(-)-Sparteine-mediated stereoselective intramolecular carbolithiation of 4-substituted 5-hexynyl carbamates. Synthesis of enantiopure 1,3- difunctionalized alkylidene cyclopentanes

Article abstract of DOI:10.1021/jo991095u

The stereoselective carbolithiation of alkynes with external chiral induction has been achieved for the first time by fusing the concepts of the asymmetric deprotonation (A) with s-BuLi/(-)-sparteine (s-BuLi/1) and the intramolecular carbolithiation (B). Several 4-functionalized 5-hexynyl carbamates with different terminal substituents have been prepared and efficiently cyclized providing enantiopure highly substituted alkylidene cyclopentanes. The presence of a sterically demanding substituent in the propargylic position is the essential feature of these cyclizations in order to suppress the abstraction of the remaining propargylic proton. Furthermore, in dependence on the terminal substituent, the 6-phenyl-substituted precursors undergo an intramolecular carbolithiation whereas for the 6- trimethylsilyl-substituted alkynes a subsequent migration of the O-carbamoyl group onto the vinylic carbanionic center follows.

Full text of DOI:10.1021/jo991095u

8616
J . Org. Chem. 1999, 64, 8616-8626
(-)-Sp a r tein e-Med ia ted Ster eoselective In tr a m olecu la r
Ca r bolith ia tion of 4-Su bstitu ted 5-Hexyn yl Ca r ba m a tes. Syn th esis
of En a n tiop u r e 1,3-Difu n ction a lized Alk ylid en e Cyclop en ta n es
Martin Oestreich, Roland Fro¨hlich,1 and Dieter Hoppe*,†
Organisch-chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Corrensstrasse 40,
D-48149 Mu¨nster, Germany
Received J uly 7, 1999
The stereoselective carbolithiation of alkynes with external chiral induction has been achieved for
the first time by fusing the concepts of the asymmetric deprotonation (A) with s-BuLi/(-)-sparteine
(s-BuLi/1) and the intramolecular carbolithiation (B). Several 4-functionalized 5-hexynyl carbamates
with different terminal substituents have been prepared and efficiently cyclized providing
enantiopure highly substituted alkylidene cyclopentanes. The presence of a sterically demanding
substituent in the propargylic position is the essential feature of these cyclizations in order to
suppress the abstraction of the remaining propargylic proton. Furthermore, in dependence on the
terminal substituent, the 6-phenyl-substituted precursors undergo an intramolecular carbolithiation
whereas for the 6-trimethylsilyl-substituted alkynes a subsequent migration of the O-carbamoyl
group onto the vinylic carbanionic center follows.
In tr od u ction
Our approach to stereoselective intramolecular carbo-
lithiation reactions (C) is based on the fusion of the
concepts of the enantiotopos-differentiating deprotonation
(A) and the stereospecific intramolecular carbolithiation
(B)5,7 (Scheme 1).
The asymmetric deprotonation (A) of carbamic esters
2 derived from primary alkanols with the chiral base
s-BuLi/(-)-sparteine (s-BuLi/1) and the subsequent ste-
reospecific electrophilic substitution of the intermediate
lithium-carbanion pairs with external electrophiles rep-
resent a powerful tool for the synthesis of enantioen-
riched secondary alkanols 3 (2 f 3).8 The intramolecular
carbolithiation (B) of alkenes9 and alkynes10,11 of type 4,
respectively, is a well-known, high-yielding process with
the carbon-carbon multiple bond acting as an internal
electrophile since the pioneering work of Bailey (4 f 5).
The fusion of both methods A and B, applied to alkynes,
The carbometalation of carbon-carbon multiple bonds
ranks among the most efficient methods for the formation
of new carbon-carbon bonds.2 However, the development
of asymmetric variants still remains as a major endeavor
in stereoselective synthesis although some enantioselec-
tive carbometalation reactions have appeared in recent
years.3 The reports on the first asymmetric intermolecu-
lar4 as well as intramolecular5 carbolithiation of alkenes
with external chiral induction have therefore attracted
considerable interest.6 Moreover, we were able to ac-
complish the first stereoselective intramolecular carbo-
lithiation of alkynes.7
† Fax: (+49) 251-8339772.
(1) Crystal structure analyses.
(2) For reviews, see: (a) Marek, I.; Normant, J . F. In Metal-catalyzed
Cross-coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-
VCH: Weinheim, Germany, 1998; pp 271-337. (b) Knochel, P. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 4, pp 865-911. (c) Normant, J . F.;
Alexakis, A. Synthesis 1981, 841-871. (d) Negishi, E. Pure Appl. Chem.
1981, 53, 2333-2356.
(3) For a recent review with focus on enantioselective modifications,
see: Marek, I. J . Chem. Soc., Perkin Trans. 1 1999, 535-544.
(4) (a) Klein, S.; Marek, I.; Poisson, J .-F.; Normant, J . F. J . Am.
Chem. Soc. 1995, 117, 8853-8854. (b) Norsikian, S.; Marek, I.;
Normant, J . F. Tetrahedron Lett. 1997, 38, 7523-7526. (c) Norsikian,
S.; Marek, I.; Poisson, J .-F.; Normant, J . F. J . Org. Chem. 1997, 62,
4898-4899.
(5) (a) Woltering, M. J .; Fro¨hlich, R.; Hoppe, D. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1764-1766. (b) Woltering, M. J .; Fro¨hlich, R.;
Wibbeling, B.; Hoppe, D. Synlett 1998, 797-800. (c) Hoppe, D.;
Woltering, M. J .; Oestreich, M.; Fro¨hlich, R. Helv. Chim. Acta, in press.
(d) Tomooka, K.; Komine, N.; Sasaki, T.; Shimizu, H.; Nakai, T.
Tetrahedron Lett. 1998, 39, 9715-9718. (e) For the stereoselective
carbolithiation of conjugated double bonds, see: Oestreich, M.; Hoppe,
D. Tetrahedron Lett. 1999, 40, 1881-1884.
(8) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422-1423. For reviews, see: (b) Hoppe, D.; Hense, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282-2316. (c) Hoppe, D.; Hintze, F.;
Tebben, P.; Paetow, M.; Ahrens, H.; Schwerdtfeger, J .; Sommerfeld,
P.; Haller, J .; Guarnieri, W.; Kolczewski, S.; Hense, T.; Hoppe, I. Pure
Appl. Chem. 1994, 66, 1479-1486. For the asymmetric deprotonation
of carbamates derived from amines, see: (d) Kerrick, S. T.; Beak, P.
J . Am. Chem. Soc. 1991, 113, 9708-9710. (e) Beak, P.; Basu, A.;
Gallagher, D. J .; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 552-560.
(9) (a) Bailey, W. F.; Nurmi, T. T.; Patricia, J . J .; Wang, W. J . Am.
Chem. Soc. 1987, 109, 2442-2448. (b) Bailey, W. F.; Khanolkar, A. D.
J . Org. Chem. 1990, 55, 6058-6061. (c) Bailey, W. F.; Khanolkar, A.
D.; Gavaskar, K.; Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J .
Am. Chem. Soc. 1991, 113, 5720-5727. (d) Bailey, W. F.; Gavaskar,
K. V. Tetrahedron 1994, 50, 5957-5970. See also: (e) Krief, A.; Kenda,
B.; Maertens, C.; Remacle, B. Tetrahedron 1996, 52, 7465-7473. (f)
Hoffmann, R. W.; Koberstein, R.; Harms, K. J . Chem. Soc., Perkin
Trans. 2 1999, 183-191.
(6) For enantiospecific intramolecular carbolithiations starting from
enantiomerically enriched R-amino- and R-oxy-substituted stannanes,
see: (a) Coldham, I.; Hufton, R.; Snowden, D. J . Am. Chem. Soc. 1996,
118, 5322-5323. (b) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron
Lett. 1997, 38, 8939-8942. For a diastereofacially controlled intramo-
lecular carbolithiation, see: Krief, A.; Bousbaa, J . Synlett 1996, 1007-
1009.
(10) (a) Bailey, W. F.; Ovaska, T. V.; Leipert, T. K. Tetrahedron Lett.
1989, 30, 3901-3904. (b) Wu, G.; Cederbaum, F. E.; Negishi, E.
Tetrahedron Lett. 1990, 31, 493-496. (c) Bailey, W. F.; Ovaska, T. V.
Tetrahedron Lett. 1990, 31, 627-630. (d) Bailey, W. F.; Ovaska, T. V.
J . Am. Chem. Soc. 1993, 115, 3080-3090.
(11) (a) For a first report, see: Ward, H. R. J . Am. Chem. Soc. 1967,
89, 5517-5518. (b) Subsequent investigations presented convincing
evidence that free radicals are involved under Ward’s conditions:
Ohnuki, T.; Yoshida, M.; Simamura, O. Chem. Lett. 1972, 999-1004.
(7) For a preliminary communication of our work, see: Oestreich,
M.; Fro¨hlich, R.; Hoppe, D. Tetrahedron Lett. 1998, 39, 1745-1748.
10.1021/jo991095u CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

(-)-Sparteine-Mediated Carbolithiation
J . Org. Chem., Vol. 64, No. 23, 1999 8617
Sch em e 1a
The treatment of a solution of 6 in Et2O with s-BuLi/1
at -78 °C for 18 h (step a) produced after quenching with
methanol (step b) a mixture of 6, the allene 11, and the
desired cyclopentane 716 (eq 1).
The low yield of 7 proved to be already optimal since
any change of the reaction conditions (temperature, -78,
-60, or -40 °C; solvent, Et2O or toluene)17a lead to a
decrease of the yield. These observations are due to the
relatively high acidity of the propargylic protons at C-4
competing with the kinetic acidity of the activated
protons at C-1 as indicated by the presence of the allene
11. The abstraction of acidic protons, particularly termi-
nal and propargylic, has generally been a major difficulty
in the carbolithiation of alkynes.2c As a re´sume´, the
formation of small amounts of 7 indicates that, in
principle, the concepts A and B could be successfully
fused if the deprotonation in the propargylic position is
suppressed.
We became aware of a communication by Marek and
Normant, who investigated in another context the depro-
tonation of 3-hydroxy-1,7-diynes with s-BuLi in THF.18
The abstraction of a propargylic proton could be directed
in dependence on the steric bulk of the hydroxy protecting
group toward the less sterically hindered position with
moderate regioselectivity. Consequently, a complete block-
ing of the deprotonation in the propargylic position could
possibly be achieved by the introduction of a large
substituent such as N,N-dibenzylamino, trityloxy, or
silyloxy groups at C-4 in 6 and the use of a sterically
demanding base such as s-BuLi/1.
The refinement of the 6-phenyl-5-hexynyl carbamate
6 lead to the cyclization precursors 12 and 13 which were
synthesized in both enantioenriched and racemic forms.
The enantiomerically pure 4-amino-6-phenyl-5-hexynyl
carbamate (S)-12 was prepared in six steps from the
previously described alkanol (S)-14 which is derived from
(S)-glutamic acid19 (Scheme 3).
The phenyl-substituted triple bond was again intro-
duced by employing the four-step sequence consisting of
a Swern oxidation,12 a Corey-Fuchs conversion,14 and a
Sonogashira coupling15 wherein the intermediate R-ste-
reogenic aldehyde12b did not suffer racemization.20 After-
ward the resulting propargylic amine (S)-15 was desily-
a
reagents. a. s-BuLi/1, Et2O, -78 °C. b. EX, -78 °C to rt. c.
t-BuLi, Et2O/pentane (3:2), -78 °C then warm. d. MeOH, -78 °C
to rt. R ) alkyl, E ) electrophile. X ) leaving group.
Sch em e 2a
a
reagents. a. (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 87%. b.
CBr4, PPh3, CH2Cl2, 0 °C, 92%. c. n-BuLi, THF, -78 °C to rt, 90%,
d. Pd(PPh3)2Cl2, CuI, PhI, Et3N, rt, 88%.
results in a transformation such as C (6 f 7) with control
of the stereochemistry of the resulting double bond and
stereoselectively creating a new stereocenter at the
former lithium-bearing carbon atom.
Herein, we wish to report our comprehensive studies
toward the stereoselective carbolithiation (C) of several
terminally substituted 5-hexynyl carbamates.7
Resu lts a n d Discu ssion
P h en yl-Su bstitu ted Alk yn es. The requisite 6-phen-
yl-5-hexynyl carbamate 6 was prepared by following the
reaction sequence summarized in Scheme 2.
(15) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470.
(16) The (E)-configuration of the double bond was assigned by a
nuclear Overhauser effect of the vinylic proton and the proton at the
carbon bearing the carbamate group.
(17) (a) Oestreich, M. Dissertation, Universita¨t Mu¨nster, 1999. (b)
Further functionalization of the alkylidene cyclopentanes in the vinylic
position was representatively demonstrated for the stannylation of the
intermediate vinylic lithium species.
(18) Meyer, C.; Marek, I.; Normant, J . F.; Platzer, N. Tetrahedron
Lett. 1994, 35, 5645-5648.
A Swern oxidation12a of the alkanol 813 gave the
aldehyde 9 which was then transformed into the terminal
alkyne 10 by the Corey-Fuchs formyl ethynyl conver-
sion.14 After the cross-coupling of 10 with iodobenzene
following the Sonogashira protocol15 the cyclization pre-
cursor 6 was isolated in an overall yield of 64%.
(12) (a) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482. (b) For an excellent review on the synthesis and
reactions of N,N-dibenzylamino aldehydes, see: Reetz, M. T. Chem.
Rev. 1999, 99, 1121-1162.
(19) (a) Guarnieri, W.; Grehl, M.; Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1734-1737. (b) Guarnieri, W.; Sendzik, M.; Fro¨hlich,
R.; Hoppe. D. Synthesis 1998, 1274-1286. (c) Sendzik, M.; Guarnieri,
W.; Hoppe, D. Synthesis 1998, 1287-1297. See also: (d) Gmeiner, P.;
J unge, D.; Ka¨rtner, A. J . Org. Chem. 1994, 59, 6766-6776.
(20) For the Corey-Fuchs transformation of R-chiral aldehydes,
see: Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T.
K.; Minowa, N.; Koide, K. Chem. Eur. J . 1995, 1, 318-333.
(13) (a) Ahrens, H. Dissertation, Universita¨t Mu¨nster, 1994. (b)
Paetow, M.; Ahrens, H.; Hoppe, D. Tetrahedron Lett. 1992, 33, 5323-
5326.
(14) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.

8618 J . Org. Chem., Vol. 64, No. 23, 1999
Oestreich and Hoppe
Sch em e 3a
Ta ble 1. Ster eoselective Cycliza tion of 4-Su bstitu ted
6-P h en yl-5-h exyn yl Ca r ba m a tes
entry alkyne
era
carbocycleb,16
drc
yieldd/%
1
2
3
4
5
(S)-12
>99:1 cis-18
>99:1
95:5
5:95
50:50
95:5
50:50
50:50
70
88
99
80e
82
96
89
(S)-13a
(R)-13a
rac-13a
(S)-13b
rac-13b
(S)-13b
95:5 cis-19a
5:95 trans-19a
50:50 cis-/trans-19a
95:5 cis-19b
50:50 cis-/trans-19b
95:5 cis-/ent-trans-19b
6
7f
a
The er was determined from the 1H NMR and 19F NMR
b
a
spectra of the Mosher esters (except for compound (S)-12). Each
reagents. a. (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 90%. b.
diastereomer is enantiopure. c The dr (cis:trans ratio) was deter-
CBr4, PPh3, CH2Cl2, 0 °C 69%. c. n-BuLi, THF, -78 °C to rt, 93%.
d. Pd(PPh3)2Cl2, CuI, PhI, Et3N, rt, 94%. e. TBAF, Et2O, THF, rt,
94%. f. CbyCl, NaH, THF, reflux, 64%.
mined from the 1H NMR spectra of the crude products. Isolated
d
yield of analytically pure product. e Mixture of rac-13a and cis-/
trans-19a (20:80). f In this case TMEDA (20) was used instead of
(-)-sparteine (1); the diastereomers cis-19b (1R,3S) and ent-trans-
19b (1S,3S) are both formed with enantiomeric ratios of 95:5.
Sch em e 4a
ing the cyclization precursors 13a ,b in overall yields of
21-48% for 13a and 48-88% for 13b.
Using the standard conditions, to a solution of the
4-(dibenzylamino)-6-phenyl-5-hexynyl carbamate (S)-12
in Et2O, the chiral base s-BuLi/1 was added at -78 °C
(step a); then the reaction mixture was allowed to stir
for 20 h at this temperature followed by quenching with
methanol (step b). The purification, surprisingly, afforded
the desired alkylidene cyclopentane cis-18 in diastereo-
merically pure16 form as a single product in 70% yield
(eq 2, Table 1, entry 1).
a
reagents. a. (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 89%. b.
n-BuLi, phenylacetylene, THF, -78 °C to -18 °C, 99%. c. PCC,
sodium acetate, CH2Cl2, rt, 69%. d. (S)-Alpine borane, rt, 85% or
(R)-Alpine borane, rt, 77%. e. PG ) Tr: TrCl, Et3N, DMAP,
CH2Cl2, reflux, rac: 54%, (S): 45%, (R): 46%. PG ) TBDPS:
TBDPSCl, Et3N, DMAP, CH2Cl2, reflux, rac: 100%, (S): 94%.
lated21 and subsequently reacted with CbyCl22 furnishing
the desired enantiopure cyclization precursor (S)-12 in
33% overall yield from (S)-14.
The racemic and enantiomerically enriched 4-hydroxy-
6-phenyl-5-hexynyl carbamates 13 were prepared within
a straightforward synthesis as outlined in Scheme 4.
The Swern oxidation12a of the alkanol 1613 provided the
corresponding aldehyde which was quantitatively alkyn-
ylated with n-BuLi/phenylacetylene. After the oxidation
of the resulting propargylic alkanol rac-17 with PCC the
intermediate R,â-ynone was reduced with (S)- or (R)-
Alpine-borane,23 respectively, furnishing the alkanols (S)-
17 and (R)-17, respectively, in enantiomeric ratios of 95:5
and 5:95.24 The absolute configuration of the propargylic
alcohols 17 can be predicted by a model in which a six-
membered transition state exhibits a boatlike conforma-
tion;25 (S)-Alpine-borane provides the (S)-configured al-
kanol and vice versa in any known case if the alkynyl
group is of higher priority than the alkyl group.26 The
tritylation27 (PG ) Tr) or silylation (PG ) TBDMS) of
the all three alkanols 17 completed the syntheses provid-
This promising result prompted us to investigate the
(S)-configured 4-alkoxy- (S)-13a and 4-siloxy-6-phenyl-
5-hexynyl carbamate (S)-13b which upon treatment with
s-BuLi/1 in Et2O also cyclized smoothly (Scheme 5, Table
1, entries 2 and 5).
The diastereomeric ratio (cis:trans ) 95:5) of the
functionalized cyclopentanes cis-19a and cis-19b directly
corresponded to the enantiomeric ratio (er ) 95:5) of each
individual cyclization precursor (S)-13. The relative
configuration of the carbocycles derived from (S)-config-
ured alkynes was determined on the basis of a crystal
structure analysis of cis-19a (Figure 1).28 The (1R)-
configuration at the former lithium-bearing carbon atom
coincides with our observations that carbamates of type
2 (Scheme 1) are deprotonated by chiral base s-BuLi/1
with high preference for the pro-S-proton and the result-
ing lithium-carbanion pairs are substituted by electro-
philes with retention of the configuration.5,8a-c
These instructive experiments (Table 1, entries 1, 2,
and 5) obviously confirm that the deprotonation of
(21) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
(22) Hintze, F.; Hoppe, D. Synthesis 1992, 1216-1218.
(23) For a representative procedure, see: Brown, H. C.; Pai, G. G.
J . Org. Chem. 1985, 50, 1384-1394.
(28) X-ray crystal structure analysis of cis-19a : formula C39H41NO4,
M ) 587.73, 0.2 × 0.1 × 0.1 mm, a ) 8.837(1) Å, b ) 15.141(2) Å, c )
(24) The enantiomeric ratios were determined by Mosher ester
analysis: Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543-2549.
24.831(3) Å, V ) 3322.4(7) Å3, Fcalc ) 1.175 g cm-3, µ ) 5.93 cm-1
,
empirical absorption correction via ψ-scan data (0.950 e C e 0.999),
Z ) 4, orthorhombic, space group P212121 (No. 19), λ ) 1.541 78 Å, T
) 223 K, ω/2θ scans, 3795 reflections collected (+h,-k,+l), [(sin θ)/λ]
) 0.62 Å-1, 3795 independent and 1737 observed reflections [I g 2σ-
(I)], 402 refined parameters, R ) 0.050, wR2 ) 0.103, maximum
residual electron density 0.19 (-0.18) e Å-3, Flack parameter 1.0(5),
hydrogens calculated and riding (structure was already published in
ref 7). See also ref 35.
(25) Midland, M. M.; McLoughlin, J . I.; Gabriel, J . J . Org. Chem.
1984, 49, 1316-1317.
(26) For a review, see: Midland, M. M. Chem. Rev. 1989, 89, 1553-
1561.
(27) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20,
95-98.

(-)-Sparteine-Mediated Carbolithiation
J . Org. Chem., Vol. 64, No. 23, 1999 8619
Sch em e 5a
Sch em e 6a
a
reagents. a. (TMSOCH2)2, TMSOTf, CH2Cl2, -78 °C, 31%. b.
s-BuLi/1, Et2O, -78 °C. c. MeOH, -78 °C to rt.
conditions furnishing the trans-substituted cyclopentane
trans-19a in quantitative yield (Scheme 5, Table 1, entry
3). Thus, the chiral base s-BuLi/1 selectively abstracts
the pro-S-proton independent of the configuration of the
propargylic stereocenter. The racemic precursors rac-13a
and rac-13b were also treated with s-BuLi/1 in Et2O for
several hours at -78 °C. The NMR analysis of the crude
products exhibited a mixture of the diastereomeric car-
bocycles cis-/trans-19a or cis-/trans-19b in cis:trans ratios
of 50:50 even when the cyclization had not been com-
pleted yet (Scheme 5, Table 1, entries 4 and 6). The fact
that the er of the starting material is in full agreement
with the dr of the cyclization product certifies that there
is no kinetic resolution of the enantiomeric alkynes
operating.
a
reagents. a. s-BuLi/1, Et2O, -78 °C. b. MeOH, -78 °C to rt.
Ligands (1 and Et2O) at the lithium center are omitted for the
The effect of the existing stereogenic center on the
stereochemical course of the deprotonation step was
checked in a simple experiment by replacing (-)-
sparteine (1) by the achiral ligand TMEDA (20) within
the cyclization of the enantioenriched carbamate (S)-13b.
Since the ring closure yielded a 50:50 mixture of cis-/ent-
trans-19b, epimers at the former lithium-bearing carbon
atom, the deprotonation of (S)-13b proceeded completely
unselectively indicating that the formation of the new
stereocenter is not influenced by the existing one (Table
1, entry 7).17
sake of clearness.
Another more evident strategy to suppress propargylic
deprotonation is the introduction of two substituents at
C-4. The dioxolane 22 was chosen as a model system and
was prepared in one step from the R,â-ynone 21 previ-
ously described in Scheme 4. Quite a number of ketal-
izations failed because of the lability of the aminoacetal
moiety in the Cby group until Noyori’s method31 gave 22
in 31% yield (Scheme 6).
Upon treatment of the carbamate 22 with s-BuLi in
the presence of 1 no ring closure was observed. Instead
of isolation of the expected cyclopentane derivative 23
after methanolysis only the starting material 22 was
detected in the 1H NMR spectra of the crude reaction
mixture. The intermediacy of the stable tricyclic chelate
24 appears to be very likely since such interactions had
been reported by us for similar systems.32 The intra-
molecular coordination of the lithium center by three
oxygens delineates a thermodynamic sink preventing
the precomplexation of the lithium to the triple bond
(Scheme 6).
F igu r e 1. Crystal structure of cis-19a .
propargylic hydrogens is entirely suppressed by the
introduction of a bulky substituent in this position and
the use of a sterically demanding base. Nevertheless,
since solely (S)-configured precursors were cyclized in the
presence of (-)-sparteine (1), two questions arise con-
cerning the influence of the existing stereocenter in the
alkyne: (a) Can a racemic alkyne be kinetically resolved
in the presence of 1?5b,c,29 (b) Can a stereoselective
deprotonation be internally induced by the propargylic
stereocenter using the achiral base s-BuLi/TMEDA
(s-BuLi/20)?19a,30
The cyclization of the (R)-configured alkyne (R)-13a
itself was accomplished under the standard reaction
(29) For kinetic resolutions using the s-BuLi/1 reagent, see also: (a)
Haller, J .; Hense, T.; Hoppe, D. Synlett 1993, 726-728. (b) Hense, T.;
Hoppe, D. Synthesis 1997, 1394-1398.
(30) See for example: Schwerdtfeger, J .; Hoppe, D. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1505-1507.
(31) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357-1358.
(32) An dioxolane ring acting as a chelating group during carbamate
lithiation has been described before: Helmke, H.; Hoppe, D. Synlett
1995, 978-980.

8620 J . Org. Chem., Vol. 64, No. 23, 1999
Oestreich and Hoppe
Sch em e 7a
Sch em e 9a
a
reagents. a. TrCl, Et3N, CH2Cl2, rt, 100%. b. TBAF, Et2O, THF,
rt, 100%. c. CbyCl, NaH, THF, reflux, 87%. d. TFA, MeOH/CH2Cl2
(1:1), 0 °C to rt, 78%. e. (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C,
96%, f. CBr4, PPh3, CH2Cl2, 0 °C, 93%. g. n-BuLi, THF, -78 °C
then TMSCl, -78 °C to rt, 83%.
Sch em e 8a
a
reagents. a. s-BuLi/1, Et2O, -78 °c. b. MeOH, -78 °C to rt.
Ligands (1 and Et2O) at the lithium center are omitted for the
sake of clearness.
a
reagents. a. (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 89%. b.
n-BuLi, trimethylsilylacetylene, THF, -78 °C to -18 °C, 96%. c.
PCC, sodium acetate, CH2Cl2, rt, 82%. d. (S)-Alpine borane, rt,
96%. e. TBDPSCl, Et3N, DMAP, CH2Cl2, reflux 94%.
Tr im eth ylsilyl-Su bstitu ted Alk yn es. The activation
of alkynes toward nucleophilic attack by terminal sub-
stituents can also be achieved by the introduction of a
trimethylsilyl group10b,d since carbanionic centers are
stabilized by R-silyl groups.33 Therefore we synthesized
the carbamates (S)-25 and (S)-26sagain with the es-
sential propargylic substituentscorresponding to (S)-12
and (S)-13b, respectively.
The synthesis of the 4-amino-6-(trimethylsilyl)-5-hexy-
nyl carbamate (S)-25 starting from the enantiopure
alkanol (S)-1419 is summarized in Scheme 7. After
standard protecting group manipulations19c the alkanol
(S)-27 was isolated in 68% overall yield.34 The trimeth-
ylsilyl-substituted alkyne moitey was again constructed
by applying the reaction sequence of Swern oxidation12
and a slightly modified Corey-Fuchs conversion14 to (S)-
27. The cyclization precursor (S)-25 was isolated after
seven steps from (S)-14 in an overall yield of 52%.
The 4-hydroxy-6-(trimethylsilyl)-5-hexynyl carbamate
(S)-26 was prepared in analogy to the phenyl-substituted
derivative (S)-13b (see Scheme 4) from 1613 by following
the procedure depicted in Scheme 8. The (S)-Alpine-
borane23 reduction gave the (S)-28 in an enantiomeric
ratio of 96:4.24
F igu r e 2. Crystal structure of cis-30.
mixture by TLC surprisingly indicated a major product
of significantly higher polarity than the starting material
(S)-25 whereas in the case of the phenyl-substituted
alkynes the cyclization precursor and product were of
similar polarity and difficult to separate. The purification
by flash chromatography then furnished cis-30 in 70%
yield along with 10% of (S)-25 (Scheme 9). The constitu-
tion of cis-30 was assigned on the basis of a single-crystal
structure analysis (Figure 2).35 Furthermore, the absolute
configuration was determined as [2(2R),2(5S)], which is
in agreement with the fact that the cyclization precursor
is derived from (S)-glutamic acid and the observation that
the (1S)-configured lithium-carbanion pair inserts the
triple bond with retention of the configuration.
The carbocycle cis-30 is the outcome of a domino-
cyclization/rearrangement sequence36 in which the in-
termediate vinylic lithium species cis-29 is intramolec-
ularly captured by the carbamic ester group (OCby). The
intramolecular carbolithiation of the trimethylsilyl-
substituted triple bond proceeded highly regioselectively
in a syn-fashion providing the vinylic lithium compound
cis-29. The (1-silyl-1-alkenyl)lithium cis-29 seems to be
more reactive than the corresponding phenyl-substituted
derivative and therefore attacks the carbonyl carbon
atom in the proximity of the carbon-lithium bond giving
a lithium alcoholate and, finally, the fully substituted
acrylamide cis-30.
The cyclization experiment of (S)-25 was conducted
under the standard conditions (s-BuLi/1, Et2O, -78 °C,
several hours), but the analysis of the crude reaction
(33) (a) Sakurai, H. Organosilicon and Bioorganosilicon Chemistry:
Structure, Bonding, Reactivity, and Synthetic Applications; Halsted:
New York, 1985. (b) Weber, W. P. Silicon Reagents for Organic
Synthesis; Springer-Verlag: Berlin, 1983.
(34) Unfortunately, this lengthy sequence is required since the direct
carbamoylation of (S)-2-(N,N-dibenzylamino)-1,5-pentanediol with
CbyCl22 provided a 1:1 mixture of (S)-27 and its regioisomer. After a
difficult separation of the regioisomers by flash chromatography (S)-
27 was isolated in 29% yield.
To prove whether this domino-cyclization/rearrange-
ment sequence is a general reaction of trimethylsilyl-
substituted alkynes we investigated the 4-hydroxy-6-
(trimethylsilyl)-5-hexynyl carbamate (S)-26. Upon treat-
ment with s-BuLi/1 in Et2O at -78 °C the precursor (S)-

(-)-Sparteine-Mediated Carbolithiation
J . Org. Chem., Vol. 64, No. 23, 1999 8621
Sch em e 10a
Sch em e 11a
a
reagents. a. (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 89%. b.
n-BuLi, 3,3-dimethyl-1-butyne, THF, -78 °C to -18 °C to -18 °C,
100%. c. TBDPSCl, Et3N, DMAP, CH2Cl2, reflux, 88%. d. s-BuLi/
1, Et2O, -78 °C. e. MeOH, -78 °C to rt.
that a terminal phenyl or trimethylsilyl substituent
accelerates the insertion of a carbon-carbon triple bond
into a carbon-lithium bond.10 In contrast, the activity
of alkynes bearing an alkyl group in the terminal position
toward nucleophilic attack is significantly lowered al-
though Bailey has reported the cyclization of a n-butyl-
substituted alkyne.10a,d The possibilty of 1,3-allylic strain40
in the cyclization products has not been considered for
the ring closures of the tert-butyl- as well as phenyl- and
trimethylsilyl-substituted alkynes since we think that
this steric effect plays a minor role in these processes.
The racemic cyclization precursor rac-35, easily pre-
pared from alkanol 16 by our standard reaction sequence
in 78% overall yield, could not be cyclized in the presence
of the chiral base s-BuLi/1 in Et2O at -78 °C (Scheme
11); rac-35 was reisolated in 91% yield.
a
reagents. a. s-BuLi/1, Et2O, -78 °C. b. MeOH, -78 °C to rt.
Ligands (1 and Et2O) at the lithium center are omitted for the
sake of clearness.
26 in fact cyclizes and rearranges in the predicted
manner as illustrated in Scheme 10.
But the carbocycle cis-33 which is the primary product
of the domino reaction was contaminated with a further
cyclization product which was identified as the regioiso-
1
mer cis-34 from the H NMR spectra. The formation of
cis-34 is due to a O to O-[1,5] silyl shift of the TBDPS
ether having a lithium alcoholate in its proximity. The
capability of silyl groups of type SiR3 to undergo anionic
migrations in dependence on the steric demand of the
group Rsthe larger R, the more unlikely is the shift of
SiR3shas been extensively discussed, and examples of
migrating TBDPS groups are scarce.37 We think that the
ease of this [1,5]-shift can be attributed to the steric
situation in the cis-1,3-substituted carbocycles cis-31 and
cis-32.38 The resulting products cis-33 and cis-34 were
isolated in a ratio of 80:20 in 50% yield.39
Con clu sion
In summary, we have reported the first stereoselective
carbolithiiation of alkynes with external chiral induction
on the basis of the fusion of the concepts of the asym-
metric deprotonation8 (A) and the intramolecular carbo-
lithiation9,10 (B). Our studies show that the success of the
cyclization is strongly dependent on two essential supple-
mentary features in order to avoid propargylic deproto-
nation: a sterically demanding substituent in the prop-
argylic position and the use of a large base. The
4-substituted 5-hexynyl carbamates undergo the ring
closure highly regioselectively (5-exo-dig exclusively),
diastereoselectively as the double bond is concerned (syn-
addition of the lithium-carbanion pair to the triple bond),
and diastereoselectively with respect to the newly formed
stereocenter (retention of the configuration at the former
lithium-bearing carbon atom). Terminal substituents
such as a phenyl or trimethylsilyl group facilitate the
insertion of the carbon-carbon triple bond into the
carbon-lithium bond whereas a tert-butyl-substituted
alkyne is too electron-rich for being nucleophilically
attacked under our reaction conditions. Moreover, the
intermediate (1-(trimethylsilyl)-1-alkenyl)lithium and (1-
phenyl-1-alkenyl)lithium species, respectively, are of
different reactivity with the further being more reactive
and quantitatively intramolecularly captured by the
carbamate.
ter t-Bu tyl-Su bstitu ted Alk yn es. The above-men-
tioned studies are compatible with previous observations
(35) X-ray crystal structure analysis of cis-30: formula C31H44N2O3-
Si, M ) 520.77, 0.6 × 0.5 × 0.3 mm, a ) 10.259(1) Å, b ) 13.099(1) Å,
c ) 23.465(2) Å, V ) 3153.3(5) Å3, Fcalc ) 1.097 g cm-3, µ ) 8.94 cm-1
,
empirical absorption correction via ψ-scan data (0.969 e C e 0.999),
Z ) 4, orthorhombic, space group P212121 (No. 19), λ ) 1.541 78 Å, T
) 223 K, ω/2θ scans, 6394 reflections collected (-h,+k,(l), [(sin θ)/λ]
) 0.62 Å-1, 6004 independent and 5689 observed reflections [I g 2σ-
(I)], 373 refined parameters, R ) 0.038, wR2 ) 0.106, max. residual
electron density 0.17 (-0.17) e Å-3, Flack parameter 0.01(2), disorder
(51%:49%) around C15 (C14 and C151), hydrogens calculated and
riding. The data set was collected with an Enraf Nonius CAD4
diffractometer. Programs used: data acquisation EXPRESS; data
reduction MolEN; structure solution SHELXS-86; structure refinement
SHELXL-93 and SHELXL-97; graphics DIAMOND.
(36) For domino reactions, see: Tietze, L. F. Chem. Rev. 1996, 96,
115-136.
(37) Colvin, E. W. Silicon in Organic Synthesis; Butterworth:
London, 1981.
(38) The migration of a TBDPS group in a cis-1,3-cyclopentanediol
system has already been observed: Torisawa, Y.; Shibasaki, M.;
Ikegami, S. Chem. Pharm. Bull. 1983, 31, 2607-2615. We thank one
of the reviewers for drawing our attention to this reference.
(39) Another byproduct which was void of the trimethylsilyl group,
compared to cis-34, was isolated in small quantities. The loss of the
trimethylsilyl group may be due to the fact the lithium-oxygen bond
in cis-32 is in the proximity of two silyl groups. A O to O-[1, 5]-shift
regenerates the primary product cis-31, and a C to O-[1, 4]-shift of
the trimethylsilyl group leads to the C-desilylated product after
aqueous workup. For an example of such a migration, see eq 2 in:
Lautens, M.; Delanghe, P. H. M.; Goh, J . B.; Zhang, C. H. J . Org. Chem.
1992, 57, 3270-3272.
This novel method allows the stereoselective synthesis
of enantiopure functionalized alkylidene cyclopentanes
in good to excellent yields and selectivities.
(40) For a comprehensive review on 1,3-allylic strain, see: Hoff-
mann. R. W. Chem. Rev. 1989, 89, 1841-1860.

8622 J . Org. Chem., Vol. 64, No. 23, 1999
Oestreich and Hoppe
as a colorless liquid. IR (neat, cm-1): 1696 (CdO, s). 1H NMR
(CDCl3, 300 MHz): δ 7.43-7.36 (m, 2H), 7.29-7.25 (m, 3H),
4.17 (t, J ) 6.2 Hz, 2H), 3.74 (s, 2H), 2.49 (t, J ) 6.8 Hz, 2H),
1.93-1.81 (m, 2H), 1.80-1.67 (m, 2H), 1.58/1.56/1.44/1.40 (4s,
12H). 13C NMR (CDCl3, 75.5 MHz): δ 152.8/152.1, 131.5, 128.1,
127.5, 123.8, 95.8/94.8, 89.4, 81.0, 76.6/76.3, 64.0, 60.5/59.6,
28.2, 25.5, 26.6/25.3/24.1, 19.1. MS (EI): m/z 329 [M+, 18%].
Anal. Calcd for C20H27NO3: C, 72.92; H, 8.26; N, 4.25. Found:
C, 72.77; H, 8.25; N, 4.51.
Exp er im en ta l Section
Gen er a l Meth od s.5c The doubling of some signals in the
NMR spectra occurs as a result of the E/Z isomerism of the
carbamate group; these signals are separated by slashes. (-)-
Sparteine (1) is commercially available (Aldrich or Sigma) and
was stored under argon; TMEDA (20) was distilled from CaH2
and kept under argon. s-BuLi was received as a 1.4 M solution
in cyclohexane/n-hexane (92:8) from Fluka and n-BuLi as a
1.6 M solution in n-hexane from Acros; both were titrated
before use.41
Typ ica l P r oced u r e for th e Ster eoselective Cycloca r -
bolith ia tion of Alk yn es. (-)-[1R,2(1E)]-2-Ben zylid en ecy-
clop en tyl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-ca r box-
yla te (7). To a solution of 6 (0.300 g, 0.91 mmol) and 1 (0.320
g, 1.37 mmol, 1.5 equiv) in Et2O (8 mL) was added s-BuLi (1.09
mL, 1.37 mmol, 1.5 equiv, 1.34 M) at -78 °C. This solution
was stirred for 18 h at -78 °C, and after methanolysis (2.5
mL) at -78 °C the reaction mixture was brought to ambient
temperature. The organic phase was washed with H2O and
dried (MgSO4). The solvent was removed under reduced
pressure, and the purification of the residue by flash chroma-
tography (1:9 Et2O-hexanes; TLC, Rf ) 0.56 in 1:1 Et2O-
hexanes) afforded 7 (0.035 g, 12%) as a white solid.42 Mp )
Typ ica l P r oced u r e for th e Cor ey-F u ch s F or m yl Eth y-
n yl Con ver sion .14 5-Hexyn yl 2,2,4,4-Tetr a m eth yl-1,3-ox-
a zolid in e-3-ca r boxyla te (10). Step A. After cooling of a
solution of tetrabromomethane (5.23 g, 15.8 mmol, 2.0 equiv)
and triphenylphosphine (8.28 g, 31.6 mmol, 4.0 equiv) in CH2-
Cl2 (80 mL) to 0 °C, the aldehyde 9 (2.03 g, 7.89 mmol),
dissolved in CH2Cl2 (20 mL), was slowly added. The reaction
was monitored by TLC and quenched with H2O (10 mL) after
complete conversion of 9 (1 h). The organic layer was sepa-
rated, the aqueous phase extracted twice with CH2Cl2, and
the combined organic phases were dried over MgSO4. The
solvent was evaporated under reduced pressure and the crude
product, dissolved in a small volume of CH2Cl2, purified by
flash chromatography (1:1 Et2O-hexanes; TLC, Rf ) 0.53)
furnishing 6,6-dibromo-5-hexenyl 2,2,4,4-tetramethyl-1,3-ox-
azolidine-3-carboxylate (36) (3.00 g, 92%) as a colorless liquid.
87-88 °C. [R]20 ) -21.6 (c ) 0.45). IR (KBr, cm-1): 1685
D
1
(CdO, s). H NMR (CDCl3, 300 MHz): δ 7.30-7.17 (m, 5H),
6.67 (s, 1H), 5.67-5.62 (m, 1H), 3.72 (s, 2H), 2.80-2.66 (m,
1H), 2.65-2.51 (m, 1H), 2.00-1.80 (m, 4H), 1.59/1.51/1.45/1.35
(4s, 12H). 13C NMR (CDCl3, 75.5 MHz): δ 152.7/151.9, 143.3,
137.8, 128.3, 126.7, 126.2, 95.8/94.9, 79.1, 76.4/76.1, 60.6/59.7,
32.4, 29.6, 26.8/25.4/24.3, 23.6. MS (EI): m/z 329 [M+, 15%].
Anal. Calcd for C20H27NO3: C, 72.92; H, 8.26; N, 4.25. Found:
C, 72.92; H, 8.27; N, 4.21.
1
IR (neat, cm-1): 1695 (CdO, s). H NMR (CDCl3, 300 MHz):
δ 6.37 (t, J ) 7.4 Hz, 1H), 4.07 (t, J ) 6.4 Hz, 2H), 3.70 (s,
2H), 2.12 (ψ-q, J ) 7.4 Hz, 2H), 1.74-1.58 (m, 2H), 1.57-1.45
(2s, m, 8H), 1.39/1.34 (2s, 6H). 13C NMR (CDCl3, 90 MHz): δ
152.7/152.0, 138.0, 95.8/94.7, 89.3, 76.3/76.1, 63.9, 60.5/59.6,
32.5, 28.4, 24.5, 26.5/25.3/24.1. MS (EI): m/z 398 [(M - CH3)+,
100%]. Anal. Calcd for C14H23NO3Br2: C, 40.70; H, 5.61; N,
3.39. Found: C, 40.37; H, 5.66; N, 3.58.
Typ ica l P r oced u r e for th e Sw er n Oxid a tion .12a (-)-(S)-
5-(ter t-Bu tyld im eth ylsilyloxy)-2-(N,N-d iben zyla m in o)-1-
p en ta n a l ((S)-37). A solution of oxalyl chloride (0.368 g, 2.90
mmol, 1.2 equiv) in CH2Cl2 (10 mL) was cooled to -78 °C and
subsequently treated with a solution of DMSO (0.453 g, 5.80
mmol, 2.4 equiv) in CH2Cl2 (5 mL) and a solution of (S)-1419
(1.000 g, 2.42 mmol) in CH2Cl2 (10 mL). The temperature of
the reaction mixture was kept at -78 °C and stirred for 15
min after each addition. To this reaction mixture Et3N (1.223
g, 12.1 mmol, 5.0 equiv) was slowly injected. The reaction
mixture was stirred for further 30 min at -78 °C and after
removal of the cooling bath for another 30 min at room
temperature. The resulting white suspension was poured into
H2O (50 mL), and the organic layer was separated and washed
with H2O. The aqueous phase was extracted with CH2Cl2, and
the combined organic phases were dried (MgSO4). The solvents
were evaporated in vacuo, and the residue was purified by
flash chromatography (3:7 Et2O-hexanes; TLC, Rf ) 0.65)
Step B. At -78 °C, n-BuLi (3.0 mL, 4.84 mmol, 2.0 equiv,
1.6 M) was added dropwise to a solution of 36 (1.000 g, 2.42
mmol) in THF (35 mL). The solution was stirred for 1 h at
-78 °C and was then allowed to warm to ambient temperature.
After a further 90 min at this temperature the reaction
mixture was first quenched with methanol (3 mL) and
afterward hydrolyzed with H2O (5 mL). The organic layer was
separated, the aqueous phase was extracted with Et2O, and
the combined organic phases were dried with Na2SO4. After
evaporation of the solvents in vacuo the crude product was
purified by flash chromatography (1:9 Et2O-hexanes; TLC,
Rf ) 0.27) yielding 10 (0.550 g, 90%) as a colorless liquid. IR
(neat, cm-1): 3306 (tC-H, m), 2110 (CtC, w), 1701 (CdO,
s). 1H NMR (CDCl3, 300 MHz): δ 4.08 (t, J ) 6.3 Hz, 2H),
3.69 (s, 2H), 2.21 (dt, J ) 6.9 Hz, J ) 2.6 Hz, 2H), 1.92 (t, J )
2.6 Hz, 1H), 1.81-1.71 (m, 2H), 1.66-1.53 (m, 2H), 1.52/1.49/
1.39/1.33 (4s, 12H). 13C NMR (CDCl3, 90 MHz): δ 152.7/152.0,
95.7/94.7, 83.8, 76.2/76.0, 68.6, 63.9, 60.5/59.6, 28.2, 25.2, 26.5/
25.3/25.1/24.1, 18.0. MS (EI): m/z 238 [(M - CH3)+, 100%].
Anal. Calcd for C14H23NO3: C, 66.37; H, 9.15; N, 5.53. Found:
C, 66.28; H, 9.24; N, 5.67.
Typ ica l P r oced u r e for th e Son oga sh ir a Cou p lin g.15
6-P h en yl-5-h exyn yl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-
3-ca r boxyla te (6). A mixture of copper(I) iodide (1.3 mg, 6.91
µmol) and bis(triphenylphosphine)palladium(II) dichloride (9.7
mg, 13.8 µmol) was suspended in a solution of 10 (0.350 g,
1.38 mmol) and iodobenzene (0.282 g, 1.38 mmol, 1.0 equiv)
in Et3N (9 mL) at ambient temperature. The reaction mixture
was stirred for 6 h at this temperature before the addition of
1 M HCl (25 mL). The organic layer was separated, and the
aqueous phase was extracted with Et2O several times. The
combined organic phases were washed with H2O and dried
with Na2SO4. After removal of the solvents under reduced
pressure the crude product was purified by flash chromatog-
raphy (1:2 Et2O-hexanes; TLC, Rf ) 0.54 in 1:1 Et2O-
hexanes) furnishing the cross-coupled product 6 (0.400 g, 88%)
furnishing (S)-37 (0.901 g, 90%) as a colorless liquid. [R]20
)
D
-35.8 (c ) 1.57). IR (neat, cm-1): 1729 (CdO, s). 1H NMR
(CDCl3, 300 MHz): δ 9.69 (s, 1H), 7.35-7.17 (m, 10H), 3.77
(d, J ) 13.8 Hz, 2H), 3.69 (d, J ) 13.8 Hz, 2H), 3.64-3.40 (m,
2H), 3.14 (ψ-t, J ) 6.5 Hz, 1H), 1.82-1.65 (m, 2H), 1.58-1.49
(m, 2H), 0.87 (s, 9H), 0.01 (s, 6H). 13C NMR (CDCl3, 75.5
MHz): δ 203.6, 139.2, 128.8, 128.3, 127.2, 66.6, 62.5, 54.8, 30.1,
25.9, 20.5, 18.3, -5.3. MS (EI): m/z 411 [M+, 1%]. Anal. Calcd
for C25H37NO2Si: C, 72.94; H, 9.06; N, 3.40. Found: C, 72.79;
H, 8.89; N, 3.66.
(-)-(S)-6-(ter t-Bu tyld im eth ylsilyloxy)-3-(N,N-d iben zyl-
a m in o)-1-h exyn e ((S)-39). Step A. According to the typical
procedure for the Corey-Fuchs formyl ethynyl conversion, (S)-
37 (1.66 g, 4.03 mmol) was transformed into (+)-(S)-1,1-
dibromo-6-(tert-butyldimethylsilyloxy)-3-(N,N-dibenzylamino)-
1-hexene ((S)-38) with tetrabromomethane (2.67 g, 8.07 mmol,
2.0 equiv) and triphenylphosphine (4.23 g, 16.1 mmol, 4.0
equiv) in CH2Cl2 (40 mL). The crude product was purified by
flash chromatography (1:1 Et2O-hexanes; TLC, Rf ) 0.76)
yielding (S)-38 (1.58 g, 69%) as a colorless liquid. [R]20D ) +9.0
(42) The cyclization precursor 6 was reisolated in a 67:33 mixture
with the allene 11. The characteristic NMR data of 11 are as follows:
1H NMR (CDCl3, 300 MHz) δ 6.00 (ψ-quint, J ) 6.0 Hz, J ) 3.1 Hz,
1H), 5.43 (ψ-quart, J ) 6.8 Hz, J ) 6.0 Hz, 1H); 13C NMR (CDCl3,
75.5 MHz) δ 205.3, 95.8, 93.9.
(41) (a) Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503-
2506. (b) Kofron, W. G.; Baclawski, L. M. J . Org. Chem. 1976, 41,
1871-1880.

(-)-Sparteine-Mediated Carbolithiation
J . Org. Chem., Vol. 64, No. 23, 1999 8623
(c ) 1.09). 1H NMR (CDCl3, 300 MHz): δ 7.37-7.14 (m, 10H),
6.53 (d, J ) 9.5 Hz, 1H), 3.83 (d, J ) 13.8 Hz, 2H), 3.58-3.44
(m, 2H), 3.37 (d, J ) 13.8 Hz, 2H), 3.41-3.36 (m, 1H), 1.80-
12 (0.145 g, 64%) as a colorless liquid. [R]20D ) -191 (c ) 0.58).
1
IR (neat, cm-1): 1701 (CdO, s). H NMR (CDCl3, 300 MHz):
δ 7.52-7.15 (m, 15H), 4.06-3.99 (m, 2H), 3.89 (d, J ) 13.8
Hz, 2H), 3.70 (s, 2H), 3.51 (d, J ) 13.8 Hz, 2H), 3.40 (ψ-t, J )
7.3 Hz, 1H), 1.97-1.61 (m, 4H), 1.54/1.48/1.40/1.32 (4s, 12H).
13C NMR (CDCl3, 75.5 MHz): δ 152.8/152.0, 139.6, 131.8,
128.8, 128.3, 128.0, 126.9, 95.8/94.8, 87.3, 85.6, 76.3/76.1, 64.1,
60.5/59.6, 55.0, 52.1, 30.7, 26.2, 26.6/25.3/24.1. MS (EI): m/z
524 [M+, 24%]. Anal. Calcd for C34H40N2O3: C, 77.83; H, 7.68;
N, 5.34. Found: C, 77.65; H, 7.58; N, 5.33.
1.61 (m, 2H), 1.58-1.40 (m, 2H), 0.86 (s, 9H), 0.00 (s, 6H). 13
C
NMR (CDCl3, 75.5 MHz): δ 139.6, 137.9, 128.7, 128.1, 126.9,
90.0, 65.8, 61.4, 54.2, 29.3, 28.3, 26.0, 18.3, -5.3. MS (EI): m/z
567 [M+, 1%]. Anal. Calcd for C26H37NOSiBr2: C, 55.03; H,
6.57; N, 2.47. Found: C, 55.13; H, 6.77; N, 2.75.
Step B. (S)-38 (0.432 g, 0.76 mmol) was treated with n-BuLi
(0.95 mL, 1.52 mmol, 2.0 equiv, 1.6 M) in THF (15 mL). The
purification of the crude product by flash chromatography (1:4
Et2O-hexanes; TLC, Rf ) 0.71) furnished (S)-39 (0.290 g, 93%)
as a colorless liquid. [R]20D ) -79.3 (c ) 0.98). IR (neat, cm-1):
3305 (tC-H, m). 1H NMR (CDCl3, 300 MHz): δ 7.40-7.10
(m, 10H), 3.84 (d, J ) 13.8 Hz, 2H), 3.58-3.46 (m, 2H), 3.41
(d, J ) 13.8 Hz, 2H), 3.44-3.39 (m, 1H), 2.32 (d, J ) 2.4 Hz,
1H), 1.86-1.49 (m, 4H), 0.86 (s, 9H), 0.00 (s, 6H). 13C NMR
(CDCl3, 75.5 MHz): δ 139.7, 128.8, 128.3, 126.9, 82.0, 72.6,
62.5, 54.8, 51.3, 30.0, 29.6, 26.0, 18.3, -5.3. MS (EI): m/z 407
[M+, 15%]. Anal. Calcd for C26H37NOSi: C, 76.60; H, 9.15; N,
3.44. Found: C, 76.54; H, 9.40; N, 3.54.
(+)-(S)-6-(ter t-Bu tyld im eth ylsilyloxy)-3-(N,N-d iben zyl-
a m in o)-1-p h en yl-1-h exyn e ((S)-15). The terminal alkyne
(S)-39 (0.542 g, 1.33 mmol) was cross-coupled with iodobenzene
(0.271 g, 1.33 mmol, 1.0 equiv) in the presence of copper(I)
iodide (1.3 mg, 6.65 µmol) and bis(triphenylphosphine)palla-
dium(II) dichloride (9.3 mg, 13.3 µmol) in Et3N (9 mL) by
following the typical procedure for the Sonogashira reaction.
The crude product was purified by flash chromatography (1:9
to 1:4 Et2O-hexanes; TLC, Rf ) 0.71 in 1:4 Et2O-hexanes)
giving (S)-15 (0.604 g, 94%) as a colorless liquid. [R]20D ) +181
(c ) 0.77). 1H NMR (CDCl3, 300 MHz): δ 7.51-7.20 (m, 15H),
3.89 (d, J ) 13.8 Hz, 2H), 3.63-3.55 (m, 2H), 3.49 (d, J ) 13.8
Hz, 2H), 3.54-3.46 (m, 1H), 1.92-1.50 (m, 4H), 0.87 (s, 9H),
0.00 (s, 6H). 13C NMR (CDCl3, 75.5 MHz): δ 139.8, 131.8,
128.9, 128.2, 128.0, 127.8, 126.8, 123.6, 87.9, 85.3, 62.6, 55.0,
52.1, 30.1, 29.7, 25.9, 18.3, -7.2. MS (EI): m/z 483 [M+, 4%].
Anal. Calcd for C32H41NOSi: C, 79.45; H, 8.54; N, 2.90.
Found: C, 79.39; H, 8.81; N, 3.02.
Typ ica l P r oced u r e for th e Alk yn yla tion of Ald eh yd es.
r a c-4-Hyd r oxy-6-p h en yl-5-h exyn yl 2,2,4,4-Tetr a m eth yl-
1,3-oxa zolid in e-3-ca r boxyla te (r a c-17). At -78 °C, to a
solution of phenylacetylene (1.08 g, 10.6 mmol, 1.3 equiv) in
THF (20 mL) was slowly added n-BuLi (6.35 mL, 10.2 mmol,
1.25 equiv, 1.6 M). The solution was allowed to warm to -18
°C and stirred for 15 min at this temperature. The cooling bath
was removed, and the solution was stirred at ambient tem-
perature for 30 min. After being cooled back to -78 °C, a
solution of 4-oxobutyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-
carboxylate (1.98 g, 8.14 mmol) in THF (20 mL) was added
within 10 min. The reaction mixture was stirred for 1 h before
the temperature was raised to -18 °C and kept for another
45 min at this temperature. After the hydrolysis with satu-
rated aqueous NH4Cl (50 mL), the organic layer was separated
and the aqueous phase was extracted several times with Et2O.
Drying (Na2SO4), concentration in vacuo, and purification of
the crude product by flash chromatography (1:1 to 3:1 Et2O-
hexanes; TLC, Rf ) 0.19 in 1:1 Et2O-hexanes) provided rac-
17 (2.80 g, 99%) as a colorless oil. IR (neat, cm-1): 3436 (OH,
s), 1707 (CdO, s). 1H NMR (CDCl3, 300 MHz): δ 7.44-7.39
(m, 2H), 7.35-7.28 (m, 3H), 4.68-4.65 (m, 1H), 4.22-4.15 (m,
2H), 3.73 (s, 2H), 2.21 (bs, 1H), 1.91 (bs, 4H), 1.57/1.54/1.43/
1.38 (4s, 12H). 13C NMR (CDCl3, 90 MHz): δ 152.8/152.1,
131.6, 128.5, 128.3, 122.5, 95.8/94.8, 89.6, 85.1, 76.3/76.1, 64.1,
62.4, 60.6/59.7, 34.5, 26.6/25.4/25.3/24.1, 24.9. MS (EI): m/z
330 [(M - CH3)+, 40%]. Anal. Calcd for C20H27NO4: C, 69.54;
H, 7.88; N, 4.05. Found: C, 69.29; H, 7.75; N, 4.25.
Typ ica l P r oced u r e for t h e P CC Oxid a t ion . 4-Oxo-6-
p h en yl-5-h exyn yl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-
ca r boxyla te (21). At 0 °C, to a suspension of PCC (2.62 g,
12.2 mmol, 1.5 equiv) and sodium acetate (0.73 g, 8.92 mmol,
1.1 equiv) in CH2Cl2 (60 mL) rac-17 (2.80 g, 8.11 mmol),
dissolved in CH2Cl2 (20 mL), was added over a period of 5 min.
The conversion of rac-17 to 21 was monitored by TLC; after
complete conversion the reaction mixture was filtrated through
a short silica gel column. The volatiles were removed in vacuo,
and the residue was purified by flash chromatography (1:1
Et2O-hexanes; TLC, Rf ) 0.40) yielding 21 (1.93 g, 69%) as a
viscous oil which slowly solidified upon standing to give 21 as
a white solid. Mp ) 78-79 °C. IR (KBr, cm-1): 1675 (CdO,
(-)-(S)-4-(N,N-Dib en zyla m in o)-6-p h en yl-5-h exyn -1-ol
((S)-40). At room temperature, a solution of (S)-15 (0.112 g,
0.23 mmol) in Et2O (2 mL) was reacted with TBAF (0.70 mL,
0.69 mmol, 3.0 equiv, 1 M in THF) and stirred overnight. The
reaction mixture was quenched with H2O (0.5 mL), and
stirring was continued for a further 2 h for complete hydroly-
sis. The organic layer was separated, and the aqueous phase
was extracted twice with Et2O. The combined organic phases
were dried (Na2SO4) and concentrated under reduced pressure.
The purification of the residue by flash chromatography (1:1
Et2O-hexanes; TLC, Rf ) 0.30) afforded (S)-40 (0.080 g, 94%)
as a colorless oil. [R]20 ) -299 (c ) 0.29). IR (neat, cm-1):
D
1
3348 (OH, m). 1H NMR (CDCl3, 300 MHz): δ 7.59-7.27 (m,
15H), 3.97 (d, J ) 13.6 Hz, 2H), 3.71 (dd, J ) 8.1 Hz, J ) 6.9
Hz, 1H), 3.59 (ψ-t, J ) 6.3 Hz, 2H), 3.56 (d, J ) 13.6 Hz, 2H),
2.04-1.84 (m, 3H), 1.83-1.69 (m, 2H). 13C NMR (CDCl3, 75.5
MHz): δ 139.4, 131.8, 129.0, 128.3, 128.0, 127.0, 123.4, 87.5,
85.7, 62.4, 55.1, 52.3, 30.5, 29.9. MS (EI): m/z 310 [(M -
C3H7O)+, 100%]. Anal. Calcd for C26H27NO: C, 84.51; H, 7.38;
N, 3.79. Found: C, 84.24; H, 7.68; N, 3.92.
CdO, broad, s). H NMR (CDCl3, 300 MHz): δ 7.56-7.36 (m,
5H), 4.18 (t, J ) 6.5 Hz, 2H), 3.74 (s, 2H), 2.80 (t, J ) 6.9 Hz,
2H), 2.12 (ψ-quint, J ) 6.9 Hz, J ) 6.5 Hz, 2H), 1.57/1.55/
1.43/1.39 (4s, 12H). 13C NMR (CDCl3, 75.5 MHz): δ 186.4,
152.7/152.0, 133.0, 130.7, 128.6, 119.8, 95.8/94.8, 91.1, 87.6,
76.3/76.1, 63.4, 60.6/59.6, 42.1, 26.6/25.3/24.1, 23.5. MS (EI):
m/z 328 [(M - CH3)+, 52%]. Anal. Calcd for C20H25NO4: C,
69.95; H, 7.34; N, 4.08. Found: C, 69.97; H, 7.40; N, 4.11.
Typ ica l P r oced u r e for En a n tioselective Red u ction of
r,â-Yn on es w ith Alp in e-Bor a n e.23 (+)-(S)-4-Hyd r oxy-6-
p h en yl-5-h exyn yl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-
ca r boxyla te ((S)-17). At 0 °C, the R,â-ynone 21 (1.20 g, 3.49
mmol) was dissolved in (S)-Alpine-borane (14.0 mL, 6.99 mmol,
2.0 equiv, 0.5 M in THF). The vigorously stirred reaction
mixture was immediately concentrated under reduced pressure
to give a sticky suspension which turned into a liquid while
stirring overnight at room temperature. To destroy the excess
of the reducing agent, freshly distilled acetaldehyde (1 mL)
was added dropwise at 0 °C. After 15 min the cooling bath
was removed and the liberated R-pinene was pumped off in
vacuo at 60-70 °C (oil bath temperature) for 2 h. The reaction
mixture was again cooled to 0 °C, and the residue was
dissolved in Et2O (10 mL). To this solution ethanolamine (0.47
g, 7.69 mmol, 2.2 equiv) was slowly added furnishing a white
(-)-(S)-4-(N,N-Dibenzylamino)-6-phenyl-5-hexynyl2,2,4,4-
Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te ((S)-12). A so-
lution of (S)-40 (0.160 g, 0.43 mmol) in THF (2 mL) was added
dropwise to a suspension of NaH (0.012 g, 0.52 mmol, 1.2
equiv, 60% in mineral oil) in THF (1 mL). The reaction mixture
was allowed to stir for 1 h at room temperature for complete
deprotonation before 2,2,4,4-tetramethyl-1,3-oxazolidine-3-car-
bonyl chloride (CbyCl)22 (0.100 g, 0.48 mmol, 1.1 equiv) in THF
(3 mL) was added. After being heated under reflux overnight
and cooled to room temperature, the reaction mixture was
poured into H2O (1 mL) and Et2O (10 mL). The organic layer
was separated, and the aqueous phase was extracted with
Et2O. The combined organic phases were dried with MgSO4,
and the solvents were removed in vacuo. The crude product
was purified by flash chromatography (1:9 to 1:1 Et2O-
hexanes; TLC, Rf ) 0.65 in 1:1 Et2O-hexanes) yielding (S)-

8624 J . Org. Chem., Vol. 64, No. 23, 1999
Oestreich and Hoppe
precipitate which was then filtered off and washed with Et2O.
The etheral phase was extracted with H2O and brine, dried
over MgSO4, and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatog-
raphy (1:1 Et2O-hexanes) yielding (S)-17 (1.03 g, 85%, er )
Ster eoselective Cycloca r bolith ia tion of 13a . (+)-
[1R,3S,2(1E)]-2-Ben zylid en e-3-(tr ip h en ylm eth oxy)cyclo-
p en tyl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te
(cis-19a ). Following the typical procedure for the stereoselec-
tive cyclocarbolithiation of alkynes, (S)-13a (0.100 g, 0.17
mmol) was treated with s-BuLi (0.18 mL, 0.24 mmol, 1.4 equiv,
1.32 M) and 1 (0.060 g, 0.26 mmol, 1.5 equiv) in Et2O (3 mL)
for 18.5 h at -78 °C. The crude product was purified by flash
chromatography (1:9 to 1:3 Et2O-hexanes; TLC, Rf ) 0.48 in
1:1 Et2O-hexanes) affording cis-19a (0.088 g, 88%, dr ) 95:
95:524) as a colorless oil. [R]20 ) +4.2 (c ) 0.42).
D
Gen er a l P r oced u r e for th e Tr ityla tion 27 of 17. r a c-6-
P h en yl-4-(t r ip h en ylm et h oxy)-5-h exyn yl 2,2,4,4-Tet r a -
m eth yl-1,3-oxa zolid in e-3-ca r boxyla te (r a c-13a ). At room
temperature, trityl chloride (0.749 g, 2.69 mmol, 1.1 equiv) and
DMAP (0.012 g, 0.10 mmol, 0.04 equiv) were dissolved in CH2-
Cl2 (15 mL). To this solution Et3N (0.371 g, 3.66 mmol, 1.5
equiv) and rac-17 (0.844 g, 2.44 mmol), dissolved in CH2Cl2 (5
mL), were subsequently added. After being refluxed overnight
the reaction mixture was quenched with H2O (5 mL) at room
temperature. The organic layer was separated, and the aque-
ous phase was extracted twice with Et2O. The combined
organic phases were dried (MgSO4) and concentrated under
reduced pressure. Flash chromatography (1:1 Et2O-hexanes;
TLC, Rf ) 0.48) of the residue gave rac-13a (0.387 g, 54%) as
a colorless liquid. IR (neat, cm-1): 1691 (CdO, s). 1H NMR
(CDCl3, 300 MHz): δ 7.66-7.60 (m, 6H), 7.39-7.23 (m, 12H),
7.20-7.14 (m, 2H), 4.33 (t, J ) 5.5 Hz, 1H), 4.14 (t, J ) 5.8
Hz, 2H), 3.77 (s, 2H), 2.08-1.73 (m, 4H), 1.62/1.58/1.48/1.42
(4s, 12H). 13C NMR (CDCl3, 75.5 MHz): δ 152.8/152.0, 144.4,
131.5, 129.1, 128.0, 127.9, 127.7, 127.1, 123.1, 95.8/94.8, 89.5,
87.8, 85.8, 76.4/76.1, 64.5, 60.5/59.6, 33.7, 26.6/25.4/24.2, 24.7.
MS (EI): m/z 588 [(M + H)+, 2%]. Anal. Calcd for C39H41NO4:
C, 79.70; H, 7.03; N, 2.38. Found: C, 79.54; H, 7.17; N, 2.39.
Typ ica l P r oced u r e for th e Silyla tion of Alk a n ols. r a c-
4-(ter t-Bu tyldiph en ylsilyloxy)-6-ph en yl-5-h exyn yl 2,2,4,4-
Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te (r a c-13b). To
a solution of DMAP (0.056 g, 0.46 mmol, 0.5 equiv) in CH2Cl2
(10 mL) TBDPSCl (0.304 g, 1.10 mmol, 1.2 equiv), Et3N (0.112
g, 1.10 mmol, 1.2 equiv), and rac-17 (0.318 g, 0.92 mmol),
dissolved in CH2Cl2 (5 mL), were subsequently added at room
temperature. The reaction mixture was stirred under reflux
overnight and hydrolyzed with H2O (1 mL) at room temper-
ature. The organic layer was separated, and the aqueous phase
was extracted with Et2O. The combined organic phases were
dried over MgSO4, and the solvents were evaporated in vacuo.
The residue was purified by flash chromatography (1:9 to 1:3
Et2O-hexanes; TLC, Rf ) 0.61 in 1:1 Et2O-hexanes) to give
rac-13b (0.538 g, 100%) as a colorless liquid. IR (neat, cm-1):
5) as a white solid. Mp ) 165-166 °C. [R]20 ) +11.4 (c )
D
1
0.22). H NMR (CDCl3, 300 MHz): 7.41-7.37 (m, 6H), 7.22-
6.98 (m, 14H), 6.78 (s, 1H), 5.62 (t, J ) 6.9 Hz, 1H), 4.32 (d,
4.7 Hz, 1H), 3.70 (s, 2H), 2.04-1.97 (m, 2H), 1.80-1.70 (m,
1H), 1.65/1.61/1.58/1.51/1.49/1.46/1.44 (7s, 12H), 1.25-1.11 (m,
1H). 13C NMR (CDCl3, 75.5 MHz): δ 152.8/152.0, 145.2, 143.6,
136.9, 132.4, 129.6, 129.3, 128.4, 127.9, 127.8, 127.5, 95.9/95.0,
86.9, 78.1, 76.6/76.2, 74.3, 60.7/59.9, 31.0, 29.5, 27.2/26.7/25.8/
25.5/24.3.
(-)-[1R,3R,2(1E)]-2-Ben zyliden e-3-(tr iph en ylm eth oxy)-
cyclop en t yl 2,2,4,4-Tet r a m et h yl-1,3-oxa zolid in e-3-ca r -
boxyla te (tr a n s-19a ). As described in the typical procedure
for the stereoselective cyclocarbolithiation of alkynes, (R)-13a
(0.046 g, 0.08 mmol) was cyclized with s-BuLi (0.10 mL, 0.11
mmol, 1.4 equiv, 1.30 M) in the presence of 1 (0.028 g, 0.12
mmol, 1.5 equiv) in Et2O (1.5 mL) for 23 h at -78 °C. Flash
chromatography (1:3 Et2O-hexanes) of the crude product
furnished trans-19a (0.046 g, 100%, dr ) 5:95) as a white solid.
1
Mp ) 67-68 °C. [R]20 ) -50.6 (c ) 0.25). H NMR (CDCl3,
D
300 MHz): 7.48-7.44 (m, 6H), 7.32-7.10 (m, 14H), 6.79 (s,
1H), 6.04-6.00 (m, 1H), 4.56 (d, J ) 4.3 Hz, 1H), 3.72 (s, 2H),
2.41-2.33 (m, 1H), 1.74-1.23 (m, 15H). 13C NMR (CDCl3, 150
MHz): δ 152.6/151.9, 144.7, 143.9, 143.8, 136.5, 136.4, 129.5,
129.1, 128.9, 128.0, 127.9, 127.5, 127.3, 127.0, 95.9/94.8, 86.7,
77.5, 76.3/76.0, 74.0/73.9, 60.5/59.7, 30.5, 29.7/29.6, 28.9/26.8/
26.6/25.7/25.5/25.3/24.2.
[1R,3RS,2(1E)]-2-Ben zylid en e-3-(t r ip h en ylm et h oxy)-
cyclop en t yl 2,2,4,4-Tet r a m et h yl-1,3-oxa zolid in e-3-ca r -
boxyla te (cis-/tr a n s-19a ). rac-13a (0.195 g, 0.33 mmol) was
treated with s-BuLi (0.33 mL, 0.43 mmol, 1.3 equiv, 1.32 M)
and 1 (0.101 g, 0.43 mmol, 1.3 equiv) in Et2O (8 mL) for 6.5 h
at -78 °C according to the typical procedure for the stereose-
lective cyclocarbolithiation. The purification of the crude
product by flash chromatography (1:9 to 1:3 Et2O-hexanes)
gave a mixture of cis-/trans-19a (0.157 g, 80%, dr ) 50:50) and
rac-13a (0.038 g, 20%) as a white solid. IR (KBr, cm-1): 1694
1
1697 (CdO, s). H NMR (CDCl3, 300 MHz): δ 7.76-7.66 (m,
4H), 7.40-7.27 (m, 6H), 7.22-7.12 (m, 5H), 4.62-4.59 (m, 1H),
4.08 (bs, 2H), 3.67 (s, 2H), 1.86 (bs, 4H), 1.52/1.47/1.38/1.31
(4s, 12H), 1.07 (s, 9H). 13C NMR (CDCl3, 75.5 MHz): δ 152.8/
152.0, 136.0, 135.4, 133.6, 131.5, 129.6, 128.1, 127.6, 122.9,
95.8/94.8, 90.2, 85.2, 76.4/76.2, 64.4, 64.0, 60.5/59.6, 35.4, 27.0,
26.6/25.3/24.2, 24.6, 19.3. MS (EI): m/z 583 [M+, 1%]. Anal.
Calcd for C36H45NO4Si: C, 74.06; H, 7.77; N, 2.40. Found: C,
74.37; H, 7.93; N, 2.30.
(CdO, s). MS (EI): m/z 587 [M+, 6%]. Anal. Calcd for C39H41
-
NO4: C, 79.70; H, 7.03; N, 2.38. Found: C, 79.58; H, 7.12; N,
2.58.
Ster eoselective Cycloca r bolith ia tion of 13b. (+)-
[1R,3S,2(1E)]-2-Ben zylid en e-3-(ter t-b u t yld ip h en ylsilyl-
oxy)cyclop en tyl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-
ca r boxyla te (cis-19b). In analogy to the typical procedure
for the stereoselective cyclocarbolithiation, (S)-13b (0.500 g,
0.86 mmol) was cyclized with s-BuLi (0.92 mL, 1.20 mmol, 1.4
equiv, 1.30 M) and 1 (0.301 g, 1.28 mmol, 1.5 equiv) in Et2O
(15 mL) for 20 h at -78 °C. The crude product was purified
by flash chromatography (1:9 Et2O-hexanes; TLC, Rf ) 0.57
in 1:1 Et2O-hexanes) to give cis-19b (0.410 g, 82%, dr ) 95:
(-)-[1R,3S,2(1E)]-2-Ben zyliden e-3-(N,N-diben zylam in o)-
cyclop en t yl 2,2,4,4-Tet r a m et h yl-1,3-oxa zolid in e-3-ca r -
boxyla te (cis-18). According to the typical procedure for the
stereoselective cyclocarbolithiation of alkynes, (S)-12 (0.110 g,
0.21 mmol) was cyclized with s-BuLi (0.25 mL, 0.31 mmol, 1.5
equiv, 1.25 M) in the presence of 1 (0.074 g, 0.31 mmol, 1.5
equiv) in Et2O (3 mL) for 20 h at -78 °C. The crude product
was purified by flash chromatography (3:7 Et2O-hexanes;
TLC, Rf ) 0.65 in 1:1 Et2O-hexanes) to yield cis-18 (0.077 g,
5) as a colorless, highly viscous oil. [R]20 ) +34.5 (c ) 0.31).
D
1H NMR (CDCl3, 300 MHz): δ 7.71-7.64 (m, 4H, Ph), 7.41-
7.22 (m, 8H), 7.12-7.00 (m, 3H), 6.76 (s, 1H), 5.64 (t, J ) 6.8
Hz, 1H), 4.82 (d, J ) 4.1 Hz, 1H), 3.72 (s, 2H), 2.24-1.90 (m,
4H), 1.60/1.59 (2bs, 6H), 1.45/1.44 (2bs, 6H), 1.03 (s, 9H). 13C
NMR (CDCl3, 75.5 MHz): δ 153.0/152.2, 144.1, 136.5, 135.9,
134.8, 134.4, 133.8, 131.3, 129.6, 129.5, 128.9, 128.0, 127.5,
127.3, 95.8/95.1, 77.3, 76.6/76.1, 72.7, 60.6/59.9, 34.2, 29.3,
27.0, 26.7/25.8/25.4/24.3, 19.3.
70%) with traces of (S)-12 as a colorless oil. [R]20 ) -76.6 (c
D
) 0.15). IR (neat, cm-1): 1697 (CdO, s). 1H NMR (CDCl3, 600
MHz): δ 7.40-7.16 (m, 12H), 7.04-7.02 (m, 3H), 6.92 (m, 1H),
5.56 (m, 1H), 4.20 (m, 1H), 3.85 (ψ-t, J ) 12.6 Hz, 2H), 3.70
(2s, 2H), 3.24 (2d, J ) 12.6 Hz, 2H), 2.28-2.18 (m, 1H), 2.04-
1.96 (m, 2H), 1.85-1.78 (m, 1H), 1.60/1.56/1.49/1.45/1.42/1.39/
1.33 (7s, 12H). 13C NMR (CDCl3, 150 MHz): δ 152.6/151.9,
141.8, 141.7, 139.2, 136.0, 135.9, 130.3, 129.3, 128.7, 128.3,
127.9, 127.6, 127.1, 126.8, 96.0/94.6, 80.3, 76.4/76.0, 60.4, 60.8/
59.5, 54.9/54.8, 30.4/30.3, 22.1, 26.7/26.6/25.5/25.4/25.3/25.2/
24.2/24.1. MS (EI): m/z 524 [M+, 1%]. Anal. Calcd for
(-)-[1R,3RS,2(1E)]-2-Ben zylid en e-3-(ter t-b u t yld ip h e-
n ylsilyloxy)cyclop en tyl 2,2,4,4-Tetr a m eth yl-1,3-oxa zoli-
d in e-3-ca r boxyla te (cis-/tr a n s-19b). Following the typical
procedure for the stereoselective cyclocarbolithiation, rac-13b
(0.100 g, 0.17 mmol) was allowed to react with s-BuLi (0.18
mL, 0.24 mmol, 1.4 equiv, 1.30 M) and 1 (0.060 g, 0.26 mmol,
1.5 equiv) in Et2O (3 mL) for 23.5 h at -78 °C. Flash
C
34H40N2O3: C, 77.83; H, 7.68; N, 5.34. Found: C, 77.56; H,
7.67; N, 5.41.

(-)-Sparteine-Mediated Carbolithiation
J . Org. Chem., Vol. 64, No. 23, 1999 8625
chromatography (1:3 to 1:1 Et2O-hexanes; TLC, Rf ) 0.57/
0.58 in 1:1 Et2O-hexanes) afforded cis-/trans-19b (0.096 g,
(-)-(S)-4-(N,N-Diben zyla m in o)-5-(tr ip h en ylm eth oxy)-
1-p en ta n ol ((S)-42). At room temperature, (S)-41 (8.62 g, 13.1
mmol) was desilylated with TBAF (39.4 mL, 39.4 mmol, 3.0
equiv, 1 M in THF) in Et2O (40 mL). After being stirred
overnight, the reaction mixture was treated with H2O (15 mL)
and stirred for a further 2 h at room temperature. The organic
layer was separated, and the aqueous phase was extracted
twice with Et2O. The organic phases were combined, dried over
Na2SO4, and concentrated in vacuo. The crude product was
purified by flash chromatography (1:1 Et2O-hexanes; TLC,
96%, dr ) 50:50) a colorless, highly viscous oil. [R]20 ) -19.4
D
(c ) 0.48). IR (neat, cm-1): 1691 (CdO, s). H NMR (CDCl3,
1
300 MHz): δ 7.72-7.59 (m, 4H), 7.41-7.22 (m, 8H), 7.14-
7.01 (m, 3H), 6.76 (s, 0.5H, cis), 6.68 (s, 0.5H, trans), 5.88-
5.86 (m, 0.5H, trans), 5.64 (t, J ) 6.8 Hz, 0.5H, cis), 5.01 (m,
0.5H, trans), 4.82 (d, J ) 4.1 Hz, 0.5H, cis), 3.72 (s, 1H, cis),
3.69 (bs, 1H, trans), 2.43-1.70 (m, 4H), 1.65-1.25 (m, 12H),
1.05/1.02/0.97 (3s, 9H). 13C NMR (CDCl3, 75.5 MHz): δ 153.0/
152.2, 145.0, 144.1, 136.5, 135.9, 135.8, 134.8, 134.7, 133.8,
131.3, 129.6, 129.5, 128.9, 128.1, 128.0, 127.7, 127.5, 127.3,
127.2, 95.8/95.3/95.1, 77.6/77.3, 76.5/76.0, 72.8/72.7, 60.6/59.9/
59.8, 34.2, 33.7, 29.7, 29.4, 27.0/26.9, 26.6/25.8/25.5/25.3/24.2,
Rf ) 0.26) to give (S)-42 (7.12 g, 100%) as a colorless oil. [R]20
D
) -59.0 (c ) 1.24). IR (neat, cm-1): 3386 (OH, s). 1H NMR
(CDCl3, 300 MHz): δ 7.48-7.44 (m, 5H), 7.33-7.14 (m, 20H),
3.72 (d, J ) 13.7 Hz, 2H), 3.46 (d, J ) 13.7 Hz, 2H), 3.50-
3.43 (m, 2H), 3.34 (dd, J ) 9.6 Hz, J ) 5.7 Hz, 1H), 3.15 (dd,
J ) 9.6 Hz, J ) 5.3 Hz, 1H), 2.88 (m, 1H), 2.42-2.36 (m, 1H),
1.67-1.17 (m, 4H). 13C NMR (CDCl3, 75.5 MHz): δ 144.1,
140.3, 128.8, 128.1, 127.7, 126.9, 126.7, 87.0, 62.9, 62.8, 57.3,
54.1, 30.1, 25.7. MS (EI): m/z 541 [M+, 0.4%]. HRMS Calcd
for C38H39NO2: 541.29808. Found: 541.29645.
19.3/19.0. MS (EI): m/z 583 [M+, 1%]. Anal. Calcd for C36H45
-
NO4Si: C, 74.06; H, 7.77; N, 2.40. Found: C, 73.82; H, 7.79;
N, 2.31.
(+)-[1RS,3S,2(1E)]-2-Ben zylid en e-3-(ter t-b u t yld ip h e-
n ylsilyloxy)cyclop en tyl 2,2,4,4-Tetr a m eth yl-1,3-oxa zoli-
d in e-3-ca r boxyla te (cis-/en t-tr a n s-19b). Analogously to the
typical procedure for the stereoselective cyclocarbolithiation,
(S)-13b (0.100 g, 0.17 mmol) was treated with s-BuLi (0.18
mL, 0.24 mmol, 1.4 equiv, 1.30 M) in the presence of TMEDA
(20) (0.030 g, 0.26 mmol, 1.5 equiv)sinstead of (-)-sparteine
(1)sin Et2O (3 mL) for 20 h at -78 °C. Flash chromatography
of the crude product provided cis-/ent-trans-19b (0.089 g, 89%,
(-)-(S)-4-(N,N-Diben zyla m in o)-5-(tr ip h en ylm eth oxy)-
p en tyl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te
((S)-43). To a suspension of NaH (0.30 g, 7.50 mmol, 1.1 equiv,
60% in mineral oil) in THF (5 mL) a solution of (S)-42 (3.51 g,
6.82 mmol) in THF (30 mL) was added dropwise at room
temperature. The reaction mixture was stirred for 1 h at
ambient temperature to achieve complete deprotonation. Then
a solution of 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyl
chloride (CbyCl)22 (1.44 g, 7.50 mmol, 1.1 equiv) in THF (15
mL) was injected into the reaction mixture. After being
refluxed overnight and cooled to room temperature, the
resulting white suspension was poured into H2O (10 mL) and
Et2O (50 mL). The organic layer was separated, and the
aqueous phase was extracted with Et2O. The combined organic
phases were dried (MgSO4), and the solvents were evaporated
under reduced pressure. Purification by flash chromatography
(6:4 Et2O-hexanes; TLC, Rf ) 0.60) gave (S)-43 (4.15 g, 87%)
dr ) 50:50) as a colorless, highly viscous oil. [R]20 ) +47.1
D
(c ) 0.48).
4,4-(1,2-E t h a n ed iyld ioxy)-6-p h en yl-5-h exyn yl 2,2,4,4-
Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te (22). At -78
°C, a drop of TMSOTf was dissolved in CH2Cl2 (1 mL). To this
solution 1,2-bis(trimethylsilyloxy)ethane (0.413 g, 2.00 mmol,
1.0 equiv) and the R,â-ynone 21 (0.687 g, 2.00 mmol) in CH2-
Cl2 (3 mL) were subsequently added. The reaction was
terminated with pyridine (0.2 mL) after stirring overnight at
-78 °C. The reaction mixture was poured into saturated
aqueous NaHCO3 (25 mL), the organic layer was separated,
and the aqueous phase was extracted with Et2O. The combined
organic phases were dried (1:1 mixture of Na2CO3 and Na2-
SO4), and the solvents were evaporated under reduced pres-
sure.31 The residue was purified by flash chromatography (1:9
to 1:3 to 1:1 Et2O-hexanes; TLC, Rf ) 0.39 in 1:1 Et2O-
hexanes, silica gel passified with Et3N) furnishing 22 (0.243
g, 31%) as colorless liquid. IR (neat, cm-1): 2222 (CtC, w),
as a white foam. [R]20 ) -34.0 (c ) 1.08). IR (neat, cm-1):
D
1
1689 (CdO, s). H NMR (CDCl3, 300 MHz): δ 7.44-7.37 (m,
5H), 7.35-7.16 (m, 20H), 3.98 (m, 2H), 3.71 (d, J ) 14.0 Hz,
2H), 3.70 (s, 2H), 3.46 (d, J ) 14.0 Hz, 2H), 3.34 (dd, J ) 9.5
Hz, J ) 5.3 Hz, 1H), 3.15 (dd, J ) 9.5 Hz, J ) 5.3 Hz, 1H),
2.86 (ψ-dq, J ) 5.3 Hz, J ) 2.6 Hz, 1H), 1.86-1.81 (m, 1H),
1.71-1.32 (m, 15H). 13C NMR (CDCl3, 75.5 MHz): δ 152.7/
152.0, 144.1, 140.4, 128.7, 128.6, 128.1, 127.7, 126.9, 126.7,
95.8/94.7, 87.0, 76.4/76.2, 64.7, 62.7, 60.5/59.6, 57.2, 54.1, 26.5,
26.2/25.3/24.1. MS (EI): m/z 696 [M+, 0.2%]. Anal. Calcd for
1
1706 (CdO, s). H NMR (CDCl3, 300 MHz): δ 7.44-7.40 (m,
2H), 7.32-7.26 (m, 3H), 4.17 (t, J ) 6.2 Hz, 2H), 4.17-4.13
(m, 2H), 4.04-3.99 (m, 2H), 3.70 (s, 2H), 2.14-2.04 (m, 2H),
2.03-1.92 (m, 2H), 1.54/1.52/1.40/1.36 (4s, 12H). 13C NMR
(CDCl3, 75.5 MHz): δ 152.8/152.0, 131.8, 128.7, 128.2, 121.9,
103.4, 95.8/94.8, 86.5, 84.0, 76.3/76.1, 64.8, 64.2, 60.7/59.7,
36.3, 26.6/25.3/24.1, 23.8. MS (EI): m/z 373 [M+, 21%]. Anal.
Calcd for C22H29NO5: C, 68.20; H, 7.54; N, 3.62. Found: C,
68.07; H, 7.66; N, 3.83.
C
46H52N2O4: C, 79.28; H, 7.52; N, 4.02. Found: C, 79.02; H,
7.54; N, 4.34.
(+)-(S)-4-(N,N-Diben zylam in o)-5-h ydr oxypen tyl 2,2,4,4-
Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te ((S)-27). A so-
lution of (S)-43 (0.830 g, 1.19 mmol) in CH2Cl2 (15 mL) and
methanol (15 mL) was cooled to 0 °C before TFA (0.679 g, 5.95
mmol, 5.0 equiv) was added dropwise. The yellowish reaction
mixture was stirred for 30 min at room temperature and then
carefully neutralized with saturated aqueous NaHCO3 until
the evolution of CO2 had stopped. The organic layer was
separated, and the aqueous phase was extracted twice with
Et2O. The combined organic phases were washed with brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography (1:3 to 1:1 Et2O-hexanes;
TLC, Rf ) 0.55 in Et2O) to yield (S)-27 (0.420 g, 78%) as a
colorless liquid. [R]20D ) +62.1 (c ) 1.23). IR (neat, cm-1): 3473
(-)-(S)-1-(ter t-Bu tyld im eth ylsilyloxy)-4-(N,N-d iben zyl-
a m in o)-5-(tr ip h en ylm eth oxy)p en ta n e ((S)-41). To a solu-
tion of trityl chloride (2.56 g, 9.17 mmol, 1.2 equiv) in CH2Cl2
(25 mL) a mixture of (S)-1419 (3.16 g, 7.64 mmol) and Et3N
(1.08 g, 10.6 mmol, 1.4 equiv), dissolved in CH2Cl2 (25 mL),
was added at room temperature. The reaction mixture was
allowed to stir for 36 h before quenching with H2O (25 mL).
The organic layer was separated and the aqueous phase
extracted with CH2Cl2. The combined organic phases were
dried over MgSO4, and the solvent was removed in vacuo. The
residue was purified by flash chromatography (1:1 Et2O-
hexanes; TLC, Rf ) 0.60) to afford (S)-41 (5.00 g, 100%) as a
1
(OH, m), 1695 (CdO, s). H NMR (CDCl3, 300 MHz): δ 7.37-
7.15 (m, 10H), 4.07 (t, J ) 6.0 Hz, 2H), 3.80 (d, J ) 13.5 Hz,
2H), 3.73 (s, 2H), 3.47 (m, 2H), 3.45 (d, J ) 13.5 Hz, 2H), 2.99
(bs, 1H), 2.84-2.75 (m, 1H), 1.90-1.76 (m, 1H), 1.75-1.21 (m,
15H). 13C NMR (CDCl3, 75.5 MHz): δ 152.6/151.9, 139.1, 128.8,
128.3, 127.1, 95.7/94.6, 76.2/76.0, 64.2, 60.8, 60.5/59.5, 58.6,
53.2, 26.7, 26.5/25.3/25.2/24.0, 22.0. MS (EI): m/z 454 [M+,
0.1%]. Anal. Calcd for C27H38N2O4: C, 71.34; H, 8.43; N, 6.16.
Found: C, 71.12; H, 8.55; N, 6.38.
colorless oil. [R]20 ) -40.4 (c ) 1.35). 1H NMR (CDCl3, 300
D
MHz): δ 7.47-7.43 (m, 5H), 7.32-7.14 (m, 20H), 3.69 (d, J )
13.8 Hz, 2H), 3.52-3.42 (m, 4H), 3.30 (dd, J ) 9.3 Hz, J ) 5.7
Hz, 1H), 3.13 (dd, J ) 9.3 Hz, J ) 5.3 Hz, 1H), 2.85 (m, 1H),
1.66-1.25 (m, 4H), 0.86 (s, 9H), 0.00 (s, 6H). 13C NMR (CDCl3,
75.5 MHz): δ 144.2, 140.7, 128.8, 128.0, 127.7, 126.9, 126.6,
86.9, 63.2, 63.1, 57.2, 54.1, 30.2, 26.0, 25.4, 18.3, -5.2. MS
(EI): m/z 641 [(M - CH3)+, 6%]. Anal. Calcd for C44H53NO2Si:
C, 80.56; H, 8.14; N, 2.14. Found: C, 80.67; H, 8.35; N, 2.12.
(-)-(S)-4-(N,N-Diben zyla m in o)-5-oxop en tyl 2,2,4,4-Tet-
r a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te ((S)-44). Accord-
ing to the typical procedure for the Swern oxidation, (S)-27

8626 J . Org. Chem., Vol. 64, No. 23, 1999
Oestreich and Hoppe
(0.360 g, 0.79 mmol) was oxidized with oxalyl chloride (0.121
g, 0.95 mmol, 1.2 equiv), DMSO (0.148 g, 1.90 mmol, 2.4 equiv),
and Et3N (0.401 g, 3.96 mmol, 5.0 equiv) in CH2Cl2 (10 mL).
The purification of the crude product by flash chromatography
(1:1 Et2O-hexanes; TLC, Rf ) 0.27) provided (S)-44 (0.345 g,
ing the typical procedure for the stereoselective cyclocarbo-
lithiation, (S)-25 (0.311 g, 0.60 mmol) was cyclized with s-BuLi
(0.67 mL, 0.90 mmol, 1.5 equiv, 1.34 M) in the presence of 1
(0.210 g, 0.90 mmol, 1.5 equiv) in Et2O (3 mL) for 20 h at -78
°C. The crude product was purified by flash chromatography
(1:1 Et2O-hexanes to Et2O; TLC, Rf ) 0.61 in Et2O) affording
cis-30 (0.215 g, 70%, dr ) >95:5) as a white solid along with
96%) as a colorless liquid. [R]20 ) -36.6 (c ) 1.14). IR (neat,
D
cm-1): 1694 (CdO, CdO, s). 1H NMR (CDCl3, 300 MHz): δ
9.71 (s, 1H), 7.39-7.18 (m, 10H), 4.09-4.05 (m, 2H), 3.80 (d,
J ) 13.6 Hz, 2H), 3.70 (m, 4H), 3.20-3.16 (m, 1H), 1.92-1.63
(m, 4H), 1.57/1.53/1.43/1.37 (4s, 12H). 13C NMR (CDCl3, 75.5
MHz): δ 203.0, 152.7/151.9, 138.9, 128.7, 128.4, 127.3, 95.8/
94.7, 76.3/76.1, 66.5, 64.1, 60.5/59.6, 54.8, 26.6, 26.5/25.3/24.1,
20.8. MS (EI): m/z 452 [M+, 3%]. Anal. Calcd for C27H36N2O4:
C, 71.65; H, 8.02; N, 6.19. Found: C, 71.65; H, 8.30; N, 5.96.
(-)-(S)-4-(N,N-Diben zylam in o)-6-(tr im eth ylsilyl)-5-h ex-
yn yl 2,2,4,4-Tetr a m eth yl-1,3-oxa zolid in e-3-ca r boxyla te
((S)-25). Step A. Following the typical procedure for the
Corey-Fuchs formyl ethynyl conversion, (S)-44 (0.500 g, 1.10
mmol) was olefinated with tetrabromomethane (0.733 g, 2.21
mmol, 2.0 equiv) and triphenylphosphine (1.159 g, 4.42 mmol,
4.0 equiv) in CH2Cl2 (35 mL). After purification of the crude
product by flash chromatography (1:9 Et2O-hexanes; TLC, Rf
) 0.60 in 1:1 Et2O-hexanes), the (+)-(S)-6,6-dibromo-4-(N,N-
dibenzylamino)-5-hexenyl 2,2,4,4-tetramethyl-1,3-oxazolidine-
3-carboxylate ((S)-45) (0.620 g, 93%) was isolated as a yellow-
(S)-25 (0.030 g, 10%). Mp ) 148 °C. [R]20 ) -41.1 (c ) 0.63).
D
IR (KBr, cm-1): 3354 (OH, w), 1597 (CdO, s). 1H NMR (CDCl3,
300 MHz): δ 7.23-7.09 (m, 10H), 5.47 (bs, 1H), 4.35 (d, J )
5.0 Hz, 1H), 4.14 (d, J ) 14.1 Hz, 2H), 3.68 (s, 2H), 3.60 (d, J
) 5.3 Hz, 1H), 3.53 (d, J ) 14.1 Hz, 2H), 2.39-2.27 (m, 1H),
1.92-1.70 (m, 3H), 1.74/1.68/1.60/1.58/1.57/1.54/1.49/1.35 (m,
12H), 0.12 (s, 9H). 13C NMR (CDCl3, 75.5 MHz): δ 168.7, 153.2,
138.0, 137.2, 129.2, 128.4, 127.3, 97.9/94.5, 76.8, 74.2, 65.9/
65.8, 59.8, 55.1, 32.0, 25.8, 27.4/26.6/25.2/23.8, -0.5. MS (EI):
m/z 520 [M+, 4%]. Anal. Calcd for C31H44N2O3Si: C, 71.50; H,
8.52; N, 5.38. Found: C, 71.30; H, 8.59; N, 5.41.
[2(2R),2(5S),2E]-2-[5-(ter t-Bu t yld ip h en ylsilyloxy)-2-
h yd r oxycyclop e n t ylid e n e ]-2-((t r im e t h ylsilyl)a ce t yl)-
3-(2,2,4,4-t et r a m et h yl-1,3-oxa zolid in id e) (cis-33) a n d
[2(2S),2(5R),2Z]-2-[5-(ter t-Bu t yld ip h en ylsilyloxy)-2-h y-
d r oxycyclop e n t ylid e n e ]-2-((t r im e t h ylsilyl)a ce t yl)-3-
(2,2,4,4-t et r a m et h yl-1,3-oxa zolid in id e) (cis-34). As de-
scribed in the typical procedure for the stereoselective
cyclocarbolithiation, (S)-26 (0.200 g, 0.34 mmol) was treated
with s-BuLi (0.37 mL, 0.48 mmol, 1.4 equiv, 1.30 M) and 1
(0.121 g, 0.52 mmol, 1.5 equiv) in Et2O (6 mL) for 20 h at -78
°C. After purification of the crude product by flash chroma-
tography (1:1 Et2O-hexanes; TLC, Rf ) 0.28) a mixture of the
regioisomeric cyclization products cis-33 and cis-34 (0.099 g,
50%, cis-33:cis-34 ) 80:20, dr not determined) was isolated
as a white foam along with (S)-26 (0.080 g, 40%). IR (neat,
cm-1): 3460 (OH, m), 1591 (CdO, s). 1H NMR (CDCl3, 300
MHz): δ 7.77-7.64 (m, 4H), 7.48-7.33 (m, 6H), 4.68-4.55 (m,
1H), 4.53-4.38 (m, 1H), 3.82-3.66 (m, 3H), 2.09-1.97 (m, 3H),
1.84-1.24 (m, 13H), 1.06 (s, 9H), 0.08/-0.11 (2s, 9H). MS (EI):
m/z 579 [M+, 27%]. Anal. Calcd for C33H49NO4Si2: C, 68.35;
H, 8.52; N, 2.42. Found: C, 68.42; H, 8.41; N, 2.46.
ish oil. [R]20 ) +7.6 (c ) 0.80). IR (neat, cm-1): 1697 (CdO,
D
s). 1H NMR (CDCl3, 300 MHz): δ 7.37-7.18 (m, 10H), 6.56 (d,
J ) 9.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.84 (d, J ) 13.6 Hz, 2H),
3.71 (s, 2H), 3.44-3.40 (m, 1H), 3.39 (d, J ) 13.6 Hz, 2H),
1.95-1.71 (m, 2H), 1.69-1.50 (m, 2H), 1.55/1.49/1.41/1.34 (4s,
12H). 13C NMR (CDCl3, 75.5 MHz): δ 152.9/152.1, 139.4, 137.4,
128.7, 128.2, 127.0, 96.9/95.8, 90.5, 76.6/76.4, 64.1, 61.3, 60.6/
59.6, 54.2, 28.9, 25.9, 26.6/25.5/25.3/24.2. MS (EI): m/z 608
[M+, 0.1%]. Anal. Calcd for C28H36N2O3Br2: C, 55.28; H, 5.96;
N, 4.60. Found: C, 55.61; H, 6.10; N, 4.75.
Step B. In a slightly modified reaction procedure the
intermediate lithium acetylide, generated from (S)-45 (0.570
g, 0.94 mmol) upon treatment with n-BuLi (1.17 mL, 1.87
mmol, 2.0 equiv, 1.6 M) in THF (15 mL), was reacted with
TMSCl (0.305 g, 2.81 mmol, 3.0 equiv). The silylated alkyne
(S)-25 (0.408 g, 83%) was isolated after flash chromatography
(3:7 Et2O-hexanes; TLC, Rf ) 0.65 in 1:1 Et2O-hexanes) of
the crude product as a colorless liquid. [R]20D ) -120 (c ) 0.87).
IR (neat, cm-1): 2159 (CtC, w), 1699 (CdO, s). 1H NMR
(CDCl3, 300 MHz): δ 7.38-7.18 (m, 10H), 4.01-3.97 (m, 2H),
3.79 (d, J ) 13.8 Hz, 2H), 3.70 (s, 2H), 3.40 (t, J ) 7.5 Hz,
1H), 3.38 (d, J ) 13.8 Hz, 2H), 1.85-1.60 (m, 4H), 1.54/1.48/
1.40/1.32 (4s, 12H), 0.24 (s, 9H). 13C NMR (CDCl3, 75.5 MHz):
δ 152.7/151.9, 139.5, 128.7, 128.2, 126.9, 103.8, 95.7/94.4, 89.6,
76.3/76.1, 64.3, 60.8/59.8, 55.2, 52.5, 30.8, 26.4, 26.8/25.6/24.4,
0.3. MS (EI): m/z 520 [M+, 10%]. Anal. Calcd for C31H44N2O3-
Si: C, 71.50; H, 8.52; N, 5.38. Found: C, 71.50; H, 8.70; N,
5.54.
Ack n ow led gm en t. We are grateful to the Deutsche
Forschungsgemeinschaft for generous financial support.
M.O. (Kekule´ fellow 1997-1999) thanks the Fonds der
Chemischen Industrie for a fellowship and K. Gottschalk
for skillful technical assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for products (S)-13a , (R)-
13a , (S)-13b, (R)-17, (S)-26, rac-28, (S)-28, rac-35, 46, and rac-
1
47, H and 13C NMR spectra of compounds 6, 7, (S)-12, 13a ,
cis-18, cis-19a , trans-19a , 22, (S)-25, and cis-30, as well as
complete X-ray data for cis-19a and cis-30. This material is
available free of charge via the Internet at http://pubs.acs.org.
(-)-[2(2R),2(5S),2E]-2-[5-(N,N-Dib en zyla m in o)-2-h y-
d r oxycyclop e n t ylid e n e ]-2-((t r im e t h ylsilyl)a ce t yl)-3-
(2,2,4,4-tetr a m eth yl-1,3-oxa zolid in id e) (cis-30). Follow-
J O991095U