A stereoselective intramolecular halo-etherification of chiral enamides in the synthesis of halogenated cyclic ethers

Article abstract of DOI:10.1021/ol701768n

(Chemical Equation Presented) A stereoselective halo-etherification of chiral enamides is described here. This work provides an approach to halogen containing cyclic ethers and reveals further mechanistic insights to the chemistry of chiral enamides.

Full text of DOI:10.1021/ol701768n

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4459-4462
A Stereoselective Intramolecular
Halo-Etherification of Chiral Enamides in
the Synthesis of Halogenated Cyclic
Ethers
Changhong Ko, Richard P. Hsung,* Ziyad F. Al-Rashid, John B. Feltenberger,
Ting Lu, Jin-Haek Yang, Yonggang Wei, and Craig A. Zificsak
DiVision of Pharmaceutical Sciencies and Department of Chemistry, Rennebohm Hall
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received July 24, 2007
ABSTRACT
A stereoselective halo-etherification of chiral enamides is described here. This work provides an approach to halogen containing cyclic ethers
and reveals further mechanistic insights to the chemistry of chiral enamides.
With elegant advances in metal-catalyzed N-alkenylations,1-4
chiral enamides should emerge as versatile building blocks
for developing stereoselective synthetic methods.5-12 We
encountered an interesting phenomenon involving enamides
when we attempted years ago to transform enamides 1 to
chiral ynamides13 via a sequence of bromination-elimination
of the intermediate â-bromo-enamides 3 and 4 [Scheme 1].14
Two intriguing observations were made. First, the bromi-
nation behaved differently from a standard bromination of
olefins. It was reversible with or without an amine base, and
(1) For reviews, see: (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem.
Commun. 2005, 973. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046. (d) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805.
(2) For recent enamide syntheses, see: (a) Chechik-Lankin, H.; Livshin,
S.; Marek, I. Synlett 2005, 2098. (b) Han, C.; Shen, R.; Su, S.; Porco, J.
A., Jr. Org. Lett. 2004, 6, 27. (c) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004,
6, 1809. (d) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6,
1845. (e) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667. (f) Shen, R.; Lin, C. T.; Porco, J. A., Jr. J. Am. Chem. Soc.
2002, 124, 5650.
(3) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Tracey, M. R. J.
Org. Chem. 2006, 71, 4170.
(4) Tracey, M. R.; Hsung, R. P.; Antoline, J. E.; Kurtz, K. C. M.; Shen,
L.; Slafer, B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods
of Molecular Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag
KG: New York, 2005; Chapter 21.4.
(5) For reviews, see: (a) Rappoport, Z. The Chemistry of Enamines in
The Chemistry of Functional Groups; John Wiley and Sons: New York,
1994. (b) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517. (c)
Hickmott, P. W. Tetrahedron 1982, 38, 1975. (d) Hickmott, P. W.
Tetrahedron 1982, 38, 3363.
(7) For [2 + 2] cycloadditions of chiral enamides, see: (a) Hegedus, L.
S.; Bates, R. W.; Soderberg, B. C. J. Am. Chem. Soc. 1991, 113, 923. (b)
For a review, see: Hegedus, L. S. Tetrahedron 1997, 53, 4105. (c) Riches,
A. G.; Wernersbach, L. A.; Hegedus, L. S. J. Org. Chem. 1998, 63, 4691.
For Paterno`-Bu¨chi [2 + 2], see: (d) Bach, T.; Schro¨der, J.; Brandl, T.;
Hecht, J.; Harms, K. Tetrahedron 1998, 54, 4507.
(8) For Diels-Alder cycloadditions, see: (a) Gohier, F.; Bouhadjera,
K.; Faye, D.; Gaulon, C.; Maisonneuve, V.; Dujardin, G.; Dhal, R. Org.
Lett. 2007, 9, 211. (b) Crawly, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995.
(c) Palasz, A. Org. Biomol. Chem. 2005, 3, 3207. (d) Robiette, R.; Cheboub-
Benchaba, K.; Peeters, D.; Marchand-Brynaert, J. J. Org. Chem. 2003, 68,
9809. (e) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder,
J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417. (f) Abbiati, G.; Clerici, F.;
Gelmi, M. L.; Gambini, A.; Pilati, T. J. Org. Chem. 2001, 66, 6299.
(9) For epoxidations, see: (a) Xiong, H.; Hsung, R. P.; Shen, L.; Hahn,
J. M. Tetrahedron Lett. 2002, 43, 4449. (b) Adam, W.; Bosio, S. G.; Wolff,
B. T. Org. Lett. 2003, 5, 819. (c) Sivaguru, J.; Saito, H.; Poon, T.; Omonuwa,
T.; Franz, R.; Jockusch, S.; Hooper, C.; Inoue, Y.; Adam, W.; Turro, N. J.
Org. Lett. 2005, 7, 2089. (d) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.;
Nagasaka, T. Tetrahedron 2000, 56, 8855.
(6) For R-metalations of chiral enamides, see: Lander, P.; Hegedus, L.
S. J. Am. Chem. Soc. 1994, 116, 8126.
10.1021/ol701768n CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/02/2007

Scheme 1. An Arrested Bromination-Elimination of Enamides
Table 1. Temperatures and Choice of Activations
temp
[°C]
time yield
[h] [%]a pyrans drb [%]
8c
entry activation solvent
1
2
3
4
5
6
7
8
Br2
toluened -78 to rt 12 92
7-Br 6.9:1
7-Br 6.9:1
7-Br 7.0:1
7-Br 7.0:1
7-Br 7.0:1
7-Br 6.9:1
7-Br
0
0
0
0
0
0
0
0
CH2Cl2 -78
CH2Cl2 -45e
CH2Cl2 -20e
CH2Cl2 0e
2
2
2
2
1
63
73
82
81
82
CH2Cl2 rte
NBS
NBS +
TBABf
NCS
CH2Cl2 -78 to 40 24 NR
CH2Cl2 -45 to rt 42
6
7-Br 1:1.2
9
toluened -78 to 60 48 NR
CH2Cl2 -45 to rt 24 54
7-Clg
7-Cl 6.8:1 30i
0
10 NCS +
TBACh
11 l2
12 NlS
13 lCl
CH2Cl2 -78 to 40 24 30
CH2Cl2 -78 to 40 24 NR
7-lk
7-1
7-l
1:1.1 33l
0
6.0:1
j
3 and 4 were obtained only if the reaction was heated at
g80 °C without base. Although upon its addition the bromine
color disappeared rapidly in a colormetric titration manner,
the color returned upon warming to rt. Second, when R is a
TBSO or TIPSO group, the bromination led to a completely
different product, thereby failing to access ynamides 5 via
this protocol. While we suspected the N-acyl iminium salt
intermediate 2 to be responsible for the reversibility issue
[see blue arrows], we recently resolved the mystery product
in the second observation. We reported here a stereoselective
halo-etherification of chiral enamides in the synthesis of
halogen containing cyclic ethers.
When chiral enamide 615 was subjected to bromination
conditions in which 1.33 equiv of Br2 was added at -35 °C
and the resulting mixture was heated at 83 °C in ClCH2-
CH2Cl for 20 h, pyran 7-Br was isolated in 43% yield as a
single isomer. Its relative stereochemistry was unambigu-
ously assigned via single-crystal X-ray structure [Scheme
2]. No â-bromo-enamides related to 3 and 4 were found,
CH2Cl2 -78 to rt
2
70
0
a Isolated yields. NR: no reactions. b Ratios assigned using 1H and/or
13C NMR c X ) H at C3. See Scheme 2 for the structure. d Br2 was added
as a 0.5 M solution in CH2Cl2: toluene:CH2Cl2 is 3:1. e Br2 was added at
-78 °C. The reaction was stirred at the temperature and time indicated
after the addition. f TBAB: tetra-n-butyl ammonium bromide; NBS:TBAB:6
) 1.5:1.5:1. NBS and TBAB were premixed at -78 °C for 10 min. g X )
Cl at C3. h TBAC: tetra-n-butyl ammonium chloride; NCS:TBAC:6 ) 1.5:
1.5:1. NCS and TBAC were premixed at -78 °C for 10 min. i dr for 8 )
2:1. j 4 Å MS was used. k X ) I at C3. l dr for 8 ) 3:1.
bromo-etherification could take place readily at much lower
temperatures with best yields obtained between -20 °C and
rt with the diastereomeric ratio being independent of tem-
(10) For cyclopropanations of chiral enamides, see: (a) Song, Z.; Lu,
T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int.
Ed. 2007, 46, 4069. (b) Voigt, J.; Noltemeyer, M.; Reiser, O. Synlett 1997,
202. (c) Akiba, T.; Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.;
Nakatani, K.; Kamada, M.; Hayakawa, I.; Terashima, S. Tetrahedron 1994,
50, 3905. (d) Seebach, D.; Stucky, G.; Pfammatter, E. Chem. Ber. 1989,
122, 2377. (e) Seebach, D.; Stucky, G. Angew. Chem., Int. Ed. 1988, 27,
1351.
(11) For examples of cross-couplings, see: (a) Mulder, J. A.; Kurtz, K.
C. M.; Hsung, R. P.; Coverdale, H. A.; Frederick, M. O.; Shen, L.; Zificsak,
C. A. Org. Lett. 2003, 5, 1547. (b) Naud, S.; Cintrat, J.-C. Synthesis 2003,
1391. (c) Hoffmann, R. W.; Bru¨ckner, D. New J. Chem. 2001, 25, 369. (d)
Witulski, B.; Buschmann, N.; Bergstra¨âer, U. Tetrahedron 2000, 56, 8473.
(12) For an enamide-yne cycloisomerization: Kim, H.; Lee, C. J. Am.
Chem. Soc. 2006, 128, 6336.
Scheme 2. Observation of a Desilylative Bromo-Etherification
(13) For reviews on ynamides, see: (a) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (c)
Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455. (d)
For a special issue dedicated to the chemistry of ynamides, see: Tetrahedron-
Symposium-In-Print: Chemistry of Electron-Deficient Ynamines and
Ynamides. Tetrahedron 2006, 62, Issue No.16.
(14) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C.
J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
(15) See the Supporting Information.
(16) For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
(b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321. (c) Harding, K.
E.; Tiner, T. H. Comp. Org. Synh. 1991, 4, 363. (d) Rousseau, G.; Homsi,
F. Chem. Soc. ReV. 1997, 26, 453. (e) Robin, S.; Rousseau, G. Tetrahedron
1998, 54, 13681. (f) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002,
3099. (g) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman.
N. Tetrahedron 2004, 60, 5273. (h) French, A. N.; Bissmire, S.; Wirth, T.
Chem. Soc. ReV. 2004, 33, 354. (i) Tang, Y.; Oppenheimer, J.; Song, Z.;
You, L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785.
(17) For some reviews on related metal-catalyzed cyclizations of olefins
in constructions of hetereocycles, see: (a) Nakamura, I.; Yamamoto, Y.
Chem. ReV. 2004, 104, 2127. (b) Beller, M.; Seayad, J.; Tillack, A.; Jiao,
H. Angew. Chem., Int. Ed. 2004, 43, 3368. (c) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400.
and pyran 7-Br implies a bromine-promoted desilylative
cyclization had taken place instead.
Given that halogen-induced etherifications16,17 involving
enamides, especially chiral enamides,18,19 have only been
sparsely explored, we examined this reaction in greater detail.
As shown in Table 1, we were able to establish that (1) the
4460
Org. Lett., Vol. 9, No. 22, 2007

perature [entries 1-6], (2) we could achieve chloro- and
iodo-etherification using NCS/TBAC and ICl, respectively
[entries 10 and 13], and (3) while I2 [entry 11] was not as
useful, NXS [X ) Br, Cl, and I] did not work at all [entries
7, 9, and 12]. When using NCS/TBAC and I2, we isolated a
substantial amount of pyran 8 [entries 10 and 11], which is
likely a result of adventitious HCl or HI promoted cycliza-
tion.
Scheme 3. A Sequential N-Alkenylation and
Bromo-Etherification
With these protocols in hand, we investigated the effect
of the chiral auxiliary on the stereoselectivity. The dia-
stereomeric ratio appears to be sensitive to the types of
auxiliary used [Figure 1]. In comparison to Evans’ auxilia-
Given the prevalence of halogenated cyclic ethers among
natural products, we next explored the formation of halo-
genated oxacycles with various ring sizes. As shown in
Figure 2, we were able to construct 5-, 7-, 8-, as well as
Figure 1. Effect of the chiral auxiliary on stereoselectivity. All
are isolated yields. Conditions: At -78 °C in toluene or CH2Cl2,
added a respective halogen source: Br2 [0.5 M in CH2Cl2] and
NCS/TBAC; stirred from -78 °C to rt for 0.5-2 h, except it is
24-48 h for the chlorination with NCS/TBAC.
Figure 2. Halo-oxacycles of different ring sizes. All are isolated
yields.
ries,20 Seebach’s auxiliary21 appears to be better giving 12-
Br in a 7.7:1 ratio, although the ratio was lower when using
Close’s auxiliary22 for the preparation of 13-Br. Interestingly,
an additional substituent such as OBz [at C5] eroded the
ratio 14-Br/14-Br′.
The best result came when using Sibi’s auxiliary. As
shown in Scheme 3, in a sequence that is intended to
demonstrate the synthetic potential of this method in
conjunction with N-alkenylation via amidative cross-
coupling,1,2 enamide 17 substituted with Sibi’s auxiliary was
prepared employing Ma’s conditions.2c The ensuing bromi-
nation gave bromo-pyran 18-Br in 90% yield with a dr of
9:1.
10-membered rings, although yields suffered in the 10-
membered-ring case. It is noteworthy that the ratios are all
quite high in most of these examples, and for chloro-furan
19-Cl, the minor isomer is actually the cis, which was not
seen in other cases.
While synthetically this method represents a stereoselective
approach for constructing chiral secondary halides, mecha-
nistically, these halo-etherifications can provide insight to
the chemistry of chiral enamides. On the basis of the
observed stereochemical outcome, a proposed mechanistic
model is shown in Scheme 4.
(18) For some examples on halo-etherfication and halo-lactonization of
enamides, see: (a) Rudler, H.; Denise, B.; Xu, Y.; Parlier, A.; Vaissermann,
J. Eur. J. Org. Chem. 2005, 3724. (b) Rudler, H.; Denise, B.; Parlier, A.;
Daranb, J. Chem. Commun. 2002, 9, 940. (c) Mart´ın-Lo´pez, M. J.; Bermejo-
Gonza´lez, F. Tetrahedron 1998, 54, 12379. (d) Williams, R.; Milreis, G.
F. Tetrahedron Lett. 1990, 31, 4297. (e) Shin, C.; Sato, Y.; Yoshimura, J.
Tetrahedron Lett. 1981, 22, 2401.
(19) For oxidative etherifications of enamides, see: (a) Rameshkumar,
C.; Xiong, H.; Tracey, M. R.; Berry, C. R.; Yao, L. J.; Hsung, R. P. J.
Org. Chem. 2002, 67, 1339. (b) McComas, C. C.; Perales, J. B.; Vranken,
D. L. V. Org. Lett. 2002, 4, 2337. For oxidative lactonizations of enamides,
see: (c) Stolowich, N. J.; Wang, J.; Spencer, J. B.; Santander, P. J.; Roessner,
C. A.; Scott, A. I. J. Am. Chem. Soc. 1996, 118, 1657. (d) Ihara, M.;
Noguchi, K.; Fukumoto, K.; Kametani, T. Tetrahedron 1985, 41, 2109.
(20) Heathcock, C. H. Aldrichim. Acta 1990, 23, 99.
While the chiral oxazolidinone of the enamide plays a
distinct role in providing the facial bias for the halogen to
approach from the Si-face [see A],9,11a the desilylative
cyclization through N-acyl iminium ion B represents a critical
second step. An initial CdN bond isomerization [blue arrow]
in B could occur to provide C in which the iminium CdN
geometry is both devoid of allylic strain and favored for the
ensuing cyclization. The cyclization is also likely initiated
with complexation of the oxygen atom to the iminium
carbon, and the loss of TBS-X would lead to the major
diastereomer 24-X.
(21) Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998, 81, 2093.
(22) Close, W. J. J. Org. Chem. 1950, 15, 1131.
(23) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
In contrast, the pathway leading to the minor isomer 24-
X′ suffers from an unfavorable Re-face halogenation and a
Org. Lett., Vol. 9, No. 22, 2007
4461

anion to the iminium cation than I- provides a more facile
desilylation.
Scheme 4. A Proposed Stereochemical Model
Another question concerns the involvement of the halo-
nium intermediate E [Scheme 5] and its significance versus
Scheme 5. Bromination of a Z-Enamide
hindered cyclization through intermediate D. Support for this
model arises from the halo-etherification in which the minor
isomer 14-Br′ [Figure 1] was enriched relative to the reaction
leading to 7-Br/7-Br′. The only difference is the presence
of the OBz group [see the box]. This is in fact consistent
with related cation intermediates where an OR substituent
would prefer the axial position.24,25 This preference can only
be accommodated in intermediate D [not shown but the OBz
group would be equatorial in intermediate C en route to 14-
Br].
In addition, the observations that NXS did not work and
I2 was sluggish suggest that an effective desilylative cycliza-
tion through intermediate C likely depends upon not solely
the nucleophilicity of the halide anion [versus succinimido
anion: see Figure 3] since I- should be more nucleophilic
N-acyl iminium ion F. The isolation of 19-Cl-cis, arriving
from its respective E-enamide, implies that halonium cation
E is likely not important because isomerization of the C-C
bond [in blue] is required to give 19-Cl-cis. A more definitive
answer came when we brominated 6-Z3,15 and only obtained
trans-bromo pyrans 7-Br and 7-Br′ in 95% yield with a 1:2
ratio26 in favor of the latter isomer. We detected no
corresponding cis-products. The fact that the olefin geometry
is not preserved again supports a free rotation of the C-C
bond [in blue] occurring prior to the desilylative cyclization.
We have described here a stereoselective halo-etherifica-
tion of chiral enamides, leading to the synthesis of halogen-
ated cyclic ethers, which are prevalent among natural
products. While this work provides a stereoselective entry
to chiral secondary halides, these halo-etherifications also
provide mechanistic insight to the chemistry of chiral
enamides. Applications of this new synthetic method are
currently underway.
Acknowledgment.
Authors thank NIH-NIGMS
[GM066055], PRF-AC [42106], and UW-Madison for
financial support. The authors also thank Drs. Vic Young
and Maren Pink [University of Minnesota] for solving X-ray
structures.
Figure 3. Nucleophilicity and the nature of iminium ion pairs in
C.
Supporting Information Available: Experimental de-
tails, characterization data, X-ray structural analysis, and
NMR spectral for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
than Br- or Cl-. Thus, we believe the proximity of the anion,
or the “tightness” of the iminium ion pair, is also very
important. In this regard, as the TBSO group approaches the
iminium carbon, Br- or Cl- being a much tighter counter-
OL701768N
(26) This reversal in ratio is consistent with the mechanistic model in
which the same favored Si-face bromination of 6-Z would lead to an N-acyl
iminium intermediate that is slow to cyclize, whereas the hindered Re-face
bromination gives the respective N-acyl iminium intermediate that is more
favored for the desilylative cyclization.
(24) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168.
(25) Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett. 1998,
39, 1917.
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