Catalytic asymmetric synthesis of chiral propargylic alcohols for the intramolecular Pauson-Khand cycloaddition

Article abstract of DOI:10.1021/jo101545v

Several methods for the catalytic asymmetric alkyne addition to aldehydes are used to prepare the propargylic alcohol-based chiral en-ynes. Protection of the propargylic alcohols with either an acetyl or a methyl group allows the resulting en-ynes to undergo the intramolecular Pauson-Khand reaction to form the corresponding optically active 5,5- and 5,6-fused bicyclic products with high diastereoselectivity and high enantiomeric purity. In the major product, the propargylic substituent and the bridgehead hydrogen are cis with respect to each other on the fused bicyclic rings. The enantiomeric purity of the propargylic alcohols generated from the asymmetric alkyne addition is maintained in the cycloaddition products. The allylic ethers of the chiral propargylic alcohols are prepared which can also undergo the highly diastereoselective Pauson-Khand cycloaddition with retention of the high enantiomeric purity. This study has shown that the size of the substituents at the propargylic position as well as on the alkyne is important for the diastereoselectivity with the greater bulkiness of the substituents giving higher diastereoselectivity.

Full text of DOI:10.1021/jo101545v

pubs.acs.org/joc
Catalytic Asymmetric Synthesis of Chiral Propargylic Alcohols for the
Intramolecular Pauson-Khand Cycloaddition
Mark Turlington,† Yang Yue,†,‡ Xiao-Qi Yu,*,‡ and Lin Pu*,†
†Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, and
‡Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu, China 610064
lp6n@virginia.edu, xqyu@tfol.com
Received August 6, 2010
Several methods for the catalytic asymmetric alkyne addition to aldehydes are used to prepare the
propargylic alcohol-based chiral en-ynes. Protection of the propargylic alcohols with either an acetyl
or a methyl group allows the resulting en-ynes to undergo the intramolecular Pauson-Khand
reaction to form the corresponding optically active 5,5- and 5,6-fused bicyclic products with high
diastereoselectivity and high enantiomeric purity. In the major product, the propargylic substituent
and the bridgehead hydrogen are cis with respect to each other on the fused bicyclic rings. The en-
antiomeric purity of the propargylic alcohols generated from the asymmetric alkyne addition is
maintained in the cycloaddition products. The allylic ethers of the chiral propargylic alcohols are
prepared which can also undergo the highly diastereoselective Pauson-Khand cycloaddition with
retention of the high enantiomeric purity. This study has shown that the size of the substituents at the
propargylic position as well as on the alkyne is important for the diastereoselectivity with the greater
bulkiness of the substituents giving higher diastereoselectivity.
Introduction
Zn(OTf)2 or ZnR2 (R = Et or Me) were found to catalyze the
reaction of alkynes and aldehydes with high enantio-
selectivity.2 We3a and Chan4 found that 1,10-bi-2-naphthol
(BINOL, 4) in combination with Ti(OiPr)4 and ZnR2 cata-
lyzed the alkyne addition to aromatic aldehydes with high
enantioselectivity. We further demonstrated that the
BINOL-ZnEt2-Ti(OiPr)4 catalyst system was also highly
enantioselective for the alkyne addition to aliphatic aldehydes
and R,β-unsaturated aldehydes.3b This process required a
preheating of a terminal alkyne with ZnEt2 in toluene at
Propargylic alcohols are synthetically very useful func-
tional organic molecules. During the past decade, a number
of catalysts have been developed for the asymmetric alkyne
addition toaldehydes togenerate chiral propargylicalcohols.1
For example, chiral ligands such as 1-3 in combination with
€
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Moore, D.; Xie, R. G.; Pu, L. Org. Lett. 2002, 4, 4143–4146. (c) Gao, G.; Xie,
R. G.; Pu, L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5417–5420. (d) Gao, G.;
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DOI: 10.1021/jo101545v
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Published on Web 09/15/2010
J. Org. Chem. 2010, 75, 6941–6952 6941
2010 American Chemical Society

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JOCArticle
SCHEME 1. Conversion of Chiral Propargylic Alcohols to Other Products
SCHEME 2. Intermolecular and Intramolecular PK Reactions
reflux in order to prepare the nucleophilic alkynylzinc re-
agent. Addition of hexamethylphosphoramide (HMPA) to
the BINOL-ZnEt2-Ti(OiPr)4 system was found to allow the
reaction of functionalized alkynes with aromatic and R,β-
unsaturated aldehydes to be conducted entirely at room
temperature with high enantioselectivity.3c,d The Lewis base
additive HMPA accelerated the reaction of ZnEt2 with the
terminal alkynes to generate the alkynylzinc nucleophiles at
room temperature. Later, You and co-workers reported that
N-methylimidazole (NMI) could be used in place of HMPA
to increase the efficiency of the BINOL-ZnEt2-Ti(OiPr)4
catalyst system.5 We recently found that using biscyclohex-
ylamine (Cy2NH) in place of HMPA or NMI as a Lewis base
additive greatly improved the asymmetric addition of linear
alkyl alkynes to linear aldehydes.6 We also reported that the
3,30-substituted H8BINOL derivative (S)-5 in combination
with ZnEt2 and Ti(OiPr)4 catalyzed the highly enantioselec-
tive addition of a variety of alkynes to a range of aldehydes at
room temperature.7
we have conducted the catalytic hydration of chiral pro-
pargylic alcohols to generate tetronic acids8a and the amine
addition to produce amino furanones.8b We have also per-
formed a tandem ring-closing metathesis and hydrogenation
reaction in the presence of the Grubbs carbene catalyst to
generate functional cycloalkenes.7b
The Pauson-Khand (PK) reaction is a powerful tool to
construct cyclopentenones.9 Discovered first as an intermo-
lecular reaction in the early 1970s,10 the PK reaction is a
formal [2 þ 2 þ 1] cycloaddition of an alkyne, alkene, and
carbon monoxide (Scheme 2). A decade later, Schore and co-
workers pioneered the intramolecular reaction,11 opening
the access to multicyclic ring structures through this method-
ology (Scheme 2). Although propargylic alcohol-based en-
ynes including propargyl allyl ethers have been used for the
PK reaction, most of the work was conducted on achiral or
racemic propargylic alcohols.12 In cases where enantiomeri-
cally enriched propargylic alcohols were used, often addi-
tional chiral centers were present for the isolation of the
enantiomers and to contribute to the stereocontrol of the
reaction.13,14 We have investigated the use of the catalytic
asymmetric alkyne addition to aldehydes to prepare chiral
en-ynes of high enantiomeric purity for the intramolecular
With the use of the chiral catalysts based on BINOL and
its derivative 5,3,6,7 we have prepared structurally diverse chiral
propargylic alcohols with high enantiomeric purity. This has
allowed us to explore their applications in the synthesis of
various chiral organic compounds.7b,8 As shown in Scheme 1,
(9) Selected reviews: (a) Chung, Y. K. Coord. Chem. Rev. 1999, 188, 297–
341. (b) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000,
1657–1668. (c) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263–
~ ꢀ
3283. (d) Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Domınguez, G.;
´
(5) Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007,
72, 5457–5460.
(6) Du, Y. H.; Turlington, M.; Zhou, X.; Pu, L. Tetrahedron Lett. 2010,
51, 5024–5027.
(7) (a) Turlington, M.; DeBerardinis, A. M.; Pu, L. Org. Lett. 2009, 11,
2441–2444. (b) Yue, Y.; Turlington, M.; Yu, X.-Q.; Pu, L. J. Org. Chem.
2009, 74, 8681–8689.
(8) (a) Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8, 2019–2021. (b) Zhou,
L.-H.; Yu, X.-Q.; Pu, L. J. Org. Chem. 2009, 74, 2013–2017.
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Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32–42. (e) Shibata, T. Adv. Synth.
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(10) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Chem. Commun. 1971, 36. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.;
Watts, W. E. J. Chem. Soc., Perkin Trans. 1 1973, 975–977. (c) Khand, I. U.;
Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc., Perkin Trans. 1 1973,
977.
(11) Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436–5438.
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SCHEME 3. Asymmetric Alkyne Addition to Enals To Prepare Chiral En-Ynes
TABLE 1. Results for the Asymmetric Alkyne Addition to Enals in the Presence of BINOL-ZnEt2-Ti(OiPr)4 with or without Lewis Base Additives
aUnder nitrogen, a ligand (0.1 mmol, 20 mol %), NMI (0.025 mmol, 0.05 equiv), alkyne (1 mmol, 2 equiv), and ZnEt2 (1 mmol, 2 equiv) were stirred in
CH2Cl2 (6 mL) for 2 h at rt. Ti(OiPr)4 (0.5 mmol, 1 equiv) was added and the mixture was stirred for 1 h, followed by the addition of 4-pentenal
(0.5 mmol). bUnder nitrogen, a ligand (0.2 mmol, 40 mol %), HMPA (1 mmol, 2 equiv), alkyne (2 mmol, 4 equiv), and ZnEt2 (2 mmol, 4 equiv) were
stirred in CH2Cl2 (6 mL) for 1 h at rt. Ti(OiPr)4 (0.5 mmol, 1 equiv) was added and the mixture was stirred for 1 h, followed by the addition of 4-pentenal
(0.5 mmol). cUnder nitrogen, an alkyne (2 mmol, 4 equiv) and ZnEt2 (2 mmol, 4 equiv) were heated at reflux in toluene (1 mL) for 4 h. Et2O (8 mL), ligand
(0.2 mmol, 40 mol %), and Ti(OiPr)4 (0.5 mmol, 1 equiv) were added and the reaction mixture was stirred for 1 h at rt followed by the addition of
4-pentenal (0.5 mmol). dDetermined by HPLC analysis with a Chiralcel OD or Chiralpak AD-H column.
PK reaction. Two types of chiral en-ynes are prepared which
are observed to undergo highly diastereoselective intramo-
lecular PK cycloaddition with retention of their enantio-
meric purity. Herein, these results are reported.
(12) (a) Magnus, P.; Exon, R.; Albaugh-Robertson, P. Tetrahedron 1985,
41, 5861–5869. (b) Pearson, A. J.; Dubbert, R. A. Organometallics 1994, 13,
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1396–1406. (d) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.
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R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8593–8601. (g) Morimoto,
T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem. 1997, 62, 3762–3765.
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4952. (i) Ajamian, A.; Gleason, J. L. Org. Lett. 2001, 3, 4161–4164.
(j) Moradov, D.; Quntar, A.A A A.; Youssef, M.; Smoum, R.; Rubinstein,
A.; Srebnik, M. J. Org. Chem. 2009, 74, 1029–1033.
Results and Discussion
a. Using (S)-BINOL as the Chiral Ligand. 1. Catalytic
Asymmetric Alkyne Additions to Enals To Generate Chiral
Propargylic Alcohol-Based En-Ynes. We have examined
the reaction of alkynes with enals in the presence of
(S)-BINOL-ZnEt2-Ti(OiPr)4 with or without the Lewis
base additives to prepare the chiral propargylic alcohol-
based en-ynes (Scheme 3) for the intramolecular PK reaction.
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FIGURE 1. Chiral En-Ynes Prepared by Using (S)-5.
SCHEME 4. Asymmetric Addition of a Linear Alkyl Alkyne to a Linear Aldehyde
The results are summarizedinTable 1. Inentries 1 and 2, NMI
was used as the additive to allow the reaction to be
conducted at room temperature but the enantioselectivity
was low.5,6 When HMPA was used as the additive,3c,d the
enantioselectivity was much higher (entries 3 and 4).
When our original BINOL-catalyzed procedure involving
the heating of the alkyne with ZnEt2 in toluene at reflux in
the first step was used,3a,b excellent ee values and yields
were obtained for the addition of both the aryl and alkyl
alkynes to 4-pentenal (entries 5 and 6). When the partially
hydrogenated BINOL, H8BINOL, was used, the ee was
slightly lower (entries 7 and 8). The addition of the alkynes
to 5-hexenal by heating the alkynes with ZnEt2 in toluene
and using BINOL as the catalyst also gave high ee values
and yields (entries 9 and 10).
We also studied the reaction of a linear alkyl alkyne,
1-hexyne, with 4-pentenal (Scheme 4). Using (S)-BINOL as
the ligand and the conditions in the footnote c of Table 1 gave the
corresponding propargylic alcohol product with 83% ee and
76% yield. Recently, we found that the use of Cy2NH (5 mol %)
as the additive is superior to NMI and it allows the linear alkyl
alkyne addition to linear aldehydes to be conducted at room
temperature with good enantioselectivity.6 For the reaction
of 1-hexyne with 4-pentenal in the presence of (S)-BINOL
(20 mol %), ZnEt2 (2 equiv), Ti(OiPr)4 (0.5 equiv), and
Cy2NH (5 mol %) in diethyl ether at room temperature, the
propargylic alcohol product was obtained with 87% ee and
63% yield.6 When the reaction was carried out by doubling
the amount of (S)-BINOL, ZnEt2, and Ti(OiPr)4 and still
using 5 mol % Cy2NH, the product was obtained with 89%
ee and 73% yield.
addition to enals at room temperature to generate the pro-
pargylic alcohol-based chiral en-ynes shown in Figure 1. We
find that for the reaction of methyl propiolate with 4-pente-
nal and that of trimethylsilyl acetylene with 5-hexenal, the
observed enantioselectivities are very close to those reported.
However, for the reaction of trimethylsilyl acetylene with
4-pentenal, the observed enantioselectivity (88% ee) is lower
than that reported (95% ee).7b These ee values were deter-
mined by using the 1H NMR spectra of their esters prepared
with (R)-PhCH(OAc)CO2H. The discrepancy in ee is found
to be due to the use of two different NMR integration pro-
grams with MestReC (version 4.9.9.6) being the previously
used and MestReNova (version 6.0.2-5475) the current one.
HPLC (chiral columns) analysis of the analogous com-
pounds has confirmed the accuracy of the current NMR
integration program. We also tested the use of the two
(S)-BINOL methods (methods I and II in the footnote of
Table 2) for the trimethylsilyl acetylene addition to 4-pente-
nal, which gave 84% ee (37% yield) and 85% ee (58% yield),
respectively. Thus, (S)-5 is better than (S)-BINOL for the
trimethylsilyl acetylene addition to 4-pentenal and these two
ligands give the opposite enantiomers of the product.
2. Reaction of Chiral Propargylic Alcohols with Allyl
Bromide To Prepare Chiral En-Ynes. We have prepared
another type of chiral en-ynes from the reaction of the
chiral propargylic alcohols, generated from the catalytic
asymmetric alkyne addition, with allyl bromide (Scheme 5).
As shown in Table 2, the three different methods described
in the above section were used for the catalytic asymmetric
alkyne addition to aldehydes to generate the correspond-
ing propargylic alcohols with 81-95% ee. The reactions of
these propargylic alcohols with allyl bromide in entries
1-4 were conducted in the presence of KOH in DMSO at
room temperature to form the chiral propargyl allyl
ethers. The reaction with allyl bromide in entry 5 was
conducted by treatment with nBuLi (1 equiv) at -78 °C in
THF followed by the addition of allyl bromide.
b. Using the H8BINOl Derivative (S)-5 as the Chiral
Ligand. Following our recently reported procedure,7 we have
used the chiral ligand (S)-5 (20 mol %) in combination with
ZnEt2 (2 equiv) and Ti(OiPr)4 (50 mol %) in a mixed solvent
of diethyl ether/THF (1:5) to catalyze the functional alkyne
(13) (a) Almansa, C.; Moyano, A.; Serratosa, F. Tetrahedron 1988, 44,
2657–2662. (b) Alcaide, B.; Polanco, C.; Sierra, A. A. J. Org. Chem. 1998, 63,
6786–6796. (c) Mukai, C.; Kim, J. S.; Sonobe, H.; Hanaoka, M. J. Org.
Chem. 1999, 64, 6822–6832. (d) Mukai, C.; Sonobe, H.; Kim, J. S.; Hanaoka,
M. J. Org. Chem. 2000, 65, 6654–6659. (e) Ishikawa, T.; Shimizu, K.; Ishii,
H.; Ikeda, S.; Saito, S. J. Org. Chem. 2001, 66, 3834–3847. (f) Mukai, C.;
Kozaka, T.; Suzuki, Y.; Kim, I. J. Tetrahedron Lett. 2002, 43, 8575–8578.
(g) Ishikawa, T.; Ishii, H.; Shimizu, K.; Nakao, H.; Urano, J.; Kudo, T.;
Saito, S. J. Org. Chem. 2004, 69, 8133–8135. (h) Ishizaki, M.; Niimi, Y.;
Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron 2005, 61, 4053–4065.
(14) (a) Honda, T.; Kaneda, K. J. Org. Chem. 2007, 72, 6541–6547. (b)
The asymmetric homoallylzinc addition to a Co-coordinated propargyl
aldehyde was used to generate chiral propargylic alcohols for the intramo-
lecular PK reaction: Stumpf, A.; Hwang, S. H.; Kim, J. S.; Jeong, N. Bull.
Korean Chem. Soc. 2004, 25, 1621–1622.
3. The Intramolecular PK Reactions of the Chiral Pro-
pargylic Alcohol-Based En-Ynes. With the chiral propargylic
alcohol-based en-ynes in hand we explored their intramole-
cular PK reactions to generate various bicyclic enones. For a
number of years after its discovery the PK reaction suffered
from low yields and a narrow substrate scope, but recent
advances in the use of promoters have greatly expanded the
utility of this reaction.9 We chose to employ the amine oxides
(15) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289.
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TABLE 2. Preparation of the Chiral Propargyl Allyl Ethers
aMethod I: Under nitrogen, an alkyne (2 mmol, 4 equiv) and ZnEt2 (205 μL, 2 mmol, 4 equiv) were heated at reflux in toluene (1 mL) for 4 h. Et2O
(8 mL), (S)-BINOL (57.2 mg, 0.2 mmol, 40 mol %), and Ti(OiPr)4 (150 μL, 0.5 mmol, 1 equiv) were added and the reaction mixture was stirred for 1 h at rt
followed by the addition of an aldehyde (0.5 mmol). Method II: Under nitrogen, (S)-BINOL (57.2 mg, 0.2 mmol, 40%), Cy2NH (5 μL, 0.025 mmol,
5 mol %), 1-hexyne (230 μL, 2 mmol, 4 equiv), and ZnEt2 (205 μL, 2 mmol, 4 equiv) were combined in Et2O (6 mL) and the mixture was stirred at rt for
24 h. Ti(OiPr)4 (150 μL, 0.5 mmol, 1 equiv) was added and the mixture was stirred for 1 h, followedby the addition of an aldehyde (0.5 mmol). MethodIII:
Under nitrogen, (S)-5 (61.9 mg, 0.1 mmol, 20 mol %), ZnEt2 (103 μL, 1 mmol, 2 equiv), and an alkyne (1 mmol, 2 equiv) were combined in Et2O (1 mL)
and the mixture was stirred for 16 h. THF (5 mL) and Ti(OiPr)4 (74 μL, 0.25 mmol, 50 mol %) were added and the mixture was stirred for 1 h followed by
addition of an aldehyde (0.5 mmol). bDetermined by chiral HPLC analysis (Chiralcel OD column) for entries 1 and 2, and by analysis of the 1H spectra of
c
the esters prepared with (R)-PhCH(OAc)CO2H for entries 3-5. For entries 1-4: A propargylic alcohol (1 equiv) and allyl bromide (3 equiv) were
dissolved in DMSO (0.1 M). Powdered KOH (2 equiv) was added and the reaction was stirred for 1.5 h. Entry 5: A propargylic alcohol (1 equiv) was
dissolved in THF (0.2 M) and the mixtue was cooled to -78 °C. nBuLi (1 equiv) was added. After 10 min, allyl bromide (8 equiv) was added. The reaction
was warmed to -40 °C, DMSO (2 equiv) was added, and the reaction was allowed to warm to rt overnight.
SCHEME 5. Asymmetric Alkyne Addition to Enals To Prepare the Chiral Propargyl Allyl Ethers
discovered by Schreiber15 and Jeong16 because they are the
most popular and effective promoters of the PK reaction.
The amine oxides are thought to accelerate the reaction by
oxidizing one of the carbon monoxide ligands in the inter-
mediate cobalt-alkyne complex, releasing carbon dioxide
and opening a coordination site for the alkene on one of the
cobalt atoms. The use of amine oxides has made it possible to
perform the reaction at room temperature or below, where
traditionally elevated temperatures are required for the
dissociation of a carbon monoxide ligand to open a coordi-
nation site on cobalt. The amine oxides commonly used are
N-methylmorpholine N-oxide (NMO), introduced by Schreiber,
and trimethylamine N-oxide (TMANO), introduced by Jeong.
In most cases, we used NMO since this compound is much
less expensive.
from the asymmetric alkyne addition to 4-pentenal to generate
the 5,5-fused bicyclic products (Scheme 6). The results are
summarized in Table 3. We found that the direct use of the
propargylic alcohol could not give the desired product (entry 1).
Therefore, the acetyl-protected en-ynes were prepared by treat-
ment of the alcohols with acetic anhydride in the presence
of DMAP. These substrates were then treated with Co2(CO)8
(1.2 equiv) in methylene chloride at room temperature followed
by addition of NMO (method A). As shown in entries 2-4, the
PK cycloaddition products were obtained with excellent dia-
stereoselectivity from various propargylic acetates. However,
when the acetate of the propargylic alcohol prepared from the
trimethylsilyl acetylene addition to 4-pentenal was used, the
desired PK reaction product could not be obtained (entry 5).
Removal of the TMS group allowed the formation of the
cycloaddition product in good yield but with significantly
reduced diastereoselectivity (entry 6). When the cobalt complex
of the acetate was heated in acetonitrile at 72-75 °C
(method B), its decomposition was observed rather than
the desired PK cycloaddition (entry 7). We then replaced
the acetyl protecting group with a more stable methyl
a. Using En-Ynes Prepared from 4-Pentenal To Generate the
5,5-Fused Bicyclic Products. We investigated the intramolecular
PK reaction of the propargylic alcohol-based en-ynes prepared
(16) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett
1991, 204.
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SCHEME 6. Intramolecular PK Reaction of the En-Ynes Derived from the Asymmetric Alkyne Addition to 4-Pentenal
TABLE 3. Results for the Intramolecular PK Reaction To Form the 5,5-Fused Bicyclic Products
aMethod A: An en-yne (0.25 mmol) and Co2(CO)8 (102.6 mg, 0.3 mmol, 1.2 equiv) were combined in CH2Cl2 (12.5 mL, 0.02 M) and the mixture was
stirred for 2 h. NMO (293 mg, 2.5 mmol, 10 equiv) was added and the reaction was stirred for 3-5 h. Method B: An en-yne (0.25 mmol) and Co2(CO)8
(102.6 mg, 0.3 mmol, 1.2 equiv) were combined in CH2Cl2 (10 mL, 0.025 M) and the mixture was stirred for 2 h. CH2Cl2 was removed under vacuum and
MeCN (10 mL, 0.025 M) was added. The reaction was heated at 72-75 °C for 24 h. bCombined yield of diastereomers. cDiastereomers observed by
1H NMR and dr quantified by HPLC analysis (Chiralpak AD-H column).
group. As shown in entry 8, using method B led to the
formation of the biscyclopentanoid product from the
methyl ether of the propargylic alcohol with very high
diastereoselectivity. The en-yne prepared from methyl
propiolate addition to 4-pentenal could not undergo the
intramolecular PK reaction by using either method A or B
(entry 9). Substrates like this are historically challenging for
the PK reaction.
could be resolved by using a HPLC-Chiralpak AD-H col-
umn. This analysis showed that the enantiomeric purity of
the starting en-yne in entry 2 was maintained in the product
(94% ee). We also found that the diastereoselectivity for the
racemic en-yne in the PK reaction was the same as that
observed for the enantiomerically enriched one. Thus, the
intermolecular interaction of the chiral en-yne had minimum
effect on the intramolecular cyclization.
The diastereoselectivities in Table 3 were determined by
HPLC analysis with a Chiralpak AD-H column. To deter-
mine the enantiomeric purity of the PK cycloaddition pro-
duct, we prepared the racemic version of the en-yne in entry 2
and found that the enantiomers of the cycloaddition product
In our experiments, the major diastereomer in each of the
PK reactions shown in Table 3 could be easily separated by
columnchromatography, allowingthe isolation of asingleste-
reoisomer for these reactions. The products were determined
to be the cis-bicyclic compounds (Figure 2) by correlation
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with the known chemical shifts of the related compounds.17a
The NMR signal of Ha was shown to have a more upfield
chemical shift in the cis isomer than that in the trans
isomer. All of the products in Table 3 manifested this
diagnostic chemical shift pattern. For example, for the
product in entry 2, the Ha in the major cis diastereomer
resonated at 5.7 ppm while Ha in the minor trans diaster-
eomer resonated at 6.4 ppm. The assignment of the
stereochemistry in these products is in accord with the
well-documented literature precedent for this type of PK
transformation.17,18
b. Using En-Ynes Prepared from 5-Hexenal To Generate
the 6,5-Fused Bicyclic Products. We also studied the intra-
molecular PK reaction of the chiral propargylic alcohol-
based en-ynes prepared from the asymmetric alkyne addition
to 5-hexenal to generate the 6,5-fused bicyclic products
(Scheme 7). The results are summarized in Table 4. When
the acetate of the propargylic alcohol-based en-yne was used,
only a very small amount of the cycloaddition product was
obtained (entry 1). This suggests that there should be com-
petition between the decomposition of the propargylic ace-
tate and the cycloaddition. Formation of the 5,5-bicyclic
product shown in entry 2 of Table 3 might be faster than the
formation of the 6,5-bicyclic product here, resulting in the
completely different reaction outcome. We thus replaced the
acetyl protecting group with a more stable methyl group
that allowed the cycloaddition (method A) to proceed
smoothly to give the desired 6,5-bicyclic products with
FIGURE 2. The cis and trans isomers of the 5,5-fused bicyclic
products.
SCHEME 7. Intramolecular PK Reaction of the En-Ynes Derived from the Asymmetric Alkyne Addition to 5-Hexenal
TABLE 4. Results for the Intramolecular PK Reactions To Form the 6,5-Fused Bicyclic Products
aMethod A, B: See Table 3. Method C: An en-yne (0.25 mmol) and Co2(CO)8 (102.6 mg, 0.3 mmol, 1.2 equiv) were combined in CH2Cl2 (5 mL,
0.05 M) and the mixture was stirred for 2 h. CH2Cl2 was removed under vacuum and 1,4-dioxane (5 mL, 0.05 M) and n-butyl methyl sulfide (465 μL,
3.79 mmol, 15.15 equiv) were added. The reaction was heated at 100 °C for 16 h. Method D: An en-yne (0.25 mmol) and Co2(CO)8 (102.6 mg, 0.3 mmol,
1.2 equiv) were combined in toluene (5 mL, 0.05 M) and the mixture was stirred for 2 h. TMTU (132 mg, 1 mmol, 4 equiv) was added and the reaction was
heated at 112 °C for 16 h. bCombined yield of diastereomers. cDiastereomers observed by 1H NMR and dr quantified by HPLC analysis (Chiralpak
AD-H or Chiralcel OD column).
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Turlington et al.
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excellent diastereoselectivity and yield (entry 2). The
reactions of two other methyl ethers of the propargylic
alcohol-based en-ynes with the use of method A also gave
high diastereoselectivities and yields (entries 3 and 4). For
the en-yne prepared from the trimethylsilyl acetyelene
addition, when method B was used, the desired cycloaddi-
tion product was obtained with high diastereoselectivity
but in lower yield (entry 5). A different promoter n-butyl
methyl sulfide was used in place of NMO for the cycloaddi-
tion and an elevated reaction temperature of 100 °C was
applied (method C)19 that gave an increased yield also with
the same high diastereoselectivity (entry 6). When tetra-
methylthiourea (TMTU) was used as the promoter under
the refluxing toluene condition,20 the product was obtained
in high yield with a small reduction in diastereoselectivity
(entry 7). When the TMS group on the alkyne was removed,
the resulting en-yne underwent the PK reaction in the presence
of NMO with lower diastereoselectivity (entry 8). This is similar
to that observed in the formation of the fused 5,5-bicyclic
product in entry 6 of Table 3. The stereochemistry of the
cycloaddition is sensitive to the size of the substituent on the
alkyne with the smaller substituent giving lower selectivity.
In accord with literature precedence,17c the cis structure is
assigned to the major diastereomer of the 6,5-fused bicyclic
products (Figure 3). This assignment is supported by the
NOESY spectra of the product in entry 2 of Table 4. Both the
major and minor diastereomers of the product in entry 2
were isolated. The NOESY spectrum of the minor diaster-
eomer indicates an NOE effect between Ha and Hb that is
absent in the major diastereomer. That is, the minor diaster-
eomer is the trans isomer and the major diastereomer is the
cis isomer. The high enantiomeric purity of the propargylic
FIGURE 3. The cis and trans isomers of the 6,5-fused bicyclic
products.
SCHEME 8. Intramolecular PK Reaction of the Chiral
Propargyl Allyl Ethers
TABLE 5. Results for the Intramolecular PK Reactions of the Chiral Propargylic Allylic Ethers
aMethod A, B: See Table 3. Method E: An en-yne (0.2 mmol, 1 equiv), Co2(CO)8 (78.7 mg, 0.23 mmol, 1.15 equiv), and 4-A MS (8 wt. equiv) were
combined in CH2Cl2 (5 mL, 0.04 M) and the mixture was stirred for 2 h. The reaction mixture was cooled to -20 °C and TMANO (120.2 mg, 1.6 mmol,
8 equiv) was added over 10 min. After bubbling the reaction mixture with compressed air (passed through a drying filter) for 20 min the reaction was
warmed to rt and stirred 16 h. bCombined yield of diastereomers. cDiastereomers observed by 1H NMR and dr quantified by chiral HPLC analysis
(Chiralpak AD-H and Chiralcel OD column).
6948 J. Org. Chem. Vol. 75, No. 20, 2010

Turlington et al.
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is found to be maintained in the PK cycloaddition product by
analyzing the racemic product in entry 2 with a HPLC-
Chiralcel OD column.
4. Discussion about the Stereoselectivity of the Intramole-
cular PK Reaction of the Chiral Propargylic Alcohol-Based
En-Ynes. Magnus12a,18 and others17 have proposed a me-
chanistic explanation for the formation of the cis isomer in
the intramolecular PK reaction of the en-ynes analogous to
those described above. According to the proposed mechan-
ism, the stereo discriminating step occurs during the forma-
tion of the cobalt-metallocycles. Between the two possible
metallocycle intermediates A and B, B should be less favor-
able because of the 1,3-pseudoaxial steric interactions be-
tween the OR and R0 groups. This interaction is not present
in the metallocycle A, which makes its formation more
favorable to give the cis product as the major diastereomer.
This mechanism is consistent with our observation that a
larger R0 group on the alkyne gives much higher diastereos-
electivity than when R0 is a hydrogen atom. The same mech-
anistic explanation can be extended to the PK reaction of the
propargyl allyl ethers as shown in the more favorable inter-
mediate metallocycle A0 and the less favorable one B0. We
have found that when the R group of the aldehyde starting
material is a bulkier cyclohexyl ring, the diastereoselectivity
is much greater than when R is a linear alkyl group, and a
bulkier R0 group on the alkyne also gives much higher dia-
stereoselectivity than when R0 is a hydrogen atom.
FIGURE 4. The cis and trans isomers of the 5,5-fused bicyclic
products from the propargyl allyl ethers.
alcohol starting material was found to be maintained in the
6,5-fused bicyclic product by analyzing the racemic product
in entry 2 with a HPLC-Chiralcel OB-H column.
c. Using the Chiral Propargyl Allyl Ethers for the PK
Reaction. The PK reactions of the chiral en-ynes made of
the propargyl allyl ethers are studied (Scheme 8). The results
are summarized in Table 5. In most cases, NMO served as an
efficient promoter for the cycloaddition. For the en-yne
prepared from a linear aldehyde, the observed dr was 87:13
(entry 1). This diastereoselectivity was greatly enhanced
when the en-ynes prepared from the reaction of cyclohex-
anecarboxaldehyde, a branched aliphatic aldehyde, with a
variety of alkynes were used. For these substrates only one
diastereomer was observed in the cycloaddition product
(entries 2-7). For the en-yne prepared from trimethylsilyla-
cetylene, three methods were tested to promote the cycload-
dition. As shown in entries 5 -7, all three methods gave high
diastereoselectivity. Using NMO as the promoter (method
A, entry 5) or heating in acetonitrile (method B, entry 6) gave
lower yield than using TMANO as the promoter in the
presence of air (method E, entry 7).21 The small hydrogen
substituted alkyne gave much lower diastereoselectivity
(entry 8) than those bearing an alkyl, aryl, or trimethylsilyl
substituent (entries 2-7).
The cis diastereomer is expected to be the major product
for the PK reaction of the propargyl allyl ethers. Analyses of
the major and minor diastereomers of the product in entry 1
by NOESY spectroscopy support this structural assignment.
A NOE effect is observed between Ha and Hb in the minor
diastereomer but not in the major diastereomer (Figure 4).
Therefore, the minor diastereomer is determined to be the
trans isomer and the major one to be the cis isomer. Notably,
formation of the related trans isomer as the major product
was recently reported via a PK-type reaction in the presence
of a PdCl2-thiourea catalyst.22 This method in combination
with our work should provide access to all four possible
stereoisomers of the products with high optical purity. In our
study, the high enantiomeric purity of the propargylic alcohol
Summary
We have demonstrated that the use of the catalytic asym-
metric alkyne addition methodology developed in our la-
boratory can provide rapid access to a variety of chiral pro-
pargylic alcohol-based en-yne precursors with high enantio-
meric purity for the PK reaction. With the protection of the
propargylic alcohols with either an acetyl or a methyl group,
the resulting en-ynes can undergo intramolecular PK reac-
tion to form the corresponding optically active 5,5- and 5,6-
fused bicyclic products with high diastereoselectivity. In the
major product, the propargylic substituent and the bridge-
head hydrogen are cis with respect to each other on the fused
bicyclic rings. The high enantiomeric purity of the pro-
pargylic alcohols is maintained in the PK cycloaddition
products. The chiral propargyl allyl ethers are also found
to undergo highly diastereoselective PK cycloaddition with
retention of enantiomeric purity. Thus, the chiral informa-
tion in these en-yne precursors is efficiently transferred to the
fused bicyclic products. These findings expand the utility of
the chiral propargylic alcohols as precursors for diastereo-
selective transformation.
(17) (a) Mukai, C.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M. Tetra-
hedron Lett. 1995, 36, 5761–5764. (b) Mukai, C.; Kim, J. S.; Uchiyama, M.;
Sakamoto, S.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1998, 2903–2915.
(c) Mukai, C.; Kim, J. S.; Uchiyama, M.; Hanaoka, M. Tetrahedron Lett.
1998, 39, 7909–7912. (d) Castro, J.; Moyano, A.; Pericas, M. A.; Antoni
Riera, A. Tetrahedron 1995, 51, 6541–6556. (e) Breczinski, P. M.; Stumpf, A.;
Hope, H.; Krafft, M. E.; Casalnuovo, J. A.; Schore, N. E. Tetrahedron 1999,
55, 6797–6812.
(18) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851–4854.
(19) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett
1999, 771.
(20) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org.
Lett. 2005, 7, 593–595.
Experimental Section
(21) (a) Velcicky, J.; Lanver, A.; Lex, J.; Prokip, A.; Wieder, T.; Schmalz,
H. G. Chem.;Eur. J. 2004, 10, 5087–5110. (b) Lanver, A.; Schmalz, H. G.
Eur. J. Org. Chem. 2005, 1444–1458.
(22) Lan, Y.; Deng., L.; Liu, J.; Wang, C.; Wiest, O.; Yang, Z.; Wu, Y.-D.
J. Org. Chem. 2009, 74, 5049–5058.
General Procedures for the Intramolecular PK Reaction.
Method A. Under nitrogen in a 25 mL flame-dried flask, an
en-yne substrate (0.25 mmol, 1 equiv) was dissolved in CH2Cl2
(12.5 mL, 0.02 M). Co2(CO)8 (102.6 mg, 0.3 mmol, 1.2 equiv)
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Turlington et al.
JOCArticle
was added and the reaction mixture was stirred for 2 h, during
which formation of the cobalt-complexed en-yne was observed
by TLC analysis. To the dark amber colored solution was added
N-methylmorpholine N-oxide (293 mg, 2.5 mmol, 10 equiv).
The reaction was monitored by TLC. After the consumption of
the cobalt-complexed en-yne (3-5 h), the cobalt blue solution
was loaded onto a short silica gel column. Elution with hexanes/
ethyl acetate (10-40% ethyl acetate) yielded a mixture of dia-
(8 wt equiv). Co2(CO)8 (78.7 mg, 0.23 mmol, 1.15 equiv) was
added and the reaction mixture was stirred for 2 h, during which
formation of the cobalt-complexed en-yne was observed by TLC
analysis. The reaction mixture was cooled to -20 °C and
TMANO (120.2 mg, 1.6 mmol, 8 equiv) was added in 4 equal
portions over 10 min. The reaction mixture was then bubbled
with compressed air (passed through a drying filter) for 20 min.
The flask was then allowed to remain open to air, cover-
ing with drying tube. The cooling bath was removed and the
reaction was allowed to warm to room temperature and stirred
for 15 h. The cobalt blue solution was loaded onto a short silica
gel column. Elution with hexanes/ethyl acetate (10-40% ethyl
acetate) yielded the product (P15) as a single diastereomer.
Characterization of the PK Reaction Products. (1R,3aS)-5-
Oxo-6-phenyl-1,2,3,3a,4,5-hexahydropentalen-1-yl acetate (P1):
94% yield. 95:5 dr determined by HPLC analysis: Chiralpak
AD-H column, 99:1 hexanes:iPrOH, flow rate = 0.3 mL/min,
λ = 254 nm, retention time: tmajor = 56.3, 60.1, tminor = 77.1.
94% ee determined by HPLC analysis: Chiralpak AD-H col-
umn, 99:1 hexanes:iPrOH, flow rate = 0.3 mL/min, λ = 254 nm,
retention time: tmajor = 56.3, tminor = 60.1. [R]25D -89.1 (c 0.89,
CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.50 (m, 2H), 7.37 (m,
3H), 5.65 (m, 1H), 3.22 (m, 1H), 2.90 (dd, 1H, J = 18.0, 6.6 Hz),
2.65 (p, 1H, J = 7.2 Hz), 2.31 (m, 2H), 2.17 (s, 3H), 1.94 (m, 1H),
1.17 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 208.5, 175.7, 170.0,
138.3, 130.5, 128.8, 128.5, 128.0, 70.8, 43.1, 41.9, 35.1, 29.2, 21.2.
HRMS (MHþ) calcd for C16H17O3 257.1183, found 257.1179.
(1R,3aS)-5-Oxo-6-phenethyl-1,2,3,3a,4,5-hexahydropentalen-
1-yl acetate (P2): 81% yield. 93:7 dr determined by HPLC
analysis: Chiralpak AD-H column, 99:1 hexanes:iPrOH, flow
rate = 0.3 mL/min, λ = 235 nm, retention time: tmajor = 39.7,
43.0, tminor = 56.2. 94% ee determined by HPLC analysis:
Chiralpak AD-H column, 99:1 hexanes:iPrOH, flow rate =
1
stereomers. Both diastereomers were observable by H NMR
spectroscopy, and the diastereomeric ratio was determined
by HPLC equipped with a Chiralcel OD or Chiralpak AD-H
column. The major diastereomer was separated by flash column
chromatography on silica gel eluted with hexanes/ethyl acetate
(10-40% ethyl acetate).
Method B. Under nitrogen in a 25 mL flame-dried flask, an
en-yne substrate (0.25 mmol, 1 equiv) was dissolved in CH2Cl2
(10 mL, 0.025 M). Co2(CO)8 (102.6 mg, 0.3 mmol, 1.2 equiv) was
added and the flask was fitted with a stopcock vacuum/nitrogen
adaptor. After 2 h, the solvent was removed under vacuum, and
the resulting amber colored oil was redissolved in acetonitrile
(10 mL, 0.025 M). The flask was connected with a flame-dried
reflux condenser fitted with a stopcock vacuum/nitrogen adap-
tor and the reaction mixture was heated at 72-75 °C for 24 h.
The dark colored solution was loaded onto a short silica gel column.
Elution with hexanes/ethyl acetate (0-30% ethyl acetate) yielded
the product (in some cases as a mixture of diastereomers). The
diastereomers were observable by 1H NMR, and the diastereo-
meric ratio was determined by HPLC equipped wih a Chiralcel
OD or Chiralpak AD-H column. The major diastereomer was
separated by flash column chromatography on silica gel eluted
with hexanes/ethyl acetate (0-30% ethyl acetate).
Method C. Under nitrogen in a 25 mL flame-dried flask, an
en-yne substrate (0.25 mmol, 1 equiv) was dissolved in CH2Cl2
(5 mL, 0.05 M). Co2(CO)8 (102.6 mg, 0.3 mmol, 1.2 equiv) was
added and the flask was fitted with a stopcock vacuum/nitrogen
adaptor. After 2 h, the solvent was removed under vacuum, and
the resulting amber colored oil was redissolved in 1,4-dioxane
(5 mL, 0.05 M). n-Butyl methyl sulfide (465 μL, 3.79 mmol,
15.15 equiv) was then added. The flask was connected with a
flame-dried reflux condenser fitted with a stopcock vacuum/
nitrogen adaptor and the reaction mixture was heated at 100 °C
for 16 h. The dark colored solution was loaded onto a short silica
gel column. Elution with hexanes/ethyl acetate (0-30% ethyl
acetate) yielded the product (P9) as a mixture of diastereomers.
The diastereomers were observable by 1H NMR, and the
diastereomeric ratio was determined by HPLC equipped with
a Chiralcel OD column. The major diastereomer was separated
by flash column chromatography on silica gel eluted with
hexanes/ethyl acetate (0-30% ethyl acetate).
Method D. Under nitrogen in a 25 mL flame-dried flask, an
en-yne substrate (0.25 mmol, 1 equiv) was dissolved in toluene
(5 mL, 0.05 M). Co2(CO)8 (102.6 mg, 0.3 mmol, 1.2 equiv) was
added and the reaction mixture was stirred for 2 h. To the result-
ing dark amber colored solution was added tetramethylthiourea
(132 mg, 1 mmol, 4 equiv). The flask was connected with a flame-
dried reflux condenser fitted with a stopcock vacuum/nitrogen
adaptor and the reaction mixture was heated at 112 °C for 16 h.
The dark colored solution was loaded onto a short silica gel
column. Elution with hexanes/ethyl acetate (0-30% ethyl
acetate) yielded the product (P9) as a mixture of diastereomers.
The diastereomers were observable by 1H NMR, and the
diastereomeric ratio was determined by HPLC equipped with
a Chiralcel OD column. The major diastereomer was separated
by flash column chromatography on silica gel eluted with
hexanes/ethyl acetate (0-30% ethyl acetate).
0.3 mL/min, λ = 235 nm, retention time: tmajor = 39.7, tminor
=
43.0. [R]25D -84.5 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 7.17 (m, 5H), 5.17 (m, 1H), 2.94 (m, 1H), 2.85-2.75 (m, 1H),
2.66 (m, 4H), 2.11 (m, 3H), 2.01 (s, 3H), 1.82 (m, 1H), 0.95-0.82
(m, 1H). 13C NMR (75 MHz, CDCl3) δ 210.6, 176.1, 170.1,
141.3, 138.1, 128.7, 128.2, 125.9, 68.6, 42.3, 40.8, 33.7, 33.2, 28.9,
25.8, 21.0. HRMS (MHþ) calcd for C18H21O3 285.1496, found
285.1493.
(1R,3aS)-6-Butyl-5-oxo-1,2,3,3a,4,5-hexahydropentalen-1-yl
acetate (P3): 85% yield. 95:5 dr determined by HPLC analysis:
Chiralcel OD column, 98:2 hexanes:iPrOH, flow rate = 1.0 mL/
min, λ = 221 nm, retention time: tmajor = 7.6, tminor = 9.6.
[R]25 -91.9 (c 1.14, CHCl3). 1H NMR (300 MHz, CDCl3)
D
δ 5.74 (m, 1H), 3.02 (m, 1H), 2.69 (dd, 1H, J = 18.0, 6.0 Hz),
2.52 (p, 1H, J = 6.0 Hz), 2.24 (m, 3H), 2.07 (s, 3H), 2.06 (dd, 1H,
J = 18.0, 3.0 Hz), 1.94 (m, 1H), 1.33 (m, 4H), 1.06 (p, 1H, J =
9.0 Hz), 0.88 (t, 3H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3)
δ 210.7, 174.9, 170.2, 139.9, 68.8, 42.1, 41.3, 34.1, 30.3, 29.2, 23.6,
22.5, 21.0, 13.8. HRMS (MHþ) calcd for C14H21O3 237.1491,
found 237.1485.
(4S,6aR)-4-Methoxy-3-(trimethylsilyl)-4,5,6,6a-tetrahydro-
pentalen-2(1H)-one (P4): 69% yield. >99:1 dr determined by
HPLC analysis: Chiralpak AD-H column, 99:1 hexanes:iPrOH,
flow rate = 0.3 mL/min, λ = 235 nm, retention time: tmajor
=
19.3. [R]25D 138.4 (c 1.07, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 4.41 (m, 1H), 3.33 (s, 3H), 3.08 (m, 1H), 2.64 (dd, 1H, J = 18.0,
9.0 Hz), 2.24 (m, 2H), 2.03 (dd, 1H, J = 18.0, 3.0 Hz), 1.94 (m,
1H), 1.08 (m, 1H), 0.23 (s, 9H). 13C NMR (75 MHz, CDCl3)
δ 215.0, 192.0, 139.0, 76.4, 56.2, 43.9, 43.7, 32.8, 28.1, -1.1.
HRMS (MHþ) calcd for C12H21O2Si 225.1311, found 225.1308.
(1S,3aR)-5-Oxo-1,2,3,3a,4,5-hexahydropentalen-1-yl acetate
(P5): 83% yield. 75:25 dr determined by HPLC analysis:
Chiralcel OD column, 98:2 hexanes:iPrOH, flow rate = 1.0
Method E. Under nitrogen in a 25 mL flame-dried flask, an
en-yne substrate (0.2 mmol, 1 equiv) was dissolved in CH2Cl2
(5 mL, 0.04 M) containing activated 4-A molecular sieves
mL/min, λ = 215 nm, retention time: tmajor = 24.7, tminor
=
29.3. [R]25D 94.8 (c 0.67, CHCl3). 1H NMR (300 MHz, CDCl3)
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Turlington et al.
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δ 6.13 (m, 1H), 5.67-5.63 (m, 1H), 3.12 (m, 1H), 2.69 (dd, 1H,
J = 18.0 Hz, 6.0 Hz), 2.50 (p, 1H, J = 7.2 Hz), 2.31-2.22 (m,
1H), 2.11 (dd, 1H, J = 18.0 Hz, 3.0 Hz), 2.07 (s, 3H), 2.05-1.95
(m, 1H), 1.21-1.10 (m, 1H). 13C NMR (75 MHz, CDCl3) δ
210.6, 182.8, 170.3, 128.5, 69.5, 43.6, 42.6, 33.1, 28.9, 20.9.
HRMS (MHþ) calcd for C10H13O3 181.0865, found 181.0873.
(4R,7aS)-4-Methoxy-3-phenyl-5,6,7,7a-tetrahydro-1H-inden-
2(4H)-one (P6): 93% yield. 92:8 dr determined by HPLC anal-
ysis: Chiralpak AD-H column, 99:1 hexanes:iPrOH, flow rate =
0.3 mL/min, λ = 254 nm, retention time: tmajor = 43.9, 45.8,
tminor = 56.8. 93% ee determined by HPLC analysis: Chiralpak
OB-H column, 98:2 hexanes:iPrOH, flow rate = 2 mL/min, λ =
254 nm, retention time: tmajor = 17.1, tminor = 12.8. [R]25D -96.6
rate = 1.0 mL/min, λ = 254 nm, retention time: tmajor = 14.5,
15.3, tminor = 19.7. [R]25D 165.07 (c 1.28, CHCl3). 1H NMR (300
MHz, CDCl3) δ 7.42 (m, 5H), 4.81 (m, 1H), 4.39 (t, 1H, J = 6.0
Hz), 3.32 (m, 2H), 2.82 (dd, 1H, J = 18.0, 6.0 Hz), 2.30 (dd, 1H,
J = 18.0, 3.0 Hz), 1.82 (m, 2H), 1.42 (m, 4H), 0.90 (t, 3H, J = 7.2
Hz). 13C NMR (75 MHz, CDCl3) δ 207.4, 179.9, 135.0, 130.9,
128.5, 128.4, 128.2, 76.3, 71.2, 42.7, 39.7, 34.9, 27.5, 22.5, 13.9.
HRMS (MHþ) calcd for C17H21O2 257.1542, found 257.1535.
(1R,3aR)-1-Cyclohexyl-6-phenyl-3a,4-dihydro-1H-cyclopenta-
[c]furan-5(3H)-one (P12): 83% yield. >99:1 dr determined by
HPLC analysis: Chiralcel OD column, 98:2 hexanes:iPrOH,
flow rate = 1.0 mL/min, λ = 254 nm, retention time: tmajor
=
17.0. 96% ee determined by HPLC analysis: Chiralcel OD
column, 98:2 hexanes:iPrOH, flow rate = 1.0 mL/min, λ =
254 nm, retention time: tmajor = 17.0, tminor = 14.2. [R]25D 247.0
(c 2.18, CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H),
4.72 (d, 1H, J = 3.0 Hz), 4.38 (t, 1H, J = 6.0 Hz), 3.36-3.25 (m,
2H), 2.80 (dd, 1H, J = 18.0, 6.0 Hz), 2.28 (dd, 1H, J = 18.0, 3.0
Hz), 1.72-1.56 (m, 6H), 1.21 (m, 5H). 13C NMR (75 MHz,
CDCl3) δ 207.3, 179.6, 135.9, 131.2, 128.4, 128.2, 80.7, 71.2,
43.4, 43.1, 39.5, 29.4, 28.0, 26.2, 26.0. HRMS (MHþ) calcd for
C19H23O2 283.1698, found 283.1699.
1
(c 0.69, CHCl3). H NMR (300 MHz, CDCl3) δ 7.38 (m, 3H),
7.24 (m, 2H), 4.43 (t, 1H, J = 3.0 Hz), 3.19 (s, 3H), 3.07 (m, 1H),
2.74 (dd, 1H, J = 18.0, 6.0 Hz), 2.23 (m, 2H), 2.12 (dd, 1H, J =
18.0, 3.0 Hz), 1.92 (m, 1H), 1.57 (m, 2H), 1.18 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ 206.9, 174.2, 139.6, 130.8, 129.0,
128.3, 127.9, 72.9, 56.1, 41.7, 36.1, 35.6, 31.9, 19.7. HRMS
(MHþ) calcd for C16H19O2 243.1385, found 243.1285.
(4R,7aS)-4-Methoxy-3-phenethyl-5,6,7,7a-tetrahydro-1H-in-
den-2(4H)-one (P7): 77% yield. 93:7 dr determined by HPLC
analysis: Chiralpak AD-H column, 99:1 hexanes:iPrOH, flow
rate = 0.3 mL/min, λ = 221 nm, retention time: tmajor = 37.5,
38.5, tminor = 44.5. [R]25D -58.3 (c 0.86, CHCl3). 1H NMR (300
MHz, CDCl3) δ 7.16 (m, 5H), 3.99 (t, 1H, J = 3.0 Hz), 3.09 (s,
3H), 2.62 (m, 6H), 2.05 (m, 1H), 1.93 (dd, 1H, J = 18.0, 3.0 Hz),
1.85 (m, 1H), 1.72 (m, 1H), 1.41 (m, 1H), 0.85 (m, 1H), 0.70 (m,
1H). 13C NMR (75 MHz, CDCl3) δ 208.9, 173.2, 141.2, 138.5,
128.7, 128.3, 126.0, 72.6, 55.9, 41.5, 36.2, 35.3, 34.0, 31.6, 25.0,
19.6. HRMS (MHþ) calcd for C18H23O2 271.1698, found
271.1688.
(1R,3aR)-1-Cyclohexyl-6-phenethyl-3a,4-dihydro-1H-cyclopenta-
[c]furan-5(3H)-one (P13): 66% yield. >99:1 dr determined by
HPLC analysis: Chiralcel OD column, 98:2 hexanes:iPrOH,
flow rate = 1.0 mL/min, λ = 254 nm, retention time: tmajor
=
11.3. [R]25D 144.3 (c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3) δ
7.20 (m, 5H), 4.21 (t, 1H, J = 6.0 Hz), 3.91 (d, 1H, J = 6.0 Hz),
3.01 (m, 2H), 2.80 (m, 2H), 2.56 (m, 3H), 2.05 (dd, 1H, J = 18.0,
3.0 Hz), 1.68 (m, 5H), 1.46 (m, 1H), 1.23 (m, 5H). 13C NMR
(75 MHz, CDCl3) δ 209.2, 179.1, 141.2, 136.5, 128.5, 128.4,
126.2, 80.2, 71.4, 43.0, 42.6, 39.1, 33.4, 29.2, 28.8, 26.9, 26.2,
26.1, 25.9. HRMS (MHþ) calcd for C21H27O2 311.2011, found
311.2005.
(4R,7aS)-3-Butyl-4-methoxy-5,6,7,7a-tetrahydro-1H-inden-
2(4H)-one (P8): 79% yield. 95:5 dr determined by HPLC
analysis: Chiralcel OD column, 98:2 hexanes:iPrOH, flow rate =
(1R,3aR)-6-Butyl-1-cyclohexyl-3a,4-dihydro-1H-cyclopenta-
[c]furan-5(3H)-one (P14): 64% yield. >99:1 dr determined by
HPLC analysis: Chiralcel OD column, 98:2 hexanes:iPrOH,
1.0 mL/min, λ = 221 nm, retention time: tmajor = 5.7, 6.1, tminor
=
6.8. [R]25D -118.0 (c 1.335, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 4.36 (t, 1H, J = 3 Hz), 3.24 (s, 3H), 2.86 (m, 1H), 2.56 (dd, 1H,
J = 18.0, 6.3 Hz), 2.20 (m, 4H), 1.94 (dd, 1H, J = 18.0, 3.0 Hz),
1.84 (1H), 1.58 (m, 1H), 1.37 (m, 5H), 1.01 (m, 1H), 0.90 (t, 3H, J=
7.2 Hz). 13C NMR (75 MHz, CDCl3) δ 209.1, 172.2, 140.3, 72.8,
56.1, 41.5, 36.0, 35.5, 32.3, 31.1, 22.7, 22.5, 19.8, 13.9. HRMS
(MHþ) calcd for C14H23O2 223.1698, found 223.1694.
flow rate = 1.0 mL/min, λ = 254 nm, retention time: tmajor
D
=
1
7.2. [R]25 71.2 (c 1.16, CHCl3). H NMR (300 MHz, CDCl3)
δ 4.43 (d, 1H, J = 6.0 Hz), 4.29 (t, 1H, J = 6.0 Hz), 3.17 (m, 2H),
2.62 (dd, 1H, J = 18.0, 6.0 Hz), 2.20 (m, 2H), 2.06 (dd, 1H, J =
18.0 Hz, 2.7 Hz), 1.69 (m, 6H), 1.26 (m, 9H), 0.90 (t, 3H, J = 6.9
Hz). 13C NMR (75 MHz, CDCl3) δ 209.2, 177.7, 137.7, 80.3,
71.4, 42.9, 42.7, 38.9, 29.8, 29.1, 26.1, 26.0, 24.2, 22.7, 13.8.
HRMS (MHþ) calcd for C17H27O2 263.2011, found 263.2007.
(1S,3aS)-1-Cyclohexyl-6-(trimethylsilyl)-3a,4-dihydro-1H-cyclo-
penta[c]furan-5(3H)-one (P15): 50% yield. >99:1 dr determined
by HPLC analysis: Chiralcel OD column, 98:2 hexanes:iPrOH,
(4S,7aR)-4-Methoxy-3-(trimethylsilyl)-5,6,7,7a-tetrahydro-
1H-inden-2(4H)-one (P9): 47% yield. 94:6 dr determined by
HPLC analysis: Chiralcel OD column, 98:2 hexanes:iPrOH,
flow rate = 1.0 mL/min, λ = 221 nm, retention time: tmajor
D
=
1
5.5, tminor = 7.1. [R]25 100.8 (c 0.70, CHCl3). H NMR (300
MHz, CDCl3) δ 4.48 (t, 1H, J = 3.0 Hz), 3.26 (s, 3H), 2.97 (m,
1H), 2.53 (dd, 1H, J = 18.0, 6.9 Hz), 2.17 (m, 2H), 1.92 (dd, 1H,
J = 18.0, 2.4 Hz), 1.85 (m, 1H), 1.49 (m, 2H), 1.09 (m, 1H), 0.24
(s, 9H). 13C NMR (75 MHz, CDCl3) δ213.2, 188.4, 139.7, 74.5,
56.0, 42.6, 39.1, 36.1, 32.7, 19.5, -0.1. HRMS (MHþ) calcd for
C13H23O2Si 239.1467, found 239.1468.
(4S,7aR)-4-Methoxy-5,6,7,7a-tetrahydro-1H-inden-2(4H)-one
(P10): 61% yield. 84:16 dr determined by HPLC analysis:
Chiralcel OD column, 98:2 hexanes:iPrOH, flow rate = 1.0 mL/
min, λ = 235 nm, retention time: tmajor = 11.2, tminor = 15.6.
[R]25D 76.9 (c 0.37, CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.99
(m, 1H), 4.23 (br s, 1H), 3.25 (s, 3H), 2.95 (m, 1H), 2.61 (dd, 1H,
J = 18.0, 6.0 Hz), 2.20 (m, 1H), 2.16 (m, 1H), 2.00 (dd, 1H, J =
18.0, 1.8 Hz), 1.83 (m, 1H), 1.55 (m, 2H), 1.10 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ 208.9, 181.2, 129.2, 75.0, 56.3, 42.2,
37.7, 35.2, 32.6, 19.6. HRMS (MHþ) calcd for C10H15O2
167.1072, found 167.1074.
flow rate= 1.0 mL/min, λ = 254nm, retentiontime: tmajor = 6.2.
D
1
[R]25 -152.9 (c 0.95, CHCl3). H NMR (300 MHz, CDCl3)
δ 4.48 (d, 1H, J = 3.0 Hz), 4.29 (t, 1H, J = 6.9 Hz), 3.21 (m, 2H),
2.56 (dd, 1H, J = 18.0, 6.0 Hz), 2.05 (dd, 1H, J = 18.0, 3.6 Hz),
1.77 (m, 2H), 1.65 (m, 4H), 1.23 (m, 5H), 0.21 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ 213.3, 192.6, 136.3, 80.8, 71.0, 46.3, 42.8,
40.6, 30.0, 27.4, 26.5, 26.1, 26.0, -1.1. HRMS (MHþ) calcd for
C16H27O2Si 279.1780, found 279.1778.
(1S,3aS)-1-Cyclohexyl-3a,4-dihydro-1H-cyclopenta[c]furan-
5(3H)-one (P16): 55% yield. 65:35 dr determined by HPLC
analysis of the minor enantiomers since the peaks of these
diastereomers are fully resolved: Chiralcel OD column, 98:2
hexanes:iPrOH, flow rate = 1.0 mL/min, λ = 221 nm, retention
time: tmajor = 15.4, tminor = 14.1. [R]25D -151.2 (c 0.62, CHCl3).
1H NMR (300 MHz, CDCl3) δ 5.99 (s, 1H), 4.36 (d, 1H, J = 9.0
Hz), 4.31 (t, 1H, J = 6.0 Hz), 3.26 (m, 2H), 2.60 (dd, 1H, J =
18.0, 6.0 Hz), 2.11 (dd, 1H, J = 18.0, 3.0 Hz), 1.74 (m, 6H), 1.12
(m, 5H). 13C NMR (75 MHz, CDCl3) δ 209.1, 186.6, 125.3, 81.3,
71.3, 45.7, 41.7, 39.5, 29.1, 28.5, 26.2, 25.8. HRMS (MHþ) calcd
for C13H19O2 207.1385, found 207.1377.
(1R,3aR)-1-Butyl-6-phenyl-3a,4-dihydro-1H-cyclopenta[c]furan-
5(3H)-one (P11): 82% yield. 87:13 dr determined by HPLC
analysis: Chiralcel OD column, 98:2 hexanes:iPrOH, flow
J. Org. Chem. Vol. 75, No. 20, 2010 6951

Turlington et al.
JOCArticle
Acknowledgment. Partial support of this work from the
U.S. National Science Foundation (CHE-0717995), the Na-
tional Natural Science Foundation of China (Nos. 20725206
and 20732004), and the Program for Changjiang Scholars
and Innovative Research Team in University, the Key
Project of Chinese Ministry of Education in China and
Scientific Fund of Sichuan Province for Outstanding Young
Scientist 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.
6952 J. Org. Chem. Vol. 75, No. 20, 2010