General synthetic approach to functionalized dihydrooxepines

Article abstract of DOI:10.1021/ol4006689

A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer-Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.

Full text of DOI:10.1021/ol4006689

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
General Synthetic Approach to
Functionalized Dihydrooxepines
K. C. Nicolaou,* Ruocheng Yu, Lei Shi, Quan Cai,† Min Lu, and Philipp Heretsch
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
United States, and the Department of Chemistry and Biochemistry, University of
California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
kcn@scripps.edu
Received March 12, 2013
ABSTRACT
A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a
regioselective BaeyerꢀVilliger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.
4,5-Dihydrooxepines are featured as structural motifs
within various natural products, ranging from sesquiter-
penes, such as miscandenin1and endiadric acid derivative
beilshmiedin,2 to polyketides, such as conioxepinol A3
(Figure 1). This framework is also found in some of
the most interesting members of the epidithiodiketopi-
perazine family as represented by aranotin4 (Figure 1).
Consequently, a number of approaches have been devel-
oped to access this structural motif. These include acid-
catalyzed cyclization,5 Rh-catalyzed cycloisomerization,6
ring-closing metathesis,7 [4 þ 2] cycloaddition/epoxidation/
retro [4 þ 2] cycloaddition,8 Cope rearrangement,9 frag-
mentation,10 and Criegee rearrangement.11
† Visiting Scientist from Chongqing University, China.
(1) Herz, W.; Subramaniam, P. S.; Santhanam, P. S.; Aota, K.; Hall,
A. L. J. Org. Chem. 1970, 35, 1453.
(2) Chouna, J. R.; Nkeng-Efouet, P. A.; Lenta, B. N.; Wansi, J. D.;
Kimbu, S. F.; Sewald, N. Phytochem. Lett. 2010, 3, 13.
(3) Wang, Y.; Zheng, Z.; Liu, S.; Zhang, H.; Li, E.; Guo, L.; Che, Y.
J. Nat. Prod. 2010, 73, 920.
(4) Nagarajan, R.; Huckstep, L. L.; Lively, D. H.; Delong, D. C.;
Marsh, M. M.; Neuss, N. J. Am. Chem. Soc. 1968, 90, 2980.
(5) (a) Peng, J.; Clive, D. L. J. J. Org. Chem. 2009, 74, 513. (b) Peng,
J.; Clive, D. L. J. Org. Lett. 2007, 9, 2939.
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Soc. 2012, 134, 1930.
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(7) (a) Gross, U.; Nieger, M.; Brase, S. Chem.;Eur. J. 2010, 16,
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J. F.; del Pozo, C.; Acena, J. L. J. Org. Chem. 2006, 71, 2706.
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ꢁ
Giguere, D.; Sun, Y.-P.; Sarlah, D.; Nguyen, T. H.; Wolf, I. C.; Smee,
D. F.; Day, C. W.; Bopp, S.; Winzeler, E. A. J. Am. Chem. Soc. 2012,
134, 17320. (b) Marx, J. N.; Ajlouni, A. Nat. Prod. Commun. 2010, 5, 5.
(9) (a) Xu, X.; Hu, W.-H.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem.,
Int. Ed. 2011, 50, 11152. (b) Shimizu, M.; Fujimoto, T.; Liu, X.; Takeda,
Y.; Hiyama, T. Heterocycles 2008, 76, 329. (c) Shimizu, M.; Fujimoto,
T.; Liu, X.; Hiyama, T. Chem. Lett. 2004, 33, 438. (d) Chou, W.-N.;
White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658. (e) Clark,
D. L.; Chou, W.-N.; White, J. B. J. Org. Chem. 1990, 55, 3975. (f) Aitken,
R. A.; Cadogan, J. I. G.; Gosney, I.; Hamill, B. J.; McLaughlin, L. M.
J. Chem. Soc., Chem. Commun. 1982, 1164.
Figure 1. Selected natural products containing the 4,5-dihydro-
oxepine structural motif.
(10) Leyhane, A. J.; Snapper, M. L. Org. Lett. 2006, 8, 5183.
(11) (a) Goodman, R. M.; Kishi, Y. J. Org. Chem. 1994, 59, 5125. (b)
Lu, T.; Vargas, D.; Fischer, N. H. Phytochemistry 1993, 34, 737.
r
10.1021/ol4006689
XXXX American Chemical Society

Despite this progress, the synthesis of related natural
products in which the dihydrooxepine unit is highly func-
tionalized remains challenging, in part because the scope
and generality of existing methods are rather limited. Post-
functionalization of preformed dihydrooxepines is also
difficult due to the sensitive nature of these structural
moieties. Therefore, a general approach through which
substrates with a diverse array of substitution patterns can
be reliably transformed into functionalized dihydrooxe-
pines is highly desirable.
As part of our continuing efforts toward the total
synthesis of members of the dihydrooxepine epidithiodi-
ketopiperazine family,8a,12 we opted to develop a method
to synthesize 4,5-dihydrooxepines from cyclohexenones.
Sucha strategywould benefit from the ready availability of
functionalized cyclohexenones, thus allowing access to a
broad range of dihydrooxepine structures. We reasoned
that ring expansion of the cyclohexenone could be
achieved through a regioselective BaeyerꢀVilliger oxida-
tion. Further functionalization ofthe resulting enol lactone
through either reduction or CꢀC bond formation would
give rise directly to the bisenol ether moiety found in 4,5-
dihydrooxepines (Figure 2).13
Our experimentation began with the BaeyerꢀVilliger
oxidation of enone 1a (Table 1). Thus, reaction of 1a with
mCPBA gave the desired enol lactone as a single regio-
isomer, albeit in low conversion (Table 1, entry 1). Attempts
to use stronger oxidants such as CF3CO3H led to partial
decomposition of the product (entry 2). We then reasoned
that substrate activation by a suitable Lewis acid would
improve conversion under milder reaction conditions that
would avoid product decomposition. Indeed, the combina-
tion of SnCl4 and bis(trimethylsilyl)peroxide (BTSP), in the
presense of trans-1,2-diaminocyclohexane (ligand A), gen-
erated the desired product 2a in 83% yield (entry 3).14
The use of this ligand proved to be critical as it successfully
tempered the Lewis acidity of SnCl4. Neither SnCl4
itself nor its combination with other ligands tested, such
as trans-1,2-di(tosylamino)cyclohexane (ligand B), led to
Scheme 1. Enol Phosphate Formation and Pd-Catalyzed
Reduction to 4,5-Dihydrooxepine
Figure 2. Proposed synthesis of functionalized 4,5-dihydro-
oxepines from the corresponding cyclohexenones.
Table 2. Optimization of Enol Phosphate Reductiona
Table 1. Study of the BaeyerꢀVilliger Oxidation of Enonesa
entry
conditions
yield (%)b
1
mCPBA, CH2Cl2
UHP, TFAA, CH2Cl2
15
2
decomp
83
reducing
3c
4d
5d
6d
7d
BTSP, SnCl4, ligand A, 4 A MS, CH2Cl2
˚
entry
R
agent
solvent
yield (%)b (4b þ 5b) 4b:5bc
˚
BTSP, SnCl4, 4 A MS, CH2Cl2
trace
22
1
2
3
4
5
Ph Et3Al
Ph Et3Al
ClCH2CH2Cl
CH2Cl2
58
62
70
66
67
60:40
˚
BTSP, SnCl4, ligand B, 4 A MS, CH2Cl2
37:63
˚
BTSP, SnCl4, pyridine, 4 A MS, CH2Cl2
32
Et
Et
Et3Al
ClCH2CH2Cl
90:10
BTSP, SnCl4, ligand A, CH2Cl2
trace
LiBH4 THF
4b only
4b only
a Reactions were carried out on 0.25 mmol scale. b 1H NMR yield.
c Reactions were carried out at 0.1 M concentration with 0.5 equiv of
Ph LiBH4 THF
a Reactions were run on 0.1 mmol scale at 0.05 M concentration with
0.2 equiv of Pd(PPh3)4 and 2.5 equiv of Et3Al at 25 °C or 10 equiv of
LiBH4 at 0 °C. b 1H NMR yield. c Ratios determined by 1H NMR
spectroscopic analysis.
˚
SnCl4, 0.5 equiv of ligand A, 3.0 equiv of BTSP, and 50 mg of 4 A MS at
25 °C. d Reactions were carried out under the identical conditions in
entry 3 with changes indicated in the table. mCPBA = meta-chloroper-
oxybenzoic acid, UHP = urea hydrogen peroxide, TFAA = trifluoro-
acetic anhydride, BTSP = bis(trimethylsilyl)peroxide.
(13) In their elegant synthesis of acetylaranotin, Tokuyama et al.
prepared the 4,5-dihydrooxepine structural motif of the molecule from a
lactone via the corresponding enol triflate; see: Fujiwara, H.; Kurogi, T.;
Okaya, S.; Okano, K.; Tokuyama, H. Angew. Chem., Int. Ed. 2012, 51,
13062.
ꢁ
(12) (a) Nicolaou, K. C.; Giguere, D.; Totokotsopoulos, S.; Sun, Y.-P.
Angew. Chem., Int. Ed. 2012, 51, 728. (b) Nicolaou, K. C.; Totokotsopoulos,
S.; Giguere, D.; Sun, Y.-P.; Sarlah, D. J. Am. Chem. Soc. 2011, 133, 8150.
ꢁ
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Scope and Generality of the 4,5-Dihydrooxepine-Forming Sequencea
a Lactone formation: reactions were carried out on 1.0 mmol scale at 0.1 M concentration in CH2Cl2 with 0.5 equiv of SnCl4, 0.5 equiv of ligand A, 3.0
˚
equiv of BTSP, and 200 mg of 4 A MS at 25 °C. Enol phosphate formation: reactions were carried out on 0.5 mmol scale at 0.1 M concentration in THF
with 2.0 equiv of KHMDS, 2.0 equiv of (PhO)2P(O)Cl, 3.0 equiv of HMPA at ꢀ78 °C. Dihydrooxepine formation (method A): reactions were carriedout
on 0.2 mmol scale at 0.05 M concentration in ClCH2CH2Cl with 0.2 equiv of Pd(PPh3)4 and 2.5 equiv of Et3Al. Dihydrooxepine formation (method B):
reactions were carried out on 0.2 mmol scale at 0.05 M concentration in THF with 0.2 equiv of Pd(PPh3)4 and 10 equiv of LiBH4 at 0 °C. b Isolated yield
unless otherwise noted. c Using method A. d Using method B. e Due to the volatility of the product, the yield refers to 1H NMR yield. f Anhydrous K2CO3
(200 mg) was added; brsm = based on recovered starting material.
comparable yields (entries 4ꢀ6). The presence of dry
molecular sieves was essential for the success of this reac-
tion, as in its absence, only trace amounts of the product
was observed (entry 7).
our previously developed conditions (Scheme 1).15 The
phosphate group was chosen over the more common
triflate group because the former is well-known to be more
stable than the latter.15
Conversion of the BaeyerꢀVilliger product 2a to the
Pd-catalyzed reduction of the diphenyl phosphate 3a
proved to be unsuccessful when using either Ph2SiH2 or
corresponding enol phosphate 3a went smoothly under
€
€
(15) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Gartner, P.; Yang,
(14) Gotlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett
1997, 971.
Z. J. Am. Chem. Soc. 1997, 119, 5467.
Org. Lett., Vol. XX, No. XX, XXXX
C

nBu3SnH as the reducing agent. After extensive screening,
Et3Al turned out to be the optimal reducing agent, giving
the desired 4,5-dihydrooxepine 4a in 81% yield (Scheme 1).
However, when applying the same reduction conditions to
phosphate 3b (Table 2), we obtained an inseparable mixture
of the desired product 4b and the ethylated product 5b in ca.
3:2 ratio (Table 2, entry 1). This result reflects the competi-
tion between β-hydride elimination and reductive elimina-
tion of the ethylated intermediate (see Table 2).16 Attempts
to optimize the reduction of 3b by changing the solvent
(entry 2) or using the diethyl phosphate 3b0 (entry 3) gave a
mixture of 4b and 5b, albeit in different ratios (see Table 2).
We then turned to some other reducing agents and found
that LiBH4 proved to be the best, giving exclusively the
benzodihydrooxepine 4b in good yield [entries 4 (66% yield)
and 5 (67% yield)].
Scheme 2. Functionalization of the 4,5-Dihydrooxepine
Structural Motif via the Corresponding Enol Phosphate
With the developed optimized conditions in hand, we
then proceeded to assess the generality and scope of this
three-step procedure to functionalized dihydrooxepines.
As shown in Table 3, a variety of substrates with diverse
substitution patterns and functional groups could be re-
liably transformed into the corresponding 4,5-dihydro-
oxepines. Cyclohexenones with either a methyl group on
the olefinic bond (entries 3 and 5) or gem-dimethyl groups
on the 4-position (entry 4) are good substrates for these
transformations, although the latter exhibits lower reac-
tivity in the first and third steps as compared to the others.
Functional groups such as an isolated olefinic bond, an
electron-rich arene, a TBS-protected secondary alcohol, or
a ketal group are all tolerated in these procedures (entries
5ꢀ8). Most notably, the current method is also applicable
to relatively complex structures, including the protected
WielandꢀMiescher ketone 1h and the cholesterol derivative
1i (entries 8 and 9, respectively). Thus, application of the
present method to these substrates allows rapid access to the
relatively complex dihydrooxepines 4h and 4i, respectively.
In addition to the above Pd-catalyzed reduction, the enol
phosphate intermediate also provides a platform for a series
of CꢀC bond forming reactions, thereby allowing further
functionalization of the dihydrooxepine system. Thus, as
demonstrated in Scheme 2, 3b could be successfully engaged
in Ni-catalyzed Negishi (conditions a) and Kumada cou-
plings (conditions b), leading to the corresponding alkyl-
substituted products 5b and 6b, respectively, without compe-
tition from the β-hydride elimination pathway. Introduction
of phenyl (conditions c), 3-thienyl (conditions d), and
alkynyl (conditions f) substituents can also be achieved in
high yields using PdCl2(dppf) as the catalyst (products 7b,
8b, and 10b, respectively). The same catalyst is also effective
in converting the phosphate into an ester group (conditions e),
albeit in moderate yield (product 9b).
In summary, we have developed a three-step approach
for the synthesis of functionalized dihydrooxepines from
readily available cyclohexenones. This sequence features a
regioselective BaeyerꢀVilliger oxidation, subsequent enol
phosphate formation, and Pd-catalyzed functionalization.
The large variety of available cyclohexenones provides the
basis for the generality of this approach, while the mildness
ofreactionconditionsensures their reliabletransformation
to functionalized dihydrooxepines with minimal loss due
to facile decomposition. The current method holds con-
siderable promise for application to the synthesis of bioac-
tive natural products and their analogues.
Acknowledgment. Financial support for this work was
provided by the National Science Foundation (Grant
CHE-1243661) and the National Institutes of Health,
USA (Grant AI 055475).
Supporting Information Available. Experimental pro-
cedures, characterization, and spectroscopic data for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 22, 1609.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX