Total synthesis of hirsutellone B

Full text of DOI:10.1002/anie.200903382

Communications
DOI: 10.1002/anie.200903382
Natural Product Synthesis
Total Synthesis of Hirsutellone B**
K. C. Nicolaou,* David Sarlah, T. Robert Wu, and Weiqiang Zhan
Hirsutellones,[1] pyrrospirones,[2] and pyrrocidines[3] belong to
a growing class of fungal secondary metabolites whose
biological properties include antifungal and antibiotic activ-
ities. Particularly impressive are the activities of hirsutello-
nes A and B (1a and 1b, Figure 1)[1] against Mycobacterium
the other structural motifs associated with it. Its forging was
therefore designed to proceed through a sequence involving
formation of a larger ring and subsequent ring contraction.
For the equally intriguing fused tricyclic core of the target
molecule, we intended a cascade sequence from an acyclic
carbon chain precursor containing an epoxide moiety as an
initiating site and a trimethylsilyl group as a terminator.
Scheme 1 presents, in retrosynthetic format, the devised
Figure 1. Molecular structures of hirsutellones A (1a) and B (1b).
tuberculosis [MIC = 0.78 mgmLꢀ1 (MIC = minimum inhibi-
tory concentration)], the causative pathogen of tuberculosis.[4]
Isolated from the insect pathogenic fungus Hirsutella nivea
BCC 2594, the hirsutellones share a number of unique
structural features, including a 6,5,6-fused tricyclic core, a
g-lactam- or succinimide-containing moiety, a 12- or 13-
membered p-cyclophane structural motif which encompasses
an aryl ether linkage, and ten stereogenic centers. In view of
their promising biological properties as lead compounds for
new antituberculosis drugs and because of their challenging
molecular architectures, the hirsutellones are deemed impor-
tant synthetic targets.[5] Herein we report the total synthesis of
hirsutellone B (1b) in its enantiomerically pure form through
a strategy that features a number of novel cascade sequences
and chemoselective reactions.
From the five rings within the hirsutellone B molecule
(1b), the most synthetically challenging is the 13-membered
p-cyclophane, whose strain is exacerbated by the presence of
Scheme 1. Retrosynthetic analysis of hirsutellone B (1b). TMS=tri-
methylsilyl.
[*] Prof. K. C. Nicolaou, D. Sarlah, Dr. T. R. Wu, Dr. W. Zhan
Department of Chemistry and
synthetic strategy for the total synthesis of hirsutellone B
(1b) as it finally evolved. Thus, the hydroxy g-lactam moiety
was expected to be formed spontaneously from the corre-
sponding keto amide, whose origin was traced back to the
styrene-containing p-cyclophane 2. The latter compound was
then retrosynthetically expanded to the less strained 14-
membered sulfone ring 3 through a Ramberg–Bꢀcklund
reaction. Disassembly of cyclic sulfone 3 with excision of
the sulfur atom led to diol 4, whose further disconnection, as
shown in Scheme 1, generated tricyclic core 5 as its possible
precursor. Finally, rupture of the three indicated carbon–
carbon bonds within 5, through a [4+2] cycloaddition/ring
forming epoxide opening, revealed the TMS-epoxy tetraene 6
as a likely precursor. The latter compound was expected to
undergo the designed sequential ring closures upon activation
with a suitable Lewis acid to afford stereoselectively the
desired [6,5,6]-tricyclic core 5.
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
[**] We gratefully acknowledge financial support from the National
Institutes of Health (USA), National Science Foundation (CHE-
0603217), Natural Sciences and Engineering Research Council,
Canada (postdoctoral fellowship to T.R.W.) and Skaggs Institute for
Research. We thank Dr. M. Isaka and Prof. Y. Thebtaranonth for
NMR spectra of natural hirsutellone B.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903382.
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The enantioselective construction of the hirsutellone
tricyclic core 5 commenced with (R)-(+)-citronellal (7) and
proceeded as summarized in Scheme 2. Thus, Stork–Zhao
intramolecular epoxide opening/Diels–Alder reaction was
induced by Et2AlCl (CH2Cl2, ꢀ78!258C) to afford the
targeted tricyclic core 5 in 50% yield as a single diastereo-
isomer. It is assumed that this highly productive reaction
proceeds through species I (Lewis acid activation), leading to
intermediate II [of which the protonated form (6a, not
shown) was isolated and fully characterized], which then
undergoes reaction (under the Lewis acid conditions) to give
the final product (5).
=
olefination of 7 with phosphorane Ph3P CHI (generated from
The stereochemical outcome of the first ring closure
involved in this cascade is a consequence of the preferred
transition-state conformation I (shown in Scheme 3), whereas
Scheme 3. Postulated preferred transition-state conformations of I and
II leading to tricyclic core product 5.
endo transition-state II (Scheme 3) explains the stereoselec-
tivity of the incipient [4+2] cycloaddition reaction to afford
product 5 exclusively. The structure of 5 was determined by
NMR spectroscopic means and was confirmed unambigu-
ously through X-ray crystallographic analysis of its carbamate
derivative 12[10] [prepared from
5 by reaction with
pBrC6H4NCO and 4-DMAP, quant.; m.p. 2158C (hexanes/
CH2Cl2), see ORTEP drawing, Figure 2].[10]
Scheme 2. Enantioselective construction of hirsutellone core 5 and
carbamate 12. Reagents and conditions: a) Ph3PCH2I2 (1.1 equiv),
KHMDS (1.1 equiv), THF, ꢀ78!258C, 1 h; b) O3, CH2Cl2; then Me2S
=
(10.0 equiv), ꢀ78!258C, 10 h, 80% for two steps; c) Ph3P CHCHO
(1.1 equiv), CHCl3, 708C, 24 h; d) cat. 9 (10 mol%), H2O2 (aq., 35%
=
w/w, 1.3 equiv), 0!258C, 8 h, CH2Cl2; then Ph3P CHCO2Me
(1.2 equiv), 258C, 1 h, 58% overall yield from 8; e) 11 (2.0 equiv),
CuTC (3.0 equiv), NMP, 258C, 6 h, 70%; f) Et2AlCl (5.0 equiv), CH2Cl2,
ꢀ78!258C, 12 h, 50%; g) pBrC6H4NCO (3.0 equiv), 4-DMAP
(3.1 equiv), CH2Cl2, 0!258C, 10 h, quant. KHMDS=potassium hex-
amethyldisilazide, CuTC=copper(I) thiophene-2-carboxylate,
NMP=N-methyl-2-pyrrolidinone, 4-DMAP=4-dimethylaminopyridine.
Ph3PCH2I2 and KHMDS)[6] furnished the corresponding
Z-olefinic iodide, which was subjected to selective ozonolysis
to afford iodo aldehyde 8 in 80% overall yield. Reaction of
Figure 2. X-ray derived ORTEP drawing of carbamate 12 (thermal
ellipsoids at 30% probability).
=
the latter with the stabilized phosphorane Ph3P CHCHO,
and subsequent Jørgensen asymmetric epoxidation[7] of the
resulting a,b-unsaturated aldehyde, with H2O2 in the presence
of proline-derived catalyst 9,[7b] resulted in the formation of
the expected epoxy aldehyde, whose condensation with
Having reached the tricyclic core 5 of the hirsutellone
molecule, its elaboration into the macrocyclic sulfone 3
became our next objective. Scheme 4 details the conversion
of 5 into 3 through a sequence that involved a Barton
etherification,[11] a cascade-based selective functionalization
of a diol, and a macrocyclization. Thus, hydroxy methyl ester 5
was reacted with pTol4BiF in the presence of Cy2NEt and
=
Ph3P CHCO2Me furnished epoxy ester iodide 10 (58%
overall yield). Coupling of olefinic iodide 10 with the
stannane TMS derivative 11[8] in the presence of CuTC[9] led
to cyclization precursor 6 in 70% yield. The much anticipated
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catalytic amounts of Cu(OAc)2 according to the improved
etherification protocol of Mukaiyama et al.,[12] and the
resulting aryl ether methyl ester was reduced with LiAlH4
to afford, after oxidation with PhI(OAc)2-TEMPO, aldehyde
13 (78% overall yield for three steps). Extension of the
carbonyl side chain of 13 was accomplished by addition of
TBSOCH2CH2CH2MgBr and subsequent oxidation of the
resulting secondary alcohol with DMP to give ketone 14 in
91% overall yield. Functionalization of the aryl methyl group
in 14 to give the desired dihydroxy compound 4 was then
carried out with CAN in aqueous MeCN (oxidation/desilyla-
tion) and subsequent reduction of the resulting aldehyde with
NaBH(OAc)3 (81% overall yield for the two steps). Diol 4
was then exposed to the action of ZnI2 and AcSH in CH2Cl2 at
ambient temperature,[13] conditions that facilitated its chemo-
selective conversion into iodo thioacetate 15 (68% yield),
presumably through the cascade involving reactive species
III–VI, as shown in Scheme 4. Treatment of the iodo
thioacetate 15 with NaOMe in THF/MeOH (1:1) at ambient
temperature and then oxidation of the resulting macrocyclic
sulfide with H2O2 and Na2WO4 furnished targeted macro-
cyclic sulfone 3 in 79% overall yield for the two steps
(deacetylation/cyclization, oxidation).
With the 14-membered macrocyclic sulfone 3 in hand, its
contraction to a 13-membered macrocyclic olefin and addi-
tional functionalization to give hirsutellone B (1b) became
possible as demonstrated in Scheme 5. Thus, treatment of
sulfone 3 with alumina-impregnated KOH (KOH/Al2O3) in
the presence of CF2Br2 in CH2Cl2/tBuOH (1:1) at 0!258C led
to the corresponding olefin (exclusively Z and in high yield)
through a Ramberg–Bꢀcklund reaction.[14] Diastereoselective
carboxymethylation of this product (LHMDS, NCCO2Me)
then furnished keto ester 2 (61% overall yield for two
steps).[15] From the three olefinic bonds of tetracycle 2, the
one residing within the strained 13-membered p-cyclophane
ring proved the most reactive towards AD-mix-b
(MeSO2NH2, tBuOH/H2O (1:1), ambient temperature),[16]
allowing efficient generation of diol 16, which was formed
as a single crystalline diastereoisomer in 90% yield (m.p. 191–
1928C; hexane/EtOAc). Its structure was unambiguously
proven by X-ray crystallographic analysis (see ORTEP
drawing, Figure 3).[17]
The benzylic nature of the C3’ hydroxy group of 16
facilitated its selective removal through Barton deoxygena-
tion (nBu3SnH, AIBN) of its thionocarbonate (prepared by
=
exposure to Cl2C S and 4-DMAP), leading to hydroxy ester
Scheme 4. Construction of sulfone 3. Reagents and conditions:
17 (65% overall yield for two steps). Oxidation of alcohol 17
with DMP proceeded smoothly to afford keto ester 18 in 92%
yield. Finally, heating of 18 with NH3 in MeOH/H2O (1:1) at
a) pTol4BiF (2.5 equiv), Cy2NMe (2.5 equiv), Cu(OAc)2 (20 mol%),
PhMe, 258C, 12 h; b) LiAlH4 (3.0 equiv), Et2O, 0!258C, 2.5 h;
c) TEMPO (0.2 equiv), PhI(OAc)2 (1.5 equiv), CH2Cl2, 258C, 12 h, 78%
for three steps; d) BrMg(CH2)3OTBS (3.0 equiv), THF, 0!258C, 5 h;
e) DMP (1.3 equiv), CH2Cl2, 0!258C, 2 h, 91% for two steps; f) CAN
(5.0 equiv), MeCN/H2O (20:1), 258C, 2.5 h; g) NaBH(OAc)3
(5.0 equiv), PhH, 258C, 12 h, 81% for two steps; h) ZnI2 (5.0 equiv),
AcSH (2.0 equiv), CH2Cl2, 258C, 6 h, 68%; i) NaOMe (1.4 equiv),
MeOH/THF (1:1, 1.0 mm), 258C, 36 h; j) H2O2 (aq., 35% w/w,
15 equiv), Na2WO4 (1.0 equiv), THF/MeOH (1:1), 0!258C, 2 h, 79%
for two steps. Cy=cyclohexyl, Ac=acetyl, TEMPO=2,2,6,6-tetrame-
thylpiperidine-1-oxyl, TBS=tert-butyldimethylsilyl, DMP=Dess–Martin
periodinane, CAN=cerium(IV) ammonium nitrate, THF=tetrahydro-
furan.
[18]
1208C for 1 h led to hirsutellone B (1b) in 50% yield
through a cascade sequence involving amidation, epimeriza-
tion (at C17) and cyclization (through transient intermediates
VII and VIII, Scheme 5).[18] The physical properties (1H and
13C NMR, MS data) of synthetic hirsutellone B matched those
reported for the natural material.[1a] Its optical rotation
{[a]D27 = + 250 (c = 0.14, MeOH)} was essentially identical
to that of the natural substance {[a]D25 = + 256 (c = 0.20,
MeOH)},[1a] proving the absolute configuration of hirsutell-
one B as that shown in structure 1b.
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The described chemistry renders hirsutellone B (1b)
readily available through chemical synthesis, and opens the
way for the total synthesis of its naturally occurring siblings
and designed analogues for chemical biology and medicinal
chemistry studies directed toward the development of new
antituberculosis drugs.[4] Furthermore, the employed syn-
thetic strategy features a number of novel cascade reactions[19]
that may find further applications in complex molecule
construction.
Received: June 22, 2009
Published online: August 15, 2009
Keywords: antituberculosis · cascade reactions ·
.
natural products · total synthesis
[1] a) M. Isaka, N. Rugseree, P. Maithip, P. Kongsaeree, S. Prabpai,
Y. Thebtaranonth, Tetrahedron 2005, 61, 5577 – 5583; b) M.
Isaka, W. Prathumpai, P. Wongsa, M. Tanticharoen, Org. Lett.
2006, 8, 2815 – 2817.
[2] Y. Shiono, K. Shimanuki, F. Hiramatsu, T. Koseki, M. Tetsuya, N.
Fujisawa, K. Kimura, Bioorg. Med. Chem. Lett. 2008, 18, 6050 –
6053.
[3] H. He, H. Y. Yang, R. Bigelis, E. H. Solum, M. Greenstein, G. T.
Carter, Tetrahedron Lett. 2002, 43, 1633 – 1636.
[4] For selected reviews on this topic, see: a) J. C. Sacchettini, E. J.
Rubin, J. S. Freundlich, Nat. Rev. Microbiol. 2008, 6, 41 – 52;
b) D. L. Cohn, F. Bustreo, M. C. Raviglione, Clin. Infect. Dis.
1997, 24, S121 – S130; c) R. P. Tripathi, N. Tewari, N. Dwivedi,
V. K. Tiwari, Med. Res. Rev. 2005, 25, 93 – 131.
[5] For previous studies toward the total synthesis of hirsutellones,
see: a) S. D. Tilley, K. P. Reber, E. J. Sorensen, Org. Lett. 2009,
11, 701 – 703; b) M. Huang, C. Huang, B. Liu, Tetrahedron Lett.
2009, 50, 2797 – 2800.
[6] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 2173 – 2174.
[7] a) M. Marigo, J. Franzꢁn, T. B. Poulsen, W. Zhuang, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 6964 – 6965; b) Y.
Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005,
117, 4284 – 4287; Angew. Chem. Int. Ed. 2005, 44, 4212 – 4215.
[8] Stannane 11 was prepared by Negishi coupling of (E)-
Scheme 5. Completion of the total synthesis of hirsutellone B (1b).
Reagents and conditions: a) CF2Br2 (5.0 equiv), KOH/Al2O3 (15% w/w,
2 g per mmol), CH2Cl2/tBuOH (1:1), 0!258C, 2 h; b) LHMDS
(3.3 equiv), NCCO2Me (8.3 equiv), THF, ꢀ78!ꢀ508C, 0.5 h, 61% for
two steps; c) AD-mix-b (1.0 equiv), MeSO2NH2 (1.7 equiv), tBuOH/
=
=
nBu3SnCH CHZnCl and (E)-ICH CHCH2TMS using [Pd-
(PPh3)4] as a catalyst.
=
H2O (1:1), 258C, 18 h, 90%; d) S CCl2 (1.5 equiv), 4-DMAP
(3.0 equiv), CH2Cl2, 0!258C, 1 h; e) AIBN (2.0 equiv), nBu3SnH
(10 equiv), PhMe, 1008C, 2 h, 65% for two steps; f) DMP (2.0 equiv),
CH2Cl2, 258C, 2 h, 92%; g) NH3, MeOH/H2O (4:1), 1208C, 1 h, 50%.
LHMDS=lithium hexamethyldisilazide.
[9] G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc. 1996, 118,
2748 – 2749.
[10] CCDC 736469 (p-bromophenyl carbamate 12) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] R. A. Abramovitch, D. H. R. Barton, K. P. Finet, Tetrahedron
1988, 44, 3039 – 3071, and references therein.
[12] T. Mukaiyama, N. Sakurai, K. Ikegai, Chem. Lett. 2006, 35,
1140 – 1141.
[13] J. Y. Gauthier, F. Bourdon, R. N. Young, Tetrahedron Lett. 1986,
27, 15 – 18.
[14] T.-L. Chan, S. Fong, Y. Li, T.-O. Man, C.-D. Poon, J. Chem. Soc.
Chem. Commun. 1994, 1771 – 1772.
[15] The isomeric O-carboxymethylated compound was also isolated
as a minor product (20% yield) in this reaction.
[16] E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schrꢂder, K. B.
Sharpless, J. Am. Chem. Soc. 1988, 110, 1968 – 1970.
[17] CCDC 736468 (diol 16) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Figure 3. X-ray derived ORTEP drawing of diol 16 (thermal ellipsoids at
30% probability).
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[18] The corresponding decarboxymethylation compound (1,4-dike-
[19] For selected reviews, see: a) K. C. Nicolaou, T. Montagnon, S. A.
Snyder, Chem. Commun. 2003, 551 – 564; b) L. F. Tietze, G.
Brasche, K. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, 2006, p. 672; c) K. C. Nicolaou, D. J.
Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292 – 7344;
Angew. Chem. Int. Ed. 2006, 45, 7134 – 7186.
tone 18a, not shown) was also observed as a side product in this
reaction. The likely formation of imine moieties at the two
carbonyl sites of substrate 18 is reversible under the reaction
conditions (i.e. H2O), thus allowing the eventual generation of
the product (i.e. 1b). An alternative mechanism may involve
initial attack of NH3 at the C2’ carbonyl group and subsequent
ring closure.
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