Studies on Pd(II)-catalyzed synthesis of (Z)-α-haloalkylidene-β- lactones from cyclocarbonylation of 2-alkynols and the subsequent coupling reactions

Article abstract of DOI:10.1021/jo0480038

(Chemical Equation Presented) A good regio- and stereoselectivity was observed for the PdCl₂-catalyzed cyclocarbonylation of 2-alkynols with CuCl₂ affording (Z)-α-chloroalkylidene-β-lactones. The highly optically active (Z)-α-chloroa

Full text of DOI:10.1021/jo0480038

Studies on Pd(II)-Catalyzed Synthesis of
(Z)-r-Haloalkylidene-â-lactones from Cyclocarbonylation of
2-Alkynols and the Subsequent Coupling Reactions
Shengming Ma,* Bin Wu, Xuefeng Jiang, and Shimin Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
masm@mail.sioc.ac.cn
Received November 10, 2004
A good regio- and stereoselectivity was observed for the PdCl2-catalyzed cyclocarbonylation of
2-alkynols with CuCl2 affording (Z)-R-chloroalkylidene-â-lactones. The highly optically active
(Z)-R-chloroalkylidene-â-lactones could be easily prepared from the readily available optically active
propargylic alcohols. The Pd(II)-catalyzed cyclocarbonylation of 2-alkynols with CuBr2 was also
studied. Although the yields of (Z)-R-bromoalkylidene-â-lactones were low, due to the relatively
higher activity of the C-Br bond, the coupling reactions of (Z)-R-bromoalkylidene-â-lactones were
quite smooth to afford the corresponding products in high yields. A rationale for this reaction is
discussed.
Introduction
â-Lactones, an important class of strained four-
membered oxygen-containing heterocyclic compounds,
can be found in many biologically active natural prod-
ucts.1 For example, among the most widely studied
â-lactones are the antibiotic F-244 (1233A) 1 (an inhibitor
of HMG-CoA synthase)2 and the antiobesity drug tetra-
hydrolipstatin (orlistat) 2 (an inhibitor of the serine
pancreatic lipase)3 (Figure 1).
In the family of â-lactones, R-alkylidene-â-lactones are
one of the most important skeletons in some biologically
active natural products4 and are considered as useful
building blocks in organic synthesis.1b,5 These compounds
FIGURE 1. Some important inhibitors bearing a â-lactone
moiety.
are usually prepared via [2+2] cycloaddition of ketenes
with carbonyl compounds,6 lactonization of â-hydroxy
carboxylic acids or derivatives,7 deoxygenation of â-per-
oxylactones,8 Pd(0) or PdI2/KI-catalyzed cyclocarbonyla-
(4) (a) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H. Phyto-
chemistry 1981, 20, 1069. (b) Bohlmann, F.; Zdero, C.; King, R. M.;
Robinson, H. Phytochemistry 1983, 22, 2860.
(5) (a) Adam, W.; Albert, R.; Hasemann, L.; Salgado, V. O. N.;
Nestler, B.; Peters, E.-M.; Peters, K.; Prechtl, F.; Von Schnering, H.
G. J. Org. Chem. 1991, 56, 5782. (b) Danheiser, R. L.; Choi, Y. M.;
Menichincheri, M.; Sroner, E. J. J. Org. Chem. 1993, 58, 322. (c)
Martinez, I.; Andrews, A. E.; Emch, J. D.; Ndakala, A. J.; Wang, J.;
Howell, A. R. Org. Lett. 2003, 5, 399.
(6) (a) Adam, W.; Salgado, V. O. N.; Nestler, B.; Peters, E.-M.; Peters,
K.; Von Schnering, H. G. Chem. Ber. 1993, 126, 1481. (b) Payne, G. B.
J. Org. Chem. 1966, 31, 718. (c) Baxter, G. J.; Brown, R. F. C.;
Eastwood, F. W.; Gatehouse, B. M.; Nesbit, M. C. Aust. J. Chem. 1978,
31, 1757. (d) Cheikh, A. B.; Pommelet, J.-C.; Chuche, J. J. Chem. Soc.,
Chem. Commun. 1990, 615. (e) Masters, A. P.; Sorensen, T. S.
Tetrahedron Lett. 1989, 30, 5869.
(1) For reviews of natural products containing â-lactone moieties,
see: (a) Lowe, C.; Vederas, J. C. Org. Prep. Proc. Int. 1995, 27, 305.
(b) Pommier, A.; Pons, J. M. Synthesis 1993, 441. (c) Pommier, A.; Pons,
J. M. Synthesis 1995, 729. (d) For a review on the synthesis of
â-lactones, see: Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403.
(2) (a) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.;
Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem.
1998, 6, 1255. (b) Mayer, R. J.; Louis-Flamberg, P.; Elliott, J. D.; Fisher,
M.; Leber, J. Biochem. Biophys. Res. Commun. 1990, 169, 610.
(3) (a) Lu¨thi-Peng, Q.; Ma¨rki, H. P.; Hadva´ry, P. FEBS Lett. 1992,
299, 111. (b) Hadva´ry, P.; Sidler, W.; Meister, W.; Vetter, W.; Wolfer,
H. J. Biol. Chem. 1991, 266, 2021. (c) Other â-lactones may also be
found as related lipase inhibitors: Kocienski, P. J.; Pelotier, B.; Pons,
J. M.; Prideaux, H. J. Chem. Soc., Perkin Trans. 1 1998, 1373 and
references therein. (d) Parsons, P. J.; Cowell, J. K. Synlett 2000, 107.
10.1021/jo0480038 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/23/2005
2568
J. Org. Chem. 2005, 70, 2568-2575

Synthesis of (Z)-R-Haloalkylidene-â-lactones
SCHEME 1
SCHEME 3
SCHEME 4
SCHEME 2
TABLE 1. PdCl2-Catalyzed Cyclocarbonylation of
Undec-4-yn-3-ol 3a with CuCl2
CO
CuCl2
temp
(°C)
time
(h)
yielda
(%)
entry
(atm)
(equiv)
solvent
tion of 2-alkynols,9 and ruthenium-catalyzed cyclocarbonyl-
ation of 2-alkynols.10
1
2
1
14
15
15
14
15
15
20
20
20
20
20
3
3
3
3
3
3
3
5
5
5
5
5
PhH
PhH
PhH
PhH
PhH
PhH
THF
THF
THF
THF
THF
THF
20
30
30
20
20
18
25
20
30
40
50
70
18
16
24
16
24
42
17
4
29
40
33
In a recent communication, we described a PdCl2-
catalyzed cyclocarbonylation of 2-alkynols for the efficient
synthesis of (Z)-R-chloroalkylidene-â-lactones.11 Here we
wish to present a detailed study on this reaction: the
scope of the reaction, mechanism, and the subsequent
coupling reactions.
3b
4c
5d
6e
7
f
-
-
f
19
35
65
86
71
40
31
8
9
10
11
12
4
4
Results and Discussion
4
4
Preparation of the Starting Materials. All of the
propargylic alcohols were synthesized by the application
of the known procedure shown in Scheme 1.12
The optically active propargylic alcohols (S)-3k-p were
prepared according to Carreira’s method shown in Scheme
2.13
The optically active (S)-3d, (S)-3q, (R)-4d, and (R)-4q
were prepared via the enzymatic resolution of racemic
propargylic alcohols (Scheme 3).14 Then (R)-4d and (R)-
a Isolated yield. b 1.1 equiv of NaOAc was added. c 2 equiv of
Et3N was added. d 2 equiv of HC(OEt)3 was added. e 15 equiv of
tBuOH was applied. f The reaction was complicated.
4q were hydrolyzed to afford the optically active prop-
argylic alcohols (R)-3d and (R)-3q (Scheme 4).
Synthesis of (Z)-R-Chloroalkylidene-â-lactones
via the PdCl2-Catalyzed Cyclocarbonylation of
2-Alkynols. The reaction of 3a, 3 equiv of CuCl2, and
CO (1 atm) with PdCl2 as the catalyst at 20 °C in PhH
afforded (Z)-R-chloroalkylidene-â-lactone (Z)-5a in 29%
yield (entry 1, Table 1). With the pressure of CO being
14 atm, the yield was not dramatically improved (entry
2, Table 1). Although different additives were applied,
no improvement was observed (entries 3-6, Table 1).
When THF was used instead of PhH, the yield was 35%
(entry 7, Table 1). With 5 equiv of CuCl2 and 20 atm of
CO, the yield of product was improved to 65% within 4 h
(entry 8, Table 1). Further study indicated that the
(7) (a) Zhang, C.; Lu, X. Synthesis 1996, 586. (b) Bartels, A.;
Liebscher, J. Synthesis 1998, 1645.
(8) (a) Adam, W.; Albert, R.; Grau, N. D.; Hasemann, L.; Nestler,
B.; Peters, E.-M.; Peters, K.; Prechtl, F.; Von Schnering, H. G. J. Org.
Chem. 1991, 56, 5778. (b) Adam, W.; Albert, R.; Hasemann, L.; Prechtl,
F. Angew. Chem., Int. Ed. Engl. 1988, 27, 1536.
(9) (a) Consorti, C. S.; Ebeling, G.; Dupont, J. Tetrahedron Lett.
2002, 43, 753. (b) Gabriele, B.; Salerno, G.; Pascali, F. D.; Costa, M.;
Chiusoli, G. P. J. Chem. Soc., Perkin Trans 1 1997, 147.
(10) Matsuda, I.; Ogiso, A.; Sato, S. J. Am. Chem. Soc. 1990, 112,
6120.
(11) Ma, S.; Wu, B.; Zhao, S. Org. Lett. 2003, 5, 4429.
(12) Brandsma, L. In Preprative acetylenic Chemistry; Elsevier:
Amsterdam, The Netherlands, 1988.
(13) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806.
(14) (a) Xu, D.; Li, Z.; Ma, S. Eur. Chem. J. 2002, 21, 5012. (b) Xu,
D.; Li, Z.; Ma, S. Tetrahedron: Asymmetry 2003, 14, 3657.
J. Org. Chem, Vol. 70, No. 7, 2005 2569

Ma et al.
TABLE 2. PdCl2-Catalyzed Cyclocarbonylation of
reaction temperature is also important for this reaction
(entries 8-12, Table 1). The best reaction conditions are
10 mol % of PdCl2, 5 equiv of CuCl2, and CO (20 atm) in
THF at 30 °C for 4 h (Conditions A) affording (Z)-5a in
isolated 86% yield (entry 9, Table 1).
Secondary Propargylic Alcohols with CuCl2
During our studies on the chemistry of functionalized
allenes, we have developed some new methodologies for
the efficient synthesis of butenolides starting from 2,3-
allenoic acids or derivatives.15 Although we initially
envisioned that the PdCl2-catalyzed cyclocarbonylation
of 2-alkynols would afford butenolides (eq 1), after some
isolated yield
of (Z)-5 (%)
ratio of
entry
R1
R2
Z-5:E-5:6 (%)a
1
2
n-C6H13
n-C5H11
n-C3H7
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
t-Bu
C2H5
86/(Z)-5a
76/(Z)-5b
74/(Z)-5c
64/(Z)-5d
72/(Z)-5e
67/(Z)-5f
71/(Z)-5g
90/(Z)-5h
82/(Z)-5i
89/(Z)-5j
91/(Z)-5k
81/(Z)-5l
78/(Z)-5m
66/(Z)-5n
52/(Z)-5o
63/(Z)-5p
78:12:10
82:8:10
80:10:10
78:9:13
78:10:12
81:9:10
n-Bu
3
n-Bu
Me
n-C3H7
n-C5H11
i-Pr
i-Bu
cyclohexyl
n-Bu
i-Pr
i-Bu
cyclohexyl
4
5
analysis, we surprisingly found the products display
intense IR absorption at ν ) 1813 cm-1, which is the
characteristic absorption of the carbonyl groups in â-lac-
tones (ν ) 1840-1810 cm-1). Single-crystal X-ray dif-
fraction of (Z)-5k and (Z)-5n established the (Z)-R-
chloroalkylidene-â-lactone skeleton.11
6b
7
c
-
8
9
78:12:10
86:5:9
10
11b
12
13b
14
15b
16b
95: 0: 5
90: 6: 4
89: 8: 3
89: 6: 5
74:11:15
75:15:10
79:8:13
Ph
Ph
Ph
Some amounts of (E)-R-chloroalkylidene-â-lactone (E)-
5a and butenolides 6 were also formed in the reaction
mixture with their ratio determined by the analysis of
PhCH2CH2 i-Pr
PhCH2CH2 i-Bu
1
PhCH2CH2 cyclohexyl
the H NMR spectra of the crude product(s).
Some typical results under the established conditions
A are shown in Table 2. It should be pointed out that
the reaction is general with good chemo- and stereo-
selectivities to afford the products in moderate to excel-
lent yields. R1 can be an alkyl group and aryl group
a The ratio of (Z)-5:(E)-5:6 was determined by the analysis of
the 300 MHz 1H NMR spectra of the crude mixture. (E)-5 and 6
were not fully characterized due to the difficulty met in the
purification process. b The reaction time was 6 h. c The ratio could
not be determined by the analysis of the 1H NMR spectra of the
crude mixture.
t
including Bu while R2 group should be an alkyl group.
The cyclocarbonylation of 1-hexynylcyclohexan-1-ol 3r
was used to optimize the reaction conditions for tertiary
alcohols with the representative results listed in Table
3. Under Conditions A, the yield of (Z)-5r was only 16%
(entry 1, Table 3). The reaction was complicated with a
prolonged reaction time (entry 2, Table 3); the yield of
reaction was slightly higher with a shorter reaction time
(entry 3, Table 3); when the reaction was stopped after
1 h, the substrate was not completely consumed (entry
4, Table 3). With the addition of 1 equiv of Et3N, the
reaction did not proceed at all (entry 5, Table 3). When
benzoquinone (1 equiv), which has been extensively used
for the oxidation of Pd(0) to Pd(II),16 was added to the
reaction mixture, fortunately the yield of product was
improved (compare entry 1 with entry 6, entry 3 with
entry 7, Table 3). When 3 equiv of benzoquinone was
added, the yield was improved to 86% (entry 9, Table 3).
With more benzoquinone no further improvement was
observed (entry 10, Table 1).
TABLE 3. The PdCl2-Catalyzed Cyclocarbonylation of
1-Hexynylcyclohexan-1-ol 3r
time
(h)
isolated
yield (%)
entry
additive (equiv)
1
2
4
6
2
1
4
4
2
2
2
2
16
complicated
3
28
39
4
5
Et3N (1)
trace
29
6
benzoquinone (1)
benzoquinone (1)
benzoquinone (2)
benzoquinone (3)
benzoquinone (4)
7
57
8
83
9
86
10
86
Then we investigated the effect of the relative ratio of
PdCl2, CuCl2, and benzoquinone on the reaction (Table
4). With 10 mol % of PdCl2 and 1.2 equiv of CuCl2, the
reaction afforded (Z)-5r in 71% (entry 7, Table 4). With
1 or 3 equiv of CuCl2, the yield of (Z)-5r was somewhat
lower as compared to the results with 5 equiv of CuCl2
(entries 2-4, Table 4). So we established conditions B
for tertiary propargylic alcohols: PdCl2 (10 mol %), CuCl2
(5 equiv), benzoquinone (3 equiv), CO (20 atm) in THF
for 2 h.
Some typical results for the cyclocarbonylation of
tertiary propargylic alcohols are listed in Table 5, which
indicate that the reaction is general: R1 can be an alkyl
group or an aryl group and R2, R3 can be alkyl groups.
The yields of products were affected by the bulkiness of
(15) (a) For an account, see: Ma, S. Acc. Chem. Res. 2003, 36, 701.
For some of our most recent results, see: (b) Ma, S.; Duan, D.; Shi, Z.;
Wang, Y. J. Combin. Chem. 2002, 239. (c) Ma, S.; Yu, Z. Org. Lett.
2003, 5, 1507. (d) Ma, S.; Yu, Z. Angew. Chem., Int. Ed. 2003, 42, 1955.
(e) Ma, S.; Yu, Z. J. Org. Chem. 2003, 68, 6149. (f) Ma, S.; Yu, Z. Eur.
Chem. J. 2004, 10, 2078.
(16) (a) Grennberg, H.; Gogoll, A.; Ba¨ckvall, J. E. Organometallics
1993, 12, 1790. (b) Jia, C.; Lu, W.; Kitamura, T.; Fijiwara, Y. Org.
Lett. 1999, 1, 2097.
2570 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of (Z)-R-Haloalkylidene-â-lactones
TABLE 4. The Effect of the Ratio of PdCl2, CuCl2, and
Benzoquinone on the Cyclocarbonylation of the Tertiary
Propargylic Alcohol 3r
TABLE 5. The PdCl2-Catalyzed Cyclocarbonylation of
Various Tertiary Propargylic Alcohols
CuCl2
(equiv)
benzoquinone
(equiv)
yield of
entry
(Z)-5r (%)a
1
2
3
4
5
6
7
5
4
3
2
2
2
3
2
86b
86
79
79
50
75
71
5
3
1
0.5
1.2
1.2
a Isolated yield. b 6% (E)-5r was isolated, and (E)-5r was not
formed in any other cases.
the R2, R3 groups (entries 5-7, Table 5). When R3 was
an aryl group, the reaction was complicated (entry 9,
Table 5).
Preparation of Optically Active (Z)-R-Chloroalky-
lidene-â-lactones. With a range of optically active
secondary propargylic alcohols in hand, we studied the
corresponding cyclocarbonylation under the established
Conditions A. Some typical results were summarized in
Table 6. From Table 6, it can be concluded that race-
mization of the chiral center in (R)- or (S)-3 was not
observed with the yields ranging from 52% to 89%.
Synthesis of (Z)-R-Bromoalkylidene-â-lactones via
the Pd(II)-Catalyzed Cyclocarbonylation of Prop-
argylic Alcohols. After studying PdCl2-catalyzed car-
bonylation of 2-alkynols with CuCl2, we envisioned
preparing (Z)-R-bromoalkylidene-â-lactones using Pd-
(OAc)2 and CuBr2 instead of PdCl2 and CuCl2. After a
try with Pd(OAc)2 and 5 equiv of CuBr2, it was observed
that the reaction afforded (Z)-7f in only 6% yield (entry
1, Table 7). When 3 equiv of benzoquinone was added,
the yield was improved to 38% (entry 2, Table 7). When
5 equiv of LiBr was used instead of CuBr2, the reaction
did not occur (entries 3 and 4, Table 7). The reaction
proceeded in THF, PhH, n-hexane, ethyl acetate, or
toluene to affor (Z)-7f in low yields (entries 2 and 5-8,
Table 7); no reaction was observed in DMF, CH3CN,
EtOH, and PhH/THF (10:3) (entries 9-12, Table 7). The
effect of the relative ratio of CuBr2 and benzoquinone on
the yield of product (Z)-7f was also studied. After an
enormous number of tries, we established Conditions C:
Pd(OAc)2 (5 mol %), CuBr2 (2 equiv), benzoquinone
(3 equiv), CO (20 atm) in PhH for the synthesis of
(Z)-R-bromoalkylidene-â-lactones (entry 16, Table 7).
The results for Pd(II)-catalyzed cyclocarbonylation of
various propargylic alcohols with CuBr2 and benzo-
quinone are summarized in Table 8. The yields ranged
from 29% to 57%, which may be attributed to the high
activity of the in situ formed Pd(0) with the C-Br bond
in (Z)-R-bromoalkylidene-â-lactones. The stereochemistry
of these bromides was established by the X-ray diffraction
study of (Z)-7m.18 It should be noted that no (E)-isomers
were detected during the synthesis of R-bromoalkylidene-
â-lactones.
a Isolated yield. b The reaction was carried out under Conditions
A. c The reaction was complicated.
Pd-Catalyzed Coupling Reactions of (Z)-R-Bro-
moalkylidene-â-lactones. The transition metal-cata-
lyzed cross-coupling reaction has been becoming one of
the most efficient methods for the formation of C-C
bonds.19 The Pd(PPh3)4-catalyzed coupling reaction of (Z)-
7f with terminal alkynes or organoboronic acids afforded
the coupling products 8-11 in high yields (Scheme 5).20
Mechanistic Considerations. A rationale for the
palladium (II)-catalyzed regio- and stereoselective cyclo-
(18) Crystal data for compound (Z)-7m: C16H17O2Br, MW ) 321.21,
orthorhombic, space group P2(1)2(1)2(1), Mo KR, final R indices
[I > 2σ(I)], R1 ) 0.0376, wR2 ) 0.0663, a ) 8.101(6) Å, b ) 9.767(7)
Å, c ) 18.669(13) Å, R ) 90°, â ) 90°, γ ) 90°, V ) 1477.3(18) Å3,
T
) 293(2) K, Z ) 4, reflections collected/unique 8726/3200
(Rint ) 0.0779). CCDC: 249713.
(19) Metal-Catalyzed Cross-Coupling Reaction; Stang, P., Diederich,
F., Eds.; VCH: Weiheim, Germany, 1998.
(20) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467. (b) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749. (c) Suzuki,
A. Pure Appl. Chem. 1991, 63, 419. (d) Suzuki, A. Pure Appl. Chem.
1994, 66, 213.
(17) (a) Ishihara, K.; Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron
Lett. 1986, 26, 983. (b) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc.
1991, 113, 6129.
J. Org. Chem, Vol. 70, No. 7, 2005 2571

Ma et al.
TABLE 6. Synthesis of Optically Active
TABLE 7. Screening of Reaction Conditions for the
(Z)-r-Chloroalkylidene-â-lactones
Pd(II)-Catalyzed Cyclocarbonylation of Dodec-5-yn-7-ol
3f with CuBr2 and Benzoquinone
isolated
CuBr2
entry (equiv) (equiv)
BQa
additive
(equiv)
yield of
solvent
toluene
toluene
toluene
THF
THF
PhH
n-hexane
ethyl acetate
DMF
(Z)-7f (%)
1b
5
5
6
38
2c
3
3
3
3
3
3
3
3
3
3
1
3b
LiBr (5)
LiBr (5)
NR
NR
31
4b
5c
5
5
5
2
5
5
2
2
6
38
7c
35
8c
26
9b
NR
0
10c
11b
12b
CH3CN
EtOH
PhH/THF
(10:3)
PhH
NR
trace
13c
14c
15c
16
5
10
10
2
2
2
1
3
3
2
1
2
31
PhH
43
PhH
42
PhH
42
17c
18b
19c
20c
21b
22c
2
LiBr (2)
LiBr (5)
PhH
8
1
PhH
trace
38
2
PhH
2
PhH
32
trace
29
3
O2 (50 psi)
K2HPO4‚
3H2O (1)
PhH
2
3
PhH
a BQ is an abbreviation for benzoquinone. b Compound 3f was
not completely consumed. c No 3f was left.
complex M1, which was followed by cis-chlorometalation
to give M2. The subsequent coordination and insertion
of CO gave metallocyclic intermediate M3, which was
followed by reductive elimination to afford the major
product (Z)-5. PdX2 was regenerated by the oxidation
reaction of the in situ generated Pd(0) with CuX2 (cycle
A). In cycle B, the complex M1 undergoes trans-chloro-
metalation to give complex M4, which was followed by
coordination and insertion of CO to afford metallocyclic
intermediate M5. Reductive elimination of M5 afforded
the minor product (E)-5. In the cycle C, the intermediate
M6 was afforded by trans-chlorometalation with an
opposite regioselectivity. Subsequent coordination and
CO insertion gave six-membered intermediate M7, which
yielded the other minor product 6 by reductive elimina-
tion.
In conclusion, (1) we have developed a mild and
efficient methodology for the synthesis of (Z)-R-chloro-
alkylidene-â-lactones in good regio- and stereoselectivity.
(2) The highly optically active (Z)-R-chloroalkylidene-â-
lactones could be easily formed from the readily available
optically active propargylic alcohols. (3) Although the
yields of (Z)-R-bromoalkylidene-â-lactones were low, due
to the high activity, the coupling reactions of (Z)-R-
bromoalkylidene-â-lactones were quite smooth to afford
the coupling products in high yields. Further studies in
this area are being conducted in our laboratory.
a The absolute stereochemistry was established by comparison
of the specific rotation with the literature data.14,17 The enantio-
meric excess was determined by HPLC on a chiralcel OD column.
b Isolated yield. c The enantiomeric excess was determined by
HPLC on a chiralcel OD-H or AS column. d The reaction time was
6 h.
Experimental Section
carbonylation of propargylic alcohols is shown in Scheme
6. The coordination of the triple bond of 3 with PdCl2 gave
Synthesis of Starting Material. Compounds 3a-y were
prepared by the reaction of the corresponding 1-alkynyllithium
2572 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of (Z)-R-Haloalkylidene-â-lactones
TABLE 8. Pd(II)-Catalyzed Cyclocarbonylation of
Various Propargylic Alcohols in the Presence of CuBr2
and Benzoquinone
SCHEME 5
SCHEME 6
) from 40/1 to 5/1) afforded (R)-4d (3.188 g, 47%) and (S)-3d
(1.32 g, 26%). (R)-4d: 62% ee (GC condition: column, G-BP
(20 m, 0.25 mm i.d., 0.25 µm df); carrier, N2, 8.0 psi; injector,
250 °C; detector (FID, H2, 0.218 Mpa), 250 °C; oven temper-
ature, 50 °C (30 min), then 1.0 °C/min to 80 °C), tr ) 44.2
(major), 44.8 (minor); [R]20D +78.9 (c 1.0, CHCl3). (S)-3d: >99%
ee (GC condition: column, G-BP (20 m, 0.25 mm i.d., 0.25 µm
df); carrier, N2, 10.0 psi; injector, 250 °C; detector (FID, H2,
with aldehydes as reported.12 The optically active propargylic
alcohols (S)-3k-p were prepared according to Carreira’s
method.13
Compounds (S)-3d and (S)-3q were prepared via the kinetic
resolution of racemic propargylic alcohols 3d and 3q.14
Synthesis of (S)-Oct-3-yn-2-ol ((S)-3d). Typical Proce-
dure. To a solution of 3d (5.072 g, 40.3 mmol) in 150 mL of
vinyl acetate was added Novozym-435 (0.92 g). After being
stirred at 60 °C for 28 h, the reaction mixture was worked up
by filtration (ether). Evaporation and purification by flash
chromatography on silica gel (eluent: petroleum ether/ether
0.218 Mpa), 250 °C; oven temperature, 70 °C (15 min)),
1
tr ) 10.4 (major); [R]20 -23.5 (c 0.9, CHCl3); liquid; H NMR
D
(300 MHz, CDCl3) δ 5.10-4.96 (m, 1 H), 2.20 (dt, J ) 2.0 and
7.0 Hz, 2 H), 1.81 (br s, 1 H), 1.57-1.35 (m, 4 H), 1.43 (d,
J ) 6.6 Hz, 3 H), 0.91 (t, J ) 6.9 Hz, 3 H).
Synthesis of (R)-Oct-3-yn-2-ol ((R)-3d). To a solution of
3d (5.004 g, 39.7 mmol) in 150 mL of vinyl acetate was added
Novozym-435 (0.9 g). After being stirred at 30 °C for 2 h, the
J. Org. Chem, Vol. 70, No. 7, 2005 2573

Ma et al.
reaction mixture was worked up by filtration (ether). Evapora-
tion and purification by flash chromatography on silica gel
(eluent: petroleum ether/ether ) from 40/1 to 5/1) afforded
(R)-4d (2.216 g, 33%) and (S)-3d (2.498 g, 50%). (R)-4d:
>99% ee (GC condition: column, Chirasil-DEX CB (25 m, 0.25
mm i.d., 0.25 µm df); carrier, N2, 13.0 psi; injector, 250 °C;
detector (FID, H2, 0.218 Mpa), 250 °C; oven temperature,
90 °C (2 min), then 1.0 °C/min to 110 °C), tr ) 14.2 (minor),
14.7 (major); [R]20D +138.9 (c 1.05, CHCl3). (S)-3d: 62% ee (GC
condition: column, G-BP (20 m, 0.25 mm i.d., 0.25 µm df);
carrier, N2, 10.0 psi; injector, 250 °C; detector (FID, H2, 0.218
Mpa), 250 °C; oven temperature, 70 °C (15 min)); tr ) 10.4
(major), 11.2 (minor).
13.0 psi; injector, 250 °C; detector (FID, H2, 0.218 Mpa),
250 °C; oven temperature, 95 °C (20 min), then 1 °C/min to
120 °C)); tr ) 31.2 (major), 32.4 (minor); [R]20 +4.6 (c 1.05,
D
CHCl3).
PdCl2-Catalyzed Cyclocarbonylation of Secondary
Propargylic Alcohols in the Presence of CuCl2. Typical
Procedure I. In a flame-dried argon-flushed flask, a solution
of 3a (157 mg, 0.93 mmol) and anhydrous CuCl2 (635 mg,
4.7 mmol) in 9.3 mL of dry THF was stirred for 5 min at room
temperature followed by the addition of PdCl2 (16.5 mg,
0.093 mmol). Then the flask was transferred to a Parr pressure
reactor. The Parr reactor was charged with 20 atm of CO gas.
After the mixture was stirred for 4 h at 30 °C, the gas was
ventilated, and the residue was diluted with Et2O. Filtration
through a short column of silica gel, evaporation, and flash
chromatography on silica gel (eluent: petroleum ether/ethyl
acetate ) 40/1) afforded 184 mg (86%) of (Z)-5a.
To a solution of the above (R)-4d (2.176 g, 12.95 mmol,
>99% ee) in 28 mL of CH3OH was added KOH (871 mg,
15.54 mmol). After the solution was stirred at room temper-
ature for 2 h, the solvent was removed in vacuo. The residue
was extracted with 3 × 20 mL of Et2O. The combined extracts
were washed with saturated NaCl, dried with Na2SO4, filtered,
concentrated, and purified via flash chromatography on silica
gel (eluent: petroleum ether/ether ) 5/1) to afford 1.363 g
(84%) of (R)-3d with 99% ee as determined by GC analysis
(column, G-BP (20 m, 0.25 mm i.d., 0.25 µm df); carrier,: N2,
10.0 psi; injector, 250 °C; detector (FID, H2, 0.218 Mpa),
250 °C; oven temperature, 70 °C (15 min)); tr ) 10.4 (minor),
For the data of compounds (Z)-5a-p, (Z)-5u, and (S)-(Z)-
5k-p see the Supporting Information of ref 11.
PdCl2-Catalyzed Cyclocarbonylation of Various Ter-
tiary Propargylic Alcohols in the Presence of CuCl2.
Typical Procedure II. Synthesis of (Z)-3-(1-Chloropen-
tylidene)-1-oxaspiro[3.5]nonan-2-one ((Z)-5r). In a flame-
dried argon-flushed flask, a solution of 3r (180 mg, 1.0 mmol)
and anhydrous CuCl2 (675 mg, 5.0 mmol) in 10 mL of dry THF
was stirred for 5 min at room temperature followed by the
addition of PdCl2 (17.7 mg, 0.1 mmol) and benzoquinone
(324 mg, 3.0 mmol). Then the flask was transferred to a Parr
pressure reactor. The Parr reactor was charged with 20 atm
of CO gas. After the mixture was stirred at 30 °C for 2 h, the
gas was ventilated, and the residue was diluted with CH2Cl2.
Filtration through a short column of silica gel, evaporation,
and flash chromatography on silica gel (eluent: petroleum
ether/ether ) 20/1) afforded 202 mg (86%) of (Z)-5r as a liquid;
1H NMR (300 MHz, CDCl3) δ 2.34 (t, J ) 7.5 Hz, 2 H), 1.99
(dd, J ) 1.8 and 12.9 Hz, 2 H), 1.90-1.55 (m, 9 H), 1.45-1.18
(m, 3 H), 0.96 (t, J ) 7.2 Hz, 3 H); 13C NMR (75.4 MHz, CDCl3)
δ 161.6, 138.0, 136.5, 87.0, 35.4, 33.8, 28.9, 24.3, 21.8, 21.7,
13.7; MS (EI) m/z (%) 244 (M+(37Cl), 2.74), 242 (M+(35Cl), 6.85),
41 (100); IR (neat) 2934, 2862, 1813, 1700 cm-1; HRMS (EI)
calcd for C13H1935ClO2 242.1074, found 242.1077.
11.2 (major); [R]20 +23.8 (c 1.15, CHCl3).
D
Synthesis of (S)-non-4-yn-3-ol ((S)-3q). To a solution of
3q (5.003 g, 35.7 mmol) in 150 mL of vinyl acetate was added
Novozym-435 (0.9 g). After being stirred at 60 °C for 24 h, the
reaction mixture was worked up by filtration (ether). Evapora-
tion and purification by flash chromatography on silica gel
(eluent: petroleum ether/ether ) from 30/1 to 5/1) afforded
(R)-4q (3.447 g, 53%) and (S)-3q (2.007 g, 40%). (R)-4q: 79%
ee (GC condition: column, Chirasil-DEX CB (25 m, 0.25 mm
i.d. , 0.25 µm df); carrier, N2, 13.0 psi; injector, 250 °C; detector
(FID, H2, 0.218 Mpa), 250 °C; oven temperature, 90 °C (2 min),
then 1 °C/min to 110 °C)); tr ) 19.5 (minor), 20.3 (major). (S)-
3q: 98% ee (GC condition: column, Rt-âDEXcst-TM (30 m,
0.25 mm i.d. , 0.25 µm df); carrier, N2, 13.0 psi; injector,
250 °C; detector (FID, H2, 0.218 Mpa), 250 °C; oven temper-
ature, 95 °C (20 min), then 1 °C/min to 120 °C)); tr ) 31.6
(minor), 32.1 (major); [R]20 -3.1 (c 1.05, CHCl3); liquid; 1H
D
For the data of compounds (S)-(Z)-5q and (R)-(Z)-5q see the
Supporting Information of ref 11.
NMR (300 MHz, CDCl3) δ 4.40-4.25 (m, 1 H), 2.22 (t, J ) 6.3
Hz, 2 H), 1.81-1.60 (m, 3 H), 1.58-1.32 (m, 4 H), 1.00 (t,
J ) 7.5 Hz, 3 H), 0.91 (t, J ) 7.2 Hz, 3 H).
Synthesis of (Z)-R-Bromoalkylidene-â-lactones via the
Pd(II)-Catalyzed Cyclocarbonylation of Propargylic Al-
cohols in the Presence of CuBr2. Typical Procedure III.
Synthesis of (Z)-R-(1-Bromopentylidene)-â-(n-pentyl)-â-
lactone ((Z)-7f). In a flame-dried argon-flushed flask, a
solution of 3f (179 mg, 0.98 mmol) and anhydrous CuBr2
(452 mg, 2.02 mmol) in 10 mL of dry PhH was stirred for
5 min at room temperature followed by the addition of Pd-
(OAc)2 (11 mg, 0.049 mmol) and benzoquinone (323 mg,
2.99 mmol). Then the flask was transferred to a Parr pressure
reactor. The Parr reactor was charged with 20 atm of CO gas.
After the mixture was stirred at 30 °C for 2 h, the gas was
ventilated, and the residue was diluted with CH2Cl2. Filtration
through a short column of silica gel, evaporation, and flash
chromatography on silica gel (eluent: petroleum ether/ether
) 30/1) afforded 118 mg (42%) of (Z)-7f. liquid; 1H NMR
(300 MHz, CDCl3) δ 5.00 (dd, J ) 3.5 and 8.6 Hz, 1 H), 2.44
(t, J ) 7.4 Hz, 2 H), 2.03-1.88 (m, 1 H), 1.88-1.25 (m, 11 H),
0.95 (t, J ) 7.2 Hz, 3 H), 0.91 (t, J ) 6.9 Hz, 3 H); 13C NMR
(75.4 MHz, CDCl3) δ 162.0, 135.7, 129.6, 80.5, 37.6, 32.9, 31.3,
Synthesis of (R)-Non-4-yn-3-ol ((R)-3q). To a solution of
3q (3.003 g, 21.4 mmol) in 75 mL of vinyl acetate was added
Novozym-435 (0.54 g). After being stirred at 30 °C for 6 h, the
reaction mixture was worked up by filtration (ether). Evapora-
tion and purification by flash chromatography on silica gel
(eluent: petroleum ether/ether ) from 40/1 to 5/1) afforded
(R)-4q (1.336 g, 34%) and (S)-3q (1.605 g, 53%). (R)-4q:
99% ee (GC condition: column, Chirasil-DEX CB (25 m,
0.25 mm i.d. , 0.25 µm df); carrier, N2, 13.0 psi; injector,
250 °C; detector (FID, H2, 0.218 Mpa), 250 °C; oven temper-
ature, 90 °C (2 min), then 1 °C/min to 110 °C)); tr ) 19.6
(minor), 20.4 (major); [R]20 +108.4 (c 0.95, CHCl3). (S)-3q:
D
61% ee (GC condition: column, Rt-âDEXcst-TM (30 m, 0.25
mm i.d. , 0.25 µm df); carrier, N2, 13.0 psi; injector, 250 °C;
detector (FID, H2, 0.218 Mpa), 250 °C; oven temperature,
95 °C (20 min), then 1 °C/min to 120 °C)); tr ) 31.3 (minor),
31.8 (major).
To a solution of the above (R)-4q (1.256 g, 6.9 mmol, 99%
ee) in 15 mL of CH3OH was added KOH (414 mg, 7.4 mmol).
After the solution was stirred at room temperature for 10 min,
the solvent was removed in vacuo. The residue was extrated
with 3 × 20 mL of Et2O. The combined extracts were washed
with saturated NaCl, dried with Na2SO4, filtered, concen-
trated, and purified via flash chromatography on silica gel
(eluent: petroleum ether/ether ) 5/1) to afford 0.873 g (90%)
of (R)-3q with >95% ee as determined by GC analysis (column,
Rt-âDEXcst-TM (30 m, 0.25 mm i.d. , 0.25 µm df); carrier, N2,
29.6, 24.0, 22.3, 21.7, 13.8, 13.7; MS (EI) m/z (%) 291 (M+
+
1(81Br), 3.24), 289 (M+ + 1(79Br), 3.89), 41 (100); IR (neat) 1813,
1698 cm-1; HRMS (EI) calcd for C8H10BrO2 (M+ - C5H11)
216.9864, found 216.9848.
(Z)-R-(1-Hexynylpentylidene)-â-(n-pentyl)-â-lactone (8).
A mixture of (Z)-7f (78 mg, 0.27 mmol), 1-hexyne (46 mg,
0.56 mmol), Pd(PPh3)2Cl2 (1.8 mg, 0.0026 mmol), CuI (1.0 mg,
0.0052 mmol), and Et3N (1.5 mL) was stirred at 55 °C for 4 h
under nitrogen. After the reaction mixture was cooled to room
2574 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of (Z)-R-Haloalkylidene-â-lactones
temperature, evaporation and purification by flash chroma-
tography on silica gel (eluent: petroleum ether/ether ) 30/1)
afforded 73 mg (94%) of compound 8. liquid; 1H NMR
(300 MHz, CDCl3) δ 4.97 (dd, J ) 2.9 and 8.3 Hz, 1 H), 2.44
(t, J ) 6.9 Hz, 2 H), 2.10 (t, J ) 7.5 Hz, 2 H), 2.00-1.85
(m, 1 H), 1.83-1.65 (m, 1 H), 1.64-1.41 (m, 8 H), 1.41-1.24
(m, 6 H), 0.93 (m, 9 H); 13C NMR (75.4 MHz, CDCl3) δ 162.7,
139.2, 128.8, 102.2, 78.9, 76.5, 33.4, 33.1, 31.4, 30.3, 29.6, 24.2,
22.4, 22.1, 21.8, 19.4, 13.8, 13.7, 13.5; MS (EI) m/z (%) 290
(M+, 0.70), 219 (100); IR (neat) 2218, 1809, 1681 cm-1; HRMS
(EI) calcd for C19H30O2 290.2246, found 290.2239.
(Z)-R-(Phenylethynylpentylidene)-â-(n-pentyl)-â-lac-
tone (9). A mixture of (Z)-7f (72 mg, 0.25 mmol), phenylacety-
lene (56 mg, 0.55 mmol), Pd(PPh3)2Cl2 (1.7 mg, 0.0024 mmol),
CuI (1.5 mg, 0.0079 mmol), and Et3N (1.5 mL) was stirred at
50 °C for 15.5 h under nitrogen. After the reaction mixture
was cooled to room temperature, evaporation and purification
by flash chromatography on silica gel (eluent: petroleum ether/
ether ) 30/1) afforded 69 mg (90%) of compound 9 as a liquid;
1H NMR (300 MHz, CDCl3) δ 7.70-7.50 (m, 2 H), 7.50-7.25
(m, 3 H), 5.03 (dd, J ) 3.6 and 8.1 Hz, 1 H), 2.21 (t, J ) 7.4
Hz, 2 H), 2.07-1.89 (m, 1 H), 1.89-1.20 (m, 11 H), 0.96 (t, J
) 7.4 Hz, 3 H), 0.91 (t, J ) 7.5 Hz, 3 H); 13C NMR (75.4 MHz,
CDCl3) δ 162.4, 140.1, 132.1, 129.3, 128.3, 127.80, 122.0, 99.4,
85.0, 79.0, 33.1, 32.9, 31.4, 29.7, 24.2, 22.4, 22.2, 13.9, 13.8;
MS (EI) m/z (%) 310 (M+, 26.03), 239 (100); IR (neat) 2200,
1808, 1677 cm-1; HRMS (EI) calcd for C21H26O2 310.1933,
found 310.1907.
liquid; 1H NMR (300 MHz, CDCl3) δ 7.62-7.48 (m, 2 H), 7.48-
7.30 (m, 3 H), 5.04 (dd, J ) 2.9 and 8.3 Hz, 1 H), 2.64-2.35
(m, 2 H), 2.14-1.96 (m, 1 H), 1.95-1.75 (m, 1 H), 1.73-1.48
(m, 2 H), 1.48-1.20 (m, 8 H), 0.91 (t, J ) 7.1 Hz, 3 H), 0.86
(t, J ) 6.9 Hz, 3 H); 13C NMR (75.4 MHz, CDCl3) δ 163.3, 148.3,
134.8, 132.5, 129.5, 128.3, 127.9, 78.2, 33.2, 32.9, 31.4, 30.0,
24.1, 22.5, 22.4, 13.9, 13.7; MS (EI) m/z (%) 286 (M+, 15.33),
129 (100); IR (neat) 1802, 1682 cm-1; HRMS (EI) calcd for
C19H26O2 286.1933, found 286.1807.
(Z)-R-(1-(3-Phenoxy-1-(E)-propenyl)pentylidene)-â-(n-
pentyl)-â-lactone (11). A mixture of (Z)-7f (61 mg, 0.21
mmol), PhOCH2CHdCHB(OH)2 (E-isomer) (48 mg, 0.27 mmol),
Pd(PPh3)4 (11 mg, 0.0095 mmol), Bu4NBr (5 mg, 0.016 mmol),
K2CO3 (82 mg, 0.59 mmol) in H2O (0.3 mL), and THF (1.5 mL)
afforded 61 mg (85%) of compound 11 as a liquid; 1H NMR
(300 MHz, CDCl3) δ 7.38-7.25 (m, 2 H), 7.16 (dt, J ) 1.3 and
16.2 Hz, 1 H), 7.02-6.88 (m, 3 H), 6.29 (dt, J ) 5.9 and
16.2 Hz, 1 H), 4.99 (dd, J ) 3.0 and 8.4 Hz, 1 H), 4.68 (dd,
J ) 1.3 and 5.6 Hz, 2 H), 2.24 (t, J ) 7.7 Hz, 2 H), 2.04-1.88
(m, 1 H), 1.85-1.66 (m, 1 H), 1.62-1.17 (m, 10 H), 0.93
(t, J ) 7.5 Hz, 6 H); 13C NMR (75.4 MHz, CDCl3) δ 163.8, 158.2,
143.6, 134.2, 131.5, 129.4, 127.3, 121.0, 114.6, 78.6, 68.0, 33.0,
31.4, 31.2, 28.7, 24.2, 22.9, 22.4, 13.9, 13.7; MS (EI) m/z (%)
342 (M+, 4.12), 55 (100); IR (neat) 1798, 1680 cm-1; HRMS
(EI) calcd for C22H30O3 342.2195, found 342.2183.
Acknowledgment. Financial support from the Ma-
jor State Basic Research Development Program (Grant
No. G200077500), the National Nature Science Founda-
tion of China, and the Shanghai Municipal Committee
of Science and Technology is greatly appreciated.
(Z)-R-(1-Phenylpentylidene)-â-(n-pentyl)-â-lactone (10).
A mixture of (Z)-7f (62 mg, 0.21 mmol), PhB(OH)2 (33 mg, 0.27
mmol), Pd(PPh3)4 (11 mg, 0.0095 mmol), Bu4NBr (5 mg, 0.016
mmol), and K2CO3 (87 mg, 0.63 mmol) in H2O (0.3 mL) and
THF (1.5 mL) was stirred under reflux for 4.5 h under
nitrogen. After the reaction mixture was cooled to room
temperature, it was extracted with Et2O, washed with satu-
rated NaCl, and dried over Na2SO4. Evaporation and purifica-
tion by flash chromatography on silica gel (eluent: petroleum
ether/ether ) 30/1) afforded 57 mg (93%) of compound 10 as a
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all products not listed in
the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0480038
J. Org. Chem, Vol. 70, No. 7, 2005 2575