A short approach to the bicyclo[4.3.0]nonane fragment of stawamycin

Article abstract of DOI:10.1016/j.tetlet.2005.05.004

The bicyclo[4.3.0]nonane (C₁₁-C₂₁) fragment of stawamycin has been prepared by a sequence involving 11 steps (10% overall yield) from methyl (R)-(-)-3-hydroxy-2-methylpropionate. Key steps are a Pd-catalysed Stille coupling reaction

Full text of DOI:10.1016/j.tetlet.2005.05.004

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4427–4431
A short approach to the bicyclo[4.3.0]nonane
fragment of stawamycin
Luiz C. Dias,* Gliseida Z. Melgar and Luciana S. A. Jardim
´
Instituto de Quımica, Universidade Estadual de Campinas, UNICAMP C.P. 6154, 13084-971 Campinas, SP, Brazil
Received 5 April 2005; revised 3 May 2005; accepted 3 May 2005
Abstract—The bicyclo[4.3.0]nonane (C11–C21) fragment of stawamycin has been prepared by a sequence involving 11 steps (10%
overall yield) from methyl (R)-(À)-3-hydroxy-2-methylpropionate. Key steps are a Pd-catalysed Stille coupling reaction between
a vinyl iodide and a vinyl stannane followed by an intramolecular Diels–Alder cycloaddition reaction to give the desired adduct
as the major isomer in 21% overall yield.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
not determined), a doubly allylic alcohol and a sodium
carboxylate residue.3,4
Epstein-Barr virus (EBV) is a human herpes virus that
infects lymphocytes and epithelial cells. It has been esti-
mated that this virus infects a large part of the worldÕs
population.1 In 1995, stawamycin (1),2 a new natural
product from the pyrroloketoindane family was isolated
by Miao et al. from a liquid culture of Streptomyces sp.
and displayed moderate inhibitory activity against the
binding of the EBV BZLF1 transcription factor to
DNA with IC50 = 50 lM in a DNA binding assay
(Fig. 1).2 Stawamycin has a trisubstituted trans-fused
endo-bicyclo[4.3.0]nonane substructure containing five
stereogenic centres and a side chain that contains two
stereogenic centres at C3 and C9 (absolute configuration
It has been speculated that stawamycin and the other
members of its family arise biosynthetically by a
Diels–Alder cycloaddition reaction.5 To determine the
relative configurations between C3 and C9, to establish
the absolute configuration of stawamycin, and to pro-
vide material for further biological studies as well as
access to novel analogues, we initiated a study towards
the synthesis of this very interesting compound.6 We
wish to describe here our successful efforts towards the
preparation of the C11–C21 carbocyclic fragment of
stawamycin.
Our disconnection strategy summarised in Scheme 1,
involved cleavage of the C12–C20 and the C15–C19 bonds
in 2 to give the a,b-unsaturated oxazolidinone 3. Fur-
ther synthetic analysis involved the cleavage of the
C13–C14 bond in 3 to give vinyl iodide 4 (C14–C21 frag-
ment) and vinyl stannane 5 (C11–C13 fragment). Key
steps in this approach are a Pd-catalysed Stille coupling
reaction between a vinyl iodide and a vinyl stannane fol-
lowed by an intramolecular Diels–Alder cycloaddition
reaction (IMDA) to set up the remaining four stereo-
genic centres of the bicyclo[4.3.0]nonane fragment.7
O
1
NaO
3
O
N
HO
OH
21
H
11
H
9
19
Stawamycin
15
Me Et
1
16
13
H
Me
Figure 1. Stawamycin.
We decided to investigate the use of chiral and achiral
oxazolidinones attached to the dienophile part of the
triene, since the presence of two carbonyl groups would
offer a two-point binding with the Lewis acid, probably
increasing the endo selectivity under mild conditions.
Keywords: Pyrroloketoindane family; Intramolecular Diels–Alder
reaction; Stille coupling; Lactone.
*
Corresponding author. Tel.: +55 019 3788 3021; fax: +55 019 3788
3023; e-mail: ldias@iqm.unicamp.br
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.004

4428
L. C. Dias et al. / Tetrahedron Letters 46 (2005) 4427–4431
O
O
O
1
NaO
3
O
21
O
21
N
H
N
HO
OH
H
11
H
11
R
9
PMBO
19
17
15
Stawamycin
1
13
Me Et
2
13
C
11−C21
H
H
Me
Me
Fragment
Me
R
16
Intramolecular
Diels-Alder
2
21
3
OPMB
OPMB
O
N
11
O
O
Stille coupling
Bu3Sn
Me
R
+
16
I
21
O
N
5
R = H
R = (R)-Bn
R = (S)-Bn
11
4
O
O
Scheme 1. Retrosynthetic analysis.
2. Results and discussion
At this point, we carried out the preparation of achiral
phosphonate 13a and chiral phosphonates (R)-13b and
(S)-13c.11 These were easily prepared in very good yields
by acylation of the corresponding oxazolidinones 11a–c
with n-BuLi and bromoacetyl bromide followed by reac-
tion with triethyl phosphite, as described in Scheme 3.
Synthesis of the C14–C21 fragment began with the
known p-methoxybenzyl ether 7 (Scheme 2), which
was most conveniently prepared from commercially
available methyl-(R)-(À)-3-hydroxy-2-methylpropionate
6 by treatment with p-methoxybenzyltrichloroacetimi-
date under acid catalysis (CSA, CH2Cl2, 94%).
Aldehyde 10 was directly submitted to Horner–Emmons
coupling reactions with phosphonates 13a–c to give the
corresponding (E)-a,b-unsaturated oxazolidinones 14a–
c with great E:Z selectivities (E:Z >95:5) and in good
overall yields (Scheme 4). The next step involved
DDQ-mediated oxidative deprotection of p-methoxy-
benzyl ethers 14a–c in aqueous CH2Cl2 to provide the
corresponding primary alcohols 15a–c (corresponding
to the C15–C21 segment), in excellent yields.12 Oxida-
tion13 of the primary alcohol functionality in 15a–c using
the Dess–Martin periodinane reagent under the standard
conditions gave the intermediate aldehydes 16 that were
directly submitted to Takai et al.14 olefination reaction
conditions (CHI3, CrCl2, THF) to produce E-vinyl iod-
ides 4a–c in good yields and high selectivities (4a, 13:1
E/Z; 4b, 13:1 E/Z and 4c, 13:1 E/Z).
Ester 7 was smoothly reduced to aldehyde 8 on treat-
ment with diisobutylaluminium hydride in toluene at
low temperature.8,9 The unpurified aldehyde was
directly subjected to a Wittig homologation with the
requisite stabilised ylide reagent to give the (E)-a,b-
unsaturated ester 9 in 86% yield over two steps (E:Z
>95:5 diastereoselectivity). Selective hydrogenation of
the double bond in the a,b-unsaturated ester 9 under
very mild conditions (H2/Pd/C, 25 °C, 1 atm, 40 min,
91%) gave an intermediate ester leaving the PMB group
intact.10 Careful reduction of this ester with diiso-
butylaluminium hydride at À78 °C gave the desired
aldehyde 10.
Me
Me
PMB acetimidate
(1.5 eq.)
O
O
O
DIBAL-H (1.1 eq.)
MeO
MeO
1. n-BuLi (2.28M in THF, 1.1 eq.)
Br
oC, 30 min.
toluene, −90 o
45 min.
C
CSAcat., CH2Cl2
rt, 18h, 94%
O
N
6
O
NH THF, −78
O
OH
OPMB
O
7
O
12a, R = H (85%)
12b, R = (R)-Bn (86%)
12c, R = (S)-Bn (87%)
2.
Br
Br
Me
R
R
Me
(1.5 eq.)
Ph3P=CHCO2Et (1.6 eq.)
CH2Cl2, ∆, 1h (86%, 2 steps)
H
O
11a, R = H
11b, R = (R)-Bn
11c, R = (S)-Bn
EtO
9
OPMB
OPMB
O
8
E:Z > 95:5
O
O
O
P
13a, R = H (85%)
13b, R = (R)-Bn (86%)
13c, R = (S)-Bn (87%)
1. H2, Pd/C 5% (10 mol%)
MeOH, rt, 91%
Me
P(OEt)3
O
N
(OEt)2
H
50 oC, 5h
2. DIBAL-H (1.0 eq.)
10
OPMB
O
CH2Cl2, 30 min., −78 o
C
R
Scheme 2. Preparation of aldehyde 10.
Scheme 3. Preparation of phosphonates 13a–c.

L. C. Dias et al. / Tetrahedron Letters 46 (2005) 4427–4431
4429
17 (Scheme 5).15 Protection of the primary OH-func-
tionality in 17 with TBSCl gave 18 in 95% yield. Tributyl-
stannylation of 18 with Bu3SnH and AIBN under reflux
in benzene followed by TBS removal with HF–pyr in
pyridine gave pure vinyl stannane 19. Protection of the
OH-function in 19 as its PMB ether (PMB-acetimidate,
CH2Cl2, catalytic CSA) gave the corresponding C11–C13
segment 5 (E:Z 92:08) in 77% yield after purification by
flash chromatography.15
R
Me
LiCl (7 eq.), DIPEA (1.1 eq.)
CH3CN, rt, 20h
H
N
(OEt)2
O
O
+
P
O
10
PMB
O
O
O
O
O
O
13a, R = H (1.15 eq.)
13b, R = (R)-Bn (1.15 eq.)
13c, R = (S)-Bn (1.15 eq.)
R
R
Me
N
Me
DDQ (1.1 eq.)
N
CH2Cl2, H2O, 2h
OH
O
OPMB
O
O
H
15a, R = H (90%)
With the requisite C11–C13 and C14–C21 fragments in
hand, their coupling was undertaken. This was done
by using Stille coupling conditions in the presence of
the palladium dichloride bis-dibenzylideneacetone com-
plex to give the desired E,E,E trienes 3a–c in excellent
yields (Scheme 6).16
14a, R = H (70%, E/Z >95:5)
14b, R = (R)-Bn (85%, E/Z >95:5)
14c, R = (S)-Bn (74%, E/Z >95:5)
15b, R = (R)-Bn (92%)
15c, R = (S)-Bn (95%)
R
CHI3 (6 eq.)
CrCl2 (15 eq.)
Me
Dess-Martin (2.3 eq.)
O
N
THF, 0 oC, 2h
CH2Cl2, pyr, 30 min.
O
O
O
We next investigated the critical Diels–Alder reactions
for assembling the carbocyclic fragment of stawamy-
cin.6,17 Unfortunately, thermal IMDA cycloaddition of
triene 3a resulted in low diastereoselectivity (48:52,
endo(2a):others). The desired endo-cycloadduct 2a was
obtained as a mixture with three other cycloadducts
after flash chromatographic purification in 60% yield.
After extensive experimental work, we observed that
Et2AlCl as Lewis acid provided the best result in terms
of yields. Lewis acid induced cycloaddition reactions
of trienes 3a–c (Et2AlCl (1.0 equiv), CH2Cl2, À30 °C,
2–3 days) gave the desired endo-cycloadducts 2a–c as
the major isomers along with only a second endo-isomer
20a–c after flash column chromatography (Scheme 7). It
is noteworthy that the IMDA reaction with diene 3a,
bearing an achiral oxazolidinone auxiliary, gave the best
results both in terms of yields and selectivities, favouring
the desired cycloadduct 2a (endo-2a/endo-20a = 82:18,
90% yield). The use of dienes 3b and 3c led to disap-
pointing results in terms of selectivities (endo-2b/endo-
20b = 82:18, 85% yield; endo-2c/endo-20c = 42:58, 83%
yield). The observed result with triene 3b was really sur-
prising, since we were expecting much better levels of
diastereoselectivity in a matched case. The best result
with triene 3a shows that we are probably having a com-
petition between the two possible endo transition states.
16a, R = H (90%)
16b, R = (R)-Bn (92%)
16c, R = (S)-Bn (95%)
R
Me
O
N
4a, R = H (81%)
4b, R = (R)-Bn (80%)
4c, R = (S)-Bn (70%)
I
O
E:Z > 13:1
O
Scheme 4. Synthesis of vinyl iodides 4a–c.
1. Bu3SnH (1.2 eq.)
AIBN (10 mol%)
benzene, ∆, 1h, 77%
TBSCl (1.05 eq.)
imidazole (3.0 eq.)
HO
TBSO
CH2Cl2, 1h, 95%
2. HF-pyr, pyridine
2h, 96%
18
18
PMB-acetimidate
(1.5 eq.)
11
SnBu3
11
SnBu3
13
13
5
19
OH
PMBO
CSA (5 mol%), CH2Cl2
18h, 90%
E:Z/92:08
E:Z/92:08
Scheme 5. Preparation of vinyl stannane 5.
The (E)-vinylstannane 5, corresponding to the C9–C11
fragment, was smoothly prepared using a four-step pro-
tocol from commercially available propargylic alcohol
R
Pd3(dba)2 (4.6 mol%)
Me
CuCl (4.8 eq.)
PMBO
SnBu3
(1.2 eq.)
O
N
I
+
5
AsPh3 (13.2 mol%)
THF, rt, 3h
4a, R = H (1.0 eq.)
4b, R = (R)-Bn (1.0 eq.)
4c, R = (S)-Bn (1.0 eq.)
O
O
Ph
Me
Me
O
N
O
N
3a (90%)
> 95:05
3b (92%)
> 95:05
OPMB
Ph
OPMB
O
O
O
O
Me
O
N
3c (95%)
> 95:05
OPMB
O
O
Scheme 6. Stille coupling: preparation of 3a–c.

4430
L. C. Dias et al. / Tetrahedron Letters 46 (2005) 4427–4431
O
O
O
O
O
O
21
N
H
21
N
H
Me2AlCl (1M, 1.0 eq.)
11
11
3a
+
PMBO
2a
PMBO
CH2Cl2, 2 days
17
17
−30 oC, 90%
13
13
H
20a
H
Me
Me
ds 82:18
O
O
O
O
O
O
21
N
H
21
N
H
Me2AlCl (1M, 1.0 eq.)
Ph
Ph
Ph
11
11
3b
3c
PMBO
2b
PMBO
CH2Cl2, 3 days
17
17
−30 oC, 85%
+
13
13
20b
H
H
Me
ds 82:18
Me
O
O
O
O
O
O
21
N
H
21
N
H
Me2AlCl (1M, 1.0 eq.)
Ph
11
11
13
PMBO
2c
PMBO
+
CH2Cl2,3 days
17
17
−30 oC, 83%
13
20c
H
H
Me
Me
ds 42:58
Scheme 7. Intramolecular Diels–Alder reactions.
Although we have not determined the relative stereo-
chemistry at the cycloadduct stage, we have observed
H11a/H19, H11b/H12, H15/H20, H16/H19 and between
H15/Me together with the large vicinal coupling constant
between H20 with both H12 and H19 (dd, 12.2 and
8.9 Hz) confirmed the trans-diaxial relationship between
H19 and H20 as well as the cis relationship between H12
and H20 and unambiguously established the relative ste-
reochemistry of the major isomer as being that desired
for the synthesis of stawamycin. In these stereochemical
assignments, the methyl stereocentre configuration
served as an important reference point.4
that, after treatment with DDQ/H2O, all cycloadducts
led to exactly the same mixture of two lactones (Scheme
8). Treatment of cycloadducts with DDQ/H2O led to
deprotection of the PMB ether followed by lactonisation
to give lactones 21 and 22 in excellent yields. We later
found that the use of 5 equiv of Et2AlCl with 3a–c to
promote the IMDA cycloaddition led to lactones 21
and 22 directly, avoiding the use of the extra step with
DDQ. An analytical sample of lactone 21 was obtained
in order to determine the relative stereochemistry.
3. Conclusions
The observed relative stereochemistry of the major iso-
mer 21 was proved by analysis of coupling constants
This approach to the bicyclo[4.3.0]nonane fragment of
stawamycin requires 11 steps (longest linear sequence)
and produced the desired carbocyclic fragment 2a in
27% overall yield. The best result was obtained with
the use of a triene bearing an achiral oxazolidinone in
the presence of Et2AlCl to promote the IMDA cycload-
dition reaction. As a result, the route to the carbocyclic
fragment of stawamycin presented here is, in principle,
readily applicable for the preparation of stawamycin as
well as to additional analogues. Extension of this work
to the synthesis of stawamycin and analogues is under-
way and the results will be described in due course.18
1
in its H NMR spectrum as well as by NOESY experi-
ments. The illustrated NOESY interactions between
Acknowledgements
We are grateful to FAEP-UNICAMP, FAPESP (Fun-
`
dac¸a˜o de Amparo a Pesquisa do Estado de Sa˜o Paulo)
and CNPq (Conselho Nacional de Desenvolvimento
´
´
Cientıfico e Tecnologico) for financial support. We
thank also Professor Carol H. Collins for helpful sug-
gestions about English grammar and style.
Scheme 8. Lactone formation coupling constants and NOESY inter-
actions for lactone 21.

L. C. Dias et al. / Tetrahedron Letters 46 (2005) 4427–4431
4431
2149; (c) Smith, P. M.; Thomas, E. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 3541.
Supplementary data
9. Alternatively, this same aldehyde can be prepared in two
steps from ester 7 by a sequence involving LiAlH4 reduc-
tion followed by Swern oxidation, in 87% overall yield.
10. Dias, L. C.; Campano, P. L. J. Braz. Chem. Soc. 1998, 9,
97.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/
j.tetlet.2005.05.004.
11. (a) Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62,
786; (b) Evans, D. A.; Scheidt, K. A.; Downey, C. W. Org.
Lett. 2001, 3, 3009; (c) Claremon, D. A.; Dolle, R. E., III.
J. Am. Chem. Soc. 1981, 103, 6967; (d) Koch, S. S. C.;
Chamberlin, A. R. J. Org. Chem. 1993, 58, 2725.
12. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021.
13. For alcohol 15a, oxidation must be done immediately after
deprotection in order to avoid formation of the product
from intramolecular Michael addition reaction.
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O
N
O
N
OH
O
O
O
15a
O
O
Me
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18. New compounds and the additional isolated intermediates
gave satisfactory 1H and 13C NMR, IR, HRMS and
analytical data. Yields refer to chromatographically and
spectroscopically homogeneous materials.