Some limitations of an approach to the assembly of bryostatins by ring-closing metathesis

Article abstract of DOI:10.1039/c7ob00079k

Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM wa

Full text of DOI:10.1039/c7ob00079k

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DOI: 10.1039/C7OB00079K
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ARTICLE
Some limitations of an approach to the assembly of bryostatins by
ring-closing metathesis
Received 00th January 20xx,
Accepted 00th January 20xx
Raphaël Dumeunier,a Thomas Gregson,a Somhairle MacCormick,a Hiroki Omoria and Eric J.
Thomasa*
DOI: 10.1039/x0xx00000x
Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of
bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-
deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1-C16 and C17-C27
fragments. However, studies of the formation of the C16-C17 double-bond by RCM were not successful and complex
mixtures of products were obtained. To provide a insight into factors that may be involved in hindering RCM in this
system, a slightly simplified C1-C16 acid and modified C17-C25 alcohols were prepared and their use for the synthesis of
analogues of bryostatins was investigated. Although only low yields were obtained, it appeared that macrolides analogous
to the bryostatins can be prepared by RCM, using the Grubbs II catalyst, if the precursors lack the two methyl groups at
C18. RCM was not observed, however, for substrates in which these methyl groups were present.
www.rsc.org/
We identified the 20-deoxybryostatins, e.g. bryostatin 10 (2),6
as initial targets for our synthetic work in this area because
Introduction
As discussed in earlier papers,1,2 approaches to the synthesis of
the bryostatins, as exemplified by bryostatin 1 (1) and 10 (2),
see Figure 1, are of interest because of their biological
activities and relative inaccessibility from natural sources.
Indeed several outstanding total syntheses have been
reported3 and synthetic analogues have been discovered that
have potent biological effects,4,5 some with tumour
suppressing bryostatin-like activity. Overall this work has been
a significant contribution to natural product synthesis and may
lead to improved cancer chemotherapy.
they have received less attention from synthetic chemists than
their C20-oxygenated counterparts such as bryostatin 1 (1). In
planning our synthesis, it was recognised that the use of
synthetic intermediates that corresponded to the C1-C16 and
C17-C27 fragments could lead to convergent approaches, see
Figure 2. Indeed, the early syntheses of bryostatins3a-d used
Julia reactions to assemble the C16-C17 double bond from an
aldehyde that corresponded to C1-C16 fragment and a sulfone
that matched the C17-C27 component. However, in these
syntheses several functional group interconversions had to be
deferred until after the assembly steps because of the vigorous
conditions required for conventional Julia reactions and this
undermined the convergency of these syntheses.
Me
Me
Me
Me
Me
H
O
H
O
Me
Me
HO
HO
O
Me
O
MeO2C
MeO2C
H
H
H
H
H
H
O
O
O
O
OH
OH
O
O
Me
MeO
Me
H
OH
OH
OP
Me
Me
O
O
O
O
MeO2C
Me
Me
Me
H
H
Me
Me
H
O
Me
Me
HO
O
X
O
20
20
O
MeO2C
O
Me
CO2Me
OH
Me
CO2Me
OH
OP
H
H
H
1
O
16
O
O
1
nPr
O
3
OH
OH
16
17
OH
O
+
2
1
17
Y
Me
Me
O
O
OP
H
Me
O
OH
20
27
Me
Figure 1 Representative bryostatins
Me
OH
27
Me
OP
CO2Me
CO2Me
2
(X = O, Y = H, PhS(O)2, Julia;
X = Y = CH2, metathesis
P = protecting groups)
a. The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Corresponding author; tel: +44 (0)161 275 4613; e-mail:
e.j.thomas@manchester.ac.uk
4
*
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Figure 2 Disconnections of 20-deoxybryostatins
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J. Name., 2013, 00, 1-3 | 1
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Organic & Biomolecular Chemistry
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As an alternative, It was thought that a late-stage ring-closing These results were very disappointing especially as the ester 9
View Article Online
metathesis (RCM)7 could provide
a
better convergent was available in fewer than 25 linDeOarI: 10s.t1e0p39s/Cf7rOoBm000(7R9)K-
approach for assembly of bryostatins by being compatible with pantolactone. Several reasons were considered for the lack of
more of the complex functionality present in these challenging success in this ring-closing metathesis. The ketone at C19 may have
natural products. We have reported full details of syntheses of been coordinating to organometallic intermediates formed by
C1-C161 and C17-C272 fragments that could be incorporated metathesis of the proximal terminal double bond so inhibiting the
into both Julia and RCM-based syntheses, see Figure 2. We catalytic cycle. Alternatively steric hindrance due to the two
now describe full details of some preliminary studies into the geminal methyl groups at C18 may have been a critical factor
use of RCM for the synthesis of bryostatins.8
although there are examples of alkenes with geminal allylic methyl
groups successfully engaging in ring-closing metathesis.9
It was decided not to study the ring-closing metathesis of ester
9 any further at this stage. Instead RCM of simpler analogues was
Results and discussion
Unsuccessful attempts to prepare a fully functionalised investigated to see what could be learnt about the structural factors
precursor of a bryostatin by ring-closing metathesis
that might be involved in impeding RCM in this series.
The alcohol 51 was oxidised to the acid 6 that was esterified
Studies of ring-closing metathesis for the preparation of simplified
using the alcohol 8 prepared by selective deprotection of the analogues of bryostatins
SEM-ether 72 to give ester 9 (Scheme 1). However, attempts The slightly simplified C1-C16 fragment 26 was synthesised as
to carry out a RCM of this ester to give the macrolide 10 using outlined in Schemes 2 and 3. Oxidation of the alcohol 1110 with an
the Grubbs II catalyst were unsuccessful and gave mixtures of in situ Wittig reaction gave the (E)-alkene 12 that was reduced to
products that could not be properly characterised. It appeared the alcohol 13. A Sharpless asymmetric oxidation using (−)-di-
that some isomerisation of the double bond attached to the isopropyl tartrate gave the hydroxyepoxide 14 that was converted
tetrahydropyran had taken place along with partial loss of the into the iodide 15. Treatment of this with tert-butyllithium initiated
methoxy acetal, and only traces of an (E)-disubstituted alkene iodide-lithium exchange and subsequent epoxide ring-opening11 to
were detected in the crude product mixtures (1H NMR).
give the allyl alcohol 16 that was shown to have an ee of >95% by
comparison of the 1H NMR spectra of its (R)- and (S)-O-
acetylmandelates.12 After O-silylation, selective removal of the p-
methoxybenzyl ether gave the alcohol 18 that was oxidised using
the Dess-Martin periodinane to the aldehyde 19 (Scheme 2).
Me
Me
Me
Me
H
O
H
O
MeO
MeO
OBn
OBn
H
H
H
H
i
O
OSEM
O
OSEM
O
i
CO2Me
SEMO
OH
SEMO
OH
5
6
PMBO
OH
PMBO
12
11
+
ii
OTBS
CH3
OTBS
CH3
O
Me
Me
Me
Me
iii
O
OSEM
OTBS
ii
O
OH
i
PMBO
OH
PMBO
X
OTBS
14 X = OH
15 X = I
13
iv
v
8
7
OTBDPS
OTBDPS
OP
iii
OTES
vii
Me
Me
Me
Me
PMBO
HO
H
O
MeO
H
O
MeO
OBn
OBn
18
16 X = OH
H
H
H
H
vi
O
O
OSEM
O
OSEM
17 X = OTES
viii
OSEM
OSEM
O
O
OTES
OTBS
OTBS
Me
Me
Me
Me
OHC
O
O
O
19
CH3
OTBS
CH3
OTBS
Scheme 2 Synthesis of aldehyde 19 Reagents and conditions i,
DMSO, (COCl)2, DCM, −78 oC, 20 min, 11, −78 oC, 20 min, Et3N, −78
OTBDPS
OTBDPS
10
9
o
oC to rt, 20 min, −78 C, Ph3PCHCO2Me, DCM, rt, 14 h (ca. 99%); ii,
Scheme 1 Unsuccessful attempts at ring-closing metathesis DIBAL-H, hexanes, THF, −78 oC to rt, 4 h (98%); iii, (−)-DIPT, 4Å
o
Reagents and conditions i, (a) Dess-Martin periodinane, py., sieves, Ti(OiPr)4, 10 min, −20 C, tBuOOH, decanes, 30 min, 13, −20
t
DCM, rt, 5 min; (b) NaH2PO4.2H2O, 2-methylbut-2-ene, THF, oC, 4 h (ca. 99%); iv, Ph3P, I2, imid., THF, rt, 2 h (92%); v, BuLi,
NaClO2, BuOH, H2O, rt, 5 min; ii, K2CO3, MgBr2.Et2O, BuSH, hexanes, THF, −78 oC, 15 min (95%); vi, TESCl, imid., DCM, 0 oC to rt,
t
n
ether, rt, 20 min (64%); iii, 6, 2,4,6-C6H2C(O)Cl, tol., Et3N, rt, 1 16 h (ca. 100%); vii, pH 7 buffer, DCM, DDQ, rt, 10 min (73%); viii,
h, add 8, DMAP (cat.), rt, 10 min (57% from 5).
Dess-Martin periodinane, py., DCM, rt, ca. 2 h (94%).
2 | J. Name., 2012, 00, 1-3
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The aldehyde 19 was condensed with the ketophosphonate 201 to
give the enone 21. Deprotection using hydrogen fluoride-pyridine
complex removed the triethylsilyl group selectively to give the
alcohol 22 that on treatment with potasium tert-butoxide cyclised
to the 2,6-cis-disubstituted tetrahydropyran 23 in an excellent yield.
Alternatively, removal of both of the silyl protecting groups from
the bis-silyl ether 21 followed by in situ treatment with base gave
the primary alcohol 24 in a 62% yield based on the phosphonate 20,
see Scheme 3.
The silyl ether 23 was taken through to the methoxyacetal 25
using pyridinium toluene p-sulfonate and trimethyl orthoformate in
methanol, and a protection-deprototection sequence gave the
primary alcohol 27 via the SEM-ether 26. In this synthesis, the yields
in the steps between the phosphonate 20 and the C1-C17 alcohol
27 were significantly better than those in the synthesis of the fully
functionalised C1-C16 fragment 5 and the alcohol 27 was available
in a >30% overall yield from alcohol 11, see Scheme 3.
View Article Online
DOI: 10.1039/C7OB00079K
OBn
OBn
iii
OBn
i
O
OH
OTBS
31
iv
OP
28
29 P = H
30 P = TBS
ii
Me
Me
OBn
v
OBn
OHC
OTBS
32
OH
OTBS
33
vi
Me
Me
Me
O
Me
Me
O
OBn
OBn
viii
OP
OP
34 P = TBS
35 P = H
36 P = H and 37 P = CH3
vii
Scheme 4 Synthesis of hydroxyketone 35 Reagents and conditions i,
CuI, CH2=CHCH2Br, THF, −40 oC to −30 oC, 20 min, 28, THF, −40 oC, 1
o
h (83%); ii, TBSCl, imid., DCM, 0 C to rt, 22 h (93%); iii, BH3.THF,
THF, −25 oC to rt, 16 h, NaOH, 30% H2O2 (86%); iv, DMSO,
Products corresponding to simplified C17-C27 fragments of
bryostatins were now prepared, one with and one without two
geminal allylic methyl groups.
o
o
o
(COCl)2, −78 C, 10 min, 31, −78 C, 20 min, Et3N, −78 C to rt 30
min; v, 1-bromo-3-methylbut-2-ene, Zn, THF, rt, 10 min, 32, rt, 15 h
o
Reaction of the epoxide 2813 with allylmagnesium bromide,
catalysed by copper(I) iodide, gave the alcohol 29 that was
protected as its tert-butyldimethylsilyl ether 30, see Scheme 4.
Hydroboration-oxidation gave the alcohol 31 that was oxidised to
the aldehyde 32. Addition of the organozinc reagent prepared from
dimethylallyl bromide then gave a mixture of the epimers of the
alcohol 33 that was oxidised to the ketone 34. Desilylation gave the
hydroxyketone 35 with traces of its cyclic hemiacetal. Treatment of
this hydroxyketone with base and methyl iodide led to methylation
of the corresponding enolate to give ketone 36, essentially as a
single diastereoisomer, although the configuration at C5 was not
established, together with some of the corresponding methyl ether
37, see Scheme 4.
(67% from 31); vi, DMSO, (COCl)2, DCM, −78 C, 10 min, 33, DCM,
−78 C, 20 min, Et3N, −78 C to rt, 30 min; vii, TBAF, THF, rt, 16 h
(85% from 33); viii, NaH, DMF, 0 C, 30 min, MeI, 30 min (36, 39%;
o
o
o
37, 18%).
Cyclisation of the hydroxyketone 35 under acidic conditions gave
the enol ether 38 and oxidation in methanol using m-
chloroperoxybenzoic acid gave the hydroxyacetal 39 together with
ca. 25% of a side product that may have been an isomer, but which
was not purified. However, oxidation of the mixture gave the
tetrahydropyranone 40 and this on reduction using lithium
triethylborohydride gave the alcohol 39 essentially as a single
diastereoisomer. This was converted into its methyl ether 41 and
debenzylation gave the primary alcohol 42, see Scheme 5.
Me Me
Me Me
Me Me
i
ii
(MeO)2P
O
O
OBn
O
O
OTES O
OBn
O
O
OTBDPS
OTBDPS
OH
O
OBn
O
O
OTBDPS
Me
Me
Me
Me
Me
Me
22
iii
21
iv
20
Me Me
Me Me
H
O
H
O
H
H
O
OBn
O
O
OH
O
OBn
O
O
OTBDPS
Me
Me
Me
Me
23
24
v
Me
Me
Me
Me
Me
Me
H
H
O
H
MeO
MeO
MeO
OBn
OBn
OBn
vi
H
H
H
H
H
H
vii
O
O
O
O
O
SEMO
OH
SEMO
OTBDPS
OH
OTBDPS
26
25
27
Scheme 3 Synthesis of a simplified C1-C16 fragment Reagents and condtions i, Ba(OH) , THF, rt, 30 min, 19, wet THF, 18 h; ii, HF.py.,
₂
THF, py., rt, 15 min (87% from 20); iii, KO!Bu, THF, rt, 40 min (81%); iv, (a) TBAF, THF, rt, 16 h; (b) KO!Bu, THF, 40 min (24, 62% from
20 via 21); v, HC(OMe) , PPTS, MeOH, rt, 17 h (86%); vi, SEMCl, #Pr NEt, DCM, 0 XC to rt, DMAP (86%); vii, TBAF, THF, rt, 14 h (93%).
₃
₂
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DOI: 10.1039/C7OB00079K
H
O
OH
Me
Me
O
H
O
i
OBn
i
OH
OP
Me
Me
H
44 P = H
OH
43
ii
OBn
OBn
OBn
45 P = TIPS
35
38
iii
OH
OTES
OTES
ii
iv
OTIPS
OTIPS
OMe
H
iii
iv
OMe
O
H
46
O
47
Me
Me
Me
Me
OBn
3
v
4
O
HO
OMe
H
O
OTES
40
O
OP
39
vi
v
OTIPS
48
49 P = TIPS
50 P = H
OMe
O
H
vii
OMe
O
H
vi
Me
Me
Me
Me
OH
MeO
MeO
Scheme 6 Synthesis of the methoxy acetal 50 Reagents and
42
conditions: i, Red-Al, tol., THF, 0 oC, 4 h (94%); ii, TIPSCl, imid., DCM,
41
o
Scheme 5 Synthesis of the C17-C25 fragment 42 Reagents and
conditions: i, TsOH, benzene, 50 oC, 3 h, 4Å sieves, CSA, rt, 16 h (ca.
100%); ii, mCPBA, MeOH, 4Å sieves, rt, 1 h (89%); iii, Dess-Martin
periodinane, py., DCM, 0 oC to rt, 4 h (86% from 38); iv, (a) LiBHEt3,
THF, −10 oC to rt, 15 h (b) NaH, MeI, ether, −10 oC to rt, 15 h (76%
from 40); v, Na, liq. NH3, EtOH, −78 oC, 2 h (97%).
0 C to rt, 16 h (99%); iii, TESCl, imid., DCM, rt, 1 h (99%); iv, (a)
ozone, DCM, −78 oC, ca. 45 min, Me2S, rt (b) CH2=CHCH2Br, THF, rt,
16 h (67% from 46); v, Dess-Martin periodinane, py., DCM, rt, 50
min (76%); vi, HC(OMe)3, PPTS, MeOH, rt, 17 h (64%); vii, TBAF, THF,
rt, 16 h (ca. 100%).
under similar reaction conditions from the reaction with ester 54,
see Scheme 7. The metathesis product 53 was identified from its
spectroscopic data with the newly formed (E)-double-bond being
clearly evident in its 1H NMR spectrum (16-H, δ 5.68, 1 H, dd, J 15.3,
7.5; 17-H, δ 6.07, 1 H, ddd, J 15.3, 8.0, 5.4). Although the yield of
this RCM product was only modest, the reaction was not optimised.
Apart from the product 53, complex mixtures of other products
were isolated that were not characterised. For the ester 54, only
very minor traces of a product with an (E)-double-bond were
detected in the crude product mixtures from attempted RCM. The
formation of dimeric products and the loss of the double bond next
The structures shown were assigned to the products in Schemes 4
and 5 on the basis of spectroscopic data. In particular, for the
alcohol 39, H-3 was shown to be axial since it had coupling
constants of 11.4 Hz and 4.7 Hz with the axial and equatorial
protons at H-4. Similar coupling constants were found for the
methyl ethers 41 and 42. The alkyl substituents at C-2 and C-6 in the
alcohol 39 were equatorial with the methoxy group at C-2 in the
anomerically preferred axial position. The configuration at C-3
shown for alcohol 39 was also consistent with the reduction of
ketone 40 from the less hindered direction.
The acetal 50 was prepared to evaluate RCM with a substrate
that lacked the two geminal allylic methyl groups, see Scheme 6.
Epoxide 4314 was prepared from the corresponding diene using
a Sharpless asymmetric epoxidation with (+)-diethyl tartrate.
Reduction with sodium bis-(2-methoxyethoxy)aluminium hydride15
gave the diol 44 that was protected as its tri-isopropylsilyl ether 45.
This was converted into its triethylsilyl ether 46 that was taken
through to the alcohol 47 as a mixture of epimers by ozonolysis and
reaction of the ensuing aldehyde with allylmagnesium bromide.
Oxidation gave the ketone 48 that was converted into the methoxy
acetal 49 in one step using pyridinium toluene p-sulfonate and
triethyl orthoformate in methanol. The acetal was isolated
essentially as a single anomer that was assigned the configuration
shown at C-2 on the basis of the anomeric effect. Finally,
desilylation gave the alcohol 50 ready for studies of ring closing
metathesis, see Scheme 6.
1
to the tetrahydropyran were significant as indicated by MS and H
NMR, see experimental.
Summary and conclusions
The paper reports only a few preliminary results on the use of RCM
for the synthesis of bryostatins. However, the results obtained are
consistent with the geminal methyl groups at C18 providing
additional hindrance that helps to prevent effective RCM for the
esters 9 and 54. In contrast, under the same reaction conditions
using the Grubbs II catalyst, the ester 52 that lacked these methyl
substituents, gave some of the metathesis product 53, albeit in only
a very modest, albeit unoptimised, yield. In a parallel study, Trost
and his collaborators found, during a study of the synthesis of
bryostatin 1 using a relay RCM to form the C16-C17 double-bond,
that a ring-expanded bryostatin was formed but this did not
undergo the relay metathesis reaction to give a macrolide
corresponding to the naturally occurring bryostatins.16
The C1-C16 alcohol 27 was oxidised to the acid 51 via the
corresponding aldehyde and the acid was esterified with the C17-
C25 alcohols 50 and 42 to give the esters 52 and 54. Using the
Grubbs II catalyst, a modest, 17%, yield of the (E)-alkene 53 was
obtained from the ester 52 but no cyclised product was isolated
Clearly the low yield obtained for the cyclisation of ester 52
mitigates against firm conclusions being drawn from our work since
further studies using a wider range of catalysts and reaction
conditions are really required for the scope of this approach to be
4 | J. Name., 2012, 00, 1-3
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View Article Online
DOI: 10.1039/C7OB00079K
OBn
Me
Me
Me
Me
H
O
MeO
H
O
MeO
OBn
H
O
H
H
H
H
OMe
O
H
O
iii
ii
OH
OSEM
O
OSEM
Me
+
16
Me
17
O
H
O
MeO
OBn
OMe
O
H
i
OMe
O
O
O
H
27
H
50
O
O
53
52
SEMO
OH
+
Me
Me
Me
Me
H
O
MeO
H
O
MeO
51
OBn
OBn
OMe
O
H
H
H
H
H
H
OH
O
Me
Me
O
OSEM
OSEM
iii
ii
O
O
MeO
OMe
O
H
OMe
O
O
O
42
Me
Me
Me
Me
MeO
MeO
54
55
Scheme 7 Synthesis of analogues of bryostatins using RCM Reagents and conditions i, (a) Dess-Martin periodinane, py., DCM, rt,
15 min; (b) NaH PO .2H O, 2-methylbut-2-ene, tBuOH, water, THF, NaClO , 0 NC, 5 min; ii, 2,4,6-Cl C H C(O)Cl, tol., Et N, rt, 1 h, 50
₂
₄
₂
₂
₃
₆
₂
₃
or 42, tol., DMAP, rt, 30 min (52, 47% from 27); iii, Grubbs II cat., tol., 60 NC, ca. 12 h (53, 17%).
properly delineated. Of interest in this context, is the recent spectrometer. Spectra were recorded at 300 Mz (1H) and at 75 Mz
isolation of naturally occurring bryostatins in which there is only (13C) and were in in deuteriated chloroform unless otherwise
one methyl group at C18.17 Whether these natural products could indicated. Coupling constants (J) are given in Hertz (Hz) and
be synthesised by RCM is a tantalising prospect. However, at this chemical shifts are relative to tetramethylsilane. Residual non-
point, we chose not to continue with investigations of RCM deuteriated solvent was used as the internal standard.
reactions for the synthesis of naturally occuring bryostatins. Instead
Epoxide 43 was prepared from oct-2,7-dien-1-ol as desecribed
20
we decided to study the synthesis of 20-deoxybryostatins using the for its enantiomer14 but using L-(+)-diethyl tartrate, and had [α]D
C1-C16 and C17-C27 fragments we already had available, but using −28.7 (c 3.1, CHCl3), [lit.14 for the enantiomer, [α]D +38.6 (c 1.8,
23
the modified Julia reaction to assemble the 16,17-double-bond. This CHCl3)].
work eventually led to
a
successful synthesis of
a
20- (8S,10R,11R)-8,11-Bis-(tert-butyldimethylsilyloxy)-6-[(E)-(2-tert-
butyldiphenylsilyloxyethylidene]-3,3-dimethyl-10-hydroxydodec-
1-en-4-one (8). Solid potassium carbonate (278 mg, 2.01 mmol),
magnesium bromide diethyl etherate (437 mg, 1.69 mmol) and n-
butanethiol (0.18 mL, 1.68 mmol) were added to the SEM-ether 7
(181 mg, 0.20 mmol) in ether (4 mL) and the mixture stirred for 30
min then poured into water (100 mL) and ether (100 mL). The
aqueous layer was extracted with ether (3 × 50 mL) and the organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography (10:1 light petroleum:ether with 1%
triethylamine) of the residue gave the title compound 8 as a
colourless oil (99 mg, 64%), Rf = 0.5 (1:10 ether:light petroleum),
deoxybryostatin.18,19
Experimental
General experimental details
Flash column chromatography was performed using Merck silica gel
(60H; 40-60µ, 230-240 mesh). Light petroleum refers to the fraction
boiling between 40 and 60 °C and was redistilled before use.
Tetrahydrofuran was dried over sodium-benzophenone and was
distilled under nitrogen prior to use. Dichloromethane was dried
over CaH2 and was distilled before use. Ether refers to diethyl ether.
Reactions under non-aqueous conditions were carried out under an
atmosphere of nitrogen or argon.
20
[α]D +3.0 (c 7.8, CHCl3) (Found: M+ + Na, 789.4728. C44H74O5Si3Na
requires M, 789.4736); νmax/cm-1 3570, 3071, 3051, 2954, 2931,
2892, 2857, 1713, 1635, 1471, 1428, 1256, 1110, 1069, 1006, 836,
and 777; δH 0.02, 0.05, 0.06 and 0.08 (each 3 H, s, SiCH3), 0.87,
0.90 and 1.07 [each 9 H, s, SiC(CH3)3], 1.11 (3 H, d, J 6.2, 12-H3), 1.18
(1 H, m, 9-H), 1.27 (6 H, s, 2 × 3-CH3), 1.42 (1 H, m, 9-Hʹ), 2.15 (1 H,
dd, J 13.5, 8.3, 7-H), 2.20 (1 H, dd, J 13.5, 5.9, 7-Hʹ), 2.41 (1 H, d, J
5.0, OH), 3.18 and 3.28 (each 1 H, d, J 16.4, 5-H), 3.40-3.60 (2 H, m,
8-H, 10-H), 3.95 (1 H, m, 11-H), 4.27 (2 H, d, J 6.3, 2ʹ-H2), 5.17-5.25
(2 H, m, 1-H2), 5.47 (1 H, t, J 6.2, 1ʹ-H), 5.96 (1 H, dd, J 17.6, 10.5, 2-
H), 7.35-7.50 (6 H, m, ArH) and 7.60-7.75 (4 H, m, ArH); δC −4.6(2),
−4.0, −3.9, 18.2(2), 19.4, 20.2, 23.9, 26.1, 26.2, 27.1, 39.6, 40.4,
Mass spectra used electron impact ionisation (EI+), chemical
ionisation using ammonia (CI+), electrospray ionisation in the
positive mode (ES+) and atmospheric pressure chemical ionisation
in the positive or negative mode (APCI+ or APCI-). Low and high
resolution mass spectra were recorded using a Micromass Trio 200
and a Kratos Concept IS spectrometer, respectively. Infra-red
spectra were measured using a Genesis FTIR spectrometer on NaBr
plates, either neat or as evaporated films. Nuclear magnetic
resonance spectra were recorded using a Varian Unity 300 (300 Mz)
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J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
46.0, 51.4, 61.1, 68.7, 72.2, 114.8, 127.9, 129.9, 131.6, 132.2, 134.0, 1ʹʹʹ-H), 5.88 (1 H, dd, J 17.6, 10.5, 2ʹ-H), 5.93 (1 H, ddd, J 17.3, 10.4,
View Article Online
134.1, 135.8, 135.9, 142.7 and 210.7; m/z (ES+) 790 (100%).
(8S,10R,11R)-8,11-Bis-(tert-butyldimethylsilyloxy)-6-[(E)-(2-tert-
butyldiphenylsilyloxyethylidene]-3,3-dimethyl-4-oxododec-1-en-
5.4, 16-H), 7.1-7.40 (11 H, m, ArH) and 7.8D0-O7I.:9100.1(403H9/,Cm7O, BA0r0H0);79δKC
(C6D6) −4.6, −4.5, −3.8, −1.3, 15.5, 18.2, 18.3, 19.4, 23.7, 26.1, 26.3,
27.0, 43.5, 48.5, 51.4, 62.6, 65.1, 65.6, 65.8, 71.6, 75.3, 78.2, 79.1,
10-yl
(3R,5R,7S,9S,11S,15R)-7-Benzyloxy-13-[(Z)-2-(2- 93.9, 104.5, 114.3, 120.5, 127.5, 128.4(2), 129.9, 130.0, 132.6,
trimethylsilylethoxymethoxy)ethylidene]-5,9-epoxy-11,15-epoxy-
8,8-dimethyl-9-methoxy-3-(2-
135.9, 139.4 and 170.7; m/z (ES+) 1550 (M+ + 23, 100%).
Methyl (E)-7-(4-methoxybenzyloxy)hept-2-enoate (12). Dimethyl
trimethylsilylethoxymethoxy)heptadec-16-enoate (9). Pyridine (28 sulfoxide (7.1 mL, 100 mmol) was added dropwise to oxalyl chloride
mL, 7.5 eq.) and then, afer 5 min, the alcohol 5 (33 mg, 0.043 mmol) (7 mL, 80 mmol) at –78 oC in DCM (150 mL). The mixture was
o
in DCM (2 mL) were added to a suspension of the Dess-Martin stirred for 20 min at −78 C and the alcohol 11 (12 g, 53 mmol) in
periodinane (29 mg, 1.5 eq.) in DCM (1 mL). After 5 min, saturated DCM (50 mL) was added dropwise. After stirring for 20 minutes,
aqueous sodium bicarbonate (10 mL) and Et2O (10 mL) were added triethylamine (42.8 mL, 320 mmol) was added and stirring was
o
and the aqueous phase extracted with Et2O (3 × 10 mL). The organic continued at −78 C for 20 min. The mixture was allowed to warm
o
o
extracts were washed with saturated aqueous sodium thiosulfate to 0 C and stirred for 20 min then cooled to −78 C and methyl
(10 mL), dried (Na2SO4) and concentrated under reduced pressure (triphenylphosphoranylidene)acetate (1.5 g, 4.5 mmol) in DCM (75
to afford the aldehyde that was used in the next step.
mL) was added. The solution was allowed to warm to rt and stirred
Solid NaH2PO4.2H2O (67 mg, 10 eq.) and 2-methylbut-2-ene in for 16 h. Saturated aqueous ammonium chloride (100 mL) was
THF (2 M in THF, 0.43 mL, 20 eq.) were added to this aldehyde in a added and the organic layer diluted with ether (200 mL). The
mixture of t-BuOH:water (2:1, 0.5 mL). The mixture was cooled to 0 organic phase was washed with water (150 mL) and brine (150 mL).
°C and NaClO2 (24.5 mg) in t-BuOH:water (2:1, 0.5 mL) was added. A conventional work-up gave the title compound 12, a colourless oil
After stirring for 5 min, saturated sodium hydrogen carbonate in (14.9 g, 99%) with just traces of its (Z)-isomer (Found: M+ + NH4,
brine (1:1, 2 mL) and ethyl acetate (5 mL) were added. The aqueous 296.1855. C16H26O4N requires M, 296.1856); νmax/cm-1 2999, 2940,
phase was extracted with EtOAc (4 × 2 mL) and the organic extracts 2860, 1722, 1655, 1613, 1586, 1513, 1459, 1438, 1302, 1202, 1172,
were dried (Na2SO4) and concentrated under reduced pressure to 1099, 1036, 983 and 821; δH 1.50-1.70 (4 H, m, 5-H2, 6-H2), 2.21 (2
give the acid 6 that was used as soon as possible in the next step; δH H, q, J 6.4, 4-H2), 3.67 (2 H, t, J 6.4, 7-H2), 3.77 and 3.82 (each 3 H, s,
(C6D6) 1.02 and 1.05 [each 9 H, s, SiCH3)3], 0.80-1.10 (4 H, m, 2 × OCH3), 4.47 (2 H, s, ArCH2), 5.82 (1 H, dt, J 15.2, 1.5, 2-H), 6.99 (1 H,
SiCH2), 1.28 and 1.32 (each 3 H, s, 8-CH3), 1.55-1.95 ( 6 H, m, 4-H2, dt, J 15.8, 7.5, 3-H) and 6.90 and 7.29 (each 2 H, d J 8.8, ArH); δC
6-H2, 10-H, 12-H), 2.04 (1 H, br. t, J 11.0, 14-Hax), 2.25-2.45 (2 H, m, 25.0, 29.5, 32.2, 51.6, 55.5, 69.8, 72.8, 114.0, 121.3, 129.5, 130.9,
10-Hʹ, 12-Hʹ), 2.63 (1 H, br. d, J 11.0, 14-Heq), 2.68 and 2.88 (each 1 149.6, 159.4, 167.4; m/z (CI+) 296 (M+ + 18, 100%).
H, dd, J 16.0, 5.0, 2-H), 3.17 (3 H, s, OCH3), 3.50-3.95 (8 H, m, 3-H, 5- (E)-7-(4-Methoxybenzyloxy)hept-2-en-1-ol
(13).
Di-
H, 7-H, 11-H, 2 × CH2CH2Si), 4.51 (1 H, dd, J 11.9, 7.0, 2ʹ-H), 4.27 (1 isobutylaluminium hydride (1 M in hexanes, 200 mL, 200 mmol) was
o
H, m, 2ʹ-Hʹ), 4.28 (1 H, d, J 11.8, PhHCH), 4.42 (1 H, m, 15-H), 4.47 (1 added to the ester 12 (22.3 g, 80 mmol) in THF (100 mL) at −78 C
H, d, J 11.8, PhHCH), 4.70, 4.77, 4.79 and 4.80 (each 1 H, d, J 6.9, and the solution stirred at rt for 4 h. After cooling to −78 oC,
OHCHO), 5.07 (1 H, dt, J 10.5, 1.5, 17-H), 5.42 (1 H, dt, J 17.3, 1.6, methanol (60 mL) was added over 30 min before warming to rt and
17-Hʹ), 5.67 (1 H, br. t, J 6.4, 1ʹ-H), 5.94 (1 H, ddd, J 17.3, 10.4, 5.4, pouring into a vigorously stirred mixture of saturated aqueous
16-H), 7.05-7.25 (3 H, m, ArH) and 7.33 (2 H, d, J 7.0, ArH).
sodium potassium tartrate (350 mL) and ether (700 mL) at 0 oC. The
Triethylamine (12 µL) and 2,4,6-trichlorobenzoyl chloride (8 µL) mixture was stirred for 30 min and then the aqueous layer was
were added to the acid 6 (from 33 mg, 0.043 mmol of the alcohol 5) extracted with ether (3 × 300 mL). The organic extracts were dried
in toluene (1 mL) and the reaction mixture was stirred at rt for 1 h. (MgSO4)
and
concentrated
under
reduced
pressure.
The alcohol (33 mg) in toluene (1.4 mL) and 4- Chromatography (1 : 8 ethyl acetate:hexane then 1:1 ether:light
8
dimethylaminopyridiine (8 mg) were added and the mixture was petroleum) afforded the title compound 13 as a colourless oil (18.5
stirred for a further 10 min. Saturated aqueous sodium hydrogen g, 98%) (Found: M+, 250.1570. C15H22O3 requires M, 250.1563);
carbonate (10 mL) and EtOAc (10 mL) were added and the aqueous νmax/cm-1 3401, 3000, 2935, 2858, 1670, 1613, 1586, 1514, 1463,
phase was extracted with ether (3 × 10 mL). The organic extracts 1363, 1302, 1245, 1174, 1097, 1035, 972 and 821; δH 1.40-1.70 (4
were dried (Na2SO4) and concentrated under reduced pressure. H, m, 5-H2, 6-H2), 2.05-2.209 (2 H, m, 4-H2), 2.40 (1 H, s, OH), 3.44 (2
Chromatography (15:1 light petroleum:ether with 1% Et3N) of the H, t, J 6.4, 7-H2), 3.80 (3 H, s, OCH3), 4.07 (2 H, d, J 6.5, 1-H2), 4.42 (2
residue gave the title compound 9 (38 mg, 57 %); δH (C6D6) 0.02 and H, s, ArCH2), 5.60-5.80 (2 H, m, 2-H, 3-H) and 6.90 and 7.29 (each 2
0.05 [each 9 H, s, Si(CH3)3], 0.14, 0.17, 0.20 and 0.25 (each 3 H, s, H, d, J 8.8, ArH); δC 26.0, 29.5, 32.2, 55.5, 64.0, 70.2, 72.8, 114.0,
SiCH3), 1.00 and 1.03 [each 9 H, s, SiC(CH3)3], 0.98-1.06 (4 H, m, 2 × 128.5, 129.5, 131.0, 133.2 and 159.4; m/z (CI+) 268 (M+ + 18, 100%),
SiCH2), 1.22 [9 H, s, SiC(CH3)3], 1.00-1.15 (9 H, m, 2 × 8-CH3, 12ʹ-H3), 251 (M+ + 1, 10), 138 (70) and 121 (70).
1.26 and 1.34 (each 3 H, s, 3ʹ-CH3), 1.75-2.95 (18 H, m, 2-H2, 4-H2, 6-
(2R,3R)-7-(4-Methoxybenzyloxy)-2,3-epoxyheptan-1-ol (14). (−)-
H2, 10-H2, 12-H2, 14-H2, 5ʹ-H2, 7ʹ-H2, 9ʹ-H2), 3.34 (3 H, s, OCH3), 3.7- Di-isopropyl tartrate (0.32 mL, 2.1 mmol) and Ti(OiPr)4 (0.29 mL, 2
4.08 (9 H, m, 3-H, 5-H, 7-H, 11-H, 8ʹ-H, 2 × OCH2CH2Si), 4.14-4.26 (3 mmol) were added to a suspension of 4Å molecular sieves (1 g) and
H, m, 11ʹ-H, 2ʹʹ-H2), 4.32 (1 H, d, J 11.2, PhHCH), 4.40-4.60 (4 H, m, the mixture stirred for 10 min at rt then cooled to −20 oC. tert-Butyl
15-H, 2ʹʹʹ-H2, PhHCH), 4.70, 4.73, 4.82 and 4.86 (each 1 H, d, J 6.5, hydroperoxide (5 M in decanes, 6 mL, 30 mmol) was added and the
OHCHO), 5.02-5.12 (3 H, m, 17-H, 1ʹ-H2), 5.24 (1 H, m, 10ʹ-H), 5.39 suspension stirred for 0.5 h before the alcohol 13 (5 g, 20 mmol)
(1 H, dt, J 17.0, 1.5, 17-Hʹ), 5.63 and 5.72 (each 1 H, br. t, J 6.5, 1ʹʹ-H, was added. After stirring at −20 oC for 4 h, brine containing sodium
6 | J. Name., 2012, 00, 1-3
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Page 7 of 15
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
hydroxide (3 M) was added and solution allowed to warm to rt H, s, OCH3), 4.45 (2 H, s, ArCH2), 4.93 (1 H, dt, J 17.1, V1i.e3w,A1rt-iHcle),O5n.l0in2e
DOI: 10.1039/C7OB00079K
then extracted with ether (3 × 100 mL). The organic extracts were (1 H, dt, J 10.7, 1.2, 1-H’), 5.29 (1 H, q, J 5.4, 3-H), 5.62 (1 H, ddd, J
dried (MgSO4) and concentrated under reduced pressure to give the 17.0, 10.6, 5.1, 2-H), 5.95 (1 H, s, 2’-H), 6.90 and 7.28 (each 2 H, d, J
title compound 14 as a colourless oil (5.3 g, 99%) (Found: M+ + NH4, 7.8, ArH), 7.40 (3 H, m, ArH) and 7.49 (2 H, m, ArH); m/z (CI+) 444
284.1859. C15H26O4N requires M, 284.1856); δH 1.50-1.75 (6 H, m, 4- (M+ + 18, 10 %), 341 (50) and 121 (100).
H2, 5-H2, 6-H2), 1.95 (1 H, br. s, OH), 2.95-3.00 (2 H, m, 2-H, 3-H),
Following the same procedure, (S)-O-acetylmandelic acid (34
3.48 (2 H, t, J 6.3, 7-H2), 3.63 (1 H, dd, J 12.5, 4.4, 1-H), 3.83 (3 H, s, mg), the alcohol 16 (59 mg, 0.086 mmol) and dicyclohexylcarbodi-
OCH3), 3.91 (1 H, dd, J 12.6, 2.6, 1-Hʹ), 4.45 (2 H, s, ArCH2) and 6.90 imide 45 mg), after chromatography (1:2, ether:light petroleum),
and 7.29 (each 2 H, d, J 8.8, Ar-H); δC 23.0, 26.1, 29.7, 31.6, 55.5, gave (S)-O-acetylmandelate of the alcohol 16 as a colourless oil (65
56.2, 58.8, 62.0, 70.0, 72.9, 114.0, 129.5, 130.8 and 159.4; m/z (CI+) mg, 88%), Rf = 0.50 (1:1, ether:light petroleum) (Found: M+,
284 (M+ + 18, 100%).
426.2041. C25H30O6 requires M, 426.2037); δH 1.10-1.90 (6 H, m, 4-
(2R,3R)-7-(4-Methoxybenzyloxy)-2,3-epoxy-1-iodoheptane
(15). H2, 5-H2, 6-H2), 2.22 (3 H, s, CH3CO2), 3.27 (2 H, t, J 6.6, 7-H2), 3.80 (3
Imidazole (0.33 g, 4.80 mmol), triphenylphosphine (0.75 g, 2.80 H, s, OCH3), 4.39 (2 H, s, ArCH2), 5.20-5.35 (3 H, m, 1-H2, 3-H), 5.79
mmol) and iodine (0.70 g, 2.80 mmol) were added to the alcohol 14 (1 H, ddd, J 17.1, 10.5, 6.2, 2-H), 5.94 (1 H, s, 2’-H), 6.90 and 7.25
(0.50 g, 2.40 mmol) in THF (7.5 mL) at rt. The solution was stirred at (each 2 H, d, J 7.8, ArH), 7.38 (3 H, m, ArH) and 7.49 (2 H, m, ArH);
rt for 2 h, saturated aqueous sodium thiosulfate (10 mL) was added m/z (CI+) 444 (M+ + 18, 10 %), 341 (30) and 121 (100).
and the stirring was continued until the reaction mixture became (R)-7-(4-Methoxybenzyloxy)-3-triethylsilyloxyhept-1-ene (17). The
clear. Ether was added and the aqueous layer was extracted with alcohol 16 (1.4 g, 5.6 mmol) in DCM (10 mL) was added to
ether (3 × 10 mL). The organic extracts were washed with brine, triethylsilyl chloride (1 mL, 5.6 mmol) and imidazole (700 mg, 8.4
dried (MgSO4), and concentrated under reduced pressure. mmol) in DCM (40 mL) at 0 oC and the mixture stirred at rt for 16 h.
Chromatography (15:1 light petroleum:ether) of the residue gave The mixture was washed with brine (80 mL, and the aqueous layer
the title compound 15 as a colourless oil (0.69 g, 92%), [α]D20 +25 (c, extracted with DCM (50 mL). The organic extracts were dried
1.2, CHCl3) (Found: M+ + Na, 399.0430. C15H21O3INa requires M, (MgSO4)
and
concentrated
under
reduced
pressure.
399.0428); δH 1.40-1.80 (6 H, m, 4-H2, 5-H2, 6-H2), 2.83 (1 H, m, 3-H), Chromatography (1:9 ether:light petroleum) of the residue to yield
3.04 (2 H, m, 1-H2), 3.23 (1 H, m, 2-H), 3.48 (2 H, t, J 6.3, 7-H2), 3.83 the title compound 17 as a clear oil (2.24 g, ca. 100%), [α]D20 +17 (c
(3 H, s, OCH3), 4.46 (2 H, s, ArCH2) and 6.90 and 7.29 (each 2 H, d, J 2.1, CHCl3) (Found: M+ + NH4, 382.2773. C21H40O3NSi requires M,
7.8, ArH); δC 5.3, 22.9, 29.7, 31.8, 55.6, 58.5, 62.8, 69.9, 72.8, 114.0, 382.2772); δH 0.62 (6 H, q, J 7.6, 3 × SiCH2), 0.97 (9 H, t, J 7.6, 3 ×
129.5, 130.9 and 159.4; m/z (ES+) 399 (M+ + 23, 100%).
CH3), 1.25-1.70 (6 H, m, 4-H2, 5-H2, 6-H2), 3.46 (2 H, t, J 6.7, 7-H2),
(R)-7-(4-Methoxybenzyloxy)hept-1-en-3-ol (16). tert-Butyllithium 3.83 (3 H, s, OCH3), 4.09 (1 H, q, J 7.1, 3-H), 4.46 (2 H, s, ArCH2), 5.05
(1.7 M in hexanes, 0.89 mL) was added to the iodide 15 (260 mg, (1 H, dt, J 10.2, 1.5, 1-H), 5.25 (1 H, dt, J 18.4, 1.5, 1-H’), 5.89 (1 H,
o
0.69 mmol) in THF (5 mL) at −78 C and the solution stirred for 15 ddd, J 16.8, 10.4, 6.4, 2-H) and 6.90 and 7.27 (each 2 H, d, J 8.8,
o
mins at −78 C. Saturated aqueous ammonium chloride was added ArH); δC 5.2, 7.1, 22.2, 30.0, 38.2, 55.5, 70.3, 72.8, 74.1, 114.0,
and the mixture extracted with ether (3 × 20 mL). The organic 129.5, 131.0, 142.0 and 159.3; m/z (CI+) 382 (M+ + 18, 25%), 138
extracts were dried (MgSO4) and concentrated under reduced (62) and 121 (100).
pressure. Chromatography (4:1 ether:light petroleum) of the (R)-5-Triethylsilyloxyhept-6-en-1-ol (18). An aqueous pH 7 buffer (2
residue gave the title compound 16 as a colourless oil (164 mg, mL) was added to the 4-methoxybenzyl ether 17 (2.2 g, 6 mmol) in
20
95%), [α]D 32.6 (c 5.7, CHCl3) (Found: M+ + H, 251.1638. C15H23O3 DCM (20 mL) followed by dichlorodicyanoquinone (1.39 g, 6.12
requires M, 251.1642); νmax/cm-1 3392, 2934, 2859, 1686, 1613, mmol) and the mixture stirred for 10 min. Saturated aqueous
1586, 1514, 1463, 1363, 1302, 1245, 1174, 1097, 1035, 972 and sodium bicarbonate (250 mL) and ether (250 mL) were added and
821; δH 1.20-1.80 (6 H, m, 4-H2, 5-H2, 6-H2), 3.48 (2 H, t, J 6.5, 7-H2), the aqueous phase extracted with ether (3 × 100 mL). The organic
3.84 (3 H, s, OCH3), 4.13 (1 H, q, J 6.4, 3-H), 4.46 (2 H, s, ArCH2), 5.14 extracts were washed with saturated aqueous sodium bicarbonate
(1 H, dt, J 10.4, 1.3, 1-H), 5.25 (1 H, dt, J 17.1, 1.3, 1-H’), 5.89 (1 H, (30 mL), dried (MgSO4) and concentrated under reduced pressure.
ddd, J 17.1, 10.4, 6.2, 2-H) and 6.90 and 7.29 (each 2 H, d, J 7.8, Chromatography (1:4 to 1:3 to 1:2 ether:light petroleum containing
ArH); δC 22.3, 29.8, 37.0, 55.5, 70.1, 72.8, 73.3, 114.0, 114.8, 129.5, 0.5% triethylamine) of the residue gave the title compound 18 (1.08
130.9, 141.4 and 159.3; m/z (CI+) 268 (M+ + 18, 100%), 251 (M+ + 1, g, 73%) as a colourless, highly viscous oil, Rf = 0.16 (1:3 ether:light
20
50), 138 (60) and 121 (90).
petroleum), [α]D 8.7 (c 3.9, CHCl3) (Found: M+ - H, 243.1786.
(R)-O-Acetylmandelic
acid
(34
mg)
and
4- C13H27O2Si requires M, 243.1775); δH 0.63 (6 H, q, J 7.5, 3 × SiCH2),
dimethylaminopyridine (cat.) were added to the alcohol 16 (59 mg, 0.98 (9 H, t, J 7.8, 3 × CH3), 1.30-1.65 (6 H, m, 2-H2, 3-H2, 4-H2), 2.74
0.086 mmol) in THF (0.6 mL) and the solution cooled to 0 oC. (1 H, br. s, OH), 3.67 (2 H, t, J 6.6, 1-H2), 4.12 (1 H, q, J 7.1, 5-H), 5.06
Dicyclohexyl carbodi-imide (45 mg) in THF (0.5 mL) was added and (1 H, dt, J 10.4, 1.5, 7-H), 5.25 (1 H, dt, J 17.1, 1.5, 7-H’) and 5.89 (1
the mixture stirred at rt for 16 h. After dilution with ether (15 mL), H, ddd, J 16.8, 10.3, 6.4, 6-H); δC 5.1, 7.1, 21.6, 32.9, 38.0, 63.0,
filtration and concentration under reduced pressure followed by 74.1, 114.1 and 141.8; m/z (CI+) 245 (M+ + 1, 100%).
chromatography (1:2 ether:light petroleum) of the residue afforded (R)-5-Triethylsilyloxyhept-6-enal (19). Pyridine (5 mL) and the
the (R)-O-acetyl mandelate of the alcohol 16 as a colourless oil (65 alcohol 18 (500 mg, 2.0 mmol) in DCM (5 mL) were added to a
mg, 88%), Rf = 0.50 (1:1 ether:light petroleum) (Found: M+, suspension of the Dess-Martin periodinane (852 mg, 2.0 mmol) in
426.2042. C25H30O6 requires M, 426.2037); δH 1.10-1.90 (6 H, m, 4- DCM (25 mL) at rt. After 50 min, a second portion of the
H2, 5-H2, 6-H2), 2.21 (3 H, s, CH3CO2), 3.45 (2 H, t, J 6.6, 7-H2), 3.82 (3 periodinane (852 mg, 2.0 mmol) was added and the resulting
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Organic & Biomolecular Chemistry
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solution stirred for 1 h. Saturated aqueous sodium bicarbonate (100 1.5, 8-H), 7.00-7.25 (9 H, m, 7-H, ArH), 7.37 (2 H, d, JV7ie.w5,ArAticrlHe )Onalninde
DOI: 10.1039/C7OB00079K
mL) and ethyl acetate (100 mL) were added and the organic phase 7.78 (5 H, m, ArH); δC (C6D6) 12.0, 19.3, 21.0, 21.1, 24.2, 25.4, 25.7,
washed with saturated aqueous sodium thiosulfate (100 mL). The 27.0, 32.4, 36.8, 38.8, 39.3, 46.5, 51.5, 60.4, 63.3, 63.6, 72.4, 75.1,
aqueous washings were extracted with ethyl acetate (3 × 200 mL) 81.0, 100.3, 113.7, 126.2, 127.3, 128.5, 129.9, 134.2, 135.9, 139.4,
and the organic extracts were washed with brine (30 mL) and dried 141.9, 146.7 and 201.8; m/z (ES+) 750 (M+ + 23, 100%).
(MgSO4). Chromatography of the residue gave the title compound (4S,6R,8S)-4-Benzyloxy-10-tert-butyldiphenylsilyloxy-1-[(2S,6R)-6-
19 colourless oil (468 mg, 94 %), Rf = 0.3 (1:4 ether:light petroleum) ethenyltetrahydropyran-2-yl]-6,8-di-O-isopropylidene-3,3-
(Found: M+ − H, 241.1619, C13H25O2Si2 requires M, 241.1618); δH dimethyldecan-2-one (23). Potassium tert-butoxide (0.092 M in
0.61 (6 H, q, J 7.8, 3 × SiCH2), 0.95 (9 H, t, J 7.8, 3 × CH3), 1.45-1.80 THF, 1.0 mL, 0.092 mmol) was added to the alcohol 22 (259 mg,
(4 H, m, 3-H2, 4-H2), 2.45 (2 H, td, J 7.3, 1.8, 2-H2), 4.12 (1 H, q, J 6.2, 0.35 mmol) in THF (2.1 mL) at rt and the mixture stirred for 40 min.
5-H), 5.06 (1 H, d, J 10.4, 7-H), 5.17 (1 H, d, J 17.1, 7-H’), 5.89 (1 H, Saturated aqueous ammonium chloride (30 mL) and ether (50 mL)
ddd, J 17.0, 10.4, 6.0, 6-H) and 9.76 (1 H, t, J 1.8, 1-H); δC 5.1, 7.1, were added and the aqueous phase extracted with ether (2 × 50
18.0, 37.6, 44.1, 73.7, 114.4, 141.5 and 202.8; m/z (CI+) 243 (M+ + 1, mL). The organic extracts were dried (MgSO4) and concentrated
20%), 137 (50), 127 (90) and 102 (100).
(3R,7E,11S,13R,15S)-11-Benzyloxy-17-tert-butyldiphenylsilyloxy-3-
hydroxy-10,10-dimethyl-13,15-di-O-isopropylideneheptadeca-1,7-
under reduced pressure to afford the title compound 23 (210 mg,
21
81 %), Rf = 0.43 (1:2 ether:light petroleum), [α]D +17.6 (c 3.6,
CHCl3) (Found: M+ + Na, 749.4211. C45H62O6NaSi requires M,
dien-9-one (22). The ketophosphonate 20 (254 mg, 0.35 mmol) in 749.4208); νmax/cm-1 2932, 2890, 2857, 1704, 1611, 1587, 1512,
dry THF (2.5 mL) was added to a suspension of barium hydroxide 1468, 1427, 1381, 1363, 1302, 1247, 1224, 1172, 1108, 1039, 822
(37 mg, 0.88 mmol) in dry THF (2.5 mL) and the mixture stirred for and 738; δH (C6D6) 1.27 [9 H, s, SiC(CH3)3], 0.90-1.80 (24 H, m, 5-H2,
30 min before the crude aldehyde 19 (277 mg, 0.46 mmol) in 7-H2, 9-H2, 3’-H2, 4’-H2, 5’-H2, 4 × CH3), 2.49 (1 H, dd, J 17.4, 6.3, 1-
THF:water (40:1, 2 mL) was added. The mixture was stirred for 18 h H), 3.04 (1 H, dd, J 17.3, 6.0, 1-H’), 3.72 (2 H, m, 4-H, 6-H), 3.88 (1 H,
and saturated aqueous ammonium chloride (60 mL) and ether (60 m, 8-H), 4.00-4.15 (4 H, m, 10-H2, 2’-H, 6’-H), 4.65 and 4.74 (each 1
mL) were added. The aqueous phase was extracted with ether (3 × H, d, J 11.6, ArHCH), 5.01 (1 H, dt, J 10.8, 1.8, 2’’-H), 5.26 (1 H, dt, J
40 mL) and the organic extracts were washed with brine (120 mL), 17.4, 1.9, 2’’-H’), 5.64 (1 H, ddd, J 17.4, 10.8, 5.0, 1’’-H), 7.00-7.40
dried (MgSO4) and concentrated under reduced pressure to afford (11 H, m, ArH) and 7.78 (4 H, m, ArH); δC (C6D6) 19.4, 20.6, 21.2,
the enone 21 as a viscous oil that was used immediately, Rf = 0.84 23.6, 25.3, 25.6, 27.0, 30.1, 30.4, 31.5, 31.7, 38.9, 39.3, 45.6, 52.8,
(1:1 ether:light petroleum) (Found: M+
+
Na, 863.5086, 60.5, 63.3, 63.8, 74.0, 75.0, 78.1, 81.1, 100.3, 113.4, 127.3, 128.5,
C51H76O6NaSi2 requires M, 863.5073); δH 0.69 (6 H, q, J 7.5, 3 × 129.9, 134.2, 135.9 and 140.2; m/z (ES+) 749.5 (M+ + 23, 100%).
SiCH2), 1.10 (9 H, t, J 7.8, 3 × CH3), 1.26 [9 H, s, SiC(CH3)3], 1.29 and (4S,6R,8S)-4-Benzyloxy-1-[(2S,6R)-6-ethenyltetrahydropyran-2-yl]-
1.39 (each 3 H, s, 10-CH3), 1.47 and 1.51 (each 3 H, s, CCH3), 1.31- 10-hydroxy-6,8-di-O-isopropylidene-3,3-dimethyldecan-2-one
1.94 (10 H, m, 4-H2, 5-H2, 12-H2, 14-H2, 16-H2), 2.02 (2 H, br q, J 7.0, (24). Tetra-n-butylammonium fluoride (1 M in THF, 0.43 mL, 0.43
6-H2), 3.83 (1 H, m, 11-H), 3.96 (1 H, m, 13-H), 4.07 (1 H, m, 15-H), mmol) was added to the enone 21 (150 mg, 0.18 mmol) in THF (5
4.21 (3 H, m, 3-H, 17-H2), 4.77 and 4.85 (each 1 H, d, J 12.0, ArHCH), mL) at rt and the mixture stirred for 16 h. Water (50 mL) was added
5.04 (1 H, dt, J 10.4, 1.0, 1-H), 5.21 (1 H, dt, J 17.3, 1.1, 1-H’), 5.82 (1 and the mixture extracted with ether (4 × 50 mL). The organic
H, ddd, J 16.5, 10.3, 6.2, 2-H), 6.76 (1 H, d, J 15.2, 8-H), 7.10-7.40 (9 extracts were dried (MgSO4) and concentrated under reduced
H, m, 7-H, ArH), 7.47 (2 H, d, J 7.5, ArH) and 7.87 (5 H, m, ArH); m/z pressure. The residue was dissolved in THF (2.1 mL), potassium tert-
(ES+) 864 (M+ + 23, 100%).
butoxide (0.092 M in THF, 1.0 mL, 0.092 mmol) was added and the
Pyridine (0.13 mL) and then the HF-pyridine complex (0.065 mL) mixture stirred for 40 min. Saturated aqueous ammonium chloride
were added to the triethylsilyl ether 21 (100 mg, 0.12 mmol) in THF (30 mL) and ether (50 mL) were added and the aqueous phase
(1.5 mL) at 0 oC. After for stirring 15 min, saturated aqueous sodium extracted with ether (2 × 50 mL). The organic extracts were dried
bicarbonate (20 mL) was added and the mixture was warmed to rt. (MgSO4)
and
concentrated
under
reduced
pressure.
Ether (40 mL) and saturated aqueous ammonium chloride (20 mL) Chromatography of the residue gave the title compound 24 as a
were added and the aqueous phase was extracted with ether (3 × colourless oil (54 mg, 62 % from ketophosphonate 20) containing
30 mL). The organic extracts were washed with brine (30 mL), dried ca. 10% of the 2’-epimer (Found: M+ + Na, 511.3033. C29H44O6Na
(MgSO4)
and
concentrated
under
reduced
pressure. requires M, 511.3030); νmax/cm-1 2932, 2890, 2857, 1704, 1611,
Chromatography (4:5 ether:light petroleum) of the residue gave the 1587, 1512, 1468, 1427, 1381, 1363, 1302, 1247, 1224, 1172, 1108,
title compound 22 as a highly viscous colourless oil (76 mg, 87 %), Rf 1039, 822 and 738; δH (C6D6) 1.00-1.68 (24 H, m, 5-H2, 7-H2, 9-H2, 3’-
= 0.21 (1:1 ether:light petroleum) (Found: M+ + Na, 749.4201. H2, 4’-H2, 5’-H2, 4 × CH3), 2.48 and 3.04 (each 1 H, dd, J 17.3, 6.0, 1-
C45H62O6NaSi requires M, 749.4208); νmax/cm-1 3505, 2932, 2892, H), 3.50-3.70 (2 H, m, 4-H, 6-H), 3.72 (1 H, m, 8-H), 3.86 (1 H, m, 2’-
2857, 1686, 1616, 1588, 1513, 1467, 1428, 1383, 1364, 1302, 1249, H), 4.00-4.15 (3 H, m, 10-H2, 6’-H), 4.63 and 4.70 (each 1 H, d, J
1224, 1173, 1109, 1037, 910 and 823; δH (C6D6) 1.17 [9 H, s, 11.6, ArHCH), 5.00 (1 H, dt, J 10.8, 1.8, 2’’-H), 5.25 (1 H, dt, J 17.4,
SiC(CH3)3], 1.21 and 1.31 (each 3 H, s, 10-CH3), 1.39 and 1.43 (each 3 1.9, 2’’-H’), 5.85 (1 H, ddd, J 17.4, 10.8, 5.0, 1’’-H), 7.00-7.25 (3 H, m,
H, s, CCH3), 1.00-1.80 (10 H, m, 4-H2, 5-H2, 12-H2, 14-H2, and 16-H2), ArH) and 7.35 (2 H, m, ArH); δC (C6D6) 20.5, 21.3, 23.6, 25.2, 25.3,
1.89 (2 H, br. q, J 5.4, 6-H2), 3.75 (2 H, m, 11-H, 13-H), 3.87 (1 H, m, 26.7, 30.1, 30.4, 31.2, 31.7, 38.4, 38.6, 39.4, 45.6, 52.9, 60.5, 63.8,
15-H), 4.05-4.20 (3 H, m, 17-H2, 3-H), 4.68 and 4.76 (each 1 H, d, J 66.0, 74.0, 75.1, 78.1, 81.0, 100.4, 113.4, 127.2, 127.3, 128.5, 135.2,
11.6, ArHCH), 5.04 (1 H, dt, J 10.4, 1.8, 1-H), 5.21 (1 H, dt, J 17.3, 140.2 and 211.4; m/z (ES+) 511 (M+ + 23, 100%).
1.6, 1-H’), 5.64 (1 H, ddd, J 17.1, 10.3, 5.7, 2-H), 6.66 (1 H, dt, J 15.2, (3S,5R,7S,9S,11S,15R)-7-Benzyloxy-1-tert-butyldiphenylsilyloxy-
8 | J. Name., 2012, 00, 1-3
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ARTICLE
5,9-epoxy-11,15-epoxy-8,8-dimethyl-9-methoxyheptadec-16-en-3- CH3), 0.90-1.80 (12 H, m, 2-H2, 4-H2, 6-H2, 12-H2, 13-H2, and 14-H2),
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ol (25). Anhydrous methanol (5 mL) and trimethyl orthoformate 1.92 (1 H, dd, J 16.3, 3.4, 10-H), 2.22 (1 HD, OddI:,10J.11063.19/,C67.O0,B01000-H79’)K,
(0.5 mL) were added to the hydroxyketone 23 (210 mg 0.29 mmol) 3.23 (3 H, s, OCH3), 3.50-3.95 (8 H, m, 1-H2, 3-H, 5-H, 7-H, 11-H,
followed by oven-dried pyridinium toluene p-sulfonate (13 mg, 0.11 OCH2CH2Si), 4.08 (1 H, m, 15-H), 4.34 and 4.71 (each 1 H, d, J 11.9,
mmol). The mixture was stirred for 17 h, saturated aqueous sodium ArHCH), 4.69 and 4.79 (each 1 H, d, J 6.9, OHCHO), 5.05 (1 H, dt, J
bicarbonate (50 mL) and ether (50 mL) were added and the 10.7, 1.8, 17-H), 5.36 (1 H, dt J 17.3, 1.9, 17-H’), 5.88 (1 H, ddd, J
aqueous phase was extracted with ether (2 × 50 mL). The organic 17.4, 10.7, 4.7, 16-H), 7.00-7.25 (3 H, m, ArH) and 7.78 (2 H, m,
extracts were washed with saturated aqueous sodium bicarbonate ArH); δC (C6D6) −1.4, 17.1, 18.2, 20.1, 24.2, 30.1, 31.6, 33.2, 33.6,
(2
× 20 mL) and concenrated under reduced pressure. 38.6, 40.6, 42.5, 43.4, 48.6, 59.5, 65.7, 66.0, 71.6, 73.9, 74.8, 77.9,
Chromatography (1:3 light petroleum:ether with 1% triethylamine) 79.2, 95.1, 104.6, 113.4, 127.4, 127.5, 128.4, 139.9 and 140.1; m/z
of the residue gave the title compound 25 as a colourless oil (174 (ES+) 616 (M+ + 23, 100%).
20
mg, 86 %), Rf = 0.78 (1:1 ether:light petroleum), [α]D +27 (c 3.5,
(S)-1-Benzyloxyhept-6-en-3-ol
(29).
Prop-2-enylmagnesium
CHCl3) (Found: M+ + Na, 723.4055, C43H60O6NaSi requires M, bromide (1 M in ether, 28.5 mL, 28.5 mmol) was added to a
723.4051); νmax/cm-1 3514, 3071, 2932, 2858, 1644, 1589, 1472, suspension of copper(I) iodide (542 mg, 2.85 mmol) in THF (10 mL)
1454, 1428, 1382, 1361, 1337, 1260, 1199, 1092, 1028, 983, 921 at −40 oC. The mixture was warmed to −30 oC and stirred for 20 min
and 823; δH (C6D6) 1.15 [9 H, s, SiC(CH3)3], 1.34 and 1.45 (each 3 H, before cooling to −40 C. The epoxide 2813 (3.38 g, 18.99 mmol) in
o
s, 8-CH3), 0.90-1.80 (12 H, m, 2-H2, 4-H2, 6-H2, 12-H2, 13-H2, and 14- THF (34 mL) was added and the stirring continued for 1 h. Saturated
H2), 1.92 (1 H, dd, J 16.4, 2.6, 10-H), 2.22 (1 H, dd, J 16.3, 6.4, 10-H’), aqueous ammonium chloride (60 mL) and ether (60 mL) were
3.27 (3 H, s, OCH3), 3.60-3.75 (2 H, m, 3-H, 5-H), 3.80-3.95 (3 H, m, added and the mixture was allowed to warm to rt before
1-H2, 7-H), 4.08 (1 H, m, 11-H), 4.65 (2 H, m, 15-H, ArHCH), 4.74 (1 partitioning between water and ether. The aqueous layer was
H, d, J 11.6, ArHCH), 5.02 (1 H, dt, J 10.7, 1.9, 17-H), 5.36 (1 H, dt, J extracted with ether (2 × 50 mL) and the organic extracts were
17.3, 1.9, 17-H’, 5.84 (1 H, ddd, J 17.4, 10.7, 4.5, 16-H), 7.00-7.40 washed with brine (50 mL), dried (MgSO4) and concentrated under
(11 H, m, ArH) and 7.78 (4 H, m, ArH); δC (C6D6) 17.1, 19.3, 20.0, reduced pressure. Chromatography (4:1 light petroleum:ether) of
24.2, 27.0, 30.4, 31.4, 33.2, 40.1, 40.6, 43.5, 43.7, 48.3, 63.0, 65.5, the residue afforded the title compound 29 (3.48 g, 83%), Rf = 0.35
20
67.1, 71.6, 73.8, 77.7, 79.5, 104.6, 113.4, 127.3, 127.5, 128.3, 128.4, (1:1 light petroleum:ether), [α]D +5.9 (c 2.3, CHCl3) (Found: M+ +
130.0, 133.7, 133.8, 135.9 and 140.0; m/z (ES+) 745 (90%), 723 (M+ + NH4, 238.1803. C14H24O2N requires M, 238.1802); νmax/cm-1 3417,
23, 100) and 670 (80).
(3S,5R,7S,9S,11S,15R)-7-Benzyloxy-5,9-epoxy-11,15-epoxy-8,8-
dimethyl-9-methoxy-3-(2-trimethylsilylethoxymethoxy)heptadec-
3065, 3031, 2935, 2922, 2861, 1640, 1453, 1416, 1363, 1206, 1098,
1028, 997, 912 and 737; δH 1.52-1.72 (2 H, m, 4-H2), 1.78-1.85 (2 H,
m, 2-H2), 2.09-2.34 (2 H, m, 5-H2), 2.89 (1 H, br. s, OH), 3.66-3.82 (2
16-en-1-ol (27). Di-isopropylethylamine (140 µL, 0.32 mmol) and 2- H, m, 1-H2), 3.87 (1 H, m, 3-H), 4.58 (2 H, s, ArCH2), 5.02 (1 H, ddt, J
trimethylsilylethoxymethyl chloride (0.18 mL, 0.976 mmol) were 10.2, 2.0, 1.2, 7-H), 5.10 (1 H, ddt, J 17.1, 2.0, 1.6, 7-H’), 5.90 (1 H,
added to the alcohol 25 (120 mg, 0.21 mmol) in DCM (1.0 mL) at 0 ddt, J 16.9, 10.1, 6.6, 6-H) and 7.29-7.44 (5 H, m, ArH); δC 30.2, 36.7,
oC before adding 4-dimethylaminopyridine (cat.) at rt. The mixture 36.8, 69.5, 71.1, 73.6, 114.9, 128.0, 128.1, 128.8, 138.2 and 138.9;
was stirred at rt and saturated aqueous sodium bicarbonate (4 mL) m/z (CI+) 238 (M+ + 18, 66%) and 221 (M+ + 1, 100%).
and ether (4 mL) were added. After 30 min, more saturated (S)-1-Benzyloxy-3-tert-butyldimethylsilyloxyhept-6-ene (30). tert-
aqueous sodium bicarbonate (20 mL) and ether (20 mL) were added Butyldimethylsilyl chloride (2.86 g, 18.95 mmol) was added to
and the aqueous phase extracted with ether (2 × 15 mL). The imidazole (3.22 g, 47.37 mmol) in DCM (60 mL) at 0 oC followed by
organic extracts were washed with saturated aqueous sodium the alcohol 29 (3.48 g, 15.79 mmol) in DCM (20 mL). The mixture
bicarbonate (20 mL), dried (MgSO4) and concentrated under was allowed to warm to rt and was stirred for 22 h. Saturated
reduced pressure. Chromatography (1:20 then 1:4 ether:light aqueous sodium hydrogen carbonate (80 mL) was added and the
petroleum with 1 % triethylamine) of the residue gave the 2- mixture partitioned between water and DCM. The aqueous layer
trimethylsilylethoxymethyl ether 26 as a colourless oil (122 mg, was extracted with ether (3 × 80 mL) and the organic extracts were
86%), Rf = 0.77 (1:1 ether:light petroleum) (Found: M+ + Na, dried (MgSO4) and concentrated under reduced pressure.
853.4869. C49H74O7NaSi2 requires M, 853.4865); m/z (ES+) 854 (M+ + Chromatography (light petroleum to 15:1 light petroleum:ether) of
23, 100%).
the residue afforded the title compound 30 (4.93 g, 93%), Rf = 0.48
Tetra-n-butylammonium fluoride (1 M in THF, 0.43 mL, 0.43 (1:9 ether:light petroleum), [α]D −0.7 (c 2.4, CHCl3) (Found: M+ +
mmol) was added to the 2-trimethylsilylethoxymethyl ether 26 (180 H, 335.2399. C20H35O2Si requires M, 335.2401); νmax/cm-1 3065,
mg, 0.22 mmol) in THF (5 mL) at rt and the mixture stirred for 16 h 3032, 2952, 2931, 2889, 2857, 1461, 1363, 1253, 1097, 1056, 1006,
at rt before water (50 mL) was added. The mixture was extracted 836 and 775; δH 0.10 and 0.11 (each 3 H, s, SiCH3), 0.94 [9 H, s,
with ether (4 × 50 mL) and the organic extracts were dried (MgSO4) SiC(CH3)3], 1.56-1.65 (2 H, m, 4-H2), 1.78-1.87 (2 H, m, 2-H2), 2.09-
and concentrated under reduced pressure. Chromatography (1:1 2.20 (2 H, m, 5-H2), 3.60 (2 H, t, J 6.6, 1-H2), 3.93 (1 H, dq, J 6.6, 5.8,
light petroleum:ether) of the residue gave the title compound 27 as 3-H), 4.53 and 4.57 (each 1 H, d, J 11.9, ArHCH), 5.00 (1 H, ddt, J
a clear oil (120 mg, 93%), Rf = 0.20 (1:1 ether:light petroleum), 10.1, 2.0, 1.3, 7-H), 5.06 (1 H, ddd, J 17.2, 3.6, 1.6, 7-H’), 5.87 (1 H,
23
20
[α]D +27 (c 3.5, CHCl3) (Found: M+ + Na, 615.3686. C33H56O7NaSi ddt, J 16.9, 10.2, 6.6, 6-H) and 7.30-7.43 (5 H, m, ArH); δC −4.3, −4.1,
requires M, 615.3688); νmax/cm-1 3413, 2922, 2850, 1463, 1425, 18.4, 26.2, 29.6, 36.9, 37.2, 67.4, 69.2, 73.2, 114.6, 127.8, 127.9,
1381, 1359, 1248, 1108, 1057, 1026, 856 and 835; δH (C6D6) −0.01 [9 128.6, 138.8 and 139.1; m/z (CI+) 335 (M+ + 1, 100%).
H, s, Si(CH3)3], 0.98 (2 H, m, SiCH2), 1.29 and 1.42 (each 3 H, s, 8-
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 10 of 15
ARTICLE
(S)-7-Benzyloxy-5-tert-butyldimethylsilyloxyheptan-1-ol
Journal Name
(31). alcohol 31) as a 60:40 mixture of epimers, Rf = 0.36 (V3i:e7w eArtthicelerO:linglihnet
Borane in THF (1 M, 16.2 mL, 16.2 mmol) was added to the alkene petroleum) (Found: M+ + H, 421.3128. C25H45O3Si requires M,
30 (4.93 g, 14.74 mmol) in THF (50 mL) at −25 oC dropwise over 10 421.3132); νmax/cm-1 3445, 2952, 2929, 2857, 1471, 1432, 1361,
min. The mixture was warmed to rt over 1 h, stirred for 16 h, then 1255, 1098, 1054, 1006, 836, 774 and 735; δH 0.08 (6 H, s, 2 ×
added to a mixture of aqueous sodium hydroxide (3 M, 100 mL) and SiCH3), 0.92 [9 H, s, SiC(CH3)3], 1.04 and 1.05 (each 3 H, s, 3-CH3),
DOI: 10.1039/C7OB00079K
o
hydrogen peroxide (30%, 100 mL). The temperature rose to 65 C 1.26-1.86 (9 H, m, 5-H2, 6-H2, 7-H2, 9-H2, OH), 3.27 (0.6 H, br. d, J
o
and the mixture was cooled to 45 C using an ice bath then stirred 10.1, 4-H), 3.59 (2.4 H, m, 4-H, 10-H2), 3.89 (1 H, dq, J 6.0, 5.2, 8-H),
with heating at 50 oC for 30 min before being cooled to rt and 4.51 and 4.55 (each 1 H, d, J 11.9, ArHCH), 5.09 (1 H, dd, J 17.3, 1.6,
extracted with ether (3 × 50 mL). The organic extracts were washed 1-H), 4.55 (1 H, dd, J 10.7, 1.6, 1-H’), 5.85 (1 H, dd, J 10.8, 17.5, 2-H)
with brine, dried (MgSO4) and concentrated under reduced and 7.30-7.41 (5 H, m, ArH); δC −4.3, −4.1, 18.4, 22.3, 22.8, 22.9,
pressure. Chromatography (2:8 to 1:1 ether:light petroleum) of the 23.4, 26.2, 28.6, 31.8, 31.9, 37.1, 37.3, 37.7, 37.8, 41.9, 67.4, 69.6,
residue gave the title compound 31 (4.45 g, 86%), Rf = 0.33 (3:7 69.8, 73.2, 78.5, 113.6, 127.8, 127.9, 128.6, 138.9 and 145.7; m/z
20
ether:light petroleum), [α]D +4.6 (c 4.0, CHCl3) (Found: M+ + H (CI+) 421 (M+ + 1, 30%) and 289 (100).
353.2501. C20H37O3Si requires M, 353.2506); νmax/cm-1 3356, 2930, (8S)-10-Benzyloxy-8-tert-butyldimethylsilyloxy-3,3-dimethyldec-1-
2883, 2857, 1471, 1461, 1361, 1254, 1100, 1061, 836, 775 and 736; en-4-one (34). Dimethyl sulfoxide (0.25 mL) was added to oxalyl
o
δH 0.10 (6 H, s, 2 × SiCH3), 0.93 [9 H, s, Si(CH3)3], 1.37-1.72 (7 H, m, chloride (0.15 mL) in DCM (6 mL) at −78 C dropwise over 5 min.
2-H2, 3-H2, 4-H2, OH), 1.73-1.89 (2 H, m, 6-H2), 3.60 (2 H, t, J 6.6, 7- After 10 min at −78 C the alcohol 33 (0.438 g) in DCM (4 mL) was
o
H2), 3.66 (2 H, t, J 6.6, 1-H2), 3.90 (1 H, dq, J 6.8, 5.3, 5-H), 4.52 and added and the mixture stirred for 20 min. Triethylamine (1.1 mL)
o
4.57 (each 1 H, d, J 11.9, ArHCH) and 7.31-7.43 (5 H, m, ArH); δC was added and the mixture was stirred for 15 min at −78 C then
−4.3, −4.1, 18.4, 21.4, 26.2, 33.2, 37.1, 37.5, 63.1, 67.4, 69.6, 73.3, allowed to warm to rt and stirred for 30 min. Saturated aqueous
127.8, 128.0, 128.6 and 138.8; m/z (CI+) 353 (M+ + 1, 100%) and 221 ammonium chloride was added and the mixture was partitioned
(86).
between water and ether. The aqueous layer was extracted with
(S)-7-Benzyloxy-5-tert-butyldimethylsilyloxyheptanal
(32). ether and the organic extracts were washed with brine, dried
Dimethyl sulfoxide (1.83 mL, 25.24 mmol) was added to oxalyl (MgSO4) and concentrated under reduced pressure to give the title
o
chloride (1.15 mL, 13.25 mmol) in DCM (42 mL) at −78 C over 5 compound 34 that was used directly in the next reaction, Rf = 0.65
20
min. The solution was stirred for 10 min at −78 oC before the (3:8 ether:light petroleum), [α]D + 7.3 (c 3.3, CHCl3) (Found: M+ +
alcohol 31 (4.45 g, 12.62 mmol) in DCM (14 mL) was added. The H, 419.2971. C25H43O3Si requires M, 419.2976); νmax/cm-1 2953,
mixture stirred for 20 min, triethylamine (8.4 mL, 59.32 mmol) was 2931, 2889, 2857, 1710, 1464, 1363, 1253, 1098, 1008, 836, 775
added and the stirring was continued for 15 min before the reaction and 736; δH 0.09 and 0.10 (each 3 H, s, SiCH3), 0.93 [9 H, s,
was allowed to warm to rt for 30 min. Saturated aqueous SiC(CH3)3], 1.27 (6 H, s, 2 × 3-CH3), 1.38-1.51 (2 H, m, 7-H2), 1.53-
ammonium chloride was added and the mixture partitioned 1.70 (2 H, m, 6-H2), 1.71-1.89 (2 H, m, 9-H2), 2.49 (2 H, dt, J 7.4, 1.8,
between water and ether. The aqueous layer was extracted with 5-H2), 3.58 (2 H, t, J 6.5, 10-H2), 3.88 (1 H, dq, J 6.6, 5.7, 8-H), 4.51
ether (3 × 50 mL) and the organic extracts were washed with brine, and 4.57 (each 1 H, d, J 11.9, ArHCH), 5.15-5.25 (2 H, m, 1-H2), 5.96
dried (MgSO4) and concentrated under reduced pressure to afford (1 H, dd, J 17.6, 10.5, 2-H) and 7.31-7.41 (5 H, m, ArH); δC −4.4, −4.1,
the title compound 32 that was used directly in the next reaction, Rf 18.4, 19.9, 23.8, 26.2, 37.2(2), 37.8, 51.0, 67.4, 69.5, 73.2, 114.5,
= 0.40 (3:7 ether:light petroleum) (Found: M+ + H, 351.2345. 127.8, 127.9, 128.6, 138.4, 142.9 and 210.2; m/z (CI+) 436 (M+ + 18,
C20H35O3Si requires M, 351.2350); νmax/cm-1 2952, 2929, 2884, 2%), 419 (M+ + 1, 2) and 287 (100).
2857, 1727, 1471, 1462, 1455, 1361, 1255, 1100, 1064, 836, 775 (8S)-10-Benzyloxy-8-hydroxy-3,3-dimethyldec-1-en-4-one
(35).
and 736; δH 0.10 (6 H, s, 2 × SiCH3), 0.93 [9 H, s, Si(CH3)3], 1.47-1.57 Tetra-n-butylammonium fluoride (1 M in THF, 19 mL) was added to
(2 H, m, 4-H2), 1.65-1.78 (2 H, m, 3-H2), 1.81 (2 H, q, J 6.3, 6-H2), the silyl ether 34 (8.3 mmol) in THF (50 mL) at rt and the mixture
2.47 (2 H, td, J 7.3, 1.8, 2-H2), 3.58 (2 H, t, J 6.5, 7-H2), 3.94 (1 H, m, stirred for 16 h. Saturated aqueous sodium hydrogen carbonate (50
5-H), 4.51 and 4.56 (each 1 H, d, J 11.9, ArHCH), 7.31-7.43 (5 H, m, mL) was added and the mixture partitioned between water and
ArH) and 9.80 (1 H, t, J 1.8, 1-H); δC −4.3, −4.1, 17.9, 18.3, 26.1, ether. The aqueous layer was extracted with ether and the organic
37.0, 37.1, 44.3, 67.2, 69.3, 73.3, 127.8, 127.9, 128.6, 138.8 and extracts were washed with brine, dried (MgSO4) and concentrated
202.9; m/z (CI+) 368 (M+ + 18, 10%), 351 (M+ + 1, 42) and 219 (100).
(4RS,8S)-10-Benzyloxy-8-tert-butyldimethylsilyloxy-3,3-
under reduced pressure. Chromatography (4:6 ether:light
petroleum to 6:4 ether:light petroleum) of the residue gave the title
dimethyldec-1-en-4-ol (33). 1-Bromo-3-methylbut-2-ene (90%, 2.45 compound 35 (2.15 g, 85% from alcohol 33) containing traces of the
mL, 18.93 mmol) was added to a suspension of non-activated corresponding hemiacetal, Rf 0.17/0/59 (1:1 ether:light
=
powdered zinc (2.446 g, 37.87 mmol) in THF (60 mL) at rt. After petroleum) (Found: M+ + Na, 327.1928. C19H28O3Na requires M,
stirring for 10 min, the aldehyde 32 (from 4.45 g of the alcohol 31) 327.1931); νmax/cm-1 3422, 2929, 2867, 1708, 1454, 1412, 1365,
in THF (18 mL) was added and the mixture stirred for 16 h. 1262, 1205, 1097, 1026, 920 and 739; δH (C6D6) 1.08 (6 H, s, 2 × 3-
Saturated aqueous ammonium chloride was added and the mixture CH3), 1.24-1.82 (6 H, m, 6-H2, 7-H2, 9-H2), 2.24 (2 H, t, J 7.0, 5-H2),
filtered through celite then partitioned between water and ether. 3.36 (1 H, ddd, J 9.2, 7.6, 4.7, 10-H), 3.45 (1 H, ddd, J 9.2, 6.1, 4.8,
The aqueous layer was extracted with ether and the organic 10-H’), 3.71 (1 H, m, 8-H), 4.23 (2 H, s, ArCH2), 4.93 (1 H, dd, J 10.7,
extracts washed with brine, dried MgSO4) and concentrated under 1.0, 1-H), 4.95 (1 H, dd, J 17.4, 1.0, 1-H’), 5.74 (1 H, dd, J 17.4, 10.7,
reduced pressure. Chromatography (2:8 ether:light petroleum) of 2-H) and 7.01-7.26 (5 H, m, ArH); δC (C6D6) 20.2, 23.5, 37.1, 37.3,
the residue gave the title compound 33 as an oil (3.56 g, 67% from
10 | J. Name., 2012, 00, 1-3
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Page 11 of 15
Organic & Biomolecular Chemistry
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ARTICLE
50.6, 69.0, 70.5, 73.1, 113.8, 127.6, 127.7, 128.5, 138.7, 143.1 and
(2S,6S)-6-(2-Benzyloxyethyl)-2-methoxy-2-(2-methylbut-3-en-2-
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yl)tetrahydropyran-3-one (40). Molecular sDieOvIe:s10(.41Å03,99/0C07OmBg0)0t0h7e9Kn
211.4; m/z (ES+) 327 (M+ + 23, 100%).
(8S)-10-Benzyloxy-8-hydroxy-3,3,5-trimethyldec-1-en-4-one (36) m-chloroperoxybenzoic acid (70% pure, 633 mg, 2.56 mmol) were
and (8S)-10-benzyloxy-8-methoxy-3,3,5-trimethyldec-1-en-4-one added to the dihydropyran 38 (615 mg, 2.147 mmol) in anhydrous
(37). Sodium hydride (60% in mineral oil, 6.3 mg, 0.16 mmol) was MeOH (20 mL) and the mixture stirred for 1 h at rt. Saturated
added to the hydroxyketone 35 (32 mg, 0.105 mmol) in DMF (1 mL) aqueous sodium hydrogen carbonate and then saturated aqueous
o
at 0 C. After stirring for 30 min, methyl iodide was added (13 μL, sodium sulfite were added and the mixture was partitioned
0.21 mmol) and the mixture was stirred for 30 min. Saturated between water and ether. The aqueous layer was extracted with
aqueous ammonium chloride was added and the mixture ether and the organic extracts were washed with brine, dried
partitioned between water and ether. The aqueous layer was (MgSO4)
and
concentrated
under
reduced
pressure.
extracted with ether and the organic extracts were washed with Chromatography (16% ether and 1% Et3N in light petroleum) of the
brine, dried (MgSO4) and concentrated under reduced pressure. residue afforded the alcohol 39 containing ca. 25% of a minor side
Chromatography (2:8 then 1:1 ether:light petroleum with 1% Et3N) product probably an isomer (640 mg, 89%), Rf = 0.44 (1:1 ether:light
of the residue gave the title compound 37 (6 mg, 18%), Rf = 0.50 petroleum) (Found: M+ + Na, 357.2039. C20H30O4Na requires M,
(1:1 ether:light petroleum) (Found: M+ + Na, 355.2241. C21H32O3Na 357.2036); δH (C6D6) 1.00 (1 H, m, 1’’-H), 1.15 and 1.22 (each 0.75 H,
requires M, 355.2244); νmax/cm-1 2968, 2932, 2870, 1706, 1634, s, CH3), 1.30 and 1.33 (each 2.25 H, s, CH3), 1.49-1.76 (5 H, m, 1’’-H’,
1455, 1365, 1260, 1095, 1027, 1013, 993, 919, 737; δH 0.96 (3 H, d, J 4-H2, 5-H2), 3.19 (2.25 H, s, OCH3), 3.24 (0.75 H, s, OCH3), 3.33-3.68
6.8, 5-CH3), 1.12 (6 H, s, 2 × 3-CH3), 1.29-1.49 and 1.67-1.83 (6 H, m, (3 H, m, 2’’-H2, 6-H), 3.72 (0.75 H, dd, J 11.4, 4.7, 3-H), 3.82 (0.25 H,
6-H2, 7-H2 and 9-H2), 2.70 (1 H, hex, J 6.7, 5-H), 3.15 (3 H, s, OCH3), t, J 3.0, 3-H), 4.26-4.37 (2 H, m, ArCH2), 4.82 (0.25 H, dd, J 10.9, 1.6,
3.26 (1 H, pent, J 6.8, 8-H), 3.38-3.55 (2 H, m, 10-H2), 4.33 (2 H, s, 4’-H), 4.91 (0.25 H, dd, J 17.7, 1.7, 4’-H’), 4.99 (0.75 H, dd, J 10.9,
ArCH2), 4.95 (1 H, dd, J 10.6, 1.1, 1-H), 4.98 (1 H, dd, J 17.4, 1.1, 1- 1.6, 4’-H), 5.10 (0.75 H, dd, J 17.7, 1.7, 4’-H’), 6.45 (0.75 H, dd, J
Hʹ), 5.79 (1 H, dd, J 17.4, 10.6, 2-H) and 7.07-7.33 (5 H, m, ArH); m/z 17.7, 10.9, 3’-H), 6.52 (0.25 H, dd, J 17.9, 10.8, 3’-H) and 7.07-7.30
(ES+) 355 (M+ + 23, 100%). The more polar product was the title (5 H, m, ArH); δC (C6D6) 21.5, 24.0, 24.5, 24.8, 24.9, 27.3, 30.3, 31.0,
compound 36 (13 mg, 39%), Rf = 0.19 (1:1 ether:light petroleum) 36.2, 36.8, 45.9, 46.7, 50.5, 51.6, 66.5, 66.8, 67.4, 68.0, 69.0, 70.1,
(Found: M+ + Na, 341.2087. C20H30O3Na requires M, 341.2087); 73.1, 101.1, 103.0, 110.1, 110.4, 127.8, 127.9, 128.4, 139.0, 147.1
νmax/cm-1 3481, 2968, 2932, 2871, 1705, 1634, 1454, 1414, 1365, and 148.1; m/z (ES+) 357 (M+ + 23, 100%).
1262, 1099, 1013, 921, 803 and 738; δH (C6D6) 0.97 (3 H, d, J 6.8, 5-
Pyridine (1.05 mL) and the Dess-Martin periodinane (1.09 g)
CH3), 1.14 and 1.15 (each 3 H, s, 3-CH3), 1.19-1.83 (6 H, m, 6-H2, 7- were added to this mixture of alcohols 39 (640 mg) in DCM (20 mL)
H2 and 9-H2), 2.61 (1 H, br. s, OH), 2.76 (1 H, hex, J 6.8, 5-H), 3.32 (1 at 0 oC and the mixture was allowed to warm to rt and stirred for 4
H, ddd, J 9.2, 8.8, 4.4, 10-H), 3.47 (1 H, ddd, J 9.2, 5.9, 4.7, 10-Hʹ), h. Saturated aqueous sodium hydrogen carbonate was added and
3.65 (1 H, m, 8-H), 4.20 (2 H, s, ArCH2), 4.97 (1 H, dd, J 10.6, 1.0, 1- the mixture was partitioned between water and ether. The aqueous
H), 4.99 (1 H, dd, J 17.4, 1.0, 1-Hʹ), 5.82 (1 H, dd, J 17.4, 10.6, 2-H) layer was extracted with ether and the organic extracts were dried
and 7.04-7.23 (5 H, m, ArH); δC (C6D6) 18.8, 23.4, 30.6, 35.7, 37.0, (MgSO4)
and
concentrated
under
reduced
pressure.
40.4, 51.2, 69.1, 70.9, 73.2, 114.1, 127.6, 127.9, 128.5, 138.6, 142.6 Chromatography (9:1 light petroleum:ether with 1% Et3N) of the
and 214.9; m/z (ES+) 341 (M+ + 23, 100%).
(2S)-2-(2-Benzyloxyethyl)-6-(2-methylbut-3-en-2-yl)-3,4-dihydro-
residue gave the title compound 40 (614 mg, 86% from 38), Rf =
0.47 (1:1 ether:light petroleum) (Found: M+ + Na, 355.1878.
2H-pyran (38). Toluene p-sulfonic acid (5.5 mg, 32 μmol) was added C20H28O4Na requires M, 355.1880); νmax/cm-1 2942, 2866, 1727,
to the hydroxyketone 35 (68 mg, 0.16 mmol) in benzene (0.7 mL) 1453, 1413, 1363, 1112, 1052, 915 and 739; δH (C6D6) 1.24 and 1.45
and the solution was heated at 50 oC for 3 h. Molecular sieves (4Å, (each 1 H, m, 5-H), 1.27 and 1.34 (each 3 H, s, CH3), 1.54-1.61 (2 H,
200 mg) and chlorosulfonic acid (10 mg, 64 μmol) were added and m, 1’’-H2), 2.06 (1 H, ddd, J 17.3, 7.3, 3.2, 4-H), 2.17 (1 H, ddd, J
the mixture stirred for 16 h. More molecular sieves (4Å, 200 mg) 17.4, 10.7, 7.5, 4-H’), 3.16 (3 H, s, OCH3), 3.35 (1 H, dt, J 9.1, 5.2, 2’’-
were added and the mixture heated at 80 oC for 1.5 h. The mixture H), 3.52 (1 H, dt, J 9.4, 6.7, 2’’-H’), 3.83 (1 H, m, 6-H), 4.25 (2 H, s,
was allowed to cool and was filtered through a basic alumina plug PhCH2), 4.95 (1 H, dd, J 10.9, 1.5, 4’-H), 5.01 (1 H, dd, J 17.7, 1.5, 4’-
with ether washings. Concentration under reduced pressure gave H’), 6.35 (1 H, dd, J 17.7, 10.9, 3’-H) and 7.03-7.26 (5 H, m, ArH); δC
the title compound 38 (68 mg, ca. 100%), Rf = 0.73 (1:1 ether:light (C6D6) 22.4, 22.8, 30.2, 36.1, 37.3, 45.0, 51.5, 66.4, 69.4, 73.1, 103.7,
20
petroleum), [α]D +39.9 (c 3.0, CHCl3) (Found: M+ + Na, 309.1827. 112.1, 127.8, 128.5, 138.9, 145.0 and 204.3; m/z (ES+) 355 (M+ + 23,
C19H26NaO2 requires M, 309.1830); νmax/cm-1 2962, 2946, 2923, 100%).
2851, 1663, 1453, 1359, 1291, 1091, 1003, 911 and 735; δH (C6D6) (2S,3R,6S)-6-(2-Benzyloxyethyl)-2,3-dimethoxy-2-(2-methylbut-3-
1.25 and 1.26 (each 3 H, s, CH3), 1.36 and 1.49 (each 1 H, m, 3-H), en-2-yl)tetrahydropyran (41). Lithium triethyborohydride (1 M in
1.67-1.98 (4 H, m, 1’-H2 and 4-H2), 3.49 (1 H, ddd, J 9.1, 6.3, 5.2, 2’- THF, 2.21 mL, 2.21 mmol) was added to the ketone 40 (614 mg,
H), 3.60 (1 H, ddd, J 9.0, 8.2, 5.7, 2’-H’), 3.92 (1 H, dddd, J 9.3, 8.6, 1.85 mmol) in THF (6 mL) at −10 oC and the mixture was allowed to
4.2, 2.4, 2-H), 4.35 (2 H, s, ArCH2), 4.60 (1 H, ddd, J 4.5, 2.9, 0.8, 5- warm to rt and stirred overnight. Saturated aqueous sodium
H), 5.01 (1 H, dd, J 10.7, 1.5, 4’’-H), 5.10 (1 H, dd, J 17.5, 1.5, 4’’-H’), hydrogen carbonate and ether and were added and the aqueous
6.07 (1 H, dd, J 17.5, 10.6, 3’’-H), 7.06-7.21 (3 H, m, ArH) and 7.28- layer was extracted with ether. The organic extracts were dried
7.33 (2 H, m, ArH); δC 20.6, 25.5(2), 27.8, 35.7, 41.6, 66.9, 72.4, 73.1, (MgSO4), filtered and concentrated under reduced pressure to give
93.4, 110.9, 127.5, 127.6, 128.4, 139.3, 146.3 and 159.1; m/z (ES+) the (3R)-alcohol 39 containing <3% of minor somers.
309 (M+ + 23, 43%) and 186 (100).
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J. Name., 2013, 00, 1-3 | 11
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Organic & Biomolecular Chemistry
Page 12 of 15
ARTICLE
Journal Name
Sodium hydride (90 mg) and methyl iodide (0.18 mL) were Chromatography (1:1 ether:light petroleum) of the residue gave the
View Article Online
20
added to this alcohol in THF (10 mL) at −10 oC and the mixture title compound 45 as a clear oil (3.1 g, 9D9O%I:)1,0[.α10]3D9/C–71O3B0(0c077.93K,
stirred for 16 h at rt. Saturated aqueous sodium hydrogen CHCl3) (Found: M+ + H, 301.2552. C17H37O2Si requires M, 301.2557);
carbonate was added and the mixture partitioned between water νmax/cm-1 3430, 3078, 2935, 1641, 1463, 1095, 996, 910 and 883; δH
and ether. The aqueous layer was extracted with ether and the 1.11 [21 H, m, 3 × SiCH(CH3)2], 1.40-1.65 (4 H, m, 4-H2, 5-H2), 1.71 (2
organic extracts were dried (Na2SO4) and concentrated under H, m, 6-H2), 2.12 (2 H, m, 2-H2), 3.57 (1 H, s, OH), 3.85-4.10 (3 H, m,
reduced pressure. Chromatography (9:1 light petroleum:ether with 1-H2, 3-H), 4.95-5.10 (2 H, m, 8-H2) and 5.86 (1 H, ddt, J 16.6, 10.1,
1% Et3N) afforded the title compound 41 (487 mg, 76% from 40) 6.8, 7-H); δC 12.0, 18.2, 25.1, 34.1, 37.3, 38.5, 63.9, 72.7, 114.7 and
containing <3% of minor isomers; δH (C6D6) 0.97-1.12 (2 H, m, 1’’- 139.1; m/z (CI+) 301 (M+ + 1, 100%).
H2), 1.37 and 1.39 (each 3 H, s, CH3), 1.60-1.72 (3 H, m, 4-H, 5-H2), (8S)-8-Triethylsilyloxy-10-tri-isopropylsilyloxydec-1-en-4-ol (47).
1.85 (1 H, dddd, J 13.5, 12.0, 11.4, 4.2, 4-H’), 3.07 (3 H, s, OCH3), The alcohol 45 (3 g, 10 mmol) was added to a suspension of
3.21 (1 H, dd, J 11.7, 4.5, H-3), 3.26 (3 H, s, OCH3), 3.48 (1 H, dt, J triethylsilyl chloride (1.85 mL, 11 mmol) and imidazole (1.02 g, 15
6.9, 4.8, 2’’-H), 3.62 (1 H, m, 2’’-H’), 3.7 (1 H, dddd, J 11.7, 8.7, 3.9, mmol) in DCM (40 mL) at rt and the reaction mixture stirred for 1 h
2.7, H-6); 4.38 (2 H, s, PhCH2), 5.02 (1 H, dd, J 10.8, 1.5, 3’-H); 5.1 (1 then washed with brine (80 mL). Following extraction of the
H, dd, J 17.7, 1.5, 3’-H’), 6.58 (1 H, dd, J 17.7, 10.8, 2’-H) and 7.45- aqueous layer with DCM (50 mL), the organic extracts were dried
7.15 (5 H, m, ArH).
(MgSO4)
and
concentrated
under
reduced
pressure.
(2S,3R,6S)-6-(2-Hydroxyethyl)-2,3-dimethoxy-2-(2-methylbut-3-en- Chromatography (40:60 ether:light petroleum) of the residue gave
2-yl)tetrahydropyran (42). Ethanol (4 mL) was added to liquid the bis-silyl ether 46 as a clear oil (4.2 g, 99 %); δH 0.64 (6 H, q, J 7.5,
ammonia (30 mL) followed by the benzyl ether 41 (487 mg) in THF 3 × SiCH2), 1.04 (9 H, t, J 7.5, 3 × SiCH2CH3), 1.13 [21 H, m, 3 ×
(4 mL) at −78 oC. Small pieces of sodium were added until the SiCH(CH3)2], 1.40-1.60 (4 H, m, 4-H2, 5-H2), 1.73 (2 H, q, J 6.7, 6-H2),
solution turned blue. The mixture was stirred for 2 h at −78 oC 2.11 (2 H, m, 2-H2), 3.81 (2 H, t, J 6.4, 1-H2), 3.92 (1 H, m, 3-H), 4.96-
during which time it remained blue and then solid ammonium 5.15 (2 H, m, 8-H2) and 5.87 (1 H, m, 7-H); δC 5.3, 7.2, 12.3, 18.3,
chloride (1 g) was added followed by saturated aqueous ammonium 24.9, 34.2, 37.2, 40.7, 60.5, 69.5, 114.6 and 139.2.
chloride (10 mL) and ether (10 mL). The mixture was allowed to
The bis-silyl ether 46 (3.8 g, 9.18 mmol) was dissolved in DCM
warm to rt and, after allowing the ammonia to evaporate, the (40 mL) and the solution cooled to −78 oC. Ozone was bubbled
aqueous layer was extracted with ether. The organic extracts were through the solution at −78 oC until the solution turned blue
dried (Na2SO4) and concentrated under reduced pressure. (approx 45 min) and then oxygen was bubbled through for a further
Chromatography gave the title compound 42 (350 mg, 97%); δH 5 min. Dimethyl sulphide (1.35 mL, 18.36 mmol) was added and the
(C6D6) 0.97-1.12 (2 H, m, 1’’-H2) 1.37 and 1.39 (each 3 H, s, CH3), solution was allowed to warm to rt then concentrated under
1.20-1.72 (3 H, m, 4-H, 5-H2), 1.95 (1 H, dddd, J 13.5, 12.0, 11.1, 4.2, reduced
4-H’), 1.97 (1 H, br. s, OH), 3.07 (3 H, s, OCH3), 3.22 (1 H, dd, J 11.4, isopropylsilyloxyheptanal.
4.5, 3-H), 3.26 (3 H, s, OCH3), 3.50-3.72 (3 H, m, 6-H, 2’’-H2), 5.02 (1 Prop-2-enylmagnesium bromide (1 M in THF, 13 mL, 13 mmol)
pressure
to
leave
(5S)-5-triethylsilyloxy-7-tri-
H, dd, J 10.8, 1.5, 3’-H), 5.1 (1 H, dd, J 17.7, 1.5, 3’-H’) and 6.5 (1 H, was added to this aldehyde in THF (20 mL) at rt and the solution
dd, J 17.7, 11.1, 2’-H); δC (C6D6) 23.3, 24.5, 24.7, 30.1, 31.1, 38.4, stirred for 16 h. Saturated aqueous ammonium chloride (50 mL)
45.7, 50.5, 54.7, 60.2, 69.3, 80.2, 101.7, 110.2 and 147.4.
and ether (50 mL) were added. The aqueous phase was extracted
(3S)-Oct-7-ene-1,3-diol (44). The hydroxyepoxide 4314 (4 g, 28.2 with ether (3 × 100 mL) and the organic extracts dried (MgSO4) and
mmol) in THF (20 mL) was added to sodium bis-(2- concentrated under reduced pressure. Chromatography (3:1
methoxyethoxy)aluminium hydride (65 wt % in toluene, 2.8 mL) in ether:light petroleum) of the residue gave the title compound 47 as
THF (12 mL) at 0 oC and the solution stirred at 0 oC for 4 h. Ether and a colourless oil (2.65 g, 67 % from 45), as a mixture of epimers,
saturated aqueous Rochelle’s salt (30 mL) were added and the [α]D –13 (c 1.0, CHCl3) (Found: M+ + H, 459.3688. C25H55O3Si2
20
aqueous phase extracted with ethyl acetate (3 × 100 mL). After requires M, 459.3684); νmax/cm-1 3362, 2951, 2868, 1460, 1415,
drying (MgSO4) the organic extracts, concentration under reduced 1239, 1064, 1013 and 883; δH 0.64 (6 H, q, J 8.1, 3 × SiCH2), 0.90 (2
pressure gave the title compound 44 as a clear oil (3.8 g, 94 %), H, m, 6-H2), 0.99 (9 H, t, J 8.2, 3 × SiCH2CH3), 1.09 [21 H, m, 3 ×
20
[α]D –31 (c 5.9, CHCl3) (Found: M+ + NH4, 162.1486. C8H20O2N SiCH(CH3)2], 1.40-1.60 (4 H, m, 5-H2, 7-H2), 1.72 (2 H, q, J 6.3, 9-H2),
requires M, 162.1489; νmax/cm-1 3345, 3078, 2935, 1641, 1438, 2.10-2.40 (2 H, m, 3-H2), 3.68 (1 H, m, 8-H), 3.78 (2 H, t, J 6.6, 10-
1056, 996 and 910; δH 1.55-1.60 (4 H, m, 4-H2, 5-H2), 1.60-1.80 (2 H, H2), 3.91 (1 H, m, 4-H), 5.17 (2 H, br. d, J 12.7, 1-H2) and 5.86 (1 H,
m, 6-H2), 2.00-2.20 (2 H, m, 2-H2), 3.22 (2 H, s, 2 × OH), 3.75-3.95 (3 m, 2-H); δC 5.3, 7.2, 12.2, 18.3, 21.6, 37.2, 37.7, 40.6, 42.1, 60.5,
H, m, 1-H2, 3-H), 4.95-5.10 (2 H, m, 8-H2) and 5.84 (1 H, ddt, J 16.8, 69.6, 70.9, 118.4 and 135.1; m/z (CI+) 459 (M+ + 1, 30%), 419 (25)
10.2, 6.6, 7-H); δC 25.0, 33.9, 37.3, 38.4, 61.7, 72.1, 114.9 and 138.8; and 132 (100).
m/z (CI+) 162 (M+ + 18, 100%) and 145 (M+ + 1, 90).
(8S)-8-Triethylsilyloxy-10-tri-isopropylsilyloxydec-1-en-4-one (48).
(3S)-1-Tri-isopropylsilyloxyoct-7-en-3-ol (45). The diol 44 (1.44 g, Pyridine (6 mL, 74.6 mmol) and the alcohol 47 (2.5 g, 5.46 mmol) in
10 mmol) was added to a suspension of tri-isopropylsilyl chloride DCM (5 mL) were added to a suspension of the Dess-Martin
(2.2 mL, 10 mmol) and imidazole (1.02 g, 15 mmol) in DCM (40 mL) periodinane (2.5 g, 5.87 mmol) in DCM (10 mL) at rt and the
at 0 oC and the reaction mixture allowed to warm to rt then stirred mixture stirred for 50 min. Saturated aqueous sodium bicarbonate
for 16 h. The mixture was washed with brine (80 mL) and the (50 mL) and ethyl acetate (50 mL) were added and the organic
aqueous layer extracted with DCM (50 mL). The organic extracts phase was washed with saturated aqueous sodium thiosulfate (20
were dried (MgSO4) and concentrated under reduced pressure. mL). The aqueous layers were extracted with ethyl acetate (3 × 100
12 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
mL) and the organic extracts were washed with brine (30 mL), dried suspension of the Dess-Martin periodinane (81 mg) iVnieDwCAMrticl(e2OnmlinLe)
DOI: 10.1039/C7OB00079K
pressure. and the mixture stirred for 15 min. Saturated aqueous sodium
(MgSO4)
and
concentrated
under
reduced
Chromatography of the residue gave the title compound 48 as a bicarbonate (10 mL) and ether (10 mL) were added and the
colourless oil (1.9 g, 76 %), Rf = 0.48 (1:1 ether:light petroleum), aqueous phase was extracted with ether (3 × 10 mL). The organic
21
[α]D –6.1 (c 2.4, CHCl3) (Found: M+ + H, 457.3532. C25H53O3Si2 extracts were washed with saturated aqueous sodium thiosulfate
requires M, 457.3528); νmax/cm-1 2868, 1735, 1463, 1383, 1242, (10 mL), dried (Na2SO4) and concentrated under reduced pressure
1101, 1069, 1014, 882 and 843; δH 0.63 (6 H, q, J 7.5, 3 × SiCH2), to afford the corresponding aldehyde; δH (C6D6) 0.00 [9 H, s,
0.99 (9 H, t, J 7.6, 3 × SiCH2CH3), 1.09 [21 H, m, 3 × SiCH(CH3)3], 1.49 Si(CH3)3], 0.85-1.70 (18 H, m, 4-H2, 6-H2, 12-H2, 13-H2, 14-H2, 2 × 8-
(2 H, m, 6-H2), 1.60-1.80 (4 H, m, 7-H2, 9-H2), 2.47 (2 H, m, 5-H2), CH3, SiCH2), 1.91 (1 H, dd, J 16.0, 3.2, 10-H), 2.16 (1 H, dd, J 16.0,
3.19 (2 H, m, 3-H2), 3.77 (2 H, t, J 6.3, 10-H2), 3.91 (1 H, m, 8-H), 5.5, 10-H’), 2.45 (1 H, ddd, J 16.0, 4.8, 1.6, 2-H), 2.52 (1 H, ddd, J
5.15-5.24 (2 H, m, 1-H2) and 5.96 (1 H, ddt, J 17.0, 10.3, 7.0, 2-H); 16.0, 6.4, 2.5, 2-H’), 3.19 (3 H, s, OCH3), 3.50 (1 H, m, 11-H), 3.60-
m/z (CI+) 457 (M+ + 1, 10%), 325 (30) and 132 (100).
(2R,6S)-2-Methoxy-2-(prop-2-enyl)-6-(2-tri-
3.88 (5 H, m, 3-H, 5-H, 7-H, OCH2CH2Si), 4.32 (1 H, m, 15-H), 4.33
and 4.49 (each 1 H, d, J 12.0, ArHCH), 4.67 and 4.75 (each 1 H, d, J
isopropylsilyloxyethyl)tetrahydropyran (49). Anhydrous methanol 7.0, OHCHO), 5.05 (1 H, dt, J 10.7, 1.8, 17-H), 5.35 (1 H, dt, J 17.4,
(10.5 mL) and trimethyl orthoformate (0.1 mL) were added to the 1.8, 17-H’), 5.87 (1 H, ddd, J 17.4, 10.7, 4.7, 16-H), 7.03-7.40 (5 H, m,
ketone 48 (1.30 g, 2.85 mmol) followed by oven dried pyridinium ArH) and 9.70 (1 H, dd, J 2.5, 1.6, 1-H); δC (C6D6) −1.4, 17.1, 18.1,
toluene 4-sulfonate (72 mg, 0.29 mmol). The mixture was stirred for 20.2, 24.2, 26.7, 30.4, 31.6, 33.1, 33.4, 40.5, 42.5, 43.5, 48.4, 50.3,
17 h, saturated aqueous sodium bicarbonate (50 mL) and ether (50 65.5, 71.6, 72.0, 73.8, 78.0, 79.1, 95.3, 104.5, 113.4, 127.4, 128.4,
mL) were added and the aqueous phase was extracted with ether (2 129.7, 135.2, 140.1 and 199.8.
× 20 mL). The organic extracts were washed with saturated
Solid NaH2PO4.2H2O (195 mg, 10 equiv) and 2-methyl-but-2-ene
aqueous sodium bicarbonate (2 × 20 mL), dried and concentrated in THF (2 M, 1.25 mL, 20 equiv) were added to this aldehyde in a
under rediced pressure. Chromatography (1:3 light petroleum:ether mixture of tert-butanol:water (2:1, 1.5 mL) and the mixture cooled
with 1% triethylamine) of the residue gave the title compound 49 as to 0 oC. A solution of NaClO2 (72 mg) in tert-butanol:water (2:1, 1.5
a colourless oil (650 mg, 64 %), Rf = 0.8 (1:9 ether:light petroleum), mL) was added and the mixture stirred for 5 min. A mixture of
[α]D21 +3.1 (c 10.1, CHCl3) (Found: M+ + Na, 379.2641. C20H40O3NaSi saturated aqueous sodium hydrogen carbonate and brine (1:1, 5
requires M, 379.2639); νmax/cm-1 3077, 2867, 1642, 1464, 1096, mL) was added followed by ethyl acetate (10 mL). The aqueous
1057, 1039, 1009 and 882; δH (C6D6) 0.95-1.05 (2 H, m, 4-H2), 1.11 phase was extracted with ethyl acetate (4 × 5 mL) and the organic
[21 H, m, 3 × SiCH(CH3)3], 1.35-1.45 (2 H, m, 5-H2), 1.60-2.00 (4 H, extracts were dried (Na2SO4) and concentrated under reduced
m, 3-H2, 1’’-H2), 2.32 (1 H, ddt, J 15.2, 7.3, 1.0, 1’-H), 2.52 (1 H, ddt, J pressure to give the carboxylic acid 51; m/z (ES-) 605 (M+ − 1, 100%).
15.2, 7.0, 1.0, 1’-H’), 3.21 (3 H, s, OCH3), 3.75-3.95 (3 H, m, 6-H, 2’’-
This acid was dissolved in toluene (3 mL) and triethylamine (36
H2), 4.98-5.10 (2 H, m, 3’-H2) and 5.87 (1 H, ddt, J 17.7, 10.5, 7.0, 2’- µL) and 2,4,6-trichlorobenzoyl chloride (24 µL) were added. The
H); δC (C6D6) 12.3, 18.2, 19.3, 31.3, 33.1, 40.1, 41.7, 47.1, 60.1, 66.9, reaction mixture was stirred at rt for 1 h and the alcohol 50 (27 mg,
98.8, 117.3 and 134.0; m/z (ES+) 379 (M+ + 23, 60%) and 325 (100).
(2R,6S)-2-Methoxy-2-(prop-2-enyl)-6-(2-
0.135 mmol) in toluene (4 mL) and 4-dimethylaminopyridine (24
mg) were added. The mixture was stirred for 15 min before
hydroxyethyl)tetrahydropyran
(50).
Tetra-n-butylammonium saturated sodium hydrogen carbonate (15 mL) and EtOAc (15 mL)
fluoride (1 M in THF, 1.4 mL, 1.4 mmol) was added to the tri- were added. The aqueous phase was extracted with ether (3 × 15
isopropylsilyl ether 49 (450 mg, 1.26 mmol) in THF (10 mL) at rt and mL) and the organic extracts were dried (Na2SO4) and concentrated
the mixture stirred for 16 h at rt. Water (50 mL) was added, the under reduced pressure. Chromatography (15:1 to 1:1 light
mixture was extracted into ether (4 × 50 mL) and the organic petroleum:ether with 1% Et3N) gave the title compound 52 (47 mg,
extracts were dried (MgSO4) and concentrated under reduced 47%) as a pale yellow oil (Found: M+ + Na, 811.4796. C44H72O10NaSi
pressure. Chromatography (20:80 light petroleum:ether with 1 % requires M, 811.4787); δH (C6D6) 0.02 [9 H, s, Si(CH3)3], 0.84-2.00 (21
Et3N) of the residue gave the title compound 50 as a clear oil (253 H, m, 4-H2, 6-H2, 10-H, 12-H2, 13-H2, 14-H2, 2’-H2, 3’’-H2, 4’’-H2, 5’’-
mg, ca. 100 %), [α]D21 +3.1 (c 5.2, CHCl3) (Found: M+ + Na, 223.1300. H2, SiCH2), 1.27 and 1.40 (each 3 H, s, 8-CH3), 2.14-2.37 (2 H, m, 10-
C11H20O3Na requires M, 223.1305); νmax/cm-1 3351, 2954, 2926, H’, 1’’’-H), 2.46 (1 H, dd, J 14.3, 7.5, 1’’’-H’), 2.70 (1 H, dd, J 15.5, 5.5,
2873, 1699, 1453 and 1049; δH (C6D6) 1.05 and 1.19 (each 1 H, m, 4- 2-H), 2.84 (1 H, dd J 15.5, 6.3, 2-H’), 3.00-3.15 (2 H, m, OCH2CH2Si),
H), 1.25-1.45 (2 H, m, 3-H2), 1.50-1.75 (3 H, m, 1’’-H, 5-H2), 1.83 (1 3.13 and 3.24 (each 3 H, s, OCH3), 3.55-4.00 (5 H, m, 3-H, 5-H, 7-H,
H, m, 1’’-H’), 2.16 (1 H, ddt, J 14.3, 7.0, 1.3, 1’-H), 2.23 (1 H, br. s, 11-H, 6’’-H), 4.27-4.53 (5 H, m, 15-H, 1’-H2, PhCH2), 4.82 and 4.88
OH), 2.36 (1 H, ddt, J 14.3, 7.0, 1.3, 1’-H’), 3.07 (3 H, s, OCH3), 3.50- (each 1 H, d, J 7.0, OHCHO), 4.97-5.09 (3 H, m, 17-H, 3’’’-H2), 5.37 (1
3.85 (3 H, m, 6-H, 2’’-H2), 4.92-5.05 (2 H, m, 3’-H2) and 5.75 (1 H, H, dt, J 17.3, 1.6, 17-H’), 5.72-5.97 (2 H, m, 16-H, 2’’’-H), 7.06-7.24 (3
ddt, J 17.3, 10.3, 7.0, 2-H); δC (C6D6) 18.9, 31.0, 32.8, 38.6, 41.5, H, m, ArH) and 7.33 (2 H, m, ArH); δC (C6D6) −1.4, 17.1, 18.2, 19.1,
47.1, 60.9, 70.3, 99.0, 117.6 and 133.5; m/z (ES+) 223 (M+ + 23, 100 20.1, 24.2, 31.1, 31.6, 32.9, 33.2, 33.5, 35.6, 40.6, 41.5, 41.9, 42.3,
%).
43.4, 47.2, 48.5, 61.3, 65.5, 65.6, 65.8, 66.9, 71.5, 73.7, 73.9, 78.0,
79.2, 95.4, 98.9, 104.5, 113.4, 117.4, 127.3, 127.5, 128.4, 133.8,
139.9, 140.2 and 171.0; m/z (ES+) 812 (M+ + 23, 60%).
2-[(2R,6S)-2-Methoxy-2-(prop-2-enyl)tetrahydropyran-6-yl]ethyl
(3R,5R,7S,9S,11S,15R)-7-benzyloxy-5,9-epoxy-11,15-epoxy-8,8-
dimethyl-9-methoxy-3-(2-trimethylsilylethoxymethoxy)heptadec-
25-(3R,5S,7S,9S,11S,15R,19R,23S,16E)-7-Benzyloxy-
16-enoate (52). Pyridine (80 µL) followed after 5 min by the alcohol 5(9),11(15),19(23)-tris-epoxy-3-(2-trimethylsilylethoxymethoxy)-
27 (75 mg, 0.127 mmol) in DCM (3.5 mL) were added to a 9,19-bis-methoxy-8,8-dimethylpentacos-16-enolide (53). Solid
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Grubbs’ II catalyst (1.8 mg) was added to the dienyl ester 52 (35 mg, have lost the double-bond attached to the tetrahydropyran; δH
View Article Online
0.044 mmol) in toluene (5.5 mL) and the mixture was warmed to 60 (C6D6) 5.01 (1 H, dd, J 10.8, 1.6, 4’’’-H), 5.51D(1OHI:,10d.d10, 3J91/7C.77O, B10.60,047’9’’K-
oC and stirred for 3 h. More catalyst (1 mg) was added and the H’), 5.98 (1 H, narrow m, 16/17-H) and 6.55 (1 H, dd, J 17.7, 10.8,
heating continued for 5.5 h. After cooling to rt, chromatography on 3’’’-H). Some dimeric products were evident from the low
neutral alumina (15:1 light petroleum:ether with 1% Et3N) gave the resolution MS; m/z (ES+) 1689 (M+ + 23, 100%).
title compound 53 (6 mg, 17%) (Found: M+ + Na, 783.4481.
C42H68O10NaSi requires M, 783.4474); δH (C6D6) −0.02 [9 H, s,
Si(CH3)3], 0.80-2.15 (29 H, m, 4-H2, 6-H2, 10-H2, 12-H2, 13-H2, 14-H2,
Ackowledgements
18-H, 20-H2, 21-H2, 22-H2, 24-H2, 2 × 8-CH3, SiCH2), 2.42 (1 H, m, 18- We thank the EPSRC for support (for R. D.) and for studentships (to
H’), 2.60 (1 H, dd, J 16.7, 9.2, 2-H), 2.92 (1 H, m, 2-H’), 3.02-3.23 (2 S. McC. and T. G.).
H, m, OCH2CH2Si), 3.34 (6 H, s, 2 × OCH3), 3.40-4.20 (7 H, m, 3-H, 5-
H, 7-H, 11-H, 15-H, 23-H, 25-H), 4.32 and 4.49 (each 1 H, d, J 11.7,
PhHCH), 4.49 (1 H, m, 25-H’), 4.78 and 4.97 (each 1 H, d, J 7.0,
Notes and references
1
2
3
1. M. Ball, A. Baron, B. Bradshaw, R. Dumeunier, M. O’Brien and
OHCHO), 5.68 (1 H, dd, J 15.3, 7.5, 16-H), 6.07 (1 H, ddd, J 15.3, 8.0,
5.4, 17-H) and 7.10-7.35 (5 H, m, ArH); δC (C6D6) −1.5, 16.7 18.3,
19.1, 21.3, 24.3, 30.1, 30.3, 32.2, 32.4, 33.6, 34.3, 39.1, 40.2, 41.2,
42.6, 43.9, 46.6, 48.2, 48.4, 60.1, 64.9, 65.2, 67.5, 71.4, 74.2, 79.3,
79.25 96.6, 98.9, 104.3, 127.3, 128.3, 128.9, 134.5, 140.0 and 171.0;
m/z (ES+) 784 (M+ + 23, 100%).
2-[(2S,3R,6S)-2,3-Dimethoxy-2-(2-methylbut-3-en-2-
yl)tetrahydropyran-6-yl]ethyl (3R,5R,7S,9S,11S,15R)-7-benzyloxy-
5,9-epoxy-11,15-epoxy-8,8-dimethyl-9-methoxy-3-(2-
E. J. Thomas, Org. Biomol. Chem., 2016, 14, 9650.
M. Ball, T. Gregson, H. Omori and E. J. Thomas, submitted to
Org. Biomol. Chem., 2017.
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K. Woo and M. J. Krische, J. Am. Chem. Soc., 2011, 133, 13876.
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Herald, Y. Kamano, G. R. Pettit and P. M. Blumberg, Proc. Natl.
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trimethylsilylethoxymethoxy)heptadec-16-enoate (54). Following
the procedure outlined above, the alcohol 27 (75 mg, 0.127 mmol)
gave the carboxylic acid 51. This acid was dissolved in toluene (3
mL) and triethylamine (36 µL) and 2,4,6-trichlorobenzoyl chloride
(24 µL) were added. The mixture was stirred at rt for 1 h and then
the alcohol 40 (33 mg) in toluene (4 mL) and 4-
dimethylaminepyridine (24 mg) were added. The mixture was
stirred for 30 min and saturated aqueous sodium hydrogen
carbonate (15 mL) and EtOAc (15 mL) were added. The aqueous
phase was extracted with ether (3 × 15 mL) and the organic extracts
were dried (Na2SO4) then concentrated under reduced pressure.
Chromatography (15:1 to 1:1 light petroleum:ether + 1% Et3N) of
the residue gave the title compound 54; δH (C6D6) 0.02 [9 H, s,
Si(CH3)3], 0.85-1.85 (18 H, m, 4-H2, 6-H2, 12-H2, 13-H2, 14-H2, 2’-H2,
4’’-H2, 5’’-H2, SiCH2), 1.26, 1.32, 1.36 and 1.40 (each 3 H, s, CH3),
1.95 (1 H, dd, J 16.0, 3.5, 10-H), 2.20 (1 H, dd, J 16.0, 5.5, 10-H’),
2.69 (1 H, dd, J 15.3, 5.3, 2-H), 2.86 (1 H, dd J 15.3, 6.7, 2-H’), 3.04,
3.24 and 3.30 (each 3 H, s, OCH3), 3.40-3.95 (8 H, m, 3-H, 5-H, 7-H,
11-H, 3’’-H, 6’’-H, OCH2CH2Si), 4.25-4.40 (2 H, m, 1’-H2), 4.32 and
4.48 (each 1 H, d, J 11.8, PhHCH), 4.49 (1 H, m, 15-H), 4.82 and 4.90
(each 1 H, d, J 7.0, OHCHO), 5.02 (1 H, dd, J 10.8, 1.6, 4’’’-H), 5.02-
5.14 (2 H, m, 17-H, 4’’’-H’), 5.37 (1 H, dt, J 17.3, 1.9, 17-H’), 5.90 (1
H, ddd, J 17.4, 10.7, 4.7, 16-H), 6.53 (1 H, dd, J 17.7, 10.8, 3’’’-H),
7.04-7.25 (3 H, m, ArH) and 7.34 (2 H, d, J 7.0, ArH); δC (C6D6) −1.4,
17.1, 18.2, 20.1, 23.2, 24.2, 24.5, 24.6, 30.1, 31.1, 33.3, 33.5, 35.2,
40.6, 42.0, 42.4, 43.5, 45.7, 48.5, 50.5, 54.7, 61.5, 65.6, 65.8, 67.3,
71.6, 73.7, 73.9, 78.0, 79.2, 80.2, 95.5, 101.4, 104.5, 109.8, 113.4,
127.3, 127.5, 128.4, 139.9, 140.2, 147.5 and 171.0; m/z (ES+) 865
(M+ + 18, 70%) and 816 (40).
4
5
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Attempts to carry out RCM using the conditions outlined for the
synthesis of the macrolide 53, led to mixtures of compounds
containing only traces of a product containing a disubstituted (E)-
double-bond; δH (C6D6) 6.31 (1 H, dd, J 16.0, 5.5, 16-H) and 6.78 (1
H, br. d, J 16.0, 17-H). The major products appeared to have
retained the double-bond next to the geminal methyl groups but to
6
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