A concise total synthesis of (+)-okaramine C

Article abstract of DOI:10.1039/b410180d

The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]-indole core, which was modified by selective epimerisation to the commo

Full text of DOI:10.1039/b410180d

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C O M M U N I C A T I O N
A concise total synthesis of (+)-okaramine C
Peter R. Hewitt, Ed Cleator and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223 336442;
Tel: +44 (0)1223 336398
Received 6th July 2004, Accepted 30th July 2004
First published as an Advance Article on the web 9th August 2004
The first total synthesis of (+)-okaramine C is described. Our
previously described selenocyclisation-oxidative deselenation
sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]-
indole core, which was modified by selective epimerisation to
the common pyrrolo[2,3-b]indole of the okaramines.
The okaramines are a family of natural products isolated by Hayashi
et al.1 from fermentation extracts of Penicillium simplicissimum and
Aspergillus aculeatus cultured on okara (the soybean residue from
soymilk production).2 The okaramines have been found to have
Scheme 2 Synthetic strategy for okaramine C synthesis.
insecticidal properties; okaramine C 1 itself has an LD50 of 7 g g−1
towards the larvae of silkworm on oral administration,3 and as such
is one of the most potent within the series. Synthetic efforts have
recently led to the total synthesis of two members of the family,
okaramine N 2, by Corey et al.4 and okaramine J 3, by Ganesan
et al. (Fig. 1).5
alcohol 11 in 92% yield. Having used the D-tryptophan stereocentre
to induce selectively the correct stereochemistry at the [5,5]-ring
junction, we needed to epimerise this centre to complete the pyrrolo-
indole core of okaramine C. Systems similar to 11 have been shown
to be sterically crowded due to the all syn relationship around the
[5,5]-ring junction.8 We hoped to exploit this sterically demanding
environment to facilitate the desired epimerisation. Unfortunately,
whilst the desired epimerised alcohol 12 could be produced under
various conditions, it was formed only as a mixture along with the
starting alcohol 11.
In order to increase the steric bulk for this epimerisation
the same reaction was attempted on the precursor selenide 10.
Pleasingly, when 10 was treated with one equivalent of LiH-
MDS at −10 °C in THF, followed by quenching with methanol
at −78 °C, the desired ester 13 was formed as a single epimer in
quantitative yield (Scheme 3). As before, treatment of 13 with wet
m-CPBA resulted in oxidative deselenation giving tertiary alcohol
14 in 85% yield.
Unfortunately a problem was encountered with the deprotec-
tion steps. We had previously observed that the Boc group in the
enantiomer of 11 was removed rapidly in the presence of trifluoro-
acetic acid (TFA).7 However, the relief of steric strain achieved by
epimerising the ester functionality led to 14 being destroyed by
these harsh conditions. Fortunately, a newly described milder alter-
native for Boc deprotections was found to be effective for this trans-
formation.9 Thus treatment of 14 with 1:1 phosphoric acid:CH2Cl2
gave deprotected aniline 15.
Fig. 1 Okaramines C (1), N (2) and J (3).
Although okaramine C appears to be the simplest target within
the series, it has so far proven to be synthetically inaccessible.
Indeed, during the aforementioned okaramine J synthesis, the initial
target was okaramine C. Unfortunately when advanced intermedi-
ate 4 was treated with acid, a facile aza-Claisen rearrangement was
observed. This however allowed a neat synthetic entry to okaramine
J (Scheme 1).5
Finally, removal of the Z group was achieved upon hydro-
genolysis in methanol to give 3a-hydroxy-pyrroloindole 6 as a
single enantiomer in 93% yield over two steps, and overall the left
hand fragment in eight steps and 50% yield.
Scheme 1 Reagents and conditions: a) CF3CO2H (5 eq.), CH2Cl2, 16 h,
84%. Anth = 9-anthracenyl.
The synthesis of a reverse-prenylated tryptophan derivative 16
has been previously described by Danishefsky et al.10 Starting from
phthalimide protected L-tryptophan methyl ester, treatment with
tert-butyl hypochlorite followed by nucleophilic attack of prenyl-
9-BBN on the resulting chloroimine gave the corresponding reverse
prenylated tryptophan 16. Saponification of the methyl ester with
lithium hydroxide in THF/H2O gave the desired carboxylic acid 7
in quantitative yield (Scheme 4).
Coupling of fragments 6 and 7 was carried out by treating acid 7
with HATU followed by pyrroloindole 6. The crude product from
this coupling was then deprotected with hydrazine in methanol at
60 °C. As expected under these conditions cyclisation also occurred
as indicated by HPLC-MS. Unfortunately attempts to isolate the
desired product from this mixture failed.
In order to suppress this aza-Claisen rearrangement we decided
to install the N-reverse-prenyl appendage at a late stage. This led to
diketopiperazine 5 as an advanced intermediate, which in turn could
be assembled from key fragments 6 and 7 (Scheme 2).
The synthesis of 3a-hydroxy-pyrrolo[2,3-b]indole 6 began from
unnatural D-tryptophan 8. Benzyloxycarbonyl (Z)-protection of 8
followed by formation of the methyl ester and t-butyloxycarbonyl
(Boc) protection of the indolic nitrogen afforded 9 in 71% yield
over three steps. Treatment of 9 with N-(phenylseleno)phthal-
imide (N-PSP)6 resulted in cyclisation in accord with our previously
reported work with the corresponding L-tryptophan derivative.7
This gave the selenocyclised product 10 as a single diastereomer in
an excellent 89% yield.
In order to perform the deprotection-cyclisation under
milder conditions, a different N-protecting group was required.
Oxidative deselenation of 10 was effected on addition of wet
meta-chloroperbenzoic acid (m-CPBA) giving the corresponding
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 1 5 – 2 4 1 7
2 4 1 5

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Scheme 3 Reagents and conditions: a) Z–Cl, H2O, NaOH, 88%. b) SOCl2, MeOH, 90%. c) Boc2O, NaOH, DCM, Bu4NHSO4, 90%. d) N-PSP, DCM, PPTS,
Na2SO4, 89%. e) LiHMDS, THF, −10 °C, 10 min, then MeOH, −78 °C → rt, 100%. f) wet m-CPBA 5 eq., K2CO3, DCM, 0 → 25 °C, 85%. g) H3PO4 (aq.),
CH2Cl2. h) H2, Pd/C, MeOH, 93% over two steps.
Accordingly, the phthalimide group was removed from ester 16 in
moderate yield, as reported by Danishefsky,10 and subsequent ester
hydrolysis using barium hydroxide afforded the corresponding free
amino acid. After considerable experimentation, conditions were
found which facilitated the desired coupling and cyclisation. Pro-
tection of the amine as its 2-trimethylsilylethoxycarbonyl (Teoc)
derivative gave acid 17 in good yield. Coupling of this fragment
with amine 6 mediated by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-
tetramethyluronium hexafluorophosphate (HATU), followed by
deprotection with tris(dimethylamino)sulfur(trimethylsilyl) diflu-
oride (TAS-F) and concomitant cyclisation, gave the diketopipera-
zine 5 in excellent yield (Scheme 5). Problems were encountered
using a variety of other protecting groups, for example Z removal
via hydrogenation resulted in over-reduction and removal of Fmoc
with base also caused epimerisation of 5 to yield a mixture of
diastereomers.
(88% yield at 80% conversion). The recovered starting material
could efficiently be recycled in the alkylation step.
Finally, partial reduction of the alkyne 18 completed the synthesis
of okaramine C 1. After attempting to perform this transformation
under a number of conditions, it was found that careful hydrogena-
tion using Lindlar’s catalyst poisoned with 1% pyridine in methanol
gave 1 in 95% yield.
All the data for synthetic okaramine C12 are in accordance with
those published for natural okaramine C.3
In summary, we have completed the first synthesis of okaramine
C 1, using the recently described selenocyclization-oxidative desel-
enation protocol developed in our laboratory to furnish the hydroxy-
pyrroloindole skeleton. In addition, a totally selective epimerisation
of the C2 position of the initial selenide is reported, allowing this
method to be adapted to the total synthesis of the okaramine family
of natural products. We will report the synthesis of more complex
members of this family in due course.
Acknowledgements
We gratefully acknowledge financial support from the ESPRC, BP
endowment and the Novartis Research Fellowship (to SVL). We
thank Professor Hideo Hayashi for providing authentic spectra of
okaramine C for comparison.
Scheme 4 Reagents and conditions: a) t-BuOCl, THF, NEt3, prenyl-9-
BBN, 51%. b) LiOH, 1:1 THF:H2O, rt, 100%.
Notes and references
With the advanced intermediate 5 in hand, all that remained
was the installation of the reverse prenyl fragment on the anilinic
nitrogen. Our initial attempts at this transformation utilised the two-
step procedure described by Corey et al. during their okaramine N
synthesis, namely treatment of a propargylic acetate with copper(I)
chloride in refluxing THF. Unfortunately, in our system these condi-
tions did not afford any of the alkylated product.
However, subjecting 5 to the corresponding alkynyl bromide
in the presence of copper(I) chloride11 effected the transformation
smoothly. Under these conditions the desired alkyne 18 could be
isolated in a 70% yield along with 20% unreacted starting material
1 (a) S. Muaro, H. Hayashi, K. Takiuchi and M. Arai, Agric. Biol. Chem.,
1988, 52, 885; (b) H. Hayashi, K. Takiuchi, S. Muaro and M. Arai, Agric.
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M. Arai, Agric. Biol. Chem., 1989, 53, 461; (d) H. Hayashi, Y. Asabu,
S. Muroa and M. Arai, Biosci. Biotechnol. Biochem., 1995, 59, 246;
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Biosci. Biotechnol. Biochem., 2000, 64, 103.
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Scheme 5 Reagents and conditions: a) H2NNH2, MeOH, rt, 51%. b) Ba(OH)2·8H2O, MeOH, rt, 100%. c) TeocOSu, H2O, NEt3, dioxane, 95%. d) HATU,
DMF, 6, NEt3, rt, 16 h, 95%. e) TAS-F, DMF, rt, 8 h, 97%. f) 2-bromo-2-methyl-but-3-yne, CuCl, THF, DIPEA, rt, 4 days, 88% at 80% conversion. g) Lindlar’s
catalyst, H2, 99:1 methanol:pyridine, 95%.
2 4 1 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 1 5 – 2 4 1 7

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12 Data for synthetic okaramine C: []2d5 +4 (0.1, MeOH); 1H NMR
3 H. Hayashi, T. Fujiwara, S. Muroa and M. Arai, Agric. Biol. Chem.,
1991, 55, 3143.
4 P. S. Baran, C. A. Guerrero and E. J. Corey, J. Am. Chem. Soc., 2003,
125, 5628.
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8 L. E. Overman and D. V. Paone, J. Am. Chem. Soc., 2001, 123, 9465.
9 B. Li, R. Beamish, R. A. Buzon, C. K. F. Chiu, S. T. Colgan, W. Kissel,
T. Le, K. R. Leeman, L. Newell and J. Roth, Tetrahedron Lett., 2003, 44,
8113.
(500 MHz, acetone-d6).  1.51, s C13 Me;  1.53, s, C13′ and C14′ Me;
 1.72 C14 Me;  2.48, dd, J = 13.4 and 10.0 Hz; C3 H;  3.00, dd,
J = 13.4 and 5.5 Hz, C3 H;  3.04, dd, J = 15.2 and 11.0 Hz, C1′H;
 3.68, dd, J = 11.0 and 4.5 Hz, C1′;  4.38 dd, J = 11.0 and 4.3 Hz,
C2′H;  4.48, dd, J = 10.0 and 5.5 Hz, C2 H;  4.61, s, OH;  4.97, d,
J = 10.6 Hz, C4′ H;  5.05, d, J = 17.6 Hz, C4′ H;  5.07, d, J = 10.7 Hz,
C12 H,  5.20, d, J = 17.7 Hz, C12 H;  5.44, s, C8 H;  5.46, br s NH;
 6.16, dd, J = 17.5 and 10.6 Hz, C5′ H,  6.48, dd, J = 17.8 and 10.8 Hz,
C11 H;  6.73, t, J = 7.4 Hz, C5 H;  6.94, d, J = 7.9 Hz, C7 H;  6.95, m
C9′ H;  7.07, m, C6 H and C10′ H;  7.23, d, J = 7.3 Hz, C4 H,  7.32,
d, J = 8.0 H, C8′ H;  7.45, d, J = 7.8 Hz, C11′ H;  9.97, br s, C7′ H.
13C (125 MHz acetone-d6) ppm 170.2, 170.1, 150.0, 149.7, 145.6, 142.8,
136.5, 135.1, 130.4, 130.0, 124.8, 122.5, 120.4, 120.3, 118.8, 115.6,
112.5, 112.3, 111.9, 106.1, 86.0, 84.9, 60.1, 58.7, 56.9, 40.2, 35.3, 28.7,
28.6, 28.5, 26.7, 25.9. The numbering system is the same as appears in
reference 3. The table of 13C chemical shifts in reference 3 contains an
error; the correct values are in agreement with the above.
10 (a) T. M. Kamenecka and S. J. Danishefsky, Angew. Chem., Int. Ed.,
1998, 37, 2993; (b) T. M. Kamenecka and S. J. Danishefsky, Angew.
Chem., Int. Ed., 1998, 37, 2995; (c) T. M. Kamenecka and S. J.
Danishefsky, Chem. Eur. J., 2001, 7, 41.
11 G. F. Hennion and R. S. Hanzel, J. Am. Chem. Soc., 1960, 82, 428.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 1 5 – 2 4 1 7
2 4 1 7