A total synthesis of tarchonanthuslactone exploiting N-pyrrole carbinols as efficient stereocontrolling elements

Article abstract of DOI:10.1021/ol052333c

(Chemical Equation Presented) A short stereoselective total synthesis of the polyketide natural product, tarchonanthuslactone, has been achieved. The key sequence involves the first reported catalytic enantioselective reduction of an N-acyl pyrrole and su

Full text of DOI:10.1021/ol052333c

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5813-5816
A Total Synthesis of
Tarchonanthuslactone Exploiting
N-Pyrrole Carbinols as Efficient
Stereocontrolling Elements
Mark S. Scott,† Chris A. Luckhurst,‡ and Darren J. Dixon*,§
UniVersity Chemical Laboratory, UniVersity of Cambridge, Lensfield Road,
Cambridge, CB2 1EW, United Kingdom, AstraZeneca R&D Charnwood,
Bakewell Road, Loughborough, LE11 5RH, United Kingdom, and School of Chemistry,
The UniVersity of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
darren.dixon@man.ac.uk
Received September 26, 2005
ABSTRACT
A short stereoselective total synthesis of the polyketide natural product, tarchonanthuslactone, has been achieved. The key sequence involves
the first reported catalytic enantioselective reduction of an N-acyl pyrrole and subsequent use of this stereocenter in a diastereoselective
reductive cascade. This proceeded with unprecedentedly high stereocontrol and offered an elegant method of generating the desired syn
stereochemistry present in the final target in one step.
Tarchonanthuslactone 1, a polyketide natural product, was
first isolated from the leaves of Tarchonanthus trilobus in
1979.1 It has been shown to lower the blood plasma glucose
level in diabetic rats.2 As part of its structural makeup it
contains an R,â-unsaturated δ-lactone as well as two ste-
reogenic acyloxy groups in a 1,3-syn relationship. The
compound belongs to a group of biologically active natural
products possessing these structural motifs and its relatives
include passifloricin and the cryptocarya family.3 As a
consequence tarchonanthuslactone 1 and its cousins have
been the subject of a number of total syntheses.4
metric synthetic methodology for its construction. More
specifically, we believed this natural product offered us the
perfect opportunity to develop a new method for the catalytic
asymmetric construction, and subsequent application of the
N-pyrrole carbinol motif in total synthesis.
Pyrrole carbinols are remarkably stable R-amino alcohols5
that have been used as protecting groups for aldehydes,6
isolated as intermediates in synthesis,7 and, most recently,
(3) (a) Andrianaivoravelona, J. O.; Sahpaz, S.; Terreaux, C.; Hostettmann,
K.; Stoeckli-Evans, H.; Rasolondramanitra, J. Phytochemistry 1999, 52, 265.
(b) Echeverri, F.; Arango, V.; Quinones, W.; Torres, F.; Escobar, G.; Rosero,
Y.; Archbold, R. Phytochemistry 2001, 56, 881. (c) Bouzbouz, S.; Cossy,
J. Org. Lett. 2003, 5, 1995.
(4) (a) Nakata, T.; Hata, N.; Iida, K.; Oishi, T. Tetrahedron Lett. 1987,
28, 5661. (b) Mori, Y.; Kageyama, H.; Suzuki, M. Chem. Pharm. Bull.
1990, 38, 2574. (c) Mori, Y.; Suzuki, M. J. Chem. Soc., Perkin Trans. 1
1990, 1809. (d) Solladie, G.; GressotKempf, L. Tetrahedron: Asymmetry
1996, 7, 2371. (e) Reddy, M. V. R.; Yucel, A. J.; Ramachendran, P. V. J.
Org. Chem. 2001, 66, 2512. (f) Garaas, S. D.; Hunter, T. J.; O’Doherty, G.
A. J. Org. Chem. 2002, 67, 2682. (g) Enders, D.; Steinbusch, D. Eur. J.
Org. Chem. 2003, 4450.
The attractive structure and biological activity of tarcho-
nanthuslactone made it an ideal target to develop new asym-
† University of Cambridge.
‡ AstraZeneca R&D Charnwood.
§ University of Manchester.
(1) Bohlmann, F.; Suwita, A. Phytochemistry 1979, 18, 677.
(2) Hsu, F. L.; Chen, Y. C.; Cheng, J. T. Planta Med. 2000, 66, 228.
10.1021/ol052333c CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/30/2005

exploited as stereodirecting groups in diastereoselective
transformations.6b The formation of pyrrole carbinols is
possible by addition of metal pyrrolates to aldehydes or by
reaction of N-acyl pyrroles with organometallic or hydride
reagents.5,6 To date, an efficient, catalytic enantioselective
synthesis of this masked aldehyde equivalent remains elusive
despite its potential value in asymmetric synthesis.
The reactivity and spectroscopic properties of N-acyl pyrrol-
es (νmaxCdO 1713-1722 cm-1) are similar to those of ke-
tones.5,8 This led us to believe that N-acyl pyrroles could be
ideal substrates in catalytic asymmetric reduction reactions,
where reagents such as acetophenone are reduced with high
enantioselectivity.9 Because such reactions are now common-
place in the literature and N-acyl pyrroles are readily prepared
by a variety of methods5,8 we believed this approach could
provide powerful asymmetric access to the N-pyrrole carbinol
motif.
Table 1. Enantioselective CBS Reductions of N-Acyl Pyrroles
entry
R
temp/°C
ee/%a
productb
yield/%c
a
b
c
d
e
f
Me
Me
Me
H
n-Pr
OBn
10
0
-10
0
90
89
92
82
79
98
6a
6a
6a
6b
6c
6d
92
87
89
95
85
98
0
0
a Determined by chiral stationary phase HPLC. b The (S)-stereochemistry
of 6a was determined by Mosher ester analysis; 6b-d were assigned by
analogy. c Isolated yield after chromatography on silica gel.
We envisaged that the successful asymmetric generation
of the pyrrole carbinol could be exploited as a key step in
the total synthesis of tarchonanthuslactone 1. Our synthetic
strategy is shown in Scheme 1. Asymmetric reduction of
sulfide complex. We were pleased to find the reaction was
complete in 90 minutes, and after workup and purification,
carbinol 6a was isolated in an excellent yield (92%) and with
89% enantiomeric excess favoring the (S)-enantiomer
(entry a).11 Subsequent experiments demonstrated that cool-
ing the reaction mixture had little effect on yield or
enantioselectivity (entries b and c).
A substrate screen revealed that the enantioselective
reduction was general. Thus at 0 °C, N-acetyl, N-pentoyl,
and N-benzyloxyacetyl pyrroles were all reduced with good
enantioselectivity and afforded the respective N-pyrrole
carbinols in high yield (entries d-f).
Scheme 1. Synthetic Plan for Tarchonanthuslactone
Employing a Key N-Pyrrole Carbinol Intermediate
Having established proof of principle, we turned our
attention to the synthesis of tarchonanthuslactone. To avoid
Scheme 2. Highly Enantioselective Synthesis of Key
N-Pyrrole Carbinol Intermediate 3
N-acyl pyrrole 4 possessing a masked 1,3-diketone func-
tionality should provide pyrrole carbinol 3, bearing a 1,3-
related dione, after chemical manipulation. Exploitation of
this newly formed stereocenter in a syn-selective reductive
cascade should afford the syn,syn-1,3,5-triol and application
of our deprotective olefination reaction6 should furnish ester
2. Subsequent pyranone formation and esterification of the re-
maining alcohol was expected to complete the total synthesis.
To assess the feasibility of this approach the reduction of
N-propionoyl pyrrole 5a was studied using commercially
available Me-(R)-CBS reagent under standard conditions
(Table 1).10 Thus a solution of 5a in toluene at 0 °C was
treated with Me-(R)-CBS (20 mol %) and borane dimethyl
(5) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem., Int. Ed. 2002,
41, 3188 and references therein.
(6) (a) Dixon, D. J.; Scott, M. S.; Luckhurst, C. A. Synlett 2003, 2317.
(b) Dixon, D. J.; Scott, M. S.; Luckhurst, C. A. Synlett 2005, 2420. (c) See
also: Cheeseman, M.; Feuillet, F. J. P.; Johnson, A. L.; Bull, S. D. Chem.
Commun. 2005, 2372.
(7) (a) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2005, 44, 4365. (b) Matsunaga, S.; Kinoshita, T.; Okada,
S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559.
(8) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595.
chemoselectivity issues, we reasoned that the desired 1,3-
diketone functionality would have to be masked during the
5814
Org. Lett., Vol. 7, No. 26, 2005

reduction of the N-acyl pyrrole functionality. An isoxazole
was an attractive solution to this problem as the subsequent
chemical manipulations required to liberate the 1,3-diketone
were thought to be compatible with the pyrrole carbinol
motif. Consequently, N-acyl pyrrole 4 was synthesized in
high yield over two steps from 1,1′-carbonyldipyrrole
(CDP).5 Treatment of 2,5-dimethylisoxazole 7 with n-butyl-
lithium at -78 °C followed by CDP gave 4 in multigram
quantities after workup and treatment of the crude product
with DBU.5 To our initial disappointment, enantioselective
reduction of 4 with Me-(S)-CBS reagent following the
previously optimized conditions gave only a trace of product.
This low reactivity was attributed to coordination of borane
to the nitrogen of the isoxazole ring, and the low solubility
of 4 in toluene.12 To overcome this problem, the reaction
was repeated in dichloromethane and an additional equivalent
of borane dimethyl sulfide complex was employed. Gratify-
ingly this resulted in the formation of carbinol 9 in 98% yield
and 95% ee on a multigram scale. Recrystallization gave 9
in 92% yield and greater than 99.5% ee.13
Scheme 3. Completion of the Total Synthesis of
Tarchonanthuslactone via a Highly Diastereoselective Reductive
Cascade on 3 to syn,syn-1,3,5-Triol 11
Reductive cleavage of the N-O bond with molybdenum
hexacarbonyl in wet acetonitrile proceeded in good yield to
give enamine 10.14 This was hydrolyzed to the diketone 3
in quantitative yield using aqueous acetic acid (Scheme 2).
Despite the potential synthetic value in the simultaneous
creation of syn-1,3-related polyol sequences from parent
hydroxy polyones, to the best of our knowledge there has
been only one report of a moderately syn-selective reductive
cascade to afford a syn,syn-1,3,5-triol.15 This reaction
employed a combination of titanium tetraisopropoxide and
sodium borohydride on a 1-hydroxy-3,5-diketone starting
material and gave at best 88:12 selectivity for the syn,syn
diastereomer over all others combined.15a
In our case, treatment of 3 with diethylmethoxy borane
and sodium borohydride in THF/methanol16 at -78 °C
smoothly reduced the hydroxydione 3 to the syn,syn-1,3,5-
triol 11, introducing all of the necessary stereocenters in our
target, in excellent diastereoselectivity (75:1:1:1) and good
yield (Scheme 3). This high diastereoselectivity is thought
to arise through two, sequential diastereoselective keto group
reductions, accelerated in each case by a boron chelate to
the proximal â-carbinol. Thus, an initial axial attack of
hydride on the 3-keto group, activated through a six-mem-
bered-ring boron chelate to the proximal N-pyrrole carbinol,
lead to the formation of the first stereocenter with high
stereocontrol. This was followed by a similar stereoselective
process on the 5-keto group but controlled by a boron chelate
to the newly formed 3-carbinol.16 Pyrrole carbinol 11 was
then subjected to our deprotective HWE conditions6,17 to give
the key R,â-unsaturated ester 2 in 97% yield as a single
diastereomer after purification. Base-catalyzed conjugate
addition of benzenethiol followed by acid-catalyzed lacton-
ization gave alcohol 12,18 which was coupled with known
acid 134d to afford ester 14. Treatment of this ester with DBU
in CH2Cl2 at 0 °C facilitated the elimination of benzene thiol
to afford 15. Finally, reaction of 15 with benzoic acid-
buffered tetrabutylammonium fluoride (TBAF) afforded
tarchonanthuslactone 1 in excellent yield (98%).19
(9) Cyclic meso-imides have been desymmetrized by reduction; see: (a)
Dixon, R. A.; Jones, S. Tetrahedron: Asymmetry 2002, 13, 1115. (b)
Ostendorf, M.; Romagnoli, R.; Cabeza Pereiro, I.; Roos, E. C.; Moolenaar,
M. J.; Speckamp, W. N.; Hiemstra, H. Tetrahedron: Asymmetry 1997, 8,
1773. (c) Romagnoli, R.; Roos, E. C.; Hiemstra, H.; Moolenaar, M. J.;
Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E. Tetrahedron Lett. 1994,
35, 1087.
(10) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987.
(11) The absolute stereochemistry was determined by Mosher’s ester
analysis (ref 6b) and is consistent with that predicted by the standard CBS
model (ref 10).
In summary, an efficient total synthesis of tarchonanthus-
lactone has been achieved in 12 steps and 28% yield from
1,1′-carbonyldipyrrole. The stereocontrol in the sequence is
the result of an enantioselective catalytic asymmetric reduc-
tion of an N-acyl pyrrole, followed by a highly diastereo-
(17) For a similar transformation of N-hydroxyalkyl-5,5-dimethyloxazo-
lidin-2-ones see: Bach, J.; Blache`re, C.; Bull, S. D.; Davies, S. G.;
Nicholson, R. L.; Price, P. D.; Sanganee, H. J.; Smith, A. D. Org. Biomol.
Chem. 2003, 1, 2001 and references therein.
(12) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 785.
(13) Determined by chiral stationary phase HPLC.
(14) Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans. 1 1985, 1401.
(15) (a) Bonini, C.; Righi, G.; Rossi, L. Tetrahedron 1992, 48, 9801.
For a moderately selective 1,3,5-all-anti reduction see: (b) Evans, D. A.;
Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
(16) Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M.
J. Tetrahedron Lett. 1987, 28, 155.
(18) Bernardi, R.; Ghiringhelli, D. Gazz. Chim. It. 1992, 122, 395.
(19) The spectroscopic data and specific rotation of the synthetic material
are in good agreement with the literature values and confirmed the absolute
and relative stereochemistry of the intermediates in the sequence. [R]25
D
-80.0 (c 0.4, CHCl3) [lit.4d [R]D -83.0 (c 0.4, CHCl3)].
Org. Lett., Vol. 7, No. 26, 2005
5815

selective syn-selective reductive cascade. Further work in
this and related areas will be reported in due course.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We wish to thank AstraZeneca and
EPSRC for a studentship (to M.S.S.). We are also indebted
to the EPSRC National Mass Spectrometry Service Centre,
Swansea, UK for analysis.
OL052333C
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Org. Lett., Vol. 7, No. 26, 2005