Diastereoselective reactions of δ-oxy-substituted allylic acetates with organocopper reagents

Article abstract of DOI:10.1021/jo016310x

SN2′ (γ) substitutions of δ-substituted allylic acetates with Grignard reagents and copper catalysts proceed with high diastereoselectivities. With benzyloxy, methoxymethoxy, and tert-butyldimethylsiloxy groups, reactions favor the anti-isomer with selectivities up to anti:syn = >99:1. With a hydroxyl group, selectivities are reversed and the syn-isomer is favored with selectivities up to anti:syn = <1:99.

Full text of DOI:10.1021/jo016310x

3000
J . Org. Chem. 2002, 67, 3000-3006
Dia ster eoselective Rea ction s of δ-Oxy-Su bstitu ted Allylic Aceta tes
w ith Or ga n ocop p er Rea gen ts
J ennifer L. Belelie and J . Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry,
University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
jmchong@uwaterloo.ca
Received November 21, 2001
SN2′ (γ) substitutions of δ-substituted allylic acetates with Grignard reagents and copper catalysts
proceed with high diastereoselectivities. With benzyloxy, methoxymethoxy, and tert-butyldimethyl-
siloxy groups, reactions favor the anti-isomer with selectivities up to anti:syn ) >99:1. With a
hydroxyl group, selectivities are reversed and the syn-isomer is favored with selectivities up to
anti:syn ) <1:99.
Sch em e 1
In tr od u ction
The SN2′ substitution of various allylic substrates with
organometallic, particularly organocopper, reagents is a
well-established method for C-C bond formation.1 There
is a large body of knowledge on factors influencing
regioselectivity2 in these reactions, but there is a surpris-
ing paucity of information regarding diastereoselectivity.3
With R-substituted carbonyl compounds, it is now pos-
sible to reliably predict (usually) the stereochemistry of
nucleophilic addition using rational models.4 With Michael
additions of organocopper reagents, there are many
examples demonstrating that the stereoselectivity of
conjugate additions to R,â-unsaturated carbonyl com-
pounds is influenced by adjacent5 or remote6 stereo-
centers. In SN2′ substitution reactions, many researchers
have examined how the stereochemistry of the incoming
nucleophile is influenced by the stereochemistry of/
around the leaving group.7 In contrast, only Nakamura
has addressed the issue of how the diastereoselectivity
of an SN2′ displacement might be influenced by an
adjacent stereocenter.8
Sch em e 2
Nakamura worked principally with allylic chlorides
and found that reactions with organocopper and organo-
zinc reagents could proceed with very high diastereo-
selectivities, but only if R is a branched alkyl group
(Scheme 1). Primary alkyl groups gave modest selectivi-
ties, and anti-isomers predominated regardless of the
oxygen protecting group.
It is clear that further development of such diastereo-
selective SN2′ reactions is needed. Since the products
should be easily transformed (e.g., by ozonolysis) to aldol-
type products (Scheme 2), control of the stereochemistry
of these reactions would provide stereoselective routes
to syn- or anti-aldol products, compounds of considerable
interest as synthetic intermediates.9 We now report that
both syn- and anti-adducts may be prepared with good
to excellent selectivities using suitable δ-oxy-substituted
allylic acetates.
(1) For reviews, see: (a) Lipshutz, B. H.; Sengupta, S. Org. React.
1992, 41, 135-631. (b) Lipshutz, B. H. In Organometallics in Synthesis;
Schlosser, M., Ed.; Wiley: Chichester, 1994; pp 283-382.
(2) Meuzelaar, G. J .; Karlstrom, A. S. E.; van Klaveren, M.; Persson,
E. S. M.; del Villar, A.; van Koten, G.; Backvall, J . E. Tetrahedron 2000
56, 2895-2903 and references cited within.
(3) For a review of enantioselective transition-metal-catalyzed allylic
alkylations, see: Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395-422.
(4) For an excellent discussion of the evolution of current working
models, see: Gawley, R. E.; Aube´, J . Principles of Asymmetric
Synthesis; Pergamon: New York, 1996; Chapter 4.
(5) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J . Am. Chem. Soc. 1992, 114, 7652-7660. (b) Hanessian, S.; Ma, J .;
Wang, W. Tetrahedron Lett. 1999, 40, 4627-4630. (c) Raczko, J .
Tetrahedron: Asymmetry 1997, 8, 3821-3828. (d) Hanessian, S.; Wang,
W.; Gai, Y.; Olivier, E. J . Am. Chem. Soc. 1997, 119, 10034-10041.
(e) Roush, W. R.; Murphy, M. J . Org. Chem. 1992, 57, 6622-6629. (f)
Hanessian, S.; Sumi, K. Synthesis 1991, 1083-1089. (g) Linderman,
R. J .; McKenzie, J . R. Tetrahedron Lett. 1988, 29, 3911-3914.
(6) Hale, M. R.; Hoveyda, A. H. J . Org. Chem. 1994, 59, 4370-4374.
(7) (a) Spino, C.; Beaulieu, C.; Lafrenie`re, J . J . Org. Chem. 2000,
65, 7091-7097. (b) Rakotoarisoa, H.; Perez, R. G.; Mangeney, P.;
Alexakis, A. Organometallics 1996, 15, 1957-1959. (c) Kang, S.-K.;
Cho, D.-G.; Park, C.-H.; Namkoong, E.-Y.; Shin, J .-S. Synth. Commun.
1995, 25, 1659. (d) Ibuka, T.; Nakao, T.; Yamamoto, Y. J . Am. Chem.
Soc. 1986, 108, 7420-7422. (e) Torneiro, M.; Fall, Y.; Castedo, L.;
Mourino, A. J . Org. Chem. 1997, 62, 6344-6352. (f) Belelie, J . L.;
Chong, J . M. J . Org. Chem. 2001, 66, 5552-5555.
Resu lts a n d Discu ssion
Initial reactions were carried out using allylic acetate
1 (Scheme 3). Unfortunately, this substrate tended to give
(8) (a) Nakamura, E.; Sekiya, K.; Arai, M.; Aoki, S. J . Am. Chem.
Soc. 1989, 111, 3091-3093. (b) Arai, M.; Kawasujji, T.; Nakamura, E.
J . Org. Chem. 1993, 58, 5121-5129.
(9) Recent reviews: Cowden, C. I.; Paterson, I. Org. React. 1997,
51, 1-200. (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000,
33, 432-440.
10.1021/jo016310x CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/05/2002

Reactions of δ-Oxy-Substituted Allylic Acetates
J . Org. Chem., Vol. 67, No. 9, 2002 3001
Ta ble 2. Cop p er Cya n id e Med ia ted Rea ction s of
Gr ign a r d Rea gen ts w ith δ-Alk oxy-Su bstitu ted Allylic
Aceta tesa
Sch em e 3
Ta ble 1. Rea ction s of n -Bu tylcop p er Rea gen ts w ith
Aceta tes 4a
entry
acetate
R2
product
yieldb
drc
1
2
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
5b
5c
6b
6c
n-Bu
i-Pr
t-Bu
Ph
n-Bu
i-Pr
t-Bu
Ph
n-Bu
i-Pr
t-Bu
Ph
Me
Et
n-Bu
n-Bu
n-Bu
n-Bu
7a
8a
9a
10a
7b
8b
9b
10b
7c
8c
9c
10c
11c
12c
13b
13c
14b
14c
72
70
73
64
89
85
89
68
80
76
94
75
77
84
89
81
85
88
86:14
74:26
83:17
79:21
90:10
79:21
87:13
88:12
98.5:1.5
98.5:1.5
>99:1
>99:1
98:2
3
4d
5
6
7
entry
substrate
reagent
yieldb
drc
8d
9
1
2
3
4
5
4a
4a
4c
4c
4c
n-Bu2CuLi
40
72
37
12
80
76:24
86:14
79:21
84:16
98.5:1.5
10
11
12d
13d
14d
15
16
17
18
n-BuMgBr/CuCN
n-BuMgBr/CuI
n-BuMgBr/CuBr
n-BuMgBr/CuCN
99:1
80:20
95:5
83:17
98:2
a
Entry 1 was carried out with 2.0 equiv of reagent in ether;
entries 2-5 employed 2.0 equiv of n-BuMgBr with 10 mol % CuX.
b
Percentage isolated yields of chromatographed products. c De-
termined by GC/MS of crude products.
a
Reactions were carried out using 2.0 equiv of RMgX with 10
considerable amounts of R- (SN2) substitution. Thus,
reaction of 1 with n-Bu2CuLi afforded exclusively 2, while
n-BuMgBr/cat. CuI gave a mixture of regioisomers (2:3
) 60:40). With n-BuMgBr/cat. CuCN, 3 was the major
product (2:3 ) 4:96, dr ) 75:25), but it was clear that
primary acetates would have problems with regioselec-
tivity.
b
mol % CuCN in ether. Percentage isolated yields of chromato-
graphed products. The diastereomers were not chromatographi-
cally separable except for compound 9a . c Determined by GC/MS
d
of crude products. 50 mol % CuCN was used.
Sch em e 4
To circumvent the problem of regioselectivity, we
designed a series of substrates 4 containing tertiary
acetates that, for steric reasons, would be unlikely to
undergo SN2 substitutions. A survey of n-butylcopper
reagents (Table 1) showed that these substrates do not
give competing R-substitution, but other side reactions,
including elimination, occurred in many cases so that low
yields of γ-substitution products were obtained. Fortu-
nately, one of the reagents surveyed, n-BuMgBr/cat.
CuCN, gave reasonably clean reactions with good dias-
tereoselectivities (entries 2, 5).
(e.g., OTBS) alkoxy groups.4 The relatively minor varia-
tions in selectivity observed here suggest that coordina-
tion is not a major factor in determining stereoselectivity
in these SN2′ reactions.
We therefore reacted a series of reagents RMgX/CuCN
with substrates 4-6 to examine the scope of this reaction
(Table 2). For the benzyloxy-substituted substrates, the
following generalizations may be made: (1) Reactions are
generally clean and good isolated yields of substitution
products were obtained. (2) The stereoselectivity depends
on the structure of 4 such that larger R1 groups show
higher selectivities. (3) For most of the Grignard reagents
examined, reasonable levels of selectivity could be ob-
tained when R1 is a methyl group or an n-alkyl group.
(4) When R1 is branched (e.g., i-Pr in 4c), stereoselec-
tivities of >98:2 were consistently obtained. (5) Addition
of an i-Pr group tends to give the lowest selectivities.
A comparison of other protecting groups (MOM and
TBS) showed that there is only a small dependence of
selectivity on the protecting group (compare Table 2,
entries 5, 15, and 17; entries 9, 16, 18). In reactions of
R-alkoxy carbonyl compounds with organometallic nucleo-
philes, reversal of stereoselectivity is often observed with
coordinating (e.g., OBn, OMOM) versus noncoordinating
Introduction of a phenyl group proved to be somewhat
problematic. With acetate 4c and PhMgCl under the
usual reaction conditions (10 mol % CuCN), the major
product isolated was alkene 15 with <10% 10c isolated
(Scheme 4). After considerable experimentation, it was
found that the formation of 15 could be suppressed
almost completely by using PhMgBr with 50 mol %
CuCN. Under these conditions, 10c could be isolated in
good yields with very high diastereoselectivity. Applica-
tion to acetates 4a and 4b gave 10a and 10b, respec-
tively, in good yields, although with only moderate
selectivities. In experiments with PhMgBr, increasing the
amount of CuCN used increased the yield of substitution
products but did not affect the diastereoselectivities. With
other Grignard reagents, varying the amount of CuCN
from 10 to 50 mol % had little effect on either yields or
selectivities.
In all cases the major diastereomer produced had the
anti-configuration. This relationship was established by
conversion of some of the products 7-12 to 1,3-diols

3002 J . Org. Chem., Vol. 67, No. 9, 2002
Belelie and Chong
Ta ble 4. Cop p er Cya n id e Med ia ted Rea ction s of
Gr ign a r d Rea gen ts w ith δ-Hyd r oxy-Su bstitu ted Allylic
Aceta tesa
Sch em e 5
entry
acetate
R2
product
yieldb
drc
1
2d
3
18a
18a
18a
18a
18b
18b
18b
18b
18c
18c
18c
n-Bu
n-Bu
i-Pr
t-Bu
n-Bu
n-Bu
i-Pr
t-Bu
n-Bu
i-Pr
20a
20a
21a
22a
20b
20b
21b
22b
20c
21c
22c
69
76
71
79
84
68
68
83
79
68
83
89:11
80:20
79:21
97:3
Ta ble 3. Effect of Solven t on th e Rea ction of 18c w ith
4
n -Bu MgBr a
5
93:7
6d
7
86:14
86:14
>99:1
88:12
56:44
94:6
8
9
10
11
t-Bu
a
Reactions were carried out using 2.5 equiv of RMgX with 50
entry
solvent
yieldb
drc
b
mol % CuCN in CH2Cl2 unless otherwise noted. Percentage
isolated yields of chromatographed products. c Determined by GC/
1
2
3
4
5
Et2O
THF
CH2Cl2
toluene
TBME
57
45
46
48
44
75:25
59:41
92:8
70:30
72:28
d
MS of crude product. Reaction in Et2O using 10 mol % CuCN.
On the basis of our previous experience with acetate
4c and reactions with PhMgX, the quantity of CuCN was
increased to 50 mol %. This change effectively eliminated
the formation of other side products, and the desired
substitution product could be isolated in good yield. Other
substrates and Grignard reagents were allowed to react
under these new conditions (Table 4). In general, good
yields of products were isolated and good to excellent
selectivities were observed for transfer of n-butyl or tert-
butyl groups. Variable selectivities were obtained for
transfer of an i-Pr group. Lower than expected selectivi-
ties were also sometimes observed for the transfer of an
i-Pr group to benzyloxy-substituted substrates (Table 1,
entries 2, 6). It is not obvious why this anomalous
behavior is observed. For the transfer of an n-Bu group,
reactions were also run in ether (Table 2, entries 1 vs 2,
5 vs 6) and, as expected on the basis of previous results,
higher selectivities were consistently obtained in CH2-
Cl2.
a
Reactions were carried out using 2.0 equiv of RMgX with 10
b
mol % CuCN. Percentage isolated yields of chromatographed
products. c Determined by GC/MS of crude products.
(Scheme 5), cyclization of these diols to 1,3-dioxanes, and
examination of their 1H NMR spectra.10 For all of the
dioxanes so prepared, the major isomer showed a large
ax-ax coupling (J ab ≈ 10-11 Hz), consistent with an
anti-configuration for the diols. As well, an X-ray crystal
structure of the bis(3,5-dinitrobenzoate) of the diol de-
rived from 9c clearly showed anti-stereochemistry. Other
products are tentatively assigned anti-stereochemistry
1
based on trends in H NMR spectra (the anti-diastereo-
mers show vinyl proton doublets 0.10-0.35 ppm down-
field of the corresponding signals from the syn-isomer)
and GC elution profiles (anti elutes before syn on a DB5
column).
Having established that alkoxy groups could effectively
participate in 1,2-asymmetric induction such that anti-
isomers are preferentially formed, we searched for sub-
strates that might provide the syn-isomer selectively. The
only group examined that gave syn selectivity was a
hydroxyl group (Table 3). Using acetate 18c as a probe
substrate, it was found that the stereoselectivity was
strongly solvent dependent. For example, with n-BuMg-
Br, selectivities varied from 17 to 84% de depending on
the solvent used. The best selectivity was observed with
CH2Cl2 as solvent.11 Unfortunately, while reactions in
CH2Cl2 using 10 mol % CuCN gave high selectivities,
other side reactions occurred, resulting in modest yields.
Similar side reactions occurred under the same conditions
in other solvents. With substrate 18c, the major side-
product isolated was 19c, which probably arises from
competing E2 elimination of the acetoxy group.
The anti-selectivity observed with δ-alkoxy substitu-
ents (e.g., MOMO, BnO, TBSO) may be rationalized using
Felkin-Anh/Cram arguments as previously noted by
Nakamura.8 The syn-selectivity observed with a hydroxyl
group (which is likely to exist as a Mg alkoxide under
the reaction conditions) suggests that coordination to the
reagent is taking place so that the alkyl group is delivered
from the same face. A similar reversal of stereoselectivity
has been previously observed in zirconium-catalyzed
ethylmagnesiation of alkenes.12 The ability of hydroxyl
groups to control stereoselectivity in a multitude of
reactions (e.g., epoxidations, Simmons-Smith, hydroge-
nations) is well-documented.13
(10) Isaac, M. B.; Chan, T. H. Tetrahedron Lett. 1995, 36, 8957-
8960.
(11) Recently, enantioselective SN2′ reactions of Grignard reagents
in CH2Cl2 have been reported: Alexakis, A.; Malan, C.; Lea, L.;
Benhaim, C.; Fournioux, X. Synlett 2001, 927-930.
(12) Hoveyda, A. H.; Xu, Z. J . Am. Chem. Soc. 1991, 113, 5079-
5080.
(13) For a review of substrate-directed reactions, see: Hoveyda, A.
M.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307-1370.

Reactions of δ-Oxy-Substituted Allylic Acetates
J . Org. Chem., Vol. 67, No. 9, 2002 3003
82.7*; 71.9*, 71.8; 41.7, 41.1*; 31.5, 31.0*; 30.7; 30.0*, 29.7;
28.6*, 27.7; 26.0; 22.9 (2C); 18.4, 18.2*; 14.1 (2C); MS (EI) m/z
(%) 245 (M+ - n-Bu, 0.1), 95 (100). Anal. Calcd for C21H34O:
C, 83.38; H, 11.33. Found: C, 83.12; H, 11.15.
Overall, our results suggest that this approach is a
viable means of controlling stereochemistry and accessing
a wide variety of stereochemically defined homoallylic
alcohols that are useful synthetic intermediates (e.g., as
precursors to aldol-type products). Since compounds such
as 4 are readily accessible in enantiomerically enriched
form,14 this chemistry could be used for the synthesis of
enantiomerically enriched compounds.
5-Ben zyloxy-4-bu tyl-2,6-d im eth yl-2-h ep ten e (7c). Gen-
eral procedure A was followed using acetate 4c (198 mg, 0.68
mmol), n-BuMgBr (0.51 mL, 2.71 M, 1.4 mmol), and CuCN (7
mg, 0.08 mmol). The crude oil (anti:syn ) 98.5:1.5 by GC/MS
analysis) was purified via column chromatography (10:1
hexane:CH2Cl2) to give 158 mg (80%) of a clear, colorless oil:
IR (neat) 1672, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.37-
7.24 (5H, m), 5.17 (1H, d, J ) 10.2 Hz), 4.61-4.53 (2H, m),
3.00 (1H, dd, J ) 7.3, 3.6 Hz), 2.53-2.43 (1H, m), 1.79 (1H,
dqq, J ) 7.3, 6.7, 6.7 Hz), 1.71 (3H, s), 1.60 (3H, s), 1.50-1.08
(6H, m), 0.99 (3H, d, J ) 6.7 Hz), 0.89 (3H, d, J ) 6.7 Hz),
0.87 (3H, t, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 139.4,
131.6, 128.2 (2C), 127.6 (2C), 127.2, 126.0, 88.8, 75.0, 41.2, 33.1,
31.5, 29.8, 26.0, 23.0, 20.0, 18.9, 18.4, 14.2; MS (EI) m/z (%)
245 (M+ - i-Pr, 0.6), 91 (100). Anal. Calcd for C20H32O: C,
83.27; H, 11.18. Found: C, 83.51; H, 10.91.
5-Ben zyloxy-4-isop r op yl-2-m eth yl-2-h exen e (8a ). Gen-
eral procedure A was followed using acetate 4a (202 mg, 0.77
mmol), i-PrMgCl (0.66 mL, 2.30 M, 1.5 mmol), and CuCN (7
mg, 0.08 mmol). The crude oil (anti:syn ) 74:26 by GC/MS
analysis) was purified via column chromatography (3:1 hexane:
CH2Cl2) to give 132 mg (70%) of a clear, colorless oil: IR (neat)
1674, 697 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.60-7.24 (5H,
m), 5.13 (0.74H, d, J ) 10.3 Hz), 4.90 (0.26H, d, J ) 10.7 Hz),
4.62 (1H, A of AB, d, J obs ) 11.9 Hz), 4.44 (0.26H, B of AB, d,
J obs ) 11.6 Hz), 4.40 (0.74H, B of AB, J obs ) 11.9 Hz), 3.68
(0.74H, qd, J ) 6.2, 3.8 Hz), 3.45 (0.26H, dq, J ) 8.6, 6.1 Hz),
2.31 (0.26H, ddd, J ) 10.7, 8.6, 4.4 Hz), 2.22-2.05 (0.26H, m),
1.98-1.90 (0.74H, m), 1.84-1.75 (0.74H, m), 1.75 (2.22H, s),
1.74 (0.78H, s), 1.63 (0.78H, s), 1.59 (2.22H, s), 1.12 (3H, d, J
) 6.2 Hz), 0.88 (2.22H, d, J ) 6.6 Hz), 0.82 (3H, d, J ) 6.7
Hz), 0.77 (0.78H, d, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ
139.5*, 139.2; 133.9, 132.8*; 128.4, 128.3* (2C); 127.9, 127.6*;
127.5*, 127.3 (2C); 124.4; 76.1, 75.9*; 70.8, 70.7*; 51.1*, 49.8;
29.3, 27.8; 26.3*, 26.2; 21.5, 21.4*; 20.5*, 18.7; 18.5*, 17.5;
17.8*, 17.2; MS (EI) m/z (%) 231 (M+ - Me, 0.2), 91 (100). Anal.
Calcd for C17H26O: C, 82.87; H, 10.64. Found: C, 82.68; H,
10.50.
5-Ben zyloxy-4-isop r op yl-2-m eth yl-2-n on en e (8b). Gen-
eral procedure A was followed using acetate 4b (205 mg, 0.67
mmol), i-PrMgCl (0.80 mL, 1.65 M, 1.3 mmol), and CuCN (7
mg, 0.08 mmol). The crude oil (anti:syn ) 79:21 by GC/MS
analysis) was purified via column chromatography (6:1 hexane:
CH2Cl2) to give 166 mg (85%) of a clear, colorless oil: IR (neat)
1674, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (5H,
m), 5.16 (0.79H, d, J ) 10.8 Hz), 4.90 (0.21H, d, J ) 10.9 Hz),
4.57 (0.79H, A of AB, d, J obs ) 11.6 Hz), 4.55 (0.21H, A of AB,
d, J obs ) 11.2 Hz), 4.49 (0.21H, B of AB, d, J obs ) 11.2 Hz),
4.47 (0.79H, B of AB, d, J obs ) 11.6 Hz), 3.51-3.45 (0.79H,
m), 2.45-2.35 (0.21H, m), 2.10-2.00 (1H, m), 1.80 (1H, dqq,
J ) 6.8, 6.8, 6.8 Hz), 1.74 (3H, s), 1.62 (0.63H, s), 1.59 (2.37H,
s), 1.43-1.20 (6H, m), 0.91-0.77 (9H, m); 13C NMR (75 MHz,
CDCl3) δ 139.4*, 139.0; 133.3, 132.5*; 128.1*, 128.0 (2C);
127.5*, 127.4 (2C); 127.2; 124.2*, 122.7; 80.6*, 79.8; 71.7*, 71.3;
48.4*, 47.0; 31.7*, 30.7; 29.2; 28.2*, 27.0; 26.2, 26.0*; 23.0;
21.5*, 21.4; 20.5; 18.5; 14.1; MS (EI) m/z (%) 197 (M+ - Bn,
0.2), 91 (100). Anal. Calcd for C20H32O: C, 83.27; H, 11.18.
Found: C, 83.51; H, 10.99.
5-Ben zyloxy-4-isop r op yl-2,6-d im eth yl-2-h ep ten e (8c).
General procedure A was followed using acetate 4c (206 mg,
0.71 mmol), i-PrMgCl (0.83 mL, 1.65 M, 1.4 mmol), and CuCN
(8 mg, 0.09 mmol). The crude oil (anti:syn ) 98.5:1.5 by GC/
MS analysis) was purified via column chromatography (6:1
hexane:CH2Cl2) to give 148 mg (76%) of a clear, colorless oil:
IR (neat) 1673, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36-
7.24 (5H, m), 5.24 (1H, d, J ) 10.8 Hz), 4.58 (2H, m), 3.22
(1H, dd, J ) 6.8, 3.8 Hz), 2.17 (1H, ddd, J ) 10.8, 7.2, 3.8 Hz),
1.88-1.76 (2H, m), 1.73 (3H, s), 1.59 (3H, s), 0.98 (3H, d, J )
6.7 Hz), 0.95 (3H, d, J ) 6.6 Hz), 0.90 (3H, d, J ) 6.7 Hz),
0.83 (3H, d, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 139.5,
132.2, 128.1 (2C), 127.4 (2C), 127.1, 124.2, 86.2, 74.7, 47.5, 31.4,
Exp er im en ta l Section
Gen er a l. All reactions were performed using flame-dried
glassware under an argon atmosphere. Diethyl ether and THF
were freshly distilled from Na/benzophenone. Dichloromethane
was freshly distilled from CaH2. Grignard reagents (EtMgBr,
n-BuMgBr, i-PrMgCl, t-BuMgCl) were prepared in ether under
standard conditions and stored in sealed bottles under argon.
The titer of the reagents was determined by titration with
salicylaldehyde phenylhydrazone.15 MeMgBr and PhMgBr
were used as purchased from Aldrich Chemical Co. after
titration. CuBr·SMe2 was prepared as described by Wuts16 and
purified by recrystallization from Me2S-hexanes. Elemental
analyses were performed by MHW Laboratories, Phoenix, AZ.
In the 13C NMR peak listings, peaks due to the major
diastereomer are denoted with an asterisk (*) if signals due
to both diastereomers are distinguishable.
Gen er a l P r oced u r e A: Cop p er Cya n id e Ca ta lyzed
Gr ign a r d Rea ction s of Aceta tes 4-6. The Grignard re-
agents (2.0 equiv) were added slowly dropwise to a slurry of
the acetate (1.0 equiv) and CuCN (0.10 equiv, unless otherwise
noted) in Et2O (1 mL/10 mg substrate) at -78 °C. The reactions
were allowed to warm slowly to room temperature, after which
they were quenched with 10% NH4OH in NH4Cl. The aqueous
layers were extracted with Et2O (3×) and the combined organic
layers were dried over Na2SO4. An aliquot was removed for
analysis by GC/MS. After the solvent was removed in vacuo,
the crude alkenes were typically purified via column chroma-
tography.
5-Ben zyloxy-4-bu tyl-2-m eth yl-2-h exen e (7a ). General
procedure A was followed using acetate 4a (125 mg, 0.48
mmol), n-BuMgBr (0.35 mL, 2.71 M, 0.95 mmol), and CuCN
(22 mg, 0.25 mmol). The crude oil (anti:syn ) 86:14 by GC/
MS analysis) was purified via column chromatography (4:1
hexane:CH2Cl2) to give 90 mg (72%) of a clear, colorless oil:
IR (neat) 1672, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-
7.24 (5H, m), 4.99 (0.86H, d, J ) 9.9 Hz), 4.88 (0.14H, d, J )
8.3 Hz), 4.60 (1H, A of AB, d, J obs ) 12.1 Hz), 4.48 (0.86H, B
of AB, d, J obs ) 12.1 Hz), 4.47 (0.14H, B of AB, d, J obs ) 11.7
Hz), 3.45 (0.86H, qd, J ) 6.9, 3.9 Hz), 3.30 (0.14H, dq, J )
6.7, 6.7 Hz), 2.43-2.34 (1H, m), 1.72 (3H, s), 1.63 (0.42H, s),
1.59 (2.58H, s), 1.32-1.21 (6H, m), 1.15 (0.42H, d, J ) 6.7 Hz),
1.11 (2.58H, d, J ) 6.9 Hz), 0.87 (3H, t, J ) 6.9 Hz); 13C NMR
(75 MHz, CDCl3) δ 139.3; 132.5; 128.2 (2C); 127.6, 127.5* (2C);
127.3, 127.2*; 126.2; 78.7, 77.8*; 70.8, 70.6*; 44.0, 43.0*; 31.6,
30.4*; 29.9*, 29.5; 26.0; 23.0; 18.2; 17.1, 16.6*; 14.2; MS (EI)
m/z (%) 260 (M+, 0.3), 91 (100). Anal. Calcd for C18H28O: C,
83.02; H, 10.84. Found: C, 82.89; H, 10.68.
5-Ben zyloxy-4-bu tyl-2-m eth yl-2-n on en e (7b). General
Procedure A was followed using acetate 4b (203 mg, 0.67
mmol), n-BuMgBr (0.48 mL, 2.71 M, 1.3 mmol) and CuCN (8
mg, 0.09 mmol). The crude oil (anti:syn ) 90:10 by GC/MS
analysis) was purified via column chromatography (6:1 hex-
ane: CH2Cl2) to give 178 mg (89%) of a clear, colorless oil. IR
(neat) 1672, 697 cm-1 1H NMR (300 MHz, CDCl3) δ 7.35-
;
7.26 (5H, m), 5.02 (0.90H, d, J ) 9.5 Hz), 4.92 (0.10H, d, J )
9.6 Hz), 4.57-4.51 (2H, m), 3.29-3.16 (1H, m), 2.55-2.39 (1H,
m), 1.72 (3H, s), 1.60 (3H, s), 1.62-1.12 (12H, m), 0.96-0.79
(6H, m); 13C NMR (75 MHz, CDCl3) δ 139.3*, 139.0; 132.3*,
132.2; 128.2* (2C), 127.9; 127.7 (2C); 127.3; 126.5, 126.2*; 83.0,
(14) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J . Am. Chem. Soc.
2000, 122, 1806-1807.
(15) Love, B. E.; J ones, E. J . J . Org. Chem. 1999, 64, 3755-3756.
(16) Wuts, P. G. M. Synth. Commun. 1981, 11, 139-140.

3004 J . Org. Chem., Vol. 67, No. 9, 2002
Belelie and Chong
29.3, 26.1, 21.7, 19.9 (2C), 18.6 (2C); MS (EI) m/z (%) 231 (M+
- i-Pr, 0.6), 91 (100). Anal. Calcd for C19H30O: C, 83.15; H,
11.02. Found: C, 83.40; H, 10.81.
127.5 (2C); 127.2; 125.9*, 125.8; 124.8; 80.0, 79.9*; 71.0; 50.9,
50.5*; 26.0; 18.2; 17.9*, 17.5; MS (EI) m/z (%) 173 (M+ - OBn,
4), 91 (100). Anal. Calcd for C20H24O: C, 85.67; H, 8.63.
Found: C, 85.50; H, 8.48.
5-Ben zyloxy-4-ter t-bu tyl-2-m eth yl-2-h exen e (9a ). Gen-
eral procedure A was followed using acetate 4a (200 mg, 0.76
mmol), t-BuMgCl (1.5 mL, 1.03 M, 1.6 mmol), and CuCN (7
mg, 0.08 mmol). The crude oil (anti:syn ) 83:17 by GC/MS
analysis) was purified via column chromatography (6:1 hexane:
CH2Cl2) to give 144 mg of a n ti-9a and 32 mg of syn -9a (total
5-Ben zyloxy-2-m eth yl-4-p h en yl-2-n on en e (10b). Gen-
eral procedure A was followed using acetate 4b (201 mg, 0.66
mmol), PhMgBr (0.47 mL, 2.82 M, 1.3 mmol), and CuCN (31
1
mg, 0.34 mmol). The crude oil (anti:syn ) 88:12 by H NMR
analysis) was purified via column chromatography (4:1 hexane:
CH2Cl2) to give 145 mg (68%) of a clear, colorless oil: IR (neat)
1671, 1093, 699 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.33-7.18
(10H, m), 5.63 (0.88H, d, J ) 9.4 Hz), 5.47 (0.12H, J ) 9.5
Hz), 4.44 (1H, A of AB, d, J obs ) 11.3 Hz), 4.38 (1H, B of AB,
d, J obs ) 11.3 Hz), 3.71 (1H, dd, J ) 9.5, 5.1 Hz), 3.60-3.54
(1H, m), 1.76 (2.64H, s), 1.72 (0.36H, s), 1.64 (0.36H, s), 1.61
(2.64H, s), 1.47-1.35 (2H, m), 1.35-1.20 (4H, m), 0.88-0.82
(3H, m); 13C NMR (75 MHz, CDCl3) δ 143.7*, 143.5; 138.9*,
138.6; 133.2*, 132.7; 128.5, 128.3* (2C); 128.2 (2C); 128.1 (2C);
128.0, 127.9* (2C); 127.7, 127.3*; 125.9; 124.8, 124.4*; 83.6;
72.5, 72.4*; 49.0, 48.3*; 32.3*, 31.8; 28.0*, 27.7; 26.1, 26.0*;
22.8; 18.2; 14.1; MS (EI) m/z (%) 265 (M+ - n-Bu, 0.1), 91 (100).
Anal. Calcd for C23H30O: C, 85.66; H, 9.38. Found: C, 85.72;
H, 9.48.
176 mg, 89%) as clear, colorless oils: IR (neat) 1672, 696 cm-1
;
1H NMR (300 MHz, CDCl3) a n ti-9a , δ 7.34-7.26 (5H, m), 5.41
(1H, d, J ) 11.0 Hz), 4.60 (1H, A of AB, d, J obs ) 11.7 Hz),
4.38 (1H, B of AB, J obs ) 11.7 Hz), 3.90 (1H, qd, J ) 6.2, 1.6
Hz), 1.92 (1H, dd, J ) 11.0, 1.6 Hz), 1.78 (3H, s), 1.59 (3H, s),
1.08 (3H, d, J ) 6.2 Hz), 0.91 (9H, s); syn -9a , δ 7.36-7.24 (5H,
m), 5.06 (1H, d, J ) 11.0 Hz), 4.51 (2H, m), 3.62 (1H, qd, J )
6.1, 5.0 Hz), 2.40 (1H, dd, J ) 11.0, 5.0 Hz), 1.75 (3H, s), 1.65
(3H, s), 1.13 (3H, d, J ) 6.1 Hz), 0.90 (3H, s); 13C NMR (75
MHz, CDCl3) a n ti-9a , δ 139.3, 133.0, 128.1 (2C), 127.4, 127.1
(2C), 122.3, 75.0, 70.2, 53.5, 34.2, 28.8 (3C), 26.3, 18.6, 18.3;
syn -9a , δ 139.1, 132.8, 128.2 (2C), 127.7 (2C), 127.3, 123.2,
76.0, 70.1, 51.7, 33.4, 28.7 (3C), 26.2, 18.5, 18.1; MS (EI) m/z
(%) both diastereomers: 91 (100). Anal. Calcd for C18H28O: C,
83.02; H, 10.84. Found: C, 83.29; H, 10.61.
5-Ben zyloxy-2,6-dim eth yl-4-ph en yl-2-h epten e (10c). Gen-
eral procedure A was followed using acetate 4c (201 mg, 0.69
mmol), PhMgBr (0.49 mL, 2.82 M, 1.4 mmol), and CuCN (32
mg, 0.36 mmol). The crude oil (only one isomer by GC/MS
analysis) was purified via column chromatography (6:1 hexane:
CH2Cl2) to give 160 mg (75%) of a clear, colorless oil: IR (neat)
1671, 699 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.32-7.16 (10H,
m), 5.67 (1H, d, J ) 9.6 Hz), 4.32 (1H, A of AB, d, J obs ) 10.7
Hz), 4.13 (1H, B of AB, d, J obs ) 10.7 Hz), 3.78 (1H, dd, J )
9.6, 5.6 Hz), 3.31 (1H, dd, J ) 5.6, 5.6 Hz), 1.73 (3H, s), 1.72-
1.66 (1H, m), 1.59 (3H, s), 0.97 (3H, d, J ) 7.5 Hz), 0.92 (3H,
d, J ) 7.3 Hz); 13C NMR (75 MHz, CDCl3) δ 144.0, 139.0, 132.9,
128.4 (2C), 128.3 (2C), 128.1 (2C), 127.9 (2C), 127.3, 125.9,
124.2, 89.6, 75.2, 47.1, 31.4, 26.0, 20.1, 18.2, 18.0; MS (EI) m/z
(%) 265 (M+ - i-Pr, 0.3), 91 (100). Anal. Calcd for C22H28O: C,
85.66; H, 9.15. Found: C, 85.80; H, 9.12.
5-Ben zyloxy-4-ter t-bu tyl-2-m eth yl-2-n on en e (9b). Gen-
eral procedure A was followed using acetate 4b (202 mg, 0.66
mmol), t-BuMgCl (1.3 mL, 1.03 M, 1.3 mmol), and CuCN (6
mg, 0.07 mmol). The crude oil (anti:syn ) 87:13 by GC/MS
analysis) was purified via column chromatography (10:1
hexane:CH2Cl2) to give 180 mg (89%) of a clear, colorless oil:
IR (neat) 1671, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.34-
7.26 (5H, m), 5.41 (0.87H, d, J ) 11.0 Hz), 5.10 (0.13H, d, J )
9.2 Hz), 4.58 (0.87H, A of AB, d, J obs ) 11.6 Hz), 4.55 (0.13H,
A of AB, d, J obs ) 10.2 Hz), 4.43 (0.87H, B of AB, d, J obs ) 11.6
Hz), 4.39 (0.13H, B of AB, d, J obs ) 10.2 Hz), 3.62-3.58 (0.87H,
m), 3.51-3.45 (0.13H, m), 2.48-2.44 (0.13H, m), 2.06 (0.87H,
d, J ) 11.0 Hz), 1.77 (2.61H, s), 1.74 (0.39H, s), 1.64 (0.39H,
s), 1.59 (2.61H, s), 1.42-1.15 (6H, m) 0.91 (9H, s), 0.91 (3H,
m); 13C NMR (75 MHz, CDCl3) δ 139.3*, 138.9; 132.9*, 132.7;
128.2, 128.1* (2C); 127.4*, 127.3 (2C); 127.1; 123.0, 122.5*;
80.1, 79.9*; 70.6; 50.3*, 49.5; 34.1*, 33.2; 32.1*, 32.0; 28.9*,
28.8 (3C); 28.7*, 28.1; 26.3; 23.0*, 22.8; 18.5*, 18.4; 14.2, 14.1*;
MS (EI) m/z (%) 245 (M+ - t-Bu, 0.1), 91 (100). Anal. Calcd
for C21H34O: C, 83.38; H, 11.33. Found: C, 83.52; H, 11.42.
5-Ben zyloxy-4-ter t-bu tyl-2,6-d im eth yl-2-h ep ten e (9c).
General procedure A was followed using acetate 4c (499 mg,
1.7 mmol), t-BuMgCl (3.3 mL, 1.03 M, 3.4 mmol), and CuCN
(17 mg, 0.19 mmol) to give 464 mg (94%) of a clear, colorless
oil. The resulting product was sufficiently clean and did not
5-Ben zyloxy-2,4,6-tr im eth yl-2-h ep ten e (11c). General
procedure A was followed using acetate 4c (152 mg, 0.52
mmol), MeMgBr (0.35 mL, 2.94 M, 1.0 mmol), and CuCN (26
mg, 0.29 mmol). The crude oil (anti:syn ) 98:2 by GC/MS
analysis) was purified via column chromatography (6:1 hexane:
CH2Cl2) to give 99 mg (77%) of a clear, colorless oil: IR (neat)
1672, 697 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.36-7.24 (5H,
m), 5.21 (1H, d, J ) 9.6 Hz), 4.61 (1H, A of AB quartet, d, J obs
) 11.2 Hz), 4.56 (1H, B of AB quartet, d, J obs ) 11.2 Hz), 2.93
(1H, dd, J ) 6.5, 4.6 Hz), 2.69-2.63 (1H, m), 1.80 (1H, qqd, J
) 6.9, 6.7, 6.5 Hz), 1.69 (3H, s), 1.61 (3H, s), 0.99 (3H, d, J )
1
require purification: IR (neat) 1671, 696 cm-1; H NMR (300
MHz, CDCl3) δ 7.38-7.22 (5H, m), 5.49 (1H, d, J ) 10.8 Hz),
4.61 (1H, A of AB, d, J obs ) 11.5 Hz), 4.57 (1H, B of AB, d, J obs
) 11.5 Hz), 3.39 (1H, d, J ) 6.9 Hz), 2.17 (1H, d, J ) 10.8 Hz),
1.87 (1H, dqq, J ) 6.9, 6.9, 6.8 Hz), 1.74 (3H, s), 1.59 (3H, s),
0.98 (3H, d, J ) 6.9 Hz), 0.91 (9H, s), 0.87 (3H, d, J ) 6.8 Hz);
13C NMR (75 MHz, CDCl3) δ 139.5, 131.7, 128.1 (2C), 127.0
(3C), 123.6, 84.3, 72.3, 48.7, 34.4, 32.2, 28.7 (3C), 26.3, 19.4,
19.0, 18.8; MS (EI) m/z (%) 245 (M+ - i-Pr, 0.3), 91 (100). Anal.
Calcd for C20H32O: C, 83.27; H, 11.18. Found: C, 83.09; H,
11.15.
6.9 Hz), 0.98 (3H, d, J ) 6.7 Hz), 0.90 (3H, d, J ) 6.8 Hz); 13
C
NMR (75 MHz, CDCl3) δ 139.4, 130.5, 128.2 (2C), 127.5 (2C),
127.3, 127.2, 89.6, 75.1, 35.6, 31.3, 25.9, 20.0, 19.0, 18.3, 17.9;
MS (EI) m/z (%) 246 (M+, 0.03), 91 (100). Anal. Calcd for
C
17H26O: C, 82.89; H, 10.64. Found: C, 82.55; H, 10.60.
5-Ben zyloxy-4-eth yl-2,6-d im eth yl-2-h ep ten e (12c). Gen-
eral procedure A was followed using acetate 4c (151 mg, 0.52
mmol), EtMgBr (0.55 mL, 1.89 M, 1.0 mmol), and CuCN (24
mg, 0.26 mmol). The crude oil (anti:syn ) 99:1 by GC/MS
analysis) was purified via column chromatography (6:1 hexane:
CH2Cl2) to give 114 mg (84%) of a clear, colorless oil: IR (neat)
1672, 1097, 697 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37-7.24
(5H, m), 5.16 (1H, d, J ) 10.3 Hz), 4.60-4.55 (2H, m), 3.02
(1H, dd, J ) 7.4, 3.6 Hz), 2.42-2.37 (1H, m), 1.79 (1H, dqq, J
) 7.4, 6.8, 6.7 Hz), 1.72 (3H, s), 1.61 (3H, s), 1.55-1.48 (1H, A
of AB, m), 1.41-1.35 (1H, B of AB, m), 0.98 (3H, d, J ) 6.7
Hz), 0.88 (3H, d, J ) 6.8 Hz), 0.84 (3H, t, J ) 7.4 Hz); 13C
NMR (75 MHz, CDCl3) δ 139.4, 131.9, 128.2 (2C), 127.5 (2C),
127.2, 125.5, 88.8, 75.0, 43.1, 31.6, 26.3, 26.0, 19.9, 19.0, 18.4,
12.2; MS (EI) m/z (%) 217 (M+ - i-Pr, 0.7), 91 (100). Anal. Calcd
for C18H28O: C, 83.02; H, 10.84. Found: C, 83.21; H, 10.76.
4-Bu t yl-5-ter t-b u t yld im et h ylsilyloxy-2-m et h yl-2-n on -
en e (13b). General procedure A was followed using acetate
5b (149 mg, 0.45 mmol), n-BuMgBr (0.51 mL, 2.77 M, 1.4
mmol), and CuCN (6 mg, 0.07 mmol). The crude oil (anti:syn
5-Ben zyloxy-2-m eth yl-4-p h en yl-2-h exen e (10a ). General
procedure A was followed using acetate 4a (202 mg, 0.77
mmol), PhMgBr (0.54 mL, 2.82 M, 1.5 mmol), and CuCN (37
1
mg, 0.41 mmol). The crude oil (anti:syn ) 79:21 by H NMR
analysis) was purified via column chromatography (3:2 hexane:
CH2Cl2) to give 139 mg (64%) of a clear, colorless oil: IR (neat)
1672, 699 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.18 (10H,
m), 5.58 (0.79H, d, J ) 9.4 Hz), 5.42 (0.21H, d, J ) 9.3 Hz),
4.57 (0.79H, A of AB, d, J obs ) 12.0 Hz), 4.48 (0.21H, A of AB,
d, J obs ) 11.6 Hz), 4.43 (0.79H, B of AB, d, J obs ) 12.0 Hz),
4.27 (0.21H, B of AB, d, J obs ) 11.6 Hz), 3.75-3.65 (1H, m),
3.62-3.55 (1H, m), 1.75 (2.37H, s), 1.72 (0.63H, s), 1.65 (0.63H,
s), 1.61 (2.37H, s), 1.20 (0.63H, d, J ) 5.9 Hz), 1.09 (2.37H, d,
J ) 6.2 Hz); 13C NMR (75 MHz, CDCl3) δ 143.4; 138.9*, 138.6;
133.1*, 132.9; 128.8*, 128.7 (2C); 128.2 (2C); 128.1*, 128.0 (2C);

Reactions of δ-Oxy-Substituted Allylic Acetates
J . Org. Chem., Vol. 67, No. 9, 2002 3005
) 81:19 by 1H NMR analysis) was purified via column
chromatography (hexane) to give 130 mg (89%) of a clear,
colorless oil: IR (neat) 1672 cm-1; 1H NMR (300 MHz, CDCl3)
δ 4.94 (0.81H, d, J ) 10.0 Hz), 4.90 (0.19H, d, J ) 10.0 Hz),
3.51-3.45 (0.81H, m), 3.46 (0.19H, dt, J ) 5.5, 5.5 Hz), 2.28-
2.21 (1H, m), 1.69 (0.57H, s), 1.68 (2.43H, s), 1.58 (3H, s), 1.46-
0.96 (12H, m), 0.88-0.83 (6H, m), 0.87 (9H, s), 0.02 (2.43, s),
0.01 (3.57, s); 13C NMR (75 MHz, CDCl3) δ 131.9*, 131.2; 127.6,
126.5*; 76.0, 75.4*; 43.6, 43.2*; 34.4, 33.6*; 30.7, 30.6*; 30.1*,
29.7; 28.3*, 27.0; 26.1; 26.0 (3C); 23.0 (2C); 18.4*, 18.3; 18.2,
18.1*; 14.2 (2C); -4.2, -4.3*; -4.4*, -4.5; MS (EI) m/z (%)
312 (M+ - 15, 1), 73 (100). Anal. Calcd for C20H42OSi: C, 73.54;
H, 12.96. Found: C, 73.35; H, 12.78. The major isomer was
identified as the anti-isomer by desilylation and comparison
of GC retention times with 20b.
4-Bu t yl-5-ter t-b u t yld im et h ylsilyloxy-2,6-d im et h yl-2-
h ep ten e (13c). General procedure A was followed using
acetate 5c (200 mg, 0.63 mmol), n-BuMgBr (0.47 mL, 2.71 M,
1.3 mmol), and CuCN (8 mg, 0.09 mmol). The crude oil (anti:
syn ) 95:5 by GC/MS analysis) was purified via column
chromatography (hexane) to give 160 mg (81%) of a clear,
colorless oil: IR (neat) 1672 cm-1; 1H NMR (300 MHz, CDCl3)
δ 5.06 (1H, d, J ) 10.0 Hz), 3.29 (1H, dd, J ) 5.1, 3.8 Hz),
2.35-2.26 (1H, m), 1.74-1.64 (1H, m), 1.68 (3H, s), 1.56 (3H,
s), 1.39-1.05 (6H, m), 0.88 (9H, s), 0.87-0.79 (9H, m), 0.00
(6H, s); 13C NMR (75 MHz, CDCl3) δ 130.6, 127.2, 80.4, 42.2,
33.1, 32.3, 30.0, 26.2 (3C), 26.1, 23.1, 20.2, 18.6, 18.5, 18.4,
14.2, -3.7 (2C); MS (EI) m/z (%) 312 (M+, 0.1), 187 (100). Anal.
Calcd for C19H40OSi: C, 73.00; H, 12.90. Found: C, 72.84; H,
12.83. The major isomer was identified as the anti-isomer by
desilylation followed by benzylation and comparison of GC
retention times with 7c.
AB, d, J obs ) 12.1 Hz), 4.37 (1H, B of AB, d, J obs ) 12.1 Hz),
3.44 (1H, dd, J ) 8.5, 7.4 Hz), 1.84 (1H, dqq, J ) 7.4, 6.8, 6.7
Hz), 1.45 (3H, s), 1.43 (3H, s), 0.98 (3H, d, J ) 6.7 Hz), 0.90
(3H, d, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 148.7, 144.6,
139.1, 128.2 (2C), 128.1 (2C), 127.6 (2C), 127.2, 126.1 (2C),
125.8, 125.4, 85.6, 69.9, 40.6, 33.0, 28.8 (2C), 19.0, 18.6; MS
(EI) m/z (%) 265 (M+ - i-Pr, 3), 91 (100). Anal. Calcd for
C
22H28O: C, 85.66; H, 9.15. Found: C, 85.80; H, 8.96.
Gen er a l P r oced u r e B: Gr ign a r d Ad d ition s to Hyd r oxy
Aceta tes 18. The desired Grignard reagent (2.5 equiv) was
added to a slurry of the acetate (1.0 equiv) and CuCN (0.5
equiv) in CH2Cl2 (1 mL/10 mg substrate) at -78 °C. The
reaction was allowed to warm to -25 °C, where it was kept
until completion (monitored by TLC, 2-12 h). Quench and
workup of the reaction mixture was performed as outlined
previously.
2,6-Dim eth yl-5-h ep ten -3-on e (19c).17 This was the main
side product from reactions of 18c with Grignard reagents
1
using 10 mol % CuCN: IR (neat) 1714, 1677 cm-1; H NMR
(300 MHz, CDCl3) δ 5.30 (1H, t, J ) 7.0 Hz), 3.17 (2H, d, J )
7.0 Hz), 2.66 (1H, septet, J ) 6.9 Hz), 1.75 (3H, s), 1.63 (3H,
s), 1.11 (6H, d, J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 213.2,
135.2, 116.1, 40.2 (2C), 25.7, 18.2 (2C), 18.0; MS (EI) m/z (%)
140 (M+, 13), 71 (100).
3-Bu tyl-5-m eth yl-4-h exen -2-ol (20a ). General procedure
B was followed using hydroxy acetate 18a (76 mg, 0.44 mmol),
n-BuMgBr (0.39 mL, 2.77 M, 1.1 mmol), and CuCN (20 mg,
0.23 mmol). The crude oil (anti:syn ) 11:89 by GC/MS
analysis) was purified via column chromatography (30% Et2O
in hexane) to afford 52 mg (69%) of a clear, colorless oil: IR
(neat) 3369 (br), 1675 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.90
(1H, d, J ) 10.2 Hz), 3.66 (0.89H, dq, J ) 6.3, 6.3 Hz), 3.53
(0.11H, dq, J ) 6.3, 6.3 Hz), 2.40-2.30 (0.89H, m), 2.22-2.09
(0.11H, m), 1.77 (0.33H, s), 1.75 (2.67H, s), 1.65 (3H, s), 1.60-
1.21 (7H, m), 1.18 (0.33H, d, J ) 6.3 Hz), 1.11 (2.67H, d, J )
6.3 Hz), 0.90 (3H, t, J ) 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ
134.5; 125.9, 124.9*; 71.2*, 70.7; 46.4, 45.4*; 31.5*, 31.2; 29.6;
26.1*, 26.0; 22.9*, 22.8; 20.3, 19.9*; 18.5; 14.1; MS (EI) m/z
(%) 170 (M+, 0.1), 69 (100). Anal. Calcd for C11H22O: C, 77.58;
H, 13.02. Found: C, 77.46; H, 12.98.
4-Bu tyl-2-m eth yl-2-n on en -5-ol (20b). General procedure
B was followed using hydroxy acetate 18b (100 mg, 0.47
mmol), n-BuMgBr (0.42 mL, 2.77 M, 1.2 mmol), and CuCN
(22 mg, 0.25 mmol). The crude oil (anti:syn ) 7:93 by GC/MS
analysis) was purified via column chromatography (15% Et2O
in hexane) to afford 83 mg (84%) of a clear, colorless oil: IR
(neat) 3368 (br), 1675 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.94
(0.07H, d, J ) 11.2 Hz), 4.90 (0.93H, d, J ) 10.2 Hz), 3.48-
3.34 (1H, m), 2.42-2.30 (1H, m), 1.77 (0.21H, s), 1.74 (2.79H,
s), 1.64 (3H, s), 1.56 (1H, br s), 1.51-1.08 (12H, m), 0.90 (3H,
t, J ) 6.8 Hz), 0.88 (3H, t, J ) 7.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 135.1, 133.8*; 125.6*, 125.4; 75.3*, 74.6; 44.5*, 44.4;
34.2, 33.6*; 31.5, 31.1*; 29.6; 28.3*; 28.0; 26.0; 22.9; 22.7; 18.5,
18.4*; 14.1 (2C); MS (EI) m/z (%) 194 (M+ - H2O, 7), 95 (100).
4-Bu tyl-5-m eth oxym eth yl-2-m eth yl-2-n on en e (14b). Gen-
eral procedure A was followed using acetate 6b (150 mg, 0.58
mmol), n-BuMgBr (0.43 mL, 2.71 M, 1.17 mmol), and CuCN
(7 mg, 0.08 mmol). The crude oil (anti:syn ) 83:17 by GC/MS
analysis) was purified via column chromatography (1:1 hexane:
CH2Cl2) to afford 126 mg (85%) of a clear, colorless oil: IR
1
(neat) 1675 cm-1; H NMR (300 MHz, CDCl3) δ 4.98 (0.83H,
d, J ) 8.9 Hz), 4.95 (0.17H, d, J ) 8.9 Hz), 4.70-4.62 (2H, m),
3.47-3.32 (1H, m), 3.39 (3H, s), 2.50-2.33 (1H, m), 1.72 (3H,
s), 1.62 (3H, s), 1.58-1.03 (12H, m), 0.90-0.86 (6H, m); 13C
NMR (75 MHz, CDCl3) δ 132.8*, 132.5; 126.1, 125.9*; 96.2*,
95.9; 81.5; 55.8, 55.6*; 41.7*, 41.6; 31.5*, 31.4; 31.2, 31.0*;
30.1*, 29.8; 28.4*, 27.7; 26.1; 23.1; 23.0; 18.4, 18.3; 14.2 (2C);
MS (EI) m/z (%) 167 (49), 81 (100). Anal. Calcd for C16H32O2:
C, 74.94; H, 12.58. Found: C, 75.12; H, 12.70. The major
isomer was identified as the anti-isomer by comparison with
the MOM ether prepared from 20b.
4-Bu tyl-5-m eth oxym eth yl-2,6-dim eth yl-2-h epten e (14c).
General procedure A was followed using acetate 6c (150 mg,
0.61 mmol), n-BuMgBr (0.45 mL, 2.71 M, 1.22 mmol), and
CuCN (6 mg, 0.07 mmol). The crude oil (anti:syn ) 97.5:2.5
by GC/MS analysis) was purified via column chromatography
(1:1 hexane:CH2Cl2) to afford 130 mg (88%) of a clear, colorless
oil: IR (neat) 1663, 1149, 1096, 1042 cm-1; 1H NMR (300 MHz,
4-Bu tyl-2,6-d im eth yl-5-h ep ten -3-ol (20c). General pro-
cedure B was followed using hydroxy acetate 18c (101 mg, 0.50
mmol), n-BuMgBr (0.45 mL, 2.77 M, 1.3 mmol), and CuCN
(24 mg, 0.27 mmol). The crude oil (anti:syn ) 12:88 by GC/
MS analysis) was purified via column chromatography (7.5%
Et2O in hexane) to afford 73 mg (73%) of a clear, colorless oil:
CDCl3) δ 5.08 (1H, d, J ) 9.4 Hz), 4.69 (1H, A of AB, d, J obs
)
6.8 Hz), 4.64 (1H, B of AB, d, J obs ) 6.8 Hz), 3.40 (3H, s), 3.13
(1H, dd, J ) 6.7, 3.8 Hz), 2.51-2.36 (1H, m), 1.83 (1H, qqd, J
) 6.8, 6.7, 6.7 Hz), 1.72 (3H, s), 1.61 (3H, s), 1.48-1.10 (6H,
m), 0.94 (3H, d, J ) 6.8 Hz), 0.91 (3H, t, J ) 6.8 Hz), 0.90
(3H, d, J ) 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 131.8, 126.0,
98.2, 88.0, 56.0, 40.8, 32.9, 31.1, 29.7, 26.0, 23.0, 19.9, 18.7,
18.4, 14.2; MS (EI) m/z (%) 167 (78), 69 (100). Anal. Calcd for
1
IR (neat) 3401 (br), 1676 cm-1; H NMR (300 MHz, CDCl3) δ
4.98 (0.12H, d, J ) 10.2 Hz), 4.86 (0.88H, d, J ) 10.1 Hz),
3.18 (1H, dd, J ) 7.5, 4.0 Hz), 2.36-2.26 (1H, m), 1.80-1.69
(1H, m), 1.76 (0.36H, s), 1.72 (2.64H, s), 1.65 (0.36H, s), 1.62
(2.64H, s), 1.44 (1H, br s), 1.34-1.04 (6H, m), 0.95 (3H, d, J )
C
15H30O2: C, 74.33; H, 12.47. Found: C, 74.50; H, 12.58. The
major isomer was identified as the anti-isomer by comparison
with the MOM ether prepared from 20c.
6.9 Hz), 0.90 (3H, t, J ) 7.1 Hz), 0.85 (3H, d, J ) 6.7 Hz); 13
C
NMR (75 MHz, CDCl3) δ 134.8, 132.1*; 126.6*, 125.4; 80.0*,
79.0; 42.0*, 41.6; 31.8, 30.8*; 30.4*, 30.2; 29.4; 25.9; 23.0; 20.3*,
20.1; 18.4; 16.4, 15.6*; 14.2; MS (EI) m/z (%) 198 (M+, 0.1), 69
(100). Anal. Calcd for C13H26O: C, 78.72; H, 13.21. Found: C,
78.58; H, 13.24.
(E)-5-Ben zyloxy-2,6-d im eth yl-2-p h en yl-3-h ep ten e (15).
General procedure A was followed using acetate 4c (199 mg,
0.68 mmol), PhMgBr (0.49 mL, 2.82 M, 1.4 mmol), and CuCN
(7 mg, 0.07 mmol) in THF. The crude oil was purified via
column chromatography (6:1 hexane:CH2Cl2) to give 182 mg
(86%) of 15 as a clear, colorless oil: IR (neat) 1663, 698 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.37-7.17 (10H, m), 5.82 (1H,
d, J ) 15.8 Hz), 5.40 (1H, dd, J ) 15.8, 8.5 Hz), 4.62 (1H, A of
(17) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem.
Soc. J pn. 1984, 57, 242-246.

3006 J . Org. Chem., Vol. 67, No. 9, 2002
Belelie and Chong
3-Isop r op yl-5-m eth yl-4-h exen -2-ol (21a ). General pro-
cedure B was followed using hydroxy acetate 18a (101 mg, 0.58
mmol), i-PrMgCl (0.89 mL, 1.64 M, 1.5 mmol), and CuCN (26
mg, 0.29 mmol). The crude oil (anti:syn ) 21:79 by GC/MS
analysis) was purified via column chromatography (25% Et2O
in hexane) to afford 64 mg (71%) of a clear, colorless oil: IR
(neat) 3368 (br), 1674 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.05
(0.21H, d, J ) 10.7 Hz), 4.93 (0.79H, J ) 10.7 Hz), 3.86 (0.79H,
qd, J ) 6.9, 6.3 Hz), 3.77 (0.21H, dq, J ) 6.4, 6.2 Hz), 2.22
(0.79H, ddd, J ) 10.7, 6.8, 6.3 Hz), 2.05-1.95 (0.21H, m), 1.87-
1.70 (1H, m), 1.80 (0.63H, s), 1.77 (2.37H, s), 1.65 (3H, s), 1.51
(1H, br s), 1.18 (0.63H, d, J ) 6.2 Hz), 1.10 (2.37H, d, J ) 6.9
Hz), 0.89 (3H, d, J ) 6.9 Hz), 0.84 (2.37H, d, J ) 6.9 Hz), 0.82
(0.63H, d, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 136.8,
135.6*; 122.1*, 122.0; 68.5; 51.9*, 51.5; 28.8, 28.7*; 26.2; 21.7,
20.9*; 20.8, 19.9*; 19.0; 18.5*, 17.8; MS (EI) m/z (%) 156 (M+,
0.2), 69 (100). Anal. Calcd for C10H20O: C, 76.86; H, 12.90.
Found: C, 76.75; H, 12.78.
mg, 0.30 mmol). The crude oil (anti:syn ) 3:97 by GC/MS
analysis) was purified via column chromatography (25% Et2O
in hexane) to afford 79 mg (79%) of a clear, colorless oil: IR
(neat) 3392 (br), 1672 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.12
(1H, d, J ) 11.2 Hz), 4.03-3.87 (1H, m), 2.34 (1H, dd, J )
11.2, 4.8 Hz), 1.79 (3H, s), 1.66 (3H, s), 1.34 (1H, d, J ) 8.4
Hz), 1.14 (3H, d, J ) 6.4 Hz), 0.92 (9H, s); 13C NMR (75 MHz,
CDCl3) δ 135.5, 121.6, 68.4, 54.3, 33.3, 28.6 (3C), 26.3, 21.2,
18.4; MS (EI) m/z (%) 170 (M+, 0.1), 57 (100). Anal. Calcd for
C
11H22O: C, 77.58; H, 13.02. Found: C, 77.60; H, 13.25.
4-ter t-Bu tyl-2-m eth yl-2-n on en -5-ol (22b). General pro-
cedure B was followed using hydroxy acetate 18b (99 mg, 0.46
mmol), t-BuMgBr (1.2 mL, 0.99 M, 1.2 mmol), and CuCN (21
mg, 0.24 mmol). The crude oil was purified via column
chromatography (12.5% Et2O in hexane) to afford 83 mg (83%)
of a clear, colorless oil that was homogeneous by GC/MS and
1
1H NMR analysis: IR (neat) 3436 (br), 1671 cm-1; H NMR
(300 MHz, CDCl3) δ 5.08 (1H, d, J ) 11.2 Hz), 3.79-3.63 (1H,
m), 2.31 (1H, dd, J ) 11.2, 5.0 Hz), 1.77 (3H, s), 1.65 (3H, s),
1.55-1.13 (6H, m), 1.20 (1H, d, J ) 8.2 Hz), 0.92 (9H, s), 0.90
(3H, t, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 134.7, 122.5,
72.8, 54.2, 34.7, 33.5, 28.9 (3C), 28.5, 26.4, 22.8, 18.4, 14.2;
MS (EI) m/z (%) 194 (M+ - H2O, 5), 57 (100). Anal. Calcd for
4-Isop r op yl-2-m eth yl-2-n on en -5-ol (21b). General pro-
cedure B was followed using hydroxy acetate 18b (101 mg,
0.47 mmol), i-PrMgCl (0.71 mL, 1.64 M, 1.2 mmol), and CuCN
(22 mg, 0.24 mmol). The crude oil (anti:syn ) 14:86 by GC/
MS analysis) was purified via column chromatography (20%
Et2O in hexane) to afford 63 mg (68%) of a clear, colorless oil:
C
14H28O: C, 79.18; H, 13.29. Found: C, 79.32; H, 13.31.
1
IR (neat) 3368 (br), 1673 cm-1; H NMR (300 MHz, CDCl3) δ
4-ter t-Bu tyl-6-m eth yl-5-h ep ten -3-ol (22c). General pro-
5.07 (0.14H, d, J ) 10.7 Hz), 4.91 (0.86H, d, J ) 10.7 Hz),
3.58 (1H, ddd, J ) 6.8, 6.8, 2.1 Hz), 2.19 (0.86H, ddd, J ) 10.7,
6.8, 6.8 Hz), 2.06 (0.14H, ddd, J ) 10.7, 6.8, 6.0 Hz), 1.87 (1H,
dqq, J ) 6.8, 6.7, 6.7 Hz), 1.79 (0.42H, s), 1.76 (2.58H, s), 1.64
(3H, s), 1.58-1.05 (7H, m), 0.92 (3H, t, J ) 7.0 Hz), 0.91
(0.42H, d, J ) 6.7 Hz), 0.88 (2.58H, d, J ) 6.7 Hz), 0.83 (2.58H,
J ) 6.7 Hz), 0.82 (0.42H, d, J ) 6.7 Hz); 13C NMR (75 MHz,
CDCl3) δ 135.8, 135.1*; 122.5*, 122.3; 72.5*, 72.1; 50.7*, 50.0;
34.7, 33.4*; 28.8, 28.5*; 28.3*, 27.9; 26.2; 22.8, 22.7*; 21.5,
21.0*; 18.6; 18.5; 14.1; MS (EI) m/z (%) 180 (M+ - H2O, 4), 69
(100). Anal. Calcd for C13H26O: C, 78.72; H, 13.21. Found: C,
78.36; H, 13.01.
4-Isop r op yl-6-m eth yl-5-h ep ten -2-ol (21c). General pro-
cedure B was followed using hydroxy acetate 18c (100 mg, 0.50
mmol), i-PrMgCl (0.76 mL, 1.64 M, 1.3 mmol), and CuCN (23
mg, 0.25 mmol). The crude oil (anti:syn ) 44:56 by GC/MS
analysis) was purified via column chromatography (15% Et2O
in hexane) to afford 63 mg (68%) of a clear, colorless oil: IR
(neat) 3401 (br), 1673 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.09
(0.50H, d, J ) 9.3 Hz), 4.84 (0.50H, d, J ) 10.7 Hz), 3.41
(0.50H, dd, J ) 9.8, 2.8 Hz), 3.35 (0.50H, dd, J ) 5.9, 5.9 Hz),
2.30 (0.50H, ddd, J ) 10.7, 9.8, 2.8 Hz), 2.21-2.09 (1H, m),
1.82-1.68 (1.50H, m), 1.77 (1.50H, s), 1.72 (1.50 H, s), 1.64
(1.50H, s), 1.63 (1.50H, s), 1.44 (0.50H, br s), 1.43 (0.50H, br
s), 1.00-0.74 (12H, m); 13C NMR (75 MHz, CDCl3) δ 135.3,
133.4, 122.3, 121.8, 76.8, 76.4, 47.2, 47.1, 30.4, 30.2, 28.7, 27.9,
26.2, 26.1, 21.6, 21.4, 20.8, 19.9, 18.7, 18.6, 18.5, 16.8, 16.0,
13.9; MS (EI) m/z (%) 184 (M+, 0.1), 69 (100). Anal. Calcd for
cedure B was followed using hydroxy acetate 18c (100 mg, 0.50
mmol), t-BuMgBr (1.3 mL, 0.99 M, 1.3 mmol), and CuCN (22
mg, 0.25 mmol). The crude white solid (anti:syn ) 6:94 by GC/
MS analysis of the derived acetates) was purified via column
chromatography (10% Et2O in hexane) to afford 82 mg (83%)
of a white, crystalline solid (mp ) 45-47 °C): IR (KBr) 3415
1
(br), 1385 cm-1; H NMR (300 MHz, CDCl3) δ 5.26 (0.06H, d,
J ) 10.9 Hz), 4.88 (0.94H, d, J ) 11.0 Hz), 3.49 (0.94H, dd, J
) 9.0, 7.0 Hz), 3.41 (0.06H, dd, J ) 8.6, 7.6 Hz), 2.17 (0.06H,
dd, J ) 10.9, 8.6 Hz), 2.08 (0.94H, dd, J ) 11.0, 9.0 Hz), 1.79-
1.72 (1H, m), 1.60 (3H, s), 1.55 (3H, s), 1.09 (1H, d, J ) 7.0
Hz), 0.93 (9H, s), 0.93-0.89 (3H, m), 0.72 (3H, d, J ) 6.8 Hz);
13C NMR (75 MHz, CDCl3) δ 134.4, 131.5*; 124.5*, 121.0; 77.3,
76.9*; 51.6*, 48.9; 34.2*, 34.0; 33.3, 30.8*; 29.0*, 28.5 (3C); 26.4,
26.0*; 20.9*, 19.8; 19.0, 18.6*; 13.6; MS (EI) m/z (%) 198 (M+,
0.03), 57 (100). Anal. Calcd for C13H26O: C, 78.72; H, 13.21.
Found: C, 79.02; H, 13.07.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada for finan-
cial support and a postgraduate scholarship (to J .L.B.).
We are grateful to Dr. Nicholas J . Taylor for carrying
out X-ray diffraction experiments.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of compounds 1-6 and 18, spectral
data for compounds 1-6 and 18, details for GC analysis of
diastereomer ratios, and determination of relative configura-
tions. This material is available free of charge via the Internet
at http://pubs.acs.org.
C
12H24O: C, 78.20; H, 13.12. Found: C, 78.28; H, 12.93.
3-ter t-Bu tyl-5-m eth yl-4-h exen -2-ol (22a ). General pro-
cedure B was followed using hydroxy acetate 18a (101 mg, 0.59
mmol), t-BuMgBr (1.5 mL, 0.99 M, 1.5 mmol), and CuCN (27
J O016310X