Synthesis of macrocyclic precursors of lankacidins using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure

Article abstract of DOI:10.1016/j.tet.2010.04.129

In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones and their participation in Stille coupling reactions have been investigated. 1-tert-Butyldimethylsilyl-4-(2-iodoethenyl) azetidinone was found to

Full text of DOI:10.1016/j.tet.2010.04.129

Tetrahedron 66 (2010) 6613e6625
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of macrocyclic precursors of lankacidins using Stille reactions of
4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure
*
Christopher T. Brain, Anqi Chen, Adam Nelson, Nongluk Tanikkul, Eric J. Thomas
The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones
and their participation in Stille coupling reactions have been investigated. 1-tert-Butyldimethylsilyl-4-(2-
iodoethenyl)azetidinone was found to undergo a Stille coupling reaction with a 3-hydroxy-1-tributyl-
stannylhepta-1,5-diene to give an acceptable yield of the corresponding conjugated diene but the analo-
gous reaction with a 3-tert-butyldimethylsilyloxy-1-tributylstannylhepta-1,5-diene was unsuccessful. A
series of 4-[(E)-2-iodoprop-1-enyl]azetidinones, a ring-opened ester and a lactone were also found to
undergo Stille reactions with 3-tributylstannylprop-2-enol albeit with variable yields. Asymmetric syn-
theses of methyl(2R,3R,5S)-3-tert-butyldimethylsilyloxy-2-methyl-5-(2-trimethylsilylethoxy)methoxy-6-
Received 9 February 2010
Received in revised form 15 April 2010
Accepted 29 April 2010
Available online 6 May 2010
Keywords:
Natural products
Macrocyclization
Palladium catalyzed coupling
Total synthesis
Stereoselectivity
Chemoselectivity
oxohexanoate,
(3R,4S)-1-tert-butyldimethylsilyl-4-[(E)-2-iodoprop-1-enyl]-3-methylazetidin-2-one,
and (5S,2E,6E)-5-tert-butyldimethylsilyloxy-2-methyl-1-phenylsulfonyl-7-tributylstannylhepta-2,6-di-
ene and their incorporation into macrocyclic precursors of the lankacidins were then investigated. Key
reactions were a Julia reaction between the aldehyde and the sulfone to form the 12,13-double-bond,
a stereoselective acylation of the azetidinone, and formation of macrocycles using intramolecular Stille
reactions in the presence of a free hydroxyl group at C(8) (lankacidin numbering).
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
independently by Kende and ourselves, was based on the stereo-
selective acylation of an azetidinone followed by a ring-opening
The lankacidins are a small group of macrocyclic natural prod-
ucts, which display antibiotic activity against Gram-positive bac-
teria.1 They have also been found to enhance the survival times of
mice with leukemia and solid tumours.2 The structures of the
lankacidins are unusual in that they have a 17-membered carbo-
cyclic ring with a carbonyloxy bridge forming a six-membered
lactone, see lankacidin C (1). A type of Favorskii reaction is believed
to be involved in their biosynthesis.3
rearrangement of the acylated azetidinone with formation of a d-
lactone.4,5 For example, acylation of azetidinone 2 gave the 3,3-
disubstituted azetidinone 3, which was taken through to the
lactone 5 by reductive rearrangement of the N-acylazetidinone 4
using sodium borohydride see Scheme 1.5 Lactone 5 corresponds
to the C16eC6 fragment of lankacidin C (1) and has the required
configuration at its stereogenic centres including the quaternary
centre corresponding to C2 of the lankacidins. Using this approach,
Kende completed a formal synthesis of lankacidin C (1).4
O
Me
O
O
HN
Me
Me
Me
Me
O
OTBS
17
Me
Me
OR1
3
N
Me
TBS
1
16
O
6
OR1
N
Me
O
R2
O
O
13
OH
3 R1= R2 = TBS
HO
12
2
4 R1 = H R2 = C(O)Et
Me
1
NaBH4
70%
EtOH
HO
O
The lankacidins have interested synthetic organic chemists
because of their unusual structures and biological activities.4e7
Me
Me
NH
Me
Me
An approach to the
d-lactone containing fragment, studied
OH
O
O
* Corresponding author. E-mail address: e.j.thomas@manchester.ac.uk (E.J.
Thomas).
5
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.129

6614
C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
Me
Me
CHO
TBS
Me
O
Me
i
iii
vii
+
N
N
Br
N
N
N
O
O
R
O
H
TBS
O
TBS
8
9 R = TBS
10 R = H
11 R = H
12 R = TBS
iv
ii
17
16
viii
v
SnBu3
SnBu3
I
Me
O
vi
N
R
N
O
N
Me
TBS
O
TBS
13 R = H
14 R = TBS
15
iv
18
Scheme 1. Synthesis of 4-(2-iodoethenyl)azetidinones; reagents and conditions: (i) Ph3P]CHBr, ꢀ78 ꢁC to rt, 1 h (58%); (ii) HCl, H2O, MeOH, rt, 1 h (70%); (iii) nBuLi, hexanes, THF,
0
ꢁC, 1.5 h (77%); (iv) TBSCl, Et3N, DMF, rt (12, 88%; 14, 67%); (v) Bu3SnH, AIBN (trace), 140 ꢁC, 4 h (13, 62%; 14, 64%); (vi) I2, CCl4, rt, 15 min (63%); (vii) 2 LDA, ꢀ78 ꢁC, MeI, ꢀ78 ꢁC to rt
(16, 48%; 17, 9%); (viii) Bu3SnH, AIBN (trace), 100 ꢁC, 6 h (73%).
Based on this work, a synthesis of lankacidin C (1) was planned
in which an azetidinone-fused macrocycle 6 would be a key
intermediate since reductive ring-opening of the azetidinone
should lead to lactone 7, which has the required configuration at
the C2 quaternary carbon and the characteristic bicyclic structure of
the lankacidins. A convergent synthesis of the azetidinone 6 was
required and its assembly from three starting materials was con-
sidered, see structure 6. At the time of planning the synthesis, the
stereoselective acylation of azetidinones was precedented, e.g., by
the synthesis of azetidinone 3,4,5 and several reactions could be
envisaged for formation of the 12,13-double-bond although only
modest yields had been obtained during preliminary studies of
macrocyclisation via 12,13-double-bond formation using a Wad-
swortheEmmonseHorner reaction.7 It was recognised that late
stage formation of the C5eC6 bond would provide a convergent
synthesis and the use of a Stille reaction8 was considered for this
assembly step and for macrocyclisation.
A 4-[(E)-2-iodoprop-1-enyl]azetidinone was required to provide
the C5 methyl group of the lankacidins. However, although bis-
methylation of the N-tert-butyldimethylsilyl-4-ethynyl-azetidi-
none 12 was achieved using lithium diisopropylamide and methyl
iodide, addition of tributyltin hydride to the major 3,4-trans-di-
substituted azetidinone 16 gave rise to the 4-[(E)-1-tributyl-
stannylprop-1-enyl]-azetidinone 18 and not to the regioisomer
required for a synthesis of a 4-(2-iodoprop-1-enyl)azetidinone.
To avoid this problem, the racemic 3,4-cis- and 3,4-trans-3-
methyl-4-(2-iodoprop-1-enyl)azetidinones 24 and 26 were prepared
from the open-chain imine 21 as outlined in Scheme 2. (E)-3-Tribu-
tylstannylbut-2-enal (20)14 was obtained from the alcohol 19 by
oxidation using manganese dioxide as under Swern conditions
extensive isomerisation to the corresponding (Z)-aldehyde was
observed. The imine 21 was then generated in situ by the addition of
aldehyde 20 to lithium hexamethyldisilazide in tetrahydrofuran,15
and addition of the lithium enolate of ethyl propanoate gave a mix-
ture of the 3,4-cis- and -trans-azetidinones 22. With iodine, this
mixture gave the 4-[(E)-2-iodoprop-1-enyl]azetidinones 23 and 25,
which were separately converted into their N-silylated derivatives 24
and 26, the cis/trans-configuration of the products being assigned on
the basis of their 3,4-1H-coupling constants.
In this paper, studies of Stille reactions of 4-(2-iodo-alkenyl)
azetidinones and related compounds are described, which led to
the use of this chemistry for the synthesis of advanced macrocyclic
precursors of lankacidins.9
Acyl
O
HO
HN
Me
Me H
Me
6
H
5
Me
Me
Me
HO
SnBu3
SnBu3
2
i
OHC
N
Acyl
Me
H
O
O
Me
O
OH
20
ii
12
H
19
OP
PO
OP
PO
13
Me
SnBu3
Me
Me
6
7
N
SnBu3
Me3Si
(P = a protecting group)
N
Me
Me
O
Me
21
22
iii
2. Results and discussion
Me
I
Me
I
+
N
R
Me
N
2.1. Preliminary studies of Stille reactions of 4-(2-iodo-
alkenyl)azetidinones and related compounds
O
O
R
23 R = H
24 R = TBS
25 R = H
26 R = TBS
iv
iv
(S)-4-Ethynylazetidinone (11)10,11 was prepared from aldehyde
812 by a modification of the published synthesis, see Scheme 1. A
Wittig reaction using bromomethylidenetriphenylphosphorane13
gave the (Z)-vinyl bromide 9, which, after N-desilylation, was
converted into the 4-ethynylazetidinone 11 on treatment with
n-butyllithium. Following resilylation, addition of tributyltin
hydride under free-radical conditions led to the 4-[(E)-2-tributyl-
stannylethenyl]azetidinone 14. Alternatively, addition of tributyltin
hydride to the NH-azetidinone 11 gave the 4-ethenyl-NH-azetidi-
none 13, which was N-silylated. Treatment of the vinylstannane 14
with iodine in carbon tetrachloride then provided the (S)-4-[(E)-2-
iodoethenyl]azetidinone 15 ready for studies of Stille reactions.
Scheme 2. Synthesis of racemic 4-(2-iodopropenyl)azetidinones; reagents and con-
ditions: (i) MnO2, acetone, rt, 12 h (100%); (ii) LiN(SiMe3)2, THF, ꢀ78 ꢁC, 1 h, then
MeCHLiCO2Et, ꢀ78 ꢁC, 45 min, rt, 1 h (49%; 3,4-cis:3,4-trans¼75:25); (iii) I2, CCl4, rt,
1.5 h (23, 48%; 25, 29%); (iv) TBSCl, Et3N, DMF, rt, 2 h (24; 88%; 26, 87%).
Stille reactions of the 4-(2-iodoethenyl)- and 4-(2-iodoprop-1-
enyl)-azetidinones 15, 24 and 26 were now investigated. Under
standard conditions using bis(acetonitrile)palladium(II) chloride as
the catalyst, (S)-4-(2-iodoethenyl)azetidinone 15 was coupled with
racemic (E)-4-tributylstannylbut-3-enol 27 to give a mixture of the
50-epimers of diene 28. Oxidation then gave the ketone 29, the
E,E-geometry being confirmed by 1H NMR, see Scheme 3.

C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
6615
OH
Me
OH
I
+
Bu3Sn
OSEM
N
i
15
+
37
O
TBS
Me
N
27
15
O
TBS
38
i
Scheme 5. A further Stille reaction of a 4-(2-iodoethenyl)azetidinone; reagents and
conditions: (i) (MeCN)2PdCl2, DMF, rt, 1 h (50%).
O
OH
Me
Me
ii
N
N
Stille reactions of the racemic cis- and trans-4-[(E)-2-iodo-
prop-1-enyl]azetidinones 24 and 26 with (E)-3-tributylstannyl-
prop-2-enol18 were now investigated. Using bis(acetonitrile)
palladium(II) chloride as the catalyst, good yields of the dienes 39
and 40 were obtained so showing that the additional methyl
group in the vinyl iodide was compatible with these Stille
couplings, albeit with a relatively unhindered vinylstannane, see
Scheme 6.
O
TBS
O
TBS
29
28
Scheme 3. A Stille reaction of a 4-(2-iodoethenyl)azetidinone; reagents and condi-
tions: (i) Pd(MeCN)2Cl2, DMF, rt, 45 min (76%); (ii) TPAP, NMO, 4 Å sieves, rt 2 h (86%).
The formation of the dienyl azetidinone 28 was encouraging and
so the Stille coupling of the (S)-4-(2-iodoethenyl)azetidinone 15
with more complex vinylstannanes was investigated. (E)-3-
Tributylstannyl-prop-2-enal 3016 was converted into the (S)-aldol
product 31 by reaction with (S)-2-hydroxy-1,2,2-(triphenyl)ethyl
acetate followed by ester exchange using sodium methoxide, see
Scheme 4.17 The configuration at C3 in the ester 31 followed from
the known stereoselectivity of aldol reactions of the chiral acetate,17
and was confirmed using its (R)- and (S)-Mosher’s derivatives,
which indicated that the ee of the ester 31 was ca. 90%. Following
O-silylation, reduction of the silyl ether 32 using di-isobutyl-
aluminium hydride gave the aldehyde 33 together with a small
amount of the corresponding alcohol, which was oxidized to the
aldehyde under Swern conditions. A phosphonate condensation
then gave the (E)-ester 34, which was reduced to the alcohol 35.
Protection of the primary alcohol with triethylsilyethoxymethyl
chloride gave the SEM-ether 36, which was O-desilylated to give
the secondary alcohol 37.
Me
Me
I
i
OH
N
N
Me
TBS
N
Me
TBS
O
O
39
24
Me
Me
I
i
OH
Me
TBS
N
Me
TBS
O
O
40
26
Scheme 6. Stille reactions of 4-(2-iodopropenyl)azetidinones; reagents and condi-
tions: (i) (E)-Bu3SnCH]CHCH2OH, (MeCN)2PdCl2, DMF, rt, 45 min (39, 93%; 40, 80%).
OP
At this point, it was decided to study Stille reactions of other
vinyl iodides prepared from azetidinone 24 with (E)-tributyl-
stannylprop-2-enol to evaluate their potential for the introduction
of the C4-C7-dienyl fragment of lankacidins.
i
CO2Me
CHO
Bu3Sn
Bu3Sn
31 P = H
32 P = TBS
30
ii
The azetidinone 24 was converted into the 3-acylated azetidi-
none 41 by addition to 3-tert-butyldimethylsilyloxypropanal
followed by oxidation, see Scheme 7. Reduction using the hindered
reducing agent, potassium triethylborohydride, gave the alcohol 42
with excellent stereocontrol, the configuration at the newly formed
stereogenic centre initially being assigned by analogy with earlier
work4,5 and was confirmed later in the synthesis. Following
O-silylation using tert-butyldimethylsilyl triflate, selective N-desi-
lylation was achieved using potassium fluoride in methanol and
treatment of the resulting azetidinone 43 with Boc anhydride gave
the carbamate 44. Rearrangement to the lactone 45 was now
achieved using tetrabutylammonium fluoride and the lactone was
taken through to the bicyclic carbonate 46 by acid-catalysed
removal of the tert-butyloxycarbonyl group followed by reaction
with carbonyl di-imidazole.
The stereochemistry shown was assigned to the carbamate 46
on the basis of 1H NMR observations. In particular the cis-ring
fusion was confirmed by the observation of nuclear Overhauser
enhancements between the quaternary methyl group and the
cis-disposed bridgehead hydrogen. The relative configuration
between the quaternary centre and the nitrogen bearing stereo-
genic centre followed the stereoselectivity of acylation of azetidi-
none 244,5 and was confirmed by nuclear Overhauser
enhancements between the 1,3-cis-disposed 6-H and 10-H. Nuclear
Overhauser enhancements between the 30-H3 and 10-H also
confirmed that the geometry of the double-bond, which had been
assigned on the basis of the known geometry of aldehyde 20, had
not changed during the course of the synthesis.14
iii
OTBS
OTBS
iv
CO2Et
CHO
Bu3Sn
Bu3Sn
Me
Me
34
33
v
OH
OTBS
vii
Bu3Sn
OSEM
Bu3Sn
OP
Me
37
35 P = H
36 P = SEM
vi
Scheme 4. Synthesis of a 1-tributylstannylhepta-1,5-dien-3-ol; reagents and condi-
tions: (i) (a) (2-hydroxy-1,1,2-(triphenyl)ethyl acetate, LDA, ꢀ78 ꢁ
C to rt, MgBr2,
ꢀ78 ꢁC, 1 h, add 30, ꢀ78 ꢁC, 2 h (56%) (b) NaOMe, MeOH, rt, 15 min (73%); (ii) TBSOTf,
2,6-lutidine, DCM, ꢀ78 ꢁC to rt, 30 min (99%); (iii) DIBAL-H, hexanes, THF, ꢀ78 ꢁC,
20 min (79%); (iv) (EtO)2P(O)CHMeCO2Et, NaH, THF, 0 ꢁC, 10 min, 33, rt, 1.5 h (97%); (v)
DIBAL-H, THF, 0 ꢁC to rt, 1.25 h (65%); (vi), SEMCl, EtNiPr2, DCM, 0 ꢁC to rt, 2.5 h (96%);
(vii) TBAF, THF, 0 ꢁC to rt, 3.5 h (66%).
The Stille reaction is sensitive to steric effects.8 It was found that
stannane 36 in which the allylic hydroxyl group is protected as its
tert-butyldimethylsilyl ether, failed to undergo a Stille coupling
with the 4-(2-iodoethenyl)-azetidinone 15 in the presence of either
bis(acetonitrile)palladium(II) chloride or tetrakis(triphenylphos-
phine)palladium even after prolonged reaction times. In contrast,
stannane 37 in which the secondary allylic hydroxyl group is
unprotected, underwent a Stille coupling with the vinyl iodide 15 to
give the conjugated diene 38 as a single diastereoisomer in a 50%
yield see Scheme 5, the diene geometry again being consistent with
1H NMR data.
Azetidinone 24 was similarly taken through to the 3,3-di-
substituted N-tert-butoxycarbonylazetidinone 50 and methanolysis,

6616
C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
TBSO
O
OH
Me
HO
O
NHBoc
O
Me
Me
Me
I
I
I
Me
I
Me
I
v
i
iii
ii
N
Me
N
Me
TBS
N
Me
TBS
N Me
TBS
24
TBSO
iv
TBSO
TBSO
O
R
O
O
O
41
42
43 R = H
44 R = Boc
45
vi
vii
O
TBSO
O
HO
3'
TBSO
Me
NHBoc
Me
Me
Me
Me
O
NH
Me
I
I
I
Me
viii
Me
iii
ii
6
10
O
I
1
Me
N
Me
Me
N
Me
TBS
Me
N
Me
TBS
I
CO2Me
O
R
O
O
O
47
46
48
49 R = H
50 R = Boc
51
iv
Scheme 7. Further synthesis of 4-(2-iodopropenyl)azetidinones and analogues; reagents and conditions: (i) (a) LiNEt2, ꢀ78 ꢁC, 1 h, TBSOCH2CH2CHO, ꢀ78 ꢁC, 30 min (b) PDC, DCM,
4 Å sieves, rt, 6 h (53%); (ii) KBEt3H, THF, Et2O, ꢀ78 ꢁC, 10e20 min (42, 91%; 48, 91%); (iii) (a) TBSOTf, 2,6-lutidine, DCM, rt, 3 h (b) KF, MeOH, rt, 30 min (43, 94%; 49, 64%); (iv)
NaHMDS, ꢀ78 ꢁC, 15 min, (tBuO2C)2O, ꢀ78 ꢁC, 20 min (44, 98%; 50, 89%); (v) TBAF, THF, rt, 45 min (62%); (vi) (a) TFA, rt, 15 min (b) Et3N, rt, 20 min, Im2CO, rt, 16 h 60%); (vii) (a)
LiNEt2, ꢀ78 ꢁC, 1 h, EtCHO, ꢀ78 ꢁC, 30 min (b) PDC, DCM 4 Å sieves (19%); (viii) KCN, MeOH, DMF, rt, 16 h (85%).
O
using potassium cyanide and methanol19 in N,N-dimethylformamide,
gave the methyl ester 51, see Scheme 7.
Me H
N
Me
Me
Stille reactions of the NH- and Boc-protected azetidinones
43 and 44, the lactone 45 and the ester 51 with (E)-3-tribu-
tylstannylprop-2-enol catalysed by bis(acetonitrile)palladium(II)
chloride were successful and gave the conjugated dienes 52e55
albeit in modest, unoptimised, yields. The use of other
catalysts for these reactions was not investigated. Nevertheless,
this work confirmed that Stille reactions could be used to
Lankacidin C (1)
O
OH
Acyl
PO
OP
Me
(P protecting groups)
6
assemble dienyl substituted esters, d-lactones and azetidinones
reminiscent of synthetic precursors of the C16eC7 fragment
of lankacidins.
Me
CO2Me
OTBS
SnBu3
OTBS
H
Me
O
I
S(O)2Ph
+
+
N
Me
TBS
SEMO
CHO
56
Me
Boc
57
(3R,4S)-26
HO
O
NH
Me
Me
OH
OH
The synthesis of aldehyde 56 started with dimethyl (S)-malate
58, see Scheme 8. This was reduced regioselectively using the
borane dimethyl sulfide complex together with sodium borohy-
dride.20 Selective protection of the resulting primary alcohol gave
the mono(dimethoxytrityl) ether 59, which was further protected
as the (2-trimethylsilylethoxy)-methyl ether 60. This was reduced
to the aldehyde 61 using di-isobutylaluminium hydride, the small
amount of alcohol 62, which was obtained being oxidised to
TBSO
Me
O
OH
54 (40%)
N
Me
TBSO
Boc
NH Me
O
R
TBSO
52 R = H (33%)
53 R = Boc (36%)
Me
Me
CO2Me
CO2Me
R
55 (33%)
CO2Me
CO2Me
iii
i, ii
R1O
SEMO
HO
OR2
ODMT
2.2. Synthesis of fragments for macrocycle assembly
59 R1 = H, R2 = DMT
61 R = CHO
62 R = CH2OH
58
60 R1 = SEM, R2 = DMT
Based on these preliminary studies, it was decided to study
the use of a Stille reaction for formation of the macrocyclic ring of
the lankacidins, and the convergent synthesis of azetidinone 6,
indicated above, was planned in more detail. The ester-aldehyde
56, the azetidinone (3R,4S)-26 and the vinylstannane-sulfone
57 were identified as key building blocks. A Julia reaction
between the aldehyde 56 and sulfone 57 would give a long-chain
ester, which would be converted into the corresponding
thioester. Following acylation of the azetidinone 26 using
the thioester, a ring-closing Stille reaction of the 4-(2-iodopro-
penyl)azetidinone would lead to a synthesis of the required
bicyclic intermediate 6. The end-game of a synthesis of lank-
acidin C could then include an azetidinoneelactone rearrange-
ment, although the details of the later stages of the synthesis
could only be worked out after the assembly steps had been
completed.
iv
Me
CO2Me
OP
CO2Me
Me
CO2Me
v, vi
vii, viii
OH
OTBS
SEMO
SEMO
SEMO
R
ODMT
ODMT
66 R = CH2OH
56 R = CHO
64 P = H
65 P = TBS
63
Scheme 8. Synthesis of aldehyde 56; reagents and conditions: (i) BH3$DMS, THF, rt,
30 min, NaBH4, rt, 1 h, then DMTCl, DMAP, rt, 1.5 h (93%); (ii) SEMCl, EtNiPr2, DCM, rt,
14 h (99%); (iii) DIBAL-H, hexanes, THF, ꢀ78 ꢁC, 2 h (75%); (iv) (a) (S)-2-hydroxy-1,1,2-
(triphenyl)ethyl acetate, LDA, ꢀ78 ꢁC to rt, MgBr2, ꢀ78 ꢁC, add 61, ꢀ78 ꢁC, 2 h (b)
NaOMe, MeOH, rt, 3 h (68%); (v) 2 LDA, THF, ꢀ50 ꢁC to ꢀ10 ꢁC, TMEDA, MeI, ꢀ78 ꢁC,
5 h (80%); (vi) TBSOTf, 2,6-lutidine, DCM, ꢀ78 ꢁC, 1 h (93%); (vii) Cl2CHCO2H, DCM, rt,
2 h (74%); (viii) TPAP, NMO, 4 Å sieves, DCM, rt, 2 h (82%).

C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
6617
aldehyde 61 using the Swern procedure. A stereoselective aldol
reaction of aldehyde 61 with (S)-2-hydroxy-1,2,2-(triphenyl)ethyl
acetate17 then gave the ester 63 after ester exchange with meth-
anol together with ca. 25% of its epimer at C3, which were sepa-
rated by chromatography. The configuration of the major product
at C3 was assigned as shown in structure 63 by analogy with the
literature.17 An anti-selective methylation of hydroxy ester 63 was
achieved using Frater’s procedure21 to give the tert-butyldime-
thylsilyl ether 65 after silylation of the resulting alcohol 64 using
tert-butyldimethylsilyl triflate. Selective removal of the dimeth-
oxytrityl group was carried out using dichloroacetic acid and
oxidation using tetrapropylammonium perruthenate22 gave the
aldehyde-ester 56.
stereoselectivity of aldol reactions of (R)-2-hydroxy-1,2,2-(tri-
phenyl)ethyl acetate.17 Azetidinone 75 was then methylated ster-
eoselectively to give the (3R,4S)-azetidinone 26, the 3,4-trans-
stereochemistry being assigned by 1H NMR; J3,4¼2.5 Hz.
The vinylstannane-sulfone 57 was prepared from (5S,2E,6E)-
5-tert-butyldimethylsilyloxy-7-tributylstannyl-2-methylhept-2,6-
dien-1-ol (35). Conversion to the bromide 77 and substitution
using sodium benzenesulfinate gave the required sulfone 57, see
Scheme 10.
X
OTBS
OH
OTBS
i
SnBu3
SnBu3
Me
Me
77 X = Br
The racemic 3,4-cis- and -trans-azetidinones 24 and 26 had been
prepared earlier, see Scheme 2, but it was now necessary to develop
an asymmetric synthesis for the synthesis of advanced lankacidin
intermediates. Stereoselective conjugate addition of a tributyltin
cuprate to methyl but-2-ynoate 67 gave the (E)-adduct 68,23 which
was taken through to the aldehyde 70 by reductioneoxidation with
manganese dioxide being the preferred oxidant to prevent (E)/(Z)-
isomerisation, see Scheme 9. Aldol addition with lithiated (R)-2-
hydroxy-1,2,2-(triphenyl)ethyl acetate mediated by magnesium
dibromide followed by ester exchange using sodium methoxide17
gave the (3R)-aldol adduct 71, which was converted into the
iodide 72 by a tineiodine exchange. Reaction of this methyl ester
with lithium 4-methoxyanilide gave the hydroxyamide 73 and
cyclisation with inversion of configuration under Mitsunobu
conditions24 formed the azetidinone 74.
35
57 X = PhS(O)2
Scheme 10. Synthesis of sulfone 57; reagents and conditions: (i) (a) MsCl, Et3N, THF,
ꢀ78 ꢁC, 1 h then LiBr, rt, 12 h (81%); (b) PhSO2Na, DMF, rt, 12 h (88%).
2.3. Assembly of macrocyclic precursors of lankacidins
A Julia olefination between the aldehyde 56 and sulfone 57
gave the conjugated diene 78, the (E)-configuration across the
newly formed double-bond being assigned on the basis of the H
(6)eH(7) coupling constant of 15.7 Hz. Saponification of the
methyl ester and coupling of the resulting carboxylic acid with
2-mercaptopyridine gave the thioester 79. Following the
procedure developed in earlier work,5 deprotonation of the
(3R,4S)-azetidinone 26 using lithium diethylamide followed by
the addition of the thioester 79 gave the 3-acylated azetidinone
80. This was reduced stereoselectively to the alcohol 81 using
potassium triethylborohydride, the configuration shown at the
newly introduced hydroxyl bearing stereogenic centre being
assigned by analogy with earlier work.4,5
SnBu3
SnBu3
R
ii, iii
i
MeO2C
MeO2C
Me
Me
Me
67
69 R = CH2OH
70 R = CHO
68
The earlier studies on Stille reactions of 4-(2-iodo-alkenyl)aze-
tidinones with (E)-1-(tributylstannyl)-alkenes had shown that
better results were obtained if a 3-hydroxyl group was unprotected.
Therefore before the attempted macrocyclisation, the tris-silylated
azetidinone 81 was desilylated using tetrabutylammonium fluoride
to give the triol 82. Initial studies into the cyclisation of this
vinylstannane using a Stille reaction were carried out using bis
(acetonitrile)palladium(II) chloride as the catalyst, which had given
useful results in the intermolecular Stille reactions of 3-hydroxyalk-
1-enylstannanes and 4-(2-iodo-alkenyl)azetidinones, but only
modest, ca. 27%, yields of the required macrocyclic product 83 were
obtained. However, when tris(dibenzylideneacetone)bis-palladium
(0)26 in the presence of triphenylarsine was used as the catalyst,
a significantly better yield, 52%, of the macrocyclic intermediate 83
was isolated, see Scheme 11.
iv, v
H
N
X
I
vi
MeO2C
OH Me
O
73
OH Me
71 X = SnBu3
72 X = I
Me
vii
H
N
H
N
H
N
I
I
I
viii
ix
Me
Me
Me
O
C6H4-4-OMe
O
O
O
TBS
TBS
(3R,4S)-26
75
74
x
H
OH
The structure assigned to the Stille product 83 was consistent
with spectroscopic data. In particular, the 15-CH3 substituent was
N
TBS
observed as a singlet at
methyl group in the vinyl iodide 82 was seen as a narrow doublet at
2.48 (J 1.3), cf. analogous chemical shifts observed during the
d
1.69 in its 1H NMR, whereas the analogous
76
Scheme 9. Synthesis of azetidinone (3R,4S)-26; reagents and conditions: (i) Li
(Bu3SnCuBr)$DMS, ꢀ78 ꢁC, 3 h (91%); (ii) DIBAL-H, hexanes, ꢀ78 ꢁC to 0 ꢁC, 1 h (98%);
(iii) MnO2, acetone, rt, 12 h (100%); (iv) (a) (R)-2-hydroxy-1,1,2-(triphenyl)ethyl acetate,
LDA, ꢀ78 ꢁC to rt, MgBr2, ꢀ78 ꢁC, add 70, ꢀ78 ꢁC, 2 h (b) NaOMe, MeOH, rt (96% from
70); (v) I2, CCl4, rt, 20 min (98%); (vi) 4-MeOC6H4NHLi, THF, ꢀ78 ꢁC, 40 min (73%); (vii)
Ph3P, DEAD, THF, rt, 1 h (83%); (viii) CAN, MeCN, H2O, rt, 20 min then TBSCl, Et3N, DMF,
rt, 30 min (78% from 74); (ix) LDA, ꢀ78 ꢁC, 30 min, then MeI, ꢀ78 ꢁC, 2 h (85%); (x) O3,
ꢀ78 ꢁC, then NaBH4, MeOH.
d
earlier intermolecular Stille reactions. The (13E)-geometry was
consistent with J13,14 (15.5 Hz).
As an improved yield had been obtained from the intra-
molecular Stille reaction of the iodostannane 82 using tris(diben-
zylideneacetone)bis-palladium(0) as the catalyst, the use of this
catalyst to promote a Stille cyclisation of the (E)-tert-butyldime-
thylsilyloxyalkenylstannane 81 was studied. However, as had been
observed during the earlier studies of intermolecular Stille
reactions, only mixtures of unidentifiable compounds were
obtained. It appeared that in this system the hydroxyl group, which
is allylic to the vinylstannane cannot be silylated. The compatibility
of other hydroxyl protecting groups with the Stille reaction was
not investigated.
Oxidative N-deprotection and silylation then delivered the
azetidinone 75, which was ozonolyzed with reduction using
sodium borohydride to the 4-(hydroxymethyl)-azetidinone 76.
Comparison of azetidinone 76 with a sample prepared from
L
-aspartic acid following the literature procedure12,25 showed that
it had an enantiomeric excess of ca. 90% and confirmed its absolute
configuration which had been assigned on the basis of the known

6618
C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
O
O
I
Me H
NTBS
Me
Me
SnBu3
OTBS
X
Me
i, ii
iii
S(O)2Ph
Me
O
OTBS
OTBS
OTBS
OTBS
SnBu3
SnBu3
SEMO
SEMO
Me
Me
80
57
78 X = OMe
79 X = S-(2-Py)
iv
HO
OH
HO
I
I
Me H
NTBS
Me H
Me H
NH
Me
15
Me
Me
Me
vi
v
Me
Me
OH
NH
O
O
OTBS
O
13
OH
OH
OTBS
OH
SnBu3
SEMO
SEMO
SnBu3
SEMO
Me
81
Me
83
Me
82
Scheme 11. Synthesis of the azetidinone-fused macrocycle 83; reagents and conditions: (i) (a) LiNiPr2, ꢀ78 ꢁC, THF, ꢀ78 ꢁC, 10 min, add 56, 2 h (b) Ac2O, Et3N, DCM, DMAP (trace),
ꢀ20 ꢁC, 30 min then rt, 1 h (c) Na/Hg, MeOH, EtOAc, 20 ꢁC, 1 h (54%); (ii) (a) NaOH, MeOH, THF, H2O, rt, 32 h (b) 2-mercaptopyridine, DCC, DCM, DMAP (cat), 0 ꢁC, 4 h (91%); (iii)
(3R,4S)-26, LiNEt2, ꢀ78 ꢁC, 15 min, add 79, 3 h (57%); (iv) KEt3BH, Et2O, ꢀ78 ꢁC, 15 min (79%); (v) TBAF, THF, 0 ꢁC to rt, 12 h (84%); (vi) (MeCN)2PdCl2, DMF, rt 12 h (27%) or Pd2(dba)3,
AsPh3, DMF, THF, rt, 22 h (52%).
Although the bicyclic structure of the azetidinone-macrocycle 83
corresponded to the azetidinone 6 identified as a possible in-
termediate for a synthesis of lankacidin C (1), the presence of three
unprotected secondary hydroxyl groups, as well as the unprotected
azetidinone, meant that several selective functional group in-
terconversions would be necessary if a total synthesis were to be
completed. It was therefore decided to study additional chemistry of
the azetidinone 81 to see whether some of these selective functional
group transformations could be carried out before macrocyclisation.
Reaction of the azetidinone 81 with potassium fluoride in
methanol resulted in the selective removal of the N-silyl group
and gave the NH-azetidinone 84, which was acylated on nitrogen
to give the N-propanoyl azetidinone 85, see Scheme 12. The
3-(1-acetoxyalkyl)azetidinone 88 was also prepared from the
azetidinone 81 by acetylation of the 10-hydroxyl group to give
the acetate 86, selective N-desilylation, and tert-butoxycarbonyl
N-protection of the resulting NH-azetidinone 87. Interestingly,
O-desilyation of the bis-tert-butyldimethylsilyl ether 88 under
mild conditions proceeded by selective deprotection of the 110-
hydroxyl group and gave the azetidinone 89 in which the
30-silyloxy group was intact.27 Moreover treatment of the N-ac-
ylated azetidinone 88 with potassium cyanide and methanol in
N,N-dimethylformamide resulted in ring-opening and gave the
methyl ester 90.19 Monodesilylation of this acetoxy-substituted
intermediate was also selective for the remote allylic silyl ether
and gave alcohol 91, the regioselectivity of this desilylation
being confirmed by conversion to the bis-acetate 92. Finally, an
intramolecular Stille reaction of the hydroxyvinylstannane 91
AcO
OH
Me H
HO
I
I
I
Me H
NP
Me H
NP
Me
Me
Me
Me
Me
Me
iii, iv
i, ii
NTBS
O
O
OTBS
OTBS
O
OTBS
OTBS
OTBS
OTBS
SnBu3
SnBu3
SEMO
SEMO
SnBu3
SEMO
Me
Me
Me
84 P = H
86 P = TBS
87 P = H
81
85 P = C(O)Et
v
AcO
AcO
I
I
Me
Me H
Me H
Me
Me
Me
vi
3'
NBoc
NBoc
O
OTBS
O
OH
OTBS
OTBS
11'
SnBu3
SEMO
SnBu3
SEMO
Me
Me
88
89
vii
NHBoc
AcO
NHBoc
AcO
AcO
17
NHBoc
Me
Me
Me
Me
I
Me
I
Me
Me
Me
Me
x
1
viii, ix
CO2Me
CO2Me
CO2Me
OTBS
OP
OTBS
OTBS
OTBS
13
7
OH
SnBu3
SEMO
SnBu3
SEMO
SEMO
Me
Me
Me
93
91 P = H
90
92 P = Ac
Scheme 12. Further macrocyclisation studies; reagents and conditions: (i) KF, MeOH, 0 ꢁC, 20 min (92%); (ii) NaHMDS, ꢀ78 ꢁC, 15 min then EtCOCl ꢀ78 ꢁC, 30 min (78%); (iii) Ac2O,
Et3N, DMAP (trace), rt, 3 h (89%); (iv) KF, MeOHeTHF, rt, 30 min (93%); (v) Boc2O, DMAP, MeCN, rt, 16 h (84%); (vi) TBAF, THF, rt, 16 h (48%); (vii) MeOH, KCN, DMF, rt, 48 h (88%);
(viii) TBAF, THF, rt, 4 h (84%); (ix) Ac2O, Et3N, DMAP (cat), rt, 24 h (52%); (x) Pd2(dba)3, AsPh3, DMF, THF, rt, 18 h (48%).

C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
6619
using tris(dibenzylideneacetone)bis-palladium(0) as the catalyst
was successful and gave the 17-membered macrocycle 93 in
a 48% isolated yield. In this macrocyclic intermediate, all four of
the hydroxyl groups are already differentiated, which will facil-
itate future regiospecific functionalisation.
iodoethenyl)azetidinone 15 but the analogous 3-tert-butyldime-
thylsilyloxyalkenylstannane 35 did not. An analogous discrepancy
was also noticed in the reactivities of the more complex (E)-vinyl-
stannanes 81 and 82 towards intramolecular Stille reactions.
cis-Disposed allylic hydroxyl groups, which can co-ordinate to the
trialkyltin moietyare known to accelerate Stille reactions,14,29 but this
is not possible for the (E)-3-hydroxyalkenylstannanes discussed here.
Stille reactions can be sensitive to steric effects8 and it may be that the
different reactivities of (E)-3-hydroxy- and their tert-butyldime-
thylsilylprotectedderivatives towardsStillereactions areduetosteric
hindrance from the bulky allylic silyloxy groups. However, the
(E)-geometry of the vinylstannanes means that this must be a rather
subtle effect perhaps influenced by the hindered nature of the
palladium complexes involved in Stille processes.
The stereoselective acylation of suitably functionalised azetidi-
nones has again proved useful for the synthesis of advanced in-
termediates for a synthesis of lankacidins. Several other potentially
useful selective transformations have also been developed during
the course of this work including the selective cleavage of N-silyl
groups in the presence of analogous O-silylated derivatives, and the
regioselective monodeprotection of 30,110-bis-tert-butyldime-
thylsilyl ethers in the presence of a 10-acetoxy group.27
2.4. Introduction of a N-(2-alkoxy)propanoate
Having prepared the macrocyclic intermediate 93, it was of in-
terest to prepare analogous compounds with an N-substituent,
which could be converted into the N-(2-hydroxy)propanoyl and N-
pyruvyl groups found in natural lankacidins.1
N-Acylation of the NH-azetidinone 87 was carried out using (S)-
2-(4-methoxy)benzyloxypropanoyl chloride, which was prepared
from the corresponding ethyl ester,28 to give the N-acylazetidinone
94 in a 70% yield, see Scheme 13. Selective methanolysis of the
azetidinone was again achieved using potassium cyanide in
methanol and gave the open-chain methyl ester 95 in which the
N-[(S)-2-(4-methoxy)benzyloxypropanoyl] group was intact. As
before, selective deprotection of the 13-hydroxyl group could now
be carried out using tetrabutylammonium fluoride and provided
the hydroxy ester 96 ready for macrocyclisation via an intra-
molecular Stille reaction. Preliminary studies of this reaction were
promising and gave a product, which had the expected molecular
ion in its mass spectrum, but which could not be formally charac-
terised because of insufficient material. Nevertheless, this study
showed that advanced intermediates with N-2-(4-methoxy)ben-
zyloxypropanoyl substituents are accessible and compatible with
late-stage transformations. Moreover, the 4-methoxybenzyloxy
protecting group should be orthogonal to those to be used for the
hydroxy groups of the macrocyclic ring, cf. ester 93.
To complete the synthesis of a lankacidin, it remains to effect
a macrocyclisation of the Stille precursor 96. Formation of the
d
-lactone, oxidation of the 18-hydroxyl group, and deprotection
should then deliver lankacidinol and further selective oxidation
to introduce the pyruvyl group would complete a total syn-
thesis of lankacidin C (1).
4. Experimental
4.1. General procedures
AcO
AcO
I
Me
I
Me
Me H
NH
Me H
NP
Me
Me
Melting points were recorded on a Gallenkamp apparatus, and
optical rotations measured on an AA-100 polarimeter at 589 nm.
Proton NMR spectra were recorded using Varian Unity A300 and 500
spectrometers. Coupling constants are given in hertz and chemical
shifts relative to Me4Si. IR spectra were recorded on a PerkineElmer
1710FT or an ATI Mattson Genesis FTIR spectrometer and were run as
liquid films unless otherwise stated. Low resolution mass spectra
were measured on a Micromass Trio 200 spectrometer and high
resolution spectra on a Kratos Concept IS spectrometer.
Chromatography refers to flash chromatography using Merck
silica gel 60H (40e63 nm3, 230e400 mesh). Light petroleum refers
to the fraction boiling at 40e60 ꢁC and ether to diethyl ether. All
solvents and reagents were purified by standard techniques and all
non-aqueous reactions were performed under an atmosphere of
dry argon or nitrogen.
i
O
O
OTBS
OTBS
OTBS
OTBS
SnBu3
SEMO
SnBu3
SEMO
Me
Me
87
94 P = (S)-MeCH(4-MeOC H CH O)CO
6
4
2
ii
PMBO
Me
PMBO
Me
O
HN
Me
O
AcO
HN
Me
AcO
Me
Me
Me
iii
Me
I
I
CO2Me
OTBS
CO2Me
OTBS
OH
OTBS
SnBu3
SEMO
SnBu3
SEMO
Me
96
Me
95
Racemic (E)-4-tributylstannylbut-3-enol 2730 was prepared by
the addition of tributyltin hydride to but-3-ynol under free-radical
conditions (catalytic azobis-isobutyronitrile, toluene, 100 ꢁC, 4 h).
(S)-2-(4-Methoxy)benzyloxypropanoyl chloride was prepared from
the corresponding ethyl ester28 by hydrolysis to the acid (lithium
hydroxide, THFewater, ambient temperature, 1 h; acidified using
glacial acetic acid) followed by treatment with oxalyl chloride
(benzeneeDMF, ambient temperature, 3 h), and was used without
purification.
Scheme 13. Introduction of an N-(2-alkoxy)propanoyl substituent; Reagents and
conditions: (i) KHMDS, THF, ꢀ78 ꢁC, 15 min, (S)-2-(4-methoxybenzyloxy)propanoyl
chloride, THF, ꢀ78 ꢁC, 4 h (70%); (ii) MeOH, KCN, DMF, room temperature, 5 h (87%);
(iii) TBAF, THF, room temperature, 4 h (81%).
3. Summary and conclusions
A range of 4-(2-iodoalk-1-enyl)azetidinones and related com-
pounds have been shown to participate in intermolecular Stille
coupling reactions with (E)-1-(tributylstannyl)alk-1-en-3-ols.
These studies were followed by a study of macrocycle-forming
intramolecular Stille reactions, which led to the completion of
convergent syntheses of the azetidinone-fused macrocycle 83
and the 17-membered macrocyclic ester 93. These are advanced
intermediates for a proposed total synthesis of lankacidins.
4.1.1. (S)-1-tert-Butyldimethylsilyl-4-[(5SR,1E,3E)-5-hydroxyhexa-
1,3-dienyl]azetidin-2-one 28. Bis(acetonitrile) palladium(II) chlo-
ride (ca. 2 mg, 5 mol %) was added to the vinyl iodide 15 (39 mg,
0.11 mmol) and the vinylstannane 27 (62 mg, 0.17 mmol) in
degassed DMF (1 ml) and the mixture was stirred in the dark at
room temperature for 45 min. Saturated aqueous ammonium
chloride (2 ml) was added and the suspension filtered through
Celite. The filtercake was washed with ethyl acetate and the organic
Interestingly, the (E)-3-hydroxyalkenyl stannane 37 was shown
to participate in an intermolecular Stille reaction with the 4-(2-

6620
C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
and aqueous phases were separated. The aqueous phase was
extracted with ethyl acetate (3ꢂ2 ml) and the organic extracts were
dried (MgSO4) and concentrated under reduced pressure. Flash
chromatography of the residue using light petroleumeethyl acetate
(2:1þ2% triethylamine) gave the title compounds 28 (24 mg,
86 mmol, 76%) as a colourless oil (found: MþþH, 282.1881;
C15H28NO2Si requires M, 282.1889); nmax 3413, 1742, 1627, 1471,
0.16 mmol) in degassed DMF (1 ml) in the dark. The reaction was
stirred for 45 min, saturated aqueous ammonium chloride (10 ml)
was added, and the mixture filtered through Celite, eluting with
ethyl acetate. The aqueous layer was extracted with ethyl acetate
(3ꢂ10 ml) and the organic extracts were dried (MgSO4) and con-
centrated under reduced pressure. Flash chromatography of the
residue using light petroleumeethyl acetateetriethylamine
(60:40:1) as eluant gave the title compound 39 (28 mg, 93%) as
a colourless oil, Rf 0.30 (3:2 light petroleumeethyl acetate) (found:
MþþH, 296.2050; C16H30O2NSi requires M, 296.2046); nmax 3261,
1411, 1364, 1255, 1189, 1128, 988 and 968 cmꢀ1
; dH (300 MHz,
CDCl3) 0.16 and 0.21(each 3H, s, SiCH3), 0.94 [9H, s, SiC(CH3)3], 1.28
(3H, d, J 6.9, 60-H3),1.74 (1H, s, OH), 2.75 (1H, dd, J 3.1,16.1, 3-H), 3.29
(1H, dd, J 5.8, 16.1, 3-H0), 4.03 (1H, ddd, J 3.1, 5.8. 8.7, 4-H), 4.36 (1H,
quin, J 6.9, 50-H) and 5.71 and 6.19 (each 2H, m, vinylic H); m/z (CI)
282 (Mþ, 32%), 280 (26), 264 (24), 222 (70) and 107 (100).
1752, 1255, 1095 and 836 cmꢀ1
; dH (300 MHz, CDCl3) 0.01 and 0.06
(each 3H, SiCH3), 0.80 [9H, s, SiC(CH3)3], 0.93 (3H, d, J 7.7, 3-CH3),
1.62 (1H, s, OH), 2.02 (3H, br s, 20-CH3), 3.35 (1H, m, 3-H), 4.11 (2H,
d, J 5.5, 50-H2), 4.33 (1H, dd, J 9.6, 5.9, 4-H), 5.31 (1H, d, J 9.6, 10-H),
5.71 (1H, dt, J 15.6, 5.9, 40-H) and 6.17 (1H, d, J 15.6, 30-H); dC
(75 MHz, CDCl3) ꢀ5.69, ꢀ5.61, 9.87, 12.76, 18.24, 26.18, 50.26, 50.94,
63.42, 127.84, 129.99, 134.74, 136.37 and 176.64; m/z (CI) 296
(Mþþ1, 30%) and 121 (100).
4.1.2. (S)-1-tert-Butyldimethylsilyl-4-[(1E,3E)-5-oxohexa-1,3-dienyl]aze-
tidin-2-one 29. N-Methylmorpholine-N-oxide (18 mg, 0.15 mmol),
tetrapropylammonium perruthenate (ca. 5 mg, 16 mol %) and pow-
dered activated 4 Å molecular sieves (ca. 20 mg) were added to the
alcohol 28 (24 mg, 86.5 mmol) in dichloromethane (1 ml) and mix-
ture stirred at room temperature for 2 h. Ethyl acetate (5 ml) was
added and the mixture filtered through Celite. The filtrate was dried
(MgSO4) and concentrated under reduced pressure. Flash chroma-
tography using light petroleumeethyl acetate (3:2) gave the title
4.1.5. (3RS,4RS)-1-tert-Butyldimethylsilyl-4-(5-hydroxy-2-methyl-
penta-1,3-dienyl)-3-methylazetidin-2-one 40. Following the pro-
cedure outlined for the synthesis of the diene 39, bis(acetonitrile)
palladium(II) dichloride (2 mg, 7 mmol), the vinyl iodide 26 (40 mg,
compound 29 (21 mg, 74.2 mmol, 86%) as a yellow oil (found: MþþH,
0.11 mmol)
and
(E)-3-tributylstannylprop-2-enol
(58 mg,
18
280.1726; C15H26NO2Si requires M, 280.1732); [
a
]
ꢀ61 (c 1.36 in
0.17 mmol) gave the title compound 40 (25 mg, 80%) as a colourless
oil, Rf 0.30 (3:2 light petroleumeethyl acetate) (found: MþþH,
296.2052; C16H30O2NSi requires M, 296.2045); nmax 3261, 1750,
D
CH2C12); nmax 1746, 1667, 1599, 1363, 1253, 1184, 989 and 841 cmꢀ1
;
dH (300 MHz, CDC13) 0.16 and 022 (each 3H, s, SiCH3), 0.95 [9H, s, SiC
(CH3)3], 2.29 (3H, s, 60-H3), 2.81 (1H, dd, J 2.7, 15.5, 3-H), 3.36 (1H, dd,
J 5.6 and 15.5, 3-H0), 4.11 (1H, ddd, J 2.7, 5.6, 9.0, 4-H), 6.13 (1H, dd, J
9.0,15.2,10-H), 6.16 (1H, d, J 15.4, 40-H), 6.36 (1H, dd, J 10.7, 15.2, 20-H)
and 7.09 (1H, dd, J 10.8, 15.7, 30-H); dC (75 MHz, CDCl3) ꢀ5.62, ꢀ5.42,
18.36, 26.22, 27.52, 45.78, 50.57, 130.58, 131.42, 141.23, 143.57, 171.64
and 198.31; m/z (EI) 280 (MþþH, 48%), 222 (100), 180 (94), 148 (41),
123 (73) and 122 (43).
1255, 1093 and 836 cmꢀ1
; dH (300 MHz, CDCl3) 0.08 and 0.13 (each
3H, SiCH3), 0.86 [9H, s, SiC(CH3)3], 1.25 (3H, d, J 7.6, 3-CH3), 1.41 (1H,
t, J 5.5, OH), 1.76 (3H, d, J 1.2, 20-CH3), 2.82 (1H, qd, J 7.4, 2.5, 3-H),
3.91 (1H, dd, J 9.7, 2.6, 4-H), 4.19 (2H, t, J 5.5, 50-H2), 5.41 (1H, d, J 9.7,
10-H), 5.77 (1H, dt, J 15.6, 5.5, 40-H) and 6.17 (1H, d, J 15.6, 30-H); m/z
(CI) 296 (Mþþ1, 25%) and 121 (100).
4.1.6. Methyl (2R,3R,5S,11S,6E,8E,12E)-3,11-di-tert-butyldimethylsily-
loxy-2,8-dimethyl-13-tributylstannyl-5-(2-trimethylsilylethoxy)me-
thoxytrideca-6,8,12-trienoate 78. Butyllithium (2.7 ml; 1.34 M in
hexane, 3.61 mmol) was added to N,N-di-isopropylamine (0.51 ml,
3.63 mmol) in THF (20 ml) at 0 ꢁC and the solution stirred for
15 min. After being cooled to ꢀ78 ꢁC, the sulfone 57 (2.2 g,
3.3 mmol) in THF (5 ml) was added dropwise and the resulting
solution was stirred at ꢀ78 ꢁC for 10 min before the aldehyde 56
(1.43 g, 3.3 mmol) in THF (5 ml) was added. The mixture was stirred
for 2 h before being allowed to warm to room temperature. Satu-
rated aqueous ammonium chloride (30 ml) was added and the
aqueous phase was extracted with ether (2ꢂ30 ml). The organic
extracts were washed with brine, dried (MgSO4) and concentrated
under reduced pressure to give a residue (3.58 g), which was dis-
solved in DCM (20 ml) and the solution cooled to ꢀ20 ꢁC. Trie-
thylamine (1.85 ml, 13.2 mmol), DMAP (ca. 10 mg) and acetic
anhydride (0.63 ml, 6.6 mmol) were added and the mixture was
stirred for 30 min before being warmed to room temperature. After
1 h, saturated aqueous sodium hydrogen carbonate (10 ml) and
ether (50 ml) were added and the aqueous phase was extracted
with ether (2ꢂ15 ml). The organic extracts were washed with brine,
dried (MgSO4) and concentrated under reduced pressure to give
a residue (3.76 g), which was dissolved in anhydrous methanol/
ethyl acetate (40 ml of a 2:1 mixture). The solution was cooled to
ꢀ20 ꢁC, sodium amalgam (15.0 g; e5% Na w/w, e32.4 mmol) was
added portionwise, and the mixture was stirred for 1 h at ꢀ20 ꢁC.
After warming to room temperature, the liquid phase was poured
into a mixture of water (25 ml) and ether (50 ml). The aqueous
phase was extracted with ether (2ꢂ30 ml) and the organic extracts
were washed with brine and dried (MgSO4) and concentrated un-
der reduced pressure. Column chromatography of the residue
eluting with ether in light petroleum (1:20) afforded the title
4.1.3. (4S)-1-tert-Butyldimethylsilyl-4-[(5S,1E,3E,7E)-5-hydroxy-8-
methyl-9-(2-trimethylsilylethoxy)methoxy-nona-1,3,7-trienyl]azeti-
din-2-one 38. Bis(acetonitrile)palladium(II) chloride (ca. 0.5 mg,
5 mol %) was added to the vinyl iodide 15 (10 mg, 30
mmol) and the
vinylstannane 37 (14 mg, 26 mol) in degassed DMF (0.2 ml) and the
m
mixture stirred at room temperature in the dark for 0.5 h. More cat-
alyst (ca. 0.5 mg) was added and the mixture was stirred for a further
0.5 h. Ethyl acetate (2 ml) and brine (2 ml) were added and the
aqueousphasewasextractedwithethylacetate(3ꢂ2 ml). Theorganic
extracts were dried (MgSO4) and concentrated under reduced pres-
sure. Flash chromatography of the residue using light petroleum-
eethyl acetate (4:1þ2% triethylamine) as eluant gave the title
compound 38 (6 mg, 13
482.3123; C25H48NO4Si2 requires M, 482.3122); [
m
mol, 50%) as a yellow oil (found: MþþH,
21
a]
ꢀ15 (c 0.51 in
D
CH2Cl2); nmax 3424, 1746, 1467, 1290, 1251, 1188, 1056, 989 and
838 cmꢀ1
;
dH (500 MHz,CDCl3)0.002[9H, s, Si(CH3)3],0.141and0.181
(each3H, s, SiCH3), 0.919[11H, m, SiC(CH3)3 and CH2Si],1.628(1H, brs,
OH),1.670(3H, s,80-CH3), 2.311(2H,m,60-H2),2.730(1H, dd, J2.8,15.4,
3-H), 3.281 (1H, dd, J 5.6,15.4, 3-H0), 3.608 (2H, m, OCH2CH2Si), 3.945
(2H, s, 90-H2), 4.005 (1H, ddd, J 2.8, 5.6, 8.7, 4-H), 4.208 (1H, m, 50-H),
4.645 (2H, s, OCH2O), 5.450 (1H, t, J 7.1, 70-H), 5.641 (1H, dd, J 9.2,14.3,
10-H), 5.725 (1H, dd, J 6.2,14.5, 40-H) and 6.194 (2H, m, 20-H and 30-H);
dC (75 MHz, CDCl3) ꢀ5.62, ꢀ5.40, ꢀ1.39, 14.39, 18.13, 18.32, 26.27,
35.93, 45.76, 50.98, 65.27, 71.79, 73.50, 93.99, 122.76, 129.00, 132.02,
134.46, 135.87, 136.57 and 172.20; m/z (CI) 499 (Mþþ18, 80%), 482
(Mþþ1, 53), 369 (21), 107 (46), 91(53), 90 (73) and 69 (100).
4.1.4. (3RS,4SR)-1-tert-Butyldimethylsilyl-4-(5-hydroxy-2-methyl-
penta-1,3-dienyl)-3-methylazetidin-2-one 39. Bis(acetonitrile)pal-
ladium(II) chloride (2 mg, 7 mmol) was added to the vinyl iodide 24
(37 mg, 0.10 mmol) and (E)-3-tributylstannylprop-2-enol (55 mg,

C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
6621
24
compound 78 as a colourless oil (1.7 g, 54%); [
a
]
ꢀ47.5 (c 1.1 in
brine, dried (MgSO4) and concentrated under reduced pressure.
Column chromatography of the residue eluting with ether in light
petroleum (1:20) gave the title compound 80 (1.08 g, 57%) as a vis-
D
CHCl3) (found: MþþNa, 969.5263; C46H94NO6Si3120SnNa requires
M, 969.5278); nmax 1742, 1646, 1601, 1463, 1251, 1098, 1056, 1028,
836 and 775 cmꢀ1
;
dH (300 MHz, CDCl3) 0.06e0.11 (21H, over-
cous colourless oil; [
a]
20 ꢀ55 (c 0.8 in CHCl3); nmax 1750, 1703, 1633,
D
lapping s, 7ꢂSiCH3), 1.18 (3H, d, J 7.1, 2-CH3), 1.77 (3H, s, 8-CH3),
0.90e1.99 [49H, m, Sn(C4H9)3, eCH2Si, 2ꢂSiC(CH3)3 and 4-H2], 2.37
(2H, m, 10-H2), 2.81 (1H, m, 2-H), 3.54 (1H, m, OHCHCH2Si), 3.68
(3H, s, OCH3), 3.76 (1H, m, OHCHCH2Si), 4.01e4.15 (2H, m, 5-H and
11-H), 4.31 (1H, m, 3-H), 4.62 and 4.72 (each 1H, d, J 7.5, OHCHO),
5.33 (1H, dd, J 8.4, 15.7, 6-H), 5.56 (1H, br t, J 7.0, 9-H), 5.99 (1H, dd, J
5.2, 19.0, 12-H), 6.12 (1H, d, J 19.0, 13-H) and 6.26 (1H, d, J 15.7, 7-H);
dC (75 MHz, CDCl3) ꢀ4.74, ꢀ4.41, ꢀ4.28, ꢀ1.42, 9.48, 12.08, 12.73,
13.72, 17.98, 18.17, 18.31, 25.80, 25.90, 27.24, 29.11, 37.37, 40.02,
45.29, 51.31, 65.33, 70.93, 73.71, 76.28, 91.56, 126.13, 126.85, 129.70,
134.03, 138.59, 151.25 and 174.80; m/z (FAB) 969 (Mþþ23, 2%), 742
(4), 171 (100) and 136 (65).
1464, 1252, 1021, 836 and 776 cmꢀ1
;
dH (300 MHz, CDCl3) 0.05 (3H,
s, SiCH3), 0.08 [15H, s, Si(CH3)3 and 2ꢂSiCH3], 0.09, 0.18 and 0.27
(each 3H s, SiCH3), 0.88e2.00 [56H, m, Sn(C4H9)3, eCH2Si and
3ꢂSiC(CH3)3], 1.05 (3H, d, J 6.7, 20-CH3), 1.40 (3H, s, 3-CH3), 1.74 (3H,
s, 80-CH3),1.74 and 1.94 (each 1H, m, 40-H), 2.35 (2H, m,100-H2), 2.54
(3H, d, J 1.3, 300-H3), 3.48 (1H, m, 20-H), 3.60 and 3.79 (each 1H, m,
OHCHCH2Si), 4.08 (2H, m, 50-H and 110-H), 4.34 (1H, m, 30-H), 4.64
and 4.74 (each 1H, d, J 7, OHCHO), 4.81 (1H, d, J 9.4, 4-H), 5.35 (1H,
dd, J 8.5, 15.6, 60-H), 5.54 (1H, br t, J 7.4, 90-H), 5.98 (1H, dd, J 5.2,
19.0, 120-H), 6.11 (1H, d, J 19.0, 130-H), 6.14 (1H, dd, J 1.4, 9.3, 100-H)
and 6.23 (1H, d, J 15.6, 70-H); dC (75 MHz, CDCl3) ꢀ5.64, ꢀ4.63,
ꢀ4.52, ꢀ4.52, ꢀ4.30, ꢀ4.21, ꢀ1.26, 9.55, 12.80, 13.81, 14.49, 18.11,
18.25, 18.38, 18.61, 26.11, 26.17, 27.29, 28.36, 29.02, 29.29, 37.40,
38.19, 40.19, 48.49, 54.04, 65.47, 71.07, 72.74, 73.74, 76.26, 91.90,
98.77, 126.47, 126.69, 129.61, 133.81, 137.94, 138.72, 151.09, 172.14
and 208.68; m/z (ESþ) 1302 (Mþþ23, 45%), 1176 (6), 1012 (5), 830
(6), 761 (26), 515 (9), 461 (34), 339 (23), 227 (41) and 121 (100).
4.1.7. S-(2-Pyridinyl) (2R,3R,5S,11S,6E,8E,12E)-3,11-di-tert-butyldi-
methylsilyloxy-2,8-dimethyl-13-tributyl-stannyl-5-(2-trimethylsilyle-
thoxy)methoxytrideca-6,8,12-trienethioate 79. Sodium hydroxide
(1.45 g, 36 mmol) in methanol (15 ml) and water (5 ml) were added
to the methyl ester 78 (1.7 g, 1.8 mmol) in THF (20 ml) and the
solution stirred at room temperature for 32 h. Water (20 ml) and
ether (40 ml) were added and the solution was acidified with gla-
cial acetic acid. The aqueous phase was extracted with ether
(3ꢂ30 ml) and the organic extracts were washed with brine, dried
(MgSO4) and concentrated under reduced pressure to leave a vis-
cous oil (1.67 g), which was dissolved in DCM (20 ml). Dicyclo-
hexylcarbodi-imide (740 mg, 3.6 mmol), DMAP (10 mg, cat.) and 2-
mercaptopyridine (300 mg, 2.7 mmol) were added at 0 ꢁC and the
yellow suspension stirred at room temperature for 4 h. The mixture
was diluted with ether (20 ml) and filtered through a pad of silica
gel. The filtrate was concentrated under reduced pressure and
column chromatography of the residue eluting with ether in light
petroleum (1:9) gave the title compound 79 (1.69 g, 91%) as a col-
4.1.9. (3S,4R)-1-tert-Butyldimethylsilyl-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-
3,11-di-tert-butyldimethylsilyloxy-2,8-dimethyl-1-hydroxy-13-tribu-
tylstannyl-5-(2-trimethylsilylethoxy)methoxytrideca-6,8,12-trienyl]-4-
((E)-2-iodoprop-1-enyl)-3-methylazetidin-2-one 81. Potassium trie-
thylborohydride (0.54 ml; 1.0 M in THF, 0.54 mmol) was added to the
ketone 80 (0.63 g, 0.49 mmol) in ether (10 ml) dropwise at ꢀ78 ꢁC
and the mixture stirred for 15 min. Saturated aqueous ammonium
chloride (5 ml) was added and, after being warmed to room
temperature, the mixture was extracted with ether (3ꢂ10 ml). The
organic extracts were washed with brine, dried (MgSO4) and con-
centrated under reduced pressure. Column chromatography of the
residue eluting with ether in light petroleum (1:9) afforded the title
compound 81 (0.49 g, 79%) as a colourless gum; [
a
]
22 ꢀ42 (c 1.03 in
D
ourless viscous oil; [
a]
21 ꢀ76.5 (c 1.1 in CHCl); nmax 2120, 1705, 1660,
CH2Cl2) (found: MþþNa, 1124.5232; C54H107NO6ISi4120SnNa requires
D
1573, 1518, 1463, 1250, 1092, 1027, 836 and 776 cmꢀ1
;
dH (300 MHz,
M, 1124.5243); nmax 3463, 1748, 1630, 1464, 1252, 1092, 1069, 1022,
CDCl3) ꢀ0.05e0.15 (21H, overlapping s, 7ꢂSiCH3), 0.88e1.61 [50H,
m, Sn(C4H9)3, eCH2Si, 2ꢂSiC(CH3)3 and 2-CH3], 1.75 (3H, s, 8-CH3),
1.94 (2H, m, 4-H2), 2.35 (2H, m, 10-H2), 3.16 (1H, m, 2-H), 3.55 and
3.78 (each 1H, m, OHCHCH2Si), 4.12 (2H, m, 5-H and 11-H), 4.37 (1H,
m, 3-H), 4.63 and 4.74 (each 1H, d, J 7, OHCHO), 5.34 (1H, dd, J 8.4,
15.7, 6-H), 5.55 (1H, br t, J 7.0, 9-H), 5.97 (1H, dd, J 5.2, 19.0, 12-H),
6.10 (1H, d, J 19.0, 13-H), 6.26 (1H, d, J 15.7, 7-H), 7.30 (1H, t, J 7.8, 50-
H), 7.63 (1H, d, J 7.8, 60-H), 7.76 (1H, dt, J 1.8, 7.8, 40-H) and 8.65 (1H,
m, 30-H); dC (75 MHz, CDCl3) ꢀ4.73, ꢀ4.52, ꢀ4.40, ꢀ4.28, ꢀ1.32,
9.46, 12.60, 12.76, 13.77, 18.07, 18.21, 18.33, 24.73, 25.91, 27.27, 29.12,
37.94, 37.17, 39.64, 54.59, 65.48, 70.88, 73.49, 76.29, 91.59, 123.30,
125.95, 126.82, 129.90, 134.03, 136.92, 138.82, 150.35, 151.24, 151.96
and 198.65; m/z (ESþ) 1048 (Mþþ23, 13%), 969 (30), 761 (30), 497
(31), 388 (100), 247 (33) and 227 (28).
836 and 776 cmꢀ1
;
dH (500 MHz, CDCl3) ꢀ0.01 (3H, s, SiCH3), 0.00
[9H, s, Si(CH3)3], 0.01, 0.09, 0.10, 0.13 and 0.21 (each 3H, s, SiCH3),
0.83e1.50 [56H, m, Sn(C4H9)3, eCH2Si, 3ꢂSiC(CH3)3], 1.04 (3H, s, 3-
CH3), 1.20 (3H, d, J 7.0, 20-CH3), 1.74 (3H, s, 80-CH3), 1.84 (3H, m, 20-H
and 40-H2), 2.34 (2H, m, 100-H2), 2.44 (3H, d, J 1.5, 300-H3), 3.42 and
3.67 (each 1H, m, OHCHCH2Si), 3.89e4.45 (5H, m, 10-H, 30-H, 50-H,
110-H and OH), 4.45 (1H, d, J 9.4, 4-H), 4.49 and 4.62 (each 1H, d, J 7,
OHCHO), 5.28 (1H, dd, J 5.0, 15.6, 60-H), 5.51 (1H, m, 90-H), 5.92 (1H,
dd, J 5.56, 19.0, 120-H), 6.05 (1H, dd, J 1.0, 19.0, 130-H), 6.12 (1H, d, J
15.6, 70-H) and 6.17 (1H, dd, J 1.5, 9.6, 100-H); dC (75 MHz, CDCl3)
ꢀ5.59, ꢀ5.50, ꢀ4.80, ꢀ4.60, ꢀ4.28, ꢀ4.04, ꢀ1.27, 9.57, 12.86, 13.28,
13.83, 14.07, 17.97, 18.22, 18.40, 18.81, 25.89, 26.14, 26.25, 27.31, 28.43,
29.17, 34.89, 37.48, 41.64, 54.85, 65.02, 65.64, 72.61, 73.91, 76.16,
76.36, 91.54, 97.04, 125.80, 126.80, 130.19, 133.79, 137.91, 140.65,
150.98 and 175.79; m/z (FAB) 1224 (Mþþ23, 0.6%), 1076 (1.0), 508
(0.6), 405 (10), 289 (8) and 227 (100).
4.1.8. (3S,4R)-1-tert-Butyldimethylsilyl-3-[(2R,3R,5S,11S,6E,8E,12E)-
3,11-di-tert-butyldimethylsilyloxy-2,8-dimethyl-13-tributylstannyl-5-
(2-trimethylsilylethoxy)-methoxy-1-oxotrideca-6,8,12-trienyl]-4-
((E)-2-iodoprop-1-enyl)-3-methylazetidin-2-one 80. Butyllithium
(1.41 ml; 1.36 M in hexane, 1.9 mmol) was added to N,N-diethyl-
amine (0.20 ml, 1.9 mmol) in THF (10 ml) at 0 ꢁC. The solution was
stirred for 15 min then cooled to -78 ꢁC and added to the (3S,4R)-
azetidinone 26 (0.65 g, 1.77 mmol) in THF (5 ml) dropwise at
ꢀ78 ꢁC. The solution was stirred for 15 min before the thioester 79
(1.52 g, 1.48 mmol) in THF (5 ml) cooled to ꢀ78 ꢁC was added, and
the mixture stirred for 3 h. Saturated aqueous ammonium chloride
(2 ml) and ether (10 ml) were added and the mixture was allowed
to warm to room temperature. The aqueous phase was extracted
with ether (2ꢂ5 ml) and the organic extracts were washed with
4.1.10. (3S,4R)-3-[(1S,2R,3R,5S,11S,6E,8E,12E)-2,8-di-methyl-13-tri-
butylstannyl-5-(2-trimethylsilylethoxy)-methoxy-1,3,11-trihydroxy-
trideca-6,8,12-trienyl]-4-((E)-2-iodoprop-1-enyl)-3-methylazetidin-
2-one 82. Tetrabutylammonium fluoride (250 ml; 1.0 M in THF,
250 mmol) was added to the azetidinone 81 (36 mg, 30 mmol) in
THF (250 ml) at 0 ꢁC and the solution was stirred a ambient tem-
perature for 15 h. Saturated aqueous ammonium chloride (2 ml)
and ethyl acetate (10 ml) were added and the aqueous phase was
extracted with ethyl acetate (3ꢂ5 ml). The organic extracts were
washed with brine, dried (MgSO4) and concentrated under reduced
pressure. Column chromatography of the residue eluting with ethyl
acetate in light petroleum (3:2) afforded the title compound 82

6622
C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
20
(22 mg, 84%) as a colourless gum; [
a
]
D
ꢀ35 (c 0.65 in CH2Cl2)
eluting with ether in light petroleum (1:4) afforded the title com-
(found MþþNa, 962.3240; C40H74NO6ISi120SnNa requires M,
962.3251); nmax 3401, 3054, 1753, 1627, 1463, 1265, 1218, 1056 and
pound 84 (0.46 g, 92%) as a viscous oil; [
a
]
21 ꢀ28 (c 0.85 in CH2Cl2)
D
(found: MþþNa, 1190.5028; C52H102NO6ISi3120SnNa requires M,
738 cmꢀ1
; dH (500 MHz, CDCl3) 0.00 [9H, s, Si(CH3)3], 0.80e1.60
1190.4980); nmax 3473, 3287, 1758, 1632, 1463, 1250, 1069, 1021 and
[35H, m, Sn(C4H9)3, eCH2Si, 20-H, 20-CH3 and 40-H2], 1.17 (3H, s, 3-
CH3), 1.74 (3H, s, 80-CH3), 2.40 (3H, m, 100-H2 and OH), 2.48 (3H, d, J
1.3, 300-H3), 3.48 and 3.63 (each 1H, m, OHCHCH2Si), 3.67 (1H, s,
OH), 3.86 (1H, dd, J 3.2, 9.6, 10-H), 4.03e4.15 (3H, m, 50-H, 110-H and
OH), 4.35 (1H, m, 30-H), 4.56 (1H, d, J 9.2, 4-H), 4.58 and 4.72 (each
1H, d, J 7, OHCHO), 5.36 (1H, dd, J 8.1, 15.6, 60-H), 5.53 (1H, br t, J 7.0,
90-H), 5.74 (1H, s, NH), 6.01 (1H, dd, J 5.13,19.0, 120-H), 6.16 (1H, dd, J
0.8, 19.0, 130-H), 6.19 (1H, dd, J 1.5, 9.6, 100-H) and 6.23 (1H, d, J 15.6,
70-H); dC (75 MHz, CDCl3) ꢀ1.39, 9.48, 12.15, 12.76, 13.74, 13.91,
18.18, 27.27, 28.58, 29.08, 36.15, 39.45, 41.36, 53.25, 65.31, 65.78,
72.56, 74.731, 77.25, 78.02, 91.52, 99.02, 125.49, 128.33, 129.39,
134.99, 138.33, 138.49, 150.00 and 171.50; m/z (FAB) 962 (Mþþ23,
11%), 446 (6), 196 (84) and 177 (100).
836 cmꢀ1
;
dH (500 MHz, CDCl3) 0.00 [15H, s, Si(CH3)3 and 2ꢂSiCH3],
0.09 and 0.11 (each 3H, s, SiCH3), 0.78e1.51 [50H, m, Sn(C4H9)3,
eCH2Si, 20-CH3 and 2ꢂSiC(CH3)3], 1.10 (3H, s, 3-CH3), 1.70 (3H, s, 80-
CH3), 1.90 (3H, m, 20-H and 40-H2), 2.35 (2H, m, 100-H2), 2.45 (3H, d, J
1.28, 300-H3), 3.43 and 3.68 (each 1H, m, OHCHCH2Si), 3.94e4.10
(5H, m,10-H, 30-H, 50-H,110-H and OH), 4.49 (1H, d, J 7, OHCHO), 4.56
(1H, d, J 8.9, 4-H), 4.61 (1H, d, J 7, OHCHO), 5.28 (1H, dd, J 8.1, 15.6,
60-H), 5.52 (1H, t, J 7.2, 90-H), 5.76 (1H, br s, NH), 5.92 (1H, dd, J 5.5,
19.0, 120-H), 6.05 (1H, dd, J 1.0, 19.0, 130-H), 6.13 (1H, d, J 15.6, 70-H)
and 6.20 (1H, dd, J 1.5, 8.9, 100-H); dC (125 MHz, CDCl3) ꢀ4.84, ꢀ4.76,
ꢀ4.43, ꢀ4.38, ꢀ1.39, 9.42, 12.75, 13.02, 13.74, 13.94, 17.84, 18.09,
18.30, 25.85, 27.22, 28.57, 29.07, 34.53, 37.39, 41.59, 53.18, 65.41,
65.65, 72.23, 73.85, 76.12, 76.37, 91.36, 98.50, 125.67, 126.89, 130.45,
133.82, 138.13, 138.74, 151.02 and 170.72; m/z (FAB) 1190 (Mþþ23,
2%), 259 (19), 227 (100) and 171 (48).
4.1.11. (1S,2S,3R,4R,6S,12S,17R,7E,9E,13E,15E)-1,3,9,15-Tetramethyl-6-
(2-trimethylsilylethoxy)methoxy-19-oxo-18-azabicyclo[15.2.0]non-
adeca-7,9,13,15-tetraene-2,4,12-triol 83. (Bisacetonitrile)palladium
(II) chloride (1 mg,e30 mol %) was added to a degassed solution of
the iodostannane 82 (10 mg, 10 mmol) in DMF (4 ml) and the
mixture stirred in the dark for 12 h. Saturated aqueous ammonium
chloride (2 ml) and ethyl acetate (20 ml) were added, and the or-
ganic phase washed with brine and dried (MgSO4). Concentration
under reduced pressure and column chromatography of the residue
using gradient elution with ethyl acetate in light petroleum (4:1
then 3:2) afforded the title compound 83 (1.5 mg, 27%) as a colour-
less gum (found MþþNa, 544.3093; C28H47NO6SiNa requires M,
544.3070); nmax 3389, 1742, 1620, 1461, 1379, 1249, 1088, 1023, 966
and 836; dH (500 MHz, CDCl3) ꢀ0.006 [9H, s, Si(CH3)3], 0.90 (2H, m,
CH2Si), 1.06 (3H, d, J 7, 3-CH3), 1.24 (3H, s, 1-CH3), 1.32 (1H, m, 3-H),
1.66 and 1.69 (each 3H, s, 9- and 15-CH3), 1.90e2.00 (2H, m, 5-H2),
2.40e2.50 (2H, m, 11-H2), 3.30 (1H, s, OH), 3.44 (1H, m,
OHCHCH2Si), 3.66 (2H, m), 3.88, 3.97 and 4.30 (each 1H, m), 4.45
(1H, d, J 7, OHCHO), 4.58 (1H, d, J 9.8, 17-H), 4.61 (1H, d, J 7, OHCHO),
5.09 (1H, m 10-H), 5.28 (1H, dd, J 9.4, 15.6, 13-H), 5.36 (1H, dd, J 9.4,
15.8, 7-H), 5.46 (1H, d, J 9.8, 16-H), 5.70 (1H, s, NH), 6.015 and 6.025
(each 1H, d, J 15.6, 8-H and 14-H); dC ꢀ1.69, 12.33, 12.68, 12.77,
13.84, 17.79, 29.41, 35.74, 37.25, 42.18, 51.75, 64.47, 64.93, 72.55,
73.79, 74.12, 91.06, 126.24, 127.06, 129.18, 131.05, 133.59, 134.94,
138.02, 138.06 and 173.04; m/z (FAB) 544 (Mþþ23, 100%).
4.1.13. (3S,4R)-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-3,11-Di-tert-butyldi-
methylsilyoxy-2,8-dimethyl-1-hydroxy-13-tributylstannyl-5-(2-tri-
methylsilylethoxy)methoxytrideca-6,8,12-trienyl]-4-((E)-2-iodoprop-
1-enyl)-3-methyl-1-propanoylazetidin-2-one 85. Sodium hexame-
thyldisilylamide (0.46 ml; 1.0 M in THF, 0.46 mmol) was added to
azetidinone 84 (0.235 g, 0.20 mmol) in THF (4 ml) dropwise at
ꢀ78 ꢁC and the solution stirred for 15 min. Propionyl chloride
(0.22 ml; 1.0 M in THF, 0.22 mmol) was added dropwise and the
mixture stirred at ꢀ78 ꢁC for 30 min. Triethylamine (0.2 ml), satu-
rated aqueous sodium hydrogen carbonate (5 ml) and ether (10 ml)
were added and the mixture was allowed to warm to room tem-
perature. The aqueous phase was extracted with ether (2ꢂ5 ml)
and the organic extracts were washed with brine, dried (MgSO4)
and concentrated under reduced pressure. Column chromatogra-
phy of the residue eluting with ether in light petroleum (1:9)
afforded the title compound 85 (0.192 g, 78%) as a colourless viscous
22
oil; [
a
]
D
ꢀ47 (c 0.95 in CHCl3) (found MþþNa, 1246.5260);
C55H106NO7ISi3120SnNa requires M, 1246.5242); nmax 3449, 1787,
1710,1638,1462,1376,1251,1067,1021 and 836 cmꢀ1
; dH (500 MHz,
CDCl3) 0.00 (3H, s, SiCH3), 0.01 [12H, s, Si(CH3)3], 0.10 and 0.15 (each
3H, s, SiCH3), 0.83e1.48 (48H, m, Sn(C4H9)3, eCH2Si, 20-H and 2ꢂSiC
(CH3)3], 1.12 (3H, s, 3-CH3), 1.12 (3H, t, J 7.4, CH2CH3), 1.18 (3H, d, J
7.0, 20-CH3), 1.70 (3H, s, 80-CH3), 1.90 (2H, m, 40-H2), 2.32 (2H, m,100-
H2), 2.50 (3H, d, J 1.5, 300-H3), 2.60e2.78 (2H, m, CH2CH3), 3.43 and
3.68 (each 1H, m, OHCHCH2Si), 3.92e4.10 (5H, m, 10-H, 30-H, 50-H,
110-H and OH), 4.50 and 4.63 (each 1H, d, J 7, OHCHO), 4.86 (1H, d, J
8.7, 4-H), 5.28 (1H, dd, J 8.1, 15.6, 60-H), 5.53 (1H, t, J 7.3, 90-H), 5.93
(1H, dd, J 5.3, 19.0, 120-H), 6.06 (1H, dd, J 0.8, 19.0, 130-H), 6.12 (1H,
dd, J 1.5, 8.9, 100-H) and 6.12 (1H, d, J 15.6, 70-H); m/z (FAB) 1246
(Mþþ23, 1%), 259 (37), 227 (100), 171 (78) and 136 (145).
Triphenylarsine (7 mg, 23.26
neacetone)palladium (5 mg, 5.82
ambient temperature followed by the iodostannane 82 (18 mg,
19.39 mol) in DMFeTHF (4 ml; 1:1) and the mixture stirred in the
m
mol) was added to bis(benzylide-
mmol) in DMFeTHF (8 ml; 1:1) at
m
dark (wrapped in aluminium foil) for 22 h. Water (5 ml) and ethyl
acetate (10 ml) were added and the aqueous phase extracted with
ethyl acetate (3ꢂ10 ml). Theorganicextractswerewashed withbrine,
dried (MgSO4) and concentrated under reduced pressure. Chroma-
tography of the residue using light petroleumeethyl acetate (3:2;
with1%triethylamine)aseluantgavethemacrocycle 83 (4.5 mg, 52%)
as an oil with spectroscopic data identical to those obtained earlier.
4.1.14. (3S,4R)-1-tert-Butyldimethylsilyl-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-
1-acetoxy-3,11-di-tert-butyldimethylsilyloxy-2,8-dimethyl-13-tributyl-
stannyl-5-(2-trimethylsilylethoxy)methoxytrideca-6,8,12-trienyl]-4-((E)-
2-iodoprop-1-enyl)-3-methylazetidin-2-one 86. N,N-Dimethylamino-
4.1.12. (3S,4R)-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-3,11-Di-tert-butyldi-
methylsilyoxy-2,8-dimethyl-1-hydroxy-13-tributylstannyl-5-(2-tri-
methylsilylethoxy)methoxytrideca-6,8,12-trienyl]-4-((E)-2-iodoprop-
1-enyl)-3-methylazetidin-2-one 84. Solid anhydrous potassium
fluoride (75 mg, 1.29 mmol) was added to the N-silylazetidinone 81
(0.55 g, 0.43 mmol) in MeOHeTHF (10 ml; 4:1) at 0 ꢁC and the
mixture stirred at room temperature for 20 min. Saturated aqueous
ammonium chloride (5 ml) and ether (20 ml) were added and the
aqueous phase was extracted with ether (3ꢂ5 ml). The organic
extracts were washed with brine, dried (MgSO4) and concentrated
under reduced pressure. Column chromatography of the residue
pyridine (1 mg, ca. 7
acetic anhydride (30
m
mol), triethylamine (45
ml, 0.32 mmol) and
ml, 0.20 mmol) were added to the alcohol 81
(23 mg, 18 mmol) in dry dichloromethane (0.20 ml) and the reaction
stirred for 3 h. Saturated aqueous ammonium chloride (5 ml) and
ether (5 ml) were added and the aqueous layer extracted with ether
(2ꢂ5 ml). The organic extracts were washed with brine (5 ml), dried
(MgSO4) and concentrated under reduced pressure. Column chro-
matography of the residue eluting with light petroleumeether (10:1)
gave the title compound 86 (21 mg, 89%) as a colourless oil, Rf 0.21 (6:1
light petroleumeethyl acetate); [
a
]
24 ꢀ80 (c 0.25 in CHCl3); nmax 1748,
D
1250, 1071, 1024 and 836 cmꢀ1
;
dH (300 MHz, CDCl3) ꢀ0.01 [18H, s,

C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
6623
3ꢂSiCH3 and Si(CH3)3], 0.00, 0.04 and 0.16 (each 3H, s, SiCH3),
0.80e1.00 [44H, 3ꢂSiC(CH3)3, 3ꢂCH2CH2CH2CH3 and SiCH2], 1.11 (3H,
18.07, 18.23, 20.92, 25.83, 25.98, 27.16, 27.91, 28.48, 29.02, 37.29,
39.18, 40.50, 55.91, 62.15, 65.30, 72.73, 73.99, 76.17, 83.35, 91.44,
100.38, 125.86, 126.74, 129.91, 133.89, 135.12, 138.46, 147.31, 151.92,
166.96, 170.32; m/z (ESþ) 1327 (Mþþ18, 10%) and 816 (65).
d,
J
7.0, 20-CH3), 1.15 (3H, s, 3-CH3), 1.20e1.60 [12H, m,
3ꢂCH3CH2CH2CH2Sn], 1.72 (3H, s, 80-CH3), 1.62e1.85 (2H, m, 40-H2),
2.04 (1H, m, 20-H), 2.06 (3H, s, CH3CO), 2.32 (2H, m, 100-H2), 2.42 (3H,
d, J 1.0, 300-H3), 3.45 (1H, m, OHCHCH2Si), 3.65 (2H, m, 30-H and
OHCHCH2Si), 4.00e4.18 (3H, m, 4-H, 50-H and 110-H), 4.53 and 4.65
(each 1H, d, J 6.9, OHCHO), 5.20 (1H, br s,10-H), 5.27 (1H, dd, J 15.6, 8.5,
60-H), 5.52 (1H, t, J 7.0, 90-H), 5.95 (1H, dd, J 19.1, 5.2, 120-H), 6.06 (1H,þd,
J 19.0, 130-H), 6.13 (1H, m, 100-H) and 6.15 (1H, d, J 15.6, 70-H); m/z (ES )
1346 (Mþþ23, 4%), 305 (100) and 123 (95).
4.1.17. (3S,4R)-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-1-Acetoxy-3-tert-bu-
tyldimethylsilyloxy-2,8-dimethyl-11-hydroxy-13-tributylstannyl-5-
(2-trimethylsilylethoxy)-methoxytridec-6,8,12-trienyl]-1-tert-butox-
ycarbonyl-4-((E)-2-iodoprop-1-enyl)-3-methylazetidin-2-one
89.
Tetrabutylammonium fluoride (20 ml; 1.0 M in THF, 21 mmol) was
added dropwise to the bis-tert-butyldimethylsilyl ether 88 (7 mg,
5 mmol)indryTHF(0.1 ml)andthemixturestirredfor16 h.Saturated
aqueous ammonium chloride (5 ml) and ethyl acetate (5 ml) were
added and the aqueous layer extracted with ethyl acetate (2ꢂ5 ml).
The organic extracts were dried (MgSO4) and concentrated under
reduced pressure. Flash chromatography of the residue eluting with
light petroleumeethyl acetate (6:1) gave the title compound 89 (3 mg,
48%) as a colourless oil, Rf 0.45 (3:1 light petroleumeethyl acetate);
4.1.15. (3S,4R)-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-1-Acetoxy-3,11-di-tert-
butyldimethylsilyloxy-2,8-dimethyl-13-tributylstannyl-5-(2-trime-
thylsilylethoxy)methoxytrideca-6,8,12-trienyl]-4-((E)-2-iodoprop-1-
enyl)-3-methylazetidin-2-one 87. Potassium fluoride (9 mg,
0.15 mmol) was added the azetidinone 86 (70 mg, 52 mmol) in
MeOHeTHF (3:1, 1.6 ml) and the reaction stirred for 30 min. Sat-
urated aqueous ammonium chloride (5 ml) and ether (5 ml) were
added and the aqueous layer extracted with ether (2ꢂ5 ml). The
organic extracts were washed with brine (5 ml), dried (MgSO4)
and concentrated under reduced pressure. Column chromatogra-
phy of the residue eluting with light petroleumeethyl acetate
(4:1) gave the title compound 87 (60 mg, 93%) as a colourless oil, Rf
[a]
24 þ5 (c 0.20 in CHCl3); nmax 3423,1809,1733,1651 and 1064 cmꢀ1
;
D
dH (300 MHz, CDCl3) 0.00 [9H, s, Si(CH3)3], 0.06 and 0.07 (each 3H, s,
SiCH3), 0.85e0.95 [29H, SiC(CH3)3, 3-CH3, 3ꢂCH3CH2CH2CH2 and
SiCH2],1.06 (3H, d, J 7.0, 20-CH3),1.30e1.59 (12H, 3ꢂCH3CH2CH2CH2),
1.57 [9H, s, OC(CH3)3],1.78 (3H, s, 80-CH3),1.82 (2H, m, 40-H2),1.97 (1H,
m, 20-H), 2.05(3H, s, CH3CO), 2.33(2H, t, J 6.5,10-H2), 2.49 (3H, brs, 300-
H3), 3.48(1H, m, OHCHCH2Si), 3.66(2H, m, OHCHCH2Siand 30-H), 4.15
(2H, m, 50-H and 110-H), 4.44 (1H, d, J 8.9, 4-H), 4.53 and 4.65 (each 1H,
d, J 6.8, OHCHO), 5.28 (1H, br s, 10-H), 5.34 (1H, dd, J 15.6, 8.3, 60-H),
5.54(1H,t, J7.1, 90-H), 6.04(1H, dd, J19.3, 4.6,120-H),6.08e6.12(2H,m,
100-H and 130-H) and 6.18 (1H, d, J 15.6, 70-H).
0.09 (2:1 light petroleumeether); [
a
]
24 þ12 (c 0.30 in CHCl3); nmax
1760, 1247, 1071, 1024 and 835 cmꢀD1
; dH (300 MHz, CDCl3) 0.00
[15H, s, 2ꢂSiCH3 and Si(CH3)3], 0.06 (6H, s, 2ꢂSiCH3), 0.8e1.00
[35H, 2ꢂSiC(CH3)3, 3ꢂCH3CH2CH2CH2Sn and SiCH2], 1.08 (3H, d, J
6.9, 20-CH3), 1.17 (3H, s, 3-CH3), 1.26 [6H, hex, CH3CH2CH2CH2Sn],
1.47 (6H, m, CH3CH2CH2CH2Sn), 1.66 (1H, m, 40-H), 1.72 (3H, s, 80-
CH3), 1.82 (1H, m, 40-H0), 2.02 (1H, m, 20-H), 2.08 (3H, s, CH3CO),
2.31 (2H, m, 100-H2), 2.46 (3H, d, J 1.0, 300-H3), 3.46 (1H, m,
OHCHCH2Si), 3.65 (2H, m, 30-H and OHCHCH2Si), 4.10 (2H, m, 50-H
and 110-H), 4.20 (1H, d, J 8.8, 4-H), 4.54 and 4.64 (each 1H, d, J 6.9,
OHCHO), 5.27 (2H, m, 10-H and 60-H), 5.51 (1H, t, J 6.6, 90-H), 5.71
(1H, br s, NH), 5.94 (1H, dd, J 19.1, 5.2, 120-H), 6.07 (1H, d, J 19þ.1,
130-H), 6.16 (1H, m, 100-H) and 6.19 (1H, d, J 15.6, 70-H); m/z (ES )
1232 (Mþþ23, 15%), 839 (95) and 305 (100).
4.1.18. Methyl (2S,3S,4S,5R,7S,13S,8E,10E,14E)-3-acetoxy-2-[(1R,2E)-
1-tert-butoxycarbonylamino-3-iodobut-2-enyl]-5,13-di-tert-butyldi-
methylsilyloxy-2,4,10-trimethyl-7-(2-trimethylsilylethoxy)methoxy-
15-tributylstannylpentadeca-8,10,14-trienoate 90. Methanol (102 ml,
2.52 mmol) and potassium cyanide (164 mg, 2.52 mmol) were
added to the azetidinone 88 (178 mg, 0.13 mmol) in dry DMF (2 ml)
and the reaction stirred for 2 days. Saturated aqueous ammonium
chloride (5 ml) and ethyl acetate (5 ml) were added and the aqueous
layer extracted with ethyl acetate (2ꢂ5 ml). The organic extracts
were washed with brine (5 ml), dried (MgSO4) and concentrated
under reduced pressure. Column chromatography of the residue
eluting with light petroleumeether (15:1) gave the title compound
4.1.16. (3S,4R)-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-1-Acetoxy-3,11-di-tert-
butyldimethylsilyloxy-2,8-dimethyl-13-tributylstannyl-5-(2-trime-
thylsilylethoxy)methoxytrideca-6,8,12-trienyl]-1-tert-but-
oxycarbonyl-4-((E)-2-iodoprop-1-enyl)-3-methylazetidin-2-one 88.
Di-tert-butyl dicarbonate (105 mg, 0.48 mmol) and N,N-dimethyla-
minopyridine (30 mg, 0.24 mmol) were added to the azetidinone 87
(197 mg, 0.16 mmol) in dry acetonitrile (3 ml) and the reaction stir-
red for 16 h. Saturated aqueous ammonium chloride (5 ml) and ether
(5 ml) were added and the aqueous layer extracted with ether
(2ꢂ5 ml). The organic extracts were washed with brine (5 ml), dried
(MgSO4) and concentrated under reduced pressure. Column chro-
matography of the residue eluting with light petroleumeether (6:1)
gave the title compound 88 (180 mg, 84%) as a colourless oil, Rf 0.50
90 (160 mg, 88%) as a colourless oil, Rf 0.76 (4:1 light petroleum-
24
eethyl acetate); [
a
]
D
ꢀ48 (c 1.25 in CHCl3); nmax 1747, 1721, 1465,
1248,1162,1076,1025 and 835 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 [18H,
s, 3ꢂSiCH3 and Si(CH3)3], 0.09 (3H, s, SiCH3), 0.85e0.92 [38H, 2ꢂSiC
(CH3)3, 4-CH3, 3ꢂCH3CH2CH2CH2 and SiCH2], 1.14 (3H, s, 2-CH3),
1.10e1.55 (12H, 3ꢂCH3CH2CH2CH2), 1.40 [9H, s, OC(CH3)3], 1.73 (2H,
m, 6-H2),1.78 (3H, s,10-CH3), 2.04 (3H, s, CH3CO), 2.10e2.40 (3H, 4-H
and 12-H2), 2.50 (3H, br s, 40-H3), 3.47 (2H, m, 5-H and OHCHCH2Si),
3.63 (3H, s, OCH3), 3.65 (1H, m, OHCHCH2Si), 4.07 (1H, m,13-H), 4.20
(1H, m, 7-H), 4.55 (1H, m, 10-H), 4.57 and 4.68 (each 1H, d, J 6.9,
OHCHO), 5.17 (1H, br s, 3-H), 5.32 (1H, dd, J 15.7, 8.8, 8-H), 5.52 (1H, t,
J 6.3, 11-H), 5.63 (1H, d, J10.0, NH), 5.95 (2H, m, 20-H and 14-H), 6.07
(1H, d, J 19.1, 15-H) and 6.22 (1H, J 15.8, 9-H); dC (75 MHz, CDCl3)
ꢀ4.83, ꢀ4.47, ꢀ3.81, ꢀ1.50, 9.14, 9.36,12.81,13.63,17.99,18.02,18.20,
20.88, 25.81, 25.92, 27.14, 28.24, 28.55, 29.00, 37.30, 38.59, 39.58,
52.23, 53.15, 64.85, 72.33, 73.52, 74.11, 76.23, 91.23, 125.92, 126.81,
129.47, 134.15, 137.55, 139.46, 151.17, 154.91, 169.58 and 173.89; m/z
(ESþ) 1364 (Mþþ23, 60%), 847 (20), 659 (30) and 460 (100).
(2:1 light petroleumeether); [
a
]
24 þ35.2 (c 0.25 in CHCl3); nmax 1814,
D
1730, 1638, 1463, 1328, 1249, 1154, 1072, 1064, 1024, 836 and
776 cmꢀ1
;
dH (300 MHz, CDCl3) 0.00 [15H, s, 2ꢂSiCH3 and Si(CH3)3],
0.06 and 0.07 (each 3H, s, SiCH3), 0.85e0.95 [35H, 2ꢂSiC(CH3)3,
3ꢂCH3CH2CH2CH2 and SiCH2],1.05 (3H, d, J 7.0, 20-CH3),1.19 (3H, s, 3-
CH3), 1.30e1.59 (12H, 3ꢂCH3CH2CH2CH2), 1.58 [9H, s, OC(CH3)3], 1.74
(3H, s, 80-CH3), 1.85 (2H, m, 40-H2), 1.97 (1H, m, 20-H), 2.06 (3H, s,
CH3CO), 2.33 (2H, m, 100-H2), 2.49 (3H, d, J 1.2, 300-H3), 3.46 and 3.65
(each 1H, m, OHCHCH2Si), 3.69 (1H, m, 30-H), 4.09 (1H, m,110-H), 4.13
(1H, m, 50-H), 4.44 (1H, d, J 9.3, 4-H), 4.53 and 4.64 (each 1H, d, J 6.9,
OHCHO), 5.28 (1H, dd, J 15.5, 8.4, 60-H), 5.30 (1H, br s, 10-H), 5.51 (1H,
t, J 7.1, 90-H), 5.94 (1H, dd, J 18.9, 5.2, 120-H), 6.06 (1H, d, J 18.9, 130-H),
6.12 (1H, m, 100-H) and 6.15 (1H, d, J 15.5, 70-H); dC (75 MHz, CDCl3)
ꢀ4.81, ꢀ4.46, ꢀ4.36, ꢀ1.46, 9.37, 10.94, 12.66, 13.27, 13.66, 18.03,
4.1.19. Methyl (2S,3S,4S,5R,7S,13S,8E,10E,13R,14E)-3-acetoxy-2-[(1R,2E)-
1-tert-butoxycarbonylamino-3-iodo-but-2-enyl]-5-tert-butyldimethylsi-
lyloxy-13-hydroxy-2,4,10-trimethyl-7-(2-trimethylsilylethoxy)methoxy-
15-tributylstannylpentadeca-8,10,14-trienoate 91. Tetra-n-butylammo-
nium fluoride (0.16 ml; 1.0 M in THF) was added to the bis-tert-

6624
C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
butyldimethylsilyl ether 90 (70 mg, 50
m
mol) in dry THF (0.4 ml) and
93 (5 mg, 48%) as a pale yellow oil, [
a
]
24 ꢀ130.66 (c 0.3 in CH2C12)
D
the reaction stirred for 4 h. Water (0.1 ml) was added and the mixture
extracted with ether. The ethereal extracts were dried (MgSO4) and
concentrated under reduced pressure. Column chromatography of the
residue eluting with light petroleumeethyl acetate (4:1) gave the title
(found MþþNa, 832.4855. C42H75O10NSi2Na requires M, 832.4827);
nmax 3426, 1727, 1498, 1367, 1249, 1166, 1091, 1023, 909 and
836 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 [9H, s, Si(CH3)3], 0.09 and 0.12
(each 3H, s, SiCH3), 0.89 (2H, m, SiCH2), 0.90 (3H, d, J 7,16-CH3), 0.93
[9H, s, SiC(CH3)3],1.27 (3H, s,1-CH3),1.39 [9H, s, OC(CH3)3],1.57 (2H,
m,14-H2),1.70(3H, s,10-CH3),1.87 (3H, s, 4-CH3), 2.00 (3H, s, CH3CO),
2.01 (1H, m, 16-H), 2.49 (2H, m, 8-H2), 3.28 (1H, dd, J 9.5, 2.5, 15-H),
3.45 and 3.64 (each 1H, m, OHCHCH2Si), 3.70 (3H, s, CH3O),
4.09e4.15 (2H, m, 7-H and 13-H), 4.46 (1H, br, OH), 4.55 and 4.67
(each 1H, d, J 6.5, OHCHO), 4.68 (1H, br s,17-H), 4.99 (1H, t, J 9.5, 2-H),
5.20 (1H, dd, J 16, 9, 6-H), 5.22 (1H, d, J 9.5, 3-H), 5.35 (1H, t, J 7.5, 9-H),
5.58 (1H, dd, J 15.5, 8.5,12-H), 5.89 (1H, d, J 15.5,11-H) and 5.81 (1H,
d, J 16, 5-H); m/z (FAB) 832 (Mþþ23, 85%), 562 (75), 430 (75), 370
(79), 352 (71) and 334 (100).
compound 91 (54 mg, 84%) as a colourless oil, Rf 0.25 (4:1 light
24
petroleumeethyl acetate); [
a
]
ꢀ36 (c 1.80 in CHCl3); nmax 3458,
D
1722, 1654, 1482, 1367, 1248, 1163, 1074, 1024 and 836 cmꢀ1
; dH
(300 MHz, CDCl3) 0.00 [9H, s, Si(CH3)3], 0.03 and 0.08 (each 3H, s,
SiCH3), 0.85e0.95 [29H, SiC(CH3)3, 4-CH3, 3ꢂCH3CH2CH2CH2 and
SiCH2], 1.13 (3H, s, 2-CH3), 1.26e1.55 (12H, 3ꢂCH3CH2CH2CH2), 1.39
[9H, s, OC(CH3)3], 1.73 (2H, m, 6-H2), 1.81 (3H, s, 10-CH3), 2.04 (3H, s,
CH3CO), 2.14 (2H, m, 4-H), 2.39 (2H, m, 12-H2), 2.51 (3H, br s, 40-H3),
3.47 (2H, m, 5-H and OHCHCH2Si), 3.68 (3H, s, OCH3), 3.68 (1H, m,
OHCHCH2Si), 4.15 (2H, m, 7-H and 13-H), 4.58 (1H, m, 10-H), 4.58 and
4.70 (each 1H, d, J 6.9, OHCHO), 5.19 (1H, br s, 3-H), 5.38 (1H, dd, J 15.7,
8.8, 8-H), 5.57 (1H, t, J 6.3, 11-H), 5.64 (1H, d, J10.0, NH), 5.95 (1H, d, J
8.4, 20-H), 6.04 (1H, dd, J 18.8, 4.9, 14-H), 6.20 (1H, d, J 18.8, 15-H) and
6.26 (1H, J 15.7, 9-H); dC (75 MHz, CDCl3) ꢀ4.68, ꢀ3.83, ꢀ1.51, 9.14,
9.38, 12.83, 13.61, 17.99, 18.03, 20.88, 25.91, 27.15, 28.24, 28.57, 28.96,
29.10, 36.25, 38.55, 39.57, 52.25, 53.21, 64.88, 72.31, 73.48, 74.08, 74.61,
76.49, 79.53, 91.44, 126.67, 128.01, 135.65, 137.53, 138.78, 150.04,
154.91 and 169.58; m/z (ESþ) 1249 (Mþþ23, 60%), 734 (60), 142 (100).
4.1.22. (3S,4R)-3-[(1S,2S,3R,5S,11S,6E,8E,12E)-1-Acetoxy-3,11-di-tert-
butyldimethylsilyloxy-2,8-dimethyl-13-tributylstannyl-5-(2-trime-
thylsilylethoxy)methoxytrideca-6,8,12-trienyl]-4-((E)-2-iodoprop-1-
enyl)-3-methyl-1-[(2S)-2-(4-methoxy)benzyloxy]propanoylazetidin-
2-one 94. Potassium hexamethyldisilazide (140
m
l; 1 M in THF,
mol) in
140 mol) was added to the NH-azetidinone 87 (113 mg, 93
m
m
THF (3 ml) at ꢀ78 ꢁC and the pale yellow solution stirred for 15 min.
A freshly prepared solution of the (2S)-2-(4-methoxy)benzylox-
ypropanoyl chloride (28 mg, 0.121 mmol) in THF (0.2 ml) was added
at ꢀ78 ꢁC and the mixture stirred for 4 h. Saturated aqueous sodium
hydrogen carbonate (50 mg) and ether (10 ml) were added and the
mixture was allowed to warm to ambient temperature. The aqueous
layer was extracted with ether (3ꢂ10 ml) and the organic extracts
were washed with brine, dried (MgSO4), filtered and concentrated
under reduced pressure. Column chromatography of the residue
eluting with light petroleumeether (5:1) gave the title compound 94
4.1.20. Methyl
(2S,3S,4S,5R,7S,13S,8E,10E,13R,14E)-3,13-diacetoxy-2-
[(1R,2E)-1-tert-butoxycarbonylamino-3-iodobut-2-enyl]-5-tert-butyldi-
methylsilyloxy-2,4,10-trimethyl-7-(2-trimethylsilylethoxy)methoxy-15-
tributylstannylpentadeca-8,10,14-trienoate 92. Triethylamine (15 ml,
0.11 mmol) and acetic anhydride (10 ml, 0.10 mmol) were added to
the alcohol 91 (4 mg, 3 mmol) in dry dichloromethane (0.1 ml) and
the reaction stirred for 24 h. Saturated aqueous ammonium chloride
(5 ml) and ethyl acetate (5 ml) were added and the aqueous layer
extracted with ethyl acetate (2ꢂ5 ml). The organic extracts were
dried (MgSO4) and concentrated under reduced pressure. Column
chromatography of the residue eluting with light petroleumeethyl
acetate (4:1) gave the title compound 92 (2 mg, 52%) as a colourless
(91 mg, 70%)as a colourless oil, [
a
]
22 ꢀ54 (c 1.7 in CH2C12); nmax 1812,
D
1729, 1639, 1502, 1325, 1024 and 836 cmꢀ1
;
dH (300 MHz, CDCl3)
0.00 [9H, s, Si(CH3)3], 0.05 and 0.06 [each 6H, s, 2ꢂSi(CH3)2],
0.75e0.92 [35H, m, SiCH2, 2ꢂSiC(CH3)3 and Sn(CH2CH2CH2CH3)3],
1.06 (3H, d, J 7, 200-CH3), 1.24 (3H, s, 3-CH3), 1.26 (6H, hex, J 7.5, Sn
(CH2CH2CH2CH3)3), 1.41 (3H, d, J 6.5, 30-H3), 1.47 [6H, m, Sn
(CH2CH2CH2CH3)3],1.62e1.88 (1H, m, 400-H),1.72 (3H, s, 800-CH3),1.96
(1H, m, 400-H0), 2.00 (3H, s, CH3CO), 2.02 (1H, m, 200-H), 2.31 (2H, m,
1000-H2), 2.52 (3H, d, J 1.5, 3000-H3), 3.45 (1H, m, OHCHCH2Si),
3.62e3.75 (2H, m, OHCHCH2Si and 300-H), 3.77 (3H, s, OCH3),
4.02e4.15 (2H, m, 500-H and 1100-H), 4.31 (1H, d, J 10.5, 4-H),
4.49e4.63 (5H, m, OCH2O, ArCH2O, and 20-H), 5.26 (1H, dd, J 15.5, 8.5,
600-H), 5.34 (1H, s, 100-H), 5.51 (1H, t, J 7, 900-H), 5.94 (1H, dd, J 19, 5.5,
1200-H), 5.99 (1H, dq, J 10.5, 1.5, 1000-H), 6.06 (1H, d, J 19, 1300-H), 6.15
(1H, d, J 15.5, 700-H) and 6.84 and 7.26 (each 2H, d, J 8.5, ArH); m/z
(FAB) 1425 (Mþþ23, 28%), 259 (32), 227 (100) and 171 (72).
oil, Rf 0.45 (4:1 light petroleumeethyl acetate); [
a
]
24 ꢀ31.6 (c 0.25 in
D
CHCl3); nmax 1744, 1722, 1480, 1247, 1073 and 1024 cmꢀ1
; dH
(300 MHz, CDCl3) 0.01 (3H, SiCH3), 0.09 [12H, s, Si(CH3)3 and SiCH3],
0.85e0.95 [29H, SiC(CH3)3, 4-CH3, 3ꢂCH3CH2CH2CH2 and SiCH2],
1.10e1.55 (15H, 3ꢂCH3CH2CH2CH2 and 2-CH3), 1.59 [9H, s, OC(CH3)3],
1.76 (2H, m, 6-H2), 1.81 (3H, s, 10-CH3), 2.08 (6H, s, 2ꢂCH3CO), 2.16
(1H, m, 4-H), 2.44 (2H, m,12-H2), 2.52 (3H, br s, 40-H3), 3.51 (1H, m, 5-
H), 3.52 (1H, m, OHCHCH2Si), 3.68 (3H, s, OCH3), 3.69 (1H, m,
OHCHCH2Si), 4.19 (1H, m, 7-H), 4.54 (1H, m, 10-H), 4.57 and 4.69 (each
1H, d, J 6.8, OHCHO), 5.17 (1H, J 1.7, 3-H), 5.25 (1H, q, J 5.8, 13-H), 5.37
(1H, dd, J 15.7, 8.9, 8-H), 5.45 (1H, t, J 7.3,11-H), 5.64 (1H, d, J 10.6, NH),
5.94 (1H, dd, J 19.2, 5.8, 14-H), 5.96 (1H, br d, J 10.8, 20-H), 6.19 (1H, dd,
J 19.2, 0.8, 15-H) and 6.22 (1H, J 15.7, 9-H); m/z (ESþ) 1287 (Mþþ18,
40%), 1274 (30), 1121 (56), 1062 (60), 242 (70), 150 (100).
4.1.23. Methyl
(2S,3S,4S,5R,7S,13S,8E,10E,14E)-3-acetoxy-5,13-di-
tert-butyldimethylsilyloxy-2-{(1R,2E)-3-iodo-1-[(S)-2-(4-methoxy)
benzyloxypropanoylamino]-but-2-enyl}-7-(2-trimethylsilylethoxy)
methoxy-15-tributylstannyl-2,4,10-trimethylpentadeca-8,10,14-trien-
4.1.21. Methyl (1S,2R,7S,13S,15R,16S,17S)-17-acetoxy-2-tert-butoxy-
carbonylamino-15-tert-butyldimethylsilyl-oxy-7-hydroxy-1,4,10,16-
tetramethyl-13-(2-trimethylsilylethoxy)methoxycycloheptadeca-
oate 95. Anhydrous methanol (52
cyanide (84 mg, 1.29 mmol) were added to the N-acylazetidinone
94 (81 mg, 54.62 mol) in DMF (2 ml) and the mixture stirred at
ml, 1.29 mmol) and potassium
3,5,9,11-tetraenecarboxylate 93. Triphenylarsine(5 mg,15.64
was added to bis(dibenzylideneacetone)palladium (3.5 mg,
3.9 mol) in a degassed mixture of DMF and THF (8 ml; 1:1) at room
temperature followed by the vinylstannane 91 (16 mg, 13 mol) in
mmo1)
m
m
room temperature for 5 h. Saturated aqueous ammonium chloride
(2 ml) and ether (5 ml) were added and the aqueous phase was
extracted with ether (3ꢂ10 ml). The organic extracts were washed
with brine, dried (MgSO4), filtered and concentrated under reduced
pressure. Column chromatography of the residue eluting with light
m
a degassed mixture of DMF and THF (4 ml; 1:1) over 5 min. The
resulting dark-green solution was stirred, wrapped in aluminium
foil in the dark, at room temperature for 18 h. Water (5 ml) and ethyl
acetate (10 ml) were added and the aqueous phase extracted with
ethyl acetate (3ꢂ10 ml). The organic extracts were washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Column chromatography of the residue eluting with light petroleum
and ethyl acetate (4:1þ1.0% triethylamine) gave the title compound
petroleumeether (5:1) gave the title compound 95 (71 mg, 87%) as
22
a colourless oil, [
a
]
D
ꢀ32 (c 0.9 in CH2C12); nmax 3405, 1748, 1682,
1613, 1513, 1463, 1376, 1249, 1100, 1027, 836 and 776 cmꢀ1
; dH
(300 MHz, CDCl3) 0.00 [9H, s, Si(CH3)3], 0.02 (6H, s, 2ꢂSiCH3), 0.04
and 0.11 (each 3H, s, SiCH3), 0.81e0.96 [38H, m, 4-CH3, SiCH2, 2ꢂSiC

C.T. Brain et al. / Tetrahedron 66 (2010) 6613e6625
6625
(CH3)3 and Sn(CH2CH2CH2CH3)3], 1.16 (3H, s, 2-CH3), 1.30 (3H, d, J
6.5, 300-H3), 1.31 [6H, m, Sn(CH2CH2CH2CH3)3], 1.49 [6H, m, Sn
(CH2CH2CH2CH3)3], 1.5e1.8 (2H, m, 6-H2), 1.74 (3H, s, 10-CH3), 2.03
(3H, s, CH3CO), 2.08 (1H, m, 4-H), 2.21e2.43 (2H, m, 12-H2), 2.54
(3H, d, J 1.5, 40-H3) 3.46 (2H, m, OHCHCH2Si and 5-H), 3.55 (3H, s,
CH3O), 3.66 (1H, m, OHCHCH2Si), 3.82 (3H, s, OCH3), 3.86 (1H, q, J
6.5, 200-H), 4.06 (1H, m, 13-H), 4.16 (1H, m, 7-H), 4.38 and 4.50 (each
1H, d, J 11, OHCHAr), 453 and 4.65 (each 1H, d, J 6.5, OHCHO), 4.87
(1H, t, J 10, 10-H), 5.11 (1H, br s, 3-H), 5.28 (1H, dd, J 15.5, 8.5, 8-H),
5.51 (1H, t, J 7, 11-H), 5.88 (1H, dq, J 10, 1.5, 2’-H), 5.95 (1H, dd, J 19,
5.5, 14-H), 6.07 (1H, d, J 19, 15-H), 6.19 (1H, d, J 15.5, 9-H), 6.90 and
7.27 (each 2H, d, J 8, ArH) and 7.74 (1H, d, J 10, NH); m/z (FAB) 1455
(Mþþ23, 4%), 227 (100) and 171 (61).
supplementary data. Supplementary data associated with this ar-
ticle can be found in online version at doi:10.1016/j.tet.2010.04.129.
References and notes
1. (a) Uramoto, M.; Otake, N.; Cary, L.; Tanabe, M. J. Am. Chem. Soc. 1978, 100,
3616; (b) Kakinuma, K.; Uzawa, J.; Uramoto, M. Tetrahedron Lett. 1982, 23,
5303; (c) Harada, S.; Kishi, T. Chem. Pharm. Bull. 1974, 22, 99; (d) Harada, S.
Chem. Pharm. Bull. 1975, 23, 2201; (e) Uramoto, M.; Otake, N.; Ogawa, Y.;
Yonehara, H. Tetrahedron Lett. 1969, 27, 2249; (f) Kamiya, K.; Harada, S.; Wada,
Y.; Nishikawa, M.; Kishi, T. Tetrahedron Lett. 1969, 27, 2245; (g) Harada, S.;
Okada, J.; Takeda, M.; Yamazi, T. J. Antibiot. 1985, 38, 877.
2. (a) Tsuchiya, K.; Yamazaki, T.; Takeuchi, Y. J. Antibiot. 1971, 24, 29; (b) Ootsu, K.;
Matsumoto, T.; Harada, S.; Kishi, T. Cancer Chemother. Rep., Part 1 1975, 59, 919.
3. (a) Kakinuma, K. Tetrahedron Lett. 1982, 23, 5303; (b) Tatsuno, S.; Arakawa, K.;
Kinashi, H. J. Antibiot. 2007, 60, 700; (c) Arakawa, K.; Sugino, F.; Kodama, K.;
Ishii, T.; Kinashi, H. Chem. Biol. 2005, 12, 249.
4.1.24. Methyl (2S,3S,4S,5R,7S,13S,8E,10E,14E)-3-acetoxy-5-tert-bu-
tyldimethylsilyloxy-13-hydroxy-2-{(1S,2E)-3-iodo-1-[(S)-2-(4-me-
thoxy)benzyloxypropanoylamino]but-2-enyl}-7-(2-trimethylsilyle-
thoxy)-methoxy-15-tributylstannyl-2,4,10-trimethylpentadeca-
4. Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J. Am. Chem. Soc. 1995, 117,
8258.
5. (a) Thomas, E. J.; Williams, A. C. J. Chem. Soc., Perkin Trans. I 1995, 351; (b) Roe, J.
M.; Thomas, E. J. J. Chem. Soc., Perkin Trans. I 1995, 359.
6. Williams, D. R.; Rojas, C. M.; Bogen, S. L. J. Org. Chem. 1999, 64, 736.
7. Mata, E. G.; Thomas, E. J. J. Chem. Soc., Perkin Trans. I 1995, 785.
8. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b) Stille, J. K.; Tanaka,
M. J. Am. Chem. Soc. 1987, 109, 3785; (c) Kalivretenos, A.; Stille, J. K.; Hegedus, L.
S. J. Org. Chem. 1991, 56, 2883.
9. For preliminary communications on part of this work see: (a) Brain, C. T.; Chen,
A.; Nelson, A.; Tannikkul, N.; Thomas, E. J. Tetrahedron Lett. 2001, 42, 1247; (b)
Chen, A.; Nelson, A.; Tanikkul, N.; Thomas, E. J. Tetrahedron Lett. 2001, 42, 1251.
10. (a) Boys, M. L. Tetrahedron Lett. 1998, 39, 3449; (b) Basak, A.; Khamrai, U. K.
Tetrahedron Lett. 1996, 37, 2475.
8,10,14-trienoate 96. TBAF (68 ml; 1 M in THF, 68 mmol) was added
to the bis-silyl ether 95 (33 mg, 22.68 mmol) in THF (0.5 ml) at
room temperature and the mixture stirred for 4 h. Water (0.2 ml)
was added and the mixture concentrated under reduced pressure.
Column chromatography eluting with light petroleumeether (3:1)
22
gave the title compound 96 (24 mg, 81%) as a colourless oil, [a]
D
ꢀ40 (c 1.4 in CH2C12); nmax 3407, 1748, 1680, 1613, 1514, 1463, 1377,
1249, 1102, 1027 and 836 cmꢀ1
dH (300 MHz, CDCl3) 0.00 [9H, s, Si
11. Yamanaka, T.; Ohkube, M.; Takahashi, F.; Kato, M. Tetrahedron Lett. 2004, 45,
;
2843.
(CH3)3], 0.05 and 0.11 (each 3H, s, SiCH3), 0.85e0.93 [29H, m, 4-CH3,
SiCH2, SiC(CH3)3 and Sn(CH2CH2CH2CH3)3], 1.16 (3H, s, 2-CH3), 1.31
[6H, m, Sn(CH2CH2CH2CH3)3], 1.31 (3H, d, J 6.5, 300-H3), 1.44e1.53
[6H, m, Sn(CH2CH2CH2CH3)3], 1.69 (2H, m, 6-H2), 1.77 (3H, s, 10-
CH3), 2.03 (3H, s, CH3CO), 2.08 (1H, m, 4-H), 2.39 (2H, m, 12-H2),
2.54 (3H, d, J 1.5, 40-H3), 3.47 (2H, m, OHCHCH2Si and 5-H), 3.55 (3H,
s, CH3O), 3.65 (1H, m, OHCHCH2Si), 3.81 (3H, s, CH3O), 3.86 (1H, q, J
6.5, 200-H), 4.15 (3H, m, 7-H, 13-H and OH), 4.38 and 4.50 (each 1H,
d, J 11, ArHCH), 4.54 and 4.66 (each 1H, d, J 7, OHCHO), 4.87 (1H, t, J
10, 10-H), 5.10 (1H, br s, 3-H), 5.35 (1H, dd, J 15.5, 8.5, 8-H), 5.52 (1H,
t, J 7, 11-H), 5.88 (1H, dq, J 10, 1.5, 20-H), 6.04 (1H, dd, J 19, 5.5, 14-H),
6.19 (1H, d, 19, 15-H), 6.22 (1H, d, J 15.5, 9-H), 6.90 and 7.27 (each
2H, d, J 8, ArH) and 7.73 (1H, d, J 10, NH); m/z (FAB) 1343 (Mþþ23,
19%), 1262 (27), 694 (90), 634 (30), 388 (37), 267 (100) and 176 (83).
12. Labia, R.; Morin, C. Chem. Lett. 1984, 1007.
13. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
14. Dominguez, B.; Pazos, Y.; de Lera, A. R. J. Org. Chem. 2000, 65, 5917.
15. (a) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447; (b) Hart, D. J.; Kanai, K.;
Thomas, D. G.; Yang, T. K. J. Org. Chem. 1983, 48, 289.
16. Amans, D.; Barelle, L.; Bellosta, V.; Cossy, J. J. Org. Chem. 2009, 74, 7665.
17. (a) Braun, M.; Devant, R. Tetrahedron Lett. 1984, 25, 5031; (b) Braun, M. Angew.
Chem., Int. Ed. Engl. 1987, 26, 24; (c) Braun, M.; Waldmuller, D. Synthesis 1989,
856.
18. Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851.
19. Palomo, C.; Aizpurua, J. M.; Cuevas, C.; Mielgo, A.; Galarza, R. Tetrahedron Lett.
1995, 36, 9027.
20. Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.; Moriwake, T.
Chem. Lett. 1984, 1389.
21. (a) Fráter, G. Helv. Chim. Acta 1979, 62, 2825; (b) Fráter, G. Helv. Chim. Acta 1979,
62, 2829.
22. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
23. Chong, J. M.; Morton, H. E.; Piers, E. Tetrahedron 1989, 45, 363.
24. (a) Townsend, C. A.; Nguyen, L. T. J. Am. Chem. Soc. 1981, 103, 4582; (b) Town-
send, C. A.; Nguyen, L. T. Tetrahedron Lett. 1982, 23, 4859.
Acknowledgements
25. Saltzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem.
Soc. 1980, 102, 6161.
We thank the EPSRC for a studentship (to C.T.B.) and for post-
doctoral support (to A.C. and A.N.). We should also like to thank the
Thai Government for support (to N.T.).
26. Jyojima, T.; Miyamoto, N.; Katohno, M.; Nakata, M.; Matsumura, S.; Toshia, K.
Tetrahedron Lett. 1998, 39, 6007.
27. Interestingly, preliminary studies indicated that when the 10-hydroxyl group
was unprotected, selective desilylation of a 30,11’-bis-tert-butyldimethylsilyl
ether took place at the 30-position.
28. (a) Carr, K.; Greener, N. A.; Mullah, K. B.; Somerville, F. M.; Sutherland, J. K.
J. Chem. Soc., Perkin Trans. I 1992, 15, 1975; (b) Hanessian, S.; Khai, H. H.
Tetrahedron Lett. 1999, 40, 671.
29. Quayle, P.; Wang, J.; Xu, J.; Urch, C. J. Tetrahedron Lett. 1998, 39, 485.
30. Johnson, C. R.; Kadow, J. F. J. Org. Chem. 1987, 52, 1493.
Supplementary data
Full experimental procedures and spectroscopic data for all
steps and new compounds not included here are available as