Formal synthesis of (+)-neooxazolomycin via a Stille cross-coupling/ deconjugation route

Article abstract of DOI:10.1016/j.tet.2011.09.037

A formal synthesis of neooxazolomycin is described via the preparation of Kende's key intermediate in a longest linear sequence of 23 steps. This work is founded upon the union of three fragments: Moloney's lactam-derived triflate, a vinyl stannane and a

Full text of DOI:10.1016/j.tet.2011.09.037

Tetrahedron 67 (2011) 10026e10044
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal synthesis of (þ)-neooxazolomycin via a Stille cross-coupling/
deconjugation route
Reyhan Bastin, James W. Dale, Michael G. Edwards, Julien P.N. Papillon, Michael R. Webb,
*
Richard J.K. Taylor
Department of Chemistry, University of York, Heslington, York, YO10 5AA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2011
Received in revised form 9 September 2011
Accepted 12 September 2011
Available online 17 September 2011
A formal synthesis of neooxazolomycin is described via the preparation of Kende’s key intermediate in
a longest linear sequence of 23 steps. This work is founded upon the union of three fragments: Moloney’s
lactam-derived triflate, a vinyl stannane and a JuliaeKocienski sulfone and encompasses three key steps:
(i) a Stille cross-coupling to combine the triflate and vinyl stannane, (ii) a base-promoted enone de-
conjugation to derive the dihydroxylation precursor and (iii) our previously reported JuliaeKocienski
methodology to assemble the pentadienyl amine side chain with the sulfone precursor.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Neooxazolomycin
Oxazolomycin
Stille coupling
JuliaeKocienski
Deconjugation
Total synthesis
1. Introduction
neooxazolomycin concerns the left-hand pyroglutamate core
where a distinctive arrangement is observed; in contrast to the
b-
The first members of the oxazolomycin natural product family
(Fig. 1), oxazolomycin A1 and neooxazolomycin,2 were isolated in
1985 from strains of Streptomyces by Uemura and co-workers. Since
that time, several other members have also been isolated. Although
there is structural variation within the family, all members adhere
to a common template with a left-hand pyroglutamate core, central
polyene and right-hand oxazole fragments. The left-hand fragment
lactone observed in all other family members, a -lactone is present
g
via connection through the C-4 hydroxyl, leaving a free primary
alcohol in the C-16 position. There are several other derivative
families of natural products with structural similarity to the oxa-
zolomycins including the inthomycins/phthaloxazins,9e11 lajolla-
mycin12 and clathrynamides,13,14 which all contain fragments of the
structure to a greater or lesser degree, but not all elements of the
oxazolomycins.
contains a glutamate core featuring a lactam fused to either a
b- or
g
-lactone. The central fragment comprises a pentadienyl amine,
The members of the oxazolomycin family possess widespread
15
€
that is, common to all members of the family. Finally, the right-
hand amide fragment comprises a triene featuring a secondary
alcohol and oxazole terminating unit in the allylic positions; these
fragments comprise a family of natural products in their own
rightdthe inthomycins. Oxazolomycins A, B3 and C3 (1e3) are
geometrical isomers differing only in the configuration of the tri-
ene. The other closely related members all possess extra sub-
stituents in addition to varied alkene stereochemistry with one
unique exception, neooxazolomycin (9). For example, the curro-
mycins4,5 feature a C-130 methyl group on the oxazole and 16-Me-
oxazolomycin (4),6,7 KSM-2690B (7)8 and KSM-2690C (8)8 feature
biological activity and a detailed study by Grafe and co-workers
demonstrated in vitro antiviral activity against herpes simplex
type I (HSV I), influenza A (WSN; H1N1), vaccinia (Lister) and
Coxsackie A9 viruses. Moreover, anti-cancer activity in the form of
in vivo Ehrlich ascites antitumour activity2 and activity against P-
388 leukaemia1 have also been demonstrated. Finally, widespread
activity against Gram positive bacteria has been demonstrated for
all members of the family including neooxazolomycin. There has
been interest in the mode of action of these compounds and this
has been reflected in several studies.16,17
In contrast to the two reported syntheses of neooxazolomycin 9,
a b-methyl group in the b-lactone (C-16). The unique structure of
by Kende and co-workers (1990)18 and Hatakeyama and co-
workers (2007),19 none of the
b-lactone oxazolomycins have suc-
cumbed to total synthesis. There have been several reports de-
scribing approaches to key-elements of the core structure. We were
* Corresponding author. Tel.: þ44 0 1904 432606; fax: þ44 0 1904 434523;
e-mail address: rjkt1@york.ac.uk (R.J.K. Taylor).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.037

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10027
R1
13'
O
9'
7'
11'
10'
5
N
Me
2
HO
HO
6'
Me
8
O
10
OH
4
12
12'
8'
5
OH
7
Me
4'
2'
3
5'
O
6
O
N
H
2
3'
1'
O
1
1
9
11
N
4
Me Me
HO
OMe
Me
3
O
16
Me
N
Me
R2
O
16
Neooxazolomycin
O
core structure
R3
LEFT
spirocyclic core
CENTRAL
pentadienyl amine
RIGHT
oxazole triene amide
OxazolomycinA 1, R1 = H, R2 = H, R3 = H, 4'
Oxazolomycin B 2, R1 = H, R2 = H, R3 = H, 4'
Z
, 6'
Z
, 8'
E
E
, 6'
E
, 8'E
E
Oxazolomycin C 3, R1 = H, R2 = H, R3 = H, 4'
Z
, 6'
E
, 8'
16-Me-oxazolomycin 4, R1 = H, R2 = H, R3 = Me, 4'
Z
, 6'
Z
, 8'
E
Curromycin A 5, R1 = Me, R2 = CH2OMe, R3 = H, 4'
Z
, 6'
Z
, 8'
E
Curromycin B 6, R1 = Me, R2 = H, R3 = Me, 4'
Z
, 6'
, 6' , 8'
, 6' , 8'
, core structure on right, 4' , 6'
Z
, 8'
E
E
KSM-2690 B 7, R1 = H, R2 = H, R3 = Me, 4'
KSM-2690 C 8, R1 = H, R2 = H, R3 = Me, 4'
Neooxazolomycin
Z
E
E
E
E
9
Z
Z
, 8'
E
Fig. 1. The oxazolomycin natural product family.
the first to disclose the successful construction of the left-hand
b
-
1.1. Retrosynthesis
lactone spirocyclic core of oxazolomycin via a Mitsunobu cyclisa-
tion to form the key four membered ring;20 subsequent studies by
the groups of Mohapatra,21 Donohoe,22 Pattenden,23 Ohfune/Solo-
shonok24 and Mondal25 have also delineated alternative ap-
proaches. The central fragment has also been the subject of study
and papers on the construction of pentadienyl amines from
Kende26 and Moloney,27 along with our approach28 using
JuliaeKocienski chemistry, have been reported. With respect to the
right-hand triene amide fragment, representing the inthomycin
family of natural products, in addition to the complete syntheses by
Kende18 and Hatakeyama,19 we have reported a route that allows
access to any member of the inthomycin family via stereocontrolled
olefination/Stille cross-coupling;29,30 a similar racemic approach to
inthomycin A has also been reported by Whiting and Henaff.31,32
Kende’s synthesis18 of neooxaozolomycin splits the molecule
neatly into left- and right-hand fragments (Scheme 1). For the left-
Our synthetic plan to prepare neooxazolomycin (Scheme 3)
envisaged the same late stage peptide coupling of fragments 15 and
17 also prepared by both Kende and Hatakeyama. Compound 17
itself was available as an intermediate from our previously reported
synthesis of inthomycin A.29,33 A convergent synthesis of amine 15
from three smaller building blocks: sulfone 22, triflate 25 and
stannane 26 defined our overall plan. Initially a JuliaeKocienski
olefination between aldehyde 21 and sulfone 22 utilising our pre-
viously reported methodology28 for the construction of pentadienyl
amines would afford Kende’s advanced intermediate 15. The chal-
lenge then became the preparation of the highly functionalized
spirocyclic lactam core 21. We postulated that if the (E)-configured
tri-substituted olefin 23 could be obtained then a dihydroxylation
(with concomitant lactonisation) would lead to 12. The difficulty in
constructing this alkene stereoselectively via an olefination re-
action led us to consider alternative possibilities. The preparation of
enone 24 appeared facile via a cross-coupling strategy, thus a base-
promoted deconjugation process, via a dienolate with a kinetic
protonation, recommended itself. Stille disconnection then affords
vinyl stannane 26 and tetramic acid derived core 25. Vinyl stannane
26 should arise via a series of transformations featuring Sharpless
asymmetric epoxidation (on allylic alcohol 29) to set the C-7 centre
and regioselective alanate opening of epoxide 28 to introduce the
C-6 methyl group. Triflate 25 can be accessed via a straightforward
triflation of bicyclic polyglutamate core 27 available via Moloney’s
elegant chemistry for the preparation of tetramic acids34dthis
hand fragment
a readily available sugar derivative, anhy-
drogalactoside 10, is converted into 11, which then undergoes
cyclocondensation with 12 to afford 13, which itself undergoes
a key acid-promoted rearrangement/fragmentation to afford bi-
cycle 14. Further transformations including Takai olefination and
then Stille cross-coupling provided intermediate 15. The right-hand
fragment was constructed in a linear sequence featuring a key
Evans auxiliary controlled Reformatsky reaction to construct 16
that underwent further manipulation including Stille cross-
coupling to afford acid 17.
Hatakeyama and co-workers19 used an essentially identical
approach to Kende to prepare the right-hand fragment. However,
a very different approach was employed to realise the left-hand
fragment (Scheme 2). Intermediate 18, derived from the common
building block, methyl (3S)-hydroxy-2-methylpropanoate, un-
derwent Tamao-type hydrosilylation/iodination to generate the
(E)-olefin 19, which in the key step was cyclised under palladium
catalysis to dihydroxylation precursor 20. Subsequent functionali-
sation and a NozakieHiyamaeKishi (NHK) reaction installed the
pentadienyl amine fragment.
strategy led back to D-serine.
2. Results and discussion
2.1. The lactam core
Our inspiration for the left hand core was derived from the
previous work reported by Moloney and co-workers for the syn-
thesis of functionalised tetramic acids.34 They described an ap-
proach based upon Seebach’s self-regeneration of chirality
principle35 to construct the key quaternary centre present in the
Herein we describe our synthetic efforts towards the oxazolo-
mycin family and the formal synthesis of neooxazolomycin.

10028
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
Left hand Side
Me
Me
O
Me
Me
O
O
OBn
O
2Li
Me
O
cyclocondensation
5 steps
O
O
Me
O
HO
CO2Me
N
O
Me
Me
HO
OMe
O
CO2Me
CO2Me
13
CO2Me
MeO2C
Me
N
Me
10
11
12
acid-promoted
rearrangement
Me SEt
SEt
Me
Me
I
Fmoc
Me
OH
Me
N
H
Me
OH
OH
Takai
Stille
OH
OTBS
OAc
O
N
Me
O
O
O
O
O
N
Me
N
Me
O
O
OTBS
O
OAc
CO2Me
15
14
Right hand side
O
TMS
TMS
Me
O
N
O
Br
Me
Me
Me
Reformatsky
Stille
N
O
OH
O
OH
CHO
Me
CO2H
R
Me
Me Me
Me Me
Me
16
17
Scheme 1. Kende’s synthesis of the neooxazolomycin fragments.
Me
Me
Tamao hydrosilylation/
Iodination
Me
OBn
steps
Me
CO2Me
Me Me
N
OBn
HO
MeO2C
O Si H
Me
I
MeO2C
O
Me
18
19
Pd-catalysed
cyclisation
Me
Me
Me
Fmoc
CHO
Me
N
H
CHO
Me
OH
Me
OAc
O
O
O
O
O
N
Me
O
dihydroxylation
Nozaki-
N
Me
CO2Me
N
O
i-Pr
Si
Hiyama-
Kishi
O
O
Me CO2Me
OAc
i-Pr
15
20
Scheme 2. Hatakeyama’s approach to the left-hand fragment 15.
bicyclic core 25 via a regioselective, counter-intuitive, Dieckmann
cyclisation. The synthesis of lactam core 25 commenced with
serine, which was converted into its methyl ester (Fieser condi-
tions) before condensation with pivaldehyde in the presence of
triethylamine to afford oxazolidine 30 in 95% yield and a 1:1 cis/
trans-ratio. N-Acylation with racemic acid chloride 31 in the pres-
ence of pyridine afforded the acyl oxazolidine 32, the cyclisation
precursor in 92% yield (as a 1:1 mixture of diastereomers at the
D
-

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10029
O
N
O
N
Me
O
OH
OH
(i) Deprotection
HO2C
Me
N
H
HO
HO
Me Me
HO
Me Me
Me
(ii) Amide formation
Me
O
O
Inthomycin A derived
(Taylor, Ref 29)
17
N
Me
O
Neooxazolomycin 9
Me
Me
Fmoc
N
Me
OH
Me
OH
H
Fmoc
NH
OAc
Julia-Kocienski
O
O
O
O
OAc
O
O
O
S
O
N
Me
5-PT
N
Me
O
OAc
OAc
15
22 (5-PT = 5-
phenyltetrazole)
21
Dihydroxylation
Me
Me
OBn
OBn
Me
OTBS
Me
OTBS
CO2Me
(i) Reduction
CO2Me
O
O
N
(ii) Deconjugation
N
O
O
t-Bu
Stille
t-Bu
23
24
OTf
CO2Me
Me
(i) Regioselective
Me
Me
O
Epoxide Opening
n-Bu3Sn
OBn
TMS
AlMe3
O
OBn
28
N
N
(ii) Hydrostannylation
OH
O
t-Bu
26
25
SAE
Me
OH
CO2Me
Me
Moloney
Ref. 34
TMS
OH
D-Serine
O
29
O
t-Bu
27
Scheme 3. Retrosynthetic analysis.
malonate centre); the oxazolidine C-2 centre is set with cis-ste-
reochemistry relative to the inherent stereocentre according to the
previous precedent.36 Regioselective Dieckmann condensation to
the bicyclic oxazolidine core promoted by potassium tert-butoxide
afforded the desired 33 in 93% yield and as a single diastereomer,
albeit as a 9:1 mixture of enol/keto tautomers. The unexpected
Dieckmann cyclisation occurs via the less stable enolate rather than
the more stable ‘malonate enolate’. This has been rationalized by
the consideration that the product derived from the more stable
enolate is too sterically hindered to form because it places a tert-
butyl group on the endo-face of the product. With Moloney’s
derivative 33 in hand, it was necessary only for it to be converted
into crystalline triflate 25 (Tf2O, i-Pr2NEt) in 70% yield. Thus, in five
linear steps from chiral pool material, the Stille partner 25 was
assembled in 60% yield. The crystalline nature of 25 allowed the
material to be obtained on a large scale (65 g) without the need for
chromatography (Scheme 4).
2.2. The stannane cross-coupling partner
The required (E)-tri-substituted alkene 29, was readily prepared
in two-steps from (trimethylsilyl)propargyl alcohol according to

10030
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
CO2Me
O
was obtained in 85% yield and 95:5 er with (þ)-DIPT; the enan-
Et3N
CO2Me
OH
tioselectivity of the epoxidation was determined by Mosher’s ester
formation with both (S)- and (R)-MTPA-Cl and 1H NMR analysis.
Subsequent benzyl protection of the alcohol and desilylation of the
epoxide 37, both under standard conditions, afforded (2R,3S)-ep-
oxide 28. Regioselective epoxide opening at the C-3 position was
achieved under Lewis acidic conditions with the alanate reagent
derived from lithium trimethylsilylacetylide and trimethylalumi-
nium.39 At ꢀ40 ꢁC in Et2O, a 9:1 mixture of regioisomers in favour of
the desired alcohol 38 was obtained; the control of temperature in
this reaction was essential to ensure high regioselectivity. Ulti-
mately, the minor regioisomer was readily removed after desily-
lation of the alkyne with TBAF in THF at 0 ꢁC to afford alkyne 39 in
83% yield over the two-steps. Finally, radical hydrostannylation
with n-Bu3SnH at 80 ꢁC afforded the Stille cross-coupling partner
26 in 67% yield as a 10:1 mixture of (E/Z)-isomers. Ultimately, we
were able to perform the asymmetric epoxidation on a 65 mmol
scale without deleterious effect on either the enantioselectivity or
yield; this material was then converted into more than 18 g of
stannane 26 (Scheme 5).
HN
t-Bu
t-BuCHO
pentane
rt
H2N
30, 95%
1:1 d.r.
O
pyridine
CH2Cl2, rt
EtO2C
31
Cl
Me
CO2Et
OH
CO2Me
Me
OTf
CO2Me
Me
O
CO2Me
Me
Tf2O
KOt-Bu
i-Pr2NEt
CH2Cl2
50 °C
N
O
O
N
t-BuOH
Δ
N
O
O
O
t-Bu
t-Bu
t-Bu
32, 92%
25, 70%
(65 g obtained)
33, 93%
1:1 d.r.
9:1 enol/keto
Scheme 4. Moloney’s tetramic acid chemistry and further elaboration.
the robust procedure of Denmark and co-workers.37 Sharpless
epoxidation of alkene 29 proved to be somewhat troublesome and
rigorously anhydrous conditions were required. The use of tert-
butylhydroperoxide in decane or toluene solution as the oxidant
led to successful oxidation but in moderate enantioselectivity (2:1
er). However, the preparation of a solution of TBHP in methylene
chloride gave a major improvement. Presumably the improvement
in selectivity arises from the elimination of traces of water in the
TBHP in toluene when prepared according to the procedure of
Sharpless and co-workers from aqueous TBHP.38 Thus, epoxide 34
2.3. Stille cross-coupling and subsequent modification
The union of two of the key fragments, 25 and 26, was accom-
plished via Stille coupling [Pd2(dba)3/P(2-fur)3] in DMF at 50 ꢁC for
6 h. Control of the temperature was essential in this reaction; if the
reaction was run at higher temperatures the persistent formation of
an unwanted isomer was observed. This being the case, unified
diene 24 was obtained in 87% yield with the same crude ratio of (E/
Z)-isomers as present in the stannane precursor; chromatography
afforded 87% of pure (E)-24 and 4% of pure (Z)-24. Selective
Ti(Oi-Pr)4
(+)−TIPT
Me
Me
O
O
Me
(R)- or (S)-MTPA
TBHP
Ph
TMS
O
TMS
OH
DCC, DMAP
CH2Cl2, 0 °C
CH2Cl2
TMS
OH
O
F3C OMe
−
70 °C
29
34, 85%
(R)-MTPA: 35, 58%, 94:6 d.r.
(S)-MTPA: 36, 63%, 5:95 d.r.
NaH, BnBr
THF, 0 °C to rt
Me
Me
O
TBAF
OBn
TMS
OBn
O
THF, Δ
37, 85%
28, 85%
AlMe3
TMS
Li
THF, 78 to 40 °C
AIBN
n-Bu3SnH
Me
Me
Me
TBAF
THF, 0 °C
n-Bu3Sn
OBn
OBn
OBn
80 °C
TMS
OH
38, 97%
OH
39, 86%
OH
26, 67%, 10:1 (E/Z)
(18 g scale)
Scheme 5. Preparation of the key stannane cross-coupling partner.

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10031
reduction of the di-substituted alkene 24 was accomplished with
diimide (generated in situ from p-tosylhydrazine with sodium ac-
etate). The hindered nature of the alkene was evident from the
difficulty of the reduction and this necessitated the use of a vast
excess of diimide (25 equiv) to ensure complete conversion. It is
noteworthy that the (E)-alkene proved to be much easier to reduce
than the (Z)-isomer; if fewer equivalents of reagent were applied
then the (Z)-isomer was recovered and this compound could not
then be removed at a later stage. Subsequent silylation proved facile
(TBSOTf, 2,6-lutidine) and afforded the key deconjugation pre-
cursor 41 in 88% yield over the two steps. Perhaps unsurprisingly, if
the order of the last two steps was reversed then the troublesome
(Z)-isomer could be removed after silylation but then diimide re-
duction of the remaining (E)-isomer proved to be impossible
(Scheme 6).
To our disappointment, when the same conditions were applied
to substrate 41, no isomerisation occurred and only starting ma-
terial was recovered. Through a series of experiments we identified
that the desired reaction could be accomplished with KHMDS and
a rapid quench by pouring into stirred water. Though not ideal, this
afforded a 10:1 mixture of
a-23 and b-23 in 50% and 5% yield,
respectively,dthe remainder of the mixture was recovered starting
material (Scheme 8). The configuration of the
a-centre was
assigned by NOE studies41 and the tri-substituted alkene geometry
was also assigned the (E)-configuration by NOE studies;42 it should
be noted that the formation of an (E)-alkene is also in accord with
observations of Kende and Toder from their studies on the decon-
jugation of a,b-unsaturated esters for the synthesis of the litseno-
lide natural product family.43 Furthermore, if a longer reaction time
or more base was applied then none of the desired deconjugation
Me
OTf
CO2Me
Me
10 mol% Pd2(dba)3
40 mol% P(2-Fur)3
Me
OBn
Me
OH
O
CO2Me
O
n-Bu3Sn
OBn
N
DMF, 50 °C
N
O
OH
t-Bu
O
t-Bu
10:1 (E/Z) crude
25
26 (10:1 E/Z)
(E)-24, 87% [+4% (Z)-24]
p-TsNHNH2
KOAc
DME−H2O
Δ
Me
Me
OBn
OTBS
CO2Me
OBn
Me
Me
TBSOTf
2,6-lutidine
OH
O
CO2Me
O
N
CH2Cl2, 10 °C
N
O
O
t-Bu
t-Bu
41, 99%
40, 89%
Scheme 6. Stille cross-coupling and subsequent elaboration.
2.4. Deconjugation
product was obtained. Initially, the result of this deconjugation
appeared disheartening with the major product bearing the wrong
In order to introduce the necessary oxygenation, the deconju-
gation of -unsaturated lactam 41 to give the non-conjugated
configuration at the a-methyl centre. However, subsequent osmy-
lation studies showed this to be a serendipitous result.
a,
b
lactam 23 was required; this step was the cornerstone of our
strategy. We anticipated that deconjugation could be realised via
2.5. Oxidation/epimerisation
dienolate formation and kinetic protonation in the
afford the (E)-alkene 23. To our delight, model studies40 on simple
analogues without the -methyl group showed this could be
a-position to
The next step was to introduce the required C-3/C-4 oxygena-
a
tion and form the
lenging than expected as
environment around the tri-substituted olefin (Scheme 9). In fact,
-23 possessing the correct configuration at the C-2 methine centre
g-lactone ring; this proved to be more chal-
readily accomplished in high yield (Scheme 7); the structure of the
product was also secured by X-ray crystallography,40 confirming
the (E)-alkene configuration.
a
result of the crowded steric
b
proved to be inert to dihydroxylation under any of the conditions
examined and we recovered solely the starting material. In con-
Me
Me
(i) LDA, −78 °C, THF, 2 h
trast, although
a
-23 also displayed retarded reactivity, we were
-42 in 58% yield via classical
O
O
CO2Me
CO2Me
able to obtain tricyclic lactone core
a
(ii) aq. NH4Cl
N
N
stoichiometric dihydroxylation with concomitant lactonisation;
even then, six days at rt were required to ensure complete reaction.
In this respect, the failure of all the catalytic conditions we
attempted is unsurprising.44 Dihydroxylation proved to be entirely
facially selective, yielding a single oxidation product derived from
O
O
t-Bu
t-Bu
91%
Scheme 7. Model system for deconjugation.

10032
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
Me
Me
Me
OBn
OBn
OTBS
CO2Me
OBn
OTBS
CO2Me
(i) 2 eq. KHMDS,
THF, −78 °C
45 min
Me
Me
Me
OTBS
CO2Me
(ii) H2O quench
O
O
O
N
N
N
O
O
O
t-Bu
t-Bu
t-Bu
41
α-23, 50%
(92% BRSM)
β-23, 5%
(8% BRSM)
(+45% RSM)
Scheme 8. Deconjugation to afford the dihydroxylation precursor 23.
Synthetically, epimerisation could be accomplished under these
conditions in 76% yield to afford -42 (with 10% recovered starting
material -42). Having achieved the correct oxidation level and
rectified the stereochemistry of the -centre, the remaining chal-
lenges were to methylate the lactam nitrogen and reveal the al-
dehyde necessary for JuliaeKocienski coupling with sulfone 22.
Because of the requirement to perform several protecting group
manipulations, we examined several sequences to divine how best
this might be achieved with respect to the order of the steps. The
first step in all these sequences was acidic deprotection of the
oxazolidine moiety (under standard Corey conditions45) to afford
the poorly soluble triol 43 in 75% yield (Scheme 9).
Me
Me
OBn
b
Me
OsO4
NMO
OH
O
a
Me
OTBS
CO2Me
OBn
a
OTBS
O
O
4:1 t-BuOH-H2O
O
N
N
rt, 6 d
O
t-Bu
O
t-Bu
α-23
α-42, 58%
CHCl3, rt
10 mol% DBU
2.6. Lactam methylation
Me
Me
SH
HS
Me
OH
Me
OH
O
We examined several strategies for the lactam methylation with
the intention of accomplishing methylation without the need for
protecting some (or indeed all) of the hydroxyl groups. Un-
fortunately, we found that competitive methylation was unavoid-
able with the 1ꢁ/2ꢁ alcohols. Although it was possible to perform N-
methylation without 3ꢁ alcohol protection, we found that the di-
minished yields and skeletal rearrangements did not recommend
this approach. Our aspiration to effect an early introduction of the
acetate protecting groups present in 15 (and accomplish methyla-
tion on such a derivative) proved unsuccessful; thus, a strategy
involving the preparation of a tris-silyl derivative, preferably in
a single step, evolved. This process was complicated by the poor
solubility of triol 43 in anything but methanol or DMF. Attempted
TBS protection, even with an excess of TBSOTf, afforded only mono-
silyl derivative 44 (in 55% yield), presumably due to steric hin-
drance; application of the less hindered TESOTf led to double
silylation and the formation of 45 in 90% yield. In order to protect
the 3ꢁ alcohol functionality in 45 it was necessary to use a TMS
group and forcing conditions. Thus, 25 equiv of TMSOTf at ambient
temperature for 24 h afforded 46 as an approximately 3:1 mixture
of compounds 46/47 in 84% yield. The metathesis of one of the TES
groups with a TMS group proved unavoidable, since the use of
fewer equivalents of TMSOTf led to the reaction stalling. Though the
mixture of silyl isomers could be separated by careful chromatog-
raphy, this proved to be unnecessary. Methylation of the mixed
silylated lactam (n-BuLi/MeI/THF/ꢀ78 ꢁC), subsequent global silyl
deprotection with HCl and standard acetylation (Py/Ac2O) afforded
diacetate 50 in 69% yield over a straightforward three-step se-
quence (Scheme 10).
HCl(g)
OBn
OBn
OH
OTBS
O
O
O
O
O
CF3CH2OH, rt
N
N
H
O
t-Bu
OH
43, 75%
β-42, 76% (84% BRSM)
Scheme 9. Dihydroxylation and epimerisation.
attack on the concave face of alkene
counter-intuitive, this can be clearly inferred from the diagram
shown in Fig. 2.
a-23; although perhaps
Successful oxidation of the a-23 epimer necessitated inversion
of the configuration of the centre adjacent to the carbonyl group. In
this respect, we found that a catalytic amount of DBU (10 mol %)
was sufficient to effect epimerisation in an equilibrium process.
This isomerisation process was studied by 1H NMR spectroscopy on
discrete lactam core
a-42 and proved to be a slow equilibrium
process proceeding to >95% conversion over 24 h (Fig. 3)dof in-
terest was the observation that increasing the mol % of DBU used
served only to attenuate the desired reaction.
OsO4
convex face
hindered
Me
Me
O
OMe
O
N
2.7. Aldehyde reveal/JuliaeKocienski
R
O
H
OsO4
The required JuliaeKocienski partner 22 was obtained in three
steps from sulfide 51, an intermediate in our methodological study
of the synthesis of pentadienyl amines.28 Thus, in a facile fashion,
sequential acidic Boc cleavage (TFA) afforded amine 52 in 90% yield
concave face
R = t-Bu
more accesible
Fig. 2. Model for dihydroxylation of alkene a-23.

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10033
Fig. 3. 1H NMR study of the epimerisation of
a-42 to b-42.
and then Fmoc re-protection (Fmoc-Cl) in aqueous THF afforded
Fmoc sulfide 53 in 87% yield. Oxidation of this precursor proved
frustratingly difficult, surprisingly so given our previous success
with similar substrates. The problem proved to be the formation of
side-product 55 via [2,3]-sigmatropic rearrangement46 of the in-
termediate allylic sulfoxide 54 and subsequent hydrolysis. Ulti-
mately, this problem was circumvented by the use of
a polyoxometallate-catalysed47 oxidation using high concentration
with a vast excess of hydrogen peroxide (30 equiv) to increase the
rate of the second oxidation relative to the undesired [2,3]-
sigmatropic rearrangement; this afforded 54% of the desired sul-
fone 22 (Scheme 11).
acetate migration from the secondary to primary alcohol com-
menced, but none of this could be detected after 1 h. The primary
alcohol was then oxidised to the corresponding aldehyde 21 in 51%
yield via a DMP oxidation. Although this reaction proved prob-
lematic, the product rapidly decomposes under other oxidation
conditions, e.g., Swern, Ley-Griffith, success was ultimately ach-
ieved with an excess of DMP (3.3 equiv) and a short reaction time
(45 min). The product obtained from rapid chromatography was
then subjected to the key JuliaeKocienski olefination step.28
Treatment of sulfone 22 with a single equivalent of NaHMDS at
ꢀ78 ꢁC and then addition of aldehyde 21 afforded after 1 h at
ꢀ78 ꢁC a 4.5:1 mixture of (4E,6E)/(4Z,6E) isomers. Careful chro-
matography afforded the desired Kende intermediate, (4E,6E)-15, in
63% yield along with 14% of the isomer (4Z,6E)-15. The data ob-
The end-game sequence commenced with careful deprotection
of the benzyl group [Pd(OH)2eC/H2/1 h] to afford primary alcohol
56. If the reaction was left to proceed for longer periods a process of
tained corresponded well to those reported by Kende, e.g., ½a D
ꢂ
Me
OR
Me
Me
Me
OTMS
OTMS
TESOTf
2,6-lutidine
TMSOTf
Me
Me
Me
Me
OH
OH
2,6-lutidine
OBn
OBn
OBn
OBn
OTES
OTES
O
T
O
O
O
O
O
O
O
O
CH2Cl2, rt
DMF, rt
N
N
N
N
M
S
H
H
H
H
O
O
O
O
OH
OTES
OTES
OTES
~3:1, 84%
R = H, 43
45, 90%
46
47
(a)
R = TBS, 44 (55%)
n-BuLi
MeI
THF, −78 °C to rt
Me
Me
Me
OTMS
Me
Me
Me
OH
OH
Ac2O/pyridine
rt
HCl(g)
OBn
OBn
OBn
OAc
O
OH
OSiR3
O
O
O
O
O
CF3CH2OH
rt
N
Me
N
Me
N
Me
O
O
O
OAc
OH
49
OTES
50, 69%, 3-steps
48
Scheme 10. Lactam methylation. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, DMF, rt.

10034
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
Ph
S
Ph
S
4. Experimental
N
N
TFA
N
N
N
Boc
N
N
N
NH2
CH2Cl2, rt
N
Boc
4.1. General experimental detail
51
52, 90%
1H NMR and 13C NMR spectra were recorded on either a JEOL
ECX400 spectrometer operating at 400 MHz and 100 MHz, re-
spectively, or a Bruker AV500 spectrometer operating at 500 MHz
and 125 MHz, respectively. All spectral data was acquired at 295 K.
Chemical shifts are quoted in parts per million (ppm) using the
residual solvent peak as an internal standard (1H NMR 7.26 ppm for
CHCl3 and 13C NMR 77.0 ppm for CDCl3; 1H NMR 4.84 (s), 3.31
(quintuplet) and 13C NMR 49.05 (septuplet) for D3COD). Coupling
constants (J) are reported in Hertz to the nearest 0.1 Hz. Signal
assignments were accomplished via analysis of COSY, NOESY, HSQC
and HMBC experiments where necessary. Infrared spectra were
recorded on a ThermoNicolet IR100 spectrometer using NaCl plates.
Low and high-resolution mass spectra were obtained for all novel
compounds. Electrospray ionization (ESI) spectra were measured
on a Bruker MicrOTOF spectrometer and electron ionization (EI)
spectra on a Waters GCT Premier Spectrometer. Melting points
were determined using Gallenkamp apparatus and are uncorrected.
Thin layer chromatography (TLC) was performed using Merck silica
gel 60 F254 pre-coated aluminium-backed plates. The compounds
were visualized using UV light (254 nm) and the stain specified.
Fmoc-Cl
NaHCO3
THF-H2O (2:1)
H2O2
Ph
H
O
Ph
Mo7O24(NH4)6
N
N
N
S
N
Fmoc
H
N
N
O
N
EtOH, rt
[2,3]
N
S
Fmoc
N
N
22, 54%
53, 87%
Ph
N
N
N
H2O
Fmoc
N
N
H
S
O
H
OH
N
Fmoc
55
54
Scheme 11. Preparation of the JuliaeKocienski sulfone.
þ2.0, lit.18 þ3.6; nmax 1771, 1728 cmꢀ1, lit.18 1780, 1730 cmꢀ1
; dH
(CDCl3) 5.56 (1H, dd, J 15.0, 7.0 Hz, H-8), lit.18 5.59 (1H, dd, J 14.6,
6.9 Hz, H-8); and the majority of the data reported by Hata-
keyama.19 Significantly, our 13C NMR data were different in several
respects to Hatakeyama’s although through careful 2D analysis and
assignment of all the signals we were confident in the fidelity of our
datadProfessor Hatakeyama subsequently confirmed there were
errors in his published 13C NMR data (Scheme 12).48
Flash chromatography was performed at medium pressure using
ꢀ
slurry packed Fluka silica gel 35e70
m
m, 60 A with the eluant
specified. Petrol refers to the fraction of petroleum ether with bp
40e60 ꢁC. Tetrahydrofuran was distilled from sodium-
benzophenone ketyl immediately before use. Anhydrous toluene
and dichloromethane were obtained from an MBraun SPS solvent
Me
Me
Me
Me
Me
Me
OH
OH
OH
H2
DMP
OBn
OH
O
OAc
OAc
OAc
O
O
O
O
O
O
CH2Cl2, rt
Pd(OH)2-C
MeOH, rt
N
Me
N
Me
N
Me
O
O
O
OAc
OAc
OAc
50
56, quantitative
21, 51%
Me
Fmoc
N
H
Me
Ph
H
N
OH
O
S
2 steps
NaHMDS
THF, −78 °C to rt
OAc
N
9
Fmoc
O
N
O
O
Refs
N
N
Me
N
18, 19
O
OAc
(4E, 6E)-15, 63%
22
[+ 14% (4Z, 6E)-15]
Scheme 12. The neooxazolomycin end-game.
3. Conclusion
purification system. Water refers to deionised water. All numbering
on the structures below is for the benefit of structural assignment
and does not conform to IUPAC rules.
We have completed
a 23-step formal synthesis of neo-
oxazolomycin with the preparation of Kende’s key intermediate 15.
In contrast to the previously reported approaches by Kende18 and
Hatakeyama19 who used mid-stage cyclisation events to form the
lactam, our distinct approach commenced with the formation of
the lactam via Moloney’s tetramic acid chemistry and features
a modular route to achieve the union of three key fragments via key
Stille coupling and JuliaeKocienski olefination. The elaboration of
the Stille adduct was accomplished with a strategic deconjugation/
dihydroxylation sequence to achieve the stereoselective construc-
tion of the bicyclic core.
Except where specified, all reagents were purchased from
commercial sources and were used without further purification.
(E)-3-(Trimethylsilyl)but-2-en-1-ol 29 was prepared according to
the procedure of Denmark and co-workers.37 The solution of tert-
butylhydroperoxide in dichloromethane was obtained from an
anhydrous solution of tert-butylhydroperoxide in toluene (pre-
pared according to the Sharpless protocol38) by careful concentra-
tion and re-dissolution of the neat tert-butylhydroperoxide in
dichloromethane. (E)-Di-tert-butyl (4-(1-phenyl-1H-tetrazol-5-
ylthio)but-2-enyl)iminodicarbonate 51 was synthesised according

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10035
to our previous procedure.28 Compounds 30e33 were prepared
chromatography (SiO2, 4:1 petrol/EtOAc) to afford the title com-
according to the report of Moloney and co-workers.34
pound, 34, (5.50 g, 85%) as a colourless oil. Rf (3:1 petrol/EtOAc)
0.16; ½a 2D3
ꢂ
ꢀ13.9 (c 1.00, CHCl3); nmax 3437, 2958, 1743, 1250, 1105,
4.2. Specific compound procedures
1028, 843, 752 cmꢀ1
; dH (400 MHz, CDCl3) 3.82 (1H, dd, J 12.0,
4.0 Hz, CH2(2a)), 3.69 (1H, dd, J 12.0, 6.5 Hz, CH2(2b)), 2.98 (1H, dd, J
6.5, 4.0 Hz, CH(3)), 1.21 (3H, s, CH3(5)), 0.00 (9H, s, CH3(6)); dC
(100 MHz, CDCl3) 61.2 (CH2(2)), 60.0 (CH(3)), 54.9 (C(4)), 14.7
(CH3(5)), ꢀ4.3 (CH3(6)); m/z (ESI): 161 (MHþ), 183 (MNaþ); HRMS
(ESI): MNaþ, found 183.0814. C7H16NaO2Si requires 183.0812
(1.2 ppm error).
4.2.1. (3S,7aS)-Methyl 3-tert-butyl-6-methyl-5-oxo-7-(trifluorome-
thylsulfonyloxy)-1,3,5,7a-tetrahydropyrrolo[1,2-c]oxazole-7a-carbox-
ylate 25.
F
F
F
12
O S
O
4.2.3. [(2S,3S)-3-Methyl-3-(trimethylsilyl)oxiranyl]methyl (2R)-3,3,
3-trifluoro-2-methoxy-2-phenylpropanoate 35.
O
Me
O
2
9
3
11
10
1
12
4
6
OMe
2
O
11
13
N
5
Me
O
1
5
3
O
7
Me
Me
8
7
10
6
Si
Me
O
4
O
F3C OMe
9
8
To a solution of lactam 33 (62.3 g, 231 mmol) in CH2Cl2 (1.5 L) was
added, via syringe, i-Pr2NEt (44.4 mL, 254 mmol). The resultant so-
lution was cooled to ꢀ50 ꢁC and triflic anhydride (42.0 mL,
254 mmol) added via syringe pump over 1 h 15 min. Once the ad-
dition was complete, the reaction mixture was stirred at ꢀ50 ꢁC for
15 min then warmed to rt and transferred to a separating funnel
containing CH2Cl2 (2.0 L). The organic layers were washed with
water (3ꢃ500 mL), dried (MgSO4), filtered and concentrated in
vacuo. The residue was passed twice through a plug of silica
(CH2Cl2), then recrystallised (pentane) to afford the title compound
(16) (65.0 g, 70%) as a cream coloured microcrystalline solid; mp
60e62 ꢁC; Rf (9:1 petrol/Et2O) 0.28; nmax 1754, 1733, 1689, 1436,
To a stirred solution of epoxide 34 (11.0 mg, 68.0
8.0 mol) in CH2Cl2 (1 mL) at
mol) and (R)-(ꢀ)-MTPA (19 mg, 81.0
0 ꢁC was added DCC (17 mg, 82.0
mol). The mixture was stirred for
mmol), DMAP (1 mg,
m
m
m
30 min at 0 ꢁC and then the volatiles were evaporated in vacuo. The
residue was taken up in Et2O (5 mL) and filtered through a small SiO2
plug. The resultant residue was then purified by flash silica column
chromatography (SiO2, 19:1 petrol/EtOAc) to afford the title com-
pound, 25, (15 mg, 40.0
separable 94:6 mixture of diastereomers. Rf (9:1 petrol/Et2O) 0.29;
a 2D0
mmol, 58%) as a colourless oil and an in-
½
ꢂ
þ33.3(c0.73, CHCl3);nmax 2958,1753,1251,1171,1122,1022, 841,
719 cmꢀ1; m/z (CI, NH3): 394 (MNHþ4 , 52), 377 (MHþ, 50), 90 (100%).
Major diastereomer: dH (400 MHz, C6D6) 7.65 (2H, dd, J 7.5,1.0 Hz,
CH(11)), 6.95e7.08 (m, 3H, CH(12 and 13)), 4.25 (1H, dd, J 12.0,
6.5 Hz, CH2(5a)), 4.08 (1H, dd, J 12.0, 5.0 Hz, CH2(5b)), 3.39 (s, 3H,
CH3(9)), 2.83 (1H, dd, J 6.5, 5.0 Hz, CH(4)), 0.97 (3H, s, CH3(2)),
ꢀ0.18 (9H, s, CH3(1)).
1230,1137,1110, 819 cmꢀ1; ½a D21
ꢀ106.5 (c 1.25, CHCl3); dH (400 MHz,
ꢂ
CDCl3) 4.79 (1H, d, J 8.5 Hz, CH2(5a)), 4.71 (1H, s, CH(6)), 3.79 (3H, s,
CH3(11)), 3.48 (1H, d, J 8.5 Hz, CH2(5b)),1.91 (3H, s, CH3(9)), 0.93 (9H,
s, CH3(8)); dC (100 MHz, CDCl3) 173.7 (C]O(10)), 166.7 (C]O(1)),
154.8 (C(3)), 127.2 (C(2)), 118.2 (d, JCF 319 Hz, CF3(12)), 96.7 (CH(6)),
74.1 (C(4)), 70.6 (CH2(5)), 53.6 (CH3(11)), 35.1 (C(7)), 24.6 (CH3(8)),
8.1 (CH3(9)); m/z (ESI): 402 (MHþ); HRMS (ESI): MHþ, found
402.0841. C14H19F3NO7S requires 402.0834 (1.5 ppm error).
Minor diastereomer: Same as above except, dH (C6D6) 4.17 (1H, d,
J 6.0 Hz, CH2(5a)), 4.16 (1H, d, J 6.0 Hz, CH2(5b)), 3.38 (3H, s, CH3(9)),
2.90 (1H, dd, J 6.0, 6.0 Hz, CH(4)), 0.97 (3H, s, CH3(2)), ꢀ0.17 (9H, s,
CH3(1)).
4.2.2. [(2S,3S)-3-Methyl-3-(trimethylsilyl)oxiranyl]methanol 34.
4.2.4. [(2S,3S)-3-Methyl-3-(trimethylsilyl)oxiranyl]methyl (2S)-3,3,
5
3-trifluoro-2-methoxy-2-phenylpropanoate 36.
Me
6
2
4
1
Me
Me
12
Si
OH
2
3
11
13
O
Me
O
1
Me
Me
Me
5
3
7
10
6
Si
Me
O
A solution of allylic alcohol 19 (5.86 g, 40.6 mmol) in CH2Cl2 (90 mL)
(pre-stirred with 3 A molecular sieves (3 g) for 30 min), was cooled
L-tartrate (0.57 mL, 2.40 mmol) then
Ti(Oi-Pr)4 (0.57 mL, 2.00 mmol), (both of which were pre-dried over
4
O
F3C OMe
ꢀ
9
8
to ꢀ20 ꢁC and (þ)-diisopropyl
To a stirred solution of epoxide 34 (12.0 mg, 75.0
(1 mg, 8.0 mol) in CH2Cl2
mol) and (S)-(ꢀ)-MTPA (21 mg, 90.0
(1 mL) at 0 ꢁC was added DCC (19 mg, 92.0
mol). The mixture was
mmol), DMAP
ꢀ
3 A molecular sieves) added via syringe. The reaction mixture was
m
m
stirred for 1.5 h before the addition of tert-butylhydroperoxide
([3.50 M in CH2Cl2], 12.0 mL, 6.50 mmol) added and then stirred for
a further 21 h, maintaining at ꢀ20 ꢁC. At this time the reaction
mixture was warmed to rt and quenched with a solution of citric
acid (463 mg, 2.40 mmol) in EtOAc/Me2CO (9:1, 50 mL). The
quenched solution was stirred at rt for 2 h and then concentrated in
vacuo. The residue was dissolved in EtOAc (100 mL) and filtered
through CeliteÒ rinsing with EtOAc (2ꢃ100 mL). Water (300 mL)
was added, the layers separated and the aqueous extracted with
EtOAc (6ꢃ200 mL). The combined organics were stirred for 1 h with
a solution of saturated aqueous sodium sulfite (300 mL) to destroy
residual tert-butylhydroperoxide. The layers were separated, the
aqueous extracted with EtOAc (4ꢃ300 mL), the combined organics
washed with brine (200 mL), dried (MgSO4), filtered and concen-
trated in vacuo. The crude residue was purified by flash
m
stirred for 30 min at 0 ꢁC and then the volatiles were evaporated in
vacuo. The residue was taken up in Et2O (5 mL) and filtered through
a small SiO2 plug. The resultant residue was then purified by flash
silica column chromatography (SiO2, 19:1 petrol/EtOAc) to afford
the title compound, 26, (18 mg, 48.0 mmol, 90%) as a colourless oil
and an inseparable 95:5 mixture of diastereomers. Rf (9:1 petrol/
Et2O) 0.29; ½a 2D0
ꢀ49.4 (c 0.85, CHCl3); nmax 2958, 1753, 1251, 1171,
ꢂ
1122, 1022, 841, 754 cmꢀ1; HRMS (ESI): MHþ, found 377.1403.
C17H24F3O4Si requires 377.1396 (1.9 ppm error).
Major diastereomer: dH (400 MHz, C6D6) 7.65 (2H, d, J 7.5 Hz,
CH(11)), 6.94e7.08 (m, 3H, CH(12 and 13)), 4.17 (1H, d, J 6.0 Hz,
CH2(5a)), 4.16 (1H, d, J 6.0 Hz, CH2(5b)), 3.38 (3H, s, CH3(9)), 2.90
(1H, dd, J 6.0, 6.0 Hz, CH(4)), 0.97 (3H, s, CH3(2)), ꢀ0.17 (9H, s,
CH3(1)).

10036
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
Minor diastereomer: Same as above except, dH (C6D6) 4.25 (1H,
4.2.7. (2R,3R)-1-[(Benzyloxy)-3-methyl-5-trimethylsilylpent-4-yn-2-
ol 38.
dd, J 12.0, 6.5 Hz, CH2(5a)), 4.08 (1H, dd, J 12.0, 5.0 Hz, CH2(5b)),
3.39 (s, 3H, CH3(9)), 2.83 (1H, dd, J 6.5, 5.0 Hz, CH(4)), ꢀ0.18 (9H, s,
CH3(1)).
13
Me
6
9
7
3
5
8
The er of the epoxide 34 was therefore determined to be 95:5.
10
11
2
4
O
Me
Me
Si
Me
OH
4.2.5. (2S,3S)-3-[(Benzyloxy)methyl]-2-methyloxiranyl(trimethyl)si-
lane 37.
12
1
2
Me
O
1
Me
Me
5
6
8
To a solution of trimethylsilylacetylene (8.2 mL, 58.1 mmol,
1.07 equiv) in Et2O (300 mL) at ꢀ78 ꢁC was added dropwise via
syringe over 10 min n-butyllithium [1.57 M in hexanes] (37.0 mL,
58.1 mmol, 1.07 equiv). The reaction mixture was stirred at ꢀ78 ꢁC
for 40 min then trimethylaluminium [2.0 M in hexanes] (29.1 mL,
58.1 mmol, 1.07 equiv) added via syringe pump over 60 min. The
reaction mixture was then warmed to ꢀ40 ꢁC and stirred for 1 h,
after which time it was re-cooled to ꢀ78 ꢁC. Epoxide 28 (9.68 g,
54.3 mmol, 1.00 equiv) in Et2O (25 mL) was added via cannula over
25 min and the mixture stirred for 15 min then 3$OEt2 (8.0 mL,
65.2 mmol, 1.2 equiv) added via syringe pump over 15 min. Once
addition was complete the solution was stirred for 15 min then
quenched with saturated aqueous ammonium chloride (250 mL)
and allowed to warm to rt. The layers were separated, the aqueous
extracted with Et2O (5ꢃ250 mL), the combined organics washed
with brine (100 mL), dried (MgSO4), filtered and concentrated in
vacuo to afford the title compound, 38, (14.6 g, 53.0 mmol, 97%) as
a yellow oil in a 15:1 inseparable mixture of regioisomers. Rf (1:1
3
Si
Me
7
9
O
4
10
To a stirred solution of epoxide 34 (15.3 g, 95.4 mmol, 1.0 equiv) in
THF (250 mL) at 0 ꢁC was added in four portions sodium hydride
(60% dispersion in mineral oil, 4.80 g, 120 mmol, 1.25 equiv). The
solution was stirred at 0 ꢁC for 1 h then benzyl bromide (12.9 mL,
109 mmol, 1.1 equiv) and tetrabutylammonium iodide (1.85 g,
5.00 mmol, 0.05 equiv) were added. The reaction was stirred for
16 h warming from 0 ꢁC to rt then quenched with aqueous satu-
rated ammonium chloride (250 mL). The resultant solution was
transferred to a separating funnel containing water (250 mL) and
Et2O (500 mL), the layers separated and the aqueous extracted with
Et2O (3ꢃ500 mL). The combined organic layers were washed with
brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo
to afford the title compound (37) (20.4 g, 81.1 mmol, 85%) as an
orange oil contaminated with residual benzyl bromide (6.8 g). A
sample was purified for characterisation by flash chromatography
(SiO2, 9:1 petrol/Et2O) to afford 37 as a colourless oil. Rf (9:1 petrol/
petrol/Et2O) 0.37; ½a D22
ꢂ
þ28.5 (c 1.30, CHCl3); nmax 3455, 3031, 2960,
2900, 2873, 2167, 1453, 1368, 1250, 1099 cmꢀ1
;
dH (400 MHz, CDCl3)
7.28e7.39 (5H, m, CH(9, 10 and 11)), 4.57 (2H, s, CH2(7)), 3.71 (1H,
ddd, J 6.5, 6.0, 4.5 Hz, CH(5)), 3.58 (1H, dd, J 9.5, 4.5 Hz, CH2(6a)),
3.54 (1H, dd, J 9.5, 6.5 Hz, CH2(6b)), 2.80 (1H, qd, J 7.0, 4.5 Hz,
CH(4)), 2.39 (1H, d, J 6.0 Hz, OH(12)), 1.22 (3H, d, J 7.0, CH3(13)), 0.15
(9H, s, CH3(1)); dC (100 MHz, CDCl3) 138.0, (C(8)), 128.5 (CH), 127.8
(CH), 127.8 (CH), 107.1 (C(3)), 87.3 (C(2)), 73.4 (CH2(7)), 72.6 (CH(5)),
72.0 (CH2(6)), 30.7 (CH(4)), 17.0 (CH3(13)), 0.2 (CH3(1)); m/z (ESI):
277 (MHþ); HRMS (ESI): MHþ found 277.1625. C16H25O2Si requires
277.1618 (2.4 ppm error).
Et2O) 0.26; ½a 2D2
ꢂ
ꢀ4.1 (c 2.85, CHCl3); nmax 2956, 2858, 1454, 1248,
1101, 840, 748, 696 cmꢀ1
;
dH (400 MHz, CDCl3) 7.27e7.31 (5H, m,
CH(8, 9 and 10)), 4.65 (1H, d, J 12.0 Hz, CH2(6a)), 4.54 (1H, d, J
12.0 Hz, CH2(6b)), 3.77 (1H, dd, J 11.0, 4.5 Hz, CH2(5a)), 3.60 (1H, dd,
J 11.0, 6.0 Hz, CH2(5b)), 3.04 (1H, dd, J 6.0, 4.5 Hz, CH(4)), 1.21 (3H, s,
CH3(2)), 0.05 (9H, s, CH3(1)); dC (100 MHz, CDCl3) 138.0 (C(7)), 128.4
(CH(8)), 127.7 (CH(9)), 127.7 (CH(10)), 73.1 (CH2(6)), 68.9 (CH2(5)),
58.3 (CH(4)), 53.5 (C(3)),14.8 (CH3(2)), ꢀ4.2 (CH3(1)); m/z (ESI): 251
(MHþ), 273 (MNaþ); HRMS (ESI): MNaþ found 273.1276.
C14H22NaO2Si requires 273.1281 (1.9 ppm error).
4.2.8. (2R,3R)-1-(Benzyloxy)-3-methyl-4-pentyn-2-ol 39.
12
4.2.6. (2S,3R)-2-[(Benzyloxy)methyl]-3-methyloxirane 28.
Me
5
8
6
2
4
7
1
9
1
3
O
Me
4
5
7
2
6
OH
10
8
9
11
O
3
O
To a solution of alkyne 38 (3.60 g, 13.1 mmol, 1.0 equiv) in THF
(170 mL) at 0 ꢁC was added dropwise via syringe tetra-n-buty-
lammonium fluoride [1.0 M in THF] (14.4 mL, 14.4 mmol, 1.1 equiv)
solution and the resultant mixture stirred for 1 h at 0 ꢁC. At this
time the reaction was concentrated in vacuo and the crude purified
by flash chromatography (SiO2, 1:1 petrol/Et2O) to afford the title
compound, 39, (2.30 g, 11.3 mmol, 86%) as a colourless oil. Rf (1:1
To epoxide 37 (19.8 g, 79.2 mmol, 1.0 equiv) in THF (250 mL) was
added tetra-n-butylammonium fluoride ([1.0 M in THF], 95.0 mL,
95.0 mmol, 1.2 equiv) and the reaction mixture heated to reflux for
4 h. At this time, the mixture was concentrated in vacuo and the
crude purified by flash chromatography (SiO2, 4:1 petrol/Et2O) to
afford the title compound, 28, (12.0 g, 67.3 mmol, 85%) as a col-
ourless oil. Rf (4:1 petrol/Et2O) 0.25; ½a D21
ꢂ
þ15.5 (c 2.20, CHCl3), lit.50
petrol/Et2O) 0.44; ½a D26
ꢂ
þ20.5 (c 1.15, CHCl3); nmax 3428, 3294, 2873,
þ17.7 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 7.26e7.39 (5H, m, CH(7, 8
and 9)), 4.65 (1H, d, J 12.0 Hz, CH2(6a)), 4.54 (1H, d, J 12.0 Hz,
CH2(6b)), 3.69 (1H, dd, J 11.0, 4.5 Hz, CH2(5a)), 3.57 (1H, dd, J 11.0,
6.0 Hz, CH2(5b)), 3.18 (1H, ddd, J 6.0, 4.5, 4.5 Hz, CH(3)), 3.10 (1H, qd,
J 5.5, 4.5 Hz, CH(2)), 1.27 (3H, d, J 5.5 Hz, CH3(1)); dC (100 MHz,
CDCl3) 137.8 (C(6)), 128.3 (CH(7)), 127.6 (CH(8)), 127.6 (CH(9)), 73.1
(CH2(5)), 68.0 (CH2(4)), 54.9 (CH(3)), 51.6 (CH(2)), 13.2 (CH3(1)); m/
z (ESI): 179 (MHþ), 201 (MNaþ); HRMS (ESI): MNaþ found 201.0887.
C11H14NaO2 requires 201.0886 (0.3 ppm error). The spectral data
were consistent with those reported.49
1454, 1367, 1207, 1099, 739, 698 cmꢀ1
; dH (400 MHz, CDCl3)
7.28e7.39 (5H, m, CH(8, 9 and 10)), 4.57 (2H, s, CH2(6)), 3.74 (1H,
dddd, J 7.0, 5.0, 4.5, 4.5 Hz, CH(4)), 3.59 (1H, dd, J 9.5, 4.5 Hz,
CH2(5a)), 3.55 (1H, dd, J 9.5, 7.0 Hz, CH2(5b)), 2.75 (1H, qdd, J 7.5,
4.5, 2.5 Hz, CH(3)), 2.40 (1H, d, J 5.0 Hz, OH(11)), 2.13 (1H, d, J 2.5 Hz,
CH(1)), 1.25 (3H, d, J 7.5 Hz, CH3(12)); dC (100 MHz, CDCl3) 137.7
(C(7)), 128.3 (CH), 127.6 (CH), 84.7 (C(2)), 73.3 (CH2(6)), 72.3
(CH(4)), 72.0 (CH2(5)), 70.6 (CH(1)), 29.2 (CH(3)), 16.9 (CH3(12)); m/
z (ESI): 205 (MHþ), 227 (MNaþ); HRMS (ESI): MNaþ found 227.1044.
C13H16NaO2Si requires 227.1043 (0.8 ppm error).

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10037
4.2.9. (2R,3R,4E)-1-(Benzyloxy)-3-methyl-5-(tri-n-butylstannyl)-4-
penten-2-ol 26.
concentrated in vacuo, then water (50 mL) and CH2Cl2 (50 mL)
added. The layers were separated and the aqueous extracted
CH2Cl2 (3ꢃ50 mL), the combined organics were washed with brine
(50 mL) dried (MgSO4), filtered and concentrated in vacuo. The
crude mixture was purified by careful flash chromatography (SiO2,
3:2/1:1 petrol/EtOAc) to afford the title compound, (1E)-24,
(3.28 g, 7.17 mmol, 87%) and isomer (1Z)-24 (0.15 g, 0.33 mmol,
4%) as viscous yellow oils that solidified as yellow glasses upon
standing.
Me
12
Me
5
1
8
6
Me
4
7
9
3
Sn
O
2
OH
10
13
14
11
(1E)-24: Rf (3:2 petrol/Et2O) 0.20; ½a D25
ꢀ74.8 (c 1.10, CHCl3);
ꢂ
15
Me
nmax 3464, 2960, 2927, 2870, 1746, 1712, 1650, 1455, 1359, 1278,
16
1228,1119 cmꢀ1
; dH (400 MHz, CDCl3) 7.28e7.39 (5H, m, CH(1, 2 and
To alkyne 39 (11.6 g, 56.8 mmol, 1.0 equiv) was added tri-n-
butyltin hydride (26 mL, 96.5 mmol, 1.7 equiv) at rt. The neat re-
action mixture was stirred and gently heated to 80 ꢁC then AIBN
(1.86 g, 11.4 mmol, 0.20 equiv) added portionwise. [Caution: upon
initial addition of AIBN the internal temperature raises to 130 ꢁC
and vigorous nitrogen evolution is observed!] Once the reaction
cooled to 80 ꢁC the slow portionwise addition of AIBN is continued
to maintain constant temperature. The reaction was then stirred at
80 ꢁC for 50 min before being cooling to rt and directly purified by
flash chromatography (SiO2, 4:1 petrol/Et2O) to afford the title
compound, 26, as a viscous colourless oil (18.8 g, 37.9 mmol, 67%)
and an inseparable 10:1 E/Z mixture. Data given for (E)-26: Rf (4:1
3)), 6.30 (1H, d, J 16.5 Hz, CH(12)), 5.95 (1H, dd, J 16.5, 7.5 Hz,
CH(11)), 4.89 (1H, d, J 8.5 Hz, CH2(20a)), 4.65 (1H, s, CH(21)), 4.55
(2H, s, CH2(5)), 3.64e3.73 (4H, m, CH(7) and CH3(19)), 3.50 (1H, dd,
J 9.5, 3.5 Hz, CH2(6a)), 3.37 (1H, dd, J 9.5, 7.5 Hz, CH2(6b)), 3.22 (1H,
d, J 8.5 Hz, CH2(20b)), 2.46 (1H, qdd, J 7.5, 6.5, 6.5 Hz, CH(9)), 2.28
(1H, br s, OH(8)), 1.89 (3H, s, CH3(15)), 1.06 (3H, d, J 6.5 Hz, CH3(10)),
0.92 (9H, s, CH3(23)); dC (100 MHz, CDCl3) 178.8 (C]O(16)), 170.6
(C]O(18)), 149.6 (C(13)), 140.9 (CH(11)), 137.8 (C(4)), 130.8 (C(14)),
128.6 (CH), 128.0 (CH), 127.9 (CH), 120.9 (CH(12)), 96.1 (CH(21)),
75.6 (C(17)), 73.6 (CH2(5)), 73.5 (CH(7)), 72.4 (CH2(6)), 70.3
(CH2(20)), 53.0 (CH3(19)), 40.7 (CH(9)), 35.3 (C(22)), 24.8 (CH3(23)),
16.2 (CH3(10)), 9.3 (CH3(15)); m/z (ESI): 458 (MHþ), 480 (MNaþ);
HRMS (ESI): MNaþ found 480.2354. C26H35NNaO6 requires
480.2357 (0.3 ppm error).
petrol/Et2O) 0.36; ½a D21
ꢂ
þ13.6 (c 1.96, CHCl3); nmax 3455, 3030,
2957, 2925, 2871, 1655, 1597, 1455, 1375, 1095, 999 cmꢀ1
;
dH
(400 MHz, CDCl3) 7.28e7.38 (5H, m, CH(8, 9 and 10)), 5.85e6.07
(2H, m, CH(1 and 2)), 4.59 (2H, s, CH2(6)), 3.66e3.69 (1H, m,
CH(4)), 3.54 (1H, dd, J 9.5, 3.0 Hz, CH2(5a)), 3.42 (1H, dd, J 9.5,
7.5 Hz, CH2(5b)), 2.40 (1H, qdd, J 7.0, 6.5, 6.5 Hz, CH(3)), 2.23 (1H,
d, J 3.0 Hz, OH(11), 1.44e1.52 (6H, m, CH2(15)), 1.25e1.34 (6H, m,
CH2(14)), 1.03e1.06 (3H, d, J 7.0 Hz, CH3(12)), 0.85e0.92 (15H, m,
CH2(13) and CH3(16)); dC (100 MHz, CDCl3) 150.3 (CH(1)), 138.2
(C(7)), 129.6 (CH(2)), 128.6 (CH), 127.8 (CH), 127.8 (CH), 73.5
(CH(4)), 73.5 (CH2(6)), 72.6 (CH2(5)), 44.7 (CH(3)), 29.2 (CH2(15)),
27.4 (CH2(14)), 16.3 (CH3(12)), 13.9 (CH3(16)), 9.6 (CH2(13)); m/z
(CI, NH3): 497 MHþ(120Sn), 13), 439 (100), 308 (46), 291 (41), 91
(62%). HRMS (CI, NH3): MH (116Sn)þ found 493.2428. C25H45O1216Sn
requires 493.2437 (0.1 ppm error).
(1Z)-24: Rf (3:2 petrol/Et2O) 0.19; ½a D25
ꢀ112.5 (c 1.10, CHCl3);
ꢂ
nmax 3464, 2960, 2927, 2870, 1746, 1712, 1650, 1455, 1359, 1278,
1228, 1119 cmꢀ1
; dH (400 MHz, CDCl3) 7.28e7.39 (5H, m, CH(1,2 and
3)), 5.77 (1H, dd, J 11.5, 10.5 Hz, CH(11)), 5.65 (1H, dd, J 11.5, 1.0 Hz,
CH(12)), 4.73 (1H, d, J 8.5 Hz, CH2(20a)), 4.66 (1H, s, CH(21)), 4.54
(2H, s, CH2(5)), 3.71 (3H, s, CH3(19)), 3.60 (1H, m, CH(7)), 3.50 (1H,
dd, J 9.5, 3.0 Hz, CH2(6a)), 3.30 (1H, dd, J 9.5, 8.0 Hz, CH2(6b)), 3.27
(1H, d, J 8.5 Hz, CH2(20b)), 2.41 (1H, d, J 2.5 Hz, OH(8)), 2.29e2.39
(1H, m, CH(9)), 1.83 (3H, s, CH3(15)), 0.94 (3H, d, J 6.5 Hz, CH3(10)),
0.92 (9H, s, CH3(23)); dC (100 MHz, CDCl3) 178.8 (C]O(16)), 170.1
(C]O(18)), 149.7 (C(13)), 141.2 (CH(11)), 137.7 (C(4)), 132.1 (C(14)),
128.7 (CH),128.1 (CH),127.8 (CH),118.9 (CH(12)), 96.9 (CH(21)), 77.5
(C(17)), 73.6 (CH2(5)), 73.5 (CH(7)), 72.6 (CH2(6)), 70.8 (CH2(20)),
53.0 (CH3(19)), 41.0 (CH(9)), 37.2 (C(22)), 24.9 (CH3(23)), 16.8
(CH3(10)), 10.9 (CH3(15)); m/z (ESI): 458 (MHþ), 480 (MNaþ); HRMS
(ESI): MNaþ found 480.2352. C26H35NNaO6 requires 480.2357
(0.5 ppm error).
The 1H and 13C NMR spectra exhibited additional signals for
(4Z)-26: dH (400 MHz, CDCl3) 6.42 (1H, dd, J 12.5, 10.0 Hz, CH(2)),
4.56 (2H, m, CH2(6)), 2.28 (1H, d, J 3.0 Hz, OH(11)), 2.08e2.15 (1H,
m, CH(3)); dC (100 MHz, CDCl3) 130.3 (CH(2)), 17.7 (CH3(12)), 10.5
(CH2(13)).
4.2.11. (3S,7aR)-Methyl 7-((3R,4R)-5-(benzyloxy)-4-hydroxy-3-
methylpentyl)-3-tert-butyl-6-methyl-5-oxo-1,3,5,7a-tetrahy-
dropyrrolo[1,2-c]oxazole-7a-carboxylate 40.
4.2.10. (3S,7aR)-Methyl 7-((3R,4R,1E)-5-(benzyloxy)-4-hydroxy-3-
methylpent-1-enyl)-3-tert-butyl-6-methyl-5-oxo-1,3,5,7a-tetrahy-
dropyrrolo[1,2-c]oxazole-7a-carboxylate 24.
10
5
Me
4
10
5
6
Me
4
6
7
O
1
7
9
15
Me
14
O
11
13
1
3
9
15
Me
14
11
13
2
3
12 OH
2
8
12 OH
O
8
O
18
17
O
16
18
17
O
N
OMe
16
N
OMe
19
20
21
19
20
O
21
Me
Me
O
22
Me
Me
22
Me
23
Me
23
To a solution of triflate 25 (3.31 g, 8.20 mmol, 1.0 equiv) in
degassed DMF (40 mL), was added 2-trifurylphosphine (153 mg,
0.66 mmol, 0.08 equiv) and bis-palladium tris-dibenzylidenace-
tone (150 mg, 0.16 mmol, 0.02 equiv). The solution was stirred at rt
for 5 min changing colour from brown to orange. Stannane 26
(4.08 g, 8.2 mmol, 1.0 equiv) in degassed DMF (20 mL) was then
added via cannula. The reaction mixture was heated at 50 ꢁC for
15 h. Once the reaction was complete the solution was
To a solution of alkene (1E)-24 (7.22 g, 15.8 mmol, 1.0 equiv) in
DME (800 mL) was added p-tosylhydrazine (57.0 g, 306 mmol,
20 equiv) and the solution was heated to reflux. A solution of
aqueous sodium acetate [1.0 M] (306 mL, 306 mmol, 20 equiv) was
added dropwise over 1 h. The reaction mixture was heated at
reflux overnight, then further tosylhydrazine (20 g, 107 mmol,
6.8 equiv) and aqueous sodium acetate [1.0 M] (100 mL, 100 mmol,
6.3 equiv) added in single portions. The mixture was heated for

10038
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
a further 24 h then cooled to rt and concentrated in vacuo. To the
crude mixture was added aqueous sodium hydroxide
CH3(8)), 0.02 (3H, s, CH3(9)); dC (100 MHz, CDCl3) 179.2 (C]
O(19)), 170.4 (C]O(25)), 154.7 (C(16)), 138.2 (C(4)), 131.5 (C(17)),
128.5 (CH), 127.8 (CH), 127.8 (CH), 96.3 (CH(20)), 77.8 (C(24)), 75.2
(CH(7)), 73.5 (CH2(5)), 72.5 (CH2(21)), 70.9 (CH2(6)), 53.0
(CH3(26)), 36.0 (CH(12)), 35.3 (C(22)), 28.4 (CH2(14)), 26.0
(CH3(11)), 25.2 (CH2(15)), 24.9 (CH3(23)), 18.3 (C(10)), 16.2
(CH3(13)), 9.1 (CH3(18)), ꢀ4.1 (CH3(8)), ꢀ4.7 (CH3(9)); m/z (CI,
NH3): 574 (MHþ, 100%); HRMS (CI, NH3): MHþ found 574.3561.
C32H52NO6Si requires 574.3564 (0.6 ppm error).
3
M
(300 mL) and CH2Cl2 (3ꢃ250 mL) and this was stirred for 30 min
during, which time a white precipitate formed. The layers were
separated and the aqueous extracted with CH2Cl2 (3ꢃ250 mL). The
organics were filtered to remove the precipitated tosyl salts, dried
(MgSO4), filtered and concentrated in vacuo. The resulting crude
was purified by flash chromatography (SiO2, 1:1 petrol/Et2O) to
afford the title compound, 40, (6.45 g, 14.2 mmol, 89%) as a clear
glass. Rf (2:1 petrol/EtOAc) 0.32; nmax 3443, 2959, 2870, 1742, 1709,
1455, 1284, 1229, 1115 cmꢀ1; ½a D21
ꢂ
ꢀ129.2 (c 1.00, CHCl3); dH
4.2.13. Deconjugation of enone 41 under basic conditions. Prepara-
tion of (3S,6S,7aR,E)-methyl 7-((3R,4R)-5-(benzyloxy)-4-(tert-bu-
tyldimethylsilyloxy)-3-methylpentylidene)-3-tert-butyl-6-methyl-5-
(400 MHz, CDCl3) 7.28e7.37 (5H, m, CH(1, 2 and 3)), 4.79 (1H, d, J
8.5 Hz, CH2(20a)), 4.63 (1H, s, CH(21)), 4.56 (1H, d, J 12.0 Hz,
CH2(5a)), 4.53 (1H, d, J 12.0 Hz, CH2(5b)), 3.72 (3H, s, CH3(19)),
3.56 (1H, dd, J 9.0, 3.0 Hz, CH2(6a)), 3.48e3.54 (1H, m, CH(7)), 3.34
(1H, dd, J 9.0, 7.5 Hz, CH2(6b)), 3.21 (1H, d, J 8.5 Hz, CH2(20b)), 2.47
(1H, br s, OH(8)), 2.37 (1H, ddd, J 14.0, 9.5, 5.5 Hz, CH2(12a)), 2.10
(1H, dddd, J 14.0, 6.5, 5.0, 1.0 Hz, CH2(12b)), 1.79 (3H, d, J 1.0 Hz,
CH3(15)), 1.62 (1H, dddd, J 14.0, 9.5, 6.5, 3.5 Hz, CH2(11a)),
1.47e1.54 (1H, m, CH (9)), 1.23e1.27 (1H, m, CH2(11b)), 0.92 (9H, s,
CH3(23)), 0.87 (3H, d, J 7.0 Hz, CH3(10)); dC (100 MHz, CDCl3) 179.1
(C]O(16)), 170.4 (C]O(18)), 154.4 (C(13)), 137.8 (C(4)), 131.8
(C(14)), 128.6 (CH), 128.0 (CH), 127.9 (CH), 96.4 (CH(21)), 77.9
(C(17)), 73.9 (CH(7)), 73.6 (CH2(5)), 72.6 (CH2(6)), 71.0 (CH2(20)),
53.0 (CH3(19)), 35.8 (CH(9)), 35.3 (C(22)), 30.1 (CH2(11)), 24.8
(CH3(23)), 24.4 (CH2(12)), 15.2 (CH3(10)), 9.1 (CH3(15)); m/z (ESI):
460 (MHþ), 482 (MNaþ); HRMS (ESI): MNaþ found 482.2522.
C26H37NNaO6 requires 482.2513 (1.9 ppm error).
oxohexahydropyrrolo[1,2-c]oxazole-7a-carboxylate
a-23. To a stir-
red solution of enone 41 (6.60 g, 11.5 mmol, 1.0 equiv) in THF
(500 mL) at ꢀ78 ꢁC was added dropwise via syringe KHMDS [0.5 M
in toluene] (46 mL, 23.0 mmol, 2.0 equiv). The resultant bright
yellow solution was stirred at ꢀ78 ꢁC for 45 min then removed from
the cool and rapidly poured into conical flask containing vigorously
stirred water (1.75 L). Immediately after quenching, CH2Cl2
(500 mL) was added and the layers separated. The aqueous layer
was further extracted with CH2Cl2 (3ꢃ500 mL), the combined or-
ganics washed with saturated brine (150 mL), dried (MgSO4), fil-
tered and concentrated in vacuo to afford a pale yellow glass. 1H
NMR analysis of the crude reaction mixture identified a w10:1:10
mixture of
Repeated purification by flash chromatography (SiO2, 3:1 petrol/
Et2O) afforded -23 (3.30 g, 5.75 mmol, 50%, 92% BRSM), -23
a-23 and b-23 with starting material 41, respectively.
a
b
(300 mg, 0.52 mmol, 5%, 8% BRSM) and recovered enone 41 (3.00 g,
5.23 mmol, 45%), respectively as viscous yellow oils that solidified
on standing as yellow glasses.
4.2.12. (3S,7aR)-Methyl 7-((3R,4R)-5-(benzyloxy)-4-(tert-butyldime-
thylsilyloxy)-3-methylpentyl)-3-tert-butyl-6-methyl-5-oxo-1,3,5,7a-
tetrahydropyrrolo[1,2-c]oxazole-7a-carboxylate 41.
4.2.14. (3S,6S,7aR,E)-Methyl
tyldimethylsilyloxy)-3-methylpentylidene)-3-tert-butyl-6-methyl-5-
oxohexahydropyrrolo[1,2-c]oxazole-7a-carboxylate a-23.
7-((3R,4R)-5-(benzyloxy)-4-(tert-bu-
13
5
Me
4
6
7
O
1
12
15
O
18
Me
17
14
16
8
3
Me
Si 10 Me
Me
2
O
3
Me
Me
25
24
13
5
O
9
19
2
4
6
Me
N
OMe
11
7
26
21
20
O
1
O
Me
Me
12
15
O
9
14
18
22
Me
Me
Me
O
Si
Me
Me
23
17
8
10
Me
16
24
Me
OMe
O
25
23
19
N
To a stirred solution of alcohol 40 (6.34 g, 13.8 mmol, 1.0 equiv) in
CH2Cl2 (330 mL) cooled to ꢀ10 ꢁC (ice/salt cooling bath) was
added 2,6-lutidine (3.20 mL, 27.6 mmol, 2.0 equiv). The reaction
mixture was stirred for 5 min then TBSOTf (4.75 mL, 20.7 mmol,
1.5 equiv) was added dropwise via syringe. After 40 min the so-
lution was poured into a stirred solution of saturated aqueous
ammonium chloride (400 mL) and diluted with CH2Cl2 (200 mL).
The layers were separated, the aqueous extracted with CH2Cl2
(3ꢃ500 mL), the organics combined, washed with brine (200 mL),
dried (MgSO4), filtered and concentrated in vacuo. The crude was
purified by flash chromatography (SiO2, 3:1 petrol/Et2O) to afford
the title compound, 41, (7.86 g, 13.7 mmol, 99%) as a pale yellow
glass. Rf (3:1 petrol/Et2O) 0.23; nmax 2957, 2859, 1744, 1713, 1461,
11
26
20
O
Me
Me
21
Me
22
Rf (3:1 petrol/Et2O) 0.27; ½a D19
ꢂ
ꢀ31.7 (c 0.81, CHCl3); nmax 2957,
dH (400 MHz, CDCl3)
2933, 2859, 1727, 1462, 1322, 1290, 1120 cmꢀ1
;
7.25e7.34 (5H, m, CH(1,2 and 3)), 5.41e5.46 (1H, m, CH(15)), 4.87
(1H, s, CH(20)), 4.82 (1H, d, J 8.0 Hz, CH2(23a)), 4.50 (1H, d, J 12.0 Hz,
CH2(5a)), 4.47 (1H, d, J 12.0 Hz, CH2(5b)), 3.75 (3H, s, CH3(26)),
3.65e3.70 (1H, m, CH(7)), 3.36e3.44 (2H, m, CH2(6a, 6b)), 3.32 (1H,
d, J 8.0 Hz, CH2(23b)), 3.23 (1H, q, J 8.0 Hz, CH(17)), 2.17e2.22 (1H, m,
CH(14a)), 1.72e1.84 (2H, m, CH(12, 14b)), 1.46 (3H, d, J 7.5 Hz,
CH3(18)), 0.88 (9H, s, CH3(22)), 0.86 (9H, s, CH3(11)), 0.81 (3H, d, J
6.5 Hz, CH3(13)), 0.01 (6H, br s, CH3(8,9)); dC (100 MHz, CDCl3) 181.6
(C]O(19)), 171.7 (C]O(25)), 138.2 (C(16)), 137.4 (C(4)), 128.4 (CH),
127.7 (CH), 127.7 (CH), 127.1 (CH(15)), 97.4 (CH(20)), 75.4 (C(24)),
75.0 (CH(7)), 73.4 (CH2(5)), 72.8 (CH2(23)), 72.6 (CH2(6)), 52.8
(CH3(26)), 44.2 (CH(17)), 36.5 (CH(12)), 35.4 (C(21)), 30.0 (CH2(14)),
25.9 (CH3(22)), 24.9 (CH3(11)), 18.2 (C(10)), 18.2 (CH3(18)), 16.4
(CH3(13)), ꢀ4.2 (CH3(8)), ꢀ4.8 (CH3(9)); m/z (ESI): 574 (MHþ), 596
1254, 1228, 1115 cmꢀ1; ½a D21
ꢀ46.7 (c 0.70, CHCl3); dH (400 MHz,
ꢂ
CDCl3) 7.28e7.36 (5H, m, CH(1, 2, and 3)), 4.75 (1H, d, J 8.0 Hz,
CH2(21a)), 4.62 (1H, s, CH(20)), 4.50 (1H, d, J 12.0 Hz, CH2(5a)),
4.46 (1H, d, J 12.0 Hz, CH2(5b)), 3.72 (3H, s, CH3(26)), 3.66e3.70
(1H, m, CH(7)), 3.39 (1H, dd, J 10.0, 5.5 Hz, CH2(6a)), 3.36 (1H, d, J
10.0, 6.0 Hz, CH2(6b)), 3.16 (1H, d, J 8.0 Hz, CH2(21b)), 2.32 (1H,
ddd, J 14.5, 11.0, 6.5 Hz, CH2(15a)), 2.06 (1H, ddd, J 14.5, 12.0,
4.5 Hz, CH2(15b)), 1.79 (3H, s, CH3(18)), 1.61e1.68 (1H, m, CH(12)),
1.37e1.47 (1H, m, CH2(14a)), 1.16e1.24 (1H, m, CH2(14b)),
0.90e0.94 (12H, m, CH3(13, 23)), 0.87 (9H, s, CH3(11)), 0.03 (3H, s,

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10039
(MNaþ); HRMS (ESI): MNaþ found 596.3394. C32H51NNaO6S re-
quires 596.3378 (2.8 ppm error).
3437, 2957, 2932, 2858, 1788, 1735, 1705, 1463, 1364, 1327, 1299,
1252, 1146, 1104, 1038 cmꢀ1
dH (400 MHz, CDCl3) 7.29e7.37 (5H, m,
;
CH(1, 2 and 3)), 4.83 (1H, s, CH(23)), 4.48e4.51 (1H, m, CH(15)), 4.48
(2H, s, CH2(5)), 4.21 (1H, d, J 9.0 Hz, CH2(26a)), 3.79 (1H, d, J 9.0 Hz,
CH2(26b)), 3.73e3.78 (1H, m, CH(7)), 3.42e3.50 (2H, m, CH2(6a,
6b)), 3.25 (1H, s, OH(22)), 2.56 (1H, q, J 7.5 Hz, CH(19)), 1.93e2.04
(2H, m, CH(12) and CH2(14a)), 1.36e1.44 (1H, m, CH(14b)), 1.23 (3H,
d, J 7.5 Hz, CH3(20)), 1.04 (3H, d, J 6.5 Hz, CH3(13)), 0.97 (9H, s,
CH3(25)), 0.88 (9H, s, CH3(11)), 0.05 (3H, s, CH3(8)), 0.03 (3H, s,
CH3(9)); dC (100 MHz, CDCl3) 182.1 (C]O(21)), 173.0 (C]O(18)),
137.6 (C(4)), 128.6 (CH), 128.2 (CH), 128.1 (CH), 100.1 (CH(23)), 81.3
(C(16)), 80.9 (CH(15)), 74.2 (CH(7)), 73.8 (CH2(5)), 72.8 (C(17)), 72.6
(CH2(6)), 67.7 (CH2(26)), 50.7 (CH(19)), 35.5 (C(24)), 33.7 (CH(12)),
31.8 (CH2(14)), 26.0, 25.7, 18.2 (C(10)), 17.7 (CH3(13)), 11.2 (CH3(20)),
ꢀ4.2 (CH3(8)), ꢀ4.7 (CH3(9)); m/z (CI, NH3): 593 (MNHþ4 , 29), 576
(MHþ, 100), 518 (25), 91 (27%); HRMS (CI, NH3): MHþ found
576.3356. C31H50NO7Si requires 576.3357 (0.2 ppm error).
4.2.15. (3S,6R,7aR,E)-Methyl
tyldimethylsilyloxy)-3-methylpentylidene)-3-tert-butyl-6-methyl-5-
oxohexahydropyrrolo[1,2-c]oxazole-7a-carboxylate b-23.
7-((3R,4R)-5-(benzyloxy)-4-(tert-bu-
3
13
5
2
4
6
Me
7
O
1
12
15
9
14
18
Me
Me
O
Si
Me
Me
O
17
8
10
Me
16
Me
OMe
O
25
23
19
24
N
11
26
20
O
Me
Me
21
Me
22
Rf (3:1 petrol/Et2O) 0.30; ½a D19
ꢂ
ꢀ11.5 (c 1.25, CHCl3); nmax 2957,
dH (400 MHz, CDCl3)
4.2.17. (3S,6R,6aS,7S,9aS)-7-[(2R,3R)-4-(Benzyloxy)-3-{[tert-bu-
tyl(dimethyl)silyl]oxy}-2-methylbutyl]-3-tert-butyl-6a-hydroxy-6-
methyldihydrofuro[30,40:2,3]pyrrolo[1,2-c][1,3]oxazole-5,9(6H)-dione
2930, 2858, 1728, 1456, 1325, 1288, 1120 cmꢀ1
;
7.26e7.34 (5H, m, CH(1, 2 and 3)), 5.47 (1H, ddd, J 7.5, 7.5, 2.5 Hz,
CH(15)), 4.85 (1H, s, CH(20)), 4.82 (1H, d, J 8.5 Hz, CH2(23a)), 4.52
(1H, d, J 12.0 Hz, CH2(5a)), 4.46 (1H, d, J 12.0 Hz, CH2(5b)), 3.71 (3H, s,
CH3(26)), 3.66e3.69 (1H, m, CH(7)), 3.48 (1H, qd, J 7.5, 2.5 Hz,
CH(17)), 3.33e3.42 (2H, m, CH2(6a, 6b)), 3.27 (1H, d, J 8.5 Hz,
CH2(23b)), 2.16e2.27 (1H, m, CH2(14a)), 1.97e2.05 (1H, m,
CH2(14b)), 1.75e1.82 (1H, m, CH(12)), 1.35 (3H, d, J 7.5 Hz, CH3(18)),
0.90 (9H, s, CH3(22)), 0.85e0.88 (12H, m, CH3(11, 13)), 0.03 (6H, br s,
CH3(8, 9)); dC (100 MHz, CDCl3) 181.4 (C]O(19)), 172.0 (C]O(25)),
138.3 (C(16)), 136.6 (C(4)), 128.5 (CH), 127.8 (CH(15)), 127.8 (CH),
127.8 (CH), 98.5 (CH(20)), 75.0 (C(24)), 74.6 (CH(7)), 73.4 (CH2(5)),
72.7 (CH2(23)), 72.6 (CH2(6)), 52.8 (CH3(26)), 42.2 (CH(17)), 36.6
(CH(12)), 35.5 (C(21)), 30.1 (CH2(14)), 26.0 (CH3(22)), 24.9 (CH3(11)),
18.3 (C(10)), 16.5 (CH3(13)), 16.2 (CH3(18)), ꢀ4.7 (CH3(8)), ꢀ4.1
(CH3(9)); m/z (ESI): 574 (MHþ), 596 (MNaþ); HRMS (ESI): MNaþ
found 596.3393. C32H51NNaO6Si requires 596.3378 (2.6 ppm error).
b-42.
13
Me
3
5
6
7
4
14
2
1
22
HO
19
12
O
20
8
15
Me
Me
O
16
26
Si 10 Me
Me
O
17
18
Me
O
21
Me
9
N
O
11
23
O
Me
Me
24
Me
25
To a stirred solution of tricycle
a-42 (210 mg, 0.365 mmol,
1.0 equiv)in CHCl3 (7 mL) was added dropwise via microsyringe DBU
(5 L, 0.036 mmol, 0.10 equiv). The resultant solution was stirred for
m
24 h at rt and then concentrated onto silica and purified by flash
chromatography (SiO2, 1:1 petrol/Et2O/Et2O) to afford in order of
elution, the title compound,
0.276 mmol, 76% [84% BRSM]) and then recovered starting material,
b-35, as a colourless foam (159 mg,
4.2.16. (3S,6S,6aS,7S,9aS)-7-[(2R,3R)-4-(Benzyloxy)-3-{[tert-bu-
tyl(dimethyl)silyl]oxy}-2-methylbutyl]-3-tert-butyl-6a-hydroxy-6-
methyldihydrofuro[30,40:2,3]pyrrolo[1,2-c][1,3]oxazole-5,9(6H)-dione
a
-42, as aviscous, colourless oil (21 mg, 0.036 mmol,10%). Data for b-
42: Rf (1:2 petrol/Et2O) 0.43; ½a D20
ꢀ19.2 (c 2.96, CHCl3); nmax 3364,
ꢂ
a-42.
2951, 2933,1791,1765,1710,1459,1362,1347,1254,1168,1094,1079,
13
1035 cmꢀ1
; dH (400 MHz, CDCl3) 7.29e7.37 (5H, m, CH(1, 2 and 3)),
Me
3
5
6
7
4
14
4.88 (1H, s, CH(23)), 4.49 (2H, s, CH2(5)), 4.38 (1H, dd, J 8.5, 6.0 Hz,
CH2(15)), 4.14 (1H, d, J 9.0 Hz, CH2(26a)), 3.96 (1H, d, J 9.0 Hz,
CH2(26b)), 3.82 (1H, s, OH(22)), 3.71e3.75 (1H, m, CH(7)), 3.44e3.54
(2H, m, CH2(6a, 6b)), 2.86 (1H, q, J 7.5 Hz, CH(19)), 2.03 (1H, ddd, J
14.5, 8.5, 4.0 Hz, CH2(14a)),1.78e1.85 (1H, m, CH(12)),1.33 (1H, ddd, J
14.5, 9.0, 6.0 Hz, CH2(14b)), 0.97e1.03 (15H, m, CH3(13, 20 and 25)),
0.87 (9H, s, CH3(11)), 0.05 (3H, s, CH3(8)), 0.01 (3H, s, CH3(9)); dC
(100 MHz, CDCl3) 180.5 (C]O(21)), 173.1 (C]O(18)), 137.1 (C(4)),
128.6 (CH), 128.3 (CH), 128.3 (CH), 99.0 (CH(23)), 82.6 (C(16)), 81.5
(CH(7)), 74.0 (CH2(5)), 73.6 (CH(7)), 72.8 (C(17)), 72.5 (CH2(6)), 68.6
(CH2(26)), 48.3 (CH(19)), 36.0 (C(24)), 32.4 (CH2(12)), 32.2 (CH2(14)),
25.9, 25.6, 18.1 (C(10)), 17.6 (CH3(13)), 7.7 (CH3(20)), ꢀ4.3 (CH3(8)),
ꢀ4.8 (CH3(9)); m/z (CI, NH3): 593 (MNHþ4 , 78), 576 (MHþ, 100), 518
(72), 91 (28%); HRMS (CI, NH3): MHþ found 576.3352. C31H50NO7Si
requires 576.3357 (0.8 ppm error).
2
1
22
HO
19
12
O
20
8
15
Me
Si 10 Me
Me
Me
O
16
26
O
17
18
Me
O
21
Me
9
N
O
11
23
O
Me
Me
24
Me
25
To a stirred solution of alkene a-23 (2.66 g, 4.64 mmol,1.0 equiv)
in tert-BuOH (37 mL) and water (9 mL) at rt, was added OsO4
(1.25 g, 4.87 mmol, 1.05 equiv) and N-methylmorpholine-N-oxide
[NMO] (0.57 g, 4.87 mmol, 1.05 equiv). The flask was sealed, pro-
tected from the light with foil, and stirred at rt for 6 days, with the
addition of an extra portion of NMO (0.57 g, 4.87 mmol, 1.05 equiv)
every 24 h. The resultant black mixture was then quenched by the
addition of a solution of saturated aqueous sodium sulfate (50 mL)
and the mixture stirred for 12 h. The resultant slurry was filtered
through CeliteÒ and the filter pad rinsed with EtOAc (250 mL).
Water (50 mL) was added, the layers separated and the aqueous
further extracted with EtOAc (3ꢃ50 mL). The combined organics
were dried (MgSO4), filtered and concentrated in vacuo. The crude
residue was purified by flash chromatography (SiO2, 1:1 petrol/
4.2.18. (3R,3aS,4S,6aS)-4-[(2R,3R)-4-(Benzyloxy)-3-hydroxy-2-
methylbutyl]-3a-hydroxy-6a-(hydroxymethyl)-3-methyldihydro-1H-
furo[3,4-b]pyrrole-2,6(3H,4H)-dione 43.
Anhydrous HCl gas was bubbled through a vigorously stirred
solution of tricycle
b-42 (516 mg, 0.896 mmol, 1.0 equiv) and 1,3-
propanedithiol (99
mL, 0.986 mmol, 1.1 equiv) in 2,2,2-
Et2O/Et2O) to afford the title compound,
a
-42, as a colourless
trifluoroethanol (10 mL) for 45 min at rt. Upon completion, the re-
sidual acid was purged with a stream of argon for 10 min. The
foam. Rf (1:1 petrol/Et2O) 0.26; ½a D20
ꢂ
ꢀ33.4 (c 1.00, CHCl3); nmax

10040
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10
O(21)), 173.1 (C]O(18)), 136.9 (C(4)), 128.5 (CH), 128.4 (CH), 128.3
Me
3
5
6
8
(CH(1)), 86.4 (CH(15)), 81.8 (C(16)), 73.9 (CH2(5)), 73.8 (CH(7)), 71.7
(CH2(6)), 68.3 (C(17)), 62.2 (CH2(23)), 46.2 (CH(19)), 31.3 (CH(12)),
28.7 (CH2(14)), 25.7 (CH3(11)), 18.0 (C(10)), 17.2 (CH3(13)), 10.9
(CH3(20)), ꢀ4.3 (CH3(8)), ꢀ4.9 (CH3(9)); m/z (ESI): 508 (MHþ), 530
(MNaþ); HRMS (ESI): MHþ found 508.2725. C26H42NO7Si2 requires
508.2725 (0.1 ppm error).
7
4
11
2
1
18
HO
19
9
O
20
12
Me
OH
13
O
14
15
O
21
N
O
16
22H
OH
17
4.2.20. (3R,3aS,4S,6aS)-4-{(2R,3R)-4-(Benzyloxy)-2-methyl-3-[trie-
thylsilyloxy]butyl}-3a-hydroxy-3-methyl-6a{triethylsilyloxymethyl}
dihydro-1H-furo[3,4-b]pyrrole-2,6(3H,4H)-dione 45.
mixture was then concentrated in vacuo and purified by flash
chromatography (SiO2, 14:1 CH2Cl2/MeOH) to afford the title com-
pound, 43, as a colourless foam (231 mg, 0.673 mmol, 75%);
recrystallisation from boiling CHCl3 afforded colourless microcrys-
11
Me
5
3
6
4
7
12
14
24
HO
2
1
tals. Mp 153e154 ꢁC; Rf (14:1 CH2Cl2/MeOH) 0.34; ½a D24:5
ꢂ
þ4.9 (c 1.0,
10
13
O
Me
O
MeOH); nmax 3382, 3030, 2941, 2870, 1769, 1691, 1453, 1429, 1366,
18
Me
Si
O
17
1318,1235,1204,1152,1099,1066, 951, 736, 698 cmꢀ1
; dH (400 MHz,
8
15
16
Me
O
3:1 CDCl3/CD3OD) 7.11e7.19 (5H, m, CH(1, 2 and 3)), 4.36 (1H, d, J
11.9 Hz, CH2(5a)), 4.32 (1H, d, J 11.9 Hz, CH2(5b)), 4.23 (1H, dd, J 8.2,
4.9 Hz, 1H, CH(12)), 3.66 (1H, d, J 12.0 Hz, CH2(16a)), 3.61 (1H, d, J
12.0 Hz, CH2(16b)), 3.35e3.39 (2H, m, CH(7) and CH2(6a)), 3.25 (1H,
dd, J 10.6, 3.5 Hz, CH2(6b)), 2.25 (1H, q, J 7.6Hz, CH(19)),1.90 (1H, ddd,
J 14.5, 4.9, 4.9 Hz, CH2(11a)),1.56e1.63 (1H, m, CH(9)),1.43 (1H, ddd, J
14.5, 8.2, 7.3 Hz, CH2(11b)),1.02 (3H, d, J 7.6 Hz, CH3(20)), 0.77 (3H, d, J
6.8 Hz, CH3(10)); dC (100 MHz, 3:1 CDCl3/CD3OD) 181.7 (C]O(21)),
176.9 (C]O(15)), 140.9 (C(4)), 131.5 (CH(2)), 131.0 (CH(1)), 131.0
(CH(3)), 90.5 (CH(12)), 84.9 (C(13)), 77.7 (CH(7)), 76.6 (CH2(5)), 75.5
(CH2(6)), 71.4 (C(14)), 63.9 (CH2(16)), 51.6 (CH(19)), 36.6 (CH(9)),
34.7 (CH2(11)), 20.1 (CH3(10)), 13.7 (CH3(20)); m/z (ESI): 394 (MHþ),
416 (MNaþ); HRMS (ESI): MHþ found 394.1866. C20H28NO7 requires
394.1860 (1.4 ppm error).
19
20
Me
N
O
21
H
9
O
22
Si
23
Me
Me
Me
To a stirred solution of triol 43 (228 mg, 0.58 mmol,1.0 equiv) and
2,6-lutidine (470 mL, 4.06 mmol, 7.0 equiv) in DMF (17 mL) cooled to
ꢀ10 ꢁC (ice/salt cooling bath) was added TESOTf (790
mL, 3.48 mmol,
6.0 equiv) dropwise via syringe. The reaction was stirred for 2 h at
ꢀ10 ꢁC and then quenched by the addition of saturated aqueous
NH4Cl (20 mL). Following warming to rt, the mixture was diluted
with water (150 mL) and extracted with Et2O (4ꢃ50 mL). The com-
bined organic extracts were dried (MgSO4), filtered and concen-
trated in vacuo. The crude product was purified by flash
chromatography (SiO2, 30:1/9:1 CH2Cl2/Me2CO) to afford the title
compound, 45, as a colourless, viscous oil (326 mg, 0.52 mmol, 90%).
4.2.19. (3R,3aS,4S,6aS)-4-((2R,3R)-4-(Benzyloxy)-3-(tert-butyldime-
thylsilyloxy)-2-methylbutyl)-3a-hydroxy-6a-(hydroxymethyl)-3-
methyldihydro-1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione 44.
Rf (19:1 CH2Cl2/Me2CO) 0.30; ½a D24
þ10.7 (c 1.05, CHCl3); nmax 3422,
ꢂ
3263, 2956, 2912, 2878, 1778, 1710, 1457, 1413, 1378, 1238, 1090,
1009, 986, 911, 734, 698, 673 cmꢀ1
; dH (400 MHz, CDCl3) 7.28e7.36
13
Me
(5H, m, CH(1, 2 and 3)), 5.90 (1H, s, NH(20)), 4.49 (2H, s, CH2(5)), 4.35
(1H, dd, J 7.7, 6.4 Hz, CH(13)), 4.04 (1H, s, OH(24)), 4.02 (1H, d, J
10.7 Hz, CH2(21a)), 3.84 (1H, d, J 10.7 Hz, CH2(21b)), 3.74 (1H, ddd, J
6.3, 5.8, 3.1 Hz, CH(7)), 3.49 (1H, dd, J 9.7, 6.3 Hz, CH2(6a)), 3.41 (1H,
5
3
6
4
7
14
24
2
1
12
O
Me
10
20
8
HO 15
Me
19
O
Si
O
16
17
9
Me
18
(6b)), 2.40 (1H, q, J 7.6 Hz, CH(17)), 2.07 (1H, ddd, J
dd, J 9.7, 5.8 Hz, CH2
Me
O
Me
21
N
Me
14.4, 6.4, 4.2 Hz, CH2(12a)),1.80e1.85 (1H, m, CH(10)),1.59 (1H, ddd, J
14.4, 8.8, 7.7 Hz, CH2(12b)),1.19 (3H, d, J 7.6 Hz, CH3(18)),1.01 (3H, d, J
6.9 Hz, CH3(11)), 0.95 (9H, t, J 8.0 Hz, CH3), 0.93 (9H, t, J 8.0 Hz, CH3),
0.64 (6H, q, J 8.0 Hz, CH2), 0.58 (6H, q, J 8.0 Hz, CH2); dC (100 MHz,
CDCl3) 177.9 (C]O(19)), 173.1 (C]O(16)), 138.1 (C(4)), 128.6 (CH),
128.1 (CH), 128.0 (CH(1)), 87.5 (CH(13)), 81.5 (C(14)), 74.5 (CH(7)),
73.4 (CH2(5)), 72.2 (CH2(6)), 67.6 (C(15)), 62.3 (CH2(21)), 45.8
(CH(17)), 33.2 (CH(10)), 29.8 (CH2(12)), 16.5 (CH3(11)), 10.6
(CH3(18)), 6.5 (CH3), 6.1 (CH3), 4.6 (CH2), 3.6 (CH2); m/z (ESI): 622
(MHþ), 644 (MNaþ); HRMS (ESI): MHþ found 622.3599.
C32H55NO7Si2 requires 622.390 (1.4 ppm error).
23
O
11
H
22
HO
24
To a stirred solution of triol 43 (31 mg, 79.0
m
mol, 1.0 equiv) and
2,6-lutidine (37 mL, 316 mmol, 4.0 equiv) in DMF (2 mL) cooled to
ꢀ10 ꢁC (ice/salt cooling bath) was added dropwise via syringe
TBSOTf (54 mL, 237 mmol, 3.0 equiv). The reaction was stirred for 2 h
at ꢀ10 ꢁC and then quenched by the addition of saturated aqueous
NH4Cl (2 mL). Following warming to rt, the mixture was diluted
with water (50 mL) and extracted with Et2O (5ꢃ10 mL). The com-
bined organic extracts were dried (MgSO4), filtered and concen-
trated in vacuo. The crude product was purified by flash
chromatography (SiO2, 19:1 CH2Cl2/MeOH) to afford the title
4.2.21. (3R,3aS,4S,6aS)-4-{(2R,3R)-4-Benzyloxy-2-methyl-3-[trie-
thylsilyloxy]butyl}-3-methyl-6a-{[triethylsilyloxy]methyl}-3a-[trime-
thylsilyloxy]dihydro-1H-furo[3,4-b]pyrrole-2,6(3H,4H)-dione 46.
To a solution of alcohol 45 (259 mg, 0.416 mmol, 1.0 equiv) and
2,6-lutidine (1.45 mL, 12.5 mmol, 30.0 equiv) in CH2Cl2 (13 mL),
cooled to 0 ꢁC was added dropwise via syringe TMSOTf (1.89 mL,
10.4 mmol, 25.0 equiv). The cool bath was then removed and the
reaction was stirred for 20 h at rt. The reaction was quenched by the
addition of saturated aqueous NH4Cl (20 mL) and then extracted
with CH2Cl2 (3ꢃ30 mL). The combined organic extract was dried
(MgSO4), filtered and concentrated in vacuo to afford an oily yellow
residue. Flash chromatography (SiO2, 39:1 CH2Cl2/Me2CO) afforded
compound, 44, as a colourless, viscous oil (22 mg, 43.0
mmol, 55%).
Rf (19:1 CH2Cl2/MeOH) 0.19; ½a D24:5
ꢂ
þ18.4 (c 0.47, CHCl3); nmax 3394,
2954, 2930, 2883, 2856, 1769, 1696, 1457, 1362, 1252, 1071, 1038,
1007, 835, 776, 734, 698 cmꢀ1
; dH (400 MHz, CDCl3) 7.29e7.36 (5H,
m, CH(1, 2 and 3)), 6.92 (1H, s, NH(22)), 4.50 (2H, s, CH2(5)), 4.37
(1H, dd, J 9.2, 5.2 Hz, CH(15)), 4.21 (1H, s, OH(25)), 3.80e3.88 (2H,
m, CH2(23a, 23b)), 3.73 (1H, ddd, J 7.3, 5.6, 2.7 Hz, CH(7)), 3.53 (1H,
dd, J 9.8, 7.3 Hz, CH2(6a)), 3.46 (1H, dd, J 9.8, 5.6 Hz, CH2(6b)), 2.37
(1H, q, J 7.7 Hz, CH(19)), 2.09 (1H, dd, J 11.9, 9.2 Hz, CH2(14a)),
1.56e1.66 (2H, m, CH(12) and CH2(14b)), 1.01 (3H, d, J 6.5 Hz,
CH3(13)), 0.99 (3H, d, J 7.7 Hz, CH3(20)), 0.86 (9H, s, CH3(11)), 0.03
(3H, s, CH3(8)), 0.01 (3H, s, CH3(9)); dC (100 MHz, CDCl3) 177.5 (C]
a
w3:1 mixture of the title compound, 46, and putative

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10041
11
a stream of argon for 10 min and the mixture was then concen-
trated in vacuo to afford the crude triol 49. This material was dis-
solved in a mixture of acetic anhydride (2.5 mL) and pyridine
(2.5 mL) and stirred for 16 h at rt. The reaction was quenched by the
addition of 10% aqueous HCl (50 mL) and then extracted with
CH2Cl2 (4ꢃ30 mL). The combined organic were washed with sat-
urated aqueous NaHCO3 (50 mL), saturated aqueous brine (150 mL),
dried (MgSO4), filtered and concentrated in vacuo. Purification of
the crude residue by flash chromatography (SiO2, 9:1 CH2Cl2/
Me2CO) afforded the title compound, 50, as a colourless film
(119 mg, 0.242 mmol, 69% over the three-steps). Rf (9:1 CH2Cl2/
24
Me
Me
Me
5
3
6
10
7
4
Si
Me
Me
2
1
O
12
13
O
O
Me
18
Si
14
O
17
8
16
15
Me
O
19
Me
N
O
21
9
H
20
O
Si
Me
Me
22
Me
23
Et2O) 0.36; ½a D23:5
þ26.3 (c 1.01, CHCl3); nmax 3368, 2933, 1772, 1739,
ꢂ
1703, 1674, 1640, 1580, 1544, 1459, 1424, 1378, 1231, 1106, 1039, 955,
735 cmꢀ1
; dH (400 MHz, CDCl3) 7.29e7.36 (5H, m, CH(1, 2 and 3)),
metathesised silyl compound 47 (246 mg, w0.349 mmol, w84%).
This mixture was carried through without further purification al-
though an analytical sample of 46 was obtained by preparative TLC
4.95 (1H, ddd, J 7.0, 5.7, 4.1 Hz, CH(7)), 4.65 (1H, d, J 12.7 Hz,
CH2(21a)), 4.53 (2H, s, CH2(5)), 4.33 (1H, dd, J 9.0, 5.7 Hz, CH(13)),
4.24 (1H, d, J 12.7 Hz, CH(21b)), 3.66 (1H, dd, J 10.2, 5.7 Hz, CH2(6a)),
3.58 (1H, dd, J 10.2, 7.1 Hz, CH2(6b)), 3.58 (1H, s, OH(24)), 2.84 (3H,
s, CH3(20)), 2.38 (1H, q, J 7.7 Hz, CH3(17)), 2.05e2.12 (1H, m,
CH2(12a)), 2.07 (3H, s, CH3), 2.06 (3H, s, CH3), 1.82e1.89 (1H, m,
CH(10)), 1.68 (1H, ddd, J 14.2, 10.0, 5.7 Hz, CH2(12b)), 1.03 (3H, d, J
7.7 Hz, CH3(18)), 1.02 (3H, d, J 6.4 Hz, CH3(11)); dC (100 MHz, CDCl3)
174.8 (C(19)), 170.6 (C), 169.9 (C), 169.8 (C(16)), 136.6 (C(4)), 128.5
(CH), 128.4 (CH), 128.3 (CH(1)), 85.9 (CH(13)), 79.8 (C(14)), 74.9
(CH(7)), 74.0 (CH2(5)), 71.5 (C(15)), 67.9 (CH2(6)), 57.5 (CH2(21)),
45.1 (CH(17)), 29.3 (CH(10)), 29.3 (CH2(12)), 26.1 (CH3(20)), 21.0
(CH3), 20.8 (CH3), 16.7 (CH3(11)), 10.6 (CH3(18)); m/z (ESI): 492
(MHþ), 514 (MNaþ); HRMS (ESI): MNaþ found 514.2049.
C25H33NNaO9 requires 514.2048 (0.3 ppm error).
(SiO2, 1:2 petrol/Et2O). Rf (39:1 CH2Cl2/Me2CO) 0.33; ½a D24
ꢀ3.9 (c
ꢂ
1.04, CHCl3); nmax 3179, 3104, 2955, 2912, 2877, 1772, 1718, 1684,
1456, 1378, 1279, 1234, 1179, 1087, 1032, 1005, 973, 840, 802,
736 cmꢀ1
; dH (400 MHz, CDCl3) 7.29e7.36 (5H, m, CH(1, 2 and 3)),
5.65 (1H, s, NH(20)), 4.50 (1H, d, J 12.0 Hz, CH2(5a)), 4.43 (1H, d, J
12.0 Hz, CH2(5b)), 4.27 (1H, dd, J 10.6, 2.0 Hz, CH(13)), 3.85 (1H, dd, J
11.4 Hz, CH2(21a)), 3.77 (1H, d, J 11.4 Hz, CH2(21b)), 3.74e3.79 (1H,
m, CH(7)), 3.41 (1H, dd, J 9.5, 6.3 Hz, CH2(6a)), 3.36 (1H, dd, J 9.5,
5.5 Hz, CH2(6b)), 2.30 (1H, q, J 7.6 Hz, CH(17)), 1.90e1.96 (1H, m,
CH(10)), 1.86 (1H, ddd, J 14.8, 5.3, 2.0 Hz, CH2(12a)), 1.48 (1H, ddd, J
14.8, 10.6, 7.5 Hz, CH2(12b)), 1.19 (3H, d, J 7.6 Hz, CH3(18)), 1.03 (3H,
d, J 6.8 Hz, CH3(11)), 0.94 (9H, t, J 7.9 Hz, CH3), 0.92 (9H, t, J 7.9 Hz,
CH3), 0.63 (6H, q, J 7.9 Hz, CH2), 0.56 (6H, q, J 7.9 Hz, CH2), 0.16 (9H, s,
CH3(24)); dC (100 MHz, CDCl3) 176.8, (C]O(19)), 172.9 (C]O(16)),
137.9 (C(4)), 128.4 (CH), 127.8 (CH), 127.7 (CH(1)), 87.1 (CH(13)), 86.8
(C(14)), 74.4 (CH(7)), 73.4 (CH2(5)), 72.5 (CH2(6)), 68.4 (C(15)), 60.4
(CH2(21)), 45.0 (CH(17)), 35.0 (CH(10)), 30.5 (CH2(12)), 17.7
(CH3(11)), 11.4 (CH3(18)), 6.9 (CH3), 6.7 (CH3), 5.0 (CH2), 4.3 (CH2),
2.6 (CH3(24)); m/z (ESI): 694 (MHþ), 716 (MNaþ); HRMS (ESI): MHþ
found 694.3989. C35H64NO7Si3 requires 694.3985 (0.5 ppm error).
4.2.23. (E)-4-(1-Phenyl-1H-tetrazol-5-ylthio) but-2-en-1-amine 52.
1
2
N
N
4
3
N
10
NH2
8
N
6
5
S
9
To a solution of bis-Boc-protec7ted amine 51 (1.00 g, 2.23 mmol,
1.0 equiv) in CH2Cl2 (50 mL), was added trifluoroacetic acid
(1.70 mL, 22.3 mmol, 10.0 equiv) at rt. After 12 h at rt, the mixture
was poured into a separating funnel, washed with cold (0 ꢁC) sat-
urated aqueous NaHCO3 (2ꢃ50 mL), dried (MgSO4), filtered and
concentrated in vacuo. The resulting crude product was purified by
flash chromatography (SiO2, 9:1 CH2Cl2/MeOH) to afford the allylic
amine 52 (0.46 g, 1.86 mmol, 83%) as a viscous, yellow oil. Rf (9:1
CH2Cl2/MeOH) 0.15; nmax 3422, 2914, 1500, 1438, 1205, 1138, 843,
4.2.22. ((3R,3aS,4S,6aS)-4-((2R,3R)-4-(Benzyloxy)-3-(ethanoyloxy)-
2-methylbutyl)-3a-hydroxy-1,3-dimethyl-2,6-dioxohexahydro-1H-
furo[3,4-b]pyrrol-6a-yl)methyl ethanoate 50.
11
Me
5
3
6
7
4
12
24
2
1
10
O
O
HO
13
Me
17
O
18
14
O
8
16
15
801, 762, 724, 689 cmꢀ1
; dH (400 MHz, CDCl3) 7.51e7.55 (5H, m,
Me
O
19
9
N
Me
O
21
O
CH(1,2 and 3)), 6.70 (2H, d, J 7.5 Hz, CH2(9)), 5.94 (1H, dt, J 14.5,
5.5 Hz, CH(7)), 5.77 (1H, dt, J 14.5, 7.5 Hz, CH(8)), 3.29 (2H, d, J
5.5 Hz, CH2(6)), 2.18 (2H, br s, NH(10)); dC (100 MHz, CDCl3) 154.3
(C(5)), 137.4 (CH(1)), 134.2 (C(4)), 130.6 (CH(8)), 130.3 (CH(2)), 124.3
(CH(3)), 123.7 (CH(7)), 43.7 (CH2(9)), 35.1 (CH2(6)); m/z (ESI): 248
(MHþ); HRMS (ESI): MHþ found 248.1134. C11H14N5S requires
248.0964 (3.6 ppm error).
20
22
O
Me
23
To
a solution of the w3:1 mixture of 46/47 (246 mg,
w0.349 mmol, 1.0 equiv) in THF (16 mL) cooled to ꢀ78 ꢁC was
added dropwise via microsyringe n-butyllithium [1.53 M in hex-
anes] (285 mL, 0.436 mmol, 1.25 equiv). The reaction was stirred for
4.2.24. (9H-Fluoren-9-yl)methyl (E)-4-(1-phenyl-1H-tetrazol-5-
ylthio) but-2-enylcarbamate 53.
30 min at ꢀ78 ꢁC and then methyl iodide (220
mL, 3.49 mmol,
10.0 equiv) added via syringe. The reaction was stirred for a further
1 h at ꢀ78 ꢁC and then the cool bath was removed and the reaction
warmed to rt and stirred for an additional 45 min. Quenched by the
addition of saturated aqueous NH4Cl (20 mL) and extracted with
CH2Cl2 (3ꢃ50 mL). The combined organics were dried (MgSO4),
filtered and concentrated in vacuo to afford the crude methylated
lactam mixture, 48, as the same (inseparable) 3:1 mixture. The
crude lactam was dissolved in 2,2,2-trifluoroethanol (10 mL) and
anhydrous HCl gas was bubbled through the stirred solution for
45 min at rt. Upon completion, the residual acid was purged with
1
2
10
N
N
4
3
N
19
8
H
N
18
17
6
13
11
N
O
5
S
14
15
12
9
7
O
To a stirred solution of amine 52 (0.78 g, 3.15 m1m6ol, 1.0 equiv) in
THF/H2O (2:1, 90 mL) at rt were added sequentially in single por-
tions Fmoc-Cl (1.14 g, 4.4 mmol, 1.4 equiv) followed by NaHCO3

10042
R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
(0.61 g, 7.24 mmol, 2.3 equiv). After stirring for 1 h, the reaction
mixture was diluted with Et2O (100 mL). The organic layer was
separated and the aqueous layer was extracted with Et2O
(3ꢃ100 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
flash chromatography (9:1 petrol/EtOAc) to afford compound 53
(1.29 g, 2.74 mmol, 87%) as a viscous, clear oil. Rf (7:3 petrol/EtOAc)
CH(13)), 7.31 (2H, dt, J 7.5, 1.0 Hz, CH(12)), 5.84 (1H, ddd, J 17.0, 10.5,
5.5 Hz, CH(2)), 5.33 (1H, d, J 17.0 Hz, CH2(1a)), 5.20 (1H, d, J 10.5 Hz,
CH2(1b)), 4.48e4.41 (3H, m, CH2(8), NH(6)), 4.25e4.17 (2H, m,
CH(3, 9)), 3.42 (1H, ddd, J 13.5, 5.5, 3.5 Hz, CH2(5a)), 3.15 (1H, ddd, J
13.5, 7.0, 5.5 Hz, CH2(5b)), 2.77 (1H, s, OH(4)); dC (100 MHz, CDCl3)
157.8 (C]O(7)), 144.5 (C(10)), 141.9 (CH(15)), 138.3 (CH(2)), 128.3
(CH(13)), 127.6 (CH(12)), 125.6 (CH(11)), 120.5 (CH(14)), 117.1
(CH2(1)), 72.4 (CH(3)), 66.1 (CH2(8)), 47.4 (CH(9)), 46.6 (CH2(5)); m/
z (ESI): 310 (MHþ); HRMS (ESI): MHþ found 310.1428. C19H20NO3
requires 310.1438 (3.1 ppm error).
0.41; nmax 2924, 1712, 1502, 1243, 908, 732, 689 cmꢀ1
; dH (400 MHz,
CDCl3) 7.56e7.76 (9H, m, CH(1, 2, 3, 15 and 16)), 7.39 (2H, t, J 7.5 Hz,
CH(18)), 7.31 (2H, dt, J 7.5, 1.0 Hz, CH(17)), 5.70e5.93 (2H, m, CH(7,
8)), 4.84 (1H, t, J 5.5 Hz, NH(10)), 4.41 (2H, d, J 7.0 Hz, CH2(12)), 4.20
(1H, t, J 7.0 Hz CH(13)), 4.01 (2H, d, J 6.5 Hz, CH2(6)), 3.79 (2H, t, J
5.0 Hz, CH2(9)); dC (100 MHz, CDCl3) 156.6 (C]O(11)), 154.1 (C(5)),
144.1 (C(14)), 141.4 (C(19)), 133.6 (C(4)), 132.6 (CH(1)), 130.3
(CH(2)), 129.9 (CH(7)), 127.8 (CH(17)), 127.2 (CH(16)), 125.1
(CH(15)), 124.9 (CH(3)), 123.9 (CH(18)), 120.2 (CH(8)), 66.5
(CH2(12)), 46.9 (CH(13)), 41.8 (CH2(9)), 34.3 (CH2(6)); m/z (ESI): 470
(MHþ); HRMS (ESI): MHþ found 470.1572; C26H24N5O2S requires
470.1645 (0.1 ppm error).
4.2.27. ((3R,3aS,4S,6aS)-4-((2R,3R)-3-(Ethanoyloxy)-4-hydroxy-2-
methylbutyl)-3a-hydroxy-1,3-dimethyl-2,6-dioxohexahydro-1H-furo
[3,4-b]pyrrol-6a-yl)methyl ethanoate 56.
7
Me
2
3
8
20
HO
13
6
OH
O
1
9
Me
O
14
10
O
4
12
11
N
Me
Me
O
15
5
4.2.25. (9H-Fluoren-9-yl)methyl (E)-4-(1-phenyl-1H-tetrazol-5-
ylsulfonyl)but-2-enylcarbamate 22.
O
17
O
16
18
1
O
Me
2
19
10
N
N
4
3
N
Benzyl ether 50 (82 mg, 0.167 mmol, 1.0 equiv) was dissolved in
MeOH (6 mL) and then Pd(OH)2/C [20% w/w] (12 mg, 17 mol,
19
8
H
N
18
17
6
13
11
N
O
m
5
S
14
15
12
0.10 equiv) added. The reaction flask was connected to a three-way
tap connected to vacuum and a hydrogen balloon and purged under
five vacuum/hydrogen cycles. The reaction was then stirred for 1 h
under an atmosphere of hydrogen. The catalyst was removed by
filtration through a small pad of CeliteÒ, which was rinsed with
MeOH (3ꢃ10 mL). The filtrate was then concentrated in vacuo to
afford the title compound, 56, as a colourless foam (67 mg,
9
7
O
O
O
16
To a vigorously stirred rt solution of sulfide 53 (1.10 g,
2.34 mmol, 1.0 equiv) and Mo7O24(NH4)6$4H2O (0.87 g, 0.70 mmol,
0.70 equiv) in EtOH (10 mL) was added dropwise H2O2 solution
[34% w/v in water] (15 mL, 70.3 mmol, 30.0 equiv). The resultant
solution was stirred for 7 h at room temperature before being
quenched by the careful addition of saturated aqueous Na2S2O3
(30 mL). The reaction mixture was then diluted with EtOAc
(100 mL) and water (100 mL), extracted with further EtOAc
(3ꢃ30 mL) before being dried (Na2SO4), filtered and concentrated
in vacuo. The crude residue was purified by flash chromatography
(1:1 petrol/EtOAc) to afford the title compound, sulfone 22, as
a colourless solid (630 mg, 1.26 mmol, 54%). Mp 141e143 ꢁC; Rf (7:3
0.167 mmol, quantitative). Rf (19:1 CH2Cl2/MeOH) 0.19; ½a D24:5
ꢂ
þ33.2 (c 1.095, CHCl3); nmax 3403, 2945, 1770, 1736, 1679, 1458,
1430, 1386, 1232, 1041, 1018, 957 cmꢀ1
; dH (400 MHz, CDCl3) 4.84
(1H, ddd, J 6.1, 6.0, 4.4 Hz, CH(3)), 4.70 (1H, d, J 12.8 Hz, CH2(17a)),
4.35 (1H, dd, J 8.1, 6.2 Hz, CH(9)), 4.25 (1H, d, J 12.8 Hz, CH2(17b)),
3.84 (1H, ddd, J 11.7, 6.1, 5.5 Hz, CH2(2a)), 3.71 (1H, s, OH(20)), 3.70
(1H, ddd, J 11.7, 6.0, 5.5 Hz, CH2(2b)), 2.86 (3H, s, CH3(16)), 2.48 (1H,
q, J 7.6 Hz, CH(13)), 2.22 (1H, dd, J 5.5, 5.5 Hz, OH(1)), 2.08e2.13 (1H,
m, CH2(8a)), 2.09 (3H, s, CH3), 2.08 (3H, s, CH3), 1.91e1.98 (1H, m,
CH(6)), 1.69 (1H, ddd, J 14.4, 9.5, 6.2 Hz, CH2(8b)), 1.25 (3H, d, J
7.6 Hz, CH3(14)), 1.06 (3H, d, J 6.9 Hz, CH3(7)); dC (100 MHz, CDCl3)
174.9 (C]O(15)), 171.3 (C]O(4)), 170.1 (C]O(12)), 169.8 (C]
O(18)), 86.2 (CH(9)), 80.0 (C(10)), 77.3 (CH(3)), 71.5 (C(11)), 61.4
(CH2(2)), 57.6 (CH2(17)), 45.0 (CH(13)), 29.7 (CH3), 29.6 (CH3), 26.2
(CH3(16)), 21.0 (CH(6)), 20.8 (CH2(8)), 16.7 (CH3(7)), 10.9 (CH3(14));
m/z (ESI): 402 (MHþ), 424 (MNaþ); HRMS (ESI): MNaþ found
424.1581. C18H27NNaO9 requires 424.1578 (0.8 ppm error).
petrol/EtOAc) 0.21; nmax 1714, 1503, 1344, 1245, 1149 cmꢀ1
; dH
(400 MHz, CDCl3) 7.84e7.47 (9H, m, CH(1, 2, 3, 15 and 16)), 7.40 (2H,
t, J 7.5 Hz, CH(18)), 7.32 (2H, dt, J 7.5, 1.0 Hz, CH(17)), 6.10e5.92 (1H,
m, CH(8)), 5.74e5.59 (1H, m, CH(7)), 4.84 (1H, s, NH(10)), 4.46e4.39
(4H, m, CH2(6, 12)), 4.21 (1H, t, J 6.5 Hz, CH(13)), 3.84 (2H, t, J 4.5 Hz,
CH2(9)); dC (100 MHz, CDCl3) 156.1 (C]O(11)), 153.0 (C(5)), 143.7,
141.3 (CH(7)), 140.0, 132.9, 131.5, 129.7, 127.7, 127.0, 125.1, 124.9,
120.0, 114.7 (CH(8)), 66.8 (CH2(12)), 59.0 (CH2(6)), 47.2 (CH(13)),
42.2 (CH2(9)); m/z (ESI): 502 (MHþ), 519 (MNH4þ); HRMS (ESI): MHþ
found 502.1540. C26H24N5O4S requires 502.1444 (0.6 ppm error).
If the reactions were conducted at higher dilution or with fewer
equivalents of hydrogen peroxide then the predominant product
obtained was alcohol 55.
4.2.28. ((3R,3aS,4S,6aS)-4-((2R,3R)-3-(Ethanoyloxy)-2-methyl-4-
oxobutyl)-3a-hydroxy-1,3-dimethyl-2,6-dioxohexahydro-1H-furo
[3,4-b]pyrrol-6a-yl)methyl ethanoate 21.
4.2.26. (ꢄ)-(9H-Fluoren-9-yl)methyl 2-hydroxybut-3-enylcarbamate
55.
6
Me
1
2
7
O
19
HO
12
5
O
O
2
8
5
3
9
8
Me
1
O
7
N
H
O
13
9
O
3
10
11
OH
10
N
Me
Me
15
14
6
O
4
14
4
11
O
16
12
O
13
15
Mp 82e84 ꢁC; Rf (7:3 petrol/EtOAc) 0.19; nmax 3450, 2922, 1714,
1500, 1344, 1248, 1149, 760 cmꢀ1
dH (400 MHz, CDCl3) 7.76 (2H, d, J
7.5 Hz, CH(14)), 7.59 (2H, d, J 7.5 Hz, CH(11)), 7.40 (2H, t, J 7.5 Hz,
17
O
Me
;
18

R. Bastin et al. / Tetrahedron 67 (2011) 10026e10044
10043
2.87 (3H, s), 2.38 (1H, q, J 7.6 Hz), 2.00e2.09 (2H, m), 2.03 (3H, s),
1.99 (3H, s), 1.62e1.68 (1H, m), 1.21 (3H, d, J 7.6 Hz), 1.04 (3H, d, J
6.9 Hz). This compound proved unstable in solution, undergoing
isomerisation to (4E,6E)-15. This prevented the collection of any
further characterisation data.
To a stirred suspension of alcohol 56 (90 mg, 225
1.0 equiv) in CH2Cl2 (5.5 mL) cooled to 0 ꢁC was added in a single
portion DMP (317 mg, 747 mol, 3.3 equiv) before the cooling bath
mmol,
m
was removed. After stirring for 45 min at rt, the reaction was di-
luted with Et2O (25 mL) and then quenched with a 1:1 solution of
saturated aqueous NaHCO3/saturated aqueous Na2S2O3 (25 mL) and
the mixture was stirred until homogeneous (15 min). The layers
were separated and then the residual aqueous further extracted
with Et2O (3ꢃ25 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated in vacuo. The crude residue was
rapidly purified by flash chromatography (SiO2, 3:1 CH2Cl2/Me2CO)
to afford the title compound, 21, an unstable colourless foam that
(4E,6E)-15: Rf (9:1 CH2Cl2/Me2CO) 0.26; ½a D24
þ2.0 (c 1.0,
ꢂ
CH2Cl2), lit. ½a D23
þ3.6 (c 1.0, CH2Cl2); nmax 3398, 2941, 1771, 1728,
ꢂ
1694, 1525, 1450, 1429, 1383, 1232, 1145, 1107, 1041, 1018, 994, 759,
737 cmꢀ1
; dH (500 MHz, CDCl3) 7.76 (2H, d, J 7.6 Hz, CH(1)), 7.60 (2H,
d, J 7.60 Hz, CH(4)), 7.40 (2H, ddd, J 7.6, 7.6, 1.1 Hz, CH(2)), 7.30 (2H,
ddd, J 7.6, 7.6, 1.1 Hz, CH(3)), 6.21 (1H, dd, J 14.9, 10.9 Hz, CH(14)),
6.13 (1H, dd, J 14.3, 10.9 Hz, CH(13)), 5.72 (1H, dt, J 14.5, 6.0 Hz,
CH(12)), 5.56 (1H, dd, J 15.0, 7.0 Hz, CH(15)), 5.27 (1H, br t, J 5.5 Hz,
NH(10)), 5.19 (1H, t, J 5.5 Hz, CH(16)), 4.69 (1H, d, J 12.9 Hz,
CH2(24a)), 4.37e4.41 (2H, m, CH(8)), 4.30 (1H, dd, J 8.8, 4.3 Hz,
CH(22)), 4.24 (1H, d, J 12.9 Hz, CH2(24b)), 4.19e4.22 (1H, m, CH(7)),
3.76e3.91 (2H, m, CH2(11a, 11b)), 3.32 (1H, s, OH(28)), 2.86 (3H, s,
CH3(33)), 2.41 (1H, q, J 7.5 Hz, CH(31)), 2.07 (3H, s, CH3), 2.05 (3H, s,
CH3), 1.85e1.98 (2H, m, CH2(21a) and CH(19)), 1.61 (1H, ddd, J 15.1,
8.8, 6.8 Hz, CH2(21b)), 1.24 (3H, d, J 7.7 Hz, CH3(32)), 1.00 (3H, d, J
6.8 Hz, CH3(20)); dC (125 MHz, CDCl3) 174.6 (C]O(30)), 170.3 (C]
O), 170.2 (C]O), 169.8 (C]O), 156.4 (C(9)), 143.9 (C(5)), 141.3 (C(6)),
132.8 (CH(14)), 131.3 (CH(12)), 130.5 (CH(13)), 128.7 (CH(15)), 127.7
(CH(2)), 127.0 (CH(3)), 125.1 (CH(4)), 120.0 (CH(1)), 86.8 (CH(22)),
80.2 (C(27)), 77.5 (CH(16)), 71.4 (C(29)), 66.8 (CH2(8)), 57.8
(CH2(24)), 47.3 (CH(7)), 44.3 (CH(31)), 42.6 (CH2(11)), 34.0 (CH(19)),
30.6 (CH2(21)), 26.2 (CH3(33)), 21.2 (CH3), 20.9 (CH3), 16.7
(CH3(20)), 11.0 (CH3(32)); m/z (ESI): 675 (MHþ), 697 (MNaþ); HRMS
(ESI): MHþ found 675.2912. C37H43N2O10 requires 675.2915
(0.4 ppm error).
decomposes at rt (45.5 mg, 113
m
mol, 51%). Rf (3:1 CH2Cl2/Me2CO)
þ35.0 (c 0.40, CHCl3); nmax 3399, 2919, 2851, 1771, 1746,
dH (400 MHz,
0.39; ½a 1D8:5
ꢂ
1678, 1459, 1432, 1375, 1228, 1149, 1041, 1019 cmꢀ1
;
CDCl3) 9.56 (1H, s, CH(1)), 4.97 (1H, d, J 3.9 Hz, CH(2)), 4.72 (1H, d, J
13.0 Hz, CH2(16a)), 4.31 (1H, dd, J 7.4, 6.2 Hz, CH(8)), 4.24 (1H, d, J
13.0 Hz, CH2(16b)), 2.96 (1H, s, OH(19)), 2.86 (3H, s, CH3(15)), 2.50
(1H, q, J 7.6 Hz, CH(12)), 2.25e2.33 (1H, m, CH(5)), 2.21 (3H, s, CH3),
2.10 (3H, s, CH3), 1.81e1.89 (2H, m, CH2(7a, 7b)), 1.26 (3H, d, J 7.6 Hz,
CH3(13)), 1.14 (3H, d, J 7.0 Hz, CH3(6)); dC (100 MHz, CDCl3) 199.5
(C]O(1)), 174.4 (C]O(14)), 170.6 (C]O), 170.3 (C]O(11)), 169.6
(C]O), 85.9 (CH(8)), 80.9 (CH(2)), 80.3 (C(9)), 71.4 (C(10)), 57.9
(CH2(16)), 44.4 (CH(12)), 31.0 (CH(5)), 30.0 (CH2(7)), 26.2 (CH3(15)),
21.0 (CH3), 20.6 (CH3), 16.9 (CH3(6)), 11.0 (CH3(13)); m/z (ESI): 400
(MHþ), 422 (MNaþ); HRMS (ESI): MHþ found 400.1596. C18H26NO9
requires 400.1602 (0.8 ppm error).
4.2.29. [(3R,3aS,4S,6aS)-4-[(2R,3R,4E,6E)-3-Acetoxy-8-{[(9H-fluo-
ren-9-ylmethoxy)carbonyl]amino}-2-methylocta-4,6-dien-1-yl]-3a-
hydroxy-1,3-dimethyl-2,6-dioxotetrahydro-1H-furo[3,4-b]pyrrol-
6a(6H)-yl]methyl acetate 15.
Acknowledgements
20
Me
O
We are grateful for Ph.D. funding (R.B., EPSRC GR/T 19971;
J.P.N.P., Pharmacia/Upjohn; M.R.W., EPSRC/Astra Zeneca) and for
postdoctoral funding (J.W.D., EPSRC GR/R 69624; M.G.E., Elsevier).
We would also like to thank Prof. Hatakeyama (Nagasaki University,
Japan) for helpful discussions.
15
13
14
11
16
21
28
19
22
N
H
10
O
9
12
HO
Me
17
7
32
O
Me
8
31
O
27
24
18
5
3
29
23
O
6
O
30
N
4
O
1
O
Me
References and notes
33
25
2
O
Me
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26
To a solution of sulfone 22 (55 mg, 109 mmol, 1.0 equiv) in THF
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