Studies toward the total synthesis of the hirsutellones

Article abstract of DOI:10.1016/j.tetlet.2009.03.158

A strategy of tandem ketene-trapping/IMDA toward the total synthesis of the hirsutellones was attempted. The AB ring moiety of the hirsutellones was constructed with the proper stereochemistry.

Full text of DOI:10.1016/j.tetlet.2009.03.158

Tetrahedron Letters 50 (2009) 2797–2800
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies toward the total synthesis of the hirsutellones
*
Mingzheng Huang, Chong Huang, Bo Liu
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A strategy of tandem ketene-trapping/IMDA toward the total synthesis of the hirsutellones was
attempted. The AB ring moiety of the hirsutellones was constructed with the proper stereochemistry.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 January 2009
Revised 18 March 2009
Accepted 24 March 2009
Available online 27 March 2009
In 2005, a family of interesting natural products named as
hirsutellones A–E was isolated from the insect pathogenic fungus
Hirsutella nivea BCC 2594, showing strong antimycobacterial
activities.1 One year later, hirsutellone F, with a unique dimer
structure, was isolated from the seed fungus Trichoderma sp.
BCC 7579, also displaying antitubercular activity.2 Structurally,
these novel alkaloids were similar to GKK1032,3 pyrrocidines,4
and pyrrospirones.5 All of these four families have a similar poly-
cyclic core structure which consists of a tricyclic polyketide sys-
none via HWE reaction. The stereochemistry of the phenyl ether
could be ensured by using a Pd-catalyzed allylic substitution.
According to the above retrosynthetic analysis, the known com-
pound 129 was prepared following
a routine synthetic se-
quence,10,11 and then coupled with compound 1712 using
O’Doherty’s allylic phenoxylation reaction9,13 (Scheme 2). The ste-
reochemistry of compound 18 was confirmed by NOESY correla-
tion of its derivative 21. DIBAL-H reduction of 18, followed by
Lüch reduction, afforded alcohol 22, whose primary allylic alcohol
was selectively protected with TES at low temperature. While
hydrogenation of 23 with Pd/C proved sluggish, the use of
Pd(OH)2/C saturated the double bond and removed benzyl protec-
tion simultaneously in 62% yield, though a certain amount of triol
25 was also isolated in 20% yield.
tem, a
c-lactam or succinimide ring, a substituted phenyl ether,
and a strained 12- or 13-membered ring (Fig. 1). The complex
molecular skeleton and diverse bioactivities of these families
make them very attractive target molecules for the synthetic
community; however, few synthetic efforts were reported besides
Kuwajima group’s6 and Katoh group’s7 work on the fragment
synthesis of GKK1032s, as well as Sorensen group’s very recent
research on the synthesis of the decahydrofluorene core of the
hirsutellones.8 Herein, we describe our synthesis of AB ring of
the hirsutellones and the efforts to realize the cyclization of the
strained phenyl-ether-containing ring.
Oxidative cleavage of diol 24 afforded an aldehyde intermedi-
ate, which was directly coupled with HWE reagent 26.14 In spite
of many trials, the concomitant deprotection of TES ether could
not be circumvented; thus a major THP-type cyclization product
27 was obtained, along with the desired alcohol 28. All attempts
to transform 27 to 28 failed, leading to either no reaction or
decomposition of 27. It is probably caused by the labile 2,2-di-
methyl-1,3-dioxinone segment in 27, and is consistent with a re-
ported example of ring opening of tetrahydropyranyl ketone.15
In order to furnish the key substrate 31, a three-step procedure
was applied, including Dess–Martin oxidation,16 Takai reaction,17
and Stille coupling18 of 29 with (E)-buta-1,3-dienyltributylstann-
ane 3019 at room temperature. As for Stille coupling to form triene
31, different Pd catalysts, such as Pd2(dba)3/PPh3, and Pd2(dba)3/
AsPh3, Pd(PPh3)4, were screened, and PdCl2(MeCN)2 afforded the
best result among them. Inspired by the reported successful inter-
molecular capture of ketene by oxazolidinone20 and amide,21 we
then tried the intramolecular ketene trapping/Diels–Alder tandem
strategy. Interestingly, heating a highly diluted solution of 31 at
115 °C in a sealed tube did not achieve the desired product, but
afforded bicycle 32 as an isolatable major product. The relative
stereochemistry of 32 was confirmed to fortunately match that
of the hirsutellones by NOESY (Scheme 3).22
The most unique and challenging motif of the hirsutellones to a
synthetic chemist is the highly strained 12- or 13-membered ring
containing a c-lactam or succinimide ring and a phenyl ether sub-
structure. We envisioned that the lactam bond might be con-
structed via the amine trapping of a reactive intermediate, which
would help to overcome the ring strain. As illustrated in Scheme
1, an ambitious tandem intramolecular ketene trapping/Diels–Al-
der strategy was designed, in which the highly reactive ketene gen-
erated in situ acts as such an important intermediate. This strategy
is very similar to that of Sorensen’s group.8 To probe the feasibility
of this strategy, a model substrate, simplified by omitting ring C of
the hirsutellones, was proposed, which would be prepared by
installation of the triene segment with sequential Takai reaction
and Stille coupling, and subsequent installation of the 1,3-dioxi-
* Corresponding author. Tel./fax: +86 28 8541 3712.
E-mail address: chembliu@scu.edu.cn (B. Liu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.158

2798
M. Huang et al. / Tetrahedron Letters 50 (2009) 2797–2800
OH
NH
H
O
OH
NH
NH
O
A
O
H
H
O
O
O
H
O
H
H
H
O
O
O
H
H
O
B
C
H H
H H
R
R
H H
R = H, Hirsutellone A
R = Me, Hirsutellone D
R = H, Hirsutellone B
R = Me, Hirsutellone E
Hirsutellone C
OH
H
H
OH
NH
O
O
H
NH
O
O
O
H
O
O
H
H
H
H
H
H
H
H
N
O
O
O
H
H
GKK1032A2
Hirsutellone F
O
H
OH
NH
OH
NH
18
NH
O
H
O
O
O
O
O
H
17
H
HH
H
H
O
O
H
O
1R2
H
R
H
H
H
Pyrrocidine A: 17, 18-dehydroa Pyrrospirone A: R1=H, R2=OH
GKK1032B
Pyrrospirone B: R1=OH, R2=H
Pyrrocidine B
Figure 1. Molecular structures of hirsutellone, GKK1032, pyrrocidine, and pyrrospirone families.
OR2
NR1
OH
NH
O
O
O
O
H
H
O
Hirsutellones
H
H
O
H H
2
H H
1
tandem
ketene
trapping/
IMDA
OR2
OR2
NHR1
O
NHR1
O
retro-
H
H
O
H
D.-A.
H
O
C
H
O
O
releasing
acetone
H
O
H
4
3
OR2
NHR1
Ar =
OAr
OR2
NHR1
O
OR4
O
O
R3O
O
HWE
rxn.
O
O
+ ArOH
O
O
8
OTES
Taikai
rxn.
O
7
6
Stille
coupling
5, model substrate
Scheme 1. Synthetic strategy and retrosynthetic analysis of model substrate.

M. Huang et al. / Tetrahedron Letters 50 (2009) 2797–2800
2799
O
Pd2(dba)3, PPh3
OTBS
NHBoc
OEt
BnO
+
TEA, DCM
88%
O
O
HO
17
12
O
1) DIBAL-H
DCM
OH
O
OH
TESCl, TEA
BnO
BnO
OEt
OH 2) CeCl3
NaBH4
DCM, -78-0ºC
95%
18
OAr
OAr
22
91% for 2 steps
OH
H2, Pd(OH)2/C
MeOH
86%
BnO
OTES
O
OH
DIBAL-H
OH
O
HO
ArO
OAr 23
HO
DCM
-78ºC, 87%
OEt
H2, Pd(OH)2/C
EtOAc/MeOH
20
OAr 19
OH
2) Dess-Martin
oxid., DCM
1) TBDPSCl
imid., DMF
HO
OR
51% for 2 steps
OAr
H
24: R=TES
62% yeild
+
H
O
OTBS
NHBoc
TBDPSO
Ar =
O
H
H
25
: R=H
H
20% yield
NOE
H
OAr
21
Scheme 2.
OH
O
O
O
1) NaIO4, THF/H2O
2) 26, tBuOK, THF
HO
OTES
O
27
OAr
24
OAr
62% for 2 steps
X
+
I
1) Dess-Matin
oxidation
30
PdCl2(MeCN)2, DMF
SnBu3
O
O
HO
O
O
2) CrCl2, CHI3
O
O
28
27% for 2 steps
88%
THF, 78%
OAr
29 OAr
for 2 steps
O
O
O
O
OTBS
NHBoc
Ar =
PO(OEt)2
O
O
26
31 OAr
OTBS
H
H
OTBS
NHBoc
H
NHBoc
O
O
H
sealed
H
O
O
tube
H
O
H
H
H
toluene
0.002 M
115ºC, 6h
59%
O
O
H
O
Ar
H
H
H
NOE
32
Scheme 3.
31
A tentative pathway from 31 to 32 was proposed as shown in
Scheme 4. In our opinion, the weak nucleophilicity of carbamate
and the steric hindrance around the amino group in 31 might
hamper the preferred intramolecular capture of ketene, but instead
benefit intermolecular reaction of ketene with some adventitious
water in the system to form an unstable b-keto acid, leading to a
methyl ketone 35 by releasing one molecule of carbon dioxide.
Then 32 was formed through an IMDA reaction via a favored
endo-type transition-state (TS-1). However, though this stereo-
chemical preference is in agreement with other reported exam-
ples,8,23 a reasonable explanation is still required.24
The synthetic route described above completed the
construction of AB ring moiety of the hirsutellones with the
proper stereochemistry, and acted as a guide for tuning the
reactivity of intramolecular ketene trapping. We are currently
endeavored to promote the lactam formation and optimize
the synthesis sequence as well to improve the total yield of
31.

2800
M. Huang et al. / Tetrahedron Letters 50 (2009) 2797–2800
OTBS
NHBoc
OTBS
OTBS
NHBoc
NHBoc
O
O
toluene
115 ºC
O
O
O
C
H2O
O
O
O
O
O
O
-acetone
H
31
33
34
O
H
OTBS
NHBoc
Me
OTBS
NHBoc
OAr
endo TS-1
, favored
O
O
-CO2
IMDA
O
+
H
H
O
O
ArO
Me
, unfavored
35
H
32, major
endo TS-2
Scheme 4.
12. A routine synthetic sequence was followed to afford 17:
Acknowledgments
O
(Boc)2O
O-Methyl-
L-tyrosine
13
NaBH4
OH
NHBoc
OMe
NHBoc
The financial support from the National Natural Science Foun-
dation of China (20702032) and the Ministry of Education of China
(NCET) is appreciated. We also thank Sichuan University Analytical
and Testing Center for NMR determination.
TEA, MeOH
MeOH
93%
15
TBSCl
HO
90%
14
HO
DMF
LiOH, DMF
OTBS
NHBoc
OTBS
NHBoc
91% for 2 steps
17
16
TBSO
Supplementary data
HO
For selective deprotection of phenolic TBS ether, see: (a) Ankala, S. V.; Fenteany,
G. Synlett 2003, 825–828; (b) Ankala, S. V.; Fenteany, G. Tetrahedron Lett. 2002,
43, 4729–4732.
Supplementary data (characterization data and NMR spectra of
selected new compounds were provided) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.158.
13. Gao, D.; O’Doherty, G. A. J. Org. Chem. 2005, 70, 9932–9939.
14. Boeckman, R. K.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111, 8286–8288.
15. Goodwin, T. E.; Ratcliff, D. G.; Crowder, C. M.; Seitzinger, N. K. J. Org. Chem.
1982, 47, 815–820.
16. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
17. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410.
18. Tsuchikawa, H.; Matsushita, N.; Matsumori, N.; Murata, M.; Oishi, T.
Tetrahedron Lett. 2006, 47, 6187–6191.
19. Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37,
3967–3975.
20. For an example, see: Cook, G. R.; Sun, L. Org. Lett. 2004, 6, 2481–2484.
21. For an example, see: Padwa, A.; Harring, S. R.; Semones, M. A. J. Org. Chem.
1998, 63, 44–54.
References and notes
1. Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.; Thebtaranonth,
Y. Tetrahedron 2005, 61, 5577–5583.
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2815–2817.
3. Koizumi, F; Hasegawa, A.; Ando, K.; Ogawa, T.; Hara, M. Jpn. Kokai Tokkyo Koho
2001, JP 2001247574.
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Tetrahedron Lett. 2002, 43, 1633–1636.
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Kimura, K. Bioorg. Med. Chem. Lett. 2008, 18, 6050–6053.
6. Arai, N.; Ui, H.; Omura, S.; Kuwajima, I. Synlett 2005, 1691–1694.
7. (a) Asano, M.; Inoue, M.; Katoh, T. Synlett 2005, 1539–1542; (b) Asano, M.;
Inoue, M.; Katoh, T. Synlett 2005, 2599–2602; (c) Inoue, M.; Watanabe, K.; Abe,
H.; Latoh, T. J. Org. Chem. 2006, 71, 6942–6951.
8. When this manuscript is in preparation, an elegant synthesis of the
decahydrofluorene core of the hirsutellones is reported: Tilley, S. D.; Reber, K.
P.; Sorensen, E. J. Org. Lett. 2009, 11, 701–703.
22. Compound 32: 1H NMR (400 MHz, CDCl3) d 7.05 (br d, J = 8.0, 2H), 6.67 (br d,
J = 8.0, 2H), 5.96 (d, J = 9.6, 1H), 5.54–5.60 (m, 1H), 5.46 (dt, J = 9.6, 3.2, 1H),
5.03 (m, 2H), 4.89 (t, J = 4.8, 1H), 4.71 (br d, J = 7.2, 1H), 3,77 (br s, 1H), 3.50 (dd,
J = 9.6, 3.6, A of AB, 1H), 3.47 (dd, J = 9.6, 3.2, B of AB, 1H), 3.33 (m, 1H), 2.73 (br
d, J = 6.8, 2H), 2.52 (m, 1H), 2.20–2.25 (m, 1H), 2.04 (s, 3H), 1.90–1.97 (m, 1H),
1.71–1.80 (m, 2H), 1.41 (s, 9H), 1.20–1.30 (m, 2H), 0.07 (s, 6H); HRMS (ESI)
calculated for [C33H51NO5Si+Na]+ 592.3434, found 592.3445.
23. (a) Suzuki, T.; Tanaka, N.; Matsumura, T.; Hosoya, Y.; Nakada, M. Tetrahedron
Lett. 2006, 47, 1593–1598; (b) Asano, M.; Inoue, M.; Watanabe, K.; Abe, H.;
Katoh, T. J. Org. Chem. 2006, 71, 6942–6951.
24. Houk’s modeling on conformational preferenes of allylic groups in transition
structures does not account for our result, see: (a) Houk, K. N.; Paddon-Row, M.
N.; Rondan, N. G.; Wu, Y.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.;
Loncharich, R. J. Science 1986, 231, 1108–1117; For the examples of similar
IMDA reactions consistent with Houk’s modeling, see: (b) Jarosz, S.; Boryczko,
B.; Cmoch, P.; Gomez, A. M.; Lopez, C. Tetrahedron: Asymmetry 2005, 16, 513–
518; (c) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531–13540.
9. (a) Ahmed, M. M.; O’Doherty, G. A. Carbohydr. Res. 2006, 341, 1505–1521; (b)
Ahmed, M. M.; O’Doherty, G. A. Tetrahedron Lett. 2005, 46, 3015–3019.
10. Gupta, S.; Rajagopalan, M.; Alhamadsheh, M. M.; Tillekeratne, L. M. V.; Hudson,
R. A. Synthesis 2007, 3512–3518.
11. A seven-step sequence was followed to prepare 12:
O
BnO
OH
1) Swern [O]
ref. 10
BnO
OEt
Dimethyl L- tartrate
O
O
56% for
3 steps
2)(EtO)2P(O)CH2CO2Et
K2CO3, THF/H2O
O
O
9
10
11
93% for 2 steps
O
1) TsOH, MeOH
BnO
OEt
O
2) triphosgene
DCM, Et3N
58% for 2 steps
O
12
O
.