The biomimetic synthesis of SNF4435C and SNF4435D, and the total synthesis of the polyene metabolites aureothin, N-acetyl-aureothamine and spectinabilin

Article abstract of DOI:10.1016/j.tet.2005.11.058

Full details of the biomimetic conversion of polyene metabolite spectinabilin (5) into the isomeric natural products SNF4435C (1) and SNF4435D (2) by a cascade of E/Z-isomerizations and electrocyclizations are reported. Additionally, short total syntheses

Full text of DOI:10.1016/j.tet.2005.11.058

Tetrahedron 62 (2006) 1675–1689
The biomimetic synthesis of SNF4435C and SNF4435D,
and the total synthesis of the polyene metabolites aureothin,
N-acetyl-aureothamine and spectinabilin
*
Mikkel F. Jacobsen, John E. Moses, Robert M. Adlington and Jack E. Baldwin
Chemistry Research Laboratory, University of Oxford, Mansfield road, Oxford, OX1 3TA, United Kingdom
Received 19 October 2005; accepted 24 November 2005
Available online 20 December 2005
Abstract—Full details of the biomimetic conversion of polyene metabolite spectinabilin (5) into the isomeric natural products SNF4435C
(1) and SNF4435D (2) by a cascade of E/Z-isomerizations and electrocyclizations are reported. Additionally, short total syntheses of the
related natural products (G)-aureothin (3), (G)-N-acetyl-aureothamine (4) and (G)-spectinabilin (5) are presented. The key steps in
the synthesis of (G)-3, (G)-4 and (G)-5 are the construction of the tetrahydrofuran motif using a palladium-catalyzed cycloaddition and the
ruthenium-catalyzed cross metathesis of alkene 17 to form the common intermediate, boronic ester 24, which was further transformed using a
trans-selective Suzuki coupling with a dibromide and a stereospecific Negishi-type methylation.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cytotoxicity and antibacterial effects, but also possess
structurally interesting and complex motifs. Our continued
interest in polypropionate natural products and biomimetic
synthesis motivated us to consider the recently isolated
nitrophenyl pyrones SNF4435C (1) and SNF4435D (2)
reported by Snow Brand Milk Products Co., Ltd, Japan as
targets for synthesis (Fig. 1).1–3
In recent years, a plethora of polypropionates metabolites
have been isolated from various terrestrial and marine
systems as phylogenetically diverse as bacteria and sponges.
Several of these compounds not only feature interesting
biological activities, including immunosuppression,
O
O
O2N
O2N
O
O
6
6
O
O
H
H
O
O
SNF4435C (1)
SNF4435D (2)
O
O
9
11
15
10
14
8
6
6
O
O
O
O
O
O
R
O2N
Spectinabilin (5)
Aureothin (R = NO2) (3)
N-Acetyl-aureothamine (R = NHCOMe) (4)
Figure 1. Metabolites from Streptomyces.
Keywords: Metabolite; Total synthesis; Metathesis; C–C coupling reaction; Biomimetic synthesis; Electrocyclization; Isomerization.
*
Corresponding author. Tel.: C44 865 275 671; fax: C44 865 275 6732; e-mail: jack.baldwin@chem.ox.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.058

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M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
Biologically, the SNF compounds are potent immunosup-
pressants, exhibiting activities at submicromolar concen-
trations, isolated from a strain of Streptomyces spectabilis
found in a soil sample collected on the main island of
Okinawa, Japan. Structurally, the SNF compounds are
pentacyclic structures featuring a rare hexasubstituted
bicyclo[4.2.0] core connected to a spirofuran unit, which
in turn is linked to a g-pyrone moiety. The tetrahydrofuran
ring-substituted g-pyrone motif is also found in the related
polyenes aureothin (3) (Streptomyces thioluteu),4,5
N-acetyl-aureothamine (4) (Streptomyces netropsis)6 and
spectinabilin (5) (S. spectabilis).7–9 N-Acetyl-aureothamine
(4) has been shown to be a highly selective agent against
Helicobacter pylori, a common cause of chronic gastritis.6
Recently, studies on the biosynthesis of 3 have revealed that
two novel oxygenases are involved.10,11 An N-oxygenase
catalyzes the oxidation of p-aminobenzoate to the corres-
ponding nitro compound, which serves as starter unit for the
polyketide synthase (PKS) resulting in 3.10 Secondly, a
cytochrome P450 monooxygenase catalyzes the formation
of the exomethylene tetrahydrofuran ring.11 The biosyn-
thesis of 5 is likely to proceed in a similar manner.12
E/Z-isomerizations and electrocyclisations. Firstly, the
(E,E,E,Z)-configuration of 5 could be changed to (E,Z,Z,Z)
via double E to Z isomerization. Secondly, the transformed
(E,Z,Z,Z)-isomer of 5 could undergo a thermally allowed
conrotatory 8p-electrocyclization with some bias towards 6
versus 7 via 1,3-asymmetric induction from the C6-
stereocenter, followed by an endo-selective disrotatory
6p-electrocyclization to form 1 and 2 (Scheme 1).
The transition structures 8 and 9 may possess a
helical geometry in accord with studies of conrotatory
8p-electrocyclizations using ab initio molecular orbital
theory.20
In the course of this work, Parker and co-workers have
synthesized (K)-1 and (C)-2, both of approximately 70%
ee, by forming the (E,Z,Z,Z)-isomer in situ via a Stille
coupling.16 Similarly (K)-aureothin (3) of 27% ee has
previously been synthesized,21 but the approach employed
lacked efficiency (0.01% overall yield) and we believed that
it would not be compatible with the more complex tetraene
5. In order to achieve the synthesis of tetraene 5, we initially
chose the simpler dienes 3 and 4 as model systems.22 It is
reported that both 321 and 59 are prone to racemization even
under mild conditions due to the labile C6-proton.
Accordingly, any intermediate bearing similar allylic
proton(s) in the g-position to the ketone of a g-pyrone
motif may suffer from such racemization/epimerization.
Therefore, we chose instead to devise novel synthesis
of (G)-3, (G)-4 and (G)-5. We have previously communi-
cated our main findings in these synthetic endeavors and in
the biomimetic conversion of 5 to 1 and 2.14,22 We now
report full details of these studies.
It is apparent that spectinabilin (5) is a constitutional isomer
of 1 and 2. Interestingly, it has been isolated from the same
actinomycete producing the SNF compounds.3 These
observation have led us13,14 and others15,16 to propose a
biogenetic hypothesis for the transformation of 5 into 1
and 2,17 resembling Black’s hypothesis for the formation of
the endiandric acids,18 which has been experimentally
corroborated by the work of Nicolaou.19 We envisaged
that 1 and 2 could be formed from 5 via a cascade of
5
2x double-bond
isomerization
Ar
H
H
O
6
Pyr
O
H
H
Ar
6
8
9
(E,Z,Z,Z)
Pyr
8 -conrotatory
electrocyclization
Pyr
H
H
H
Pyr
O
Ar
H
Ar
6
7
O
O
O
Pyr =
endo-selective
6 -disrotatory electrocyclization
O
1
2
Ar = p-NO2-Ph
Scheme 1. Biogenetic hypothesis for the formation of 1 and 2 from 5.

M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
1677
R
12
Regioselective
Hydroboration
O
O
9
B(OR)2
R
+
R
I
10
O
O
O
O
O
O
10
Cross
11
metathesis
Suzuki coupling
(±)-3, (±)-4 and (±)-5
Trost [3+2] cycloaddition
O
O
O
O
O
O
O
14
13
Scheme 2. First retrosynthesis of (G)-3, (G)-4 and (G)-5.
2. Results and discussion
metathesis (CM) and iodination should furnish 11. Our
synthesis of 11 started from ethyl pyrone 14, which
was converted to the phenylselenyl compound 15, and
oxidation–elimination of 15 yielded the unstable alkene 16
(Scheme 3). 16 was subjected to the Lemieux–Johnson
protocol24 to afford aldehyde 13 in excellent overall yield
(63% from 14). This route to 13 is a considerable
improvement compared to the previously reported route.23
We were pleased to find that aldehyde 13 reacted smoothly
with the palladium-bound trimethylenemethane complex
generated from 2-[(tributylstannyl)methyl]-2-propen-1-yl
acetate and Pd(OAc)2/PPh3 to afford the alkene 17 in 88%
2.1. Synthesis of key boronic ester 24 and initial synthetic
studies towards (G)-3, (G)-4 and (G)-5
Our initial retrosynthetic analysis of the polyenes 3–5
revealed that the C9–C10 double bond may be formed from
the Suzuki coupling of boronic ester 10 with the advanced
intermediate, alkenyl iodide 11 (Scheme 2). The former
would be formed by regioselective hydroboration of alkyne
12. We believed that subjection of known aldehyde 1321,23
to a sequence of Trost [3C2] cycloaddition, cross
b)
c)
a)
Pyr
Pyr
PhSe
Pyr
Pyr
82%
O
13
14
15
16
77% from 15
d)
TMS
OAc
92%
18
O
O
Pyr
or
B
O
O
O
19
e)
23
f)
Pyr
(±)-17
O
R
O
O
Mes
N
N
Mes
Ph
21: R =
: 65%, 1:1.2 E/Z
Cl
Ru
g)
h)
Cl
PCy3
22: R = CHO
: 99%, 1:1.2 E/Z
: 98%, 1:1.2 E/Z
20
O
O
O
24: R =
B
Pyr =
O
O
11: R = I
: 47%, 1:1.2 E/Z
Scheme 3. Synthesis of tetrahydrofuran fragments 11 and 24. (a) KHMDS, PhSeBr, THF, K78 8C/rt; (b) NaIO4, cat. NaHCO3, aq MeOH, rt; (c) cat. OsO4,
NaIO4, aq THF, rt; (d) 18, 5 mol% Pd(PPh3)4, 10 mol% In(acac)3, PhMe, reflux; (e) 19 (3.0 equiv), 5 mol% 20, CH2Cl2, reflux; (f) 23 (2.0 equiv), 5 mol% 20,
CH2Cl2, reflux; (g) PTSA, acetone–H2O, rt; (h) I2, aq NaOH, THF, rt.

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M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
a) (71%)
or b) (18%)
or (c) (0%)
d)
O
86%
O
P
O
O2N
O2N
O2N
27
25
28
MeO
Complex
MeO
e), f) or g)
X mixtures
29
N2
R
B
R
B
e)
R
R
X
Complex
mixture
O2N
O2N
O2N
26
Scheme 4. Synthesis of alkyne 25 and attempted hydroborations of 25 and 26. (a) TMSCHN2, LHMDS, THF, K78 8C; (b) Ph3PCHBrCBrK, KOtBu, THF,
K78 8C; (c) 29, K2CO3, MeOH, rt; (d) LHMDS, MeI, rt; (e) catecholborane, neat, 70 8C; (f) 9-BBN; (g) pinacolborane.
yield.25 A minor improvement in yield (93%) was observed
by employing the silyl acetate 18 instead and In(acac)3 as
co-catalyst.26 Pleasingly, the sequence 14/17 can be
performed without column chromatography; simple crystal-
lizations of the crude products from CH2Cl2-pentanes is
sufficient.
Instead, we decided to evaluate a modified Julia coupling of
sulfone 30 with (G)-aureonone 31 for the disconnection of
the C8–C9 double bond in (G)-3, (G)-4 and (G)-5
(Scheme 5). The known alcohol 32 reacted with MsCl and
Et3N to afford a mesylate 33, which was then efficiently
converted to sulfone 34 [substitution of 33 with the sodium
anion of 2-mercaptobenzothiazole to the yield a sulfide 35,
followed by ammonium molybdate-mediated oxidation to
34].33 (G)-Aureonone 31 was easily obtained from alkene
(G)-17 by oxidative cleavage with OsO4/NaIO4, and the
spectral data (IR, 1H and 13C NMR) were in excellent
agreement with those previously reported.21 Unfortunately,
treatment of the lithium anion of sulfone 34 with aureonone
31 did not provide detectable amounts of 3 and/or 3a
presumably due to the stability of the anion of 34. We
were therefore impelled to consider alternative pathways to
(G)-3, (G)-4 and (G)-5 (Scheme 6).
The recent report of 1,1-disubstituted alkenes as excellent
substrate for CM with alkenyl boronic esters led us to
attempt such transformations with 17.27 Initially, we
attempted the CM with 19 and catalyst 20. In our hands,
this led to a good yield of acetal 21 provided that 19 was
added slowly to the reaction mixture to suppress homo-
dimerisation of itself. Treatment of acetal 21 with PTSA
smoothly furnished 22, a potentially useful building block.
On the other hand, boronic ester 23 reacted with 17 without
the need for slow addition and furnished 24 in almost
quantitative yield, albeit with low E/Z-selectivity.28 The
stereochemistry of (E)-24 and (Z)-24 was confirmed by
NOE experiments. 24 could easily be converted to the
required iodides 11 in 47% yield (14% recovered 24) with
retention of the E/Z ratio (1:1.2 E/Z) upon treatment with I2
and NaOH in aq THF.27a
2.2. Completion of the synthesis of (G)-aureothin (3),
(G)-N-acetyl-aureothamine (4) and (G)-spectinabilin (5)
Since we had already established an efficient route to 24, the
use of it in a trans-selective Suzuki coupling with a
dibromide 36 to form the C9–C10 double bond followed by
a Negishi-type methylation seemed an attractive approach
to (G)-3, (G)-4 and (G)-5 (Scheme 7). Therefore, the
Suzuki coupling of 24 and 3734 was examined under the
influence of various bases (Scheme 8 and Table 1). While
NaOH afforded exclusively the dehydrohalogenated
product, alkyne 38 (entry 1), Tl2CO3 gave rise to a mixture
of products, 38, 39 and 40 (entry 2). Gratifyingly, the use of
TlOEt afforded (E)-40 and (Z)-40 as a separable mixture of
isomers (1:1.2 E/Z) in 72% yield (entry 3).35 The
stereochemistry of the C9–C10 double-bond of (Z)-40,
Next, we turned our attention towards the hydroboration of
the alkynes 25 and 2629 (Scheme 4). Initially, alkyne 27 was
synthesized by reacting known aldehyde 28 with the lithium
anion of TMSCHN2.30 The use of a Wittig dehalogenation
procedure instead furnished a lower yield (18%) of 27,31
while employing the Ohira reagent 2932 only led to the
decomposition of 28. Subsequently, facile methylation of 27
provided 25. To our disappointment, the hydroboration of
either 25 or 26 under a variety of conditions proved fruitless,
as this only led to intractable tarry product mixtures.
O
O
9
X
R
SO2Ar
+
R
8
O
O
O
OMe
30
O
O
Oxidative cleavage
17, X = CH2
31, X = O
Julia coupling
(±)-3, (±)-4 and (±)-5
Trost [3+2] cycloaddition
Scheme 5. Second retrosynthesis of (G)-3, (G)-4 and (G)-5.

M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
1679
N
S
a)-c)
OH
S
O
O
72%
(three steps)
O2N
O2N
32
34
NO2
O
O
O
O
(±)-3a
8
9
e)
d)
82%
O
(±)-17
X
O
No reaction
O
O
+
O
(±)-31
9
8
O
O
O
O2N
(±)-3
Scheme 6. Synthesis of Julia–Kocienski fragment 34 and (G)-aureonone 31, and attempted Julia–Kocienski coupling to form (G)-3 and/or (G)-3a. (a) MsCl,
Et3N, CH2Cl2, K10/K15 8C; (b) 2-mercaptobenzothiazole, NaH, DMF, 0 8C/rt; (c) (NH4)6Mo7O24$4H2O, H2O2, EtOH:THF, 0 8C/rt; (d) OsO4, NaIO4,
aq THF, rt; (e) LHMDS, 34, THF, K78 8C/rt.
Suzuki coupling
O
O
O
9
10
Br
O
R
+
B
R
OMe
O
O
Br
36
O
O
O
24
Negishi-type
methylation
(±)-3, (±)-4 and (±)-5
Scheme 7. Third retrosynthesis of (G)-3, (G)-4 and (G)-5.
base,
10 mol % Pd(PPh3)4,
aq. THF, rt
Br
Pyr
+
O
Br
O
B
O2N
O
24
37
Pyr
O
Pyr
Pyr
+
+
Ar
Ar
O
O
Ar
38
39
O
O
nOe
Ar
Br
Pyr =
Pyr
O
Pyr
Br
(Z)-40
Scheme 8. Influence of base on Suzuki coupling of 24 with 37 (see Table 1).
O
O
(E)-40
Ar = p-NO2-Ph

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M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
Table 1. Influence of base on the Suzuki coupling of 24 with 37 (see
Scheme 8)a,b,c
64%, which could be separated by silica gel chromato-
graphy. The light sensitive (Z)-43 reacted smoothly with
Me2Zn under palladium catalysis to yield (G)-spectinabilin
(5) in 89% yield, while (E)-43 was converted to 5a, the
Entry
Base (equiv)
NaOH (1.5)
Tl2CO3 (1.5) 20
TlOEt (1.8)
Yield 38 (%) Yield 39 (%) Yield 40 (%)
1
2
3
70
—
20
—
—
20
72
1
(E,E,E,E)-isomer of 5. (G)-5 exhibited identical H NMR
spectra to that of an authentic sample, and the spectral
data (1H, 13C NMR and IR) were in excellent agreement
with those previously reported.7 The previously tentative
assignment7 of the (E,E,E,Z)-geometry to 5 was confirmed
by 1D NOE experiments.
—
1
a The ratio of 38, 39 and 40 was determined by H NMR analysis of the
crude product.
b Compounds 38 and 40 were obtained as 1:1.2 E/Z mixtures of isomers.
c Compound 39 was obtained as a mixture of isomers.
was confirmed by a NOESY experiment. The precursor
(Z)-40 of (G)-aureothin (3) was methylated under the
recently reported Negishi-type conditions (cat. Pd(tBu3P),
Me2Zn) to afford (G)-3 in excellent yield with complete
retention of stereochemistry (Scheme 9).36 (G)-3
was subjected to Zn-mediated reduction under aqueous
conditions to furnish pure (G)-aureothamine (41) in
high yield,4 which was then acetylated to afford the
antibiotic (G)-N-acetyl-aureothamine (4).6 The spectral
data for (G)-321 and (G)-46 (IR, 1H and 13C NMR) were in
excellent agreement with those previously reported.
2.3. The biomimetic conversion of (G)-5 to (G)-1
and (G)-2
Since we were not aware of the specific conditions by which
Nature might convert 5 to 1 and 2, we examined three types
of reaction conditions in attempts to affect the required E/Z
isomerizations and initiate the cascade of electrocycli-
zations in vitro: light, heat and a Pd(II) source.
During initial exposure of 5 to sunlight in solution, it
underwent E to Z isomerization of the C14–C15 double
bond as observed by 1H NMR. The same is true for the C10–
C11 double bond in aureothin (3). Unfortunately, prolonged
exposure of (G)-5 in solution to sunlight resulted ultimately
in very complex product mixtures in which neither 1 nor 2
In a similar manner boronic ester 24 was subjected to Suzuki
coupling with dibromide 42 (made from aldehyde 2837) to
afford the isomers (E)-43 and (Z)-43 in a combined yield of
a)
Pyr
Pyr
95%
Br
O
O
O2N
O2N
(Z)-40
(±)-3
99%
b)
O
O
Pyr
O
Pyr =
R
O
41, R = NH2
c)
77%
(±)-4, R = NHCOMe
d)
a)
O
24
(±)-5a
Br
89%
O2N
(E)-43
29%
Pyr
+
a)
Pyr
(±)-5
Br
89%
O
O2N
(Z)-43
35%
Br
e)
O
Br
98%
O2N
O2N
28
42
Scheme 9. Completion of the total synthesis of (G)-3, (G)-4 and (G)-5. (a) Me2Zn, 2 mol% Pd(tBu3P)2, THF, rt; (b) Zn, NH4Cl, aq acetone, rt; (c) AcCl,
pyridine, CH2Cl2, 0 8C; (d) 42, 10 mol% Pd(PPh3)4, TlOEt, aq THF, rt; (e) CBr4, Zn, PPh3, pyridine, CH2Cl2, rt.

M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
1681
Table 2. Synthesis of (G)-SNF4435C (1), (G)-SNF4435D (2) and isomers 48 and 49 from (G)-5 and (G)-5aa,b
O
O
O
O
Pyr
+
Pyr
+
Pyr
Pyr
+
Ar
Ar
Ar
Ar
(±)-5 or (±)-5a
1
49
2
48
Entry
Substrate
PdCl2(MeCN)2
(Mol%)
Temperature (8C)
Ratio/1:2:48:49c
Yield (%)
1
2
3
4
5
6
7
5
5
5
5
5
5
5a
0
25
25
25
25
100
25
70
20
70
50
110
70
70
3.6:1.0:0:0
23
4.5:1.0:4.5:1.7
2.8:1.1:2.1:1.0
3.9:1.0:2.8:1.2
2.9:1.0:2.0:1.1
nd
!5d
40
nd
nd
w0
31
2.0:1.0:5.7:3.0
a Reactions were performed in DMF in the dark.
b nd, not determined.
1
c Ratio of 1, 2, 48 and 49 was determined from analysis of H NMR spectra of crude product.
1
d Estimated from analysis of H NMR spectra of crude product.
could be detected by 1H NMR. On the other hand, heating a
solution of (G)-5 in DMF at 70 8C for 3 days resulted in
23% of (G)-1 and (G)-2 as a 3.6:1 mixture after extensive
purification by preparative TLC (Table 2, entry 1).
Interestingly, the related tetraene 44 having an electron-
withdrawing ester group behaved differently (Scheme 10).
The crispatene core structure 45 was produced when 44 was
subjected to light, while heat afforded the tricyclic structure
46 in high yield (Scheme 10).37,38
5 was subjected to the standard conditions at rt only small
amounts of 1 and 2 could be detected, suggesting that the
E/Z-isomerizations were too slow at this temperature (entry
2). By varying both the catalyst loading and temperature, we
found the best conditions to involve heating a solution of 5
in DMF with 25 mol% PdCl2(MeCN)2 at 70 8C for 1 day in
the dark (entry 3). This afforded 22% of (G)-SNF4435C (1)
and (G)-SNF4435D (2) in a slightly different ratio of 2.5:1
compared to that resulting from heating alone (entry 1 vs 3).
Surprisingly, 18% of two unexpected isomers 48 and 49
could also be isolated in a 2.1:1 ratio from the reaction
mixture. Apparently, their formation is intrinsically related
to the use of the Pd(II) source, as neither 48 nor 49 could be
detected by heating alone. Lower temperatures led to a more
complex reaction mixture (entry 4), whereas elevated
temperatures or higher catalyst loading led to increased
decomposition (entries 5 and 6). Also, the individual ratios
1:2 and 48:49 decreased with increasing temperature, while
the overall ratio of 1 and 2 to 48 and 49 remained nearly
constant (entries 2–4). Interestingly, the ratios of 1 and 2
are close throughout to that found in Nature (2.3:1),2a
thus supporting our biogenetic hypothesis for their
formation. The 1,3-diastereoselection induced from the
C6-stereocenter in the 8p-electrocyclization step is almost
of the same magnitude for 48 and 49 compared to 1 and 2,
resulting in roughly equal ratios 1:2 and 48:49.
Ar
E
H
47
PdCl2(MeCN)2, 48%
E
Ar
44
∆ ,95%
hν, 60%
E = CO2Et
Ar = p-NO2-Ph
E
E
Ar
The formation of 48 and 49 is consistent with the 8p/6p-
electrocyclization cascade of either of the (Z,Z,Z,Z)- and
(E,Z,Z,E)-isomers, 5b and 5c (Scheme 11). We have not
observed this ‘over-isomerization’ previously with similar
tetraenes, for example, 44.13,37 X-ray structures have
indicated a lack of planarity of the polyene backbone of
structures similar to 5, for example, 44, presumably due to
1,3-steric interactions between the methyl groups.37 Firstly,
such interactions for the reactive (E,Z,Z,Z)-isomer of 5 may
be partly relieved in conformations like 8 and 9 thus
facilitating the subsequent cascade of electrocyclizations
(Scheme 1). Secondly, it should lead to a decrease in the
H
H
H
Ar
45
46
Scheme 10. Cascade electrocyclization pathways of tetraene ester 44.
Previous results in our group have demonstrated that the
bicyclo[4.2.0]octadiene core of 1 and 2 can be obtained
from (E,E,E,E)-tetraenes by employing a palladium(II)
source (PdCl2(MeCN)2) for the requisite E to Z isomeri-
zation, that is, (E,E,E,E) to (E,Z,Z,E), exemplified by the
conversion of 44 to 47 in 48% yield.13,37,38 However, when

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M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
(±)-5
3x double-bond
isomerization
PdCl2(MeCN)2
15
14
Ar
Ar
9
8
15
or
14
9
8
O
Pyr
5b
(Z,Z,Z,Z)
5c
(E,Z,Z,E)
Pyr
O
8 -conrotatory
electrocyclization
O
H
H
Ar O
H
Ar
Pyr
O
O
H
Pyr
Pyr =
endo-selective
6 -disrotatory electrocyclization
O
48
49
Ar = p-NO2-Ph
Scheme 11. Mechanistic rationale for the formation of isomers 48 and 49.
conjugation of the C8–C9 double bond with the electron
deficient p-nitrophenyl ring. The more electron-rich C8–C9
double bond is expected to be more prone to isomerizations
with the cationic palladium moiety versus the C14–C15
double bond.39 Hence, we favor that 48 and 49 may be
formed predominately via the (E,Z,Z,E)-isomer 5c. In
support of this was the observation that subjection of the
(E,E,E,E)-isomer 5a to the Pd(II) conditions provided 23%
of a 1.9:1 mixture of 48 and 49 and minor amounts of 1 and
2 (8%) (entry 7).
4. Experimental
4.1. General experimental
Unless otherwise stated, all reactions were carried out under
nitrogen. Tetrahydrofuran (THF) and dichloromethane
(CH2Cl2) were dried by passing through activated alumina
˚
columns. N,N-dimethylformamide (DMF) was dried over 3 A
molecular sieves. Pentanes of bp 30–40 8C were used
exclusively. All reagents were purchased at the highest
commercial quality and used without further purification.
NMR spectra were recorded at 200, 400 or 500 MHz
(1H NMR), and calibrated to the residual solvent peak. The
following abbreviations are used for NMR data: s, singlet;
d, doublet; t, triplet; qn, quintet; m, multiplet; br, broad; app,
apparent. Coupling constants are rounded to nearest 0.5 Hz.
The following abbreviations are used for IR data: s, strong; m,
medium; w, weak; br, broad. Room temperature (rt) is 22 8C.
Column chromatography was carried out using Sorbsil C60
(40–63 mm, 230–240 mesh) silica gel. Preparative thin-layer
chromatography was performed on Whatman precoated silica
gel 60F-254 glass-supported plates with 1.0 mm thickness.
Reactions were monitored by thin-layer chromatography
(TLC) analysis. Spots were visualized by exposure to
ultraviolet (UV) light (254 nm), or by staining with a 5%
solution of phosphomolybdenic acid (PMA) in ethanol or
basic aq potassium permangante (KMnO4) and then heating.
Crystallization solvents are in parenthesis. Melting points are
uncorrected. All compounds synthesized were determined to
3. Conclusion
We have developed short and efficient synthesis of the
metabolites (G)-aureothin (3), (G)-N-acetyl-aureotha-
mine (4) and (G)-spectinabilin (5) by using several
palladium-catalyzed reactions to assemble the congested
polyene structures (23, 17, and 18% overall yield,
respectively, from ethyl pyrone 14). In addition, the key
boronic ester 24 was synthesized via ruthenium-catalyzed
cross metathesis of alkene 17. Alternative routes to (G)-3,
(G)-4 and (G)-5 via hydroboration or a modified Julia
coupling proved ineffective. The successful biomimetic
conversion of spectinabilin (5) to SNF4435C (1) and
SNF4435D (2) shows that our biogenetic hypothesis
connecting these natural products is chemically viable.
The isolation of the isomers 48 and 49 was demonstrated
to be a side effect of the Pd(II) conditions employed for
the E/Z-isomerizations. Due to the lower efficiency of the
biomimetic conversion and the general complexity of the
product mixtures, we can only speculate that Nature uses
efficient enzyme-mediated E/Z-isomerizations of 5, which
the subsequent cyclization cascade may benefit from as
well.40
be O95% pure by H NMR. Compounds 14,41 23,27 26,29
1
28,37 3237 were prepared according to literature procedures.
4.1.1. (G)-2-Methoxy-3,5-dimethyl-6-(1-(phenylselenyl)-
ethyl)-4H-pyran-4-one (15). To a solution of THF (20 mL)
containing g-pyrone 1441 (1.50 g, 8.23 mmol) at K78 8C

M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
1683
was added slowly a solution of KHMDS (19.8 mL, 0.5 M in
toluene, 9.90 mmol) with stirring. The resulting solution
was allowed to stir for 30 min at K78 8C after which time
the reaction had developed a bright orange-red color. A
solution of phenyl selenium bromide (2.34 g, 9.9 mmol) in
THF (5 mL) was then added dropwise, and the reaction
mixture was allowed to warm to rt over the course of 1 h.
Satd aq NH4Cl (30 mL) was added, and the aqueous layer
was extracted with EtOAc three times. The combined
organics were washed with brine and dried over MgSO4,
and the solvent was removed by evaporation in vacuo. The
residue was subjected to column chromatography (pentanes/
EtOAc, gradient elution) to give 15 as a white solid (2.28 g,
82%). Mp 103–105 8C (CH2Cl2/pentanes); RfZ0.4 (1:1
pentanes/EtOAc); IR (KBr) 1660 (s), 1618 (m), 1592 (s); 1H
NMR (400 MHz, CDCl3) dH 1.63 (s, 3H), 1.72 (t, JZ
7.0 Hz, 1H), 1.83 (s, 3H), 3.81 (s, 3H), 4.41 (q, JZ7.0 Hz,
1H), 7.21–7.26 (m, 2H), 7.31–7.37 (m, 1H), 7.47–7.50 (m,
2H); 13C NMR (100 MHz, CDCl3) dC 6.9, 9.6, 18.4, 36.1,
55.1, 99.2, 117.8, 127.3, 129.1 (3C), 136.8 (2C), 157.1,
161.7, 180.5; HRMS (ESI) m/e calcd for C16H19O830Se
(MHC) 339.0499, found 339.0489.
4.1.4. (G)-2-Methoxy-3,5-dimethyl-6-(4-methylene-
tetrahydrofuran-2-yl)-4H-pyran-4-one (17). A solution
of In(acac)3 (229 mg, 0.555 mmol) and Pd(PPh3)4 (321 mg,
0.278 mmol) in toluene (20 mL) was stirred for 10 min at rt.
To the resulting yellow suspension was added a solution of
aldehyde 13 (1.01 g, 5.54 mmol) in toluene (40 mL) and 18
(1.50 mL, 7.22 mmol). The reaction mixture heated at reflux
for 5 h. The mixture was cooled to rt, and evaporated to
dryness in vacuo. The residue was filtered through a pad of
silica gel eluting with 1:1 CH2Cl2/EtOAc to afford (G)-17
as a white solid, that was further purified by crystallization
from CH2Cl2 with pentanes (1.21 g, 92%). Mp 115–117 8C
(CH2Cl2/pentanes); RfZ0.3 (1:1 CH2Cl2/EtOAc); IR (KBr)
1
1667 (s), 1606 (s), 1458 (s), 1322 (s); H NMR (200 MHz,
CDCl3) dH 1.83 (s, 3H), 2.01 (s, 3H), 2.71–2.98 (m, 2H),
3.93 (s, 3H), 4.42 (br d, JZ13.0 Hz, 1H), 4.54 (br d, JZ
13.0 Hz, 1H), 5.02 (qn, JZ2.0 Hz, 1H), 5.10 (qn, JZ
2.0 Hz, 1H), 5.18 (dd, JZ6.5, 7.5 Hz, 1H); 13C NMR
(50 MHz, CDCl3) dC 6.8, 9.3, 35.9, 55.2, 71.7, 74.8, 99.7,
105.1, 119.7, 146.4, 155.0, 162.0, 180.5; HRMS (ESI) m/e
calcd for C13H17O4 (MHC) 237.1127, found 237.1131.
4.1.5. (G)-(E)- and (G)-(Z)-2-(4-((1,3-Dioxolan-2-yl)-
methylene)-tetrahydrofuran-2-yl)-6-methoxy-3,5-
dimethyl-4H-pyran-4-one (21). To a solution of catalyst
20 (17 mg, 0.02 mmol) and pyrone (G)-17 (95 mg,
0.40 mmol) in CH2Cl2 (2 mL) was added over a period of
3 h a solution of 2-vinyl-1,3-dioxolane (19) (120 mL,
1.20 mmol) in CH2Cl2 (3 mL) at reflux. The resulting
solution was heated for a further 2 h at reflux, and then
cooled to rt. The solvent was removed by evaporation in
vacuo, and the residue was subjected to column chromato-
graphy (1:1 pentanes/EtOAc/EtOAc) to afford a 1:1.2 E/Z
mixture of 21 (81 mg, 65%) as a viscous oil. RfZ0.35 (1:1
CH2Cl2/EtOAc); IR (film) 2930 (s), 1672 (s), 1664 (s),
1584 (br, s) cmK1; 1H NMR (400 MHz, CDCl3) dH 1.82 (s,
2!3H), 2.00 (s, 2!3H), 2.77–3.08 (m, 2!2H), 3.83–4.05
(m, 2!4H), 3.92 (s, 2!3H), 4.46 (d, JZ13.5 Hz, 1H), 4.57
(d, JZ14.5 Hz, 1H), 4.58 (d, JZ13.5 Hz, 1H), 4.72 (d, JZ
14.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) dC 6.9 (2C), 9.4
(2C), 32.4, 36.3, 55.4 (2C), 64.9 (4C), 69.1, 71.9, 73.8, 75.1;
HRMS (ESI) m/e calcd for C16H21O6 (MHC) 309.1338,
found 309.1335.
4.1.2. 2-Methoxy-3,5-dimethyl-6-vinyl-4H-pyran-4-one
(16). To a solution of phenylselenyl pyrone 15 (4.22 g,
12.5 mmol) in MeOH (90 mL) and H2O (57 mL) was added
a catalytic quantity of NaHCO3 followed by NaIO4 (5.35 g,
25.0 mmol) at rt. The resulting mixture was stirred for 1 h at
rt. The methanol was removed by evaporation in vacuo, and
the aqueous layer was extracted twice with CH2Cl2. The
combined organics were dried over MgSO4 and evaporated
to dryness to yield a light yellow solid. The resulting crude
alkene 16 was carried on to the next step without further
purification. A small amount was purified for characteri-
zation purposes by column chromatography (CH2Cl2/
EtOAc, gradient elution) to yield 16 as a white solid. Mp
95–98 8C (CH2Cl2/pentanes); RfZ0.6 (1:1 pentanes/
1
EtOAc); IR (KBr) 1657 (s), 1601 (m), 1572 (s); H NMR
(400 MHz, CDCl3) dH 1.86 (s, 3H), 2.03 (s, 3H), 4.02 (s,
3H), 5.53 (d, JZ11.0 Hz, 1H), 5.93 (d, JZ17.0 Hz, 1H),
6.71 (dd, JZ11.0, 17.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) dC 6.9, 9.5, 55.3, 99.7, 119.0, 119.4, 126.6, 151.3,
161.8, 181.0; HRMS (ESI) m/e calcd for C10H13O3 (MHC)
181.0865, found 181.0865.
4.1.6. (E)- and (Z)-2-(5-(6-Methoxy-3,5-dimethyl-4-oxo-
4H-pyran-2-yl)-dihydrofuran-3(2H)-ylidene)acetalde-
hyde (22). To a solution of acetal 21 (432 mg, 1.40 mmol)
in acetone (25 mL) was added water (200 mL) and
p-toluenesulfonic acid (40 mg, 0.21 mmol). The resulting
solution was stirred for 1 h. Satd aq NaHCO3 (5 mL) was
added, and the acetone was removed in vacuo. The aqueous
phase was extracted with CH2Cl2 twice. The combined
organic layers were washed with brine and dried over
MgSO4. Removal of the solvent in vacuo yielded pure 22
(366 mg, 99%) as 1:1.2 E/Z mixture and as an unstable
oil, which required no further purification. RfZ0.45 (1:1
CH2Cl2/EtOAc); IR (film) 1665 (s), 1593 (s), 1266 (s) cm-1;
1H NMR (200 MHz, CDCl3) dH 1.83 (s, 3H), 1.84 (s, 3H),
2.96–3.51 (m, 2!2H), 3.88 (s, 3H), 3.90 (s, 3H), 4.63 (d,
JZ17.0 Hz, 1H), 4.78 (d, JZ17.0 Hz, 1H), 4.87 (d, JZ
17.5 Hz, 1H), 5.09 (d, JZ17.5 Hz, 1H), 5.23 (t, JZ6.5 Hz,
1H), 5.32 (t, JZ7.0 Hz, 1H), 6.09–6.15 (m, 1H), 6.26–6.32
(m, 1H), 9.70 (d, JZ4.5 Hz, 1H), 9.85 (d, JZ6.5 Hz, 1H);
4.1.3. 6-Methoxy-3,5-dimethyl-4-oxo-4H-pyran-2-car-
baldehyde (13).21,24 To a solution of crude alkene 16 (see
above) in THF–H2O (1/1 v/v, 180 mL) was added NaIO4
(5.35 g, 25.0 mmol) followed by the slow addition of OsO4
(1.9 mL, 4% w/w in H2O, 0.31 mmol). The resulting
mixture was stirred for 1 h at rt. The THF was removed
by evaporation in vacuo, and the remaining aqueous phase
was extracted twice with CH2Cl2. The combined organics
were dried over MgSO4, and evaporated to dryness in
vacuo. The crude aldehyde was purified by crystallization
from CH2Cl2-pentanes to yield 13 (1.76 g, 77% for two
steps) as a white, crystalline solid. Mp 143–145 8C (CH2Cl2/
pentanes); RfZ0.45 (1:1 CH2Cl2/EtOAc); IR (KBr) 1694
(s), 1648 (s), 1590 (s), 1174 (s); 1H NMR (200 MHz,
CDCl3) dH 1.90 (s, 3H), 2.35 (s, 3H), 4.09 (s, 3H), 10.1 (s,
1H); 13C NMR (50 MHz, CDCl3) dC 7.1, 8.3, 55.8, 102.4,
130.3, 147.3, 162.3, 179.9, 182.9; HRMS (ESI) m/e calcd
for C9H11O4 (MHC) 183.0657, found 183.0660.

1684
M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
13C NMR (50 MHz, CDCl3) dC 6.8 (2C), 9.4 (2C), 33.5,
37.2, 55.2, 55.3, 71.2, 72.4, 73.3, 75.4, 100.1 (2C), 119.8,
120.2, 120.5 (2C), 153.5 (2C), 162.0 (2C), 162.9, 163.2,
180.3 (2C), 189.3, 190.1; HRMS (ESI) m/e calcd for
C14H17O5 (MHC) 265.1076, found 265.1079.
(20 mL) was added dropwise at K78 8C. The resulting
mixture was stirred for 1 h at K78 8C, and allowed to warm
slowly to rt. Satd aq NH4Cl (10 mL) was added. The
aqueous phase was extracted twice with CH2Cl2, and the
combined organics were washed with brine and dried over
MgSO4. The solvent was removed in vacuo, and the residue
was subjected to column chromatography (50:1 pentanes/
EtOAc) to furnish 27 (802 mg, 71%) as a yellow paste. RfZ
0.6 (9:1 pentanes/EtOAc); IR (KBr) 2283 (m), 1594 (m),
4.1.7. (G)-(E)- and (G)-(Z)-2-Methoxy-3,5-dimethyl-6-
(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methy-
lene)-tetrahydrofuran-2-yl)-4H-pyran-4-one (24). To a
solution of alkene 17 (869 mg, 3.68 mmol) and alkenyl
boronic ester 2327 (1.24 g, 7.36 mmol) in CH2Cl2 (5 mL)
was added catalyst 20 (156 mg, 0.184 mmol). The resulting
was heated at reflux for 3 h, cooled to rt and evaporated to
dryness in vacuo. The residue was subjected to column
chromatography (CH2Cl2/EtOAc, gradient elution) to afford
24 (1.31 g, 98%) as a 1:1.2 E/Z mixture and as an oil. RfZ
0.35 (4:1 CH2Cl2/EtOAc); IR (film) 3054 (m), 2982 (s),
1665 (s), 1595 (s); 1H NMR (200 MHz, CDCl3) dH 1.22 (s,
2!3H), 1.23 (s, 2!6H), 1.25 (s, 2!3H), 1.82 (s, 3H), 1.83
(s, 3H), 2.00 (s, 3H), 2.01 (s, 3H), 2.77–3.22 (m, 2!2H),
3.89 (s, 3H), 3.90 (s, 3H), 4.45 (br d, JZ14.5 Hz, 1H), 4.58
(br d, JZ14.5 Hz, 1H), 4.58 (br d, JZ15.5 Hz, 1H), 4.79 (d,
JZ15.5 Hz, 1H), 5.13–5.25 (m, 2H), 5.33 (qn, JZ2.0 Hz,
1H), 5.45 (qn, JZ2.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) dC 6.7 (2C), 9.2, 9.3, 24.5, 24.6 (2C), 24.6, 24.7
(4C), 35.8, 38.8, 55.0, 55.1, 72.0, 73.4, 73.7, 75.3, 83.0 (2C),
83.1 (2C), 95.6 (2C), 99.5 (2C), 119.5, 119.7, 154.9, 155.1,
161.9 (2C), 162.6, 163.2, 180.4, 180.5; HRMS (ESI) m/e
calcd for C19H28BO6 (MHC) 363.1979, found 363.1975.
1
1514 (m), 1342 (s) cmK1; H NMR (400 MHz, CDCl3) dH
2.1 (s, 6H), 2.99 (s, 1H), 6.50 (s, 1H), 7.33 (s, 1H), 7.45 (d,
JZ8.5 Hz, 2H), 8.31 (d, JZ8.5 Hz, 2H); 13C NMR
(125.7 MHz, CDCl3) dC 19.2, 19.9, 77.0, 87.8, 119.8,
123.9 (2C), 130.0 (2C), 134.0, 138.7, 141.4, 144.5, 146.5;
HRMS (CI(NH3)) calcd for C14H17N2O2 (MNHC4 )
245.1290, found 245.1286.
4.1.10. 1-((1E,3E)-2,4-Dimethylhepta-1,3-dien-5-ynyl)-4-
nitrobenzene (25). To a stirred solution of alkyne 27
(773 mg, 3.40 mmol), in THF (20 mL), was added LHMDS
(4.1 mL, 1.0 M solution in THF, 4.1 mmol) dropwise at rt.
MeI (1.70 mL, 27.3 mmol) was added after 5 min. Water
(10 mL) was added after another 10 min. The organic layer
was separated, and the aqueous layer extracted with CH2Cl2
twice. The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
Purification of the crude oil using column chromatography
(50:1 pentanes/EtOAc) gave 25 as a yellow solid (707 mg,
86%). Mp 54–55 8C (CH2Cl2/pentanes); RfZ0.55 (9:1
pentanes/EtOAc); IR (KBr) 1587 (s), 1522 (m), 1337
(s) cmK1; 1H NMR (250 MHz, CDCl3) dH 2.03 (s, 3H), 2.08
(s, 6H), 6.31 (s, 1H), 6.43 (s, 1H), 7.43 (d, JZ8.5 Hz, 2H),
8.21 (d, JZ8.5 Hz, 2H); 13C NMR (62.9 MHz, CDCl3) dC
4.8, 19.4, 20.3, 84.0, 86.0, 121.5, 123.9 (2C), 129.1, 130.0
(2C), 138.7, 139.1, 144.8, 146.4; HRMS (CI(NH3)) calcd
for C15H16NO2 (MHC) 242.1181, found 242.1178.
4.1.8. (E)- and (Z)-2-(4-(Iodomethylene)-tetra-
hydrofuran-2-yl)-6-methoxy-3,5-dimethyl-4H-pyran-4-
one (11). To boronic ester 24 (362 mg, 1.0 mmol) in THF
(2.5 mL) was added NaOH (1.0 mL, 3.0 M in H2O,
3.00 mmol). The solution was stirred vigorously at rt for
10 min. The mixture was titrated with iodine (7.0 mL, 0.2 M
in THF, 1.40 mmol) at such rate that only towards the end of
addition was the mixture allowed to develop a persistent red
color (w2 h). Satd aq sodium thiosulfate (0.5 mL) and
water (4 mL) were added. The aqueous phase was extracted
with CH2Cl2 twice and the combined organics were dried
over MgSO4. The solvent was removed in vacuo, and the
residue was subjected to column chromatography (10:1/
1:1 CH2Cl2/EtOAc) to afford 11 (169 mg, 47%) as a 1.2:1 E/
Z mixture followed by recovered 24 (51 mg, 14%) both as
clear oils. Data for 11: RfZ0.3 (5:1 CH2Cl2/EtOAc); IR
(film) 3054 (w), 2957 (w), 1664 (s), 1590 (s), 1467 (s), 1265
(s) cmK1; 1H NMR (200 MHz, CDCl3) dH 1.82 (s, 3H), 1.83
(s, 3H), 1.98 (s, 3H), 2.01 (s, 3H), 2.71–3.03 (m, 2!2H),
3.22 (s, 2!3H), 4.29–4.57 (m, 2!2H), 5.26 (dd, JZ6.5,
7.5 Hz, 1H), 5.34 (dd, JZ6.0, 7.5 Hz, 1H), 6.10–6.17 (m,
2H); 13C NMR (50 MHz, CDCl3) dC 6.8 (2C), 9.4 (2C),
37.9, 40.3, 55.4 (2C), 67.5, 68.2, 71.7, 74.1, 76.0, 76.1, 99.9
(2C), 119.9, 120.4, 149.8, 150.7, 154.1, 154.5, 162.0 (2C),
180.4 (2C); HRMS (ESI) m/e calcd for C13H16IO4 (MHC)
363.0093, found 363.0098.
4.1.11. (E)-2-Methyl-3-(4-nitrophenyl)allyl methanesul-
fonate (33). To a solution of alcohol 3237 (2.55 g,
13.2 mmol) in CH2Cl2 (50 mL) was added Et3N (2.76 mL,
19.8 mmol) at 0 8C, followed by the dropwise addition of
MsCl (1.22 mL, 15.8 mmol) at K10 8C. The resulting
solution was stirred at K10 to K15 8C for 1 h, then satd aq
NH4Cl (10 mL) was added. The organic phase was washed
with water and brine, and dried over MgSO4. The solvent
was removed by evaporation in vacuo to yield a crude
yellow-orange oil, that was purified by passing through a
plug of silica gel eluting with 2:1 pentanes/EtOAc to yield
33 (3.48 g, 97%) as a unstable yellow solid. RfZ0.35 (2:1
1
pentanes/EtOAc); H NMR (200 MHz, CDCl3) dH 1.97 (s,
3H), 3.08 (s, 3H), 4.78 (s, 2H), 6.68 (s, 1H), 7.43 (d, JZ
8.5 Hz, 2H), 8.20 (d, JZ8.5 Hz, 2H); 13C NMR (50 MHz,
CDCl3) dC 15.4, 37.9, 74.4, 123.6 (2C), 128.2, 129.6 (2C),
134.7, 142.9, 146.6; HRMS (ESI) m/e calcd for
C11H14NO5S (MHC) 272.0593, found 272.0588.
4.1.12. (E)-2-(2-Methyl-3-(4-nitrophenyl)allylthio)benzo-
[d]thiazole (35). To a solution of 2-mercaptobenzothiazole
(1.76 g, 10.5 mmol) in DMF (10 mL) was added sodium
hydride (420 mg, 60 w/w % in oil, 10.5 mmol) slowly at 0 8C.
The resulting suspension was stirred for 20 min at 0 8C. A
solution of mesylate 33 (950 mg, 3.50 mmol) in DMF (5 mL)
was added at 0 8C, and the mixture was allowed to warm to rt
4.1.9. 1-((1E,3E)-2,4-Dimethylhexa-1,3-dien-5-ynyl)-4-
nitrobenzene (27). To a solution of LHMDS (6.0 mL,
1.0 M in THF, 6.00 mmol) in THF (25 mL) was added
dropwise TMSCHN2 (3.0 mL, 2.0 M in Et2O, 6.00 mmol) at
K78 8C. The resulting was stirred for 30 min, and then a
solution of aldehyde 2836 (1.16 g, 5.00 mmol) in THF

M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
1685
then stirred for 2 h. Satd aq NaHCO3 (10 mL) was added, and
the aqueous phase was extracted with CH2Cl2 twice. The
combined organics were dried over MgSO4 and evaporated to
dryness in vacuo. The residue was subjected to column
chromatography (20:1 pentanes/EtOAc) to afford 35 (1.07 g,
89%) as a light yellow solid. Mp 114–116 8C (CH2Cl2/
pentanes); RfZ0.1 (20:1 pentanes/EtOAc); IR (KBr) 1593
4.1.15. 1-(2,2-Dibromovinyl)-4-nitrobenzene (37).34 To a
solution of PPh3 (7.87 g, 30.0 mmol), Zn powder (1.96 g,
30.0 mmol) and pyridine (2.4 mL, 30 mmol) in CH2Cl2
(50 mL) was added portionwise solid CBr4 (9.95 g,
30.0 mmol) at rt. The resulting suspension was stirred for
30 min. A solution of p-nitrobenzaldehyde (1.51 g,
10.0 mmol) in CH2Cl2 (25 mL) was added slowly at rt.
The resulting reaction mixture was stirred for 2 h. Water
(25 mL) was added. The organic phase was diluted with
pentanes (w150 mL) with stirring and the resulting
suspension was filtered through a pad of Celitew, and
evaporated to dryness in vacuo. The residue was subjected
to column chromatography (pentanes/EtOAc, gradient
elution) to afford 37 (2.67 g, 87%) as an orange solid. Mp
101–103 8C (CH2Cl2/pentanes); RfZ0.75 (10:1 pentanes/
1
(m), 1507 (s), 1425 (s), 1338 (s) cm-1; H NMR (200 MHz,
CDCl3) dH 2.06 (s, 3H), 4.20 (s, 2H), 6.70 (s, 1H), 7.28–7.48
(m, 4H), 7.77 (d, JZ8.0 Hz, 1H), 7.90 (d, JZ8.0 Hz, 1H),
8.17 (d, JZ9.0 Hz, 2H); 13C NMR (50 MHz, CDCl3) dC 17.3,
43.1, 121.0, 121.6, 123.4 (2C), 124.4, 126.1, 127.7, 129.4
(2C), 135.3, 137.1, 143.9, 146.2, 153.0, 165.8; HRMS
(CI(NH3)) m/e calcd for C17H15N2O2S2 (MHC) 343.0575,
found 343.0567.
1
EtOAc); IR (KBr) 1586 (s), 1512 (s), 1342 (s), 860 (s); H
NMR (200 MHz, CDCl3) dH 7.55 (s, 1H), 7.69 (d, JZ
9.0 Hz, 2H), 8.21 (d, JZ9.0 Hz, 2H); 13C NMR (125 MHz,
CDCl3) dC 94.0, 123.7 (2C), 129.1 (2C), 134.8, 141.4,
147.1; HRMS (ESI) m/e calcd for C8H769Br2NO2 (MHC)
4.1.13. (E)-2-(2-Methyl-3-(4-nitrophenyl)allylsulfonyl)-
benzo[d]thiazole (34). To a solution of sulfide 35
(599 mg, 1.75 mmol) in THF–EtOH (2/1, 30 mL) was
added at 0 8C a solution of ammonium heptamolybdate
tetrahydrate (433 mg, 0.35 mmol) in H2O2 (1.5 mL, 33% w/
w, 17.5 mmol) over a period of 5 min. The resulting solution
was allowed to warm to rt, and it was stirred for 20 h. A
solution of Na2SO3 (2 g) in H2O (20 mL) was added, and the
aqueous phase was extracted with CH2Cl2 (3!30 mL). The
combined organics were washed with brine and dried over
MgSO4, and then the solvent was removed by evaporation
in vacuo. The residue was subjected to column chromato-
graphy (7:1 pentanes/EtOAc, then CH2Cl2) to give 34
(544 mg, 83%) as a white solid. Mp 115–117 8C (CH2Cl2/
pentanes); RfZ0.6 (CH2Cl2); IR (KBr) 1595 (m), 1511 (s),
1
305.8765, found 305.8770. The H and 13C NMR spectral
data are in good agreement with those previously
published.34
4.1.16. (G)-2-((E)-4-((Z)-2-Bromo-3-(4-nitrophenyl)ally-
lidene)-tetrahydrofuran-2-yl)-6-methoxy-3,5-dimethyl-
4H-pyran-4-one ((E)-40) and (G)-2-((Z)-4-((Z)-2-bromo-
3-(4-nitrophenyl)allylidene)-tetrahydrofuran-2-yl)-6-
methoxy-3,5-dimethyl-4H-pyran-4-one ((Z)-40). To a
solution of dibromide 37 (169 mg, 0.55 mmol), boronic
ester 24 (181 mg, 0.50 mmol) and Pd(PPh3)4 (58 mg,
0.05 mmol) in THF–H2O (3/1, 10 mL) was added slowly
TlOEt (71 mL, 1.00 mmol) at rt. The resulting suspension
was stirred for 75 min at rt. Brine (5 mL) and CH2Cl2
(20 mL) was added, and the separated aqueous layer was
extracted twice with CH2Cl2. The combined organics were
dried over MgSO4 and the solvent was removed in vacuo.
The crude product 40 was obtained as a 1:1.2 E/Z mixture as
1
1337 (s) cmK1; H NMR (400 MHz, CDCl3) dH 2.11 (s,
3H), 4.37 (s, 2H), 6.42 (s, 1H), 7.19 (d, JZ8.5 Hz, 2H), 7.62
(app t, JZ7.0 Hz, 1H), 7.67 (app t, JZ7.0 Hz, 1H), 8.01 (d,
JZ8.0 Hz, 1H), 8.13 (d, JZ8.5 Hz, 2H), 8.25 (d, JZ
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) dC 19.0, 65.0,
122.3, 123.5 (2C), 125.5, 127.9, 128.3, 128.7, 129.5 (2C),
133.9, 136.9, 142.7, 146.6, 152.6, 165.2; HRMS (CI(NH3))
m/e calcd for C17H15N2O4S2 (MHC) 375.0473, found
375.0475.
1
determined by H NMR, which was subjected to column
chromatography (pentanes/EtOAc, gradient elution) to
afford (E)-40 (69 mg, 30%) followed by (Z)-40 (98 mg,
42%) as yellow solids. Data for (E)-40: Mp 117–119 8C
(CH2Cl2/pentanes); RfZ0.5 (1:1 CH2Cl2/EtOAc); IR (KBr)
4.1.14. (G)-Aureonone (31).21 To a solution of alkene 17
(165 mg, 0.70 mmol) in THF–H2O (1/1, 6 mL) was added
NaIO4 (299 mg, 1.40 mmol) followed by OsO4 (0.22 mL,
4% w/w in H2O, 0.018 mmol) at rt. The resulting solution
was stirred for 15 h, and the THF was removed by
evaporation in vacuo, and the aqueous phase was extracted
twice with CH2Cl2. The combined organics were dried over
Na2SO4, and evaporated to dryness. The residue was
subjected to column chromatography (3:1 CH2Cl2/EtOAc)
to yield 31 (136 mg, 82%) as a white solid. Mp 119–121 8C
(CH2Cl2/pentanes); RfZ0.25 (2:1 CH2Cl2/EtOAc); IR
(KBr) 2927 (w), 1755 (s), 1666 (s), 1593 (s), 1328
1
1667 (s), 1607 (s), 1514 (s), 1343 (s); H NMR (400 MHz,
CDCl3) dH 1.82 (s, 3H), 2.01 (s, 3H), 3.11–3.40 (m, 2H),
3.94 (s, 3H), 4.59 (br s, JZ14.0 Hz, 1H), 4.71 (br d, JZ
14.0 Hz, 1H), 5.27 (dd, JZ6.0, 7.5 Hz, 1H), 6.25 (br s, 1H),
6.93 (s, 1H), 7.76 (d, JZ8.5 Hz, 2H), 8.19 (d, JZ8.5 Hz,
2H); 13C NMR (100 MHz, CDCl3) dC 6.9, 9.5, 34.4, 55.4,
73.0, 75.4, 100.0, 120.2, 121.3, 123.3, 123.4 (2C), 129.3,
129.8 (2C), 141.9, 144.2, 146.9, 154.3, 162.1, 180.5; HRMS
79
21
(Cl(NH3)) m/e calcd for C21H BrNO6 (MHC) 462.0552,
found 462.0562. Data for (Z)-40: Mp 146–148 8C (CH2Cl2/
pentanes); RfZ0.4 (1:1 CH2Cl2/EtOAc); IR (KBr) 1665 (s),
1603 (s), 1510 (s), 1345 (s); 1H NMR (200 MHz, CDCl3) dH
1.85 (s, 3H), 2.03 (s, 3H), 2.98 (br dd, JZ6.0, 16.5 Hz, 1H),
3.14 (br dd, JZ7.5, 16.5 Hz, 1H), 3.95 (s, 3H), 4.87 (br d,
JZ15.0 Hz, 1H), 5.05 (br d, JZ15.0 Hz, 1H), 5.19 (dd, JZ
6.0, 7.5 Hz, 1H), 6.39 (br s, 1H), 6.83 (s, 1H), 7.77 (d, JZ
8.5 Hz, 2H), 8.23 (d, JZ8.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) dC 6.9, 9.4, 38.0, 55.4, 70.1, 73.2, 100.1, 120.2,
122.6, 123.1, 123.5 (2C), 129.2, 129.8 (2C), 141.9, 144.8,
1
(s) cmK1; H NMR (400 MHz, CDCl3) dH 1.84 (s, 3H),
2.05 (s, 3H), 2.71 (dd, JZ6.0, 18.0 Hz, 1H), 2.87 (dd, JZ
8.0, 18.0 Hz, 1H), 3.89 (s, 3H), 4.05 (d, JZ17.0 Hz, 1H),
4.16 (d, JZ17.0 Hz, 1H), 5.54 (dd, JZ6.0, 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) dC 6.9, 9.5, 39.2, 55.4, 70.6, 73.0,
100.4, 120.9, 153.3, 161.9, 190.2, 212.3; HRMS (ESI) m/e
calcd for C12H15O5 (MHC) 239.0919, found 239.0919. The
IR, 1H and 13C NMR spectral data were in excellent
agreement with those previously published.21

1686
M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
147.0, 154.5, 162.1, 180.5; HRMS (Cl(NH3)) m/e calcd for
a white solid (30.5 mg, 77%). Mp 175–177 8C (CH2Cl2/
pentanes); RfZ0.2 (1:1 CH2Cl2/EtOAc); IR (KBr) 1683 (s),
1661 (s), 1572 (s); 1H NMR (400 MHz, CDCl3) dH 1.84 (s,
3H), 2.00 (s, 3H), 2.02 (s, 3H), 2.17 (s, 3H), 2.90 (dd, JZ
6.5, 16.0 Hz, 1H), 3.04 (dd, JZ7.5, 16.0 Hz, 1H), 3.94 (s,
3H), 4.73 (d, JZ14.0 Hz, 1H), 4.85 (d, JZ14.0 Hz, 1H),
5.13 (dd, JZ6.5, 7.5 Hz, 1H), 6.15 (s, 1H), 6.28 (s, 1H),
7.20 (d, JZ8.5 Hz, 2H), 7.52 (d, JZ8.5 Hz, 2H), 7.94 (s,
1H); 13C NMR (100 MHz, CDCl3) dC 6.9, 9.4, 17.5, 24.5,
38.2, 55.3, 70.1, 73.1, 99.9, 119.5 (2C), 119.8, 126.7, 129.6
(2C), 130.1, 133.2, 134.2, 136.8, 137.6, 155.2, 162.2, 168.5,
180.7; HRMS (ESI) m/e calcd for C24H28NO5 (MHC)
410.1967, found 410.1967. The IR, 1H and 13C NMR
spectral data are in excellent agreement with those
previously published.6
79
21
C21H BrNO6 (MHC) 462.0552, found 462.0555.
4.1.17. (G)-Aureothin (3).4,21 To a solution of bromide
(Z)-40 (69.5 mg, 0.15 mmol) and Pd(tBu3P)2 (1.5 mg,
3 mmol) in THF (3 mL) was added slowly Me2Zn
(150 mL, 0.30 mmol) at rt. The resulting was stirred for
30 min at rt, and then satd aq NH4Cl (1 mL) was added
carefully, followed by brine (1 mL). The mixture was
extracted twice with CH2Cl2, and the combined organics
were dried over MgSO4 and evaporated to dryness in vacuo.
The residue was subjected to column chromatography
(CH2Cl2/EtOAc, 1:1) to afford (G)-aureothin (3) (57 mg,
95%) as a light sensitive crystalline, yellow solid. Mp 173–
175 8C (CH2Cl2/pentanes); RfZ0.45 (1:1 CH2Cl21/EtOAc);
IR (KBr) 1666 (s), 1586 (s), 1510 (m), 1332 (s); H NMR
(400 MHz, CDCl3) dH 1.83 (s, 3H), 2.01 (s, 3H), 2.03 (s,
3H), 2.95 (br dd, JZ6.0, 16.0 Hz, 1H), 3.05 (br dd, JZ6.0,
16.0 Hz, 1H), 3.93 (s, 3H), 4.74 (br d, JZ14.0 Hz, 1H), 4.86
(br d, JZ14.0 Hz, 1H), 5.13 (t, JZ6.0 Hz, 1H), 6.19 (br s,
1H), 6.36 (s, 1H), 7.38 (d, JZ8.5 Hz, 2H), 8.18 (d, JZ
8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) dC 6.9, 9.4, 17.7,
38.2, 55.2, 70.1, 73.2, 99.9, 120.1, 123.5 (2C), 125.9, 128.3,
129.5 (2C), 138.6, 140.6, 144.2, 146.0, 154.6, 162.0, 180.5;
HRMS (ESI) m/e calcd for C22H24NO6 (MHC) 398.1604,
found 398.1600. The IR, 1H and 13C NMR spectral data are
in excellent agreement with those previously published.21
4.1.20. 1-((1E,3E)-6,6-Dibromo-2,4-dimethylhexa-1,3,
5-trienyl)-4-nitrobenzene (42). To a solution of PPh3
(11.8 g, 45.0 mmol), Zn powder (2.94 g, 45.0 mmol) and
pyridine (3.6 mL, 45.0 mmol) in CH2Cl2 (150 mL) was
added portionwise solid CBr4 (14.9 g, 45.0 mmol) at rt. The
resulting was stirred for 30 min. A solution of aldehyde 28
(3.47 g, 15.0 mmol) in CH2Cl2 (50 mL) was added slowly.
The resulting reaction mixture was stirred for 2 h then water
(50 mL) was added. The organic phase was diluted with
pentanes (w400 mL) with stirring and the resulting
suspension was filtered through a pad of Celitew, and
evaporated to dryness in vacuo. The residue was subjected
to column chromatography (20:1/10:1 pentanes/EtOAc)
to afford 42 (5.67 g, 98%) as a light sensitive yellow-orange
solid. Mp 76–78 8C (CH2Cl2/pentanes); RfZ0.55 (9:1
pentanes/EtOAc); IR (KBr) 1590 (m), 1513 (m), 1340
(m); 1H NMR (250 MHz, CDCl3) dH 2.08 (3H, s), 2.13 (3H,
s), 6.22 (1H, s), 6.50 (1H, s), 7.02 (1H, s), 7.44 (d, JZ
8.5 Hz, 2H), 8.22 (d, JZ8.5 Hz, 2H); 13C NMR (62.9 MHz,
CDCl3) dC 18.1, 19.5, 85.5, 124.0, 129.6, 130.0, 134.3,
4.1.18. (G)-Aureothamine (41)4 To a solution of (G)-
aureothin (3) (80.5 mg, 0.20 mmol) in acetone–H2O (5/1,
10 mL) was added Zn powder (165 mg, 2.52 mmol) and
solid NH4Cl (225 mg, 4.20 mmol) at rt. The bright yellow
suspension was heated at reflux for 15 min. The resulting
almost colorless mixture was cooled to rt and concentrated
under reduced pressure. The aqueous mixture was extracted
several times with CH2Cl2, and the combined organics were
dried over MgSO4 and evaporated to dryness in vacuo. The
residue was filtered through a pad of silica gel eluting with
1:1 CH2Cl2/EtOAc to afford (G)-41 (73.5 mg, 99%) as a
white, crystalline solid. Mp 177–179 8C (CH2Cl2/pentanes);
RfZ0.25 (1:1 CH2Cl2/EtOAc); IR (KBr) 3454 (s), 3343 (s),
3227 (m), 1660 (s), 1582 (s), 1326 (s); 1H NMR (200 MHz,
CDCl3) dH 1.84 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 2.87 (dd,
JZ6.0, 15.5 Hz, 1H), 3.04 (dd, JZ7.5, 15.5 Hz, 1H), 3.93
(s, 3H), 4.73 (br d, JZ14.0 Hz, 1H), 4.86 (br d, JZ14.0 Hz,
1H), 5.12 (dd, JZ6.0, 7.5 Hz, 1H), 6.14 (br s, 1H), 6.24 (s,
1H), 6.67 (d, JZ8.5 Hz, 2H), 7.09 (d, JZ8.5 Hz, 2H); 13C
NMR (100 MHz, CDCl3) dC 6.9, 9.4, 17.5, 38.2, 55.2, 70.1,
73.0, 99.8, 114.7 (2C), 119.7, 127.1, 127.8, 130.2 (2C),
130.8, 132.1, 136.4, 145.1, 155.2, 162.1, 180.6; HRMS
(ESI) m/e calcd for C22H26NO4 (MHC) 368.1862, found
368.1863.
137.8, 138.0, 141.4, 144.6, 146.5; HRMS (Cl(NH3)) m/e
calcd for C14H Br2N2O2 (MNHC4 ) 402.9657, found
79
17
402.9655.
4.1.21. (G)-2-((Z)-4-((2Z,4E,6E)-2-Bromo-4,6-dimethyl-
7-(4-nitrophenyl)hepta-2,4,6-trienylidene)-tetrahydro-
furan-2-yl)-6-methoxy-3,5-dimethyl-4H-pyran-4-one
(43) and (G)-2-((E)-4-((2Z,4E,6E)-2-bromo-4,6-
dimethyl-7-(4-nitrophenyl)hepta-2,4,6-trienylidene)-
tetrahydrofuran-2-yl)-6-methoxy-3, 5-dimethyl-4H-
pyran-4-one (43). To a solution of dibromide 42 (852 mg,
2.20 mmol), boronic ester 24 (724 mg, 2.00 mmol) and
Pd(PPh3)4 (231 mg, 0.20 mmol) in THF–H2O (3/1, 40 mL)
was added slowly TlOEt (283 mL, 4.00 mmol) at rt. The
resulting suspension was stirred for 30 min at rt. Brine
(20 mL) and CH2Cl2 (40 mL) was added, and the separated
aqueous layer was extracted twice with CH2Cl2. The
combined organics were dried over MgSO4 and the solvent
was removed in vacuo. The crude product 43 was obtained
as a 1:1.2 E/Z mixture as determined by 1H NMR. The crude
product was subjected to column chromatography (2:1/
1:1 pentanes/EtOAc) to afford (E)-43 (315 mg, 29%) as a
stiff red foam followed by (Z)-43 (380 mg, 35%) as an
yellow solid, both as light sensitive compounds. Data for
(E)-43: RfZ0.25 (1:1 pentanes/EtOAc); IR (KBr) 1665 (s),
1594 (s), 1512 (s), 1339 (s); 1H NMR (400 MHz, CDCl3) dH
1.83 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 3.10
4.1.19. (G)-N-Acetyl-aureothamine (4).6 To a solution of
aureothamine (41) (35.5 mg, 97 mmol) in CH2Cl2 (1.5 mL)
was added pyridine (16 mL, 0.20 mmol) at 0 8C. Acetyl
chloride (11 mL, 0.15 mmol) was added slowly to the
resulting solution. The mixture was stirred for 45 min at
0 8C. Satd aq NH4Cl (2 mL) was added, and the aqueous
phase was extracted twice with CH2Cl2. The combined
organics were dried over MgSO4, and the solvent was
removed in vacuo. The residue was subjected to column
chromatography (CH2Cl2/EtOAc, 1:1) to afford (G)-4 as

M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
1687
(dd, JZ5.0, 17.0 Hz, 1H), 3.24 (dd, JZ7.5, 17.0 Hz, 1H),
3.94 (s, 3H), 4.58 (d, JZ13.5 Hz, 1H), 4.65 (d, JZ13.5 Hz,
1H), 5.25 (dd, JZ5.0, 7.5 Hz, 1H), 6.11 (s, 1H), 6.28 (s,
1H), 6.44 (s, 1H), 6.50 (s, 1H), 7.42 (d, JZ8.5 Hz, 2H), 8.18
(d, JZ8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) dC 6.8,
9.4, 19.2, 18.6, 34.2, 55.4, 72.8, 75.2, 99.8, 118.1, 120.0,
122.0, 123.5 (2C), 129.0, 129.5 (2C), 134.2, 135.7, 137.5,
to afford (G)-5a (153 mg, 89%) as a light sensitive orange
foam. RfZ0.55 (1:1 CH2Cl2/EtOAc); IR (film) 1666 (s),
1595 (s), 1514 (s), 1340 (s); 1H NMR (400 MHz, CDCl3) dH
1.84 (s, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.07 (s, 3H), 2.08 (s,
3H), 2.98 (dd, JZ6.0, 16.5 Hz, 1H), 3.16 (dd, JZ7.5,
16.5 Hz, 1H), 3.94 (s, 3H), 4.53 (d, JZ13.0 Hz, 1H), 4.63
(d, JZ13.0 Hz, 1H), 5.22 (dd, JZ6.0, 7.5 Hz, 1H), 5.94 (s,
1H), 5.97 (s, 1H), 5.98 (s, 1H), 6.46 (s, 1H), 7.42 (d, JZ
8.5 Hz, 2H), 8.19 (d, JZ8.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) dC 6.9, 9.4, 18.2, 19.5, 19.6, 34.3, 55.3, 73.8, 75.7,
99.8, 119.8, 123.5 (2C), 125.4, 128.1, 129.5 (2C), 133.9,
134.4, 135.6, 135.7, 137.0, 139.4, 144.6, 145.8, 155.0,
162.1, 180.6; HRMS (ESI) m/e calcd for C28H32NO6
(MHC) 478.2230, found 478.2228.
138.7, 141.4, 144.3, 145.9, 154.7, 162.0, 180.5; HRMS
79
29
(ESI) m/e calcd for C27H BrNO6 (MHC) 542.1178, found
542.1181. Data for (Z)-43: Mp 101–103 8C (CH2Cl2/
pentanes); RfZ0.15 (1:1 pentanes/EtOAc); IR (KBr) 1665
(s), 1594 (s), 1512 (s), 1339 (s); 1H NMR (400 MHz,
CDCl3) dH 1.84 (s, 3H), 2.02 (s, 3H), 2.08 (s, 3H), 2.17 (s,
3H), 2.91 (dd, JZ5.0, 16.0 Hz, 1H), 3.08 (dd, JZ7.5,
16.0 Hz, 1H), 3.95 (s, 3H), 4.80 (d, JZ15.0 Hz, 1H), 4.96
(d, JZ15.0 Hz, 1H), 5.16 (dd, JZ5.0, 7.5 Hz, 1H), 6.24 (s,
1H), 6.28 (s, 1H), 6.34 (s, 1H), 6.51 (s, 1H), 7.44 (d, JZ
9.0 Hz, 2H), 8.19 (d, JZ9.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) dC 6.9, 9.4, 18.6, 19.2, 37.8, 55.4, 70.1, 73.1, 99.9,
117.9, 119.9, 123.2, 123.5 (2C), 129.1, 129.6 (2C), 134.2,
4.1.24. (G)-SNF4435C (1), (G)-SNF4435D (2), and
isomers 48 and 49 from (G)-5. To (G)-spectinabilin (5)
(311 mg, 0.65 mmol) was added PdCl2(MeCN)2 (42 mg,
0.163 mmol) and then dry DMF (10 mL). The resulting red-
brown solution was heated in the dark at 70 8C for 23 h. At
the end of the reaction, a precipitate of palladium black had
formed and the solution had a pale yellowish color. After
cooling to rt the reaction mixture was evaporated to dryness
in vacuo. The residue was directly subjected to column
chromatography (2:1 pentanes/EtOAc) to afford a slightly
impure mixture of 1, 2, 48 and 49 (160 mg). The mixture
was subjected to preparative TLC (1:1 hexanes/Et2O,
multiple elutions) to afford a 2.1:1 mixture of 48 and 49
(56 mg, 18%) as a yellowish stiff foam, followed by a 2.5:1
mixture of 1 and 2 (68.5 mg, 22%) as a yellowish stiff foam.
(G)-SNF4435C (1) and (G)-SNF4435D (2) could be
separated by preparative TLC (3:1 pentanes/EtOAc,
multiple elutions) to provide 1 and 2 as pale yellow solids.
135.6, 137.5, 138.7, 141.9, 144.3, 146.0, 154.9, 162.1,
79
29
180.5; HRMS (ESI) m/e calcd for C27H BrNO6 (MHC)
542.1178, found 542.1177.
4.1.22. (G)-Spectinabilin (5).7 To a solution of bromide
(Z)-43 (1.01 g, 1.86 mmol) and Pd(tBu3P)2 (19 mg,
37.2 mmol) in THF (40 mL) was added slowly Me2Zn
(1.87 mL, 2.0 M in PhMe, 3.74 mmol) at rt. The resulting
was stirred for 45 min at rt. Satd aq NH4Cl (10 mL) was
added carefully, followed by brine (10 mL). The mixture
was extracted twice with CH2Cl2, and the combined
organics were dried over MgSO4 and evaporated to dryness
in vacuo. The residue was subjected to column chromatog-
raphy (silica gel, 2:1 CH2Cl2/EtOAc) to afford (G)-5
(795 mg, 89%) as a light sensitive yellow solid. Mp 133–
135 8C (CH2Cl2/pentanes); RfZ0.55 (1:1 CH2Cl21/EtOAc);
IR (KBr) 1667 (s), 1601 (s), 1517 (s), 1338 (s); H NMR
(400 MHz, CDCl3) dH 1.85 (s, 3H), 2.00 (s, 3H), 2.02 (s,
3H), 2.04 (s, 3H), 2.09 (s, 3H), 2.89 (dd, JZ6.0, 15.5 Hz,
1H), 3.02 (dd, JZ7.5, 15.5 Hz, 1H), 3.94 (s, 3H), 4.71 (d,
JZ14.0 Hz, 1H), 4.81 (d, JZ14.0 Hz, 1H), 5.12 (dd, JZ
6.0, 7.5 Hz, 1H), 5.83 (s, 1H), 5.96 (s, 1H), 6.08 (s, 1H), 6.46
(s, 1H), 7.42 (d, JZ9.0 Hz, 2H), 8.18 (d, JZ9.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) dC 6.8, 9.4, 17.8, 19.4, 19.6,
38.2, 55.2, 70.0, 73.1, 99.8, 119.9, 123.5 (2C), 126.8, 128.1,
129.5 (2C), 133.9, 134.3, 135.2, 135.6, 137.7, 139.3, 144.6,
145.8, 155.0, 162.0, 180.6; HRMS (ESI) m/e calcd for
C28H32NO6 (MHC) 478.2230, found 478.2241. The IR, 1H
and 13C NMR spectral data are in excellent agreement with
those previously published.7
Data for mixture of 48 and 49: RfZ0.2 (2:1 pentanes/
EtOAc); IR (KBr) 2954 (m), 2856 (m), 1667 (s), 1601 (s),
1519 (s), 1346 (s); HRMS (ESI) m/e calcd for C218H32NO6
(MHC) 478.2230, found 478.2236. Data for 48: H NMR
(400 MHz, CDCl3) dH 1.26 (s, 3H), 1.64 (s, 3H), 1.69 (s,
3H), 1.76 (s, 3H), 1.80 (s, 3H), 2.05 (dd, JZ10.0, 14.0 Hz,
1H), 2.46 (dd, JZ6.5, 14.0 Hz, 1H), 2.74 (s, 1H), 3.56 (s,
1H), 3.91 (s, 3H), 4.02 (d, JZ9.0 Hz, 1H), 4.06 (d, JZ
9.0 Hz, 1H), 4.14 (dd, JZ6.5, 10.0 Hz, 1H), 5.20 (s, 1H),
5.61 (s, 1H), 7.61 (d, JZ8.5 Hz, 2H), 8.81 (d, JZ8.5 Hz,
2H); 13C NMR (100 MHz, CDCl3) dC 6.8, 9.0, 22.2, 22.9,
30.7, 32.0, 42.3, 49.1, 52.6, 55.2, 63.3, 75.0, 81.5, 99.9,
119.5, 122.3, 123.3 (2C), 124.0, 129.5 (2C), 130.7, 130.8,
1
145.1 (2C), 154.7, 162.0, 180.4. Data for 49: H NMR
(400 MHz, CDCl3) dH 1.22 (s, 3H), 1.75 (s, 3H), 1.77 (s,
3H), 1.86 (s, 3H), 1.91–1.94 (m, 1H), 1.92 (s, 3H), 2.57 (dd,
JZ6.5, 13.0 Hz, 1H), 2.72 (s, 1H), 3.42 (s, 3H), 3.61 (s, 1H),
3.78 (d, JZ9.0 Hz, 1H), 4.04 (d, JZ9.0 Hz, 1H), 4.85 (dd,
JZ6.5, 10.0 Hz, 1H), 5.00 (s, 1H), 5.73 (s, 1H), 7.49 (d, JZ
8.5 Hz, 2H), 8.81 (d, JZ8.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) dC 6.7, 9.4, 22.2, 22.3, 30.5, 32.3, 43.2, 51.9, 54.6,
54.9, 58.6, 75.5, 80.6, 99.8, 119.6, 123.1 (3C), 124.4, 130.6
(2C), 130.9, 131.4, 143.6, 147.0, 154.9, 162.0, 180.4.
4.1.23. (G)-2-Methoxy-3,5-dimethyl-6-((E)-4-((2E,4E,6E)-
2,4,6-trimethyl-7-(4-nitrophenyl)hepta-2,4,6-trienyli-
dene)-tetrahydrofuran-2-yl)-4H-pyran-4-one (5a). To a
solution of bromide (E)-43 (195 mg, 0.36 mmol) and
Pd(tBu3P)2 (3.5 mg, 7.2 mmol) in THF (7.5 mL) was
added slowly Me2Zn (360 mL, 2.0 M in PhMe,
0.72 mmol) at rt. The resulting was stirred for 20 min at
rt. Satd aq NH4Cl (3 mL) was added carefully, followed by
brine (3 mL). The mixture was extracted twice with CH2Cl2,
and the combined organics were dried over MgSO4 and
evaporated to dryness in vacuo. The residue was subjected
to column chromatography (silica gel, 2:1 CH2Cl2/EtOAc)
Data for mixture of (G)-1 and (G)-2: HRMS (ESI) m/e
calcd for C28H32NO6 (MHC) 478.2230, found 478.2238.
Data for (G)-SNF4435C (1): RfZ0.16 (2:1 pentanes/
EtOAc); 1H NMR (400 MHz, CDCl3) dH 1.30 (s, 3H),
1.72 (s, 3H), 1.74 (s, 3H), 1.84 (s, 3H), 1.89 (s, 3H), 2.43

1688
M. F. Jacobsen et al. / Tetrahedron 62 (2006) 1675–1689
(d, JZ8.5 Hz, 2H), 2.84 (s, 1H), 3.64 (s, 1H), 3.96 (s, 3H),
3.96 (d, JZ10.0 Hz, 1H), 4.32 (d, JZ10.0 Hz, 1H), 4.76 (t,
JZ8.5 Hz, 1H), 4.94 (s, 1H), 5.58 (s, 1H), 7.54 (d, JZ
9.0 Hz, 2H), 8.20 (d, JZ9.0 Hz, 2H); 13C NMR (125 MHz,
CDCl3) dC 6.9, 9.4, 22.2, 23.0, 30.4, 42.9, 46.3, 51.1, 51.8,
55.5, 63.6, 70.5, 73.5, 100.2, 119.6, 122.0, 123.6 (2C),
123.8, 129.1 (2C), 130.4, 131.0, 145.1, 146.9, 155.0, 162.0,
180.5. Data for (G)-SNF4435D (2): RfZ0.15 (2:1
and Biotechnology, Klong Luang, Pathumthani 12120,
Thailand.
References and notes
1. (a) Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.;
Baldwin, J. E. Org. Lett. 2005, 7, 585–588. (b) Rodriguez, R.;
Adlington, R. M.; Moses, J. E.; Cowley, A.; Baldwin, J. E.
Org. Lett. 2004, 6, 3617–3619. (c) Moses, J. E.; Baldwin, J. E.;
Marquez, R.; Adlington, R. M.; Claridge, T. D. W.; Odell, B.
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Baldwin, J. E.; Adlington, R. M. Org. Lett. 2003, 5, 2987–2988.
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Chem. Eur. J. 1999, 5, 3154–3161. (f) Schwaebisch, D.;
Tchabanenko,K.;Adlington,R.M.;Cowley,A.M.;Baldwin,J.E.
Chem. Commun. 2004, 2552–2553.
1
pentanes/EtOAc); H NMR (400 MHz, CDCl3) dH 1.30 (s,
3H), 1.73 (s, 3H), 1.79 (s, 3H), 1.84 (s, 3H), 1.97 (s, 3H),
2.28 (dd, JZ9.5, 13.0 Hz, 1H), 2.48 (dd, JZ7.0, 13.0 Hz,
1H), 2.73 (s, 1H), 3.53 (s, 3H), 3.74 (s, 1H), 3.83 (d, JZ
9.0 Hz, 1H), 4.18 (d, JZ9.0 Hz, 1H), 4.89 (s, 1H), 4.93 (dd,
JZ7.0, 9.5 Hz, 1H), 5.70 (s, 1H), 7.47 (d, JZ9.0 Hz, 2H),
8.15 (d, JZ9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) dC
6.8, 9.4, 22.1, 22.5, 30.7, 43.0, 45.4, 51.1, 54.8, 55.2, 61.0,
70.6, 72.5, 99.9, 119.7, 121.9, 123.2 (2C), 124.4, 129.9
(2C), 131.2, 131.3, 144.0, 146.9, 154.9, 161.9, 180.5. The
spectral data (1H and 13C NMR) for (G)-1 and (G)-2 in
CDCl3 are in excellent agreement with those previously
reported.3 The spectral data (1H and 13C NMR) for (G)-1
and (G)-2 in DMSO-d6 are also in excellent agreement with
those previously reported.2b Minor errors in the reported
data for (K)-1 (13C NMR) and (C)-2 (1H and 13C NMR) in
CDCl3 by Parker and co-workers are evident by comparison
to their own included copies of spectra, thus making slight
differences from ours.16
2. (a) Kurosawa, K.; Takahashi, K.; Tsuda, E. J. Antibiot. 2001,
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4.1.25. (G)-SNF4435C (1), (G)-SNF4435D (2), 48 and 49
from (G)-5a. To (G)-5a (115 mg, 0.24 mmol) was added
PdCl2(MeCN)2 (15.5 mg, 0.06 mmol) and then dry DMF
(3 mL). The resulting red-brown solution was heated in the
dark at 70 8C for 23 h. Towards the end a precipitate of
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data (1H and 13C NMR) for (G)-1 and (G)-2 were identical
to those above.
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40 and 4%, respectively [Chem. Abstr., 128, 47383].3 In
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Acknowledgements
We thank Roche for funding to Mikkel F. Jacobsen
and EPSRC for funding to John E. Moses. We thank
Dr. B. Odell for NMR assistance. We are grateful for an
authentic sample of (K)-spectinabilin (5) donated by
Dr. M. Isaka, National Center for Genetic Engineering
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