Stereoselective ring expansion of vinyl oxiranes: Mechanistic insights and natural product total synthesis

Article abstract of DOI:10.1002/anie.200906830

"Chemical Equation Presented" What a (strain) relief! The first broadly applicable, catalytic, and stereoselective vinyl oxirane ring expansion is described (see scheme; hfacac = hexafluoroacetylacetonate). The stereoselectivity was influenced by several reaction parameters, and kinetic studies support a mechanistic proposal involving the in situ formation of a more reactive catalytic species. This ring-expansion reaction has been employed in the asymmetric total synthesis of (+)-goniothalesdiol.

Full text of DOI:10.1002/anie.200906830

Communications
DOI: 10.1002/anie.200906830
Synthetic Methods
Stereoselective Ring Expansion of Vinyl Oxiranes: Mechanistic
Insights and Natural Product Total Synthesis**
Matthew Brichacek, Lindsay A. Batory, and Jon T. Njardarson*
À
The central part of our research program is the development
of broadly applicable atom-efficient synthetic methods to
generate structural complexity. We recently reported a new
copper-catalyzed ring expansion of vinyl oxiranes using
commercially available, structurally simple, and air-stable
copper(II) catalysts.[1] These studies demonstrated the success
of this reaction for a broad range of substrates. Missing from
these early studies were experiments focused on assessing the
stereoselective potential of the ring expansion. The studies
presented herein are aimed at addressing this point to learn if
steric crowding during formation of the new C O bond, vinyl
oxiranes 3 and 5 emerge as more suitable precursors for
accessing the 2,5-cis- and 2,5-trans-dihydrofuran products,
respectively.
Therefore we synthesized vinyl oxiranes 7 and 8,[3] which
differ only in the oxirane stereochemistry (trans- or cis-
substituted oxiranes). Ring expansion of these two substrates
afforded the symmetrically substituted cis- and trans-dihy-
drofurans 9 and 10 (Table 1). Under the standard reaction
conditions used in our previous paper (Table 1, entries 2 and
À
the oxirane C O bond, which is broken during the ring
expansion, could be stereoselectively transferred to the olefin
terminus. Moreover, an added benefit to the proposed studies
would be critical mechanistic insights that could shed addi-
tional light on the exact mechanism of this unique catalytic
ring-expansion reaction. If vinyl oxiranes can indeed be
stereoselectively ring expanded using copper catalysts then
the practical benefits of this new reaction would be signifi-
cantly expanded. Also this transformation would rival exist-
ing methods[2] to stereoselectively access 2,5-dihydrofurans in
terms of efficiency and scope.
Table 1: Stereoselective synthesis of dihydrofurans
9
and 10.
Entry
Substr.
Cat.
t
Chemosel.
Stereosel. Yield
[mol%]
[h]
(9+10)/11
9/10
[%][a]
Our studies have focused on disubstituted vinyl oxirane
substrates (Scheme 1), which depending on their stereochem-
istry and olefin geometry could serve as precursors for
accessing either a 2,5-cis- or a 2,5-trans-substituted 2,5-
dihydrofuran product. In the case of a stereoselective ring
expansion, vinyl oxiranes 3 and 4 would be expected to afford
the cis product 1. whereas 5 and 6 should afford the trans
product 2. When these substrates are ranked with respect to
1
2
3
4
5
6
7
7
7
7
8
8
8
8
10
5
15
1
6
8
1
2
15
3
1:1
3:1
3:1
11:1
1:7
2:1
10:1
45
69
75 (70)
86 (79)
11
62
44
68 (66)
11:1
>20:1
15:1
1
5[b]
10
5
1:10
1:12
1:8
7
1
5
1:1
2.5:1
8[c]
1:18
[a] Estimated by NMR analysis (yield of isolated product). [b] Added by
syringe pump (1.25 mol% hÀ1 for 4 h). [c] 0.13m in benzene. hfacac=
hexafluoroacetylacetonate.
6) we were able to obtain both dihydrofurans in good
diastereomeric purity but with low chemical yield because
of the formation of the by-product 11. Reaction optimization
revealed that the success of the reaction relied most strongly
on the reaction temperature and appropriate catalyst loading.
After thorough optimization we were delighted to learn that
the dihydrofuran products 9 and 10 could be obtained with
high levels of stereoselectivity and good chemical yield
(Table 1, entries 4 and 8). In general, we observe that both a
lower catalyst loading and slow addition of the catalyst
improves the yield (chemoselectivity) of the product. These
results establish for the first time that vinyl oxiranes can be
stereoselectively ring expanded to 2,5-dihydrofurans.[4]
Scheme 1. Stereoselective vinyl oxirane ring expansions.
[*] M. Brichacek, L. A. Batory, Prof. J. T. Njardarson
Department of Chemistry and Chemical Biology, Baker Laboratory
Cornell University, Ithaca, NY 14853-1301 (USA)
Fax: (+1)607-255-4137
E-mail: jn96@cornell.edu
[**] We would like to thank Cornell University, Boehringer Ingelheim,
NSF (CHE-0848324), and the NIH (training grant, T32GM008500,
to M.B. and L.A.B.) for financial support
These results are even more profound when one considers
the stability of reactants and products. DFT calculations[5]
(B3LYP/6-311 + G(d,p)) on 7–11 revealed that the vinyl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906830.
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Chemie
oxiranes 7 and 8 are very similar in energy. Closer examina-
tion reveals that oxirane 7 (0.0 kcalmolÀ1) forms the less
stable cis product 9 (À13.7 kcalmolÀ1), whereas oxirane 8
(1.1 kcalmolÀ1) affords the preferred trans product 10
(À13.9 kcalmolÀ1). Both dihydrofuran products 9 and 10 are
less stable than the by-product 11 (À27.1 kcalmolÀ1) formed
in the reaction. These energy relationships strongly discredit a
mechanism involving a carbocation intermediate.
We have expanded our studies to include the seven
additional examples[6] presented in Table 2. Our results are in
agreement with what we learned from the ring expansion of
vinyl oxiranes 7 and 8, wherein high selectivity was achieved
Scheme 2. Asymmetric total synthesis of (+)-goniothalesdiol.
Table 2: Stereoselective ring expansion of vinyl oxiranes. Reaction
conditions: 5 mol% [Cu(hfacac)2] in toluene at 1508C.
=
Reagents and conditions: a) H2O2, 25, 80%; b) CH2 CHMgBr, 47%;
c) CH3C(OMe)3, cat. propionic acid, 83%; d) 1 mol% [Cu(hfacac)2],
toluene, 1508C, 70%; e) cat. OsO4, NMO, acetone, H2O, 99%;
f) SOCl2, Et3N then NaIO4, RuCl3·3H2O, CH3CN, H2O, 88%; g) 15%
H2SO4, THF, 658C, 87%; h) Amberlyst-15, MeOH, 99%. NMO=N-
methylmorpholine-N-oxide, TMS=trimethylsilyl.
Starting material
Product (rac)
Yield [%] cis/trans
94[a,b]
88[a,b]
84[a,c]
>20:1
13:1
8:1
enantiopure oxirane substrate. (+ )-Goniothalesdiol,
a
densely decorated tetrahydrofuran-based structure, seemed
like a perfect target for this task. Towards that end,
cinnamaldehyde (24) was converted into chiral epoxy alde-
hyde 26 using Jorgensen’s asymmetric organocatalytic epox-
idation protocol.[8] Treatment of 26 with vinyl magnesium
bromide and subsequent Johnson–Claisen rearrangement[9] of
the resulting allylic alcohol efficiently formed vinyl oxirane 27
as a single olefin isomer. The copper-catalyzed rearrangement
of this chiral oxirane afforded cis-2,5-dihydrofuran 28 in 70%
yield and excellent enantiopurity after separation from the
trans diastereomer. Substrate-controlled epoxidation of the
olefin was expected to give an epoxide that could be opened
in an intramolecular fashion to lactone 30.[10] Surprisingly,
epoxidation proved troublesome affording only the furan.
This situation was solved by constructing a cyclic sulfate
instead of an epoxide. Gao and Sharpless have shown that
these reactive synthons can be obtained from vicinal hydroxy
groups.[11] Dihydroxylation of 28 selectively afforded 4-epi-
goniothalesdiol in high yield. Upon treatment of this diol with
thionyl chloride and ruthenium tetroxide, the cyclic sulfate 29
was obtained. This activated diol was efficiently opened in an
intramolecular fashion to lactone 30 by the carboxylate
group.[12] Opening of the lactone with Amberlyst-15 in
methanol afforded goniothalesdiol in only eight steps from
cinnamaldehyde. This short asymmetric synthesis of (+ )-
goniothalesdiol is a testament to the value of our new
stereoselective ring-expansion protocol.
70[a,d]
92[e,f]
96[f,g]
93[f]
8:1
1:6
1:8
1:7
[a] Yield of diastereomerically pure material upon isolation. [b] Added by
syringe pump (0.6 mol% hÀ1 for 8 h). [c] 2 mol% added by syringe
pump (0.11 mol% hÀ1 for 17 h). [d] Added by syringe pump
(2.5 mol% hÀ1 for 2 h). [e] 1008C. [f] Yield of both diastereomers upon
isolation. [g] Benzene.
by lowering the catalyst loading. As expected, cis-2,5-dihy-
drofuran products (19–21) were stereoselectively obtained
from (trans,E)-vinyl oxirane precursors (12–15), and trans-
2,5-dihydrofuran products (22–23) were accessed by ring
expanding (cis,E)-vinyl oxirane substrates (16–18). Both the
yields (isolated) and stereoselectivies are excellent for all
substrates. Functional groups such as ethers, esters, enoates,
and aryl groups are well-tolerated. These new stereoselective
results allow strategic design of routes to either cis- or trans-
2,5-dihydrofuran targets by employing the appropriate vinyl
oxirane precursor.
As part of our program to use synthetic chemistry to
efficiently access natural products, the anticancer agent (+ )-
goniothalesdiol[7] (Scheme 2) was chosen as a target for
assessing the value of the new stereoselective copper-cata-
lyzed ring-expansion protocol and to showcase it using an
Detailed kinetic studies of vinyl oxirane 7 revealed a
sigmoidal curve for the formation of dihydrofuran product 9,
which is in perfect agreement with our vinyl aziridine trace.[1c]
When similar kinetic analyses for cis-vinyl oxirane substrate 8
are performed, the same general observations are made with
the added insight that formation and disappearance of small
amounts of trans-vinyl oxirane 7 can also be observed in the
kinetic trace. This suggests that the active catalyst accom-
modates oxirane isomerization while suppressing the other-
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fluorobenzene negatively impacts stereo-
selectivity, n-pentane almost completely
erodes it, and benzene and fluorobenzene
are on par with toluene. The ring expan-
sion can be done at several different
temperatures with very comparable ste-
reochemical
outcomes
(Table 3,
entries 10–12). When this data is analyzed
and put together (Table 3, entries 5, 8, and
11), the result was excellent, affording
dihydrofuran product 33 in 92% ee
(Table 3, entry 13).
In summary, we have demonstrated
that this new copper-catalyzed vinyl oxi-
rane ring expansion can be performed
stereoselectively, therein providing access
to cis or trans products simply by starting
with the matching oxirane precursor.
Similarly we have demonstrated that
chiral 2-substituted dihydrofuran prod-
ucts of high optical purity can also be
obtained. We propose that the active
Scheme 3. Proposed catalytic cycle.
wise detrimental hydride-shift pathway (also observed for 16–
18). Based on our data, the catalytic cycle shown in Scheme 3
is proposed.
Table 3: Stereoselective ring expansion of vinyl oxirane 32. Reaction
conditions: [Cu(hfacac)2] at 0.1m for 15h.
The kinetic data seems to suggest that after an induction
period a more active catalyst is formed, which then proceeds
to stereoselectively ring-expand vinyl oxiranes. We envision
that [Cu(hfacac)2] (II) reversibly coordinates to the oxirane I
lone pair of electrons thereby forming substrate–catalyst
complex III, which upon reacting with another [Cu(hfacac)2]
(II), is transformed into chelated substrate-bound cationic
copper(II) complex IV, wherein [Cu(hfacac)3]À serves as the
non-nucleophilic counterion (XÀ).[13] This cationic catalyst
acts as the optimal Lewis acid which holds the substrate
Entry
Cat. [mol%]
T [8C]
Solvent
ee [%][a]
1
2
3
4
5
6
7
8
10
5
2.5
1
0.5
1
1
1
1
1
1
150
150
150
150
150
125
150
150
150
125
175
200
175
toluene
toluene
toluene
toluene
toluene
n-pentane
benzene
fluorobenzene
hexafluorobenzene
toluene
61
63
72
73
77[b]
20
77
78
56
78
À
together in such a way that the chirality of C O bond is
9
transferred without scrambling to the olefin terminus and
thereby form the dihydrofuran-bound copper complex V. This
complex is a weaker chelate than IV, which prompts
coordination to another vinyl oxirane (I) and concomitant
release of the product VI thereby reforming IV and complet-
ing the first round of the catalytic cycle. Furthermore, we
propose that the competing hydride-shift product (VIII) is
10
11
12
13
toluene
toluene
fluorobenzene
81
1
0.5
79
92[c,d]
[a] The ee value for 33 was determined by chiral HPLC analysis. [b] 45 h.
[c9 24 h. [d] 60% yield of isolated product. Bn=benzyl.
À
formed from copper complex VII, wherein the C O oxirane
bond has already been broken. An equilibrium arrow is
placed between catalyst–substrate complexes III and VII
based on the kinetic data obtained for vinyl oxirane 8 as
discussed above.[14]
catalyst for the ring expansion is an in situ generated cationic
copper(II) catalyst. These results were utilized to accomplish
the shortest asymmetric synthesis of the natural product
goniothalesdiol, highlighting the powerful retrosynthetic
option this new catalytic synthetic method offers.
Challenging the reaction additionally, we decided to
evaluate if chiral monosubstituted vinyl oxirane substrates
such as 32[15] could be ring expanded into dihydrofuran 33[16]
without any stereochemical scrambling.[17] As is evident from
entries 1–5 in Table 3, the [Cu(hfacac)2] catalyst loading
impacts the stereoselectivity of the reaction, with 0.5 mol%
being optimal.[18] We decided to evaluate how changing the
solvent would impact the stereoselectivity. When the standard
toluene (Table 3, entry 4) conditions are compared to that
used in Table 3, entries 6–9, it was determined that hexa-
Received: December 3, 2009
Published online: February 4, 2010
Keywords: copper · natural products · oxiranes ·
.
stereoselectivity · total synthesis
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1970, 92, 741 – 743; b) D.-H. Lee, S.-W. Lee, Tetrahedron Lett.
1997, 38, 7909 – 7910.
[10] M. Babjak, P. Kapitan, T. Gracza, Tetrahedron 2005, 61, 2471 –
2479.
[11] Y. Gao, K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 7538 –
7539.
[1] a) L. A. Batory, C. E. McInnis, J. T. Njardarson, J. Am. Chem.
Soc. 2006, 128, 16054 – 16055. We have since shown that vinyl
thiiranes and vinyl aziridines can be ring expanded using the
same catalyst: b) E. Rogers, H. Araki, L. A. Batory, C. E.
McInnis, J. T. Njardarson, J. Am. Chem. Soc. 2007, 129, 2768 –
2769; c) M. Brichacek, D. Lee, J. T. Njardarson, Org. Lett. 2008,
10, 5023 – 5026.
[2] a) M. Brichacek, J. T. Njardarson, Org. Biomol. Chem. 2009, 7,
1761 – 1770; b) T. G. Kilroy, T. P. O’Sullivan, P. J. Guiry, Eur. J.
Org. Chem. 2005, 4929 – 4949; c) G. Jalce, X. Franck, B. Figadere,
Tetrahedron: Asymmetry 2009, 20, 2537 – 2581.
[3] Synthesis of 7: a) B. M. Lynch, K. H. Pausacker, J. Chem. Soc.
1955, 1525 – 1531. Synthesis of 8: b) R. W. Murray, M. Singh,
Org. Synth. 1997, 74, 91 – 96.
[4] The Z-olefin counterparts of vinyl oxiranes 7 and 8 have also
been synthesized and evaluated. These inferior substrates can be
ring expanded, but the chemoselectivity and stereoselectivity are
worse than that for 7 and 8. The exceptions to this observation
are cyclic vinyl oxiranes. See: N. A. McGrath, E. S. Bartlett, S.
Sittihan, J. T. Njardarson, Angew. Chem. 2009, 121, 8695 – 8698;
Angwe. Chem. Int. Ed. 2009, 48, 8543 – 8546.
[12] This cyclization could also be performed using bases such as
KOH and NaOH, but yields of 30 were significantly lower.
Lactone 30 has previously been prepared and completes the
formal syntheses of (+)-altholactone (P. Somfai, Tetrahedron
1994, 50, 11315 – 11320) and (À)-etharvensin (A. Bermejo, M. A.
Blazquez, A. Serrano, M. Carmen Zafra-Polo, D. Cortes, J. Nat.
Prod. 1997, 60, 1338 – 1340).
[13] This octahedral copper complex is known: M. R. Truter, D. E.
Fenton, B. L. Vickery, J. Chem. Soc. D 1971, 93 – 94.
[14] CuI mechanistic proposals do not seem to match our data.
[Cu(hfacac)(BTMSA)] (BTMSA = bis(trimethylsilyl)acetylene)
is the only CuI catalyst that we have shown to ring-expand vinyl
oxiranes, which results from the fact that it disproportionates
under the reaction conditions to the active catalyst, [Cu-
(hfacac)2], and Cu0. This fact is commonly exploited in the
field of chemical vapor deposition (CVD), wherein fluorinated
acetylacetonate copper catalysts are routinely employed: J.
Rickerby, J. H. G. Steinke, Chem. Rev. 2002, 102, 1525 – 1549.
Neither spectroscopic data or in situ reduction experiments of
[Cu(hfacac)2] using classic reducing agents such as cobaltocene,
hydrazine, or AIBN support a CuI mechanism.
[5] Details regarding calculations can be found in the Supporting
Information.
[6] See the Supporting Information for the synthesis of epoxides 12–
18.
[7] Isolation: S.-G. Cao, X.-H. Wu, K.-Y. Sim, B. K. H. Tan, J. T.
Pereira, S.-H. Goh, Tetrahedron 1998, 54, 2143 – 2148. Synthetic
approaches: a) H. Yoda, Y. Nakaseko, K. Takabe, Synlett 2002,
1532 – 1534; b) M. Babjak, P. Kapitan, T. Gracza, Tetrahedron
Lett. 2002, 43, 6983 – 6985; c) J. Murga, P. Ruiz, E. Falomir, M.
Carda, G. Peris, J. A. Marco, J. Org. Chem. 2004, 69, 1987 – 1992;
d) J. S. Yadav, A. K. Raju, P. P. Rao, G. Rajaiah, Tetrahedron:
Asymmetry 2005, 16, 3283 – 3290; e) M. Babjak, P. Kapitan, T.
Gracza, Tetrahedron 2005, 61, 2471 – 2479; f) M. C. Carreno, G.
Hernandez-Torres, A. Urbano, F. Colobert, Org. Lett. 2005, 7,
5517 – 5520; g) K. R. Prasad, S. L. Gholap, J. Org. Chem. 2006,
71, 3643 – 3645; h) S. Ghosh, C. N. Rao, S. K. Dutta, Synlett 2007,
1464 – 1466.
[15] For a synthesis of this chiral vinyl oxirane, see: J. A. Marshall,
J. D. Trometer, Tetrahedron Lett. 1987, 28, 4985 – 4988.
[16] Both enantiomers of dihydrofuran 33 are known: a) S. Aragones,
S. Bravo, Y. Diaz, M. A. Matheu, S. Castillon, Tetrahedron:
Asymmetry 2003, 14, 1847 – 1856; b) J. Cleophax, S. D. Gero,
Tetrahedron Lett. 1966, 7, 5505 – 5510.
[17] The product 33 does not epimerize under the reaction con-
ditions.
[18] This increase in enantioselectivity with a decrease in catalyst
loading, although rare, is not without precedence for metal-
catalyzed reactions; a) I. J. S. Fairlamb, G. C. Lloyd-Jones,
Chem. Commun. 2000, 2447 – 2448; b) D. A. Evans, K. R.
Fandrick, H.-J Song, J. Am. Chem. Soc. 2005, 127, 8942 – 8943;
c) D. A. Evans, K. R. Fandrick, . H.-J. Song, K. A. Scheidt, R.
Xu, J. Am. Chem. Soc. 2007, 129, 10029 – 10041.
[8] M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang, K. E.
Jorgensen, J. Am. Chem. Soc. 2005, 127, 6964 – 6965.
[9] a) W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brock-
som, T.-T. Li, D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc.
Angew. Chem. Int. Ed. 2010, 49, 1648 –1651
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