.1490. C18H23F3O5 requires M, 376.1497); νmax/cm-1 2983, 2934,
(4S,6R,7R)-6,7-Di-O-isopropylidene-4-(4-methoxybenzyloxy)oct-1-
2872, 1750, 1453, 1380, 1261, 1172, 1122, 1100, 1025, 859 and yne (18). The alcohol 17 (728 mg, 3.67 mmol) in THF (4.7 mL) was
719; δF −68.05 (10%) and –68.02 (90%); δH 1.19 (3 H, d, J 5.9, 5-H3), added to sodium hydride (60% by wt suspension in mineral oil, 176
1.36 [6 H, s, C(CH3)2], 1.80-2.00 (2 H, m, 2-H2), 3.54 (1 H, td, J 8.5, mg, 4.40 mmol) in THF (7.4 mL) at 0 oC and the mixture warmed to
3.4, 3-H), 3.56 (3 H, s, OCH3), 3.69 (1 H, dq, J 8.3, 5.9, 4-H), 4.38-4.58 rt. After 1 h and cooling to 0 oC, tetra-n-butylammonium iodide (30
(2 H, m, 1-H2), 7.43 (3 H, m, ArH) and 7.53 (2 H, m, ArH); m/z (CI+) mg, 0.08 mmol) and 4-methoxybenzyl chloride (1.0 mL, 7.38 mmol)
377 (M+ + 1, 100%).
were added. The mixture was warmed to rt, stirred for 20 h then
(3R,4R)-3,4-Di-O-isopropylidenepentanal (16). Dimethyl sulfoxide cooled to 0 oC. Saturated aqueous ammonium chloride (0.6 mL),
(6.11 mL, 86.13 mmol) in DCM (28.8 mL) was added over 20 min to ether (100 mL) and water (100 mL) were added, and the aqueous
o
oxalyl chloride (3.75 ml, 42.99 mmol) in DCM (57.6 mL) at –78 C. phase extracted with ether (2 × 50 mL). The organic extracts were
After 20 min at −78 oC, the alcohol 15 (4.60 g, 28.71 mmol) in DCM washed with brine (150 ml), dried (MgSO4) and concentrated under
(28.8 mL) was added over 20 min. After 45 min at −78 oC, reduced pressure. Chromatography of the residue (1:4 then 2:3
triethylamine (15.61 mL, 112 mmol) was added over 20 min. After a ether:light petroleum) afforded the title compound 18, a colourless
further 20 min and warming to 0 oC, saturated aqueous ammonium oil (890 mg, 76%), Rf = 0.52 (2:3 ether:light petroleum), [α]D21 +55 (c
chloride:water (1:1 v/v, 23 mL) was added. After 10 min, the 4.9, CHCl3); νmax/cm-1 1613, 1515, 1463, 1455, 1379, 1369, 1302,
solution was warmed to rt and the aqueous phase extracted with 1092, 1072, 1036, 868 and 823; δH 1.27 (3 H, d, J 5.6, 8-H3), 1.42 [6
8 | J. Name., 2012, 00, 1-3
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OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
H, s, C(CH3)2], 1.65-1.90 (2 H, m, 5-H2), 2.06 (1 H, t, J 2.6, 1-H), 2.47- (2E,5R,7R,8R)-1-tert-Butyldiphenylsilyl)oxy-7,8-di-O- View Article Online
2.55 (2 H, m, 3-H2), 3.70-3.80 (2 H, m, 6-H, 7-H), 3.84 (3 H, s, OCH3), isopropylidene-5-(4-methoxybenzyloxy)-3-tDriObIu: t1y0l.1s0ta3n9/nCy7lOnoBn00-20-76F
3.85 (1 H, m, 4-H), 4.52 and 4.68 (each 1 H, d, J 11.2, ArHCH) and ene (23). Di-isobutylaluminium hydride (1.0 M in hexanes, 2.30 mL,
6.91 and 7.32 (each 2 H, d, J 8.7, ArH); δC 17.0, 24.4, 27.2, 37.3, 2.30 mmol) was added to the ester 21 (515 mg, 0.77 mmol) in THF
55.2, 70.3, 71.7, 73.9, 76.9, 78.6, 80.7, 107.7, 113.7, 129.5, 130.3 (3.8 mL) at –78 oC. After 2 h at −78 oC, the mixture was warmed to
and 159.2; m/z (EI+) 318 (M+, 1%), 137 (73) and 121 (100).
rt, stirred for 30 min, cooled to 0 oC and saturated aqueous sodium
(5S,7R,8R)-7,8-di-O-isopropylidene-5-(4- potassium tartrate (25 mL) and ether (50 mL) were added. The
Methyl
methoxybenzyloxy)non-2-ynoate (20). n-Butyllithium (1.47 M in aqueous phase was extracted with ether (3 × 15 mL) and the
hexanes, 2.86 mL, 4.21 mmol) was added to the alkyne 18 (1.22 g, organic extracts were washed with an equal volume of brine, dried
o
3.83 mmol) in THF (15.5 mL) at –78 C and the solution stirred at - (MgSO4) and concentrated under reduced pressure to afford the
78 oC for 45 min before the addition of methyl chloroformate (0.89 alcohol 22 (477 mg) as a colourless oil which was used without
mL, 11.52 mmol). After stirring at −78 oC for 3.5 h, saturated further purification, Rf = 0.28 (3:2 ether:light petroleum); νmax/cm-1
aqueous ammonium chloride (7 mL) was added and the mixture 3444, 2955, 2871, 1613, 1514, 1463, 1378, 1248, 1172, 1089, 1038,
warmed to rt. Ether (120 mL) and water (120 mL) were added and 869 and 823; δH 0.90-1.00 (15 H, m, 3 × CH2CH3), 1.26 (3 H, d, J 5.4,
the aqueous phase extracted with ether (2 × 80 mL). The organic 9-H3), 1.30-1.40 (6 H, m, 3 × CH2), 1.40 [6 H, s, C(CH3)2], 1.50-1.65 (6
extracts were washed with brine (180 mL), dried (MgSO4) and H, m, 3 × CH2), 1.65-1.80 (2 H, m, 6-H2), 2.34 (1 H, br. m, OH), 2.45
concentrated under reduced pressure. Chromatography (1:3 then (1 H, dd, J 13.7, 6.9, 4-H), 2.82 (1 H, dd, J 13.7, 7.8, 4-Hʹ), 3.60-3.75
1:1 ether:light petroleum) afforded the title compound 20 as a pale (3 H, m, 5-H, 7-H, 8-H), 3.81 (3 H, s, OCH3), 4.03 and 4.26 (each 1 H,
21
yellow oil (1.30 g, 90%), Rf = 0.27 (2:3 ether:light petroleum), [α]D
m, 1-H), 4.52 (2 H, s, ArCH2), 6.02 (1 H, t, J 6.5, 2-H) and 6.90 and
+39.4 (c 4.3, CH2Cl2); νmax/cm-1 2983, 2936, 2239, 1714, 1613, 1514, 7.28 (each 2 H, d, J 8.6, ArH); δC 9.7, 13.6, 17.0, 27.2, 27.4, 29.0,
1435, 1379, 1252, 1173, 1074, 1035, 824 and 753; δH 1.26 (3 H, d, J 37.6, 39.5, 55.1, 58.3, 72.2, 76.2, 77.0, 79.0, 107.8, 113.7, 129.5,
5.6, 9-H3), 1.40 [6 H, s, C(CH3)2], 1.69 (1 H, m, 6-H), 1.83 (1 H, ddd, J 130.0, 141.8, 144.6 and 159.2; m/z (EI+) 663 [M+ + 23, 100%].
13.6, 9.6, 2.0, 6-Hʹ), 2.55-2.75 (2 H, m, 4-H2), 3.70-3.75 (2 H, m, 7-H,
This alcohol in dry DMF (1.1 mL) was added to a suspension of
8-H), 3.79 (3 H, s, C(O)OCH3), 3.83 (3 H, s, ArOCH3), 3.89 (1 H, m, 5- tert-butyldiphenylsilyl chloride (0.33 mL, 1.27 mmol) and imidazole
H), 4.52 and 4.66 (each 1 H, d, J 11.1, ArHCH) and 6.90 and 7.32 (99 mg, 1.45 mmol) in dry DMF (0.8 mL) at 0 oC. After warming to rt
(each 2 H, d, J 8.7, ArH); δC 17.0, 24.9, 27.2(2), 37.6, 52.5, 55.2, 71.9, and stirring for 15 h, ether (50 mL) was added and the solution
73.6, 74.4, 76.9, 78.5, 86.1, 107.8, 113.8, 129.5, 130.0, 153.9 and washed with brine (50 mL), dried (MgSO4) and concentrated under
159.3; m/z (CI+) 394 (M+ + 18, 68%), 377 (M+ + 1, 4) and 121 (100). reduced pressure. Chromatography (2:8 ether:light petroleum
Alkyne 18 (0.13 g, 9%) was also recovered.
Methyl (2E,5R,7R,8R)-7,8-di-O-isopropylidene-5-(4- colourless oil (558 mg, 82%), Rf = 0.47 (2:8 ether:light petroleum),
methoxybenzyloxy)-3-tributylstannylnon-2-enoate
containing 1% triethylamine) afforded the title compound 23 as a
21
(21).
n- [α]D +21 (c 1.6, CHCl3); νmax/cm-1 2955, 2928, 2856, 1613, 1513,
Butyllithium (1.47 M in hexanes, 9.35 mL, 13.74 mmol) was added 1463, 1428, 1377, 1368, 1247, 1172, 1110, 1089, 1075, 1006, 823
to hexabutylditin (6.94 mL, 13.74 mmol) in THF (9.7 mL) at 0 oC and and 740; δH 0.85-1.99 (15 H, m, 3 × CH2CH3), 1.08 [9 H, s, SiC(CH3)3],
the solution stirred at 0 oC for 20 min then added to a suspension of 1.18 (3 H, d, J 5.8, 9-H3), 1.30-1.45 (8 H, m, 3 × CH2, 6-H2), 1.36 [6 H,
CuBr.DMS (2.83 g, 13.77 mmol) in THF (6.5 mL) at –50 oC. The s, C(CH3)2], 1.40-1.60 (6 H, m, 3 × CH2), 2.27 (1 H, dd, J 13.4, 7.9, 4-
mixture was stirred at –50 oC for 25 min and cooled to –78 oC H), 2.51 (1 H, dd, J 13.4, 5.0, 4-Hʹ), 3.54-3.62 (2 H, m, 7-H, 8-H), 3.69
before the ester 20 (1.72 g, 4.57 mmol) in THF (4.3 mL) was added. (1 H, m, 5-H), 3.82 (3 H, s, OCH3), 4.36 (2 H, d, J 5.4, 1-H2), 4.37 and
o
The solution was stirred at –78 C for 4.25 h, methanol (13.8 mL) 4.50 (each 1 H, d, J 11.0, ArHCH), 5.88 (1 H, t, J 5.4, 2-H), 6.85 and
was added and the mixture warmed to rt. Ether (150 mL) and water 7.22 (each 2 H, d, J 8.4, ArH), 7.35-7.50 (6 H, m, ArH) and 7.69-7.73
(150 mL) were added and the mixture filtered through celite. The (4 H, m, ArH); δC 9.8, 13.7, 17.0, 19.1, 26.8, 27.2, 27.3, 27.4, 29.0,
aqueous phase was extracted with ether (80 mL) and the organic 37.2, 39.2, 55.2, 61.2, 71.6, 76.2, 78.6, 107.5, 113.6, 127.5, 129.3,
extracts washed with an equal volume of brine, then dried (MgSO4) 129.5, 130.8, 133.9, 135.5, 140.8, 142.7 and 159.0; m/z (ES+) 901
and concentrated under reduced pressure. Chromatography of the (M+ + 23, 23%) and 247 (100).
residue (3:7 ether:light petroleum containing 1% triethylamine) (2E,5R,7R,8R)-3-Bromo-1-tert-butyldiphenylsilyloxy-7,8-di-O-
afforded the title compound 21 as a colourless oil (2.78 g, 91%), Rf = isopropylidene-5-(4-methoxybenzyloxy)non-2-ene (24). Stannane
0.47 (3:7 ether:light petroleum), [α]D21 +29.6 (c 0.5, CHCl3); νmax/cm- 23 (1.11 g, 1.26 mmol) in DCM (14.5 mL) was added to N-
1
2955, 2929, 2871, 2855, 1718, 1613, 1588, 1513, 1462, 1433, bromosuccinimide (0.29 g, 1.63 mmol) in DCM (9 mL) and the
1377, 1368, 1353, 1247, 1198, 1170, 1093, 1075, 1038, 869 and mixture was stirred at rt for 1 h before concentration under
822; δH 0.90-1.00 (15 H, m, 3 × CH2CH3), 1.24 (3 H, d, J 5.9, 9-H3), reduced pressure. Chromatography of the residue (3:7 ether:light
1.28-1.40 (6 H, m, 3 × CH2), 1.38 and 1.39 (each 3 H, s, CCH3), 1.45- petroleum containing 1% triethylamine) afforded the title
1.55 (6 H, m, 3 × CH2), 1.65-1.70 (2 H, m, 6-H2), 3.23 (1 H, dd, J 12.6, compound 24 as a colourless oil (0.81 g, 94%), Rf = 0.47 (3:7
21
7.4, 4-H), 3.32 (1 H, dd, J 12.6, 4.7, 4-Hʹ), 3.60-3.75 (2 H, m, 7-H, 8- ether:light petroleum), [α]D +42 (c 0.6, CHCl3); νmax/cm-1 3071,
H), 3.72 (3 H, s, CO2CH3), 3.83 (3 H, s, ArOCH3), 3.84 (1 H, m, 5-H), 3048, 2932, 2858, 1648, 1613, 1587, 1513, 1463, 1428, 1378, 1248,
4.52 and 4.62 (each 1 H, d, J 11.1, ArHCH), 6.10 (1 H, s, 2-H) and 1173, 1111, 1092, 1040, 821 and 740; δH 1.09 [9 H, s, SiC(CH3)3],
6.89 and 7.30 (each 2 H, d, J 8.7, ArH); δC 10.2, 13.6, 17.0, 27.2, 1.23 (3 H, d, J 5.6, 9-H3), 1.42 [6 H, s, C(CH3)2], 1.56 (2 H, m, 6-H2),
27.3, 28.8, 37.3, 40.0, 50.8, 55.1, 71.3, 76.1, 77.0, 78.6, 107.5, 2.41 (1 H, dd, J 14.4, 5.3, 4-H), 2.65 (1 H, dd, J 14.4, 7.2, 4-Hʹ), 3.68 (2
113.6, 129.2, 129.7, 130.9, 159.0, 164.4 and 170.0.
H, m, 7-H, 8-H), 3.83 (3 H, s, OCH3), 3.97 (1 H, m, 5-H), 4.18 (1 H, dd,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 26
ARTICLE
Journal Name
J 13.0, 6.3, 1-H), 4.26 (1 H, dd, J 13.0, 7.3, 1-Hʹ), 4.47 and 4.55 (each m, 8-H2), 2.26 (1 H, dd, J 14.0, 6.5, 6-H), 2.38 (1 H, dd,VJie1w4A.0rti,cle6O.2n,lin6e-
1 H, d, J 10.8, ArHCH), 6.24 (1 H, dt, J 6.7, 2-H), 6.86 and 7.24 (each Hʹ), 3.42 and 3.47 (each 1 H, d, J 17.3, 4-H), D3O.5I0: 1(02.1H03, 9s/,C17-OHB2)0,030.7565F-
2 H, d, J 8.7, ArH), 7.40-7.50 (6 H, m, ArH) and 7.72 (4 H, m, ArH); δC 3.75 (3 H, m, 7-H, 9-H, 10-H), 3.81 (3 H, s, OCH3), 4.34 (2 H, m, 2ʹ-
17.1, 19.1, 26.7, 27.3, 37.5, 42.5, 55.2, 61.2, 72.6, 74.4, 76.5, 76.9, H2), 4.42 and 4.52 (each 1 H, d, J 11.1, ArHCH), 5.62 (1 H, t, J 6.1, 1ʹ-
78.5, 107.7, 113.7, 123.8, 127.7, 129.5, 129.7, 130.4, 133.2, 134.0, H), 6.86 and 7.24 (each 2 H, d, J 8.5, ArH), 7.43 (6 H, m, ArH), 7.54-
135.5 and 159.1; m/z (ES+) 691 and 689 (each M+ + 23, 92%).
(7S,9R,10R)-5-[(E)-2-tert-Butyldiphenylsilyloxyethylidene]-7-(4-
methoxybenzyloxy)-2,2-dimethyl-1-phenylsulfanyl-9,10-di-O-
7.69 (3 H, m, ArH), 7.73 (4 H, m, ArH) and 7.93 (2 H, m, ArH); δC
17.0, 19.1, 24.9, 25.1, 26.8, 27.2, 27.3, 35.6, 37.6, 45.6, 46.9, 55.2,
60.8, 64.8, 71.6, 75.2, 78.8, 107.6, 113.6, 127.5, 127.6, 129.1, 129.4,
isopropylideneundecan-3-one (27).
tetrachloropalladate(II) (121 mg, 0.41 mmol) in dry methanol (0.50 210.3; m/z (ES+) 849 (M+ + 23, 100%) and 844 (M+ + 18, 85).
mL) was added to a suspension of tri(o-tolyl)phosphine (250 mg, (7S,9R,10R)-5-[(E)-2-tert-Butyldiphenylsilyloxyethylidene]-7-
A suspension of sodium 129.5, 130.8, 131.6, 131.9, 133.4, 133.7, 135.5, 141.3, 159.0 and
0.82 mmol) in dry ethanol (0.88 mL) under argon and the mixture hydroxy-2,2-dimethyl-1-phenyl-ulfonyl-9,10-di-O-isopropylidene-
o
heated under reflux (90 C) for 45 min. After filtering, washing the undecan-3-one (29). An aqueous phosphate pH 7 buffer (1.0 M, 100
precipitate with copious amounts of water, ethanol and ether gave µL) was added to the PMB-sulfone 28 (280 mg, 0.34 mmol) in DCM
an amber solid that was dried under reduced pressure for 2 h to (1.8 mL) at rt and DDQ (85 mg, 0.37 mmol) was added to the rapidly
give the catalyst used without further purification (typically 170 – stirred mixture. After 30 min, more pH 7 buffer (3.3 mL) and DCM
240 mg).
(60 mL) were added and the organic phase was washed with pH 7
The enol acetate 811 (208 mg, 0.83 mmol) in toluene (0.84 mL) buffer (4 × 20 mL) and brine (30 mL). The organic extracts were
was added to the bromide 24 (377 mg, 0.55 mmol) in toluene (0.84 dried (Na2SO4) and concentrated under reduced pressure.
mL) rt before degassing the solution using nitrogen for 7 min. Chromatography (1:3 then 3:1 ether:light petroleum) of the residue
Tributyltin methoxide (0.25 mL, 0.87 mmol) and PdCl2(o-tolyl3P)2 gave the title compound 29 as a colourless viscous oil (218 mg,
(40 mg, 0.05 mmol, 9 mol %) were added and the mixture was 91%), Rf = 0.29/0.47 (3:1 ether:light petroleum), [α]D20 +11.3 (c 1.7,
heated under reflux using an oil bath (120 C) for 1 h. The dark CHCl3) (Found: M+ + NH4, 724.3694. C40H58NO7SSi requires M,
o
green mixture was concentrated under reduced pressure and 724.3698); νmax/cm-1 3493, 2961, 2932, 2895, 2858, 1708, 1472,
chromatography of the residue (3:7 ether:light petroleum) gave the 1447, 1428, 1379, 1368, 1308, 1238, 1152, 1110, 1087, 1057, 822,
title compound 27 as a colourless viscous oil (360 mg, 82%), Rf = 738 and 704; δH 1.08 [9 H, s, SiC(CH3)3], 1.25 (3 H, d, J 5.4, 11-H3),
0.46 (3:7 ether:light petroleum), [α]D21 +21 (c 3.2, CHCl3); νmax/cm-1 1.35 and 1.36 (each 3 H, s, 2-CH3), 1.48 [6 H, s, C(CH3)2], 1.60 (2 H,
3070, 2960, 2931, 2857, 1708, 1612, 1513, 1466, 1428, 1379, 1247, m, 8-H2), 2.03 (1 H, dd, J 14.0, 7.3, 6-H), 2.15 (1 H, dd, J 14.0, 9.3, 6-
1110, 1089, 1060, 1040, 823 and 740; δH 1.08 [9 H, s, SiC(CH3)3], Hʹ), 3.14 (1 H, d, J 3.3, OH), 3.46 (1 H, d, J 18.0, 4-H), 3.53 (2 H, m, 1-
1.20 (3 H, d, J 5.8, 11-H3), 1.27 and 1.36 (each 6 H, s, 2 × CH3) 1.41 H2), 3.58 (1 H, d, J 18.0, 4-Hʹ), 3.75 (2 H, m, 9-H, 10-H), 3.85 (1 H, m,
(2 H, m, 8-H2), 2.23 and 2.65 (each 1 H, dd, J 14.1, 6.5, 6-H), 3.19 (2 7-H), 4.33 (2 H, d, J 6.5, 2ʹ-H2), 5.68 (1 H, t, J 6.5, 1ʹ-H), 7.42 (6 H, m,
H, s, 1-H2), 3.28 and 3.38 (each 1 H, d, J 17.0, 4-H), 3.58-3.75 (3 H, ArH), 7.54-7.68 (3 H, m, ArH), 7.72 (4 H, m, ArH) and 7.91 (2 H, m,
m, 7-H, 9-H, 10-H), 3.82 (3 H, s, OCH3), 4.31 (2 H, m, 2ʹ-H2), 4.40 and ArH); δC 17.1, 19.1, 25.1, 25.2, 26.7, 27.2(2), 39.2, 39.6, 46.0, 46.8,
4.49 (each 1 H, d, J 11.0, ArHCH), 5.55 (1 H, t, J 6.1, 1ʹ-H), 6.86 and 60.4, 65.0, 66.6, 76.7, 79.5, 99.7, 107.7, 127.5, 127.6, 129.2, 129.6,
7.22 (each 2 H, d, J 8.6, ArH), 7.30 (3 H, m, ArH), 7.42 (8 H, m, ArH) 131.9, 132.6, 133.5, 13.5, 141.1 and 211.9; m/z (ES+) 745.4 (M+ + 39,
and 7.73 (4 H, m, ArH); δC 17.0, 19.1, 24.3(2), 26.8, 27.2, 27.3, 35.6, 32%), 729.5 (M+ + 23, 100) and 724.5 (M+ + 18, 73).
37.5, 44.0, 45.7, 49.0, 55.2, 60.7, 71.6, 75.0, 78.7, 107.5, 113.6,
Complex mixtures containing minor products in which the βγ-
126.1, 127.6, 128.8, 129.4, 129.5(2), 130.7, 131.6, 131.8, 133.7, double-bond had migrated into conjugation with the ketone were
135.5, 137.4, 159.0 and 211.5; m/z (ES+) 817 (M+ + 23, 100%).
(7S,9R,10R)-5-[(E)-2-tert-Butyldiphenylsilyloxyethylidene]-7-(4-
methoxybenzyloxy)-2,2-dimethyl-1-phenylsulfonyl-9,10-di-O-
obtained when hydroxyketone 29 was reacted at rt for 60 – 75 min
with the following: (a) toluene p-sulfonic acid (50 mol%) in
methanol, (b) catalytic toluene p-sulfonic acid and trimethyl
isopropylideneundecan-3-one (28). Solid sodium hydrogen orthoformate in methanol, (c) titanium(IV) chloride and
carbonate (63 mg, 0.75 mmol) and mCPBA (70 - 75 wt % with water, triethylamine in methanol.25 No reaction was observed with the
168 mg, 0.68 – 0.73 mmol) were added to the sulfide 27 (270 mg, following overnight: (a) camphor sulfonic acid (10 or 30 mol%), 4Å
0.34 mmol) in DCM (1.4 mL) at rt and the resulting thick white mol. sieves in methanol, (b) camphor sulfonic acid (30 mol%),
suspension stirred at rt for 4.25 h before the addition of saturated trimethyl orthoformate and 4Å mol. sieves in methanol.
aqueous sodium sulfite (1.8 mL). After stirring for 20 min, the Methoxytrimethylsilane, trimethylsilyl triflate (cat.), 2,2-
mixture was partitioned between DCM (60 mL) and water (60 mL). dimethoxypropane and 4Å sieves in methanol overnight at rt led to
The aqueous phase was extracted with DCM (50 mL) and the decomposition.
organic extracts were dried (Na2SO4) and concentrated under
2,6-Lutidine (9 µL, 0.07 mmol) and tert-butyldimethylsilyl
reduced pressure. Chromatography of the residue (1:1 ether:light triflate (13 µL, 0.57 mmol) were added to the alcohol 29 (25 mg,
petroleum) gave the title compound 28 as a colourless viscous oil 0.035 mmol) in DCM (0.3 mL) at 0 oC and the mixture stirred for 15
21
(201 mg, 72%), Rf = 0.18 (1:1 ether:light petroleum), [α]D +17 (c min. Water was added and the mixture extracted with ether. The
0.7, CHCl3); νmax/cm-1 2959, 2930, 2857, 1710, 1612, 1513, 1467, ether extracts were dried (Na2SO4) and concentrated under reduced
1447, 1379, 1368, 1309, 1248, 1152, 1108, 1087, 1062, 1038, 822, pressure. Chromatography (1:1 ether: light petroleum) gave the
739 and 705; δH 1.09 [9 H, s, SiC(CH3)3], 1.21 (3 H, d, J 5.8, 11-H3), tert-butyldimethylsilyl ether 30 (18 mg, 60%; νmax/cm-1 2956, 2930,
1.37 (6 H, s, 2 × 2-CH3), 1.43 and 1.45 (each 3 H, s, CH3), 1.46 (2 H, 2857, 1725, 1471, 1378, 1318, 1308, 1287, 1258, 1153, 1111, 1087,
10 | J. Name., 2012, 00, 1-3
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OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
1069, 827 and 776; δH 0.01 and 0.04 (each 3 H, s, SiCH3), 0.85 and added to the hydroxylactone 33 (6.12 g, 52.70 mmol) in DCM (59
View Article Online
o
DOI: 10.1039/C7OB00076F
1.05 [each 9 H, s, SiC(CH3)3], 1.15-1.35 (2 H, m, 8-H2), 1.17 (3 H, d, J mL) at 0 C before warming to rt with the addition of 4-
5.5, 11-H3), 1.32 and 1.34 (each 3 H, s, 2-CH3), 1.44 (6 H, s, 2 × CH3), dimethylaminopyridine (190 mg). After stirring for 3 d, the mixture
o
2.21 (2 H, m, 6-H2), 3.36 and 3.43 (each 1 H, d, J 17.2, 1-H), 3.44 and was cooled to 0 C before the addition of water (57 mL) and ethyl
3.53 (each 1 H, d, J 13.9, 4-H), 3.53-3.62 (2 H, m, 9-H, 10-H), 3.69 (1 acetate (300 mL). The aqueous phase was extracted with ethyl
H, m, 7-H), 4.28 (2 H, m, 2ʹ-H2), 5.57 (1 H, t, J 6.1, 1ʹ-H), 7.39 (6 H, m, acetate (3 × 100 mL), and the organic extracts were washed with
ArH), 7.56 (3 H, m, ArH), 7.71 (4 H, m, ArH) and 7.90 (2 H, m, ArH); brine (200 mL), dried (MgSO4) and concentrated under reduced
δC −5.0, −4.2, 16.9, 17.9, 19.1, 24.7, 25.3, 25.8, 26.7, 27.2, 27.4, pressure. Chromatography (1:2 then 2:1 ether:light petroleum)
39.3, 39.4, 45.6, 46.9, 60.8, 64.7, 68.3, 76.7, 78.5, 107.7, 127.5, gave the title compound 34 as a pale yellow oil (12.33 g, 95%), Rf =
21
127.6, 129.1, 129.5, 131.3, 131.8, 133.4, 133.6, 133.7, 135.5, 141.3, 0.63 (20:1 ether:light petroleum), [α]D −6.6 (c 1.7, CHCl3) (Found:
and 210.1.
M+ + NH4, 264.1631. C11H26NO4Si requires M, 264.1631); νmax/cm-1
2953, 2894, 1783, 1410, 1249, 1212, 1164, 1139, 1106, 1055, 1034,
(4R,5R)-4-Hydroxy-5-methyltetrahydrofuran-2-one
(33).17
A
mechanically stirred three-necked flask was charged with tert- 942, 860 and 836; δH 0.03 [9 H, s, Si(CH3)3], 0.83-1.00 (2 H, m,
butanol (250 mL), water (250 mL) and AD-mix β (122.4 g, 1.4 g per SiCH2), 1.42 (3 H, d, J 6.5, 5-CH3), 2.64 (1 H, dd, J 17.7, 2.4, 3-H), 2.74
mmol alkene). Gentle heating gave a clear, biphasic system that was (1 H, dd, J 17.7, 5.4, 3-Hʹ), 3.55-3.70 (2 H, m, OCH2CH2Si), 4.35 (1 H,
cooled to 0 oC. Methyl (E)-3-pent-3-enoate (9.98 g, 87.43 mmol) m, 4-H), 4.65 (1 H, dq, J 6.5, 4.5, 5-H) and 4.68 and 4.72 (each 1 H, d,
o
was added and the mixture was warmed to 10 C. After 18 h, the J 7.3, OHCHO); δC –1.53, 14.1, 18.0, 36.6, 65.6, 73.6, 80.0, 93.7 and
o
mixture was cooled to 0 C and stirred for a further 36 h. Sodium 175.0; m/z (CI+) 264 (M+ + 18, 100%).
sulfite (131.0 g, 1.5 g per mmol alkene) was added and the mixture (3R,4R)-4-tert-Butyldimethylsilyloxy-3-(2-
warmed to rt over 1.5 h. After reducing the volume of the reaction trimethylsilylethoxymethoxy)pentanoic
acid
mixture to approximately 300 mL under reduced pressure, the methoxymethylamide (36). Trimethylaluminium (2.0 M in hexanes,
resulting deep green liquor was decanted from the excess sodium 45.3 mL, 90.60 mmol) was added to N,O-dimethylhydroxylamine
sulfite that was rinsed thoroughly with ethyl acetate (2 × 100 mL). hydrochloride (8.84 g, 90.60 mmol) in DCM (900 mL) at 0 oC over 10
The organic extracts were subjected to continuous extraction using min. The reaction mixture was warmed to rt over 20 min and stirred
ethyl acetate heated under reflux for 24 h. The extracts were dried for 50 min before the dropwise addition of lactone 34 (11.16 g,
o
(MgSO4)
and
concentrated
under
reduced
pressure. 45.30 mmol) in DCM (430 mL). After 2 h and cooling to 0 C, an
Chromatography (1:20 then 20:1 ethyl acetate:light petroleum) of aqueous phosphate buffer (pH 8.0, 300 mL,) was added and the
the residue gave the title compound 33 as a colourless viscous oil mixture filtrated through Celite®. Following the addition of DCM
20
(5.71 g, 59%), Rf = 0.17 (20:1 ether:light petroleum), [α]D +66 (c (300 mL), the aqueous phase was extracted with DCM (4 × 200 mL)
1.8, CHCl3), lit. +73.2 (c 1.1, EtOH)17a; νmax/cm-1 3429, 2990, 2938, and the organic extracts were washed with brine (300 mL), dried
1769, 1404, 1387, 1345, 1293, 1237, 1207, 1173, 1137, 1101, 1058, (MgSO4) and concentrating under reduced pressure to give the
943, 886, 807 and 738; δH 1.48 (3 H, d, J 6.6, 5-CH3), 2.60 (1 H, dd, J amide 35 as an oil (11.85 g). This was azeotroped with benzene
17.7, 1.1, 3-H), 2.61 (1 H, br. m, OH), 2.85 (1 H, dd, J 17.7, 5.6, 3-Hʹ), before use, Rf = 0.16 (4:1, ether:light petroleum).
4.48 (1 H, m, 4-H) and 4.61 (1 H, dq, J 6.6, 3.7, 5-H); δC 13.6, 39.3,
tert-Butyldimethylsilyl chloride (6.97 g, 46.24 mmol) was added
to imidazole (6.30 g, 92.5 mmol) in DCM (30 mL) and the solution
69.4, 81.0 and 176.0, m/z (CI+) 134 (M+ + 18, 100%).
The alcohol 33 (166 mg, 1.43 mmol) in DCM (2.7 mL) was added cooled to 0 oC. The hydroxy-amide 35 (11.85 g) in DCM (33 mL) was
to tert-butyldimethylsilyl chloride (301 mg, 2.00 mmol) and added before warming to rt. 4-Dimethylaminopyridine (cat.) and
imidazole (272 mg, 4.0 mmol) in DCM (2.2 mL) at 0 oC and the tetra-n-butylammonium iodide (cat.) were added and the solution
solution stirred at rt for 18 h. The mixture was diluted with DCM (40 stirred for 14 h. After dilution with DCM (200 mL) and filtration,
mL) and brine (20 mL), and the aqueous phase extracted with DCM water (250 mL) was added and the aqueous phase was extracted
(2 × 15 mL). The organic extracts were dried (MgSO4) and with DCM (2 × 200 mL). The organic extracts were washed with
concentrated under reduced pressure. Chromatography (1:4 then brine (300 mL), dried (MgSO4), and concentrated under reduced
1:1, ether:light petroleum) of the residue gave (4R,5R)-4-tert- pressure. Chromatography (1:5 to 1:3 to 4:1 ether:light petroleum)
butyldimethylsilyloxy-5-methyltetrahydrofuran-2-one as white of the residue gave the title compound 36 as a pale yellow oil (12.6
20
needles (248 mg, 75%), Rf = 0.65 (20:1 ether:light petroleum), m.p. g, 66% from 34), Rf = 0.69 (8:2 ether:light petroleum), [α]D –15.6
o
21
52-53 C, [α]D +14.5 (c 2.2, CHCl3) (Found: M+ + NH4, 248.1683. (c 2.2, CHCl3) (Found: M+ + H, 422.2768. C19H44NO5Si2 requires M,
C11H26NO3Si requires M, 248.1682); νmax/cm-1 3054, 2956, 2932, 422.2758); νmax/cm-1 2954, 2932, 2894, 1669, 1467, 1415, 1383,
2858, 1779, 1421, 1265, 1166, 1070, 1028, 927, 836 and 738; δH 1251, 1105, 1055, 859, 836 and 777; δH 0.02 [9 H, s, Si(CH3)3], 0.07
0.08 (6 H, s, 2 × SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.36 (3 H, d, J 6.5, 5- and 0.08 (each 3 H, s, SiCH3), 0.89 [9 H, s, SiC(CH3)3], 0.92 (2 H, m,
CH3), 2.45 (1 H, dd, J 17.3, 1.7, 3-H), 2.73 (1 H, dd, J 17.3, 5.4, 3-Hʹ), CH2Si), 1.15 (3 H, d, J 6.2, 5-H3), 2.67 (2 H, br. d, J 4.3, 2-H2), 3.20 (3
4.38 (1 H, m, 4-H) and 4.54 (1 H, dq, J 6.5, 4.0, 5-H); δC –5.2, -4.9, H, s, NCH3), 3.50 and 3.66 (each 2 H, ddd, J 11.1, 9.1, 3.1,
14.2, 18.0, 25.5, 39.7, 70.0, 81.1 and 175.4; m/z (CI+) 248 (M+ + 18, OHCHCH2Si), 3.70 (3 H, s, OCH3), 4.00-4.10 (2H, m, 3-H, 4-H) and
100%) and 231 (M+ + 1, 7).
(4R,5R)-5-Methyl-4-(2-
4.69 and 4.80 (each 1 H, d, J 6.9, OHCHO); δC –4.9, -4.8, −1.6, 17.4,
18.0(2), 25.8, 31.6, 61.0, 65.0, 68.8, 78.1, 95.7 and 173.0; m/z (CI+)
trimethylsilylethoxymethoxy)tetrahydrofuran-2-one (34). Di- 422 (M+ + 1, 91%), 304 (98) and 90 (100). Some SEM protected
isopropylethylamine (37.37 mL, 215.99 mmol) and 2- lactone 34 (1.27 g, 11%) was also isolated.
trimethylsilylethoxymethyl chloride (20.51 mL, 115.90 mmol) were (3R,4R)-4-tert-Butyldimethylsilyloxy-3-(2-
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
trimethylsilylethoxymethoxy)pentanal (37). Di-isobutylaluminium SiC(CH3)3], 0.95 (2 H, m, CH2Si), 1.22 (3 H, d, J 6.3, 8-H3), 1.66 (1 H,
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hydride (1.0 M in hexanes, 60.0 mL, 60.0 mmol) was added to the m, 5-H), 1.95-2.04 (2 H, m, 1-H, 5-Hʹ), 2.41 (D2OHI:, 1m0.,1033-H9/2C),73O.B4010(0176HF,
amide 36 (12.6 g, 29.9 mmol) in DCM (215 mL) at –78 oC. After d, J 3.2, OH), 3.55-3.70 (3 H, m, 7-H, OCH2CH2Si), 3.98 (2 H, m, 4-H,
o
stirring at –78 C for 1 h, methanol (32 mL) and saturated aqueous 6-H) and 4.73 and 4.78 (each 1 H, d, J 6.9, OHCHO); δC –4.9, −4.7,
ammonium chloride (75 mL) were added and the mixture warmed −1.5, 17.4, 17.9, 18.1, 25.7, 27.0, 34.6, 65.7, 69.0, 69.6, 70.2, 81.0,
to rt. After 30 min, ethyl acetate (350 mL) was added and the 81.4 and 95.1; m/z (CI+) 420 (M+ + 18, 3%), 403 (M+ + 1, 20), 285
mixture filtered through Celite®. The organic extracts were washed (71) and 90 (100).
with water (400 mL) and the aqueous washings washed with ethyl
Triphenylphosphine (16.77 g, 63.92 mmol) was added to the
acetate (200 mL). The organic extracts were dried (MgSO4) and alcohol 39 (6.43 g, 15.98 mmol) in THF (150 mL) and the solution
o
concentrated under reduced pressure. Chromatography (1:30 then cooled to 0 C before the addition of dichloroacetic acid (5.27 mL,
1:5 ether:light petroleum) of the residue gave the title compound 63.92 mmol) and di-isopropyl azodicarboxylate (12.58 mL, 63.92
37 as a colourless oil (9.43 g, 87%), Rf = 0.80 (1:1 ether:light mmol). The mixture was stirred at 0 oC for 10 min and at rt for 18 h
20
petroleum), [α]D –4.7 (c 1.2, CHCl3) (Found: M+ + H, 363.2360, then cooled to 0 oC before the addition of saturated sodium
C17H39O4Si2 requires M, 363.2387); νmax/cm-1 2954, 2932, 2892, bicarbonate (80 mL). The aqueous phase was extracted with ethyl
2859, 1729, 1468, 1381, 1252, 1104, 1055, 1033, 860, 835 and 777; acetate (3 × 100 cm3), dried (MgSO4) and concentrated under
δH 0.03 [9 H, s, Si(CH3)3], 0.06 and 0.07 (each 3 H, s, OSiCH3), 0.89 [9 reduced pressure. Chromatography (1 : 40 ether : light petroleum)
H, s, SiC(CH3)3], 0.92 (2 H, m, CH2Si), 1.12 (3 H, d, J 6.2, 5-H3), 2.54 (1 gave a mixture of (3ZE,6R,7R)-7-tert-butyldimethylsilyloxy-6-(2-
H, ddd, J 16.3, 8.0, 2.7, 2-H), 2.71 (1 H, ddd, J 16.3, 4.2, 1.7, 2-Hʹ), trimethylsilylethoxymethoxy)oct-3-en-1-ynes (1.37 g, 22%), (Z):(E) =
21
3.55-3.62 (2 H, m, OCH2CH2Si), 3.95-4.08 (2 H, m, 3-H, 4-H), 4.73 (2 75:25 (1H NMR), Rf = 0.50 (1 : 20, ether : light petroleum), [a]D
H, s, OCH2O) and 9.76 (1 H, dd, J 2.7, 1.7, 1-H); δC –4.9, −4.7, −1.6, +12.9 (c 0.9, CHCl3) (Found: M+ + H, 385.2590. C20H41O3Si2 requires
17.4, 17.9, 18.0, 25.7, 43.7, 65.3, 68.6, 76.3, 95.0 and 201.2; m/z M, 385.2594); νmax/cm-1 3314, 2954, 2930, 2889, 2858, 2361, 2340,
(CI+) 380 (M= + 18, 6%), 363 (M+ + 1, 7) and 287 (100).
(4S,6R,7R)- and
trimethylsilylethoxymethoxy)-oct-1-yn-4-ol
1471, 1381, 1251, 1189, 1148, 1104, 1056, 1034, 938, 860, 836 and
(4R,6R,7R)-7-tert-Butyldimethylsilyloxy-6-(2- 776; δH major (Z)-isomer 0.00 [9 H, s, Si(CH3)3], 0.06 (6 H, s, 2 ×
(38) and (39). SiCH3), 0.88 [9 H, s, SiC(CH3)3], 0.90 (2 H, m, CH2Si), 1.12 (3 H, d, J
Propargyl bromide (80 wt % in toluene, 1.80 mL, 20.16 mmol) was 6.3, 8-H3), 2.47 (1 H, m, 5-H), 2.65 (1 H, m, 5-Hʹ), 3.07 (1 H, d, J 1.8,
added to a rapidly stirred suspension of activated zinc (5.27 g, 80.62 1-H), 3.40-3.70 (3 H, m, 6-H, OCH2CH2Si), 3.89 (1 H, m, 7-H), 4.70
mmol) in THF (13.5 mL) with cooling. Once heat evolution had and 4.72 (each 1 H, d, J 7.2, OHCHO), 5.51 (1 H, m, 3-H) and 6.13 (1
ceased, the reaction mixture was cooled to –15 oC before the H, dt, J 11.0, 7.2, 4-H); minor (E)-isomer 1.08 (3 H, d, J 6.2, 8-H3),
addition of more propargyl bromide (80 wt % in toluene, 7.18 mL, 2.20 (1 H, m, 5-H), 2.77 (1 H, d, J 2.1, 1-H) and 6.29 (1 H, dt, J 15.5,
80.62 mmol). After 30 min at −15 oC, the resulting mixture was 7.5, 4-H); m/z (CI+) 385 (M+ + 1, 9%), 327 (60), 298 (22), 267 (40) and
o
cooled to –78 C before the dropwise addition of the aldehyde 37 90 (100). The second fraction was the dichloroacetate of the alcohol
o
(5.85 g, 16.13 mmol) in THF (15.5 mL). After stirring at −78 C for 38 as a colourless oil (4.97 g, 61%), Rf = 0.32 (1 : 20 ether : light
20
4.5 h, saturated aqueous ammonium chloride (14 mL) was added petroleum), [a]D +18.9 (c 2.1, CHCl3) (Found: M+ + NH4, 530.2289.
and the mixture warmed to rt. Ethyl acetate (200 mL) was added C22H46NO5Cl2Si2 requires M, 530.2291); νmax/cm-1 3313, 2954, 2931,
and the mixture filtered through celite®. Water (300 mL) was added, 2892, 2858, 2360, 2339, 1767, 1747, 1470, 1380, 1278, 1252, 1165,
the aqueous phase was washed with ether (3 × 100 mL) and the 1105, 1029, 860, 832 and 776; δH 0.04 [9 H, s, Si(CH3)3], 0.08 (6 H, s,
organic extracts were washed with brine (300 mL). After drying 2 × SiCH3), 0.90 [9 H, s, SiC(CH3)3], 0.94 (2 H, m, CH2Si), 1.12 (3 H, d,
(MgSO4)
and
concentration
under
reduced
pressure, J 6.2, 8-H3), 1.77 (1 H, ddd, J 14.7, 10.6, 2.6, 5-H), 2.04 (1 H, t, J 2.6,
chromatography (1:20 ether:light petroleum) of the residue gave 1-H), 2.15 (1 H, ddd, J 14.7, J 10.4, 1.7, 5-Hʹ), 2.64 (2 H, m, 3-H2),
recovered aldehyde 37 (0.46 g, 8%) followed by the title compound 3.45-3.70 (3 H, m, 6-H, OCH2CH2Si), 4.05 (1 H, pent, J 6.2, 7-H), 4.63
20
38 (2.91 g, 45%), Rf = 0.36 (1:4 ether:light petroleum), [α]D +42.6 and 4.73 (each 1 H, d, J 7.1, OHCHO), 5.20 (1 H, m, 4-H) and 5.95 (1
(c 2.6, CHCl3) (Found: M+ + H, 403.2685. C20H43O4Si2 requires M, H, s, 2ʹ-H); δC –5.0, −4.8, −1.6, 16.9, 17.9(2), 24.2, 25.7, 32.1, 64.3,
403.2700); νmax/cm-1 3458, 3314, 2954, 2930, 2894, 2859, 1469, 65.4, 68.5, 71.1, 72.6, 78.2, 78.4, 95.8 and 163.9; m/z (CI+) 530, 532
1380, 1252, 1103, 1057, 1031, 860, 834 and 776; δH 0.02 [9 H, s, (M+ + 18, 5%), 457 (20), 455 (22), 395 (17), 365 (20) and 90 (100).
Si(CH3)3], 0.08 (6 H, s, 2 × OSiCH3), 0.90 [9 H, s, SiC(CH3)3], 0.95-0.99
Finely ground sodium hydroxide (3.67 g, 91.66 mmol) was
(2 H, m, CH2Si), 1.12 (3 H, d, J 6.3, 8-H3), 1.65-1.75 (2 H, m, 5-H2), added to the dichloroacetate of alcohol 38 (5.88 g, 11.46 mmol) in
o
2.01 (1 H, m, 1-H), 2.37 and 2.45 (each 1 H, ddd, J 10.0, 6.4, 2.6, 3- methanol (80 mL) at 0 C before warming the mixture to rt. After
H), 3.50-3.75 (3 H, m, 6-H, OCH2CH2Si), 3.80 (1 H, d, J 4.0, OH), 3.82- 3.5 h, the reaction mixture was concentrated under reduced
3.98 (2 H, m, 4-H, 7-H) and 4.82 and 4.77 (each 1 H, d, J 6.9, pressure until approximately 20 mL remained. After dilution with
OHCHO); δC –4.9, −4.8, −1.6, 17.9, 18.0, 18.5, 25.7, 26.9, 36.6, 65.7, ether (400 mL) and addition of saturated aqueous ammonium
66.4, 70.1, 70.7, 80.0, 81.2 and 96.0; m/z (CI+) 420 (M+ + 18, 2%), chloride (400 mL), the aqueous phase was extracted with ether
403 (M+ + 1, 16) and 285 (100). The third fraction was the title (3 × 150 mL). The organic extracts were dried (MgSO4) and
compound 39 (2.92 g, 45%), Rf = 0.24 (1:4 ether:light petroleum), concentrated under reduced pressure. Chromatography (1:20 then
20
[α]D +24 (c 1.2, CHCl3) (Found: M+ + H, 403.2706. C20H43O4Si2 1:5, ether:light petroleum) of the residue gave the title compound
requires M, 403.2700); νmax/cm-1 3449, 3313, 2954, 2930, 2892, 38 as a colourless oil (3.9 g, 85%).
2858, 1470, 1379, 1251, 1150, 1104, 1056, 1031, 860, 836 and 776;
Pyridine (50 µL, 0.62 mmol) and 4-dimethylaminopyridine (cat.)
δH 0.03 [9 H, s, Si(CH3)3], 0.08 (6 H, s, 2 × SiCH3), 0.89 [9 H, s, were added to the alcohol 38 (25 mg, 0.062 mmol) in DCM (0.16
12 | J. Name., 2012, 00, 1-3
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OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
mL) and the solution was cooled to 0 oC. (R)-O-Acetylmandelyl H, s, 2 × SiCH3), 0.88 [9 H, s, C(CH3)3], 0.94 (2 H, m, CH2Si), 1.09 (3 H,
View Article Online
DOI: 10.1039/C7OB00076F
chloride (39 mg, 0.186 mmol) in DCM (0.16 mL) was added and the d, J 6.3, 8-H3), 1.55 (2 H, m, 5-H2), 2.24 (2 H, m, 3-H2), 3.45-3.75 (4
solution stirred for 2 h at rt. Saturated aqueous ammonium chloride H, m, 6-H, OH, OCH2CH2Si), 3.83 (2 H, m, 4-H, 7-H), 4.69 and 4.75
(1 mL) was added and the mixture partitioned between ether (30 (each 1 H, d, J 6.7, OHCHO), 5.06 (2 H, m, 1-H2) and 5.85 (1 H, m, 2-
mL) and water (30 mL). The organic phase was washed with H); δC −4.9, −1.6, 18.0(2), 18.5, 25.7, 37.2, 41.8, 65.7, 67.2, 70.8,
saturated aqueous ammonium chloride (20 mL), dried (MgSO4) and 80.1, 96.0, 116.8 and 135.3; m/z (CI+) 405 (M+ + 1, 7%), 287 (70) and
concentrated under reduced pressure. Chromatography (1:10 269 (100). The second fraction was the title compound 42 (50 mg,
ether:light petroleum) of the residue gave the (R)-O- 25%), Rf = 0.12 (2:1 ether:light petroleum), [α]D22 +9.8 (c 1.3, CHCl3)
acetylmandelate of the alcohol 38 as a colourless oil (28 mg, 78%), (Found: M+ + H, 405.2871. C20H45O4Si2 requires M, 405.2856);
20
Rf = 0.57 (1:4 ether:light petroleum), [α]D –24.5 (c 2.4, CHCl3) νmax/cm-1 3441, 2954, 2930, 2897, 2859, 1469, 1378, 1251, 1150,
(Found: M+ + NH4, 596.3440. C30H54NO7Si2 requires M, 596.3439); 1104, 1056, 1033, 917, 859, 835 and 776; δH 0.00 [9 H, s, Si(CH3)3],
νmax/cm-1 3313, 2955, 2930, 2894, 2857, 1750, 1375, 1252, 1232, 0.04 and 0.05 (each 3 H, s, SiCH3), 0.86 [9 H, s, SiC(CH3)3], 0.94 (2 H,
1208, 1176, 1103, 1055, 1028, 860, 835, 806 and 778; δH 0.02 [9 H, m, CH2Si), 1.08 (3 H, d, J 6.3, 8-H3), 1.52 (1 H, dt, J 14.6, 8.8, 5-H),
s, Si(CH3)3], 0.09 and 0.12 (each 3 H, s, SiCH3), 0.87 (2 H, m, CH2Si), 1.81 (1 H, dt, J 14.6, 3.6, 5-Hʹ), 2.24 (2 H, m, 3-H2), 3.18 (1 H, d, J 2.7,
0.93 [9 H, s, SiC(CH3)3], 1.10 (3 H, d, J 6.3, 8-H3), 1.70 (1 H, m, 5-H), OH), 3.61 (3 H, m, 6-H, OCH2CH2Si), 3.83 (1 H, m, 4-H), 3.96 (1 H, m,
1.78 (1 H, t, J 2.5, 1-H), 2.07 (1 H, m, 5-Hʹ), 2.19 (3 H, s, C(O)CH3), 7-H), 4.70 and 4.75 (each 1 H, d, J 6.9, OHCHO), 5.08 (2 H, m, 1-H2)
2.36 (2 H, m, 3-H2), 3.46 (2 H, m, 6-H, OHCHCH2Si), 3.65 (1 H, m, and 5.83 (1 H, m, 2-H); δC –4.9, −4.7, −1.5, 17.3, 17.9, 18.1, 25.7,
OHCHCH2Si), 4.07 (1 H, pent, J 6.3, 7-H), 4.57 and 4.66 (each 1 H, d, 35.1, 41.8, 65.6, 69.0, 70.3, 81.4, 95.1, 117.2 and 134.9; m/z (CI+)
J 6.9, OHCHO), 5.14 (1 H, m, 4-H), 5.86 (1 H, s, 2ʹ-H), 7.37 (3 H, m, 405 (M+ + 1, 9%), 347 (16), 304 (38) and 287 (100).
ArH) and 7.51 (2 H, m, ArH); δC –5.0, −4.8, −1.6, 16.8, 17.9(2), 20.5,
Pyridine (58 µL, 0.72 mmol) and 4-dimethylaminopyridine (cat.)
24.1, 25.7, 31.9, 65.1, 68.5, 70.0, 70.3, 74.5, 78.4, 78.7, 96.0, 127.4, were added to the alcohol 40 (29 mg, 0.07 mmol) in DCM (0.19 mL).
128.5, 129.0, 133.5, 168.3 and 169.9; m/z (CI+) 596 (M+ + 18, 4%), After cooling to 0 oC, (R)-O-acetylmandelyl chloride (47 mg, 0.22
461 (87) and 90 (100).
mmol) in DCM (0.19 mL) was added and the mixture was warmed
Following this procedure, the alcohol 38 (26 mg, 0.097 mmol) to rt then stirred for 5 h. Ether (30 mL) and saturated aqueous
and (S)-O-acetylmandelyl chloride gave the (S)-O-acetylmandelate ammonium chloride (30 mL) were added and the organic phase was
of the alcohol 38 as a colourless oil (30 mg, 81%), Rf = 0.64 (1:4 washed with saturated aqueous ammonium chloride (20 mL). The
ether:light petroleum), [α]D20 +47.4 (c 2.7, CHCl3) (Found: M+ + NH4, mixture was concentrated under reduced pressure and
596.3428. C30H54NO7Si2 requires M, 596.3439); νmax/cm-1 3313, chromatography (1:8, ether:light petroleum) of the residue gave
2954, 2930, 2894, 2858, 1750, 1470, 1428, 1375, 1250, 1232, 1208, the (R)-O-acetylmandelate of the alcohol 40 as a colourless oil (23
22
1177, 1104, 1054, 1030, 860, 836 and 777; δH −0.03 and 0.00 (each mg, 55%), Rf = 0.61 (1:4 ether:light petroleum), [α]D –35.6 (c 1.8,
3 H, s, SiCH3), 0.02 [9 H, s, Si(CH3)3], 0.86 (2 H, m, CH2Si), 0.87 [9 H, CHCl3) (Found: M+ + NH4, 598.3586. C30H56NO7Si2 requires M,
s, C(CH3)3], 1.01 (3 H, d, J 6.3, 8-H3), 1.70 (1 H, ddd, J 14.6, 10.5, 3.0, 598.3595); νmax/cm-1 2954, 2930, 2893, 2857, 1749, 1469, 1374,
5-H), 1.93 (1 H, ddd, J 14.6, 10.4, 2.3, 5-Hʹ), 2.00 (1 H, t, J 2.7, 1-H), 1250, 1233, 1210, 1179, 1104, 1056, 1031, 919, 860, 836 and
2.20 (3 H, s, CH3C(O)O), 2.58 (2 H, m, 3-H2), 3.00 (1 H, ddd, J 10.5, 777; δH 0.00 [9 H, s, Si(CH3)3], 0.07 and 0.11 (each 3 H, s, SiCH3),
4.8, 2.3, 6-H), 3.42 and 3.55 (each 1 H, m, OHCHCH2Si), 3.85 (1 H, m, 0.80-1.00 (2 H, m, CH2Si), 0.91 [9 H, s, SiC(CH3)3], 1.06 (3 H, d, J 6.3,
7-H), 4.16 and 4.38 (each 1 H, d, J 6.7, OHCHO) 5.05 (1 H, m, 4-H), 8-H3), 1.51 (1 H, ddd, J 14.6, 10.6, 2.3, 5-H), 1.87 (1 H, ddd, J 14.6,
5.93 (1 H, s, 2ʹ-H), 7.38 (3 H, m, ArH) and 7.49 (2 H, m, ArH); δC −5.0, 10.7, 1.7, 5-Hʹ), 2.10-2.21 (2 H, m, 3-H2), 2.17 (3 H, s, C(O)CH3), 3.38-
−4.8, −1.5, 17.1, 17.8(2), 20.6, 24.3, 25.7, 32.0, 65.1, 68.8, 70.5, 3.50 (2 H, m, 6-H, OHCHCH2Si), 3.66 (1 H, m, OHCHCH2Si), 4.06 (1 H,
70.8, 74.6, 78.5, 79.0, 95.8, 127.7, 128.7, 129.3, 133.7, 168.2 and pent, J 6.3, 7-H), 4.57 and 4.65 (each 1 H, d, J 6.9, OHCHO), 4.65-
170.1; m/z (CI+) 597 (M+ + 18, 3%), 461 (50) and 90 (100).
(4S,6R,7R)- And (4R,6R,7R)-7-tert-butyldimethylsilyloxy-6-(2- s, 2ʹ-H), 7.34 (3 H, m, ArH) and 7.43 (2 H, m, ArH); δC −5.0, −4.8,
4.80 (2 H, m, 1-H2), 5.11 (1 H, m, 4-H), 5.40 (1 H, m, 2-H), 5.81 (1 H,
trimethylsilylethoxymethoxy)oct-1-en-4-ol (40) and (42). The −1.6, 16.8, 17.9(2), 20.6, 25.7, 32.3, 39.0, 65.1, 68.5, 71.7, 74.5,
aldehyde 37 (180 mg, 0.50 mmol) in dry ether (0.33 mL) was added 78.7, 96.2, 117.7, 127.5, 128.5, 128.9, 132.5, 133.8, 168.3 and
to allyl(di-isopinocampheyl) borane derived from (+)-α-pinene (0.70 169.8; m/z (CI+) 598 (M+ + 18, 5%), 463 (7) and 90 (100).
mmol) at –78 oC and, after 1.5 h, the reaction mixture was warmed
Following the same procedure, alcohol 40 (29 mg, 0.07 mmol)
to rt before the addition of aqueous sodium hydroxide (3 M, 0.52 and (S)-O-acetylmandelyl chloride (47 mg, 0.22 mmol) gave the (S)-
mL, 1.56 mmol) and aqueous hydrogen peroxide (30% v/v, 0.2 mL, O-acetylmandelate of alcohol 40 as a colourless oil (29 mg, 69%), Rf
o
22
1.8 mmol). The mixture was heated under reflux (90 C) for 1 h, = 0.61 (1:4 ether:light petroleum), [α]D +40.6 (c 2.1, CHCl3)
cooled to rt and partitioned between ether (40 mL) and water (40 (Found: M+ + NH4, 598.3591. C30H56NO7Si2 requires M, 598.3595);
mL). The aqueous phase was extracted with ether (2 × 20 mL) and νmax/cm-1 2953, 2930, 2893, 2857, 1748, 1470, 1460, 1374, 1250,
the organic extracts were washed with water (30 mL) and brine (30 1233, 1210, 1178, 1103, 1054, 1031, 919, 860, 836 and 777; δH 0.00
mL), dried (MgSO4) and concentrated under reduced pressure. and 0.04 (each 3 H, s, SiCH3), 0.07 [9 H, s, Si(CH3)3], 0.90 [9 H, s,
Chromatography gave the title compound 40 (110 mg, 55%), Rf = SiC(CH3)3], 0.80-1.00 (2 H, m, CH2Si), 1.03 (3 H, d, J 6.3, 8-H3), 1.51
20
0.36 (1:4 ether:light petroleum), [α]D +17.2 (c 2.3, CHCl3) (Found: and 1.80 (each 1 H, ddd, J 14.7, 10.6, 2.6, 5-H), 2.24 (3 H, s,
M+ + H, 405.2862. C20H45O4Si2 requires M, 405.2856); νmax/cm-1 C(O)CH3), 2.46 (2 H, dd, J 7.0, 5.9, 3-H2), 3.00 (1 H, ddd, J 10.6, 4.8,
3481, 2954, 2930, 2895, 2858, 1642, 1470, 1378, 1251, 1152, 1103, 2.3, 6-H), 3.45 and 3.60 (each 1 H, m, OHCHCH2Si), 3.86 (1 H, pent, J
1056, 1033, 917, 860, 835 and 776; δH 0.00 [9 H, s, Si(CH3)3], 0.06 (6 6.0, 7-H), 4.21 and 4.44 (each 1 H, d, J 6.9, OHCHO), 5.05-5.20 (3 H,
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
m, 1-H2, 4-H), 5.81 (1 H, m, 2-H), 5.92 (1 H, s, 2ʹ-H), 7.42 (3 H, m, 859, 835 and 775; δH 0.00 [9 H, s, Si(CH3)3], 0.04 (12 H, s, 4 × SiCH3),
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ArH) and 7.53 (2 H, m, ArH); δC −4.9, −4.8, −1.5, 17.2, 17.8, 17.9, 0.86 and 0.87 [each 9 H, s, SiC(CH3)3], 0.9D0O-0I:.9150.1(0239H/C, 7mO,B0C0H027S6i)F,
20.7, 25.8, 32.3, 39.0, 65.1, 69.0, 72.2, 74.7, 78.6, 96.0, 118.1, 1.06 (3 H, d, J 6.3, 8-H3), 1.54 (1 H, ddd, J 14.0, 9.6, 4.3, 5-H), 1.75 (1
127.7, 128.7, 129.2, 132.9, 133.9, 168.3 and 170.1; m/z (CI+) 598 H, ddd, J 14.0, 8.9, 2.9, 5-Hʹ), 2.12-2.40 (2 H, m, 3-H2), 3.42 (1 H, m,
(M+ + 18, 2%), 463 (14) and 90 (100).
(4S,6R,7R)-4,7-Bis-(tert-butyldimethylsilyloxy)-6-(2-
6-H), 3.59 (2 H, m, OCH2CH2Si), 3.88 (2 H, m, 4-H, 7-H), 4.64 and
4.71 (each 1 H, d, J 7.1, OHCHO), 5.03 (2 H, m, 1-H2) and 5.85 (1 H,
trimethylsilylethoxymethoxy)oct-1-ene (41). Imidazole (52 mg, m, 2-H); δC −4.8, −4.7, −4.5, −4.4, −1.5, 17.9, 18.0(2), 18.1, 25.8,
0.76 mmol), tert-butyldimethylsilyl chloride (57 mg, 0.38 mmol) and 36.5, 40.9, 65.3, 69.3(2), 78.9, 95.0, 116.7 and 135.3; m/z (CI+) 519
4-dimethylaminopyridine (cat.) were added to the alcohol 40 (77 (M+ + 1, 4%), 432 (13) and 401 (100).
mg, 0.19 mmol) in DCM (0.7 mL) at 0 oC before warming the (4S)-3-[(2S,3R,5R,6R)-6-tert-Butyldimethylsilyloxy-3-hydroxy-2-
mixture to rt and stirring for 18 h. After adition of DCM (20 mL), the methylsulfanyl-5-(2-trimethylsilylethoxymethoxy)heptanoyl]-4-
mixture was filtered and washed with brine (20 mL) with extraction isopropyloxazolidin-2-one (45). Dibutylboron triflate (1.0 M in
of the aqueous phase with DCM (2 × 15 mL). After drying (MgSO4), DCM, 0.39 mL, 0.39 mmol) and di-isopropylethylamine (96 µL, 0.55
the organic extracts were concentrated under reduced pressure mmol)
were
added
to
(4S)-4-isopropyl-3-(2-
and chromatography (1:100 ether:light petroleum) of the residue methylsulfanylacetyl)oxazolidin-2-one 44 (80 mg, 0.37 mmol) in
gave the title compound 41 as a colourless oil (76 mg, 77%), Rf = DCM (0.5 mL) at 0 oC and the mixture was stirred at 0 oC for 30 min
22
o
0.77 (1:4 ether:light petroleum), [α]D +9.8 (c 2.0, CHCl3) (Found: before cooling to –78 C. The aldehyde 37 (94 mg, 0.26 mmol) in
M+ + H, 519.3720. C26H59O4Si3 requires M, 519.3716); νmax/cm-1 DCM (0.2 mL) was added and the mixture warmed to rt. After 24 h,
2955, 2930, 2892, 2858, 1469, 1378, 1253, 1102, 1057, 937, 914, an aqueous pH 7.2 buffer (0.3 mL) was added at 0 C followed by
o
860, 835, 809 and 774; δH 0.00 [9 H, s, Si(CH3)3], 0.03 and 0.04 (each aqueous hydrogen peroxide (30% v/v in methanol, 43 µL, 0.26
o
3 H, s, SiCH3), 0.06 (6 H, s, 2 × SiCH3), 0.86 and 0.87 [each 9 H, s, mmol). After stirring at 0 C for 1.5 h, DCM (40 mL) and pH 7.2
SiC(CH3)3], 0.90 (2 H, m, CH2Si), 1.06 (3 H, d, J 6.3, 8-H3), 1.46 (1 H, buffer (40 mL) were added and the aqueous phase was extracted
ddd, J 14.3, 9.5, 3.4, 5-H), 1.66 (1 H, ddd, J 14.3, 8.5, 2.3, 5-Hʹ), 2.20- with DCM (2 × 40 mL). The organic extracts were dried (MgSO4) and
2.30 (2 H, m, 3-H2), 3.52 (2 H, m, 6-H, OHCHCH2Si), 3.65 (1 H, ddd, J concentrated under reduced pressure. Chromatography (1:4 then
10.7, 9.8, 6.3, OHCHCH2Si), 3.89 (1 H, m, 4-H), 3.98 (1 H, m, 7-H), 1:3 ether:light petroleum) of the residue gave the title compound
4.68 and 4.72 (each 1 H, d, J 7.0, OHCHO), 5.02 (2 H, m, 1-H2) and 45 as a colourless oil (93 mg, 62%), Rf = 0.52 (1:1 ether:light
21
5.79 (1 H, m, 2-H); δC −5.0, −4.5, −4.1, −3.7, −1.2, 17.7, 18.4(2), petroleum), [α]D +27.7 (c 1.2, CHCl3) (Found: M+ + H, 580.3160.
26.2(2), 36.3, 43.1, 65.5, 69.2, 69.6, 80.1, 96.1, 117.2 and 135.2; m/z C26H54NO7SSi2 requires M, 580.3159); νmax/cm-1 3513, 2956, 2930,
(APCI+) 519 (M+ + 1, 10%), 401 (17), 193 (45) and 157 (100).
2890, 2859, 1781, 1690, 1467, 1386, 1371, 1302, 1251, 1203, 1102,
n-Butyllithium (1.6 M in hexanes, 99 µL, 0.16 mmol) was added 1056, 1026, 835 and 775; δH 0.00 [9 H, s, Si(CH3)3], 0.06 (6 H, s, 2 ×
to a suspension of methyltriphenylphosphonium bromide (74 mg, SiCH3), 0.87 [9 H, s, SiC(CH3)3], 0.91 (3 H, d, J 6.5, CHCH3), 0.92 (2 H,
0.21 mmol) in THF (0.3 mL) at −78 oC before warming the mixture to m, CH2Si), 0.94 (3 H, d, J 6.2, CHCH3), 1.09 (3 H, d, J 6.0, 7ʹ-H3), 1.56
rt. After 30 min, the mixture was cooled to −78 oC and the aldehyde (1 H, m, 4ʹ-H), 1.78 (1 H, ddd, J 13.5, 9.9, 3.2, 4ʹ-Hʹ), 2.15 (3 H, s,
49 (29 mg, 0.05 mmol) in THF (0.2 mL) was added. The rmixture was SCH3), 2.35 (1 H, m, 4-CH), 3.53 (1 H, d, J 2.6, OH), 3.57-3.66 (2 H, m,
warmed to rt and stirred for 16 h. After addition of saturated OCH2CH2Si), 3.69 (1 H, m, 5ʹ-H), 3.91 (1 H, pent, 6.0, 6ʹ-H), 4.14-4.30
aqueous ammonium chloride (1.0 mL), the mixture was partitioned (3 H, m, 3ʹ-H, 5-H2), 4.46 (1 H, m, 4-H) and 4.66-4.80 (3 H, m, 2ʹ-H,
between ether (20 mL) and water (20 mL). The aqueous phase was OCH2O); δC –4.9, −4.8, −1.5, 12.9, 14.5, 17.8, 18.0, 18.1, 25.8, 28.2,
extracted with ether (3 × 10 mL), the organic extracts were washed 34.5, 49.8, 58.1, 62.9, 65.4, 65.6, 69.9, 79.6, 95.9, 153.2 and 170.0;
with water (20 mL) and brine (20 mL) then dried (MgSO4) and m/z (CI+) 580 (M+ + 1, 3%), 550 (5), 522 (5) and 235 (100).
concentrated under reduced pressure. Chromatography (light (4S)-3-[(3R,5R,6R)-6-tert-Butyldimethylsilyloxy-3-hydroxy-5-(2-
petroleum then 1:30 ether:light petroleum) of the residue gave the trimethylsilylethoxymethoxy)heptanoyl]-4-isopropyloxazolidin-2-
title compound 41 as a colourless oil (20 mg, 69%).
(4R,6R,7R)-4,7-Bis-(tert-butyldimethylsilyloxy)-6-(2-
one (46). Azo-bis-isobutyronitrile (6 mg, 0.035 mmol) and tri-n-
butyltin hydride (172 µL, 0.64 mmol) were added to a degassed
trimethylsilylethoxymethoxy)oct-1-ene (43). 2,6-Lutidine (17 µL, solution of the sulfide 45 (184 mg, 0.32 mmol) in benzene (3 mL)
o
0.15 mmol) and tert-butyldimethylsilyl triflate (23 µL, 0.10 mmol) and the solution was heated under reflux (90 C) for 40 min. After
were added to the alcohol 42 (21 mg, 0.05 mmol) in DCM (0.45 mL) concentration under reduced pressure, chromatography (1:3 then
at 0 oC and the reaction mixture stirred at 0 oC for 1.5 h before the 1:1 ether:light petroleum) of the residue gave the title compound
addition of water (0.5 mL) and warming to rt. After partitioning 46 as a colourless viscous oil (136 mg, 80%), Rf = 0.37 (1:1
21
between ether (20 mL) and water (20 mL), the aqueous layer was ether:light petroleum), [α]D +41.6 (c 2.8, CHCl3) (Found: M+ + H,
extracted with ether (2 × 15 mL) and the organic extracts were 534.3270. C25H52NO7Si2 requires M, 534.3282); νmax/cm-1 3521,
washed with water (15 mL) and brine (15 mL) before drying 2955, 2930, 2892, 2859, 1785, 1700, 1468, 1386, 1303, 1252, 1205,
(Na2SO4). After concentration under reduced pressure, 1149, 1103, 1058, 1029, 977, 936, 860, 835 and 776; δH 0.00 [9 H, s,
chromatography (1:30 ether:light petroleum) of the residue gave Si(CH3)3], 0.06 (6 H, s, 2 × SiCH3), 0.86 [9 H, s, SiC(CH3)3], 0.86-0.90 (8
the title compound 43 as a colourless viscous oil (24 mg, 89%), Rf = H, m, CH2Si, 2 × CHCH3), 1.08 (3 H, d, J 6.3, 7ʹ-H3), 1.54 (1 H, ddd, J
20
0.80 (DCM), [α]D +10.7 (c 2.4, CHCl3) (Found: M+ + H, 519.3733. 14.5, 9.9, 2.6, 4ʹ-H), 1.72 (1 H, ddd, J 14.5, 10.3, 3.4, 4ʹ-Hʹ), 2.37 (1
C26H59O4Si3 requires M, 519.3721); νmax/cm-1 2955, 2930, 2892, H, m, 4-CH), 2.90 (1 H, dd, J 16.6, 3.4, 2ʹ-H), 3.30 (1 H, dd, J 16.6,
2858, 1641, 1469, 1378, 1253, 1151, 1102, 1059, 1031, 936, 913, 9.1, 2ʹ-Hʹ), 3.55-3.70 (4 H, m, 5ʹ-H, OH, OCH2CH2Si), 3.89 (1 H, pent,
14 | J. Name., 2012, 00, 1-3
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Page 15 of 26
OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
J 6.0, 6ʹ-H), 4.15-4.30 (3 H, m, 3ʹ-H, 5-H2), 4.42 (1 H, m, 4-H), 4.70 was stirred at rt for 2.5 h before the addition of aqVuieewouArsticsleoOdinulinme
DOI: 10.1039/C7OB00076F
and 4.75 (each 1 H, d, J 6.9, OHCHO); δC –4.8, −1.6, 14.6, 17.9(2), hydroxide (1.3 M, 1.5 mL). Following extraction of the aqueous
18.2, 25.8, 28.3, 36.7, 42.6, 58.3, 63.3, 64.5, 65.7, 70.2, 79.6, 96.2, phase with ether (2 × 20 mL) and washing the organic extracts with
154.0 and 171.9; m/z (CI+) 551 (M+ + 18, 3%), 534 (M+ + 1, 16) and aqueous sodium hydroxide (1.3 M, 20 mL) and water (20 mL), the
189 (100).
organic extracts were dried (MgSO4), and concentrated under
reduced pressure to give the aldehyde 49 as a pale yellow oil (75
mg, 97%) which was used without further purification, Rf = 0.78
(4S)-3-[(3R,5R,6R)-3,6-bis-(tert-Butyldimethylsilyloxy)-5-(2-
trimethylsilylethoxymethoxy)heptanoyl]-4-isopropyloxazolidin-2-
one (47). 2,6-Lutidine (27 µL, 0.23 mmol) and tert-butyldimethylsilyl (1:3, ether:light petroleum); δH 0.06 [9 H, s, Si(CH3)3], 0.09, 0.10,
triflate (37 µL, 0.16 mmol) were added to the alcohol 46 (53 mg, 0.12 and 0.14 (each 3 H, s, 4 × SiCH3), 0.91 and 0.92 [each 9 H, s,
0.10 mmol) in DCM (0.9 mL) at 0 oC and the mixture stirred at 0 oC SiC(CH3)3], 0.90-1.00 (2 H, m, CH2Si), 1.11 (3 H, d, J 7.3, 7-H3), 1.59 (1
for 1 h. Water (1 mL) was added and the mixture warmed to rt then H, ddd, J 14.4, 9.4, 5.2, 4-H), 1.95 (1 H, ddd, J 14.4, 7.4, 2.6, 4-Hʹ),
partitioned between ethyl acetate (30 mL) and water (30 mL). The 2.57 and 2.68 (each 1 H, ddd, J 16.0, 7.0, 2.9, 2-H), 3.57 (2 H, m, 5-
aqueous phase was extracted with ethyl acetate (2 × 30 mL) and H, OHCHCH2Si), 3.70 (OHCHCH2Si), 4.09 (1 H, m, 3-H), 4.38 (1 H, m,
the organic extracts were dried (MgSO4) and concentrated under 6-H), 4.72 and 4.76 (each 1 H, d, J 7.0, OHCHO) and 9.87 (1 H, t, J
reduced pressure. Chromatography through a silica plug (1:5 then 2.5, 1-H).
2:5 ether:light petroleum) of the residue gave the title compound (4S,6R,7R)-4,7-Bis-(tert-butyldimethylsilyloxy)-6-(2-
47 as a colourless oil (53 mg, 80%), Rf = 0.63 (1:2 ether:light trimethylsilylethoxymethoxy)oct-1-yne (50). 2,6-Lutidine (4.22 mL,
petroleum), [α]D21 +11.7 (c 2.7, CHCl3) (Found: M+ + NH4, 665.4409. 36.20 mmol) and tert-butyldimethylsilyl triflate (5.78 mL, 25.18
C31H69N2O7Si3 requires M, 665.4407); νmax/cm-1 2955, 2931, 2891, mmol) were added to the alcohol 38 (6.33 g, 15.74 mmol) in DCM
o
o
2858, 1786, 1704, 1468, 1386, 1304, 1252, 1204, 1102, 1060, 1033, (125 mL) at 0 C and the mixture was stirred at 0 C for 1 h before
938, 859, 836 and 776; δH 0.00 [9 H, s, Si(CH3)3], 0.03, 0.04, 0.06 and the addition of water (125 mL) and warming to rt. Following
0.09 (each 3 H, s, SiCH3), 0.85 and 0.86 [each 9 H, s, SiC(CH3)3], 0.86- partitioning between ether (800 mL) and water (800 mL), the
0.95 (8 H, m, CH2Si, 2 × CHCH3), 1.05 (3 H, d, J 6.3, 7ʹ-H3), 1.52 (1 H, aqueous phase was extracted with ether (2 × 500 mL) and the
ddd, J 14.3, 9.8, 4.7, 4ʹ-H), 1.79 (1 H, ddd, J 14.3, 7.7, 2.2, 4ʹ-Hʹ), organic extracts were dried (MgSO4) then concentrated under
2.36 (1 H, m, 4-CH), 3.05 (1 H, dd, J 16.2, 6.2, 2ʹ-H), 3.26 (1 H, dd, J reduced pressure. Chromatography (1:60 ether:light petroleum) of
16.2, 6.0, 2ʹ-Hʹ), 3.45-3.55 (2 H, m, 6ʹ-H, OHCHCH2Si), 3.65 (1 H, m, the residue gave the title compound 50 as a colourless viscous oil
20
OHCHCH2Si), 4.03 (1 H, m, 5ʹ-H), 4.18 (1 H, dd, J 9.7, 3.7, 5-H), 4.20 (15.25 g, 94%), Rf = 0.57 (1:20 ether:light petroleum), [α]D +12 (c
(1 H, d, J 9.1, 5-Hʹ), 4.34.3.44 (2 H, m, 3ʹ-H, 4-H), 4.68 and 4.71 0.9, CHCl3) (Found: M+ + NH4], 534.3828. C26H60NO4Si3 requires M,
(each 1 H, d, J 7.0, OHCHO); δC −4.8, −4.5(2), −1.5, 14.4, 17.0, 17.9, 534.3830); νmax/cm-1 3315, 2955, 2930, 2888, 2858, 1471, 1378,
18.0(2), 25.8, 28.1, 36.6, 44.3, 58.3, 63.0, 65.2, 66.3, 68.9, 79.8, 1252, 1150, 1102, 1073, 1056, 1035, 990, 973, 938, 861, 836, 809
95.7, 153.8 and 170.7; m/z (CI+) 665.4 (M+ + 18, 48%), 648.5 (M+ + 1, and 775; δH 0.06 [9 H, s, Si(CH3)3], 0.10 (6 H, s, 2 × SiCH3), 0.12 and
23), 590.4 (60) and 562.4 (100).
0.14 (each 3 H, s, SiCH3), 0.92 and 0.93 [each 9 H, s, SiC(CH3)3], 0.98
(3R,5R,6R)-3,6-Bis-(tert-butyldimethylsilyloxy)-5-(2-
(2 H, m, CH2Si), 1.13 (3 H, d, J 6.2, 8-H3), 1.71 (1 H, ddd, J 14.3, 9.5,
trimethylsilylethoxymethoxy)heptan-1-ol (48). Methanol (29 µL, 3.7, 5-H), 1.84 (1 H, ddd, J 14.3, 8.5, 2.6, 5-Hʹ), 2.01 (1 H, t, J 2.6, 1-
0.72 mmol) and lithium borohydride (16 mg, 0.72 mmol) were H), 2.41 (2 H, m, 3-H2), 3.60 (2 H, m, OCH2CH2Si), 3.70 (1 H, m, 6-H),
added to the oxazolidinone 47 (157 mg, 0.24 mmol) in THF (1 mL) at 4.03 (2 H, m, 4-H, 7-H), 4.74 and 4.78 (each 1 H, d, J 6.9, OHCHO); δC
0
oC and the reaction mixture stirred at 0 oC for 5 h before the –4.5(2), −4.2, −3.9, −1.2, 17.6, 18.3, 18.4, 26.1, 28.5, 36.4, 65.5,
addition of aqueous sodium hydroxide (1.3 M, 1.8 mL, 2.34 mmol) 68.4, 69.4, 70.4, 80.0, 81.7 and 96.1; m/z (CI+) 534 (M+ + 18, 7%),
and warming to rt. After partitioning between ethyl acetate (40 mL) 517 (M+ + 1, 9), 459 (30) and 399 (100).
and brine (40 mL), extraction of the aqueous phase with ethyl Methyl
(5S,7R,8R)-5,8-bis-(tert-butyldimethylsilyloxy)-7-(2-
acetate (4 × 30 mL), drying the organic extracts (MgSO4) and trimethylsilylethoxymethoxy)non-2-ynoate (51). n-Butyllithium
concentration under reduced pressure, chromatography (1:5 then (10.16 mL, 1.60 M in hexanes, 16.25 mmol) was added to the alkyne
o
1:2 ether:light petroleum) of the residue gave the title compound 50 (7.63 g, 14.77 mmol) in THF (60 mL) at –78 C and the resulting
o
48 as a colourless viscous oil (91 mg, 70%), Rf = 0.33 (1:2 ether:light yellow solution stirred at –78 C for 45 min before the addition of
21
petroleum), [α]D −5.8 (c 0.9, CHCl3) (Found: M+ + H, 523.3663. methyl chloroformate (3.42 mL, 44.31 mmol). After stirring for 3.5 h
C25H59O5Si3 requires M, 523.3671); νmax/cm-1 3439, 2954, 2930, at −78 oC, saturated aqueous ammonium chloride (30 mL) was
2890, 2858, 1469, 1381, 1252, 1104, 1056, 1033, 835 and 775; added and the mixture warmed to rt. After partitioning between
δH 0.00 [9 H, s, Si(CH3)3], 0.04, 0.05, 0.08 and 0.10 (each 3 H, s, ether (300 mL) and water (300 mL), the aqueous layer was
4 × SiCH3), 0.80-0.95 (2 H, m, CH2Si), 0.87 and 0.88 [each 9 H, s, extracted with ether (2 × 250 mL) and the organic extracts were
SiC(CH3)3], 1.08 (3 H, d, J 6.3, 7-H3), 1.54-1.75 and 1.82-1.97 (each 2 washed with brine (300 mL), dried (MgSO4) and concentrated under
H, m, 2-H, 4-H), 2.46 (1 H, br. s, OH), 3.50-3.80 (4 H, m, 1-H, 5-H, reduced pressure. Chromatography (1:50 ether:light petroleum) of
OCH2CH2Si), 3.86 (1 H, m, 1-Hʹ), 4.00 (1 H, m, 6-H), 4.09 (1 H, m, 3- the residue gave the title compound 51 as a pale yellow oil (15.58 g,
21
H) and 4.69 and 4.70 (each 1 H, d, J 7.1, OHCHO); δC –4.8(2), −4.5, 92%), Rf = 0.26 (1:20 ether:light petroleum), [α]D +5.0 (c 6.3,
−1.5, 17.1, 17.8, 18.0, 18.1, 25.8, 35.7, 38.8, 59.9, 65.3, 69.1, 69.7, CHCl3) (Found: M++ NH4, 592.3864. C28H62NO6Si3 requires M,
79.8 and 95.3; m/z (CI+) 523 (M+ + 1, 12%) and 405 (100).
592.3885); νmax/cm-1 2954, 2930, 2892, 2858, 2241, 1721, 1471,
Dess-Martin periodinane (120 mg, 0.28 mmol) was added to the 1435, 1378, 1253, 1150, 1102, 1074, 1057, 1035, 861, 836, 810 and
alcohol 48 (77 mg, 0.14 mmol) in DCM (0.8 mL) and the suspension 776; δH 0.03 [9 H, s, Si(CH3)3], 0.06 (6 H, s, 2 × SiCH3), 0.09 and 0.12
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Organic & Biomolecular Chemistry
Page 16 of 26
ARTICLE
Journal Name
(each 3 H, s, SiCH3), 0.89 (18 H, s, 2 × SiC(CH3)3], 0.90 (2 H, m, 3438, 2955, 2928, 2898, 2857, 1464, 1416, 1378, 1252, 1104, 1057,
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CH2Si), 1.09 (3 H, d, J 6.3, 9-H3), 1.60 (1 H, ddd, J 14.2, 9.6, 4.0, 6-H), 1033, 836, 810 and 774; δH −0.05 [9 H, s, Si(DCOHI3:)130],.100.3090/C(67OHB,0s0,0726×F
1.85 (1 H, ddd, J 14.2, 8.1, 2.2, 6-Hʹ), 2.49 (1 H, dd, J 17.2, 5.4, 4-H), SiCH3), 0.03 and 0.04 (each 3 H, s, SiCH3), 0.79-0.92 [35 H, m,
2.57 (1 H, dd, J 17.2, 5.8, 4-Hʹ), 3.54 (2 H, m, OHCHCH2Si, 7-H), 3.68 3 × CH2CH3, CH2Si, 2 × SiC(CH3)3], 1.97 (3 H, d, J 6.2, 9-H3), 1.26-1.44
(1 H, m, OHCHCH2Si), 3.75 (3 H, s, OCH3), 4.04 (2 H, m, 5-H, 8-H), (14 H, m, 3 × CH2CH2, 6-H2), 1.86 (1 H, m, OH), 2.37 (1 H, dd, J 13.5,
4.69 and 4.73 (each 1 H, d, J 7.0, OHCHO); δC –5.0, −4.8, −4.6, −4.5, 8.3, 4-H), 2.57 (1 H, dd, J 13.5, 5.4, 4-Hʹ), 3.41 (1 H, m, OHCHCH2Si),
−1.6, 17.1, 17.9, 18.0, 25.7, 28.4, 36.3, 52.3, 65.3, 67.6, 68.8, 74.3, 3.40 (1 H, m, 7-H), 3.66 (1 H, m, OHCHCH2Si), 3.79 (1 H, m, 5-H),
79.5, 86.9, 95.6 and 154.0; m/z (CI+) 592 (M++ 18, 18%), 457 (47), 4.04 (2 H, m, 1-H, 8-H), 4.24 (1 H, dd, J 12.8, 6.2, 1-Hʹ), 4.62 and
329 (46) and 90 (100).
4.66 (each 1 H, d, J 7.0, OHCHO) and 5.81 (1 H, t, J 6.2, 2-H); δC –
Methyl (2E,5R,7R,8R)-5,8-Bis-(tert-butyldimethylsilyloxy)-3- 4.5(2), −4.1, −3.2, −1.2, 10.0, 13.9, 17.1, 18.4, 26.1, 26.3, 27.8, 29.3,
tributylstannyl-7-(2-trimethylsilylethoxymethoxy)non-2-enoate
35.3, 42.8, 59.7, 65.4, 69.0, 69.8, 80.4, 96.3, 128.6, 141.9 and 144.3;
(52). n-Butyllithium (1.60 M in hexanes, 43.84 mL, 70.15 mmol) was m/z (CI+) 839 (M+ + 1, 61%), 721 (33), 589 (46), 431 (78), 308 (55)
added to hexabutylditin (35.45 mL, 70.15 mmol) in THF (23 mL) at 0 and 90 (100).
o
oC. After stirring for 25 min at 0 C, the yellow solution was added (2E,5R,7R,8R)-1,5,8-Tris-(tert-butyldimethylsilyloxy)-3-
to a suspension of copper(I) bromide-dimethyl sulfide complex tributylstannyl-7-(2-trimethylsilylethoxymethoxy)non-2-ene (54).
o
(14.42 g, 70.15 mmol) in THF (43 mL) at –50 C. The black mixture The alcohol 53 (396 mg, 0.47 mmol) in DCM (0.65 mL) was added to
was stirred at –50 oC for 25 min then cooled to –78 oC over a period a stirred suspension of tert-butyldimethylsilyl chloride (85 mg, 0.56
o
of 30 min. The alkynoate 51 (8.06 g, 14.03 mmol) and methanol mmol) and imidazole (77 mg, 1.13 mmol) in DCM (0.7 mL) at 0 C
(0.97 mL, 23.85 mmol) in THF (14 mL) were added and the mixture and the reaction mixture warmed to rt before the addition of tetra-
stirred at –78 oC for 4 h before addition of further methanol (16 mL) n-butylammonium iodide (cat.) and 4-dimethylaminopyridine (cat.).
and warming to rt. After diluting with ether (200 mL), the reaction After stirring for 16 h, DCM (10 mL) was added, the mixture was
mixture was filtered through Celite® with copious ether washings filtered, more DCM (50 mL) was added and the mixture was washed
and the aqueous phase was extracted with ether (4 × 100 mL). The with brine (20 mL). The aqueous phase was extracted with DCM (20
organic extracts were washed with an equal volume of brine, dried mL) and the organic extracts were dried (MgSO4) and concentrated
(MgSO4)
and
concentrated
under
reduced
pressure. under reduced pressure. Chromatography (1:50 ether:light
Chromatography (1:70 ether:light petroleum + 1% triethylamine) of petroleum containing 1% triethylamine) of the residue gave the title
the residue gave the title compound 52 as a colourless oil (10.73 g, compound 54 as a colourless oil (436 mg, 97%), Rf = 0.85 (1:20
21
88%), Rf = 0.23 (1:20 ether:light petroleum), [α]D –16.4 (c 3.7, ether:light petroleum), [α]D19 –12.4 (c 3.7, CHCl3) (Found: M+ + NH4,
CHCl3) (Found: M+ − C4H9, 809.4058. C36H77O6Si3Sn requires M, 970.5998. C45H104NO5Si4Sn requires M, 970.6008); νmax/cm-1 2955,
809.4049); νmax/cm-1 2956, 2929, 2899, 2857, 1723, 1590, 1464, 2929, 2896, 2857, 1465, 1378, 1253, 1100, 1070, 836 and 774; δH
1433, 1378, 1252, 1169, 1104, 1078, 1055, 1033, 861, 836 and 775; 0.04 [9 H, s, Si(CH3)3], 0.08 (6 H, s, 2 × SiCH3), 0.09 (3 H, s, SiCH3),
δH –0.07 [9 H, s, Si(CH3)3], −0.04 (6 H, s, 2 × SiCH3), 0.00 and 0.04 0.11 (6 H, s, 2 × SiCH3), 0.12 (3 H, s, SiCH3), 0.91 [9 H, s, SiC(CH3)3],
(each 3 H, s, SiCH3), 0.79 and 0.80 [each 9 H, s, SiC(CH3)3], 0.81-0.94 0.92 [18 H, s, 2 × SiC(CH3)3], 0.90-0.95 (17 H, m, CH2Si, 3 × CH2CH3),
(20 H, m, 3 × CH2CH3, OCH2Si, 9-H3), 1.20-1.30 (7 H, m, 3 × CH2, 6- 1.05 (3 H, d, J 6.2, 9-H3), 1.30-1.55 (14 H, m, 6-H2, 3 × CH2CH2), 2.46
H), 1.35-1.40 (7 H, m, 3 × CH2, 6-Hʹ), 2.87 (1 H, dd, J 12.1, 7.0, 4-H), (2 H, m, 4-H2), 3.44 (1 H, m, OHCHCH2Si), 3.62 (1 H, m, 7-H), 3.75 (1
3.25 (1 H, dd, J 12.1, 9.5, 4-Hʹ), 3.34 (1 H, m, OHCHCH2Si), 3.53 (1 H, H, m, OHCHCH2Si), 3.84 (1 H, m, 5-H), 4.13 (1 H, pent, J 6.7, 8-H),
m, 7-H), 3.61 (3 H, s, OCH3), 3.64 (1 H, m, OHCHCH2Si), 3.93 (1 H, m, 4.34 (2 H, m, 1-H2), 4.69 and 4.73 (each 1 H, d, J 7.3, OHCHO) and
5-H), 3.99 (1 H, m, 8-H), 4.60 and 4.63 (each 1 H, d, J 7.3, OHCHO) 5.73 (1 H, t J 5.2, 2-H); m/z (ES+) 975.9 (M+ + 23, 100%).
and 5.92 (1 H, s, 2-H); δC −4.5(2), −4.1, −2.9, −1.2, 10.5, 13.9, 17.3, (2E,5R,7R,8R)-5,8-Bis-(tert-butyldimethylsilyloxy)-1-
18.3, 18.4(2), 26.2, 26.3, 27.7, 29.2, 35.6, 44.3, 51.1, 65.3, 69.1, triethylsilyloxy-3-tributylstannyl-7-(2-
69.2, 80.3, 96.6, 129.8, 164.7 and 169.4; m/z (CI+) 809 (M+ − 57, 13), trimethylsilylethoxymethoxy)non-2-ene (55). Triethylsilyl chloride
749 (20) and 90 (100).
(2E,5R,7R,8R)-5,8-Bis-(tert-butyldimethylsilyloxy)-3-
tributylstannyl-7-(2-trimethylsilylethoxymethoxy)non-2-en-1-ol
(0.22 ml, 1.31 mmol) was added to imidazole (172 mg, 2.53 mmol)
in dry DMF (1.7 mL) and the solution was cooled to 0 oC before the
alcohol 53 (707 mg, 0.84 mmol) in dry DMF (2.0 mL) was added. The
(53). Di-isobutylaluminium hydride (1.0 M in hexanes, 6.63 mL, 6.63 mixture was warmed to rt, tetra-n-butylammonium iodide (cat.)
mmol) was added to the ester 52 (1.91 g, 2.21 mmol) in THF (10.5 and 4-dimethylaminopyridine (cat.) were added and the mixture
mL) at –78 oC. After 1 h at −78 oC and 3 h at rt, the reaction mixture was stirred for 24 h then partitioned between ether (150 mL) and
was cooled to 0 oC and ether (15 mL) and saturated aqueous water (150 mL). The aqueous layer was extracted with ether
sodium potassium tartrate (7.5 mL) were added. After the solution (2 × 100 mL) and the organic extracts were washed with brine (100
became clear, further ether (100 mL) and water (100 mL) were mL), dried (MgSO4) and concentrated under reduced pressure.
added and the aqueous phase was extracted with ether (3 × 60 mL). Chromatography (1:60 then 1:10 ether:light petroleum + 1%
The organic extracts washed with brine (150 mL), dried (MgSO4) triethylamine) of the residue gave the title compound 55 as a
and concentrated under reduced pressure. Chromatography (1:10 colourless oil (775 mg, 97%), Rf = 0.71 (1:30 ether:light petroleum),
20
ether:light petroleum containing 1% triethylamine) of the residue [α]D
−12.6 (c 1.4, CHCl3) (Found: M+
+ NH4, 970.6000.
gave the title compound 53 as a colourless oil (1.53 g, 83%), Rf = C45H104NO5Si4Sn requires M, 970.6008); νmax/cm-1 2956, 2928, 2876,
21
0.13 (1:9 ether:light petroleum), [α]D –11.5 (c 7.0, CHCl3) (Found: 2857, 1463, 1415, 1377, 1250, 1101, 1070, 860, 835 and 774; δH
M+ + H, 839.4863. C39H87O5Si3Sn requires M, 839.4882); νmax/cm-1 0.04 [9 H, s, Si(CH3)3], 0.06 (6 H, s, 2 × SiCH3), 0.08 and 0.11 (each 3
16 | J. Name., 2012, 00, 1-3
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Page 17 of 26
OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
H, s, SiCH3), 0.65 (6 H, q, J 7.9, 3 × SiCH2CH3), 0.90 and 0.91 [each 9 (7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-tert-
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H, s, SiC(CH3)3], 0.92 (17 H, m, CH2Si, 3 × CH2CH3), 0.99 (9 H, t, J 7.9, butyldimethylsilyloxyethylidene]-2,2-dimetDhOylI-:11-0p.1h0e3n9y/Cls7uOlfBa0n0y0l7-96F-
3 × CH2CH3), 1.04 (3 H, d, J 6.3, 9-H3), 1.25-1.55 (14 H, m, 6-H2, (2-trimethylsilylethoxymethoxy)undecan-3-one (58). The enol
6 × CH2), 2.46 (2 H, m, 4-H2), 3.43 (1 H, m, OHCHCH2Si), 3.60 (1 H, acetate 8 (137 mg, 0.548 mmol) in dry toluene (0.54 mL) was added
m, 7-H), 3.74 (1 H, m, OHCHCH2Si), 3.83 (1 H, m, 5-H), 4.12 (1 H, m, to the bromide 56 (271 mg, 0.366 mmol) in dry toluene (0.54 mL) at
8-H), 4.33 (2 H, m, 1-H2), 4.68 and 4.72 (each 1 H, d, J 7.2, OHCHO) rt before a brief degassing (N2, 5 min). Tributyltin methoxide (0.17
and 5.73 (1 H, t, J 5.0, 2-H); δC −4.6, −4.5, −4.2, −3.1, −1.2, 4.8, 7.0, mL, 0.586 mmol) and PdCl2(o-tolyl3P)2 (26 mg, 0.033 mmol, 9 mol
o
9.9, 13.9, 17.0, 18.3(2), 18.4, 26.1, 26.2, 27.8, 29.4, 34.9, 43.7, 60.7, %) were added before heating under reflux (120 C) for 1 h. The
65.3, 68.9, 69.3, 80.3, 96.6, 140.6 and 143.5; m/z (ES+) 975.7 (M+ + resulting dark green solution was concentrated under reduced
23, 32%), 413.3 (26), 329.3 (84), 251.1 (60) and 99.9 (100).
(2E,5R,7R,8R)-3-Bromo-1,5,8-tris-(tert-butyldimethylsilyloxy)-7-(2-
pressure to approximately half its volume and chromatography
(gradual gradient from 1% triethylamine in light petroleum to 1:20
trimethylsilylethoxymethoxy)non-2-ene (56). The stannane 54 ether:light petroleum containing 1% triethylamine) gave the title
(436 mg, 0.46 mmol) in DCM (5.3 mL) was added to a suspension of compound 58 as a colourless viscous oil (254 mg, 80%), Rf = 0.69
N-bromosuccinimide (107 mg, 0.60 mmol) in DCM (3.2 mL) at rt. (1:10 ether:light petroleum), [α]D20 −10.9 (c 1.9, CHCl3) (Found: M+ +
After 1.5 h, concentration under reduced pressure and flash NH4, 886.5713. C45H92NO6Si4S requires M, 886.5717); νmax/cm-1
chromatography of the residue (1:100 to 1:20 ether:light 2954, 2930, 2890, 2857, 1709, 1584, 1468, 1440, 1407, 1383, 1253,
petroleum) gave the title compound 56 as a colourless oil (326 mg, 1148, 1100, 1058, 937, 836 and 776; δH 0.03 [9 H, s, Si(CH3)3], 0.05
19
96%), Rf = 0.38 (1:30 ether:light petroleum), [α]D +1.2 (c 6.1, (3 H, s, SiCH3), 0.06 and 0.07 (each 6 H, s, 2 × SiCH3), 0.08 (3 H, s,
CHCl3) (Found: M+ + NH4, 758.4050. C33H77O5N79BrSi4 requires M, SiCH3), 0.88, 0.89 and 0.90 [each 9 H, s, SiC(CH3)3], 0.94 (2 H, m,
758.4057); νmax/cm-1 2954, 2931, 2890, 2858, 1648, 1468, 1378, CH2Si), 1.05 (3 H, d, J 6.2, 11-H3), 1.27 (6 H, s, 2 × 2-CH3), 1.40 and
1254, 1102, 1054, 936, 836 and 776; δH −0.02 [9 H, s, Si(CH3)3], 0.02 1.57 (each 1 H, m, 8-H), 2.32 (2 H, m, 6-H2), 3.18 (2 H, s, 1-H2), 3.22
(12 H, s, 4 × SiCH3), 0.03 and 0.06 (each 3 H, s, SiCH3), 0.83, 0.84 and and 3.32 (each 1 H, d, J 17.0, 4-H), 3.45 (1 H, m, OHCHCH2Si), 3.54 (1
0.85 [each 9 H, s, SiC(CH3)3], 0.86 (2 H, m, CH2Si), 1.02 (3 H, d, J 6.2, H, m, 9-H), 3.70 (1 H, m, OHCHCH2Si), 3.88 (1 H, m, 7-H), 4.06 (1 H,
9-H3), 1.46 (1 H, ddd, J 14.4, 9.7, 4.4, 6-H), 1.64 (1 H, m, 6-Hʹ), 2.59 m, 10-H), 4.25 (2 H, m, 2ʹ-H2), 4.69 and 4.72 (each 1 H, d, J 7.3,
(2 H, d, J 6.3, 4-H2), 3.49 (1 H, m, 7-H), 3.60 (2 H, m, OCH2CH2Si), OHCHO), 5.37 (1 H, t, J 6.0, 1ʹ-H), 7.17 (1 H, m, ArH), 7.27 (2 H, m,
3.88 (1 H, m, 5-H), 4.04 (1 H, m, 8-H), 4.09 (1 H, dd, J 13.2, 6.0, 1-H), ArH) and 7.36 (2 H, m, ArH); δC −4.8, −4.5(2), −4.2, −3.5, −1.2, 17.4,
4.15 (1 H, dd, J 13.2, 6.9, 1-Hʹ), 4.66 and 4.70 (each 1 H, d, J 7.2, 18.2, 18.4, 18.6, 24.5, 24.6, 24.7, 26.1, 26.2, 35.8, 39.8, 44.3, 46.0,
OHCHO) and 6.03 (1 H, dd, J 6.9, 6.0, 2-H); δC –5.1, −4.6, −4.2, −3.9, 49.3, 60.4, 65.4, 68.8, 69.1, 80.6, 96.4, 126.4, 129.1, 129.8, 131.7,
−1.3, 17.4, 18.1, 18.2, 18.3, 18.5, 26.1, 36.2, 45.6, 60.8, 65.6, 68.9, 132.2, 137.6 and 211.6; m/z (APCI+) 890 (44%), 804 (87) and 391
69.2, 80.1, 95.9, 124.3 and 134.2; m/z (APCI+) 624 (12%) and 391 (100); (ES+) 805 (M+ − 63, 100%).
(100).
Dess-Martin periodinane (30 mg, 0.071 mmol) was added to a
(2E,5R,7R,8R)-3-Bromo-5,8-bis-(tert-butyldimethylsilyloxy)-1-
mixture of the epimeric alcohols 61 (20 mg, 0.023 mmol) in DCM
triethylsilyloxy-7-(2-trimethylsilylethoxymethoxy)non-2-ene (57). (0.12 mL) and the mixture stirred for 25 min. Saturated aqueous
Solid sodium hydrogen carbonate (122 mg, 1.45 mmol) was added sodium hydrogen carbonate (15 mL) and ether (15 mL) were added
to the stannane 55 (767 mg, 0.81 mmol) in DCM (9.0 mL) at rt and the aqueous phase extracted with ether (2 × 10 mL). The
followed by a slurry of N-bromosuccinimide (187 mg, 1.05 mmol) in organic extracts were dried (MgSO4) and concentrated under
DCM (7.0 mL). After stirring for 25 min, the mixture was partitioned reduced pressure. Chromatography (1:10 ether:light petroleum +
between ether (200 mL) and saturated aqueous sodium 1% triethylamine) of the residue gave the title compound 58 (18
bicarbonate (200 mL). The aqueous phase was extracted with ether mg, 90%).
(3 × 100 mL) and the ether extracts were dried (MgSO4) and (7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-
concentrated under reduced pressure. Chromatography (light triethylsilyloxyethylidene]-2,2-dimethyl-1-phenylsulfanyl-9-(2-
petroleum then 1:30 ether:light petroleum + 1% triethylamine) of trimethylsilylethoxymethoxy)undecan-3-one (59). Following the
the residue gave the title compound 57 as a colourless oil (547 mg, procedure used to prepare the undecanone 58, the vinylic bromide
21
92%), Rf = 0.57 (1:30 ether:light petroleum), [α]D −0.8 (c 1.0, 57 (73 mg, 0.99 mmol), the enol acetate 8 (39 mg, 0.16 mmol),
CHCl3) (Found: M+ + NH4, 758.4063. C33H77N79BrO5Si4 requires M, tributyltin methoxide (46 μL, 0.16 mmol) and PdCl2(o-tolyl3P)2 (8
758.4057); νmax/cm-1 2955, 2932, 2882, 2859, 1648, 1466, 1413, mg, 0.01 mmol), after chromatography (1:20 ether:light petroleum
1379, 1253, 1102, 1055, 835 and 776; δH 0.05 [9 H, s, Si(CH3)3], 0.10 + 1% triethylamine) gave the title compound 59 as a colourless oil
(6 H, s, 2 × SiCH3), 0.12 and 0.13 (each 3 H, s, SiCH3), 0.64 (6 H, q, J (69 mg, 80%), Rf = 0.39 (1:10 ether:light petroleum), [α]D21 −13.3 (c
8.0, 3 × SiCH2CH3), 0.89 (2 H, m, CH2Si), 0.90 and 0.92 [each 9 H, 2.1, CHCl3) (Found: M+ + NH4, 886.5720. C45H92NO6SSi4 requires M,
s, SiC(CH3)3], 0.99 (9 H, t, J 8.0, 3 × SiCH2CH3), 1.09 (3 H, d, J 6.3, 9- 886.5717); νmax/cm-1 2956, 2930, 2879, 2858, 1711, 1585, 1472,
H3), 1.52 and 1.70 (each 1 H, m, 6-H), 2.71 (2 H, d, J 6.3, 4-H2), 3.56 1461, 1413, 1384, 1250, 1147, 1102, 1058, 938, 836, 810, 775 and
(1 H, m, 7-H), 3.68 (2 H, m, 8-H, OHCHCH2Si), 4.01-4.25 (4 H, m, 5-H, 740; δH 0.03 [9 H, s, Si(CH3)3], 0.05 (3 H, s, SiCH3), 0.06 (6 H, s,
OHCHCH2Si, 1-H2), 4.73 and 4.77 (each 1 H, d, J 7.2, OHCHO) and 2 × SiCH3), 0.08 (3 H, s, SiCH3), 0.62 (6 H, q, J 8.0, 3 × SiCH2CH3),
6.10 (1 H, t, J 6.5, 2-H); δC −4.5, −4.2, −3.9, −1.2, 4.6, 7.0, 17.5, 18.1, 0.88 (2 H, m, CH2Si), 0.89 [18 H, s, 2 × SiC(CH3)3], 0.97 (9 H, t, J 8.0, 3
18.3, 18.4, 26.1(2), 36.2, 45.7, 60.4, 65.7, 69.0, 69.2, 80.2, 96.0, × SiCH2CH3) 1.05 (3 H, d, J 6.1, 11-H3), 1.27 (6 H, s, 2 × 2-CH3), 1.41
124.6 and 134.2; m/z (APCI+) 740, 738 (M+, 40%), 665, 663 (72), and 1.56 (each 1 H, m, 8-H), 2.29 (1 H, dd, J 13.8, 8.1, 6-H), 2.37 (1
624, 622 (68), 510 (43) and 329 (100).
H, dd, J 13.8, 5.6, 6-Hʹ), 3.18 (2 H, s, 1-H2), 3.28 and 3.33 (each 1 H,
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Organic & Biomolecular Chemistry
Page 18 of 26
ARTICLE
Journal Name
d, J 17.0, 4-H), 3.46 (1 H, m, OHCHCH2Si), 3.54 (1 H, m, 9-H), 3.71 (1 s, Si(CH3)3], 0.02 (6 H, s, 2 × SiCH3), 0.07 (9 H, s, 3 × SiCH3), 0.09 (3 H,
View Article Online
DOI: 10.1039/C7OB00076F
H, m, OHCHCH2Si) 3.89 (1 H, m, 7-H), 4.06 (1 H, m, 10-H), 4.25 (2 H, s, SiCH3), 0.89, 0.90 and 0.92 [each 9 H, s, SiC(CH3)3], 0.94 (2 H, m,
m, 2ʹ-H2), 4.69 and 4.72 (each 1 H, d, J 7.5, OHCHO), 5.39 (1 H, t, J CH2Si), 1.04 and 1.05 (each 3 H, s, 2 × 2-CH3), 1.06 (3 H, d, J 6.2, 11-
5.9, 1ʹ-H), 7.18 (1 H, m, ArH), 7.28 (2 H, m, ArH) and 7.37 (2 H, m, H3), 1.40-1.70 (2 H, m, 8-H2), 1.93 (0.45 H, dd, J 13.3, 11.7, 4-H),
ArH); δC −4.5, −4.2, −3.5, −1.2, 4.7, 7.1, 17.3, 18.3, 18.4, 24.6, 24.7, 2.01 (0.55 H, J 13.3, 11.3, 4-H), 2.15-2.45 (3 H, m, 4-Hʹ, 6-H2), 2.97
26.1, 26.2, 35.8, 39.8, 44.3, 46.0, 49.3, 60.0, 65.4, 68.7, 69.1, 80.6, (0.55 H, d, J 12.1, 1-H), 2.99 (0.45 H, d, J 12.1, 1-H), 3.53 (1 H, d, J
96.4, 126.3, 129.1, 129.8, 131.8, 132.1, 137.6 and 211.5; m/z (APCI+) 12.1, 1-Hʹ), 3.44 (1 H, m, OHCHCH2Si), 3.55 (1 H, m, 9-H), 3.69 (2 H,
886 (M+ + 18, 4%), 869 (M+, 10), 737 (38), 619 (34) and 209 (100).
(7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-
hydroxyethylidene]-2,2-dimethyl-1-phenylsulfanyl-9-(2-
m, 3-H, OHCHCH2Si), 3.92 (2 H, m, 7-H, OH), 4.07 (1 H, m, 10-H),
4.26 (2 H, d, J 5.9, 2ʹ-H2), 4.69 (0.9 H, s, OCH2O), 4.70 and 4.73 (each
0.55 H, d, J 6.9, OCH2O), 5.51 (0.45 H, t, J 5.9, 1ʹ-H), 5.52 (0.55 H, t, J
trimethylsilylethoxymethoxy)undecan-3-one
fluoride-pyridine complex (1.2 M in dry THF, 128 μL, 0.2 mmol) and ArH); δC −4.9, −4.5(2), −3.7, −3.5, −3.4, −1.2, 17.3, 18.2, 18.3(2),
pyridine (7 μL) were added to the tris-(tert- 18.4, 18.6, 22.3, 22.5, 23.9, 26.1, 26.2, 35.6, 35.7, 39.2, 39.3, 39.6,
(60).
Hydrogen 5.9, 1ʹ-H), 7.16 (1 H, m, ArH), 7.27 (2 H, m, ArH) and 7.37 (2 H, m,
butyldimethylsilyloxy)sulfone 58 (29 mg, 0.033 mmol) in THF (0.1 40.5, 44.7, 60.2, 60.5, 65.5(2), 68.6, 69.0, 69.4, 73.4, 73.8, 77.3,
mL) and the solution stirred for 20 h at rt. Ethyl acetate (20 mL) was 80.5, 80.8, 96.4, 125.8, 128.9, 129.0, 129.1, 129.2, 131.7, 131.9,
added and the solution washed with saturated aqueous sodium 135.0, 135.4, 138.4(2) and 142.2; m/z (ES+) 893.7 (M+ + 23, 100%)
bicarbonate (20 mL) and brine (10 mL). The aqueous phase was and 889 (M+ + 18, 69%).
extracted with ethyl acetate (2 × 10 mL) and the organic extracts
A aqueous pH 7 buffer (7 µL) was added to the 4-
dried (MgSO4) and concentrated under reduced pressure. methoxybenzyl ether 62 (19 mg, 0.019 mmol) in DCM (0.12 mL)
Chromatography (1:20 then 1:2 ether:light petroleum) of the followed by dichlorodicyanoquinone (5 mg, 0.023 mmol). After
residue gave the title compound 60 as a colourless oil (13 mg, 52%), stirring for 35 min, more pH 7 buffer (1.0 mL) and DCM (30 mL)
21
Rf = 0.36 (1:1 ether:light petroleum), [α]D −8.9 (c 1.3, CHCl3) were added and the organic phase was washed with pH 7 buffer
(Found: M+ + NH4, 772.4848. C39H78NO6SSi3 requires M, 772.4852); (5 × 15 mL) and brine, then dried (Na2SO4) and concentrated under
νmax/cm-1 3442, 2955, 2930, 2892, 2857, 1706, 1584, 1468, 1440, reduced pressure. Chromatography of the residue (1:15
1408, 1383, 1252, 1147, 1102, 1057, 1032, 936, 835 and 775; δH ether:hexane + 1% triethylamine) gave the title compound 61 as a
0.01 [9 H, s, Si(CH3)3], 0.04 (3 H, s, SiCH3), 0.05 (6 H, s, 2 × SiCH3) and colourless viscous oil (17 mg, ca. 100%).
0.06 (3 H, s, SiCH3), 0.87 and 0.88 [each 9 H, s, SiC(CH3)3], 0.90 (2 H, (3RS,7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-(tert-
m, CH2Si), 1.05 (1 H, d, J 6.3, 11-H3), 1.26 (6 H, s, 2 × 2-CH3), 1.45 (1 butyldimethylsilyloxyethylidene]-2,2-dimethyl-1-phenylsulfanyl-9-
H, m, 8-H), 1.65 (1 H, m, 8-Hʹ), 1.96 (1 H, br. s, OH), 2.29 and 2.48 (2-trimethylsilylethoxymethoxy)-3-(4-
(each 1 H, dd, J 14.0, 6.5, 6-H), 3.16 (2 H, s, 1-H2), 3.26 and 3.35 methoxybenzyloxy)undecane (62). The mixture of epimeric
(each 1 H, d, J 16.8, 4-H), 3.47 (2 H, m, 9-H, OHCHCH2Si), 3.68 (1 H, alcohols 61 (103 mg, 0.12 mmol) in dry DMF (0.30 mL) was added to
m, OHCHCH2Si), 3.90 (1 H, m, 7-H), 4.05 (2 H, m, 10-H, 2ʹ-H), 4.21 (1 a suspension of sodium hydride (60 wt % dispersion in mineral oil,
H, dd, J 12.6, 6.9, 2ʹ-Hʹ), 4.70 (2 H, s, OCH2O), 5.53 (1 H, t, J 6.9, 1ʹ- 47 mg, 1.18 mmol) in dry DMF (0.24 mL) at 0 oC and the suspension
H), 7.17 (1 H, m, ArH), 7.26 (2 H, m, ArH) and 7.35 (2 H, m, ArH); δC warmed to rt and stirred for 20 min before cooling to 0 oC. 4-
−4.5, −4.2, −3.6, −1.2, 1.3, 17.4, 18.3(2), 18.4, 24.7, 26.2(2), 30.0, Methoxybenzyl chloride (48 µL, 0.35 mmol) was added and the
36.2, 39.3, 44.4, 46.2, 49.4, 59.2, 65.6, 69.3, 69.4, 80.5, 96.1, 124.2, mixture warmed to rt before the addition of tetra-n-
126.5, 129.2, 129.9, 131.2, 134.8 and 211.6; m/z (APCI+) 755 (M+ + butylammonium iodide (cat.). After stirring for 2 h, saturated
o
1, 100%) and 737 (80).
aqueous ammonium chloride (0.3 mL) was added at 0 C, and the
Following this procedure, the triethylsilyl ether 59 (21 mg, 0.024 mixture partitioned between ether (40 mL) and water (40 mL). The
mmol) with the hydrogen fluoride-pyridine complex for 1 h at rt aqueous phase was extracted with ether (3 × 30 mL) and the ether
gave the title compound 60 (14 mg, 78%).
(3RS,7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-tert-
extracts were washed with brine (50 mL), dried (MgSO4) and
concentrated under reduced pressure. Chromatography (1:40 then
butyldimethylsilyloxyethylidene]-2,2-dimethyl-1-phenylsulfanyl-9- 1:20 ether:light petroleum) of the residue gave the title compound
(2-trimethylsilylethoxymethoxy)undecan-3-ol (61). Lithium 62 as a colourless oil (64 mg, 55%), a mixture of epimers, Rf =
triethylborohydride (1.0 M in THF, 0.53 mL, 0.53 mmol) was added 0.70/0.72 (1:4 ether:light petroleum), [α]D −11.8 (c 1.9, CHCl3)
to the ketone 58 (311 mg, 0.358 mmol) in THF (1.0 mL) at 0 oC and (Found: M+
NH4, 1008.6457. C53H102NO7SSi4 requires M,
21
+
the solution stirred at rt for 16 h. Methanol (3 mL) was added and 1008.6449); νmax/cm-1 2954, 2930, 2895, 2857, 1613, 1586, 1513,
the mixture stirred for 15 min before being partitioned between 1466, 1383, 1300, 1249, 1174, 1092, 1062, 1039, 835 and 725; δH
ether (50 mL) and brine (50 mL). The aqueous layer was extracted 0.02 [9 H, s, Si(CH3)3], 0.08 (6 H, s, 2 × SiCH3), 0.09 (12 H, s,
with ether (3 × 30 mL) and the organic extracts dried (MgSO4) then 4 × SiCH3), 0.88, 0.90 and 0.91 [each 9 H, s, SiC(CH3)3], 0.92 (2 H, m,
concentrated under reduced pressure. Chromatography (1:15 then CH2Si), 1.05 (6 H, s, 2 × 2-CH3), 1.06 (3 H, d, J 5.6, 11-H3), 1.45-1.65
1:10 ether:hexane) of the residue gave the title compound 61 as a (2 H, m, 8-H2), 2.10-2.50 (4 H, m, 4-H2, 6-H2), 2.95 (1 H, d, J 11.8, 1-
colourless viscous oil (218 mg, 70%), a 55:45 mixture of epimers, Rf H), 3.14 (0.55 H, J 11.8, 1-Hʹ), 3.19 (0.45 H, J 11.8, 1-Hʹ), 3.45 (1 H,
21
= 0.46/0.50 (1:10 ether:light petroleum), [α]D −4.9 (c 1.8 , CHCl3) m, OHCHCH2Si), 3.57 (2 H, m, 3-H, 9-H), 3.72 (1 H, m, OHCHCH2Si),
(Found: M+ + NH4, 888.5869. C45H94NO6SSi4 requires M, 888.5873); 3.80 (3 H, s, OCH3), 3.94 (1 H, m, 7-H), 4.09 (1 H, dq, J 6.0, 5.7, 10-
νmax/cm-1 3484, 2954, 2930, 2917, 2899, 1657, 1585, 1471, 1439, H), 4.26 (2 H, m, 2ʹ-H2), 4.35 and 4.37 (each 0.45 H, d, J 10.4,
1380, 1252, 1189, 1147, 1101, 1058, 937, 836 and 775; δH 0.01 [9 H, ArHCH), 4.57 and 4.60 (each 0.55 H, d, J 10.1, ArHCH), 4.68 (0.9 H, s,
18 | J. Name., 2012, 00, 1-3
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Page 19 of 26
OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
OCH2O), 4.74 (1.1 H, s, OCH2O), 5.62 (1 H, t, J 6.1, 1ʹ-H), 6.82 (2 H, d, (3 × 10 mL), the organic extracts were dried (MgSO4) and
View Article Online
DOI: 10.1039/C7OB00076F
J 8.5, ArH) and (7 H, m, ArH); δC −4.9, −4.5(2), −4.1, −4.0, −3.5, −3.2, concentrated under reduced pressure. Chromatography (1:10,
−1.2, 17.4(2), 18.3(2), 18.4, 18.7, 23.1, 23.2, 24.3, 24.5, 26.1, 26.2, ether:light petroleum) of the residue gave the title compound 64 as
26.3, 35.5, 35.9, 38.4, 39.0, 39.8, 40.6, 40.7, 41.3, 44.6, 55.5, 60.4, a colourless oil (14 mg, 70%), Rf = 0.15 (1:10 ether:light petroleum),
60.6, 65.4, 68.7, 68.9, 69.2, 74.5, 74.6, 80.6, 82.7, 84.6, 96.4(2), [α]D22 +2.3 (c 0.7, CHCl3) (Found: M+ + NH4, 756.4905. C39H78NO5SSi3
113.8, 125.7, 129.0(2), 129.7, 129.9, 130.4, 130.5, 131.4, 131.5, requires M, 756.4903); νmax/cm-1 3580, 3472, 2955, 2930, 2890,
135.5, 135.8, 138.5, 159.1 and 159.2; m/z (ES+) 1013.7 (M+ + 23, 2857, 1709, 1584, 1468, 1440, 1385, 1365, 1255, 1069, 836, 776
100%).
and 739; δH 0.08 (12 H, s, 4 × SiCH3), 0.09 and 0.10 (each 3 H, s,
SiCH3), 0.89 and 0.90(2) [each 9 H, s, SiC(CH3)3], 1.13 (3 H, d, J 6.2,
(3RS,7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-tert-
butyldimethylsilyloxyethylidene]-2,2-dimethyl-1-phenylsulfonyl-9- 11-H3), 1.27 and 1.28 (each 3 H, s, 2-CH3), 1.29 and 1.50 (each 1 H,
(2-trimethylsilylethoxymethoxy)-3-(4- m, 8-H), 2.29 (1 H, dd, J 14.0, 8.1, 6-H), 2.38 (1 H, dd, J 14.0, 6.2, 6-
methoxybenzyloxy)undecane (63). Solid sodium hydrogen Hʹ), 2.48 (1 H, d, J 5.0, OH), 3.18 (2 H, s, 1-H2), 3.22 and 3.33 (each 1
carbonate (5 mg, 0.060 mmol) and mCPBA (9.5 mg, 0.038 mmol) H, d, J 16.6, 4-H), 3.50 (1 H, m, 7-H), 3.60 (1 H, m, 10-H), 4.04 (1 H,
were added to the mixture of epimeric sulfides 62 (19 mg, 0.019 m, 9-H), 4.25 (2 H, d, J 6.1, 2ʹ-H2), 5.38 (1 H, t, J 6.1, 1ʹ-H), 7.19 (1 H,
mmol) in DCM (0.10 mL) and the mixture stirred for 25 min before m, ArH), 7.28 (2 H, m, ArH) and 7.37 (2 H, m, ArH); δC −5.0(2),
the addition of saturated aqueous sodium thiosulfate (0.4 mL). −4.7(2), −4.0(2), 1.2, 18.1, 18.4, 20.0, 24.4, 24.5, 25.9, 26.0, 26.1,
After 15 min, the suspension had dispersed to give a clear solution 29.8, 39.5, 40.3, 44.2, 45.9, 49.1, 60.1, 68.6, 72.0, 72.1, 126.1,
that was partitioned between DCM (20 mL) and water (20 mL). The 128.8, 129.6, 129.7, 131.3, 132.0 and 211.1; m/z (APCI-) 737 (M+
aqueous phase was extracted with DCM (3 × 10 mL) and the organic − 1, 27%), 606 (92), 473 (70) and 417 (100).
extracts were washed with saturated aqueous sodium bicarbonate (2E,5R,7R,8R)-1-tert-Butyldiphenylsilyloxy-5,8-bis-(tert-
(20 mL), dried (Na2SO4) and concentrated under reduced pressure. butyldimethylsilyloxy)-3-tributylstannyl-7-(2-
Chromatography (1:10 ether:light petroleum + 1% triethylamine) of trimethylsilylethoxymethoxy)non-2-ene (65). The alcohol 53 (3.97
the residue gave the title compound 63 as a colourless oil (15 mg, g, 4.74 mmol) in DCM (12 mL) was added to a tert-butyldiphenylsilyl
77%), a mixture of epimers, Rf = 0.26/0.28 (1:4 ether:light chloride (1.69 g, 6.15 mmol) and imidazole (0.84 g, 12.34 mmol) in
o
petroleum), [α]D20 −10.7 (c 1.5, CHCl3) (Found: M+ + NH4, 1040.6358. DCM (12 mL) at 0 C and the reaction mixture stirred at rt for 3 h.
C53H102NO9SSi4 requires M, 1040.6347); νmax/cm-1 2954, 2930, 2890, After dilution with DCM (30 mL), the mixture was filtered through
2857, 1613, 1587, 1514, 1467, 1386, 1318, 1251, 1150, 1088, 1060, Celite and the residue washed with DCM (60 mL). The filtrate and
937, 836 and 775; δH (400 MHz) 0.01 [9 H, s, Si(CH3)3], 0.02, 0.03, DCM washings were washed with brine (25 mL) and the aqueous
0.05, 0.06(2) and 0.07 (each 3 H, s, SiCH3), 0.88(2) and 0.89 [each 9 phase was extracted with DCM (50 mL). The organic extracts were
H, s, SiC(CH3)3], 0.90 (2 H, CH2Si), 1.03 (3 H, d, J 6.2, 11-H3), 1.20 dried (MgSO4) and concentrated under reduced pressure.
(1.65 H, s, 2-CH3), 1.25 (1.35 H, s, 2-CH3), 1.33 (1.65 H, s, 2-CH3ʹ), Chromatography (1 : 50 ether:light petroleum containing 1%
1.38 (1.35 H, s, 2-CH3ʹ), 1.50 (2 H, m, 8-H2), 2.03 (0.45 H, dd, J 14.0, triethylamine) of the residue gave the title compound 65 as a
9.8, 4-H), 2.10 (0.55 H, dd, J 13.8, 9.5, 4-H), 2.30-2.50 (3 H, m, 4-Hʹ, colourless oil (5.16 g, ca. 100%), Rf = 0.5 (1 : 30 ether:light
6-H2), 2.98 (0.45 H, d, J 14.0, 1-H), 3.00 (0.55 H, d, J 14.0, 1-H), 3.28 petroleum), [α]D20 –18.1 (c 3.1, CHCl3) (Found: M+ + Na, 1099.5885.
(0.55 H, d, J 14.0, 1-Hʹ), 3.30 (0.45 H, d, J 14.0, 1-Hʹ), 3.45 (1 H, m, C55H104O5NaSi4Sn requires M, 1099.5875); νmax/cm-1 2955, 2928,
HCHCH2Si), 3.55 (2 H, m, 3-H, 9-H), 3.70 (1 H, m, HCHCH2Si), 3.80 (3 2895, 2856, 1462, 1250, 1106, 1069, 834 and 773; δH 0.00 and 0.01
H, s, OCH3), 3.90 (1 H, m, 7-H), 4.08 (1 H, m, 10-H), 4.23 (2 H, m, 2ʹ- (each 3 H, s, SiCH3), 0.04 [9 H, s, Si(CH3)3], 0.05 and 0.06 (each 3 H, s,
H2), 4.38 (0.55 H, d, J 10.4, ArHCH), 4.39 (0.45 H, d, J 8.5, ArHCH), SiCH3), 0.80-1.06 (17 H, m, 3 × CH2CH3, CH2Si), 0.86 and 0.88 [each 9
4.56 (0.45 H, J 8.5, ArHCH), 4.60 (0.55 H, J 10.4, ArHCH), 4.70 (0.9 H, H, s, SiC(CH3)3], 1.00 (3 H, d, J 6.3, 9-H3), 1.12 [9 H, s, SiC(CH3)3],
s, OCH2O), 4.71 and 4.73 (each 0.55 H, d, J 7.0, OHCHO), 5.55 (0.45 1.14-1.62 (14 H, m, 3 × SnCH2CH2, 6-H2), 2.20-2.43 (2 H, m, 4-H2),
H, t, J 6.5, 1ʹ-H), 5.58 (0.55 H, t, J 6.3, 1ʹ-H), 6.80 and 7.20 (each 2 H, 3.45 (1 H, m, OHCHCH2Si), 3.56 (1 H, m, 5-H), 3.68-3.82 (2 H, m, 7-H,
d, J 8.5, ArH), 7.53 (2 H, m, ArH), 7.63 (1 H, m, ArH) and 7.85 (2 H, OHCHCH2Si), 4.09 (1 H, m, 8-H), 4.30-4.44 (2 H, m, 1-H2), 4.60 and
m, ArH); δC (100 MHz) −5.2, −4.8, −4.7, −4.4, −4.3, −3.8, −3.6, −1.4, 4.70 (each 1 H, d, J 7.0, OHCHO), 5.82 (1 H, t, J 5.1, 2-H), 7.35-7.48
17.0, 17.1, 18.0(2), 18.1, 18.4, 23.3(2), 24.5, 24.7, 25.9, 26.0, 29.4, (6 H, m, ArH) and 7.65-7.77 (4 H, m, ArH); δC –4.5(2), −4.2, −3.1,
29.7, 35.3, 35.6, 37.9, 38.4, 39.5, 40.6, 40.7, 41.0, 55.2, 60.1, 60.2, −1.2, 10.0, 14.0, 17.2, 18.3, 18.4, 19.5, 22.9, 26.2, 26.3, 27.1, 27.8,
62.8, 62.9, 65.2, 68.5, 68.7, 68.8, 74.2, 74.3, 80.2, 80.3, 84.0, 85.3, 29.4, 35.0, 43.5, 61.6, 65.2, 69.0, 69.4, 80.4, 96.5, 127.9(2), 129.8,
96.1, 96.2, 113.6, 127.4, 129.1, 129.5, 129.6, 130.6, 130.8, 133.2, 134.3, 135.9(2), 140.9 and 142.9; m/z (APCI+) 1099 (M+ + 23, 100%).
134.8, 134.9, 142.1 and 159.0; m/z (ES+) 1045.8 (M+ + 23, 63%), (2E,5R,7R,8R)-3-Bromo-1-tert-butyldiphenylsilyloxy-5,8-bis-(tert-
1040.9 (M+ + 18, 41), 391.4 (28) and 129.9 (100).
butyldimethylsilyloxy)-7-(2-trimethylsilylethoxymethoxy)non-2-
(7S,9R,10R)-7,10-Bis-(tert-butyldimethylsilyloxy)-5-[(E)-2-tert-
ene (66). N-Bromosuccinimide (1.07 g, 6.01 mmol) was added to
butyldimethylsilyloxyethylidene]-2,2-dimethyl-1-phenylsulfanyl-9- the stannane 65 (5.0 g, 4.64 mmol) in DCM (35 mL) at rt and the
hydroxyundecan-3-one (64). Solid potassium carbonate (39 mg, mixture stirred for 2 h. After concentration under reduced pressure,
0.282 mmol), solid MgBr2.Et2O (59 mg, 0.229 mmol) and n- chromatography (1 : 50 ether:light petroleum containing 1%
butanethiol (25 µL, 0.233 mmol) were added to the SEM ether 58 triethylamine) of the residue gave the title compound 66 as a
(24 mg, 0.028 mmol) in dry ether (0.45 mL) at rt and the suspension colourless oil (3.89 g, 97%), Rf = 0.62 (1 : 10 ether:light petroleum),
was stirred for 10 min before the addition of water (15 mL) and [α]D20 +0.8 (c 2.1, CHCl3) (Found: M+ + Na, 887.3928. C43H77O579BrSi4
ether (15 mL). After extraction of the aqueous phase with ether requires M, 887.3924); νmax/cm-1 3072, 3052, 2954, 2930, 2892,
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
2858, 1649, 1471, 1463, 1428, 1378, 1251, 1108, 1074, 1055, 835 61.2, 65.4, 68.8, 69.2, 80.6, 96.4, 114.6, 127.9, 128.0, 128.6, 129.8,
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+
DOI: 10.1039/C7OB00076F
and 776; δH 0.05 [9 H, s, Si(CH3)3], 0.06, 0.07, 0.08 and 0.09 (each 3 131.5, 132.2, 134.1, 135.8, 135.9, 142.8 and 210.7; m/z (ES ) 919
H, s, SiCH3), 0.85 and 0.90 [each 9 H, s, SiC(CH3)3], 0.90-1.02 (2 H, m, (M+ + 23, 100%). The second fraction was (8S,10R,11R)-8,11-bis-
CH2Si), 1.05 (3 H, d, J 6.3, 9-H3), 1.08 [9 H, s, SiC(CH3)3], 1.44 and (tert-butyldimethylsilyloxy)-6-[(E)-2-tert-
1.60 (each 1 H, m, 6-H), 2.47 (2 H, d, J 6.3, 4-H2), 3.48-3.76 (3 H, m, butyldiphenylsilyloxyethylidene]-3,3-dimethyl-10-(2-
7-H, OCH2CH2Si), 3.95-4.10 (2 H, m, 5-H, 8-H), 4.14-4.28 (2 H, m, 1- trimethylsilylethoxymethoxy)dodec-4-en-2-one 69 (1.3 g, 38%); δH
H2), 4.65 and 4.75 (each H, d, J 7.0, OHCHO), 6.13 (1 H, t, J 6.6, 2-H), −0.03 and −0.02 (each 3 H, s, SiCH3), 0.03 [9 H, s, Si(CH3)3], 0.04 and
7.38-7.58 (6 H, m, ArH) and 7.67-7.74 (4 H, m, ArH); δC –4.6, −4.3, 0.05 (each 3 H, s, SiCH3), 0.75 and 0.88 [each 9 H, s, SiC(CH3)3], 0.90-
−4.0, −1.3, 17.4, 18.0, 18.2, 19.3, 26.0, 26.9, 36.1, 45.4, 61.4, 65.5, 0.94 (2 H, m, CH2Si), 0.98 (3 H, d, J 6.3, 12-H3), 1.08 [9 H, s,
68.7, 69.2, 80.0, 95.8, 124.6, 127.8, 129.8, 133.4, 133.7 and 135.7; SiC(CH3)3], 1.29 (6 H, s, 2 × 3-CH3), 1.45-1.70 (2 H, m, 9-H2), 2.15 (3
m/z (APCI+) 889, 887 (M+ + 23, 100%).
H, s, 1-H3), 2.23 (1 H, dd, J 13.5, 7.9, 7-H), 2.34 (1 H, dd, J 13.5, 6.7,
3,3-Dimethyl-2-acetoxypenta-1,4-diene (67). Isopropenyl acetate 7-Hʹ), 3.42 (1 H, m, OHCHCH2Si), 3.49 (1 H, m, 8-H), 3.68 (1 H, m,
(5.9 mL, 53.6 mmol) and toluene p-sulfonic acid monohydrate (120 OHCHCH2Si), 3.75 (1 H, m, 10-H), 4.10 (1 H, m, 11-H), 4.37-4.43 (2 H,
mg, 0.63 mmol) were aded to 3,3-dimethylpent-4-en-2-one (3.0 g, m, 2ʹ-H2), 4.63 (2 H, s, OCH2O), 5.72 (1 H, d, J 16.1, 4-H), 5.75 (1 H, t,
o
26.7 mmol) and the mixture heated under reflux (120 C) for 24 h. J 6.2, 1ʹ-H), 6.08 (1 H, d, J 16.1, 5-H), 7.35-7.50 (6 H, m, ArH) and
After addition of more isopropenyl acetate (6.0 mL, 18.29 mmol), 7.67-7.75 (4 H, m, ArH); m/z (APCI+) 919 (M+ + 23, 30%), 779 (30)
the solution was heated under reflux for a further 24 h. More and 667 (100).
isopropenyl acetate (6.0 mL, 18.29 mmol) was then added and the (3R,4R)-4-tert-Butyldiphenylsilyloxy-3-(2-
heating under reflux continued for 66 h. After cooling to rt, the trimethylsilylethoxymethoxy)pentanoic
acid
mixture was diluted with ether (100 mL) and washed with saturated methoxymethylamide (70). Trimethylaluminium (2 M, 61.5 mL, 31
aqueous sodium bicarbonate (100 mL). The aqueous washing was mmol) was added to N,O-dimethylhydroxylamine (11.99 g, 123
extracted with ether (3 × 100 mL) and the organic extracts were mmol) in DCM (1200 mL) at 0 °C and the mixture allowed to warm
dried (MgSO4) and concentrated under reduced pressure. to rt over 40 min then stirred for 1 h. The lactone 34 (15.13 g, 61.5
Chromatography (1:30 ether : pentane) of the residue gave the title mmol) in DCM (300 mL) was added and the mixture stirred at rt for
compound 67 as a pale yellow oil (2.01 g, 49%), Rf = 0.33 (1:10 ether 2 h before cooling to 0 °C. A pH 8.0 aqueous buffer and DCM were
: light petroleum) (Found: M+ + H, 155.1072. C9H15O2 requires M, added and the aqueous layer extracted with DCM. The organic
155.1072); νmax/cm-1 2975, 2934, 1765, 1651, 1464, 1415, 1370, extracts were washed with brine, dried (MgSO4) and concentrated
1205, 1134, 1019, 917 and 883; δH 1.22 (6 H, s, 2 × 3-CH3)2), 2.18 [3 under reduced pressure to afford the Weinreb amide 35 (18.1 g).
H, s, C(O)CH3], 4.74 and 4.96 (each 1 H, d, J 2.1, 1-H), 5.06 (1 H, dd, J This was azeotroped with benzene and dried under high vacuum,
10.5, 1.0, 5-H), 5.09 (1 H, dd, J 17.0, 1.0, 5-Hʹ) and 5.87 (1 H, dd, J before adding as a solution in DCM (30 mL) to imidazole (12.55 g,
17.0, 10.5, 4-H); δC 21.3, 25.2, 42.4, 101.1, 112.7, 144.3, 160.3 and 184.5 mmol) and tert-butyldiphenylsilyl chloride (24 mL, 92.25
169.3; m/z (CI+) 155 (M+ + 1, 20%), 69 (74) and 60 (100).
(8S,10R,11R)-8,11-Bis-(tert-butyldimethylsilyloxy)-6-[(E)-2-tert-
butyldiphenylsilyloxyethylidene]-3,3-dimethyl-10-(2-
mmol) in DCM (57 mL) at 0 °C. After the addition of 4-
dimethylaminopyridine (cat.) and tetra-n-butylammonium iodide
(cat.) the mixture was stirred for 18 h at rt. Saturated aqueous
trimethylsilylethoxymethoxy)dodec-1-en-4-one (68). The enol ammonium chloride was added and the mixture was partitioned
acetate 67 (0.88 g, 5.71 mmol) in dry toluene (7.1 mL) was added to between water and DCM. The aqueous layer was extracted with
the bromide 66 (3.29 g, 3.80 mmol) in toluene (7.1 mL) at rt DCM and the organic extracts were washed with brine, dried
followed by tributyltin methoxide (1.64 mL, 5.70 mmol) and (MgSO4)
and
concentrated
under
reduced
pressure.
PdCl2dppe (197 mg, 0.34 mmol, 9 mol%). The reaction mixture was Chromatography (1:5 to 1:1 ether:light petroleum) of the residue
heated under reflux using an oil bath at 120 oC for 5 h. After cooling gave recovered lactone 34 (170 mg, 1%) and the title compound 70
and concentration under reduced presure, chromatography (1 : 40 (24 g, 72%), Rf = 0.76 (8:2 ether:light petroleum), [α]D20 −4.6 (c 11.9,
ether:light petroleum containing 1% triethylamine) of the residue CHCl3) (Found: M+ + H, 546.3064. C29H48NO5Si2 requires M,
gave the title compound 68 as a pale yellow oil (1.37 g, 40%), Rf = 546.3066); νmax/cm-1 3068, 2952, 2892, 2862, 1669, 1466, 1425,
0.42 (1 : 10 ether:light petroleum), [α]D20 −5.7 (c 2.8, CHCl3) (Found: 1383, 1251, 1185, 1152, 1106, 1048, 935, 856, 835, 774 and 742; δH
M+ + Na, 919.5547. C50H88O6Si4Na requires M, 919.5550); νmax/cm-1 −0.02 [9 H, s, Si(CH3)3], 0.68 (1 H, ddd, J 13.8, 11.4, 5.5, SiCH), 0.84
3072, 2956, 2930, 2894, 2858, 1713, 1471, 1463, 1428, 1380, 1252, (1 H, ddd, J 13.8, 11.7, 5.9, SiCHʹ), 1.08 (3 H, d, J 7.2, 5-H3), 1.10 [9 H,
1109, 1057, 859 and 836; δH 0.01 and 0.02 (each 3 H, s, SiCH3), 0.04 s, SiC(CH3)3], 2.81 (2 H, d, J 5.5, 2-H2), 3.24 (3 H, s, NCH3), 3.39 (1 H,
[9 H, s, Si(CH3)3], 0.05 and 0.06 (each 3 H, s, SiCH3), 0.86 and 0.89 ddd, J 11.4, 9.6, 2.9, OHCHCH2Si), 3.50 (1 H, ddd, J 11.6, 9.6, 5.5,
[each 9 H, s, SiC(CH3)3], 0.89-1.00 (2 H, m, CH2Si), 1.02 (3 H, d, J 6.2, OHCHCH2Si), 3.74 (3 H, s, OCH3), 4.09-4.23 (2 H, m, 3-H, 4-H), 4.56
12-H3), 1.06 [9 H, s, SiC(CH3)3], 1.27 (6 H, s, 2 × 3-CH3), 1.30-1.58 (2 and 4.65 (each 1 H, d, J 6.9, OHCHO), 7.37-7.51 (6 H, m, ArH) and
H, m, 9-H2), 2.05-2.28 (2 H, m, 7-H2), 3.24 (2 H, br. s, 5-H2), 3.40- 7.70-7.78 (4 H, m, ArH); δC −1.2, 17.3, 18.1, 19.5, 27.3, 32.0, 61.5,
3.53 (2 H, m, 8-H, OHCHCH2Si), 3.68 (1 H, m, OHCHCH2Si), 3.82 (1 H, 65.2, 69.8, 78.1, 95.9, 127.8, 127.9, 129.8, 130.0, 133.9, 134.7,
m, 10-H), 4.05 (1 H, m, 11-H), 4.28 (2 H, d, J 6.0, 2ʹ-H2), 4.63 and 136.1, 136.2 and 173.2; m/z (CI+) 546 (M+ + 1, 20%), 428 (62) and 90
4.67 (each 1 H, d, J 7.0, OHCHO), 5.14-5.25 (2 H, m, 1-H2), 5.47 (1 H, (100).
t, J 6.0, 1ʹ-H), 5.97 (1 H, dd, J 17.4, 10.5, 2-H), 7.36-7.48 (6 H, m, (3R,4R)-4-tert-Butyldiphenylsilyloxy)-3-(2-
ArH) and 7.63-7.75 (4 H, m, ArH); δC −4.5(2), −4.3, −3.6, −1.2, 17.4, trimethylsilylethoxymethoxy)pentanal (71). Amide 70 (12 g, 22.0
18.2, 18.3, 18.4, 19.4, 23.9, 26.2(2), 27.1, 35.9, 39.8, 46.0, 51.5, mmol) in DCM (160 mL) was added to di-isobutylaluminium hydride
20 | J. Name., 2012, 00, 1-3
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OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
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ARTICLE
o
(1 M in hexanes, 44.0 mL, 44.0 mmol) at −78 C and the solution H, m, CH2CH2Si, 6-H), 3.92 (1 H, m, 4-H), 4.02 (1 H, dq, J 6.1, 4.9, 7-
View Article Online
DOI: 10.1039/C7OB00076F
stirred at −78 °C for 1.5 h. Methanol (23 mL) and saturated aqueous H), 4.37 and 4.42 (each 1 H, d, J 6.6, OHCHO), 7.34-7.48 (6 H, m,
ammonium chloride (50 mL) were added and the mixture stirred for ArH) and 7.65-7.72 (4 H, m, ArH); δC −1.2, 16.9, 18.2, 19.4, 27.3,
30 min at rt. The mixture was diluted with EtOAc and filtered 27.4, 34.1, 65.8, 69.3, 70.5, 70.6, 81.4, 81.8, 95.1, 127.9, 128.0,
through Celite. The filtrate was washed with water and the aqueous 130.0, 130.1, 134.1, 134.3 and 136.1(2); m/z (ES+) 549 (M+ + 23,
layer was extracted with EtOAc. The organic extracts were dried 100%).
(MgSO4), filtered and concentrated under reduced pressure.
Powdered sodium hydroxide (464 mg, 11.6 mmol) was added to
Chromatography (1:5 ether:light petroleum) of the residue gave the the ester 74 (742 mg, 1.17 mmol) in MeOH (10 mL) at 0 °C and the
title compound 71 (10.6 g, ca. 99%), Rf = 0.72 (1:1 ether:light mixture stirred at rt for 2 h before concentrating under reduced
petroleum), [α]D20 +4.4 (c 11.9, CHCI3); νmax/cm-1 2954, 2858, 1730, pressure (2 mL). Ether and saturated aqueous ammonium chloride
1472, 1428, 1382, 1249, 1105, 1033, 938, 861, 836 and 740; δH were added and the aqueous layer extracted with ether. The
−0.03 [9 H, s, Si(CH3)3], 0.66-0.85 (2 H, m, CH2Si), 1.02-1.07 (3 H, m, organic extracts were dried (MgSO4) and concentrated under
5-H3), 1.06 [9 H, s, SiC(CH3)3], 2.58 (1 H, ddd, J 16.2, 8.4, 2.7, 2-H), reduced pressure. Chromatography (1:19 then 1:4, ether:light
2.81 (1 H, ddd, J 16.1, 3.2, 1.5, 2-Hʹ), 3.37-3.47 (2 H, m, CH2CH2Si), petroleum) of the residue afforded the title compound 72 (502 mg,
4.01-4.10 (2 H, m, 3-H, 4-H), 4.45 and 4.51 (each 1 H, d, J 7.1, 82%).
OCHHO), 7.35-7.48 (6 H, m, ArH), 7.64-7.71 (4 H, m, ArH), 9.78 (1 H, (4S,6R,7R)-7-tert-Butyldiphenylsilyloxy-6-(2-
dd, J 2.8, 1.8, l-H); δC −1.2, 17.1, 18.1, 19.4, 27.2, 43.8, 65.4, 69.5, trimethylsilylethoxymethoxy)oct-1-yn-4-yl dichloroacetate (74).
76.1, 95.1, 127.9, 128.0, 130.0, 130.1, 133.8, 134.2, 136.0, 136.1 Triphenylphosphine (15.6 g, 59.7 mmol) was added to the alcohol
and 201.6; m/z (CI+) 504 (M+ + 18,7%), 411 (60) and 90 (100).
73 (6.0 g, 11.4 mmol) in THF (138 mL) and the mixture cooled to 0
(4R,6R,7R)-7-tert-Butyldiphenylsilyloxy-6-(2- °C before dichloroacetic acid (4.93 mL, 59.7 mmol) and di-isopropyl
trimethylsilylethoxymethoxy)yoct-1-yn-4-ol (72) and (73). azodicarboxylate (11.74 mL, 59.7 mmol) were added. The mixture
(4S,6R,7R)-
and
Propargyl bromide (80 % wt. in toluene, 2.95 mL, 26.51 mmol) was was stirred at rt for 18 h, saturated aqueous sodium hydrogen
added to a suspension of activated zinc (6.94 g, 106 mmol) in THF carbonate was added and the mixture was partitioned between
(18 mL) at 0 °C and the mixture stirred for 20 min then cooled to water and EtOAc. The aqueous layer was extracted with EtOAc and
−15 °C. More propargyl bromide (80 % wt. in toluene, 11.8 mL, 106 the organic extracts were dried (MgSO4) and concentrated under
mmol) was added and, after 30 min, the mixture was cooled to −78 reduced pressure. Chromatography (1:9 ether:light petroleum) of
°C before the addition of the aldehyde 71 (10.31 g, 21.2 mmol) in the residue afforded (3Z,6R,7R)-7-tert-butyldiphenylsilyloxy-6-(2-
THF (21 mL). The mixture was stirred at −78 °C for 5 h then trimethylsilylethoxymethoxy)oct-3-en-1-yne (1.44 g, 25%) (Found:
saturated aqueous ammonium chloride was added and the mixture M+ + NH4, 526.3172. C30H48O3NSi2 requires M, 526.3167); νmax/cm-1
warmed to rt then filtered through Celite. Water was added and the 3309, 3071, 3050, 2953, 2932, 2891, 2859, 1469, 1427, 1380, 1249,
aqueous phase was extracted with ether. The organic extracts were 1152, 1106, 1032, 859, 835 and 740; δH 0.01 [9 H, s, Si(CH3)3], 0.73-
washed with brine, dried (MgSO4) and concentrated under reduced 0.92 (2 H, m, CH2Si), 1.09 (3 H, d, J 6.3, 8-H3), 1.10 [9 H, s, SiC(CH3)3],
pressure. Chromatography (1:20 ether:light petroleum) of the 2.55 and 2.88 (each 1 H, m, 5-H), 3.11 (1 H, d, J 2.3, 1-H), 3.41-3.62
residue gave the (4S)-epimer of the title compound 72 (4.39 g, (3 H, m, 6-H, OCH2CH2Si), 4.01 (1 H, dq, J 6.3, 4.6, 7-H), 4.51 (2 H, s,
20
44%), Rf = 0.35 (2:8 ether:light petroleum), [α]D +30.6 (c 4.4, OCH2O), 5.56 (1 H, dd, J 10.9, 2.3, 3-H), 6.15 (1 H, dt, J 10.9, 6.9, 4-
CHCl3) (Found: M+ + H, 527.3003. C30H47O4Si2 requires M, 527.3007); H), 7.38-7.50 (6 H, m, ArH) and 7.69-7.75 (4 H, m, ArH); m/z (CI+)
νmax/cm-1 3468, 3308, 2953, 2933, 2893, 2860, 1469, 1426, 1381, 526 (M+ + 18, 35) and 90 (100). The more polar product was the
1250, 1151, 1106, 1056, 1032, 935, 859 and 836; δH 0.02 [9 H, s, title compound 74 (5.13 g, 71%), Rf = 0.42 (1:9 ether:light
20
Si(CH3)3], 0.80-0.97 (2 H, m, CH2Si), 1.05 (3 H, d, J 6.3, 8-H3), 1.09 [9 petroleum), [α]D +29 (c 2.3, CHCl3) (Found: M+ + NH4, 654.2595.
H, s, SiC(CH3)3], 1.72 (1 H, ddd, J 14.3, 10.0, 2.9, 5-H), 1.84 (1 H, ddd, C32H50O5NSi2Cl2, requires M, 654.2599); νmax/cm-1 3308, 3071, 3050,
J 14.3, 10.0, 3.7, 5-Hʹ), 2.05 (1 H, t, J 2.7, 1-H), 2.45 (2 H, dd, J 6.1, 2954, 2934,2892, 2859, 1766, 1747, 1469, 1427, 1379, 1278, 1250,
2.6, 3-H2), 3.32 (1 H, d, J 4.5, OH), 3.46 (1 H, ddd, J 10.3, 9.5, 6.5, 1164, 1106, 1031, 935, 859, 836, 772 and 740; δH −0.01 [9 H, s,
OHCHCH2Si), 3.61 (1 H, ddd, J 11.1, 9.8, 6.3, OHCHCH2Si), 3.68 (1 H, Si(CH3)3], 0.68 and 0.83 (each 1 H, ddd, J 13.8, 10.8, 6.2, HCHSi),
ddd, J 9.7, 4.8, 3.6, 6-H), 3.92-4.02 (2 H, m, 4-H, 7-H), 4.36 and 4.40 1.08 (3 H, d, J 7.0, 8-H3), 1.11 [9 H, s, SiC(CH3)3], 1.84 (1 H, ddd, J
(each 1 H, d, J 6.9, OHCHO), 7.37-7.49 (6 H, m, ArH) and 7.68-7.76 (4 14.2, 10.7, 2.6, 5-H), 2.09 (1 H, t, J 2.6, 1-H), 2.36 (1 H, ddd, J 14.6,
H, m, ArH); δC −1.2, 17.8, 18.2, 19.5, 27.3, 27.4, 35.7, 65.9, 66.6, 10.5, 1.5, 5-Hʹ), 2.61 (1 H, ddd, J 17.0, 5.1, 2.7, 3-H), 2.72 (1 H, ddd, J
70.5, 70.7, 79.3, 81.5, 96.0, 127.8, 128.0, 129.9, 130.1, 133.9, 134.5, 17.0, 5.9, 2.6, 3-Hʹ), 3.37-3.52 (2 H, m, OCH2CH2Si), 3.55 (1 H, ddd, J
136.1 and 136.2; m/z (APCI+) 549 (M+ + 23, 100%). Following a 10.9, 4.3, 1.6, 6-H), 4.11 (1 H, dq, J 4.6, 6.4, 7-H), 4.40 and 4.44
mixed fraction (832 mg, 7%), the more polar product was the (4R)- (each 1 H, d, J 6.9, OHCHO), 5.20 (1 H, ddd, J 10.8, 5.8, 2.6, 4-H),
epimer of the title compound 73 (4.17 g, 37%), Rf = 0.28 (2:8 5.84 (1 H, s, 2ʹ-H), 7.37-7.52 (6 H, m, ArH) and 7.67-7.77 (4 H, m,
20
ether:light petroleum), [α]D +20.8 (c 4.1, CHCl3) (Found: M+ + H, ArH); δC −1.2, 16.7, 18.0, 19.5, 24.6, 27.3, 32.1, 64.6, 65.6, 69.3,
527.3001. C30H47O4Si2 requires M, 527.3007); νmax/cm-1 3463, 3308, 71.6, 72.9, 77.9, 78.7, 95.8, 127.8, 127.9, 129.9, 130.1, 134.0, 134.5,
2953, 2932, 2892, 2859, 1469, 1426, 1379, 1249, 1188, 1150, 1106, 136.1(2) and 164.3; m/z (CI+) 654 (M+ + 18, 6%) and 90 (100).
1055, 1029, 936, 859, 836, 770 and 740; δH −0.01 [9 H, s, Si(CH3)3], Recovered alcohol 73 (405 mg, 7%) was also isolated.
0.70-0.39 (2 H, m, CH2Si), 1.04-1.10 [12 H, m, SiC(CH3)3, and 8-H3], (4S,6R,7R)-7-tert-Butyldiphenylsilyloxy-4-triethylsilyloxy-6-(2-
1.65 (1 H, ddd, J 14.5, 9.6, 8.0, 5-H), 2.04 (1 H, dt, J 2.6, 0.6, 1-H), trimethylsilylethoxymethoxy)oct-1-yne (75). Triethylsilyl chloride
2.20 (1 H, dt, J 14.5, 2.7, 5-Hʹ), 2.39-2.45 (2 H, m, 3-H2), 3.29-3.59 (3 (1.92 mL, 11.4 mmol) and the alcohol 72 (3.0 g, 5.7 mmol) in DCM
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Organic & Biomolecular Chemistry
Page 22 of 26
ARTICLE
Journal Name
(25 mL) were added to imidazole (1.16 g, 17.1 mmol) in DCM (25 mixture warmed to −60 oC then stirred for 30 min. After cooling to
View Article Online
DOI: 10.1039/C7OB00076F
o
mL) at 0 oC and the mixture stirred at rt for 16 h. Saturated aqueous −78 C, the alkynoate 76 (2.02 g, 2.89 mmol) in THF (20 mL) was
ammonium chloride was added and the mixture partitioned added and the solution stirred at −78 oC for 1 h. Saturated aqueous
between water and DCM, the aqueous layer being extracted with ammonium chloride was added and the mixture allowed to warm to
more DCM. The organic extracts were dried (MgSO4) and rt then parttioned between water and ether. The aqueous phase
concentrated under reduced pressure. Chromatography of the was extracted with ether and the organic extracts were washed
residue (2% ether in light petroleum with 1% triethylamine) gave with brine, dried (MgSO4) and concentrated under reduced
the title compound 75 as an oil (3.38 g, 93%), Rf = 0.50 (1:9 pressure to give the title compound 77 as an oil (1.97 g), Rf = 0.40
20
20
ether:light petroleum), [α]D +9.6 (c 8.6, CHCl3) (Found: M+ + Na, (1:9 ether:light petroleum), [α]D −24.6 (c 0.73, CHCl3) (Found: M+
663.3697. C36H60O4Si3Na requires M, 663.3692); νmax/cm-1 3311, + Na, 763.4209. C41H68O6Si3Na requires M, 763.4216); νmax/cm-1
3071, 2953, 2882, 1463, 1425, 1380, 1248, 1105, 1056, 938, 859, 3073, 3051, 2954, 2878, 2859, 1719, 1644, 1249, 1192, 1178, 1462,
834 and 739; δH −0.02 [9 H, s, Si(CH3)3], 0.68 (1 H, m, HCHSi), 0.67 (6 1428, 1377, 1105, 1057, 936, 920, 861, 836 and 740; δH −0.02 [9 H,
H, q, J 7.6, 3 × SiCH2), 0.84 (1 H, ddd, J 13.8, 11.6, 5.9, HCHSi), 1.01 s, Si(CH3)3], 0.66 (6 H, q, J 8.0, 3 × SiCH2), 0.82 (1 H, ddd, J 13.7, 11.9,
(9 H, t, J 7.8, 3 × SiCH2CH3), 1.02 (3 H, d, J 7.8, 8-H3), 1.10 [9 H, s, 5.8, HCHSi), 0.92-1.04 (4 H, m, HCHSi, 9-H3), 1.00 (9 H, t, J 7.9, 3 ×
SiC(CH3)3], 1.78 (1 H, ddd, J 14.1, 10.0, 3.8, 5-H), 2.01 (1 H, ddd, J SiCH2CH3), 1.12 [9 H, s, SiC(CH3)3], 1.56 (1 H, ddd, J 14.3, 9.9, 5.2, 6-
14.1, 8.5, 2.2, 5-Hʹ), 2.03 (1 H, t, J 2.7, 1-H), 2.45 (2 H, dd, J 5.7, 2.7, H), 2.01 (1 H, ddd, J 14.2, 7.4, 1.1, 6-Hʹ), 2.67 (1 H, dd, J 12.5, 7.1, 4-
3-H2), 3.42 and 3.53 (each 1 H, ddd, J 11.4, 9.5, 5.9, OHCHCH2Si), H), 3.03 (2 H, d, J 6.4, 1ʹ-H2), 3.17 (1 H, dd, J 12.5, 5.7, 4-Hʹ), 3.36 (1
3.71 (1 H, ddd, J 10.1, 4.4, 2.0, 6-H), 4.05 (1 H, m, 4-H), 4.14 (1 H, H, ddd, J 11.5, 9.5, 5.8, OHCHCH2Si), 3.55 (1 H, m, OHCHCH2Si), 3.74
dq, J 6.1, 4.4, 7-H), 4.53 and 4.59 (each 1 H, d, J 6.8, OHCHO), 7.36- (3 H, s, OCH3), 3.76 (1 H, ddd, J 10.0, 4.2, 1.2, 7-H), 4.12-4.25 (2 H,
7.49 (6 H, m, ArH) and 7.69-7.75 (4 H, m, ArH); δC −1.3, 5.5, 7.3, m, 5-H, 8-H), 4.62 and 4.63 (each 1 H, d, J 6.8, OHCHO), 5.14 (1 H,
17.0, 18.2, 19.5, 27.3, 28.6, 36.1, 65.4, 68.4, 69.9, 70.5, 79.6, 81.7, dd, J 16.9, 1.6, 3ʹ-H), 5.18 (1 H, d, J 9.8, 3ʹ-Hʹ), 5.78 (1 H, s, 2-H), 5.83
95.9, 127.7, 127.8, 129.7, 129.9, 134.2, 135.0, 136.1 and 136.2; m/z (1 H, m, 2ʹ-H), 7.38-7.50 (6 H, m, ArH) and 7.71-7.78 (4 H, m, ArH);
(ES+) 680 (100%) and 663 (71%).
δC −1.3, 5.5, 7.3, 16.9, 18.2, 19.5, 27.3, 36.6, 40.7, 44.2, 51.1, 65.3,
Methyl (5S,7R,8R)-8-tert-Butyldiphenylsilyloxy-5-triethylsilyloxy-7- 70.1, 70.5, 80.0, 96.2, 117.5, 118.2, 127.7, 127.8, 129.7, 129.8,
(2-trimethylsilylethoxymethoxy)non-2-ynoate (76). n-Butyllithium 134.3, 134.8, 135.0, 136.1, 136.2, 160.1 and 166.8; m/z (ES+) 786
(1.6 M in hexanes, 1.23 mL, 1.97 mmol) was added to the alkyne 75 (15%) and 763 (M+ + 23, 100).
o
(1.05 g, 1.64 mmol) in THF (7 mL) at −78 C. After stirring for 45 (5S,7R,8R,2Z)-8-tert-Butyldiphenylsilyloxy-3-(prop-2-enyl)-5-
min, methyl chloroformate (0.38 mL, 4.92 mmol) was added and triethylsilyloxy-7-(2-trimethylsilylethoxymethoxy)non-2-en-1-ol
the mixture stirred for 3 h before the addition of saturated aqueous (78). Di-isobutylaluminium hydride (1 M in THF, 7.98 mL, 7.98
ammonium chloride. The mixture was allowed to warm to rt and mmol) was added to the ester 77 (1.97 g, 2.66 mmol) in THF (14 mL)
o
o
then partitioned between water and ether. The aqueous phase was at −78 C and the mixture stirred for 1 h at −78 C. After allowing
extracted with ether and the organic extracts were washed with the mixture to warm to rt, ether and saturated aqueous
brine, dried (MgSO4) and concentrated under reduced pressure. potassium/sodium tartrate were added and the mixture stirred
Chromatography of the residue (2% to 3% ether in light petroleum vigorously for 1 h. The aqueous layer was extracted with ether and
with 1% triethylamine gave the title compound 76 as an oil (1.11 g, the organic extracts were washed with brine, dried (MgSO4) and
20
97%), Rf = 0.29 (1:9 ether:light petroleum), [α]D +8.1 (c 12.2, concentrated under reduced pressure to give the title compound 78
20
CHCl3) (Found: M+ + Na, 721.3746. C38H62O6Si3Na requires M, (1.81 g), Rf = 0.28 (2:8 ether:light petroleum), [α]D −2.7 (c 1.5,
721.3746); νmax/cm-1 2954, 2883, 2240, 1719, 1465, 1429, 1378, CHCl3) (Found: M+ + Na, 735.4264. C40H68O5Si3Na requires M,
1255, 1104, 935, 859, 835 and 742; δH −0.02 [9 H, s, Si(CH3)3], 0.66 735.4267); νmax/cm-1 3436, 3072, 2955, 2924, 2879, 1638, 1462,
(1 H, m, HCHSi), 0.67 (6 H, q, J 7.6, 3 × SiCH2), 0.83 (1 H, ddd, J 13.8, 1428, 1378, 1249, 1105, 1058, 1034, 918, 861, 836, 740 and 702; δH
11.6, 5.9, HCHSi), 1.01 (9 H, t, J 7.7, 3 × SiCH2CH3), 1.02 (3 H, d, J 7.7, −0.02 [9 H, s, Si(CH3)3], 0.66 (1 H, m, HCHSi), 0.66 (6 H, q, J 7.9, 3 ×
9-H3), 1.10 [9 H, s, SiC(CH3)3], 1.70 (1 H, ddd, J 14.3, 10.1, 4.4, 6-H), SiCH2), 0.82 (1 H, ddd, J 13.7, 11.8, 5.9, HCHSi), 0.99 (3 H, d, J 7.8, 9-
2.06 (1 H, ddd, J 14.2, 8.2, 1.9, 6-Hʹ), 2.55 (1 H, dd, J 17.1, 5.3, 4-H), H3), 1.00 (9 H, t, J 7.8, 3 x SiCH2CH3), 1.12 [9 H, s, SiC(CH3)3], 1.60 (1
2.65 (1 H, dd, J 17.1, 5.7, 4-Hʹ), 3.40 and 3.52 (each 1 H, ddd, J 11.4, H, ddd, J 14.3, 9.6, 6.0, 6-H), 1.97 (1 H, ddd, J 14.1, 6.3, 1.7, 6-Hʹ),
9.5, 5.5, OHCHCH2Si), 3.66 (1 H, ddd, J 10.0, 4.2, 1.8, 7-H), 3.78 (3 H, 2.26 (1 H, dd, J 13.6, 5.5, 4-H), 2.47 (1 H, dd, J 13.6, 7.8, 4-Hʹ), 2.79-
s, OCH3), 4.05-4.19 (2 H, m, 5-H, 8-H), 4.49 and 4.56 (each 1 H, d, J 2.86 (2 H, m, 1ʹ-H2), 3.37 (1 H, ddd, J 11.4, 9.5, 5.9, OHCHCH2Si),
6.8, OHCHO), 7.37-7.50 (6 H, m, ArH) and 7.68-7.75 (4 H, m, ArH); δC 3.44-3.62 (2 H, m, OHCHCH2Si, 7-H), 3.97 (1 H, m, 5-H), 4.05 (1 H,
−1.3, 5.4, 7.2, 16.9, 18.2, 19.5, 27.3, 28.9, 36.4, 52.8, 65.4, 68.1, dd, J 12.2, 6.9, 1-H), 4.11 (1 H, dq, J 6.3, 4.2, 8-H), 4.23 (1 H, dd, J
69.7, 74.7, 79.5, 87.3, 95.9, 127.7, 127.9, 129.8, 129.9, 134.1, 134.8, 12.3, 7.3, 1-Hʹ), 4.51 and 4.56 (each 1 H, d, J 6.8, OHCHO), 5.09 (1 H,
136.1, 136.2 and 154.4; m/z (ES+) 720 (100%).
Methyl (5S,7R,8R,2Z)-8-tert-Butyldiphenylsilyloxy-5- 7.2, 2-H), 5.82 (1 H, ddt, J 17.4, 10.7, 6.9, 2ʹ-H), 7.38-7.50 (6 H, m,
dd, J 17.5, 1.2, 3ʹ-H), 5.10 (1 H, dd, J 10.7, 1.2, 3ʹ-Hʹ), 5.69 (1 H, t, J
triethylsilyloxy-3-prop-2ʹ-enyl-7-(2-
ArH) and 7.69-7.76 (4 H, m, ArH); δC −1.3, 5.4, 7.2, 16.9, 18.2, 19.5,
trimethylsilylethoxymethoxy)non-2-enoate (77).
A
mixture of 27.3, 36.5, 39.3, 41.9, 58.9, 65.4, 69.3, 69.9, 80.1, 95.9, 116.8,
anhydrous lithium chloride (292 mg, 6.95 mmol) and anhydrous 127.6, 127.8, 127.9, 129.9, 130.0, 134.2, 134.7, 136.1, 136.5, 139.9;
copper(I) iodide (1.32 g, 6.95 mmol) in THF (20 mL) was stirred until m/z (ES+) 773 (41%), 759 (24%) and 735 (M+ + 23, 100).
nearly dissolved then cooled to −78 oC. Prop-2-enylmagnesium
bromide (1 M in ether, 12.4 mL, 12.4 mmol) was added and the
22 | J. Name., 2012, 00, 1-3
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Page 23 of 26
OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
Methyl (5S,7R,8R,2Z)-8-tert-butyldiphenylsilyloxy-3-(2-oxoethyl)- Na, 835.4787. C45H76O7Si3Na requires M, 835.4791); νVmiaexw/cAmrtic-1le3O4n6lin7e,
DOI: 10.1039/C7OB00076F
1104, 1058, 860, 836 and 739; m/z (ES+) 851.3 (M+ + 39, 17%) and
5-triethylsilyloxy-7-(2-trimethylsilylethoxymethoxy)non-2-enoate
(80).
2954, 2933, 2879, 1717, 1640, 1464, 1429, 1378, 1248, 1189, 1155,
N-Methylmorpholine N-oxide (17.5 mg, 148 μmol) and one crystal 835.6 (M+ + 23, 100).
of osmium tetroxide were added to the diene 77 (100 mg, 135
Dess-Marin periodinane (19.5 mg, 46 μmol) was added to the
μmol) in acetone (1.35 mL) and water (0.15 mL) and the mixture mixture of the epimeric alcohols 81 (30 mg, 37 μmol) in DCM (1 mL)
stirred for 4 h. Another crystal of osmium tetroxide was added and at rt was added. After stirring for 1.5 h water was added and the
the mixture stirred for 1.5 h. Aqueous sodium sulfite was added and mixture partitioned between water and ether. The aqueous layer
the mixture partitioned between water and EtOAc. The aqueous was extracted with ether and the organic extracts were washed
layer was extracted with EtOAc, and the organic extracts were with brine, dried (MgSO4) and concentrated under reduced
washed with brine, dried (MgSO4) and concentrated under reduced pressure. Chromatography (1:19 ether:light petroleum) of the
pressure. Chromatography (2:8 EtOAc:light petroleum) of the residue afforded the title compound 82 (16 mg, 53%), Rf = 0.54 (2:8
residue afforded the diol 79 (72 mg, 69%) as a mixture of epimers, ether:light petroleum) (Found: M+ + H, 811.4814. C45H74O7Si3
Rf = 0.46 (3:7 EtOAc:light petroleum) (Found: M+ + Na, 797.4268. requires M, 811.4815); νmax/cm-1 2954, 2933, 2879, 1719, 1642,
C41H70O8Si3Na requires M, 797.4271); νmax/cm-1 3414, 2953, 2880, 1463, 1429, 1378, 1248, 1193, 1145, 1105, 1055, 933, 860, 835,
1718, 1642, 1462, 1430, 1379, 1248, 1189, 1150, 1105, 1057, 1035, 739; δH −0.03 [9 H, s, Si(CH3)3], 0.62 (1 H, m, HCHSi), 0.64 (6 H, q, J
935, 861, 836, 740 and 706; δC −1.3, 5.4, 5.5, 7.2, 7.3, 14.5, 16.8, 8.0, 3 × SiCH2), 0.80 (1 H, ddd, 13.7, 11.8, 5.6, HCHSi), 0.97 (3 H, d, J
16.9, 18.1, 19.5, 21.4, 27.3, 36.5, 36.9, 40.5(2), 43.7, 44.5, 51.2, 6.1, 9-H3), 0.99 (9 H, t, J 7.9, 3 × SiCH2CH3), 1.11 [9 H, s, SiC(CH3)3],
60.7, 65.3, 66.5, 66.9, 70.0, 70.1, 70.6, 70.7, 71.8, 80.1, 80.3, 96.1, 1.29 and 1.30 (each 3 H, s, 3ʹ-CH3), 1.51 (1 H, ddd, J 14.2, 9.8, 5.8, 6-
96.2, 119.4, 119.6, 127.7, 127.9, 129.8, 129.9, 134.2, 134.9, 136.1, H), 2.01 (1 H, ddd, J 14.1, 6.7, 1.0, 6-Hʹ), 2.52 (1 H, dd, J 12.8, 7.7, 4-
136.2, 157.6, 158.7, 166.4, 166.5; m/z (ES+) 815 (53%), 813 (M+ + 39, H), 3.23 (1 H, dd, J 12.8, 5.2, 4-Hʹ), 3.32 (1 H, ddd, J 11.7, 9.6, 5.8,
35), 797 (M+ + Na, 100), 537 (41) and 515 (60).
HCHCH2Si), 3.34 (1 H, d, J 16.9, 1ʹ-H), 3.52 (1 H, ddd, J 11.9, 9.5, 5.2,
Sodium periodate (70 mg, 326 μmol) was added to the diol 79 HCHCH2Si), 3.66 (1 H, d, J 16.8, 1ʹ-Hʹ), 3.72 (3 H, s, OCH3), 3.74 (1 H,
(63 mg, 81 μmol) in an aqueous pH 7 buffer (0.4 mL) and THF (0.8 m, 5-H), 4.09-4.23 (2 H, m, 7-H, 8-H), 4.62 and 4.63 (each 1 H, d, J
mL) and the mixture was stirred for 30 min at rt. Water and ether 6.9, OHCHO), 5.24 (1 H, dd, J 17.8, 0.7, 5-Hʹ), 5.25 (1 H, dd, J 10.2,
were added and the aqueous layer was extracted with ether. The 0.7, 5ʹ-Hʹ), 5.71 (1 H, s, 2-H), 5.96 (1 H, dd, J 17.8, 10.2, 4ʹ-H), 7.37-
organic extracts were washed with brine, dried (MgSO4) and 7.49 (6 H, m, ArH) and 7.70-7.77 (4 H, m, ArH); δC −1.3, 5.5, 7.3,
concentrated under reduced pressure to afford the title compound 16.8, 18.1, 19.5, 23.7, 27.3, 36.9, 40.8, 48.4, 51.2, 51.5, 65.2, 70.0,
80 (58 mg, 96%), Rf = 0.69 (2:8 EtOAc:light petroleum) (Found: M+ + 71.5, 80.3, 96.3, 115.2, 120.4, 127.7, 127.8, 129.7, 129.9, 134.2,
Na, 765.4003. C40H66O7Si3Na requires M, 765.4009); νmax/cm-1 2953, 135.0, 136.1, 136.2, 142.3, 155.8, 166.2 and 209.5; m/z (ES+) 812
2933, 2879, 1723, 1644, 1463, 1430, 1379, 1249, 1229, 1146, 1104, (M+ + 1, 100%) and 693 (62).
1057, 936, 861, 836 and 740; δH −0.02 [9 H, s, Si(CH3)3], 0.64 (6 H, q, (5S,7R,8R,2Z)-1,8-bis-(tert-Butyldiphenylsilyloxy)-3-(prop-2-enyl)-
J 8.0, 3 × SiCH2), 0.65 (1 H, m, HCHSi), 0.82 (1 H, ddd, J 13.5, 11.8, 5-triethylsilyloxy-7-(2-trimethylsilylethoxymethoxy)non-2-ene
5.7, HCHSi), 0.99 (3 H, d, J 6.2, 9-H3), 0.99 (9 H, t, J 7.9, 3 × (83). tert-Butyldiphenylsilyl chloride (0.76 mL, 2.93 mmol) was
SiCH2CH3), 1.10 [9 H, s, SiC(CH3)3], 1.57 (1 H, ddd, J 14.5, 9.7, 5.7, 6- added to imidazole (0.54 g, 7.98 mmol) in DCM (30 mL) at 0 oC
H), 2.03 (1 H, dd, J 13.9, 6.4, 6-Hʹ), 2.77 (1 H, dd, J 12.8, 7.1, 4-H), followed by the alcohol 78 (1.81 g) in DCM (20 mL). The mixture
3.19 (1 H, dd, J 12.9, 4.9, 4-Hʹ), 3.35 (1 H, ddd, J 12.0, 9.5, 5.5, was stirred for 16 h then saturated aqueous ammonium chloride
OHCHCH2Si), 3.42 (2 H, m, 1ʹ-H2), 3.53 (1 H, ddd, J 12.0, 9.6, 5.5, was added and the mixture partitioned between water and DCM.
OHCHCH2Si), 3.73 (1 H, m, 7-H), 3.76 (3 H, s, OCH3), 4.13-4.25 (2 H, The aqueous layer was extracted with DCM and the organic extracts
m, 5-H, 8-H), 4.61 (2 H, s, OCH2O), 5.87 (1 H, s, 2-H), 7.37-7.50 (6 H, were dried (MgSO4) and concentrated under reduced pressure.
m, ArH), 7.70-7.77 (4 H, m, ArH) and 9.72 (1 H, t, J 1.9, 2ʹ-H); δC Chromatography (2% ether in light petroleum) of the residue
−1.3, 5.4, 7.3, 16.8, 18.1, 19.5, 27.3, 36.6, 40.9, 51.4, 54.3, 65.3, afforded the title compound 83 (2.05 g, 81% from alkynoate 76), Rf
21
69.9, 70.9, 80.1, 96.1, 121.4, 127.7, 127.8, 129.8, 129.9, 134.2, = 0.77 (1:9 ether:light petroleum), [α]D −7.4 (c 0.76, CHCl3)
134.9, 136.1, 136.2, 152.4, 166.0, 198.5; m/z (APCI+) 797 (26%), 766 (Found: M+ + Na, 973.5443. C56H86O5Si4Na requires M, 973.5445);
(M+ + 1, 100), 657 (42%) and 626 (36%).
νmax/cm-1 3071, 2953, 2933, 2885, 2860, 1463, 1427, 1385, 1251,
Methyl
(5S,7R,8R,2E)-8-tert-butyldiphenylsilyloxy)-3-(3,3- 1107, 1056, 861, 831 and 739; δH −0.02 [9 H, s, Si(CH3)3], 0.57 (6 H,
q, J 8.0, 3 × SiCH2), 0.66 (1 H, ddd, J 13.8, 11.4, 5.4, HCHSi), 0.81 (1
dimethyl-2-oxopent-4-enyl)-5-triethylsilyloxy-7-(2-
trimethylsilylethoxymethoxy)non-2-enoate (82). The aldehyde 80 H, ddd, J 13.8, 11.7, 5.9, HCHSi), 0.91 (3 H, d, J 6.6, 9-H3), 0.95 (9 H,
(55 mg, 74 μmol) in THF (0.8 mL) and 1-bromo-3-methylbut-2-ene t, J 7.9, 3 × SiCH2CH3), 1.08 and 1.10 [each 9 H, s, SiC(CH3)3], 1.39
(12.5 μL, 97 μmol) were added to zinc powder (15 mg, 234 μmol) at and 1.65 (each 1 H, m, 6-H), 2.08 (1 H, dd, J 13.3, 7.9, 4-H), 2.17 (1
rt and the mixture stirred for 1.5 h. Water was added and the H, dd, J 13.3, 5.8, 4-Hʹ), 2.80 (2 H, d, J 7.1, 1ʹ-H2), 3.34 (1 H, ddd, J
mixture partitioned between water and ether. The aqueous layer 11.4, 9.5, 5.9, OHCHCH2Si), 3.50 (1 H, ddd, J 11.7, 9.5, 5.4,
was extracted with ether and the organic extracts were washed OHCHCH2Si), 3.62 (1 H, ddd, J 9.9, 4.1, 1.1, 7-H), 3.88 (1 H, m, 5-H),
with brine, dried (MgSO4) and concentrated under reduced 4.11 (1 H, dq, J 6.2, 4.3, 8-H), 4.34 (2 H, d, J 6.1, 1-H2), 4.47 and 4.53
pressure. Chromatography (1:9 ether: light petroleum) of the (each 1 H, d, J 6.8, OHCHO), 5.09 (1 H, dd, J 17.7, 1.6, 3ʹ-H), 5.10 (1
residue afforded the alcohol 81 (33 mg, 55%) as a mixture of H, dd, J 10.3, 1.6, 3ʹ-Hʹ), 5.54 (1 H, t, J 6.0, 2-H), 5.82 (1 H, ddt, J
epimers, Rf = 0.25/0.27 (2:8, ether:light petroleum) (Found: M+ + 17.7, 10.3, 6.9, 2ʹ-H), 7.35-7.49 (6 H, m, ArH) and 7.67-7.78 (4 H, m,
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ArH); δC −1.2, 5.6, 7.3, 17.0, 18.2, 19.5, 27.2, 27.3, 35.9, 40.0, 42.3, 61.2, 65.3, 68.9, 69.7, 80.0, 96.0, 127.7, 127.9, 128.0(2), 129.5,
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61.5, 65.2, 68.7, 69.9, 79.9, 96.1, 116.5, 127.7, 127.8, 127.9(2), 129.8, 129.9(2), 133.2, 133.9, 134.0, 134.2D, O13I:41.09.1,013395/C.87,O1B3060.017(62F)
128.4, 129.7, 129.8, 134.3, 135.0, 135.9, 136.1, 136.2, 136.3 and and 200.5; m/z (APCI+) 1007 (40%), 976 (M+ + 23, 100) and 719 (36).
136.9; m/z (ES+) 974 (M+ + 23, 100%).
(4RS,8S,10R,11R)-11-tert-Butyldiphenylsilyloxy-6-[(Z)-2-tert-
(6S,8R,9R)-9-tert-Butyldiphenylsilyloxy-4-[(Z)-2-tert-
butyldiphenylsilyloxyethylidene]-6-triethylsilyloxy-8-(2-
butyldiphenylsilyloxyethylidene]-3,3-dimethyl-8-triethylsilyloxy-
10-(2-trimethylsilylethoxymethoxy)dodec-1-en-4-ol
(86).
trimethylsilylethoxymethoxy)decane-1,2-diol (84). AD-mix β (3.02 Powdered zinc (56 mg, 0.87 mmol) and 3-methylbut-2-enyl bromide
g, 1.4 g/mmol of 83) was added to a suspension of diene 83 (2.05 g, (53 μL, 0.41 mmol) were added to the aldehyde 85 (275 mg, 0.29
2.16 mmol) in t-butanol/water (1:1, 20 mL) at rt. After stirring for 30 mmol) in THF (4 mL) at rt. After stirring for 1.5 h, saturated aqueous
h, osmium tetroxide (2 crystals) was added followed, after a further sodium hydrogen carbonate was added and the mixture filtered
48 h, by saturated aqueous sodium sulfite. The mixture was through celite. Water and ether were added and the aqueous layer
partitioned between water and EtOAc and the aqueous layer was extracted with ether. The organic extracts were washed with brine,
extracted with EtOAc. The organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure.
dried (MgSO4) and concentrated under reduced pressure. Chromatography (1:3:96 Et3N:ether:light petroleum) of the residue
Chromatography (2:8 EtOAc:light petroleum then 5% MeOH in afforded the title compound 86 (262 mg, 88%) as a mixture of
EtOAc) of the residue afforded the title compound 84 (1.66 g, 78%) epimers, Rf = 0.59 (1:9 ether:light petroleum) (Found: M+ + Na,
as a mixture of epimers, Rf = 0.33 (3:7 EtOAc:light petroleum) 1045.6017. C60H94O6Si4Na requires M, 1045.6020); νmax/cm-1 2955,
(Found: M+ + Na, 1007.5490. C56H88O7Si4Na requires M, 1007.5499); 2934, 2878, 2859, 1467, 1427, 1381, 1249, 1190, 1108, 1058, 936,
νmax/cm-1 3409, 3071, 2952, 2932, 2878, 1590, 1468, 1428, 1386, 918, 859, 834 and 740; δH −0.02 [9 H, s, Si(CH3)3], 0.51-0.71 (7 H, m,
1248, 1189, 1110, 937, 861, 836 and 739; δH −0.02 [9 H, s, Si(CH3)3], 3 × SiCH2, SiHCH), 0.80 (1 H, ddd, J 13.8, 11.8, 6.0, SiHCH), 0.90-1.02
0.51-0.70 (7 H, m, 3 × SiCH2, SiHCH), 0.80 (1 H, m, SiHCH), 0.87-1.00 (12 H, m, 3 × SiCH2CH3, 12-H3), 1.08-1.13 [24 H, 2 × SiC(CH3)3, 2 × 3-
(12 H, m, 10-H3, 3 × SiCH2CH3), 1.08 and 1.10 [each 9 H, s, CH3], 1.60-2.42 (6 H, m, 5-H2, 7-H2 and 9-H2), 3.25-3.66 (4 H, m,
SiC(CH3)3], 1.45 and 1.71 (each 1 H, m, 7-H), 2.05-2.30 (4 H, m, 3-H2, OCH2CH2Si, 4-H, 10-H), 3.78-3.93 (1 H, m, 8-H), 4.09-4.18 (1 H, m,
5-H2), 3.26-3.92 (7 H, m, OCH2CH2Si, 8-H, 6-H, 2-H and 1-H2), 4.11 (1 11-H), 4.27-4.40 (2 H, m, 2ʹ-H2), 4.43-4.54 (2 H, m, OCH2O), 5.05-
H, m, 9-H), 4.33 (2 H, d, J 5.8, 2ʹ-H2), 4.43 (1 H, d, J 6.6, OHCHO), 5.14 (2 H, m, 1-H2), 5.58-5.70 (1 H, m, 1ʹ-H), 5.95 (1 H, dd, J 17.3,
4.49 and 4.50 (each 0.5 H, d, J 6.6, OHCHO), 5.60 (1 H, t, J 5.5, 1ʹ-H), 11.0, 2-H), 7.35-7.50 (12 H, m, ArH) and 7.67-7.77 (8 H, m, ArH); δC
7.35-7.51 (6 H, m, ArH) and 7.66-7.78 (4 H, m, ArH); δC −1.3, 5.5, −1.2, 5.5, 5.6, 7.3, 7.4, 15.6, 16.9, 18.1, 19.4, 22.9, 23.1, 3.5, 27.1,
7.3, 16.9, 18.1, 19.4, 19.5, 21.3, 27.1, 27.3, 35.8, 35.9, 40.1, 41.8, 27.3, 35.6, 35.8, 39.5, 40.2, 40.6, 40.8, 41.3, 41.4, 50.5, 61.1, 61.3,
60.7, 61.2, 65.4, 66.6, 66.8, 69.2, 69.7, 70.1, 70.3, 79.9, 96.0, 127.7, 65.2, 66.2, 68.9, 69.4, 69.8, 75.4, 75.8, 80.0, 80.2, 96.1, 112.8,
127.8, 128.0, 129.8, 129.9, 130.9, 134.1, 134.2(2), 134.5, 134.9, 127.7, 127.8, 127.9, 128.0, 129.5, 129.7, 129.9(2), 130.7, 130.9,
135.8 and 136.1; m/z (ES+) 1008 (89%), 538 (100%), 516 (92) and 133.2, 134.0, 134.1, 134.2, 135.0, 135.6, 135.8, 136.1(2), 145.6 and
236 (57). A mixture of tetrols (310 mg, 14%) was also isolated.
(5S,7R,8R)-8-tert-Butyldiphenylsilyloxy)-3-[(E)-2-tert-
butyldiphenylsilyloxyethylidene]-5-triethylsilyloxy-7-(2-
145.7; m/z (ES+) 1041 (100%).
(8S,10R,11R)-11-tert-Butyldiphenylsilyloxy-6-[(E)-2-tert-
butyldiphenylsilyloxyethylidene]-3,3-dimethyl-8-triethylsilyloxy-
trimethylsilylethoxymethoxy)nonanal (85). The diol 84 (682 mg, 10-(2-trimethylsilylethoxymethoxy)dodec-1-en-4-one (87). The
0.69 mmol) in THF (10 mL) was added to sodium periodate (590 mg, Dess-Martin periodinane (262 mg, 0.62 mmol) was added to the
2.76 mmol) in pH 7 aqueous buffer solution (5 mL) at rt and the mixture of epimeric alcohols 86 (262 mg, 0.26 mmol) and pyridine
mixture stirred for 30 min. Saturated aqueous sodium hydrogen (0.40 mL, 5.0 mmol) in DCM (4 mL) at rt and the reaction stirred for
carbonate was added and the mixture partitioned between water 1 h. Saturated aqueous sodium hydrogen carbonate was added and
and EtOAc. The aqueous layer was extracted with EtOAc and the the mixture partitioned between water and ether. The aqueous
organic extracts were washed with brine, dried (MgSO4) and layer was extracted with ether and the organic extracts were dried
concentrated under reduced pressure. Chromatography (1:10:89 (MgSO4)
and
concentrated
under
reduced
pressure.
Et3N:ether:light petroleum) of the residue afforded the title Chromatography (1:2:97 Et3N:ether:light petroleum) of the residue
compound 85 (489 mg, 75%), Rf = 0.53 (1:9 ether:light petroleum) afforded the title compound 87 (210 mg, 80%), Rf = 0.73 (1:9
24
(Found: M+ + Na, 975.5256. C55H84O6Si4Na equires M, 975.5237); ether:light petroleum), [α]D −1.2 (c 1.0, CHCl3) (Found: M+ + Na,
νmax/cm-1 2956, 2933, 2880, 2860, 1726, 1466, 1427, 1382, 1256, 1043.5865. C60H92O6Si4Na requires M, 1043.5863); νmax/cm-1 3071,
1107, 1058, 860, 828 and 739; δH −0.02 [9 H, s, Si(CH3)3], 0.57 (6 H, 2956, 2934, 2879, 2860, 1712, 1466, 1427, 1381, 1249, 1108, 1058,
q, J 8.0, 3 × SiCH2), 0.65 (1 H, ddd, J 13.8, 11.3, 5.3, SiHCH), 0.80 (1 936, 922, 860, 830 and 739; δH −0.03 [9 H, s, Si(CH3)3], 0.57 (6 H, q, J
H, ddd, J 13.8 11.7, 5.9, SiHCH), 0.91 (3 H, d, J 6.3, 9-H3), 0.94 (9 H, t, 7.8, 3 × SiCH2), 0.62 (1 H, ddd, J 13.9, 11.4, 5.3, SiHCH), 0.79 (1 H,
J 7.9, 3 x SiCH2CH3), 1.08 and 1.10 [each 9 H, s, SiC(CH3)3], 1.40 (1 H, ddd, J 13.8, 11.7, 5.9, SiHCH), 0.93 (3 H, d, J 6.3, 12-H3), 0.94 (9 H, t,
ddd, J 14.3, 10.7, 3.7, 6-H), 1.72 (1 H, ddd, J 14.3, 8.0, 1.7, 6-Hʹ), J 7.9, 3 × SiCH2CH3), 1.08 and 1.09 [each 9 H, s, SiC(CH3)3], 1.29 (6 H,
2.16 (2 H, d, J 6.2, 4-H2), 3.12 (2 H, s, 2-H2), 3.31 and 3.48 (each 1 H, s, 2 × 3-CH3), 1.43 (1 H, ddd, J 14.3, 10.7, 3.9, 9-H), 1.69 (1 H, ddd, J
ddd, J 11.3, 9.6, 5.9, OHCHCH2Si), 3.57 (1 H, m, 7-H), 3.86 (1 H, m, 5- 14.1, 8.6, 1.0, 9-Hʹ), 2.18 (1 H, dd, J 13.5, 7.6, 7-H), 2.27 (1 H, dd, J
H), 4.13 (1 H, dq, J 6.2, 4.2, 8-H), 4.35 (2 H, d, J 6.1, 2ʹ-H2), 4.41 and 13.6, 5.7, 7-Hʹ), 3.28 (2 H, s, 5-H2), 3.30 (1 H, ddd, J 11.4, 9.5, 5.9,
4.49 (each 1 H, d, J 6.8, OHCHO), 5.66 (1 H, t, J 6.0, 1ʹ-H), 7.35-7.49 OHCHCH2Si), 3.48 (1 H, ddd, J 11.6, 9.4, 5.3, OHCHCH2Si), 3.61 (1 H,
(12 H, m, ArH), 7.66-7.76 (8 H, m, ArH) and 9.61 (1 H, t, J 2.5, 1-H); dd, J 9.5, 3.9, 10-H), 3.83 (1 H, m, 8-H), 4.13 (1 H, dq, J 6.2, 4.3, 11-
δC −1.2, 5.5, 7.3, 16.9, 18.2, 19.4, 19.5, 27.1, 27.3, 35.8, 40.6, 52.5, H), 4.33 (2 H, d, J 6.0, 2ʹ-H2), 4.43 and 4.51 (each 1 H, d, J 6.8,
24 | J. Name., 2012, 00, 1-3
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OrgaPnleicas&e dBoionmoot laedcjuuslatrmCahrgeimnsistry
Journal Name
ARTICLE
1999, 121, 7540; (c) K. Ohmori, Y. Ogawa, T. Obitsu, Y. Ishikawa,
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2290; (d) S. Manaviazar, M. FrigerioD, OGI:.10S.1.03B9h/aCt7iaO,B0M00. 76GF.
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K. Woo and M. J. Krische, J. Am. Chem. Soc., 2011, 133, 13876.
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2011, 47, 7200.
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Acad. Sci. USA., 1988, 85, 7197; (b) P. A. Wender, J. L. Baryza, C.
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Kan, E. Lacôte, B. Lippa, P. G. Nell and T. M. Turner, J. Am.
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Lett., 2014, 16, 5140; (g) B. A. Loy, A. B. Lesser, D. Staveness,
K. L. Billingsley, L. Cegelski and P. A Wender, J. Am. Chem.
Soc., 2015, 137, 3678; (h) D. Staveness, R. Abdelnabi, A. J.
Schrier, B. A. Loy, V. A. Verma, B. A. DeChristopher, K. E.
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Prod., 2016, 79, 675; (i) D. Staveness, R. Abdelnabi, K. E.
Near, Y. Nakagawa, J. Neyts, L. Delang, P. Leyssen and P. A.
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OHCHO), 5.21 (1 H, dd, J 10.8, 0.9, 1-H), 5.22 (1 H, dd, J 17.4, 0.9, 1-
Hʹ), 5.50 (1 H, t, J 6.0, 1ʹ-H), 5.99 (1 H, dd, J 17.5, 10.6, 2-H), 7.34-
7.48 (12 H, m, ArH) and 7.67-7.76 (8 H, m, ArH); δC −1.2, 5.5, 7.3,
16.9, 18.1, 19.5, 23.9, 27.1, 27.3, 35.8, 40.0, 46.1, 51.4, 61.2, 65.2,
68.9, 69.8, 80.1, 96.2, 114.6, 127.7, 127.8, 127.9, 128.0, 129.7,
129.8, 131.6, 132.1, 134.1, 134.2, 135.0, 135.8, 136.1, 136.2, 142.8
and 210.7; m/z (ES+) 1043 (M+ + 23, 20%), 892 (12), 722 (25), 516
(47), 298 (52), 195 (100).
4
5
(2S)-4-[(E)-2-tert-Butyldiphenylsilyloxyethylidene]-2-[(2R,3R)-3-
tert-butyldiphenylsilyloxy-2-(2-
trimethylsilylethoxymethoxy)butyl]-6-(1,1-prop-2-enyl)-3,4-
dihydro-2H-pyran (88). Trimethyl orthoformate (0.16 mL, 1.47
mmol) and pyridinium toluene p-sulfonate (1.2 mg, 5 μmol) were
added to the ketone 87 (50 mg, 49 μmol) in anhydrous MeOH (0.3
mL) at rt and the mixture stirred for 1 h. Saturated aueous sodium
hydrogen carbonate was added and the mixture partitioned
between water and ether. The aqueous layer was extracted with
ether and the organic extracts were dried (MgSO4) and
concentrated under reduced pressure. Chromatography (5% EtOAc
1% Et3N in light petroleum) of the residue afforded the title
compound 88 (10 mg, 22%), Rf = 0.47 (1:9, ether:light petroleum),
20
[α]D (CHCl3) (Found: M+ + H, 889.5077. C54H77O5Si3 requires M,
889.5073); νmax/cm-1 2959, 2928, 2895, 2855, 1641, 1620, 1468,
1426, 1380, 1314, 1260, 1102, 1052, 1029, 860, 800 and 739; δH
(C6D6) −0.05 [9 H, s, Si(CH3)3], 0.73 and 0.86 (each 1 H, ddd, J 14.1,
10.6, 5.9, HCHSi), 1.22 (3 H, d, J 7.0, 4ʹ-H3), 1.20 and 1.24 [each 9 H,
s, SiC(CH3)3], 1.27 and 1.30 (each 3 H, s, 1ʹʹʹ-CH3), 1.53 and 1.82
(each 1 H, m, 1ʹ-H), 2.04-2.18 (2 H, m, 3-H2), 3.42 and 3.57 (each 1
H, ddd, J 10.7, 9.5, 6.2, OHCHCH2Si), 4.00 (1 H, m, 2-H), 4.14 (1 H,
ddd, J 10.7, 4.0, 1.1, 2ʹ-H), 4.28-4.43 (3 H, m, 2ʹʹ-H2, 3ʹ-H), 4.52 and
4.59 (each 1 H, d, J 6.7, OHCHO), 5.03 (1 H, dd, J 10.6, 1.3, 3ʹʹʹ-H),
5.10 (1 H, dd, J 17.5, 1.3, 3ʹʹʹ-Hʹ), 5.48 (1 H, s, 5-H), 5.60 (1 H, t, J 6.6,
1ʹʹ-H), 6.05 (1 H, dd, J 17.5, 10.6, 2ʹʹʹ-H), 7.22-7.31 (12 H, m, ArH)
and 7.81-7.90 (8 H, m, ArH); δC (C6D6) −1.4, 16.8, 18.1, 19.4, 19.5,
25.3, 25.5, 27.0, 27.3, 31.5, 34.4, 41.8, 60.7, 65.1, 69.9, 72.8, 77.9,
96.0, 101.6, 111.6, 120.2, 129.9, 130.0, 132.4, 134.2, 134.4, 135.0,
136.0(2), 136.2, 136.3, 145.6 and 162.0; m/z (APCI+) 889 (M+ + 1,
5%), 772 (5) and 633 (100). Some starting ketone 87 (10 mg) was
also recovered.
6
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Ackowledgements
We thank Dr. Alastair Rae and Dr. P. Almendros for preliminary
studies of the palladium catalysed couplings and the EPSRC for
studentships (to M. B. and T. G.).
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Notes and references
9
M. Ball, A. Baron, B. Bradshaw, R. Dumeunier, M. O’Brien and E.
J. Thomas, Org. Biomol. Chem., 2016, 14, 9650.
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
14 B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal, J. M.
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DOI: 10.1039/C7OB00076F
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