Synthesis and stereochemical assignment of angucycline antibiotic, PD-116740

Article abstract of DOI:10.1246/cl.2008.470

The first total synthesis and absolute structure assignment of PD-116740 (2) was achieved by exploiting two key steps: 1) a thermal ring expansion of a benzocyclobutene derivative, and 2) pinacol cyclization of biaryl dialdehyde. Copyright

Full text of DOI:10.1246/cl.2008.470

470
Chemistry Letters Vol.37, No.4 (2008)
Synthesis and Stereochemical Assignment of Angucycline Antibiotic, PD-116740
Keiji Mori, Yuuya Tanaka, Ken Ohmori, and Keisuke Suzukiꢀ
Department of Chemistry, Tokyo Institute of Technology,
SORST-JST Agency, O-okayama, Meguro-ku, Tokyo 152-8551
(Received February 4, 2008; CL-080126; E-mail: ksuzuki@chem.titech.ac.jp)
Ar
RO
Ar
MeO
The first total synthesis and absolute structure assignment
MeO
MeO
Ar
C6
6π
Z
of PD-116740 (2) was achieved by exploiting two key steps:
1) a thermal ring expansion of a benzocyclobutene derivative,
and 2) pinacol cyclization of biaryl dialdehyde.
∆
toluene
3 h
OMe
OTBS
H
OSi
RO
BnO MeO
OTBS
BnO
RO OR
4
A
5
MeO
RO
RO
Ar
[1,7] H shift
Ar
The angucycline antibiotics, sharing a curved tetracyclic
skeleton, have attracted much synthetic attention due to their in-
teresting biological activities.1 Besides fully aromatized conge-
ners as 1, a structurally unique class of compounds have been
identified, including PD-116740 (2)2 and TAN-1085 (3), pos-
sessing a characteristic ‘‘off-aromatic’’ ring with dihydroxylation
(Chart 1). The synthesis of the latter class is particularly chal-
lenging, due to the difficulty of the stereocontrolled construction
of the diol moieties.3 In spite of much endeavor, the only exam-
ple of a total synthesis is limited to our recent synthesis of 3.4
H
O
RO
Si
RO
H
BnOMeOOMeOTBS
H
97%
6
(1) raising the oxidation level of C6
(2) changing the geometry of styryl group
Ar
Ar
RO
RO
RO
Ar
OSi
OSi
E
∆
RO
CHO
OR
OR
H
RO
RO
RO
H
RO
RO
B
C
D
Scheme 2. Two solutions for suppressing [1,7] hydrogen shift.
In pursuit of a general synthetic route as well as clarifying
the unknown absolute stereochemistry, we tested the latter idea
within the context of the synthesis of 2, which will be described
in this communication.
The first task along these lines was the preparation of vinyl-
stannane 9 (Scheme 3). 2-Propynyl alcohol 74 was subjected to
the Pd-catalyzed hydrostannylation, which proceeded smoothly
in rigorous regioselectivity to give the vinylstannane 8 with
desired E geometry. Silylation of the primary alcohol afforded 9.
HO
Me
HO
OH
O
O
A
D
C
B
OH
HO
O
RO
O
OR'
tetrangulol (1)
PD-116740 (2): R = Me, R' = H
TAN-1085 (3): R = H, R' = rhodinose
Chart 1.
Scheme 1 highlights two key steps in the synthesis of 3: 1) a
sequential electrocyclic reaction for facile construction of the
biaryl II,5 and 2) the SmI2-mediated pinacol cyclization to give
trans-diol III.6
Among these, step 1 deserves a special note: all attempts to
effect the ring expansion of benzocyclobutene 4 under thermal
conditions failed, because of the competing [1,7] hydrogen shift
(Scheme 2).7
OMOM
OMOM
OTBDPS
OTBDPS
OR
a
BnO
BnO
Bu3Sn
E
8: R = H
OH
b
7
9: R = TBS
Scheme 3. (a) Bu3SnH, Pd(OAc)2 (50 mol %), PPh3 (100 mol %),
THF, rt, 14 h, 90%; (b) TBSCl, imidazole, DMF, rt, 12 h, 92%;
TBDPS = t-butyldiphenylsilyl, TBS = t-butyldimethylsilyl.
OR
RO
RO
OR
RO
RO
OR
OR
RO
RO
SmI2
Scheme 4 illustrates the construction of the tetracycle. The
vinyllithium species generated from 9 (MeLi, THF, ꢁ78 ꢂC,
2 h) was combined with benzocyclobutenone 108 to afford
adduct 11 in 83% yield. Alcohol 11 was converted to the corre-
sponding methyl ether 12, ready for the thermal ring expansion.
Indeed, the planned reaction of 12 nicely proceeded upon reflux-
ing in toluene for 3 h, giving the desired biaryl 13 in quantitative
yield. Delightedly, no [1,7] hydrogen shift was observed.
Removal of two silyl groups in 13 followed by oxidation of
the resulting diol gave dialdehyde 14. Pinacol cyclization of 14
with SmI2 proceeded smoothly to give, after acetylation of the
resulting diol, diacetate 15 in 98% yield (trans/cis = 10/1,
1H NMR). Recrystallization (hexane–EtOAc) afforded trans-15
in pure form.
CHO
CHO
Step 1
Step 2
OH
OR
RO RO
OH
RO RO
OR
RO
I
II
III
RO
Scheme 1. Outline of our synthetic route to 3.
At this juncture, we envisioned two possible solutions.
One was to ‘‘delete’’ the C6 hydrogen that participates in the
sigmatropy. To our pleasant surprise, the ring expansion was
remarkably facilitated at the aldehyde oxidation level as B,
which was exploited in the synthesis of 3.4
However, we had an alternative idea: If one employed the
(E)-styryl group as C, the C6 hydrogens are disposed away from
the cyclobutene ring as D, rendering the [1,7] hydrogen shift
topologically impossible.
At this stage, optical resolution was carried out (Scheme 5).
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.4 (2008)
471
OMOM
OMOM
OR
BnO
MeO
OMOM
a
BnO
OR
BnO
R''O
Bu3Sn
OR'
c
9
O
OR'
E
OR
OMe
MeO MeO
OR'
OMe
MeO
b
13
MeO
10
MeO
11: R'' = H
MeO
12: R'' = Me
R = TBDPS, R' = TBS
Figure 1. X-ray structure of 17a. Hydrogen atoms are omitted for
clarity.
BnO OMOM
MeO
BnO
MeO
OMOM
d, e
f, g
BnO
MeO
OH
BnO
MeO
CO2Me
CHO
CHO
OAc
MeO MeO
MeO MeO
15
trans/cis = 10/1
OAc
a
b,
c
d
17a
14
S
OAc
OAc
S
MeO MeO
OAc
MeO MeO
OAc
Scheme 4. (a) MeLi, THF, ꢁ78 ꢂC, 2 h; 10, THF, ꢁ78 !
ꢁ10 ꢂC, 2.5 h, 83%; (b) n-BuLi, Et2O, ꢁ78 ꢂC, 15 min; MeOTf,
Et2O, ꢁ78 ! 0 ꢂC, 1 h, 88%; (c) toluene, reflux, 3 h, quant.; (d)
TBAF, THF, rt, 4 h, 93%; (e) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢁ78 ! 0 ꢂC, 1.5 h, 83%; (f) SmI2, THF, 0 ꢂC, 5 min; (g) Ac2O,
DMAP, pyridine, rt, 12.5 h, 98% (2 steps), trans/cis = 10/1.
(S, S)-16
(S, S)-18
BnO
HO
HO
O
OH
e, f
OH
OH
MeO
O
S
R
OH
OH
OH
S
R
MeO MeO
OH
MeO
O
OH
MeO
O
OH
(S, S)-19
(S, S)-20 (= 2)
(R, R)-20
[α]D24 = +3.1 x 102 (c 0.43, MeOH) [α]D25 = −307 (c 0.383, MeOH)
lit. [α]D = +311 (c 0.44, MeOH)
BnO
MeO
OR*
Scheme 6. (a) N,N-dimethyl-1,3-propanediamine, THF, rt, 5.5 h,
quant.; (b) Tf2O, i-Pr2NEt, CH2Cl2, ꢁ78 ! ꢁ35 ꢂC, 1 h, 81%;
(c) CO, Pd(OAc)2 (30 mol %), dppf (30 mol %), Et3N, MeOH,
DMF, 60 ꢂC, 2.5 h, 60%; (d) DIBAL, CH2Cl2, ꢁ78 ! ꢁ35 ꢂC,
1 h, 98%; (e) H2, 10% Pd/C, MeOH, rt, 30 min; (f) CAN, CH3CN,
H2O, 0 ꢂC, 20 min, 67% (2 steps); dppf = 1,10-bisdiphenylphos-
phinoferrocene, CAN = cerium ammonium nitrate.
S
BnO
MeO
OH
OAc
S
MeO MeO
OAc
17a
a
b
15
5
BnO
MeO
OR*
OAc
Me
6
MeO MeO
OAc
O
rac-16
R
R*
O
O
OAc
R
MeO MeO
OAc
17b
progress to develop a general, enantioselective synthetic route
to this class of compounds.
Scheme 5. (a) 0.5 M H2SO4, DME, 60 ꢂC, 5.5 h, 67%; (b) (ꢁ)-
camphanic chloride, DMAP, CH2Cl2, rt, 2 h, 93%; DME = 1,2-di-
methoxyethane.
This work was partially supported by the Global COE
Program (Chemistry) and a Grant-in-Aid for Scientific Research
(JSPS). JSPS Research Fellowship for Young Scientists to
K. M. is also acknowledged.
After detaching the MOM group in 15, the resulting phenol
16 was combined with (ꢁ)-camphanic chloride and DMAP to
give diastereomeric esters 17a/17b. Separation by recycled
HPLC with chiral stationary phase [DAICEL CHIRALPAKÒ
IA (hexane/EtOAc = 2/1)] gave diastereomers 17a (tR ¼
16:2 min) and 17b (tR ¼ 11:2 min).9 The diastereomer 17a
gave nice single crystals (i-PrOH–EtOAc, colorless plates, mp
141.5–142.0 ꢂC), and X-ray analysis established the (S, S)
stereochemistry (Figure 1).10
Having assigned the stereostructures of the two diastereom-
ers, removal of each camphanoyl group afforded an enantiomer-
ic pair of diacetates (S, S)-16 and (R, R)-16, which were further
converted to the final product, respectively. Scheme 6 represents
the transformation of (S, S)-16, which started with the Pd-cata-
lyzed carbonylation of the corresponding triflate to methyl ester
(S, S)-18. Treatment of (S, S)-18 with DIBAL effected ester
reduction and the removal of two acetyl groups to give triol
(S, S)-19. Finally, hydrogenolysis of the benzyl group followed
by oxidation with CAN afforded (S, S)-20 in 67% yield.
The same sequence of transformations converted (R, R)-16 into
(R, R)-20. It turned out that the sign and magnitude of optical
rotation of (S, S)-20 coincided to that of 2, thereby establishing
the absolute stereochemistry of the natural product as 5S, 6S.9
In summary, the first synthesis of 2 was achieved, establish-
ing the absolute stereochemistry. Further work is now in
References and Notes
1
2
For a review, see: J. Rohr, R. Thiericke, Nat. Prod. Rep. 1992, 9, 103.
J. H. Wilton, D. C. Cheney, G. C. Hokanson, J. C. French, H. Cunheng,
J. Clardy, J. Org. Chem. 1985, 50, 3936.
3
On synthesis of angucyclines, see: a) D. S. Larsen, M. D. O’Shea, J.
Org. Chem. 1996, 61, 5681. b) F. M. Hauser, W. A. Dorsch, D. Mal,
Org. Lett. 2002, 4, 2237. c) M. C. Carren˜o, A. Urbano, Synlett 2005, 1.
K. Ohmori, K. Mori, Y. Ishikawa, H. Tsuruta, S. Kuwahara, N. Harada,
K. Suzuki, Angew. Chem., Int. Ed. 2004, 43, 3167.
a) T. Matsumoto, T. Hamura, M. Miyamoto, K. Suzuki, Tetrahedron
Lett. 1998, 39, 4853. b) T. Hamura, M. Miyamoto, T. Matsumoto,
K. Suzuki, Org. Lett. 2002, 4, 229. c) T. Hamura, M. Miyamoto, K.
Imura, T. Matsumoto, K. Suzuki, Org. Lett. 2002, 4, 1675.
a) K. Ohmori, K. Kitamura, K. Suzuki, Angew. Chem., Int. Ed. 1999,
38, 1226. b) K. Kitamura, K. Ohmori, T. Kawase, K. Suzuki,
Angew. Chem., Int. Ed. 1999, 38, 1229.
4
5
6
7
8
For computational study on these competing processes, see: Z. R.
Akerling, J. E. Norton, K. N. Houk, Org. Lett. 2004, 6, 4273.
T. Hamura, T. Hosoya, H. Yamaguchi, Y. Kuriyama, M. Tanabe,
M. Miyamoto, Y. Yasui, T. Matsumoto, K. Suzuki, Helv. Chim. Acta
2002, 85, 3589, and references therein.
9
Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett.
10 Crystallographic data reported in this manuscript have been deposited
with Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC-676052.
Published on the web (Advance View) March 25, 2008; doi:10.1246/cl.2008.470