Multiple chirality transfers in the enantioselective synthesis of 11-O-debenzoyltashironin. Chiroptical analysis of the key cascade

Article abstract of DOI:10.1016/j.tetlet.2008.07.139

The mechanism of the cascade oxidative dearomatization-transannular Diels-Alder was investigated in the context of an asymmetric route to (-)-11-O-debenzoyltashironin. Although the oxidative dearomatization provides two acetal intermediates, the transannu

Full text of DOI:10.1016/j.tetlet.2008.07.139

Tetrahedron Letters 49 (2008) 5906–5908
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Multiple chirality transfers in the enantioselective synthesis of
11-O-debenzoyltashironin. Chiroptical analysis of the key cascade
Alessandra Polara a, Silas P. Cook a, Samuel J. Danishefsky a,b,
*
a Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The mechanism of the cascade oxidative dearomatization–transannular Diels–Alder was investigated in
the context of an asymmetric route to (ꢀ)-11-O-debenzoyltashironin. Although the oxidative dearoma-
tization provides two acetal intermediates, the transannular Diels–Alder proceeds spontaneously from
only one of the acetal isomers. Access to enantioenriched tetracyclic adduct was gained through the
use of optically active allene.
Received 18 June 2008
Revised 23 July 2008
Accepted 24 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
In our ongoing efforts devoted to the total synthesis and evalu-
ation of small natural products with neurotrophic activity,1,2 we
recently described the total synthesis of racemic ( )-11-O-deben-
zoyltashironin 1 (Scheme 1).3 Compound 1 was isolated from the
Eastern Asian Illicium merrillianum and its structure was elucidated
by Fukuyama in 1995. (ꢀ)-11-O-Debenzoyltashironin has been
shown to induce neurite outgrowth in fetal rat cortical neurons
sites for further structural modifications to probe the resultant
neurotrophic activity. After extensive investigations,5,6 a strategy
toward the synthesis of 1 was developed. It employed an intramo-
lecular Tamura–Pelter oxidative dearomatization of the simple
allenic phenol 2. This step was followed by a microwave-assisted
transannular Diels–Alder reaction to rapidly generate the complex
tetracyclic compound 3.7–10 The latter was advanced to racemic 1
as described previously.
at concentrations as low as 0.1 l
M.4 Additionally, we were fasci-
nated by the structural architecture of the natural product, which
incorporates a tetracyclic, highly oxygenated and densely function-
alized core structure with five contiguous stereogenic centers. A
highly concise route3 was developed in our laboratories to gain ra-
pid access to the core tetracyclic framework, 3. The IMDA cycload-
In designing a second generation, enantiodirected synthesis of
1, we considered the possibility of stereospecifically preparing
the enantioenriched antipodes of 2, which would undergo Tam-
ura–Pelter oxidation to provide enantioenriched 4. Subsequent
transannular Diels–Alder cyclization of 4 would yield correspond-
ingly enantiomerically enriched 3. Globally, the axial chirality
information of the enantioenriched allene 2 would have been re-
layed to the tetracyclic adduct 3. Moreover, the chirality in the al-
lene 2 would have been induced from an sp3 center (through SN20
nucleophilic methylation of a mesylate), whose chirality (vide in-
fra) dated back to the asymmetric reduction of a ketone. Since
the study was conducted in an enantioenriched context, it allowed
for differentiation between mechanistic alternatives which would
not be distinguishable in the racemic series. The surprising results
thus uncovered are described below.
The first objective was the synthesis of optically active 2. One of
the most commonly employed methods by which to gain access to
enantiomerically enriched allenes is by subjecting enantioenriched
propargylic substrates to nucleophilic methylation conditions with
organocopper reagents, as pioneered by Rona and Crabbé.11,12 The
enantioenriched propargylic alcohol can be reached through asym-
metric reduction of the corresponding ynone. Subsequent activa-
tion of the alcohol then sets the stage for a copper-mediated
stereospecific SN20 displacement reaction of the leaving group to
produce enantioenriched allene.13
duct
3 not only possesses the necessary functionality for
advancement to the target molecule, but also provides convenient
OH
O
OBn
O
OBn
Me
Δ
PIDA
HO
65%
Me
Me
Me
OTs
OTs
(
)-4
(
)-2
HO
O
O
H
Me
OH
O
OBn
HO
O
OTs
Me
Me
)-3
Me
( )-11-
tashironin (1)
Me
(
O
-debenzoyl-
Scheme 1. Route to ( )-11-O-debenzoyltashironin (1).
* Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691.
E-mail address: danishes@mskcc.org (S. J. Danishefsky).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.139

A. Polara et al. / Tetrahedron Letters 49 (2008) 5906–5908
5907
Racemic propargylic alcohol 5, obtained in nine steps from com-
mercially available 2-methylresorcinol, was oxidized to the ketone
by treatment with Dess–Martin periodinane. Alpine Borane
emerged from a screening survey as the most selective reducing
agent, providing 5 in good yield (73%) and with high enantioexcess
(93%).14 Enantioenriched (+)-5 was converted to the corresponding
mesylate, which was then subjected to SN20 reaction with the high-
er order Lipshutz cyanocuprate, Me2Cu(CN)Li2, in THF at ꢀ78 °C.
This transformation provided allene (+)-6 in 78% overall yield from
(+)-5. Deprotection of both TBS groups yielded (ꢀ)-2 in 81% yield
and 93% ee. As hoped, the organocuprate reaction had proceeded
with high stereospecificity. An analogous sequence was followed
for the preparation of the enantiomeric allene, (+)-2. The absolute
configuration of the allene 6 was independently corroborated via
the Lowe–Brewster rules15 (Scheme 2).
With (ꢀ)-2 in hand, we were now prepared to investigate the
key Tamura–Pelter oxidation–transannular Diels–Alder cyclization
cascade sequence. As outlined in Scheme 3, a solution of PIDA was
added to diol (ꢀ)-2 in toluene at 0 °C. After an hour, the solution
was heated in a sealed tube at 135 °C for 20 min. The desired ad-
duct (+)-3 was formed as a single product, in 65% yield and 89%
ee. The same sequence was repeated in the enantiomeric series,
and chiral HPLC analysis of the products confirmed the stereospec-
ificity of the transformations.
Seemingly then, significant levels of IMDA reaction had occurred
at room temperature. We wondered as to why microwave or heat-
ing in a sealed tube was necessary to complete transformation to 3
since it had already formed at room temperature.3
Closer consideration of these seemingly strange findings ob-
liged us to question a key hypothesis, that is, that the chirality
transfer of the acetal-forming reaction would be unidirectional,
leading to a single product, 4. Thus, the observations described
above could be rationalized if the chirality transfer of the Tam-
ura–Pelter reaction were non-selective, leading to stereoisomeric
acetals. One of these acetals (4) is not observed because it under-
goes spontaneous IMDA reaction, leading to 3. The other Tam-
ura–Pelter acetal stereoisomer persists until it is thermolyzed,
thereby also producing 3. We hoped to isolate the precursor to
the non-spontaneous Diels–Alder cyclization, which we now pre-
sumed to be the stable acetal intermediate, 7. In the event, allene
(+)-2 was treated with PIDA and, upon workup, we isolated IMDA
product (ꢀ)-3 (25%) as well as the presumed acetal (27%). In fact,
full spectral characterization and X-ray crystallographic analysis
revealed that the isolated compound was indeed structure 7 in
which the acetal bond had formed on the face of the aromatic ring
(Fig. 1) opposite to that involved with the formation of 4.
Thus, as we had not expected at the outset, the Tamura–Pelter
oxidation of 2 may in fact occur from either face of the aromatic
system, providing stereoisomeric intermediate acetals, 4 and 7. In
acetal 4, the diene and allene orbitals are ideally positioned to
spontaneously undergo the transannular intramolecular Diels–Al-
der reaction, yielding tetracyclic adduct 3. By contrast, in interme-
diate 7, the orbitals are not aligned for cyclization, and this acetal
per se is not a productive intermediate in the cascade.
Although acetal 7 is unable to undergo the transannular Diels–
Alder reaction, upon thermolysis, it too is transformed to 3, pre-
sumably via the labile 4 which does suffer spontaneous cyclization.
Two alternative modes for the conversion of 7?4 come to mind. As
outlined in Scheme 4, epimerization of the acetal in 7 would again
yield the productive 4. Upon Diels–Alder cyclization, tetracyclic
adduct (ꢀ)-3 would be produced. Alternatively, if the allene link-
age of 7 were to epimerize under thermolysis, acetal ent-4 would
be produced. Spontaneous Diels–Alder reaction would yield ent-3
[(+)-3].
In the event, when allene (+)-2 was treated with PIDA for 1 h at
0 °C, we observed formation of acetal (+)-7 (27%) and Diels–Alder
cycloadduct (ꢀ)-3 (25%, 93% ee) (Scheme 5). Compound (+)-7
was isolated, and upon heating (135 °C, sealed tube, 15 min), the
acetal was converted to the Diels–Alder adduct (ꢀ)-3. It may thus
be concluded that 7 is converted to the Diels–Alder viable acetal 4
via epimerization of the acetal center (see Scheme 4).
With the newly gained insight as to the subtleties of the cascade
reaction came the opportunity to achieve a significant improve-
ment in the synthesis of 1 at the operational level. Rehabilitation
of unproductive acetal 7 in the synthesis had involved equilibra-
tion at the acetal center, thereby allowing it to progress to 4 en
route to 3.
In the hopes of improving the yield and simplicity of the overall
transformation leading to 3, we wondered whether equilibration at
the acetal center might be facilitated by acidic catalysis. In the
event, it was found that with the use of a more acidic hypervalent
iodine reagent, such as PIFA, we were able to obtain the desired
Diels–Alder adduct 3 from 7 at ambient temperatures in high yield
and without erosion of enantiomeric excess. Thus, as shown in
Scheme 6, slow addition of 1.1 equiv of PIFA (in CH2Cl2) to a tolu-
ene solution of diol (+)-2 in the dark afforded tetracyclic (ꢀ)-3 in
76% yield, with complete retention of enantiomeric excess (93%
ee). Apparently, the acetal linkage can be stereoequilibrated more
rapidly in the more acidic PIFA medium, thus providing an enantio-
conserved pathway to 3 without the need for thermolysis.
Careful monitoring of the reaction progress by 1H NMR led to
the observation that, shortly after addition of the oxidizing agent,
the reaction mixture is composed of a ca. 0.7:1 mixture of two
compounds, which we initially believed to be the pre-Diels–Alder
acetal intermediate 4 and the Diels–Alder adduct 3. Remarkably
at that time, this ratio did not change even when the reaction mix-
ture was left to stir at ambient temperature for two days. Upon
heating the reaction at reflux (90 °C, overnight), complete conver-
sion to 3 was observed, though the isolated yield was only 40%.
OH
OTBS
OBn
OH
OTBS
OBn
a,b
c,d
Me
Me
OH
OTBS
Me
OTBS
OTs
OTs
(+)-5
(
)-5
H
H
OTBS
OBn
Me
OBn
Me
e
Me
OH
OTBS
(+)-6
OTs
OTs
(—)-2
93% ee
Scheme 2. Synthesis of (ꢀ)-2. Reagents and conditions: (a) Dess–Martin period-
inane, CH2Cl2; (b) (S)-Alpine Borane, ꢀ78 °C, 6 h; then rt, 120 h, 73% over two steps
yield, 93% ee; (c) MsCl, Et3N, CH2Cl2; (d) Me2Cu(CN)Li2, THF, ꢀ78 °C, 78% over two
steps; (e) TBAF, AcOH, 81% yield, 93% ee.
O
O
H
OH
HO
O
BnO
O
H
OBn
Me
Δ
OBn
Me
Me
TsO
4
Me
OTs
Me
OTs
OH
(+)-2
(—)-3
94% ee
91% ee
O
H
O
OBn
OBn
Me
O
OBn
Me
HO
O
Δ
H
ent-
Me
OTs
OTs
Me
Me
4
OTs
(—)-2
(+)-3
93% ee
89% ee
Scheme 3. Stereoselective Tamura–Pelter oxidation–transannular Diels–Alder cas-
cade. Reagents and conditions: PIDA (1 equiv), toluene 0 °C, 1 h; then 135 °C,
20 min. 65% yield [(+)-3]; 63% yield [(ꢀ)-3].

5908
A. Polara et al. / Tetrahedron Letters 49 (2008) 5906–5908
Figure 1. Intermediate 7 (left) and Diels–Alder adduct 3 (right).
In summary, the chemistry presented above describes an
O
O
instructive sequence of chirality transfers which was orchestrated
en route to enantioenriched tashironin intermediates (+)- and (ꢀ)-
3. A particularly novel pathway in the cascade which creates these
intermediates has been identified and exploited for significant
mechanism-based improvement of the synthesis of tashironin.
Further experiments in this area are ongoing and will be described
in due course.
epimerize
acetal
O
BnO
H
O
OBn
Me
Me
*
TsO
O
Me
4
OTs
Me
O
OBn
(—)-3
H
a
*
O
O
Me
(+)-7
92% ee
OBn
O
OBn
O
OTs
epimerize
allene
H
ent—
Me
Me
OTs
OTs
Me
(+)-3
Acknowledgments
Me
4
Support for this research was provided by the National Insti-
tutes of Health (HL25848). Postdoctoral support from Marie Curie
Outgoing International Fellowship to A.P. is gratefully acknowl-
edged. We acknowledge Daniela Buccella (Columbia University,
NSF grant CHE-0619638) for her kind help with the X-ray analysis.
Scheme 4. Possible modes of epimerization for acetal 7.
O
H
O
(—)-3
OBn
93% ee
Supplementary data
Me
H
OH
4
HO
OTs
Me
OBn
Me
a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.139.
Me
O
(+)-2
94% ee
OTs
O
H
b
OBn
Me
(—)-3
84% ee
References and notes
(+)-7
1. Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539–549.
2. Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2007, 72, 4293–4305.
3. Cook, S. P.; Polara, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 16440–
16441.
4. Fukuyama, Y.; Shida, N.; Kodama, M. Tetrahedron Lett. 1995, 36, 583–586.
5. Cook, S. P.; Danishefsky, S. J. Org. Lett. 2006, 8, 5693–5695.
6. Cook, S. P.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 843–847.
7. Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856–866.
8. Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677–680.
9. Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927–3930.
10. Tamura, Y.; Yakura, T.; Terashi, H.; Haruta, J.; Kita, Y. Chem. Pharm. Bull. 1987,
35, 570–577.
OTs
Scheme 5. Reagents and conditions: (a) PIDA (1 equiv), 0 °C, 1 h, (ꢀ)-3, 25%, 93% ee
and (+)-7, 27%; (b) 135 °C, sealed tube, (ꢀ)-3, 84% ee.
Me
O
O
O
H
O
(-)-3
(+)-2
93% ee
H
OBn
OBn
93% ee
11. Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1968, 90, 4733–4734.
12. Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1969, 91, 3289–3292.
13. Alexakis, A.; Hanaizi, J.; Jachiet, D.; Normant, J. F.; Toupet, L. Tetrahedron Lett.
1990, 31, 1271–1274.
Me
76% yield
Me
(+)-7
4
OTs
OTs
14. Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500, 1–19.
15. Lowe, G. Chem. Commun. 1965, 411–412.
Scheme 6. Reagent and conditions: PIFA (1.1 equiv), CH2Cl2 rt, 1 h.