New general method for regio- and stereoselective allylic substitution with aryl and alkenyl coppers derived from grignard reagents

Article abstract of DOI:10.1021/jo802426g

Allylic substitution with sp²-carbon reagents (aryl and alkenyl anions) was realized by using allylic picolinates and copper reagents derived from RMgBr and CuBr-Me₂S to afford anti S_N² products regioand stereoselectively. Steric and electronic factors in the reagents and the size of the methylene substituents around the allylic moiety marginally affected the selectivity. The reaction system was compatible with alkyl reagents as well. Furthermore, the substitution was applied to construction of a quaternary center and synthesis of (-)-sesquichamaenol. Electron-withdrawing nature of the pyridyl group and chelation of the C(=O)-C₅H₄N to MgBr₂ generated in situ were found to be responsible for the high efficiency of the substitution.

Full text of DOI:10.1021/jo802426g

New General Method for Regio- and Stereoselective Allylic
Substitution with Aryl and Alkenyl Coppers Derived from Grignard
Reagents
Yohei Kiyotsuka, Yuji Katayama, Hukum P. Acharya, Tomonori Hyodo, and
Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259,
Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
ReceiVed NoVember 5, 2008
Allylic substitution with sp2-carbon reagents (aryl and alkenyl anions) was realized by using allylic
picolinates and copper reagents derived from RMgBr and CuBr · Me2S to afford anti SN2′ products regio-
and stereoselectively. Steric and electronic factors in the reagents and the size of the methylene substituents
around the allylic moiety marginally affected the selectivity. The reaction system was compatible
with alkyl reagents as well. Furthermore, the substitution was applied to construction of a quaternary
center and synthesis of (-)-sesquichamaenol. Electron-withdrawing nature of the pyridyl group and
chelation of the C(dO)-C5H4N to MgBr2 generated in situ were found to be responsible for the high
efficiency of the substitution.
SCHEME 1. Two Types of Allylic Substitutiona
Introduction
Copper-promoted substitution of allylic alcohol derivatives
with hard nucleophiles is a potentially useful method for
construction of CsC bond.1 Generally, copper reagents prefer
reaction at the γ position of the allylic moiety with inversion
of stereochemistry. This propensity has stimulated intensive
investigation shown in Scheme 1 to afford chiral compounds
of structural types 22-7 and 48 from secondary and primary
allylic substrates 1 and 3, respectively. Among these types, we
were attracted to the former because of the wider option in
a L ) leaving group.
choosing substituents (i.e., R1 and R2 vs R1 in the latter), which
will provide a wider flexibility in designing synthesis of a target
compound. We were also attracted by the availability of the
various preparations of optically active allylic alcohols,9 which
are converted to allylic substrates 1. However, the regio- and
stereoselectivities of the former are highly susceptible to steric
and electronic biases and nucleophilicity of the reagents. To
improve the low reliability, the following leaving group/reagent
systems have been developed to date: C6F5CO2-,2 2,6-
F2C6H3CO2- (in one occasion),2f and o-(Ph2P(dO))C6H4CO2-
(o-DPPB oxide group)3 with R2Zn/CuCN·2LiCl; (RO)2P(O)O-4
with R2Zn/CuCN·2LiCl; MsO in γ-mesyloxy-R,ꢀ-unsaturated
(1) (a) Negishi, E.; Liu, F. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 1. (b)
Negishi, E. Handbook of Organopalladium Chemistry for Organic Synthesis;
Wiley-VCH: Weinheim, 2002; Vol. 1. (c) Kar, A.; Argade, N. P. Synthesis 2005,
2995–3022. (d) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. 1997, 36, 186–
204.
(2) (a) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel,
P. Org. Lett. 2003, 5, 2111–2114. (b) Calaza, M. I.; Yang, X.; Soorukram, D.;
Knochel, P. Org. Lett. 2004, 6, 529–531. (c) Leuser, H.; Perrone, S.; Liron, F.;
Kneisel, F. F.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 4627–4631. (d)
Soorukram, D.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3686–3689. (e)
Soorukram, D.; Knochel, P. Org. Lett. 2007, 9, 1021–1023. (f) Perrone, S.;
Knochel, P. Org. Lett. 2007, 9, 1041–1044.
(3) (a) Breit, B.; Demel, P.; Studte, C. Angew. Chem., Int. Ed. 2004, 43,
3786–3789. (b) Breit, B.; Demel, P.; Grauer, D.; Studte, C. Chem. Asian J. 2006,
1, 586–597.
10.1021/jo802426g CCC: $40.75
Published on Web 02/06/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1939–1951 1939

Kiyotsuka et al.
esters5 with R2Cu(CN)Li2 ·BF3 or RCu(CN)Li ·BF3; o-(Ph2P)-
C6H4CO2- (o-DPPB group)6 with RMgX/CuBr·Me2S, etc.7
Among these leaving groups, the o-DPPB group shows espe-
cially excellent selectivity and reactivity even with a slightly
excess quantity of the reagent and led to stereoselective synthesis
of certain polyketides of deoxy-type and tocopherol.10-12
However, the o-DPPB group is compatible mainly with alkyl
reagents; additionally, the group is quite expensive. On the other
hand, the other leaving groups require a large quantity of the
reagents.13
SCHEME 2. Expected Activations of the Picolinoxy Group
in the Allylic Substitution
The reaction systems mentioned above have been developed
for alkyl reagents (sp3-C reagents). Unfortunately, application
of the systems to aryl and alkenyl reagents (sp2-C reagents) has
resulted in low selectivity and/or reactivity4b,14 except for several
reactive or sterically biased substrates.2f,15,16 The low nucleo-
philicity of the sp2-C reagents is responsible for the inefficient
results.17
new mechanism. We selected the picolinoxy group (2-pyridyl-
CO2-), for which we expected double activation as illustrated
in Scheme 2, i.e., (1) electrostatic activation by the electron-
withdrawing pyridyl group as for the case of the C6F5 group in
the C6F5CO2 moiety and (2) dynamic activation by the carbonyl
oxygen and the pyridyl nitrogen chelating to MgBr2 that is
generated in situ from R3MgBr and CuBr. In addition, picolinic
acid is quite inexpensive.18 As communicated earlier, this
hypothesis was found to be correct, giving anti SN2′ products 6
quite efficiently.19 Herein, we present a full account of the allylic
substitution with additional results. Furthermore, we disclose
new results that include substitution with alkyl reagents,
construction of a quaternary center, and synthesis of (-)-
sesquichamaenol.
The drawback associated with the sp2-C reagents prompted
us to develop a totally new leaving group that is activated by a
(4) (a) Yanagisawa, A.; Nomura, N.; Noritake, Y.; Yamamoto, H. Synthesis
1991, 1130–1136. (b) Torneiro, M.; Fall, Y.; Castedo, L.; Mourino, A. J. Org.
Chem. 1997, 62, 6344–6352. (c) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett.
2003, 5, 1059–1061. (d) Piarulli, U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari,
C. Angew. Chem., Int. Ed. 2003, 42, 234–236. (e) Soorukram, D.; Knochel, P.
Org. Lett. 2004, 6, 2409–2411. (f) L. Belelie, J.; Chong, J. M. J. Org. Chem.
2001, 66, 5552–5555. (g) Whitehead, A.; McParland, J. P.; Hanson, P. R. Org.
Lett. 2006, 8, 5025–5028. (h) Niida, A.; Tanigaki, H.; Inokuchi, E.; Sasaki, Y.;
Oishi, S.; Ohno, H.; Tamamura, H.; Wang, Z.; Peiper, S. C.; Kitaura, K.; Otaka,
A.; Fujii, N. J. Org. Chem. 2006, 71, 3942–3951.
(5) (a) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1987, 1596–1598. (b) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto,
Y. J. Am. Chem. Soc. 1989, 111, 4864–4872. (c) Ibuka, T.; Akimoto, N.; Tanaka,
M.; Nishii, S.; Yamamoto, Y. J. Org. Chem. 1989, 54, 4055–4061.
(6) (a) Breit, B.; Demel, P. AdV. Synth. Catal. 2001, 343, 429–432. (b) Demel,
P.; Keller, M.; Breit, B. Chem. Eur. J. 2006, 12, 6669–6683.
Results and Discussion
1. Preliminary Investigation. First, substitution was inves-
tigated by using racemic cis allylic picolinate 5a (R1
)
(7) Other studies: (a) Gallina, C.; Ciattini, P. G. J. Am. Chem. Soc. 1979,
101, 1035–1036. (b) M. Trost, B.; Klun, T. P. J. Org. Chem. 1980, 45, 4256–
4257. (c) Goering, H. L.; Tseng, C. C. J. Org. Chem. 1985, 50, 1597–1599. (d)
Persson, E. S. M.; Ba¨ckvall, J.-E. Acta Chem. Scand. 1995, 49, 899–906. (e)
Smitrovich, J. H.; Woerpel, K. A. J. Am. Chem. Soc. 1998, 120, 12998–12999.
(8) (a) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 3765–3780.
(b) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 4554–4558. (c) Alexakis, A.; Hajjaji, S. E.; Polet, D.;
Rathgeb, X. Org. Lett. 2007, 9, 3393–3395. (d) Yorimitsu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2005, 44, 4435–4439. (e) Tissot-Croset, K.; Polet, D.; Alexakis,
A. Angew. Chem., Int. Ed. 2004, 43, 2426–2428. (f) Kacprzynski, M. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 10676–10681. (g) Evans, P. A.;
Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158–7159. (h) Malda, H.; Van
Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett. 2001, 3, 1169–1171. (i)
Du¨bner, F.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 379–381.
(9) Selected methods: (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780. (b)
Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997,
119, 8738–8739. (c) Ramachandran, P. V.; Teodorovic, A. V.; Rangaishenvi,
M. V.; Brown, H. C. J. Org. Chem. 1992, 57, 2379–2386. (d) Helal, C. J.;
Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996, 118, 10938–10939.
(10) (a) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43, 3790–3792.
(b) Herber, C.; Breit, B. Chem. Eur. J. 2006, 12, 6684–6691.
(CH2)2Ph, R2 ) CH2OTBS) and its trans isomer 15 with a
phenyl copper reagent derived from PhMgBr (2 equiv) and
CuBr·Me2S (1 equiv) in THF at 0 °C for 1 h (Scheme 3). The
SN2′ product 6a was produced from 5a with high regioselectivity
(ca. 99:1) over the SN2 product 820 by H NMR spectroscopy
1
(Table 1, entry 2), whereas the trans isomer 15 produced a
mixture of 6a and the regioisomer 8 in a ratio of 60:40. Other
byproducts such as alcohol 9 and the cis isomers of 6a and 8
were not detected.21 The amount of the reagent was also
examined to find that reaction was completed even with 1.2
equiv of PhMgBr within 1 h (entry 4). However, we decided to
use 2 equiv of RMgBr for further investigation to avoid any
technical error.
Other phenyl coppers (Ph/Cu ) 4:1 and 1:1) derived from
PhMgBr (2 equiv) and CuBr·Me2S (0.5 and 2 equiv, respec-
tively) were also satisfactory reagents as presented in entries 1
and 3, thus indicating the practical merit that precise measure-
ment of PhMgBr and CuBr · Me2S is no longer necessary to
attain good efficiency. The selectivity being independent of the
(11) (a) Herber, C.; Breit, B. Angew. Chem., Int. Ed. 2005, 44, 5267–5269.
(b) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512–3519.
(12) Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew. Chem.,
Int. Ed. 2007, 46, 8670–8673.
(13) For example, more than 2 equiv of Ph2Zn/CuCN · 2LiCl has been used
in the literatures. The quantity is equal to >4 equiv of the Ph anion.
(14) (a) Fujii, N.; Habashita, H.; Shigemori, N.; Otaka, A.; Ibuka, T.; Tanaka,
M.; Yamamoto, Y. Tetrahedron Lett. 1991, 32, 4969–4972. (b) Habashita, H.;
Kawasaki, T.; Takemoto, Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 2392–
2396. (c) Borthwick, S.; Dohle, W.; Hirst, P. R.; Booker-Milburn, K. I.
Tetrahedron Lett. 2006, 47, 7205–7208.
(15) (a) Yamazaki, T.; Umetani, H.; Kitazume, T. Tetrahedron Lett. 1997,
38, 6705–6708. (b) Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998, 120, 11832–
11833. (c) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2002, 67, 3000–3006.
(16) The PPh2 ligand attached to an appropriate position of allyl ethers directs
the reaction course of the nickel-catalyzed substitution of allyl ethers. However,
removal of the PPh2 group in the products is the another problem of this
approach: Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc.
1995, 117, 7273–7274.
(17) Recently, the regioselection of a racemic allylic o-DPPB ester with sp2-C
copper reagents such as those derived from PhMgBr and CH2dC(Me)MgBr was
improved by using CH2Cl2 in place of Et2O or by slow addition, but the scope
of substrates to be covered by the improved conditions and the chirality transfer
(C.T.)23 thereof are uncertain.6b
(18) Relative prices (Aldrich) of the major leaving groups as compared with
picolinic acid (28 $/mol): C6F5CO2H, 43 times; o-(Ph2P)C6H4CO2H, 330 times;
o-(Ph2P(dO))C6H4CO2H, available by oxidation of o-(Ph2P)C6H4CO2H;
(EtO)2P(O)Cl, 4 times; cf. DCC 2.1 times.
(19) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi,
Y. Org. Lett. 2008, 10, 1719–1722.
(20) Regioisomer 8 possessing the trans olefin in it was synthesized
unambiguously. See entry 10 of Table 2 for the enantiomerically enriched version
of 8 as (S)-6e.
1940 J. Org. Chem. Vol. 74, No. 5, 2009

Allylic Substitution with Aryl and Alkenyl Coppers
SCHEME 3. Preliminary Study
(Ph2Zn and PhZnBr) derived from Ph-M (M ) Li, MgBr) and
ZnBr2 (therefore one more step of the transmetalation is
required) were briefly examined with scientific interest. Surpris-
ingly, copper reagents derived from Ph2Zn (prepared from PhLi
and ZnBr2) and CuBr · Me2S and that from Ph2Zn and
CuCN·2LiCl (Knochel reagent)2a,c-f,4c,d,22 were ill-suited to 5a
(entries 15, 16). On the other hand, use of Ph2Zn derived from
PhMgBr and ZnBr2 afforded the SN2′ product 6a efficiently
(entries 17, 18). These results indicate that MgBr2 is a real
species to which the picolinoxy group chelates. Additional
evidence supporting the effect of MgBr2 was obtained with
PhZnBr·MgBr2 derived from PhMgBr and ZnBr2, though the
reaction was slightly less efficient (entries 19, 20).
Next, pentafluorobenzoate 12 and phosphonate 13 were
subjected to the substitution with PhMgBr/CuBr ·Me2S to
compare the reactivity of the picolinoxy group (entries 13, 14).
The former produced alcohol 8 competitively, and the latter
afforded a mixture of 6a and the cis isomer as stated in footnote
e of Table 1 (ca. 20%).21 On the other hand, an attempted
synthesis of mesylate 14 from the alcohol was unsuccessful,
giving a mixture of products.
3. Chirality Transfer. We then studied the stereochemistry
and chirality transfer (C.T.)23 of the reaction using enantio-
merically enriched allylic picolinate (S)-5a. Synthesis of (S)-
5a is delineated in Scheme 4, in which other substrates that we
have examined in Table 2 are also presented. Among them, (S)-
5c was prepared as a complementary substrate of (S)-5a. Epoxy
alcohol 17 was prepared from aldehyde 16 via the Sharpless
asymmetric epoxidation using L-(+)-DIPT.9a The chloride 18
derived from 17 was converted according to the protocol
published by Yadav24 to the propargylic anion, which was
trapped by paraformaldehyde to give diol 19 in 73% yield.
Silylation followed by hydrogenation of the acetylene afforded
alcohol 21 in good yield. Finally, condensation of 21 with
PyCO2H, DCC, and DMAP produced picolinate (S)-5a, which
was 90% ee by chiral HPLC analysis. Picolinate (S)-5b (89%
ee) was synthesized from 18 in a similar way. Next, aldehyde
26, prepared from mannitol according to the literature proce-
dure,25 was subjected to Wittig reaction with [Ph(CH2)3-
PPh3]+Br- and NaN(TMS)2 to afford an olefin, which was
converted to diol 27 by hydrolysis in 68% yield. Selective
silylation of the diol at the primary OH group followed by DCC-
assisted condensation at the remaining secondary OH group with
PyCO2H furnished (S)-5c, which was 95% ee by chiral HPLC
analysis. Synthesis of (S)-5d commenced with the TBDPS
ether26 of natural ethyl (S)-lactate, which was converted to the
propargyl alcohol derivative 30 in three steps. Reaction of an
anion derived from 30 with paraformaldehyde afforded alcohol
31, which was transformed to 32 by PMB protection followed
by desilylation. Finally, esterification of 32 with PyCO2H
followed by hydrogenation of the resulting ester 33 over Lindlar
catalyst (Pd/CaCO3, Pb-poisoned) afforded picolinate (S)-5d
(97% ee by chiral HPLC analysis). Note that use of Pd/BaSO4
and quinoline was not suited in this case since (S)-5d and
quinoline was inseparable by chromatography on silica gel.
Ph/Cu ratios is a rare case in the allylic substitution. In addition,
the reactions were found to be successful at lower temperatures
(see Table 2).
Copper bromide (CuBr) in place of CuBr ·Me2S and other
copper salts (CuCl, CuI, CuCN) gave similarly good results
(Table 1, entries 5-10). However, except for CuCN, the other
reagents derived from CuX (X ) Cl, Br, I) showed slightly
decreased reactivity at lower temperatures (e.g., ca. 10%
recovery of 5a, entry 6).
We then carried out several reactions using substrates 10 and
11 to clarify the proposed mechanism. Reaction of isonicotinate
10 proceeded slowly even at somewhat higher temperatures
(0 °Csrt) (entry 11), whereas benzoate 11 was inert under the
same reaction conditions (entry 12). These results are consistent
with the double activation we proposed for the picolinoxy group
as mentioned above: chelation 5a > 10; electron-withdrawal
5a, 10 > 11.
2. Additional Study. Although we have achieved satisfactory
results using PhMgBr as a reagent source, phenyl zinc reagents
(21) The cis isomers of 6a and 8 (i.e., i and iii) were synthesized by methods
shown below. Isomer i: 1H NMR (300 MHz, CDCl3) δ-0.07 (s, 3 H),-0.06 (s,
3 H), 0.83 (s, 9 H), 2.26-2.49 (m, 2 H), 2.52-2.70 (m, 2 H), 3.62-3.79 (m, 3
H), 5.56 (dt, J ) 11, 7 Hz, 1 H), 5.65 (dd, J ) 11, 8 Hz, 1 H), 7.10-7.31 (m,
10 H); 13C NMR (75 MHz, CDCl3) δ-5.37 (-),-5.35 (-), 18.4 (+), 26.0 (-),
29.8 (+), 35.8 (+), 46.5 (-), 67.9 (+), 125.9 (-), 126.3 (-), 128.1 (-), 128.32
(-), 128.34 (-), 128.5 (-), 130.6 (-), 130.9 (-), 142.0 (+), 142.9 (+). Isomer
iii: 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.89 (s, 9 H),
1.87-2.13 (m, 2 H), 2.47-2.68 (m, 2 H), 3.45-3.60 (m, 1 H), 4.15 (dd, J )
13, 4 Hz, 1 H), 4.27 (dd, J ) 13, 5 Hz, 1 H), 5.54-5.66 (m, 2 H), 7.12-7.34
(m, 10 H); 13C NMR (75 MHz, CDCl3) δ-5.08 (-),-5.05 (-), 18.4 (+), 26.0
(-), 33.7 (+), 38.5 (+), 43.3 (-), 59.7 (+), 125.9 (-), 126.2 (-), 127.4 (-),
128.4 (-), 128.5 (-), 128.6 (-), 130.0 (-), 134.1 (-), 142.1 (+), 144.7 (+).
(22) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988,
53, 2390–2392.
(23) Defined as (% ee of product/% ee of substrate) × 100.
(24) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990,
46, 7033–7046.
(25) (a) Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K. Agric.
Biol. Chem. 1984, 48, 1841–1844. (b) Chattopadhyay, A.; Mamdapur, V. R. J.
Org. Chem. 1995, 60, 585–587.
(26) Duffield, J. J.; Pettit, G. R. J. Nat. Prod. 2001, 64, 472–479.
J. Org. Chem. Vol. 74, No. 5, 2009 1941

Kiyotsuka et al.
TABLE 1. Allylic Substitution of 5a and 10-13 with “Ph-Cu” derived from Ph-M and CuX
ratio of 6a:8:9:SMa
yield (%)b c
,
entry
substrate
reagent sources (equiv)
temp (°C)
time (h)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
10
11
12
13
5a
5a
5a
5a
5a
5a
PhMgBr (2), CuBr ·Me2S (0.5)
PhMgBr (2), CuBr ·Me2S (1)
PhMgBr (2), CuBr ·Me2S (2)
PhMgBr (1.2), CuBr ·Me2S (0.5)
PhMgBr (2), CuBr (0.5)
PhMgBr (3), CuBr (1.5)
PhMgBr (2), CuCl (0.5)
PhMgBr (2), CuI (0.5)
PhMgBr (2), CuCN (0.5)
0
0
0
0
1
1
1.5
1
1
1
1
1
1
1
13
20
18
3
4
4
1
1.5
1
99:1:0:0
99:1:0:0
98:2:0:0
98:0:1:1
97:3:0:0
90:0:0:10
98:2:0:0
90:2:8:0
96:0:2:2
99:1:0:0
46:0:0:54
0:0:0:100
60:0:40:0
99e:1:0:0
31:0:46:23
25:0:60:15
99:1:0:0
85:1:5:10
85:2:0:13
93:1:0:6
85
91
84
92
ND
83
ND
ND
88
0
-50 to -20
0
0
0
9
10
11
12
13
14
15
16
17
18
19
20
PhMgBr (3), CuCN (1.5)
-50 to -20
0 to rt
0 to rt
0 to rt
0d
-15 to 0
-15 to 0
-15 to 0
-15 to 0
-15 to 0
-15 to 0
86
ND
PhMgBr (2), CuBr ·Me2S (1)
PhMgBr (2), CuBr ·Me2S (1)
PhMgBr (2), CuBr ·Me2S (2)
PhMgBr (3), CuBr ·Me2S (1)
Ph2Zn·2LiBrf (3), CuBr ·Me2S (1.5)
Ph2Zn·2LiBrf (3), CuCN ·2LiCl (1.5)
ND
90
ND
ND
91
ND
ND
ND
g
Ph2Zn·2MgBr2 (2), CuBr ·Me2S (1)
g
Ph2Zn·2MgBr2 (2), CuCN ·2LiCl (1)
g
PhZnBr·MgBr2 (2), CuBr ·Me2S (1)
g
PhZnBr·MgBr2 (2), CuCN ·2LiCl (1)
1
a
SM: starting materials (substrates). Zero (0) is given in the cases where the product signal(s) was not detected by H NMR spectroscopy. b Isolated
1
yield of 6a (and 8, if produced). c ND: not determined. d Almost no reaction took place at -50 to -30 °C for 4 h. e An olefinic impurity (cis isomer in
ca. 20%) was seen in the H NMR spectrum. f Derived from PhLi and ZnBr2. g Derived from PhMgBr and ZnBr2.
1
TABLE 2. Allylic Substitution of Enantiomerically Enriched Allylic Picolinates
a Absolute configurations of 6a, 6d, and 6e were determined unambiguously (for 6a, see Scheme 5; for 6d,e, see Experimental Section), while that of
the products 6b, 6c, and 6f were determined by analogy. b Regioselectivities of >98:2 were determined by 1H NMR spectroscopy. c Chirality transfers
were determined by chiral HPLC analysis of the derivatives.
Reaction of (S)-5a (90% ee) was carried out with the Ph/Cu
reagents of 2/0.5 and 2/1 equiv (Table 2, entries 1-4). The
absolute configuration of product 6a in entry 4 was determined
to be R by comparison of the [R]D of the derived (S)-alcohol
establishing the anti SN2′ pathway (Scheme 5). The same
configuration for the major enantiomers of entries 1-3 was
assigned by comparison of the retention times on chiral HPLC.
Unexpectedly, the C.T. of the reaction with the Ph/Cu (2/0.5
34 ([R]25 -13 (c 0.12, CHCl3)) with that of the (R)-alcohol
D
reported ([R]23D +14.6 (c 1.03, CHCl3)),27,28 thus unambiguously
(28) In addition to (R)-6a (Table 2), the absolute configuration of (R)-6d
and (S)-6e in Table 2, (S)-6g in Scheme 6, (S)-6k and (S)-6m in Scheme 7, and
41 in Scheme 8 was determined by transformation into known compounds. See
the Experimental Section for (R)-6d and (S)-6e,g,k,m; Scheme 9 for 41. Other
products of the allylic substitution were assigned by analogy.
(27) Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamoto, H. Tetrahedron 1991,
47, 6983–6998.
1942 J. Org. Chem. Vol. 74, No. 5, 2009

Allylic Substitution with Aryl and Alkenyl Coppers
SCHEME 4. Preparation of Picolinates (S)-5a-d
SCHEME 5. Determination of the Absolute Configuration
of (R)-6a
SCHEME 6. Allylic Substitution of (S)-5a with Alkenyl
Reagents 35 (R ) H, C5H11, Ph)a b
,
equiv) at 0 °C (corresponding to conditions of Table 1, entry
1) was unacceptable (entry 1). However, we were pleased to
attain high level of C.T. (98%) at -60 to -40 °C (entry 3, cf.
entry 2). High efficiency was also recorded with the Ph/Cu
reagent at 2/1 equiv (entry 4). Additionally, reaction of entry 4
was successfully repeated with (S)-5a of 98% ee as presented
in entry 5. High C.T. was also attained with a reduced quantity
of the reagent (entry 6).
To clarify the steric as well as electronic effect on the
selectivity and reactivity, the following reagents and picolinates
were examined next. Substitution reactions with copper reagents
derived from o-Me and o-MeO-C6H4MgBr proceeded well to
produce the (R)-6b and (R)-6c, respectively (entries 7 and 8).
Importantly, yield, C.T., and regioselectivity were little influ-
enced by the substituent at the ortho position of the phenyl ring.
Next, substrates (S)-5b and (S)-5c produced (R)-6d and (S)-6e,
respectively, with efficiency comparable to that of (S)-5a (entries
9 and 10). These results clearly indicate that the anti SN2′
selectivity and the reactivity are not affected by any methylene
substituents at the R and γ positions. An additional result
presented in entry 11 is consistent with this generalization.
4. Alkenyl Reagents. We then investigated substitution of
(S)-5a with three alkenyl reagents derived from the Grignard
a The stereochemistry of (S)-6g was determined as described in the
Experimental Section, and that of (R)-6h,i was assigned by analogy.
b Chirality transfer (C.T.) was determined by chiral HPLC.
reagents 35 (R ) H, C5H11, Ph, each 2 equiv) and CuBr ·Me2S
(1 equiv) (Scheme 6), which afforded anti SN2′ products (S)-
6g, (R)-6h, and (R)-6i, respectively, in good yields with
efficiencies similar to those of the aryl reagents. The anti SN2′
course of the reaction was established by the absolute config-
uration of (S)-6g, which was determined by derivation to the
known compound as described in the Experimental Section.
Since the vinyl copper reagent 35 of R ) H is one of the least
reactive reagents, it is reasonable that the high reactivity of the
allylic picolinate compensates for the low reactivity29 of the
vinyl reagent.
(29) For example, refs 4b and 14a.
J. Org. Chem. Vol. 74, No. 5, 2009 1943

Kiyotsuka et al.
SCHEME 7. Allylic Substitution with Alkyl Reagentsa b
SCHEME 9. Determination of the Absolute Configuration
of 41
,
SCHEME 10. Two Possible Routes to the Key Intermediate
47
a The stereochemistry of (S)-6k and (S)-6m was determined as described
in the Experimental Section, and that of the other products was assigned
by analogy. b Chirality transfer (C.T.) was determined by chiral HPLC.
SCHEME 8. Construction of a Quaternary Center
duction of the ester with DIBAL followed by protection of the
resulting alcohol 37 with PMBCl afforded the PMB ether, which
was hydrolyzed to diol 38 in good yield. Monosilylation with
TBSCl was followed by esterification with PyCO2H to afford
the picolinate 40, which was 98% ee by chiral HPLC analysis.
Reaction of 40 with PhMgBr/CuBr·Me2S was carried out under
the conditions optimized above for (S)-5a to produce 41 in 81%
yield with ∼100% C.T. and with 82% regioselectivity. The
absolute configuration was determined by degradation to the
known compound 4330 (Scheme 9), which established anti SN2′
substitution unambiguously. Previously, this issue was realized
with alkyl reagents.31,32
7. Synthesis of (-)-Sesquichamaenol. To apply the present
allylic substitution reaction, we investigated synthesis of (-)-
sesquichamaenol (48 in Scheme 10), which was isolated from
several kinds of woods.32,33 Previously, several syntheses of
racemic 48 have been reported,32,34 whereas construction of the
asymmetric center of 48 seems hardly attainable by using
standard CsC bond-forming reactions such as enolate alkylation
because of steric reasons. We envisioned two allylic substitutions
to afford the key intermediate 47 (Scheme 10). Among these
possibilities, picolinate 44 and the Grignard reagent 45 in the
upper reaction are sterically more crowded than the picolinates/
reagents described in the above paragraphs, whereas the lower
reaction seemed difficult to effect regioselectively due to the
conjugation of the double bond to the aromatic ring in 46 and
5. Alkyl Reagents. Alkyl copper reagents derived from
RMgBr (R ) Me, Et, n-Bu) and CuBr ·Me2S were subjected to
substitution with (S)-5a according to the protocol developed for
PhMgBr to afford (S)-6j-l with excellent regioselectivity and
C.T. as shown in Scheme 7. Reaction of (S)-5c with EtMgBr
proceeded as well to furnish (S)-6m, which is the regioisomer
1
of (S)-6k. Comparison of the H NMR spectra of (S)-6k and
(S)-6m clearly indicated no contamination of the regioisomer
in each product. The absolute configuration of (S)-6k and (S)-
6m was determined by conversion to the known compounds
(see Experimental Section), thus establishing anti SN2′ selection
of the substitution.
6. Construction of a Quaternary Carbon. This subject was
investigated using picolinate 40, which was prepared by the
procedure shown in Scheme 8. In brief, Wittig reaction of
aldehyde 26 used in Scheme 4 with Ph3P ) C(Me)CO2Et gave
(E)-ester 36 stereoselectively, whereas use of the corresponding
phosphonate resulted in somewhat worse stereoselection. Re-
(30) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
448–451.
(31) (a) Nakamura, E.; Sekiya, K.; Arai, M.; Aoki, S. J. Am. Chem. Soc.
1989, 111, 3091–3093. (b) Spino, C.; Beaulieu, C. Angew. Chem., Int. Ed. 2000,
39, 1930–1932. (c) Kimura, M.; Tamazaki, T.; Kitazume, T.; Kubota, T. Org.
Lett. 2004, 6, 4651–4654.
(32) Ando, M.; Ibe, S.; Kagabu, S.; Nakagawa, T.; Asao, T.; Takase, K.
J. Chem. Soc., Chem. Commun. 1970, 1538.
(33) (a) Kuo, Y.-H.; Yu, M.-T. Chem. Pharm. Bull. 1996, 44, 2150–2152.
(b) Koorbanally, N. A.; Randrianarivelojosia, M.; Mulholland, D. A.; Van Ufford,
L. Q.; Van den Berg, A. J. J. J. Nat. Prod. 2002, 65, 1349–1352.
(34) Singh, V.; Khurana, A.; Kaur, I.; Sapehiyia, V.; Kad, G. L.; Singh, J.
J. Chem. Soc., Perkin Trans. 1 2002, 1766–1768.
1944 J. Org. Chem. Vol. 74, No. 5, 2009

Allylic Substitution with Aryl and Alkenyl Coppers
SCHEME 11. Synthesis of (-)-Sesquichamaenol (48)
mmol) in THF (3 mL) was added PhMgBr (0.20 mL, 0.90 M in
THF, 0.18 mmol) dropwise. After 30 min of stirring, the resulting
mixture was cooled to -60 °C. A solution of (S)-5a (36.5 mg,
0.0877 mmol, 90% ee) in THF (1 mL) was added to the mixture
dropwise. The resulting mixture was allowed to warm to -40 °C
over 1 h and diluted with hexane and saturated NH4Cl with vigorous
stirring. The layers were separated, and the aqueous layer was
extracted with hexane twice. The combined extracts were washed
with brine, dried over MgSO4, and concentrated to give a residue,
which was purified by chromatography on silica gel (hexane/EtOAc)
due to the steric bulkiness at the olefinic carbon and the i-Pr
group. Although both of the reactions are uncertain, we decided
to investigate the upper possibility.
Aldehyde 26 was subjected to Wittig reaction with an ylide
derived from [i-PrCH2PPh3]+Br- and NaN(TMS)2 to afford cis
olefin 49 as the sole product by 1H and 13C NMR spectroscopy
(Scheme 11). Cleavage of the acetal group and selective
protection of the primary OH of diol 50 produced the TBS ether
51. Subsequent Mitsunobu inversion with PyCO2H, DIAD, and
PPh3 proceeded regioselectively to afford the key compound
52 () 44 with CH2OTBS as R) in 74% yield and with 99% ee
by chiral HPLC analysis. Substitution of 52 with the reagent
derived from 45 (2 equiv) and CuBr ·Me2S (1 equiv) at -40
°C for 2 h proceeded smoothly to furnish 53 regioselectively.
Without purification, 53 was subjected to desilylation with
Bu4NF to afford alcohol 54 in 61% yield from 52 with 98% ee
and 99% C.T. Acid 55 was obtained from 54 by reduction of
the olefin and oxidation of the hydroxyl group. Finally,
demethylation with HBr in hot AcOH followed by reaction with
MeLi cleanly afforded (-)-sesquichamaenol (48), which was
confirmed by 1H and 13C NMR spectra.33 Note that 48 obtained
by the reverse sequence (MeLi then HBr/AcOH) was contami-
nated by minor byproducts.
to afford (R)-6a (29 mg, 89%): [R]26 -7.7 (c 0.626, CHCl3); IR
D
(neat) 1255, 1102, 836, 698 cm-1; 1H NMR (300 MHz, CDCl3) δ
-0.06 (s, 3 H), -0.05 (s, 3 H), 0.84 (s, 9 H), 2.35 (dt, J ) 6, 8 Hz,
2 H), 2.68 (dd, J ) 8, 7.5 Hz, 2 H), 3.42 (ddd, J ) 8, 7, 7 Hz, 1
H), 3.74 (dd, J ) 10, 7 Hz, 1 H), 3.76 (dd, J ) 10, 7 Hz, 1 H),
5.55 (dt, J ) 15, 6 Hz, 1 H), 5.67 (dd, J ) 15, 7 Hz, 1 H),
7.12-7.38 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ -5.3, 18.4,
26.0, 34.8, 36.0, 51.4, 67.6, 125.8, 126.4, 128.26, 128.34, 128.6,
131.2, 142.1, 142.6; HRMS (FAB) calcd for C24H34OSiNa [(M +
Na)+] 389.2277, found 389.2278. The enantiomeric information
(88% ee, 98% C.T.) was determined by HPLC analysis of the
corresponding alcohol: Chiralcel AD-H, hexane/i-PrOH ) 98/2,
0.4 mL/min, tR (min) ) 47.7 (S), 49.1 (R).
Determination of the Absolute Configuration (Scheme 5). To
an ice-cold solution of (R)-6a (120 mg, 0.327 mmol) in acetone/
H2O (4:1, 3 mL) were added NMO (50 mg, 0.43 mmol) and OsO4
(0.33 mL, 0.02 M in t-BuOH, 0.0066 mmol). After 3 h at 0 °C, the
mixture was diluted with H2O and Et2O. The layers were separated,
and the aqueous layer was extracted with Et2O twice. The combined
extracts were dried over MgSO4 and concentrated to give a residue,
which was purified by chromatography on silica gel (hexane/EtOAc)
to afford the corresponding diol (115 mg, 87%).
Next, the enantiomer of 52 was synthesized by DCC-assisted
esterification of 51 with PyCO2H and converted to ent-53 as
well (scheme not shown). This example demonstrates an easy
access to the both enantiomers of picolinates for the allylic
substitution from an available one enantiomer.
Conclusion
To an ice-cold solution of the above diol (110 mg, 0.244 mmol)
in MeOH/H2O (4:1, 2.5 mL) were added Bu4NI (27 mg, 0.073
mmol) and NaIO4 (68 mg, 0.32 mmol). After 3 h at 0 °C, NaBH4
(40 mg, 1.06 mmol) was added to the mixture. The mixture was
stirred at 0 °C for 30 min and diluted with saturated NH4Cl and
Et2O. The layers were separated, and the aqueous layer was
extracted with Et2O twice. The combined extracts were washed with
aqueous Na2S2O3, dried over MgSO4, and concentrated to give a
residue, which was purified by chromatography on silica gel
(hexane/EtOAc) to afford 34 (51 mg, 78%): [R]25D -13.0 (c 0.12,
We have developed allylic substitution for aryl and alkenyl
reagents for the first time using the picolinoxy group as a
powerful leaving group. The reaction proceeded with high anti
SN2′ selectivity and with efficient chirality transfer (C.T.).
Almost the same result was observed with alkyl-MgBr/
CuBr·Me2S as well. Furthermore, construction of a quaternary
carbon and synthesis of (-)-sesquichamaenol (48) have been
achieved. Additionally, PyCO2H, DCC, RMgBr, and
CuBr·Me2S are inexpensive, and both enantiomers of the
starting allylic alcohols are easily available by asymmetric
reactions and from natural sources. The concept of the chelation-
induced activation of the picolinoxy leaving group seems
applicable to other types of coupling reactions. We are continu-
ing investigation along this line.
CHCl3); cf. [R]23 +14.6 (c 1.03, CHCl3) for the R enantiomer;27
D
1H NMR (300 MHz, CDCl3) δ 0.07 (s, 6 H), 0.91 (s, 9 H), 2.75
(dd, J ) 7, 4 Hz, 1 H), 3.09 (ddd, J ) 7, 7, 5 Hz, 1 H), 3.89 (ddd,
J ) 11, 7, 5 Hz, 1 H), 3.93 (d, J ) 7 Hz, 2 H), 4.08 (ddd, J ) 11,
1
7, 4 Hz, 1 H), 7.19-7.36 (m, 5 H). The H NMR spectrum was
identical with the data reported.27
(R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(2-methylphenyl)-6-
phenyl-3-hexene ((R)-6b) (Table 2, entry 7). Yield 81% from (S)-
Experimental Section
5a (90% ee), 89% ee, 99% C.T.; IR (neat) 1255, 1102, 837 cm-1
;
General Procedure of the Allylic Substitution (Table 2,
entry 4). To an ice-cold suspension of CuBr ·Me2S (18 mg, 0.088
1H NMR (300 MHz, CDCl3) δ -0.04 (s, 3 H), -0.02 (s, 3 H),
0.85 (s, 9 H), 2.28-2.39 (m, 2 H), 2.33 (s, 3 H), 2.67 (dd, J ) 8,
J. Org. Chem. Vol. 74, No. 5, 2009 1945

Kiyotsuka et al.
6 Hz, 2 H), 3.67-3.84 (m, 3 H), 5.50 (dt, J ) 15, 7 Hz, 1 H), 5.64
(dd, J ) 15, 6 Hz, 1 H), 7.11-7.32 (m, 9 H); 13C NMR (75 MHz,
CDCl3) δ -5.34, -5.30, 18.4, 19.9, 26.0, 34.8, 36.0, 46.6, 67.1,
125.8, 125.9, 126.1, 127.0, 128.3, 128.5, 130.3, 131.0, 131.2, 136.4,
140.6, 142.1; HRMS (FAB) calcd for C25H36OSiNa [(M + Na)+]
403.2433, found 403.2432. The enantiomeric information was
determined by HPLC analysis of the corresponding alcohol:
Chiralcel AD-H, hexane/i-PrOH ) 97/3, 0.5 mL/min, tR (min) )
39.0 (S), 40.7 (R).
(R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(2-methoxyphenyl)-6-
phenyl-3-hexene ((R)-6c) (Table 2, entry 8). Yield 85% from (S)-
5a (90% ee), 88% ee, 98% C.T.; [R]28D -9.7 (c 0.682, CHCl3); IR
(neat) 1241, 1103, 837, 751 cm-1; 1H NMR (300 MHz, CDCl3) δ
-0.041 (s, 3 H), -0.038 (s, 3 H), 0.84 (s, 9 H), 2.34 (dt, J ) 7, 8
Hz, 2 H), 2.68 (dd, J ) 8, 6 Hz, 2 H), 3.71 (dd, J ) 10, 8 Hz, 1
H), 3.78 (dd, J ) 10, 5 Hz, 1 H), 3.80 (s, 3 H), 3.85-3.93 (m, 1
H), 5.57 (dt, J ) 16, 7 Hz, 1 H), 5.73 (dd, J ) 16, 7 Hz, 1 H), 6.84
(dd, J ) 8, 1 Hz, 1 H), 6.88 (ddd, J ) 8, 8, 1 Hz, 1 H), 7.10 (dd,
J ) 8, 2 Hz, 1 H), 7.13-7.21 (m, 4 H), 7.22-7.29 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ -5.3 (-), 18.4 (+), 26.0 (-), 34.8 (+),
36.1 (+), 44.5 (-), 55.4 (-), 66.5 (+), 110.6 (-), 120.5 (-), 125.7
(-), 127.2 (-), 128.3 (-), 128.6 (-), 128.9 (-), 130.7 (+), 130.9
(-), 131.1 (-), 142.3 (+), 157.1 (+); HRMS (FAB) calcd for
C25H36O2SiNa [(M + Na)+] 419.2382, found 419.2385. The
enantiomeric information was determined by HPLC analysis of the
corresponding alcohol: Chiralcel OD-H, hexane/i-PrOH ) 97/3,
0.5 mL/min, tR (min) ) 45.2 (S), 54.1 (R).
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-4,6-diphenyl-2-hexene
((S)-6e) (Table 2, entry 10). According to the typical procedure,
a solution of (S)-5c (59 mg, 0.143 mmol, 95% ee) dissolved in
THF (1 mL) was added to a mixture of CuBr·Me2S (29 mg, 0.14
mmol) in THF (5 mL) and PhMgBr (0.27 mL, 1.07 M in THF,
0.287 mmol) at -40 °C, and the mixture was stirred -40 °C for
1 h to furnish (S)-6e (49 mg, 93%): [R]24 +14 (c 0.59, CHCl3);
D
1
IR (neat) 1254, 836, 776 cm-1; H NMR (300 MHz, CDCl3) δ
0.06 (s, 6 H), 0.91 (s, 9 H), 2.05 (ddd, J ) 8, 8, 8 Hz, 2 H),
2.48-2.68 (m, 2 H), 3.30 (ddd, J ) 8, 8, 8 Hz, 1 H), 4.16 (d, J )
5 Hz, 2 H), 5.57 (dt, J ) 15, 5 Hz, 1 H), 5.82 (dd, J ) 15, 8 Hz,
1 H), 7.10-7.35 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ -5.0
(-), 18.5 (+), 26.0 (-), 33.8 (+), 37.5 (+), 47.9 (-), 63.9 (+),
125.8 (-), 126.3 (-), 127.7 (-), 128.4 (-), 128.52 (-), 128.54
(-), 129.5 (-), 134.3 (-), 142.3 (+), 144.4 (+); HRMS (FAB)
calcd for C24H34OSiNa [(M + Na)+] 389.2277, found 389.2287.
The enantiomeric information (92% ee, 97% C.T.) was determined
by HPLC analysis of the corresponding alcohol: Chiralcel AD-H,
hexane/i-PrOH ) 98/2, 0.3 mL/min, tR (min) ) 95.4 (S), 99.2 (R).
Determination of the Absolute Configuration. A stream of O3
in O2 was gently bubbled into a solution of (S)-6e (92 mg, 0.25
mmol) in MeOH at -78 °C for 20 min. Excess O3 remaining in
the solution was purged by bubbling argon at -78 °C, and NaBH4
(95 mg, 2.51 mmol) was added at -78 °C. The cooling bath was
removed. The mixture was stirred at room temperature for 1 h and
diluted with saturated NH4Cl. The resulting mixture was extracted
with EtOAc three times. The combined extracts were dried over
MgSO4 and concentrated. The residue was purified by chromatog-
raphy on silica gel (hexane/EtOAc) to furnish the alcohol 57 (56
(R,E)-1,5-Diphenyl-3-hexene ((R)-6d) (Table 2, entry 9).
According to the typical procedure, a solution of (S)-5b (114 mg,
0.405 mmol, 89% ee) in THF (4 mL) was added to a mixture of
CuBr·Me2S (84 mg, 0.41 mmol) in THF (10 mL) and PhMgBr
(0.86 mL, 0.95 M in THF, 0.82 mmol) at -60 °C, and the mixture
was allowed to warm to -40 °C over 1 h to afford a mixture of
1
(R)-6d and Ph2 in a 83:17 ratio by H NMR analysis (93 mg in
1
total, 86% yield of (R)-6d): H NMR (300 MHz, CDCl3) δ 1.31
mg, 99%): [R]24 -11 (c 0.41, CHCl3); cf. [R]D +6.92 (c 1.82,
(d, J ) 7 Hz, 3 H), 2.33 (dt, J ) 7, 7 Hz, 2 H), 2.68 (t, J ) 7 Hz,
2 H), 3.40 (dq, J ) 7, 7 Hz, 1 H), 5.48 (dt, J ) 15, 7 Hz, 1 H),
5.60 (dd, J ) 15, 7 Hz, 1 H), 7.14-7.20 (m, 4 H), 7.23-7.28 (m,
6 H); 13C NMR (75 MHz, CDCl3) δ 21.5 (-), 34.5 (+), 36.1 (+),
42.3 (-), 125.8 (-), 126.0 (-), 127.3 (-), 128.3 (-), 128.4 (-),
128.6 (-), 135.8 (-), 142.1 (+), 146.4 (+); HRMS (EI) calcd for
236.1565 C18H20 (M+), found 236.1567.
D
CHCl3) for the (S)-enantiomer;36 1H NMR (300 MHz, CDCl3) δ
1.33 (br s, 1 H), 1.81-2.12 (m, 2 H), 2.40-2.62 (m, 2 H),
2.73-2.88 (m, 1 H), 3.67-3.80 (m, 2 H), 7.05-7.40 (m, 10 H);
13C NMR (75 MHz, CDCl3) δ 33.5 (+), 33.7 (+), 48.2 (-), 67.7
(+), 125.9 (-), 127.0 (-), 128.25 (-), 128.39 (-), 128.45 (-),
1
128.8 (-), 142.0 (+), 142.1 (+). The H NMR and 13C NMR
spectra were identical with the data reported.36
(R,E)-1-[(2-Phenylpent-3-enyloxy)methyl]-4-methoxyben-
zene ((R)-6f) (Table 2, entry 11). According to the typical
procedure, a solution of (S)-5d (60.0 mg, 0.183 mmol, 97% ee) in
THF (1 mL) was added to a mixture of CuBr ·Me2S (40 mg, 0.195
mmol) and PhMgBr (0.50 mL, 0.75 M in THF, 0.50 mmol) in THF
(5 mL) at -60 °C. The resulting mixture was allowed to warm to
-40 °C over 1 h and diluted with hexane and saturated NH4Cl to
afford a residue, which was purified by chromatography on silica
gel (hexane/EtOAc) to give (R)-6f (43 mg, 83%): IR (neat) 1612,
Determination of the Absolute Configuration and C.T. A
stream of O3 in O2 was gently bubbled into a solution of the mixture
of (R)-6d and Ph2 (222 mg in total, (R)-6d/Ph2 ) 81:19) in MeOH
at -78 °C for 20 min. Excess O3 remaining in the solution was
purged by bubbling argon at -78 °C for 10 min and NaBH4 (309
mg, 8.17 mmol) was added. After stirring for 1 h at -78 °C, the
resulting mixture was allowed to warm to room temperature, and
diluted with EtOAc and saturated NH4Cl. The layers were separated,
and the aqueous layer was extracted with EtOAc three times. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated to give a residue, which was purified by chromatog-
raphy on silica gel (hexane/EtOAc) to afford alcohol 56: 89% ee
and 99% C.T. by HPLC analysis (Chiralcel OB-H, hexane/i-PrOH
1
1513, 1248 cm-1; H NMR (300 MHz, CDCl3) δ 1.68 (d, J ) 6
Hz, 3 H), 3.53-3.68 (m, 3 H), 3.80 (s, 3 H), 4.45 (s, 2 H), 5.51
(dq, J ) 15, 6 Hz, 1 H), 5.63 (dd, J ) 15, 7 Hz, 1 H), 6.85 (d, J
) 8 Hz, 2 H), 7.15-7.23 (m, 5 H), 7.25-7.33 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 18.2 (-), 48.9 (-), 55.3 (-), 72.7 (+), 73.7
(+), 113.8 (-), 126.4 (-), 126.7 (-), 128.0 (-), 128.4 (-), 129.3
(-), 130.6 (+), 131.9 (-), 142.5 (+), 159.1 (+); HRMS (EI) calcd
for C19H22O2 (M+) 282.1620, found 282.1627. The enantiomeric
information (97% ee, 99% C.T.) was determined by HPLC analysis
of the corresponding alcohol: Chiralcel AD-H; hexane/i-PrOH )
97/3, 0.3 mL/min, tR (min) ) 29.9 (R), 33.7 (S).
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-ethenyl-6-phenyl-3-
hexene ((S)-6g) (Scheme 6). Yield 81%, 88% ee, 98% C.T.; IR
(neat) 1256, 1104, 836 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.05
(s, 6 H), 0.90 (s, 9 H), 2.35 (dt, J ) 7, 8 Hz, 2 H), 2.69 (dd, J )
) 98/2, 0.2 mL/min, tR (min) ) 56.6 (S), 61.3 (R)); [R]28 -11.7
D
(c 1.2, CHCl3); cf. [R]20D -10.8 (c 1.0, CHCl3) for the S enantiomer
of 78% ee;351H NMR (300 MHz, CDCl3) δ 1.26 (d, J ) 7 Hz, 3
H), 2.93 (tq, J ) 7, 7 Hz, 1 H), 3.67 (d, J ) 7 Hz, 2 H), 7.19-7.26
1
(m, 2 H), 7.28-7.34 (m, 3 H). The H NMR spectrum of the
product was identical with that reported.35
(35) Xie, J.-H.; Zhou, Z.-T.; Kong, W.-L.; Zhou, Q.-L. J. Am. Chem. Soc.
2007, 129, 1868–1869.
(36) Spino, C.; Gund, V. G.; Nadeau, C. J. Comb. Chem. 2005, 7, 345–352.
1946 J. Org. Chem. Vol. 74, No. 5, 2009

Allylic Substitution with Aryl and Alkenyl Coppers
7, 6 Hz, 2 H), 2.87 (ddt, J ) 8, 8, 7 Hz, 1 H), 3.54 (d, J ) 7 Hz,
2 H), 4.98-5.08 (m, 2 H), 5.40 (dd, J ) 16, 8 Hz, 1 H), 5.55 (dt,
J ) 16, 7 Hz, 1 H), 5.79 (ddd, J ) 17, 11, 7 Hz, 1 H), 7.15-7.23
(m, 3 H), 7.25-7.32 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ -5.2,
18.5, 26.0, 34.8, 36.0, 49.5, 66.6, 115.4, 125.8, 128.3, 128.5, 130.2,
131.3, 138.9, 142.1. The enantiomeric information was determined
by HPLC analysis of the corresponding alcohol: Chiralcel AD-H,
hexane/i-PrOH ) 97/3, 0.3 mL/min, tR (min) ) 30.5 (R), 31.9 (S).
HPLC analysis (Chiralcel OB-H, hexane/i-PrOH ) 98/2, 0.2 mL/
min, tR (min) ) 32.6 (S), 33.8 (R)) showed that retention time of
60 thus synthesized was identical with that of 60 synthesized from
(S)-6k (R ) Et in Scheme 7) ((i) H2, Pd/C, MeOH and EtOAc; (ii)
Bu4NF; (iii) BzCl, pyridine, CH2Cl2), while determination of the
absolute configuration of (S)-6k was independently carried out as
described below.
(R,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-(1-pentylethenyl)-6-
phenyl-3-hexene ((R)-6h) (Scheme 6). Yield 75%, 87% ee, 97%
1
C.T.; H NMR (300 MHz, CDCl3) δ 0.02 (s, 3 H), 0.03 (s, 3 H),
0.88 (s, 9 H), 0.89 (m, 3 H), 1.21-1.48 (m, 6 H), 1.97 (t, J ) 8
Hz, 2 H), 2.32 (ddd, J ) 8, 8, 7 Hz, 2 H), 2.67 (t, J ) 8 Hz, 2 H),
2.76 (ddd, J ) 7, 7, 7 Hz, 1 H), 3.55 (dd, J ) 10, 7 Hz, 1 H), 3.65
(dd, J ) 10, 7 Hz, 1 H), 4.71 (s, 1 H), 4.78 (s, 1 H), 5.37 (dd, J )
15, 8 Hz, 1 H), 5.50 (dt, J ) 15, 6 Hz, 1 H), 7.14-7.30 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ -5.22 (-), -5.16 (-), 14.2 (-),
18.4 (+), 22.7 (+), 26.0 (-), 27.5 (+), 31.8 (+), 34.7 (+), 35.6
(+), 36.1 (+), 51.5 (-), 66.0 (+), 109.3 (+), 125.8 (-), 128.3
(-), 128.5 (-), 130.8 (-), 131.3 (-), 142.2 (+), 150.4 (+); HRMS
(FAB) calcd for C25H42OSiNa [(M + Na)+] 409.2903, found
409.2905. The enantiomeric information was determined by HPLC
analysis of the corresponding alcohol: Chiralcel AD-H, hexane/i-
PrOH ) 97/3, 0.3 mL/min, tR (min) ) 26.0 (R), 28.0 (S).
Determination of the Absolute Configuration. To a solution
of (S)-6g (42 mg, 0.153 mmol) in MeOH and EtOAc (1:1, 2 mL)
was added 10% Pd/C (20 mg). The mixture was stirred at room
temperature for 2 h under H2 atmosphere and filtered through a
pad of Celite. The filtrate was concentrated to give a residue, which
was purified by chromatography on silica gel (hexane/EtOAc) to
afford 58 (40 mg, 94%): [R]28D 0 (c 0.80, CHCl3); IR (neat) 1256,
1094, 835, 774 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 6 H),
0.85 (t, J ) 7 Hz, 3 H), 0.89 (s, 9 H), 1.18-1.42 (m, 8 H),
1.54-1.66 (m, 1 H), 2.60 (t, J ) 8 Hz, 2 H), 3.46 (d, J ) 5 Hz, 2
H), 7.15-7.20 (m, 3 H), 7.23-7.30 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ -5.3 (-), 11.3 (-), 18.4 (+), 23.6 (+), 26.0 (-), 26.7
(+), 30.4 (+), 32.0 (+), 36.0 (+), 42.0 (-), 65.3 (+), 125.6 (-),
128.3 (-), 128.5 (-), 143.0 (+).
(R,E)-1-[(tert-Butyldimethylsilyl)oxy]-6-phenyl-2-(1-phenylethe-
nyl)-3-hexene ((R)-6i) (Scheme 6). Yield 85%, 87% ee, 97% C.T.;
1
IR (neat) 1256, 1103, 836 cm-1; H NMR (300 MHz, CDCl3) δ
-0.09 (s, 6 H), 0.79 (s, 9 H), 2.22-2.32 (m, 2 H), 2.60 (dd, J )
8, 8 Hz, 2 H), 3.28 (ddd, J ) 7, 7, 6 Hz, 1 H), 3.52 (dd, J ) 10,
7 Hz, 1 H), 3.62 (dd, J ) 10, 6 Hz, 1 H), 4.96 (s, 1 H), 5.22 (s, 1
H), 5.44 (dd, J ) 16, 7 Hz, 1 H), 5.52 (dt, J ) 16, 6 Hz, 1 H),
7.04-7.33 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ -5.3, -5.2,
18.4, 26.0, 34.7, 36.0, 50.2, 66.2, 113.7, 125.8, 126.7, 127.2, 128.1,
128.3, 128.6, 131.1, 131.3, 142.1, 142.6, 149.6; HRMS (FAB) calcd
for C26H36OSiNa [(M + Na)+] 415.2433, found 415.2430. The
enantiomeric information was determined by HPLC analysis of the
corresponding alcohol: Chiralcel AD-H, hexane/i-PrOH ) 97/3,
0.3 mL/min, tR (min) ) 47.6 (S), 59.9 (R).
To an ice-cold solution of 58 (40 mg, 0.125 mmol) in THF (1
mL) was added Bu4NF (0.19 mL, 1.0 M in THF, 0.19 mmol). The
reaction was carried out at room temperature for 3 h, and quenched
by addition of saturated NH4Cl. The organic phase was separated,
and the aqueous phase was extracted with EtOAc three times. The
combined organic layers were dried over MgSO4 and concentrated
to afford a residue, which was purified by chromatography on silica
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-methyl-6-phenyl-3-
hexene ((S)-6j) (Scheme 7). Yield 90% from (S)-5a (90% ee), 86%
ee, 96% C.T.; IR (neat) 1257, 1078, 837, 775 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.04 (s, 6 H), 0.89 (s, 9 H), 0.96 (d, J ) 7 Hz, 3
H), 2.20-2.35 (m, 3 H), 2.67 (t, J ) 7 Hz, 2 H), 3.34 (dd, J ) 9,
7 Hz, 1 H), 3.46 (dd, J ) 9, 6 Hz, 1 H), 5.35 (dd, J ) 16, 7 Hz,
1 H), 5.49 (dt, J ) 16, 7 Hz, 1 H), 7.14-7.21 (m, 3 H), 7.24-7.31
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ -5.21, -5.18, 16.8, 18.5,
26.0, 34.7, 36.2, 39.4, 68.4, 125.8, 128.3, 128.6, 129.3, 133.6, 142.2.
HRMS (FAB) calcd for C19H32OSiNa [(M + Na)+] 327.2120, found
327.2122. The enantiomeric information was determined by HPLC
analysis of the corresponding alcohol: Chiralcel AD-H, hexane/i-
PrOH ) 97/3, 0.3 mL/min, tR (min) ) 30.0 (R), 31.3 (S).
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-ethyl-6-phenyl-3-hex-
ene ((S)-6k) (Scheme 7). Yield 91% from (S)-5a (90% ee), 87%
ee, 97% C.T.; IR (neat) 1256, 1103, 836 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.03 (s, 6 H), 0.82 (t, J ) 7 Hz, 3 H), 0.89 (s, 9 H),
1.07-1.34 (m, 1 H), 1.46-1.62 (m, 1 H), 1.94-2.08 (m, 1 H),
2.28-2.38 (m, 2 H), 2.68 (dd, J ) 7, 6 Hz, 2 H), 3.43 (dd, J ) 10,
7 Hz, 1 H), 3.48 (dd, J ) 10, 6 Hz, 1 H), 5.20 (dddd, J ) 15, 8,
2, 2 Hz, 1 H), 5.48 (dt, J ) 15, 7 Hz, 1 H), 7.13-7.35 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ -5.2, 11.7, 18.5, 24.0, 26.0, 34.8,
36.3, 47.3, 66.9, 125.8, 128.3, 128.6, 130.9, 132.3, 142.2; HRMS
(FAB) calcd for C20H34OSiNa [(M + Na)+] 341.2277, found
341.2269. The enantiomeric information was determined by HPLC
analysis of the corresponding alcohol: Chiralcel AD-H, hexane/i-
PrOH ) 97/3, 0.3 mL/min, tR (min) ) 28.7 (R), 29.8 (S).
gel (hexane/EtOAc) to furnish 59 (24 mg, 93%): [R]28 -1.2 (c
D
1
0.803, CHCl3); IR (neat) 3351, 1453, 1030 cm-1; H NMR (300
MHz, CDCl3) δ 0.89 (t, J ) 7 Hz, 3 H), 1.21 (br s, 1 H), 1.26-1.45
(m, 6 H), 1.56-1.68 (m, 3 H), 2.61 (t, J ) 8 Hz, 2 H), 3.54 (d, J
) 4 Hz, 2 H), 7.13-7.22 (m, 3 H), 7.23-7.30 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 11.2 (-), 23.4 (+), 26.7 (+), 30.4 (+), 31.9
(+), 36.0 (+), 42.0 (-), 65.3 (+), 125.7 (-), 128.3 (-), 128.5
(-), 142.8 (+).
To an ice-cold solution of 59 (24 mg, 0.117 mmol) in pyridine
and CH2Cl2 (1:1, 1 mL) was added BzCl (0.027 mL, 0.233 mmol).
The resulting mixture was stirred at room temperature overnight
and diluted with EtOAc and H2O. The excess reagent was quenched
with N,N-dimethyl-1,3-propanediamine (0.050 mL, 0.40 mmol). The
mixture was stirred at room temperature for 20 min. The organic
phase was separated, and the aqueous phase was extracted with
EtOAc three times. The combined organic layers were dried over
MgSO4 and concentrated to give a residue, which was purified by
chromatography on silica gel (hexane/EtOAc) to afford 60 (23 mg,
1
63%): [R]28 -1.8 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3)
D
δ 0.94 (t, J ) 8 Hz, 3 H), 1.35-1.52 (m, 6 H), 1.58-1.77 (m, 3
H), 2.62 (t, J ) 8 Hz, 2 H), 4.24 (d, J ) 6 Hz, 2 H), 7.13-7.21
(m, 3 H), 7.22-7.30 (m, 2 H), 7.44 (dddd, J ) 8, 8, 1, 1 Hz, 2 H),
7.56 (dddd, J ) 8, 8, 1, 1 Hz, 1 H), 8.04 (ddd, J ) 8, 1, 1 Hz, 2
H); 13C NMR (75 MHz, CDCl3) δ 11.2 (-), 24.1 (+), 26.6 (+),
30.9 (+), 31.9 (+), 36.0 (+), 39.0 (-), 67.3 (+), 125.7 (-), 128.3
(-), 128.43 (-), 128.45 (-), 129.6 (-), 130.6 (+), 132.9 (-), 142.7
(+), 152.1 (+), 166.8 (+); HRMS (EI) calcd for C21H26O2 (M+)
310.1934, found 310.1933.
Determination of the Absolute Configuration. To an ice-cold
solution of (S)-6k (110 mg, 0.345 mmol) in acetone/H2O (4:1, 3.5
mL) were added NMO (53 mg, 0.45 mmol) and OsO4 (0.175 mL,
0.02 M in t-BuOH, 0.0035 mmol). After 5 h at 0 °C, the mixture
was diluted with H2O and Et2O. The layers were separated, and
J. Org. Chem. Vol. 74, No. 5, 2009 1947

Kiyotsuka et al.
NH4Cl. The organic phase was separated, and the aqueous phase
was extracted with EtOAc three times. The combined organic layers
were dried over MgSO4 and concentrated to afford a residue, which
was purified by chromatography on silica gel (hexane/EtOAc) to
1
furnish 63 (14 mg, 95%): H NMR (300 MHz, CDCl3) δ 0.85 (t,
J ) 7 Hz, 3 H), 1.24-1.78 (m, 5 H), 1.88-2.02 (m, 1 H),
2.45-2.70 (m, 2 H), 4.13 (dd, J ) 6, 1 Hz, 1 H), 5.46 (dd, J ) 15,
9 Hz, 1 H), 5.64 (dt, J ) 15, 6 Hz, 1 H), 7.14-7.22 (m, 3 H),
7.24-7.32 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 11.7 (-), 27.9
(+), 33.7 (+), 36.6 (+), 43.9 (-), 63.9 (+), 125.7 (-), 128.4 (-),
128.5 (-), 129.6 (-), 137.0 (-), 142.8 (+); HRMS (EI) calcd for
C14H20O (M+) 204.1514, found 204.1516. The enantiomeric
information (92% ee, 97% C.T.) was determined by chiral HPLC
analysis: Chiralcel OB-H, hexane/i-PrOH ) 98/2, 0.3 mL/min, tR
(min) ) 31.8 (R), 33.8 (S).
the aqueous layer was extracted with Et2O twice. The combined
extracts were dried over MgSO4 and concentrated to give a residue,
which was purified by chromatography on silica gel (hexane/EtOAc)
to afford 61 (105 mg, 85%).
To an ice-cold solution of 61 (55 mg, 0.16 mmol) in MeOH/
H2O (5:1, 2 mL) were added Bu4NI (18 mg, 0.049 mmol) and NaIO4
(48 mg, 0.22 mmol). After 4 h at 0 °C, NaBH4 (20 mg, 0.53 mmol)
was added to the mixture. The mixture was stirred at 0 °C for 30
min and diluted with saturated NH4Cl and Et2O. The layers were
separated, and the aqueous layer was extracted with Et2O twice.
The combined extracts were washed with aqueous Na2S2O3, dried
over MgSO4, and concentrated to give a residue, which was purified
by chromatography on silica gel (hexane/EtOAc) to afford 62 (21
mg, 61%): [R]25D -10.0 (c 0.10, CHCl3); cf. [R]26D -11.41 (c 1.42,
CHCl3);371H NMR (300 MHz, CDCl3) δ 0.07 (s, 6 H), 0.90 (s, 9
H), 0.92 (t, J ) 8 Hz, 3 H), 1.19-1.35 (m, 2 H), 1.58-1.72 (m, 1
H), 2.92 (dd, J ) 6, 4 Hz, 1 H), 3.60 (dd, J ) 10, 7 Hz, 1 H),
3.60-3.68 (m, 1 H), 3.70-3.80 (m, 1 H), 3.81 (dd, J ) 10, 4 Hz,
1 H); 13C NMR (75 MHz, CDCl3) δ -5.55, -5.49, 11.9, 18.2,
20.7, 25.9, 43.7, 66.7, 67.4.
Determination of the Absolute Configuration. A stream of O3
in O2 was gently bubbled into a solution of (S)-6m (78 mg, 0.245
mmol) in MeOH at -78 °C for 20 min. Excess O3 remaining in
the solution was purged by bubbling argon at -78 °C, and NaBH4
(93 mg, 2.45 mmol) was added. The cooling bath was removed,
and the solution was stirred at room temperature for 1 h. Saturated
NH4Cl was added to the solution, and the resulting mixture was
extracted with EtOAc three times. The combined extracts were dried
over MgSO4 and concentrated to obtain a residue, which was
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-2-butyl-6-phenyl-3-hex-
purified by chromatography on silica gel (hexane/EtOAc) to give
ene ((S)-6l) (Scheme 7). Yield 89%, 86% ee, 96% C.T.; IR (neat)
1
alcohol 64 (38 mg, 87%): [R]23 0 (c 0.2, CHCl3); H NMR (300
1
1256, 1077, 837, 775 cm-1; H NMR (300 MHz, CDCl3) δ 0.05
D
MHz, CDCl3) δ 1.92 (t, J ) 7 Hz, 3 H), 1.36-1.54 (m, 2 H),
1.56-4.74 (m, 2 H), 2.64 (t, J ) 8 Hz, 2 H), 3.60 (d, J ) 5 Hz, 2
H), 7.14-7.33 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 11.3 (-),
23.3 (+), 32.6 (+), 33.5 (+), 41.8 (-), 65.3 (+), 125.9 (-), 128.6
(-), 142.9 (+). The 1H NMR and 13C NMR spectra were identical
with the data reported.38
(s, 6 H), 0.82-1.00 (br s, 12 H), 1.16-1.35 (m, 5 H), 1.44-1.54
(m, 1 H), 2.03-2.16 (m, 1 H), 2.33 (dt, J ) 7, 7 Hz, 2 H), 2.69 (t,
J ) 7 Hz, 2 H), 3.37-3.53 (m, 2 H), 5.21 (dd, J ) 15, 8 Hz, 1 H),
5.48 (dt, J ) 15, 7 Hz, 1 H), 6.85-7.22 (m, 3 H), 7.25-7.32 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ -5.21, -5.17, 14.2, 18.5,
22.9, 26.0, 29.3, 30.9, 34.7, 36.2, 45.5, 67.2, 125.8, 128.3, 128.6,
130.6, 132.7, 142.2; HRMS (FAB) calcd for C22H38OSiNa [(M +
Na)+] 369.2590, found 369.2594. The enantiomeric information was
determined by HPLC analysis of the corresponding alcohol:
Chiralcel AD-H, hexane/i-PrOH ) 97/3, 0.3 mL/min, tR (min) )
25.9 (R), 27.6 (S).
To an ice-cold solution of the above alcohol (25 mg, 0.14 mmol)
in CH2Cl2 (5 mL) were added CBr4 (56 mg, 0.169 mmol) and PPh3
(48 mg, 0.183 mmol) portionwise. The mixture was stirred at 0 °C
for 2 h and filtered through a pad of Celite. The filtrate was
concentrated to afford a residual oil, which was purified by
chromatography on silica gel (hexane/EtOAc) to furnish bromide
65 (20 mg, 59%): [R]25D +6 (c 0.2, CHCl3), cf. [R]D +10.8 (c 1.5,
CHCl3) for the same enantiomer;391H NMR (300 MHz, CDCl3) δ
0.91 (t, J ) 8 Hz, 3 H), 1.43-1.80 (m, 5 H), 2.53-2.73 (m, 2 H),
3.52 (d, J ) 4 Hz, 2 H), 7.16-7.24 (m, 3 H), 7.25-7.34 (m, 2 H);
13C NMR (75 MHz, CDCl3) δ 10.9 (-), 25.2 (+), 33.0 (+), 34.1
(+), 38.8 (+), 40.5 (-), 125.9 (-), 128.4 (-), 128.5 (-), 142.2
(+); HRMS (EI) calcd for C12H17Br (M+) 242.0514, found
242.0518. The 1H NMR and 13C NMR spectra were identical with
the data reported.39
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-4-ethyl-6-phenyl-2-hex-
ene ((S)-6m) (Scheme 7). Yield 92% from (S)-5c (95% ee), 92%
ee, 97% C.T.; [R]23 +4.7 (c 0.42, CHCl3); IR (neat) 1462, 1255,
D
1
1092, 837 cm-1; H NMR (300 MHz, CDCl3) δ 0.099 (s, 3 H),
0.101 (s, 3 H), 0.86 (t, J ) 7 Hz, 3 H), 0.93 (s, 9 H), 1.18-1.80
(m, 6 H), 1.87-2.00 (m, 1 H), 2.45-2.70 (m, 2 H), 4.19 (d, J )
5 Hz, 2 H), 5.43 (dd, J ) 15, 8 Hz, 1 H), 5.55 (dt, J ) 15, 5 Hz,
1 H), 7.12-7.22 (m, 3 H), 7.24-7.32 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ -4.9 (-), 11.7 (-), 18.5 (+), 26.1 (-), 28.1 (+), 33.7
(+), 36.8 (+), 43.8 (-), 64.1 (+), 125.6 (-), 128.3 (-), 128.5
(-), 130.0 (-), 134.9 (-), 143.0 (+). The enantiomeric information
was determined by HPLC analysis of the corresponding alcohol
shown below.
(S,E)-Ethyl 2-Methyl-3-(1,4-dioxaspiro[4.5]decan-2-yl)prop-
2-enoate (36). A solution of 26 (1.20 g, 7.05 mmol) and Ph3P )
C(Me)CO2Et (3.06 g, 8.44 mmol) in toluene (15 mL) was stirred
at 100 °C for 30 min. After being stirred at room temperature for
12 h, the solvent was removed to afford a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to furnish
1
36 (1.49 g, 94%): IR (neat) 1713, 1250, 929, 746 cm-1; H NMR
(300 MHz, CDCl3) δ 1.26 (t, J ) 7 Hz, 3 H), 1.20-1.80 (m, 10
H), 1.85 (s, 3 H), 3.58 (t, J ) 8 Hz, 1 H), 4.04-4.22 (m, 3 H),
4.82 (q, J ) 7 Hz, 1 H), 6.65 (d, J ) 7 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 13.0 (-), 14.2 (-), 23.89 (+), 23.93 (+), 25.1
(+), 35.4 (+), 36.2 (+), 60.9 (+), 68.3 (+), 72.4 (-), 110.4 (+),
Determination of C.T. To a solution of the above product (23
mg, 0.072 mmol) in THF (2 mL) was added Bu4NF (0.14 mL, 1.0
M in THF, 0.14 mmol) dropwise. The reaction was carried out at
room temperature for 1 h and quenched by addition of saturated
(38) Jones, R. V. H.; Standen, M. C. H. Tetrahedron 1998, 54, 14617–14634.
(39) Yang, Z.; Attygalle, A. B.; Meinwald, J. Synthesis 2000, 13, 1936–
1943.
(37) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Fukumoto, K.;
Kametani, T. J. Chem. Soc., Perkin Trans. 1 1989, 897–903.
1948 J. Org. Chem. Vol. 74, No. 5, 2009

Allylic Substitution with Aryl and Alkenyl Coppers
130.9 (+), 138.4 (-), 167.4 (+); HRMS (FAB) calcd for
C14H22O4Na [(M + Na)+] 277.1416, found 277.1416.
temperature for 2 h and filtered through a pad of Celite. The filtrate
was concentrated to afford a residual oil, which was purified by
chromatography on silica gel (hexane/EtOAc) to furnish 40 (121
mg, 86%): 98% ee by HPLC analysis (Chiralcel OD-H, hexane/i-
PrOH ) 97/3, 0.3 mL/min, tR (min) ) 50.4 (S), 61.5 (R)); IR (neat)
1718, 1513, 1247, 1131, 837 cm-1; 1H NMR (300 MHz, CDCl3) δ
-0.01 (s, 3 H), 0.01 (s, 3 H), 0.80 (s, 9 H), 1.82 (s, 3 H), 3.73 (s,
3 H), 3.70-3.92 (m, 2 H), 3.86 (s, 2 H), 4.35 (s, 2 H), 5.57 (d, J
) 9 Hz, 1 H), 5.89-5.98 (m, 1 H), 6.81 (d, J ) 9 Hz, 2 H), 7.20
(d, J ) 9 Hz, 2 H), 7.39 (dd, J ) 8, 5 Hz, 1 H), 7.76 (dt, J ) 8,
1 Hz, 1 H), 8.06 (d, J ) 8 Hz, 1 H), 8.70 (dt, J ) 5, 1 Hz, 1 H);
13C NMR (75 MHz, CDCl3) δ -5.5 (-), 14.6 (-), 18.1 (+), 25.7
(-), 55.1 (-), 64.6 (+), 71.4 (+), 72.9 (-), 74.4 (+), 113.6 (-),
121.5 (-), 125.0 (-), 126.6 (-), 129.2 (-), 130.2 (+), 136.8 (-),
139.3 (+), 148.2 (+), 149.7 (-), 159.0 (+), 164.3 (+); HRMS
(FAB) calcd for C26H38NO5Si [(M + H)+] 472.2519, found
472.2518.
(S,E)-2-Methyl-3-(1,4-dioxaspiro[4.5]decan-2-yl)prop-2-en-1-
ol (37). To a solution of ester 36 (271 mg, 1.20 mmol) in THF (10
mL) was added DIBAL (3.09 mL, 0.97 M in hexane, 3.00 mmol)
dropwise at -78 °C. After being stirred at -78 to -60 °C for 15
min, the reaction was quenched with H2O (0.34 mL, 12 mmol)
and NaF (1.0 g, 24 mmol) at 0 °C with vigorous stirring. After 30
min of additional stirring, the resulting suspension was filtered
through a pad of Celite with EtOAc. The filtrate was concentrated
to afford a residue, which was purified by chromatography on silica
gel (hexane/EtOAc) to furnish alcohol 37 (242 mg, 95%): IR (neat)
1
3422, 1104, 930 cm-1; H NMR (300 MHz, CDCl3) δ 1.2-1.8
(m, 10 H), 1.67 (s, 3 H), 2.3-2.6 (br s, 1 H), 3.47 (t, J ) 8 Hz, 1
H), 3.92-4.11 (m, 3 H), 4.75-4.82 (m, 1 H), 5.42 (dt, J ) 8, 2
Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.0 (-), 23.8 (+), 23.9
(+), 25.1 (+), 35.5 (+), 36.3 (+), 67.4 (+), 68.9 (+), 72.1 (-),
109.6 (+), 122.1 (-), 140.7 (+).
(R,E)-1-[(tert-Butyldimethylsilyl)oxy]-5-(4-methoxybenzyloxy)-
4-methyl-4-phenylpent-2-ene (41). To an ice-cold suspension of
CuBr·Me2S (135 mg, 0.657 mmol) in THF (10 mL) was added
PhMgBr (1.40 mL, 0.94 M in THF, 1.32 mmol). The mixture was
stirred at 0 °C for 30 min and cooled to -60 °C. A solution of 40
(310 mg, 0.657 mmol, 98% ee) dissolved in THF (1 mL) was added
to the mixture. The reaction was carried out -60 °C for 1 h and
quenched by addition of saturated NH4Cl. The resulting mixture
was extracted with hexane three times. The combined extracts were
dried over MgSO4 and concentrated to obtain a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to furnish
41 (227 mg, 81%): 98% ee, 100% C.T. by HPLC analysis (Chiralcel
OJ-H, hexane/i-PrOH ) 99/1, 0.3 mL/min, tR (min) ) 18.4 (R),
21.2 (S)); [R]30D +1.5 (c 0.40, CHCl3); IR (neat) 1513, 1249, 1099,
836 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 6 H), 0.96 (s, 9
H), 1.49 (s, 3 H), 3.60 (d, J ) 9 Hz, 1 H), 3.66 (d, J ) 9 Hz, 1 H),
3.82 (s, 3 H), 4.26 (dd, J ) 5, 2 Hz, 2 H), 4.48 (s, 2 H), 5.62 (dt,
J ) 16, 5 Hz, 1 H), 5.98 (dt, J ) 16, 2 Hz, 1 H), 6.89 (d, J ) 8
Hz, 2 H), 7.20-7.42 (m, 7 H); 13C NMR (75 MHz, CDCl3) δ -5.0
(-), 18.5 (+), 23.7 (-), 26.0 (-), 44.5 (+), 55.2 (-), 64.3 (+),
73.0 (+), 77.5 (+), 113.7 (-), 126.1 (-), 127.0 (-), 128.0 (-),
128.1 (-), 129.1 (-), 130.6 (+), 136.7 (-), 145.7 (+), 159.0 (+);
HRMS (FAB) calcd for C26H38O3SiNa [(M + Na)+] 449.2488,
found 449.2493.
Determination of the Absolute Configuration (Scheme 9). To
an ice-cold solution of 41 (578 mg, 1.35 mmol) in CH2Cl2 (13 mL)
and H2O (0.6 mL) was added DDQ (460 mg, 2.03 mmol). The
mixture was stirred at 0 °C for 1 h, and diluted with saturated
NaHCO3. The organic layer was separated, and the aqueous layer
was extracted with Et2O three times. The combined organic layers
were dried over MgSO4 and concentrated. The residue was passed
through a short column of silica gel (hexane/EtOAc) to afford a
1:1 mixture of the corresponding alcohol and p-MeOC6H4CHO (573
mg in total, 69% yield of the alcohol), which was used for the
next reaction without further purification.
(S,E)-5-(4-Methoxybenzyloxy)-4-methylpent-3-ene-1,2-diol (38).
To an ice-cold solution of 37 (255 mg, 1.20 mmol) in THF (10
mL) was added NaH (58 mg, 60% in mineral oil, 1.45 mmol). The
mixture was stirred at room temperature for 30 min. Bu4NI (90
mg, 0.24 mmol) and PMBCl (0.21 mL, 1.54 mmol) were added to
the mixture. The reaction was carried out at room temperature for
12 h and quenched by addition of saturated NH4Cl. The resulting
mixture was extracted with hexane three times. The combined
extracts were dried over MgSO4 and concentrated. The residue was
passed through a short column of silica gel (hexane/EtOAc) to
afford the corresponding PMB ether, which was used for the next
reaction without further purification.
A solution of the above ether in CF3CO2H (0.37 mL, 4.8 mmol),
H2O (1 mL), and THF (1 mL) was stirred at room temperature for
3 h and diluted with saturated NaHCO3 and EtOAc. The organic
layer was separated, and the aqueous layer was extracted with
EtOAc. The combined extracts were dried over MgSO4 and
concentrated to afford a residue, which was purified by chroma-
tography on silica gel (hexane/EtOAc) to furnish 38 (248 mg, 82%
from 37): IR (neat) 3364, 1515, 1208, 728 cm-1; H NMR (300
1
MHz, CDCl3) δ 1.67 (s, 3 H), 3.40-3.65 (m, 2 H), 3.78 (s, 3 H),
3.83 (s, 2 H), 4.38 (s, 2 H), 4.58 (dt, J ) 8, 3 Hz, 1 H), 5.40 (d,
J ) 8 Hz, 1 H), 6.86 (d, J ) 9 Hz, 2 H), 7.23 (d, J ) 9 Hz, 2 H);
13C NMR (75 MHz, CDCl3) δ 14.4 (-), 55.3 (-), 65.2 (+), 68.8
(-), 72.0 (+), 74.6 (+), 113.9 (-), 124.0 (-), 129.5 (-), 130.1
(+), 138.2 (+), 159.3 (+).
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-5-(4-methoxybenzyloxy)-
4-methylpent-3-en-2-ol (39). To a solution of 38 (1.07 g, 4.24
mmol) and imidazole (959 mg, 6.36 mmol) in DMF (10 mL) at
-40 °C was added TBSCl (346 mg, 5.08 mmol) in DMF (2 mL)
dropwise. After 30 min at -40 °C, the resulting solution was diluted
with saturated NaHCO3 and EtOAc with vigorous stirring. The
organic layer was separated, and the aqueous layer was extracted
with EtOAc three times. The combined organic layers were dried
over MgSO4 and concentrated to afford a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to furnish
39 (1.40 g, 98%): IR (neat) 3437, 1514, 1249, 1110, 836 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.09 (s, 6 H), 0.91 (s, 9 H), 1.74 (d, J
) 1 Hz, 3 H), 3.44 (dd, J ) 10, 8 Hz, 1 H), 3.59 (dd, J ) 10, 4
Hz, 1 H), 3.80 (s, 3 H), 3.89 (s, 2 H), 4.40 (s, 2 H), 4.47 (dt, J )
8, 4 Hz, 1 H), 5.43 (dq, J ) 8, 1 Hz, 1 H), 6.87 (d, J ) 9 Hz, 2 H),
7.26 (d, J ) 9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ -5.33 (-),
-5.26 (-), 14.5 (-), 18.4 (+), 25.9 (-), 55.3 (-), 66.7 (+), 69.0
(-), 71.6 (+), 75.1 (+), 113.8 (-), 125.5 (-), 129.4 (-), 130.4
(+), 137.0 (+), 159.2 (+); HRMS (FAB) calcd for C20H34O4SiNa
[(M + Na)+] 389.2124, found 389.2117.
A stream of O3 in O2 was gently bubbled into a solution of the
1:1 mixture of the alcohol and p-MeOC6H4CHO (180 mg, 0.67
mmol) in MeOH at -78 °C for 20 min. Excess O3 remaining in
the solution was purged by bubbling argon at -78 °C for 10 min,
and PPh3 (200 mg, 0.76 mmol) was added. The cooling bath was
removed, and the solution was stirred at room temperature for 2 h.
The reaction was concentrated to obtain a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to furnish
1
42 (43 mg, 90%): H NMR (300 MHz, CDCl3) δ 1.57 (s, 3 H),
3.72 (d, J ) 11 Hz, 1 H), 4.09 (d, J ) 11 Hz, 1 H), 7.20-7.45 (m,
5 H), 9.57 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 16.6 (-), 56.4
(+), 67.7 (+), 127.4 (-), 128.1 (-), 129.3 (-), 137.5 (+), 203.3
(-).
(S,E)-1-[(tert-Butyldimethylsilyl)oxy]-5-(4-methoxybenzyloxy)-
4-methylpent-3-en-2-yl Pyridine-2-carboxylate (40). To an ice-
cold solution of 39 (100 mg, 0.30 mmol) in CH2Cl2 (3 mL) were
added DCC (80 mg, 0.39 mmol), DMAP (44 mg, 0.36 mmol), and
picolinic acid (44 mg, 0.36 mmol). The mixture was stirred at room
A solution of commercial m-CPBA (95 mg, 77% purity, 0.423
mmol) in CH2Cl2 (1 mL) was washed with buffer pH 7.6 and dried
over MgSO4. To a solution of 42 (43 mg, 0.28 mmol) in CH2Cl2
(5 mL) were added the dried m-CPBA (73 mg, ca. 100% purity,
J. Org. Chem. Vol. 74, No. 5, 2009 1949

Kiyotsuka et al.
0.45 mmol) and Na2HPO4 (40 mg, 0.28 mmol). The reaction was
carried out at room temperature for 5 h and quenched by addition
of H2O. The mixture was extracted with Et2O three times. The
combined organic layers were dried over MgSO4 and concentrated.
The residue was purified by chromatography on silica gel (hexane/
EtOAc) to furnish the corresponding formate, which was used for
the next reaction without further purification.
J ) 11, 9 Hz, 1 H), 5.39 (ddd, J ) 11, 10, 1 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ -5.3 (-), -5.2 (-), 18.4 (+), 23.2 (-), 23.5
(-), 26.0 (-), 27.5 (-), 67.2 (+), 68.6 (-), 125.4 (-), 141.4 (-).
(R,Z)-1-[(tert-Butyldimethylsilyl)oxy]-5-methylhex-3-en-2-yl
Pyridine-2-carboxylate (52). To a solution of PPh3 (2.15 g, 8.20
mmol) in THF (18 mL) at -78 °C were added picolinic acid (1.01
g, 8.20 mmol) and a solution of alcohol 51 (1.54 g, 6.30 mmol) in
THF (3 mL). After 15 min, DIAD (1.66 mL, 7.87 mmol) was added
dropwise. The solution was warmed to room temperature over 12 h
and diluted with saturated NaHCO3 and EtOAc. The organic layer
was separated, and the aqueous layer was extracted with EtOAc
three times. The combined organic layers were dried over MgSO4
and concentrated to obtain a residue, which was purified by
chromatography on silica gel (hexane/EtOAc) to furnish 52 (1.63
g, 74%): 99% ee by HPLC analysis (Chiralcel AD-H, hexane/i-
To a solution of the above formate in MeOH (1 mL) was added
aqueous KOH (0.46 mL, 1.83 M, 0.85 mmol). The mixture was
stirred at room temperature for 2 h and diluted with H2O. The
resulting mixture was extracted with Et2O three times. The
combined extracts were dried over MgSO4 and concentrated to
obtain a residue, which was purified by chromatography on silica
gel (hexane/EtOAc) to furnish 43 (16 mg, 37%): [R]27 -2.9 (c
D
0.90, EtOH); cf. [R]23 -4.4 (c 0.96, EtOH) for the R enantiomer
D
of 82% ee);30 IR (neat) 3397, 1216, 1043, 759 cm-1; H NMR
PrOH ) 98/2, 0.2 mL/min, tR (min) ) 25.4 (S), 26.2 (R)); [R]25
1
D
1
(300 MHz, CDCl3) δ 1.53 (s, 3 H), 1.70-2.20 (br s, 1 H),
2.40-2.80 (br s, 1 H), 3.62 (d, J ) 11 Hz, 1 H), 3.79 (d, J ) 11
Hz, 1 H), 7.23-7.50 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 26.1
(-), 71.2 (+), 74.9 (+), 125.1 (-), 127.3 (-), 128.5 (-), 145.0
(+); HRMS (EI) calcd for C9H12O2 (M+) 152.0837, found 152.0839.
Synthesis of (-)-Sesqichamaenol (48).
+18 (c 0.188, CHCl3); IR (neat) 1718, 1247, 837 cm-1; H NMR
(300 MHz, CDCl3) δ -0.02 (s, 3 H), 0.05 (s, 3 H), 0.84 (s, 9 H),
0.99 (d, J ) 6 Hz, 6 H), 2.80-2.94 (m, 1 H), 3.76 (dd, J ) 11, 5
Hz, 1 H), 3.89 (dd, J ) 11, 7 Hz, 1 H), 5.36 (dd, J ) 11, 9 Hz, 1
H), 5.50 (dd, J ) 11, 11 Hz, 1 H), 5.97 (ddd, J ) 9, 7, 5 Hz, 1 H),
7.45 (ddd, J ) 8, 5, 1 Hz, 1 H), 7.82 (ddd, J ) 8, 8, 2 Hz, 1 H),
8.11 (ddm, J ) 8, 1 Hz, 1 H), 8.76 (ddm, J ) 5, 2 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ -5.48 (-), -5.46 (-), 18.2 (+), 22.7
(-), 23.1 (-), 25.7 (-), 27.4 (-), 64.9 (+), 72.4 (-), 121.8 (-),
125.0 (-), 126.6 (-), 136.8 (-), 143.6 (-), 148.3 (+), 149.7 (-),
164.2 (+); HRMS (FAB) calcd for C19H31NO3SiNa [(M + Na)+]
372.1971, found 372.1968.
(S,Z)-2-(3-Methylbut-1-enyl)-1,4-dioxaspiro[4.5]decane (49).
To a suspension of [i-PrCH2PPh3]+Br- (10.50 g, 26.2 mmol) in
THF (35 mL) was added NaN(TMS)2 (24.4 mL, 1.0 M in THF,
24.4 mmol) at 0 °C. The mixture was stirred 0 °C for 20 min and
cooled to -78 °C. Aldehyde 26 (2.97 g, 17.5 mmol) was added to
the mixture. The reaction was carried out first at -78 °C for 1 h
and then at room temperature for 12 h, and quenched by addition
of saturated NH4Cl. The resulting mixture was extracted with
hexane three times. The combined extracts were dried over MgSO4
and concentrated to afford a residue, which was purified by
chromatography on silica gel (hexane/EtOAc) to afford 49 (3.52
(R,E)-4-(2-Methoxy-5-methylphenyl)-5-methylhex-2-en-1-ol (54).
To a suspension of CuBr ·Me2S (280 mg, 1.05 mmol) in THF (5
mL) was added Grignard reagent 45 (2.65 mL, 0.80 M in THF,
2.12 mmol) at 0 °C. The mixture was stirred at 0 °C for 20 min
and cooled to -40 °C. Picolinate 52 (370 mg, 1.06 mmol) dissolved
in THF (2 mL) was added to the mixture. The reaction was carried
out at -40 °C for 2 h and quenched by addition of saturated NH4Cl.
The resulting mixture was extracted with hexane three times. The
combined extracts were dried over MgSO4 and concentrated to
obtain a residue, which was purified by chromatography on silica
gel (hexane/EtOAc) to afford 53, which was used for the next
reaction without further purification.
1
g, 96%): IR (neat) 1108, 931 cm-1; H NMR (300 MHz, CDCl3)
δ 0.92 (d, J ) 7 Hz, 3 H), 0.98 (d, J ) 7 Hz, 3 H), 1.31-1.42 (m,
2 H), 1.50-1.66 (m, 8 H), 2.53-2.71 (m, 1 H), 3.47 (dd, J ) 8, 8
Hz, 1 H), 4.02 (dd, J ) 8, 6 Hz, 1 H), 4.82 (ddd, J ) 8, 8, 6 Hz,
1 H), 5.25 (dd, J ) 11, 9 Hz, 1 H), 5.42 (dd, J ) 11, 10 Hz, 1 H);
13C NMR (75 MHz, CDCl3) δ 23.0 (-), 23.7 (-), 23.9 (+), 24.0
(+), 25.2 (+), 27.3 (-), 35.6 (+), 36.4 (+), 69.3 (+), 71.8 (-),
109.7 (+), 125.1 (-), 142.2 (-).
To a solution of the above compound 53 in THF (3 mL) was
added Bu4NF (1.8 mL, 1.0 M in THF, 1.8 mmol) dropwise. The
solution was stirred at room temperature for 1 h and diluted with
saturated NH4Cl. The mixture was extracted EtOAc three times.
The combined organic layers were dried over MgSO4 and concen-
trated to afford a residue, which was purified by chromatography
on silica gel (hexane/EtOAc) to furnish alcohol 54 (152 mg, 61%
from 52): 98% ee, 99% C.T.; IR (neat) 3408, 1501, 1244, 1036,
804 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.73 (d, J ) 7 Hz, 3 H),
0.95 (d, J ) 7 Hz, 3 H), 1.56-1.86 (br s, 1 H), 1.90-2.30 (m, 1
H), 2.27 (s, 3 H), 3.33 (dd, J ) 9, 9 Hz, 1 H), 3.78 (s, 3 H), 4.08
(dd, J ) 6, 1 Hz, 2 H), 5.65 (dt, J ) 15, 6 Hz, 1 H), 5.91 (dd, J
) 15, 9 Hz, 1 H), 6.75 (d, J ) 8 Hz, 1 H), 6.90-6.99 (m, 2 H);
13C NMR (75 MHz, CDCl3) δ 20.7 (-), 21.1 (-), 31.8 (-), 49.8
(-), 55.7 (-), 63.7 (+), 111.0 (-), 127.1 (-), 129.1 (-), 129.5
(-), 129.6 (+), 132.5 (+), 135.1 (-), 155.0 (+). The enantiomeric
information was determined by HPLC analysis: Chiralcel AD-H,
hexane/i-PrOH ) 99/1, 0.2 mL/min, tR (min) 65.6 (S), 70.7 (R).
(S)-4-(2-Methoxy-5-methylphenyl)-5-methylhexanoic Acid (55).
To a mixture of 10% Pd/C (75 mg, 0.070 mmol) in EtOAc (1 mL)
was added 54 (152 mg, 0.649 mmol) in EtOAc (1 mL). The mixture
was stirred at room temperature for 2 h under H2 atmosphere and
filtered through a pad of Celite. The filtrate was concentrated to
afford the corresponding alcohol, which was used for the next
reaction without further purification.
(S,Z)-1-[(tert-Butyldimethylsilyl)oxy]-5-methylhex-3-en-2-ol (51).
A solution of 49 (500 mg, 2.38 mmol) in CF3CO2H (0.73 mL, 9.5
mmol), H2O (1 mL), and THF (1 mL) was stirred at room
temperature for 12 h and diluted with saturated NaHCO3 and
EtOAc. The organic layer was separated, and the aqueous layer
was extracted with EtOAc. The combined extracts were dried over
MgSO4 and concentrated to afford a residue, which was purified
by chromatography on silica gel (hexane/EtOAc) to furnish diol
50 (210 mg, 68%): IR (neat) 3391, 1075, 756 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.92 (d, J ) 7 Hz, 3 H), 0.96 (d, J ) 7 Hz, 3 H),
2.50-2.69 (m, 1 H), 3.42 (dd, J ) 12, 8 Hz, 1 H), 3.51 (dd, J )
12, 3 Hz, 1 H), 3.65 (br s, 2 H), 4.51 (ddd, J ) 8, 8, 3 Hz, 1 H),
5.19 (dd, J ) 11, 9 Hz, 1 H), 5.35 (dd, J ) 11, 10 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 23.1 (-), 23.4 (-), 27.4 (-), 66.6 (+),
68.9 (-), 125.4 (-), 141.5 (-).
To a solution of the above diol 50 (915 mg, 7.03 mmol) and
imidazole (1.59 g, 10.5 mmol) in DMF (10 mL) at -40 °C was
added TBSCl (573 mg, 8.42 mmol) in DMF (4 mL) dropwise. After
2 h at -40 °C, the resulting solution was diluted with saturated
NH4Cl and EtOAc. The organic layer was separated, and the
aqueous layer was extracted with EtOAc three times. The combined
organic layers were dried over MgSO4 and concentrated to afford
a residue, which was purified by chromatography on silica gel
(hexane/EtOAc) to furnish 51 (1.54 g, 90%): IR (neat) 3424, 1106,
836, 777 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 6 H), 0.91
(s, 9 H), 0.94 (d, J ) 7 Hz, 3 H), 0.99 (d, J ) 7 Hz, 3 H), 2.56 (br
s, 1 H), 2.53-2.69 (m, 1 H), 3.40 (dd, J ) 10, 8 Hz, 1 H), 3.56
(dd, J ) 10, 4 Hz, 1 H), 4.47 (ddm, J ) 8, 8 Hz, 1 H), 5.19 (dd,
To an ice-cold solution of the above alcohol in acetone (4.3 mL)
was added Jones reagent (0.28 mL, 4.7 M, 0.88 mmol) dropwise.
The reaction was quenched by addition of i-PrOH and the aqueous
layer was extracted EtOAc three times. The combined organic layers
1950 J. Org. Chem. Vol. 74, No. 5, 2009

Allylic Substitution with Aryl and Alkenyl Coppers
were dried over MgSO4 and concentrated to afford a residue, which
was purified by chromatography on silica gel (hexane/EtOAc) to
furnish 55 (121 mg, 75% from 54): [R]30D -4.17 (c 0.24, CHCl3);
residue, which was purified by chromatography on silica gel
(hexane/EtOAc) to furnish (-)-sesquichamaenol (48) (75 mg, 59%
from 55): [R]27 -8.1 (c 0.72, CHCl3) and [R]27 -9.2 (c 0.72,
D
CH2Cl2); cf. [RD]25 -4.3 (c 0.6, CHCl3)33a and [R]22 -5.95 (c
1
IR (neat) 2957, 1244, 1037 cm-1; H NMR (300 MHz, CDCl3) δ
D
D
0.042, CH2Cl2);33b 1H NMR (300 MHz, CDCl3) δ 0.73 (d, J ) 7
Hz, 3 H), 1.01 (d, J ) 7 Hz, 3 H), 1.66-1.93 (m, 2 H), 2.05 (s, 3
H), 2.04-2.24 (m, 3 H), 2.25 (s, 3 H), 2.61 (ddd, J ) 12, 9, 3 Hz,
1 H), 5.55 (br s, 1 H), 6.68 (d, J ) 8 Hz, 1 H), 6.85 (d, J ) 8 Hz,
2 H); 13C NMR (75 MHz, CDCl3) δ 20.8 (-), 20.9 (-), 21.3 (-),
26.7 (+), 30.1 (-), 33.0 (-), 42.0 (+), 44.2 (-), 115.7 (-), 127.3
(-), 128.6 (-), 129.8 (+), 129.9 (+), 152.1 (+), 211.1 (+); HRMS
(FAB) calcd for C15H22O2Na [(M + Na)+] 257.1517, found
257.1512. The spectral data were consistent with those reported.33
0.73 (d, J ) 7 Hz, 3 H), 1.00 (d, J ) 7 Hz, 3 H), 1.74-1.96 (m,
3 H), 2.04-2.20 (m, 2 H), 2.27 (s, 3 H), 2.77 (dd, J ) 9, 9 Hz, 1
H), 3.75 (s, 3 H), 6.74 (d, J ) 8 Hz, 1 H), 6.88 (d, J ) 2 Hz, 1 H),
6.96 (dd, J ) 8, 2 Hz, 1 H) 9.5-11.0 (br s, 1 H); 13C NMR (75
MHz, CDCl3) δ 20.6 (-), 20.8 (-), 21.3 (-), 27.3 (+), 32.56 (+),
32.59 (-), 44.2 (-), 55.6 (-), 110.6 (+), 127.2 (-), 128.8 (-),
129.6 (-), 131.7 (-), 156.0 (-), 180.7 (+).
(-)-Sesquichamaenol (48). To an ice-cold solution of 55 (130
mg, 0.523 mmol) in AcOH (2.6 mL) was added 30% HBr in AcOH
(1.31 mL). The mixture was refluxed for 2 h and poured into
saturated NaHCO3. The organic phase was separated, and the
aqueous was extracted EtOAc three times. The combined organic
layers were dried over MgSO4 and concentrated to afford a residue,
which was passed through a short column of silica gel (hexane/
EtOAc) to afford the corresponding phenol (103 mg), which was
used for the next reaction without further purification.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan and in part by a Grant-in-
Aid for Young Scientists from JSPS.
Supporting Information Available: Synthesis of allylic
picolinates (S)-5a,b,c,d (Scheme 4) and spectral data of
compounds described herein. This material is available free of
charge via the Internet at http://pubs.acs.org.
To a solution of the above phenol (103 mg) in Et2O (5 mL) was
added MeLi (2.19 mL, 1.02 M in Et2O, 2.23 mmol) dropwise at
-55 °C. After 3 h at -55 °C, the resulting solution was diluted
with saturated NH4Cl and EtOAc. The organic layer was separated,
and the aqueous layer was extracted with EtOAc. The combined
extracts were dried over MgSO4 and concentrated to afford a
JO802426G
J. Org. Chem. Vol. 74, No. 5, 2009 1951