Synthesis of eight-membered lactones: Intermolecular [6+2] cyclization of amphoteric molecules with siloxy alkynes

Article abstract of DOI:10.1002/anie.201200513

That's about the size of it: The title molecules react with siloxy alkynes in the presence of a Bronsted acid to deliver medium-sized lactones through a [6+2] cyclization (see scheme; TIPS=triisopropylsilyl). This process is the first intermolecular synthesis of such lactones and involves a sequence of several selective ring-opening/ring-closing events. Copyright

Full text of DOI:10.1002/anie.201200513

Angewandte
Chemie
DOI: 10.1002/anie.201200513
Homogeneous Catalysis
Synthesis of Eight-Membered Lactones: Intermolecular [6+2]
Cyclization of Amphoteric Molecules with Siloxy Alkynes**
Wanxiang Zhao, Zhaobin Wang, and Jianwei Sun*
Medium-sized lactones (8- to 11-membered rings) are impor-
tant structural motifs that occur in a wide range of biologically
active natural products.[1] The efficient synthesis of these
medium-sized lactones has attracted considerable attention in
organic synthesis.[2–5] Nevertheless, there are only a limited
number of methods available, with lactonization and ring-
closing metathesis (RCM) being the most popular choices.[2–5]
Owing to ring strain and transannular interactions,[6] the
formation of medium-sized lactones have proven difficult.[2,7]
Although the yields can sometimes be improved under high
dilution or slow addition conditions, the results are unpre-
dictable and highly dependent upon the substrates. Thus,
there remains a great need for the development of new
strategies for the synthesis of medium-sized lactones. Herein
we report our design of a new type of amphoteric molecule for
the synthesis of eight-membered ring lactones through [6+2]
cyclization.
Amphoteric molecules, which bear both nucleophilic and
electrophilic moieties, have been demonstrated as a versatile
platform for the development of new processes with high
bond-forming efficiency and atom economy.[8,9] For example,
isocyanides are well-known (1,1)-amphoteric molecules
because the terminal carbon atom can be both nucleophilic
and electrophilic sites for bond formation.[8] Recently, Yudin
and co-workers demonstrated that aziridine aldehydes (1;
Scheme 1A) can serve as three-atom “connectors”, thus
representing a (1,3)-amphoteric system.[9] With this system,
they have developed a range of efficient and chemoselective
transformations which circumvent using protecting groups.[9]
We envisaged that the design of (1,n)-amphoteric molecules
(where n > 5) may provide new opportunities for the for-
mation of medium- and large-sized rings upon cyclization
with dipolarophiles. However, the nucleophilic and electro-
philic sites in such systems may react in the more favored
intramolecular fashion, for example, the formation of a six-
membered ring in a (1,6)-amphoteric system (Scheme 1B,
path a), thereby invoking difficulty in designing such systems
for intermolecular cyclizations.
Scheme 1. Examples of amphoteric molecules and their reaction top-
ology. A) (1,3)-Amphoteric system (e.g., Yudin’s aziridine aldehyde 1).
B) (1,6)-Amphoteric system (our design).
Oxetanes represent a useful structural unit that is less
reactive than epoxides and aldehydes, but still prone to ring-
opening upon activation.[10–11] We decided to take advantage
of such a combination of stability and reactivity to design
a new (1,6)-amphoteric system. Our initial design is exempli-
fied in structure 2 (Scheme 1B), in which an oxetane moiety is
connected to an aldehyde group through a two-atom linker.
The aldehyde carbon atom (C1) serves as the electrophilic
center. Upon attack by a nucleophile, the resulting nucleo-
philic oxygen atom is expected to initiate an intramolecular
ring-opening process and concomitantly generate another
nucleophilic oxygen center at the 6-position. Thus, the system
is (1,6)-amphoteric overall.
Next, we began to test our designed system for the
synthesis of medium- and large-sized rings. We initially aimed
at developing new [6+2] cyclization processes for the
formation of eight-membered rings. After some trials, we
were pleased to identify siloxy alkynes[12] as excellent reaction
partners for our (1,6)-amphoteric system to form eight-
membered lactones. Specifically, the reaction between 2-
(oxetan-3-yl)benzaldehyde (3) and siloxy alkyne 4, in the
presence of triflimide (HNTf2, 10 mol%) as the catalyst and
CH2Cl2 as the solvent, proceeds efficiently at room temper-
ature to form the eight-membered lactone 5 in 71% yield
upon isolation (Table 1, entry 1). The structure assignment of
5 was based on the X-ray crystallography of its crystalline
derivative (see the Supporting Information). Unlike the
conventional formation of medium-sized lactones using
[*] W. Zhao, Z. Wang, Prof. Dr. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong (China)
E-mail: sunjw@ust.hk
[**] Financial support was provided by the HKUST and NSFC
(21102024). We thank Profs. H. Yamamoto, S. A. Kozmin
(UChicago), L. Zhang (UCSB), and Dr. S. Lou (BMS) for helpful
discussions. We also thank H. H. Sung and Prof. I. Williams for
assistance in structure determination by X-ray.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200513.
Angew. Chem. Int. Ed. 2012, 51, 6209 –6213
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6209

.
Angewandte
Communications
Table 1: Effect of reaction conditions on the 8-membered lactone
Table 2: Scope of the eight-membered lactone formation.
formation.[a]
Entry
(1,6)-Amphoteric molecules
R
Yield
[%][a]
Entry
Catalyst (mol%)
Solvent
Yield [%][b]
1
2
nBu
71
62
1
2
3
4
5
6
7
8
HNTf2 (10)
AgNTf2 (5)
AgOTf (5)
AuCl3 (5)
TfOH (10)
p-TsOH (10)
MsOH (10)
TFA (10)
HNTf2 (10)
HNTf2 (10)
HNTf2 (10)
HNTf2 (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
71
50
3
4
5
6
tBu
nOct
60
64
41
47
39[c]
36[c]
52
Ph
trace
trace
trace
trace
trace
56
7
8
nBu
70
49
9
10
11
12
9
10
11
tBu
nOct
87
74
51
EtOAc
CH2Cl2
52[d]
12
71
[a] All reactions were performed on a 0.25 mmol scale of 3 with catalyst
(5-10 mol%) and 4 (1.2 equiv) in 2.5 mL of solvent (0.1m) at room
temperature for 12 h. [b] Yield of isolated product. [c] Yield determined
by NMR spectroscopy using mesitylene as the internal standard.
[d] Reaction run at 0.5m concentration. Ms=methanesulfonyl, Tf=tri-
fluoromethanesulfonyl, TFA=trifluoroacetic acid, TIPS=triisopropyl-
silyl, Ts=4-toluenesulfonyl.
13
14
nBu
tBu
47
52
15
16
17
nBu
tBu
Ph
49
53
48
intramolecular lactonization or RCM strategies, this unusual
eight-membered lactone formation is an intermolecular
process involving a sequence of several efficient bond-
forming/breaking events (see below).[13]
[a] Yield of isolated product.
9). Aryl substitution on the siloxy alkynes is tolerated
(entries 6 and 17). Finally, the TIPS-protected primary
alcohol is retained under our standard protocol (entry 12),
thus illustrating functional group compatibility of the reaction
conditions with the silyl protecting groups.
The use of silver triflimide (AgNTf2), which was previ-
ously reported to be the catalyst of choice for aldehyde
olefination with siloxy alkynes,[14] proved less effective in our
lactone formation reaction (Table 1, entry 2). Other Lewis
acids, such as AgOTf and AuCl3, did not improve the
efficiency. Among all the Brønsted acids evaluated, triflic
acid (TfOH) can promote the process, albeit with lower
efficiency (entry 5).[15] Other weaker acids, such as MsOH, p-
TsOH, and TFA, could not promote the desired lactone
formation (entries 6–8). In addition, the reaction proceeds
less efficiently in other solvents, such as toluene, Et2O, and
EtOAc (entries 9–11). Finally, a decreased yield was obtained
when the reaction was run at a higher concentration
(entry 12). The observed excellent efficiency with HNTf2 as
the catalyst can be explained by its high Brønsted acidity in
a polar aprotic solvent combined with the low nucleophilicity
of its counterion (Tf2NÀ).[15–17]
We examined the reaction scope using our standard
reaction conditions (Table 1, entry 1). As shown in Table 2,
a range of (1,6)-amphoteric molecules, such as those having
aryl linkers substituted with electron-withdrawing and elec-
tron-donating groups, as well as those with a thiophene linker,
can all participate successfully in the [6+2] cyclization process
to form the desired eight-membered lactone products. With
regard to the substitutions on the siloxy alkynes, it is
noteworthy that the increased steric hindrance does not
result in a significant decrease in efficiency (entries 2, 3, and
Although the use of an aryl linker between the oxetane
and aldehyde moieties proved successful, molecules having
3
3
À
a C(sp ) C(sp ) linker give low yields for these
[6+2] cyclization reactions. It is also worth noting
that the substitution of an oxirane (e.g., 6) for the
oxetane moiety does not carry a similar intermo-
lecular reaction pattern with siloxy alkynes.
Instead, when subjected to our standard reaction
conditions, aldehyde 6 undergoes a known intermolecular
homocyclization between the oxirane and the aldehyde
functionalities,[18] and no desired lactone product is observed.
This observation can be explained by the higher reactivity
(lower stability) of the oxirane relative to that of the oxetane
functionality.
With regard to the reaction mechanism, we have proposed
two possible pathways (Scheme 2). In path a, the reaction
begins with the oxetane ring-opening to form the oxonium
intermediate A[19] with subsequent attack of the electron-rich
alkyne to give the ketenium intermediate B. Furthermore, 8-
exo-dig cyclization forms cyclic silyl ketene acetal C. Next, C
undergoes a ring-opening step to form D, which is silylated to
deliver the observed eight-membered lactone E. Alterna-
tively, as shown in path b, a [2+2] cycloaddition between the
6210 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6209 –6213

Angewandte
Chemie
Scheme 2. Plausible reaction mechanisms.
alkyne and aldehyde 3 forms oxetene F,[20] which undergoes
ring-opening to give the a,b-unsaturated ester G.[21] Upon
activation of the oxetane by the acid catalyst, an 8-exo-tet
cyclization step gives the same intermediate D via H. We have
made alkene G (R = H) separately and subjected it to our
strategies available for the elaboration of medium-sized
lactones. The development of other useful processes employ-
ing these new amphoteric molecules is underway.
reaction conditions. The corresponding eight-membered Experimental Section
General procedure: The aldehyde (0.2 mmol), the siloxy alkyne
lactone E (R = H) was obtained (see the Supporting Infor-
mation), thus suggesting that G can be a viable intermediate.
However, for path a, we were able to isolate the ester 10 by
quenching the reaction with EtOH at partial conversion
[Eq. (1)], and it is likely formed from the intermediate B by
(0.24 mmol), and anhydrous CH2Cl2 (2.0 mL) were added to an oven-
dried 4 mL vial was added under N2. Next, HNTf2 (0.1 gmLÀ1 in
CH2Cl2, 56 mL, 0.02 mmol) was added via syringe at room temper-
ature. The reaction mixture was stirred at the same temperature and
monitored by thin layer chromatography. Upon completion (ca. 12 h),
the reaction was quenched with saturated NaHCO3 aqueous solution
(10 mL) and diluted with CH2Cl2 (2 mL). The organic layer was
separated and washed with H2O (3 ꢀ 10 mL) and brine (3 ꢀ 10 mL),
dried over MgSO4, filtered, and concentrated. The desired product
was purified by flash chromatography on silica gel.
Received: January 18, 2012
Revised: April 2, 2012
Published online: May 15, 2012
a silyl shift and ethanol addition to the ketene B’. When the
product E is subject to EtOH in the presence of HNTf2
compound 10 is not formed.
Keywords: alkynes · cyclization · homogeneous catalysis ·
lactones · medium-ring compounds
.
In summary, we have designed a new type of (1,6)-
amphoteric molecule by appropriate positioning of the
oxetane and aldehyde functional groups within a molecule.
Enabled by this design, we have successfully demonstrated an
efficient [6+2] cyclization process between these (1,6)-
amphoteric molecules and siloxy alkynes to form a range of
eight-membered lactones. Unlike the conventional intramo-
lecular approaches, such as lactonization and ring-closing
metathesis, our method represents the first intermolecular
reaction for the eight-membered lactone synthesis. Prelimi-
nary mechanistic analysis suggests that this unusual process
involves a sequence of several selective ring-opening/ring-
closing events with concomitant bond formation and cleav-
age. This approach is now added to the limited number of
[1] For a review, see: a) G. Rousseau, Tetrahedron 1995, 51, 2777 –
2849; For other examples of natural products containing
medium-ring lactones, see: b) S. Sang, X. Cheng, H. Fu, D.
Shieh, N. Bai, K. Lapsley, R. E. Stark, R. T. Rosen, C. Ho,
Tetrahedron Lett. 2002, 43, 2547 – 2549; c) M. Tsoukatou, H.
Siapi, C. Vagias, V. Roussis, J. Nat. Prod. 2003, 66, 444 – 446;
d) A. Bermejo, J. R. Tormo, N. Cabedo, E. Estornell, B.
Figadere, D. Cortes, J. Med. Chem. 1998, 41, 5158 – 5166.
[2] For reviews on the formation of medium- and large-sized
lactones, see: a) A. Parenty, X. Moreau, J.-M. Campagne, Chem.
Rev. 2006, 106, 911 – 939; b) I. Shiina, Chem. Rev. 2007, 107, 239 –
273.
[3] For examples of RCM approaches to the synthesis of medium-
sized lactones, see: a) A. K. Chatterjee, J. P. Morgan, M. Scholl,
Angew. Chem. Int. Ed. 2012, 51, 6209 –6213
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6211

.
Angewandte
Communications
R. H. Grubbs, J. Am. Chem. Soc. 2000, 122, 3783 – 3784; b) K. R.
Buszek, N. Sato, Y. Jeong, Tetrahedron Lett. 2002, 43, 181 – 184;
c) T. Takahashi, H. Watanabe, T. Kitahara, Heterocycles 2002,
58, 99 – 104; d) Y. Baba, G. Saha, S. Nakao, C. Iwata, T. Tanaka,
T. Ibuka, H. Ohishi, Y. Takemoto, J. Org. Chem. 2001, 66, 81 – 88;
e) C. O. Kangani, A. M. Brꢁckner, D. P. Curran, Org. Lett. 2005,
7, 379 – 382; f) P. Davoli, A. Spaggiari, L. Castagnetti, F. Prati,
Org. Biomol. Chem. 2004, 2, 38 – 47; g) R. V. Anand, S.
Baktharaman, V. K. Singh, J. Org. Chem. 2003, 68, 3356 – 3359;
h) M. K. Gurjar, R. Nagaprasad, C. V. Ramana, Tetrahedron
Lett. 2003, 44, 2873 – 2875; i) E. Diez, D. J. Dixon, S. V. Ley, A.
Polara, F. Rodriguez, Synlett 2003, 1186 – 1188; j) D. Liu, S. A.
Kozmin, Org. Lett. 2002, 4, 3005 – 3007; k) A. Fꢁrstner, K.
Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J.
Am. Chem. Soc. 2002, 124, 7061 – 7069; l) J. I. Aird, A. N. Hulme,
J. W. White, Org. Lett. 2007, 9, 631 – 634; m) N. Brown, G. Gao,
M. Minatoya, B. Xie, D. VanderVelde, G. H. Lushingto, J. H.
Perchellet, E. M. Perchellet, K. R. Crow, K. R. Buszek, J. Comb.
Chem. 2008, 10, 628 – 631.
[10] For excellent reviews of oxetanes in organic synthesis and
medicinal chemistry, see: a) J. A. Burkhard, G. Wuitschik, M.
Rogers-Evans, K. Mꢁller, E. M. Carreira, Angew. Chem. 2010,
122, 9236 – 9251; Angew. Chem. Int. Ed. 2010, 49, 9052 – 9067;
b) G. Wuitschik, E. M. Carreira, B. Wagner, H. Fischer, I.
Parrilla, F. Schuler, M. Rogers-Evans, K. Mꢁller, J. Med. Chem.
2010, 53, 3227 – 3246.
[11] For examples of acid-promoted ring-opening reactions of
oxetanes, see: a) M. Mizuno, M. Kanai, A. Iida, K. Tomioka,
Tetrahedron 1997, 53, 10699 – 10708; b) T. Bach, K. Kather, O.
Kramer, J. Org. Chem. 1998, 63, 1910 – 1918; c) M. M.-C. Lo,
G. C. Fu, Tetrahedron 2001, 57, 2621 – 2634; d) F. Bertolini, S.
Crotti, V. D. Bussolo, F. Macchia, M. Pineschi, J. Org. Chem.
2008, 73, 8998 – 9007; e) R. Loy, E. N. Jacobsen, J. Am. Chem.
Soc. 2009, 131, 2786 – 2787; f) J. A. Burkhard, B. H. Tchitchanov,
E. M. Carreira, Angew. Chem. 2011, 123, 5491 – 5494; Angew.
Chem. Int. Ed. 2011, 50, 5379 – 5382; g) D. Rix, R. Ballesteros-
Garrido, W. Zeghida, C. Besnard, J. Lacour, Angew. Chem. 2011,
123, 7446 – 7449; Angew. Chem. Int. Ed. 2011, 50, 7308 – 7311.
[12] For examples of cyclization reactions employing siloxy alkynes,
see: a) C. J. Kowalski, G. S. Lal, J. Am. Chem. Soc. 1988, 110,
3693 – 3695; b) M. P. Schramm, D. S. Reddy, S. A. Kozmin,
Angew. Chem. 2001, 113, 4404 – 4407; Angew. Chem. Int. Ed.
2001, 40, 4274 – 4277; c) J. Sun, S. A. Kozmin, J. Am. Chem. Soc.
2005, 127, 13512 – 13513; d) T. B. Clark, K. A. Woerpel, Org.
Lett. 2006, 8, 4109 – 4112; e) M. Movassaghi, M. D. Hill, O. K.
Ahmad, J. Am. Chem. Soc. 2007, 129, 10096 – 10097; f) E. C.
Minnihan, S. L. Colletti, F. D. Toste, H. C. Shen, J. Org. Chem.
2007, 72, 6287 – 6289; g) X. Qi, J. M. Ready, Angew. Chem. 2008,
120, 7176 – 7178; Angew. Chem. Int. Ed. 2008, 47, 7068 – 7070;
h) W. F. Austin, Y. Zhang, R. L. Danheiser, Tetrahedron 2008,
64, 915 – 925.
[13] To the best of our knowledge, there have been no previous
reports on intermolecular reactions for the formation of eight-
membered lactones.
[14] J. Sun, V. A. Keller, S. T. Meyer, S. A. Kozmin, Adv. Synth. Catal.
2010, 352, 839 – 842.
[15] The acidity of TfOH was found to be lower than that of HNTf2 in
the gas phase (Ref. [16a]), but the trend in protic solvents is
reversed (Ref. [16b]), see: a) I. A. Koppel, R. W. Taft, F. Anvia,
S. Zhu, L. Hu, K. Sung, D. D. DesMarteau, L. M. Yagupolskii,
Y. L. Yagupolskii, N. V. Ignatꢃev, N. V. Kondratenko, A. Y.
Volkonskii, V. M. Vlasov, R. Notario, P. Maria, J. Am. Chem.
Soc. 1994, 116, 3047 – 3057; b) J. Foropoulos, D. D. DesMarteau,
Inorg. Chem. 1984, 23, 3720 – 3723.
[16] For a review on HNTf2 in organic synthesis, see: a) K. Takasu,
Synlett 2009, 1905 – 1914; b) J. Sun, Triflimide in Encyclopedia of
Reagents for Organic Synthesis, Wiley, Hoboken, 2010, DOI:
10.1002/047084289X.rn01222.
[4] For examples of lactonization approaches to the synthesis of
medium-sized lactones, see: a) T. Tabuchi, K. Kawamura, J.
Inanaga, M. Yamaguchi, Tetrahedron Lett. 1986, 27, 3889 – 3890;
b) B. Simonot, G. Rousseau, J. Org. Chem. 1993, 58, 4 – 5;
c) K. R. Buszek, N. Sato, Y. Jeong, J. Am. Chem. Soc. 1994, 116,
5511 – 5512; d) A. N. Hulme, G. E. Howells, Tetrahedron Lett.
1997, 38, 8245 – 8248; e) I. Shiina, M. Kubota, H. Oshiumi, M.
Hashizume, J. Org. Chem. 2004, 69, 1822 – 1830; f) I. Shiina, M.
Hashizume, Y. Yamai, H. Oshiumi, T. Shimazaki, Y. Takasuna,
R. Ibuka, Chem. Eur. J. 2005, 11, 6601 – 6608; g) E. Metay, E.
Lꢂonel, J. Nꢂdꢂlec, Synth. Commun. 2008, 38, 889 – 904; h) J. D.
White, C. M. Lincoln, J. Yang, W. H. C. Martin, D. B. Chan, J.
Org. Chem. 2008, 73, 4139 – 4150; i) J. Pietruszka, A. C. M.
Rieche, Adv. Synth. Catal. 2008, 350, 1407 – 1412.
[5] For alternative approaches to the synthesis of medium-sized
lactones, see: a) D. M. Tapiolas, M. Roman, W. Fenical, T. J.
Stout, J. Clardy, J. Am. Chem. Soc. 1991, 113, 4682 – 4683; b) S.
Inoue, Y. Iwabuchi, H. Irie, S. Hatakeyama, Synlett 1998, 735 –
736; c) Ref. [1d]; d) H. Ohi, S. Inoue, Y. Iwabuchi, H. Irie, S.
Hatakeyama, Synlett 1999, 1757 – 1759; e) R. A. Pilli, M. M.
Victor, Tetrahedron Lett. 2002, 43, 2815 – 2818; f) E. A. Ander-
son, J. E. P. Davidson, J. R. Harrison, P. T. OꢃSullivan, J. W.
Burton, I. Collins, A. B. Holmes, Tetrahedron Lett. 2002, 58,
1943 – 1971; g) P. T. OꢃSullivan, W. Buhr, M. A. M. Fuhry, J. R.
Harrison, J. E. Davies, N. Feeder, D. R. Marshall, J. W. Burton,
A. B. Holmes, J. Am. Chem. Soc. 2004, 126, 2194 – 2207.
[6] G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981, 14, 95 – 102.
[7] For a recent example demonstrating the particular difficulty in
the formation of medium-sized lactones, see: A. Lumbroso, N.
Abermil, B. Breit, Chem. Sci. 2012, 3, 789 – 793.
[8] A. Dçmling, I. Ugi, Angew. Chem. 2000, 112, 3300 – 3344;
Angew. Chem. Int. Ed. 2000, 39, 3168 – 3210.
[17] For some examples demonstrating the superiority of HNTf2 over
other acids, see: a) Ref. [12c]; b) K. Inanaga, K. Takasu, M.
Ihara, J. Am. Chem. Soc. 2005, 127, 3668 – 3669; c) K. Ishihara,
K. Nakano, J. Am. Chem. Soc. 2007, 129, 8930 – 8931.
[18] This process forms a cyclic acetal product, and is a known
process: P. Krasik, M. Bohemier-Bernard, Q. Yu, Synlett 2005,
854 – 856.
[9] a) R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772 –
14773; b) R. Hili, A. K. Yudin, Angew. Chem. Int. Ed. 2008, 47,
4188 – 44191; c) R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2009,
131, 16404 – 16406; d) R. Hili, V. Rai, A. K. Yudin, J. Am. Chem.
Soc. 2010, 132, 2889 – 2891; e) B. H. Rotstein, V. Rai, R. Hili,
A. K. Yudin, Nat. Protoc. 2010, 5, 1813 – 1822; f) S. Bakthara-
man, N. A. Afagh, A. Vandersteen, A. K. Yudin, Org. Lett. 2010,
12, 240 – 243; g) N. Assem, A. Natarajan, A. K. Yudin, J. Am.
Chem. Soc. 2010, 132, 10986 – 10987; h) Z. He, A. K. Yudin,
Angew. Chem. 2010, 122, 1651 – 1654; Angew. Chem. Int. Ed.
2010, 49, 1607 – 1610; i) N. A. Afagh, A. K. Yudin, Angew. Chem.
2010, 122, 270 – 320; Angew. Chem. Int. Ed. 2010, 49, 262 – 310;
j) L. L. W. Cheung, Z. He, S. M. Decker, A. K. Yudin, Angew.
Chem. 2011, 123, 12002 – 12006; Angew. Chem. Int. Ed. 2011, 50,
11798 – 11802.
[19] As suggested by one of the referees, Et3SiH was used as the
nucleophile and the following product was obtained.
[20] Oxetene adducts formed from a [2+2] cycloaddition reaction
between an alkyne and an aldehyde or ketone have been
6212
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6209 –6213

Angewandte
Chemie
previously observed. For some examples, see: a) W. J. Middle-
ton, J. Org. Chem. 1965, 30, 1307; b) L. E. Friedrich, J. D. Bower,
J. Am. Chem. Soc. 1973, 95, 6869 – 6870; c) K. Aikawa, Y. Hioki,
N. Shimizu, K. Mikami, J. Am. Chem. Soc. 2011, 133, 20092 –
20095.
H. Koroniak, K. N. Houk, C. Sheu, Acc. Chem. Res. 1996, 29,
471 – 477, and references therein; b) T. Yoshikawa, S. Mori, M.
Shindo, J. Am. Chem. Soc. 2009, 131, 2092 – 2093, and references
therein; For an example of dramatic catalyst dependence for
torquoselectivity, see: c) N. Shindoh, K. Kitaura, Y. Takemoto,
K. Takasu, J. Am. Chem. Soc. 2011, 133, 8470 – 8473.
[21] The alkene configuration of the electrocyclic ring-opening
process is controlled by torquoselectivity; a) W. R. Dolbier, Jr.,
Angew. Chem. Int. Ed. 2012, 51, 6209 –6213
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6213