Facial selectivity and stereospecificity in the (4 + 3) cycloaddition of epoxy enol silanes

Article abstract of DOI:10.1021/ol102897d

The scope of the (4 + 3) cycloaddition using epoxy enol silanes has been examined. Unhindered and nucleophilic dienes react to give the highest yields, but hindered dienes give rise to higher diastereoselectivities. Notably, the cycloaddition shows facial

Full text of DOI:10.1021/ol102897d

ORGANIC
LETTERS
2011
Vol. 13, No. 5
864–867
Facial Selectivity and Stereospecificity
in the (4 þ 3) Cycloaddition of
Epoxy Enol Silanes
Brian Lo and Pauline Chiu*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
pchiu@hku.hk
Received November 30, 2010
ABSTRACT
The scope of the (4 þ 3) cycloaddition using epoxy enol silanes has been examined. Unhindered and nucleophilic dienes react to give the highest
yields, but hindered dienes give rise to higher diastereoselectivities. Notably, the cycloaddition shows facial selectivity and stereospecificity for
the stereochemistry of the epoxy enol silane.
The (4 þ 3) cycloaddition of allyl cations and dienes is an
efficient entry into the synthesis of seven-membered rings.1
Recent research in this field seeks to develop mild and
chemoselective methods to assemble and generate the oxy-
allyl cation for maximum functional group compatibility,
for applications in intramolecular cycloadditions, and in
late stages of the syntheses of complex natural products.2
Polyfunctionalized oxyallyl cations that can engage in
cycloaddition are also desirable to furnish more sophisti-
cated cycloadducts with a greater potential for synthesis.
Recently we reported on the development and optimiza-
tion of an intermolecular (4 þ 3) cycloaddition which
employed epoxy enol silanes as the dienophile.3 This cyclo-
addition afforded hydroxymethylenated bicyclo[3.2.1]-
octenones under mild reaction conditions and in good
yields (Table 1, entry 1). We have found that TES-enol
ether 1a, instead of the previously reported TMS-derivative,4
reacted at low temperatures with a significant improve-
ment in cycloaddition efficiency. Herein we report on the
scope of this reaction and have delineated aspects of the
mechanism that could account for the yields and diaster-
eoselectivities. Notably, this (4 þ 3) cycloaddition was
found to be both facial selective and stereospecific with
respect to the epoxy enol silane.
(1) Reviews of (4 þ 3) cycloadditions: (a) Harmata, M. Chem.
Commun. 2010, 46, 8904–8922. (b) Battiste, M. A.; Pelphrey, P. M.;
Wright, D. L. Chem.;Eur. J. 2006, 12, 3438–3447. (c) Harmata, M.
Adv. Synth. Catal. 2006, 348, 2297–2306. (d) Hartung, I. V.; Hoffmann,
H. M. R. Angew. Chem., Int. Ed. 2004, 43, 1934–1947. (e) Harmata, M.;
Rashatasakhon, P. Tetrahedron 2003, 59, 2371–2395. (f) Harmata, M.
Acc. Chem. Res. 2001, 34, 595–605. (g) Cha, J. K.; Oh, J. Curr. Org.
Chem. 1998, 2, 217–232. (h) Rigby, J. H; Pigge, F. C. Org. React. 1997,
51, 351–478. (i) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984,
23, 1–19.
(2) Representative recent work on (4 þ 3) cycloadditions: (a) Anto-
line, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org. Lett. 2007, 9,
1275–1278. (b) Pascual, M. V.; Proemmel, S.; Beil, W.; Warchow, R.;
€
Hoffmann, H. M. R. Org. Lett. 2004, 6, 4155–4158. (c) Fohlisch, B.;
Flogaus, R.; Henle, G. H.; Sendelbach, S.; Henkel, S. Eur. J. Org. Chem.
2006, 2160–2173. (d) Harmata, M.; Wacharasindhu, S. Org. Lett. 2005,
We have observed that silyl triflates were able to pro-
mote the cycloaddition through epoxide activation
ꢀ
ꢀ
7, 2563–2565. (e) Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.;
Hayes, J. F.; Shipman, M. Angew. Chem., Int. Ed. 2004, 43, 6517–6519.
(f) Trillo, B.; Lopez, F.; Gulias, M.; Castedo, L.; Mascarenas, J. L.
Angew. Chem., Int. Ed. 2008, 47, 951–954. (g) Xiong, H.; Hsung, R. P.;
Berry, C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174–
7175. (h) Fujita, M.; Oshima, M.; Okuno, S.; Sugimura, T.; Okuyama,
T. Org. Lett. 2006, 8, 4113–4116.
(3) Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.-T.; Chiu,
P. J. Am. Chem. Soc. 2009, 131, 4556–4557.
(4) Ohno, M.; Mori, K.; Hattori, T.; Eguchi, S. J. Org. Chem. 1990,
55, 6086–6091.
r
10.1021/ol102897d
Published on Web 01/28/2011
2011 American Chemical Society

Table 1. Reaction Conditions for Cycloaddition of 1a and
Furan
Table 2. (4 þ 3) Cycloaddition of 1a with Various Dienes
entry dienea
X
R1
R2
R3
yield
R-2:β-2
entry
acids
t (°C)
yield of 2a
1b
2c
3
3a
3b
3c
3d
4a
4b
4c
O
O
O
O
H
H
H
H
H
2a, 75%
2b, 32%d
2c, 70%
55:45
66:34
50:50e
45:55
55:45
77:23
43:57
1
2
3a
4
5
6
7
8
TESOTf (10 mol %)
TESOTf (100 mol %)
TMSOTf (10 mol %)
TBSOTf (20 mol %)
TfOH (10 mol %)
-91
-91
-94
-91
-91
-91
-91
-78
75%
75%
70%
58%
57%b
36%b
59%
21%c
Me
H
H
Me
4
H
Me Me 2d, 73%
5
CH2
H
H
H
H
H
H
H
2e, 76%
2f, 47%
2g, 22%
Tf2NH (10 mol %)
Tf2NH (100 mol %)
TFA (100 mol %)
6
C(CH2)2
(CH2)2
H
7
H
a 5 equiv used. b Reference 3. c Yield improved from ref 3. d 5a (31%)
also obtained. e 2:1 mixture of regioisomers, total of 4 diastereomeric
products.
a Reference 3. b Result improved from ref 3. c Not all of 1a is
consumed.
bond formation hindered cycloaddition, resulting in lower
yields compared with the reactions of their corresponding
unsubstituted parent dienes (Table 2, entry 1 vs 2; entry 5
vs 6, 7). Dienes having substituents farther from the site of
bond formation (e.g., 3c and 3d) underwent cycloaddition
with good yields (Table 2, entries 2, 3), but the reaction
with the unsymmetrical furan 3c was not very regioselec-
tive (2:1). Electron-deficient dienes such as 3,4-dibromo-
furan were not reactive (<15% yields), while diphenylfulvene
and 2,3-dimethylbutadiene predominantly underwent poly-
merization under the reaction conditions. The overall
diastereoselectivity (R-2:β-2) of this cycloaddition with
1a as the dienophile was not high, although a preference
for endo cycloaddition5 to give R-2f was observed in the
reaction with the hindered spirocyclopentadiene, 4b.
A systematic study on the scope of the epoxy enol silanes
1 was undertaken next, and the results are shown in Tables 3
and 4.6 With enol silanes bearing sterically more hindered
silyl groups (1b-d), the cycloaddition with furan (3a) or
cyclopentadiene (4a) required more than 10 mol %
TESOTf for complete reaction. According to the catalytic
cycle (Scheme 1), after the initiating step, the silyl group of
the enol ether ultimately propagates the reaction, and it
may be that bulky silyl groups are not as effective in acti-
vating the epoxides in subsequent rounds. Although low
diastereoselectivities were observed with unhindered dienes
(Table 3, entries 3-7, 9), the cycloadditions with the bulky
TBDPS-substituted enol ether 1d showed a dramatic range
in the mode of cycloaddition. A preference for the exo-
cycloadducts β-2 could be seen in the reactions of 1d with
furans 3a and 3d (Table 3, entries 7-8), but with the
hindered spirocyclopentadiene 4b, the endo-cycload-
Scheme 1. Proposed Catalytic Cycle
(Table 1, entries 1-3), initially yielding silylated 2a
(Scheme 1, A = TES) as expected from the proposed
catalytic cycle (Scheme 1). Because an aqueous workup
resulted in varying degrees of desilylation, all product
mixtures were treated with HF-Et3N to induce complete
desilylation for consistency. The bulkier TBSOTf was able
to initiate the reaction, but more catalyst was needed for
complete reaction. Strong Brønsted acids also activated
the epoxide for cycloaddition, even though protonation of
the silyl enol ether could be a competing pathway (Table 1,
entries 5-7). However, weaker acids such as TFA could
not mediate the reaction effectively even in stoichiometric
amounts (Table 1, entry 8).
(5) Endo refers to a syn relationship between the diene and the oxygen
in the dienophile, whereas Hoffmann used the term “compact” to
describe this cycloaddition mode: Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. 1973, 12, 819–835.
(6) The structures of all cycloadducts were determined by 2-D NMR
and NOE correlations about the rigid bicyclic system; see the Supporting
Information.
A screening of dienes (Table 2) showed that a range of
structural types participate in this cycloaddition. The high-
est cycloaddition yields were obtained with unhindered
dienes of good nucleophilicity (Table 2, entries 1, 3-5).
Substituents at or proximate to the site of carbon-carbon
Org. Lett., Vol. 13, No. 5, 2011
865

Table 3. (4 þ 3) Cycloaddition of Epoxy Enol Silanes 1a-1g
Table 4. (4 þ 3) Cycloaddition of Epoxy Enol Silanes 1h-1i
entry
enol silane 1
dienea yield of 2 R-2:β-2
1b
2
3c
4c
5c
6c
7c
1a (R = TES; R4, R5, R6 = H)
3a
4a
3a
4a
3a
4a
3a
2a, 75% 55:45
2e, 76% 55:45
2a, 38% 65:35
2e, 56% 52:48
2a, 60% 60:40
2e, 60% 58:42
2a, 59% 35:65
entry
enol silane 1
dienea
yield
dr
1a
1
2
3
4
5
6
(Z)-1h (R7 = Me)
(Z)-1h
3a
4a
3a
4a
3a
4a
82%
57%
7w:7x:7y = 45:45:10
8w:8z = 50:50
1b (R = TBS; R4, R5, R6 = H)
1b
(Z)-1i (R7 = Ph)
(Z)-1i
66%b,c 9w:9x = 25:75
1c (R = TIPS; R4, R5, R6 = H)
1c
97%
14%d
60%
10w:10z = 45:55
9y only
(E)-1i (R7 = Ph)
(E)-1i
1d (R = TBDPS; R4,
R5, R6 = H)
10x:10y = 28:72
8c,d 1d
9c
1d
10c,d 1d
3d
4a
4b
3a
2d, 43% 30:70
2e, 55% 55:45
2f, 46% R-2f only
2h, 57% 72:28
a 5 equiv used. b Yield improved from ref 3. c 5c (26%) also obtained.
d 5c (31%) also obtained.
11
1e (R = TES; R4 = Me,
R5, R6 = H)
1e
12
13
14
15
3b
4a
4b
3a
2j, 27%e 75:25
2i, 56% 45:55
1e
1e
NR
--
1f (R = TES; R4, R6 = H,
2k, 56%f 65:35g
R5 = C5H11
)
16
1f
3b
3d
4a
4b
3a
2m, 25% 68:32
2n, 56% 35:65
2l, 80% 51:49
2o, 67%h R-2o only
2p, 27% 47:53
17d 1f
18
19
20
1f
1f
Figure 1. (4 þ 3) Cycloaddition Side Products 5a-c, 6a-b.
1g (R = TES; R4, R5 = H,
R6 = C5H11
1g
)
different yields and stereodiscrimination in the cycloaddi-
tion. Cycloaddition of 1f (R5 = C5H11) bearing a sub-
stituent on a trans-epoxide with various dienes resulted in
moderate to good yields of cycloadducts (Table 3, entries
15-19). The decreased yield in the cycloaddition of 1f with
furan was due to the formation of a bisfuran side product
6a (Figure 1, Scheme 2) from the quenching of the cationic
intermediate by silyl ether addition, a Class C product as
defined by Hoffmann.1i Significantly, in the reaction of 1f
and spirocyclopentadiene 4b, only one endo diastereomeric
cycloadduct R-2o was obtained (Table 3, entry 19). The
cycloaddition of 1g with various dienes proceeded with
generally lower yields than in the case of 1f, showing that a
cis-substituent in the epoxide is sterically more de-
manding in the cycloaddition than a trans-substituent
(Table 3, entries 20-22). The observation of only two
diastereomers, instead of four, from the cycloadditions of
1f and 1g indicates that the cycloaddition proceeded with
facial selectivity with respect to the dienophiles. This infers
that there is significant epoxide character in the transition
state of the cycloaddition.
21
22d 1g
4a
3d
2q, 51% 40:60
2r, 35% 22:78
a 5 equiv of diene used. b Reference 3. c Reaction completed using a
total of 20 mol % TESOTf. d t = -78 °C. e 5b (14%) also obtained. f 6a
(24%) also obtained. g endo/exo ratio = 50:50, taking into account that
6a resulted from an exo attack. h 6b (7%) also obtained.
duct R-2f was obtainedexclusively (Table 3, entry 10). This
example demonstrates that it is possible to modify and
increase the diastereoselectivities of the cycloadditions by
the use of 1bearing silyl groups with varying steric demands.
Epoxides with substituents at the site of carbon-carbon
bond formation (e.g., 1e, R4 = Me) would be expected to
favor C-O cleavage to yield a more substituted and sta-
bilized oxyallyl cation species; on the other hand, this electro-
phile would also be more hindered. In the event, 1e under-
went cycloaddition with unhindered dienes in slightly
diminished yields (Table 3, entries 11, 13), and with a
hindered furan such as 2,5-dimethylfuran (3b) in signifi-
cantly lower yield along with rearomatized product 5b
(Table 3, entry 12), revealing the deleteriouseffects of steric
hindrance toward cycloaddition. In the extreme case, no
reaction was observed between 1f and hindered spirocy-
clopentadiene 4b (Table 3, entry 14).
Epoxides substituted at the enol silane (R7 ¼
6
H) would
be expected to yield electronically more stabilized but
sterically more demanding electrophilic intermediates.
The reactions of (Z)-1h and (Z)-1i produced good to
excellent yields of cycloadducts (Table 4, entries 1-4).
The (E)-enol ether 1i was sterically more demanding as a
dienophile, as can be seen from the decreased yields of
A trans- or cis-substituent (R5, R6 ¼
6
H) on the distal
carbon of 1f and 1g, respectively, would not be able to
stabilize the electrophilic species compared to its parent
epoxide 1a but could impose steric demands resulting in
866
Org. Lett., Vol. 13, No. 5, 2011

Scheme 2. Formation of Type C Products
Scheme 3. Proposed Stereochemical Model
cycloadducts and the concomitant formation of a signifi-
cant amount of 5c (Figure 1, Scheme 2), resulting from
termination by rearomatization.
hindered end of the diene having an oxygen with its lone
pairs when X = O for 3a, or the cyclopropyl moiety when
X = C(CH2)2 for 4b, orients to cycloadd via the endo mode
(Table 3, entry 19). When the steric demands of the western
hemisphere of the dienophile is exacerbated by the use of
R = TBDPS, the preference for endo cycloaddition is
further increased to the point of being exclusive (Table 3,
entry 10). On the other hand, when the steric demands of
the diene increase at furan substituents R2 and R3 as found
in 3d, exo-cycloaddition becomes favored (Table 3, entries
8, 17, 22). When both the diene and dienophile are ste-
rically encumbered, cycloaddition does not proceed
(Table 3, entry 14).
Inconclusion, the examination of the scope of the (4 þ 3)
cycloaddition of epoxy enol silanes revealed that the reac-
tion proceeded with facial selectivity and stereospecificity
with respect to the epoxy enol silane, indicating that the
transition state is reactant-like and has significant epoxide
and alkene character. Unhindered and nucleophilic dienes
react to give the best yields, and the steric factors of the
diene and the dienophile could be manipulated to increase
the diastereoselectivity of the cycloaddition. A model to
account for the stereochemical outcomes has been pro-
posed. Our studies are ongoing to further delineate the
mechanistic pathway through both experimental and com-
putational work.11
The observation of 8w,z and 10w,z from the cycloaddi-
tion reactions of (Z)-1h7 and (Z)-1i respectively with
cyclopentadiene (4a) clearly indicated that both endo and
exo cycloaddition modes were operative (Table 4, entries 2, 4).
Notably, the reactions of (Z)-1i and (E)-1i generated com-
plementary pairs of diastereomeric cycloadducts (Table 4,
entries 4, 6), which infers that the reaction is stereospecific
with respect to the geometry of the enol silane.
The corresponding cycloadditions of (Z)-1h and (Z)-1i
with furan yielded cycloadducts 7w and 9w from endo
cycloaddition (Table 4, entries 1, 3), while diastereomers
7x and 9x could be understood as having been derived
from aninitial exo attack at the epoxides of (Z)-1h and (Z)-
1i, followed by the enol ether reacting from the opposite
face after bond rotation, to set R7 at the pseudoequatorial
positions.8 This explanation is consistent with the known
preference of furan to undergo cycloaddition in an asyn-
chronous manner9 and with the structures of products
5a-c and 6a from interrupted cycloaddition, which show
that bond formation with furan first occurred at the
epoxide in the dienophile.
Summing up the observations of these experiments, the
(4 þ 3) cycloadditions of epoxy enol silanes occur with
good to excellent yields provided that the dienes are suffi-
ciently electron-rich and unencumbered. The stereochemi-
cal outcome could be explained by a reactant-like transi-
tion state which resembles 1 adopting the conformation as
shown (Scheme 3)10 and the diene approaching the dieno-
phile anti with respect to the epoxide via both endo and exo
cycloaddition modes. Based on our empirical observa-
tions, the eastern hemisphere of 1 (Scheme 3) appears to
be the less sterically demanding end. The sterically more
Acknowledgment. This work was supported by the
University of Hong Kong Strategic Research Theme on
Drugs, and by the ResearchGrants Council of Hong Kong
SAR (GRF HKU 7017/06P, 7015/10P). B.L. thanks the
HKU Department of Chemistry for conference support.
Supporting Information Available. Experimental pro-
1
cedures, full characterization, H, 13C NMR spectra for
1a-i, 2a-r, 5a-c, 6a,b, 7w-y, 8w,z, 9w-y, 10w-z. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) (E)-1h could not be obtained in pure form for use in cycloaddi-
tion.
(8) The loss of the original oxyallyl cation stereochemistry has been
observed and explained previously; see: Rawson, D. I.; Carpenter, B. K.;
Hoffmann, H. M. R. J. Am. Chem. Soc. 1979, 101, 1786–1793.
ꢀ
ꢀ
ꢀ
(9) Fernandez, I.; Cossıo, F. P.; de Cozar, A.; Lledos, A.;
ꢁ
(11) (a) Lohse, A. G.; Krenske, E. H.; Antoline, J. E.; Houk, K. N.;
Hsung, R. P. Org. Lett. 2010, 12, 5506–5509. (b) Krenske, E. H.; Houk,
K. N.; Harmata, M. Org. Lett. 2010, 12, 444–447. (c) Krenske, E. H.;
Houk, K. N.; Lohse, A. G.; Antoline, J. E.; Hsung, R. P. Chem. Sci.
2010, 1, 387–392.
Mascarenas, J. L. Chem.;Eur. J. 2010, 16, 12147–12157.
(10) While detailed transition state calculations remain to be done,
the shown conformation of 1 is rationalized by π-σ* alignment and
minimization of A-strain when R4 = H.
Org. Lett., Vol. 13, No. 5, 2011
867