3,3′-anisyl-substituted BINOL, H4BINOL, and H 8BINOL ligands: Asymmetric synthesis of diverse propargylic alcohols and their ring-closing metathesis to chiral cycloalkenes

Article abstract of DOI:10.1021/jo9018446

(Chemical Equation Presented) A series of optically active BINOL, H ₄BINOL, and H₈BINOL derivatives were prepared. These compounds in combination with ZnEt₂ and Ti(OⁱPr) ₄ were used to catalyze the asymmetric reaction of alkynes with aldehydes to generate chiral propargylic alcohols at room temperature. Through this comparative study, a 3,3′-bisanisyl-substituted H₈BINOL (S)-7 was found to be a generally enantioselective catalyst for the reaction of structurally diverse terminal alkynes with a variety of aldehydes. It catalyzed the reactions of alkyl propiolates with 88-99% ee; the reactions of phenylacetylene with 81-87% ee; the reactions of 4-phenyl-1-butyne, an alkyl alkyne, with 77-89% ee; and the reactions of trimethylsilylacetylene with 92-97% ee. The optically active propargylic alcohols generated from this catalytic asymmetric alkyne addition were observed to undergo efficient ring-closing-metathesis (RCM) reaction in the presence of the Grubbs II catalyst to produce chiral cycloalkenes. It was further found that some of the chiral propargylic alcohols underwent a highly chemoselective tandem RCM hydrogenation reaction with retention of the enantiomeric purity. 2009 American Chemical Society.

Full text of DOI:10.1021/jo9018446

pubs.acs.org/joc
3,30-Anisyl-Substituted BINOL, H4BINOL, and H8BINOL Ligands:
Asymmetric Synthesis of Diverse Propargylic Alcohols and Their
Ring-Closing Metathesis to Chiral Cycloalkenes
Yang Yue,†,‡ Mark Turlington,† Xiao-Qi Yu,*,‡ and Lin Pu*,†
†Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, and ‡Department of
Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education),
Sichuan University, Chengdu, China 610064
lp6n@virginia.edu
Received August 28, 2009
A series of optically active BINOL, H4BINOL, and H8BINOL derivatives were prepared. These
compounds in combination with ZnEt2 and Ti(OiPr)4 were used to catalyze the asymmetric reaction
of alkynes with aldehydes to generate chiral propargylic alcohols at room temperature. Through this
comparative study, a 3,30-bisanisyl-substituted H8BINOL (S)-7 was found to be a generally
enantioselective catalyst for the reaction of structurally diverse terminal alkynes with a variety of
aldehydes. It catalyzed the reactions of alkyl propiolates with 88-99% ee; the reactions of
phenylacetylene with 81-87% ee; the reactions of 4-phenyl-1-butyne, an alkyl alkyne, with
77-89% ee; and the reactions of trimethylsilylacetylene with 92-97% ee. The optically active
propargylic alcohols generated from this catalytic asymmetric alkyne addition were observed to
undergo efficient ring-closing-metathesis (RCM) reaction in the presence of the Grubbs II catalyst to
produce chiral cycloalkenes. It was further found that some of the chiral propargylic alcohols
underwent a highly chemoselective tandem RCM hydrogenation reaction with retention of the
enantiomeric purity.
Introduction
the partially hydrogenated BINOLs including the derivatives
of H4BINOL (1)2 and H8BINOL (2)3 have also been studied.
The partially hydrogenated naphthalene rings in H4BINOL
and H8BINOL contain sp3 hybridized carbons that can
1,10-Bi-2-naphthol (BINOL) and its substituted deriva-
tives have found extensive applications in the development of
chiral catalysts for asymmetric synthesis.1 In recent years,
(1) For reviews on using BINOL-based compounds in asymmetric cata-
lysis, see: (a) Chen, Y.; Yekta, S.; Yudin, A. Chem. Rev. 2003, 103, 3155–
3211. (b) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. Rev. 2003, 103,
3213–3245. (c) Brunel, J. M. Chem. Rev. 2005, 105, 857–897. (d) Shibasaki,
M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269–279. (e) Pu, L. Chem. Rev.
1998, 98, 2405–2494.
(2) (a) Shen, X.; Guo, H.; Ding, K. Tetrahedron: Asymmetry 2000, 11,
4321–4327. (b) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc.
2002, 124, 10–11. (c) Lu, Y.-N.; Guo, Q.-S.; Jiang, F.-Y.; Li, J.-S. Tetra-
hedron: Asymmetry 2006, 17, 1842–1845. (d) Heumann, L. V.; Keck, G. E.
J. Org. Chem. 2008, 73, 4725–4727.
(3) (a) A review: Au-Yeung, T. L.-L.; Chan, S.-S.; Chan, A. S. C. Adv.
Synth. Catal. 2003, 345, 537–555. (b) Matsunaga, S.; Kinoshita, T.; Okada,
S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559–7570.
(c) Kumaraswamy, G.;Jena, N.;Sastry, M.N. V.;Padmaja, M.;Markondaiah,
B. Adv. Synth. Catal. 2005, 347, 867–871. (d) Huang, H.; Liu, X.; Chen, H.;
Zheng, Z. Tetrahedron: Asymmetry 2005, 16, 693–697. (e) Kim, J. G.; Camp, E.
H.; Walsh, P. J. Org. Lett. 2006, 8, 4413–4416. (f) Wu, K.-H.; Gau, H.-M.
J. Am. Chem. Soc. 2006, 128, 14808–14809. (g) Muramatsu, Y.; Harada, T.
Chem.;Eur. J. 2008, 14, 10560–10563. (h) Jiang, J.; Yu, J.; Sun, X.-X.; Rao,
Q.-Q.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47, 2458–2462. (i) Zhou, S.;
Wu, K.-H.; Chen, C.-A.; Gau, H.-M. J. Org. Chem. 2009, 74, 3500–3505.
DOI: 10.1021/jo9018446
r
Published on Web 10/27/2009
J. Org. Chem. 2009, 74, 8681–8689 8681
2009 American Chemical Society

Yue et al.
JOCArticle
SCHEME 1. Synthesis of the BINOL Derivative (S)-4
increase the steric bulkiness of these ligands and change the
biaryl dihedral angle. In a number of cases, these structurally
modified BINOLs have led to improved enantioselectivity in
asymmetric catalysis.
To further develop the asymmetric reaction of the struc-
turally diverse terminal alkynes with various aldehydes, we
have synthesized the H4BINOL and H8BINOL derivatives
of (R)-4 and compared their catalytic properties. Through
this study, a highly enantioselective catalyst that is generally
applicable for the asymmetric reaction of various alkynes
with aldehydes is discovered. We have also conducted the
ring-closing metathesis (RCM) and tandem RCM hydro-
genation of the chiral propargylic alcohol products gener-
ated from the asymmetric alkyne additions to synthesize a
number of functional chiral cycloalkenes. Herein, these
results are reported.7
Previously, we found that the 3,30-aryl ether-substituted
BINOL (R)-3 could catalyze the diethylzinc and diphenylzinc
additions to aldehydes with high enantioselectivity.4a,b The
3,30-aryl ether-substituted BINOLs were also used to catalyze
the asymmetric alkyne addition to aldehydes,4c,d,5 resulting in
the synthetically useful chiral propargylic alcohols.6 Although
(R)-3 was found to be a poor catalyst for the alkyne addition
to aldehydes, through a systematic variation of the 3,30-anisyl
groups, compound (R)-44c was obtained as a good catalyst for
the enantioselective phenylacetylene addition to aromatic
aldehydes in the presence of ZnEt2 and Ti(OiPr)4.
Results and Discussion
1. Synthesis of the Anisyl-Substituted BINOL, H4BINOL,
and H8BINOL Derivatives. Compound (S)-4 was synthe-
sized as shown in Scheme 1 by modifying the literature
procedure.4c (S)-BINOL was protected with two MOM
groups in 84% yield by reaction with dimethoxymethane in
the presence of P2O5. Upon ortho-metalation8 and treatment
with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
(S)-5 was obtained in 80% yield. The Suzuki coupling of
(S)-5 with 2-bromo-4-tert-butylanisole followed by treat-
ment with trifluoroacetic acid gave (S)-4 in 84% yield.
(S)-BINOL was partially hydrogenated to a mixture of
(S)-H4BINOL and (S)-H8BINOL by slightly modifying a
literature procedure.9 The isolated (S)-H4BINOL and (S)-
H8BINOL were used to prepare the corresponding 3,30-
bisanisyl-substituted derivatives, respectively. The synthesis
of the H4BINOL derivative (S)-6 parallels that of (S)-4
(Scheme 2). The yield for each step is also very close to that
in the preparation of the BINOL derivative.
(S)-H8BINOL exhibits different reactivity from (S)-BI-
NOL in the electrophilic aromatic substitution. When (S)-
BINOL was treated with bromine, the substitution occurred
first at the 6,60-positions and then at the 4,40-positions.10
(4) (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1998, 63, 1364–
1365. (b) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222–4223. (c) Moore,
D.; Huang, W.-S.; Pu, L. Tetrahedron Lett. 2002, 43, 8831–8834. (d) Xu,
M.-H.; Pu, L. Org. Lett. 2002, 4, 4555–4557.
(6) For reviews on the asymmetric alkyne addition to aldehydes, see: (a)
€
2000, 33, 373–381. (b) Pu, L. Tetrahedron 2003, 59, 9873–9886. (c) Cozzi, P.
G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095–4105. (d)
Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem. Rev. 2005, 249,
1736–1744.
(7) Part of this work has been communicated: Turlington, M.; DeBerardinis,
A. M.; Pu, L. Org. Lett. 2009, 11, 2441–2444.
(8) Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253–
2256.
Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res.
(5) Examples of other BINOL-based catalysts used in the asymmetric
alkyne addition to aldehydes: (a) Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C.
J. Am. Chem. Soc. 2002, 124, 12636–12637. (b) Gao, G.; Moore, D.; Xie,
R.-G.; Pu, L. Org. Lett. 2002, 4, 4143–4146. (c) Marshall, J. A.; Bourbeau,
M. P. Org. Lett. 2003, 5, 3197–3199. (d) Liu, Q.-Z.; Xie, N.-S.; Luo, Z.-B.;
Cui, X.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. J. Org. Chem. 2003,
68, 7921–7924. (e) Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.; Maruoka, K.
Org. Biomol. Chem. 2004, 2, 3312–3319. (f) Yang, F.; Xi, P.; Yang, L.; Lan, J.;
Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457–5460. (g) Zou, X.-W.; Zheng,
L.-F.; Wu, L.-L.; Zong, L.-L.; Cheng, Y.-X. Chin. J. Chem. 2008, 26, 373–378.
(9) Korostyleve, A.; Tararov, V. I.; Fischer, C.; Monsees, A.; Borner, A.
J. Org. Chem. 2004, 69, 3220–3221.
(10) Hu, Q.-S.; Pugh, V.; Sabat, M.; Pu, L. J. Org. Chem. 1999, 64, 7528–
7536.
8682 J. Org. Chem. Vol. 74, No. 22, 2009

Yue et al.
JOCArticle
SCHEME 2. Synthesis of the H4BINOL Derivative (S)-6
SCHEME 3. Synthesis of the H8BINOL Derivatives (S)-7 and (S)-8
SCHEME 4. Synthesis of the H4BINOL Derivative (S)-10
SCHEME 5. Reactions of Various Alkynes with Pentyl Aldehyde
Catalyzed by the BINOL, H4BINOL, and H8BINOL Derivatives
aldehyde, pentyl aldehyde, are compared (Scheme 5). The
results are summarized in Table 1. As shown in Table 1, the
H8BINOL derivative (S)-7 is generally more enantioselective
than the other chiral compounds except in the trimethylsilyl-
acetylene addition where the BINOL derivative (S)-4 is
slightly more enantioselective. The BINOL derivative (S)-4
and the H8BINOL derivative (S)-7 are both C2 symmetric
and they provide much greater enantioselectivity than the
C1 symmetric H4BINOL derivative (S)-6. The monoanisyl-
substituted H8BINOL (S)-8 also showed quite high enantio-
selectivity in the asymmetric alkyne additions, but the H4BI-
NOL derivative (S)-10 gave very low and opposite enantio-
selectivity. This indicates that the bromine atom in (S)-8 could
also contribute to the enantioselectivity. Compound (S)-10
has one less substituent adjacent to the central hydroxyl
groups than (S)-7 and (S)-8, leading to a dramatically differ-
ent stereocontrol in the catalysis. We also examined the use of
(S)-3,30-dibromoH8BINOL to catalyze the reaction of methyl
propiolate with pentyl aldehyde, but only a trace amount of
the product was generated. This demonstrates that the meth-
oxy group in (S)-7 and (S)-8 is important for the catalysis.
Because of the generally high enantioselectivity of the
C2 symmetric H8BINOL derivative (S)-7 as shown in Table 1,
we have explored the use of this compound to catalyze the
reaction of various alkynes with a few representative aliphatic
and aromatic aldehydes. As the results summarized in Table 2
show, (S)-7in combination with ZnEt2 and Ti(OiPr)4 catalyzed
The 3,30-positions of (S)-BINOL cannot be directly bromi-
nated and the ortho-metalation of its MOM-protected deri-
vative followed by treatment with bromine is needed.8
However, theortho-positions of (S)-H8BINOL canbe directly
brominated by the reaction with bromine to generate (S)-3,30-
dibromoH8BINOL in 92% yield (Scheme 3). This allows a
significantly more efficient synthesis of the H8BINOL deriva-
tive (S)-7 than (S)-4 and (S)-6. As shown in Scheme 3, the two-
step reaction from (S)-H8BINOL led to the formation of (S)-7
in overall yields of 86-94%.11 Different from the transforma-
tions in Schemes 1 and 2, no protection and deprotection steps
were needed for those in Scheme 3. This sequence also gave a
small amount of the monocoupling product (S)-8 (<10%).
When (S)-H4BINOL was treated with bromine directly, the
unsymmetric 3,60-dibromide (S)-9wasobtainedin91%yield.The
Suzuki coupling of (S)-9 with an anisyl boronate gave the 3,60-
bisanisyl-substituted H4BINOL (S)-10 in 89% yield (Scheme 4).
2. Asymmetric Alkyne Addition to Aldehydes Catalyzed by
the BINOL, H4BINOL, and H8BINOL Derivatives. The
catalytic properties of the BINOL, H4BINOL, and H8BINOL
derivatives for the asymmetric alkyne addition to an aliphatic
(11) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; Kockritz, A.;
Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008, 64, 1316–1322.
J. Org. Chem. Vol. 74, No. 22, 2009 8683

Yue et al.
JOCArticle
TABLE 1. Comparison of the BINOL, H4BINOL, and H8BINOL Derivatives in the Asymmetric Alkyne Addition to Pentyl Aldehyde
diverse alkyne additions to aldehydes at room temperature
with high enantioselectivity. These results demonstrate that
(S)-7 is generally useful for the asymmetric alkyne addition to
aldehydes. The absolute configuration of the propargylic
alcohol product generated in entry 7 is determined to be S by
comparing its optical rotation with the literature data.12 The
absolute configurations of all other propargylic alcohol pro-
ducts generated by (S)-7 were assigned by analogy.
3. Ring-Closing Metathesis of the Optically Active Propargylic
Alcohols. To demonstrate the utility of the chiral propargylic
alcohols, we have explored the ruthenium carbene-catalyzed
ring-closing metathesis reaction (RCM)13 of the optically active
enynes14 generated from the asymmetric alkyne additions
catalyzed by (S)-7. We found that the propargylic alcohols
need to be protected with an acyl group for the RCM reaction.15
The RCM of the propargylic alcohol 11, prepared from the
reaction of phenylacetylene with 5-hexenal in the presence of
(S)-7 (87% ee, entry 13 in Table 2) was first investigated. To
determine the enantiomeric purity of the RCM product with 1H
NMR spectroscopy, we have prepared (R)-(-)-acetylmandelic
ester 12 from 11 (Scheme 6). When 12 was treated with the
second generation Grubbs carbene catalyst (Grubbs II),16 it
underwent RCM reaction to generate the cyclohexene product
13 in 85% yield. The 1H NMR spectrum of 13 showed that this
compound had essentially the same enantiomeric purity (86%
ee) as the starting propargylic alcohol 11.
A few optically active propargylic alcohols were converted
to their acetates (Scheme 7). The RCM reactions of these
acetates in the presence of Grubbs II were conducted to
produce various chiral cycloalkene products. These results
are summarized in Table 3. Excellent yields were obtained for
the substrates derived from both aromatic and aliphatic
alkynes (entries 1-4). In entry 5, the substrate derived from
allyl propiolate led to the formation of a bicyclic diene
product.
4. Highly Chemoselective Tandem Ring-Closing Metathesis
and Hydrogenation of the γ-Hydroxy-r,β-acetylenic Esters.
The ruthenium complex used in the RCM reaction can be
converted to a hydrogenation catalyst in the presence of
hydrogen.17 This makes it possible to conduct a tandem
RCM and hydrogenation reaction. We have investigated the
(12) Johansson, M.; Kopcke, B.; Anke, H.; Sterner, O. Tetrahedron 2002,
58, 2523–2528.
(13) Selected reviews on the RCM reactions: (a) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18–29. (b) Hoveyda, A. H.; Zhugralin, A. R.
Nature 2007, 450, 243–251.
(14) Selected reviews on the enyne metathesis: (a) Diver, S. T.; Giessert,
A. J. Chem. Rev. 2004, 104, 1317–1382. (b) Villar, H.; Frings, M.; Bolm, C.
Chem. Soc. Rev. 2007, 36, 55–66.
(16) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.;
Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 2546–2558.
(15) A report on the RCM of propargylic acetates: Yoshida, K.;
Shishikura, Y.; Takahashi, H.; Imamoto, T. Org. Lett. 2008, 10, 2777–2780.
(17) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312–11313.
8684 J. Org. Chem. Vol. 74, No. 22, 2009

Yue et al.
JOCArticle
TABLE 2. Reactions of Various Alkynes with Aliphatic and Aromatic Aldehydes Catalyzed by (S)-7a
a(S)-7:ZnEt2:Ti(OiPr)4:alkyne:aldehyde = 0.2:2:0.5:2:1. THF was used as the solvent for the addition to the aliphatic aldehydes, and a THF/Et2O
(1:4) mixed solvent was used for the addition to the aromatic aldehydes. bThe ee values of the products of entries 5, 10, 13, 14, 15, 19, 20, and 28 were
determined by using the 1H NMR spectra of their esters prepared with (R)-PhCH(OAc)CO2H; that of entry 1 by HPLC-Chiralcel OD column (2%
isopropanol in hexane, 0.5 mL/min); those of entries 2, 6, 7, 11, and 12 by HPLC-Chiralcel OD column (2% isopropanol in hexane, 1.0 mL/min); those of
entries 3, 8, 18, 22, 23, 24, 27, and 29 by HPLC-OD column (10% isopropanol in hexane, 1.0 mL/min); those of entries 4, 9, 16, and 17 by HPLC-
Chiralpak AD-H column (1% isopropanol in hexane, 0.3 mL/min); and those of entries 21, 25, and 26 by HPLC-Chiralcel OD column (5% isopropanol
in hexane, 1.0 mL/min).
tandem RCM hydrogenation of the optically active propargylic
alcohols, particularly the γ-hydroxy-R,β-acetylenic esters.
First, the optically active (S)-γ-hydroxy-R,β-acetylenic
ester 14 (95% ee, entry 6 in Table 2) was converted to ester
15a (Scheme 8). This compound was then subjected to the
tandem RCM hydrogenation conditions. It was first treated
with the Grubbs II catalyst (5 mol %) in toluene at room
temperature for 1 h. Then, H2 (100 psi) was introduced and
J. Org. Chem. Vol. 74, No. 22, 2009 8685

Yue et al.
JOCArticle
SCHEME 6. RCM of the Mandelate of the Propargylic Alcohol 11
TABLE 3. Results for the RCM of the Acetates of Various Propargylic Alcohols
tiomeric purity of the product 16b was 94% for both diaster-
1
eomers by using H NMR spectroscopy. This demonstrates
SCHEME 7. RCM of the Acetates of Various Propargylic
Alcohols
that the tandem RCM hydrogenation maintains the enantio-
meric purity of the starting γ-hydroxy-R,β-acetylenic ester.
To determine the configuration of the newly formed
stereogenic center (R) after hydrogenation, compound 16a
was reduced to the diol 17 by using LiAlH4, which was then
converted to the Mosher’ esters 18 and 19, respectively
(Scheme 9). The 1H NMR signals of the two diastereotopic
protons Ha and Hb in compounds 18 and 19 are analyzed.
The chemical shift difference of Ha and Hb is Δδ. According
to that established previously by Kobayashi, the Δδ of the
compound whose configuration at R is the same as its
Mosher’s ester fragment should be greater than the one
whose configuration at R is different from its Mosher’s
ester.18 The chemical shifts of the Ha and Hb of 19 from
the major diastereomer of 16a are at δ = 4.250 (dd) and
4.192 (dd) (Δδ = 0.058), and those of 18 are at δ = 4.114 (dd)
and 4.078 (dd) (Δδ = 0.036). Since the Δδ of 19 is greater
than that of 18, the configuration at R could be assigned to S.
Thus, the major diastereomer of 16a could be assigned to
the mixture was heated at 75 °C. After 10 h, product 16a was
obtained in 88% yield from the propargylic alcohol. It was
found that hydrogenation occurred with high chemoselectiv-
ity, hydrogenating only the terminal alkene with the internal
alkene untouched. The product from the tandem RCM
hydrogenation contained two diastereomers with a 2:1 ratio.
To determine the enantiomeric purity of the tandem RCM
hydrogenation product with NMR spectroscopy, compound
14 was reacted with (R)-(-)-R-acetylmandelic acid to prepare
the chiral acetyl group protected 15b. The tandem RCM
hydrogenation of this compound was found to proceed with
the same chemoselectivity and diastereoselectivity as the Ac-
protected 15a. This implies that a bulkier chiral acyl group has
no influence on the RCM hydrogenation process. The enan-
(18) Tsuda, M.; Toriyabe, Y.; Endo, T.; Kobayashi, J. Chem. Pharm.
Bull. 2003, 51, 448–451.
8686 J. Org. Chem. Vol. 74, No. 22, 2009

Yue et al.
JOCArticle
SCHEME 8. The Tandem RCM Hydrogenation of γ-Hydroxy-R,β-acetylenic Esters
SCHEME 9. Synthesis of Compounds 18 and 19 for Configuration Assignment
TABLE 4. The Chemoselective Tandem RCM Hydrogenation of γ-Hydroxy-R,β-acetylenic Esters
have S and the minor diastereomer R configuration at the R
position.
tandem RCM hydrogenation, high diastereoselectivity was
observed (up to 16:1 as indicated by 1H NMR spectroscopy),
but the products could not be fully purified. For the pro-
pargylic alcohols prepared from the phenylacetylene addi-
tion to aldehydes, introduction of H2 to the RCM products
could not lead to hydrogenation.
Other optically active γ-hydroxy-R,β-acetylenic esters
were also subjected to the tandem RCM hydrogenation
and the results are summarized in Table 4. As shown in the
table, both chiral cyclopentene and cyclohexene products
were generated efficiently with high chemoselectivity. The
propargylic alcohols produced from ethyl propiolate showed
slightly higher diastereoselectivity than those from methyl
propiolate. When the propargylic alcohols obtained from the
aliphatic alkyne addition to aldehydes were examined for the
Summary
We have prepared 3- or 3,30-anisyl substituted optically
active BINOL, H4BINOL, and H8BINOL derivatives and
J. Org. Chem. Vol. 74, No. 22, 2009 8687

Yue et al.
JOCArticle
studied their use in the catalytic asymmetric reaction of
alkynes with aldehydes. It was found that the H8BINOL
derivative (S)-7 in combination with ZnEt2 and Ti(OiPr)4 is a
generally enantioselective catalyst for the reaction of struc-
turally diverse alkynes with a variety of aldehydes at room
temperature. The resulting optically active propargylic alco-
hols can undergo an efficient RCM reaction in the presence
of the Grubbs II catalyst to generate chiral functional
cycloalkenes. We have further found a highly chemoselective
tandem RCM hydrogenation reaction of some of the chiral
propargylic alcohols. These findings expand the application
of the chiral propargylic alcohols in the synthesis of chiral
functional organic compounds.
(S)-7 was dissolved in CH2Cl2 and stirred with 2 equiv of trifluor-
oacetic acid for 1 h to remove trace metal impurities. After
flash chromatography over silica gel, the product was dried by
dissolving in THF and pumping under vacuum.
Characterization of (S)-7: 98% ee determined by HPLC
analysis (Chiralcel OD column, 99:1 hexanes:iPrOH, flow rate =
0.3 mL/min, λ = 254 nm, retention time tmajor = 18.71 min and
tminor = 22.98 min). [R]D -7.01 (c 1.14, THF). 1H NMR
(75 MHz, CDCl3) δ 1.34 (s, 18H), 1.77 (br, 8H), 2.27-2.35
(m, 2H), 2.50-2.58 (m, 2H), 2.84 (br, 4H), 3.81 (s, 6H), 5.85
(s, 2H), 6.91 (d, 2H, J = 8.7 Hz), 7.05 (s, 2H), 7.35 (d, 2H, J =
8.4 Hz), 7.43 (d, 2H, J = 2.4 Hz). 13C NMR (300 MHz, CD-
Cl3) δ 23.2, 23.2, 27.2, 29.4, 31.5, 34.2, 56.0, 110.7, 124.0,
124.0, 125.4, 127.0, 129.4, 129.5, 131.3, 136.5, 144.2, 148.7,
153.5. HRMS (MHþ) for C42H51O4 calcd 619.3782, found
619.3792.
Experimental Section
Characterization of (S)-8: 99% ee determined by HPLC
analysis (Chiralcel OD column, 99:1 hexanes:iPrOH, flow rate =
0.3 mL/min, λ = 254 nm, retention time tmajor = 22.12 min and
Preparation and Characterization of (S)-3,30-Bis(5-tert-butyl-
2-methoxyphenyl)-5,6,7,8-tetrahydro-1,10-binaphthyl-2,20-diol, (S)-6.
Under nitrogen, 2-((10S)-2,20-bis(methoxymethoxy)-30-(4,4,5-tri-
methyl-1,3,2-dioxaborolan-2-yl)-50,60,70,80-tetrahydro-1,10-binaph-
thyl-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.15 g, 5 mmol),
2-bromo-4-tert-butyl-1-methoxybenzene (4.86 g, 20 mmol, 4 equiv),
and Pd(PPh3)4 (410 mg, 0.5 mmol, 10 mol %) were placed in a
2-necked flask equipped with a reflux condenser that was connected
with a vacuum adaptor. Degassed THF (50 mL) and 2 M K2CO3
(40 mL) were cannula-transferred into the flask. To ensure the
removal of oxygen, the reaction vessel was freeze-pumped at -78 °C
and refilled with nitrogen three times. The reaction mixture was then
heated at 95 °C for 24 h. After being cooled to room temperature,
the mixture was extracted with CH2Cl2 (3 ꢀ 40 mL). The combined
organic layers were washed with 2 M HCl (3 ꢀ 40 mL), dried, and
concentrated. The crude product was dissolved in CH2Cl2 (25 mL)
and trifluoroacetic acid (5 mL) was added. After the mixture was
stirred at room temperature for 10 h, it was concentrated and
purified by column chromatograph on silica gel eluted with 10%
EtOAc/hexanes to give (S)-6 as a white solid in 84% yield. An ee
value of 99% was determined by HPLC analysis (Chiralcel OD
column, 99:1 hexanes:iPrOH, flow rate = 0.3 mL/min, λ = 305 nm,
retention time tmajor = 24.37 min and tminor = 33.45 min). [R]D
-39.1 (c0.72, CHCl3)). 1H NMR (300 MHz, CDCl3) δ1.40 (s, 9H),
1.42 (s, 9H), 1.70-1.77 (m, 2H), 1.80-1.87 (m, 2H), 2.27-2.37 (m,
1H), 2.51-2.61 (m, 1H), 2.94 (t, 2H, J = 6.0 Hz), 3.85 (s, 3H), 3.86
(s, 3H), 5.88 (s, 1H), 6.04 (s, 1H), 6.97 (d, 1H, J = 8.4 Hz), 7.03 (d,
1H, J = 8.4 Hz), 7.21 (s, 1H), 7.38-7.45 (m, 3H), 7.46-7.52 (m,
3H), 7.57 (d, 1H, J = 2.4 Hz), 7.88-7.93 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 23.5, 27.4, 29.8, 31.9, 34.6, 55.4, 111.0, 111.2,
117.8, 122.3, 123.8, 124.8, 125.8, 126.0, 126.4, 126.6, 127.0, 127.1,
128.5, 129.2, 129.4, 129.9, 130.0, 130.2, 130.8, 132.3, 133.2. HRMS
(MHþ) for C42H47O4 calcd 615.3474, found 615.3474.
Preparation of (S)-3,30-Bis(5-tert-butyl-2-methoxyphenyl)-
5,50,6,60,7,70,8,80-octahydro-1,10-binaphthyl-2,20-diol, (S)-7. Under
nitrogen, (S)-3,30-dibromoH8BINOL (2.0 g, 4.4 mmol), 2-(5-tert-
butyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(3.85 g, 13.3 mmol, 3 equiv), and Pd(PPh3)4 (512 mg, 0.4 mmol,
10 mol %) were placed in a 2-necked flask equipped with a reflux
condenser that was connected with a vacuum adaptor. Degassed
dimethoxyethane (25 mL) and 2 M Na2CO3 (20 mL) were
cannula-transferred into the flask. To ensure the removal of
oxygen, the reaction vessel was freeze-pumped at -78 °C and
refilled with nitrogen three times. The reaction mixture was then
heated at 95 °C for 24 h. After being cooled to room temperature,
the mixture was extracted with CH2Cl2 (3 ꢀ 40 mL). The
combined organic layers were washed with 2 M HCl (3 ꢀ
40 mL), dried, and concentrated. The residue was purified
by column chromatography on silica gel eluted with 8% EtOAc/
hexanes to afford (S)-7 as a white solid in 94% yield (2.57 g).
A small amount of (S)-8was also obtained. Prior to use in catalysis,
t
minor = 18.65 min). [R]D -8.34 (c 1.01, CH2Cl2). 1H NMR (300
MHz, CDCl3) δ 1.36 (s, 9), 1.72-1.81 (m, 8H) 2.16-2.46 (m,
4H), 2.76-2.84 (m, 4H), 3.84 (s, 3H), 5.12 (s, 1H), 6.08 (s, 1H),
6.94 (d, 1H, J = 8.4 Hz), 7.10 (s, 1H), 7.27 (s, 1H), 7.37-7.40 (m,
2H). 13C NMR (75 MHz, CDCl3) δ 23.1, 23.2, 23.3, 23.3, 27.3,
27.3, 29.4, 29.6, 31.8, 34.5, 56.4, 106.8, 111.1, 122.3, 124.5, 125.0,
126.1, 126.6, 129.8, 130.4, 131.2, 132.3, 132.4, 136.7, 137.0,
144.9, 147.4, 149.2, 153.5. HRMS (MHþ) for C36H39O3Br calcd
535.1842, found 535.1840.
Preparation and Characterization of (S)-3-(5-tert-Butyl-2-
methoxyphenyl)-60-(2-tert-butyl-5-methoxyphenyl)-5,6,7,8-tetrahy-
dro-1,10-binaphthyl-2,20-diol, (S)-10. (a) (S)-H4BINOL (2.0 g, 6.79
mmol) was dissolved in CH2Cl2 (75 mL) and cooled to 0 °C.
Bromine (0.73 mL, 14.3 mmol) was added in one portion, and after
30 min the reaction mixture was quenched with sodium sulfite
(saturated, aqueous, 75 mL). The organic layer was separated
and the aqueous layer was extracted twice with CH2Cl2 (30 mL).
The resulting organic layers were dried and concentrated, and
purified by flash chromatography on silica gel (10% EtOAc/
1
hexanes) to yield (S)-9 as a white solid in 91% yield. H NMR
(300 MHz, CDCl3) δ 1.59-1.62 (m, 2H), 1.71-1.75 (m, 2H),
2.00-2.08 (m, 1H), 2.16-2.24 (m, 1H), 2.78 (t, 2H, J = 3.3 Hz),
4.98 (d, 1H, J= 2.7 Hz), 5.16 (s, 1H), 7.08 (d, 1H, J= 9.0 Hz), 7.30
(d, 1H, J = 9.0 Hz), 7.40-7.44 (m, 2H), 7.77 (d, 1H, J = 9.0
Hz), 7.98 (d, 1H, J = 2.1 Hz). (b) Under nitrogen, (S)-9 (2.0 g,
4.4 mmol), 2-(5-tert-butyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (3.85 g, 13.3 mmol, 3 equiv), and Pd(PPh3)4
(512 mg, 0.4 mmol, 10 mol %) were placed in a 2-necked flask
equipped with a reflux condenser that was connected with a
vacuum adaptor. Degassed 1,2-dimethoxyethane (25 mL) and
2 M Na2CO3 (20 mL) were cannula-transferred into the flask.
To ensure the removal of oxygen, the reaction vessel was freeze-
pumped at -78 °C and refilled with nitrogen three times. The
reaction mixture was then heated at 95 °C for 24 h. After being
cooled to room temperature, the mixture was extracted with
CH2Cl2 (3 ꢀ 40 mL). The combined organic layers were washed
with 2 M HCl (3 ꢀ 40 mL), dried, and concentrated. The residue
was purified by column chromatograph on silica gel eluted with
10% EtOAc/hexanes to afford (S)-10 as a white solid in 89% yield.
Prior to use in catalysis, (S)-10 was dissolved in CH2Cl2 and stirred
with 2 equiv of trifluoroacetic acid for 1 h to remove trace metal
impurities. After flash chromatography over silica gel, the product
was dried by dissolving in THF and pumping under. [R]D -127.6
(c 1.04, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 1.37 (s, 9H), 1.38
(s, 9H), 1.68-1.70 (m, 2H), 1.80-1.89 (m, 2H), 2.25-2.45 (m,
1H), 2.90 (t, 1H, J = 6.6 Hz), 3.76 (t, 2H, J = 6.6 Hz), 3.82 (s, 3H),
3.85 (s, 3H), 5.26 (s, 1H), 5.84 (s, 1H), 6.96 (dd, 2H, J = 3.6,
8.7 Hz), 7.21 (s, 1H), 7.31-7.45 (m, 6H), 7.60 (dd, 1H, J = 1.8,
8.7 Hz), 7.89 (d, 1H, J =8.7 Hz), 7.98 (s, 1H). 13C NMR (75 MHz,
8688 J. Org. Chem. Vol. 74, No. 22, 2009

Yue et al.
JOCArticle
An Example for the Characterization of the Ring-Closing
Metathesis Products. 2-(1-Phenylvinyl)cyclopent-2-enyl acetate,
CDCl3) δ 23.3, 25.9, 27.3, 29.7, 31.8, 34.4, 34.5, 55.9, 56.4, 68.2,
111.0, 115.9, 117.6, 119.8, 124.0, 125.1, 125.3, 126.1, 126.6, 128.7,
129.1, 129.4, 129.6, 130.2, 130.4, 130.5, 132.2, 132.9, 134.4, 138.7,
143.7, 144.6, 150.5, 151.0, 153.9, 154.7. HRMS (MHþ) for
C42H47O4 calcd 615.3469, found 615.3469.
1
P-7: 94% yield. [R]D -19.67 (c 1.73, CH2Cl2). H NMR (300
MHz, CDCl3) δ 1.92-1.98 (m, 1H), 2.05 (s, 3H), 2.36-2.45 (m,
2H), 2.57-2.61 (m, 1H), 5.15 (s, 1H), 5.22 (s, 1H), 5.92 (t, 1H,
J = 2.7 Hz), 6.07-6.10 (m, 1H), 7.30-7.33 (m, 5H). 13C NMR
(75 MHz, CDCl3) δ 21.6, 31.2, 31.8, 79.3, 114.9, 127.6, 128.3,
128.5, 137.4, 141.8, 141.9, 144.2, 171.4. HRMS (M - H) for
C15H15O2 calcd 227.1067, found 227.1070.
General Procedure for the Asymmetric Alkyne Addition to
Aldehydes. Under nitrogen, a chiral ligand (0.1 mmol, 20 mol %)
was dissolved in THF (5 mL) (for addition to an aliphatic
aldehyde) or THF/Et2O (1:4, 5 mL) (for addition to an aromatic
aldehyde) in a 10 mL flame-dried flask. ZnEt2 (103 μL, 1 mmol,
2 equiv) and an alkyne (1 mmol, 2 equiv) were added sequen-
tially and the mixture was stirred at room temperature for 16 h,
yielding a light yellow solution. Ti(OiPr)4 (74 μL, 0.25 mmol,
50 mol %) was then added and the reaction mixture was stirred
for 1 h. To the resulting dark orange solution was added an
aldehyde and the reaction was monitored by using TLC or
NMR. Upon consumption of the aldehdye, the reaction was
quenched with saturated aqueous ammonium chloride (5 mL).
The reaction mixture was extracted three times with CH2Cl2 and
the organic layer was dried with sodium sulfate and concen-
trated by rotary evaporation. The residue was purified by flash
chromatography on silica gel. An initial eluent of 2:1 CH2Cl2:
hexanes cleanly separated the ligand from the product. Then,
the column was eluted with hexanes/ethylacetate (10-20%
ethyl acetate) to give the product as an oil.
An Example for the Characterization of the Optically Active
Propargylic Alcohol Products. 1-Phenylnon-3-yn-5-ol, P-1: 78%
yield. 84% ee determined by HPLC analysis (AD column, 99:1
hexanes:iPrOH, flow rate = 0.3 mL/min, λ = 221 nm, retention
time tmajor = 51.43 min and tminor = 54.968 min). [R]D -6.20
(c 0.34, THF). 1H NMR (300 MHz, CDCl3) δ 0.93-0.98 (t, 3H,
J = 7.2 Hz), 1.37-1.48 (m, 4H), 1.65-1.74 (m, 2H), 2.02 (br,
1H), 2.55 (td, 2H, Jt = 8.4 Hz, Jd = 2.1 Hz), 2.87 (t, 2H, J =
7.5 Hz), 4.37 (tt, 1H, J1 = 6.6 Hz, J2 = 2.1 Hz), 7.25-7.37 (m,
5H). 13C NMR (75 MHz, CDCl3) δ 14.3, 21.2, 22.7, 27.6,
35.3, 38.1, 63.0, 82.5, 84.9, 126.6, 128.6, 128.7, 140.9. HRMS
(M - Hþ) for C15H19O calcd 215.1430, found 215.1434.
General Procedure for the Ring-Closing Metathesis of the Opti-
cally Active Propargylic Alcohols. To a 10 mL round-bottomed
flask were added a propargylic alcohol (1 equiv), Ac2O (2 equiv),
DMAP (0.1 equiv), and CH2Cl2 (5 mL) at room temperature. After
the mixture was stirred for 10 min, it was passed through a short silica
gelcolumnelutedwith10%EtOAc/hexanes to give the Ac-protected
propargylic alcohol. This compound (1 equiv) was then dissolved in
toluene (0.14 M) and combined with Grubbs II (5 mol %) in a 50 mL
round-bottomed flask under nitrogen. After the mixture was stirred
at room temperature for 2 h, it was passed through a short silica gel
column eluted with 10% EtOAc/hexanes to give the product.
General Procedure for the Tandem Ring-Closing Metathesis
and Hydrogenation of the γ-Hydroxy-r,β-acetylenic Esters. In a
50 mL round-bottomed flask under nitrogen, an Ac group
protected propargylic alcohol (1 equiv) was dissolved in toluene
(0.14 M) and combined with Grubbs II (5 mol %). After the
mixture was stirred at room temperature for 1 h, it was trans-
ferred to a parr reactor. Hydrogen (100 psi) was introduced and
the reactor was heated at 75 °C with stirring for 10 h. The crude
mixture was passed through a short silica gel column eluted with
20% EtOAc/hexanes to give the product.
An Example for the Characterization of the Tandem Ring-
Closing Metathesis and Hydrogenation Products. Methyl 2-(5-
acetoxycyclopent-1-enyl)propanoate, P-12: 88% yield. The ratio
of the two diastereomers is 2:1, determined by analyzing the 1H
1
NMR spectrum. [R]D -1.77 (c 1.10, CH2Cl2). H NMR (300
MHz, CDCl3) δ 1.34 (d, 3H, J = 7.2 Hz), 1.72-1.90 (m, 2H),
2.02 (s, 3H), 2.31-2.51 (m, 2H), 3.20-3.30 (m, 1H), 3.66 (s, 3H),
5.70-5.73 (m, 1H), 5.90 (br s, 1H). Following are the resolved
signals of another diastereomer: δ 1.29 (d, 3H, J = 7.2 Hz), 3.68
(s, 3H), 5.86 (br, 1H). 13C NMR (75 MHz, CDCl3) δ 16.0, 21.5,
30.4, 31.2, 38.6, 52.2, 80.5, 132.9, 141.0, 171.2, 174.6. Following
are the resolved signals of another diastereomer: δ 16.8, 39.6,
80.6, 132.7, 174.9. HRMS (MNaþ) for C11H16O4Na calcd
235.0946, found 235.0949.
Acknowledgment. Partial support of this work from the
U.S. National Science Foundation (CHE-0717995), the
donors of the Petroleum Research Fund, administered by
the American Chemical Society, the National Natural
Science Foundation of China (Nos. 20725206 and
20732004), and the Specialized Research Fund for the Doc-
toral Program of Higher Education in China is gratefully
acknowledged. Y.Y. also thanks the fellowship from the
China Scholarship Council [No.(2007)3020].
Supporting Information Available: Detailed synthesis and
characterization of the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8689