Asymmetric synthesis of the C(6-18) bis(tetrahydropyran)spiroacetal fragment of the lituarines

Article abstract of DOI:10.1016/j.tet.2011.03.116

We describe efforts to achieve a multigram synthesis of the tricyclic spiroacetal core of the lituarines based on the addition of acyl anion equivalent to 4-(2-furyl)butan-2-one (18). We report the first cases of chemoselective Achmatowicz reaction in the presence of a second furan ring that lacks an α-hydroxyl group. The use of lithiated methoxyallene provides an efficient one-step conversion of ketone 18 into a tricyclic Diels-Alder adduct (27). In the final route, asymmetric cyanosilylation of ketone 29 achieved the construction of the stereogenic C(12) 3°-alcohol centre. Subsequent butenylation, diastereoselective reduction of keto-alcohol (+)-33 and alkene cross metathesis set up an oxy-Michael reaction to close the C(8-12) tetrahydropyran ring. The second ring-closure, which completed the route, was achieved by oxidative spirocyclisation following our earlier work.

Full text of DOI:10.1016/j.tet.2011.03.116

Tetrahedron 67 (2011) 5011e5023
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of the C(6e18) bis(tetrahydropyran)spiroacetal fragment
of the lituarines
*
Jeremy Robertson , Christopher North, Jessie E.R. Sadig
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe efforts to achieve a multigram synthesis of the tricyclic spiroacetal core of the lituarines
Received 1 February 2011
Accepted 29 March 2011
Available online 8 April 2011
based on the addition of acyl anion equivalent to 4-(2-furyl)butan-2-one (18). We report the first cases of
chemoselective Achmatowicz reaction in the presence of a second furan ring that lacks an a-hydroxyl
group. The use of lithiated methoxyallene provides an efficient one-step conversion of ketone 18 into
a tricyclic DielseAlder adduct (27). In the final route, asymmetric cyanosilylation of ketone 29 achieved
the construction of the stereogenic C(12) 3ꢀ-alcohol centre. Subsequent butenylation, diastereoselective
reduction of keto-alcohol (þ)-33 and alkene cross metathesis set up an oxy-Michael reaction to close the
C(8e12) tetrahydropyran ring. The second ring-closure, which completed the route, was achieved by
oxidative spirocyclisation following our earlier work.
Keywords:
Achmatowicz
Asymmetric
Cyanohydrin
Diastereoselective
Oxy-Michael
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Me
The occurrence in nature of the spiro[furan-2,20-pyrano[3,2-b]
pyran] structural motif is limited to marine metabolites of the
okadaic acid type1 and the lituarines2 (Fig. 1). The latter are a group
of three macrolactones isolated from the New Caledonian sea pen
Lituaria australasiae, with cytotoxicity towards KB cells
(IC50¼1.0e6.0 ng mLꢁ1) and growth inhibitory effects against the
fungi Fusarium oxysporum, Helminthosporium turscicum, Penicillium
italicum and Phytophtora parasitica. Their structures were proposed
on the basis of extensive NMR investigations as samples of the
natural products suitable for X-ray crystallographic analysis were
not available. However, Smith’s group completed total syntheses of
the structures proposed for lituarines B and C and found that the
spectroscopic data for these compounds did not match those
reported.3 Thus, more recent synthetic efforts have been aimed at
securing the correct structures for the lituarines.
OH
O
H
H
H
HO2C
HO Me
O
O
Me
O
OH
O
O
H
H
Me
O
H
H
OH Me
okadaic acid
Me
8
Me
16
15
O
lituarine A, R1 = R2 = H
O
O
lituarine B, R1 = OAc, R2 = OH
lituarine C, R1 = R2 = OH
6
R1
R2
O
H
O
19 18
O
1
24
O
Me
O
O
Me
Me
O
O
O
octahydro-3H,3'H-
N
H
In Smith’s total synthesis, the C(8e12) tetrahydropyran
(2, Scheme 1) was formed by acid-mediated O-cyclisation onto
allylic epoxide 1 with inversion of stereochemistry at the newly-
formed C(12) centre. The second tetrahydropyranyl ring,
spiro[furan-2,2'-pyrano[3,2-b]pyran]
Fig. 1. Natural products containing the spiro[furan-2,20-pyrano[3,2-b]pyran] structural
motif.
comprising carbons C(11e15), was then obtained by classical
ketodiol spiroacetalisation (3/4) in a reaction that had to be run at
high dilution with a short reaction time in order to minimise
epimerisation at the C(15) and C(16) centres.
* Corresponding author. E-mail address: jeremy.robertson@chem.ox.ac.uk
(J. Robertson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.116

5012
J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
R
Me
O
Although the oxy-Michael reaction with 3ꢀ-alcohols is scarcely
Me
silica gel
precedented, the reaction with 2ꢀ-alcohols is a classic strategy for
constructing tetrahydropyrans in natural product synthesis. Among
over 90 publications referring to the transformation (with enoates),
examples include applications to: ambructin,9 aspergillides A and
B,10 bistramides A and D,11 brevetoxin B,12 ciguatoxin fragments,13
clavosolides A and B,14 decarestrictine L,15 gambierol,16 goniotha-
lesdiol A,17 halichondrins,18 herboxidiene,19 lasonolide A,20 leu-
cascandrolide A,21 miyakolide,22 montanacin,23 mucocin,24
neopeltolide,25 phorboxazoles A and C,26 polycavernoside A,27 pyr-
anicin,28 spirastrellolide A,29 spongistatin 1,30 vermiculine31 and
zampanolide.32
R
O
OPMB
OPMB
Me
column
HO
(ca. 90%)
OH
O
1
2
cat. TsOH·H2O
O
BnO
OPMB
CH2Cl2, 0 °C, 0.5 h
OH Me
HO
(ca. 90%)
3
Me
Me
OPMB
OH
O
O
In general, the geometry of the enoate double bond dictates the
stereochemical outcome although the stereoselectivity may vary
depending on the reaction conditions. Thus, the most common
outcome is for E-enoates to cyclise kinetically to give the trans-2,6-
disubstituted tetrahydropyrans, with the cis-diastereomers pre-
dominating under equilibrating conditions. A single example, taken
from Yonemistu’s PM3 study of the oxy-Michael cyclisation, shows
kinetic cyclisation to trans-product 11 (Scheme 4), which then
converts tothecis-product 12 followingequilibrationwith t-BuOK.33
The few reported examples of cyclisations of Z-enoates usually
afford cis-2,6-disubstituted tetrahydropyrans. In both E- and Z-
substrates, substituents in the allylic position can perturb these
trends.
BnO
=
R
O
H
OH Me
4
OBn
Scheme 1. Key steps in Smith’s route to the lituarine tricyclic spiroacetal.
Our own approach to the lituarine tricyclic spiroacetal (5,
Scheme 2), initiated before Smith’s first publications on the subject,
was shaped by concerns that we would not be able to achieve
spiroacetalisation in a sufficiently stereoselective manner. Thus, we
opted to introduce the C(16) methyl substituent by kinetic 1,4-ad-
dition to butenolide spiroacetal 6, which, in turn, was expected to
exhibit an essentially complete preference for an axial disposition
of the butenolide CeO acyl bond. Shown retrosynthetically, this
butenolide would arise by furan oxidative spirocyclisation of tet-
rahydropyran 7, a general transformation known since the late
1950s4 and developed for application in natural product synthesis
notably by Bohlmann,5 Kociensky6 and more recently by
Vassilikogiannakis.7
Me
O
Me
O
Me
Me
TES
O
RO2C
*
H
H
H
O
O
O
1) TBAF, THF
RO2C
2) t-BuOK, THF
O
O
O
O
H
O
O
11, -H
Me
Me
Me
Me 12, -H
Scheme 4. Yonemitsu’s results in the context of halichondrin B synthesis.
Me
Me
Me
With this background we were confident that the cyclisation of
hydroxy enoate 8 to tetrahydropyran 7 could be achieved and, in-
deed, this key step, the oxidative spirocyclisation and the stereo-
selective conjugate addition of methyl, giving tricycle 5, all
proceeded as planned.34 This intermediate was taken forward to an
advanced lituarine B and C precursor (14, Fig. 2) in readiness for
macrocyclisation and introduction of the C(24) side-chain.35
O
O
OP
OP
O
O
O
H
O
H
O
5
O
6
CO2Et
Me
Me
OH
O
OP
O
O
HO
TBSO
7
8
Me
Me
Scheme 2. An approach to the lituarine tricyclic spiroacetal based on oxy-Michael
cyclisation and furan oxidative spirocyclisation [P¼t-BuPh2Si].
OR1
O
O
O
R2O
O
H
Me
Me
O
O
O
O
Me
Of the various possibilities for producing the oxidative spi-
rocyclisation substrate (7) we selected the oxy-Michael cyclisation
of enoate 8. When we initiated our work the only precedent that we
could find for the stereoselective cyclisation of a 3ꢀ-alcohol onto an
O
Me
Me
13, R1 = t-BuPh2Si, R2 = PMB
14, R1 = R2 = H
a,b-unsaturated ester was in Nicolaou’s assembly of the J-ring of
Fig. 2. Advanced intermediates towards lituarines B and C.
brevetoxin B by base-treatment of alcohol 9 to give bis(tetrahy-
dropyran) 10 (Scheme 3). The stereochemical outcome in this
transformation was assumed to be thermodynamically-controlled,
leading to an equatorial CH2CO2Me substituent.8
The later stages of our lituarine synthetic route (from 8 all the
way through to diol 14) were reliable but further progress was
hampered because of difficulties in scaling up our published route
to intermediate 8. On a multigram scale the addition of organo-
metallics of the form 16 to ketone 15 (Scheme 5) proved to be
particularly problematic and the desired product was generated
along with the other diastereomer (in variable ratio) and various
cyclisation and degradation products, all close-running on TLC. In
this paper we describe a more practically reproducible route that
allowed us to prepare 1.5 g of tricycle 5 in the first run.36
MeO2C
OBn
Me
MeO2C
OBn
Me
HO
O
NaH, THF
OP
OP
25 °C, 5 h
(72%)
TMSO
O
TMSO
O
H
H
9
10
Scheme 3. Oxy-Michael reaction in Nicolaou’s synthesis of brevetoxin
termediates [P¼t-BuPh2Si].
B in-

J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
5013
CO2Et
+
transition state. Given the relative ease with which this reaction pro-
ceeded we speculate that the enone carbonyl is protonated at the time
of cycloaddition. More forcing conditions led to the dehydration
product 26.44 Milder acid sources led to much the same result under
aqueous conditions but the use of camphorsulfonic acid in methanol
gave a stable product, acetal 28.
Me
O
THF, –40 °C
1.5 h (<45%)
8
MgBr
O
16
TBSO
15
Scheme 5. Low-yielding step in the first route to oxy-Michael precursor 8.
2. Results
Me
OH
Me
OH
a
O
O
18
The initial challenge was to by-pass the low-yielding bond for-
mation in Scheme 5, corresponding to the C(12e13) bond in the
lituarines, and we soon identified furan derivative 18 (Scheme 6) as
a starting material, which was readily available37 on large scale and,
which already contained the intact C(12e13) bond. In a preliminary
study38 we envisaged formation of the C(12) 3ꢀ-alcohol centre by
addition of furyllithium, giving difuran derivative 17 and sub-
sequent Achmatowicz reaction39 directed by the hydroxyl group.40
Our preferred peracid conditions for furan oxidation generated
spiroacetal 19 by oxidation of the more electron rich furan, distal to
the hydroxyl centre, along with a small amount of the desired
product (20) and recovered starting material. Fortunately, appli-
cation of Sharpless’ conditions for directed epoxidation41 gave the
Achmatowicz product (20) and some dione 21. This idea was ap-
plied successfully to substrate 22, incorporating a C(8) substituent,
which was prepared by addition of lithiated 2-[(tert-butyldime-
thylsilyloxy)methyl]furan42 to ketone 18. In this case the hydrox-
MeO
H
C
O
25
24
c
b
d
Me
OH
O
O
H
H
MeO
MeO
28
Me
Me
OH
O
O
27
OH
26
Scheme 7. Reagents: (a) 1-methoxypropadiene/BuLi, THF, ꢁ78 ꢀC; (b) aq HCl (5.0 M),
CH2Cl2, 0 ꢀC (39%); (c) aq HCl (1.0 M), THF, 0 ꢀC (86%); (d) 1.0 mol % CSA, MeOH,
0/20 ꢀC (58%). [arrows in 27 indicate key NOEs].
Whilst this intermediate (28) may ultimately have proven useful,
the need to prevent intramolecular DielseAlder reaction by block-
ing the carbonyl group created inefficiencies. Use of the simpler
organolithium derived45 from ethyl vinyl ether avoided this prob-
lem by omitting the enone C]C, and methyl ketone 31 (Scheme 8)
was obtained reliably in good yield after hydrolysis of adduct 30.
This ketone was taken forward byallylation either with the hydroxyl
function free or protected as the TMS-ether 32. Cross metathesis of
ypyranone product 23 was formed as
a 3:1 mixture of
diastereomers but attempts to elaborate this selectively and effi-
ciently to an intermediate similar to 7 failed and work on this route
was discontinued.
g,d-enones 33 or 34 with methyl acrylate did not proceed at rt with
Grubbs II catalyst (39) but in dichloromethane at reflux the reaction
was essentially complete within 0.5e3 h depending on scale; in
both cases, essentially complete E-selectivity was observed.
O
O
O
18
O
17
Me OH
b
Me
a
c
a
b
O
O
57%
OH
O
29
O
18
Me
Me
Me
Me
O
O
R
O
O
O
b
O
O
HO
O
Me
Me
OH
Me
OR
c
d
O
O
O
19, 31%
20, 55%
21, 11%
[R = (CH2)2Fu]
(+ 20, 6%)
30
EtO
O
O
Me
31, R = H
32, R = TMS
b
Me OH
O
Me
OR
e
Me
OR
f
OTBS
OTBS
O
O
O
O
O
80%
*
Me OH
O
CO2Me
O
33, R = H
35, R = H
22
23, *dr = 3:1
34, R = TMS
36, R = TMS
Scheme 6. Reagents: (a) MCPBA, CH2Cl2, 0 ꢀC/rt; (b) 0.25 mol % VO(acac)2, t-BuOOH,
Mes
N
Cl
Cl
N Mes
Me
H
CH2Cl2, 20 ꢀC; (c) 10 mol % TPAP, NMO, CH2Cl2, 20 ꢀC.
O
CO2Me
O
*
Ru
39
Ph
37, -H
38, -H
O
PCy3
Despite our inability to progress enones 21 or 23 satisfactorily, the
use of a lithiated enol ether to construct the 3ꢀ-alcohol centre was
consideredsoundandthenextdevelopmentof theproposalevaluated
the organolithium reagent derived43 from methoxyallene. Hydrolysis
oftheexpectedadduct24 (Scheme 7)wasexpectedtoleadtoenone25
that we considered could be elaborated to intermediate 8 or its
equivalent by conjugate addition to the enone and ketone reduction.
Adduct 24 was generated cleanly but could not be isolated as a pure
compound owing to its instability on silica or alumina and it was
subsequently taken on crude into the hydrolysis conditions. Hydro-
lysis with dilute hydrochloric acid led to tricycle 27 by intramolecular
furan DielseAlder reaction; the stereochemistrydestablished by the
key NOE correlations showndcorresponds to an exo-DielseAlder
Scheme 8. Reagents: (a) H2, 0.3 mol % Pd/C (5%), EtOAc, 20 ꢀC (66%); (b) ethyl vinyl
ether/t-BuLi, THF, ꢁ78/20 ꢀC (83%); (b0) (/32) ethyl vinyl ether/t-BuLi, THF,
ꢁ78/20 ꢀC then TMSCl, NaI (71%); (c) (/31) TsOH, THF, 20 ꢀC (87%); (d) LDA, THF,
ꢁ78 ꢀC then allyl iodide, ꢁ78/20 ꢀC (33, 58% from 31) or LDA, THF, 0 ꢀC then allyl
bromide, 0/20 ꢀC (34, 75% from 32); (e) methyl acrylate, 5.0 mol % 39, CH2Cl2, 40 ꢀ
C
(35, 87% from 33; 36, 57% from 34); (f) KHMDS, THF, ꢁ78/20 ꢀC (69%, 37 and 38,
dr¼3:4).
In our earlier work34 the oxy-Michael reaction (from 8) was most
reliably achieved under equilibrating conditions with LHMDS in THF
at ꢁ40 ꢀC, generating the tetrahydropyran in 65% yield as a single
diastereomer. These and similar conditions led to recovery of

5014
J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
33
starting material when applied to substrate 35 in which the
CH(OTBS) function was replaced by C]O. The best that could be
achieved was with a slight excess of KHMDS added at ꢁ78 ꢀC and
warming to rt; even then, only a moderate yield of a 3:4 di-
astereomeric mixture of tetrahydropyranones 37 and 38 was
obtained.
Me
OH
Me
OH
a
or
O
O
46
(+)-33
45 or
HO
HO
(+)-45
Me
OH
Me
b
e
d
O
CO2Me
O
O
We next attempted to invert the order of steps: ketone re-
duction then oxy-Michael reaction. Stereoselective reduction of the
ketone in substrate 35 turned out to be non-trivial. The simplest
reagent, NaBH4, led to non-selective reduction (dr¼1.0e1.6:1) and
partial oxy-Michael cyclisation of either hydroxyl group. Tetrame-
thylammonium triacetoxyborohydride was an ineffective reducing
agent for this hindered ketone, and the combination of L-Selectride
and ZnCl2 led to efficient reduction but the initially-formed borate
adduct (40, Scheme 9) could not be decomposed without disrupt-
ing the furan ring. Finally, based on Nakata’s precedent,46 Zn(BH4)2
was found to give a 4.0e5.0:1 ratio of diastereomers in favour of the
desired isomer (41) in acceptable yield in trial reactions. Pre-
dictably, diol mixture 41 and 42 cyclised to give the tetrahydrofu-
rans 43 and 44 under basic and oxidative conditions, respectively,
therefore protection of the 2ꢀ-hydroxyl group was indicated (in 41/
42). Installation of a tert-butyldimethylsilyl group, to give the
methyl ester analogue of desired intermediate 8, was an inefficient
process, with yields never surpassing ca. 30%.
TESO
R
TESO
(+)-49
47a or (+)-47a, R = H
c
48a or (+)-48a, R = CO2Me
Mes
N
N
Mes
Me
Cl
Cl
O
OR1
Ru
52
O
O
R2O
i-Pr
(+)-50, R1 = H, R2 = TES
f
(+)-51, R1 = R2 = H
g
(+)-7, R1 = t-BuPh2Si, R2 = H
Scheme 10. Reagents: (a) Zn(BH4)2, THF, 0 ꢀC (dr¼4:1); (b) TESCl, imidazole, DMF,
20 ꢀC [(þ)-47a, 42% from (þ)-33]; (c) methyl acrylate, 1.0 mol % 52, CH2Cl2, 40 ꢀ
C
[(þ)-48a, 82%]; (d) LHMDS, THF, ꢁ78/ꢁ40 ꢀC [76% based on recovered (þ)-48a]; (e)
DIBAL, THF, 0 ꢀC (quant.); (f) TBAF, THF, 20 ꢀC; (g) t-BuPh2SiCl, imidazole, DMF, 20 ꢀ
C
[76% from (þ)-50]. [Yields for the racemic route appear in the Experimental section.].
a,b-unsaturated substrates. After scoping a few of the alterna-
tives, we soon settled on Feng’s use of sodium phenylglycinate (53)
as a Lewis base additive for asymmetric cyanosilylation47 because
of the ready availability of both enantiomers of the catalyst. Ap-
plication of the reported conditions to ketone 18 with (þ)-53 led,
unsurprisingly, to racemic product (55, Scheme 11); however, with
enone 29, ees up to 90% could be achieved with high isolated yields.
Variability in the ee was attributed to its sensitivity to the levels of
water present in the system; nevertheless, in our hands this pro-
cedure proved sufficiently reliable that the reaction carried out on
a 0.3 mol scale gave the product in 85% ee although the reaction did
not run to completion on this scale.
Me
O
R =
CO2Me
O
a
b
B
s-Bu
O
35
R
40
Me
Me
OH
OH
O
O
HO
R
HO
R
41
42
c
d
Me
OTMS
Me
OTMS
O
Me
OH
a or a
b
29
O
O
O
O
CN
CN
54 or
55 or
O
(–)-54
(–)-55
43
44
O
Me
HO
MeO2C
CO2Me
Me
OH
as refs.
34, 35
as Scheme 10
c
Scheme 9. Reagents: (a) ZnCl2, L-Selectride, CH2Cl2, ꢁ78 ꢀC (65%); (b) Zn(BH4)2, THF,
ꢁ20 ꢀC (53%, 41 and 42, dr¼4:1); (c) LHMDS, THF, ꢁ40/20 ꢀC (64%); (d) MCPBA,
CH2Cl2, 0 ꢀC then 1.0 mol % TPAP, NMO, 20 ꢀC (38%).
(+)-7
O
33 or
O
(+)-33
At this point, we decided to defer the cross metathesis step until
after the hydroxyketone functionality in 33 had been adjusted to
the correct mono-protected diol diastereomer. Rejecting TBS in
favour of the less sterically-demanding TES group improved the
protection step and intermediate 47 (Scheme 10) was obtained,
initially as a 4:1 diastereomeric mixture. Cross metathesis trials
with separated diastereomer 47a showed that switching to the
HoveydaeGrubbs II catalyst 52 allowed the catalyst loading to be
reduced to 1% (from 5% with Grubbs II) and slightly increased the
yield. The product 48a was taken through our reported oxy-
Michael cyclisation, desilylation and ester reduction steps to pro-
vide known intermediate 7 whose spectroscopic data correlated
with enantiomerically enriched material,34 thus confirming the
sense of diastereoselective reduction in keto-alcohol 33.
These studies had mapped out a reproducible route for the
production of racemic 7 via 33 but the prospects appeared limited
for modifying the organometallic addition step in order to yield
enantiomerically enriched keto-alcohol 31. However, the asym-
metric addition of cyanide to methyl ketones is reasonably
well-established, particularly for electronically-differentiated
Me
O
Me
OTMS
Me
OSi(t-Bu)Ph2
O
O
O
H
NH2
56
(+)-5
O
Scheme 11. Reagents: (a) TMSCN, K2CO3, DMF, 20 ꢀ
C
(98%); (a0) TMSCN, (ꢁ)-53,
CF3CH2OH, THF, ꢁ20 ꢀC (43%); (b) H2, 0.3 mol % Pd/C (5%), EtOAc, 20 ꢀC [55, 96%;
(ꢁ)-55, 93%, ee¼85%]; (c) 4-butenyllithium, THF, ꢁ78/20 ꢀC [33, 64%; (þ)-33, 44%].
Following uneventful hydrogenation [/(ꢁ)-55] the route con-
nected with the earlier route at ketone 33 by addition of 3-bute-
nyllithium, which was reasonably efficient when only a slight
excess (1.3e1.5 equiv) of organolithium was employed. In the ra-
cemic series we had noted that addition of a threefold excess, or
more, of the organometallic resulted in double addition to produce
amine 56. Completion of the route to intermediate (þ)-7 on large
scale was marred only by the oxy-Michael reaction that gave a ca.
50% conversion to the tetrahydropyran, the rest being starting
material. Following our previous work, the second tetrahydropyran

J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
5015
ring was formed by oxidative spirocyclisation to give 3.7 g of tri-
110.1 (CH, A and B), 126.5 and 126.9 (CH, A and B), 140.9 and 140.1
(CH, A and B), 145.3 and 146.4 (CH, A and B), 155.1 and 155.4 (C, A
and B), 198.5 and 198.7 (C, A and B); HRMS (ESIþ) found 245.0787,
C12H14NaO4 (MNaþ) requires 245.0784.
cycle (þ)-634 and then 1.5 g of (þ)-5.35
3. Conclusion
Our whole lituarine programme, now running for almost a de-
cade, has been hampered by difficulties in scaling to gram quanti-
ties reactions that worked efficiently on multi-milligram scale. The
route summarised in Schemes 10 and 11, above, satisfied our im-
mediate needs, with the low-yielding steps [29/(ꢁ)-54,
(ꢁ)-55/(þ)-33 and (þ)-48a/(þ)-49] returning mostly unreacted
starting materials to account for the mass balance in each case.
However, Smith’s report, during the course of this work,3 that the
structures of the lituarines are incorrectly assigned, adds to the list
of ‘molecules that were never there’48 and a re-evaluation of the
original structural data needs to be undertaken before further ef-
forts are expended on this endeavour.
4.3. 6-[2-(Furan-2-yl)ethyl]-6-methyl-2H-pyran-2,5(6H)-
dione (21)
To a stirred solution of pyranone 20 (0.58 g, 2.61 mmol) in
dichloromethane (20 mL) was added NMO (1.07 g, 9.11 mmol) and,
after stirring for 10 min, TPAP (93 mg, 0.26 mmol) was added and
the mixture stirred for 3 h. The reaction mixture was passed
through a short plug of silica and the filtrate concentrated in vacuo.
Flash chromatography (petrol/ether, 1:1) afforded the title com-
pound (21) as a pale yellow oil (0.33 g, 57%). Rf 0.28 (petrol/ether
1:1); nmax (thin film)/cmꢁ1 3119m, 2981s, 2934s, 1694s, 1622s,
1598s, 1508s, 1450s, 1375s, 1292s, 1011s; dH (400 MHz, CDCl3) 1.61
(3H, s, CH3), 2.13e2.20 (1H, m) and 2.43e2.49 (1H, m, CH2C(CH3)),
2.63e2.80 (2H, m, FuCH2), 5.96 (1H, dd, J 3.0, 1.0 Hz, Fu(H-3)), 6.24
(1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 6.65 (1H, d, J 10.0 Hz, ]CHCO), 6.87
(1H, d, J 10.0 Hz, CH]CHCO), 7.29 (1H, dd, J 2.0. 1.0 Hz, Fu(H-5)); dC
(125 MHz, CDCl3) 22.9 (CH2), 26.3 (CH3), 37.9 (CH2), 89.1 (C), 106.1
(CH), 110.1 (CH), 135.1 (CH), 137.2 (CH), 141.3 (CH), 153.4 (C), 160.4
(C), 195.3 (C); HRMS (CI, NH3) found 221.0817, C12H13O4 (MHþ)
requires 221.0808. Also obtained as a side-product in the prepara-
tion of 20.
4. Experimental section
4.1. 2,4-Di(furan-2-yl)butan-2-ol (17)
To a stirred solution of furan (0.3 mL, 3.98 mmol) in THF (2.5 mL)
at 0 ꢀC was added TMEDA (0.6 mL, 3.98 mmol) followed by butyl-
lithium (2.5 mL, 1.6 M solution in hexanes, 4.0 mmol). After stirring
for 0.5 h, ketone 1837 (0.50 g, 3.62 mmol) was added and the so-
lution stirred for 2 h. The reaction was quenched with water
(50 mL) and the aqueous phase was extracted with ether
(2ꢂ50 mL). The combined organic phases were washed with satd
aq NaHCO3 (2ꢂ50 mL), dried (MgSO4) and concentrated in vacuo.
Flash chromatography (petrol/ether, 5:1) afforded the title com-
pound (17) as a pale yellow oil (0.57 g, 77%). Rf 0.21 (petrol/ether,
5:1); nmax (thin film)/cmꢁ1 3416br, 2980m, 1597m, 1507m, 1451m,
1372m, 1149m, 1071m, 1010m; dH (400 MHz, CDCl3) 1.59 (3H, s,
CH3), 2.04 (1H, s, OH), 2.18e2.23 (2H, m, CH2C(OH)), 2.61e2.65 (2H,
m, FuCH2), 5.98 (1H, dd, J 3.0, 1.0 Hz, Fu(H-3)), 6.24 (1H, dd, J 3.0,
1.0 Hz, Fu’(H-3)), 6.27 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 6.33 (1H, dd, J
3.0, 2.0 Hz, Fu’(H-4)), 7.30 (1H, dd, J 2.0, 1.0 Hz, Fu(H-5)), 7.37 (1H,
dd, J 2.0, 1.0 Hz, Fu’(H-5)); dC (100 MHz, CDCl3) 23.0 (CH2), 26.7
(CH3), 39.6 (CH2), 71.3 (C), 104.7 (2ꢂ CH), 110.1 (2ꢂ CH), 140.9 (CH),
141.7 (CH), 155.6 (C), 159.0 (C); HRMS (ESIþ) found 229.0838,
C12H14NaO3 (MNaþ) requires 229.0835.
4.4. 2-{5-[(tert-Butyldimethylsilyloxy)methyl]furan-2-yl}-4-
(furan-2-yl)butan-2-ol (22)
To a stirred solution of 2-[(tert-butyldimethylsilyloxy)methyl]
furan42 (1.0 g, 4.71 mmol) in THF (10 mL) at ꢁ78 ꢀC was added
butyllithium (3.2 mL, 1.6 M solution in hexanes, 5.12 mmol) drop-
wise and the mixture stirred for 1.5 h. The solution was then
warmed to 0 ꢀC, stirred for 0.5 h and re-cooled to ꢁ78 ꢀC. Ketone
1837 (0.59 g, 4.28 mmol) was added dropwise and the mixture
stirred for 1.5 h at ꢁ78 ꢀC and 0.5 h at rt. Water (30 mL) and ether
(20 mL) were added; the aqueous phase was extracted with ether
(2ꢂ20 mL) and the combined organic portions washed successively
with water (2ꢂ20 mL) and brine (20 mL). The solution was dried
(MgSO4) and concentrated in vacuo. Flash chromatography (petrol/
ether, 8:1) afforded the title compound (22) as a pale yellow oil
(0.84 g, 56%). Rf 0.18 (petrol/ether, 4:1); nmax (thin film)/cmꢁ1
3423br, 2930m, 2858m, 1256m, 1077m, 1009m; dH (400 MHz,
CDCl3) 0.09 (6H, s, Si(CH3)2), 0.91 (9H, s, C(CH3)3), 1.58 (3H, s,
CH3C(OH)), 2.10 (1H, br s, OH), 2.17e2.22 (2H, m, CH2C(OH)),
2.62e2.66 (2H, m, FuCH2), 4.62 (2H, s, FuCH2OTBS), 5.96e5.97 (1H,
m, Fu(H-3)), 6.17 (2H, s, Fu0(H-3) and Fu0(H-4)), 6.27 (1H, dd, J 3.0,
2.0 Hz, Fu(H-4)), 7.29e7.30 (1H, m, Fu(H-5)); dC (100 MHz, CDCl3)
e5.2 (2ꢂ CH3), 18.4 (C), 23.0 (CH2), 25.8 (3ꢂ CH3), 26.7 (CH3), 39.5
(CH2), 58.2 (CH2), 71.3 (C), 104.6 (CH), 105.3 (CH), 107.8 (CH), 110.1
(CH), 140.8 (CH), 153.4 (C), 155.7 (C), 158.6 (C); HRMS (ESIþ) found
373.1806, C19H30NaO4Si [M (28Si)Naþ] requires 373.1806.
4.2. 2-[2-(Furan-2-yl)ethyl]-6-hydroxy-2-methyl-2H-pyran-
3(6H)-one (20)
To a stirred solution of difuran 17 (1.0 g, 4.85 mmol) in
dichloromethane (20 mL) was added tert-butylhydroperoxide
(1.0 mL, ca. 5.5 M in decane, ca. 5.50 mmol) and VO(acac)2 (3.0 mg,
11.3 mmol). After 2 h the reaction mixture was poured into water
(50 mL) and the aqueous phase extracted with dichloromethane
(3ꢂ50 mL). The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Flash chromatography (petrol/ether, 2:1)
afforded the title compound (20) as a pale yellow oil and as a 1:1
mixture of inseparable diastereomers (A and B; 0.59 g, 55%). Rf 0.09
(petrol/ether, 2:1); nmax (thin film)/cmꢁ1 3417br, 2934m, 1687s,
1598m, 1509m, 1448s, 1376m, 1261m, 1148s; dH (400 MHz, CDCl3)
1.39 (3H, s, CH3, A), 1.51 (3H, s, CH3, B), 1.87e2.03 (2H, m) and
2.19e2.37 (2H, m, CH2C(CH3), A and B), 2.58e2.82 (4H, m, FuCH2, A
and B), 3.78 (2H, br s, OH, A and B), 5.71e5.72 (2H, m, CHOH, A and
B), 5.96 (2H, dd, J 3.0, 1.0 Hz, Fu(H-3), A and B), 6.06e6.09 (2H, m, ]
CHCO, A and B), 6.24e6.26 (2H, m, Fu(H-4), A and B), 6.87 (1H, dd J
4.0, 2.5 Hz, CH]CHCO, B), 6.89 (1H, dd, J 4.0, 2.5 Hz, CH]CHCO, A),
7.27e7.28 (2H, m, Fu(H-5), A and B); dC (100 MHz, CDCl3) 21.6 (CH3,
A), 22.0 and 22.2 (CH2, A and B), 25.5 (CH3, B), 35.8 (CH2, B), 36.8
(CH2, A), 81.1 (C, A and B), 87.7 (CH, A and B), 105.0 (CH, A and B),
4.5. 6-(tert-Butyldimethylsilyloxy)methyl-2-[2-(furan-2-yl)
ethyl]-6-hydroxy-2-methyl-2H-pyran-3(6H)-one (23)
To a stirred solution of difuran 22 (0.84 g, 2.40 mmol) in
dichloromethane (10 mL) was added tert-butylhydroperoxide
(0.50 mL, ca. 5.5 M in decane, ca. 2.75 mmol) and VO(acac)2 (1.5 mg,
5.66 mmol). After 3 h the reaction mixture was poured into water
(10 mL), the aqueous phase was extracted with dichloromethane
(3ꢂ20 mL) and the combined organic phases were dried (MgSO4)
and concentrated in vacuo. Flash chromatography (petrol/ether,
3:1) afforded the title compound (23) as a colourless oil and as a 3:1
ratio of diastereomers (0.70 g, 80%). Data for major diastereomer: Rf

5016
J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
0.20 (petrol/ether, 3:1); nmax (thin film)/cmꢁ1 3424br, 2931m,
2858m, 1689m, 1111m, 838m; dH (400 MHz, CDCl3) 0.11e0.14 (6H,
m, Si(CH3)2), 0.93 (9H, s, C(CH3)3), 1.35 (3H, s, CH3C(OR)), 1.90e2.04
and 2.22e2.30 (2ꢂ 1H, 2ꢂ m, CH2C(CH3)), 2.36e2.55 and 2.66e2.93
(2ꢂ 1H, 2ꢂ m, FuCH2), 3.61e3.71 (2H, m, CH2OSi), 5.94 (1H, d, J
3.0 Hz, Fu(H-3)), 6.09 (1H, d, J 10.0 Hz, ]CHCO), 6.24e6.26 (1H, m,
Fu(H-4)), 6.80 (1H, d, J 10.0 Hz, CH]CHCO), 7.27e7.28 (1H, m, Fu(H-
5)); dC (100 MHz, CDCl3) ꢁ5.4 (2ꢂ CH3), 18.3 (C), 22.3 (CH2), 25.8
(3ꢂ CH3), 27.3 (CH3), 37.8 (CH2), 69.2 (CH2), 80.8 (C), 92.1 (C), 104.7
(CH), 110.1 (CH), 126.6 (CH), 140.8 (CH), 145.1 (CH), 155.6 (C), 199.0
(C); HRMS (ESIþ) found 389.1751, C19H30NaO5Si [M (28Si)Naþ] re-
quires 389.1755. Data for minor diastereomer: Rf 0.31 (petrol/ether,
3:1); nmax (thin film)/cmꢁ1 3424br, 2931m, 2858m, 1689m, 1111m,
838m; dH (400 MHz, CDCl3) 0.12 and 0.13 (2ꢂ 3H, 2ꢂ s, Si(CH3)2),
0.93 (9H, s, C(CH3)3), 1.36 (3H, s, CH3C(OR)), 1.96e2.04 and
2.37e2.44 (2ꢂ 1H, 2ꢂ m, CH2C(CH3)), 2.67e2.75 and 2.85e2.93 (2ꢂ
1H, 2ꢂ m, FuCH2), 3.62 and 3.68 (2ꢂ 1H, 2ꢂ d, J 10 Hz, CH2OSi), 3.82
(1H, s, OH), 5.97e5.98 (1H, m, Fu(H-3)), 6.09 (1H, d, J 10.0 Hz, ]
CHCO), 6.26e6.27 (1H, m, Fu(H-4)), 6.78 (1H, d, J 10.0 Hz, CH]
CHCO), 7.28e7.30 (1H, m, Fu(H-5)); dC (100 MHz, CDCl3) ꢁ5.4 (2ꢂ
CH3), 18.3 (C), 21.7 (CH2), 22.2 (CH3), 25.8 (3ꢂ CH3), 37.1 (CH2), 69.4
(CH2), 80.8 (C), 92.1 (C), 104.7 (CH), 110.1 (CH), 126.0 (CH), 140.8
(CH), 144.9 (CH), 155.6 (C), 199.0 (C); HRMS (ESIþ) found 389.1751,
C19H30NaO5Si [M (28Si)Naþ] requires 389.1755.
(1.0 mL) and extracted with ethyl acetate (3ꢂ5.0 mL). The combined
organic extracts were concentrated in vacuo and the residues dis-
solved inTHF (3.0 mL), cooledto0 ꢀC andhydrochloric acid(0.72 mL,
1.0 M, 0.72 mmol) was added with stirring. After 45 min NaHCO3
(0.06 g, 0.72 mmol) was added and the separated aqueous phase
extracted with ethyl acetate (3ꢂ5.0 mL). The organic extracts were
combined, dried (MgSO4) and concentrated in vacuo. Flash chro-
matography (petrol/ether, 2:1) afforded a single diastereomer of the
title compound (27) as a waxy white solid (0.12 g, 86%). Rf 0.11
(petrol/ether, 1:1); mp 74e79 ꢀC; nmax (KBr disc)/cmꢁ1 3450br,
2985m, 2954s, 1710s, 1455m, 1434m, 1367s, 1266s, 1181m, 1170m,
1151s, 1135s, 1087s, 1031s; dH (400 MHz, CDCl3) 1.12 (1H, dd, J 11.5,
8.0 Hz, C(7)HH0),1.24 (3H, s, CH3),1.85e1.95 (2H, m, C(3)HH0 and C(2)
HH0), 2.05 (1H, dd, J 8.0, 3.0 Hz, C(6)H), 2.11e2.23 (2H, m, C(3)HH0
and C(2)HH0), 2.78 (1H, ddd, J 11.5, 4.5, 3.0 Hz, C(7)HH0), 4.33 (1H, s,
OH), 4.58 (1H, d, J 4.5 Hz, C(8)H), 5.64 (1H, d, J 5.5 Hz, C(10)H), 5.96
(1H, d, J 5.5 Hz, C(9)H); dC (100 MHz, CDCl3) 24.1 (CH3), 25.7 (CH2),
29.4 (CH2), 36.9 (CH2), 47.3 (CH), 76.2 (C), 78.0 (CH), 91.1 (C), 136.8
(CH),138.6 (CH), 211.7 (C); HRMS (ESIþ) found 217.0836, C11H14NaO3
(MNaþ) requires 217.0835.
4.8. 1-(Furan-2-yl)-4,4-dimethoxy-3-methylhex-5-en-3-ol (28)
To a stirred solution of 1-methoxypropa-1,2-diene49 (0.15 g,
2.14 mmol) in THF (1.5 mL) at ꢁ78 ꢀC was added butyllithium
(0.91 mL, 1.6 M solution in hexanes, 1.46 mmol). After 0.5 h the
solution was warmed to 0 ꢀC, stirred for 0.5 h and cooled to ꢁ78 ꢀC;
a solution of ketone 1837 (0.10 g, 0.72 mmol) in THF (3 mL) was then
added. After 3 h the reaction was quenched with satd aq NH4Cl
(1.0 mL) and extracted with ethyl acetate (3ꢂ5 mL). The combined
organic extracts were concentrated in vacuo and the residue dis-
solved in methanol (2.0 mL), cooled to 0 ꢀC and camphorsulfonic
4.6. 2-Hydroxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one
(26)44
To a stirred solution of 1-methoxypropa-1,2-diene49 (0.15 g,
2.14 mmol) in THF (1.0 mL) at ꢁ78 ꢀC was added butyllithium
(0.91 mL, 1.6 M solution in hexanes, 1.46 mmol). After 0.5 h the so-
lution was warmed to 0 ꢀC, stirred for 0.5 h and cooled to ꢁ78 ꢀC;y
a solution of ketone 1837 (0.10 g, 0.72 mmol) in THF (0.5 mL) was
then added. After 3 h the reaction was quenched with satd aq NH4Cl
(1.0 mL) and extracted with dichloromethane (3ꢂ5.0 mL). The
combined organic extracts were concentrated in vacuo, the residue
dissolved in dichloromethane (3.0 mL), cooled to 0 ꢀC and hydro-
chloric acid (5.0 mL, 5.0 M) was added with stirring. After 15 min
solid NaHCO3 was added until gas evolution ceased, the aqueous
phase was separated and extracted with ethyl acetate (3ꢂ5.0 mL).
The organic extracts were combined, dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (petrol/ether, 1:1) afforded
the title compound (26) as a pale yellow oil (49.2 mg, 39%). Rf 0.26
(petrol/ether, 1:1); dH (400 MHz, CDCl3) 1.40 (3H, s, CH3), 2.17e2.30
(2H, m, C(3)H2), 2.98e3.16 (2H, m, C(4)H2), 3.85 (1H, br s, OH), 7.26
(1H, d, J 8.0 Hz, C(6)H), 7.34 (1H, app. t, J 7.5 Hz, C(8)H), 7.52 (1H, app.
t, J 7.5 Hz, C(7)H), 8.03 (1H, d, J 8.0 Hz, C(9)H); dC (100 MHz, CDCl3)
23.9 (CH3), 26.8 (CH2), 35.9 (CH2), 73.6 (C), 126.9 (CH), 128.0 (CH),
129.0 (CH), 129.9 (C), 134.1 (CH), 143.4 (C), 201.8 (C).
acid (1.6 mg, 6.9 mmol) was added to the stirred solution. The
mixture was allowed to warm to rt over 5 h and the solvent was
removed in vacuo. Flash chromatography on basic alumina (petrol/
ether, 5:1) afforded the title compound (28) as a colourless oil
(0.10 g, 58%). Rf 0.50 (petrol/ether, 1:1); nmax (thin film)/cmꢁ1
3553br, 2945s, 2836m, 1508m, 1453m, 1406m, 1370m, 1180s, 1148s,
1092s, 1064s, 1009s; dH (400 MHz, CDCl3) 1.26 (3H, s, C(3)CH3), 1.90
(1H, ddd, J 13.5, 12.5, 5.0 Hz) and 2.23 (1H, app. td, J 13.0, 4.5 Hz,
C(2)H2), 2.38 (1H, br s, OH), 2.85 (1H, ddd, J 15.5, 12.5, 5.0 Hz) and
3.10e3.19 (1H, m, C(1)H2), 3.20 and 3.26 (2ꢂ 3H, 2ꢂ s, 2ꢂ OCH3),
5.23 (1H, dd, J 10.5, 2.5 Hz, C(6)HH0), 5.57 (1H, dd, J 17.0, 10.5 Hz,
C(5)H), 5.67 (1H, dd, J 17.0, 2.5 Hz, C(6)HH0), 6.02 (1H, dd, J 3.0,
0.5 Hz, Fu(H-3)), 6.23 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 7.25 (1H, dd, J
2.0, 0.5 Hz, Fu(H-5)); dC (100 MHz, CDCl3) 21.7 (CH3), 22.5 (CH2),
36.2 (CH2), 50.7 and 50.8 (2ꢂ CH3), 77.6 (C), 102.6 (C), 104.9 (CH),
110.4 (CH), 120.1 (CH2), 136.2 (CH), 141.0 (CH), 157.2 (C); HRMS
(ESIþ) found 263.1252, C13H20NaO4 (MNaþ) requires 263.1254.
4.9. 2-Ethoxy-5-(furan-2-yl)-3-methylpent-1-en-3-ol (30)
4.7. (1R
*
,4R
*
,6S
*
,8R )-4-Hydroxy-4-methyl-11-oxatricyclo
*
[6.2.1.01,6]undec-9-en-5-one (27)
To a stirred solution of ethyl vinyl ether (2.08 mL, 21.7 mmol) in
THF (6.0 mL) at ꢁ78 ꢀC was added tert-butyllithium (10.2 mL, 1.7 M
solution in pentane,17.3 mmol). The resulting solution was warmed
to 0 ꢀC for 15 min then re-cooled to ꢁ78 ꢀC and a solution of ketone
1837 (0.60 g, 4.34 mmol) in THF (3.0 mL) added dropwise. After
0.5 h the reaction mixture was allowed to warm to rt over 1 h and
quenched with satd aq NH4Cl (5.0 mL) then extracted with ethyl
acetate (3ꢂ15 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography on basic
alumina (petrol/ether, 2:1) afforded the title compound (30) as
a pale yellow oil (0.76 g, 83%). Rf 0.44 (petrol/ether, 1:1); nmax (thin
film)/cmꢁ1 3476br, 2978s, 2932s, 1710s, 1621m, 1508s, 1448s, 1361s,
1237m, 1148s, 1113s, 1071s, 1009m; dH (400 MHz, CDCl3) 1.31 (3H, t,
J 7.0 Hz, OCH2CH3), 1.38 (3H, s, C(3)CH3), 1.89e2.07 (2H, m, C(4)H2),
To a stirred solution of 1-methoxypropa-1,2-diene49 (0.15 g,
2.14 mmol) in THF (1.5 mL) at ꢁ78 ꢀC was added butyllithium
(0.91 mL, 1.6 M solution in hexanes, 1.46 mmol). After 0.5 h the so-
lution was warmed to 0 ꢀC, stirred for 0.5 h and cooled to ꢁ78 ꢀC;
a solution of ketone 1837 (0.10 g, 0.72 mmol) in THF (3.0 mL) was
then added. After 3 h the reaction was quenched with satd aq NH4Cl
y
Quenching at this point allows the allene adduct 24 to be observed. NMR data
for 1-(furan-2-yl)-4-methoxyhexa-4,5-dien-3-ol dH (200 MHz, CDCl3) 1.36 (3H, s,
C(3)(CH3)), 1.95e2.05 (2H, m, C(2)H2), 2.26 (1H, br s, OH), 2.62e2.73 (2H, m, C(1)
H2), 3.45 (3H, s, OCH3), 5.61 (2H, s, C(6)H2), 5.98 (1H, dq, J 3.0, 1.0 Hz, Fu(H-3)), 6.27
(1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 7.30 (1H, dd, J 2.0, 1.0 Hz, Fu(H-5)).

J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
5017
2.30 (1H, br s, OH), 2.58e2.72 (2H, m, C(5)H2), 3.75 (2H, q, J 7.0 Hz,
OCH2), 3.99 and 4.24 (2ꢂ 1H, 2ꢂ d, J 2.5 Hz, C(1)H2), 5.97e5.99 (1H,
m, Fu(H-3)), 6.26e6.28 (1H, m, Fu(H-4)), 7.29e7.30 (1H, m, Fu(H-
5)); dC (100 MHz, CDCl3) 14.4 (CH3), 22.9 (CH2), 26.6 (CH3), 38.6
(CH2), 63.1 (CH2), 73.6 (C), 79.7 (CH2), 104.5 (CH), 110.1 (CH), 140.7
(CH), 156.3 (C), 165.7 (C); HRMS (CI, NH3) found 228.1601,
aqueous phase was separated and washed with ether (3ꢂ5.0 mL).
The organic extracts were combined, dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (petrol/ether, 5:1) afforded
the title compound (33) as a colourless oil (80.7 mg, 58%) along with
a little dialkylated product (11.1 mg, 7%). See below for data.
From 55: To a stirred solution of 4-iodobut-1-ene (1.00 g,
5.49 mmol) in ether (13 mL) at ꢁ78 ꢀC was added tert-butyllithium
(6.45 mL, 1.7 M solution in pentane, 11.0 mmol) and stirring con-
tinued for 1 h at ꢁ78 ꢀC and 1 h at rt. The mixture was re-cooled to
ꢁ78 ꢀC and a solution of nitrile 55 (1.00 g, 4.21 mmol) in ether
(10 mL) was added via cannula. The reaction mixture was allowed to
warm to rt over 16 h, diluted with ether (10 mL) and quenched by
stirring with satd aq NH4Cl (25 mL) for 0.5 h. The phases were sep-
arated, the aqueous phase extracted with ether (3ꢂ10 mL) and the
combined organic phases were dried (MgSO4) and concentrated in
vacuo. Flash chromatography (petrol/ether, 5:1/1:1) afforded the
title compound (33) as a yellow oil (0.60 g, 64%). Rf 0.47 (petrol/ether,
1:1); nmax (thin film)/cmꢁ1 3456br, 2958m, 2926m, 1707s, 1642m,
1454m, 1370m, 1250m, 1148m, 1111m, 1069m, 1009s; dH (400 MHz,
CDCl3) 1.39 (3H, s, C(3)CH3), 2.00e2.14 (2H, m, C(2)H2), 2.27e2.40
(2H, m, C(6)H2), 2.41e2.54 (2H, m, C(1)HH0 and C(5)HH0), 2.64 (1H,
ddd, J 17.0, 8.5, 6.5 Hz, C(5)HH0), 2.76 (1H, ddd, J 15.5, 9.5, 6.0 Hz, C(1)
HH0), 3.97 (1H, s, OH), 5.01 (1H, ddt, J 10.0, 2.0, 1.0 Hz) and 5.06 (1H,
app. dq, J 17.0, 2.0 Hz, C(8)H2), 5.79 (1H, ddt, J 17.0,10.0, 6.5 Hz, C(7)H),
5.96 (1H, dd, J 3.0,1.0 Hz, Fu(H-3)), 6.27 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)),
7.29 (1H, dd, J 2.0, 1.0 Hz, Fu(H-5)); dC (100 MHz, CDCl3) 22.2 (CH2),
25.7 (CH3), 27.5 (CH2), 34.9 (CH2), 37.6 (CH2), 78.1 (C),105.4 (CH),110.2
(CH), 115.8 (CH2), 136.7 (CH), 141.0 (CH), 154.8 (C), 213.2 (C); HRMS
(ESIþ) found 245.1157, C13H18NaO3 (MNaþ) requires 245.1148.
C12H22NO3 (MNH4þ) requires 228.1594.
4.10. 5-(Furan-2-yl)-3-hydroxy-3-methylpentan-2-one (31)
To a stirred solution of enol ether 30 (68.0 mg, 0.32 mmol) in
THF (0.7 mL) at rt was added p-toluenesulfonic acid monohydrate
(61.6 mg, 0.32 mmol). After 5 min the reaction was partitioned
between water (1.0 mL) and ether (1.0 mL); the aqueous phase was
extracted with ether (3ꢂ1.0 mL) and the combined extracts were
dried (MgSO4) and concentrated in vacuo. Flash chromatography
(petrol/ether, 3:1) afforded the title compound (31) as a yellow oil
(50.7 mg, 87%). Rf 0.24 (petrol/ether, 1:1); nmax (thin film)/cmꢁ1
3474br, 2976s, 2930s, 1709s, 1598m, 1508s, 1455s, 1359s, 1169s,
1109s, 1072m, 1009s; dH (400 MHz, CDCl3) 1.39 (3H, s, C(3)CH3),
2.01e2.14 (2H, m, C(4)H2), 2.16 (3H, s, C(1)H3), 2.42e2.52 (1H, m)
and 2.77 (1H, ddd, J 15.5, 9.5, 6.0 Hz, C(5)H2), 3.97 (1H, s, OH),
5.95e5.97 (1H, m, Fu(H-3)), 6.26e6.28 (1H, m, Fu(H-4)), 7.29e7.30
(1H, m, Fu(H-5)); dC (100 MHz, CDCl3) 22.2 (CH2), 23.3 (CH3), 25.6
(CH3), 37.4 (CH2), 78.2 (C), 105.6 (CH), 110.3 (CH), 141.0 (CH), 154.8
(C), 211.8 (C); HRMS (CI, NH3) found 183.1029, C10H15O3 (MHþ)
requires 183.1016.
4.11. 5-(Furan-2-yl)-3-methyl-3-(trimethylsilyloxy)pentan-2-
one (32)
4.13. (S)-1-(Furan-2-yl)-3-hydroxy-3-methyloct-7-en-4-one
[(D)-33]
To a stirred solution of ethyl vinyl ether (0.35 mL, 3.62 mmol) in
THF (1.0 mL) at ꢁ78 ꢀC was added tert-butyllithium (1.71 mL, 1.7 M
solution in pentane, 2.91 mmol). The resulting solution was
warmed to 0 ꢀC for 15 min then re-cooled to ꢁ78 ꢀC and a solution
of ketone 1837 (0.10 g, 0.72 mmol) in THF (0.5 mL) added dropwise.
After 0.5 h at ꢁ78 ꢀC the reaction mixture was allowed to warm to
rt over 1.5 h and chlorotrimethylsilane (0.37 mL, 2.90 mmol) and
NaI (0.43 g, 2.87 mmol) were added causing a white precipitate to
form immediately. After stirring for 5 min the reaction mixture was
diluted with water (3.0 mL) and extracted with ether (3ꢂ5.0 mL).
The organic extracts were combined, dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (petrol/ether, 20:1) afforded
the title compound (32) as a colourless oil (0.13 g, 71%). Rf 0.54
(petrol/ether, 5:1); nmax (thin film)/cmꢁ1 2958br, 1720s, 1508m,
1453m, 1418m, 1371m, 1353s, 1192s, 1147m, 1120s, 1012s; dH
(400 MHz, CDCl3) 0.19 (9H, s, Si(CH3)3), 1.38 (3H, s, C(3)CH3), 1.84
(1H, ddd, J 13.5, 12.0, 4.0 Hz) and 2.14 (1H, ddd, J 13.5, 11.5, 5.5 Hz,
C(4)H2), 2.21 (3H, s, C(1)H3), 2.51 (1H, ddd, J 16.0, 12.0, 5.5 Hz) and
2.69 (1H, ddd, J 16.0, 11.5, 4.0 Hz, C(5)H2), 5.96 (1H, dd, J 3.0, 1.0 Hz,
Fu(H-3)), 6.27 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 7.30 (1H, dd, J 2.0,
1.0 Hz, Fu(H-5)); dC (125 MHz, CDCl3) 2.3 (3ꢂ CH3), 22.6 (CH2), 25.4
(CH3), 25.5 (CH3), 38.7 (CH2), 82.2 (C), 104.8 (CH), 110.1 (CH), 140.9
(CH), 155.4 (C), 213.7 (C); HRMS (CI, NH3) found 255.1407,
C13H23O3Si [M (28Si)Hþ] requires 255.1411.
Applying the above procedure from 55 to (ꢁ)-55 (24.4 g,
0.103 mol) afforded the title compound (þ)-33 (9.94 g, 44%). Data as
above. ½a 2D6
þ18.8 (c 1.76, CHCl3).
ꢃ
4.14. 1-(Furan-2-yl)-3-methyl-3-(trimethylsilyloxy)oct-7-en-
4-one (34)
To a stirred solution of diisopropylamine (0.03 mL, 0.24 mmol)
in THF (0.2 mL) at 0 ꢀC was added dropwise butyllithium (0.14 mL,
1.6 M solution in hexanes, 0.22 mmol). After 0.5 h a solution of
ketone 32 (50.0 mg, 0.20 mmol) in THF (0.5 mL) was added drop-
wise and stirring continued at 0 ꢀC for a further 0.5 h. Allyl bromide
(0.02 mL, 0.22 mmol) was added then the reaction mixture was
allowed to warm to rt over 16 h and partitioned between ether
(2.0 mL) and brine (2.0 mL). The separated organic phase was
shaken for 5 min with a buffered acetic acid solution (1.0 mL of
a solution made from 15 g anhydrous NaOAc in 50 mL acetic acid
and 50 mL water) then washed repeatedly with satd aq NaHCO3
until the washings were basic. The solution was then dried (MgSO4)
and concentrated in vacuo. Flash chromatography (petrol/ether,
40:1) afforded the title compound (34) as a colourless oil (43.9 mg,
75%). Rf 0.63 (petrol/ether, 5:1); nmax (thin film)/cmꢁ1 2958br,
2857m, 1719s, 1642m, 1452m, 1417m, 1372m, 1353m, 1252s, 1191m,
1147m, 1119s, 1077s, 1041m, 1009s; dH (400 MHz, CDCl3) 0.20 (9H, s,
Si(CH3)3), 1.37 (3H, s, C(3)CH3), 1.83 (1H, ddd, J 13.5, 12.0, 4.5 Hz)
and 2.17 (1H, ddd, J 13.5, 12.0, 5.5 Hz, C(2)H2), 2.25e2.32 (2H, m,
C(6)H2), 2.46 (1H, ddd, J 15.5, 12.0, 5.5 Hz, C(1)HH0), 2.64e2.74 (3H,
m, C(1)HH0 and C(5)H2), 4.98 (1H, app. ddt, J 10.0, 2.0, 1.0 Hz) and
5.05 (1H, app. dq, J 17.0, 1.5 Hz, C(8)H2), 5.83 (1H, ddt, J 17.0, 10.0,
7.0 Hz, C(7)H), 5.95 (1H, dd, J 3.0, 1.0 Hz, Fu(H-3)), 6.26 (1H, dd, J 3.0,
2.0 Hz, Fu(H-4)), 7.29 (1H, dd, J 2.0, 1.0 Hz, Fu(H-5)); dC (100 MHz,
CDCl3) 2.3 (3ꢂ CH3), 22.7 (CH2), 26.0 (CH3), 27.6 (CH2), 36.7 (CH2),
38.9 (CH2), 82.4 (C), 104.8 (CH), 110.1 (CH), 115.0 (CH2), 137.6 (CH),
4.12. 1-(Furan-2-yl)-3-hydroxy-3-methyloct-7-en-4-one (33)
From 31: To a stirred solution of diisopropylamine (0.36 mL,
2.60 mmol) in THF (2.0 mL) at ꢁ78 ꢀC was added dropwise butyl-
lithium (1.58 mL, 1.6 M solution in hexanes, 2.53 mmol). After
stirring for 1 h at ꢁ78 ꢀC a solution of ketone 31 (0.12 g, 0.63 mmol)
in THF (0.8 mL) was added via cannula and stirring continued for
1 h, whereupon allyl iodide (0.23 mL, 2.53 mmol) was added. The
reaction mixture was allowed to warm to rt over 17 h then diluted
with ether (5.0 mL) and quenched with satd aq NH4Cl (8.0 mL). The

5018
J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
140.9 (CH), 155.4 (C), 214.7 (C); HRMS (CI, NH3) found 295.1729,
C16H27O3Si [M (28Si)Hþ] requires 295.1724.
(1H, ddd, J 13.5, 10.5, 6.5 Hz) and 2.09 (1H, dddd, J 13.5, 6.5, 4.0,
3.0 Hz, CH2CH2CO), 2.19 (1H, ddd, J 13.5, 11.0, 5.5 Hz, CHH0C(CH3)),
2.45e2.66 (5H, m, CH2CO and CH2CO2 and FuCHH0), 2.75 (1H, ddd, J
15.5, 11.0, 5.0 Hz, FuCHH0), 3.73 (3H, s, OCH3), 4.37 (1H, dddd, J 10.5,
8.0, 5.5, 3.0 Hz, CH(OR)), 5.97 (1H, d, J 3.0 Hz, Fu(H-3)), 6.26 (1H, dd, J
3.0, 2.0 Hz, Fu(H-4)), 7.29 (1H, d, J 2.0 Hz, Fu(H-5)); dC (125 MHz,
CDCl3) 21.6 (CH3), 22.1 (CH2), 30.3 (CH2), 35.2 (CH2), 36.7 (CH2), 40.6
(CH2), 51.7 (CH3), 66.4 (CH), 82.7 (C), 104.7 (CH), 110.0 (CH), 140.7
(CH), 155.7 (C), 171.3 (C), 211.5 (C); HRMS (ESIþ) found 303.1201,
C15H20NaO5 (MNaþ) requires 303.1203. Data for 38: Rf 0.32 (petrol/
ether,1:1); nmax (thin film)/cmꢁ1 2953m,1737s,1508s,1373m,1288s,
1260s, 1210s, 1172s, 1089s, 1072s, 1010m; dH (400 MHz, CDCl3) 1.29
(3H, s, CH3C(OR)),1.85 (1H, ddd, J 14.0,12.0, 5.5 Hz, CHH0C(CH3)),1.93
(1H, ddd, J 13.5, 11.0, 6.5 Hz) and 2.12 (1H, ddt, J 13.5, 6.5, 3.0 Hz,
CH2CH2CO), 2.24 (1H, ddd, J 14.0, 12.0, 4.5 Hz, CHH0C(CH3)),
2.48e2.65 (5H, m, CH2CO and CH2CO2 and FuCHH0), 2.76 (1H, ddd, J
15.5, 12.0, 4.5 Hz, FuCHH0), 3.71 (3H, s, OCH3), 4.39 (1H, dddd, J 11.0,
8.0, 5.0, 3.0 Hz, CH(OR)), 6.02e6.04 (1H, m, Fu(H-3)), 6.29 (1H, dd, J
3.0, 2.0 Hz, Fu(H-4)), 7.31 (1H, dd, J 2.0,1.0 Hz, Fu(H-5)); dC (125 MHz,
CDCl3) 21.0 (CH2), 22.3 (CH3), 31.2 (CH2), 32.0 (CH2), 36.3 (CH2), 40.8
(CH2), 51.7 (CH3), 66.4 (CH), 82.6 (C), 104.9 (CH), 110.2 (CH), 141.0
(CH), 155.3 (C), 171.2 (C), 211.1 (C); HRMS (ESIþ) found 303.1202,
C15H20NaO5 (MNaþ) requires 303.1203.
4.15. (E)-Methyl 9-(furan-2-yl)-7-hydroxy-7-methyl-6-
oxonon-2-enoate (35)
To a degassed solution of alkene 33 (0.10 g, 0.45 mmol) and
methyl acrylate (0.10 mL, 1.40 mmol) in dichloromethane (5.0 mL)
was added Grubbs’ II catalyst (39, 19.0 mg, 22.5 mmol). The reaction
mixture was stirred at 40 ꢀC for 0.5 h and then concentrated in
vacuo. Flash chromatography (petrol/ether, 3:1/1:1) afforded the
title compound (35) as a pale brown oil (0.11 g, 87%). Rf 0.13 (petrol/
ether, 1:1); nmax (thin film)/cmꢁ1 3482br, 2952s, 2931s, 2854m,
1714s,1659s,1508m,1437s,1331m,1278s,1205s,1177s,1149s,1040s,
1010m; dH (400 MHz, CDCl3) 1.38 (3H, s, C(7)CH3), 2.00e2.15 (2H, m,
C(8)H2), 2.36e2.58 (4H, m, C(9)HH0 and C(5)HH0 and C(4)H2), 2.67
(1H, ddd, J 11.5, 8.5, 8.0 Hz, C(5)HH0), 2.75 (1H, ddd, J 15.0, 9.5, 6.0 Hz,
C(9)HH0), 3.72 (3H, s, OCH3), 3.85 (1H, s, OH), 5.85 (1H, dt, J 15.5,
1.5 Hz, C(2)H), 5.95 (1H, dd, J 3.0, 1.0 Hz, Fu(H-3)), 6.26 (1H, dd, J 3.0,
2.0 Hz, Fu(H-4)), 6.90 (1H, dt, J 15.5, 6.5 Hz, C(3)H), 7.29 (1H, dd, J 2.0,
1.0 Hz, Fu(H-5)); dC (100 MHz, CDCl3) 22.2 (CH2), 25.8 (CH2), 25.9
(CH3), 34.0 (CH2), 37.6 (CH2), 51.5 (CH3), 78.1 (C), 105.7 (CH), 110.3
(CH),122.0 (CH),141.1 (CH),146.9 (CH),154.6 (C),166.7 (C), 212.4 (C);
HRMS (ESIþ) found 303.1205, C15H20NaO5 (MNaþ) requires
303.1203.
4.18. (E)-Methyl 5-{2-sec-butyl-5-[2-(furan-2-yl)ethyl]-5-
methyl-1,3,2-dioxaborolan-4-yl}pent-2-enoate (40)
4.16. (E)-Methyl 9-(furan-2-yl)-7-methyl-6-oxo-7-
(trimethylsilyloxy)non-2-enoate (36)
To a stirred solution of ketone 35 (0.10 g, 0.36 mmol) in
dichloromethane (13.3 mL) at ꢁ78 ꢀC was added dropwise ZnCl2
(0.48 mL, 1.0 M solution in ether, 0.48 mmol). After 0.5 h, L-Selec-
tride (1.23 mL, 1.0 M solution in THF, 1.23 mmol) was added drop-
wise and stirring continued at ꢁ78 ꢀC for 1.5 h. The reaction was
quenched by the careful addition of methanol (0.31 mL), water
(0.16 mL), hydrogen peroxide (0.16 mL, 35% w/w aqueous solution)
and aq NaOH (0.16 mL, 6.0 M) and the resulting solution warmed to
rt before being diluted with water (5.0 mL) and extracted with
dichloromethane (3ꢂ15 mL). The combined organic portions were
washed with satd aq NaHCO3 (10 mL) and brine (10 mL), dried
(MgSO4) and concentrated in vacuo. Flash chromatography (petrol/
ether, 1:2/1:5) afforded the title compound (40), apparently as
a single diastereomer, as a colourless oil (81.6 mg, 65%). Rf 0.76
(petrol/ether, 1:2); nmax (thin film)/cmꢁ1 2955s, 2874m, 1726s,
1461m, 1437m, 1384m, 1272m, 1201m, 1147m, 1094m, 1042m,
1010m; dH (400 MHz, CDCl3) 0.92 (3H, t, J 7.5 Hz, CH2CH3), 0.96e1.01
(1H, m) overlapping 0.98 [3H, s (coincident resonances, coupling
lost), CHCH3], 1.31e1.34 (1H, m, CHH0CH3) overlapping 1.34 (3H, s,
CH3C(OBOe)), 1.43e1.53 (1H, m, CHH0CH3), 1.56e1.64 (1H, m,
CHH0CHO), 1.65e1.75 (2H, m, CHH0CHO and CHH0C(CH3)), 1.81e1.95
(1H, m, CHH0C(CH3)), 2.26e2.38 (1H, m) and 2.46e2.57 (1H, m,
CH2CH]), 2.66e2.77 (1H, m) and 2.83 (1H, ddd, J 15.5, 11.5, 4.5 Hz,
FuCH2), 3.74 (3H, s, OCH3), 3.90e3.95 (1H, m, CHO), 5.88 (1H, d, J
16.0 Hz, ]CHCO), 5.99 (1H, dd, J 3.0, 1.0 Hz, Fu(H-3)), 6.29 (1H, dd,
J 3.0, 2.0 Hz, Fu(H-4)), 6.96e7.05 (1H, m, CH]CHCO), 7.31 (1H, dd, J
2.0, 1.0 Hz, Fu(H-5)); dC (125 MHz, CDCl3) 13.4 (CH3), 15.1 (CH3),
18.2e18.7 (CH), 22.5 (CH2), 25.4 (CH3), 26.0 (CH2), 29.3 (CH2), 29.4
(CH2), 34.4 (CH2), 51.4 (CH3), 82.1 (C), 85.0 (CH), 104.7 (CH), 110.1
(CH), 121.5 (CH), 140.9 (CH), 148.3 (CH), 155.7 (C), 167.0 (C); HRMS
(ESIþ) found 371.2002, C19H29BNaO5 (MNaþ) requires 371.2000.
To a degassed solution of alkene 34 (0.10 g, 0.34 mmol) and
methyl acrylate (0.09 mL, 1.05 mmol) in dichloromethane (5.0 mL)
was added Grubbs’ II catalyst (39, 14.0 mg, 16.5 mmol). The reaction
mixture was stirred at 40 ꢀC for 1 h then concentrated in vacuo. Flash
chromatography (petrol/ether,15:1) afforded the title compound (36)
as a yellow oil (68.6 mg, 57%). Rf 0.06 (petrol/ether, 10:1); nmax (thin
film)/cmꢁ1 2954s, 1726s, 1659s, 1508m, 1437s, 1371m, 1253s, 1199s,
1115m,1077m,1041s; dH (400 MHz, CDCl3) 0.90 (9H, s, Si(CH3)3),1.37
(3H, s, C(7)CH3),1.83 (1H, ddd, J 13.5,11.5, 4.5 Hz) and 2.19 (1H, ddd, J
13.5, 11.5, 5.5 Hz, C(8)H2), 2.40e2.50 (3H, m, C(4)H2 and C(9)HH0),
2.67 (1H, ddd, J 15.5, 11.5, 4.5 Hz, C(9)HH0), 2.77 (2H, t, J 7.5 Hz, C(5)
H2), 3.73 (3H, s, OCH3), 5.85 (1H, dt, J 15.5,1.5 Hz, C(2)H), 5.95 (1H, dd,
J 2.5,1.0 Hz, Fu(H-3)), 6.25e6.27 (1H, m, Fu(H-4)), 6.96 (1H, dt, J 15.5,
7.0 Hz, C(3)H), 7.28e7.29 (1H, m, Fu(H-5)); dC (100 MHz, CDCl3) 2.3
(3ꢂ CH3), 22.7 (CH2), 26.0 (CH2), 26.1 (CH3), 35.7 (CH2), 38.9 (CH2),
51.5(CH3), 82.4(C),104.9(CH),110.1(CH),121.5(CH),140.9(CH),148.1
(CH), 155.2 (C), 167.0 (C), 213.9 (C); HRMS (ESIþ) found 375.1598,
C18H28NaO5Si [M (28Si)Naþ] requires 375.1598.
4.17. Methyl 2-{(2S
oxotetrahydro-2H-pyran-2-yl}acetate (37) and methyl 2-
{(2S ,6R )-6-[2-(furan-2-yl)ethyl]-6-methyl-5-oxotetrahydro-
*
,6S
*
)-6-[2-(furan-2-yl)ethyl]-6-methyl-5-
*
*
2H-pyran-2-yl}acetate (38)
To a stirred solution of alcohol 35 (66.0 mg, 0.23 mmol) in THF
(4.0 mL) at ꢁ78 ꢀC was added KHMDS (0.70 mL, 0.5 M solution in
toluene, 0.35 mmol). The reaction mixturewas allowed towarm to rt
over 20 h, water (3.0 mL) was added and the separated aqueous
phase was extracted with ether (3ꢂ5.0 mL). The combined organic
portions were washed with brine (3.0 mL), dried (MgSO4) and
concentrated in vacuo. Flash chromatography (petrol/ether, 5:1)
afforded the title compound as a colourless oil (45.4 mg, 69%) and as
a 3:4 mixture of diastereomers 37 and 38. Analytical samples were
prepared by repeated chromatography. Data for 37: Rf 0.27 (petrol/
ether,1:1); nmax (thin film)/cmꢁ1 2953s,1738s,1439s,1373m,1344m,
1289s, 1261s, 1207s, 1169s, 1093s, 1011m; dH (400 MHz, CDCl3) 1.36
(3H, s, CH3C(OR)),1.86 (1H, ddd, J 13.5,11.5, 5.0 Hz, CHH0C(CH3)),1.91
4.19. (6R
*
,7S
*
,E)-Methyl 9-(furan-2-yl)-6,7-dihydroxy-7-
,7S ,E)-methyl 9-(furan-2-
methylnon-2-enoate (41) and (6S
*
*
yl)-6,7-dihydroxy-7-methylnon-2-enoate (42)
To a stirred solution of ketone 35 (50.0 mg, 0.18 mmol) in THF
(3.0 mL) at rt was added Zn(BH4)2 (0.06 mL, 0.35 M solution in THF,
21.0 mmol). After 4.5 h the reaction mixture was diluted with ether

J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
5019
(4.0 mL) and quenched by stirring for 0.5 h with satd aq NaF
(3.0 mL). Satd aq NH4Cl (3.0 mL) was then added, the phases were
separated and the organic phase dried (Na2SO4) and concentrated
in vacuo. Flash chromatography (petrol/ether, 1:2) afforded the title
compound as a colourless oil (26.7 mg, 53%; n.b. hydride in this
reaction is limiting in order to minimise conjugate reduction etc.)
as a 4:1 mixture of diastereomers 41 and 42, respectively. Rf 0.10
(petrol/ether, 1:2); nmax (thin film)/cmꢁ1 2956s, 1721s, 1656s,
1508m, 1438s, 1264s, 1207s, 1173s, 1077s, 1041s, 1010s; dH
(400 MHz, CDCl3) data for 41: 1.21 (3H, s, C(7)CH3), 1.50e1.74 (3H,
m, C(5)H2 and C(8)HH0), 1.96 (1H, ddd, J 14.0, 11.0, 5.5 Hz, C(8)HH0),
2.24e2.37 (1H, m) and 2.45e2.55 (1H, m, C(4)H2), 2.71 (1H, ddd,
15.5,11.0, 5.5 Hz) and 2.82 (1H, ddd, J 15.5,11.0, 5.5 Hz, C(9)H2), 3.42
(1H, dd, J 10.5, 2.0 Hz, C(6)H), 3.73 (3H, s, OCH3), 5.87 (1H, dt, J 15.5,
1.5 Hz, C(2)H), 6.00 (1H, dd, J 3.0,1.0 Hz, Fu(H-3)), 6.28 (1H, dd, J 3.0,
2.0 Hz, Fu(H-4)), 7.00 (1H, ddd, J 15.5, 7.5, 6.5 Hz, C(3)H), 7.30 (1H,
dd, 2.0, 1.0 Hz, Fu(H-5)); dH (400 MHz, CDCl3) selected data for 42:
1.16 (3H, s, C(7)CH3), 1.80e1.88 (2H, m, C(8)H2), 3.44 (1H, dd, J 10.5,
2.5 Hz, C(6)H); dC (100 MHz, CDCl3) data for 41: 22.1 (CH2), 23.3
(CH3), 29.3 (CH2), 29.6 (CH2), 33.9 (CH2), 51.5 (CH3), 74.3 (C), 77.8
(CH), 104.7 (CH), 110.2 (CH), 121.4 (CH), 140.9 (CH), 148.9 (CH), 156.0
(C), 167.1 (C); dC (100 MHz, CDCl3) data for 42: 20.7 (CH3), 22.1
(CH2), 29.3 (CH2), 29.7 (CH2), 36.9 (CH2), 51.5 (CH3), 74.5 (C), 76.2
(CH), 104.9 (CH), 110.2 (CH), 121.4 (CH), 141.0 (CH), 148.9 (CH), 155.9
(C), 166.6 (C); HRMS (ESIþ) found 305.1350, C15H22NaO5 (MNaþ)
requires 305.1359.
(3H, s, CH3C(OH), C), 1.61e1.73 (2H, m, CHH0C(OH),
C
and
CHH0CH(OR)CH2 in ring, C), 1.74e1.85 (2H, m, CHH0C(OH), C and
CHH0C(OH), D), 1.86e1.97 (6H, m, CH2CH(OR)C(OH), C and D and
CHH0CH(OR)CH2 in ring, D and CHH0C(OH), D), 2.14e2.21 (2H, m,
CHH0CH(OR)CH2 in ring, C and D), 2.45e2.50 (2H, m, CHH0CO, C and
D), 2.61e2.66 (2H, m, CHH0CO, C and D), 2.67e2.85 (4H, m, FuCH2, C
and D), 3.69 (3H, s, OCH3, D), 3.70 (3H, s, OCH3, C), 3.85 (1H, dd, J 6.5,
3.0 Hz, CHC(OH), C) overlapping 3.87 (1H, dd, J 6.5, 3.5 Hz, CHC(OH),
D), 4.34e4.42 (2H, m, CH(OR)CH2CO, C and D), 5.98e6.00 (2H, m,
Fu(H-3), C and D), 6.27e6.29 (2H, m, Fu(H-4), C and D), 7.29 (1H, dd,
J 1.5, 1.0 Hz, Fu(H-5), D), 7.30 (1H, dd, J 2.0, 1.0 Hz, Fu(H-5), C); dC
(125 MHz, CDCl3) data for C: 22.2 (CH2), 23.6 (CH3), 26.3 (CH2), 32.4
(CH2), 35.0 (CH2), 40.6 (CH2), 51.6 (CH3), 73.0 (C), 76.0 (CH), 85.2
(CH), 104.5 (CH), 110.1 (CH), 140.8 (CH), 156.2 (C), 171.6 (C); data for
D: 21.0 (CH3), 22.3 (CH2), 26.6 (CH2), 32.3 (CH2), 38.1 (CH2), 40.7
(CH2), 51.8 (CH3), 72.8 (C), 76.2 (CH), 84.4 (CH), 104.4 (CH), 110.1
(CH), 140.7 (CH), 156.4 (C), 171.6 (C); HRMS (ESIþ) found 305.1360,
C15H22NaO5 (MNaþ) requires 305.1359.
4.21. (3S ,4R
* *
)-1-(Furan-2-yl)-3-methyloct-7-ene-3,4-diol (45)
and (3S ,4S
*
*
)-1-(furan-2-yl)-3-methyloct-7-ene-3,4-diol (46)
To a flask containing NaBH4 (41.7 mg, 1.10 mmol) was added
ZnCl2 (2.25 mL, 1.0 M solution in ether, 2.25 mmol) and the
resulting suspension stirred at 0 ꢀC for 5 min; a solution of ketone
33 (0.50 g, 2.25 mmol) in THF (4.5 mL) was then added via cannula
and stirring continued for 2 h at rt. The reaction was quenched by
stirring for 0.5 h with satd aq NaF (4.5 mL) and then acidified with
hydrochloric acid (1.0 M). The reaction mixture was diluted with
dichloromethane (5.0 mL), the phases separated and the aqueous
phase extracted with dichloromethane (3ꢂ5.0 mL). The organic
phases were combined, dried (Na2SO4) and concentrated in vacuo.
Flash chromatography (petrol/ether, 3:1/1:2) afforded the title
compounds as a separable mixture of diastereomers [45 and 46,
dr¼4:1, respectively], both viscous yellow oils (0.19 g, 38%, com-
bined). Data for 45: Rf 0.28 (petrol/ether, 2:1); nmax (thin film)/cmꢁ1
3417br, 2975s, 2948s, 2862m, 1641m, 1597m, 1508m, 1450m,
1415m, 1378m, 1293m, 1147s, 1065s, 1008s; dH (400 MHz, CDCl3)
1.21 (3H, s, CH3), 1.50 (1H, ddd, J 10.5, 8.5, 5.5 Hz, C(5)HH0),
1.57e1.65 (1H, m, C(5)HH0), 1.71 (1H, ddd, J 14.0, 11.0, 5.5 Hz, C(2)
HH0), 1.92e2.21 (4H, m, C(2)HH0 and C(6)HH0 and 2ꢂ OH),
2.29e2.39 (1H, m, C(6)HH0), 2.72 (1H, ddd, J 15.5, 11.0. 5.5 Hz) and
2.84 (1H, ddd, J 15.5, 11.0, 5.0 Hz, C(1)H2), 3.46 (1H, dd, J 10.5, 1.5 Hz,
C(4)H), 5.01 (1H, ddd, J 10.0, 2.0, 1.0 Hz) and 5.08 (1H, dq, J 17.0,
2.0 Hz, C(8)H2), 5.85 (1H, ddt, J 17.0, 10.0, 6.5 Hz, C(7)H), 6.01 (1H,
app. dt, J 3.0, 1.0 Hz, Fu(H-3)), 6.29 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)),
7.31 (1H, dd, J 2.0, 1.0 Hz, Fu(H-5)); dC (100 MHz, CDCl3) 22.2
(CH2), 23.2 (CH3), 30.5 (CH2), 31.0 (CH2), 33.9 (CH2), 74.2 (C), 78.2
(CH), 104.6 (CH), 110.2 (CH), 115.2 (CH2), 138.3 (CH), 140.9 (CH),
156.2 (C); HRMS (ESIþ) found 247.1303, C13H20NaO3 (MNaþ) re-
quires 247.1305. Data for 46: Rf 0.20 (petrol/ether, 2:1); nmax (thin
film)/cmꢁ1 3417br, 2976s, 2947s, 2859m, 1641m, 1508s, 1450s,
1415s, 1381m, 1212m, 1174s, 1147s, 1071s, 1008s; dH (400 MHz,
CDCl3) 1.17 (3H, s, CH3), 1.41e1.52 (1H, m, C(5)HH0), 1.53e1.65 (3H,
m, C(5)HH0 and 2ꢂ OH),1.82 (2H, app. q, J 8.0 Hz, C(2)H2), 2.10e2.20
(1H, m) and 2.29e2.39 (1H, m, C(6)H2), 2.77 (2H, t, J 8.0 Hz, C(1)H2),
3.48 (1H, dd, J 10.5, 1.5 Hz, C(4)H), 5.01 (1H, ddt, J 10.0, 1.5, 1.0 Hz)
and 5.08 (1H, app. dq, J 17.0, 1.5 Hz, C(8)H2), 5.85 (1H, ddt, J 17.0,
10.0, 7.0 Hz, C(7)H), 6.00e6.02 (1H, m, Fu(H-3)), 6.28e6.30 (1H, m,
Fu(H-4)), 7.30e7.32 (1H, m, Fu(H-5)); dC (125 MHz, CDCl3) 20.8
(CH3), 22.1 (CH2), 30.5 (CH2), 30.8 (CH2), 36.9 (CH2), 74.4 (C), 76.5
(CH), 104.7 (CH), 110.2 (CH), 115.2 (CH2), 138.3 (CH), 140.9 (CH),
155.9 (C); HRMS (ESIþ) found 247.1303, C13H20NaO3 (MNaþ) re-
quires 247.1305.
4.20. Methyl 2-{5-[4-(furan-2-yl)-2-hydroxybutan-2-yl]
tetrahydrofuran-2-yl}acetate (43)
To a stirred solution of the diol (29.7 mg, 0.11 mmol, 2:1 mixture
of diastereomers 41 and 42) in THF (2.0 mL) at ꢁ40 ꢀC was added
LHMDS (0.11 mL, 1.0 M solution in THF, 0.11 mmol). The reaction
mixture was then allowed to warm to rt over 18 h then water
(2.0 mL) and ether (2.0 mL) were added and the phases separated.
The aqueous phase was extracted with ether (3ꢂ3.0 mL) and the
combined organic phases were washed with brine (2.0 mL), dried
(MgSO4) and concentrated in vacuo. Flash chromatography (petrol/
ether, 1:1) afforded a partially separable mixture of four di-
astereomers of the title compound (43) as pale yellow oils (12.0 mg,
40%, 3:1 A and B and 7.1 mg, 24%, 1.35:1 C and D). Data for di-
astereomers A and B: Rf 0.27 (petrol/ether, 1:2); nmax (thin film)/
cmꢁ1 3417br, 2978m, 2953m, 1740s, 1508m, 1438m, 1373m, 1296m,
1278m, 1201s, 1174s, 1147s, 1069s, 1008m; dH (400 MHz, CDCl3) 1.10
(3H, s, CH3C(OH), B), 1.26 (3H, s, CH3C(OH), A), 1.64e1.73 (3H, m,
CHH0CH(OR)CH2 in ring, A and B and CHH0C(OH), A), 1.77e1.88 (4H,
m, CHH0CH(OR)C(OH), A and B, CHH0C(OH), B and CHH0C(OH), A),
1.90e2.00 (3H, m, CHH0CH(OR)C(OH), A and B and CHH0C(OH), B),
2.05e2.13 (2H, m, CHH0CH(OR)CH2 in ring, A and B), 2.46e2.58 (4H,
m, CH2CO, A and B), 2.62 (2H, br s, OH, A and B), 2.66e2.86 (4H, m,
FuCH2, A and B), 3.71 (3H, s, OCH3, B), 3.71 (3H, s, OCH3, A), 3.79 (1H,
dd, J 8.5, 6.5 Hz, CH(OR)C(OH), A) overlapping 3.81 (1H, dd, J 8.5,
6.5 Hz, CH(OR)C(OH), B), 4.37 (2H, app. tt, J 7.5, 5.0 Hz, CH(OR)
CH2CO, A and B), 5.98e6.01 (2H, m, Fu(H-3), A and B), 6.26e6.29
(2H, m, Fu(H-4), A and B), 7.29 (1H, dd, J 1.5, 1.0 Hz, Fu(H-5), B), 7.30
(1H, dd, J 1.5, 1.0 Hz, Fu(H-5), A); dC (100 MHz, CDCl3) 21.3 (CH3, B),
22.2 (CH2, A), 22.6 (CH2, B), 24.1 (CH3, A), 24.7 (CH2, A), 25.0 (CH2,
B), 31.0 (CH2, B), 31.2 (CH2, A), 35.5 (CH2, A), 38.3 (CH2, B), 40.8 (CH2,
A and B), 51.8 (CH3, A and B), 72.0 (C, A and B), 75.4 (CH, A), 75.5
(CH, B), 85.4 (CH, B), 86.2 (CH, A), 104.4 (CH, B), 104.5 (CH, A), 110.1
(CH, A and B), 140.7 (CH, B), 140.8 (CH, A), 156.2 (C, A), 156.4 (C, B),
171.8 (C, B), 171.9 (C, A); HRMS (ESIþ) found 305.1357, C15H22NaO5
(MNaþ) requires 305.1359. Data for diastereomers C and D: Rf 0.21
(petrol/ether, 1:2); nmax (thin film)/cmꢁ1 3417br, 2978m, 2953m,
1740s, 1438s, 1373m, 1318m, 1296m, 1259m, 1201s, 1174s, 1147s,
1069s, 1008m; dH (500 MHz, CDCl3) 1.11 (3H, s, CH3C(OH), D), 1.23

5020
J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
4.22. (3S
*
,4R
*
)-1-(Furan-2-yl)-3-methyl-4-(triethylsilyloxy)
,4S )-1-(furan-2-yl)-3-methyl-4-
9-(furan-2-yl)-7-hydroxy-7-methyl-6-(triethylsilyloxy)non-2-
enoate (48b)
oct-7-en-3-ol (47a) and (3S
*
*
(triethylsilyloxy)oct-7-en-3-ol (47b)
To a degassed solution of the alkene (92.0 mg, 0.27 mmol, 8.6:1
mixture of 47a and 47b) and methyl acrylate (0.08 mL, 0.84 mmol)
in dichloromethane (3.0 mL) was added HoveydaeGrubbs II cata-
To a flask containing NaBH4 (45.5 mg, 1.20 mmol) was added
ZnCl2 (2.46 mL, 1.0 M solution in ether, 2.46 mmol) and the
resulting suspension stirred at 0 ꢀC until gas evolution ceased;
a solution of ketone 33 (0.55 g, 2.47 mmol) in THF (5.0 mL) was
then added via cannula and stirring continued for 2 h at rt. The
reaction mixture was quenched by stirring for 0.5 h with satd aq
NaF (5.0 mL) and then acidified with hydrochloric acid (1.0 M). The
reaction mixture was diluted with dichloromethane (5.0 mL), the
phases were separated and the aqueous phase was extracted with
dichloromethane (3ꢂ5.0 mL). The organic phases were combined,
dried (Na2SO4) and concentrated in vacuo. The residue was dis-
solved in DMF (8.0 mL) at rt and to this solution were added se-
quentially imidazole (0.87 g, 12.7 mmol) and chlorotriethylsilane
(0.48 mL, 2.85 mol). After 3 h the reaction mixture was partitioned
between dichloromethane (10 mL) and satd aq NaHCO3 (5.0 mL).
The separated aqueous phase was extracted with dichloromethane
(2ꢂ5.0 mL); the organic phases were combined, washed with water
(2ꢂ5.0 mL), dried (MgSO4) and concentrated in vacuo. Flash chro-
matography (petrol/ether, 10:1) afforded separable diastereomers
of the title compound as pale yellow oils (47a, 0.41 g, 49% and 47b,
0.10 g, 12%). Data for 47a: Rf 0.61 (petrol/ether, 2:1); nmax (thin
film)/cmꢁ1 3474br, 2956s, 2914s, 2878s, 1459m, 1415m, 1295w,
1212m, 1137s, 1106s, 1008s; dH (400 MHz, CDCl3) 0.67 (6H, q, J
8.0 Hz, Si(CH2CH3)3), 1.00 (9H, t, J 8.0 Hz, Si(CH2CH3)3), 1.17 (3H, s,
C(3)CH3), 1.47e1.58 (1H, m) and 1.63 (1H, dddd, J 14.0, 10.0, 6.0,
3.0 Hz, C(5)H2), 1.72 (1H, ddd, J 13.5, 12.0, 5.5 Hz) and 1.92 (1H, ddd,
13.5, 12.0, 5.0 Hz, C(2)H2), 2.01e2.19 (2H, m, C(6)HH0 and OH),
2.22e2.33 (1H, m, C(6)HH0), 2.69 (1H, ddd, J 15.5, 12.0, 5.5 Hz) and
2.83 (1H, ddd, J 15.5, 12.0, 5.0 Hz, C(1)H2), 3.54 (1H, dd, J 7.5, 3.0 Hz,
C(4)H), 4.98 (1H, app. ddt, J 10.0, 1.5, 1.0 Hz) and 5.04 (1H, dd, J 17.0,
1.5 Hz, C(8)H2), 5.82 (1H, ddt, J 17.0, 10.0, 6.5 Hz, C(7)H), 6.00 (1H,
dd, J 2.0, 1.0 Hz, Fu(H-3)), 6.28e6.30 (1H, m, Fu(H-4)), 7.31 (1H, app.
s, Fu(H-5)); dC (100 MHz, CDCl3) 5.4 (3ꢂ CH2), 7.0 (3ꢂ CH3), 22.2
(CH2), 23.4 (CH3), 31.0 (CH2), 32.2 (CH2), 34.3 (CH2), 74.3 (C), 79.7
(CH), 104.4 (CH), 110.1 (CH), 114.7 (CH2), 138.5 (CH), 140.7 (CH),
156.6 (C); HRMS (ESIþ) found 361.2174, C19H34NaO3Si [M (28Si)Naþ]
requires 361.2169. Data for 47b: Rf 0.67 (petrol/ether, 2:1); nmax
(thin film)/cmꢁ1 3474br, 2956s, 2877s, 1641m, 1597m, 1508m,
1458m, 1416m, 1381m, 1240m, 1147m, 1098s, 1008s; dH (400 MHz,
CDCl3) 0.67 (6H, q, J 8.0 Hz, Si(CH2CH3)3), 1.00 (9H, t, J 8.0 Hz,
Si(CH2CH3)3), 1.14 (3H, s, C(3)CH3), 1.43e1.66 (2H, m, C(5)H2),
1.72e1.86 (2H, m, C(2)H2), 2.00e2.11 (1H, m) and 2.21e2.32 (1H, m,
C(6)H2), 2.72e2.79 (2H, m, C(1)H2), 3.56 (1H, dd, J 7.5, 3.0 Hz, C(4)
H), 4.98 (1H, ddt, J 10.0, 1.5, 1.0 Hz) and 5.04 (1H, dd, 17.0, 1.5 Hz,
C(8)H2), 5.81 (1H, ddt, J 17.0, 10.0, 6.5 Hz, C(7)H), 5.99 (1H, dd, J 3.0,
1.0 Hz, Fu(H-3)), 6.29 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 7.30e7.32 (1H,
m, Fu(H-5)); dC (125 MHz, CDCl3) 5.2 (3ꢂ CH2), 6.6 (3ꢂ CH3), 21.1
(CH3), 22.2 (CH2), 30.8 (CH2), 32.3 (CH2), 37.0 (CH2), 74.2 (C), 78.2
(CH), 104.5 (CH), 110.1 (CH), 114.8 (CH2), 138.6 (CH), 140.8 (CH),
156.4 (C); HRMS (ESIþ) found 361.2172, C19H34NaO3Si [M (28Si)Naþ]
requires 361.2169.
lyst (52, 1.7 mg, 2.7 m
mol). The reaction mixture was stirred at 40 ꢀC
for 2 h and then cooled and concentrated in vacuo. Flash chroma-
tography (petrol/ether, 25:1/10:1) afforded the title compound as
a pale yellow oil (96.1 mg, 89%) and as an 8:1 (48a:48b) ratio of
diastereomers. Samples of the separate diastereomers for analysis
were obtained by repeat chromatography. Data for 48a: Rf 0.39
(petrol/ether, 1:1); nmax (thin film)/cmꢁ1 3507br, 2955s, 2913s,
2877s, 1726s, 1657s, 1457s, 1437s, 1315s, 1277s, 1240s, 1208s, 1173s,
1148s,1104s,1046s,1009s; dH (500 MHz, CDCl3) 0.66 (6H, q, J 8.0 Hz,
Si(CH2CH3)3), 0.99 (9H, t, J 8.0 Hz, Si(CH2CH3)3), 1.17 (3H, s, C(7)
CH3), 1.62e1.75 (3H, m, C(5)H2 and C(8)HH0), 1.91 (1H, ddd, J 13.5,
12.0, 5.0 Hz, C(8)HH0), 2.07 (1H, s, br, OH), 2.19e2.28 (1H, m) and
2.38e2.49 (1H, m, C(4)H2), 2.68 (1H, ddd, J 15.5, 12.0, 5.0 Hz) and
2.82 (1H, ddd, J 15.5, 11.5, 5.0 Hz, C(9)H2), 3.55 (1H, dd, J 7.5, 3.5 Hz,
C(6)H), 3.74 (3H, s, OCH3), 5.84 (1H, d, J 15.5 Hz, C(2)H), 6.00 (1H, d, J
3.0 Hz, Fu(H-3)), 6.29 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 6.97 (1H, dt, J
15.5, 7.0 Hz, C(3)H), 7.30e7.32 (1H, m, Fu(H-5)); dC (125 MHz,
CDCl3) 5.4 (3ꢂ CH2), 7.0 (3ꢂ CH3), 22.2 (CH2), 23.5 (CH3), 29.2 (CH2),
31.2 (CH2), 34.5 (CH2), 51.4 (CH3), 74.3 (C), 79.1 (CH), 104.5 (CH),
110.1 (CH), 121.0 (CH), 140.8 (CH), 149.0 (CH), 156.3 (C), 167.0 (C);
HRMS (ESIþ) found 419.2222, C21H36NaO5Si [M (28Si)Naþ] requires
419.2224. Data for 48b: Rf 0.48 (petrol/ether, 1:1); nmax (thin film)/
cmꢁ1 3441br, 2955s, 2914m, 2877m, 1726s, 1655s, 1437m, 1277m,
1240m, 1208m, 1172m, 1148m, 1103s, 1044m, 1008s; dH (400 MHz,
CDCl3) 0.65 (6H, q, J 8.0 Hz, Si(CH2CH3)3), 0.98 (9H, t, J 8.0 Hz,
Si(CH2CH3)3), 1.13 (3H, s, C(7)CH3), 1.50e1.60 (1H, m) and 1.60e1.70
(1H, m, C(5)H2), 1.70e1.87 (2H, m, C(8)H2), 2.11e2.26 (2H, m, C(4)
HH0 and OH), 2.37e2.48 (1H, m, C(4)HH0), 2.71 (1H, ddd, J 15.5, 10.5,
6.0 Hz) overlapping 2.77 (1H, ddd, J 15.5, 10.5, 6.0 Hz, C(9)H2), 3.56
(1H, dd, J 7.0, 3.5 Hz, C(6)H), 3.72 (3H, s, OCH3), 5.83 (1H, d, J
15.5 Hz, C(2)H), 5.97 (1H, d, J 3.0 Hz, Fu(H-3)), 6.27 (1H, dd, J 3.0,
2.0 Hz, Fu(H-4)), 6.96 (1H, dt, J 15.5, 7.0 Hz, C(3)H), 7.29 (1H, d, J
2.0 Hz, Fu(H-5)); dC (125 MHz, CDCl3) 5.4 (3ꢂ CH2), 7.0 (3ꢂ CH3),
21.2 (CH3), 22.2 (CH2), 29.0 (CH2), 31.3 (CH2), 37.1 (CH2), 51.4 (CH3),
74.2 (C), 77.8 (CH), 104.5 (CH), 110.1 (CH), 121.0 (CH), 140.8 (CH),
149.1 (CH), 156.2 (C), 167.0 (C); HRMS (ESIþ) found 419.2224,
C21H36NaO5Si [M (28Si)Naþ] requires 419.2224.
4.25. (6R,7R,E)-Methyl 9-(furan-2-yl)-7-hydroxy-7-methyl-6-
(triethylsilyloxy)non-2-enoate [(D)-48a]
Applying the above procedure to (þ)-47a (13.6 g, 40.2 mmol)
afforded (þ)-48a as a pale yellow oil (13.0 g, 82%). Data as above.
½
a 1D8
ꢃ
þ5.4 (c 1.0, CHCl3).
4.26. Methyl 2-{(2S,5R,6S)-6-[2-(furan-2-yl)ethyl]-6-methyl-
5-(triethylsilyloxy)tetrahydro-2H-pyran-2-yl}acetate [(D)-49]
To a stirred solution of alcohol (þ)-48a (13.0 g, 32.8 mmol) in
THF (380 mL) at ꢁ78 ꢀC was added dropwise LHMDS [prepared
from hexamethyldisilazane (7.67 mL, 36.1 mmol) and butyllithium
(22.6 mL, 1.6 M solution in hexanes, 36.2 mmol) in THF (150 mL)].
The resulting solution was allowed to warm to ꢁ40 ꢀC over 3 h then
ether (1 L) and satd aq NH4Cl (100 mL) were added and the phases
separated. The aqueous phase was extracted with ether (3ꢂ100 mL)
and the combined organic portions were washed with brine
(200 mL), dried (MgSO4) and concentrated in vacuo. Flash chro-
matography (petrol/ether, gradient from 20:1/10:1) afforded the
title compound [(þ)-49], a colourless oil, as a single diastereomer
(6.12 g, 47%) along with recovered starting material [(þ)-48a,
4.23. (3S,4R)-1-(Furan-2-yl)-3-methyl-4-(triethylsilyloxy)oct-
7-en-3-ol [(D)-47a]
Applying the above procedure to (þ)-33 (21.4 g, 96.3 mmol)
afforded (þ)-47a (13.6 g, 42%). Data as above. ½a D25
þ7.3 (c 1.0,
ꢃ
CHCl3).
4.24. (6R
*
,7S
*
,E)-Methyl 9-(furan-2-yl)-7-hydroxy-7-methyl-
,7S ,E)-methyl
6-(triethylsilyloxy)non-2-enoate (48a) and (6S
*
*

J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
5021
4.97 g, 38%]. Rf 0.60 (petrol/ether, 1:1); ½a D25
ꢃ
þ6.0 (c 1.0, CHCl3);
2.0, 1.0 Hz, Fu(H-5)); dC (100 MHz, CDCl3) 15.2 (CH3), 21.5 (CH2),
28.1 (CH2), 31.4 (CH2), 37.5 (CH2), 38.4 (CH2), 61.6 (CH2), 70.5 (CH),
71.7 (CH), 76.7 (C), 104.5 (CH), 110.1 (CH), 140.7 (CH), 156.2 (C).
nmax (thin film)/cmꢁ1 2954s, 2877s, 1744s, 1508m, 1460s, 1437s,
1377s, 1287s, 1239s, 1197s, 1178s, 1147s, 1100s, 1008s; dH (400 MHz,
CDCl3) 0.58 (6H, q, J 8.0 Hz, Si(CH2CH3)3), 0.95 (9H, t, J 8.0 Hz,
Si(CH2CH3)3), 1.17 (3H, s, CH3C(OR)), 1.28e1.37 (1H, m, CHH0CHCH2
in ring), 1.65e1.78 (4H, m, CHH0C(CH3), CH2CH(OTES) and
CHH0CHCH2 in ring), 1.97 (1H, ddd, J 13.5, 12.0, 5.5 Hz, CHH0C(CH3)),
2.35 (1H, dd, J 15.0, 5.5 Hz) and 2.45 (1H, dd, J 15.0, 7.5 Hz, CH2CO),
2.62e2.75 (2H, m, FuCH2), 3.46e3.51 (1H, m, CH(OTES)), 3.69 (3H, s,
OCH3), 3.94 (1H, dddd, J 11.5, 7.5, 5.5, 2.0 Hz, CH(OR)CH2), 5.94 (1H,
d, J 3.0 Hz, Fu(H-3)), 6.26e6.28 (1H, m, Fu(H-4)), 7.29 (1H, d, J
1.0 Hz, Fu(H-5)); dC (125 MHz, CDCl3) 5.2 (3ꢂ CH2), 6.9 (3ꢂ CH3),
14.8 (CH3), 21.3 (CH2), 28.7 (CH2), 31.0 (CH2), 38.4 (CH2), 41.2 (CH2),
51.5 (CH3), 66.4 (CH), 73.1 (CH), 76.7 (C), 104.0 (CH), 110.0 (CH),
140.5 (CH), 157.1 (C), 171.9 (C); HRMS (ESIþ) found 419.2227,
C21H36NaO5Si [M (28Si)Naþ] requires 419.2224.
4.29. (2S,3R,6S)-6-[2-(tert-Butyldiphenylsilyloxy)ethyl]-2-[2-
(furan-2-yl)ethyl]-2-methyltetrahydro-2H-pyran-3-ol34 [(D)-7]
To a solution of crude diol (þ)-51 (4.29 g, 16.9 mmol) in DMF
(100 mL) at rt were added sequentially imidazole (1.38 g,
20.3 mmol) and tert-butyldiphenylsilyl chloride (5.28 mL,
20.3 mmol). The reaction mixture was stirred for 16 h and then
quenched by the addition of satd aq NH4Cl (50 mL). The separated
aqueous phase was extracted with ether (4ꢂ100 mL); the com-
bined organic extracts were washed with brine (50 mL), dried
(MgSO4) and concentrated in vacuo. Flash chromatography (petrol/
ether, 10:1/5:1) afforded the title compound [(þ)-7] as a viscous,
pale yellow oil (6.33 g, 76% from (þ)-50). Rf 0.36 (petrol/ether, 1:1);
a 25
a 22
½ ꢃD þ19.3 (c 1.0, CHCl3) [lit.34 ½ ꢃD þ26.3 (c 0.88, CHCl3)]; dH
(400 MHz, CDCl3) 1.09 (9H, s, C(CH3)3), 1.18 (3H, s, CH3C(OR)),
1.25e1.35 (1H, m, CHH0CH2CH(OH)), 1.57e1.72 (4H, m,
CHH0CHH0CH(OH) and CH2CH2OSi), 1.77e1.87 (2H, m, CHH0CH(OH)
and CHH0C(CH3)), 2.01 (1H, ddd, J 13.5, 11.5, 5.5 Hz, CHH0C(CH3)),
2.67 (1H, ddd, J 15.5, 11.5, 5.5 Hz) and 2.76 (1H, ddd, J 15.5, 11.5,
5.0 Hz, FuCH2), 3.44e3.52 (1H, m, CH(OH)), 3.66e3.78 (2H, m,
CH(OR) and CHH0OSi), 3.82 (1H, ddd, J 10.0, 8.5, 5.5 Hz, CHH0OSi),
5.97 (1H, d, J 3.0 Hz, Fu(H-3)), 6.27e6.29 (1H, m, Fu(H-4)), 7.30 (1H,
d, J 1.0 Hz, Fu(H-5)), 7.36e7.45 (6H, m) and 7.66e7.74 (4H, m, 2ꢂ
Ph); dC (100 MHz, CDCl3) 14.8 (3ꢂ CH3), 19.2 (C), 21.4 (CH2), 26.8
(CH3), 28.5 (CH2), 31.7 (CH2), 38.7 (CH2), 39.0 (CH2), 60.3 (CH2), 65.7
(CH), 73.0 (CH), 75.6 (C), 104.3 (CH), 110.1 (CH), 127.6e135.5 and
140.6 (CH and C), 156.9 (C).50
4.27. 2-{(2S,5R,6S)-6-[2-(Furan-2-yl)ethyl]-6-methyl-5-
(triethylsilyloxy)tetrahydro-2H-pyran-2-yl}ethanol [(D)-50]
To a stirred solution of methyl ester (þ)-49 (6.98 g, 17.6 mmol)
in THF (700 mL) at 0 ꢀC was added DIBAL (52.9 mL,1.0 M solution in
cyclohexane, 52.9 mmol) in five portions and the resulting mixture
was stirred at rt for 4 h. The reaction was quenched by the addition
of potassium sodium tartrate (200 mL, 2.0 M aq) and the phases
were separated. The aqueous phase was extracted with ether
(2ꢂ200 mL), the combined organic phases were washed with brine
(200 mL), dried (Na2SO4) and concentrated in vacuo to afford the
title compound [(þ)-50] as a thick, pale yellow oil, which was used
without further purification (6.49 g, quant.). Rf 0.14 (petrol/ether,
1:1); ½a 2D5
ꢃ
þ2.2 (c 1.0, CHCl3); nmax (thin film)/cmꢁ1 3385br, 2953s,
2914s, 2877s, 1508s, 1460s, 1415s, 1377s, 1358s, 1239s, 1211s, 1147s,
1100s, 1032s, 1009s; dH (400 MHz, CDCl3) 0.59 (6H, q, J 8.0 Hz,
Si(CH2CH3)3), 0.95 (9H, t, J 8.0 Hz, Si(CH2CH3)3), 1.20 (3H, s,
CH3C(OR)), 1.34e1.46 (1H, m, CHH0CH(OTES)), 1.59e1.87 (6H, m,
CH2CH2OH, CH2CHH0CH(OTES) and CHH0C(CH3)), 1.99 (1H, ddd, J
13.5, 10.5, 6.5 Hz, CHH0C(CH3)), 2.66e2.74 (2H, m, FuCH2), 2.87 (1H,
br s, OH), 3.52 (1H, dd, J 11.0, 5.0 Hz, CH(OR)), 3.72e3.81 (3H, m,
CH2OH and CH(OTES)), 5.95 (1H, d, J 3.0 Hz, Fu(H-3)), 6.27 (1H, dd, J
2.5, 2.0 Hz, Fu(H-4)), 7.29 (1H, app. s, Fu(H-5)); dC (100 MHz, CDCl3)
5.2 (3ꢂ CH2), 6.9 (3ꢂ CH3), 15.3 (CH3), 21.6 (CH2), 28.7 (CH2), 31.4
(CH2), 37.5 (CH2), 38.4 (CH2), 61.7 (CH2), 70.5 (CH), 72.7 (CH), 77.2
(C), 104.2 (CH), 110.0 (CH), 140.7 (CH), 156.5 (C); HRMS (ESIþ) found
391.2273, C20H36NaO4Si [M (28Si)Naþ] requires 391.2275.
4.30. (E)-4-(Furan-2-yl)-2-methyl-2-(trimethylsilyloxy)but-3-
enenitrile (54)
To a stirred solution of ketone 2937 (2.96 g, 21.4 mmol) and
K2CO3 (0.15 g, 1.09 mmol) in DMF (10 mL) was added cyano-
trimethylsilane (3.77 mL, 28.3 mmol). The resulting mixture was
stirred for 1.5 h at rt then diluted with dichloromethane (60 mL),
washed with water (3ꢂ20 mL) and brine (20 mL). The organic
phase was dried (MgSO4) and concentrated in vacuo. Flash chro-
matography (petrol/ether, 10:1) afforded the title compound (54) as
a yellow oil (4.94 g, 98%). Rf 0.66 (petrol/ether, 1:1); nmax (thin
film)/cmꢁ1 3419br, 2990m, 2961m, 2342w, 1660m, 1488m, 1448m,
1372m, 1255m, 1214m, 1192m, 1128m, 1107m, 1015m, 1001m; dH
(400 MHz, CDCl3) 0.25 (9H, s, Si(CH3)3), 1.74 (3H, s, C(2)CH3), 6.11
(1H, app. dd, J 15.5, 0.5 Hz, C(3)H), 6.38 (1H, d, J 3.5 Hz, Fu(H-3)),
6.42 (1H, dd, J 3.5, 2.0 Hz, Fu(H-4)), 6.69 (1H, d, J 15.5 Hz, C(4)H),
7.40e7.41 (1H, m, Fu(H-5)); dC (100 MHz, CDCl3) 1.4 (3ꢂ CH3), 30.8
(CH3), 69.7 (C), 110.4 (CH), 111.6 (CH), 119.2 (CH), 120.6 (C), 127.8
(CH), 143.0 (CH), 150.8 (C); HRMS (CI, NH3) found 209.1013,
C11H17O2Si [M (28Si)eCN]þ requires 209.0992.
4.28. (2S,3R,6S)-2-[2-(Furan-2-yl)ethyl]-6-(2-hydroxyethyl)-2-
methyltetrahydro-2H-pyran-3-ol34 [(D)-51]
To a stirred solution of silyl ether (þ)-50 (6.23 g, 16.9 mmol) in
THF (180 mL) at 0 ꢀC was added dropwise TBAF (44 mL, 1.0 M so-
lution in THF, 44 mmol). The reaction mixture was stirred at 0 ꢀC for
1 h and the reaction was quenched by the addition of water
(50 mL); the separated aqueous phase was extracted with ethyl
acetate (3ꢂ100 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo to afford the title compound
[(þ)-51] as a pale yellow oil (6.9 g, contains triethylsilyl residues),
which was used without further purification. A small amount was
purified by chromatography for analysis. Rf 0.09 (petrol/ether, 1:5);
4.31. (S,E)-4-(Furan-2-yl)-2-methyl-2-(trimethylsilyloxy)but-
3-enenitrile [(L)-54]
To a stirred solution of sodium (R)-phenylglycinate [(ꢁ)-53,
109 g, 0.63 mol] in THF (300 mL) at ꢁ20 ꢀC was added cyano-
trimethylsilane (94.0 g, 0.95 mol). The resulting suspension was
stirred at rt for 1 h then cooled to ꢁ20 ꢀC and a solution of ketone
2937 (86.0 g, 0.62 mol) in THF (300 mL) was added via cannula.
After 15 min, 2,2,2-trifluoroethanol (23 mL) was added and the
reaction mixture stirred for 2 h at ꢁ20 ꢀC, then left to stand in the
refrigerator (at ꢁ20 ꢀC) for 16 h. The reaction mixture was then
allowed to warm to rt and concentrated in vacuo. Flash
½
a 2D5
ꢃ
þ27.9 (c 1.0, CHCl3) [lit.34
½
a 2D2
ꢃ
þ13.0 (c 0.50, CHCl3)]; dH
(400 MHz, CDCl3) 1.22 (3H, s, CH3), 1.35e1.47 (1H, m,
CHH0CH2CH(OH)), 1.60e1.69 (4H, m, CHH0CHH0CH(OH) and
CH2CH2OH), 1.78e1.92 (2H, m, CHH0C(CH3) and CHH0CH(OH)),
1.98e2.04 (1H, m, CHH0C(CH3)), 2.15 (1H, br s, OH), 2.73 (2H, app. t, J
8.5 Hz, FuCH2), 2.98 (1H, br s, OH), 3.44e3.52 (1H, m, CH(OH)),
3.73e3.84 (3H, m, CH(OR) and CH2OH), 5.98 (1H, app. dq, J 3.0,
1.0 Hz, Fu(H-3)), 6.26 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 7.28 (1H, dd, J

5022
J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
chromatography (petrol/ether, 25:1) afforded the title compound
(ꢁ)-54 as a colourless oil (63.3 g, 43%, ee 85% by GC analysis after
ddd, J 13.5, 12.0, 5.0 Hz, CHH0C(CH3)), 1.96e2.24 (5H, m, CHH0C(CH3),
2ꢂ CH2CH]), 2.65e2.82 (2H, m, FuCH2), 4.94 (2H, app. dsext, J 10.0,
1.0 Hz, 2ꢂ ]CHH0), 5.03 (2H, ddt, J 17.0, 3.5, 1.5 Hz, 2ꢂ ]CHH0),
5.77e5.88 (2H, m, 2ꢂ CH]CH2), 6.00 (1H, dd, J 3.0, 1.0 Hz, Fu(H-3)),
6.29 (1H, dd, J 3.0, 2.0 Hz, Fu(H-4)), 7.32 (1H, dd, J 2.0, 1.0 Hz, Fu(H-
5)); dC (100 MHz, CDCl3) 2.9 (3ꢂ CH3), 22.0 (CH3), 23.7 (CH2), 29.3
(CH2), 29.4 (CH2), 35.0 (CH2), 35.9 (CH2), 36.3 (CH2), 59.6 (C), 82.1 (C),
104.4 (CH), 110.1 (CH), 114.1 (2ꢂ CH2), 139.4 (CH), 139.5 (CH), 140.8
(CH), 156.6 (C); HRMS (ESIþ) found 350.2507, C20H36NO2Si [M (28Si)
Hþ] requires 350.2510.
hydrogenation, see below). Data as above. ½a D25
ꢁ58.1 (c 1.0, CHCl3).
ꢃ
4.32. 4-(Furan-2-yl)-2-methyl-2-(trimethylsilyloxy)
butanenitrile (55)
From 18: To a stirred solution of ketone 1837 (1.50 g, 10.9 mmol)
and K2CO3 (75.0 mg, 0.54 mmol) in DMF (11 mL) was added cya-
notrimethylsilane (1.92 mL, 14.1 mmol). The resulting mixture was
stirred for 40 min at rt then diluted with dichloromethane (40 mL)
and washed successively with water (3ꢂ20 mL) and brine (20 mL).
The organic phase was dried (MgSO4) and concentrated in vacuo.
Flash chromatography (petrol/ether, 15:1) afforded the title com-
pound (55) as a yellow oil (2.13 g, 82%). See below for data.
Acknowledgements
We thank the University of Oxford and the EPSRC for a stu-
dentship (for C.N.), and Drs. Tim Claridge and Barbara Odell,
University of Oxford, for supporting NMR studies.
From 54: A 500 mL two-necked round bottom flask was charged
with nitrile 54 (1.00 g, 4.25 mmol), 5% Pd/C (26 mg) and ethyl ac-
etate (35 mL), flush-filled three times with Ar and once with H2.
The reaction mixture was stirred under an atmosphere of H2 (bal-
loon) and the disappearance of the alkene peaks was monitored by
1H NMR aliquots. On completion (ca. 3e6 h), after flush-filling the
flask with Ar, the resulting suspension was filtered through a 1.0 cm
plug of CeliteÒ, the plug was eluted with ethyl acetate (100 mL) and
the filtrate concentrated in vacuo to afford the title compound (55)
as a pale yellow oil (0.97 g, 96%). Rf 0.68 (petrol/ether, 3:1); nmax
(thin film)/cmꢁ1 2963s, 2902m, 2864m, 2232w, 1509s, 1255s,
1215m, 1187s, 1147s, 1118s, 1075s, 1043s, 1012s; dH (400 MHz,
CDCl3) 0.27 (9H, s, Si(CH3)3), 1.63 (3H, s, C(2)CH3), 2.06e2.12 (2H, m,
C(3)H2), 2.77e2.97 (2H, m, C(4)H2), 6.04 (1H, app. dt, J 3.0, 1.0 Hz,
Fu(H-3)), 6.29e6.31 (1H, m, Fu(H-4)), 7.32e7.33 (1H, m, Fu(H-5));
dC (100 MHz, CDCl3) 1.3 (3ꢂ CH3), 23.1 (CH2), 28.9 (CH3), 41.5
(CH2), 69.0 (C),105.3 (CH), 110.2 (CH),121.7 (C),141.1 (CH), 154.2 (C);
References and notes
1. Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Engen, D. V.; Clardy, J.;
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2. Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-M.; Aumelas, A. J.
Org. Chem. 1992, 57, 5857e5860.
3. Smith, A. B., III; Duffey, M. O.; Basu, K.; Walsh, S. P.; Suennemann, H. W.; Frohn,
M. J. Am. Chem. Soc. 2008, 130, 422e423.
4. Ponomarev, A. A.; Markushina, I. A. Dokl. Akad. Nauk SSSR 1959, 126, 99e102.
€
5. (a) Bohlmann, F.; Diedrich, B.; Gordon, W.; Fanghanel, L.; Schneider, J. Tetra-
€
hedron Lett. 1965, 1385e1388; (b) Bohlmann, F.; Fanghanel, L.; Kleine, K.-M.;
€
Kramer, H.-D.; Monch, H.; Schuber, J. Chem. Ber. 1965, 98, 2596e2604; (c)
Bohlmann, F.; Kramer, H.-D.; Ertingshausen, G. Chem. Ber. 1965, 98, 2605e2607.
6. (a) Kocienski, P. J.; Fall, Y.; Whitby, R. J. Chem. Soc., Perkin Trans. 11989, 841e844;
(b) Brown, R. C. D.; Kocienski, P. J. Synlett 1994, 417e419; (c) Kocienski, P. J.;
Brown, R. C. D.; Pommier, A.; Procter, M.; Schmidt, B. J. Chem. Soc., Perkin Trans. 1
1998, 9e39.
7. Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41,
1001e1011.
8. Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J. Am. Chem. Soc. 1989, 111,
6682e6690.
9. Just, G.; Potvin, P. Can. J. Chem. 1980, 58, 2173e2177.
10. (a) Fuwa, H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848e1851; (b) Fuwa,
H.; Yamaguchi, H.; Sasaki, M. Tetrahedron 2010, 66, 7492e7503.
11. (a) Bates, R. W.; Palani, K. Tetrahedron Lett. 2008, 49, 2832e2834; (b) Hiebel, M.-
A.; Pelotier, B.; Lhoste, P.; Piva, O. Synlett 2008, 1202e1204; (c) Hiebel, M.-A.;
Pelotier, B.; Piva, O. Tetrahedron Lett. 2010, 51, 5091e5093.
12. Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.; Un-
tersteller, E. J. Am. Chem. Soc. 1995, 117, 10252e10263.
HRMS (CI, NH3) found 255.1522, C12H23N2O2Si [M (28Si)NH4
quires 255.1523. {Chiral GC trace of 54: Column: -cyclodextrin
m; carrier gas: He; flow rate:
þ] re-
b
(0.22 mmꢂ30 m), thickness 0.25
m
0.8 mL/min, T injector 220 ꢀC; T detector (FID) 250 ꢀC; T initial
40 ꢀC, 5 min then 20 ꢀC/min to 90 ꢀC, 30 min then 10 ꢀC/min to
95 ꢀC, 20 min then 10 ꢀC/min to 100 ꢀC, 10 min then 20 ꢀC/min to
140 ꢀC tR¼64.98 min [(þ)-54], 65.83 min [(ꢁ)-54]}.
13. (a) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1996, 52, 12091e12110; (b) Oka,
T.; Fujiwara, K.; Murai, A. Tetrahedron Lett. 1997, 38, 8053e8056; (c) Oka, T.;
Fujiwara, K.; Murai, A. Tetrahedron 1998, 54, 21e44; (d) Nagumo, Y.; Oguri, H.;
Shindo, Y.; Sasaki, S.; Oishi, T.; Hirama, M.; Tomioka, Y.; Mizugaki, M.; Tsu-
muraya, T. Bioorg. Med. Chem. Lett. 2001, 11, 2037e2040.
14. (a) Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett. 2006, 8, 661e664; (b)
Yakambram, P.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,
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Bull. Korean Chem. Soc. 2010, 31, 653e663; (d) Bates, R. W.; Song, P. Synthesis
2010, 2935e2942.
4.33. (S)-4-(Furan-2-yl)-2-methyl-2-(trimethylsilyloxy)
butanenitrile [(L)-55]
Applying the above hydrogenation procedure to two batches of
(ꢁ)-54 (total 63.9 g, 0.272 mmol) afforded (ꢁ)-55 as a pale yellow
oil (combined 59.9 g, 93%, ee 85% by chiral GC, details above). Data
as above. ½a 1D7
ꢁ12.1 (c 1.0, CHCl3).
ꢃ
15. Machinaga, N.; Kibayashi, C. Tetrahedron Lett. 1993, 34, 5739e5742.
16. (a) Kadota, I.; Park, C.-H.; Ohtaka, M.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 6365e6368; (b) Kadota, I.; Park, C. H.; Sato, K.; Yamamoto, Y. Tetra-
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Lett. 2001, 3, 3549e3552; (d) Kadota, I.; Kadowaki, C.; Park, C.-H.; Takamura, H.;
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1799e1816; (e) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem.
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4.34. 5-[4-(Furan-2-yl)-2-(trimethylsilyloxy)butan-2-yl]nona-
1,8-dien-5-amine (56)
To a stirred solution of 4-iodobut-1-ene (6.95 g, 38.2 mmol) in
ether (90 mL) at ꢁ78 ꢀC was added tert-butyllithium (44.9 mL, 1.7 M
solution in pentane, 76.3 mmol). After 1 h at ꢁ78 ꢀC stirring was
continued for 1 h at rt then the reaction mixture was cooled to ꢁ78 ꢀC
and a solution of nitrile 55 (3.02 g, 12.7 mmol) in ether (30 mL) was
added via cannula. The reaction mixture was allowed to warm slowly
to rt over 16 h then diluted with ether (15 mL) and quenched by
stirring for 5 min with satd aq NH4Cl (20 mL). The separated aqueous
phase was extracted with ether (3ꢂ15 mL); the organic phases were
combined, dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography (petrol/ether,10:1/3:1) afforded the title compound (56) as
a light brown oil (2.70 g, 61%). Rf 0.05 (petrol/ether, 1:1); nmax (thin
film)/cmꢁ1 3327br, 2955s, 2862m, 1640m, 1452m, 1251s, 1176m,
1148s, 1111s, 1035s; dH (400 MHz, CDCl3) 0.18 (9H, s, Si(CH3)3), 1.29
(3H, s, CH3C(OTMS)), 1.43e1.61 (4H, m, 2ꢂ (CH2)2C(NH2)), 1.81 (1H,
17. (a) Venkataiah, M.; Somaiah, P.; Reddipalli, G.; Fadnavis, N. W. Tetrahedron:
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J. Robertson et al. / Tetrahedron 67 (2011) 5011e5023
5023
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M.; Jeong, J. W. Angew. Chem., Int. Ed. 2003, 42, 4779e4782; (b) Kang, S. H.;
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€
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ꢀ
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