Stereoselective synthesis of β-hydroxyallenes with multiple contiguous stereogenic centers via aldehyde addition to α-alkenyl-substituted zirconacyclopentenes

Article abstract of DOI:10.1021/jo900808k

(Chemical Equation Presented) A highly stereoselective methodology for the synthesis of β-hydroxyallenes with multiple stereogenic centers including allenic axial chirality, as well as center chirality, via addition of α-alkenylzirconacyclopentenes to ald

Full text of DOI:10.1021/jo900808k

pubs.acs.org/joc
Stereoselective Synthesis of β-Hydroxyallenes with Multiple Contiguous
Stereogenic Centers via Aldehyde Addition to r-Alkenyl-Substituted
Zirconacyclopentenes
Yebing Zhou, Jingjin Chen, Chunbin Zhao, Erjuan Wang, Yuanhong Liu,* and Yuxue Li*
State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
yhliu@mail.sioc.ac.cn
Received April 19, 2009
A highly stereoselective methodology for the synthesis of β-hydroxyallenes with multiple stereogenic
centers including allenic axial chirality, as well as center chirality, via addition of R-alkenylzircona-
cyclopentenes to aldehyde is described. Remarkably, the reaction occurs with completely different
chemoselectivity in comparison with the usual alkyl- or aryl-substituted zirconacyclopentenes; that
means, the C-C bond formation occurred selectively at the alkenylic carbon substituted with phenyl
or alkyl group, while in the latter cases, insertion of aldehydes into the alkyl-zirconium bond to
afford seven-membered oxazirconacycles has usually been observed.
Introduction
asymmetric synthesis by transferring their axial chirality to one
or several centered chiralities.3-5 Although a number of methods
for the stereoselective construction of allenes with two stereo-
genic centers have been reported,6 such as SN20 ring-opening
The development of a new reaction process for stereoselective
synthesis of complex molecules with multiple stereogenic cen-
ters in one flask occupies an important place in organic syn-
thesis.1,2 Allenes, especially functionalized allenes, are of current
interest since they serve as versatile synthetic intermediates for a
wide range of transformation reactions; they are also useful for
(3) (a) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M., Eds.;
John Wiley & Sons: New York, 1984. (b) Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(4) For reviews, see: (a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan,
F. A. Chem. Rev. 2000, 100, 3067. (b) Marshall, J. Chem. Rev. 2000, 100, 3163.
(c) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590.
(d) Bates, R.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12. (e) Ma, S. Acc.
Chem. Res. 2003, 36, 701. (f) Brandsma, L.; Nedolya, N. A. Synthesis 2004,
735. (g) Tius, M. A. Acc. Chem. Res. 2003, 36, 284. (h) Wei, L.-L.; Xiong, H.;
Hsung, R. P. Acc. Chem. Res. 2003, 36, 773. (i) Lu, X.; Zhang, C.; Xu, Z. Acc.
Chem. Res. 2001, 34, 535. (j) Wang, K. K. Chem. Rev. 1996, 96, 207. (k) Ma, S.
Chem. Rev. 2005, 105, 2829.(l) Ma, S. In Topics in Organometallic Chemistry;
Tsuji, J., Ed.; Springer-Verlag: Heidelberg, Germany, 2005; pp 183-210.
(5) Representative application of chiral allene intermediates in natural
product synthesis: (a) Shepard, M. S.; Carreira, E. M. J. Am. Chem. Soc.
1997, 119, 2597. (b) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
7885. (c) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am.
Chem. Soc. 1999, 121, 3633. (d) Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999,
121, 10012. (e) VanBrunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705.
(f) Brummond, K. M.; Lu, J.; Petersen, J. J. Am. Chem. Soc. 2000, 122, 4915.
*To whom correspondence should be addressed. Fax: (þ86) 021-
64166128.
(1) (a) Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, UK, 1991; Vol. 5. (b) Ho, T. -L. Tandem Organic
Reactions; Wiley: New York, 1992. (c) Atta-ur-Rahman; Shah, Z. Stereo-
selective Synthesis in Organic Chemistry; Springer-Verlag: New York, 1993.
(d) Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jørgensen,
K. A., Eds.; Wiley-VCH: New York, 2000. (e) Bunce, R. A. Tetrahedron 1995,
51, 13103. (f) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(2) For selected papers, see: (a) Juhl, K.; Jørgensen, K. A. Angew. Chem.
2003, 115, 1536. Angew. Chem., Int. Ed. 2003, 42, 1498. (b) Halland, N.;
Aburel, P. S.; Jørgensen, K. A. Angew. Chem. 2004, 116, 1292. Angew.
Chem., Int. Ed. 2004, 43, 1272. (c) Cauble, D. F.; Gipson, J. D.; Krische, M. J.
J. Am. Chem. Soc. 2003, 125, 1110. (d) Mitsui, K.; Sato, T.; Urabe, H.; Sato,
F. Angew. Chem. 2004, 116, 496; Angew. Chem., Int. Ed. 2004 43, 490.
(e) Enders, D.; Moster, M.; Geibel, G.; Laufer, M. C. Synthesis 2004, 12,
€
(6) For reviews, see: (a) Krause, N.; Hoffmann-Roder, A.; Canisius, J.
Synthesis 2002, 1759.(b) Krause, N.; Hoffmann-Roder, A. Tetrahedron
€
ꢀ
2040. (f) Innis, L. V.; Plancher, J. M.; Marko, I. E. Org. Lett. 2006, 8, 6111.
2004, 60, 11671. See also: (c) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993,
58, 7180. (d) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetrahedron
1991, 47, 1677. (e) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470.
(g) Donohoe, T. J.; Churchill, G. H.; Wheelhouse, K. M. P.; Glossop, P. A.
Angew. Chem., Int. Ed. 2006, 45, 8025. (h) Babu, S. A.; Yasuda, M.; Okabe,
Y.; Shibata, I.; Baba, A. Org. Lett. 2006, 8, 3029.
€
(f) Kazmaier, U.; Gorbitz, C. H. Synthesis 1996, 1489.
5326 J. Org. Chem. 2009, 74, 5326–5330
Published on Web 07/02/2009
DOI: 10.1021/jo900808k
2009 American Chemical Society
r

Zhou et al.
JOCArticle
SCHEME 1
of propargylic epoxide with organocuprate or Grignard rea-
gent,6c,6d or copper-catalyzed additions of organometallic nu-
cleophiles to β-lactones,6e those for three or more than three are
quite rare. One of the elegant syntheses of such compounds is
that reported by Sato et al.;7 they have described a stereoselective
addition of unsaturated compounds including aldehydes or
imines to an enyne-titanium alkoxide complex, which created
up to three new stereodefined carbon centers. However, accord-
ing to their report, the addition of aldehyde to a three-membered
titanacyclopropene usually gave rise to a mixture of two isomeric
alcohols.7 In this paper, we report a direct insertion of aldehyde
to R-alkenyl-substituted zirconacyclopentenes, which provides a
new and convenient procedure for the concise construction of
multisubstituted β-hydroxyallenes with high levels of stereocon-
trol. It turned out that one of the diastereomers with high purity
out of the four possibilities arising from two contiguous stereo-
genic centers and an adjacent allenic axial chirality could be
obtained after chromatography.
or ketones10 and our continued interest in metallacycles11
prompted us to explore the new synthetic potential of
R-functionalized zirconacycles toward carbon electrophiles.
Here we found that treatment of conjugated (E)-enyne non-
1-en-3-ynyl-benzene 1a with a zirconocene-ethylene com-
plex in THF at room temperature selectively generated
R-alkenylzirconacyclopentene 2a with only trace amounts
of its regioisomer of R-alkylzirconacycle 3a according to
crude NMR (Scheme 1), which afforded the stereodefined
diene product of (1E,3Z-4-ethylnona-1,3-dienyl)benzene 4a
in 80% yield after hydrolysis. The interaction of the alkenyl
moiety in the R-position with the zirconium center may
contribute to the high regioselectivity. It was also found that
addition of 1 equiv of p-chlorobenzaldehyde to zirconacycle
2a at room temperature for 5 h furnished β-hydroxyallene 5a
smoothly in 63% yield after hydrolysis. To our surprise, the
C-C bond formation occurred selectively at the alkenylic
carbon substituted with a phenyl group. The chemoselec-
tivity in this case is in marked contrast to that observed
with alkyl- or aryl-substituted zirconacyclopentenes, since
insertion of aldehydes into the alkyl-zirconium bond to
afford seven-membered oxazirconacycles has usually been
observed.12 The behavior of R-alkenylzirconacycle 2 toward
aldehyde addition is similar to that of R-alkynyl-substituted
zirconacyclopentenes as we reported recently,10 in which the
alkynylic moiety reacted preferentially to a Zr-C(sp3) bond.
The product 5a has two contiguous stereogenic centers and
an adjacent allenic axial chirality. It is interesting to note that
only one diastereomerically pure allene 5a out of the four
possible diastereoisomers was isolated. Careful analysis of
Results and Discussion
It is known that the coupling of an alkyl-substituted
conjugated enyne such as 3-ethyl-oct-3-en-5-yne with a
zirconocene-ethylene complex8 affords five-membered zir-
conacyclopentene with high regioselectivity, which means
that the alkenyl substituent is located on the R-position of a
zirconacycle.9 However, the synthetic utilities of these zirco-
nacycles have not been pursued. Our recent success in the
highly stereoselective synthesis of cis-[3]cumulenols via zir-
conium-mediated coupling of 1,3-butadiynes with aldehydes
1
the crude reaction mixture through H NMR spectra re-
vealed that there exists a small amount of another diaster-
eoisomer, the ratio of 5a with this diastereomer being 93:7.
This result indicated a high degree of stereoselectivity was
achieved in this reaction. To make clear the relative stereo-
chemistry of 5a, we proceeded to make the crystals of the
(7) Hamada, T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2000,
122, 7138.
(8) For the formationof thezirconocene-ethylene complex, see: (a) Binger,
€
€
P.; Muller, P.; Rufinsker, A.; Gabor, B.; Kruger, C.; Betz, P. Chem. Ber. 1989,
122, 1035. (b) Takahashi, T.; Murakami, M.; Kunishige, M.; Saburi, M.;
Uchida, Y.; Kozawa, K.; Uchida, T.; Swanson, D. R.; Negishi, E. Chem. Lett.
1989, 761. (c) Takahashi, T.; Suzuki, N.; Kageyama, M.; Nitto, Y.; Saburi, M.;
Negishi, E. Chem. Lett. 1991, 1579. For the formation of zirconacyclopentenes,
see: (d) Suzuki, N.; Kondakov, D. Y.; Kageyama, M.; Kotora, M.; Hara, R.;
Takahashi, T. Tetrahedron 1995, 51, 4519. (e) Xi, Z.; Hara, R.; Takahashi, T. J.
Org. Chem. 1995, 60, 4444. (f) Takahashi, T.; Xi, Z.; Kotora, M.; Xi, C.;
Nakajima, K. Tetrahedron Lett. 1996, 37, 7521. (g) Takahashi, T.; Xi, Z.;
Fischer, R.; Huo, S.; Xi, C.; Nakajima, K. J. Am. Chem. Soc. 1997, 119, 4561.
(h) Xi, Z.; Fischer, R.; Hara, R.; Sun, W.; Obora, Y.; Suzuki, N.; Nakajima, K.;
Takahashi, T. J. Am. Chem. Soc. 1997, 119, 12842. (i) Xi, Z.; Guo, R.; Mito, S.;
Yao, H.; Kanno, K.; Nakajima, K.; Takahashi, T. J. Org. Chem. 2003, 68, 1252.
(j) Takahashi, T.; Li, Y.; Tsai, F.; Nakajima, K. Organometallics 2001, 20, 595.
(k) Hara, R.; Ura, Y.; Huo, S.; Kasai, K.; Suzuki, N.;Takahashi, T. Inorg. Chim.
Acta 2000, 300-302, 741. (l) Takahashi, T.; Tsai, F.; Li, Y.; Wang, H.; Kondo,
Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
5059.
(10) Liu, Y.; Gao, H.; Zhou, S. Angew. Chem., Int. Ed. 2006, 45, 4163.
(11) (a) Song, Z.; Li, Y.; Liu, M.; Cong, L.; Liu, Y. Organometallics 2006,
25, 5035. (b) Liu, Y.; Gao, H. Org. Lett. 2006, 8, 309. (c) Liu, Y.; Yan, B.
Organometallics 2006, 25, 544. (d) Liu, Y.; Liu, M.; Song, Z. J. Am. Chem.
Soc. 2005, 127, 3662. (e) Zhou, S.; Yan, B.; Liu, Y. J. Org. Chem. 2005, 70,
4006. (f) Liu, Y.; Song, F.; Cong, L. J. Org. Chem. 2005, 70, 6999. (g) Zhou,
S.; Liu, D.; Liu, Y. Organometallics 2004, 23, 5900.
(12) For the reaction of zirconacyclopentenes with aldehydes, see: (a)
Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi, E. Tetra-
ꢀ
hedron Lett. 1993, 34, 687. (b) Coperet, C.; Negishi, E.; Xi, Z.; Takahashi, T.
Tetrahedron Lett. 1994, 35, 695. (c) Negishi, E.; Choueiry, D.; Nguyen, T. B.;
Swanson, D. R. J. Am. Chem. Soc. 1994, 116, 9751. (d) Buchwald, S. L.;
Nielsen, R. B. Chem. Rev. 1988, 88, 1047. (e) Zhao, C.; Yu, T.; Xi, Z. Chem.
Commun. 2002, 142. (f) Zhao, C.; Yan, J.; Xi, Z. J. Org. Chem. 2003, 68, 4355.
(g) Zhao, C.; Lu, J.; Yan, J.; Xi, Z. Tetrahedron Lett. 2003, 44, 6895.
(9) Takahashi, T.; Xi, Z.; Nishihara, Y.; Huo, S.; Kasai, K.; Aoyagi, K.;
Denisov, V.; Negishi, E. Tetrahedron 1997, 53, 9123.
J. Org. Chem. Vol. 74, No. 15, 2009 5327

Zhou et al.
JOCArticle
TABLE 1. Stereoselective Formation of β-Hydroxyallenes with Mul-
tiple Stereogenic Centers
SCHEME 2
SCHEME 3
SCHEME 4
compared with that of (E)-enyne (Scheme 2). The configura-
tion of the major isomer was assigned to be (1R*,2R*,R*a)-5a
according to X-ray crystallographic analysis.13 The minor
isomer was found to be identical with (1R*,2S*,R*a)-5a as
indicated by NMR analyses.
aYield of the isolated pure major isomer after chromatographic
separation on silica gel. The diastereomeric ratio of two isomers deter-
mined by the 1H NMR of the crude reaction mixture is shown in
parentheses. All the reactions were carried out at room temperature
for 3-6 h. bContaining two diastereomers, the ratio is 98:2. cContaining
two diastereomers, the ratio is ca. 95:5.
Oxidation of (1R*,2S*,R*a)-5a by DMP followed by
reduction using NaBH4 afforded the two diastereoisomers
of 5a in 25% and 58% yields, respectively (Scheme 3, eq 1).
The assignment of the relative stereochemistry of (1S*,2S*,
R*a)-5a is based on X-ray crystallographlic study.13 This
result indicated that the isomers were formed only at the
alcoholic stereogenic carbon during the reaction. The same
reaction starting from (1R*,2R*,R*a)-5a afforded a mixture
of (1R*,2R*,R*a)-5a and (1S*,2R*,R*a)-5a (Scheme 3, eq 2).
Thus, all of the four diastereoisomers of 5a could be
obtained, which enabled us to understand the diastereos-
electivity of the addition reaction well. By comparison of the
1H and 13C NMR of a crude sample shown in Scheme 1 and
the isolated diastereomers, the minor diastereoisomer
formed in the reaction mixture of p-chlorobenzaldehyde
was assigned to be (1S*,2S*,R*a)-5a.
The present allene-formation procedure has proved to be
applicable to substituted enynes with various aldehydes,
both aromatic and aliphatic, as shown in Table 1. First, we
examined the electronic effect of substitution on the alde-
hyde aromatic ring. Virtually no significant differences in the
reaction yields have been observed with electron-withdraw-
ing or electron-donating substituents on the aromatic
ring. The corresponding β-hydroxyallenes were obtained in
resulting β-hydroxyallenes or its derivatives. However, most
of the products were isolated as oily compounds. After much
effort, we were delighted to find that an allene product 5b,
derived from the reaction of zirconacyclopentene 2b with
3,4,5-trimethoxybenzaldehyde (Table 1, entry 2), formed a
good quality of crystals which were suitable for X-ray
analysis.13 X-ray crystallography of these crystals unam-
biguously verified the stereochemistry of β-hydroxyallene
5. The configuration of 5b was assigned as (1R*,2S*,R*a)-5b.
Thus the same (1R*,2S*,R*a)-configuration of 5a was de-
duced from the result of 5b.
Similarly, additionofzirconacyclepreparedfrom(Z)-enyne
14 to p-chlorobenzaldehyde proceeded to afford a mixture of
two diastereoisomers with a lower stereoselectivity (5.5:1)
6
(13) The X-ray crystal structures of (1S,2R,Sa)-5b, (1R,2R,Ra)-5a and
(1R,2R,Sa)-5a are shown in the Supporting Information. Note: The X-ray
structure of (1S,2R,Sa)-5b and (1R,2R,Sa)-5a has the ent-configuration of the
assigned configuration of (1R*,2S*,R*a)-5b and (1S*,2S*,R*a)-5a.
(14) Hydrolysis of the reaction mixture of the zirconocene-ethylene
complex with (Z)-enyne 6 afforded a mixture of several alkene isomers that
could not be separated. The mechanism of this hydrolysis experiment was not
clear yet.
5328 J. Org. Chem. Vol. 74, No. 15, 2009

Zhou et al.
JOCArticle
FIGURE 1. The optimized transition structures with selected bond lengths (in angstroms). Their relative Gibbs free energies are in kcal/mol.
Calculated at the B3LYP/6-311þG**/Lanl2DZ level.
SCHEME 5
58-72% yields as a single isomer after separation in most
cases (Table 1, entries 1-6). The functionalities of -Cl,
-NMe2, and -NO2 groups on the phenyl ring were well
tolerated during the reaction, affording the corresponding
products 5a, 5d, and 5f in good yields (63-72%, entries 1, 4,
and 6). However, p-nitrobenzaldehyde afforded lower selec-
tivities (entries 6 and 10). Heteroaryl aldehydes such as
2-thienyl aldehyde could be incorporated successfully into
the sequence, the corresponding allene being obtained
in 53% yield (entry 7). When a bulky substrate such as
1-naphthaldehyde was used, the reaction proceeded to af-
ford 5i in a yield of 65% (entry 9). Interestingly, the use of
4-(phenylethynyl)phenyl aldehyde afforded 5k in 65% yield,
in which the alkyne moiety remained intact (entry 11).
Bisalkyl-substituted enyne also proceeded smoothly to af-
ford product 5l in 63% yield (entry 12). When a ketone such
as acetophenone was used instead of aldehydes, only a slight
reaction occurred. It should be noted that when zirconacycle
2e9 derived from trisubstituted enyne (Z)-4-ethyldec-4-en-6-
yne was used for the reaction, the allene 5m was isolated as
a single isomer in 54% yield (containing small amount of
byproducts), the stereochemistry has not been defined yet
(Scheme 4).
mechanism, the reaction mixture of 2a with p-chlorobenzal-
dehyde was investigated by NMR experiment. The NMR
study of the resulting mixture indicated the formation
of a major diastereomer of 8a (R1=C5H11, R2=Ph, R3=
p-ClC6H4) in 77% NMR yield (Scheme 5), and its structure is
in good agreement with the proposed oxazirconacycle 8. The
1H NMR of 8a in C6D6/THF solution shows two singlets at
5.87 and 5.92 ppm, and its 13C NMR spectrum reveals two
singlets at 110.7 and 110.8 ppm, which are assigned to Cp
ligands. The low-field signal (204.3 ppm) is characteristic for
sp carbon in the allene skeleton.
To understand the stereoselectivity of this reaction
(Scheme 1), density functional theory (DFT) studies have
been performed with the Gaussian03 program16 by using the
B3LYP17 method. For C, H, and O, the 6-311þG** basis set
was used; for Zr, the Lanl2DZ basis set with Effective Core
Potential (ECP)18 was used. Harmonic vibration frequency
calculation was carried out and the optimized structures
are all shown to be transition states with one imaginary
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Frisch, M. J.; Nakai, H.; Klene, M.; Li, X.; Knox,
J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannengerg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision D.01;
Gaussian, Inc., Wallingford, CT, 2004.
On the basis of the above observations, a possible reaction
mechanism is proposed in Scheme 5. In the first step, the
aldehyde approaches the Zr center by coordination of its
carbonyl oxygen with the metal. This is followed by a SE20-
type15 reaction at the allylzirconium moiety via a six-mem-
bered transition state 7, yielding a nine-membered oxazir-
concycle 8 with a cyclic allenic structure. Hydrolysis of 8
affords the desired β-hydroxyallene 5. To understand the
(15) (a) Marshall, J. A.; Liu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63,
817. (b) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996, 31, 105. (c) Urabe,
H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc. 1997, 119, 11295.
(17) (a) Becke, A. D. Phys. Rev. 1988, A38, 3098. (b) Becke, A. D. J.
Chem. Phys. 1993, 98, 5648. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev.
1988, B37, 785.
€
(d) Hoppe, D.; Kramer, T. Angew. Chem., Int. Ed. Engl. 1986, 25, 160.
(18) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
J. Org. Chem. Vol. 74, No. 15, 2009 5329

Zhou et al.
JOCArticle
frequency. In the calculation models, R1=Me, R2 and R3=
Ph. The results are shown in Figure 1.
and extracted with ethyl acetate. The extract was washed with
water and brine and dried over Na2SO4. The solvent was
evaporated in vacuo and the residue was purified by chroma-
tography on silica gel (petroleum ether). Diene 4a was formed in
80% (91 mg) isolated yield as a colorless oil. (1E,3Z-4-Ethyl-
The results show that the configuarion of the favorable
transition states of E-enyne product (Ts-(1R*,2S*,R*a)) is
consistent with that of the experimental products. In this
transition state, the 4C-O-Zr six-membered ring is in a
stable chair conformation, whereas in Ts-(1S*,2S*,R*a) the
4C-O-Zr six-membered ring is in an unstable boat con-
formation. The relative stabilities of Ts-(1R*,2S*,R*a) and
Ts-(1S*,2S*,R*a) may be understood this way: if the position
of the phenyl group and the hydrogen atom of the aldehyde
are exchanged in Ts-(1R*,2S*,R*a), we get Ts-(1S*,2S*,
R*a). Obviously, if the 4C-O-Zr six-memberd ring still
keeps its chair conformation, the phenyl group of the alde-
hyde will eclipse with the Cp ring. Therefore the 4C-O-Zr
six-membered ring must be deformed to avoid this large
steric effect. Therefore, the stereoselectivity of this reaction
originates mainly from the steric effect of the phenyl group of
the aldehyde and the Cp ring. However, the stereochemical
course for (Z)-enyne 6 is unclear at this time.
1
nona-1,3-dienyl)benzene (4a): H NMR (CDCl3, Me4Si) δ 0.91
(t, J=6.9 Hz, 3H), 1.07 (t, J=7.8 Hz, 3H), 1.26-1.50 (m, 6H),
2.14 (q, J=7.5 Hz, 2H), 2.26 (t, J=7.5 Hz, 2H), 6.01 (d, J=10.8
Hz, 1H), 6.46 (d, J=15.3 Hz, 1H), 7.04 (dd, J=15.3, 10.8 Hz,
1H), 7.15-7.20 (m, 1H), 7.29 (t, J=7.5 Hz, 2H), 7.38-7.40 (m,
2H); 13C NMR (CDCl3, Me4Si) δ 12.7, 14.1, 22.6, 28.6, 30.1,
31.0, 31.9, 123.8, 125.5, 126.0, 126.8, 128.5, 129.9, 138.1, 146.6;
HRMS (EI) calcd for C17H24 228.1878, found 228.1877.
A General Procedure for the Stereoselective Construction of
β-Hydroxyallenes via the Reaction of r-Alkenylzirconacyclopen-
tenes with Aldehydes. To a solution of Cp2ZrCl2 (0.183 g, 0.625
mmol) in THF (5 mL) was added EtMgBr (1.0 M THF solution,
1.25 mmol) at ca. -50 °C. After the mixture was stirred for 1 h at
the same temperature, (E)-enyne (0.5 mmol) was added and the
reaction mixture was warmed to room temperature and stirred
for 2 h. Aldehyde (0.5 mmol) was added and the mixture was
stirred at room temperature for 3-6 h. The reaction mixture was
then quenched with 3 N HCl and extracted with ethyl acetate.
In the case of the reaction with 4-(dimethylamino)benzalde-
hyde, the reaction mixture was quenched with water. The extract
was washed with water and brine and dried over Na2SO4. The
solvent was evaporated in vacuo and the residue was purified by
chromatography on silica gel to afford β-hydroxyallene deriva-
tive 5. (1R*,2S*,R*a)-1-(4-Chlorophenyl)-5-ethyl-2-phenyl-deca-
3,4-dien-1-ol (5a): Purification by flash chromatography on
silica gel (eluent: petroleum ether:EtOAc:Et3N = 91:8:1) af-
forded the title compound in 63% isolated yield. 1H NMR
(CDCl3, Me4Si) δ 0.80 (t, J=6.9 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H),
1.20-1.31 (m, 6H), 1.89-1.97 (m, 4H), 2.74 (s, 1H), 3.46 (t, J=
7.8 Hz, 1H), 4.79 (d, J=8.1 Hz, 1H), 5.45-5.50 (m, 1H), 7.02-
7.21 (m, 9H); 13C NMR (CDCl3, Me4Si) δ 12.3, 13.9, 22.4, 25.6,
27.2, 31.5, 32.5, 55.7, 77.0, 92.2, 108.2, 126.6, 127.8, 127.9, 128.2,
128.3, 132.7, 140.3, 140.8, 201.3; HRMS (EI) calcd for
C24H29OCl 368.1907, found 368.1893.
Conclusion
In summary, we have developed an efficient zirconium-
mediated stereoselective formation of allenes with multiple
stereogenic centers under mild reaction conditions. Remark-
ably, the addition of R-alkenylzirconacyclopentenes to alde-
hydes occurred with complete chemoselectivity, in which the
allylzirconium moiety reacted preferentially to a Zr-C(sp3)
bond. The resulting β-hydroxyallenes are well suited for
further manipulation, as demonstrated recently19 by the
diastereoselective formation of pyrans via gold-catalyzed
cycloisomerizations.
Experimental Section
Formation of the Diene 4a from the Reaction of the Zircono-
cene-Ethylene Complex with (E)-Enyne 1a. To a solution of
Cp2ZrCl2 (0.183 g, 0.625 mmol) in THF (5 mL) was added
EtMgBr (1.0 M THF solution, 1.25 mmol) at ca. -50 °C. After
the mixture was stirred for 1 h at the same temperature, (E)-non-
1-en-3-ynylbenzene (0.099 g, 0.5 mmol) was added and the
reaction mixture was warmed to room temperature and stirred
for 2 h. The reaction mixture was then quenched with 3 N HCl
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20672133, 20702059, and
20732008), the Chinese Academy of Science, the Science and
Technology Commission of Shanghai Municipality, and the
Major State Basic Research Development Program (Grant
No. 2006CB806105) for financial support.
(19) (a) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485. For the
cyclizations of β-hydroxyallenes with Pd, Ag, or Ru, see: (b) Oh, C. H.;
Hyun, S.; Bang, S. Y.; Park, D. I. Org. Lett. 2002, 4, 3325. (c) Ma, S.; Gao, W.
J. Org. Chem. 2002, 67, 6104. (d) Sherry, B. D.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 15978. (e) Yoneda, E.; Zhang, S.-W.; Zhou, D.-J.; Onitsuka,
K.; Takahashi, S. J. Org. Chem. 2003, 68, 8571.
Supporting Information Available: General methods and
spectroscopic characterization of all new compounds and CIF
files giving crystallographic data of compounds (1S,2R,Sa)-5b,
(1R,2R,Ra)-5a, and (1R,2R,Sa)-5a. This material is available
free of charge via the Internet at http://pubs.acs.org.
5330 J. Org. Chem. Vol. 74, No. 15, 2009