Synthesis of Cyclic Alkenyl Dimethylsiloxanes from Alkynyl Benzyldimethylsilanes and Application in Polyene Synthesis

Article abstract of DOI:10.1021/acs.joc.9b01664

Cyclic dimethylalkenylsiloxanes, useful motifs for (Z)-selective Hiyama cross-coupling, are accessed from alkynyl benzyldimethylsilanes featuring adjacent allylic or homoallylic oxygen substituents by semihydrogenation/debenzylation/cyclization. While formation of 5- and 6-membered rings can be achieved from the free alcohols using fluoride or silanolate, allylic acetate precursors to 5-membered rings display distinct modes of activation. The utility of these compounds is demonstrated through the preparation of a variety of (Z)-alkene-containing polyenes and application to a concise total synthesis of leukotriene B₃

Full text of DOI:10.1021/acs.joc.9b01664

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Note
Synthesis of Cyclic Alkenyl Dimethylsiloxanes from Alkynyl
Benzyldimethylsilanes, and Application in Polyene Synthesis
Haraldur G. Gudmundsson, Christian J. Kuper, Damien Cornut,
Felix Urbitsch, Bryony L. Elbert, and Edward A. Anderson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01664 • Publication Date (Web): 24 Oct 2019
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The Journal of Organic Chemistry
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Synthesis of Cyclic Alkenyl Dimethylsiloxanes from Alkynyl
Benzyldimethylsilanes, and Application in Polyene Synthesis
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Haraldur G. Gudmundsson,‡ Christian J. Kuper,‡ Damien Cornut, Felix Urbitsch, Bryony L. Elbert
and Edward A. Anderson*
Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK
edward.anderson@chem.ox.ac.uk
Supporting Information Placeholder
ABSTRACT: Cyclic dimethylalkenylsiloxanes, useful motifs for (Z)-selective Hiyama cross-coupling, are accessed from
alkynyl benzyldimethylsilanes featuring adjacent allylic or homoallylic oxygen substituents by semi-hydrogenation /
debenzylation / cyclization. While formation of 5- and 6-membered rings can be achieved from the free alcohols using
fluoride or silanolate, allylic acetate precursors to 5-membered rings display distinct modes of activation. The utility of
these compounds is demonstrated through the preparation of a variety of (Z)-alkene-containing polyenes, and
application to a concise total synthesis of leukotriene B3.
Cyclic alkenylsiloxanes (1, Scheme 1) are versatile
synthetic intermediates. On activation by silaphilic
nucleophiles, they enable the synthesis of (Z)-allylic or
homoallylic alcohols via palladium-catalyzed Hiyama-
Denmark cross-coupling,1 and serve as precursors to -
or -hydroxycarbonyls through Tamao oxidation.2 In the
cross-coupling setting, cyclic alkenylsiloxanes offer
benefits over other organometallic reagents:3 they are
non-toxic (compared to organotin compounds),
inexpensive, and ensure the (Z)-stereochemistry of the
coupled alkene product due to the constrained (cyclic)
nature of the alkenylsiloxane. They also offer transient
protection for the proximal allylic or homoallylic alcohol,
thereby avoiding unnecessary protecting group
manipulations of the latter.
alternative strategy based on the semi-hydrogenation of
diethylisoproxyalkynylsilanes
4
to
acyclic
cyclic
(Z)-
diethyl
alkenylsiloxanes,
which
afford
alkenylsiloxanes on reaction with a proximal alcohol.8
The use of a diethylsilane was required due to the
hydrolytic
sensitivity
of
equivalent
dimethylalkoxyalkynylsilanes; however, the stability
conferred by the ethyl substituents also reduced
reactivity towards cross-coupling.9
Scheme 1. Approaches to cyclic alkenylsiloxanes
These motifs have typically been accessed by ring-
closing metathesis (RCM, 21),4 or intramolecular alkyne
2b,
5
hydrosilylation (31).2a,
While such methods have
been applied in a number of settings,1c,
the RCM
2a,
6
approach requires the air-sensitive Schrock catalyst to
overcome the steric hindrance imparted by the silicon
substituents, while hydrosilylation is limited to internal
alkynes and necessarily forms
a
trisubstituted
To overcome this limitation, we targeted
hydrolytically- resistant silane, where the silanol (and
a
alkenylsilane product.7 We previously reported an
1
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Page 2 of 20
cyclic siloxane) would be unmasked only after alkyne
semi-hydrogenation. The benzyldimethylsilyl (BDMS)
group was an attractive candidate (5), as it is well-
established to act as a surrogate for a dimethylsilanol,
but is stable to a wide variety of conditions in its latent
form. In seminal work, Eaborn demonstrated its lability
towards aqueous base (under warming),10 while later
studies revealed a more 'orthogonal' cleavage by the
action of hydrated fluoride (e.g. TBAF).11
(Z)-Alkenylbenzylsilanes (6) have previously been
generated via hydrozirconation or diimide reduction of
BDMS-alkynylsilanes.11a, 12 Here we describe development
of the semihydrogenation approach to these motifs, and
the implementation of various methods for benzyl
cleavage / cyclization to the cyclic siloxane. We also
compare the coupling efficiency of 5- and 6-membered
cyclic dimethylsilanes to give (Z)-alkene containing
polyenes, where the 5-membered dimethylsiloxanes
were found to exhibit significantly enhanced coupling
efficiency and reactivity compared to their acyclic
counterparts. We further apply the chemistry to a
concise seven-step synthesis (linear sequence) of the
anti-inflammatory natural product leukotriene B3.
as single diastereomer, which was somewhat
unexpected in light of our previous work in which
a
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7
8
acetate protection was required for high selectivity in the
13
reduction.8a,
Hydrogenation of 8a also proceeded in
excellent yield, albeit a small amount of the (E)-alkene
was observed (12a, Z:E = 6:1); this observation is in
keeping with other Lindlar reductions of alkynylsilanes.8b,
14
While these alcohols are direct precursors to cyclic
siloxanes, we also wished to compare the efficiency of
9
debenzylation
/
cyclization of protected alcohol
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derivatives, as might be found in synthetic contexts.
Acetate-, TBS- and PMB-protected alcohols were thus
prepared, with these groups introduced either before
(n=0) or after (n=1) semi-hydrogenation (7/12b–d
respectively). The reductions to produce 7b–d proceeded
in high yield and with good selectivity, with the
exception of silyl ether 11c (Z:E = 5.3:1). This latter result
likely relates to the increased steric crowding in this
substrate, although the mechanistic basis of the
isomerization is not clear.
With various potential precursors to 5- and 6-
membered
cyclic
dimethylsiloxanes
in
hand,
debenzylation / cyclization conditions were examined
(Table 1). Treatment of alcohol 11a with TBAF effected
rapid debenzylation and complete conversion to the
cyclic siloxane 13, while the homoallylic alcohol 12a gave
a mixture of cyclic siloxane 14 and acyclic silanol, which
cyclized to 14 on workup (74%). Interestingly, complete
debenzylation could be achieved with just 0.25
equivalents of TBAF, with products 13 and 14 isolated
after either acidic or basic workup, on multi-gram scale.
11a and 12a were also converted to their cyclic siloxanes
on treatment with KOTMS, which could permit fluoride-
free activation / in situ cross-coupling of the masked
silanol.15 This represents the first use of KOTMS to
unmask a BDMS group.
For the protected alcohol derivatives, we expected that
a two step process would be required to reveal the cyclic
siloxanes; however, 13 was unexpectedly generated on
treatment of allylic acetate 11b with TBAF•3H2O, albeit
this reaction now required a full equivalent of fluoride.
Equally surprisingly, solvolysis of 11b (K2CO3 / MeOH)
also led to exclusive formation of 13. In contrast, reaction
of homoallylic acetate 12b with TBAF gave the acyclic
silanol 16b with the acetate intact, while methanolysis
afforded the expected acyclic alcohol 18 with the BDMS
group remaining untouched. Sluggish reactions were
observed for both acetates 11b and 12b on treatment
with KOTMS, resulting in a 1:2 mixture of the cyclic
siloxanes and desilylated products 19 and 20.
Scheme 2. Synthesis of cyclic siloxane precursors
BnMe2Si
a, 89%
b, 87%
O
OBn
O
OBn
H
9
10
BnMe2Si
OR OBn
( )n ( )1-n
d, e or f
7b 7c
7d
7a: n = 0
R =
Ac TBS PMB
99% 91% 77%
8a: n = 1
c
R
R
BnMe2Si
O
O
OBn
OBn
SiMe2Bn
11a 11b 11c 11d
12a: R = H,
98%, dr 6:1
R =
H
Ac TBS PMB
d, e or f
77% 85% 67% 89%
12b 12c 12d
R = Ac TBS PMB
95% 89% 72%
dr 5.3:1
Reagents and conditions: a) n-BuLi, THF, -78 °C; 9; 89% (7a);
b) n-BuLi, THF, -78 °C; BF3•Et2O, 10, 87% (8a); c) H2,
Pd/CaCO3, quinoline, toluene; 11a: 77%, dr 20:1; 11b: 85%,
dr 20:1; 11c: 67%, dr 5.3:1; 11d: 89%, dr 20:1; 12a:
cyclohexene included as co-solvent, 98%, dr 6:1; d) Ac2O,
DMAP, Et3N, CH2Cl2; 7b: 99%; 12b: 95%; e) TBSCl, imid.,
CH2Cl2; 7c: 91%; 12c: 89%; f) PMBTCA, Sc(OTf)3, CH2Cl2; 7d:
77%; 12d: 72%.
BDMS-substituted propargylic and homopropargylic
alcohols 7a and 8a (Scheme 2) were prepared by
addition of lithium benzyldimethylsilylacetylide to
Reaction of silyl ether 11c with TBAF also gave the
cyclic siloxane 13, while for 12c a 4.5:1 mixture of cyclic
siloxane 14 and silanol 16a was produced. In contrast to
the alcohol and acetate substrates, KOTMS or
aldehyde
9
and epoxide 10 respectively. Semi-
hydrogenation of 7a afforded the (Z)-BDMS alkene 11a
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K2CO3/MeOH could not achieve cleavage of the alcohols had been noted by Eaborn, but is rarely
1
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3
4
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7
8
benzylsilane or TBS ethers. Similarly, PMB ethers 11d and
12d remained intact on treatment with any of the
'activators', with debenzylation to 15 / 16d only possible
under TBAF activation.
exploited.16 As no debenzylation /cyclization is observed
for alcohol 11a under the same conditions, the proximity
of the alkoxide (released on ester hydrolysis) to the
silicon atom appears to be important.16-17 On treatment
of 11b with TBAF (Scheme 3b), the silanol generated by
benzyl cleavage (23) could undergo transesterification
with the adjacent acetate, the liberated alkoxide (or
alcohol) then cyclizing onto the acetoxysilane. The
efficient and rapid cyclization of alcohols 11a/12a on
treatment with KOTMS (Scheme 3c), but not of silyl
ethers 11c/12c, implies that a proximal alcohol is
beneficial for this unusual debenzylation. We suggest
that reversible addition of
These observations suggest that neighbouring group
participation is crucial in the unexpected debenzylation /
cyclizations of allylic acetate 11b (Scheme 3). Under
methanolysis conditions (Scheme 3a), attack of
methoxide on the acetate leads to a tetrahedral
intermediate 21, the alkoxide derived from which may be
ideally placed to engage with the adjacent silicon atom,
promoting benzyl cleavage (22); indeed, the enhanced
rate of cleavage of trialkylbenzylsilanes by proximal
Table 1. Debenzylation and cyclization studies.
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Ac
TBS
PMB
O
BnMe2Si
OH OBn
BnMe2Si
O
OBn
BnMe2Si
HOMe2Si
OBn
OBn
BnMe2Si
O
OBn
Conditionsa
11a
11b
11c
11d
PMB
O
TBAFc
13 (99)
13 (99)
13 (99)
13 (99)f
15 (n.d.)f
K2CO3/MeOHd
no reaction
no reaction
no reaction
no reaction
no reaction
OH OBn
KOTMSe
13 (99)
12a
19, 13 (2:1)g
Conditionsb
12b
12c
12d
16d
TBAFc
K2CO3/MeOHd
KOTMSe
14 (74)
16b (n.d.)
18 (93)
(n.d.)f
14, 16a (4.5:1)f,g
no reaction
no reaction
no reaction
no reaction
14 (71)
no reaction
20, 14 (2:1)h
1
a Values in parentheses represent conversions for 5-membered ring products (as judged by H NMR spectroscopic analysis
c
of the crude reaction mixture). b Yields in parentheses represent isolated yields for 6-membered ring products. TBAF•3H2O
d
e
f
g
(0.25 equiv.), THF, rt. K2CO3 (1.5 equiv.), MeOH, rt. KOTMS (1.5 equiv.), THF, rt. 1 equiv. TBAF. Product ratio; yield not
determined. h 14 was isolated in 34% yield. For other entries, n.d. = not determined.
the silanolate ion to the benzylsilane could lead to an
electrophilic ate complex 24, which promotes attack by
the neighboring alcohol. An alternative role of silanolate
as general base cannot be ruled out, but would seem
inconsistent with the lack of debenzylation observed
with K2CO3 / MeOH. Given that 5-membered cyclic
dimethylalkenylsiloxanes are sensitive towards silica gel
column chromatography, these various modes of
activation – which require no purification other than an
aqueous work up – could improve access to the cyclic
species from stable precursors.
Scheme 3. Possible mechanisms for debenzylation of
11a / 11b.
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27a 15 min,b 99%
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2
26b 30 min,b,c 38%
+ 48% desilylation 27b 30 min,b,d 94%
25a
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3
26c
27c
25b (X=I)
25c (X=Br)
(X=I) 45 min, 78%
(X=Br) 15 min, 78%
(X=I) 16 h, 75%
(X=Br) 5 h,e 68%
Hiyama-Denmark couplings of these 5- and 6-
membered cyclic siloxanes were next studied, with a
focus on polyene synthesis, which has been less
extensively explored than equivalent arene couplings.
We aimed to compare the efficiency of reaction of the
two ring sizes with that of the previously studied cyclic
diethylsilanes,8 and acyclic (Z)-benzyldimethylsilanes 11d
and 12d, as well as to evaluate the influence of the
substitution pattern and halide of the alkene coupling
partner. As described by Denmark et al., either Pd(dba)2
(5 mol%) or [Pd(allyl)Cl]2 (2.5 mol%) were used as pre-
catalysts, with 2–3 equiv. of TBAF as activator, in THF at
room temperature.4d
An initial study of reactions with iodobenzene using
Pd(dba)2 and 2.0 equiv. of TBAF revealed very rapid
cross-coupling of both the 5-membered cyclic siloxane
13 (98%, 5 min) and the 6-membered counterpart 14
(99%, 15 min) (Table 2, Entry 1). These reactions were
markedly more rapid than the equivalent cyclic
diethylsilanes (which required 24 h to achieve similar
yields),8 underlining the critical importance of the size of
the silane substituents. Compared to 13, the acyclic
benzyldimethylsilane 11d (Entry 2) required extended
reaction times, and gave a mixture of stereoisomers (Z:E
= 3:1) as well as significant desilylation of the starting
material, which clearly illustrates the advantage of the
cyclic silane in this coupling. Interestingly, the acyclic
homoallylic PMB ether 12d coupled with equal efficiency
to cyclic siloxane 14, which
4
5
6
25d (X=I)
26d
27d
25e (X=Br) (X=I) 15 min,f 73%
(X=I) 16 h, 65%
(X=Br) 16 h, 60%
(X=Br) 3 h,e 57%
25f
26e 1 h, 84%
27e 16 h, 73%
25g (X=I)
25h (X=Br)
26f
27f
(X=I) 30 min, 81%
(X=I) 30 min, 64%
(X=Br) 16 h, 53%
(X=Br) 2 h,g 56%
26g 4 h, 52%
Fostriecin fragment
7
8
25i
25j
26h 2 h, 66%
Phoslactomycin B
fragment
aIsolated yields. Couplings in Entry 2 used 11d and 12d as
substrates. b2 equiv. TBAF•3H2O. c Coupling of 11d. Product
isolated in a 3:1 Z:E ratio. d Coupling of 12d. e[allylPdCl]2 (2.5
mol%), 1.2 equiv. siloxane. 1.2 equiv. siloxane. [allylPdCl]2
(2.5 mol%).
f
g
Table 2. Substrate scope in Hiyama-Denmark coupling
may imply that these two reactions proceed through a
similar acyclic silane species.18
Application of these conditions to iodostyrene 25b
(Entry 3), resulted in sluggish coupling of 5-membered
siloxane 13, with incomplete reaction after 1.5 h.
However, use of an additional equivalent of fluoride
enabled complete conversion in 45 min (26c, 78%).
When bromostyrene 25c was employed, 26c was
obtained in equivalent yield but, surprisingly, in a shorter
reaction time (15 min). The 6-membered siloxane 14
Product from 13
Product from 14
Entry Substrate
Time, Yield (%)a
Time, Yield (%)a
1
25a
26a 5 min,b 98%
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The Journal of Organic Chemistry
displayed a similar trend, albeit both couplings required We therefore propose that the action of fluoride on 14
1
longer reaction times (iodostyrene: 27c, 75%, 16 h;
bromostyrene: 27c, 68%, 5 h). These modified conditions
were applied to a range of mono- and dienyl halides
25f–j, giving products 26d–h / 27d–f in moderate to
excellent yields (52–90%, Entries 4-6). In all cases, shorter
reaction times were observed for 13 (15 min–3 h)
compared to 14 (typically 16 h), and aside from the
halostyrenes, vinyl iodides showed superior reactivity
compared to vinyl bromides. Most notable were the
comparatively rapid8 syntheses of the triene / diene
portions of fostriecin and phoslactomycin B (26g and
26h respectively, entries 7, 8), which involve coupling of
hindered (Z)-alkenyl iodides.
establishes a rapid equilibrium of 14 with disiloxane 28,
and that this speciesundergoes transmetalation via a
Denmark ate complex 30. The question therefore
remains as to the nature of the transmetalating species
derived from the 5-membered siloxane 13 (or, its acyclic
disiloxane 29), where experimental observations show
enhanced and distinct reactivity compared to acyclic
alkenylsilanes (see above). We suggest that while the
reactions of 13 could certainly proceed via an equivalent
fluoride ate complex 31, there is potential for
intramolecular engagement by the proximal alcohol to
form complex 32. Whether this complex exists in higher
concentration, or is more reactive than its fluoride
counterpart remains unclear, but given the precedent for
the enhanced reactivity of other -hydroxysilanes in
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The different reactivity of the five- and six-membered
ring siloxanes is worthy of discussion. Under conditions
equivalent to those employed in the present work,
Denmark proposed that the transmetalation step for
alkoxide-promoted cross-coupling,22 this seems
reasonable mechanistic proposal.
a
fluoride-promoted
cross-coupling
of
acyclic
Finally, the utility of this methodology was
demonstrated through a concise total synthesis of
leukotriene B3 (33, Scheme 5), an important agent in the
inflammatory response process.23,24 The synthesis of
cyclic siloxane 34, containing the C6–C7 (Z)-alkene of the
natural product, commenced with addition of the zinc
acetylide of BDMS acetylene to commercially available
acid chloride 35. Noyori asymmetric transfer
hydrogenation25 (99% ee) followed by acetate protection
afforded alkyne 37, which gave the 5-membered cyclic
siloxane 34 after treatment with fluoride. Its coupling
partner, dienyl iodide (R)-38, was prepared from
alkenylsilanols involves a key fluoride ate-complex of an
alkenyl disiloxane.19 We explored the behaviour of the 5-
and 6-membered siloxanes 13 and 14 on treatment with
TBAF by NMR spectroscopy (in d8-THF), and observed for
both the immediate establishment of an equilibrium with
what we propose to be acyclicdisiloxanes 28 and 29
(Scheme 4).20 While the 5-membered siloxane undergoes
gradual desilylation under these conditions, we
Scheme 4. Possible mechanisms for transmetallation of
cyclic siloxane-derived intermediates
SO3•pyridine via hydrolysis
/
iodination to an
intermediate semi-hydrogenation of iododienal,26
addition of n-octylmagnesium bromide to which gave
dienyl iodide (±)-38 as a mixture of stereoisomers (1.2:1,
E,E:E,Z) which could be enriched in the desired isomer via
recrystallization (10:1, E,E:E,Z). Swern oxidation, followed
by CBS reduction27 of the resulting enone, gave dienyl
iodide (R)-38 (90% ee, after recrystallization). Fluoride-
promoted cross-coupling of 34 and (R)-
Scheme 5. Synthesis of leukotriene B3
were able to use ECC-DOSY NMR spectroscopy21 to
support the assignment of disiloxane 28, with an
estimated molecular weight of ~600 (actual MW of silanol
monomer: 248; MW of disiloxane 28: 515).20
5
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O
O
O
room temperature. Tetrabutylammonium fluoride
(TBAF•3H2O) solution was prepared by dissolving solid
a
CO2Et
CO2Et
1
2
3
4
5
6
7
8
Cl
Si
35
36
BnMe2Si
tertabutylammonium fluoride trihydrate in anhydrous
THF. Column chromatography was performed using
Macherey-Nagel Kieselgel 60M (230-400 mesh) silica gel
as the stationary phase. Specific rotations were recorded
on a Perkin-Elmer 341 polarimeter with a 1 dm path
length cell (sodium D line, 589 nm); specific rotations [훼]
are given in deg dm2g-1, concentration (c) is reported in
g 100 mL-1. Enantiomeric excesses (ee) were determined
by HPLC using a DAICEL CHIRALPAK IB or IC column (250
mm × 4.6 mm ID). Infrared spectra were recorded on a
Bruker Tensor 27 FT-IR spectrometer equipped with a
b, c
OAc
d, e
CO2Et
CO2Et
BnMe2Si
34
37
OH
n-Octyl
OH
n-Octyl
f-h
i, j
9
I
I
N
10
11
12
13
14
15
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(±)-38
(R)-38
SO3
OH
n-Octyl
CO2Et
OH
n-Octyl
CO2H
k
l
34 + 38
1
diamond ATR module. H and 13C NMR spectra were
OH
OH
recorded on Bruker DPX200, AVIII400 or AVIII500
spectrometers. Chemical shifts (δ) are reported in parts
per million (ppm), referenced to the solvent residual
(CDCl3 δH/δC = 7.26/77.2; C6D6 δ = 7.16/128.1; CD3OD δ
= 3.31/49.0). Signals are recorded as singlet (s), broad
singlet (br s), doublet (d), triplet (t), quartet (q), quintet
(quin), and multiplet (m). Coupling constants (J) are
reported to the nearest 0.5 Hz. High resolution mass
spectra (HRMS) were recorded on a Bruker Daltonics
microTOF spectrometer (resolution = 5000 FWHM).
39
33: Leukotriene B3
Reagents and conditions: a) n-BuLi, BnMe2SiCCH, ZnCl2,
THF, 0 °C, 52%; b) RuCl(S,S)TsDPEN (2 mol%), i-PrOH,
CH2Cl2; c) Ac2O, DMAP, Et3N, CH2Cl2, 90% over two steps,
99% ee; d) H2, Pd/CaCO3 (5 mol%), quinoline, cyclohexene,
toluene, 82%, dr >20:1; e) TBAF•3H2O (1.05 equiv), THF,
87%; f) KOH, H2O; g) PPh3, I2, CH2Cl2; h) 1-bromooctane, Mg,
THF, 8% over three steps (10:1 E,E:E,Z after recrystalization);
i) (COCl)2, DMSO, Et3N, CH2Cl2; j) (S)-(‒)-2-methyl-CBS-
oxazaborolidine, BH3.THF, THF, 33% over two steps (90% ee,
12% yield after recrystalization); k) Pd(dba)2 (5 mol%),
TBAF•3H2O (3 equiv), THF, 73%; l) LiOH, H2O, i-PrOH, 99%.
Benzyl(ethynyl)dimethylsilane
was
prepared
by
variation of a literature procedure.12a To a suspension of
Mg turnings (4.74 g, 195 mmol, 1.4 equiv.) in Et2O (20
mL, sufficient to cover the turnings) was added a solution
of benzyl chloride (16.0 mL, 139 mmol, 1.0 equiv.) in Et2O
(120 mL) at a rate sufficient to maintain controlled reflux.
After addition, the mixture was heated at reflux for 2 h,
then cooled to room temperature. The resulting solution
of benzylmagnesium chloride (140 mL, ca. 1.0 M in Et2O,
1.0 equiv.) was added to dichlorodimethylsilane (24.0 ml,
199 mmol, 1.4 equiv.) via cannula. The mixture was
heated at reflux for 1 h, then cooled to room
temperature. The suspension was filtered under nitrogen
via cannula, and concentrated in vacuo to give crude
benzyldimethylchlorosilane as a pale yellow oil. The
silane was redissolved in THF (240 mL) and cooled to 0
°C. To this stirred solution was added dropwise a
solution of ethynylmagnesium bromide (304 mL, 0.5 M in
THF, 152 mmol, 1.3 equiv.). The resulting mixture allowed
to warm to room temperature, and was stirred for a
further 3 h. The reaction was quenched by addition of
NH4Cl (240 mL, sat., aq.). The organic phase was
separated, and the aqueous phase was further extracted
with Et2O (2 × 200 mL). The combined organic phases
were dried (MgSO4), filtered and concentrated.
Purification via column chromatography (5% EtOAc /
petroleum ether) gave benzyl(ethynyl)dimethylsilane
38 gave triene 39 in 73% yield. Finally, ester hydrolysis
afforded leukotriene B3 (33, 99%) in a total of seven
steps in the longest linear sequence from commercially
available starting materials, which corresponds to the
shortest synthesis of this natural product to date.
In conclusion, 5- and 6-membered cyclic dimethyl
alkenylsiloxanes can be prepared by the semi-
hydrogenation of benzyldimethyl
alkynylsilanes, with the resultant (Z)-benzyldimethyl
alkenylsilanes serving as masked cyclic siloxane
precursors. Cyclization of both allylic and homoallylic
alcohols adjacent to BDMS (Z)-alkenes can be effected
through both fluoride- and silanolate-promoted benzyl
cleavage, and allylic acetate 5-membered ring siloxane
precursors display unique modes of activation under
mild conditions. Cross-coupling was used to access a
range of (Z)-alkene containing polyenes, including
fragments of the natural products fostriecin and
phoslactomycin B. Finally, this chemistry was applied to a
concise total synthesis of leukotriene B3.
EXPERIMENTAL SECTION
General considerations. Commercial reagents were
used directly as supplied. Solvents were dried using an
alumina column solvent drying system. Unless otherwise
stated, all non-aqueous reactions were performed in
oven-dried apparatus under a nitrogen atmosphere at
1
(19.7 g, 113 mmol, 81%) as a pale yellow liquid. H NMR
(400 MHz, CDCl3) δ 7.27-7.21 (2H, m), 7.14-7.0 (3H, m),
2.42 (1H, s, CCH), 2.23 (2H, s), 0.16 (6H, s, Si(CH3)2);
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The Journal of Organic Chemistry
13C{1H} NMR (101 MHz, CDCl3) δ 140.9, 130.7, 130.6,
126.8, 96.7, 90.9, 28.2, 0.0. Spectroscopic data in
agreement with the literature.12a
3.25 mmol, 2.2 equiv.). After stirring for 10 min, 7a (500
1
2
3
4
5
6
7
8
mg, 1.48 mmol, 1.0 equiv.) was added and the mixture
was stirred overnight. The mixture was diluted with
CH2Cl2 (15 mL), then NH4Cl (15 mL, sat., aq.) was added.
The organic phase was separated, and the aqueous
phase extracted with CH2Cl2 (2 × 15 mL). The combined
organic phases were dried (MgSO4), filtered and
concentrated. Purification via column chromatography
(2% Et2O / petroleum ether) gave 7c (610 mg, 1.35
mmol, 91%) as a colourless oil. Rf 0.79 (25% Et2O /
petroleum ether); IR (thin film, νmax / cm-1) 2956, 2173,
1-(Benzyldimethylsilyl)-5-(benzyloxy)pent-1-yn-3-ol
(7a). To a solution of benzyldimethylsilylacetylene (4.37
g, 25.1 mmol, 1.1 equiv.) in THF (76 mL) at −78 °C was
added a solution of n-BuLi (9.6 mL, 2.5 M in hexanes,
23.9 mmol, 1.05 equiv.) dropwise via syringe. The
resulting mixture was stirred for 1 h, after which 3-
(benzyloxy)propanal (9) (3.74 g, 22.8 mmol, 1.0 equiv.)
was added. After stirring at −78 °C for 30 min, the
cooling bath was removed and the reaction allowed to
reach room temperature and stirred for a further 30 min.
The reaction was quenched by addition of NH4Cl (80 mL,
sat., aq.), the organic phase was separated and the
aqueous phase further extracted with Et2O (3 × 80 mL).
The combined organic phases were dried (MgSO4),
filtered and concentrated. Purification via column
chromatography (10% EtOAc / petroleum ether) gave 7a
(6.88 g, 2.32 mmol, 89%) as a clear oil. Rf 0.17 (10%
EtOAc / petroleum ether); IR (thin film, νmax / cm-1) 3410,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1250, 1020, 697; H NMR (400 MHz, CDCl3) δ 7.29-7.09
(6H, m), 7.07-6.96 (4H, m), 4.50 (1H, t, J = 6.5 Hz), 4.46-
4.35 (2H, m), 3.52 (2H, qt, J = 9.5 and 6.0 Hz), 2.10 (2H, s),
1.90 (2H, q, J = 6.0 Hz), 0.83 (9H, s), 0.05 (3H, s), 0.04-0.01
(9H, m); 13C{1H} NMR (101 MHz, CDCl3) δ 139.1, 138.6,
128.5, 128.3, 127.8, 127.7, 124.5, 108.9, 87.3, 73.2, 66.5,
60.5, 38.8, 26.3, 26.0, 18.4, ‒2.0, ‒2.1, ‒4.4, ‒4.9; HRMS
(ESI+) calc. for C27H40O2Si2Na [M+Na]+ 475.2459, found
475.2453.
General Procedure A: PMB protection. To a solution
of the alcohol (1.0 equiv.) and scandium(III) triflate (0.15
equiv.) in toluene (0.16 M, 6.4 mL / mmol substrate) was
added 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.5
equiv.). The mixture was stirred for 2 h, then NaHCO3 (15
mL mmol-1 substrate) and Et2O (15 mL mmol-1) were
added. The organic phase was separated, and the
aqueous phase extracted with Et2O (x 2, 15 mL mmol-1).
The combined organic phases were dried (MgSO4),
filtered, and concentrated.
Benzyl(5-(benzyloxy)-3-((4-methoxybenzyl)oxy)pent-1-
yn-1-yl)dimethylsilane (7d). Prepared following general
procedure A with 7a (500 mg, 1.48 mmol), toluene (9.5
mL), 4-methoxybenzyl 2,2,2-trichloroacetimidate (616 mg,
2.22 mmol) and scandium(III) triflate (109 mg, 0.221
mmol). Purification via column chromatography (10%
Et2O / petroleum ether) gave 7d (521 mg, 1.14 mmol,
77%) as a colourless oil. Rf 0.45 (25% Et2O / petroleum
ether); IR (thin film, νmax / cm-1) 3027, 2169, 1248, 1095,
698; 1H NMR (400 MHz, CDCl3) δ 7.36-6.80 (14H, m), 4.68
(1H, d, J = 11.5 Hz), 4.49-4.42 (2H, m), 4.39 (1H, d, J =
11.5 Hz), 4.27 (1H, dd, J = 7.0 and 6.5 Hz), 3.79 (3H, s),
3.64-3.55 (2H, m), 2.21 (2H, s), 2.11-1.93 (2H, m), 0.15
(6H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 159.4, 139.1,
138.6, 130.1, 129.9, 128.5, 128.5, 128.3, 127.8, 127.7,
124.5, 113.9, 106.1, 89.2, 73.1, 70.5, 66.5, 66.0, 55.4, 36.1,
26.3, −1.9; HRMS (ESI+) calc. for C29H34O3SiNa [M+Na]+
481.2169, found 481.2167.
1
2958, 2100, 832, 697; H NMR (400 MHz, CDCl3) δ 7.32-
6.95 (10H, m), 4.56-4.48 (1H, m), 4.48-4.38 (2H, m), 3.79-
3.69 (1H, m), 3.63-3.52 (1H, m), 2.99-2.92 (1H, m), 2.12
(2H, s), 2.06-1.93 (1H, m), 1.93-1.80 (1H, m), 0.06 (6H, s);
13C{1H} NMR (101 MHz, CDCl3) δ 141.0, 139.9, 130.6,
130.5, 130.3, 129.9, 129.8, 126.5, 109.6, 90.0, 75.5, 69.8,
64.0, 38.7, 28.3, 0.0; HRMS (ESI+) calc. for C21H26O2NaSi
[M+Na]+ 361.1594, found 361.1595.
1-(Benzyldimethylsilyl)-5-(benzyloxy)pent-1-yn-3-yl
acetate (7b). To a solution of 7a (950 mg, 2.81 mmol, 1.0
equiv.), acetic anhydride (0.53 mL, 5.6 mmol, 2.0 equiv.)
and Et3N (1.2 mL, 8.6 mmol, 3.0 equiv.) in CH2Cl2 (19 mL)
was added a crystal of 4-dimethylaminopyridine. The
mixture was stirred for 2 h, then water (15 mL) was
added. The organic phase was separated, and the
aqueous phase extracted with CH2Cl2 (2 × 20 mL). The
combined organic phases were dried (MgSO4), filtered
and
concentrated.
Purification
via
column
chromatography (5%10% Et2O / petroleum ether) gave
7b (1.07 g, 2.80 mmol, 99%) as a clear oil. Rf 0.37 (10%
EtOAc / petroleum ether); IR (thin film, νmax / cm-1) 2961,
2180, 1745, 1229, 837; 1H NMR (400 MHz, CDCl3) δ 7.39-
7.02 (10H, m), 5.56 (1H, t, J = 7.0 Hz), 4.53-4.45 (2H, m),
3.62-3.50 (2H, m), 2.18 (2H, s), 2.15-1.97 (2H, m), 2.06
(3H, s), 0.12 (3H, s), 0.11 (3H, s); 13C{1H} NMR (101 MHz,
CDCl3) δ 169.8,138.9, 138.3, 128.6, 128.5, 128.3, 127.8,
127.7 124.5, 103.8, 89.1, 73.2, 65.9, 61.9, 35.1, 26.1, 21.1
,‒2.1, ‒2.2; HRMS (ESI+) calc. for C23H28O3NaSi [M+Na]+
403.1700, found 403.1692.
5-(Benzyldimethylsilyl)-1-(benzyloxy)pent-4-yn-2-ol
(8a). To a solution of glycidol (3.0 mL, 45 mmol,
1.0 equiv.) and benzyl bromide (7.0 mL, 59 mmol,
1.3 equiv.) in DMF (113 mL) at 0 °C was added NaH
(1.81 g, 60 wt% dispersion in mineral oil, 45.3 mmol,
1.0 equiv.). The cooling bath was removed and the
Benzyl(5-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)
pent-1-yn-1-yl)dimethylsilane (7c). To a solution of
tert-butyldimethylsilyl chloride (468 mg, 3.11 mmol, 2.1
equiv.) in CH2Cl2 (3.0 mL) was added imidazole (221 mg,
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reaction mixture was stirred vigorously at room
temperature overnight. The mixture was then diluted
with CH2Cl2 (60 mL) and quenched by addition of water
(300 mL). The organic phase was separated, and the
aqueous phase extracted with CH2Cl2 (5 × 60 mL). The
combined organic layers were dried (MgSO4), filtered,
ether); IR (thin film, νmax / cm-1) 3482, 2593, 1600, 1493,
1248, 1097, 831, 698; H NMR (400 MHz, CDCl3) δ 7.42-
1
2
3
4
5
6
7
8
1
7.27 (5H, m), 7.20 (2H, t, J = 7.5 Hz), 7.07 (1H, t, J = 7.5
Hz), 7.01 (2H, d, J = 7.0 Hz), 6.31 (1H, dd, J = 14.5 and 8.5
Hz), 5.60 (1H, dd, J = 14.5 and 1.0 Hz), 4.51 (2H, d, J = 1.5
Hz), 4.28 (1H, td, J = 8.5 and 4.0 Hz), 3.65 (1H, ddd, J =
9.5, 6.5 and 5.0 Hz), 3.57 (1H, ddd, J = 9.5, 7.5 and 5.0
Hz), 2.44 (1H, d, J = 3.0 Hz), 2.18 (2H, s), 1.80 (1H, dtd, J =
14.5, 7.5 and 5.0 Hz), 1.67 (1H, dddd, J = 14.5, 6.5, 5.0
and 4.0 Hz), 0.14 (3H, s), 0.13 (3H, s). 13C{1H} NMR (101
MHz, CDCl3) δ 151.0, 140.1, 138.2, 128.9, 128.6, 128.4,
128.3, 127.8, 127.8, 124.3, 73.4, 71.6, 68.3, 36.8, 27.0, ‒1.2,
‒1.2.; HRMS (ESI+) calc. for C21H28O2NaSi [M+Na]+
363.1751, found 363.1751.
and
concentrated.
Purification
via
column
chromatography (20% Et2O / petroleum ether) gave 2-
((benzyloxy)methyl)oxirane (10) (7.23 g, 44.0 mmol, 98%)
as a colourless oil. Data identical to literature values.28 To
a solution of benzyldimethylsilylacetylene (4.83 g, 27.7
mmol, 1.3 equiv.) in THF (100 mL) at −78 °C was added a
solution of n-BuLi (15.3 mL, 1.6 M in hexanes, 24.5 mmol,
1.15 equiv.) dropwise via syringe. After stirring for 30 min
at −78 °C, BF3•Et2O (3.40 mL, 27.7 mmol, 1.3 equiv.) was
added over 5 min, followed by epoxide 10 (3.50 g, 21.3
mmol, 1.0 equiv.). After stirring for 1 h, the resulting
mixture was quenched by addition of HCl (30 mL, 1 M,
aq.). The cooling bath was removed and the mixture was
allowed to warm to room temperature. The organic
phase was separated, and the aqueous phase was
extracted with Et2O (3 × 30 mL). The combined organic
phases were washed with brine (50 mL), dried (MgSO4),
filtered, and concentrated. Purification via column
chromatography (30% Et2O / petroleum ether) gave 8a
(6.21 g, 18.4 mmol, 87%) as a colourless oil. Rf 0.19 (30%
Et2O / petroleum ether); IR (thin film, νmax / cm-1) 3410,
2981, 1383, 1152, 954; 1H NMR (400 MHz, CDCl3) δ 7.40-
7.02 (10H, m), 4.57 (2H, s), 3.98-3.3.89 (1H, m), 3.57 (1H,
dd, J = 9.5 and 4.0 Hz), 3.47 (1H, dd, J = 9.5 and 6.5 Hz),
2.49 (2H, dd, J = 6.5 and 4.0 Hz), 2.35 (1H, br s), 2.16 (2H,
s), 0.11 (6H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 141.1,
139.8, 130.5, 130.3, 130.1, 129.8, 129.7, 126.3, 105.9, 87.7,
75.4, 74.7, 70.8, 28.3, 27.0, 0.0; HRMS (ESI+) calc. for
C21H26O2NaSi [M+Na]+ 361.1594, found 361.1592.
General procedure B: Semihydrogenation (11a–d,
12a). A suspension of Pd / CaCO3 (5 wt% Pd, 5.0 mol%)
in toluene (10.0 mL / mmol substrate) was placed under
a hydrogen atmosphere. A solution of alkyne (1.0 equiv.)
and quinoline (20-50 mol%) in toluene or cyclohexene
(1.0 mL / mmol substrate) were added via syringe. The
solution was stirred vigorously under H2 (balloon) until
complete as monitored by TLC (visualised with vanillin).
The mixture was filtered through Celite and concentrated
to give the crude product, which was purified via column
chromatography.
(Z)-1-(Benzyldimethylsilyl)-5-(benzyloxy)pent-1-en-3-ol
(11a). Prepared following general procedure B with Pd /
CaCO3 (60 mg, 0.028 mmol) in toluene (3.0 mL), and
alkyne 7a (200 mg, 0.59 mmol) and quinoline (14.0 µL,
0.12 mmol, 20 mol%) in toluene (0.6 mL), with a 1 h
reaction time. Purification via column chromatography
(5% Et2O / petroleum ether) gave 11a (154 mg, 0.45
mmol, 77%) as a clear oil. Rf 0.12 (10% Et2O / petroleum
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-1-(Benzyldimethylsilyl)-5-(benzyloxy)pent-1-en-3-yl
acetate (11b). Prepared following general procedure B
with Pd / CaCO3 (839 mg, 5 wt% Pd, 0.39 mmol) in
toluene (70 mL), and alkyne 7b (3.00 g, 7.89 mmol) and
quinoline (0.185 mL, 1.58 mmol, 20 mol%) in toluene (10
mL), with a 2 h reaction time. Purification via column
chromatography (5% Et2O / petroleum ether) gave 11b
(2.57 g, 6.71 mmol, 85%) as a clear oil. Rf 0.39 (20% Et2O /
petroleum ether); IR (thin film, νmax / cm-1) 2956, 1737,
1
1239, 832, 699; H NMR (400 MHz, CDCl3) δ 7.37-6.94
(10H, m), 6.20 (1H, dd, J = 14.5 and 9.5 Hz), 5.69 (1H, d, J
= 14.5 Hz), 5.58-5.50 (1H, m), 4.50 (1H, d, J = 12.0 Hz),
4.44 (1H, d, J = 12.0 Hz), 3.50-3.44 (2H, m), 2.22 (1H, d, J
= 13.5 Hz), 2.18 (1H, d, J = 13.5 Hz), 2.00 (3H, s), 1.97-
1.88 (1H, m), 1.84-1.74 (1H, m), 0.16 (3H, s), 0.14 (3H, s);
13C{1H} NMR (101 MHz, CDCl3) δ 170.3, 145.9, 139.9,
138.5, 131.6, 128.5, 128.4, 128.3, 128.4, 127.8, 127.7,
124.4, 73.1, 72.2, 66.2, 35.3, 26.5, 21.4 ‒1.8 (2C); HRMS
(ESI+) calc. for C23H30O3NaSi [M+Na]+ 405.1856, found
405.1856.
(Z)-Benzyl(5-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)
pent-1-en-1-yl)dimethylsilane (11c). Prepared following
general procedure B with Pd / CaCO3 (35 mg, 0.017
mmol) in toluene (1.5 mL), and alkyne 7c (150 mg, 0.33
mmol) and quinoline (8.0 µL, 0.068 mmol, 20 mol%) in
toluene (1.8 mL), with a 2 h reaction time. Purification via
column chromatography (1% Et2O / petroleum ether)
gave 11c (101 mg, 0.22 mmol, 67%) as a clear oil. Rf 0.34
(4% Et2O / petroleum ether / Et2O); IR (thin film, νmax
/
cm-1) 2955, 1250, 1048, 1030, 697; H NMR (400 MHz,
CDCl3) δ 7.36-6.95 (10H, m), 6.29 (1H, dd, J = 14.5 and
8.5 Hz), 5.45 (1H, d, J = 14.5 Hz), 4.53-4.43 (3H, m), 3.64-
3.46 (2H, m), 2.16 (2H, s), 1.76-1.65 (2H, m), 0.87 (9H, s),
0.11 (3H, s), 0.09 (3H, s), 0.03 (3H, s), 0.02 (3H, s); 13C{1H}
NMR (101 MHz, CDCl3) δ 153.2, 139.9, 138.8, 128.4,
128.4, 128.3, 127.6, 127.5, 125.9, 124.2, 73.0, 70.2, 66.7,
39.0, 26.8, 26.0, 18.3, −1.5, −1.7, −3.9, −4.5; HRMS (ESI+)
calc. for C27H42O2Si2Na [M+Na]+ 477.2616, found:
477.2614.
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(Z)-Benzyl(5-(benzyloxy)-3-((4-methoxybenzyl)oxy)pent-
14.0 and 1.5 Hz), 5.13-5.03 (1H, m), 4.56 (1H, d, J = 12.0
Hz), 4.50 (1H, d, J = 12.0 Hz), 3.52-3.48 (2H, m), 2.41-2.35
(2H, m), 2.16 (2H, s), 2.05 (3H, s), 0.11 (6H, s); 13C{1H}
NMR (101 MHz, CDCl3) δ 170.7, 143.9, 140.0, 138.1, 130.5,
128.5, 128.3, 128.3, 127.8, 127.7, 124.2, 73.3, 72.2, 70.8,
35.1, 26.7, 21.3, ‒1.6; HRMS (ESI+) calc. for C23H30O3NaSi
[M+Na]+ 405.1856, found 405.1863.
1-en-1-yl)dimethylsilane (11d). Prepared following
general procedure B with Pd / CaCO3 (23 mg, 0.011
mmol) in toluene (1.0 mL), and alkyne 7d (100 mg, 0.22
mmol) and quinoline (5 µL, 0.042 mmol, 20 mol%) in
toluene (1.2 mL), with a 2 h reaction time. Purification via
column chromatography (10% Et2O / petroleum ether)
gave 11d (89 mg, 0.19 mmol, 88%) as a clear oil. Rf 0.45
(25% Et2O / petroleum ether); IR (thin film, νmax / cm-1)
2954, 1613, 1247, 1036, 698; 1H NMR (400 MHz, CDCl3) δ
7.34-6.80 (14H, m), 6.28 (1H, dd, J = 14.5 and 9.5 Hz),
5.74 (1H, d, J = 14.5 Hz), 4.54-4.42 (5H, m), 3.77 (3H, s),
3.68-3.51 (2H, m), 2.15 (2H, s), 1.94-1.82 (1H, m), 1.80-
1.67 (1H, m), 0.09 (3H, s), 0.08 (3H, s); 13C{1H} NMR (101
MHz, CDCl3) δ 159.2, 150.3, 139.9, 138.8, 130.7, 129.3,
128.5, 128.4, 128.4, 128.3, 127.7, 127.6, 124.3, 113.9, 75.9,
73.0, 70.1, 66.6, 55.4, 36.3, 26.8, −1.4, −1.5; HRMS (ESI+)
calc. for C29H36O3SiNa [M+Na]+ 483.2326, found:
483.2324.
2
3
4
5
6
7
8
9
(Z)-Benzyl(5-(benzyloxy)-4-((tert-butyldimethylsilyl)oxy)
pent-1-en-1-yl)dimethylsilane (12c). To a solution of
tert-butyldimethylsilyl chloride (186 mg, 1.23 mmol, 2.1
equiv.) in CH2Cl2 (1.2 mL) was added imidazole (88 mg,
1.3 mmol, 2.2 equiv.). After stirring for 10 min, alcohol
12a (200 mg, 0.587 mmol, Z:E, 6:1, 1.0 equiv.) was added
and the mixture was stirred overnight. The mixture was
then diluted with CH2Cl2 (5 mL), and NH4Cl (5 mL sat.,
aq.) was added. The organic phase was separated, and
the aqueous phase extracted with CH2Cl2 (2 × 5 mL). The
combined organic phases were dried (MgSO4), filtered
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and
concentrated.
Purification
via
column
(Z)-5-(Benzyldimethylsilyl)-1-(benzyloxy)pent-4-en-2-ol
(12a). Prepared following general procedure B with Pd /
CaCO3 (1.15 g, 0.54 mmol) in toluene (100 mL), and
alkyne 8a (3.67 g, 10.8 mmol) and quinoline (0.64 mL, 5.4
mmol, 50 mol%) in cyclohexene (10 mL), with a 1.5 h
reaction time. Purification via column chromatography
(40% Et2O / petroleum ether) gave 12a (3.78 g, 10.8
mmol, Z:E, 6:1, 99%) as a clear oil. Rf 0.40 (20% Et2O /
petroleum ether); IR (thin film, νmax / cm-1) 3444, 2895,
chromatography (2% Et2O / petroleum ether) gave 12c
(239 mg, 0.53 mmol, Z:E, 6:1, 90%) as a colourless oil. Rf
0.63 (4% Et2O / petroleum ether); IR (thin film, νmax / cm-
1) 2955, 1602, 1453, 1250, 698; 1H NMR (400 MHz, CDCl3)
δ (6:1 Z/E mixture, major isomer reported) 7.36-6.94
(10H, m), 6.40 (1H, dt, J = 14.0 and 7.5 Hz), 5.55 (1H, dd, J
= 14.0 and 1.5 Hz), 4.51 (2H, s), 3.89-3.82 (1H, m), 3.41-
3.31 (2H, m), 2.41-2.18 (2H, m), 2.16 (2H, s), 0.88 (9H, s),
0.09 (6H, s), 0.04 (6H, s); 13C{1H} NMR (101 MHz, CDCl3) δ
146.3, 140.3, 128.9, 128.4 (2C), 128.2, 127.7 (2C) 127.6,
124.1, 74.7, 73.4, 71.6, 38.9, 26.8, 26.0, 18.3, −1.6, −4.3,
−4.5; HRMS (ESI+) calc. for C27H42O2Si2Na [M+Na]+
477.2616, found 477.2614.
1
1493, 1095, 830; H NMR (400 MHz, CDCl3) δ (6:1 Z/E-
mixture, major isomer reported) 7.42-6.98 (10H, m), 6.39
(1H, dt, J = 14.0 and 7.5 Hz), 5.63 (1H, dt, J = 14.0 and 1.0
Hz), 4.56 (2H, s), 3.92-3.79 (1H, m), 3.48 (1H, dd, J = 9.5
and 3.5 Hz), 3.34 (1H, dd, J = 9.5 and 7.5 Hz), 2.41-2.19
(2H, m), 2.36 (1H, d, J = 3.5 Hz), 2.18 (2H, s), 0.13 (6H, s);
13C{1H} NMR (101 MHz, CDCl3) δ 145.0, 140.0, 138.0,
130.1, 128.6, 128.3, 128.2 (3C), 127.9, 127.8, 124.1, 74.0,
73.5, 70.2, 37.4, 26.7, ‒1.5, ‒1.6; HRMS (ESI+) calc. for
C21H28O2NaSi [M+Na]+ 363.1751, found 363.1756.
(Z)-5-(Benzyldimethylsilyl)-1-(benzyloxy)pent-4-en-2-yl
acetate (12b). To a solution of 12a (205 mg, 0.61 mmol,
Z:E, 6:1, 1.0 equiv.), acetic anhydride (0.12 mL, 1.22 mmol,
2.0 equiv.) and Et3N (0.25 mL, 1.83 mmol, 3.0 equiv.) in
(Z)-Benzyl(5-(benzyloxy)-4-((4-methoxybenzyl)oxy)pent-
1-en-1-yl)dimethylsilane (12d). Prepared following
general procedure A with 12a (200 mg, 0.59 mmol, Z:E
6:1), toluene (3.7 mL), 4-methoxybenzyl 2,2,2-
trichloroacetimidate (249 mg, 0.88 mmol) and scandium
(III) triflate (43 mg, 87 µmol). Purification via column
chromatography (10% Et2O / petroleum ether) gave 12d
(195 mg, 0.42 mmol, 72%) as a colourless oil. Rf 0.73
(30% Et2O / petroleum ether); IR (thin film, νmax / cm-1)
1
2953, 1611, 1246, 1207, 1035, 698; H NMR (400 MHz,
CH2Cl2 (4 mL) was added
a
crystal of 4-
CDCl3) δ 7.30-6.73 (14H, m), 6.31 (1H, dt, J = 14.0 and 7.5
Hz), 5.49 (1H, dt, J = 14.0 and 1.5 Hz), 4.52 (1H, d, J =
11.5 Hz), 4.46 (2H, s), 4.44 (1H, d, J = 11.5 Hz), 3.72 (3H,
s), 3.56-3.49 (1H, m), 3.47-3.37 (m, 2H), 2.28 (2H, ddd, J =
7.5, 6.0 and 1.5 Hz), 2.08 (2H, s), 0.01 (6H, s); 13C{1H} NMR
(101 MHz, CDCl3) δ 159.2, 145.6, 140.2, 138.5, 130.9,
129.5, 129.3, 128.5, 128.4, 128.2, 127.7, 124.1, 113.8, 77.8,
73.5, 72.5, 71.8, 55.4, 36.1, 26.7, −1.6 (2C); HRMS (ESI+)
calc. for C29H36O3SiNa [M+Na]+ 483.2326, found
483.2326.
dimethylaminopyridine. After stirring for 30 min, water
(10 mL) was added, the organic phase separated, and the
aqueous phase extracted with CH2Cl2 (2 × 10 mL). The
combined organic phases were dried (MgSO4), filtered
and
concentrated.
Purification
via
column
chromatography (10% Et2O / petroleum ether) gave 12b
(219 mg, 0.58 mmol, Z:E, 6:1, 95%) as a clear oil. Rf 0.40
(20% Et2O / petroleum ether); IR (thin film, νmax / cm-1)
1
3026, 1738, 1236, 905, 698; H NMR (400 MHz, CDCl3) δ
(6:1 Z/E-mixture, major isomer reported) 7.39-6.95 (10H,
m), 6.27 (1H, dt, J = 14.0 and 7.5 Hz), 5.60 (1H, dt, J =
General
Debenzylation
procedure
C:
Fluoride
Promoted
solution of
/
Cyclization. To
a
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benzyldimethylalkenylsilane (1.0 equiv.) in THF (5.0 mL CDCl3) δ 7.37-7.25 (5H, m), 6.86 (1H, dd, J = 10.5 and 1.5
1
2
3
4
5
6
7
8
mmol-1 substrate) was added TBAF•3H2O (1.0 M in THF,
0.25-1.0 equiv.). After stirring for 15 min (or until
complete as judged by TLC), the mixture was diluted with
Et2O (15 mL mmol-1 substrate), and HCl (1 M, aq., 5 mL
mmol-1 substrate) was added. The organic phase was
separated and the aqueous phase extracted with Et2O (x
2, 15 mL mmol-1). The combined organic phases were
dried (MgSO4), filtered and concentrated. 6-Membered
siloxanes were purified via rapid flash column
chromatography through a short column of silica gel
(0.2-0.4 g of silica gel / mmol substrate). 5-Membered
siloxanes are extremely unstable towards silica gel, but
generally required no further purification and were used
directly.
General procedure D: K2CO3 / MeOH Promoted
Debenzylation / Cyclization. To a solution of the
acetate (1.0 equiv.) in MeOH (3.0 mL / mmol substrate)
was added K2CO3 (1.5 equiv.), and the resulting mixture
was stirred vigorously. Upon completion (1-3 h, as
judeged by TLC), the mixture was diluted with Et2O (10
mL mmol-1 substrate), and NH4Cl (sat., aq., 5 mL mmol-1)
was added. The organic phase was separated, and the
aqueous phase extracted Et2O (x 2, 10 mL mmol-1). The
combined organic phases were dried (MgSO4), filtered
and concentrated.
Hz), 6.03 (1H, dd, J = 10.5 and 2.0 Hz), 4.87-4.80 (1H, m),
4.54 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 12.0 Hz),
3.70-3.58 (2H, m), 2.02-1.91 (1H, m), 1.76-1.66 (1H, m),
0.25 (3H, s), 0.24 (3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ
152.9, 137.9, 127.8, 127.1, 126.9, 126.1, 79.7, 72.5, 66.6,
37.0, 0.9, 0.0; HRMS (ESI+) calc. for C14H21O2Si [M+H]+
249.1305, found 249.1306.
6-((Benzyloxy)methyl)-2,2-dimethyl-5,6-dihydro-2H-
1,2-oxasiline (14). Prepared using general procedure C,
with vinylsilane 12a (6.13 g, 18.0 mmol) in THF (90 mL)
and TBAF•3H2O (4.5 mL, 1.0 M in THF, 0.25 equiv.), and a
15 min reaction time. Purification via rapid column
chromatography (5% Et2O / petroleum ether) gave 14
(3.40 g, 13.2 mmol, 74%) as a colourless oil.
Also prepared using general procedure D, with
vinylsilane 12b (50 mg, 0.13 mmol) in MeOH (0.4 mL)
and K2CO3 (27.0 mg, 0.20 mmol), and a 3 h reaction time.
Purification via rapid column chromatography (5% Et2O /
petroleum ether) gave 14 (41 mg, 0.12 mmol, 93%) as a
colourless oil.
Also prepared using general procedure E, with
vinylsilane 12a (164 mg, 0.48 mmol) in THF (2.4 mL)
andKOSiMe3 (80 mg, 0.62 mmol), and a 1 h reaction
time. Purification via rapid column chromatography (5%
Et2O / petroleum ether) gave 14 (85 mg, 0.34 mmol,
71%) as a colourless oil. Rf 0.29 (5% Et2O / petroleum
ether); IR (thin film, νmax / cm-1) 2859, 1355, 1129, 843,
789; 1H NMR (400 MHz, CDCl3) δ 7.32-7.13 (5H, m), 6.72-
6.65 (1H, m), 5.79-5.71 (1H, m), 4.52 (1H, d, J = 12.0 Hz),
4.47 (1H, d, J = 12.0 Hz), 4.10-4.00 (1H, m), 3.46 (1H, dd, J
= 9.5 and 5.5 Hz), 3.34 (1H, dd, J = 9.5 and 5.5 Hz), 2.26-
1.99 (m, 2H), 0.11 (s, 3H), 0.10 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 146.8, 138.5, 128.5, 127.8, 127.7, 127.3,
74.6, 73.5, 70.5, 33.4, −0.1, −0.4; HRMS (ESI+) calc. for
C14H21O2Si [M+H]+ 249.1305, found 249.1307.
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10
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General
procedure
E:
KOTMS
Promoted
Debenzylation / Cyclization. To a round-bottomed
flask charged with KOSiMe3 (1.3 equiv.) was added a
solution of vinylsilane (1.0 equiv.) in THF (5.0 mL / mmol
substrate). After stirring for 1 h, the mixture was diluted
with Et2O (15 mL mmol-1 substrate), and HCl (1 M, aq. 5
mL mmol-1 substrate) was added. The organic phase was
separated, and the aqueous phase extracted with Et2O (x
2, 15 mL mmol-1). The combined organic phases were
dried (MgSO4), filtered and concentrated.
5-(2-(Benzyloxy)ethyl)-2,2-dimethyl-2,5-dihydro-1,2-
oxasilole (13). Prepared using general procedure C, with
vinylsilane 11c (20 mg, 0.044 mmol) in THF (0.3 mL) and
TBAF•3H2O (44 µL, 1.0 M in THF, 1.0 equiv.), and a 15 min
reaction time. 13 (11 mg, 0.044 mmol, 99%) was
obtained as a clear oil which required no further
purification.
Also prepared using general procedure D, with
vinylsilane 11b (534 mg, 1.34 mmol) in MeOH (4.5 mL)
and K2CO3 (278 mg, 2.01 mmol), and a 3 h reaction time.
13 (334 mg, 1.34 mmol, 99%) was obtained as a clear oil
which required no further purification.
General procedure F: General Fluoride Promoted
Cross-Coupling Procedure. To a vial containing the
cyclic siloxane (1.0-1.2 equiv.), halide (1.0-1.2 equiv.) and
Pd(dba)2 (5.0 mol%) or [allylPdCl]2 (2.5 mol%) was added
TBAF•3H2O (1.0 M in THF, 2.0-3.0 equiv.). The resulting
dark brown solution was stirred at room temperature.
Upon completion (5 min to 16 h, as judged by TLC), the
crude mixture was purified directly via column
chromatography.
(Z)-5-(Benzyloxy)-1-phenylpent-1-en-3-ol
(26a).
Prepared following general procedure F with 13 (25 mg,
0.10 mmol, 1.0 equiv.), iodobenzene (25a) (24 mg, 0.12
mmol, 1.2 equiv.), Pd(dba)2 (3.0 mg, 5.0 µmol) and
TBAF•3H2O (0.2 mL, 1.0 M in THF, 0.20 mmol, 2.0 equiv.),
with a 5 min reaction time. Purification via column
chromatography (15% EtOAc / petroleum ether) gave
26a (27 mg, 0.098 mmol, 98%) as a yellow oil. Rf 0.27
(20% EtOAc / petroleum ether); IR (thin film, νmax / cm-1)
Also prepared using general procedure E, with
vinylsilane 11a (20 mg, 0.059 mmol) in THF (0.3 mL) and
KOSiMe3 (10 mg, 0.077 mmol), and a 1 h reaction time.
13 (15 mg, 0.059 mmol, 99%) was obtained as a clear oil
which required no further purification. IR (thin film, νmax
/
1
cm-1) 2858, 1251, 1097, 853, 788; H NMR (400 MHz,
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The Journal of Organic Chemistry
3432, 2860, 1452, 1028, 697; 1H NMR (400 MHz, CDCl3) δ
129.5, 128.5, 127.8, 127.7, 117.2, 113.9, 77.3, 73.1, 70.1,
66.8, 55.4, 36.0; HRMS (ESI+) calc. for C20H24O3Na
[M+Na]+ 335.1618, found: 335.1617.
1
2
3
4
5
6
7
8
7.40-7.13 (10H, m), 6.48 (1H, d, J = 11.5 Hz), 5.66 (1H, dd,
J = 11.5 and 9.0 Hz, H2), 4.83-4.74 (1H, m), 4.46 (2H, s),
3.73-3.64 (1H, m), 3.64-3.55 (1H, m), 2.76 (1H, br s),
2.01-1.89 (1H, m), 1.87-1.77 (1H, m); 13C{1H} NMR (101
MHz, CDCl3) δ 138.0, 136.6, 134.0, 128.9, 128.5, 128.3,
127.7, 127.6, 127.2, 73.3, 68.5, 67.2, 36.9; HRMS (ESI+)
calc. for C18H20O2Na [M+Na]+ 291.1356, found 291.1356.
(Z)-1-(((1-(Benzyloxy)-5-phenylpent-4-en-2-
yl)oxy)methyl)-4-methoxybenzene
(27b).
Prepared
following general procedure F with 12d (24 mg, 0.052
mmol, 1.0 equiv.), iodobenzene (25a) (13 mg, 0.063
mmol, 1.2 equiv.), Pd(dba)2 (1.5 mg, 2.6 µmol, 5.0 mol%)
and TBAF•3H2O (0.1 mL, 1.0 M in THF, 0.10 mmol, 2.0
equiv.), with a 30 min reaction time. Purification via
column chromatography (15% EtOAc / petroleum ether)
gave 27b (19 mg, 0.049 mmol, 94%) as a yellow oil. Rf
0.38 (10% Et2O / petroleum ether); IR (thin film, νmax / cm-
(Z)-1-(Benzyloxy)-5-phenylpent-4-en-2-ol
(27a).
9
Prepared following general procedure F with 14 (25 mg,
0.10 mmol, 1.0 equiv.), iodobenzene (25a) (24 mg, 0.12
mmol, 1.2 equiv.), Pd(dba)2 (3.0 mg, 5.0 µmol, 5.0 mol%)
and TBAF•3H2O (0.2 mL, 1.0 M in THF, 0.20 mmol, 2.0
equiv.), with a 15 min reaction time. Purification via
column chromatography (15% EtOAc / petroleum ether)
gave 27a (27 mg, 0.10 mmol, 99%) as a yellow oil. Rf 0.25
(20% EtOAc / petroleum ether); IR (thin film, νmax / cm-1)
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
40
41
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43
44
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1) 2902, 2860, 1613, 1495, 1208, 698; H NMR (400 MHz,
CDCl3) δ 7.31-6.14 (12H, m), 6.86-6.79 (2H, m), 6.47 (1H,
dt, J = 11.5 and 1.5 Hz), 5.70 (1H, dt, J = 11.5 and 7.5 Hz),
4.57 (1H, d, J = 11.5 Hz), 4.51 (1H, d, J = 11.5 Hz), 4.48
(2H, s), 3.76 (3H, s), 3.68 (1H, quint., J = 5.5 Hz), 3.55-3.46
(2H, m), 2.65-2.56 (2H, m); 13C{1H} NMR (101 MHz, CDCl3)
δ 159.3, 138.5, 137.5, 130.9, 130.8, 129.5, 128.9, 128.5,
128.3 (2C), 127.7 (2C) 126.8, 113.9, 77.7, 73.5, 72.5, 71.7,
55.4, 31.1; HRMS (ESI+) calc. for C26H28O3Na [M+Na]+
411.1931, found 411.1933.
1
3405, 2862, 1099, 737, 698; H NMR (400 MHz, CDCl3) δ
7.41-7.22 (10H, m) 6.58 (1H, dt, J = 11.5 and 1.5 Hz), 5.77
(1H, dt, J = 11.5 and 7.5 Hz), 4.55 (2H, s), 4.02-3.91 (1H,
m), 3.54 (1H, dd, J = 9.5 and 3.5 Hz), 3.40 (1H, dd, J = 9.5
and 7.5 Hz), 2.61-2.51 (3H, m); 13C{1H} NMR (101 MHz,
CDCl3) δ 137.9, 137.3, 131.2, 128.8, 128.5, 128.3, 127.9,
127.8, 127.7, 126.8, 74.0, 73.4, 70.5, 32.5; HRMS (ESI+)
calc. for C18H20O2Na [M+Na]+ 291.1356, found 291.1356.
(Z)-1-(((5-(Benzyloxy)-1-phenylpent-1-en-3-
(4Z,6E)-1-(Benzyloxy)-7-phenylhepta-4,6-dien-3-ol
(26c). From (E)-iodostyrene, 25b: Prepared following
general procedure F with 13 (25 mg, 0.10 mmol, 1.0
equiv.), (E)-iodostyrene (25b)29 (28 mg, 0.12 mmol, 1.2
equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%) and
TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0 equiv.),
with a 45 min reaction time. Purification via column
chromatography (20% EtOAc / petroleum ether) gave
26c (23 mg, 0.078 mmol, 78%) as a yellow oil.
From (E)-bromostyrene, 25c: Prepared following
general procedure F with 13 (50 mg, 0.20 mmol, 1.0
equiv.), (E)-bromostyrene (25c)30 (44 mg, 0.24 mmol, 1.2
equiv.), Pd(dba)2 (6.0 mg, 0.010 mmol, 5.0 mol%) and
TBAF•3H2O (0.60 mL, 1.0 M in THF, 0.60 mmol, 3.0
equiv.), with a 15 min reaction time. Purification via
column chromatography (20% EtOAc / petroleum ether)
gave 27b (46 mg, 0.16 mmol, 78%) as a yellow oil. Rf 0.25
(20% EtOAc / petroleum ether); IR (thin film, νmax / cm-1)
3403, 2861, 1453, 1094, 742; 1H NMR (400 MHz, CDCl3) δ
7.38-7.12 (10H, m), 7.03 (1H, ddd, J = 15.5, 11.5 and 1.0
Hz), 6.50 (1H, d, J = 15.5 Hz), 6.19-6.11 (1H, m), 5.50-5.40
(1H, m), 4.96-4.85 (1H, m), 4.45 (2H, s), 3.69-3.61 (1H, m),
3.61-3.52 (1H, m), 2.70 (1H, br s), 2.01-1.88 (1H, m), 1.78-
1.69 (1H, m); 13C{1H} NMR (101 MHz, CDCl3) δ 138.0,
137.1, 134.2, 133.7, 130.0, 128.6, 128.5, 127.8, 127.7,
127.6, 126.6, 123.8, 73.3, 68.1, 67.2, 37.1; HRMS (ESI+)
calc. for C20H22O2Na [M+Na]+ 317.1512, found 317.1512.
(4Z,6E)-1-(Benzyloxy)-7-phenylhepta-4,6-dien-2-ol
yl)oxy)methyl)-4-methoxybenzene (26b), and 1-(((5-
(benzyloxy)pent-1-en-3-yl)oxy)methyl)-4-
methoxybenzene (26b-desilylation). Prepared following
general procedure F with 11d (46 mg, 0.10 mmol, 1.0
equiv.), iodobenzene (25a) (24 mg, 0.12 mmol, 1.2
equiv.), Pd(dba)2 (3.0 mg, 5.0 µmol) and TBAF•3H2O (0.2
mL, 1.0 M in THF, 0.20 mmol, 2.0 equiv.), with a 30 min
reaction time. Purification via column chromatography
(15% EtOAc / petroleum ether) gave 26b (15 mg, 0.038
mmol, Z:E 3:1, 38%) and 26b-desilylation (15 mg, 0.048
mmol, 48%) as colourless oils. 26b: Rf 0.39 (25% Et2O /
petroleum ether); IR (thin film, νmax / cm-1) 2925, 1612,
1
1454, 1035, 698; H NMR (400 MHz, CDCl3) δ (3:1 Z/E
mixture, major isomer reported) 7.41-6.67 (15H, m), 5.64
(1H, dd, J = 11.5 and 9.0 Hz), 4.64 (1H, td, J = 9.0 and 4.5
Hz), 4.48-4.37 (3H, m), 4.09 (1H, d, J = 11.3 Hz), 3.73 (3H,
s), 3.69-3.52 (2H, m), 2.08-1.84 (2H, m); 13C{1H} NMR (101
MHz, CDCl3) δ 159.2, 133.5, 132.4, 130.8, 129.8, 129.6,
129.1, 128.8, 128.4, 127.9, 127.7, 127.5, 127.2, 113.9,
113.7, 73.1, 70.8, 69.9, 67.0, 55.3, 35.9; HRMS (ESI+) calc.
for C26H28O3Na [M+Na]+ 411.1931, found 411.1930. 26b-
desilylation: Rf 0.70 (25% Et2O / petroleum ether); IR
1
(thin film, νmax / cm-1) 2933, 2860, 1613, 1513, 698; H
NMR (400 MHz, CDCl3) δ 7.38-6.83 (9H, m), 5.80-5.70
(1H, m), 5.26-5.20 (2H, m), 4.52 (1H, d, J = 11.5 Hz), 4.27
(1H, d, J = 11.5 Hz), 4.01-3.90 (1H, m), 3.79 (3H, s), 3.64-
3.48 (2H, m), 1.97-1.87 (1H, m), 1.86-1.76 (m, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 159.2, 139.0, 131.0, 129.9,
(27c). From (E)-iodostyrene, 25b: Prepared following
general procedure F with 14 (25 mg, 0.10 mmol, 1.0
equiv.), (E)-iodostyrene29 (25b) (28 mg, 0.12 mmol, 1.2
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equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%) and (4Z,6E)-1-(Benzyloxy)-8-((4-methoxybenzyl)oxy)octa-
Page 12 of 20
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7
8
TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0 equiv.),
with a 16 h reaction time. Purification via column
chromatography (20% EtOAc / petroleum ether) gave
27c (22 mg, 0.075 mmol, 75%) as a yellow oil.
4,6-dien-3-ol (26d). From vinyl iodide 25d: Prepared
using general procedure F with 13 (30 mg, 0.12 mmol,
1.2 equiv.), vinyl iodide 25d (30 mg, 0.10 mmol, 1.0
equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%) and
TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0 equiv.),
with a 15 min reaction time. Purification via column
chromatography (30% EtOAc / petroleum ether) gave
26d (27 mg, 0.073 mmol, 73%) as a yellow oil.
From (E)-bromostyrene, 25c: Prepared following
general procedure F with 14 (25 mg, 0.10 mmol, 1.0
equiv.), (E)-bromostyrene30 (25c) (22 mg, 0.12 mmol, 1.2
equiv.), [allylPdCl]2 (0.9 mg, 2.5 µmol, 2.5 mol%) and
TBAF•3H2O (0.30 mL, 1 M in THF, 0.30 mmol, 3.0 equiv.),
with a 5 h reaction time. Purification via column
chromatography (20% EtOAc / petroleum ether) gave
27c (18 mg, 0.068 mmol, 68%) as a yellow oil. Rf 0.19
(20% EtOAc / petroleum ether); IR (thin film, νmax / cm-1)
3437, 2859, 1595, 1092, 695; 1H NMR (400 MHz, CDCl3) δ
7.46-7.19 (10H, m), 7.06(1H, dd, J = 15.5 and 11.0 Hz),
6.57 (1H, d, J = 15.5 Hz), 6.50 (1H, t, J = 11.0 Hz), 5.56
(1H, dt, J = 11.0 and 8.0 Hz), 4.57 (2H, s), 3.99-3.89 (1H,
m), 3.57 (1H, dd, J = 9.5 and 3.5 Hz), 3.44 (1H, dd, J = 9.5
and 7.5 Hz), 2.58-2.50 (2H, m), 2.41 (1H, br s); 13C{1H}
NMR (101 MHz, CDCl3) δ 137.9, 137.4, 133.2, 131.4,
128.6, 128.5, 127.8, 127.7, 127.6, 127.4, 126.5, 124.0, 73.7,
73.5, 70.3, 32.1; HRMS (ESI+) calc. for C20H22O2Na
[M+Na]+ 317.1512, found 317.1501.
9
From vinyl bromide 25e: Prepared using general
procedure F with 13 (30 mg, 0.12 mmol, 1.2 equiv.), vinyl
bromide 25e (26 mg, 0.10 mmol, 1.0 equiv.), [allylPdCl]2
(0.9 mg, 2.5 µmol, 2.5 mol%) and TBAF•3H2O (0.30 mL,
1.0 M in THF, 0.30 mmol, 3.0 equiv.), with a 3 h reaction
time. Purification via column chromatography (30%
EtOAc / petroleum ether) gave 26d (21 mg, 0.056 mmol,
57%) as a yellow oil. Rf 0.15 (30% EtOAc / petroleum
ether); IR (thin film, νmax / cm-1) 3430, 2854, 1513, 1247,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1096, 1033; H NMR (400 MHz, CDCl3) δ 7.32-7.16 (7H,
m), 6.80 (2H, d, J = 8.5 Hz), 6.50 (1H, dq, J = 15.0, 11.0
and 1.0 Hz), 5.98 (1H, t, J = 11.0 Hz), 5.75 (1H, dt, J = 15.0
and 6.0 Hz), 5.38 (1H, dd, J = 11.0 and 9.0 Hz), 4.80-4.71
(1H, m), 4.44 (2H, s), 4.36 (2H, s), 3.95 (2H, dd, J = 6.0 and
1.0 Hz), 3.73 (3H, s), 3.66-3.59 (1H, m), 3.58-3.50 (1H, m),
2.64 (1H, br s), 1.93-1.81 (1H, m), 1.74-1.65 (1H, m);
13C{1H} NMR (101 MHz, CDCl3) δ 159.2, 138.0, 133.6,
131.8, 130.3, 129.5, 129.1, 128.5, 128.4, 127.7, 127.6,
127.4, 113.9, 113.8, 133.7, 73.3, 72.0, 70.1, 68.2, 67.1, 55.3,
36.9; HRMS (ESI+) calc. for C23H28O4Na [M+Na]+
391.1880, found 391.1867.
(E)-1-(((3-Iodoallyl)oxy)methyl)-4-methoxybenzene
(25d). Prepared following general procedure A using (E)-
3-iodoprop-2-en-1-ol31
(320
mg,
1.74
mmol),
scandium(III) triflate (128 mg, 0.26 mmol), toluene (9 mL),
and 4-methoxybenzyl 2,2,2-trichloroacetimidate (0.54
mL, 2.61 mmol). Purification via column chromatography
(2.5% → 5% Et2O / petroleum ether) gave 25d (346 mg,
1.14 mmol, 65%) as a colourless oil. Rf 0.35 (5% Et2O /
(4Z,6E)-1-(benzyloxy)-8-((4-methoxybenzyl)oxy)octa-
4,6-dien-2-ol (27d). From vinyl iodide 25d: Prepared
using general procedure F with 14 (30 mg, 0.12 mmol,
1.2 equiv.), vinyl iodide 25d (30 mg, 0.10 mmol, 1.0
equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%) and
TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0 equiv.),
with a 16 h reaction time. Purification via column
chromatography (30% EtOAc / petroleum ether) gave
27d (24 mg, 0.065 mmol, 65%) as a yellow oil.
1
petroleum ether); H NMR (400 MHz, CDCl3) δ 7.25 (2H,
d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 6.65 (1H, dt, J =
14.5 and 5.5 Hz), 6.39 (1H, dt, J = 14.5 and 1.5 Hz), 4.45
(2H, s), 3.92 (2H, dd, J = 5.5 and 1.5 Hz), 3.81 (3H, s);
13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 142.5, 129.8,
129.4, 113.9, 78.8, 72.0, 71.5, 55.3. Spectroscopic data in
agreement with the literature.32
(E)-1-(((3-Bromoallyl)oxy)methyl)-4-methoxybenzene
(25e). Prepared following general procedure A with (E)-
From vinyl bromide 25e: Prepared using general
procedure F with 14 (30 mg, 0.12 mmol, 1.2 equiv.), vinyl
bromide 25e (26 mg, 0.10 mmol, 1.0 equiv.), [allylPdCl]2
(0.9 mg, 2.5 µmol, 2.5 mol%) and TBAF•3H2O (0.30 mL,
1.0 M in THF, 0.30 mmol, 3.0 equiv.), with a 3 h reaction
time. Purification via column chromatography (30%
EtOAc / petroleum ether) gave 27d (22 mg, 0.060 mmol,
60%) as a yellow oil. Rf 0.19 (30% EtOAc / petroleum
ether); IR (thin film, νmax / cm-1) 3433, 2856, 1513, 1247,
3-bromoprop-2-en-1-ol33
(1.00
g,
7.30
mmol),
scandium(III) triflate (539 mg, 1.10 mmol), 4-
methoxybenzyl 2,2,2-trichloroacetimidate (2.3 mL, 11
mmol) and toluene (46 mL). Purification via column
chromatography (2%→4% Et2O / petroleum ether) gave
25e (1.10 g, 4.28 mmol, 59%) as a colourless oil. Rf 0.56
(30% Et2O / petroleum ether); IR (thin film, νmax / cm-1)
2837, 1613, 1248, 1103, 820; 1H NMR (400 MHz, CDCl3) δ
7.30-6.84 (4H, m), 6.40-6.27 (2H, m), 4.45 (2H, s), 3.95
(2H, d, J = 5.0 Hz), 3.81 (3H, s); 13C{1H} NMR (101 MHz,
CDCl3) δ 159.5, 134.4, 129.9, 129.6, 114.0, 108.7, 72.1,
69.5, 55.4; HRMS (CI+) calc. for C11H17BrNO2 [M+NH4]+
274.044, found 274.044.
1
989; H NMR (400 MHz, CDCl3) δ 7.39-7.25 (7H, m), 6.87
(2H, d, J = 8.5 Hz), 6.56-6.47 (1H, m), 6.11 (1H, t, J = 11.0
Hz), 5.80 (1H, dt, J = 12.5 and 6.0 Hz), 5.47 (1H, dt, J =
11.0 and 7.5 Hz), 4.54 (2H, s), 4.43 (2H, s), 4.03 (2H, d, J =
6.0 Hz), 3.91-3.83 (1H, m), 3.78 (3H, s), 3.51 (1H, dd, J =
9.5 and 3.5 Hz), 3.37 (1H, dd, J = 9.5 and 7.5 Hz), 2.45-
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The Journal of Organic Chemistry
2.33 (3H, m); 13C{1H} NMR (101 MHz, CDCl3) δ 159.2,
s), 4.39 (2H, s), 3.93 (2H, s), 3.93-3.83 (1H, m), 3.79 (3H, s),
1
2
3
4
5
6
7
8
138.0, 130.7, 130.4, 130.3, 129.5, 128.5, 127.8, 127.7,
127.6, 127.1, 113.8, 73.8, 73.4, 71.9, 70.3, 70.2, 55.3, 31.8;
HRMS (ESI+) calc. for C23H28O4Na [M+Na]+ 391.1879,
found 391.1873.
3.52 (1H, dd, J = 9.5 and 3.5 Hz), 3.38 (1H, dd, J = 9.5 and
7.5 Hz), 2.44-2.38 (2H, m), 2.37 (1H, d, J = 3.5 Hz), 1.78
(3H, s); 13C NMR (101 MHz, CDCl3) δC 159.2, 138.0, 135.8,
130.5, 129.4, 128.5, 127.8, 127.7, 126.6, 126.5, 121.7,
113.8, 75.7, 73.9, 73.4, 70.3, 55.3, 31.7, 14.3; HRMS (ESI+)
calc. for C24H30O4Na [M+Na]+ 405.2036, found 405.2028.
(E)-1-(((3-Iodo-2-methylallyl)oxy)methyl)-4-
methoxybenzene (25f). Prepared following general
procedure A with (E)-3-iodo-2-methylprop-2-en-1-ol34
(352 mg, 1.78 mmol), scandium(III) triflate (131 mg, 0.26
mmol), toluene (9 mL) and 4-methoxybenzyl 2,2,2-
trichloroacetimidate (0.55 mL, 2.67 mmol). Purification
via column chromatography (2.5%→5% Et2O / petroleum
ether) gave 25f (420 mg, 1.32 mmol, 74%) as a clear oil.
IR (thin film, νmax / cm-1) 2835, 1612, 1513, 1247, 1035; 1H
NMR (400 MHz, CDCl3) δH 7.25 (2H, d, J = 8.5 Hz), 6.89
(2H, d, J = 8.5 Hz), 6.28-6.25 (1H, m), 4.41 (2H, s), 3.97
(2H, d, J = 1.0 Hz), 3.81 (3H, s) 1.85 (3H, d, J = 1.0 Hz);
13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 145.0, 130.0,
129.4, 113.9, 78.6, 73.7, 71.7, 55.3, 21.6; HRMS (Cl+) calc.
for C12H19INO2 [M+NH4]+ 336.0460, found 336.0459.
NMR spectroscopic data in agreement with the
literature.35
(2E,4E)-5-Iodopenta-2,4-dienal
Iodopenta-2,4-dienal. To
and
(2E,4Z)-5-
of
a
solution
9
triphenylphosphine (10.6 g, 40.4 mmol, 1.1 equiv.) in
CH2Cl2 (200 mL) at 0 °C was added iodine (10.25 g, 41.7
mmol, 1.1 equiv.), followed by glutaconaldehyde
potassium salt (5.00 g, 36.7 mmol, 1.0 equiv.).36 The
mixture was stirred in the dark for 72 h, then NaHCO3
(100 mL, 5% w/v, aq.) was added. The organic phase was
separated, and the aqueous phase extracted with Et2O (3
× 150 mL). The combined organic phases were washed
with brine (100 mL), dried (MgSO4), filtered and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
concentrated.
Purification
twice
by
column
chromatography (40% Et2O / petroleum ether; 2% Et2O /
petroleum ether) gave (2E,4Z)-5-iodopenta-2,4-dienal
(1.92 g, 9.18 mmol, 25%), and (2E,4E)-5-iodopenta-2,4-
dienal (2.18 g, 10.3 mmol 28%) as orange solids. (2E,4Z)-
5-iodopenta-2,4-dienal: Rf 0.32 (25% Et2O / petroleum
(4Z,6E)-1-(Benzyloxy)-8-((4-methoxybenzyl)oxy)-7-
methylocta-4,6-dien-3-ol (26e). Prepared using general
procedure F with 13 (25 mg, 0.10 mmol, 1.0 equiv.), vinyl
iodide 25f (38 mg, 0.12 mmol, 1.2 equiv.), Pd(dba)2 (2.9
mg, 5.0 µmol, 5.0 mol%) and TBAF•3H2O (0.3 mL, 1.0 M
in THF, 0.30 mmol, 3.0 equiv.), with a 1 h reaction time.
Purification via column chromatography (30% EtOAc /
petroleum ether) gave 26e (32 mg, 0.084 mmol, 84%) as
a yellow oil. Rf 0.20 (30% EtOAc / petroleum ether); IR
1
ether); H NMR (400 MHz, CDCl3) δ 9.70 (1H, d, J = 8.0
Hz), 7.33-7.18 (1H, m), 7.08-6.99 (2H, m), 6.37 (1H, dd, J =
15.5 and 8.0 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ 193.7,
150.0, 136.8, 135.1, 95.2. (2E,4E)-5-iodopenta-2,4-dienal:
Rf 0.24 (25% Et2O / petroleum ether); 1H NMR (400 MHz,
CDCl3) δ 9.58 (1H, d, J = 8.0 Hz), 7.31 (1H, ddd, J = 14.5,
11.0 and 1.0 Hz), 7.15 (1H, dt, J = 14.5 and 1.0 Hz), 6.97
(1H, ddd, J = 15.5, 11.0 and 1.0 Hz), 6.14 (1H, ddt, J =
15.5, 8.0 and 1.0 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ
193.4, 149.7, 143.3, 131.3, 92.3. Spectroscopic data in
agreement with the literature.26b
1
(thin film, νmax / cm-1) 3425, 2856, 1513, 1247, 1033; H
NMR (400 MHz, CDCl3) δ 7.38-7.23 (7H, m), 6.88 (2H, d, J
= 8.5 Hz), 6.38-6.25 (2H, m), 5.48 (1H, dd, J = 10.5, and
8.5 Hz), 4.89-4.81 (1H, m), 4.52 (2H, s), 4.39 (2H, s), 3.93
(2H, s), 3.80 (3H, s), 3.73-3.66 (1H, m), 3.66-3.58 (1H, m),
2.73 (1H, br s), 1.99-1.89 (1H, m), 1.82-1.70 (1H, m), 1.79
(3H, s); 13C NMR{1H} (101 MHz, CDCl3) δ 159.2, 138.0,
137.0, 133.2, 130.4, 129.4, 128.5, 127.7, 127.6, 125.0,
121.3, 113.8, 75.5, 73.3, 71.6, 68.3, 67.0, 55.3, 36.9, 14.2;
HRMS (ESI+) calc. for C24H30O4Na [M+Na]+ 405.1946,
found 405.19272.
1-((((2E,4E)-5-Iodopenta-2,4-dien-1-yl)oxy)methyl)-4-
methoxybenzene (25g). To a solution of (2E,4E)-5-
iodopenta-2,4-dienal (500 mg, 2.40 mmol, 1.0 equiv.,
prepared as described above) in CH2Cl2 (6.0 mL) at −78
°C was added DIBALH (3.6 mL, 1.0 M in cyclohexane, 3.6
mmol, 1.5 equiv.) dropwise. After stirring for 1 h, the
reaction was quenched by sequential addition of water
(0.15 mL), NaOH (0.15 mL, 15% w/v, aq.), and water (0.36
mL). The mixture was warmed to room temperature, then
MgSO4 was added. The resulting mixture was stirred for
15 min, filtered, and concentrated. Purification via
column chromatography (50% EtOAc / petroleum ether)
gave (2E,4E)-5-iodopenta-2,4-dien-1-ol (382 mg, 1.82
(4Z,6E)-1-(Benzyloxy)-8-((4-methoxybenzyl)oxy)-7-
methylocta-4,6-dien-2-ol (27e). Prepared using general
procedure F with 14 (25 mg, 0.10 mmol, 1.0 equiv.), vinyl
iodide 25f (38 mg, 0.12 mmol, 1.2 equiv.), Pd(dba)2 (2.9
mg, 5.0 µmol, 5.0 mol%) and TBAF•3H2O (0.3 mL, 1.0 M
in THF, 0.30 mmol, 3.0 equiv.), with a 16 h reaction time.
Purification via column chromatography (30% EtOAc /
petroleum ether) gave 27e (27 mg, 0.073 mmol, 73%) as
a yellow oil. Rf 0.23 (30% EtOAc / petroleum ether); IR
1
mmol, 76%) as a light yellow oil; H NMR (400 MHz,
CDCl3) δ 7.05 (1H, dd, J = 14.5 and 11.0 Hz), 6.35 (1H, d, J
= 14.5 Hz), 6.20 (1H, ddt, J = 15.5, 11.0 and 1.5 Hz), 5.86
(1H, dt, J = 15.5 and 5.5 Hz), 4.16 (2H, app. t, J = 5.0 Hz),
1.43 (1H, t, J = 6.0 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ
144.6, 133.2, 130.7, 79.6, 62.9. Spectroscopic data in
1
(thin film, νmax / cm-1) 3446, 2856, 1513, 1247, 1034; H
NMR (400 MHz, CDCl3) δ 7.38-7.28 (7H, m), 6.87 (2H, d, J
= 8.5 Hz), 6.40-6.26 (2H, m), 5.55-5.45 (1H, m), 4.54 (2H,
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agreement with the literature.16 To a solution of (2E,4E)- Hz), 1.49 (1H, t, J = 5.0 Hz); 13C{1H} NMR (101 MHz,
1
2
3
4
5
6
7
8
5-iodopenta-2,4-dien-1-ol (370 mg, 1.76 mmol, 1.0
equiv.) and scandium(III) triflate (130 mg, 264 µmol, 0.15
equiv.) in toluene (11 mL) was added 4-methoxybenzyl
2,2,2-trichloroacetimidate (0.55 mL, 2.7 mmol, 1.5 equiv.).
After stirring for 1 h, NaHCO3 (20 mL, sat., aq.) was
added, and the mixture was diluted with Et2O (20 mL).
The organic phase separated, and the aqueous phase
extracted with Et2O (2 × 20 mL). The combined organic
phases were dried (MgSO4), filtered and concentrated.
Purification via column chromatography (7% Et2O /
petroleum ether) gave 25g (476 mg, 1.44 mmol, 82%) as
a colourless oil. Rf 0.70 (30% Et2O / petroleum ether); IR
CDCl3) δC 136.8, 133.4, 128.3, 109.2, 63.0. Spectroscopic
data in agreement with the literature.37 Following general
procedure B, (2E,4E)-5-bromopenta-2,4-dien-1-ol (468
mg, 2.87 mmol), scandium(III) triflate (215 mg, 437 µmol),
4-methoxybenzyl 2,2,2-trichloroacetimidate (0.91 mL, 4.4
mmol) and toluene (19 mL) afforded 25h (478 mg, 1.00
mmol, 59%) as a yellow oil after purification via column
chromatography (2%→4% Et2O / petroleum ether). Rf
0.19 (4% Et2O / petroleum ether); IR (thin film, νmax / cm-
1) 2836, 1612, 1585, 1512, 736; 1H NMR (400 MHz, CDCl3)
δ 7.29-6.85 (4H, m), 6.72 (1H, ddd, J = 13.5, 11.0 and 1.0
Hz), 6.35-6.26 (1H, m), 6.24-6.16 (1H, m), 5.85-5.78 (1H,
m), 4.44 (s, 2H), 4.03-3.96 (m, 2H), 3.80 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 159.4, 137.0, 131.2, 130.2,
129.5, 114.0, 109.1, 72.2, 69.7, 55.4; HRMS (CI+) calc. for
C13H15O2Br [M+H]+ 283.0331, found 283.0326.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(thin film, νmax / cm-1) 2836, 1612, 1512, 1174, 820; H
NMR (400 MHz, CDCl3) δ 7.28-7.24 (2H, m), 7.04 (1H, dt, J
= 14.5 and 11.0 Hz), 6.92-6.86 (2H, m), 6.34 (1H, d, J =
14.5 Hz), 6.20 (1H, dd, J = 15.5 and 11.0 Hz), 5.81 (1H, dt,
J = 15.5 and 6.0 Hz), 4.45 (2H, s), 4.08-3.90 (2H, m), 3.81
(3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 159.4, 144.7,
132.0, 131.0, 130.3, 129.5, 114.0, 79.5, 72.2, 69.6, 55.4;
HRMS (ESI+) calc. for C13H15O2INa [M+Na]+ 353.0009,
found 353.0009.
(4Z,6E,8E)-1-(Benzyloxy)-10-((4-
methoxybenzyl)oxy)deca-4,6,8-trien-3-ol (26f). From
iododiene 25g: Prepared using general procedure F with
13 (25 mg, 0.10 mmol, 1.0 equiv.), 25g (40 mg, 0.10
mmol, 1.2 equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%)
and TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0
equiv.), with a 16 h reaction time. Purification via column
chromatography (30% EtOAc / petroleum ether) gave
26f (32 mg, 0.081 mmol, 81%) as a yellow oil.
1-((((2E,4E)-5-Bromopenta-2,4-dien-1-yl)oxy)methyl)-4-
methoxybenzene
(25h).
To
a
solution
of
triphenylphosphine (4.29 g, 16.4 mmol, 1.1 equiv.) in
CH2Cl2 (80 mL) at 0 °C was added bromine (0.82 mL, 16
mmol, 1.1 equiv.), followed by glutaconaldehyde
potassium salt (2.00 g, 14.7 mmol, 1.0 equiv.).36 The
mixture was stirred in the dark for 16 h, then NaHCO3 (50
mL, 5% w/v, aq.) was added. The organic phase was
separated, and the aqueous phase extracted with Et2O
(70 mL). The combined organic phases were washed with
brine (50 mL), dried (MgSO4), filtered and concentrated.
Purification twice by column chromatography (40% Et2O
/ petroleum ether; 2% Et2O / petroleum ether) gave
(2E,4Z)-5-Bromopenta-2,4-dienal (520 mg, 3.23 mmol,
22%) and (2E,4E)-5-Bromopenta-2,4-dienal (690 mg, 4.26
mmol, 29%) as brown solids. Spectroscopic data was in
agreement with the literature.26b To a solution of the thus
prepared (2E,4E)-5-bromopenta-2,4-dienal (680 mg, 4.22
mmol, 1.0 equiv.) in CH2Cl2 (11.0 mL) at −78 °C was
added DIBALH (6.4 mL, 1.0 M in cyclohexane, 6.4 mmol,
1.5 equiv.) dropwise. After stirring for 1 h, the reaction
was quenched by sequential addition of water (0.26 mL),
NaOH (0.26 mL, 15% w/v, aq.), and water (0.64 mL). The
mixture was warmed to room temperature, then MgSO4
was added. The mixture was stirred for 15 min, filtered,
From bromodiene 25h: Prepared using general
procedure F with 13 (25 mg, 0.10 mmol, 1.0 equiv.), 25h
(34 mg, 0.12 mmol, 1.2 equiv.), [allylPdCl]2 (0.9 mg, 2.5
µmol, 2.5 mol%) and TBAF•3H2O (0.30 mL, 1.0 M in THF,
0.30 mmol, 3.0 equiv.), with a 3 h reaction time.
Purification via column chromatography (30% EtOAc /
petroleum ether) gave 26f (23 mg, 0.058 mmol, 58%) as
a yellow oil. Rf 0.20 (30% EtOAc / petroleum ether); IR
1
(thin film, νmax / cm-1) 3428, 2861, 151, 1248, 1095; H
NMR (400 MHz, CDCl3) δ 7.37-7.20 (7H, m), 6.89 (2H, d, J
= 8.5 Hz), 6.89-6.44 (1H, m), 6.30-6.19 (2H, m), 6.10-6.01
(1H, m), 5.81 (1H, dt, J = 14.0 and 6.0 Hz), 5.44 (1H, dd, J
= 10.5 and 9.0 Hz), 4.88-4.77 (1H, m), 4.50 (2H, s), 4.43
(2H, s), 4.03 (2H, d, J = 6.0 Hz), 3.79 (3H, s), 3.71-3.65 (1H,
m), 3.63-3.55 (1H, m), 2.65 (1H, br s), 1.99-1.88 (1H, m),
1.80-1.70 (1H, m); 13C{1H} NMR (101 MHz, CDCl3) δ 159.2,
138.0, 133.8, 133.7, 132.5, 130.3, 129.6, 129.4, 128.5,
127.8, 127.7, 127.6, 113.8, 73.3, 71.8, 70.1, 68.2, 67.2, 55.3,
36.9; HRMS (ESI+) calc. for C25H30O4Na [M+Na]+
417.1911, found 417.1927.
(4Z,6E,8E)-1-(Benzyloxy)-10-((4-
and
concentrated.
Purification
via
column
methoxybenzyl)oxy)deca-4,6,8-trien-2-ol (27f). From
iododiene 25g: Prepared using general procedure F with
14 (25 mg, 0.10 mmol, 1.0 equiv.), 25g (40 mg, 0.10
mmol, 1.2 equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%)
and TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0
equiv.), with a 16 h reaction time. Purification via column
chromatography (50% EtOAc / petroleum ether) gave
(2E,4E)-5-Bromopenta-2,4-dien-1-ol (492 mg, 3.00 mmol,
71%) as a light yellow oil. H NMR (400 MHz, CDCl3) δ
6.73 (1H, dd, J = 13.5 and 11.0 Hz), 6.33 (1H, dt, J = 13.5
and 1.0 Hz), 6.20 (1H, ddt, J = 15.5, 11.0 and 1.5 Hz), 5.87
(1H, dtt, J = 15.5, 5.5 and 1.0 Hz), 4.17 (app. t, 2H, J = 4.0
1
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chromatography (30% EtOAc / petroleum ether) gave 4.67 (1H, m), 4.36 (s, 2H), 4.08 (2H, dd, J = 6.0 and 1.5
1
2
3
4
5
6
7
8
27f (25 mg, 0.063 mmol, 63%) as a yellow oil.
Hz), 3.58-3.42 (2H, m), 2.62 (1H, s), 1.86-1.73 (1H, m),
1.70-1.40 (2H, m); 13C{1H} NMR (101 MHz, CDCl3) δ 138.1,
134.6, 134.3, 130.1, 128.6, 127.9, 127.8, 125.9, 124.4,
124.2, 73.5, 68.4, 67.1, 63.5, 37.0; HRMS (ESI+) calc. for
C17H22O3Na [M+Na]+ 297.1461, found 297.1461.
From bromodiene 25h: Prepared using general
procedure F with 14 (25 mg, 0.10 mmol, 1.0 equiv.), 25h
(34 mg, 0.12 mmol, 1.2 equiv.), [allylPdCl]2 (0.9 mg, 2.5
µmol, 2.5 mol%) and TBAF•3H2O (0.30 mL, 1.0 M in THF,
0.30 mmol, 3.0 equiv.), with a 3 h reaction time.
Purification via column chromatography (30% EtOAc /
petroleum ether) gave 27f (21 mg, 0.053 mmol, 53%) as
a yellow oil. Rf 0.17 (30% EtOAc / petroleum ether); IR
(4Z,6Z)-1-(Benzyloxy)-7-cyclohexylhepta-4,6-dien-3-ol
(26h). Prepared using general procedure F with 13 (25
mg, 0.10 mmol, 1.0 equiv.), vinyl iodide 25j38 (27 mg, 0.12
mmol, 1.2 equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%)
and TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0
equiv.), with a 2 h reaction time. Purification via column
chromatography (25% EtOAc / petroleum ether) gave
26h (14 mg, 0.051 mmol, 51%) as a yellow oil. Rf 0.27
(25% EtOAc / petroleum ether); IR (thin film, νmax / cm-1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(thin film, νmax / cm-1) 3443, 2856, 1513, 1247, 944; H
1
NMR (400 MHz, CDCl3) δ 7.39-7.25 (7H, m), 6.89 (2H, d, J
= 8.5 Hz), 6.89 (1H, dd, J = 14.0 and 11.5 Hz), 6.35-6.10
(3H, m), 5.82 (1H, dt, J = 14.5 and 6.0 Hz), 5.50 (1H, dt, J
= 10.5 and 8.0 Hz), 4.55 (2H, s), 4.45 (2H, s), 4.05 (2H, d, J
= 6.0 Hz), 3.93-3.85 (1H, m), 3.81 (3H, s), 3.53 (1H, dd, J =
9.5 and 3.5 Hz), 3.39 (1H, dd, J = 9.5 and 7.0 Hz), 2.47-
2.40 (2H, m), 2.37 (1H, d, J = 4.0 Hz); 13C{1H} NMR (101
MHz, CDCl3) δ 159.2, 137.9, 132.8, 132.7, 131.0, 130.4,
130.2, 129.4, 128.5, 128.0, 127.8, 127.7, 127.4, 113.8, 73.7,
73.4, 71.8, 70.2, 70.1, 55.3, 31.9; HRMS (ESI+) calc. for
C25H30O4Na [M+Na]+ 417.2036, found 417.2045.
(2E,4Z)-5-Iodopenta-2,4-dien-1-ol (25i). To a solution
of (2E,4Z)-5-iodopenta-2,4-dienal (100 mg, 0.481 mmol,
1.0 equiv., prepared as described above) in CH2Cl2 (1.2
mL) at −78 °C was added DIBALH (0.72 mL, 1.0 M in
cyclohexane, 0.72 mmol, 1.5 equiv.) dropwise. After
stirring for 1 h, the reaction was quenched by sequential
addition of water (0.03 mL), an aqueous solution of
NaOH (0.03 mL, 15% w/v, aq.), and water (0.07 mL). The
mixture was warmed to room temperature, and MgSO4
was added. The mixture was stirred for 15 min, filtered,
1
3398, 2922, 1449, 1259, 1098, 1075, 697; H NMR (400
MHz, CDCl3) δ 7.40-7.22 (5H, m), 6.33 (1H, app. t, J = 11.5
Hz), 6.15 (1H, app. t, J = 11.5 Hz), 5.49-5.38 (1H, m), 5.41-
5.32 (1H, m), 4.87-4.78 (1H, m), 4.51 (2H, s), 3.72-3.58
(2H, m), 2.60 (s, 1H), 2.52-2.35 (1H, m), 1.99-1.87 (m, 1H),
1.82-1.01 (m, 10H); 13C{1H} NMR (101 MHz, CDCl3) δ
140.3, 138.2, 133.0, 128.6, 127.8, 127.8, 125.0, 121.3, 73.4,
68.4, 67.0, 37.0, 36.6, 33.3, 33.2, 26.1, 26.0, 25.9; HRMS
(ESI+) calc. for C20H28O2Na [M+Na]+ 323.1982, found
323.1981.
Ethyl 7-(benzyldimethylsilyl)-5-oxohept-6-ynoate (36).
To a solution of benzyldimethylsilylacetylene (177 mg,
1.02 mmol, 1.1 equiv.) in THF (1.0 mL) at −78 °C was
added a solution of n-BuLi (0.50 mL, 2.1 M in Et2O, 23.9
mmol, 1.15 equiv.) dropwise via syringe. The resulting
mixture was stirred for 10 min, then a solution of ZnCl2
(1.20 mL, 0.86 M in THF, 1.03 mmol, 1.1 equiv.) was
added. After stirring at −78 °C for 10 min, the cooling
bath was removed and the reaction was allowed to warm
to 0 °C, then stirred for a further 30 min. Ethyl 5-chloro-
5-oxopentanoate (30) (0.14 mL, 0.90 mmol, 1.0 equiv.)
was added, and the reaction was stirred for 1 h at 0 °C,
then allowed to warm to room temperature followed by
further stirring for 1 h. The mixture was diluted with Et2O
(20 mL), and quenched by addition of NH4Cl (5.0 mL, sat.,
aq.). The organic phase was separated, and the aqueous
phase was extracted with Et2O (2 × 20 mL). The
combined organic phases were dried (Na2SO4), filtered
and concentrated. Purification of the residue via column
chromatography (15% Et2O / petroleum ether) gave 36
(146 mg, 0.46 mmol, 52%) as a colourless oil. Rf 0.15
(10% Et2O / petroleum ether); IR (thin film, νmax / cm-1)
2963, 1732, 1676, 1112, 842; 1H NMR (400 MHz, CDCl3) δ
7.29-7.02 (5H, m), 4.14 (2H, q, J = 7.0 Hz), 2.63 (2H, t, J =
7.0 Hz), 2.26 (2H, t, J = 7.5 Hz), 2.26 (1H, s), 1.97 (2H, q, J
= 7.0 Hz), 1.26 (3H, t, J = 7.0 Hz), 0.20 (6H, s); 13C{1H}
NMR (101 MHz, CDCl3) δ 186.7, 173.0, 138.0, 128.5,
128.4, 124.9, 103.0, 96.7, 60.6, 44.4, 33.2, 25.5, 19.1, 14.4,
and
concentrated.
Purification
via
column
chromatography (30% EtOAc / petroleum ether) gave
25i (81 mg, 0.385 mmol, 80%) as a light yellow oil. Rf 0.17
(30% EtOAc / petroleum ether); 1H NMR (400 MHz,
CDCl3) δ 6.76 (1H, dd, J = 10.0 and 7.5 Hz), 6.50-6.40 (1H,
m), 6.30 (1H, d, J = 7.5 Hz), 6.12 (1H, dt, J = 15.5 and 5.5
Hz), 4.25 (2H, d, J = 5.0 Hz), 1.52 (1H, s); 13C{1H} NMR
(101 MHz, CDCl3) δ 137.7, 137.2, 130.9, 82.9, 63.3.
Spectroscopic data in agreement with the literature.12a
(2E,4Z,6Z)-10-(Benzyloxy)deca-2,4,6-triene-1,8-diol
(26g). Prepared using general procedure F with 13 (25
mg, 0.10 mmol, 1.0 equiv.), vinyl iodide 25i (25 mg, 0.12
mmol, 1.2 equiv.), Pd(dba)2 (2.9 mg, 5.0 µmol, 5.0 mol%)
and TBAF•3H2O (0.3 mL, 1.0 M in THF, 0.30 mmol, 3.0
equiv.), with a 4 h reaction time. Purification via column
chromatography (50% EtOAc / petroleum ether) gave
26g (14 mg, 0.051 mmol, 52%) as a yellow oil. Rf 0.22
(50% EtOAc / petroleum ether); IR (thin film, νmax / cm-1)
1
3383, 2923, 1679, 1617, 1096, 1076, 699; H NMR (400
MHz, CDCl3) δ 7.25-7.11 (5H, m), 6.62-6.53 (1H, m),
6.40-6.32 (1H, m), 6.17-6.04 (1H, m), 5.96-5.85 (1H, m),
5.75 (1H, dt, J = 15.0 and 6.0 Hz), 5.42-3.44 (1H, m), 4.74-
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–2.6; HRMS (ESI+) calc. for C18H24O3Si [M+H]+ 317.1574,
found 317.1573.
[M+NH4]+ 380.2251, found 380.2261. Using general
1
2
3
4
5
6
7
8
procedure C, a solution of this product (339 mg, 0.93
mmol) in THF (4.5 mL) and TBAF•3H2O (0.65 mL, 1.0 M in
THF, 1.05 equiv.), with a 30 min reaction time, gave 34
(185 mg, 0.81 mmol, 87%) as a colourless oil which
[α]20
Ethyl
(S)-5-acetoxy-7-(benzyldimethylsilyl)hept-6-
ynoate (37). To a degassed solution of 36 (100 mg, 0.32
mmol, 1.0 equiv.) in isopropyl alcohol (4.0 mL) under
argon was added a solution of (1S,2S)-(+)-N-tosyl-1,2-
diphenylethane-1,2-diamine[η6-1-isopropyl-4-
methylbenzene)-ruthenium(II) (4.6 mg, 6.0 µmol, 2.0
mol%) in CH2Cl2 (0.1 mL). The mixture was stirred for 1 h,
required no further purification;
+48.9 (c 1.0, CHCl3);
퐷
Rf 0.45 (50% Et2O / petroleum ether); IR (thin film, νmax
/
cm-1) 2959, 1734, 1250, 1030, 853; H NMR (400 MHz,
CDCl3) δ 6.81 (1H, dd, J = 10.5 and 1.5 Hz), 6.04 (1H, dd, J
= 10.5 and 2.0 Hz), 4.71 (1H, ddt, J = 6.5, 4.0 and 2.0 Hz),
4.10 (2H, q, J = 7.0 Hz), 2.36 (2H, t, J = 7.0 Hz), 1.84-1.59
(3H, m), 1.46 (1H, dddd, J = 12.5, 10.0, 6.5 and 5.5 Hz),
1.24 (3H, t, J = 7.0 Hz), 0.25 (3H, s), 0.23 (3H, s); 13C{1H}
NMR (101 MHz, CDCl3) δ 173.7, 153.2, 127.3, 82.5, 60.3,
36.5, 34.4, 20.8, 14.4, 1.5, 0.7; HRMS (ESI+) calc. for
C11H21O3SiN [M+H]+ 229.1255, found 229.1256.
1
9
then
concentrated
to
give
ethyl
(S)-7-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(benzyldimethylsilyl)-5-hydroxyhept-6-ynoate. This was
redissolved in CH2Cl2 (2.0 mL), and acetic anhydride (0.07
mL, 0.64 mmol, 2.0 equiv.), Et3N (0.14 mL, 0.96 mmol, 3.0
equiv.) and a crystal of 4-dimethylaminopyridine were
added. After stirring for 1 h, NH4Cl (5.0 mL sat., aq.) was
added. The organic phase was separated, and the
aqueous phase extracted with CH2Cl2 (2 × 5.0 mL). The
combined organic phases were dried (MgSO4), filtered
and concentrated. The residue was purified via column
chromatography (15%  25% Et2O / petroleum ether)
to give 37 (107 mg, 0.30 mmol, 94%) as a colourless oil.
(1E,3E)-1-Iodotrideca-1,3-dien-5-ol ((±)-38). To
a
solution of triphenylphosphine (2.58 g, 9.8 mmol, 1.1
equiv.) in CH2Cl2 (50 mL) at 0 °C, was added iodine (2.50
g, 9.8 mmol, 1.1 equiv.), followed by glutaconaldehyde
potassium salt36 (1.22 g, 9.8 mmol, 1.0 equiv.). The
reaction was stirred in the dark for 72 h, then NaHCO3
(100 mL, 5% w/v, aq.) was added. The organic phase was
separated, and the aqueous phase extracted with Et2O (3
× 150 mL). The combined organic phases were washed
with brine (100 mL), dried (MgSO4), filtered and
concentrated. Purification by column chromatography
(30% Et2O / petroleum ether) gave a mixture of (2E,4Z)-
5-iodopenta-2,4-dienal and (2E,4E)-5-iodopenta-2,4-
dienal (2.18 g, 10.3 mmol, 28%) as a pale yellow oil.26b To
a suspension of magnesium turnings (389 mg, 16.0
mmol, 2.0 equiv.) in THF (3.0 mL) at 0 °C was added
1-bromooctane (2.1 mL, 12.0 mmol, 1.0 equiv.) and THF
(25 ml). The mixture was stirred for 1 h, then cooled to
‒40 °C. To this was added dropwise a solution of the
above prepared (2E,4Z)-5-iodopenta-2,4-dienal and
(2E,4E)-5-iodopenta-2,4-dienal (2.18 g, 10.3 mmol). The
mixture was stirred for 15 minutes, then the cooling bath
was removed and the reaction was warmed to room
temperature. The reaction was then quenched by
addition of NH4Cl (20 mL, sat., aq.). The organic phase
was separated, and the aqueous phase was extracted
with Et2O (3 × 20 mL). The combined organic phases
were washed with brine (20 mL), dried (MgSO4), filtered
[α]2퐷0
‒5.8 (c 0.1, CHCl3); 99% ee (CHIRALPAK IB, 0.5% IPA
/ hexane, 1.3 mL/min, tR (5R) 6.8 min, tR (5S) 7.6 min); Rf
0.40 (50% Et2O / petroleum ether); IR (thin film, νmax / cm-
1
1) 2962, 1736, 1372, 1231, 1159, 1022, 840; H NMR (400
MHz, CDCl3) δ 7.25-7.01 (5H, m), 5.42-5.34 (1H, m), 4.14
(2H, q, J = 7.0 Hz), 2.38-2.30 (2H, m), 2.20 (1H, s), 2.09
(3H, s), 1.82-1.73 (2H, m), 1.26 (3H, t, J = 7.0 Hz), 0.14
(3H, s), 0.13 (3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ
173.2, 169.9, 138.8, 128.5, 128.3, 124.5, 103.7, 89.2, 63.9,
60.5, 34.1, 33.8, 26.1, 21.2, 20.6, 14.4, ‒2.1; HRMS (ESI+)
calc. for C20H28O4SiNa [M+Na]+ 383.1649, found
383.1653.
Ethyl
yl)butanoate
(S)-4-(2,2-dimethyl-2,5-dihydro-1,2-oxasilol-5-
(34). Ethyl (S,Z)-5-acetoxy-7-
(benzyldimethylsilyl) hept-6-enoate was prepared using
general procedure B with Pd / CaCO3 (691 mg, 0.32
mmol) in toluene (30 mL), and 32 (2.34 g, 6.49 mmol)
and quinoline (0.38 mL, 3.24 mmol, 50 mol%) in toluene
(3.0 mL) and cyclohexene (3.30 mL), with a 30 min
reaction time. Purification via column chromatography
(15% Et2O / petroleum ether) gave ethyl (S,Z)-5-acetoxy-
7-(benzyldimethylsilyl)hept-6-enoate (1.93 g, 5.32 mmol,
[α]20
82%) as a clear oil.
‒7.2 (c 1.0, CHCl3); Rf 0.45 (50%
퐷
Et2O / petroleum ether); IR (thin film, νmax / cm-1) 2957,
1734, 1494, 1370, 833; 1H NMR (400 MHz, CDCl3) δ 7.25-
7.02 (5H, m), 6.19 (1H, dd, J = 14.5 and 9.0 Hz), 5.69 (1H,
dd, J = 14.5 and 1.0 Hz), 5.38-5.28 (1H, m), 4.14 (2H, q, J
= 7.0 Hz), 2.35-2.22 (2H, m), 2.19 (2H, d, J = 3.0 Hz), 2.04
(3H, s), 1.71-1.40 (4H, m), 1.26 (3H, t, J = 7.0 Hz), 0.16
(3H, t, J = 3.0 Hz), 0.15 (3H, t, J = 3.0 Hz); 13C{1H} NMR
(101 MHz, CDCl3) δ 173.3, 170.3, 145.9, 139.8, 131.7,
128.4, 128.3, 124.2, 74.2, 60.5, 34.4, 34.1, 26.5, 21.4, 20.7,
14.4, ‒1.6, ‒1.7; HRMS (ESI+) calc. for C20H34O4SiN
and
concentrated.
Purification
via
column
chromatography (30% Et2O / petroleum ether) gave a
1.2:1 mixture of (1E,3E)-1-iodotrideca-1,3-dien-5-ol (±)-
38 and (1Z,3E)-1-iodotrideca-1,3-dien-5-ol as an orange
oil (1.27 g, 3.9 mmol). This oil was dissolved in pentane (5
mL), and stored in the freezer (‒20 °C) overnight. The
resulting white crystals of (±)-38 (409 mg, 1.27 mmol,
14%, E:Z 10:1) were collected by filtration. Rf 0.51 (50%
Et2O / petroleum ether); IR (thin film, νmax / cm-1) 3430,
1
2923, 1682, 1464, 979; H NMR (400 MHz, CDCl3) δ 7.02
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(1H, ddd, J = 14.5, 4.0 and 0.5 Hz), 6.33 (1H, d, J = 14.5
Hz), 6.19-6.11 (1H, ddd, J = 15.5, 4.5 and 0.5 Hz), 5.73
Ethyl
(5S,6Z,8E,10E,12R)-5,12-dihydroxyicosa-6,8,10-
trienoate (39). Prepared following general procedure F
with 34 (71 mg, 0.31 mmol, 1.0 equiv.), (R)-38 (120 mg,
0.37 mmol, 1.2 equiv.), Pd(dba)2 (9.0 mg, 15.7 µmol, 5.0
mol%) and TBAF•3H2O (0.93 mL, 1.0 M in THF, 0.93
mmol, 3.0 equiv.), with a 2 h reaction time. Purification
via column chromatography (30% EtOAc / petroleum
ether) gave 39 (83 mg, 0.23 mmol, 73%) as a yellow oil.
2
3
4
5
(1H, dd, J = 15.5 and 6.5 Hz), 4.15-4.08 (1H, m), 1.60-1.49
(2H, m), 1.43-1.19 (12H, m), 0.91-0.85 (3H, m); 13C{1H}
NMR (101 MHz, CDCl3) δ 144.7, 137.4, 129.9, 79.4, 72.3,
37.3, 32.0, 29.7, 29.4, 25.5, 22.8, 14.3.
6
(5R,1E,3E)-1-iodotrideca-1,3-dien-5-ol ((R)-38). DMSO
(0.88 mL, 12.4 mmol, 4.0 equiv.) was added dropwise to a
solution of oxalyl chloride (0.53 mL, 6.2 mmol, 2.0 equiv.)
in CH2Cl2 (20.0 mL) at ‒78 °C. After stirring for 30 min, a
solution of (±)-38 (1.00 g, 3.1 mmol, 1.0 eq.) in CH2Cl2
(1.0 mL) was added dropwise, and the mixture was
stirred for further 30 min. Triethylamine (2.6 mL, 18.6
mmol, 6.0 equiv.) was added dropwise, and the mixture
allowed to warm to room temperature over 1 h. The
reaction was quenched by addition of water (20 mL), and
the aqueous phase was extracted with CH2Cl2 (2 × 20
mL). The combined organic phases were washed with
brine (30 mL), dried (MgSO4), filtered and concentrated.
Filtration through silica gel (4% Et2O / petroleum ether
eluent) afforded crude (1E,3E)-1-iodotrideca-1,3-dien-5-
one (0.70 g, 2.19 mmol, 71%) as a waxy colourless solid,
which was used directly in the next transformation. Rf
7
8
9
[α]2퐷0
+1.8 (c 0.6, CHCl3); Rf 0.29 (40% EtOAc / petroleum
ether); IR (thin film, νmax / cm-1) 3369, 2926, 2360, 1734,
1463; H NMR (400 MHz, CDCl3) δ 6.49 (1H, dd, J = 14.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
and 11.5 Hz), 6.32-6.19 (2H, m), 6.08 (1H, app. t, J = 11.0
Hz), 5.75 (1H, dd, J = 14.5 and 7.0 Hz), 5.42 (1H, app. t, J
= 10.0 Hz), 4.63-4.54 (1H, m), 4.20-4.07 (3H, m), 2.33 (2H,
t, J = 7.0 Hz), 1.81-1.43 (6H, m), 1.48-1.17 (15H, m), 0.87
(1H, t, J = 7.0 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ 173.6,
137.7, 134.1, 133.7, 130.2, 130.1, 122.4, 72.7, 67.6, 60.4,
37.3, 36.8, 34.1, 31.9, 29.6, 29.5, 29.3, 25.4, 22.7, 20.8,
14.3, 14.1; HRMS (ESI+) calc. for C22H38O4Na [M+Na]+
389.2673, found 389.2666.
Leukotriene B3 (33). To a solution of 39 (66 mg, 0.18
mmol, 1.0 equiv.) in isopropanol (9 mL) and water (4.5
mL) was added LiOH (17 mg, 0.71 mmol, 4.0 eq.). After
stirring for 2 h, the mixture was acidified with HCl (1 M,
aq.), and extracted with EtOAc (3 × 10 mL). The
combined organic phases were dried (Na2SO4), filtered
and concentrated to give leukotriene B3 (60 mg, 0.18
[α]20
1
0.48 (10% Et2O / petroleum ether); H NMR (400 MHz,
C6D6) δ 6.75-6.58 (2H, m), 6.19-6.08 (1H, m), 5.74-5.62
(1H, m), 2.14 (2H, t, J = 7.5 Hz), 1.66-1.54 (2H, m), 1.34-
1.18 (10H, m), 0.90 (3H, t, J = 7.0 Hz); 13C{1H} NMR (101
MHz, C6D6) δ 198.5, 143.7, 139.6, 129.5, 89.6, 41.5, 32.3,
29.9, 29.7, 29.6, 24.4, 23.1, 14.4. To a solution of this
ketone (0.70 g, 2.20 mmol, 1.0 equiv.) and (S)-(–)-2-
methyl-CBS-oxazaborolidine (0.22 mL, 1.0 M in toluene,
0.22 mmol, 0.1 equiv.) in THF (5.5 mL) at ‒40 °C was
added dropwise a solution of BH3•THF complex (2.4 mL,
1.0 M in THF, 2.4 mmol, 1.2 equiv.). After stirring at for 2
h ‒20 °C, the reaction was warmed to ‒10 °C and stirred
for a further 1 h. The reaction was then quenched by
addition of MeOH (3 mL), and allowed to warm to room
temperature. NH4Cl (5 mL, sat., aq.) was added, the
aqueous phase was extracted with Et2O (3 × 5 mL), and
the combined organic phases were washed with brine
(10 mL), dried (MgSO4), filtered and concentrated.
Purification via column chromatography (10% Et2O /
petroleum ether) gave (R)-38 (231 mg, 0.72 mmol, 33%
over two steps) as an orange solid. The solid was
recrystallized from pentane (0.5 mL) (overnight, –20 °C
freezer), and the crystals washed with cold pentane, to
give (R)-33 (63 mg, 27% recovery, 20.4% ee). The mother
liquor was evaporated to dryness to give (R)-38 (120 mg,
90.4% ee, 52% recovery, 0.37 mmol, 12% over 2 steps
and recrystallisation) as a colourless solid. 90.4% ee
(CHIRALPAK IC, 10% IPA/hexane, 0.7 mL/min, tR (5R) 6.8
min, tR (5S) 7.6 min); m.p. 36 °C; Spectroscopic data
identical to that of (±)-38.
mmol, 99%) as a colourless oil.
+15.4 (c 1.0, CHCl3);
퐷
IR (thin film, νmax / cm-1) 3408, 2925, 2340, 1734, 970; H
NMR (500 MHz, CD3OD) δ 6.55 (1H, dd, J = 14.0 and 12.0
Hz), 6.33-6.20 (2H, m), 6.08 (1H, app. t, J = 11.0 Hz), 5.72
(1H, dd, J = 14.5 and 7.0 Hz), 5.37 (1H, app. t, J = 10.0
Hz), 4.62-4.52 (1H, m), 4.12-4.03 (1H, m), 2.34-2.24 (2H,
m), 1.76-1.17 (18H, m), 0.90 (1H, t, J = 7.0 Hz); 13C{1H}
NMR (125 MHz, CD3OD) δ 178.3, 138.6, 135.1(2), 131.2,
130.6, 128.6, 73.2, 68.2, 38.4, 38.1, 33.0, 30.7,30.6, 30.4,
26.9, 26.6, 23.7, 22.3, 14.4; HRMS (ESI‒) calc. for C20H33O4
[M‒H]‒ 337.2384, found 337.2386. Spectroscopic data in
agreement with that reported by Kobayashi et al.19
1
SUPPORTING INFORMATION
Supporting Information (Siloxane equilibria NMR spectra,
ECC DOSY NMR experiments, copies of H and 13C NMR
1
spectra) is available free of charge on the ACS Publications
website (PDF).
AUTHOR INFORMATION
Corresponding Author
* edward.anderson@chem.ox.ac.uk.
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
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Page 18 of 20
(5) Trost, B. M.; Ball, Z. T. Intramolecular Endo-dig
Hydrosilylation Catalyzed by Ruthenium: Evidence for a New
Mechanistic Pathway. J. Am. Chem. Soc. 2003, 125, 30.
The research leading to these results has received funding
from the People Programme (Marie Curie Actions) of the
European Union’s Seventh Framework Programme
(FP7/2007-2013) under REA grant agreement no 316955
(studentship to CK). DC thanks the Fondation Wiener-
Anspach for a Fellowship. FU thanks the EPSRC Centre for
Doctoral Training in Synthesis for Biology and Medicine
(EP/L015838/1) for a studentship, generously supported by
AstraZeneca, Diamond Light Source, Defence Science and
Technology Laboratory, Evotec, GlaxoSmithKline, Janssen,
Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex. EAA
thanks the EPSRC for additional support (EP/M019195/1).
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