Synthesis of the C14-C28 fragment of tetronasin

Article abstract of DOI:10.1055/s-2005-918486

A synthesis of the C14-C28 fragment of Tetronasin features an S _E2 reaction between a cationic η³-allylmolybdenum complex and and an α-metallated tetrahydrofuran. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918486

PAPER
3219
Synthesis of the C14–C28 Fragment of Tetronasin
S
ynthesis of the
l
C
14–C
y
28 Fragmen
s
t
of Tetron
e
a
sin Bourque,a Philip J. Kocienski,*a Michael Stocks,b Josephine Yuena
a
School of Chemistry, Leeds University, Leeds LS2 9JT, UK
AstraZeneca R & D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
Fax +44(113)3436401; E-mail: p.kocienski@chemistry.leeds.ac.uk
b
Received 5 May 2005
Dedicated to Professor Steven Ley on the occasion of his 60th birthday
O
1
4
5
Abstract: A synthesis of the C14–C28 fragment of Tetronasin fea-
tures an SE2 reaction between a cationic h3-allylmolybdenum com-
plex and and an a-metallated tetrahydrofuran.
O
OH
O
24
H
28
Keywords: p-allyl complex, molybdenum, copper, substitution
14
22
O
O
12
H
H
H
H
H
H
H
H
H
OMe
OH
Tetronasin (1)
Tetronasin (1) (ICI M139603) is an ionophore antibiotic
produced by Streptomyces longisporoflavus. It was first
isolated in 1981 and its structure determined by X-ray
crystallography.1 Tetronasin is structurally similar to
Tetronomycin (2), also isolated from a Streptomyces sp.,
but it has opposite absolute configurations at each of the
ten common stereogenic centres.2 Both compounds pos-
sess acyl tetronic acid and cyclohexyl moieties, which are
rare in the polyether ionophores, and the acyl tetronic acid
group confers preferential binding to the divalent cations
Ca2+ and Mg2+. Tetronasin has been evaluated as a growth
accelerator for cattle and as an antiparasitic agent.3,4
The first and only total syntheses of Tetronomycin5 and
Tetronasin6–8 were reported by Yoshii and co-workers in
1992 and 1993, respectively. Markworthy features of
these syntheses include: (a) a ZrCl4-catalysed insertion of
an a-diazoester into the C–H of an aldehyde to generate a
key b-keto ester intermediate required for the construction
of the tetronic acid moiety, and (b) a reductive cyclisation
that creates the cyclohexane ring with high diastereoselec-
tivity. The Ley group made conspicuous contributions to
the field in their two approaches to Tetronasin. The first
approach benefits from high convergency;9,10 the second
boasts a very elegant biomimetic cyclisation cascade
(Scheme 1, 3 → 4) whereby the tetrahydropyran and cy-
clohexyl rings and four stereogenic centres were con-
structed in a single operation.11 The latter synthesis is
more linear but it culminated in the construction of the en-
tire skeleton encompassing C5–C28. All that remains to
achieve a total synthesis is appendage of the tetronic acid,
a goal for which the requisite tools have been devel-
oped.12,13 The Semmelhack group14,15 explored Pd(II)-ca-
talysed heteroannulations for the synthesis of
Tetronomycin and the Lee group effectively exploited the
chiral pool in their synthesis of the C14–C28 fragment of
Tetronasin.16,17 We now report our synthesis of the C14–
O
4
O
OH
H
O
24
O
O
22
H
O
H
H
OMe
OH
Tetronomycin (2)
OMe
HO
H
O
OMe
O
OEt
3
86%
KHMDS, PhMe, 0 °C
OMe
H
O
H
O
O
H
OEt
H
H
H
OMe
O
4
Scheme 1
C28 fragment 5 of Tetronasin which features the nucleo-
philic addition of an a-metallated tetrahydrofuran 7 to a
cationic planar chiral h3-allylmolybdenum complex 6 as
the key step (Scheme 2).
The neutral h3-allylmolybdenum complex 14, the imme-
diate precursor to the cationic complex 6, was prepared in
15 steps from cheap, commercially available (R)-(+)-
pulegone (Scheme 3). A known18 four-step sequence in-
corporating a Favorskii rearrangement19 gave the alcohol
8 in 48% yield. Protection of the alcohol as its tert-butyl-
diphenylsilyl ether followed by ozonolysis of the alkene
gave the cyclopentanone 9 whereupon a regioselective
Baeyer–Villiger oxidation afforded the lactone 10 in 63%
yield. The route to 10 was amenable to large scale (200 g
SYNTHESIS 2005, No. 19, pp 3219–3224
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918486; Art ID: C05005SS
© Georg Thieme Verlag Stuttgart · New York

3220
E. Bourque et al.
PAPER
of the propargylic alcohol with LiAlH4 gave an unstable
trans-allylic alcohol. Selective protection of the primary
alcohol as its tert-butyldiphenylsilyl ether, followed by
benzoylation of the secondary alcohol completed the syn-
thesis of the allylic benzoate 13.
28
23
22
14
O
O
H
H
H
H
t-BuPh2SiO
OMe
C14–C28 Fragment [(23R)-5]
The neutral h3-allylmolybdenum complex 14 was synthe-
sised (Scheme 3) by heating a solution of Mo(CO)6 in
THF for 15 minutes [forming Mo(CO)4(THF)2],22 fol-
lowed by addition of the benzoate 13. After 13 hours, ad-
dition of LiCp gave the neutral complex 14 in 76% yield,
as an air-sensitive yellow oil, which was confirmed by 1H
NMR spectroscopy (a characteristic singlet at d = 4.81
ppm for the Cp ring and a triplet at d = 3.98 for the central
+
PF6
–
+
O
M
O
H
H
OC
H
H
Mo
Cp
t-BuPh2SiO
NO
OMe
7
6
Scheme 2
13
allyl proton), C NMR spectroscopy (d = 240.1 and d =
239.0 for the two carbonyls), IR spectroscopy (1936 cm–1
and 1856 cm–1 for the two carbonyls) and HRMS analysis.
of pulegone was used) and required only two purifications
over the seven steps.
The lithiated alkyne 11 was added to lactone 10 to give a
diastereoisomeric mixture of lactols which was immedi-
ately treated with BF3·OEt2–Et3SiH20,21 to afford a mix-
ture of 2,6-cis-disubstituted tetrahydropyrans owing to
partial deprotection of the silyl protecting groups; there-
fore, the crude reaction mixture was treated with TBAF to
give the diol 12 in 69% overall yield from 10. NOE data
of the diol 12 confirmed the 2,6-cis relationship; irradia-
tion of C6H gave a 10% enhancement of C2H. Reduction
The synthesis of the C23–C28 tetrahydrofuran fragment
(Scheme 4) began with
a
Sharpless asymmetric
dihydroxylation23 of ethyl (E)-hex-4-enoate (15). The lac-
tone 16 was produced in 82% yield and er = 94:6, deter-
mined by 1H NMR spectroscopic analysis of the
corresponding (S)-O-acetyl mandelate derivative. A Mit-
sunobu reaction24,25 using toluene as the solvent provided
the crystalline p-nitrobenzoate ester 17 in 70% yield.
Hydrolysis of the p-nitrobenzoate using KOH was accom-
panied by hydrolysis of the lactone ring. Restitution of the
five-membered ring lactone was problematic because
acidification returned an inseparable 4:1 mixture of the
five- and six-membered ring lactones.26 The problem was
solved when it was discovered that addition of water and
H2SO4 to a suspension of the potassium salt of the carbox-
ylic acid in THF gave exclusively the five-membered ring
lactone in 94% yield. It was immediately protected as its
tert-butyldiphenylsilyl ether 18 (77%). a-Methylation of
the lithium enolate of lactone 18 gave a 10:1 mixture of
separable diastereoisomers in 89% yield. The major crys-
talline lactone 19 was reduced with DIBAL-H and the re-
sultant lactols treated with benzenethiol and BF3·OEt2 to
give a 3:1 mixture of diastereoisomeric O,S-acetals. Re-
moval of the silyl protecting group and O-methylation
gave O,S-acetals (23R,S)-20 in 63% yield from 19. Final-
ly, reductive stannylation27–30 using lithium di-tert-
butylbiphenylide31 afforded a 3:1 mixture of stannanes
from which the major isomer (23S)-21 could be separated
with great difficulty. The stereochemistry of the stannanes
was deduced from the NOE data.32
(e) tBuPh2SiCl
(a)–(d)
(ref. 18)
48%
(f) O3
95%
tBuPh2SiO
O
HO
O
(R)-(+)-Pulegone
8
9
(g) MCPBA 63%
(h)
Li
OTBS
11
O
H
H
(i) Et3SiH, BF3·OEt2
(j) TBAF
O
O
HO
ButPh2SiO
OH
69%
12
10
(k) LiAlH4
(l) tBuPh2SiCl
(m) BzCl
41%
(n) Mo(CO)6
(o) LiCp
76%
O
O
H
H
OC
H
H
t
tBuPh2SiO
Mo
Cp
O
OBz
CO
SiPh2 Bu
14
13
Scheme 3 Reagents and conditions: (a) Br2 (1.0 equiv), HOAc, 0
°C, 45 min; (b) NaOEt (3.6 equiv), EtOH, reflux, 2 h (42%, 2 steps);
(c) KOH (1.0 equiv), EtOH–H2O, reflux, 16 h (99%); (d) LiAlH4,
Et2O, 0 °C (88%); (e) t-BuPh2SiCl (1.05 equiv), Et3N (2.10 equiv),
DMAP (0.1 equiv), CH2Cl2, r.t., 16 h (100%); (f) O3 (excess), MeOH,
–78 °C then Me2S, –78 °C to r.t., 4 h (95%), (g) MCPBA (2.5 equiv),
NaHCO3 (5.6 equiv), CH2Cl2, r.t., 4 h (63%); (h) 11 (1.0 equiv), THF,
–78 °C for 1 h, then r.t. for 1 h; (i) Et3SiH (5.25 equiv), BF3·OEt2 (5.1
equiv), MeCN, –15 °C, 15 min then r.t., 40 min; (j) TBAF (1.6 equiv),
THF, r.t., 16 h (69% from 10); (k) LiAlH4 (3.3 equiv), Et2O, 0 °C to
r.t., 2 h (80%); (l) t-BuPh2SiCl (1.05 equiv), imidazole (2.10 equiv),
CH2Cl2, r.t., 16 h (49%); (m) BzCl (1.2 equiv), DMAP (0.1 equiv),
CH2Cl2, r.t., 16 h (90%); (n) Mo(CO)6 (1.05 equiv), THF, reflux, 15
min then add 13, reflux 13 h; (o) LiCp (1.2 equiv), r.t., 1.5 h (76%
from 13).
The (23S)-stannane 21 was transmetallated first with n-
BuLi33 and then with CuBr (both at –78 °C) to give the tet-
rahydrofuran-2-ylcopper(I) (23S)-23 (Scheme 5) assum-
ing that both transmetallation steps proceed with retention
of configuration (see below). In a separate flask, the enan-
tiomerically pure neutral complex 14 was converted to a
diastereoisomeric mixture of cationic complexes 6 be-
cause the ligand exchange is not stereoselective. The
crude mixture of complexes 6 was added to the tetrahy-
drofuran-2-ylcopper(I) (23S)-23 at –78 °C. After three
hours at –78 °C, the reaction was quenched by the addi-
Synthesis 2005, No. 19, 3219–3224 © Thieme Stuttgart · New York

PAPER
Synthesis of the C14–C28 Fragment of Tetronasin
3221
(a) Sharpless AD
O
O
23
82% (319 mmol scale)
er = 94:6
H
O
O
OEt
15
Bu3Sn
O
OH
H
H
H
H
tBuPh2SiO
Mo
Cp
OMe
16
OC
CO
14
(23S)-21
(b) BuLi
(b) p-NO2C6H4CO2H
DIAD, Ph3P
70%
(a) NOPF6
–78 °C
(c) KOH; then H2SO4
+
PF6
–
O
O
O
O
23
(d) tBuPh2SiCl, imidazole
72%
H
H
t
M
O
OSiPh2 Bu
OPNB
O
H
H
H
H
OC
tBuPh2SiO
OMe
17
18
Mo
NO
(mp 136–137 °C)
6
(23S)-22 (M = Li)
(23S)-23 (M = Cu)
Cp
89%
(e) LDA; then MeI
(c) CuBr
(f) DIBAL-H
(g) PhSH, BF3•OEt2
dr = 10:1
O
(d) add 6 to 23
(e) O2
23
18%
PhS
O
O
23
(h) TBAF
(i) NaH, MeI
63%
H
H
t
O
dr = 3:1
O
OSiPh2 Bu
OMe
(23R,S)-20
H
H
H
H
tBuPh2SiO
OMe
19
(mp 95–96 °C)
(23S)-5
(j) LDBB, Bu3SnCl
86%
Scheme 5 Reagents and conditions: (a) NOPF6 (1.3 equiv), DME,
0 °C, 15 min; (b) BuLi (1.1 equiv), THF, –78 °C, 20 min; (c)
CuBr·SMe2 (1.1 equiv) in THF–(i-Pr)2S (5:2), –78 °C, 1 h; (d) 6 at
–10 °C added to the copper(I) reagent 23 at –78 °C, stir for 3 h; (e) O2,
CHCl3, r.t., 2 d (18% overall).
H
Bu3Sn
H
23
23
+
1:3
1.1%
7.8%
Bu3Sn
O
O
H
H
H
H
OMe
OMe
(23S)-21
3.5%
(23R)-21
(23R) adduct. Particularly telling were the large NOE en-
hancement of the C24H signal (9.5%) when C23H was ir-
radiated and the absence of enhancement of the C26H in
(23R)-5. By contrast, the C24H signal was enhanced by
only 1.8% when the C23H of (23S)-5 was irradiated. In
order to obtain corroborating evidence for the stereo-
chemistry of the addition, we reacted the homologous
complex 25 with a diastereoisomeric mixture of the
Scheme 4 Reagents and conditions: (a) AD-mix-b, t-BuOH–H2O
(1:1), methanesulfonamide, 0 °C, 24 h (82%); (b) DIAD (1.3 equiv),
PPh3 (1.3 equiv), p-NO2C6H4CO2H (1.3 equiv), PhMe, r.t., 16 h
(70%); (c) KOH (6.2 equiv), EtOH, 60 °C, 2 h then remove solvent
and add THF followed by H2O and concd H2SO4, r.t., 16 h (94%); (d)
t-BuPh2SiCl (1.05 equiv), imidazole (1.1 equiv), CH2Cl2, r.t., 16 h
(77%); (e) LDA (2 equiv), THF, –78 °C, 2 h then add MeI (4 equiv),
–78 °C, 2 h (89%); (f) DIBAL-H (1.1 equiv), CH2Cl2, –78 °C, 1 h; (g)
PhSH (1.3 equiv), BF3·OEt2 (2.6 equiv), CH2Cl2, –78 °C, 1 h; (h)
TBAF (2.6 equiv), THF, r.t., 16 h (73% from 19); (i) NaH (1.3 equiv),
MeI (1.2 equiv), DMF, r.t., 2 h (81%); (j) LDBB (3 equiv), THF, –78
°C, 2 min then add Bu3SnCl (3 equiv), –78 °C, 3 h (86%).
tetrahydrofuran-2-ylcopper(I)
reagents
(23R,S)-23
(Scheme 6). A separable mixture of adducts (23S)-26 and
(23R)-26 (2:1) was obtained in 20% yield. The tert-butyl-
1
diphenylsilyl protecting group was removed and the H
NMR spectroscopic data of the alcohols (23S)-27 and
(23R)-27 was compared with the 1H NMR spectrum of au-
thentic (23R)-27 kindly provided by Professor Yoshii.34
The comparison established that the minor component
(23R)-27 corresponded to the correct stereochemistry at
tion of aqueous NH4OH containing saturated NH4Cl and
the resultant crude h2-alkene complex dissolved in
CHCl3. Oxidative decomplexation was accomplished by
bubbling oxygen through the solution for two days. A sin-
1
gle major adduct was isolated in 18% yield. H and 13C
1
C22 and C23. Moreover, the H NMR data for (23R)-27
NMR spectroscopic analysis established that the addition
had proceeded with the correct regiochemistry but dis-
crepancies with the NMR spectrum of a homologue of
known stereochemistry (see below) invited suspicion that
one of the nascent stereogenic centres was wrong. Subse-
quent experiments established that the product was (23S)-
5 and not the desired (23R)-5.
and (23S)-27 were very similar in detail to the spectra re-
corded for (23R)-5 and (23S)-5.
The unexpected (S)-stereochemistry at C23 obtained from
the sequence depicted in Scheme 5 suggests that the tet-
rahydrofuranylcopper(I) reagent (23S)-23 reacted with
the molybdenum complex 6 by an SE2 mechanism with
inversion of configuration. This conclusion requires that
the two transmetallation steps (Sn to Li and Li to Cu) oc-
curred with retention of configuration. There is ample pre-
cedent. Quayle and co-workers35 showed that: (a) a-
tetrahydrofuranyl stannanes transmetallate to the lithium
species (BuLi, THF, –78 °C) with retention of configura-
tion; (b) the lithium species are configurationally stable at
–78 °C, and (c) the lithium reagents form cyanocuprates
that react with allyl bromide with retention. Murai and co-
workers36 have also shown that a-tetrahydrofuranyllithi-
Scheme 6 summarises the experiments that confirmed the
stereochemistry of the addition. Reaction of the complex
6 with a diastereoisomeric mixture of the tetrahydrofuran-
2-ylcopper(I) reagents (23R,S)-23 (R:S = 3:1) afforded a
wretched 12% yield of a separable mixture of two diaste-
reoisomeric adducts (23S)-5 and (23R)-5 (dr 3:2). The
major isomer corresponded to the compound derived from
the stannane (23S)-21 as described above. The minor iso-
mer gave NOE data more consistent with the desired
Synthesis 2005, No. 19, 3219–3224 © Thieme Stuttgart · New York

3222
E. Bourque et al.
PAPER
(c) add 6 to (2R,S)-23
(d) O2
(e) separate by SGC
+
PF6
3:2
+
24
23
24
23
–
26
26
O
O
O
O
O
12%
H
H
H
H
H
H
H
H
H
H
OC
Mo
Cp
RO
OMe
RO
OMe
RO
NO
6
t
t
(23S)-5 R = SiPh2 Bu
(23R)-5 R = SiPh2 Bu
t
R = SiPh2 Bu
(f) TBAF
(f) TBAF
54%
64%
(23S)-24 R = H
(23R)-24 R = H
(a) LDBB
(b) CuBr
NOE Data
23
23
Cu
PhS
O
Compound
C23H–C24H
C23H–C24Me
C23H–C26H
O
H
H
OMe
OMe
(23S)-5
(23R)-5
(23S)-27
(23R)-27
1.8%
9.5%
4.1%
5.9%
3.1%
1.1%
3.0%
0.0%
—
(23R,S)-23
(23R,S)-20
0.0%
4.8%
0.0%
+
PF6
2:1
24
23
24
23
–
20%
26
26
+
O
H
O
O
O
O
(c) add 25 to (2R,S)-23
(d) O2
(e) separate by SGC
H
H
H
H
H
H
H
H
H
Mo
Cp
OMe
OMe
OC
NO
RO
RO
RO
t
t
25
(23S)-26 R = SiPh2 Bu
(23R)-26 R = SiPh2 Bu
t
R = SiPh2 Bu
(f) TBAF
(f) TBAF
65%
(23S)-27 R = H
(23R)-27 R = H
Scheme 6
dried (MgSO4), filtered and concentrated in vacuo. The crude mate-
rial was purified using chromatography, eluting with Et2O–hexane–
Et3N (5:150:0.5) to give a mixture of the diastereoisomeric stan-
nanes. The mixture of stannanes was chromatographed twice to
give the less polar diastereoisomer (23S)-21 (252 mg), a mixture of
inseparable diastereoisomers (400 mg) and the enriched more polar
diastereoisomer (23R)-21 (130 mg); yield: 782 mg (1.8 mmol,
86%).
1H NMR (300 MHz, CDCl3): d = 4.36 (d, J = 4.6 Hz, JSn–H = 14.9
Hz, 1 H), 3.97 (td, J = 5.1, 7.2 Hz, 1 H), 3.40 (quint., J = 6.9 Hz, 1
H), 3.37 (s, 3 H), 2.64–2.51 (m, 1 H), 2.12 (dt, J = 7.7, 12.3 Hz, 1
H), 1.93–1.67 (m, 7 H), 1.54 (sext, J = 7.7 Hz, 6 H), 1.26 (d, J = 6.1
Hz, 3 H), 1.28–1.00 (m, 18 H).
ums add to carbonyl compounds with retention. There are
no examples of the reaction of a-metallated tetrahydro-
furans with cationic h3-allylmolybdenum complexes but
we have established that 2-tetrahydropyranylcopper(I) re-
agents generally react with retention.37
In conclusion the synthesis of the C14–C28 fragment 5 of
tetronasin reported herein exploited for the first time the
reaction of an a-metallated tetrahydrofuran with a cationic
h3-allylmolybdenum complex. The first synthesis of a cat-
ionic h3-allylmolybdenum complex flanked by a hetero-
cyclic ring has been achieved. The complex reacted at the
least hindered terminus anti to the molybdenum and there-
by controlled the nascent stereogenic centre at C22.38 Re-
giochemical complications arising from the central
chirality at molybdenum did not arise.39 However, the ex-
perimental complexity of the key step compounded by the
adverse stereochemistry at C2340 contributed to low
yields which together make the route impractical for a to-
tal synthesis.
13C NMR (75 MHz, CDCl3): d = 82.4 (CH), 80.5 (CH), 80.0 (CH),
57.2 (CH3), 39.1 (CH), 36.9 (CH2), 29.9 (JSn–C = 19.5 Hz, 3 × CH2),
28.2 (JSn–C = 52.9 Hz, 3 × CH2), 21.1 (CH3), 16.9 (CH3), 14.3 (3 ×
CH3), 10.3 (JSn–C = 302.3 Hz, 3 × CH2).
Synthesis of the Neutral Complex 14
Molybdenum hexacarbonyl (107 mg, 0.40 mmol) in THF (7.5 mL)
was heated to reflux for 15 min, then a solution of the benzoate 13
(200 mg, 0.37 mmol) in THF (3.5 mL) was added to it via syringe.
The reaction was heated to reflux for 13 h, then cooled to r.t. and a
solution of LiCp [prepared by the addition of n-BuLi (0.31 mL, 1.28
M, 0.40 mmol) to a solution of freshly cracked cyclopentadiene (40
mL, 0.48 mmol) in THF (2 mL) at 0 °C] was added to it via syringe.
The reaction mixture was stirred at r.t. for 1.5 h, then purified by fil-
tration through a column of alumina under N2 and washed with dis-
tilled Et2O. The filtrate was concentrated in vacuo to give the
neutral complex 14 as a bright yellow oil (180 mg, 0.28 mmol,
76%).
Synthesis of Stannane (23S)-21
Lithium wire (45 mg, 6.4 mmol) was added to a stirred solution of
4,4-di-tert-butylbiphenyl (2.05 g, 7.7 mmol) in THF (43 mL) at –10
°C under Ar. The reaction mixture was sonicated in an ice-bath until
a deep blue solution was observed (ca 2 min), then re-cooled to –10
°C. The reaction mixture was stirred at –10 °C for 4.5 h (until no
lithium metal could be observed) and sonicated periodically for 4
min every 30 min at 0 °C. The reaction mixture was cooled to –78
°C and a pre-cooled (–78 °C) solution of the thioether (23R,S)-20
(540 mg, 2.1 mmol) in THF (10 mL) was added dropwise. The re-
action remained dark blue indicating an excess of LiDBB. After 2
min, freshly distilled Bu3SnCl (1.75 mL, 6.4 mmol) was added
dropwise to the reaction mixture. The reaction mixture was stirred
at –78 °C for 30 min and was then quenched by the addition of sat.
NH4Cl solution (50 mL). The aqueous layer was extracted with
Et2O and the combined organic layers were washed with brine,
IR (neat): 1936 (CO), 1856 (CO) cm–1.
1H NMR (500 MHz, C6D6): d = 8.12–7.77 (m, 4 H), 7.31–7.20 (m,
6 H), 4.81 (s, 5 H), 3.98 (t, J = 9.5 Hz, 1 H), 3.88 (dd, J = 2.4, 11.2
Hz, 1 H), 3.82 (dd, J = 4.6, 11.2 Hz, 1 H), 3.34–3.28 (m, 1 H), 2.94
(ddd, J = 2.3, 4.5, 9.6 Hz, 1 H), 1.78–1.72 (m, 1 H), 1.62–1.46 (m,
5 H), 1.55 (d, J = 6.1 Hz, 3 H), 1.42 (dd, J = 5.4, 9.4 Hz, 1 H), 1.21
(s, 9 H), 0.70 (d, J = 6.4 Hz, 3 H).
Synthesis 2005, No. 19, 3219–3224 © Thieme Stuttgart · New York

PAPER
Synthesis of the C14–C28 Fragment of Tetronasin
3223
13C NMR (125 MHz, C6D6): d = 240.1 (C=O), 239.0 (C=O), 136.6–
128.0 (12 × C), 92.3 (5 × C, Cp), 85.0 (CH), 79.3 (CH), 69.7 (CH),
66.2 (CH2), 64.1 (CH), 58.7 (CH), 35.7 (CH2), 33.6 (CH2), 31.4
(CH), 27.2 (3 × CH3), 20.9 (CH3), 19.7 (C), 17.7 (CH3).
(Charnwood) for generous financial support. We also thank Profes-
sor Yoshii for NMR spectra of (23R)-27.
References
Synthesis of (23S)-5
(1) Davies, D. H.; Snape, E. W.; Suter, P. J.; King, T. J.;
Falshaw, C. P. J. Chem. Soc., Chem. Commun. 1981, 1073.
(2) Keller-Julsen, C.; King, H. D.; Kuhn, M.; Loosli, H. R.;
Pache, W.; Petcher, T. J.; Weber, H. P.; von Wartburg, A. J.
Antibiot. 1982, 35, 142.
(3) Newbold, C. J.; Wallace, R. J.; Watt, N. D.; Richardson, A.
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(4) Gates, R. N.; Roland, L. T.; Wyatt, W. E.; Hembry, F. G.;
Bailie, J. H. J. Anim. Sci. 1989, 67, 3419.
The stannane (23S)-21 was distilled twice using a kugelrohr appa-
ratus (240 °C, 0.2 mm Hg) immediately prior to use. A solution of
the stannane (23S)-21 (160 mg, 0.37 mmol) in THF (3 mL) was
cooled to –78 °C and n-BuLi (0.40 mL, 1.1 M, 0.44 mmol) was add-
ed dropwise. After 20 min, a solution of CuBr·SMe2 (91 mg, 0.44
mmol) in a mixture of THF (1.0 mL) and (i-Pr)2S (0.4 mL) was add-
ed dropwise and the reaction was stirred at –78 °C for 1 h. To a so-
lution of the neutral complex 14 (176 mg, 0.28 mmol) in freshly
distilled 1,2-dimethoxyethane (3 mL) was added NOPF6 (64 mg,
0.36 mmol) at 0 °C. After stirring the reaction at 0 °C for 15 min,
the reaction was cooled to –10 °C and then added dropwise via can-
nula to the solution of organocopper (23S)-23. The reaction was
stirred at –78 °C for 3 h and then quenched by the addition of
NH4OH–sat. NH4Cl solution (10 mL/10 mL). The reaction was di-
luted with Et2O (20 mL) then stirred for 30 min before extraction of
the aqueous layer with Et2O. The combined organic layers were
washed with brine, dried (MgSO4), filtered and concentrated in vac-
uo. The residue was dissolved in CHCl3 (10 mL) and oxygen was
bubbled through the solution for 2 d. The solvent was removed in
vacuo and the residue was purified using chromatography, eluting
with Et2O–hexane (1:10) to give (23S)-5 as a colourless oil (28 mg,
0.049 mmol, 18%); [a]D –38.2 (c = 0.65, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.78–7.70 (m, 4 H), 7.44–7.35 (m,
6 H), 5.68 (ddd, J = 0.9, 8.1, 15.8 Hz, 1 H), 5.55 (dd, J = 5.6, 15.8
Hz, 1 H), 3.86–3.74 (m, 4 H), 3.38 (s, 3 H), 3.30–3.21 (m, 2 H), 3.05
(ddd, J = 2.6, 4.3, 9.8 Hz, 1 H), 2.27 (app. sext, J = 6.8 Hz, 1 H),
2.08–2.00 (m, 1 H), 1.95 (ddd, J = 6.8, 8.6, 12.4 Hz, 1 H), 1.80 (dq,
J = 3.9, 12.8 Hz, 1 H), 1.70–1.60 (m, 2 H), 1.54 (ddd, J = 6.0, 7.3,
12.8 Hz, 1 H), 1.45–1.34 (m, 1 H), 1.29–1.17 (m, 1 H), 1.16 (d, J =
6.4 Hz, 3 H), 1.08 (d, J = 6.4 Hz, 3 H), 1.06 (s, 9 H), 0.99 (d, J = 6.8
Hz, 3 H), 0.82 (d, J = 6.4 Hz, 3 H).
(5) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.;
Yoshii, E. J. Org. Chem. 1992, 57, 2888.
(6) Hori, K.; Kazuno, H.; Nomura, K.; Yoshii, E. Tetrahedron
Lett. 1993, 34, 2183.
(7) Hori, K.; Mori, S.; Nomura, K.; Inagaki, A.; Yoshii, E.
Chem. Pharm. Bull. 1990, 38, 1784.
(8) Hori, K.; Nomura, K.; Kazuno, H.; Yoshii, E. Chem. Pharm.
Bull. 1990, 38, 1778.
(9) Ley, S. V.; Clase, J. A.; Mansfield, D. J.; Osborn, H. M. I. J.
Heterocycl. Chem. 1996, 33, 1533.
(10) De Laszlo, S. E.; Ford, M. J.; Ley, S. V.; Maw, G. N.
Tetrahedron Lett. 1990, 31, 5525.
(11) Ley, S. V.; Brown, D. S.; Clase, J. A.; Fairbanks, A. J.;
Lennon, I. C.; Osborn, H. M. I.; Stokes, E. S. E.; Wadsworth,
D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2259.
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1991, 47, 8285.
(14) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M.
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7455.
(16) Lee, H. W.; Lee, I. Y. C.; Kim, S. K. Tetrahedron Lett. 1990,
31, 7637.
13C NMR (125 MHz, CDCl3): d = 135.8, 135.7, 134.1, 134.0, 129.4,
127.5 (12 × C), 132.9 (CH), 131.5 (CH), 90.0 (CH), 84.1 (CH), 80.8
(CH), 79.1 (CH), 77.8 (CH), 65.6 (CH2), 57.1 (CH3), 41.3 (CH),
36.1 (CH2), 35.4 (CH), 32.8 (CH2), 32.5 (CH2), 31.3 (CH), 26.8 (3
× CH3), 19.4 (C), 19.1 (CH3), 17.6 (CH3), 16.5 (CH3), 15.8 (CH3).
(17) Lee, H. W.; Lee, I. Y. C. Synlett 1991, 871.
(18) Hill, R. K.; Foley, P. J.; Gardella, L. A. J. Org. Chem. 1967,
32, 2330.
(19) Wolinsky, J.; Chan, D. J. Org. Chem. 1965, 30, 41.
(20) Kraus, G. A.; Molina, M. T. J. Org. Chem. 1988, 53, 752.
(21) Kraus, G. A.; Frazier, K. A.; Roth, B. D.; Taschner, M. J.;
Neuenschwander, K. J. Org. Chem. 1981, 46, 2417.
(22) Cooksey, J.; Gunn, A.; Kocienski, P. J.; Kuhl, A.; Uppal, S.;
Christopher, J. A.; Bell, R. Org. Biomol. Chem. 2004, 2,
1719.
(23) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
(24) Mitsunobu, O. Synthesis 1981, 1.
(25) Hughes, D. L. Org. React. (N.Y.) 1992, 42, 335.
(26) The five- and six-membered lactones were easily
distinguished by their characteristic 13C NMR signals for the
C=O groups at d = 178.1 and 171.2, respectively.
(27) Cohen, T.; Lin, M.-T. J. Am. Chem. Soc. 1984, 106, 1130.
(28) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
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Lett. 1994, 35, 6799.
Spectroscopic Data for (23R)-5
[a]D –53.3 (c = 0.15, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.78–7.70 (m, 4 H), 7.45–7.35 (m,
6 H), 5.83 (ddd, J = 1.3, 6.8, 16.2 Hz, 1 H), 5.60 (ddd, J = 0.9, 5.6,
15.8 Hz, 1 H), 3.96 (ddd, J = 5.1, 6.8, 8.6 Hz, 1 H), 3.86–3.75 (m, 3
H), 3.55 (dd, J = 3.8, 9.0 Hz, 1 H), 3.36 (s, 3 H), 3.33 (qd, J = 1.3,
5.1 Hz, 1 H), 3.05 (ddd, J = 2.6, 4.3, 9.4 Hz, 1 H), 2.31–2.24 (m, 2
H), 1.97 (ddd, J = 6.4, 8.5, 12.4 Hz, 1 H), 1.78 (dq, J = 3.0, 12.8 Hz,
1 H), 1.68 (ddd, J = 1.7, 6.8, 12.4 Hz, 1 H), 1.66–1.60 (m, 2 H),
1.44–1.36 (m, 1 H), 1.26–1.18 (m, 1 H), 1.09 (d, J = 6.4 Hz, 3 H),
1.06 (s, 9 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 7.3 Hz, 3 H),
0.81 (d, J = 6.8 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 135.8, 135.7, 129.4, 127.5, 127.4
(12 × C, Ph), 134.0 (CH), 130.3 (CH), 85.9 (CH), 84.0 (CH), 80.2
(CH), 79.5 (CH), 78.0 (CH), 65.7 (CH2), 57.4 (CH3), 36.7 (CH),
35.3 (CH, CH2), 32.8 (CH2), 32.3 (CH2), 31.3 (CH), 26.8 (3 × CH3),
19.3 (C), 17.6 (CH3), 16.6 (CH3), 16.0 (CH3), 13.6 (CH3).
(30) Christopher, J. A.; Kocienski, P.; Procter, M. Synlett 1998,
425.
Acknowledgment
(31) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924.
We would like to thank the Engineering and Physical Sciences Re-
search Council, FCAR (Quebec), and AstraZeneca Pharmaceuticals
Synthesis 2005, No. 19, 3219–3224 © Thieme Stuttgart · New York

3224
E. Bourque et al.
PAPER
(32) A pure sample of (23R)-21 could not be obtained; therefore
the NOE data was recorded on a mixture enriched in (23R)-
21.
(37) Kocienski, P. J.; Bell, R.; Bourque, E.; Christopher, J. A.;
Cooksey, J.; Gunn, A.; Kuhl, A.; Li, Y.; Uppal, S.; Yuen, J.
Pure Appl. Chem. 2004, 76, 477.
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Chem. 1990, 383, 161.
(40) Loss of stereochemical integrity has been observed in the
conjugate addition of chiral a-alkoxyalkylcuprates to enones
and propiolate esters: Linderman, R. J.; Griedel, B. D. J.
Org. Chem. 1990, 55, 5428.
(33) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGarvey,
G. J. J. Am. Chem. Soc. 1988, 110, 842.
(34) Compound (23R)-27 is an intermediate in the Yoshii
synthesis of Tetronomycin (see ref. 5).
(35) Zhao, Y.; Beddoes, R. L.; Quayle, P. Tetrahedron Lett.
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(36) Amano, S.; Fujiwara, K.; Murai, A. Chem. Lett. 1998, 409.
Synthesis 2005, No. 19, 3219–3224 © Thieme Stuttgart · New York