Concerning Lewis acid promoted, directing-group-free epoxide-ring-opening cascades

Article abstract of DOI:10.1055/s-2006-949637

Lewis acid promoted cascades of a tris(disubstituted epoxide) triggered by silver-promoted abstraction of a bromide ion favors trans-dioxabicyclo[4.3.0] nonanes, rather than diads or triads of tetrahydropyrans (trans-dioxabicylco[4. 4.0]decanes, for examp

Full text of DOI:10.1055/s-2006-949637

CLUSTER
2329
Concerning Lewis Acid Promoted, Directing-Group-Free Epoxide-Ring-
Opening Cascades
E
poxide-Ring-O
i
pening
m
Cascades othy P. Heffron,1 Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, MA 02139, USA
Fax +1(617)3240253; E-mail: tfj@mit.edu
Received 2 May 2006
H
H
H
H
H
Cs2CO3,
CsF
(a)
HO
Me
HO
O
O
Abstract: Lewis acid promoted cascades of a tris(disubstituted ep-
oxide) triggered by silver-promoted abstraction of a bromide ion fa-
vors trans-dioxabicyclo[4.3.0]nonanes, rather than diads or triads
of tetrahydropyrans (trans-dioxabicylco[4.4.0]decanes, for exam-
ple). These results suggest that an epoxide-attacking-epoxonium
mechanism is not operative in this system.
Me3Si
O
O
Me
MeOH,
reflux
O
O
O
O
Me3Si
H
H
H
H
Me3Si
Me3Si
ref. 3
(b)
H
H
H
HO
Me
O
O
O
Key words: epoxides, cascade, ring opening, fused-ring systems,
Lewis acids
Me
OH
O
this work
O
O
H
H
H
Scheme 1
In the past twenty years significant effort has been direct-
ed toward the development of methods that prepare trans-
syn-trans polyether frameworks (‘ladder’ polyethers) by
way of sequential epoxide-opening reactions. The inspira-
tion for all of these ‘cascades’ can be traced to a hypothe-
sis that Nakanishi put forth in 1985 in order to account for
the structural and stereochemical regularities found in the
class of natural products that feature the ladder polyether
framework.2 We recently described a new strategy of this
genre, one in which a trimethylsilyl (Me3Si) group con-
trols the regioselectivity of epoxide-opening, and immedi-
ately thereafter, is removed via protiodesilylation
(Scheme 1).3 That is, the starting materials contain up to
three epoxysilanes, but the final products of the cascades
contain no Me3Si groups.
(Y+), such as a Lewis or Brønsted acid or a carbonium ion;
(2) the oxygen of the next nearest epoxide (B) attacks the
carbon at which the developing positive charge is better
stabilized (tertiary vs. secondary carbocation, in the ex-
ample shown), affording an intermediate that can be rep-
resented by an epoxonium species; (3) the oxygen of the
next epoxide (C) can now attack one of two carbons,
where (a) fragmentation of the C–O bond indicated in red
represents exo opening of the epoxide and leads to a five-
membered ring and an oxabicyclo[2.1.0]pentane, or (b)
fragmentation of the other (blue) C–O bond leads to a six-
membered ring (endo) and an oxabicyclo[3.1.0]hexane.
The latter, an endo ring-opening process (b), is required
for the formation of the ladder polyether framework, and
might be expected to be favored because it leads to the less
strained of two possible oxabicyclic ring systems. Repeti-
tion of steps 1–3 above would lead to an extended, ladder-
like array of trans-syn-trans-fused tetrahydropyrans
(THPs).
Herein, we report preliminary investigations of related
cascades of oligo(disubstituted epoxides) (Scheme 1). In
principle, these oligoepoxides would afford the same
types of products as the oligo(epoxysilanes), trans-syn-
trans polyethers in which a hydrogen atom is found at
both carbon atoms of each ring junction. In contrast to the
Me3Si-directed epoxide-opening cascades, these may be
considered to be ‘directing-group-free’.
In the model proposed above, a starting material contain-
ing at least three epoxides (A, B, and C) is required.
Murai5 investigated some aspects of this hypothesis in de-
tail with a diepoxide (1, Scheme 3), in which the electro-
philic species (Y+, see Scheme 2) is generated by
abstraction by a silver cation of a bromide atom that is
tethered to the epoxide. This design feature is ingenious in
that not only is it orthogonal to the rest of the system (i.e.,
selective for bromide abstraction over epoxide activa-
tion), but also engenders developing positive charge at
one specific carbon.
The fundamental requirement of these cascades is that an
epoxide is sufficiently nucleophilic to open another ep-
oxide that has been activated by a Brønsted or Lewis ac-
id.4 This framework also tests whether or not there may be
an inherent preference for endo-type over exo-type ep-
oxide ring-opening, thus favoring the formation of the
larger of two possible oxygen heterocyclic rings.
Such selectivity might be obtained under the following se-
quence of events (Scheme 2): (1) the cascade is initiated
by the reaction of epoxide A with an electrophilic species
Nevertheless, there are two possible mechanistic frame-
works that account for Murai’s results, one of which does
not involve an epoxide-attacking-epoxonium event
(Scheme 3). Since the formation of products containing
two fused THPs (a THP ‘diad’) were not observed, these
two mechanisms cannot be differentiated. More impor-
SYNLETT 2006, No. 14, pp 2329–2333
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949637; Art ID: Y00406ST
© Georg Thieme Verlag Stuttgart · New York

2330
T. P. Heffron, T. F. Jamison
CLUSTER
A
B
C
YO
Me
Y+
O
O
O
O
O
Me
Me
Me
YO
Me
oxabicyclo[2.1.0]pentane
does not lead to ladder
polyether framework
(a)
O
O
O
(more strained)
Me
exo
YO
Me
(b)
oxabicyclo[3.1.0]hexane
does lead to ladder
polyether framework
O
endo
(less strained)
Me
Scheme 2 Epoxide-opening cascades initiated by an electrophilic species (Y+)
H
O
AgOTf
OTBDPS
OTBDPS
OTBDPS
O
O
O
THF–H2O
(5:1)
O
O
O
Br
H
1
H2O
H2O
H
H
H
H
OH
O
H
OTBDPS
OH
O
Murai
ref. 5
OTBDPS
O
2
3
Scheme 3
tantly, the central hypothesis of our design, that epoxide- alcohol 5 in three steps in 58% overall yield. A four-step,
attacking-epoxonium should favor the endo product (see three-carbon homologation procedure was then employed
above) is not explicitly tested by the Murai system.
twice, consecutively, to convert 5 to trienol 6. Protection
of the primary alcohol as tert-butyldiphenylsilyl ether, re-
moval of the methoxymethyl protective group, and treat-
ment with phosphorus tribromide afforded triene 7.
Accordingly, we prepared a homologated version of Mu-
rai’s system (4) such that we could not only make a direct
comparison to the wealth of information gathered for the
diepoxide, but also explicitly test our hypotheses The desired triepoxide was obtained in one final transfor-
(Scheme 4).
mation, a catalyst-controlled, enantioselective and diaste-
reoselective, three-fold epoxidation of this triene using the
chiral, fructose-derived, ketone/Oxone® system devel-
Triepoxide 4 was prepared as shown in Scheme 5. Com-
mercially available 4-pentyn-1-ol was converted to allylic
AgOTf
O
O
O
O
O
OTBDPS
OTBDPS
O
Br
4
THP diad not formed
H
H
H
OH
O
OH
OTBDPS
O
H2O
O
OTBDPS
OTBDPS
O
O
O
H
H
H
H
O
O
O
OTBDPS
O
O
O
H
H
H
THP diad formed
Scheme 4
Synlett 2006, No. 14, 2329–2333 © Thieme Stuttgart · New York

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Epoxide-Ring-Opening Cascades
2331
oped by Shi.6 It is noteworthy that the bromide was toler-
ated in this reaction. Even more significant is that eight
stereoisomers are possible in this transformation, but one
is obtained in 9:1 selectivity (ratio of desired to the sum of
all others). We have observed even higher diastereoselec-
tivity (>95:5 in some cases) and enantioselectivity in mul-
tiple epoxidations of oligo(trisubstituted alkenylsilanes).3
H
H
H
OH
O
OH
OTBDPS
O
AgOTf
+
4
O
OTBDPS
THF–H2O
(5:1)
O
O
O
H
8
9
1.5 h: 70% combined yield, 3:1 ratio of 8:9
3.0 h: 64% combined yield, 1:5 ratio of 8:9
Scheme 6
1. MOMCl, i-Pr2NEt
OMOM
2. n-BuLi; (CH2O)n
Murai also investigated a series of anhydrous conditions
with the notion of preventing opening of intermediate ep-
oxonium species by water. Remarkably, he observed the
formation of cis-5,6-10, not the trans-5,6-3 obtained pre-
viously, and proposed the mechanism shown in Scheme 7
to account for this surprising observation. The most pro-
vocative aspect of this proposal is that it requires intermo-
lecular opening of the putative epoxonium by triflate to be
faster than the intramolecular opening by the neighboring
epoxide.
HO
OH
5
3. LiAlH4, THF
58% (three steps)
1. CBr4, PPh3
THPO
2.
n-BuLi, THF
CuBr⋅Me2S
OMOM
HO
6
3. p-TsOH⋅H2O
MeOH
4. LiAlH4, THF
2
Murai, ref. 5
cis
18% (eight steps)
Ag
H
H
OTf
H
H
H
OTf
O
AgOTf
CH2Cl2
0.5 h
O
OTBDPS
OTBDPS
OTf
1. TBDPSCl, imid
2. MgBr2, n-BuSH
1
Br
29%
H
O
TBDPSO
O
3. CBr4, PPh3
7
10
57% (three steps)
Scheme 7
Me
O
Me
O
cat.
O
O
We examined these anhydrous conditions (AgOTf,
CH2Cl2) for triepoxide 4, as well as about twenty others
(Table 1). In all cases, however, we observed complex
mixtures of products, rapid destruction of the starting ma-
terial to unidentifiable products, or no consumption of
starting material whatsoever.
TBDPSO
O
Br
H
O
O
O
O
4
Me
Me
52% yield, 9:1 dr
KHSO5⋅KHSO4⋅K2SO4
Scheme 5
Deserving of discussion in this context are several inves-
tigations carried out by McDonald, who has also obtained
surprising results along these lines. In one series in partic-
ular,7 in which both epoxides were trisubstituted, a THP
diad (Scheme 8, 11) was in fact obtained, but the ring
junction was not trans, as would be predicted by the ep-
oxide-attacking-epoxonium mechanism, but cis, reminis-
cent of Murai’s (diepoxide 1, Scheme 7) and ours
(triepoxide 4, Scheme 5). Thus, the difficulty in obtaining
trans-THP diads by way of epoxide-opening cascades
does not appear to be limited to cases involving trans-di-
substituted epoxides.8
With triepoxide 4 in hand, we began our investigations of
Lewis and Brønsted acid promoted cascades under condi-
tions investigated by Murai with the diepoxide mentioned
above [AgOTf (100 mol%), 0.07 M in THF–H2O (5:1),
23 °C]. As shown in Scheme 6, after 1.5 hours, a 3:1 ratio
of THP 8 and trans-5,6-9 was obtained in a combined
yield of 70% after acetylation. THP diads or triads were
not detected in these reactions, and thus our results closely
mirrored Murai’s with the diepoxide (combined yield of
53%, THP 2/trans-5,6-3, 3.4:1, Scheme 4). Exposure of
the triepoxide for three hours under otherwise identical
conditions shifted the balance of 8 and 9 to 1:5 (combined
yield 64%), again very similar to what Murai had ob-
served.
McDonald, ref. 7
cis
Me
Me
H
HO
Me
O
O
BF3⋅OEt2
O
O
Since products containing two or more THP rings were
not observed in these experiments, there appeared to be no
significant difference between Murai’s diepoxide and our
triepoxide. In other words, it appears that, at least in sys-
tems that would lead to THP diads or triads, a disubstitut-
ed epoxide is not able to open a neighboring epoxonium
species, at least not faster than water is able to.
O
NHPh
CH2Cl2
–40 °C
Me
Me
O
O
O
Me
70% yield
11
Scheme 8
Synlett 2006, No. 14, 2329–2333 © Thieme Stuttgart · New York

2332
T. P. Heffron, T. F. Jamison
CLUSTER
Table 1 Effects of Lewis Acids on Triepoxide 4
Entry
1
Promoter
AgPF6
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HFIPa
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Temperature
–78 °C
–78 °C
–78 °C
0 °C
Observations
No reaction
2
AgOTf
AgSbF6
AgPF6
No reaction
3
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
No reaction
4
5
AgOTf
AgSbF6
AgPF6
0 °C
6
0 °C
7
0 °C
8
AgOTf
AgSbF6
AgPF6
0 °C
9
0 °C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
–42 °C
–42 °C
–42 °C
–78 °C
–78 °C
–78 °C
0 °C
AgOTf
AgSbF6
AgPF6
AgOTf
AgSbF6
AgPF6
THF
No reaction
THF
THF polymerization
THF polymerization
THF polymerization
THF polymerization
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
THF
AgOTf
AgSbF6
AgPF6
THF
0 °C
THF
0 °C
Et2O
–42 °C
–42 °C
–42 °C
0 °C
AgOTf
AgSbF6
AgOTf
AgOTf
Et2O
Et2O
b
c
0 °C
a HFIP = hexafluoroisopropanol.
b THF–tert-amyl alcohol (5:1).
c THF–MeOH (5:1).
Last year, McDonald reported a very exciting result that jectory required for attack by the neighboring epoxide is
makes the above all the more puzzling.9 A similar strategy not accessible in the cases designed to form THPs, but is
is successful when applied to the formation of seven- situated appropriately in the case leading to oxepanes.
membered-ring-containing systems, that is, products con-
On a final note, is it still possible that the biosynthesis of
taining two or more oxepanes fused to each other in a
the ladder polyethers involves epoxide-opening cascades
trans-syn-trans fashion. For example, tetraepoxide 12, in
is general for all ring systems, including THP tetrads,
which are found in the majority of the ladder polyether
natural products? Yes. The experiments described here, as
well as those of Murai and McDonald, do not rule out the
the presence of BF3·OEt2, was converted to tetracycle 13
in 25% yield, corresponding to about 70% yield per ep-
oxide-opening event (Scheme 9).
Two of the epoxides are disubstituted in this latter exam- possibility of such a process in nature. Nevertheless, it
ple, suggesting that if operative, the epoxonium-opening- does appear that in this framework, the natural system
by-epoxide mechanism is much more easily accommodat- would have to possess a significant control element of
ed when the spacing between successive epoxides is in- some kind, whether it be an enzyme or another difference
creased by one CH2 group. It may thus be the case that the in the environment in which the process occurs.
putative epoxonium is highly constrained and that the tra-
Synlett 2006, No. 14, 2329–2333 © Thieme Stuttgart · New York

CLUSTER
Epoxide-Ring-Opening Cascades
2333
McDonald, ref. 8
Me
1. BF3⋅OEt2, CH2Cl2
O
O
H
H
O
H H
Me
H
H
–40 °C
O
O
O
O
O
O
NMe2
HO
Me
O
H
H
Me
H
2. Ac2O, pyridine
25% (two steps)
Me
H
O
Me
O
12
13
Scheme 9
(2) (a) Nakanishi, K. Toxicon 1985, 23, 473. (b) Lee, M. S.;
Repeta, D. J.; Nakanishi, K.; Zagorski, M. G. J. Am. Chem.
Soc. 1986, 108, 7855. (c) See also: Chou, H.-N.; Shimizu,
Y. J. Am. Chem. Soc. 1987, 109, 2184.
(3) Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F. J.
Am. Chem. Soc. 2006, 128, 1056.
(4) For examples of epoxides as nucleophiles: (a) Crisóstomo,
F. R. P.; Martín, T.; Martín, V. S. Org. Lett. 2004, 6, 565.
(b) Alvarez, E.; Díaz, M. T.; Pérez, R.; Ravelo, J. L.;
Regueiro, A.; Vera, J. A.; Zurita, D.; Martín, J. D. J. Org.
Chem. 1994, 59, 2848. (c) David, F. J. Org. Chem. 1981, 46,
3512. (d) Tokumasu, M.; Sasaoka, A.; Takagi, R.; Hiraga,
Y.; Ohkata, K. J. Chem. Commun. 1997, 875.
Lewis acid promoted cascades of a tris(disubstituted ep-
oxide) triggered by silver-promoted abstraction of a bro-
mide ion favor trans-dioxabicyclo[4.3.0]nonanes, rather
than diads or triads of THPs. These results suggest that an
epoxide-attacking-epoxonium mechanism is not opera-
tive in this system. In conjunction with other investiga-
tions,5,7,9 these results also further illustrate the
complexity and multivariate nature of such cascades. Our
work in this area is ongoing.
Acknowledgment
(5) (a) Hayashi, N.; Fujiwara, K.; Murai, A. Tetrahedron Lett.
1996, 37, 6173. (b) Hayashi, N.; Fujiwara, K.; Murai, A.
Tetrahedron 1997, 53, 1242. (c) Fujiwara, K.; Hayashi, N.;
Tokiwano, T.; Murai, A. Heterocycles 1999, 50, 561.
(6) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996,
118, 9806. (b) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
(7) Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.;
Hardcastle, K. I. Org. Lett. 2003, 5, 2123.
T.P.H. thanks Johnson & Johnson and Boehringer-Ingelheim for
graduate fellowships. We are also grateful to MIT, Amgen, Glaxo-
SmithKline, Merck Research Laboratories, and the Sloan Foundati-
on for generous financial support of this work.
References and Notes
(8) It should be noted that McDonald observed that the cis/trans
selectivity also strongly depends on the nature of the
trapping nucleophile (a carbamate in the example shown in
Scheme 7).
(1) Current address: Genentech Inc., 1 DNA Way, South San
Francisco, CA 94080, USA.
(9) Valentine, J. C.; McDonald, F. E.; Neiwert, W. A.;
Hardcastle, K. I. J. Am. Chem. Soc. 2005, 127, 4586.
Synlett 2006, No. 14, 2329–2333 © Thieme Stuttgart · New York