Synthetic studies on (-)-scabronine A

Article abstract of DOI:10.1016/j.tetlet.2007.12.109

This Letter describes synthetic studies on (-)-scabronine A utilizing a new chiral building block successfully prepared via the catalytic asymmetric intramolecular cyclopropanation (IMCP) of an α-diazo-β-keto sulfone. The crucial transformations in this s

Full text of DOI:10.1016/j.tetlet.2007.12.109

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Tetrahedron Letters 49 (2008) 1518–1522
Synthetic studies on (À)-scabronine A
Hideaki Watanabe, Masahisa Nakada *
Department of Chemistry and Biochemistry, Advanced School of Science and Engineering, Waseda University,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received 20 November 2007; revised 15 December 2007; accepted 20 December 2007
Available online 25 December 2007
Abstract
This Letter describes synthetic studies on (À)-scabronine A utilizing a new chiral building block successfully prepared via the catalytic
asymmetric intramolecular cyclopropanation (IMCP) of an a-diazo-b-keto sulfone. The crucial transformations in this study are the
coupling reaction of two fragments between the positions adjacent to a quaternary carbon center, the intramolecular aldol reaction,
the C14 hydroxyl-directed hydrogenation, and the ring-expansion reaction to furnish the 5-6-7 tricyclic cyathane skeleton.
Ó 2008 Elsevier Ltd. All rights reserved.
(À)-Scabronine A (1) (Fig. 1) was isolated from the
mushroom Sarcodon scabrosus with some congeners1 and
recognized to be a potent stimulator of nerve growth factor
(NGF) synthesis. It has attracted medicinal interest
because NGF synthesis stimulators have been expected to
serve as medicine for degenerative neuronal disorders such
as Alzheimer’s disease and to aid in peripheral nerve
regeneration.2
thetic intermediate for the total synthesis of 1 via the
convergent approach utilizing a new chiral building block
developed by us.3a,g,4,5a
We envisioned that the two methoxy groups at C11 and
C13 could be installed after the construction of the 5-6-7
tricyclic skeleton of 1. As the alkene in the A-ring of 2
(Scheme 1) could be isomerized to the more substituted
position in the later stage, our retrosynthetic analysis of 1
generated 2 as the key intermediate for the total synthesis
of 1. Then, we reasoned that 2 would be generated from
3 via the one-carbon ring-expansion, and a C5–C6 trans
junction in 3 could be constructed by the C17 or C146
hydroxyl-directed stereoselective hydrogenation of the
compound derived from 4, which would be obtained from
5 via the installation of an isopropyl group. Ketone 5 could
be prepared via the intramolecular aldol reaction of dike-
tone 6 and subsequent dehydration, and 6 was expected
to be obtained via the coupling reaction of 7 with 8.
Although a preparation of iodide 7 was previously reported
The structure of 1 was elucidated by NMR techniques,1a
and the absolute structure was unambiguously confirmed
by the single X-ray crystal structure analysis of its deriva-
tive.1b The disclosed structure features a novel tetracyclic
structure with eight stereogenic centers incorporating the
cyathane skeleton. Comparing it with the other members
of the cyathane family, we can note that its different struc-
tural features are a hemiacetal formed between the C14
hydoxyl and C15 aldehyde, two methoxy groups at C11
and C13, and the C17 carboxyl group, which is a methyl
group in the usual cyathane system.
The promising bioactivity and fascinating structure
described above prompted us and other groups to start
synthetic studies of 1,3 and herein, we report the enantio-
selective synthesis of the enantiopure 5-6-7 tricyclic syn-
O
14
HO21C7
OMe
OH
6
13
5
15
H
11
OMe
1
*
Corresponding author. Tel./fax: +81 3 5286 3240.
Fig. 1. Structure of (À)-scabronine A (1).
E-mail address: mnakada@waseda.jp (M. Nakada).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.109

H. Watanabe, M. Nakada / Tetrahedron Letters 49 (2008) 1518–1522
1519
O
1) TBDPSCl, imidazole,
O
C
OH
TBDPSO
OTBDPS
OH
CH2Cl2, rt
TBDPSO
6
B
H
5
CO2Et
1
2) DIBAL-H, CH2Cl2
-78 oC
CHO
A
13
H
H
12
H
OTBDPS
OEt
2
3
CH3C(OEt)3,
p-nitrophenol (cat.),
OMPM
OMPM
TBDPSO
toluene, reflux,
94% (3 steps)
14
TBDPSO
O
17
14
H
H
O
1) MeSO2Mes, n-BuLi (2 equiv), THF, 88%
HO
11
4
5
2) TsN3, TEA, CH3CN, 84%
OMPM
I
OMPM
Scheme 2. Preparation of 11.
TBDPSO
The catalytic asymmetric IMCP of 11 was examined
under the reported conditions optimized for the reactions
of the a-diazo-b-keto sulfones similar to 11.5a Thus, the
IMCP of 11 with CuOTf and ligand 15a–c was studied
(Scheme 3), and ligand 15c was found to be most effec-
tive, providing 10 in 87% yield with excellent selectivity
(93% ee).8
O
TBSO
7
O
6
SPh
TBDPSO
O
TBDPSO
OTBDPS
CHO
O
SO2Mes
O
O
O
10
OTBDPS
8
OTBDPS
9
CuOTf
(10 mol%)
ligand 15
SO2Mes
N2
SO2Mes
OTBDPS
SO2Mes
(15 mol%)
O
O
11
Mes=2,4,6-trimethylphenyl
10
R
R
N2
O
O
O
11
Scheme 1. Retrosynthetic analysis of (À)-scabronine A (1).
15a: R=Me
15b: R=Et
15c: R=Bn
87%, 68% ee
86%, 69% ee
87%, 93% ee
N
N
i-Pr
i-Pr
Scheme 3. Catalytic asymmetric IMCP of 11.
by us,3a 8 was a new chiral compound; hence, a new prep-
aration method for 8 was required. We thought that chiral
8 would be obtained via Pummerer rearrangement of 9,
which could be derived from cyclopropane 10, which in
turn could be generated by the catalytic asymmetric intra-
molecular cyclopropanation (IMCP) of 11 developed by
us.5 As the protecting group for the hydroxyl in 11, we
selected a TBDPS group because a bulky TBDPS group
could prevent the hydroxyl oxygen from forming the oxo-
nium ylide when the metal carbene complex was generated
in situ, thereby allowing cyclopropane to form in high
yield.
Preparation of 11 started with forming the TBDPS ether
of ethyl 2-hydroxymethylpropenoate (12) (Scheme 2),7
which was reduced with DIBAL-H to provide alcohol 13.
Claisen rearrangement of 13 using a triethyl orthoacetate
under acidic conditions provided 14 (94%, three steps),
followed by reaction with a dianion of mesityl methyl
sulfone to afford the corresponding b-keto sulfone (88%),
which was subjected to the diazotransfer reaction to
furnish 11 (84%).
SPh
TBDPSO
PhSK, t-BuOH,
10
THF, 50 oC, 99%
SO2Mes
16
O
SPh
TBDPSO
1) Li, naphthalene, THF,
-78 oC, 78%
2) p-TsOH, (CH2OH)2, CH(OEt)3,
CH2Cl2, reflux, quant.
O
O
9
TBDPSO
O
CHO
1) mCPBA, CH2Cl2, -40 oC, 99%
2) TFAA, TEA, CH2Cl2, 0 oC;
then, THF, H2O, rt, 96%
O
8
Scheme 4. Enantioselective synthesis of 8.

1520
H. Watanabe, M. Nakada / Tetrahedron Letters 49 (2008) 1518–1522
This result sufficed for the study of the next step, and
OMPM
1) SOCl2, 2,6-lutidine,
rt, 76%
further elaboration of 10 to 8 was examined (Scheme 4).
The ring-opening reaction of cyclopropane 10 was attained
with potassium thiophenoxide to provide 16 as a mixture of
diastereomers (99%), followed by desulfonation with lith-
ium naphthalenide (78%) and ethylene ketal formation to
provide 9 (quant). Oxidation of 9 with mCPBA to the
corresponding sulfoxide (99%) and subsequent Pummerer
rearrangement successfully provided aldehyde 8 in excel-
lent yield (96%).
With two fragments, 7 and 8, in hand, their coupling
reaction was executed (Scheme 5). Although this reaction
was expected to be sluggish because the reacting point in
both the fragments is adjacent to a quaternary carbon,
the optimized conditions shown in Scheme 5 provided 17
in 87% yield. Alcohol 17 was converted to the methyl xan-
thate and subsequent tinhydride reduction afforded 18
(78%, two steps). The TBS and ketal groups in 18 were
simultaneously removed under the acidic conditions
(quant), and following Dess–Martin oxidation provided
diketone 6 (92%). Various reaction conditions for the intra-
molecular aldol reaction of 6 were surveyed, but a substan-
tial amount of 6 remained in most cases. However, the use
TBDPSO
19
2) isopropenyllithium,
Et2O, -78 oC to rt
97% (73% conv)
H
HO
4
OMPM
HO
TBAF, THF,
50 oC, 100 %
17
H
HO
20
OMPM
HO
[Ir(cod)(Py)(PCy3)]PF6
(Crabtree's catalyst)
6
5
H2 (100 atm), CH2Cl2, 2 d
H
H
HO
21
Scheme 6. Installation of the isopropyl group and attempted construction
of the C5–C6 trans junction via the C17 hydroxyl-directed hydrogenation
of 20 by the use of Crabtree’s catalyst.
of t-BuOK in toluene was found to provide 19 in 98% yield
(76% conv), furnishing the 5-6-6 tricyclic skeleton.3a,g
To establish the C5–C6 trans stereochemistry, we first
attempted the C17 hydroxyl-directed hydrogenation of 20
(Scheme 6). To prepare 20, 19 was dehydrated with thionyl
chloride and 2,6-lutidine (76%),9 and the resultant b,c-
unsaturated ketone 5 was reacted with isopropenyllithium
to provide 4 (97%, 73% conv) because the alkenes in the
product were expected to be hydrogenated at the same
time. The TBDPS group in 4 was removed using TBAF
to afford 20 (100%), which was subjected to the hydroxyl-
directed hydrogenation by the use of Crabtree’s catalyst;10
however, although the isopropenyl group was hydro-
genated, the trisubstituted alkene remained intact even
under the high pressure conditions.
I
OMPM
t-BuLi, THF, Et2O, -100 oC;
then 8, 87%
TBSO
7
1) NaHMDS, CS2;
then, MeI, rt
OH
OMPM
TBDPSO
2) n-Bu3SnH, AIBN (cat.),
benzene, 80 oC,
78% (2 steps)
TBSO
O
O
O
17
OMPM
TBDPSO
1) 2N-HCl, THF,
50 oC, quant
2) Dess-Martin
periodinane
CH2Cl2, rt, 92%
TBSO
O
OH
18
TBDPSO
14
H2, Pd/C,
OMPM
4
MeOH, 95%
H
TBDPSO
t-BuOK, toluene,
HO
0 oC to rt,
98% (76% conv)
22
OH
O
O
6
TBDPSO
Crabtree's catalyst
(10 mol%),
6
OMPM
5
TBDPSO
H2 (1 atm), CH2Cl2, rt,
12 h, 92%
H
H
NOE 7.2%
NOE 6.9%
HO
OH
23
single diastereomer
H
O
19
Scheme 5. Synthesis of 19 via the coupling reaction of 7 with 8 and the
intramolecular aldol reaction of 6.
Scheme 7. Construction of the C5–C6 trans junction via the C14
hydroxyl-directed hydrogenation of 22 by use of Crabtree’s catalyst.

H. Watanabe, M. Nakada / Tetrahedron Letters 49 (2008) 1518–1522
1521
As preparation of 21 from 20 failed, we next examined
the C14 hydroxyl-directed hydrogenation (Scheme 7).
Thus, 4 was subjected to the Pd-mediated catalytic hydro-
genation to remove the MPM group by converting the iso-
propenyl group to the isopropyl group, providing 22 (95%).
The hydrogenation of 22 with Crabtree’s catalyst
(10 mol %) under atmospheric pressure successfully pro-
vided 23 as the sole product (92%), and the C5–C6 trans
stereochemistry of 23 was confirmed by NOE experiments.
It is worth noting that no reaction was observed in the
hydrogenation of 22 with Pd/C, Pt2O, or Rh/Al2O3 even
under the high pressure conditions (80 atm) at room tem-
perature after 12 h. These results indicated that the C14
hydroxyl group accelerated the hydrogenation of 22 with
Crabtree’s catalyst. Compared with the hydrogenation of
20, the C14 secondary hydroxyl of 22 is in pseudoaxial posi-
tion; hence, it would inevitably direct Crabtree’s catalyst to
the desired p-face of the alkene of 22, resulting in the exclu-
sive formation of 23.
The remaining task was the one-carbon ring-expansion
of a six-membered ring in 23 to generate the seven-mem-
bered C-ring in 2 (Scheme 8). To this end, we employed
Guerrero’s method11 because it can convert a cyclohexa-
none to a b-formyl-a,b-unsaturated cycloheptenone, which
is incorporated in the structure of 2. Hence, 23 was con-
verted to ketone 3 via Dess–Martin oxidation (85%) and
subsequent dehydration (95%). Then, ketone 3 was formy-
lated and subsequent treatment with a thiol12 under the
acidic conditions provided alkenyl sulfide 24. Reaction of
24 with a methoxy(phenylthiomethyl)lithium provided 25
as a mixture of diastereomers, which was treated with
HgCl2 under the acidic conditions productively caused
the ring-expansion reaction to furnish the desired ketoalde-
hyde
2
incorporating the 5-6-7 tricyclic cyathane
skeleton.13
Furthermore, the reaction of 25 with HgCl2 under
another condition shown in Scheme 914 provided 26 with
a methoxy group at the C13 position.13 NOE experiments
on 26 indicated that the reaction in Scheme 9 correctly con-
structed the stereochemistry of C13 position.
O
1) Dess-Martin
periodinane,
CH2Cl2, 85%
TBDPSO
23
H
H
2) SOCl2, Py,
CH2Cl2, 95%
In conclusion, a new chiral building block was success-
fully prepared via the catalytic, asymmetric, intramolecular
cyclopropanation with high ee and was effectively utilized
in this synthetic study. The C5–C6 trans junction was ste-
reoselectively constructed via the C14 hydroxyl-directed
hydrogenation using the Crabtree’s catalyst. The crucial
one-carbon ring-expansion of the 5-6-6 tricyclic compound
to the 5-6-7 tricyclic compound with a cyathane skeleton
was productively achieved employing Guerrero’s proce-
dure. In addition, preparation of the more advanced inter-
mediate possessing a methoxy group at the C13 with
correct stereochemistry was achieved. Further, synthetic
studies leading to the convergent total synthesis of (À)-
scabronine A is now being pursued and will be reported
in the future.
3
O
TBDPSO
1) NaH, HCO2Me,
DME, rt
SC12H25
H
H
2) C12H25SH,
p-TsOH (cat.),
PhH, 85% (2 steps)
24
MeO
SPh
OH
TBDPSO
MeOCH2SPh,
SC12H25
n-BuLi, THF, -78 oC
H
H
25
O
Acknowledgments
TBDPSO
HgCl2, 1N HCl,
This work was financially supported in part by a Waseda
University Grant for Special Research Projects, a Grant-in-
Aid for Scientific Research on Priority Areas (Creation
of Biologically Functional Molecules (No. 17035082)),
Young Scientists (start-up research (No. 18850023)), and
the Global COE program ‘Center for Practical Chemical
Wisdom’ of MEXT.
CHO
CH3CN, 50 oC,
79% (2 steps)
H
H
2
Scheme 8. Synthesis of the 5-6-7 tricyclic intermediate 2.
NOE 6.0%
References and notes
O
TBDPSO
H
HgCl2, HgO,
CH3CN, H2O,
OMe
1. (a) Ohta, T.; Kita, T.; Kobayashi, N.; Obara, Y.; Nakahata, N.;
Ohizumi, Y.; Takaya, Y.; Oshima, Y. Tetrahedron Lett. 1998, 39,
6229–6232; (b) Ohta, T.; Kobayashi, H.; Hosoi, S.; Kiuchi, F.; Kita,
T.; Takaya, Y.; Oshima, Y.; Obara, Y.; Nakahata, N.; Ohizumi, Y.
Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1998, 40th, 341–346.
2. (a) Rosenberg, S. Annu. Rep. Med. Chem. 1992, 27, 41–48; (b) Bigge,
C. F.; Boxer, P. A. Annu. Rep. Med. Chem. 1994, 29, 13–22; (c)
25
50 oC
54% (2 steps)
H
SC12H25
H
26
Scheme 9. Conversion of 25 to 26 possessing a b-methoxy group at C13.

1522
H. Watanabe, M. Nakada / Tetrahedron Letters 49 (2008) 1518–1522
Saragovi, H. U.; Burgess, K. Exp. Opin. Ther. Patents 1999, 9, 737–
751.
Tetrahedron Lett. 2003, 44, 9007–9011; (c) Sawada, T.; Nakada, M.
Adv. Synth. Catal. 2005, 347, 1527–1532; (d) Takeda, H.; Nakada, M.
Tetrahedron: Asymmetry 2006, 17, 2896–2906; (e) Takeda, H.;
Honma, M.; Ida, R.; Sawada, T.; Nakada, M. Synlett 2007, 579–
582; (f) Ida, R.; Nakada, M. Tetrahedron Lett. 2007, 48, 4855–4859.
6. Numbering for the cyathane system is used.
3. Enantioselective total synthesis of cyathane diterpenoids: (+)-allo-
cyathin B2: (a) Takano, M.; Umino, A.; Nakada, M. Org. Lett. 2004,
6, 4897–4900; (b) Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am.
Chem. Soc. 2005, 127, 2844–2845; (c) Trost, B. M.; Dong, L.;
Schroeder, G. M. J. Am. Chem. Soc. 2005, 127, 10259–10268; (+)-
cyanthiwigin U: (d) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem.
Soc. 2005, 127, 5334–5335; (À)-scabronine G: (e) Waters, S. P.; Tian,
Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514–
13515; (À)-cyathin A3: (f) Ward, D. E.; Shen, J. Org. Lett. 2007, 9,
2843–2846; (À)-erinacine B: (g) Watanabe, H.; Takano, M.; Umino,
A.; Ito, T.; Ishikawa, H.; Nakada, M. Org. Lett. 2007, 9, 359–
362.
7. Jean, V.; Monique, R. Synthesis 1982, 924–927.
8. Ee determined by HPLC. The absolute stereochemistry of 10 was
determined by comparing the corresponding alcohol, which was
prepared by the reaction of 10 with TBAF, with the known
compound in Ref. 5a.
9. Use of thionyl chloride and pyridine afforded an inseparable mixture
of the desired product and its regioisomer, the a,b-unsaturated
ketone.
4. Total synthesis of enantiopure natural products using the chiral
building blocks developed by us, see: (a) Miyamoto, H.; Iwamoto, M.;
Nakada, M. Heterocycles 2005, 66, 61–68; (b) Takeda, H.; Watanabe,
H.; Nakada, M. Tetrahedron 2006, 62, 8054–8063; (c) Honma, M.;
Nakada, M. Tetrahedron Lett. 2007, 48, 1541–1544; (d) Inoue, M.;
Nakada, M. J. Am. Chem. Soc. 2007, 129, 4164–4165. Also see: Ref.
3a,g.
10. (a) Crabtree, R. H.; Morris, G. E. J. Organomet. Chem. 1977, 135,
395–403; (b) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105,
1072–1073.
11. Guerrero, A.; Parrilla, A.; Camps, F. Tetrahedron Lett. 1990, 31,
1873–1876.
12. Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.-I.; Miyamoto, T.
Tetrahedron Lett. 2001, 42, 9207–9210.
5. (a) Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.; Watanabe, H.;
Umino, A.; Matsumura, T.; Hagihara, T.; Takano, M.; Nakada, M.
J. Am. Chem. Soc. 2003, 125, 2860–2861; (b) Honma, M.; Nakada, M.
13. Satisfactory spectroscopic data of 2 and 26 have been obtained.
14. Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, A.; Tatsuoka, T.;
Meinwald, J. J. Org. Chem. 1986, 51, 773–784.