Catalytic reductive carbon-carbon bond-forming reactions of alkynes

Article abstract of DOI:10.1016/j.tetasy.2003.07.010

Enantioselective nickel/phosphine-catalyzed reductive coupling of alkynes and aldehydes provides rapid access to synthetically useful allylic alcohols with high enantiomeric excess. A related reaction involving epoxides is enantiospecific, transforming al

Full text of DOI:10.1016/j.tetasy.2003.07.010

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3619–3625
Catalytic reductive carbonꢀcarbon bond-forming reactions
of alkynes
Karen M. Miller, Carmela Molinaro and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Ave., Cambridge, MA 02139, USA
Received 23 June 2003; accepted 14 July 2003
Abstract—Enantioselective nickel/phosphine-catalyzed reductive coupling of alkynes and aldehydes provides rapid access to
synthetically useful allylic alcohols with high enantiomeric excess. A related reaction involving epoxides is enantiospecific,
transforming alkynes and chiral terminal epoxides into enantiomerically pure homoallylic alcohols containing a trisubstituted
olefin of defined geometry. A gram-scale example of each of these processes is described.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
aldehydes,3 imines,4 and epoxides,5 affording chiral
allylic alcohols, allylic amines, and homoallylic alco-
hols, respectively. Examples of aldehyde and epoxide
variants that provide enantiomerically pure products on
the gram scale are illustrated below.8
Since Noyori and Nozaki first demonstrated that enan-
tioselective carbonꢀcarbon bond formation could be
catalyzed by synthetic, low molecular weight, metal–lig-
and complexes,1 the development of catalytic, highly
enantioselective transformations of many types has
been an active area of research. In contrast to other
classes of catalytic reactions, such as enantioselective
hydrogenation, epoxidation, and olefin isomerization,
few catalytic asymmetric CꢀC bond forming processes
have been implemented on an industrial scale.2 Accord-
ingly, new catalytic carbonꢀcarbon bond-forming reac-
tions that unite simple starting materials, provide useful
chiral compounds, and are amenable to implementation
on a large scale may be of significant practical impact.
2. Enantioselective, catalytic reductive coupling of
alkynes and aldehydes
Our interest in this area of catalytic multi-component
reactions9 was prompted by a structural motif found in
many natural products possessing significant biological
effects—chiral, (E)-trisubstituted allylic alcohols (Fig.
1).10–13 Our aim was to develop a method that would
allow for synthesis of this useful functional group
pattern14 from alkynes and aldehydes by way of cata-
lytic, enantioselective and regioselective reductive cou-
As part of our program on catalytic multi-component
coupling processes, we have developed several reactions
in which an alkyne undergoes nickel-catalyzed cis addi-
tion of two groups that function as nucleophile and
electrophile equivalents (Nu and El, Scheme 1).3–5
These reactions have their origins in catalytic alkyne–
alkyne oligomerizations first described by Reppe,6 and
in contrast to these pioneering investigations, a theme
currently under investigation in several laboratories is
the catalytic coupling of two different functional
groups.7 Our focus has been the use of an organoboron
reagent (RBX2) as the source of the Nu (H or R from
RBX2), and the Els that undergo coupling to date are
* Corresponding author. Tel.: +1-617-253-2135; fax: +1-617-258-7500;
e-mail: tfj@mit.edu
Scheme 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.010

3620
K. M. Miller et al. / Tetrahedron: Asymmetry 14 (2003) 3619–3625
(neomenthyl)diphenylphosphine (NMDPP, 1, Scheme
2)3c while dialkylacetylenes undergo asymmetric reduc-
tive coupling most efficiently when P-stereogenic ferro-
cenylphosphines are used (Scheme 3).3b First prepared
from menthol by Morrison in 197121 and commercially
available as its dextrorotatory antipode,22 NMDPP had
been of only limited utility in asymmetric catalysis.23
Nevertheless, catalysts derived from this chiral
monophosphine24 generally afford allylic alcohols
derived from arylꢀCꢁCꢀalkyl alkynes and branched
aldehydes in greater than 90% ee in reductive coupling
reactions.
Highly enantioselective catalytic alkyne/aldehyde reduc-
tive coupling can be performed on a gram scale. Illus-
trated by the particular case shown in Scheme 4 is the
tolerance of propargyl substitution on the alkyne and
of protected nitrogen functional groups. Allylic alcohol
2 is isolated in 52–60% yield in 94–96% ee, and can be
recrystallized to >98% ee in 44% overall yield (1.35 g).
Previously we have shown that enantiomeric purity is
Figure 1. Natural products that contain (E)-trisubstituted
allylic alcohols.
pling of alkynes and aldehydes. Development of cata-
lytic, diastereoselective methods (i.e. for chiral alkynes
and/or chiral aldehydes) were also high priorities, as
they would be useful fragment coupling operations in
target-oriented synthesis.
Nickel-catalyzed coupling of alkynes and aldehydes was
first reported by Tsuda and Saegusa,15 who proposed
that formation of the conjugated enone products
occurred by way of hydroacylation. Later, Mont-
gomery reported a nickel-catalyzed, intramolecular
alkyne/aldehyde coupling method that also effected an
overall reduction, affording racemic allylic alcohols.16,17
In the absence of a phosphine additive, transfer of an
alkyl substituent from the organozinc reagent occurred,
giving overall alkylative coupling. By analogy to related
early transition metal complexes first studied by Buch-
wald,18 Montgomery proposed an oxametallacyclopen-
tene intermediate in the catalytic cycle.19
Scheme 2.
However, intermolecular reductive coupling was not
possible with Montgomery’s method, nor was any cata-
lyst-controlled, enantioselective variant of this transfor-
mation available at that time. We found that use of a
catalyst derived from Ni(cod)2 and Bu3P, in conjunc-
tion with Et3B as the stoichiometric reductant, provided
a solution to the first part of this problem, the first
catalytic process for intermolecular alkyne/aldehyde
reductive coupling.3a,20 Exclusive cis addition to the
alkyne was observed in every case, and alkynes of the
general form arylꢀCꢁCꢀalkyl, RꢀCꢁCꢀH, and
RꢀCꢁCꢀSiMe3 displayed very high regioselectivity,
favoring CꢀC bond formation adjacent to the alkyl,
hydrogen, or trimethylsilyl substituent, respectively.
Scheme 3.
More recently, we described two catalytic asymmetric
variants of this process differing in two respects that
appear to be linked, the natures of the alkyne and the
chiral phosphine ligand. Internal acetylenes having one
aromatic substituent are coupled most effectively using
Scheme 4.

K. M. Miller et al. / Tetrahedron: Asymmetry 14 (2003) 3619–3625
3621
conserved upon ozonolysis of 2,3c affording an
(aminomethyl)hydroxyketone whose a-amino-a%-
lar cases proceed with complete endo selectivity, which
is generally disfavored in intramolecular epoxide-open-
ing reactions in the absence of a significant electronic
bias.30–32 This process may involve a nickella(II)oxetane
intermediate, and thus appears to be mechanistically
distinct from the other nickel-catalyzed multi-compo-
nent coupling reactions that we and others have
reported.
3
hydroxy pattern is found in molecules targeted against
trypanosomes, parasites that cause African sleeping
sickness upon transmission from tsetse flies,25 and in
aerothionin natural products with anti-tuberculosis
activity.26 Common methods of a-hydroxy ketone syn-
thesis via asymmetric catalysis involve dihydroxylation
or epoxidation of ketone enolate derivatives.27 The
reductive coupling/ozonolysis approach obviates
a
As shown in the example below, the utility and ease of
implementation of catalytic alkyne/epoxide coupling on
gram scale is a direct result of the availability of
terminal epoxides in >99% ee (Scheme 7).33 Using only
commercially available reagents and catalysts, this pro-
cedure is an alternative to enantioselective addition of
allylmetal reagents to aldehydes,34 and product ee is not
dependent upon the scale of the reaction. Products
corresponding to an asymmetric acetone-acetaldehyde
aldol addition reaction are obtained upon further elab-
oration of 4, affording in >99% ee b-silyloxyketones
such as 5, which has been used in natural product
synthesis.35
regioselective ketone enolization that would be required
(and difficult) for cases represented by 3 and is there-
fore complementary.28
3. Nickel-catalyzed reductive coupling of alkynes and
epoxides
In all of the nickel-catalyzed multi-component coupling
transformations reported prior to 2003,
a
car-
bonꢀcarbon bond was formed between two p-electron
systems, one of which contained a carbonyl group (e.g.
alkyne/aldehyde,3,16,20 alkyne/conjugated enone,7b 1,3-
diene/aldehyde29). Earlier this year we reported the first
examples involving
a
nitrogen-based electrophile
(imine), which also was the first utilization of boronic
acids in this family of reactions (Scheme 5).4
More recently, we described the first member of this
family that deviated from the p–p-coupling requirement
(Scheme 6), wherein the p-system of one molecule
(alkyne) combines with a functional group that has no
multiple bonds (epoxide).5 Affording synthetically use-
ful, enantiomerically pure homoallylic alcohols, this
process is effective for both cyclizations and intermolec-
ular couplings. Very high regioselectivity is observed in
nearly every example in both variants, and intramolecu-
Scheme 7.
4. Conclusion
Enantioselective nickel/phosphine-catalyzed reductive
coupling of alkynes and aldehydes provides rapid
access to synthetically useful allylic alcohols with high
enantiomeric excess. The related reaction involving
epoxides is enantiospecific, transforming alkynes and
enantiomerically pure terminal epoxides into enan-
tiomerically pure homoallylic alcohols containing a
trisubstituted olefin of defined geometry. We are contin-
uing to develop these and related transformations, such
as a highly enantioselective three-component coupling
of organoboron reagents, alkynes, and imines.4 We are
also using these methods in target-oriented synthesis as
fragment coupling operations in which the alkyne and/
or electrophile are chiral and the stereochemical out-
come of a newly installed stereogenic center may be
influenced by as many as three chiral molecules.
Scheme 5.
5. Experimental
5.1. General information
All reactions were performed under an oxygen-free
atmosphere of nitrogen or argon with rigid exclusion of
moisture from reagents and glassware. Bis(cyclooctadi-
Scheme 6.

3622
K. M. Miller et al. / Tetrahedron: Asymmetry 14 (2003) 3619–3625
enyl)nickel(0),
tetrakis(triphenylphosphine)
palla-
resulting oil was purified by flash chromatography on
dium(0), and copper iodide (98%) were purchased from
Strem Chemicals, Inc. Triethylborane (98%), tri-
butylphosphine (97%), propylene oxide (99%), and
iodobenzene were purchased from Aldrich Chemical
Co. 1-Phenyl-1-propyne and isobutyraldehyde were
purchased from Alfa Aesar and the latter was distilled
prior to use. (S)-(+)-Neomenthyldiphenylphosphine
(NMDPP) was prepared as previously reported.22
Methylene chloride, pyrrolidine, and 1,3-dimethylimi-
dazolidinone (DMI) were distilled over calcium
hydride; tetrahydrofuran was distilled from a blue solu-
tion of sodium benzophenone ketyl; ethyl acetate was
distilled over magnesium sulfate under argon
atmosphere.
silica gel (5–17% EtOAc/hexanes) to give a yellow solid.
Recrystallization from 20% EtOAc/hexanes provided
analytically pure (3-phenyl-prop-2-ynyl)-carbamic acid
tert-butyl ester as white needles (3.18 g, 63% yield).
1
Rf=0.50 (17% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) l 7.43–7.41 (m, 2H); 7.33–7.29 (m, 3H); 4.80
(bs, 1H); 4.17 (d, J=4.5 Hz, 2H); 1.48 (s, 9H); 13C
NMR (125 MHz, CDCl3) l 131.9, 128.5, 128.5, 122.9,
85.5, 83.3, 80.2, 31.4, 28.6; IR (film): 3338, 2978, 2932,
1699, 1599, 1519, 1491, 1456, 1392, 1367, 1276, 1250,
1170; HRMS-ESI (m/z): [M+Na]+ calcd for
C14H17NO2, 254.116; found 254.115; mp: 94–95°C.
5.3. (E)-(1-Benzylidene-2-hydroxy-3-methyl-butyl)-car-
bamic acid tert-butyl ester 2
Analytical thin layer chromatography (TLC) was per-
formed using silica gel 60 F254 aluminum plates pre-
coated with a fluorescent indicator or EM Reagents
0.25 mm silica gel 60-F plates. Visualization of the
developed chromatogram was accomplished with UV
light and aqueous cerium molybdate, ethanolic phos-
phomolybdic acid, or aqueous potassium permanga-
nate. Liquid chromatography was performed using a
forced flow (flash chromatography) of the indicated
solvent system on Silicycle Silica Gel (230–400 mesh).36
1H and 13C NMR spectra were recorded in deuterochlo-
roform (CDCl3), unless otherwise noted, on a Bruker
Avance 400 or Varian Inova 500 MHz. Chemical shifts
In a glovebox, Ni(cod)2 (280 mg, 1.00 mmol), and
(+)-NMDPP (648 mg, 2.00 mmol) were placed into a
100 mL oven-dried, single-necked round-bottom flask,
which was then sealed with a rubber septum. The flask
was removed from the glovebox, placed under argon,
and ethyl acetate (10 mL), and Et3B (2.90 mL, 20.00
mmol) were added sequentially via syringe. The result-
ing solution was stirred at rt for 10 min and then placed
in a precooled bath at −25°C. The solution was stirred
at this temperature for 15 min, and then a solution of
(3-phenyl-prop-2-ynyl)-carbamic acid tert-butyl ester
(2.31 g, 10.00 mmol) in DMI (10 mL) was added
dropwise via syringe. Isobutyraldehyde (1.80 mL, 20.00
mmol) was then added dropwise over 8 h via syringe
pump. The reaction was stirred at −25°C for an addi-
tional 36 h, at which point saturated aqueous NH4Cl
(20 mL) and 1 M HCl (5 mL) were added. The organic
layer was then extracted with ethyl acetate (3×50 mL),
dried and concentrated under reduced pressure. The
crude mixture was purified by flash chromatography on
silica gel (2–5% EtOAc/hexanes) to afford a 3:1 mixture
of desired allylic alcohol 2 (94% ee) and isobutyralde-
hyde aldol dimer. Recrystallization of this solid from
17% EtOAc/hexanes provided 2 as a white solid (1.35 g,
44% yield, >98% ee). The supernatant was concentrated
and further purified by flash chromatography on silica
gel to yield an additional 0.24 g of 2 (52% overall yield).
1
of H NMR spectra are reported in parts per million
(ppm) on the l scale from an internal standard of
residual chloroform (7.27 ppm). Chemical shifts of 13C
NMR spectra are reported in ppm from the central
peak of CDCl3 (77.0 ppm). Infrared (IR) spectra were
recorded on a Perkin–Elmer 2000 FT-IR System trans-
form spectrometer. High resolution mass spectra
(HRMS) were obtained on a Bruker Daltonics APEXII
3 Tesla Fourier Transform Mass Spectrometer by the
Massachusetts Institute of Technology Department of
Chemistry Instrumentation Facility. HPLC was per-
formed on a Hewlett-Packard 1100 chromatograph
equipped with a variable wavelength detector and Chi-
ralcel OD or OJ column. Optical rotations were mea-
sured on a Perkin-Elmer 241 polarimeter at 589 nm.
Low temperatures were maintained using a Thermo
Neslab CC-65 cryocool immersion cooler equipped
with Cryotrol temperature controller; rt=ambient
temperature.
1
Rf=0.17 (17% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) l 7.37–7.34 (m, 2H), 7.28–7.23 (m, 3H); 6.62 (s,
1H); 4.86 (bs, 1H); 4.02 (dd, J=15.0, 7.0 Hz, 1H);
3.91–3.85 (m, 2H); 1.92 (sept, J=7.5 Hz, 1H); 1.43 (s,
9H); 1.06 (d, J=7.0 Hz, 3H); 0.91 (d, J=7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) l 156.5, 140.0, 136.8,
130.9, 128.8, 128.7, 127.4, 82.7, 79.9, 37.9, 32.5, 28.6,
20.0, 18.8; IR (film): 3287, 3082, 2952, 1670, 1559, 1265,
1183; HRMS-ESI (m/z): [M+Na]+ calcd for
C18H27NO3, 328.188; found 328.187; HPLC analysis
(Chiralcel OD, 2% iPrOH/hexanes): tR [(R)-2]=21.7
min; tR [(S)-2]=27.1 min; [h]2D0=−3.0 (c 1.0, CHCl3);
mp: 140–141°C.
5.2. (3-Phenyl-prop-2-ynyl)-carbamic acid tert-butyl
ester
Tetrakis(triphenylphosphine) palladium(0) (508 mg,
0.44 mmol) and copper iodide (42 mg, 0.22 mmol) were
added to a 100 mL oven-dried, single-necked flask.
N-t-Butoxycarbonylprop-2-ynylamine37 (3.41 g, 22.00
mmol) dissolved in pyrrolidine (40 mL) was then
added, followed by iodobenzene (2.47 mL, 22.00
mmol). The reaction mixture was heated to 40°C for 16
h, then cooled and concentrated under reduced pres-
sure. To the resulting oil was added saturated aqueous
NH4Cl (40 mL), and the mixture was extracted with
diethyl ether (3×50 mL), dried and concentrated. The
5.4. (3-Hydroxy-4-methyl-2-oxo-pentyl)-carbamic acid
tert-butyl ester 3
Alcohol 2 (179 mg, 0.59 mmol) was dissolved in 17%
MeOH/CH2Cl2 (5 mL), and the solution was cooled to

K. M. Miller et al. / Tetrahedron: Asymmetry 14 (2003) 3619–3625
3623
−78°C. Ozone was bubbled through the cooled solution
until a blue color was obtained (ꢀ5 min). Argon was
then bubbled through for 10 min, and dimethylsulfide
(0.22 mL, 3.00 mmol) was added. The reaction was
allowed to warm to room temperature and to stir
overnight. Removal of solvent and purification by flash
chromatography on silica gel (17% EtOAc/hexanes)
provided the desired a-hydroxy ketone 3 as a clear oil
NaHCO3, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by
flash chromatography on silica gel (100% hexanes) to
afford the title compound (455 mg, 97% yield) as a
colorless liquid: Rf=0.75 (20% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) l 7.74–7.70 (m, 4H), 7.46–
7.28 (m, 11H), 7.21–7.17 (m, 3H), 6.25 (s, 1H), 4.13–
4.01 (m, 1H), 2.40 (dd, J=13.8, 5.8 Hz, 1H), 2.24 (dd,
J=13.0, 6.8 Hz, 1H), 1.64 (d, J=1.2 Hz, 3H), 1.13 (d,
J=6.1 Hz, 3H), 1.08 (s, 9H); 13C NMR (100 MHz,
CDCl3) l 138.3, 136.0, 135.9, 134.6, 134.3, 129.49,
129.45, 128.7, 127.9, 127.48, 127.43, 125.8, 68.2, 51.1,
27.0, 23.2, 19.2, 18.0; IR (film) 3071, 3024, 2964, 2931,
2894, 2857, 1959, 1889, 1824, 1651, 1599, 1589, 1488,
1472, 1462, 1446, 1427, 1390, 1376, 1361, 1111, 1084,
1027, 997, 910, 822, 739, 700, 613 cm−1; HRMS-ESI
(m/z): [M+Na]+ calcd for C28H34OSiNa, 437.2271;
found 437.2269; [h]2D0=+36.9 (c 2.1, CHCl3).
1
(103 mg, 76% yield). H NMR (500 MHz, CDCl3) l
5.19 (bs, 1H); 4.23–4.05 (m, 3H); 3.06 (bs, 1H); 2.14 (m,
1H); 1.46 (s, 9H); 1.12 (d, J=7.0 Hz, 3H); 0.79 (d,
J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) l 208.1,
155.8, 80.4, 79.9, 47.6, 32.0, 31.8, 28.5, 22.8, 19.8, 15.2,
14.4 (spectrum showed a mixture of rotomers); IR
(film): 3426, 2975, 2934, 2876, 1695, 1510, 1393, 1368,
1252, 1168, 1020; HRMS-ESI (m/z): [M+Na]+ calcd for
C11H24NO4, 254.136; found 254.136; HPLC analysis of
the corresponding benzoate 3a (Chiralcel OJ, 5%
iPrOH/hexanes, 0.3 mL/min): tR [(R)-3a]=55.3 min; tR
[(S)-3a]=61.6 min; [h]2D0=−112.5 (c 1.0, CHCl3).
5.7. (−)-(4R)-(tert-Butyldiphenylsilyloxy)pentan-2-one 5
5.5. (+)-(4E)-4-Methyl-5-phenylpent-4-en-2-ol 4
Ozone was bubbled 5 min into a stirred solution of
(+)-[(1E,4R)-4-(tert-butyldiphenylsilyloxy)-2-methylpent-
1-enyl]benzene (86 mg, 0.21 mmol) in dry CH2Cl2 (4
mL) at −78°C. Dimethylsulfide (0.7 mL) was then
added, and the solution was allowed to warm to rt. The
resulting solution was concentrated under reduced pres-
sure, and the residue was purified by flash chromatog-
raphy on silica gel (0–5% Et2O/hexanes) to afford the
title compound35 (53 mg, 78% yield) as a colorless
To Ni(cod)2 (325 mg, 1.18 mmol) at rt were added PBu3
(600 mL, 2.41 mmol), Et3B (700 mL, 4.76 mmol),
(R)-propylene oxide33 (1.70 mL, 24.26 mmol), and 1-
phenyl-1-propyne (1.50 mL, 11.98 mmol). Additional
Et3B (2.80 mL, 19.34 mmol) was added via syringe
pump over 4 h. The brownish solution was stirred at rt
for 24 h. EtOAc (25 mL) was added and the resulting
solution was quenched with 2 M aqueous NaOH (10
mL) and 30% aqueous H2O2 (3 mL). The resulting
biphasic solution was vigorously stirred for 5 min. The
layers were separated and the organic phase was
washed with saturated aqueous NaHCO3 (10 mL),
dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash
chromatography on silica gel (0–20% EtOAc/hexanes)
to afford the title compound (1.31 g, 62% yield) as a
colorless liquid: Rf=0.24 (20% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) l 7.38–7.21 (m, 5H), 6.39 (s,
1H), 4.09–4.01 (m, 1H), 2.36–2.34 (m, 2H), 2.20 (s, 1H),
1.95 (s, 3H), 1.31 (d, J=6.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) l 137.7, 135.5, 128.7, 127.94, 127.91,
126.1, 65.3, 50.6, 22.8, 17.8; IR (film) 3374, 3081, 3056,
3023, 2966, 2926, 1946, 1884, 1806, 1721, 1650, 1599,
1490, 1445, 1374, 1314, 1269, 1118, 1073, 1022, 940,
918, 815, 744, 699 cm−1; HRMS–EI (m/z): [M]+ calcd
for C12H16O, 176.1196; found 176.1202. HPLC analysis
(Chiralcel OD: 0.5% iPrOH/hexanes): tR [(S)-4]=39.7
min, tR [(R)-4]=42.4 min. [h]2D0=+1.9 (c 1.9, EtOH)
[lit.:35 [h]D=+3 (c 1, EtOH)].
1
liquid: Rf=0.50 (20% EtOAc/hexanes); H NMR (400
MHz, CDCl3) l 7.73–7.68 (m, 5H), 7.47–7.38 (m, 8H),
4.37–4.28 (m, 1H), 2.66 (dd, J=15.2, 5.9 Hz, 1H), 2.24
(dd, J=15.2, 6.3 Hz, 1H), 2.08 (s, 3H), 1.11 (d, J=6.1
Hz, 3H), 1.05 (s, 9H); [h]2D0=−5.0 (c 0.40, CHCl3) [lit.35
>97% ee: [h]2D0=−3.2 (c 0.53, CHCl3)].
Acknowledgements
We thank Torsak Luanphaisarnnont and Justin D.
Cohen for experimental assistance and Dr. Wei-Sheng
Huang, Sejal J. Patel, Elizabeth A. Colby, Johann
Chan, Chudi O. Ndubaku, Ryan T. Moslin, and
Robert D. Jackson for their contributions to areas
related to those presented here. Postdoctoral support
was provided by the Fonds Que´be´cois de la Recherche
sur la Nature et les Technologies (FQRNT, fellowship
to C.M.) and Boehringer-Ingelheim (New Investigator
Award to T.F.J.). We also thank the National Institute
of General Medical Sciences (GM-063755), the NSF
(CAREER CHE-0134704), The Donors of the
Petroleum Research Fund, Amgen, Boehringer-Ingel-
heim, Bristol-Myers Squibb, Johnson & Johnson,
Merck Research Laboratories, Pfizer, 3M, and MIT for
financial support. The NSF (CHE-9809061 and DBI-
9729592) and NIH (1S10RR13886-01) provide partial
support for the MIT Department of Chemistry Instru-
mentation Facility.
5.6. (+)-[(1E,4R)-4-(tert-Butyldiphenylsilyloxy)-2-
methylpent-1-enyl]benzene
To a stirred solution of 4 (0.20 g, 1.13 mmol) in dry
DMF (1 mL) and THF (4 mL) at rt, was added
imidazole (0.23 g, 3.38 mmol) and tert-butyldiphenylsi-
lyl chloride (0.35 mL, 1.34 mmol). The reaction mixture
was stirred 16 h, and the resulting solution was diluted
with ether and aqueous NH4Cl and extracted. The
organic layer was washed with saturated aqueous

3624
K. M. Miller et al. / Tetrahedron: Asymmetry 14 (2003) 3619–3625
16. Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997,
References
1. Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Tetra-
119, 9065–9066.
17. Crowe has also reported one example of a catalytic
alkyne/aldehyde reductive cyclization: Crowe, W. E.;
Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787–6788.
18. (a) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J.
Am. Chem. Soc. 1987, 10, 2544–2546; (b) Van Wagenen,
B. C.; Livinghouse, T. Tetrahedron Lett. 1989, 30, 3495–
3498; (c) Takagi, K.; Rousset, C. J.; Negishi, E. J. Am.
Chem. Soc. 1991, 113, 1440–1442; (d) Takai, K.;
Kataoka, Y.; Utimoto, K. J. Org. Chem. 1990, 55, 1707–
1708; (e) Kataoka, Y.; Miyai, J.; Oshima, K.; Takai, K.;
Utimoto, K. J. Org. Chem. 1992, 57, 1973–1981; (f)
Takayanagi, Y.; Yamashita, K.; Yoshida, Y.; Sato, F.
Chem. Commun. 1996, 1725–1726.
hedron Lett. 1966, 7, 5239–5244.
2. (a) Handbook of Chiral Chemicals; Ager, D. J., Ed.;
Marcel Dekker: New York, 1999; (b) Blaser, H. U.;
Spindler, F.; Studer, M. Appl. Catal. A: General 2001,
221, 119–143; (c) Blaser, H. U. Chem. Commun. 2003,
293–296.
3. (a) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett.
2000, 2, 4221–4223; (b) Colby, E. A.; Jamison, T. F. J.
Org. Chem. 2003, 68, 156–166; (c) Miller, K. M.; Huang,
W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125,
3442–3443.
4. Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003,
42, 1364–1367.
5. Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003,
125, 8076–8077.
6. (a) Cyclotetramerization: Reppe, W.; Schlichting, O.;
Klager, K.; Toepel, T. Liebigs Ann. Chem. 1948, 560, 1;
(b) Cyclotrimerization: Reppe, W.; Schweckendiek, W. J.
Liebigs Ann. Chem. 1948, 560, 104–116.
19. Oxanickella(II)cyclopentenes have not been character-
ized, but an X-ray structure of a related Ni(II)ꢀO enolate
has been reported: Amarasinghe, K. K. D.; Chowdhury,
S. K.; Heeg, M. J.; Montgomery, J. Organometallics
2001, 20, 370.
20. Recent method of complementary regioselectivity for ter-
minal alkynes: Takai, K.; Sakamoto, S.; Isshiki, T. Org.
Lett. 2003, 5, 653–655.
21. Morrison, J. D.; Burnett, R. E.; Aguiar, A. M.; Morrow,
C. J.; Philips, C. J. Am. Chem. Soc. 1971, 93, 1301–1303.
22. Both enantiomers of NMDPP can be prepared on multi-
gram scale from menthol, MsCl, Et3N, Na0, and PPh3:
Senaratne, K. P. A. Synthesis of cycloalkyldiarylphosphi-
nes. US Patent 5,710,340, April 29, 1996.
23. (a) Blum, J.; Eisen, M.; Schumann, H.; Gorella, B. J.
Mol. Catal. 1989, 56, 329–337; (b) Lee, S.; Hartwig, J. F.
J. Org. Chem. 2001, 66, 3402–3415.
24. Recent reviews of chiral monophosphines in asymmetric
catalysis: (a) Lagasse, F.; Kagan, H. B. Chem. Pharm.
Bull. 2000, 48, 315–324; (b) Hayashi, T. Acc. Chem. Res.
2000, 33, 354–362; (c) Komarov, I. V.; Bo¨rner, A. Angew.
Chem., Int. Ed. 2001, 40, 1197–1200.
25. (a) Eisenthal, R.; Game, S.; Holman, G. D. Biochem.
Biophys. Acta 1989, 985, 81–89; (b) Aze´ma, L.; Bringaud,
F.; Blonski, C.; Pe´rie´, J. Bioorg. Med. Chem. 2000, 8,
717–722.
7. Reviews: (a) Tamaru, Y. J. Organomet. Chem. 1999, 576,
215–231; (b) Montgomery, J. Acc. Chem. Res. 2000, 33,
467–473; (c) Ikeda, S.-i. Acc. Chem. Res. 2000, 33, 511–
519; (d) Houpis, I. N.; Lee, J. Tetrahedron 2000, 56,
817-846.
8. Imines undergo alkylative coupling in moderate ee,4 and
a highly enantioselective variant of this transformation is
under development.
9. Catalytic, stereoselective three-component assembly of
tetrahydrofurans by way of carbonyl ylide dipolar
cycloaddition: Skaggs, A. J.; Lin, E. Y.; Jamison, T. F.
Org. Lett. 2002, 4, 2277–2280.
10. Terpestacin: (a) Iimura, S.; Oka, M.; Narita, Y.; Konishi,
M.; Kakisawa, H.; Gao, Q.; Oki, T. Tetrahedron Lett.
1993, 34, 493–496; (b) Oka, M.; Iimura, S.; Tenmyo, O.;
Sawada, Y.; Sugawara, M.; Ohkusa, N.; Yamamoto, H.;
Kawano, K.; Hu, S.-L.; Fukagawa, Y.; Oki, T. J. Antibi-
otics 1993, 46, 367–373; (c) Oka, M.; Iimura, S.; Narita,
Y.; Furumai, T.; Konishi, M.; Oki, T.; Gao, Q.; Kak-
isawa, H. J. Org. Chem. 1993, 58, 1875–1881.
11. Acutiphycin: Moore, R. E.; Patterson, G. M. L. J. Am.
Chem. Soc. 1984, 106, 8193–8197.
26. Ciminiello, P.; Costantino, V.; Fattorusso, E.; Magno, S.;
Mangioni, A.; Pansini, M. J. Nat. Prod. 1994, 57, 705–
712.
12. Epothilones: Bollag, D. M.; McQueney, P. A.; Zhu, J.;
Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.;
Lazarides, E.; Woods, C. M. Cancer Res. 1995, 55,
2325–2333.
13. FK-506: Tanaka, H.; Kuroda, A.; Marusawa, H.;
Hatanaka, H.; Kino, T.; Goto, T.; Hashimoto, M.; Taga,
T. J. Am. Chem. Soc. 1987, 109, 5031–5033.
14. For reviews of useful reactions of allylic alcohols: (a)
Bru¨ckner, R. In Comprehensive Organic Synthesis, Trost,
B. M., Ed.; Pergamon: New York, 1991; Vol. 6, Chapter
4.6, pp. 873–908; (b) Hill, R. K. ibid. Vol. 5, Chapter 7.1,
pp. 785–826; (c) Wipf, P. ibid. Vol. 5, Chapter 7.2, pp.
827–873; (d) Godleski, S. A., ibid. Vol. 4, p. 585; (e)
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307–1370; (f) Lipshutz, B. H.; Sengupta, S. In
Organic Reactions; Wiley: New York, 1992; Vol. 41, p.
135; (g) Overman, L. E. Acc. Chem. Res. 1992, 25, 352.
15. Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem. 1990, 55,
2554–2558.
27. (a) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J.
Org. Chem. 1992, 57, 5067–5068; (b) Zhu, Y.; Tu, Y.; Yu,
H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819–7822; (c)
Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919–934.
28. See also: (a) Trost, B. M.; Pinkerton, A. B. J. Am. Chem.
Soc. 2002, 124, 7376–7389; (b) Du¨nkelmann, P.; Kolter-
Jung, D.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen,
B.; Baumann, M.; Pohl, M.; Mu¨ller, M. J. Am. Chem.
Soc. 2002, 124, 12084–12085.
29. (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J.
Am. Chem. Soc. 1998, 120, 4033–4034; (b) Sato, Y.;
Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 9310–9317;
(c) Ezoe, A.; Kimura, M.; Inoue, T.; Mori, M.; Tamaru,
Y. Angew. Chem., Int. Ed. 2002, 41, 2784–2786.
30. Coxon, J. M.; Hartshorn, M. P.; Swallow, W. H. Aust. J.
Chem. 1973, 26, 2521–2526.
31. The selectivity trends in ring-opening reactions of aryloxi-
ranes often differ from those involving alkyloxiranes: (a)
Winstein, S.; Henderson, R. B. Ethylene and Trimethylene

K. M. Miller et al. / Tetrahedron: Asymmetry 14 (2003) 3619–3625
3625
Oxides. In Heterocyclic Compounds, Elderfield, R. C.,
Ed.; Wiley: New York, 1950; Vol. 1; (b) Parker, R. E.;
Isaacs, N. S. Chem. Rev. 1959, 59, 737–799; (c) Wohl, R.
A. Chimia 1974, 28, 1–5.
B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307–1315.
34. Roush, W. R. In Comprehensive Organic Synthesis; Trost,
B. M., Ed. Allyl Organometallics; Pergamon Press:
Oxford, 1991; Vol. 2, p. 1.
35. Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1997, 62,
2678–2679.
36. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923–2925.
32. Notable exceptions (catalyst-controlled endo selectivity):
(a) Janda, K. D.; Shevlin, C. G.; Lerner, R. A. Science
1993, 259, 490–493; (b) Wu, M. H.; Hansen, K. B.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 1997, 38, 2012–
2014.
37. Prepared from propargylamine hydrochloride: Khan, S.
I.; Grinstaff, M. W. J. Am. Chem. Soc. 1999, 121, 4704–
4705.
33. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen,
E. N. Science 1997, 277, 936–938; (b) Schaus, S. E.;
Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K.