Total synthesis of pamamycin 607: Applications of remote asymmetric induction in organic synthesis

Article abstract of DOI:10.1016/S0040-4039(01)00921-2

A total synthesis of pamamycin 607 1 is described. The synthesis of the C(1)-C(18) fragment involved the tin(IV) chloride-promoted reaction between (3R)-3-(N-methyl)tosylaminohexanal 18 and the allylstannane 4 followed by cyclisation and reductive removal of the phenylselanyl group to give the tetrahydrofuran 20 which was taken through to the aldehyde 21. Aldol addition of the lithium enolate derived from 2,6-dimethylphenyl propanoate to this aldehyde followed by O-silylation gave the silyl ether 25 as the major product. This was converted into the aldehyde 31 which gave the bis-tetrahydrofuran 33 on reaction with the stannane 4, cyclisation and reduction. Exchange of the N-protecting group, hydrogenolysis and oxidation then gave the acid 34. This was esterified using the alcohol 42, which had been prepared from the aldehyde 35 and the stannane ent-4 using similar chemistry, to give the ester 43. Deprotection gave the seco-acid 44 and cyclisation, N-deprotection and N-methylation gave pamamycin 607 1.

Full text of DOI:10.1016/S0040-4039(01)00921-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4969–4974
Total synthesis of pamamycin 607: applications of remote
asymmetric induction in organic synthesis
Olivier Germay, Naresh Kumar and Eric J. Thomas*
The Department of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Received 2 April 2001; revised 11 May 2001; accepted 14 May 2001
Abstract—A total synthesis of pamamycin 607 1 is described. The synthesis of the C(1)–C(18) fragment involved the tin(IV)
chloride-promoted reaction between (3R)-3-(N-methyl)tosylaminohexanal 18 and the allylstannane 4 followed by cyclisation and
reductive removal of the phenylselanyl group to give the tetrahydrofuran 20 which was taken through to the aldehyde 21. Aldol
addition of the lithium enolate derived from 2,6-dimethylphenyl propanoate to this aldehyde followed by O-silylation gave the
silyl ether 25 as the major product. This was converted into the aldehyde 31 which gave the bis-tetrahydrofuran 33 on reaction
with the stannane 4, cyclisation and reduction. Exchange of the N-protecting group, hydrogenolysis and oxidation then gave the
acid 34. This was esterified using the alcohol 42, which had been prepared from the aldehyde 35 and the stannane ent-4 using
similar chemistry, to give the ester 43. Deprotection gave the seco-acid 44 and cyclisation, N-deprotection and N-methylation gave
pamamycin 607 1. © 2001 Elsevier Science Ltd. All rights reserved.
The pamamycins are a group of macrodiolides, exem-
plified by pamamycin 607 1, isolated from Streptomyces
alboniger, which possess interesting antifungal activi-
ties.1,2 Considerable interest has been shown in the
synthesis of these compounds and syntheses of both the
C(1)–C(18) and C(1%)–C(11%) fragments have been
described.3 A structural feature of the pamamycins is
the presence of methyl substituted stereogenic centres
adjacent to 2,5-cis-disubstituted tetrahydrofurans. This
feature is also present in (−)-nonactic acid 2.4
is based on the stereoselective cyclisation, to 2,5-cis-dis-
ubstituted tetrahydrofurans, of homoallylic alcohols 3,
which are available stereoselectively from tin(IV)
halide-promoted reactions between 5-alkoxypent-2-
enylstannanes and aldehydes.5,6
Several procedures have been reported for the stereose-
lective cyclisation of (Z)-homoallylic alcohols to 2,5-cis-
disubstituted tetrahydrofurans including those using
iodine under buffered conditions7 and phenylselenenyl
chloride8 and phenylselenenyl phthalimide9 under both
acidic and basic conditions. In our hands, iodine induced
cyclisations of alcohol 5, prepared stereoselectively (1,5-
anti:1,5-syn=96:4) from butanal using the (4R)-5-benzyl-
oxypent-2-enylstannane 4 [(E):(Z)=70:30] and tin(IV)
chloride6 (see Scheme 1) gave only low yields of the
required cyclised product due to competing debenzyla-
tion. However, cyclisations using phenylselenenyl elec-
trophiles were much more promising and reasonable
yields of the trisubstituted tetrahydrofuran 6 were
obtained using either phenylselenenyl chloride or phthal-
imide in the presence of ca. 20 mol% of tin(IV) chloride.
Only the all-cis-trisubstituted tetrahydrofuran 6 was
isolated from these reactions consistent with participa-
tion of the transition state outlined in Fig. 1,7–9 together
with minor side-products formed by competing debenzyl-
ation. Reduction of the tetrahydrofuran 6 using trib-
utyltin hydride gave the cis-2,5-disubstituted tetra-
hydrofuran 7.10
We now describe total syntheses of pamamycin 607 1
and the methyl ester of nonactic acid 2. Our approach
Me
Me
Me
O
O
1
H
H
H
H
11'
Me
O
1'
O
H
O
O
NMe2
O
H
Me
18
Me
1
OH
OH
O
BnO
R
Me
HO
O
H
H
Me
Me
2
3
A synthesis of methyl nonactate 13 was then developed
as a model for the proposed pamamycin synthesis (see
* Corresponding author. Tel.: 00 44 (0)161 275 4614; fax: 00 44
(0)161 275 4939; e-mail: e.j.thomas@man.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00921-2

4970
BnO
O. Germay et al. / Tetrahedron Letters 42 (2001) 4969–4974
In planning the synthesis of the C(1)–C(18) fragment of
BnO
OH
pamamycin 607 1, it was decided to start at the C(18) end
and to incorporate the amino group at C(15), albeit in
a protected form, early in the synthesis (see Scheme 3).
Conjugate addition of lithium (R)-(a-methylben-
zyl)benzylamide to tert-butyl (E)-hex-2-enoate 1413 fol-
lowed by transfer hydrogenolysis gave the b-amino-ester
16 with excellent enantiomeric excess.14 Protection of the
nitrogen as its toluene p-sulfonyl derivative and methyl-
ation gave the amido-ester 17 which was converted into
the aldehyde 18 by reduction followed by oxidation. This
aldehyde reacted with the allyltin trichloride generated
by transmetallation of the stannane 4 to give the alcohol
19, less than 4% of any other diastereoisomer being
detected in the product by 1H and 13C NMR. Cyclisation
of 19 using phenylselenenyl chloride and 20 mol% of
tin(IV) chloride gave the 2,5-cis-disubstituted tetra-
hydrofuran 2015 after reductive removal of the phenylsel-
anyl group although the yield of this cyclisation was only
ca. 43% because of competing O-debenzylation and
participation by the tosylamino group to give mixtures
of side-products which were not fully identified.16
Hydrogenolysis and oxidation then gave the aldehyde 21
which was treated with the lithium enolate derived from
2,6-dimethylphenyl propanoate17 to give a mixture of the
aldol products 22, 24 and 26, ratio 19:72:9, respectively.
The 2,3-syn-3,4-syn-isomer 26 could be separated
directly from this mixture by column chromatography.
The other two isomers were separated as their tert-
butyldimethylsilyl ethers 23 and 25. The structure of the
silyl ether 25 prepared from the major aldol product was
established as the required 2,3-anti-3,4-syn-diastereoiso-
mer by reduction and deprotection to give the diol 27
which was converted into the carbonate 28 (Scheme 4).
The diol and carbonate were also prepared from the
aldehyde 21 by lithium dimethyl cuprate ring-opening of
the epoxide 30 prepared by Sharpless epoxidation of the
alkenol 29 using (+)-diethyl tartrate.18 The diol and
carbonate prepared by the two routes were identical.
i
SnBu3
Me
Me
Me
4
5
ii, iii
X
Me
BnO
O
H
H
Me
6 X = SePh
7 X = H
Scheme 1. Reagents and conditions: (i) SnCl4, 5 min, −78°C,
then PrCHO, −78°C, 1 h (75%); (ii) PhSeCl or PhSePhth, 20
mol% SnCl4, rt, 4 h (50–60%); (iii) Bu3SnH, AIBN (85%).
n
R
R
OH
+
Se H
H
Ph
Figure 1.
Scheme 2). The protected hydroxyaldehyde 811 was
converted into the (Z)-1,5-anti-alkenol 9 (82%, 1,5-
anti:1,5-syn >96:4) using the stannane 4, and reaction of
9 with phenylselenenyl phthalimide followed by reduc-
tion gave the tetrahydrofuran 11 as a single stereoisomer
(>95:5) after chromatography. Hydrogenolysis and oxi-
dation using pyridinium dichromate in N,N-dimethyl
formamide led to the acid 12, and esterification using
trimethylsilyl diazomethane and desilylation gave methyl
nonactate 1312 which was identical with a sample pre-
pared from nonactin.
This synthesis of methyl nonactate confirmed the
stereoselectivity of cyclisation of (Z)-homoallylic alco-
hols and indicated that the reaction conditions required
for the cyclisation were compatible with silyl and benzyl
ether protecting groups.
The preferred formation of the 2,3-anti-3,4-syn-isomer in
the aldol reaction is consistent with addition of the
(Z)-enolate17 of the 2,6-dimethylphenyl ester to the
aldehyde according to the Felkin–Anh model.19
X
t
t
OH
OSiPh2 Bu
OSiPh2 Bu
t
ii, iii
O
OSiPh2 Bu
i
BnO
Me
Me
BnO
O
H
H
H
Me
Me
Me
8
9
10 X = SePh
11 X = H
iv
t
OSiPh2 Bu
O
OH
Me
O
v
Me
HO
O
MeO
O
H
H
H
H
Me
Me
13
12
Scheme 2. Reagents and conditions: (i) 4, SnCl4, −78°C, 1 h (82%); (ii) PhSePhth, 20% SnCl4 (62%); (iii) Bu3SnH, AIBN (85%);
(iv) (a) 10% Pd/C, H2 (73%), (b) PDC, DMF (82%); (v) (a) Me3SiCHN2 (78%), (b) Bu4NF, THF (78%).

O. Germay et al. / Tetrahedron Letters 42 (2001) 4969–4974
4971
Ph
Me
O
N
Ph
O
NH2
O
NMe.Ts
O
i
ii
iii
tBuO
Me
tBuO
Me
tBuO
Me
tBuO
Me
15
17
16
14
iv
NMe.Ts
OH
NMe.Ts
O
NMe.Ts
vi
v
Me
BnO
BnO
Me
H
Me
O
H
H
Me
Me
19
18
20
vii
NMe.Ts
NMe.Ts
O
OR
3
O
OR
3
2
4
2
4
+
Me
Me
ArO
O
ArO
O
H
H
H
NMe.Ts
H
O
Me
Me
Me
Me
viii, ix
Me
H
O
24 R = H
22 R = H
H
H
Me
t
NMe.Ts
t
O
OH
3
25 R = SiMe2 Bu
23 R = SiMe2 Bu
21
2
4
Me
ArO
+
O
H
H
Me
Me
(Ar = 2,6-dimethylphenyl)
26
n
Scheme 3. Reagents and conditions: (i) (R)-BnNH·CHMePh, BuLi, −78°C (89%); (ii) Pd(OH)2/C, HCO2NH4, HCO2H (100%);
(iii) (a) TsCl, Et3N, DMAP (91%), (b) NaH, MeI (100%); (iv) (a) LiAlH4, Et2O (94%), (b) (COCl)2, DMSO, Et3N (95%); (v) 4,
SnCl4, −78°C (64%); (vi) (a) PhSeCl, 20 mol% SnCl4 (43%), (b) Bu3SnH, AIBN (94%); (vii) (a) H2, Pd/C, EtOH (98%), (b)
t
(COCl)2, DMSO, Et3N (90%); (viii) 2,6-dimethylphenyl propanoate, LiNiPr2, −78°C (22+24, 63%; 26, 7%); (ix) BuMe2SiOTf (23,
17%; 25, 66%).
O
NMe.Ts
NMe.Ts
OH OH
NMe.Ts
NMe.Ts
O
O
i
ii
25
Me
Me
O
Me
O
H
H
H
v
H
H
Me
Me
Me
Me
Me
27
28
iii
O
iv
21
Me
HO
HO
O
O
H
H
H
Me
30
29
Scheme 4. Reagents and conditions: (i) (a) DIBAL-H (80%), (b) TBAF (89%); (ii) (imid)2CO (87%); (iii) (a) Ph3PCHCO2Me (81%),
(b) DIBAL-H (74%); (iv) Ti(OiPr)4,
-(+)-DET, TBHP (70%); (v) LiCuMe2 (57%).
L
Reduction and oxidation of the protected major aldol
product 25 gave the aldehyde 31 which reacted with the
allyltin trichloride generated from the allylstannane 4 to
give the (Z)-1,5-anti-product 325,6 (Scheme 5). Cyclisa-
tion in this case was best achieved using phenylselen-
enyl phthalimide in the presence of zinc(II) chloride and
gave the bis-tetrahydrofuran 3320 in ca. 50% yield from
the homoallylic alcohol after reductive removal of the
phenylselanyl group. The benzyl ether 33 was taken
through to the acid 34 corresponding to the C(1)–C(18)
fragment of pamamycin 607 by removal of the tosyl
group, reprotection of the nitrogen as its tert-butoxy-
carbonyl derivative, hydrogenolysis, and oxidation.
necessary to invert the configuration of the hydroxyl
bearing stereogenic centre introduced during the allyl-
stannane reaction before cyclisation (see Scheme 6).
The tin(IV) chloride-promoted reaction between the
protected hydroxyaldehyde 3521 and the allylstannane
ent-4 gave the (Z)-1,5-anti-product 36 (1,5-anti:1,5-syn
ca. 87:13). This was converted into its 1,5-syn-
diastereoisomer 37 by Mitsunobu inversion using 4-
nitrobenzoic acid followed by saponification.
Cyclisation of the 1,5-syn-alcohol 37 using phenylselen-
enyl phthalimide in the presence of 20 mol% tin(IV)
chloride then gave the tetrahydrofuran 38 (ca. 60%)
together with inseparable side-products (10–15%) which
were believed to be diastereoisomers of 38. Reduction
of this mixture by tributyltin hydride gave the 2,5-cis-
This approach was now applied to synthesise the C(1%)–
C(11%) fragment of pamamycin 607. In this case, it was

4972
O. Germay et al. / Tetrahedron Letters 42 (2001) 4969–4974
OH
NMe.Ts
OTBS
Me
NMe.Ts
O
OTBS
Me
ii
i
Me
BnO
O
25
Me
H
O
H
H
H
H
Me
Me
Me
32
31
iii
NMe.Ts
NMe.Boc
OTBS
O
OTBS
iv
Me
Me
BnO
O
O
HO
O
O
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
34
33
Scheme 5. Reagents and conditions: (i) (a) DIBAL-H (82%), (b) (COCl)2, DMSO, Et3N, (95%); (ii) 4, SnCl4 (83%); (iii) (a)
PhthSePh, ZnCl2, CH2Cl2 (54%), (b) Bu3SnH, AIBN (85%); (iv) (a) Na naphth, −60°C (84%), (b) Boc2O, Et3N (80%), (c) H2,
Pd/C, (d) Dess–Martin periodane, (e) NaOCl2, NaH2PO4 (85% over the last three steps).
tBuPh2SiO
Me
O
tBuPh2SiO
Me
OH
tBuPh2SiO
Me
OH
i
ii
H
OBn
OBn
Me
Me
35
36
37
iii, iv
t
t
Me
OP
O
Me
OSiPh2 Bu
Me
OSiPh2 Bu
H
H
H
H
H
H
vi, vii
v
OBn
OH
OBn
O
O
O
Me
Me
Me
X
t
41 P = SiPh2 Bu
42 P = H
40
38 X = SePh
39 X = H
Scheme 6. Reagents and conditions: (i) ent-4, SnCl4 (80%); (ii) (a) Ph3P, p-nitrobenzoic acid, DEAD (68%), (b) NaOH (94%); (iii)
PhSePhth, SnCl4 (74% including 60% of 38); (iv) Bu3SnH, AIBN (89%); (v) 10% Pd/C, H2 (70%); (vi) (a) Dess–Martin periodane,
i
(b) NaOCl2, NaH2PO4, (c) Pr2NEt, BnBr (81% from 40); (vii) conc. aq. HCl, MeOH (49%).
disubstituted tetrahydrofuran 39 which was converted
into the alcohol 40 by hydrogenolysis, the side-products
Oxidation and carboxylate alkylation then gave the
benzyl ester 41 which was desilylated to give the free
alcohol 42 corresponding to the C(1%)–C(11%) fragment
of pamamycin 607 1.
being
removed
at
this
stage
by
column
chromatography.
NMe.Boc
OTBS
Me
Me
O
O
O
O
H
H
H
H
H
H
i
Me
Me
Me
O
+
42
34
CO2Bn
43
Me
ii
Me
Me
NMe.Boc
OH
Me
Me
O
O
iv
O
H
iii
H
H
Me
O
O
O
1
O
Me
O
O
H
H
H
H
H
H
H
O
O
H
Me
Me
H
Me
O
NMe.Boc
Me
CO2H
Me
Me
45
44
Scheme 7. Reagents and conditions: (i) 2,4,6-trichlorobenzoyl chloride, DMAP, CH2Cl2, 3 h, rt (63%); (ii) (a) HCl, EtOH,
40–50°C, 3 h, followed by Boc2O, Et3N (80%), (b) H2, Pd/C, EtOH; (iii) 2,4,6-trichlorobenzoyl chloride, Et3N, 24 h, rt, then
DMAP, 24 h, rt (25%); (iv) (a) TFA, CH2Cl2, 45 min, rt (82%), (b) CH2O, NaBH3CN, AcOH, (60%).

O. Germay et al. / Tetrahedron Letters 42 (2001) 4969–4974
4973
3. (a) Walkup, R. D.; Park, G. Tetrahedron Lett. 1988, 29,
5505–5508; (b) Walkup, R. D.; Kim, S. W.; Wagy, S. D.
J. Org. Chem. 1993, 58, 6486–6490; (c) Walkup, R. D.;
Kim, S. W. J. Org. Chem. 1994, 59, 3433–3441; (d)
Walkup, R. D.; Kim, Y. S. Tetrahedron Lett. 1995, 36,
3091–3094; (e) Mavropoulos, I.; Perlmutter, P. Tetra-
hedron Lett. 1996, 37, 3751–3754; (f) Mandville, G.;
Bloch, R. Eur. J. Org. Chem. 1999, 2303–2307; (g) Sol-
ladie, G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron
Lett. 2000, 41, 551–554; (h) Bernsmann, H.; Hungerhoff,
B.; Fechner, R.; Frohlich, R.; Metz, P. Tetrahedron Lett.
2000, 41, 1721–1724; (i) Solladie, G.; Salom-Roig, X. J.;
Hanquet, G. Tetrahedron Lett. 2000, 41, 2737–2740; (j)
Bernsmann, H.; Frohlich, R.; Metz, P. Tetrahedron Lett.
2000, 41, 4347–4351; (k) Bernsmann, H.; Gruner, M.;
Metz, P. Tetrahedron Lett. 2000, 41, 7629–7633.
4. Solladie, G.; Dominguez, C. J. Org. Chem. 1994, 59,
3898–3901.
The completion of the synthesis of pamamycin 607 1 is
outlined in Scheme 7. The acid 34 and alcohol 42 were
coupled using 2,4,6-trichlorobenzoyl chloride23 to give
the ester 43. Attempted desilylation using tetra-
butylammonium fluoride was accompanied by elimina-
tive
tetrahydrofuran
opening
and
so
the
tert-butyldimethylsilyl group was removed using
aqueous hydrogen chloride in ethanol. This also
removed the tert-butyloxycarbonyl group which had to
be reinstated. Hydrogenolysis then gave the seco-acid
44 which was cyclised using 2,4,6-trichlorobenzoyl
chloride23 to give the macrodiolide 45 in 25% yield
accompanied by a dimer. Finally, removal of the tert-
butyloxycarbonyl group and N-methylation gave
pamamycin 607 1, characterised as its trifluoroacetate
salt, which had spectroscopic data (1H and 13C NMR,
MS) identical to those of the natural product.24
5. Thomas, E. J. J. Chem. Soc., Chem. Commun. 1997,
411–418.
6. Carey, J. S.; Thomas, E. J. Synlett 1992, 585–586.
7. Barks, J. M.; Knight, D. W.; Seaman, C. J.; Weingarten,
G. G. Tetrahedron Lett. 1994, 35, 7259–7262.
8. (a) Kang, S. H.; Hwang, T. S.; Kim, W. J.; Lim, J. K.
Tetrahedron Lett. 1990, 31, 5917–5921; (b) Kang, S. H.;
Hwang, T. S.; Kim, W. J.; Lim, J. K. Tetrahedron Lett.
1991, 32, 4015–4018; (c) Ley, S. V.; Lygo, B. Tetrahedron
Lett. 1982, 23, 4625–4628; (d) Brussani, G.; Ley, S. V.;
Wright, J. L.; Williams, D. J. J. Chem. Soc., Perkin
Trans. 1 1986, 303–307.
This total synthesis of pamamycin 607 exemplifies the
synthesis of tetrahydrofurans using reactions between
allylstannanes and aldehydes followed by phenylselen-
enyl induced cyclisation, and demonstrates that this
chemistry can be used for the synthesis of complex
natural products. In this synthesis, all the stereogenic
centres, apart from that at C(15), were introduced
either during the allylstannane–aldehyde reactions or
were induced by centres which had been introduced
during the allylstannane–aldehyde reactions. The appli-
cation of this strategy, for the synthesis of other tetra-
hydrofuran containing natural products, is under
investigation.
9. Mihelich, D.; Hite, G. A. J. Am. Chem. Soc. 1992, 114,
7318–7319.
10. The structure of the tetrahydrofuran 7 was confirmed by
a second synthesis, see Hobson, L. A.; Singh, L. W.;
Thomas, E. J., submitted to ARKIVOC.
Acknowledgements
11. Claffey, M. M.; Heathcock, C. H. J. Org. Chem. 1996,
61, 7646–7647.
The authors are very grateful indeed to Professor M.
Natsume of the Department of Applied Biological Sci-
ence in the Tokyo University of Agriculture and Tech-
nology for help in confirming the structure of the
synthetic material, in particular for the generous gift of
a sample of natural pamamycin 607 and for the provi-
sion of spectra of the natural product. They would also
like to thank Dr. P. Evans for carrying out the final two
steps and the EPSRC for support (to N.K.).
12. (a) Ahmar, M.; Duyck, C.; Fleming, I. J. Chem. Soc.,
Perkin Trans 1 1998, 2721–2732; (b) Fleming, I.; Ghosh,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 2733–2747; (c)
Deschenaux, P.-F.; Jacot-Guillarmod, A. Helv. Chim.
Acta 1990, 73, 1861–1864; (d) Sun, K. M.; Fraser-Reid,
B. Can. J. Chem. 1980, 58, 2732–2735; (e) Takatori, K.;
Tanaka, N.; Tanaka, K.; Kajiwara, M. Heterocycles
1993, 36, 1489–1492; (f) Bratt, K.; Garavelas, A.; Perl-
mutter, P.; Westman, G. J. Org. Chem. 1996, 61, 2109–
2117.
References
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15. The 2,5-cis-configuration assigned to the tetrahydrofuran
20 was established by NOE studies and confirmed by
correlation with known compounds.3
16. Lower yields were obtained for cyclisation if the nitrogen
was protected as its Cbz-derivative due to increased
participation of the N-substituent. Difficulties were
1. (a) Natsume, M. Recent Res. Dev. Agric. Biol. Chem.
1999, 3, 11–22; (b) McCann, P. A.; Pogell, B. M. J.
Antibiot. 1979, 32, 673–678; (c) Natsume, M.; Yasui, K.;
Kondo, S.; Marumo, S. Tetrahedron Lett. 1991, 32, 3087–
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Microbiol. 1992, 32, 339–345; (e) Kozone, I.; Chikamoto,
N.; Abe, H.; Natsume, M. J. Antibiot. 1999, 52, 329–331.
2. (a) Kondo, S.; Yasui, K.; Natsume, M.; Katayama, M.;
Marumo, S. J. Antibiot. 1988, 41, 1196–1204; (b) Kondo,
S.; Yasui, K.; Katayama, M.; Marumo, S.; Kondo, T.;
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4974
O. Germay et al. / Tetrahedron Letters 42 (2001) 4969–4974
encountered when the nitrogen was protected using a
21. The aldehyde 35 was prepared from (S)-2-hydroxypen-
very electron withdrawing group, e.g. triflate. The intro-
duction of the C(15)-amino group at the end of the
synthesis, e.g. from a hydroxyl group, was less efficient
overall.
tanoic acid.22
22. (a) Raddatz, P.; Minck, K.-O.; Rippmann, F.; Schmitges,
C.-J. J. Med. Chem. 1994, 37, 486–497; (b) Mori, K.;
Takaishi, H. Tetrahedron 1989, 45, 1639–1646.
23. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993; (b) Fleming, I.; Ghosh, S. K. J. Chem Soc., Perkin
Trans. 1 1998, 2733–2747; (c) White, J. D.; Carter, R. G.;
Sundermann, K. F. J. Org. Chem. 1999, 64, 684–685.
24. Pamamycin 607 trifluoroacetate25 (acetone-d6): lC 175.0
(C-1), 173.7 (C-1%), 83.2 (C-3), 81.1 (C-10), 80.0 (C-13),
79.2 (C-3%), 77.3 (C-6), 75.2 (C-6%), 75.2 (C-8), 71.5 (C-8%),
68.7 (C-15), 47.9 (C-2), 43.7 (C-23), 42.1 (C-2%), 41.5
(C-9), 39.4 (C-7%), 37.9 (C-7), 37.9 (C-9%), 36.5 (C-22), 34.2
(C-14), 32.1 (C-5%), 31.6 (C-12), 31.1 (C-4), 30.3 (C-11),
29.0 (C-16), 28.1 (C-5), 27.9 (C-4%), 20.3 (C-17), 18.8
(C-10%), 14.3 (C-11%), 14.0 (C-18), 14.0 (C-19), 10.4 (C-21),
9.8 (C-20) and 8.7 (C-12%).
17. Pirrung, M. C.; Heathcock, C. H. J. Org. Chem. 1980, 45,
1727–1728.
18. (a) Hill, J. G.; Sharpless, K. B. Org. Synth. 1985, 63,
66–78; (b) Katsuki, T.; Sharpless, K. B. J. Am. Chem.
Soc. 1980, 102, 5974–5976; (c) Rossiter, B. E.; Katsuki,
T.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 464–
465; (d) Hanson, R. M.; Sharpless, K. B. J. Org. Chem.
1986, 51, 1922–1925; (e) Gao, Y.; Hanson, R. M.; Klun-
der, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765–5780.
19. The structure of the 2,3-anti-3,4-anti-isomer 23 was simi-
larly confirmed using (−)-diethyl tartrate for the epoxida-
tion of the alkene 29.
20. The stereo- and regioselectivity of cyclisation of 32 were
confirmed by NOE and 2D NMR studies together with
chemical correlations.
25. Assignments by comparison with data of Natsume and
collaborators.
.