(R)- and (S)-4-TIPS-3-butyn-2-ol. Useful precursors of chiral allenylzinc and indium reagents

Article abstract of DOI:10.1021/jo060542k

A convenient route to the enantiomers of 4-TIPS-3-butyn-2-ol of >95% enantiomeric purity by reduction of the ynone precursor 4 with the Noyori N-tosyl-1,2-diphenylethylenediamineruthenium cymene catalyst is described. The mesylate derivative of the (S) en

Full text of DOI:10.1021/jo060542k

(R)- and (S)-4-TIPS-3-butyn-2-ol. Useful Precursors of Chiral
Allenylzinc and Indium Reagents
James A. Marshall,* Patrick Eidam, and Hilary Schenck Eidam
Department of Chemistry, UniVersity of Virginia, McCormick Road, P.O. Box 400319,
CharlottesVille, Virginia 22904-4319
jam5x@Virginia.edu
ReceiVed March 11, 2006
A convenient route to the enantiomers of 4-TIPS-3-butyn-2-ol of >95% enantiomeric purity by reduction
of the ynone precursor 4 with the Noyori N-tosyl-1,2-diphenylethylenediamineruthenium cymene catalyst
is described. The mesylate derivative of the (S) enantiomer (1c) is converted in situ to an allenylzinc or
indium reagent in the presence of a catalyst derived from Pd(OAc)2 and Ph3P and either Et2Zn or InI. A
second in situ addition of these reagents to aldehydes leads to anti homopropargylic alcohol adducts.
The additions proceed in generally high (60-90%) yield with modest to excellent diastereoselectivity
and high enantioselectivity. Only slight mismatching (<5%) is observed with chiral R-methyl and
R-silyloxy aldehydes. Additions to R-substituted enals are highly diastereoselective, while â,â-disubstituted
enals afford ca. 2:1 mixtures of anti and syn adducts.
SCHEME 1. Additions of Chiral Allenylmetal Reagents to
Aldehydes
Introduction
In recent years, we have developed methodology for the
conversion of enantioenriched propargylic mesylates to allenyl
tin, zinc, and indium reagents, which undergo enantio- and
diastereoselective additions to aldehydes affording syn or anti
homopropargylic alcohol adducts (Scheme 1).1 The methyl-
substituted allenyl reagents have proven especially useful for
the elaboration of various polyketide natural products by us2a-j
and by others.2k-o
For our earliest preparation of the enantioenriched propargylic
alcohol precursors of these reagents, we employed the Darvon
alcohol complex of LiAlH4 (Chirald) for the conversion of
methyl alkynyl ketones to (R)-propargylic alcohols of ca. 90%
enantiomeric purity (Scheme 2).3
However, this methodology is limited to the preparation of
the (R) enantiomers owing to the unavailability of ent-Darvon
alcohol. Both (R)- and (S)-3-butyn-2-ol are commercially
M. P. Org. Lett. 2002, 4, 3931. (h) Membrenone C: Marshall, J. A.; Ellis,
K. C. Org. Lett. 2003, 5, 1729. (i) Leptofuranin D: Marshall, J. A.; Schaaf,
G. M. J. Org. Chem. 2003, 68, 7428. (j) Cytostatin: Marshall, J. A.; Ellis,
K. Tetrahedron Lett. 2004, 45, 1351. (k) Vancosamine: Parker, K. A.;
Chang, W. Org. Lett. 2003, 6, 2229. (l) Zincophorin: Defosseux, M.;
Blanchard, N.; Meyer, C.; Cossy, J. Org. Lett. 2003, 6, 4037. (m) 1-Deoxy-
D-galoctomomonojirimycin: Achnatowicz, M.; Hegedus, L. S. J. Org.
Chem. 2004, 69, 2229. (n) Amphidinolide X: Lepage, O.; Kattnig, E.;
Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 15970. (o) Dictyostatin: Prusov,
E.; Ro¨hm, H.; Maier, M. E. Org. Lett. 2006, 9, 1025.
(1) Marshall, J. A. Chem. Rev. 1996, 96, 31. (b) Marshall, J. A. Chem.
Rev. 2000, 100, 3163.
(2) (a) Zincophorin: Marshall, J. A.; Palovich, M. R. J. Org. Chem. 1998,
63, 3701. (b) Discodermolide: Marshall, J. A.; Johns. B. A. J. Org. Chem.
1998, 63, 7885. (c) Callystatin A: Marshall, J. A.; Fitzgerald, R. A. J.
Org. Chem. 1999, 64, 4477. (d) Aplyronine A: Marshall, J. A.; Johns, B.
A. J. Org. Chem. 2000, 65, 1501. (e) Balifomycin: Marshall, J. A.; Adams,
N. D. Organic Lett. 2000, 2, 2897. (f) Tautomycin: Marshall, J. A.; Yanik,
M. J. Org. Chem. 2001, 66, 1373. (g) (-)-Callystatin A: Marshall, J. A.;
Bourbeau, M. P. J. Org. Chem. 2002, 67, 2751. Marshall, J. A.; Bourbeau,
(3) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 3211.
10.1021/jo060542k CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/27/2006
4840
J. Org. Chem. 2006, 71, 4840-4844

(R)- and (S)-4-TIPS-3-butyn-2-ol
SCHEME 2. Reduction of Methyl Alkynyl Ketones with
Chirald
SCHEME 4. Synthesis of 4-TIPS-3-butyn-2-one and
Subsequent Reduction with Noyori’s (S,S)-Ru Catalyst
SCHEME 3. Kinetic Resolution of Racemic Alkynyl Methyl
Carbinols with Amano AK Lipase
TABLE 2. In Situ Additions of (P)-1-TIPS-1,2-butadienylzinc
Mesylate to Achiral Aldehydes
TABLE 1. Comparison of in Situ Additions of Silylated and
Unsilylated Allenylzinc Reagents to Achiral Aldehydes
R
yield (%)
dr
R1 ) Ha
yield (%)
R1 ) TMSb
yield (%)
C6H11 (7a)
C6H13 (7b)
TBSOCH2CH2 (7c)
85
96
87
>95:5a
88:12
88:12
R2
dr
dr
C6H11
C6H13
84
70
56
96:4c
88:12
88:12
84
72
76
96:4d
85:15
85:15
a er ) 98:2 based on GC analysis on a â-Dex column.
TBSOCH2CH2
a Reaction at 0 °C. b Reaction at -20 °C. c er ) 96:4. d er ) 97:3.
The reduction of 4-TIPS-3-butyn-2-one with ca. 1 mol % of
the Noyori chiral Ru catalyst in isopropyl alcohol proceeds
rapidly to afford (S)- or (R)-4-TIPS-3-butyn-2-ol (5) in >95%
yield and >95% enantiomeric purity (Scheme 4).8,9 The alcohols
are conveniently isolated by conventional extraction without loss
from volatility or water solubility. The corresponding mesylates
are converted in situ to chiral allenylzinc reagents, which react
with aldehydes to form homopropargylic alcohols with high
diastereo- and enantioselectivity, comparable to that of the TMS
analogues.9 Additions to representative achiral aldehydes are
shown in Table 2.
Removal of the TIPS group from these adducts was easily
effected with TBAF in THF. Interestingly, even with as little
as 25 mol % of TBAF cleavage was complete in minutes.
Evidently, protonolysis of the liberated acetylide by small
amounts of water in the TBAF reagent leads to Bu4N+OH-,
which can effect desilylation of the unreacted alkynylsilane. In
accord with this surmise, we were able to effect TIPS cleavage
through a somewhat more prolonged exposure to Bu4N+OH-
in THF. The TIPS mesylate 1c could also be desilylated by
brief treatment with TBAF in THF to afford the terminal alkynyl
mesylate 1a.
available, but their high cost limits widespread or large-scale
applications.4
A solution to this problem was found in our modification of
the reported resolution of 4-TMS-3-butyn-2-ol with Amano AK
lipase (Scheme 3).5,6 By performing the resolution in pentane
and derivatizing the resolved butynol as the half-succinate, we
were able to circumvent the reported chromatographic separation
of the enantioenriched acetate and alcohol products and thereby
avoid the substantial material losses resulting from their
volatility. The diastereoselectivity of additions employing the
TMS substituted allenylzinc reagents derived from the TMS
butynyl mesylate6 were comparable to those of the parent
allenylzinc reagent (Table 1).7
Results and Discussion
The present report is concerned with a further improvement
in the methodology through use of the 4-TIPS derivatives of
(R)- and (S)-3-butyn-2-ol as precursors of chiral allenylzinc and
indium reagents. Both enantiomers of these alcohols can be
prepared in high enantiomeric purity and excellent yield, and
the derived allenylmetal reagents show comparable selectivities
to the TMS analogues in additions to a variety of aldehydes.
The TIPS allenylzinc reagent exhibited excellent reagent-
controlled addition to the chiral R-methyl-â-silyloxypropanals
(Scheme 6). Both enantiomeric aldehydes afforded a ca. 90:10
mixture of diastereomeric adducts.
(4) Typical recent price listings: $155.50/g for (S)-3-butyn-2-ol and
$114.00/g for (R)-3-butyn-2-ol.
Additions to the enantiomeric OTBS lactic aldehyde deriva-
tives also exhibited a high degree of reagent control but with a
slightly greater match/mismatch discrimination. The use of the
racemic allenylzinc reagent resulted in a nearly 1:1 ratio of the
diastereomeric anti adducts along with a small amount the two
(5) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129.
(6) Marshall, J. A.; Yanik, M. M.; Adams, N. D.; Ellis, K. C.; Chobanian,
H. R. Org Synth. 2004, 81, 157. Marshall, J. A.; Chobanian, H. R.; Yanik,
M. M. Org. Lett. 2001, 3, 3369. For an application of the lipase resolution
methodology to (E)-4-(dimethylphenylsilyl)-3-buten-2-ol and 4-(dimeth-
ylphenylsilyl)-3-butyn-2-ol, see: Beresis, R. T.; Solomon, J. S.; Yang, M.
G.; Jain, N. F.; Panek, J. S. Org. Synth. 1997, 75, 78.
(7) (a) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201. (b)
Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812. Bahadoor, A.
B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 2005, 127, 3694.
(8) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
(9) Preparation of the (R) enantiomer is described in the Supporting
Information.
J. Org. Chem, Vol. 71, No. 13, 2006 4841

Marshall et al.
SCHEME 5. Desilylation of TIPS Alkynes
SCHEME 7. Reagent-Controlled in Situ Additions of Chiral
TIPS Allenylzinc Reagents to Chiral r-OTBS Propanals
(Hoffmann Test)
SCHEME 6. Reagent-Controlled in Situ Additions of Chiral
TIPS Allenylzinc Reagents to Chiral r-Methylpropanals
(DPS ) Diphenyl-tert-butylsilyl)
SCHEME 8. In Situ Additions of
(P)-1-TIPS-1,2-butadienylzinc Mesylate to Geranial
TABLE 3. In Situ Additions of (P)-1-TIPS-1,2-Butadienylzinc
Mesylate to (E)-Enals
R
yield (%)
dra
22/23
a The enantiomeric mesylate was employed. bA trace amount of the 1,4-
ethyl adduct was detected.
TMS (1b)
TIPS (1c)
70
89
75:25
80:20
45:55
14:86
SCHEME 9. In Situ Additions of
(P)-1-TIPS-1,2-butadienylzinc Mesylate to r-Methylated
(E)-Enals
a Anti/syn ratio of the alcohol adducts. b The enantiomer was used.
syn isomers indicating that both the allenylzinc reagent and its
allenylpalladium precursor are configurationally stable under
the reaction conditions.10
Our next series of experiments was conducted with the simple
conjugated aldehyde (E)-2-heptenal (Table 3). We had not
previously employed enals as substrates for additions of chiral
allenylzinc reagents, and therefore, both the TMS and TIPS
reagents were examined for comparison of efficiency. Surpris-
ingly, in each case, the major product was the 1,4-adduct derived
from diethylzinc.11 The minor amounts of allenylzinc adduct
formed were predominantly anti, but the additions were not
highly disastereoselective.
Expecting â-substitution to disfavor 1,4-addition, we exam-
ined additions of the parent and the two silylated allenylzinc
reagents to geranial (Scheme 8). As expected, all three reagents
gave the 1,2 adducts, albeit as 2:1 mixtures of anti and syn
isomers, indicative of significant substrate control. A small
amount of the 1,4-ethyl adduct was detected from the reaction
with the TIPS reagent.
A pair of conjugated aldehydes with an R-methyl substituent
was also examined (Scheme 9). These additions proved more
diastereoselective than the previous additions to â-methylated
enals, and the TIPS analogue proved superior to the TMS or
parent allenylzinc reagents.
The poor diastereoselectivity observed in the additions to
geranial by all three allenylzinc reagents is suggestive of a high
degree of substrate control. Recent ab initio calculations of
transition-state parameters for allenylzinc addition to aldehydes
support an arrangement in which the substituents on the allenyl
terminus of the reagent are eclipsed with the aldehyde alkyl
and hydrogen substituents.12 The presence of a conjugated
(10) Hoffmann, R. W.; Lanz, J.; Hoppe, D.; Metternich, R.; Tarrana, G.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1145.
(11) Conjugate additions of organozinc compounds to conjugated ketones
in the presence of Cu, Ni, and Co catalysts have been reported, but we are
unaware of any such additions to enals or of any Pd-catalyzed additions of
alkylzinc reagents in the absence of other metal catalysts. We have found
that the 1,4-additions of Et2Zn to heptenal and geranial take place in the
absence of the propargylic mesylate but not in the absence of the palladium
catalyst. We are currently examining this interesting addition reaction in
detail to determine the scope and mechanism. For recent accounts of
alkylzinc conjugate additions, see: Lipschutz, B. H.; Wood, M. R.; Tirando,
R. J. Am. Chem. Soc. 1995, 117, 6126. Takahashi, Y. Yamamoto, Y.;
Katagiri, K.; Danjo, H.; Yamaguchi, K.; Imamato, T. J. Org. Chem. 2005,
70, 9009 and references cited.
4842 J. Org. Chem., Vol. 71, No. 13, 2006

(R)- and (S)-4-TIPS-3-butyn-2-ol
and TIPS allenylindium reagents to the R-methyl enal proved
highly diastereoselective.
In summary, Noyori reduction of 4-TIPS-3-butyn-2-one offers
a convenient and efficient route to enantiomeric propargylic
alcohol precursors of chiral allenylzinc and indium reagents
generated in situ from the propargylic mesylates and Et2Zn or
InI in the presence of a palladium catalyst.14 These reagents
react with various aldehydes to afford homopropargylic alcohols
of high enantiomeric purity. Additions of the allenylzinc reagent
to achiral aliphatic aldehydes and chiral R-methyl and R-silyloxy
aldehydes are highly diastereoselective favoring the anti isomer
with negligible mismatching. However, additions to unsubsti-
tuted conjugated enals lead to significant quantities of 1,4-adduct
arising from the diethylzinc component of the reaction. This
side reaction can be avoided through use of the related
allenylindium reagent. Allenylzinc additions to R-methylated
enals are more diastereoselective and proceed without competing
1,4-ethyl addition. â-Methylated enals, on the other hand, afford
roughly 2:1 mixtures of anti and syn adducts with both
allenylzinc and indium reagents.
FIGURE 1. Steric interactions in allenylzinc additions to â-methyl
enals.
TABLE 4. In Situ Additions of (P)-1-TIPS-1,2-butadienylindium
Reagent to Enals
Experimental Section
4-Triisopropylsilyl-3-butyn-2-ol (3). A flame-dried 250 mL
round-bottom flask equipped with a magnetic stir bar was charged
with triisopropylsilylacetylene (95%, 6.1 mL, 26.0 mmol) and THF
(54 mL). The reaction mixture was cooled to -40 °C (dry ice-
acetonitrile bath), and t-BuLi (1.7 M in pentane, 18 mL, 32.3 mmol)
was added dropwise. The resulting bright yellow mixture was stirred
at -40 °C for 30 min, and then acetaldehyde (2.3 mL, 39.2 mmol)
was added in one portion. The reaction mixture was stirred for 20
min at -40 °C and then was poured over a rapidly stirring solution
of saturated aqueous NH4Cl (75 mL). After 15 min, the phases
were separated, and the aqueous layer was extracted with diethyl
ether. The combined organic extracts were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by bulb-to-bulb distillation (5 mmHg; 104 °C)
to yield the racemic alcohol 3 as a clear oil (5.9 g, 100% yield)
contaminated with ∼3 mol % of triisopropylsilylacetylene: IR
(film) ν 3334, 2961, 2868, 2176, 1438 cm-1; 1H NMR (CDCl3) δ
4.51 (q, J ) 6.6 Hz, 1H), 1.43 (d, J ) 6.6 Hz, 3H), 1.03 (s, 21H);
13C NMR (CDCl3) δ 109.9, 84.1, 58.6, 24.5, 18.4, 11.0. Anal. Calcd
for C13H26OSi: C, 68.96; H, 11.57. Found: C, 69.09; H, 11.64.
4-Triisopropylsilyl-3-butyn-2-one (4). A flame-dried 250 mL
round-bottom flask equipped with a magnetic stir bar was charged
with CH2Cl2 (54 mL) and alcohol 3 (5.90 g, 26.0 mmol). MnO2
(85%, 34.4 g, 337 mmol) was then added in one portion. The
reaction mixture was stirred for 30 min and then filtered through a
short pad of Celite and concentrated under reduced pressure. The
resulting yellow oil was purified by bulb-to-bulb distillation (5
mmHg; 86 °C) to yield the ketone 2 as a clear oil (5.50 g, 94%
R
R1
R2
R3
yield (%)
dr
TIPS (1c)
TIPS (1c)
TIPS (1c)
TMS (1b)
H
H
Me
Me
H
Me
H
CH3(CH2)3
75
76
87
81
80:20a
67:33a
91:9a
(CH3)2CdCH(CH2)2
TBSOCH2CH2
TBSOCH2CH2
H
89:11a
a er of the anti isomer >95:5 based on 1H NMR analysis of the Mosher
ester.
double bond in the aldehyde substrate imposes a restriction for
coplanarity with the carbonyl oxygen as illustrated in Figure 1.
This restriction causes the enal â-substituents to interact with
the methyl substituent of the allenylzinc reagent in the normally
favored eclipsed arrangement of the two transition states. The
interactions of these â-substituents differ in the transition states
for the anti and syn isomer as illustrated. In the former, a type
of syn 1,4-interaction between the allenic methyl of the zinc
reagent and the â-methyl substituent of the enal is present
whereas the equivalent interaction in the process leading to the
syn isomer places the allenic methyl in more of a gauche
arrangement with the two â-substituents of the enal. The syn
1,4-interaction raises the energy of the normally favored anti
relative to the syn transition state resulting in a lower ratio of
the two products.
1
yield): IR (film) ν 2955, 2875, 2150, 1690, 1471, 1198 cm-1; H
NMR (CDCl3) δ 2.32 (s, 3H), 1.07 (s, 21H); 13C NMR (CDCl3) δ
184.1, 104.6, 94.9, 32.7, 18.4, 10.9. Anal. Calcd. for C13H24OSi:
C, 69.58; H, 10.78. Found: C, 69.32; H, 10.89.
In view of the significant 1,4-additions of diethylzinc observed
in the foregoing allenylzinc additions to unsubstituted enals,
we briefly explored the use of the TIPS allenylindium reagent
for these additions (Table 4).13 These reactions proceeded readily
but with somewhat lower diastereoselectivity than that reported
for the comparable allenylzinc additions.6 As noted for the
allenylzinc reactions, geranial proved the least selective substrate
of the three enals examined. Interestingly, addition of the TMS
RuCl[(S,S)-NTsCH(C6H5)CH(C6H5)NH2](η6-cymene). A flame-
dried 25 mL round-bottom flask equipped with a magnetic stir bar
was charged with CH2Cl2 (6 mL), (1S,2S)-(+)-N-p-tosyl-1,2-
diphenylethylenediamine (126 mg, 0.34 mmol), dichloro(p-
cymene)ruthenium(II) dimer (107 mg, 0.17 mmol), and powdered
KOH (141 mg, 2.5 mmol). The resulting orange mixture was stirred
for 5 min, and then H2O (6 mL) was added in one portion. The
resulting biphasic mixture was stirred for 10 min, during which
time the organic phase turned dark purple. The mixture was
(12) Gung, B. W.; Xue, X.; Knatz, N.; Marshall. J. A. Organometallics
2003, 22, 3158.
(13) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 8214.
(14) A more detailed procedure for preparation of (R and S)-4-TIPS-
butyn-2-ols has been submitted to Org. Synth.
J. Org. Chem, Vol. 71, No. 13, 2006 4843

Marshall et al.
transferred to a separatory funnel and diluted with H2O, and the
layers were separated. The aqueous phase was then extracted with
CH2Cl2. The combined organic extracts were dried over CaH,
filtered, and concentrated to furnish catalyst (186 mg, 90% yield)
as a dark purple solid which was used immediately in the subsequent
reduction.
reaction was quenched by pouring over a rapidly stirring solution
of saturated aqueous NH4Cl (25 mL), and after 15 min, the phases
were separated and the aqueous phase was extracted with Et2O.
The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by
flash chromatography (hexanes to 10% EtOAc/hexanes) to yield
alcohol 7a (363 mg, 85% yield of the anti diastereomer and 17
mg, 4% yield of the syn diastereomer) as a clear oil: [R]20D +5.5
(S)-4-Triisopropylsilyl-3-butyn-2-ol (5). A flame-dried 500 mL
round-bottom flask equipped with a magnetic stir bar was charged
with i-PrOH (300 mL) and ketone 4 (5.50 g, 24.6 mmol). The (S,S)-
catalyst (183 mg, 0.30 mmol) was taken up in a minimal amount
of CH2Cl2 (5 mL) and added to the reaction mixture in one portion.
The reaction mixture was stirred for 1.5 h and then concentrated
under reduced pressure. The brown oil was purified by bulb-to-
bulb distillation (5 mmHg; 104 °C) to yield the (S) alcohol 5 as a
(c 1.28, CHCl3); IR (film) ν 3562, 2925, 2864, 2165, 1462 cm-1
;
1H NMR (CDCl3) δ 3.03-3.07 (m, 1H), 2.74-2.79 (m, 1H), 1.96
(d, J ) 13.1 Hz, 1H), 1.79-1.42 (m, 5H), 1.23 (d, J ) 7.0 Hz,
3H), 1.22-0.98 (m, 27H); 13C NMR (CDCl3) δ 109.3, 83.3, 78.6,
42.3, 31.2, 29.6, 28.3, 26.4, 26.3, 26.1, 18.6, 18.3, 11.2. Anal. Calcd
for C20H38OSi; C, 74.46; H, 11.87. Found: C, 74.24; H, 12.03.
(3R,4S)-(+)-3-Methyl-1-trimethylsilyl-1-decyn-5-en-4-ol (31).
Standard Procedure for Allenylindium Additions. A flame-dried
flask was charged with THF (3 mL) and HMPA (1 mL). trans-2-
Heptenal (74 mg, 0.66 mmol, 1 equiv) was then added followed
by Pd(OAc)2 (9.8 mg, 0.05 mmol, 0.06 equiv) and PPh3 (12.2 mg,
0.05 mmol, 0.06 equiv). Upon complete dissolution of the PPh3,
the solution was cooled to 0 °C. TIPS mesylate (S)-1c (247 mg,
0.81 mmol, 1.2 equiv) was added to the solution followed by InI
powder (258 mg, 1.1 mmol, 1.6 equiv). The mixture was then stirred
at 0 °C for 15 min before being warmed to rt. After 1 h, the reaction
mixture was quenched with saturated aqueous NH4Cl solution (20
mL) and extracted with Et2O. The Et2O solution was separated,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography to yield
alcohol 31 (159 mg, 75% yield, 80:20 mixture of anti and syn
diastereomer separable by flash chromatography with 20% Et2O-
clear oil (5.30 g, 96% yield): [R]20 -19.5 (c 1.55, CHCl3); IR
D
(film) ν 3334, 2961, 2868, 2176, 1438 cm-1; 1H NMR (CDCl3) δ
4.51 (q, J ) 6.6 Hz, 1H), 2.51 (s, 1H), 1.43 (d, J ) 6.6 Hz, 3H),
1.03 (s, 21H); 13C NMR (CDCl3) δ 109.9, 84.1, 58.6, 24.5, 18.4,
11.0. Anal. Calcd for C13H26OSi: C, 68.96; H, 11.57. Found: C,
68.58; H, 11.59.
(S)-4-Triisopropylsilyl-3-butyn-2-yl Mesylate (1c). A flame-
dried 500 mL round-bottom flask equipped with a magnetic stir
bar was charged with CH2Cl2 (250 mL) and alcohol 5 (5.3 g, 23.5
mmol), and the mixture was cooled to -78 °C. Triethylamine (6.6
mL, 47.3 mmol) and MsCl (2.8 mL, 36.1 mmol) were added
successively. The reaction mixture was stirred at -78 °C for 45
min and then quenched by the addition of satd aq NaHCO3 (25
mL). The mixture was warmed to room temperature and then
transferred to a separatory funnel. The aqueous layer was extracted
with ether, and the combined organic extracts were washed with
H2O and brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The clear residual oil (6.85 g, 96%) was used
without further purification: [R]20D -80.1 (c 1.83, CHCl3); IR (film)
hexanes elutant) as a clear oil: [R]20 +13.7 (c 0.85, CHCl3); IR
D
(film) ν 3408, 2942, 2865, 2162, 1464 cm-1; 1H NMR (CDCl3) δ
5.69-5.78 (m, 1H), 5.44-5.52 (m, 1H), 3.86-3.91 (m, 1H), 2.55-
2.64 (m, 1H), 2.09 (s, 1H), 2.05 (q, J ) 2.05 Hz, 2H), 1.26-1.40
(m, 4H), 1.19 (d, J ) 6.9 Hz, 3H), 1.06 (s, 21H), 0.89 (t, J ) 7.2
Hz, 3H); 13C NMR (CDCl3) δ 134.2, 130.1, 109.7, 83.6, 75.9, 35.1,
32.2, 31.4, 22.4, 18.8, 17.5, 14.1, 11.4. Anal. Calcd for C20H38-
OSi; C, 74.46; H, 11.87. Found: C, 74.37; H, 11.72.
1
ν 2948, 2862, 1469, 1371, 1185 cm-1; H NMR (CDCl3) δ 5.30
(q, J ) 6.6 Hz, 1H), 3.13 (s, 1H), 1.66 (d, J ) 6.6 Hz, 3H), 1.03
(s, 21H); 13C NMR (CDCl3) δ 109.9, 84.1, 58.6, 24.5, 18.4, 11.0.
(1S,2R)-(+)-1-Cyclohexyl-2-methyl-4-triisopropylsilyl-3-bu-
tyn-1-ol (7a). Standard Procedure for Allenylzinc Additions. A
flame-dried 50 mL flask was charged with THF (13 mL) and Pd-
(OAc)2 (15.2 mg, 0.07 mmol, 5 mol %). Upon complete dissolution
of the Pd(OAc)2, the mixture was cooled to -78 °C, and PPh3 (17.7
mg, 0.07 mmol, 5 mol %) was added. When the mixture became
homogeneous, TIPS mesylate (S)-1c (490 mg, 1.61 mmol, 1.2
equiv) and cyclohexanecarboxaldehyde (160 µmL, 1.32 mmol, 1.0
equiv) were added, and then Et2Zn (1 M in hexanes, 4.0 mL, 4.0
mmol, 3 equiv) was added dropwise over 5 min. The resulting
yellow solution was warmed to -20 °C and stirred for 14 h. The
Acknowledgment. Support from the Vice President for
Research and Graduate Studies at the University of Virginia is
gratefully acknowledged.
Supporting Information Available: Experimental procedures
and 1H NMR spectra for key intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060542K
4844 J. Org. Chem., Vol. 71, No. 13, 2006