Asymmetric synthesis of 2-alkenyl-1-cyclopentanols via tin-lithium exchange and intramolecular cycloalkylation

Article abstract of DOI:10.1021/ol026068w

(matrix presented) We report a method for the synthesis of chiral cyclopentanes using tin-lithium exchange and cycloalkylation reactions. The sec-butyllithium/ (-)-sparteine-mediated deprotonation of an alkyl carbamate and subsequent substitution furnishe

Full text of DOI:10.1021/ol026068w

ORGANIC
LETTERS
2
002
Vol. 4, No. 13
189-2192
Asymmetric Synthesis of
-Alkenyl-1-cyclopentanols via
2
2
Tin−Lithium Exchange and
Intramolecular Cycloalkylation
,†
Guido Christoph and Dieter Hoppe*
Organisch-Chemisches Institut, Westf a¨ lische Wilhelms-UniVersit a¨ t M u¨ nster,
Corrensstrasse 40, D-48149 M u¨ nster, Germany
dhoppe@uni-muenster.de
Received April 23, 2002
ABSTRACT
We report a method for the synthesis of chiral cyclopentanes using tin−lithium exchange and cycloalkylation reactions. The sec-butyllithium/
−)-sparteine-mediated deprotonation of an alkyl carbamate and subsequent substitution furnishes a highly enantioenriched stannane as a
(
stable carbanion equivalent. It was transformed into suitable cyclization precursors, which underwent tin−lithium exchange and stereoselective
cycloalkylation when reacted with n-butyllithium, giving highly enantioenriched cyclopentanes in very good yields. A kinetic resolution was
observed with a higher substituted stannane.
1
The asymmetric deprotonation of achiral 5-alkenyl carbam-
ates of type 1 by sec-butyllithium/(-)-sparteine 5 followed
Scheme 1. Cyclocarbolithiation of 1a
2
by a 5-exo-trig cyclization was found to be a powerful route
3
to 2-substituted cyclopentanols 4 (Scheme 1).
4
The cyclocarbolithiation proceeds with strict stereoreten-
tion at C-1 and a high diastereofacial selection at the double
†
Fax: (+49) 251-8336531.
(1) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. 1990, 102,
1
457-1459; Angew. Chem., Int. Ed. Engl. 1990, 29, 1422-1423. For
reviews, see: (b) Hoppe, D.; Hense, T. Angew. Chem. 1997, 109, 2376-
410; Angew. Chem., Int. Ed. Engl. 1997, 36, 2282-2316. (c) Beak, P.;
Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
2
5
7
52-560. (d) Basu, A.; Thayumanavan, S. Angew. Chem. 2002, 114, 740-
63; Angew. Chem., Int. Ed. 2002, 41, 716-738.
(2) (a) Bailey, W. F.; Ovaska, T. V. In AdVances in Detailed Reaction
Mechanisms; Coxon, J. M., Ed.; JAI Press: Greenwich, CT, 1994; Vol. 3,
pp 251-273. (b) Bailey, W. F.; Gavaskar, K. V. Tetrahedron 1994, 50,
a
(
a) (i) 1.5 equiv of sBuLi/(-)-sparteine 5, Et
2
O, -78 °C, 20-
5
957-5970.
(
3) Woltering, M. J.; Fr o¨ hlich, R.; Hoppe, D. Angew. Chem. 1997, 109,
804-1805; Angew. Chem., Int. Ed. Engl. 1997, 36, 1764-1766.
4) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J. F. J. Am. Chem.
30 h; (ii) El-X, -78 °C to rt.
1
(
Soc. 1995, 117, 8853-8854. (b) Review: Marek, I. J. Chem. Soc., Perkin
Trans. 1 1999, 535-544. (c) 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.
bond, which leads to a mesomerically stabilized benzyl anion.
Noteworthy, the strong directing power of the carbamate
group overrides the inherent acidity of the C-4 protons in 1.
1
0.1021/ol026068w CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/25/2002

1
b
The concept could be extended to a number of substituted
alkenyl-, alkynyl-, and alkadienyl carbamates. The reaction
which was stated in numerous examples. Compound 7 was
converted into the allyl chloride 11 by standard steps.
The treatment of 11 in ethereal solution with 1.5 equiv of
n-butyllithium at -78 °C led to a rapid tin-lithium exchange
under retention of configuration, followed by a highly
stereoselective cyclization. The formed trans-configured
product 15 was isolated in essentially quantitative yield as a
single diastereomer and enantiomer (Scheme 3).9
5
requires a carbanion-stabilizing substituent in the 6-position.
Intramolecular allylic substitution extends the scope, but it
6
is only applicable to allylic carbamates. Allylic chlorine in
2
compound 1 (R ) CH Cl) does not survive the conditions
of R-deprotonation.
,10
As a result, we introduced a tributylstannyl group at an
7
early stage as a chiral carbanion equivalent, which could
be carried through the synthesis and converted stereospe-
cifically to lithium in the presence of sensitive functionality.
The use of enantioenriched R-oxy-stannanes and R-stanny-
lated N-heterocycles for stereoselective cyclizations has been
described in the literature.8
Scheme 3. Cyclization to the 2-Vinylcyclopentanol 15
Deprotonation of the 5-TBSO-pentyl carbamate 6 by sec-
butyllithium/(-)-sparteine and subsequent quench with tribut-
yltin chloride afforded the enantiopure stannane (S)-7 with
85% yield (Scheme 2). The (S)-configuration of 7 is a
a
(
a) 1.5 equiv of nBuLi, Et O, -78 °C, 96% (X ) Cl), 82%
2
20
(
X ) OMe), 44% (X ) OTMS), [R]
D
2 2
) -50.2 (c 0.99, CH Cl ).
Scheme 2. Synthesis of Cyclization Precursors 11-13a
Similar results, albeit in lower yields, were obtained when
the methyl ether 12 or the silyl ether 13 were employed
Scheme 3). These reactions can be rationalized as intra-
molecular S 2′ substitutions of the allylic leaving groups by
(
N
a lithium carbanion nucleophile.
The structure elucidation and the determination of the
enantiomeric excess were accomplished, as outlined in
Scheme 4, by the conversion of 15 to the vinylcyclopentanol
Scheme 4. Structure Elucidation of Cyclization Product 15a
a
(
a) (i) 1.4 equivof sBuLi, 1.5 equiv of (-)-sparteine 5, -78
O; (ii) 1.7 equiv of Bu SnCl, -78 °C to rt, 85%; (b) TBAF,
O, rt, quant; (c) Swern oxidation, 93%; (d) (EtO) P(O)CH CO Et,
DBU, LiCl, CH CN, rt, 94%, E/Z > 97:3; (e) DIBAL, THF, -78
C, 98%; (f) KHMDS, MsCl, LiCl, THF, -78 °C to rt, 93%; (g)
LiHMDS, MeOTf, THF, -78 °C to rt, 78%; (h) LiHMDS, TMSCl,
78 °C to rt, THF, 75%.
°
Et
C, Et
2
2
3
2
2
2
3
°
-
consequence of the high pro-S-selectivity in the deprotonation
and the retention in the substitution step of alkyl carbamates,
a
(a) (i) MeSO
3
H, MeOH, reflux; (ii) K
2 3
CO , reflux, 81%; (b)
(
5) (a) Hoppe, D.; Woltering, M. J.; Oestreich, M.; Fr o¨ hlich, R. HelV.
Swern, 93%; (c) PhCH
2
PPh Br, KOtBu, Et
3
2
O, -40 °C to rt, 93%,
2
0
Chim. Acta 1999, 82, 1860-1877. (b) Oestreich, M.; Fr o¨ hlich, R.; Hoppe,
D. J. Org. Chem. 1999, 64, 8616-8626. (c) Oestreich, M.; Hoppe, D.
Tetrahedron Lett. 1999, 40, 1881-1884. (d) Tomooka, K.; Komine, N.;
Sasaki, T.; Shimizu, H.; Nakai, T. Tetrahedron Lett. 1998, 39, 9715-9718.
E/Z ) 72:28; (d) 1.5 equiv of nBuLi, Et O, -78 °C, 56%, [R]
2
D
3
20
)
-21.9 (c 1.11, CH
2
Cl
2
) (lit. [R]
D
2 2
) -20.9 (c 0.98, CH Cl )).
(
e) For an inter-/intramolecular carbolithiation, see: Wei, X.; Taylor, R. J.
K. Angew. Chem. 2000, 112, 419-422; Angew. Chem., Int. Ed. 2000, 39,
09-412.
6) (a) Deiters, A.; Hoppe, D. J. Org. Chem. 2001, 66, 2842-2849. (b)
Deiters, A.; M u¨ ck-Lichtenfeld, C.; Fr o¨ hlich, R.; Hoppe, D. Chem. Eur. J.
1
16. Comparison of the H NMR spectra of 16 and of the
4
11
known racemate confirmed the trans configuration. The
(
2
1
3
002, 8, 1833-1842 and references therein.
7) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201-
202.
(9) Representative Cyclization Procedure. A solution of the allyl
chloride 11 (169 mg, 0.285 mmol) in dry Et2O (3 mL) under an atmosphere
of argon in a flame-dried flask, sealed with a rubber septum, was cooled to
-78 °C. n-Butyllithium (0.27 mL, 0.43 mmol, 1.5 equiv; 1.6 M in hexanes)
was added dropwise, and the mixture was stirred for 2 h. After quenching
with MeOH (0.2 mL) and H2O (0.1 mL) at -78 °C, the mixture was allowed
to warm to rt, dried (Na2SO4), filtered, and concentrated in vacuo. Flash
chromatography (silica gel, petroleum ether to Et2O/petroleum ether ) 1:4)
(
(8) (a) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron Lett. 1997,
8, 8939-8942. (b) Coldham, I.; Lang-Anderson, M. M. S.; Rathmell, R.
E.; Snowden, D. J. Tetrahedron Lett. 1997, 38, 7621-7624. (c) Coldham,
I.; Fern a` ndez, J.-C.; Price, K. N.; Snowden, D. J. J. Org. Chem. 2000, 65,
3
788-3795. (d) Ashweek, N. J.; Coldham, I.; Snowden, D. J.; Vennall, G.
20
P. Chem. Eur. J. 2002, 8, 195-207. (e) Serino, C.; Stehle, N.; Park, Y. S.;
Florio, S.; Beak, P. J. Org. Chem. 1999, 64, 1160-1165. For the synthesis
of enantioenriched R-oxy-stannanes, see: (f) Tomooka, K.; Igarashi, T.;
Nakai, T. Tetrahedron Lett. 1994, 35, 1913-1916.
afforded the product 15 as a colorless oil (73 mg, 0.273 mmol, 96%; [R]
D
) -50.2 (c 0.99, CH2Cl2)).
(10) All new compounds were characterized by H NMR, 13C NMR,
1
IR, MS, and elemental analysis.
2190
Org. Lett., Vol. 4, No. 13, 2002

ee was determined to be >95% by chiral GC. The application
of the tin-lithium exchange/asymmetric cyclization protocol
to the 6-phenyl-5-hexenyl stannane 17 afforded the known
cyclopentane 4 (El ) H), which is identical in all respects
with a sample from the direct deprotonation/cyclocarbo-
lithiation. Therefore, the retention of configuration at C-1
in the course of the tin-lithium exchange is confirmed.
These encouraging results led us to the question what
influence the exchange of a hydrogen by a methyl group at
the carbon bearing the leaving group would have concerning
the configuration of the product, either to the cis/trans-
geometry in the ring and/or to the E/Z-geometry of the newly
built double bond.
Table 1. Cyclization of Pure C-7 Epimers (7R)- and (7S)-19
entry
config 19a
yield 19b
yield 20
yield 21
RD 21
1
2
3
7RS
7R
7S
69%c
96%
86%
37%d
74%d,e
6%d
57%
25%
13%f
-13.5
+21.4
-25.3
The methyl ether 19 was prepared in a similar fashion as
compound 12. Application of the standard cyclization
conditions (-78 °C, 2 h) to 19 gave exclusively the (E)-
configured cyclization product 20 as a single diastereomer
a Configuration at C-7. b Over two steps (reduction/methylation). c The
d
e
20
reduction was carried out with DIBAL; see Scheme 5. E/Z > 97:3. [R]
D
f
)
-61.4 (c 1.515, CH2Cl2). Most of the starting material decomposed
(1,2-trans) but in a poor yield (Scheme 5). In addition, the
under the reaction conditions.
Analogously, we examined the influence of the double
bond geometry in the cyclization precursor 19. However,
the reaction of both C-7 epimers of 23 that are derived from
the alcohol 8 via the phosphonium salt 22 afforded at -78
Scheme 5. Synthesis and Cyclization of Methyl Ether 19a
°
C only the destannylated compound 24; no cyclization
product was detected (Table 2). Ring closure to 20 occurred
Table 2. Cyclization of (Z)-Methyl Ethers (7R)- and (7S)-23
a
(
a) Swern oxidation, 93%; (b) (EtO)
CN, rt, 58%, E/Z > 97:3; (c) DIBAL, THF, -78 °C,
8%; (d) KHMDS, MeOTf, Et O, -78 °C to rt, 78%; (e) 1.5 equiv
of nBuLi, Et ) -62.6 (c 0.38, CH Cl ).
O, -78 °C. 20: [R]20
2 2 3
P(O)CH C(O)CH , DBU,
LiCl, CH
3
8
2
2
D
2
2
destannylated compound 21 showed a considerable optical
activity, which led us to the assumption of a kinetic resolution
in the cyclization step.12
entry config 23a yield 23 T (°C) yield 20 yield 24 RD 24
Thus, with the intention of proving this hypothesis, the
methyl ethers (7R)- and (7S)-19 were prepared by an
1
2
3
4
7S
7S
7R
7R
77%b
-78
-40
-78
-40
0%
96%
14%
32%
26%
-6.3
35%c
e
13
enantioselective CBS-reduction as the key step and submit-
ted to the standard cyclization conditions, i.e., 1.5 equiv of
n-butyllithium at -78 °C for 2 h (Table 1). These experi-
ments furnished the cyclization product 20 in 74% yield from
66%b
0%
37%d
+0.8f
e
a
Configuration at C-7. b E/Z < 3:97. c E/Z > 97:3, [R] D ) -58.6
20
d
20
(
c 0.145, CH2Cl2). E/Z > 97:3, dr ) 95:5, [R] D ) -51.1 (c 0.73,
(R)-19. In comparison with that, the reaction of (S)-19
e
f
CH2Cl2). Not determined. Partial racemization occurred in the course of
the synthesis of (R)-2-methoxypropanal.15
afforded only traces of 20. The different ability of the pure
diastereomers 19 to undergo the cyclization (Scheme 6,
entries 2 and 3) gives strong support for an efficient kinetic
diastereomer resolution.
when the temperature was raised to -40 °C.14 Again, 20
was isolated as a single stereoisomer (1,2-trans, 2(1E)), but
with rather poor yield.
(
11) Hoffmann, R. W.; Niel, G. Liebigs Ann. Chem. 1991, 1195-1201.
(12) (a) For a kinetic resolution in the cyclization step of an enantiose-
In summary the configuration at C-7, as well as the double
bond geometry, in the cyclization precursors 19 and 23 have
no effect on the stereochemistry of the product 20. Both
influence only the cyclization rate of the compounds 19 and
lective carbolithiation, see ref 5d. (b) A cyclization onto a trisubstituted
methyl allyl ether without kinetic resolution is described by Broka et al.
There, primary stannanes were used, and the reaction mixture was allowed
to warm from -78 to 0 °C: Broka, C. A.; Lee, W. J.; Shen, T. J. Org.
Chem. 1988, 53, 1338-1340.
2
3.
(
13) Review: Corey, E. J.; Helal, C. Angew. Chem. 1998, 110, 2092-
2
118; Angew. Chem., Int. Ed. 1998, 37, 1986-2012. Usually, the (R)-CBS-
oxazaborolidine furnishes the (S)-alcohol, and the (S)-CBS-oxazaborolidine
gives the (R)-alcohol. According to the published closely related examples,
the de is assumed to be >95%.
(14) Higher temperatures have not been applied, as the configurational
and thermal stability of the intermediate R-oxy lithium compound is certain
only below -40 °C.7
Org. Lett., Vol. 4, No. 13, 2002
2191

cyclopentanols. The chiral precursors are easily prepared by
the sec-butyllithium/(-)-sparteine deprotonation method and
subsequent stannylation; the stannane unit, as a chiral
carbanion equivalent, was maintained during the construction
of the alkyllithium-sensitive internal allylic moiety. Another
application is reported in the following paper. Expanding
the scope of this asymmetric cyclization method to further
carbo- and heterocycles is in progress and will be published
in due course.
Table 3. Synthesis and Cyclization of Acetal 25
1
6
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Sonderforschungs-bere-
ich 424). We thank Mrs. C. Weitkamp for her skillful
experimental assistance.
entry
E/Z 25
T (°C)
yield 26
14%b
82%c
E/Z 26
yield 27
1
2
< 3:97
< 3:97
-78
-40
>97:3
95:5
81%
11%
a
Isomers are separatable. b [R]20D ) -66.2 (c 1.07, CH2Cl2). c dr ) 95:5.
Supporting Information Available: Detailed experi-
mental procedures for the cyclizations and spectroscopic data
for the compounds 4, 7, 15, 16, 20, 21, 24, 26, and 27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Similar results as for 23 were obtained in the cyclization
of the acetal 25 (Table 3). No cyclization was observed when
employing the standard cyclization conditions (2 h, -78 °C),
as outlined in Table 3. Cyclization occurred when the
reaction was accomplished at -40 °C, affording the (E)-
configured enol ether 26 in good yield.
OL026068W
In summary, we have shown that tin-lithium exchange
followed by intramolecular cycloalkylation proceeds with
very high stereoselection to furnish new enantioenriched
(
15) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung,
Y. S.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274-6282.
(16) Gralla, G.; Wibbeling, B.; Hoppe, D. Org. Lett. 2002, 4, 2193-2196.
2192
Org. Lett., Vol. 4, No. 13, 2002