Enantioselective total synthesis of cyathin A3

Article abstract of DOI:10.1021/ol070994z

The total synthesis of (-)-cyathin A₃ is described. The key step involves an unusual enantioselective Diels Alder reaction of 2,5-dimethyl1,4-benzoquinone with 2,4-bis(trimethylsilyloxy)-1,3-pentadiene, using Mikami's catalyst [(R)-BINOL + Cl

Full text of DOI:10.1021/ol070994z

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2843-2846
Enantioselective Total Synthesis of
Cyathin A3
†
Dale E. Ward* and Jianheng Shen
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place,
Saskatoon SK S7N 5C9, Canada
dale.ward@usask.ca
Received April 27, 2007
ABSTRACT
The total synthesis of (
−
)-cyathin A3 is described. The key step involves an unusual enantioselective Diels
−
Alder reaction of 2,5-dimethyl-
1,4-benzoquinone with 2,4-bis(trimethylsilyloxy)-1,3-pentadiene, using Mikami’s catalyst [(R)-BINOL
+
Cl2Ti(OiPr)2
+ 4 Å mol sieves] modified
by addition of Mg and SiO2. Because cyathin A3 is easily transformed into allocyathin B3, cyathin B3, cyathin C3, and neoallocyathin A4, this
route also constitutes formal syntheses of these natural products.
The cyathanes are a family of diterpenoids whose members
possess a (3aR,5aR)-3a,5a,8-trimethyl-1-(1-methylethyl)cyclo-
hept[e]indene (1; cyathane) carbon skeleton.1 They are
isolated from various mushrooms and related basidiomycetes
and include the cyathins (e.g., 2-6) (from Cyathus helenae),
the erinacines (e.g., 8, 9) (from Hericium erinaceum), the
sarcodonins (e.g., 10), and the scabronines (e.g., 11) (from
Sarcodon scabrosus), among others (Figure 1).1,2 Diverse
biological activities have been noted among the cyathanes.
In particular, the discovery that certain members can
stimulate the production of nerve growth factor (NGF) has
generated substantial interest in the synthesis of these
compounds.1,3 Several total syntheses have been reported to
date;4-7 however, the majority of these concern allocyathin
(3) (a) Kawagishi, H.; Shimada, A.; Shirai, R.; Okamoto, K.; Ojima, F.;
Sakamoto, H.; Ishiguro, Y.; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569-
1572. (b) Kawagishi, H.; Shimada, A.; Hosokawa, S.; Mori, H.; Sakamoto,
H.; Ishiguro, Y.; Sakemi, S.; Bordner, J.; Kojima, N.; Furukawa, S.
Tetrahedron Lett. 1996, 37, 7399-7402. (c) Obara, Y.; Nakahata, N.; Kita,
T.; Takaya, Y.; Kobayashi, H.; Hosoi, S.; Kiuchi, F.; Ohta, T.; Oshima,
Y.; Ohizumi, Y. Eur. J. Pharmacol. 1999, 370, 79-84. (d) Obara, Y.;
Kobayashi, H.; Ohta, T.; Ohizumi, Y.; Nakahata, N. Mol. Pharmacol. 2001,
59, 1287-1297. Also see ref 2a.
(4) Total syntheses of (()-7: (a) Snider, B. B.; Vo, N. H.; O’Neil, S.
V.; Foxman, B. M. J. Am. Chem. Soc. 1996, 118, 7644-7645. (b) Snider,
B. B.; Vo, N. H.; O’Neil, S. V. J. Org. Chem. 1998, 63, 4732-4740. (c)
Tori, M.; Toyoda, N.; Sono, M. J. Org. Chem. 1998, 63, 306-313. Total
syntheses of (+)-7: (d) Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am.
Chem. Soc. 2005, 127, 2844-2845. (e) Trost, B. M.; Dong, L.; Schroeder,
G. M. J. Am. Chem. Soc. 2005, 127, 10259-10268. (f) Takano, M.; Umino,
A.; Nakada, M. Org. Lett. 2004, 6, 4897-4900. For the conversion of (()-7
into (+)-8, see refs 4a and 4b.
(5) Total synthesis of (()-3: (a) Ward, D. E.; Gai, Y.; Qiao, Q. Org.
Lett. 2000, 2, 2125-2127. (b) Ward, D. E.; Gai, Y.; Qiao, Q.; Shen, J.
Can. J. Chem. 2004, 82, 254-267.
(6) Total synthesis of (-)-9 via a protected cyathatriol intermediate:
Watanabe, H.; Takano, M.; Umino, A.; Ito, T.; Ishikawa, H.; Nakada, M.
Org. Lett. 2007, 9, 359-362.
(7) Total synthesis of (()-10: Piers, E.; Gilbert, M.; Cook, K. L. Org.
Lett. 2000, 2, 1407-1410. Total synthesis of (-)-11: Waters, S. P.; Tian,
Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514-
13515.
† Dedicated to the memory of William A. Ayer (1932-2005).
(1) Review: Wright, D. L.; Whitehead, C. R. Org. Prep. Proced. Int.
2000, 32, 307, 309-330.
(2) Recent examples: (a) Marcotullio, M. C.; Pagiott, R.; Maltese, F.;
Obara, Y.; Hoshino, T.; Nakahata, N.; Curini, M. Planta Med. 2006, 72,
819-823. (b) Kawagishi, H.; Masui, A.; Tokuyama, S.; Nakamura, T.
Tetrahedron 2006, 62, 8463-8466. (c) Ma, B.-J.; Liu, J.-K. J. Basic
Microbiol. 2005, 45, 328-330. (d) Curini, M.; Maltese, F.; Marcotullio,
M. C.; Menghini, L.; Pagiotti, R.; Rosati, O.; Altinier, G.; Tubaro, A. Planta
Med. 2005, 71, 488. (e) Ma, B.-J.; Zhu, H.-J.; Liu, J.-K. HelV. Chim. Acta
2004, 87, 2877-2881. (f) Kenmoku, H.; Tanaka, K.; Okada, K.; Kato, N.;
Sassa, T. Biosci., Biotechnol., Biochem. 2004, 68, 1786-1789. (g) Kamo,
T.; Imura, Y.; Hagio, T.; Makabe, H.; Shibata, H.; Hirota, M. Biosci.,
Biotechnol., Biochem. 2004, 68, 1362-1365.
10.1021/ol070994z CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

Scheme 1. Goals for a Second-Generation Synthesis (dashed
arrow)
Figure 1. Selected cyathane diterpenes.
B2 (7),4 a nonprototypical cyathane.8 Cyathin A3 (2) is a
synthetic precursor to several cyathanes including 3-94b,6,9
and cyathatriol (the 14-â-alcohol derivative of 2)9b has been
proposed10 as a (bio)synthetic precursor of the erinacines.6
In this paper, we report the enantioselective synthesis of
cyathin A3 (2)11 via a second-generation route based on our
earlier synthesis5 of (()-3 (Scheme 1).
The main objectives for our second-generation synthetic
route are outlined in Scheme 1. Developing an enantio-
selective version of the key Diels-Alder (DA) reaction of
12 with 13 was a significant challenge. To the best of our
knowledge, enantioselective DA reactions of Danishefsky-
type dienes (e.g., 13) are unknown,12 presumably due to their
sensitivity to Lewis acids.13 Similarly, enantioselective DA
reactions of quinone dienophiles was an unsolved problem
that only recently has been addressed successfully.14-16
Despite these advances, no examples using quinone 12 with
unsymmetrical dienes have been reported. Indeed, reactions
of 12 gave poor regioselectivities with use of the otherwise
very effective cationic oxazaborolidine-type catalysts devel-
oped by Corey et al.16,17
In a preliminary study, we screened a variety of catalysts
for efficacy in the enantioselective DA reaction of 12 with
13 (Table 1). Diene 13 was not stable to 19 and no DA
adducts were obtained under conditions validated by using
1,3-cyclohexadiene (entry 1).16a Low yields of 14 with
modest ee values were obtained with 2018 using Rawal’s
procedure;12b however, the diene 13 did not survive the
conditions (entries 2 and 3). An excellent yield was obtained
by using the catalyst prepared from BINOL and AlMe3 (1:
1) but with moderate enantioselectivity (entry 4).19
Although 14 was obtained with good ee by using Mikami’s
catalyst (21),15e.20 yields were poor because of diene decom-
position (Table 1, entries 5-8).21 Diene 13 was stable to
(8) The vast majority of cyathanes have a trans 6,7-ring fusion.
(9) (a) Ayer, W. A.; Browne, L. M.; Mercer, J. R.; Taylor, D. R.; Ward,
D. E. Can. J. Chem. 1978, 56, 717-721. (b) Ayer, W. A.; Lee, S. P. Can.
J. Chem. 1979, 57, 3332-3337.
(10) Kenmoku, H.; Sassa, T.; Kato, N. Tetrahedron Lett. 2000, 41, 4389-
4393.
(15) Quinone monoketals: (a) Breuning, M.; Corey, E. J. Org. Lett. 2001,
3, 1559-1562. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992-9993. Naphthoquinones: (c) Kelly, T. R.; Whiting, A.;
Chandrakumar, N. S. J. Am. Chem. Soc. 1986, 108, 3510-3512. (d)
Maruoka, K.; Sakurai, M.; Fujiwara, J.; Yamamoto, H. Tetrahedron Lett.
1986, 27, 4895-4898. (e) Mikami, K.; Motoyama, Y.; Terada, M. J. Am.
Chem. Soc. 1994, 116, 2812-2820. (f) Brimble, M. A.; McEwan, J. F.
Tetrahedron: Asymmetry 1997, 8, 4069-4078.
(16) (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388-
6390. (b) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
4800-4802. (c) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 13708-13713. (d) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem.
Soc. 2007, 129, 1498-1499.
(17) This problem was solved by using 3-iodo-2,5-dimethylbenzoquinone
(ref 16a).; however, the regioselectiviy obtained with unsymmetrical dienes
is opposite to our requirements
(11) Isolation and structure: (a) Allbutt, A. D.; Ayer, W. A.; Brodie, H.
J.; Johri, B. N.; Taube, H. Can. J. Microbiol. 1971, 17, 1401-1407. (b)
Ayer, W. A.; Taube, H. Can. J. Chem. 1973, 51, 3842-3854.
(12) Enantioselectvive hetero-DA reactions of these dienes are well-
known; for example, see: (a) Jorgensen, K. A. Angew. Chem., Int. Ed.
2000, 39, 3558-3588. For enantioselective DA reactions of 1-amino-3-
silyloxy dienes, see inter alia: (b) Huang, Y.; Iwama, T.; Rawal, V. H. J.
Am. Chem. Soc. 2000, 122, 7843-7844. (c) Thadani, A. N.; Stankovic, A.
R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846-5850.
(13) Inokuchi, T.; Okano, M.; Miyamoto, T. J. Org. Chem. 2001, 66,
8059-8063.
(14) (a) Engler, T. A.; Letavic, M. A.; Lynch, K. O., Jr.; Takusagawa,
F. J. Org. Chem. 1994, 59, 1179-1183. (b) White, J. D.; Choi, Y. HelV.
Chim. Acta 2002, 85, 4306-4327. (c) Nicolaou, K. C.; Vassilikogiannakis,
G.; Magerlein, W.; Kranich, R. Chem. Eur. J. 2001, 7, 5359-5371. (d)
Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10162-10163. (e) Jarvo,
E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
6043-6046. (f) Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2005, 44, 6046-6050.
(18) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J.
Am. Chem. Soc. 1995, 117, 5897-5898.
(19) Ward, D. E.; Souweha, M. S. Org. Lett. 2005, 7, 3533-3536.
(20) The structure of Mikami’s catalyst is unknown. For a review of
Ti(IV)-based enantioselective catalysts, see: Ramon, D. J.; Yus, M. Chem.
ReV. 2006, 106, 2126-2208.
2844
Org. Lett., Vol. 9, No. 15, 2007

(S)-BINOL-derived catalyst. Although alternative models
have been proposed14b,c to rationalize the observed enantio-
selectivity, we believe that the TS model 24 can accom-
modate all the reported examples (i.e., formation of adducts
23) (Figure 2). This model is fully consistent25 with Corey’s
Table 1. Enantioselective Diels-Alder Reactions of 12 with
13 under Various Conditions
% yield of 14
entry
catalyst (equiv)a
conditionsb
(% ee)c
1
2
3
4
19 (0.2)
20 (0.1; X ) Cl)
20 (0.1; X ) SbF6) -40 to 0 °C (ref 12b)
(S)-BINOL/AlMe3 Tol, rt, 24 h (ref)
(1:1; 1.2 equiv)e
21 (0.2)
21 (0.05)
21 (0.1)
21 (0.2)
22 (0.1)
21 (0.05)
21 (0.05)
21 (0.05)
21 (0.05)e,f
21 (0.05)e-g
-78 °C (ref 16a)
-40 to 0 °C (ref 12b)
NRd
40 (-33)d
20 (-60)d
90 (-50)
Figure 2. Models to rationalize observed enantioselectivity
in quinone DA reactions with use of Mikami’s catalyst (R1 ) H,
alkyl, OMe; R2,3 ) H, alkyl; R4 ) H, alkyl, OTBS; Z ) O,
-O(CH2)2O-).
5
6
7
8
9
10
11
12
13
14
Tol, rt, 48 h (ref 14b)
rt, 48 h (ref 15a)
rt, 48 h (ref 15a)
rt, 48 h (ref 15a)
rt, 72 h (ref 22)
+Mg; rt, 48 h
+SiO2; rt, 48 h
+Mg + SiO2; rt, 48 h
+Mg + SiO2; rt, 24 h
+Mg + SiO2; rt, 24 h
NRd
25 (67)d
42 (86)d
20 (86)d
87 (70)
65 (83)
72 (75)
93 (90)
93 (95)
90h (93)
prediction rules,16b including preferential activation of the
syn alkene via H-bonding.16 In contrast, DA reaction of the
syn alkene in quinone 12 (cf. 25) is strongly attenuated by
the â-methyl substituent resulting in addition to the anti
alkene, and preferential si face attack now requires the (R)-
BINOL-derived catalyst.26
Enantioenriched 14 was converted to a 4:1 mixture of 16a
and 16b, respectively, by established procedures (Scheme
1).5 Tetraone 26 ([R]D -3.7; c 1.3, CH2Cl2) was obtained
by reaction of the 16a/16b mixture with Hg(ClO4)2 in
aqueous acetone (Scheme 2). Chemoselective reduction of
the enone carbonyl in 26 was achieved with 9-BBN to give
the expected â-alcohol that was a 1:1.5 mixture of 27a and
27b (3:1 mixture of anomers), respectively, in CDCl3
a On the basis of Ti(IV) for 21 and 22. b Reactions were in CH2Cl2
(except entries 4-5) with ca. 25 mg of 12 (0.2 M) and 5 equiv of 13 (a 1:1
mixture of isomers). c Isolated yield and ee based on the enone resulting
from acid hydrolysis of 14; see the Supporting Information for details. d 13
decomposes under the reaction conditions. e 10 equiv of 13. f Neat. g 1.0 g
of 12. h Isolated yield of 14.
2222 and a much improved yield of 14 was obtained by using
this catalyst, albeit with moderate ee (entry 9). With this
lead, we tested a variety of additives to increase the stability
of 13 to 21. Excellent results were obtained with Mg powder
and silica gel (entries 10-14) providing the DA adduct 14
in 90% yield and >90% ee under optimized conditions (1-5
g scale).23
Scheme 2. Direct Synthesis of 15b from 16
It is noteworthy that adduct 14 results from addition of
(E)-13 to the si face24 of 12 and is favored with the Mikami
catalyst prepared from (R)-BINOL.20 In all previous examples
of 21-catalyzed DA reactions of quinone-type dieno-
philes,14b,c,15a,e preferential si face attack was observed with
(21) Control experiments showed that the reaction was strongly inhibited
by the presence of 2,4-pentandione or the corresponding TMS enol ether
(i.e., putative byproducts from decomposition of 13).
(22) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka,
K. Chem. Eur. J. 2003, 9, 4405-4413. A mono-µ-oxo Ti-O-Ti catalyst
structure is proposed: [BINOLateTi(OiPr)]2O.
(23) The precise role of the additives is unknown. Mg powder was added
to remove HCl. SiO2 may preferentially absorb diene decomposition
products (ref 21) or improve catalyst performance by immobilization; for
example, see: Coperet, C.; Chabanas, M.; Saint-Arroman, R. P.; Basset,
J.-M. Angew. Chem., Int. Ed. 2003, 42, 156-181.
(24) The face designation is according to the carbon adjacent to the
activated carbonyl.
Org. Lett., Vol. 9, No. 15, 2007
2845

solution. Interestingly, merely quenching the 9-BBN reduc-
tion with methanol gave 28 (single anomer) in excellent
yield. Both 27 and 28 were very sensitive to acid, presumably
a result of the almost perfect alignment of the allylic C-O
bond with the π-bond. After much experimentation we found
that brief exposure of 28 to TFA gave the trifluoroacetate
29 where the configuration at C-7 was inverted compared
to that in 27. Addition of aqueous NaOH to 29 gave the
corresponding alcohol 30. Thus, simply by altering the
workup procedure (i.e., (i) MeOH, (ii) TFA, (iii) NaOH) for
the â-selective reduction of 26 with 9-BBN, the R-alcohol
30 could be obtained in good yield. Treatment of 30 with
KOH in refluxing MeOH gave 31 that was selectively
reduced27 to give 15, both as ca. 1:1 mixtures of diastereo-
mers. The diastereomers 15 were interconverted by NaOH
in refluxing MeOH where the equilibrium was strongly in
favor (>30:1)5 of 15b ([R]D -110; c 0.9, CH2Cl2).
The key 5-6-7 tricyclic intermediate 17 ([R]D -120; c 1.0,
CH2Cl2) was obtained from (-)-15b as described for the
racemic series (Scheme 1).5 Introduction of the required
isopropyl group to 17 is challenging. Previously, an effica-
cious though moderately efficient route (30% over 6 steps)
based on radical cyclization of a propargyl R-bromoacetal
was developed.5 Unfortunately, our plans to explore cross-
coupling approaches for a more direct introduction of the
isopropyl group have been thwarted by our inability to obtain
a suitable R-halo enone precursor.28 Consequently, 17 was
converted to 18 ([R]D -48; c 2.9, CH2Cl2) by the former
route (6 steps, 30%).5
Scheme 3. Synthesis of Cyathin A3 (2)
give (-)-35. Spectral data (1H and 13C NMR, IR, MS) for
(-)-35 ([R]D -150; c 0.8, MeOH) were essentially identical
with those reported11b ([R]D -154; c 0.24, MeOH). Synthetic
cyathin A3 (2; a mixture of hydroxy ketone and hemiacetal
tautomers) ([R]D -160; c 0.5, MeOH; lit.11b [R]D -155; c
0.26, MeOH) was obtained from 35 on exposure to aqueous
HClO4 in THF solution.
In summary, an enantioselective total synthesis of cyathin
A3 (2) has been achieved in 28 steps (0.65% overall yield)
starting with the DA reaction of 12 with 13 by using
Mikami’s catalyst (21) modifed by addition of Mg powder
and silica gel. To the best of our knowledge, this is the first
example of an enantioselective DA reaction both of quinone
12 and of a Danishefsky-type diene (e.g., 13). The conversion
of 26 to 30 via reduction with inversion of configuration on
workup is noteworthy. Because cyathin A3 (2) is easily
transformed into allocyathin B3 (3), neoallocyathin A4 (4),
cyathin B3 (5), cyathin C3 (6), and allocyathin B2 (7),9,31 this
route also constitutes a formal synthesis of these natural
products. Similarly, several erinacines (e.g., 8 and 9) can be
prepared from a protected derivative of 2 by Nakada’s elegant
route.6,10
Oxidation29 of 18 followed by selective enol triflation of
the cyclopentenone- and Pd-catalyzed reduction30a of the
resulting triflate gave the diene 32 ([R]D -70; c 0.9, CH2Cl2)
(Scheme 3). Selective hydrogenation of the less substituted
olefin in 32 was easily effected over Pd-C to obtain 33 ([R]D
-58; c 1.7, CH2Cl2). Finally, introduction of the vinyl
hydroxymethyl group was achieved by Pd-catalyzed car-
bonylation30b of the enol triflate derived from 33 followed
by DIBALH reduction of the resulting methyl ester 34 to
Acknowledgment. Financial support from the Natural
Sciences and Engineering Research Council (Canada) and
the University of Saskatchewan is gratefully acknowledged.
(25) However, activation of the less basic carbonyl predominates where
R1 is OMe (e.g., ref 14c), presumably because coordination of 21 to the
more basic carbonyl is not sufficiently activating. Because the presence of
the potentially coordinating OMe group does not alter the sense of
enantioselectivity, activation without chelation is implied. For related
examples with other catalysts, see refs 14a,e,f.
Supporting Information Available: Determination of the
ee and absolute configuration of 14; experimental procedures,
spectroscopic data, and 1H and 13C NMR spectra for all new
(26) In 19-catalyzed DA reactions of 12 with unsymmetrical dienes, poor
regioselelctivity results from selective addition to both the syn and anti
alkenes giving regioisomeric adducts each with high ee (ref 16a).
(27) Ward, D. E.; Rhee, C. K. Can. J. Chem. 1989, 67, 1206-1211.
(28) For a review on synthesis of R-substituted R,â-enones, see: Rezgui,
F.; Amri, H.; El Gaied, M. M. Tetrahedron 2003, 59, 1369-1380.
(29) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
1
compounds (26-35); and experimental procedures and H
spectra for synthetic intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL070994Z
(30) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541-5544. (b) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1985, 26, 1109-1112.
(31) Cyathins 3 and 6 are available more directly from (-)-18 (ref 5).
2846
Org. Lett., Vol. 9, No. 15, 2007