An approach to the total synthesis of lankacidins: Synthesis of the requisite building blocks

Article abstract of DOI:10.1016/S0040-4039(00)02260-7

A strategy for a total synthesis of lankacidin C 1 is outlined and the requisite building blocks synthesised. The azetidinone 4 was prepared from methyl but-2-ynoate 6 via a route which features the stereoselective addition of a tributyltin cuprate to the alkyne, an asymmetric aldol condensation and formation of the azetidinone by an intramolecular Mitsunobu reaction. The aldehyde 3 was prepared from dimethyl malate 18 and the sulfone 3 from prop-2-ynol 27 again using asymmetric aldol reactions as key steps.

Full text of DOI:10.1016/S0040-4039(00)02260-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1247–1250
An approach to the total synthesis of lankacidins: synthesis of
the requisite building blocks
Christopher T. Brain, Anqi Chen, Adam Nelson, Nongluk Tanikkul and Eric J. Thomas*
Department of Chemistry, University of Manchester, Manchester M13 9PL, UK
Received 9 October 2000; accepted 1 December 2000
Abstract—A strategy for a total synthesis of lankacidin C 1 is outlined and the requisite building blocks synthesised. The
azetidinone 4 was prepared from methyl but-2-ynoate 6 via a route which features the stereoselective addition of a tributyltin
cuprate to the alkyne, an asymmetric aldol condensation and formation of the azetidinone by an intramolecular Mitsunobu
reaction. The aldehyde 3 was prepared from dimethyl malate 18 and the sulfone 3 from prop-2-ynol 27 again using asymmetric
aldol reactions as key steps. © 2001 Elsevier Science Ltd. All rights reserved.
The lankacidins, e.g. lankacidin C 1, are a small group
of antitumour antibiotics isolated from Streptomyces
which have been of some interest to synthetic chemists
because of their novel structures and biological activi-
ties.1 Kende and ourselves independently conceived an
approach to the d-lactone component of the lankacidins
using a stereoselective acylation of a 4-substituted aze-
tidinone followed by rearrangement of a 3-(3-hydroxy-
alkyl)azetidinone to give the d-lactone.2,3 Kende subse-
quently completed a total synthesis of lankacidin C
based on this chemistry using an intramolecular addi-
tion of a protected cyanohydrin anion to an aldehyde,
a Stork–Takahashi cyclisation, to form the 17-mem-
bered ring.4 We here describe an alternative strategy for
the synthesis of lankacidins together with total synthe-
ses of the necessary precursors.
Based on earlier work, the azetidinone 2 was identified
as a possible precursor of lankacidin C.2 Macrocyclic
analogues of the lankacidins had been prepared by
using a ketophosphonate–aldehyde condensation to
form the 12,13-double-bond,5 and this chemistry is
known to be compatible with the presence of an azetidi-
none ring.2 However, the yields of the macrocycle were
only modest5 and so it was decided to investigate an
alternative strategy for formation of this ring. The Stille
reaction has been used for macrocycle formation in
complex syntheses6 and model studies, vide infra, indi-
cated that the formation of the 5,6-bond by a Stille
process could be an option for ring formation. The
2,18-bond would be formed by a stereoselective azetidi-
none acylation2,3 and the 12,13-double-bond could be
introduced connectively, e.g. via a Julia reaction. Based
H
Me
O
I
+
Me
CO2Me
N
Me
SiMe2But
CO.Me
PO
Me
Me
H
O
HN
Me
O
5
Me
OP
OSiMe2But
Me
4
Me
Me
6
Bu3Sn
18
O
NH
2
O
OP
SEMO
CHO
+
O
PO
13
3
OH
PhS(O)2
OSiMe2But
HO
12
Me
Me
2 (P = a protecting group)
5
1
Keywords: lankacidin; azetidinone; Mitsunobu reaction.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02260-7

1248
C. T. Brain et al. / Tetrahedron Letters 42 (2001) 1247–1250
on this analysis, the azetidinone 4, the aldehyde–ester 3
and the vinylstannane 5 were identified as potential
precursors of lankacidin C 1.
The ester–aldehyde 3 was prepared as shown in
Scheme 2. Selective reduction13 and protection of
dimethyl malate 18 gave the mono-dimethoxytrityl
(DMT) ether 19. This was further protected as its
trimethylsilylethoxymethyl (SEM) ether 20 which was
converted into the aldehyde 22 by reduction–oxidation.
Aldol addition of (S)-2-hydroxy-1,2,2-triphenylethyl
acetate (S)-179 followed by methanolysis gave the
methyl ester 23 together with its epimer at C(3), ratio
75:25 which were separated by chromatography. The
major isomer 23 was then methylated stereoselectively14
to give the anti-2-methyl-3-hydroxy-ester 24. After con-
version into the tert-butyldimethylsilyl ether 25, selec-
tive removal of the dimethoxytrityl ether gave the
primary alcohol 26 and oxidation using TPAP gave the
required aldehyde 3.
The (4S)-azetidinone 4 was prepared as outlined in
Scheme 1, a racemic epimer being available by a shorter
route.7 Stereoselective conjugate addition8 of a tri-
butyltin cuprate to methyl but-2-ynoate 6 gave the (E)-
vinylstannane 7 which was reduced to the alcohol 8.
Oxidation of the alcohol using Swern conditions (oxalyl
chloride, dimethyl sulfoxide) gave a mixture of the (E)-
and (Z)-aldehydes; however, manganese dioxide gave
the required (E)-aldehyde 9. An asymmetric aldol con-
densation with the chiral acetate, (R)-2-hydroxy-1,2,2-
triphenylethyl acetate (R)-17,9 followed by methan-
olysis gave the methyl ester 11 which was treated with
iodine to give the (E)-vinyl iodide 12. The methyl ester
was then converted into the amide 13 which was
cyclised under Mitsunobu conditions10 to give the aze-
tidinone 14. Oxidative removal of the p-methoxyphenyl
group gave the NH-azetidinone 15 which was repro-
tected as its N-tert-butyldimethylsilyl derivative 16,
shown to correspond to the (S)-enantiomer with an ee
of 90( 5)% by correlation with known compounds.11
Finally methylation gave the required azetidinone 4
containing ca. 10% of its epimer at C(3).11
The vinylstannane 5 was prepared as outlined in
Scheme 3. Free-radical addition of tributyltin hydride
to propargyl alcohol 27 gave a mixture of (E)- and
(Z)-vinylstananes from which the major (E)-isomer 28
was separated by chromatography.15 Oxidation using
activated manganese dioxide gave the aldehyde 29
which was converted into the hydroxy–ester 30 by a
stereoselective aldol condensation with the acetate (S)-
17.9 Methanolysis gave the methyl ester 31, ee 90( 5)%
i
ii, iii
SnBu3
iv, v
SnBu3
SnBu3
R
MeO2C
Me
MeO2C
RO2C
Me
Me
OH Me
6
8 R = CH2OH
9 R = CHO
7
10 R = (R)-CHPhCPh2OH
11 R = Me
vi
H
N
H
R2
H
N
I
xi - xi
I
viii
vii
I
I
MeO2C
Me
N
Me
OH Me
O
O
OH Me
R1
O
Ar
MeO
15 R1 = R2 = H
12
14 Ar = p-MeOC6H4
13
16 R1 = SiMe2But , R2 = H
4 R1 = SiMe2But, R2 = Me
Scheme 1. Reagents and conditions: (i) Li(Bu3SnCuBr)·DMS, −78°C (92%); (ii) DIBAL-H (98%); (iii) MnO2, acetone (100%); (iv)
(R)-17, 2LDA, MgBr2 (98%); (v) MeONa, MeOH (85%); (vi) I2, CCl4 (87%); (vii) lithium p-methoxyphenylamide (70%); (viii)
PPh3, DEAD (90%); (ix) CAN, MeCN, H2O; (x) t-BuMe2SiCl, Et3N (74% from 14); (xi) LDA, MeI (95%).
CO2Me
R
CO2Me
CO2Me
CO2Me
v, vi
i, ii
iii, iv
3
OH
SEMO
RO
HO
ODMT
SEMO
ODMT
ODMT
18
21 R = CH2OH
22 E = CHO
19 R = H
23
vii
20 R = SEM
Me
CO2Me
Me
CO2Me
Me
CO2Me
x
ix
viii
3
OSiMe2But
OH
OSiMe2But
SEMO
SEMO
SEMO
ODMT
ODMT
OH
26
25
24
Scheme 2. Reagents and conditions: (i) BH3·DMS, NaBH4 then DMTCl, EtNiPr2 (93%); (ii) SEMCl, EtNiPr2 (100%); (iii)
DIBAL-H; (iv) TPAP, NMO, 4A sieves (85% from 20); (v) (S)-17, 2 LDA, MgBr2; (vi) MeONa, MeOH (63% from 22); (vii) 2
t
LDA, TMEDA, MeI (79%); (viii) BuMe2SiOTf, 2,6-lutidine (98%); (ix) Cl2CHCO2H (83%); (x) TPAP, NMO, 4A sieves (86%).

C. T. Brain et al. / Tetrahedron Letters 42 (2001) 1247–1250
1249
OH
iii, iv
i
ii
OHC
HO
SnBu3
SnBu3
RO2C
HO
SnBu3
27
28
29
30 R = (S)-CHPhCPh2OH
v
31 R = Me
OSiMe2But
SnBu3
OSiMe2But
SnBu3
OSiMe2But
viii
vi, vii
EtO2C
R
MeO2C
SnBu3
Me
35
32
33 R = CH2OH
34 R = CHO
ix
OSiMe2But
OSiMe2But
SnBu3
x
xi
5
HO
SnBu3
Br
Me
Me
36
37
Scheme 3. Reagents and conditions: (i) Bu3SnH, AIBN, 100°C (83%; E:Z=77: 23); (ii) MnO2, acetone (98%); (iii) (S)-17, 2LDA,
t
MgBr2; (iv) MeONa, MeOH (95% from 29); (v) BuMe2SiOTf, 2,6-lutidine (97%); (vi) DIBAL-H (83%); (vii) TPAP, NMO, 4A
sieves (87%); (viii) Ph3PꢀCMeCO2Et (98%); (ix) DIBAL-H (97% from 34); (x) MsCl, Et3N, then LiBr (79%); (xi) PhSO2Na, DMF
(98%).
(Mosher’s derivatives) which, after protection as its
tert-butyldimethylsilyl ether 32, was reduced to the
alcohol 33. Oxidation gave the aldehyde 34 which was
taken through to the (E)-ab-unsaturated ester 35.
Reduction gave the alcohol 36 and this was converted
into the sulfone 5 via the bromide 37.
1974, 22, 99–108; (d) Harada, S. Chem. Pharm. Bull.
1975, 23, 2201–2210; (e) Uramoto, M.; Otake, N.;
Ogawa, Y.; Yonehara, H. Tetrahedron Lett. 1969, 27,
2249–2254; (f) Kamiya, K.; Harada, S.; Wada, Y.;
Nishikawa, M.; Kishi, T. Tetrahedron Lett. 1969, 27,
2245–2248.
2. Kende, A. S.; Luzzio, M. J.; Koch, K. In Chemistry and
Biotechnology of Biologically Active Natural Products;
Proceedings of the Fourth International Conference:
Budapest, Hungary, 1987.
3. (a) Thomas, E. J.; Williams, A. C. J. Chem. Soc., Chem.
Commun. 1987, 992–994; (b) Thomas, E. J.; Williams, A.
Preliminary studies into the Stille condensation were
carried out using the azetidinone 4. For example, cou-
pling with the (E)-vinylstannane 28 was very efficient
using bisacetonitrile dichloropalladium(II) as catalyst
and gave the conjugated diene 38 in 80% yield.
The accompanying communication describes the assem-
bly of advanced macrocyclic precursors of lankacidin C
1 from the three building blocks 3, 4 and 5.
C. J. Chem. Soc., Perkin Trans. 1 1995, 351–358; (c) Roe,
J. M.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1995,
359–368.
4. Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J.
Am. Chem. Soc. 1995, 117, 8258–8270.
5. Mata, E.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1995, 785–799.
Acknowledgements
6. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1999, 1235–1246.
We thank the EPSRC and the Thai Government for
support.
7. Preliminary attempts to hydrometalate the 4-alkynylaze-
tidinone i gave mixtures of regio- and/or stereoisomers.
However, the racemic azetidinone ( )-iii is available in
two steps from the N-trimethylsilylimine prepared from
aldehyde 9 by condensation with ethyl propanoate fol-
lowed by metal–halogen exchange. The configuration at
C(3) is unimportant for the synthesis since it is lost on
enolate anion formation.
References
1. (a) Uramoto, M.; Otake, N.; Cary, L.; Tanabe, M. J.
Am. Chem. Soc. 1978, 100, 3616–3617; (b) Kakinuma, K.;
Uzawa, J.; Uramoto, M. Tetrahedron Lett. 1982, 23,
5303–5306; (c) Harada, S.; Kishi, T. Chem. Pharm. Bull.

1250
C. T. Brain et al. / Tetrahedron Letters 42 (2001) 1247–1250
8. Piers, E.; Chong, J. M.; Morton, H. E. Tetrahedron 1989,
CH2Cl2).12 The double-bond geometry of the azetidinone
4 was established by NOE observations.
45, 363–380.
9. Braun, M.; Devant, R. Tetrahedron Lett. 1984, 25, 5031–
5034.
10. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Townsend, C.
A.; Nguyen, L. T. J. Am. Chem. Soc. 1981, 103, 4582–
4583; (c) Townsend, C. A.; Nguyen, L. T. Tetrahedron
Lett. 1982, 23, 4859–4862.
11. The (4S)-configuration of the azetidinone 16 was estab-
lished by ozonolysis followed by a reductive work up
which gave (−)-4-hydroxymethyl-1-tert-butyldimethyl-
silylazetidinone, [h]D −28 (c 1.3 CHCl3), which is known
to correspond to the (S)-enantiomer, [h]D −31.5 (c 2.7,
12. (a) Saltzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.;
Bouffard, F. A. J. Am. Chem. Soc. 1980, 102, 6161–6163;
(b) Sabia, R.; Morin, C. Chem. Lett. 1984, 1007–1008.
13. (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii,
T.; Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389–
1392; (b) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.;
Moriwake, T. Tetrahedron 1992, 48, 4067.
14. (a) Frater, G. Helv. Chim. Acta 1979, 62, 2825–2828; (b)
Frater, G. Helv. Chim. Acta 1979, 62, 2829–2832.
15. Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23,
3851–3854.
.
.