The total synthesis of spectinabilin and its biomimetic conversion to SNF4435C and SNF4435D

Article abstract of DOI:10.1021/ol0507874

(Chemical Equation Presented) A short synthesis of (±)-spectinabilin via a trans-selective Suzuki coupling and subsequent Negishi-type methylation, and its biomimetic conversion to (±)-SNF4435C and (±)-SNF4435D is described.

Full text of DOI:10.1021/ol0507874

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2473-2476
The Total Synthesis of Spectinabilin and
Its Biomimetic Conversion to SNF4435C
and SNF4435D
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
jack.baldwin@chem.ox.ac.uk
Received April 12, 2005
ABSTRACT
A short synthesis of (
±
)-spectinabilin via a trans-selective Suzuki coupling and subsequent Negishi-type methylation, and its biomimetic
)-SNF4435D is described.
conversion to ( )-SNF4435C and (
±
±
The creation of a biogenetic hypothesis for the formation of
complex natural products based on cycloadditions and/or
electrocyclizations, and supported with experimental dem-
onstration through biomimetic synthesis, has proven to be a
powerful combination in organic synthesis that is of con-
tinued interest to us.1 In this respect, the recently reported
isolation of two novel polypropionate derived metabolites
from Streptomyces spectabilis, SNF4435C (1) and SNF4435D
(2), caught our attention (Scheme 1).2,3 Biologically, both
homochiral compounds have been shown to selectively
suppress induced B-cell proliferation versus induced T-cell
proliferation and show potent immunosuppressive activity
in vitro. This activity indicates a different mode of action
from that of known immunosuppressants cyclosporine A
(CsA) and FK-506, thus opening up the possibility of
developing new immunosuppressants based on these novel
structures.4,5 These compact molecules feature five stereo-
genic centers, four of which reside on the cyclobutane ring
of the rare bicyclo[4.2.0]octadiene nucleus, that hitherto has
only been encountered in a few natural products, among them
the endiandric acids.6 Interestingly, another metabolite spec-
tinabilin (3) has been isolated from the same actinomycete.7,8
Although 3 possesses insignificant biological activities, its
complex polypropionate-acetate structure alone featuring a
(1) (a) Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.; Baldwin, J.
E. Org. Lett. 2005, 7, 585. (b) Rodriguez, R.; Adlington, R. M.; Moses, J.
E.; Cowley, A.; Baldwin, J. E. Org. Lett. 2004, 6, 3617. (c) Moses, J. E.;
Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Claridge, T. D. W.; Odell,
B. Org. Lett. 2003, 5, 661. (d) Moses, J. E.; Commeiras, L.; Baldwin, J.
E.; Adlington, R. M. Org. Lett. 2003, 5, 2987. (e) Baldwin, J. E.; Claridge,
T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead,
R. C. Chem. Eur. J. 1999, 5, 3154.
(4) Kurosawa, K.; Takahashi, K.; Fujise, N.; Yamashita, Y.; Washida,
N.; Tsuda, E. J. Antibiot. 2002, 55, 71.
(5) Kurosawa, K.; Takahashi, K.; Tsuda, E.; Tomida, A.; Tsuro, T. Jpn.
J. Cancer Res. 2001, 92, 1235.
(6) Banfield, J. E.; Black, D. St. C.; Johns, S. R.; Willing, R. I. Aust. J.
Chem. 1982, 35, 2247.
(7) Kakinuma, K.; Hanson, C. A.; Rinehart, K. L. Tetrahedron 1976,
32, 217.
(2) Kurosawa, K.; Takahashi, K.; Tsuda, E. J. Antibiot. 2001, 54, 541.
(3) Takahashi, K.; Tsuda, E.; Kurosawa, K. J. Antibiot. 2001, 54, 548.
(8) Isaka, M.; Jaturapat, A.; Kramyu, J.; Tanticharoen, M.; Thebtaranonth,
Y. Antimicrob. Agents Chemother. 2002, 46, 1112.
10.1021/ol0507874 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/12/2005

(E,E,E,Z)-3 would undergo E/Z-isomerizations to form the
(E,Z,Z,Z)-isomer,16 which would subsequently be transformed
via a thermally allowed conrotatory 8π-electrocyclization to
cyclooctatrienes 5 and 6 with possible bias toward 5 via 1,3-
asymmetric induction from the C6-stereocenter (Scheme 2).
Scheme 1. Metabolites from Streptomyces spectabilis
(SNF4435C (1), SNF4435D (2), and Spectinabilin (3)) and from
Streptomyces thioluteus (Aureothin (4))
Scheme 2. Proposed Biosynthesis of SNF4435C, SNF4435D,
1, and 2 from Spectinabilin (3)
highly substituted tetraene moiety makes it a challenging
synthetic target worth pursuing. In addition, it is a consti-
tutional isomer of 1 and 2. To this end, we9 and others10,11
have recently proposed a biogenetic hypothesis for the
formation of 1 and 2 from 3 that bears resemblance to the
hypothesis proposed by Black for the formation of the
endiandric acids,6 which was subsequently experimentally
supported by the work of Nicolaou.12 We now report the
first total synthesis of (()-3 and its subsequent biomimetic
conversion to (()-1 and (()-2 through a cascade of E/Z-
isomerizations and electrocyclizations.
Although 3 and the related simpler polypropionate-acetate
metabolite aureothin (4) are usually isolated as single
enantiomers in Nature, it has been reported that 313 and 414
are prone to racemization due to the labile C6-proton.
Therefore, we simplified the task of demonstrating our
biogenetic hypothesis by developing a short and efficient
synthesis of racemic 3 based on our strategy previously
developed for the synthesis of (()-aureothin (4).15 In our
proposed biosynthesis of 1 and 2 from 3, we envisaged that
The transition structures 7 and 8 may possess a helical
geometry in accord with studies of conrotatory 8π-electro-
cyclizations via ab initio molecular orbital theory.17 The
cyclooctatrienes 5 and 6 could last undergo an endo-selective
disrotatory 6π-electrocyclization to form 1 and 2, respec-
tively.
Our short synthesis of (()-3 starts from boronic ester 9,
which was easily synthesized from known pyrone 10
(Scheme 3).15 Suzuki coupling of 9 with dibromide 11, using
TlOEt as base, proceeded with complete trans-selectivity
with respect to 11 affording the light-sensitive 12 as a
separable E/Z mixture (E/Z, 1:1.2). The required dibromide
11 was synthesized from the known aldehyde 13,18 which
can be obtained in three steps from p-nitrobenzaldehyde. The
Negishi-type coupling of (Z)-12 with Me2Zn proceeded with
full retention of stereochemistry and efficiently afforded pure
(()-3.19 The same procedure was applied to the synthesis
of the (E,E,E,E)-isomer, isospectinabilin (3a), from (E)-12.
(9) Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Cowley,
A. R. Org. Lett. 2002, 4, 3731.
(10) Trauner and co-workers were the first to propose that 2 is
diastereomeric to 1 with respect to all stereocenters except C6, which was
later confirmed by Parker and co-workers (ref 11), see: Beaudry, C. M.;
Trauner, D. Org. Lett. 2002, 4, 2221.
1
The spectral data for (()-3 (IR, H NMR, 13C NMR) were
(11) (a) Parker, K. A.; Lim,Y.-H. J. Am. Chem. Soc. 2004, 126, 15968.
(b) Parker, K. A.; Lim, Y.-H. Org. Lett. 2004, 6, 161.
(12) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc.
1982, 104, 5560 and references therein.
(13) In fact, the isolation of partially racemized 3 has been reported,
see: Nair, M. G.; Chandra, A.; Thorogod, D. L. Pestic. Sci. 1995, 43, 361.
(14) Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yamamura, S. Bull. Chem.
Soc. Jpn. 1995, 68, 3643.
in excellent agreement to that of an authentic sample of (-)-
(16) Parker and co-workers synthesized (-)-1 and (+)-2 by forming the
(E,Z,Z,Z)-isomer in situ via a Stille coupling; see ref 11.
(17) Thomas, B. E., IV; Evanseck, J. D.; Houk, K. N. J. Am. Chem.
Soc. 1993, 115, 4165.
(18) Moses, J. E.; Baldwin, J. E.; Bru¨ckner, S.; Eade, S. J.; Adlington,
R. M. Org. Biomol. Chem. 2003, 1, 3670.
(15) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E.
Org. Lett. 2005, 7, 641.
(19) Shi, J.-C.; Zeng, X.; Negishi, E.-I. Org. Lett. 2003, 5, 1825.
2474
Org. Lett., Vol. 7, No. 12, 2005

3,20 and to the previously reported data.7 In addition, the
previously tentative assignmemt7 of the (E,E,E,Z)-geometry
of 3 was confirmed by 1D nOe experiments.21
Table 1. Synthesis of (()-1, (()-2, and Isomers 14 and 15
from (()-3 or Its (E,E,E,E)-Isomer 3aa,b
Scheme 3. Synthesis of (()-3 and Its (E,E,E,E)-Isomer 3a
from Boronic Ester 9
mol % of
entry substrate PdCl2(MeCN)2
temp,
°C
ratio
1:2:14:15c
yield,d
%
1
2
3
4
5
6
7
3
3
3
3
3
3
3a
0
25
25
25
25
70 3.6:1:0:0
23
<5
40
nd
nd
∼0
31
20 4.5:1.0:4.5:1.7
70 2.8:1.1:2.1:1.0
50 3.9:1.0:2.8:1.2
110 2.9:1.0:2.0:1.1
70 nd
100
25
70 2.0:1.0:5.7:3.0
a Reactions were performed in DMF in the dark. b nd ) not determined.
c Ratios determined from analysis of 1H NMR spectra of crude product.
d Sum of isolated yields of 1, 2, 14, and 15.
Next, we examined various conditions for the conversion
of 3 to 1 and 2. Neither 1 nor 2 could be detected (1H NMR)
by exposure of 3 in solution to sunlight.22 On the other hand,
heating a solution of (()-3 in DMF at 70 °C for 3 days
resulted in 23% of (()-1 and (()-2 as a 3.6:1 mixture after
extensive purification by preparative TLC (Table 1, entry
1). In an attempt to optimize this conversion, we considered
palladium(II) methodology to facilitate the requisite E to Z
isomerization, i.e., (E,E,E,Z) to (E,Z,Z,Z), as we have
previously demonstrated in a model study.9 However, when
3 was subjected to PdCl2(MeCN)2 under standard conditions9
at room temperature only traces 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 3 in DMF with 25 mol % of PdCl2-
(MeCN)2 at 70 °C for 1 day in the dark (entry 3). This
afforded 22% of a separable 2.5:1 mixture of (()-SNF4435C
(1) and (()-SNF4435D (2).23 To our surprise, 18% of two
unexpected isomers 14 and 15 could also be isolated in a
2.1:1 ratio from the reaction mixture.24
Lower temperatures led to a more complex reaction
mixture (entry 4), whereas elevated temperatures or higher
catalyst loading led to increased decomposition (entry 5 and
6). Also, the individual ratios 1:2 and 14:15 decreased with
increasing temperature, while the overall ratio of 1 and 2 to
14 and 15 remained nearly constant (entry 2-5). Interest-
ingly, the ratios of 1 and 2 are close throughout to that found
in Nature (2.3:1),3 thus supporting our biogenetic hypothesis
for their formation. The 1,3-diastereoselection induced from
the C6-stereocenter in the 8π-electrocyclization step is almost
of the same magnitude for 14 and 15 compared to 1 and 2,
resulting in roughly equal ratios of 1:2 and 14:15.
The formation of 14 and 15 is consistent with the 8π/6π-
electrocyclization cascade of either of the (Z,Z,Z,Z)- and
(E,Z,Z,E)-isomers, 3b and 3c (Scheme 4). We have not
observed this “over-isomerization” previously with similar
tetraenes.9,18 X-ray structures have indicated a lack of
planarity of the polyene backbone of structures similar to 3
presumably due to 1,3-steric interactions between the methyl
groups.9,18 This should lead to a decrease in the 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.25 Hence, we favor that 14 and 15 may be formed
(20) We are grateful for an authentic sample of (-)-spectinabilin (3)
donated by Dr. M. Isaka, National Center for Genetic Engineering and
Biotechnology, Klong Luang, Pathumthani 12120, Thailand.
(21) See the Supporting Information.
(22) Spectinabilin (3) is sensitive to light and will during initial exposure
to sunlight in solution undergo E to Z isomerization of the C14-C15 double
1
bond as observed by H NMR. The same is true for the C10-C11 double
(24) Isomers 14 and 15 were only formed in trace amounts (1H NMR)
when subjecting 3 to heating in DMF without PdCl2(MeCN)2. The structure
of 14 and 15 was unambiguously confirmed by NMR, IR, and HRMS; see
the Supporting Information.
bond in aureothin (4). Prolonged exposure of 3 to light leads to a complex
product mixture.
(23) 1 and 2 could be separated by preparative TLC, see the Supporting
Information.
(25) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627.
Org. Lett., Vol. 7, No. 12, 2005
2475

In conclusion, we have developed a short and efficient
total synthesis of (()-spectinabilin (3) from boronic ester
915 that demonstrates the usefulness of palladium-mediated
reactions in the efficient assembly of congested polyene
structures. The successful biomimetic conversion of spec-
tinabilin (3) to SNF4435C (1) and SNF4435D (2) shows that
our biogenetic hypothesis connecting these natural products
is chemically feasible. If the hypothesis is true, it seems likely
that Nature uses efficient enzyme-mediated E/Z-isomeriza-
tions which the subsequent cyclization cascade is likely to
benefit from as well.26
Scheme 4. Proposed Cascade for the Formation of 14 and 15
Acknowledgment. We thank Roche for funding to
Mikkel F. Jacobsen and EPSRC for funding to J. E. Moses.
We thank Dr. B. Odell for NMR assistance.
Supporting Information Available: Full experimental
details, and copies of spectra (1H NMR and 13C NMR) for
compounds (()-1, (()-2, (()-3, 3a, (E)-12, (Z)-12, 14. and
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0507874
predominately via the (E,Z,Z,E)-isomer 3c. In support of this
was the observation that subjection of the (E,E,E,E)-isomer
3a to similar conditions provided 23% of a 1.9:1 mixture of
14 and 15 and minor amounts of 1 and 2 (8%) (entry 7).
(26) For an example of enzymatic E/Z-isomerization in Nature, the
conversion of tetraene all-trans-retinol to 11-cis-retinol in the retinoid cycle,
see: Kuksa, V.; Imanishi, Y.; Batten, M.; Palczewski, K.; Moise, A. R.
Vision Res. 2003, 43, 2959.
2476
Org. Lett., Vol. 7, No. 12, 2005