Catalytic, asymmetric transannular aldolizations: Total synthesis of (+)-hirsutene

Article abstract of DOI:10.1021/ja8024164

We report an asymmetric, catalytic transannular aldolization that provides polycyclic products useful for natural product synthesis. We found that a proline-derivative catalyzes the transannular aldol reaction of 1,4-cyclooctanediones to the corresponding cyclic β-hydroxy ketones in good yields and with high enantioselectivities. The utility of our reaction has been demonstrated in a total synthesis of (+)-hirustene. Copyright

Full text of DOI:10.1021/ja8024164

Published on Web 05/03/2008
Catalytic, Asymmetric Transannular Aldolizations: Total Synthesis of
(+)-Hirsutene
Carley L. Chandler and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received April 2, 2008; E-mail: list@mpi-muelheim.mpg.de
Table 1. Catalyst Identification for the Aldolization of Dione 1
Few transformations have stimulated more research on the develop-
ment of asymmetric processes than the aldol reaction. Indeed, a great
variety of effective chiral auxiliaries, reagents, and catalysts have been
introduced that efficiently control its relative and absolute stereochem-
istry.1 Interestingly, although enzymes,2 transition metal complexes,3
and organocatalysts have all been used to catalyze direct asymmetric
intermolecular aldol reactions, only proline and its derivatives have
found general utility in intramolecular variants.4 Of these, there are
three types: (a) enolendo aldolizations,5 in which the nucleophilic
double bond is part of the ring that is being formed; (b) enolexo
aldolizations,6 in which this double bond is exocyclic; and (c)
transannular aldolizations, which may be considered enolendo and
enolexo simultaneously.
entry
R
solvent
time [h]
conversion [%]a
erb
1
2
3
4
5
6
7
8
H
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
DMSO
16
24
15
2
24
24
24
24
60
50
60
95
75
50
50
75
77:23
82:18
39:61
80:20
90:10
79:21
56:44
91:9
trans-OH
trans-OTBS
trans-Ot-Bu
trans-F
cis-F
trans-F
trans-F
a Determined by GC. b Determined by chiral-phase GC.
canedione (3), was obtained with reasonable enantioselectivity (82:18
er, entry 2). Diketone 5 did not provide the aldol addition product but
upon heating furnished only the corresponding condensation adduct 6
(entry 3). Similarly, 1,4-cyclononanedione 7 failed to deliver the desired
ꢀ-hydroxy ketone when subjected to the reaction conditions, but only
gave condensation product 8 (entry 4). Remarkably, ene-diones 9 and
11, the unsaturated analogues of diketones 5 and 7, gave high yields
of aldol adducts 10 and 12, respectively, albeit with low enantiose-
lectivities (entries 5 and 6). Finally, commercially available 1,4-
cyclooctanedione (13) provided the desired bicyclo[3.3.0]octane
derivative 14 with excellent enantioselectivity (97:3 er, entry 6).
Encouraged by these studies, we prepared several 1,4-cyclooctanedione
derivatives8 and investigated their catalytic, asymmetric transannular
aldol reactions (Table 3).
While proline-catalyzed enolendo and enolexo aldolizations have
been developed with high enantioselectivities,1 catalytic, asymmetric
transannular aldolizations, which create two new rings and at least
two new stereogenic centers, have previously been unknown with any
type of catalysis.7 Here we describe highly enantioselective transannular
aldolizations of cyclic diketones that are catalyzed by trans-4-fluoro
proline and provide polycyclic products of utility for natural product
synthesis as illustrated in a short synthesis of (+)-hirsutene.
At the outset of the investigation, we focused our attention on proline
derivatives to catalyze the transannular aldol reaction of 1,5-cy-
clononanedione (1, Table 1). (S)-proline itself catalyzed the reaction
with promising enantioselectivity (77:23 er) and conversion in DMF
at room temperature to give ꢀ-hydroxy ketone 2 as a single diastere-
omer (entry 1). During initial catalyst screenings we noticed a
pronounced effect on the reaction outcome for proline catalysts bearing
a substituent at the 4-position. For example, trans-4-hydroxy proline
gave slightly elevated levels of enantiocontrol (82:18 er), whereas the
corresponding tert-butyldimethyl silyl ether produced an adverse effect
on the enantioselectivity (entries 2 and 3). Substitution with a tert-
butyl ether linkage at this position dramatically enhanced the reaction
rate giving high conversion but modest selectivity (entry 4). The trans-
4-fluoro derivative was identified as the most promising catalyst,
providing the highest levels of enantioselectivity with good conversion
(entry 5). Changing the solvent to DMSO in combination with trans-
4-fluoro proline (entry 8) produced the highest enantioselectivity (91:9
er) for aldol adduct 2 and good conversion from 1.
In addition to diketone 13, benzocyclooctanediones 15 and 17 gave
the corresponding aldols 16 and 18 with excellent enantioselectivites
and in good yields (entries 2 and 3). Cis-fused cyclohexyl 3,6-
cyclooctanedione (19) underwent reaction to give cis/anti/cis9 tricyclic
compound 20 as a single diastereomer, in good yield and with high
enantioselectivity (97:3 er, entry 4). Interestingly, racemic cis-fused
cyclohexyl 2,5-cyclooctanedione (rac-21) underwent a kinetic resolu-
tion to provide tricyclic ꢀ-hydroxy ketone 22 in 42% yield and with
95:5 er (entry 5).10 Finally, cyclopentane annulated diketone 23
furnished the desired hydroxyl triquinane 24 in high yield and with
excellent diastero- and enantioselectivity (entry 6). The aldolization
of diketone 23 has been implemented as the key step in a synthesis of
the natural product (+)-hirustene (34) (Scheme 1). Hirsutene is a fungal
metabolite isolated from Basidomycete Coriolus consors11 which, with
its cis:anti:cis tricyclo [6.3.0.02,6]-undecane core, is a logical target
for the application of our transannular aldolization. As a biogenetic
precursor to several antibiotic and/or antitumor compounds, including
hirsutic acid C and coriolin,12,13 hirsutene has drawn considerable
interest from the synthetic community including several reports of
enantioselective total and formal syntheses.14–16
Using trans-4-fluoro proline, we set out to investigate the effect of
ring-size on the outcome of the reaction (Table 2). A variety of 8- to
10-membered ring diones were prepared following known literature
methods8 and subjected to the newly identified aldolization conditions.
Dodecanediones 3 and 5 proved to be much less reactive than substrate
1, and conversions were low (Table 2, entries 2 and 3). Notably, aldol
4, the major diastereomer observed for the reaction of 1,6-cyclode-
9
10.1021/ja8024164 CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 6737–6739 6737

C O M M U N I C A T I O N S
Table 2. Substrates Studied in Transannular Aldolizationsa
Table 3. 1,4-Cyclooctanediones in Transannular Aldolizationsa
a Reactions were run with 20 mol% of catalyst at
a substrate
concentration of 0.5 M in DMSO at room temp for 24 h. b Isolated
yield. Yields in parentheses are based on recovered starting material.
c Determined by chiral-phase GC. d dr ) 7:1. e Reaction run at 50 °C.
a Reactions were run with 20 mol% of catalyst at
a substrate
concentration of 0.5 M in DMSO at room temperature for 24 h.
b Isolated yield. Yields in parentheses are based on recovered starting
material. c Determined by chiral-phase GC. d One equivalent of water
was added to the reaction. e Reaction run for 15 h. f Only 10 mol % of
catalyst was used.
Our synthesis commences with a straightforward chain-elongation
of commercially available 3,3-dimethylpentane-1,5-diacid (25)17 to
R,ꢀ-unsaturated diester 26. Bis-enoate 26 was identified as a viable
substrate for a reductive cyclization via intramolecular trapping of the
intermediate radical anion. Indeed, desired cyclopentane 27 was formed
in 88% yield as a 1.1:1 mixture of cis:trans isomers upon treating 26
with magnesium metal in methanol.18 Cyclic diester 27 was converted
to corresponding R-diazo ketone 29 via hydrolysis to diacid 28
followed by acid chloride formation and in situ reaction with
trimethylsilyl diazomethane.19
The strategy for the preparation of requisite cyclooctanedione
23 is based on a powerful and yet relatively undeveloped method
reported by Del Zotto et al.20 for the intramolecular coupling of
diazo compounds exploiting a commercially available ruthenium(II)
catalyst. Gratifyingly, when 29 was subjected to CpRuCl(PPh3)2
in refluxing CH2Cl2, a 52% yield of cis-fused ene-dione 30 was
obtained after separation from the corresponding trans-isomer.
Following hydrogenation, 1,4-cyclooctanedione 23 was obtained
in 91% yield. Upon treating diketone 23 with trans-4-fluoro proline
(10 mol %) in DMSO at room temperature, the aldol reaction was
complete in 15 h and furnished cis/anti/cis21 ꢀ-hydroxy ketone 24
in 84% yield and with 98:2 er. The absolute and relative stereo-
chemical outcome of the reaction was rationalized by transition
state 31 on the basis of our transition state model.22 After stirring
24 overnight in the presence of aqueous 2 N sodium hydroxide,
elimination occurred to give enone 32 in near quantitative yield
without a decrease in the enantiomeric ratio (i.e., retro-aldol/aldol
pathway is not occurring). We then completed the total synthesis
of hirsutene based on the protocol Iyoda and co-workers imple-
mented in their synthesis of rac-34.23 Treatment of enone 32 with
lithium in ammonia followed by methylation of the intermediate
enolate gave ketone 33 with R20 ) +41.0 (c 0.1 M, hexane),
D
confirming the predicted absolute configuration of the transannular
aldol products. Finally, olefination of ketone 33 with methylene
triphenylphosphorane gave (+)-hirsutene (34) with R20D ) +13.0
9
6738 J. AM. CHEM. SOC. VOL. 130, NO. 21, 2008

C O M M U N I C A T I O N S
Scheme 1. Application of an Organocatalytic, Asymmetric Transannular Aldol Reaction in the Total Synthesis of (+)-Hirsutene
(c 0.1 M, hexane) in 87% yield.24 The synthetic material had
spectral properties fully consistent with those reported in the
literature.15,21
(6) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem. 2003, 115,
2891.
(7) For examples of nonasymmetric catalysis and reagent-based asymmetric
transannular aldolizations see: (a) Knopff, O.; Kuhne, J.; Fehr, C. Angew.
Chem., Int. Ed. 2007, 46, 1307. (b) Inoue, M.; Lee, N.; Kasuya, S.; Sato,
T.; Hirama, M.; Moriyama, M.; Fukuyama, Y. J. Org. Chem. 2007, 72,
3065.
In conclusion, we have described an asymmetric, catalytic transan-
nular aldol reaction that provides polycyclic products in good yields
(53-84%) and high enantioselectivities (er ) 95:5-98:2) for 1,4-
cyclooctanediones. Further work to elucidate the observed fluorine
effect is underway. The enantioselectivities for larger macrocyclic
diones currently participating in this proline-derived-catalyzed reaction
are, at the moment, only moderate (41-82% ee) offering the prospect
for further improvement. The potential of our methodology for natural
product synthesis was illustrated with the shortest asymmetric total
synthesis of (+)-hirsutene reported to date. Our observations contribute
to a further advancement of catalytic, asymmetric transannular
transformations and complement a recently discovered transannular
Diels-Alder reaction by Jacobsen et al.25
Acknowledgment. We thank Linh Hoang for her contributions
at the early stage of this project (2001). Generous support by the Max-
Planck-Society, the DFG (SPP1179, Organocatalysis), Novartis (Young
Investigator Award to B.L.), AstraZeneca (Award in Organic Chem-
istry to B.L.), and the Fond der Chemischen Industrie is gratefully
acknowledged. We also thank our GC and NMR departments for their
support.
(8) See Supporting Information.
(9) Determined on the basis of comparison with 24.
(10) The S value was calculated to be 11.7 using the KinRes program, see :
Goodman, J. M.; Ko¨hler, A.-K.; Alderton, S. C. M. Tetrahedron Lett. 1999,
40, 8715.
(11) Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Tetrahedron Lett. 1976,
17, 195.
(12) Mehta, G.; Reddy, D. S. J. Chem. Soc., Perkin Trans. 1 2001, 1, 1153.
and references cited therein.
(13) Schuda, P. F.; Phillips, J. L.; Morgan, T. M. J. Org. Chem. 1986, 51, 2742.
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(14) For reviews on syntheses of triquinane natural products see: (a) Mehta,
G.; Srikrishna, A. Chem. ReV. 1997, 97, 671. (b) Singh, V.; Thomas, B.
Tetrahedron 1998, 54, 3647.
(15) For reports of asymmetric total syntheses of hirsutene see: (a) Hua, D. H.;
Venkataraman, S.; Sinai-Zingde, G. J. Am. Chem. Soc. 1985, 107, 4088.
(b) Weinges, K.; Reichert, H.; Huber-Patz, U.; Irngartinger, H. Liebegs
Ann. Chem. 1993, 403. (c) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.;
Jolliffe, K. A. Tetrahedron 2004, 60, 535.
(16) For reports of asymmetric formal syntheses of hirsutene see: (a) Castro,
J.; Sorensen, H.; Riera, A.; Morin, C.; Moyano, A.; Pericas, M. A.; Greene,
A. E. J. Am. Chem. Soc. 1990, 112, 9388. (b) Inoue, T.; Hosomi, K.; Araki,
M.; Nishide, K.; Node, M. Tetrahedron: Asymmetry 1995, 6, 31. (c) Anger,
T.; Graalmann, O.; Schro¨der, H.; Gerke, R.; Kaiser, U.; Fitjer, L.;
Noltemeyer, M. Tetrahedron 1998, 54, 10713. (d) Leonard, J.; Bennett,
L.; Mahmood, A. Tetrahedron Lett. 1999, 40, 3965. (e) Singh, V.;
Vedantham, P.; Sahu, P. K. Tetrahedron Lett. 2002, 43, 519. (f) Hu, Q.-
Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708.
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Med. Chem. Lett. 1991, 1, 649.
Supporting Information Available: Experimental procedures, com-
pound characterization, NMR-spectra, and GC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Chavan, S. P.; Ethiraj, K. S. Tetrahedron Lett. 1995, 36, 2281.
(19) Makhey, D.; Li, D.; Zhao, B.; Sim, S.-P.; Li, T.-K.; Liu, A.; Liu, L. F.; La
Voie, E. J. Bioorg. Med. Chem. 2003, 11, 1809.
(20) Del Zotto, A.; Baratta, W.; Verardo, G.; Rigo, P. Eur. J. Org. Chem. 2000,
2795.
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