Stereoselective reactions of acyclic allylic phosphates with organocopper reagents

Article abstract of DOI:10.1021/jo0104431

A series of acyclic allylic alcohols of general structure R¹CH=CHCH(OH)R² were resolved by Sharpless kinetic resolution. The hydroxyl groups of these enantiomerically enriched alcohols were derivatized to diethyl phosphates, and the derivatives were reacted with organocopper reagents. Cleanest substitution reactions were observed with reagents R³₂CuCNLi₂. With R¹ = Me and R³ = n-Bu, the size of R² affected both the regioselectivity and stereoselectivity of the displacement. Larger R² groups gave higher regio- and stereoselectivities: with R² = 3-pentyl, >98% S_N2′ regioselectivity and > 98% anti stereoselectivity were observed. Bn₂CuCNLi₂ gave stereoselectivities comparable to those observed with n-Bu₂CuCNLi₂ but t-Bu₂CuCNLi₂ exhibited much lower diastereofacial preference.

Full text of DOI:10.1021/jo0104431

5552
J . Org. Chem. 2001, 66, 5552-5555
Ster eoselective Rea ction s of Acyclic Allylic P h osp h a tes w ith
Or ga n ocop p er Rea gen ts
J ennifer L. Belelie and J . Michael Chong*
The Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry (GWC2),
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
jmchong@uwaterloo.ca
Received April 30, 2001
A series of acyclic allylic alcohols of general structure R1CHdCHCH(OH)R2 were resolved by
Sharpless kinetic resolution. The hydroxyl groups of these enantiomerically enriched alcohols were
derivatized to diethyl phosphates, and the derivatives were reacted with organocopper reagents.
Cleanest substitution reactions were observed with reagents R3 CuCNLi2. With R1 ) Me and R3 )
2
n-Bu, the size of R2 affected both the regioselectivity and stereoselectivity of the displacement.
Larger R2 groups gave higher regio- and stereoselectivities: with R2 ) 3-pentyl, >98% SN2′
regioselectivity and >98% anti stereoselectivity were observed. Bn2CuCNLi2 gave stereoselectivities
comparable to those observed with n-Bu2CuCNLi2 but t-Bu2CuCNLi2 exhibited much lower
diastereofacial preference.
Sch em e 1
In tr od u ction
Organocopper reagents are widely used in organic
synthesis.1 Among their many applications are substitu-
tion reactions on a wide variety of allylic functionalities.
Of prime importance in such reactions are regiochemistry
and stereochemistry, and many outstanding investiga-
tions have been carried out to elucidate factors that
influence these outcomes. For example, it is now gener-
ally expected that organocuprates will undergo anti, SN2′
reaction with allylic carboxylates, halides, phosphates,
and sulfonates, but syn SN2′ reaction with allylic car-
bamates2 and allyloxybenzotriazoles.3 However, most
studies in this area have been carried out with cyclic
compounds, and relatively little attention has been paid
to acyclic systems. Thus, there are scattered examples
that demonstrate high anti, SN2′ selectivity with γ-me-
syloxy R,â-unsaturated esters,4 mesyloxy vinyl sulf-
oxides,5 allylic mesylates linked to an oxazolidine,6 and
CF3-containing allylic acetates;7 also, high syn, SN2′
selectivity has been observed with 3-silylallylic carbam-
ates,8 but it is still not possible to predict reliably the
product distribution of the general reaction shown in
Scheme 1.
Sch em e 2
We were particularly interested in examining the
reactions of organocopper reagents with substrates de-
rived from allylic alcohols 1 as these are readily available
in enantiomerically pure form.9,10 In particular, we envis-
aged their use as precursors to R-chiral carbonyl com-
pounds as shown in Scheme 2. Thus, selective γ (SN2′)
alkylation of 2 would provide alkenes 3 which could be
cleaved by ozonolysis to yield R-chiral aldehydes or
carboxylic acids. One major advantage of this approach
compared to traditional enolate alkylation strategies is
(1) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
(b) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-
204. (c) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. Engl. 2000,
39, 3750-3771.
(2) Denmark, S. E.; Marble, L. K. J . Org. Chem. 1990, 55, 1984-
1986 and refs 2-12 cited therein.
(3) Valverde, S.; Bernabe´, M.; Garcia-Ochoa, S.; Go´mez, A. M. J .
Org. Chem. 1990, 55, 2294-2298.
(4) (a) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1991, 56, 4370-4382. (b)
Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T. J . Org. Chem. 1992,
57, 1024-1026.
(5) Marino, J . P.; Viso, A.; Lee, J .-D. J . Org. Chem. 1997, 62, 645-
653.
(9) Asymmetric reduction: Seyden-Penne, J . Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; Wiley: New York, 1995; pp 209-
228.
(10) Sharpless kinetic resolution: (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) Carlier, P. R.; Mungall, W. S.; Schro¨der,
G.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 2978-2979.
(6) Agami, C.; Couty, F.; Evano, G.; Mathieu, H. Tetrahedron 2000,
56, 367-376.
(7) Yamazaki, T.; Umetani, H.; Kitamuze, T. Tetrahedron Lett. 1997,
38, 6705-6708.
(8) Smitrovich, J . H.; Woerpel, K. A. J . Org. Chem. 2000, 65, 1601-
1614.
10.1021/jo0104431 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/11/2001

Reactions of Allylic Phosphates with Organocopper Reagents
J . Org. Chem., Vol. 66, No. 16, 2001 5553
Ta ble 1. Rea ction s of P h osp h a tes 2 w ith Or ga n ocop p er
Rea gen ts
Sch em e 3
ER of
phos-
ER of
phos-
entry phate
ratioa
alkenec yieldd
reagent
Bu2CuLi
Bu2CuCNLi2
SN2′/SN2 phateb
(no.)
(%)
1
2
3
4
5
6
7
8
2c
2a
97:3
67:33
91:9
95:5
98:2
85:15
97:3
97:3 88:12 (3c) 46
97:3 70:30 (3a ) 74
95:5 88:12 (3b) 72
95:5 92:8 (3c)
92:8 91:9 (3d )
97:3 90:10 (3e) 40
97:3 90:10 (4)
95:5 66:34 (5)
2b Bu2CuCNLi2
2c Bu2CuCNLi2
2d Bu2CuCNLi2
2e
2c
2c
67
53
Me2CuCNLi2
Bn2CuCNLi2
42
67
t-Bu2CuCNLi2 95:5
a
Determined by GC-MS analysis of crude reaction mixtures.
b
Enantiomeric ratio assumed to be the same as starting alcohols
1a -e since the C-O bond is not cleaved during derivatization.
c Determined by GC-MS analysis after ozonolysis/oxidation and
d
conversion to R-methylbenzylamides. Isolated yields of chro-
matographed products. In most cases, GC yields are >90%; modest
isolated yields reflect the volatility of the hydrocarbon products.
phates (Table 1, entries 2-5). For substrates 2a -d , there
was a clear trend wherein both regioselectivity and
stereoselectivity increased with increasing size of R2.
Thus, with 2a (R2 ) n-Bu), only 67% SN2′ substitution
was observed but this increased to 91% with 2b (R2 )
i-Pr) and to 98% with 2d (R2 ) 3-pentyl). In a parallel
trend, with 2a (R2 ) n-Bu), there was substantial erosion
of stereochemical purity but with 2d (R2 ) 3-pentyl),
there was essentially no loss of stereochemistry.
that the coupling partner (RM here; RX with enolates)
is not limited to primary groups. For example, Spino has
recently applied this strategy to introduce tert-butyl and
phenyl groups to allylic carbonate derivatives of men-
thone with very high diastereoselectivities.11 We now
disclose our findings in this area.
Resu lts a n d Discu ssion
Analysis of the stereochemical purity of alkenes 3a -d
was carried out by ozonolysis/oxidation to the carboxylic
acid followed by derivatization with R-methylbenzyl-
amine15 to give diastereomeric amides that were easily
separable by GC. This derivatization procedure also
allowed for the assignment of absolute configuration for
alkenes 3a -d (Scheme 3). An authentic sample of R-6
was prepared using Evans oxazolidinone alkylation
chemistry,16 and the derived amides were compared by
GC. For each alkene, S-6 was the major acid formed.
(Alkenes 3a -d all give acid 6 since the fragment con-
taining R2 is cleaved by ozonolysis.) Since alcohols 1a -d
have R stereochemistry, reactions to form 3a -d must
have taken place in an anti fashion.
With phosphate 2e, reaction with Me2CuCNLi2 fur-
nished the enantiomer of 3c as the major product as
expected for an anti SN2′ substitution (Table 1, entry 6).
Results with phosphate 2c and Bn2CuCNLi2 were com-
parable to those with Bu2CuCNLi2. However, reaction of
2c with t-Bu2CuCNLi2 gave alkene 5 with considerable
loss of stereochemical purity (Table 1, entry 8). It is not
clear why t-Bu2CuCNLi2 is atypical in reacting with
substantial racemization. Attempts to probe the possibil-
ity of a SET pathway (which could explain partial
racemization) by adding HMPA, a reagent known to
affect SET reactions17 and cuprate structure,18 were
thwarted by the poor reactivity observed when HMPA
Since we were particularly interested in optimizing the
regioselectivity for γ-attack, a series of allylic alcohols
were prepared with varying sizes of alkyl group (R2) at
the carbinol carbon with the expectation that larger
groups would favor SN2′ reactivity. Racemic alcohols were
easily made by Grignard addition to R,â-unsaturated
aldehydes. Each of the racemic alcohols was then sub-
jected to Sharpless kinetic resolution (SKR) without
incident to obtain enantiomerically enriched alcohols in
84-94%ee and reasonable isolated yields. Transforma-
tion of the hydroxyl group into a leaving group then
furnished substrates for reaction with organocopper
reagents.
Phosphate 2c was used to probe various organocopper
reagents and reaction conditions.12 With both Bu2-
CuCNLi2 and Bu2CuLi,13 high SN2′ regioselectivity was
observed, but there was considerably greater loss of
stereochemical integrity with Bu2CuLi than with the
higher order cuprate (Table 1, entry 1 vs 4). Both THF
and ether as solvent gave similar results. In contrast to
these relatively clean reactions, use of BuMgBr with CuI
(cat.) gave a mixture of four isomeric alkenes (by GC-
MS analysis) in a ratio of 10:27:46:15, with the major
isomer corresponding to the desired SN2′ product 3c.
Interestingly, the results of this reaction are also very
different from the previous reports of allylic phosphates
reacting with Grignard reagents catalyzed by CuCN‚
2LiCl, wherein high SN2′ substitution is observed.14
Since Bu2CuCNLi2 gave the highest selectivity with
phosphate 2c, it was also examined with other phos-
(14) Highly regioselective anti SN2′ reactions of allylic phosphates
have been demonstrated: (a) Arai, M.; Nakamura, E.; Lipshutz, B. H.
J . Org. Chem. 1991, 56, 5489-5491. (b) Yanagisawa, A.; Noritake, Y.;
Nomura, N.; Yamamoto, H. Synlett 1991, 271-253. (c) Yanagisawa,
A.; Nomura, N.; Noritake, Y.; Yamamoto, H. Synthesis 1991, 1130-
1136. (d) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett 1993,
689-690. (e) Torneiro, M.; Fall, Y.; Castedo, L.; Mourin˜o, A. J . Org.
Chem. 1997, 62, 6344-6352.
(15) R-Methylbenzylamine of 97%ee was obtained from Aldrich and
purified to 99.7%ee by recrystallization of its D-tartaric acid salt: Ault,
A. Organic Syntheses; Wiley: New York, 1973; Collect. Vol. V, pp 932-
936.
(11) Spino, C.; Beaulieu, C.; Lafrenie`re, J . J . Org. Chem. 2000, 65,
7091-7097.
(12) Carboxylate esters (e.g., trifluoroacetate, pivalate) of 1c re-
turned mostly alcohol 1c when treated with Bu2CuCNLi2 or Bu2CuLi
while the benzenesulfonate of 1c gave complex mixtures.
(13) Formulas for these copper reagents are intended to show
stoichiometry only. For discussions of structure, see: (a) Lipshutz, B.
H.; Sharma, S.; Ellsworth, E. L. J . Am. Chem. Soc. 1990, 112, 4031-
4043. (b) Bertz, S. H.; Nilsson, K.; Davidson, Oˆ .; Snyder, J . P. Angew.
Chem., Int. Ed. Engl. 1998, 37, 314-317.
(16) (a) Evans, D. A.; Bartoli, J .; Shih, T L. J . Am. Chem. Soc. 1981,
103, 2127-2129. (b) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am.
Chem. Soc. 1982, 104, 1737-1739.

5554 J . Org. Chem., Vol. 66, No. 16, 2001
Belelie and Chong
(2E)-5-Eth yl-2-h ep ten -4-ol, 1d . Freshly distilled croton-
aldehyde (6.8 mL, 82.1 mmol) in Et2O (15 mL) was added to
the Grignard derivative of 3-bromopentane (12.4 mL, 0.10 mol;
2.6 g, 0.11 mol Mg) in Et2O (65 mL, 0 °C to room temperature).
The reaction mixture was quenched with aqueous NH4Cl (25
mL), and the resulting solid was washed twice with Et2O. The
combined washings were dried with MgSO4, and the solvent
was removed in vacuo. The crude product was purified by
column chromatography (30% hexane in ethyl acetate) to give
7.4 g (63%) of a clear, yellow oil: IR (neat) 3381 (br), 1672
cm-1; 1H NMR (250 MHz, CDCl3) δ 5.68 (1H, dq, J ) 15.3, 6.2
Hz), 5.50 (1H, J ) 15.3, 7.2 Hz), 4.04 (1H, m), 1.70 (3H, d, J
) 6.2 Hz), 1.49-1.15 (6H, m), 0.97-0.81 (6H, m); 13C NMR
(63 MHz, CDCl3) δ 132.9, 126.8, 74.4, 46.8, 21.6, 21.3, 17.5,
11.5, 11.2; MS (EI) m/z 142 (M+, 0.1), 71 (100). Anal. Calcd
for C9H18O: C, 76.00; H, 12.75. Found: C, 75.88; H, 12.66.
Gen er a l P r oced u r e for th e Kin etic Resolu tion of
Allylic Alcoh ols 1a -e. Each of the allylic alcohols was
kinetically resolved using the Sharpless protocol10a with L-(+)-
dicyclohexyl tartrate (DCHT). The reaction progress was
monitored by GC and was stopped when >50% complete. The
formed allylic epoxide and the desired allylic alcohol were
separated by flash chromatography. Enantiomeric purities
were determined by conversion to the corresponding (R)-MTPA
Sch em e 4
was added. Nonetheless, it seems unlikely that SET
chemistry plays a role in these reactions since Bn2-
CuCNLi2 shows a similar stereochemical outcome to Bu2-
CuCNLi2.
Overall, the regiochemistry of the reactions of phos-
phates 2 with R2CuCNLi2 can be readily explained on
steric grounds: as the size of R2 increases, SN2 reaction
is more disfavored and thus the ratio of SN2′/SN2 reaction
increases. To explain the dependence of stereochemical
outcome on the size of R2, it is tempting to suggest that
larger R2 groups serve to bias the conformation of 2 such
that anti attack will take place on only one face of the
alkene (Scheme 4). However, since the product alkenes
isolated all have E stereochemistry, anti substitution on
conformer B (which would provide alkenes of Z stereo-
chemistry) seems unreasonable. Rather, it is more likely
that the partial racemization observed arises from syn
substitution on conformer A; larger R2 groups may
decrease the amount of syn substitution observed by
inhibiting coordination of the phosphate group with the
cuprate reagent.
In summary, we have shown that acyclic allylic alco-
hols of general structure 1 can undergo SN2′ reactions
with organocopper reagents with >98% regioselectivity
and >98% anti selectivity via their phosphate esters. The
nature of the leaving group, the size of R2, and the
organocopper reagent used all influence the outcome of
these reactions. Nonetheless, we are beginning to un-
derstand how to manipulate these factors to achieve high
selectivities.
1
ester and analysis by H and/or 19F NMR spectroscopy.
(2E,4R)-2-Octen -4-ol, (R)-1a . The reaction was run using
10.30 g (80.4 mmol) of substrate for 5 h. The crude reaction
mixture was purified by column chromatography (30% Et2O
in hexane) to give 2.42 g (47%) of a clear, colorless oil: [R]D
-6.10 (c ) 3.31, EtOH); enantiomeric excess ) 94%.
)
(4E,3R)-2-Meth yl-4-h exen -3-ol, (R)-1b. The reaction was
run using 10.04 g (87.9 mmol) of substrate for 13 h using
decane as an internal standard. The crude reaction mixture
was purified by column chromatography (20% EtOAc in
hexane) to give 3.51 g (70%) of a clear, slightly yellow oil: [R]D
) -13.9 (c ) 1.17, EtOH); enantiomeric excess ) 90%.
(2E,1R)-1-Cycloh exyl-2-bu ten -1-ol, (R)-1c. The reaction
was run using 10.08 g (65.3 mmol) of substrate for 15 h. The
crude reaction mixture was purified by column chromatogra-
phy (30% Et2O in hexane) to give 3.02 g (60%) of a clear,
slightly yellow oil: [R]D ) -13.4 (c ) 3.14, EtOH); enantiomeric
excess ) 94% [lit.10a [R]D ) -13.24 (c ) 2.62, EtOH), ee ) 95%].
In another run, material of 90% ee was obtained.
(2E,4R)-5-Eth yl-2-h ep ten -4-ol, (R)-1d . The reaction was
run using 6.04 g (42.5 mmol) of (()-1d for 13 h with decane
as an internal standard. The crude reaction mixture was
purified by column chromatography (20% EtOAc in hexane)
to give 2.51 g (83%) of a clear, colorless oil: [R]D ) -11.25 (c
) 1.28, EtOH); enantiomeric excess ) 84%.
(2E,1R)-1-Cycloh exyl-2-h ep ten -1-ol, (R)-1e. The reaction
was run using 2.48 g (12.7 mmol) of substrate for 8 h with
decane as an internal standard. The crude reaction mixture
was purified by column chromatography (20% Et2O in hexane)
to give 0.66 g (53%) of a clear, colorless oil: [R]D ) -7.88 (c )
1.14, EtOH); enantiomeric excess ) 94%.
Gen er a l P r oced u r e for th e Con ver sion of Allylic Al-
coh ols 1a -e to P h osp h a te Ester s 2a -e. Diethyl chloro-
phosphate (1.1 equiv) was added dropwise to a solution of the
allylic alcohol (1.0 equiv) in pyridine (2.5 mL/g substrate) at 0
°C. After 1 h, the reaction mixture was quenched with water
(2 mL/mL pyridine) and extracted twice with the same volume
of Et2O. The combined extracts were washed with 1 M H2-
SO4, 1 M NaHCO3, and water. After the organic layer was
dried over MgSO4, the solvent was removed in vacuo. The
crude phosphate esters were unstable to silica gel chromatog-
raphy and distillation and so were used without further
purification.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed using
flame-dried glassware under an argon atmosphere. Diethyl
ether and THF were freshly distilled from Na/benzophenone.
Pyridine was distilled from CaH2. The known allylic alcohols
1a ,19 1b,20 and 1c10a were prepared by reacting freshly distilled
crotonaldehyde with the corresponding Grignard reagent in
diethyl ether under typical reaction conditions; analogously,
1e21 was prepared by reacting E-2-heptenal with cyclohexyl-
magnesium chloride in ether. Benzyltributylstannane was
prepared by a method similar to one developed by Seitz and
co-workers.22 Elemental analyses were performed by MHW
Laboratories, Phoenix, AZ.
(17) Hasegawa, E.; Curran, D. P. Tetrahedron Lett. 1993, 34, 1717-
1720.
Gen er a l P r oced u r e for Rea ction of Cu p r a tes w ith
P h osp h a te Ester s To F or m Alk en es 3-5. CuCN (2.0 equiv)
was added to a three-necked flask equipped with a stir bar,
low-temperature thermometer, argon inlet, and stopcock. The
flask was flushed with argon and evacuated three times.
Either Et2O or THF (25 mL/g substrate) was added via syringe,
and the system was cooled to -78 °C. The alkyllithium (4.0
equiv) of choice was added dropwise, and the reaction mixture
(18) Cabezas, J . J .; Oehlschlager, A. C. J . Am. Chem. Soc. 1997,
119, 3878-3886.
(19) Corey, L. D.; Singh, S. M.; Oehlschlager, A. C. Can. J . Chem.
1987, 65, 1821-1827.
(20) McKee, B. H.; Kalantar, T. H. Sharpless, K. B. J . Org. Chem.
1991, 56, 6966-6968.
(21) Wipf, P.; Ribe, S. J . Org. Chem. 1998, 63, 6454-6455.
(22) Seitz, D. D.; Carroll, J . J .; Cartaya, C. P.; Lee, S.-H.; Zapata,
A. Synth. Commun. 1983, 13, 129-134.

Reactions of Allylic Phosphates with Organocopper Reagents
J . Org. Chem., Vol. 66, No. 16, 2001 5555
was allowed to stir until a clear solution was formed. At this
time, the phosphate ester (1.0 equiv) was added in solvent (2.5
mL/g substrate). The reaction mixture was allowed to stir for
1 h at -78 °C. Completion of the reaction was checked by TLC
(hexane as solvent). When complete, the reaction was quenched
with 10% NH4OH in saturated NH4Cl solution (5 mL/mmol
cuprate). The precipitate was removed by filtration, and the
filter cake was washed thoroughly with Et2O. The organic
layer was separated and dried with MgSO4. The solvent was
removed in vacuo, and the residue was purified using column
chromatography (hexane as solvent). All enantiomeric excesses
were determined by ozonolysis followed by derivatization.
(6E,5S)-5-Meth yl-6-u n decen e, 3a, (2E)-4-Bu tyl-2-octen e,
a n d (2Z)-4-bu tyl-2-octen e.23 The reaction was performed
using 923.3 mg (3.39 mmol) of 2a in Et2O and yielded 401.9
mg (74%) of a clear, colorless oil. GC-MS analysis (30 m ×
0.25 mm DB-5, 70 °C for 2 min then 10 °C/min to 250 °C)
showed a mixture of three isomers in a ratio of 67:25:8; the
components were not separable by flash chromatography: IR
1-[(1E,3S)-3-Meth yl-4-p h en yl-1-bu ten yl]cycloh exa n e, 4.
To a mixture of CuCN (125.4 mg, 1.40 mmol) and THF (5 mL)
at 0 °C was added dropwise MeLi (1.34 M, 2.10 mL, 2.81
mmol). After 0.5 h, benzyltributyltin (823.7 mg, 2.16 mmol)
in THF (1 mL) was added, and the reaction mixture was
allowed to stir for 0 °C for 0.5 h. After the mixture was cooled
to -78 °C, phosphate 1c (209.2 mg, 0.72 mmol) in THF (0.5
mL) was added dropwise, and the mixture was stirred for 1 h.
Usual workup and purification as stated in the general
procedure yielded 69.5 mg (42%) of a clear, colorless oil: [R]D
) +26.4 (c ) 1.05, EtOH), 80% ee; IR (neat) 1699, 701 cm-1
;
1H NMR (250 MHz, CDCl3) δ7.32-7.14 (5H, m), 5.38 (1H, A
of ABXY-type pattern, dd, J obs ) 15.4, 5.9 Hz), 5.27 (1H, B of
ABXY-type pattern, dd, J obs ) 15.4, 5.4 Hz), 2.64 (1H, dd, J )
13.1, 7.0 Hz), 2.52 (1H, dd, J ) 13.1, 7.3 Hz), 2.34 (1H, X of
ABXY-type pattern, m), 1.86 (1H, Y of ABXY-type pattern, m),
1.73-1.44 (4H, m), 1.34-0.80 (6H, m), 0.99 (3H, d, J ) 6.6
Hz); 13C NMR (63 MHz, CDCl3) δ141.1, 134.9, 132.9, 129.3
(2C), 128.0 (2C), 125.6, 44.0, 40.6, 38.4, 33.3 (2C), 26.3, 26.1
(2C), 20.1; MS (EI) m/z 228 (M+, 2), 81 (100). Anal. Calcd for
1
(neat) 2959, 1466 cm-1; H NMR (300 MHz, CDCl3) δ 5.39-
5.09 (2H, m), 2.03-1.94 (2.01H, m), 1.83 (0.33H, m), 1.67
(0.75H, d, J ) 6.3 Hz), 1.60 (0.24H, d, J ) 7.0 Hz), 1.34-1.24
(10.66H, m), 0.95 (2.01H, d, J ) 6.8 Hz), 0.93-0.86 (6H, m);
13C NMR (75 MHz, CDCl3) δ136.5, 136.4, 128.4, 128.3, 124.1,
42.9, 37.0, 36.8, 35.3, 32.3, 32.2, 32.0, 31.7, 29.8, 29.7, 29.6,
29.4, 27.2, 22.9, 22.7, 22.2, 21.0, 17.9, 14.1, 14.0; GC-MS
retention times, (EI) m/z 7.31 min (25), 168 (M+, 0.6); 7.40 min
(8), 168 (M+, 7), 69 (100); 7.54 min (67), 168 (M+, 5), 69 (100).
Anal. Calcd for C12H24: C, 85.63; H, 14.37. Found: C, 85.76,
14.21.
(3E,5S)-2,5-Dim eth yl-2-n on en e, 3b. The reaction was
performed using 405.4 mg (1.62 mmol) of 2b in THF and
yielded 179.8 mg (72%) of a clear, colorless oil: [R]D ) +14.9
(c ) 1.93, CH2Cl2), 76% ee; IR (neat) 1718, 969 cm-1; 1H NMR
(250 MHz, CDCl3) δ5.30 (1H, dd, J ) 15.4, 6.3 Hz), 5.20 (1H,
dd, J ) 15.4, 7.1 Hz), 2.15 (1H, m), 2.00 (1H, m), 1.43-1.04
(9H, m), 1.03-0.79 (9H, m); 13C NMR (63 MHz, CDCl3) δ135.7,
133.4, 37.0, 36.6, 31.0, 29.6, 22.8 (3C), 20.9, 14.1; MS (EI) m/z
154 (M+, 8), 55 (100). Anal. Calcd for C13H26: C, 85.63; H,
14.37. Found: C, 85.56; H, 14.40.
C
17H24: C, 89.41; H, 10.59. Found: C, 89.19; H, 10.30.
1-[(1E,3R)-3,4,4-Tr im eth yl-1-p en ten yl]cycloh exa n e, 5.
After addition of t-BuLi, the reaction mixture was allowed to
warm to 0 °C for 5 min, after which time it was recooled to
-78 °C before addition of phosphate 1c. The reaction was
performed using 102.8 mg (0.35 mmol) of 1c in Et2O and
yielded 46.0 mg (67%) of a clear, colorless oil: [R]D ) +10.53
(c ) 7.61, CH2Cl2), ee ) 32%; IR (neat) 1664, 969 cm-1 1H
;
NMR (250 MHz, CDCl3) δ5.38-5.13 (2H, AB of ABXY-type
pattern, m), 1.71-1.56 (2H, XY of ABXY-type pattern, m),
1.25-0.96 (8H, m), 0.91 (3H, d, J ) 6.9 Hz), 0.90-0.85 (2H,
m), 0.82 (9H, s); 13C NMR (63 MHz, CDCl3) δ136.0, 131.0, 47.1,
40.8, 33.4 (2C), 29.8, 27.5 (3C), 26.3, 26.2 (2C), 15.7; MS (EI)
m/z 194 (M+, 3), 81 (100). Anal. Calcd for C14H26: C, 86.52; H,
13.48. Found: C, 86.56; H, 13.27.
Gen er a l P r oced u r e To Deter m in e F a cia l Selectivity
of Cop p er Cou p lin g Rea ction s. Derivatizations were typi-
cally run with ∼10 mg of the alkene. The alkene (1.0 equiv)
was dissolved in acetone (1 mL/mg substrate), cooled to -78
°C, and treated with an excess of ozone. The reaction mixture
was purged with argon, treated with J ones reagent (2.7 equiv),
and allowed to warm to room temperature. The excess J ones
reagent was quenched with 2-propanol (excess), and the
solvent was removed in vacuo. The resulting residue was
partitioned in Et2O and water (∼4:1 ratio) and the layers were
separated. The organic layer was washed three times with 1
M HCl. The carboxylic acids were extracted with 1 M NaOH.
The aqueous layer was cooled to 0 °C and reacidified with 6
M HCl. The carboxylic acids were extracted into Et2O. The
organic layer was dried with MgSO4, and the solvent was
removed in vacuo. The resulting mixture of carboxylic acids
(1.0 equiv each) in CH2Cl2 (0.4 mL/mg substrates) was treated
with diisopropyl carbodiimide (2.2 equiv), S-R-methylbenzy-
lamine (2.2 equiv), HOBT (0.2 equiv), and DMAP (0.2 equiv).
Completion of the reaction was monitored by TLC. Et2O was
added, and the reaction mixture was washed with cold 1 M
HCl, saturated NaHCO3, and brine. The organic layer was
dried with MgSO4, and the solvent was removed by rotary
evaporation. The crude reaction mixture was analyzed by GC-
MS to determine the diastereomeric ratio of the formed
amides.
(1E,3S)-1-Cycloh exyl-3-m eth yl-1-h ep ten e, 3c. The reac-
tion was performed using 305.8 mg (1.05 mmol) of 2c in THF
and yielded 136.0 mg (67%) of a clear, colorless oil: [R]D
)
+13.2 (c ) 1.32, EtOH), 84% ee; IR (neat) 1666 cm-1; 1H NMR
(250 MHz, CDCl3) δ5.31 (1H, A of ABXY-type pattern, dd, J obs
) 15.7, 5.9 Hz), 5.20 (1H, B of ABXY-type pattern, dd, J obs
)
15.7, 7.0 Hz), 2.02-1.81 (2H, XY of ABXY-type pattern, m),
1.71-1.67 (2H, m), 1.34-0.97 (13H, m), 0.95-0.67 (7H, m);
13C NMR (63 MHz, CDCl3) δ135.0, 134.4, 41.3, 37.6, 37.3, 34.0,
32.2, 30.2, 26.9, 26.7, 23.4, 23.2, 21.5, 14.6; MS (EI) m/z 194
(M+, 17), 81 (100). Anal. Calcd for C14H26: C, 86.52; H, 13.48.
Found: C, 86.60; H, 13.26.
(4E,6S)-3-Eth yl-6-m eth yl-4-d ecen e, 3d . The reaction was
performed using 205.3 mg (0.74 mmol) of 2d in Et2O and
yielded 70.7 mg (53%) of a clear, colorless oil: [R]D ) +16.0 (c
) 0.67, EtOH), 82% ee; IR (neat) 1664, 969 cm-1 1H NMR
;
(250 MHz, CDCl3) δ5.17 (1H, dd, J ) 15.3, 7.8 Hz), 5.02 (1H,
dd, J ) 15.3, 8.4 Hz), 2.05 (1H, m), 1.62 (1H, m), 1.43-1.01
(13H, m), 0.97-0.79 (9H, m); 13C NMR (63 MHz, CDCl3) δ
136.8, 132.5, 46.4, 37.0, 36.9, 29.7, 27.9 (2C), 22.8, 21.3, 14.1,
11.7 (2C); MS (EI) m/z 182 (M+, 5), 69 (100), 55 (99). Anal.
Calcd for C13H26: C, 85.63; H, 14.37. Found: C, 85.56; H, 14.46.
(1E,3R)-1-Cycloh exyl-3-m eth yl-1-h ep ten e, 3e () en t-
3c). The reaction was performed using 154.4 mg (0.53 mmol)
of 1e with Me2CuCNLi2 (preformed at 0 °C for 30 min) in Et2O
and yielded 41.2 mg (40%) of a clear, colorless oil: [R]D ) -13.4
(c ) 1.06, EtOH), 80% ee. Spectral data were identical to that
reported for 3c with the exception of optical rotation.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial assistance and a postgraduate scholarship
(to J .L.B.).
Su p p or tin g In for m a tion Ava ila ble: Details of the prepa-
ration of racemic allylic alcohols and acid R-6, assignment of
absolute configuration for acid S-6, and product characteriza-
tion data for phosphates 2a -e. This material is available free
of charge via the Internet at http://pubs.acs.org.
(23) The major isomer (67%) of this complex mixture is the desired,
SN2′ product as shown by the large doublet in the 1H NMR spectrum
at 0.95 ppm, representing the methyl group â to the double bond.
Evidence for the other two isomers (25 and 8%) is seen by the
appearance of doublets at 1.67 and 1.60 ppm, which presumably
represent vinyl methyl groups.
J O0104431