Diastereoselective Reduction of Cyclopropenylcarbinol: New Access to anti-Cyclopropylcarbinol Derivatives

Article abstract of DOI:10.1021/ol036143i

(Matrix presented) Cyclopropenylcarbinol derivatives are regio- and diastereoselectively reduced with LiAlH₄ in Et₂O into trans-cyclopropylcarbinols as a single isomer. The regioselectivity of the hydroalumination reaction on the cyclopropenyl ring has been mapped out by deuterium labeling experiments.

Full text of DOI:10.1021/ol036143i

ORGANIC
LETTERS
2004
Vol. 6, No. 3
341-343
Diastereoselective Reduction of
Cyclopropenylcarbinol: New Access to
anti-Cyclopropylcarbinol Derivatives
Elinor Zohar and Ilan Marek*
Department of Chemistry and Institute of Catalysis Science and Technology,
Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
chilanm@tx.technion.ac.il
Received November 2, 2003
ABSTRACT
Cyclopropenylcarbinol derivatives are regio- and diastereoselectively reduced with LiAlH in Et2O into trans-cyclopropylcarbinols as a single
4
isomer. The regioselectivity of the hydroalumination reaction on the cyclopropenyl ring has been mapped out by deuterium labeling experiments.
The directed cyclopropanation of acyclic allylic alcohols with
halomethylmetal reagents such as zinc, samarium, or alu-
minum carbenoids is nowadays a well-known process, and
many reagents and reaction conditions are known to lead to
cyclopropylcarbinols with variable selectivities.1 Interactions
between the heteroatom functionality and the reagent usually
precede the ensuing chemical transformations,2 and in some
cases, very high syn selectivities were observed either for
(E)- or (Z)-disubstituted chiral allylic alcohols.3 The nature
of the carbenoid reagent used is extremely important for good
diastereoselectivity (i.e., EtZnCH2I, Zn(CH2I)2, and IZn-
(CH2I) gave different ratios for the same substrate).1 How-
ever, the direct preparation of the anti-cyclopropylcarbinol
derivative with good diastereoselection is a much more
difficult task.
by a diastereoselective cyclopropanation of silyl-protected
chiral allylic alcohols5 with use of Shi’s zinc carbenoid
(Scheme 1).6
Scheme 1
Some of these compounds are accessible by the reduction
of the corresponding cyclopropyl ketone,4 and more recently
(1) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV.
2003, 103, 977.
Moreover, in the halomethylmetal reagents based strategy
for the cyclopropanation reactions of allylic alcohols, primary
(2) Hoveyda, A. H.; Evans, D. A.; Fu, G. A. Chem. ReV. 1993, 93, 1307.
(3) (a) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyre, M. J. Chem. Res.,
Miniprint 1978, 2309. (b) Schollkopf, U.; Tiller, T.; Bardenhagen, J.
Tetrahedron 1988, 44, 5293. (c) Molander, G. A.; Etter, J. B. J. Org. Chem.
1987, 52, 3942. (d) Molander, G. A.; Harring, L. S. J. Org. Chem. 1989,
54, 3525. (e) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1992, 57,
798. (f) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1995, 60, 2474.
(g) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001,
123, 12160. (h) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1.
(4) (a) Delanghe, P. H.; Lautens, M. Tetrahedron Lett. 1994, 35, 9513.
(b) Kazuta, Y.; Abe, H.; Yamamoto, T.; Matsuda, A.; Shuto, S. J. Org.
Chem. 2003, 68, 3511.
(5) Charette, A. B.; Lacasse, M.-C. Org. Lett. 2002, 4, 3351.
(6) Yang, Z.; Lorenz, J.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621.
10.1021/ol036143i CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/14/2004

carbenoids are mainly used, and only a few examples are
therefore described for the cyclopropanation reaction with
unstable secondary and tertiary carbenoids.7 On the other
hand, diastereoselection in the hydrometalation of acyclic
compounds is controlled by allylic,2,8 homoallylic,9 and even
more remote stereogenic centers.10 Moderate to high levels
of anti selectivity are usually achieved.8-10 Therefore, we
thought that the diastereoselective reduction of cyclopro-
penylcarbinol11 such as 1a-h (Scheme 2) should be an
Scheme 3
cyclopropylcarbinol products 2a,b but with only a moderate
anti selectivity (anti/syn 80/20; deduced from comparison
with an authentic sample).15
Scheme 2
Table 1. Diastereoselective Reduction of
Cyclopropenylcarbinol into trans-Cyclopropylcarbinol
yields
(%)b
entry pdt R1
R2
R3
dra
1
2
3
4
5
6
7
8
1a
1b
H
H
CH2CH2Ph Et
80:20
80:20
>98:2
>98:2
>98:2
>98:2
85
50
86
74
80
75
80
64
CH3
Et
1c CH3 CH3
1d CH3 CH3
1e CH3
1f CH3
1g CH3 CH3
1h CH3 Si(CH3)3
Et
CH3
Et
c-C6H11
interesting and powerful solution to the preparation of trans-
cyclopropylcarbinol derivatives.
H
H
Cyclopropenylcarbinols 1a-h are themselves obtained in
one chemical step in good to excellent isolated yields from
1,1,2-trihalogenocyclopropanes (prepared by reaction of
substituted vinyl halide derivatives with bromoform in the
presence of a phase transfer catalyst such as cetrimide)12 by
a successive 1,2-dehalogenation reaction followed by a
halogen-lithium exchange and reaction with various alde-
hydes as described in Scheme 2.13
CH2CHdCHEt >98:2
Et
>98:2c
a Diastereomeric ratio was determined by 1H and 13C NMR of the crude
reaction mixture. b Yields of isolated pure products after column chroma-
tography. c Diastereomeric ratio of the trans-cyclopropylcarbinol versus the
secondary alcohol; ratio of the cis/trans cyclopropane itself is 40/60, see
text.
For correlation purposes, we have first reduced unsubsti-
tuted cyclopropenylcarbinols 1a,b (R1 ) H, R2 ) alkyl, see
Scheme 3 and Table 1, entries 1 and 2) with 1 equiv of
LiAlH4 in Et2O at +40 °C.14 Under these conditions, we were
pleased to obtain in good chemical yields the expected
On the other hand, when the three-membered ring of the
cyclopropenylcarbinol has a geminal dialkyl group such as
in 1c-h, excellent diastereoselectivities are obtained as
described in Table 1, entries 3 to 8.16
Indeed, the reduction of the fully substituted cyclopro-
penylcarbinol 1c occurs readily with 1 equiv of LiAlH4 in
Et2O to give anti-cyclopropylcarbinol 2c as a single diaste-
reoisomer. On the other hand, if only 0.5 equiv of LiAlH4 is
used, reduced products are obtained in low yields. Similarly,
if THF is used as solvent instead of Et2O, the anti/syn ratio
of the reaction drops to only 6:1 in low yield. The presence
of a free hydroxyl group is absolutely necessary for the
reduction of cyclopropenylcarbinol derivatives (obviously the
alcohol moiety is first deprotonated with LiAlH4), and as
illustration, when alcohol 1c was protected as its tert-
butyldimethylsilyl ether, no reduced product was observed
under our experimental conditions. Similarly, neither the
Schwartz reagent Cp2Zr(H)Cl or DIBAL-H led to the reduced
product. An even smaller R3 substituent can be used in this
diastereoselective reduction, such as the methyl group (Table
1, entry 4). The reduced product 2d is obtained as a single
diastereoisomer in good overall yield. On the other hand,
when R3 is an aromatic group, the reduction also occurs but
(7) (a) Groth, U.; Schollkopf, U.; Tiller, T. Liebigs Ann. Chem. 1991,
857. (b) Charette, A. B.; Lemay, J. Angew. Chem., Int. Ed. Engl. 1997, 36,
1090. (c) Charette, A. B.; Marcoux, J.-F.; Molinaro, C.; Beauchemin, A.;
Brochu, C.; Isabel, E. J. Am. Chem. Soc. 2000, 122, 4508. (d) Shibli, A.;
Varghese, J. P.; Knochel, P.; Marek, I. Synlett 2001, 818.
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3725. (b) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
(c) Heathcock, C. H.; Jarvi, E. T.; Rosen, T. Tetrahedron Lett. 1984, 25,
243.
(9) (a) Evans, D. A.; Bartoli, J.; Godel, T. Tetrahedron Lett. 1982, 23,
4577. (b) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc.
1982, 104, 2027. (c) Schulte-Elte, K. H.; Ohloff, G. HelV. Chim. Acta 1967,
50, 153.
(10) Still, W. C.; Darst, K. P. J. Am. Chem. Soc. 1980, 102, 7387.
(11) Cyclopropene derivatives are well-known and were successfully used
in synthesis. For recent review, see: (a) Nakamura, M.; Isobe, H.; Nakamura,
E. Chem. ReV. 2003, 103, 1295. (b) Houben-Weyl, Methods in Organic
Chemistry, Carbocyclic Three-Membered Ring Compounds; de Meijere, A.,
Ed.; Thieme: Stuttgart, Germany, 1997; Vol. E 17d, p 2695. (c) Stoll, A.
T.; Negishi, E. Tetrahedron Lett. 1985, 26, 5671.
(12) Baird, M. S.; Hussain, H. H.; Nethercott, W. J. Chem. Soc., Perkin
Trans. 1 1986, 1845.
(13) (a) Baird, M. S.; Nethercott, W. Tetrahedron Lett. 1983, 24, 605.
(b) Baird, M. S.; Hussain, H. H. Tetrahedron 1987, 43, 215. (c) Al-
Dulayymi, J. R.; Baird, M. S. Tetrahedron Lett. 1988, 29, 6147. (d) Al-
Dulayymi, J. R.; Baird, M. S. Tetrahedron 1989, 45, 7601. (e) Al-Dulayymi,
A. R.; Baird, M. S. J. Chem. Soc., Perkin Trans. 1 1994, 1547.
(14) (a) Vincens, M.; Dumont, C.; Vidal, M.; Domnin, I. N. Tetrahedron
1983, 39, 4281. (b) Vidal, M.; Arnaud, P. Bull. Soc. Chim. Fr. 1972, 675.
(15) (a) Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966.
(16) Diastereoselectivity is measured by 1H and 13C NMR on the crude
reaction mixture.
342
Org. Lett., Vol. 6, No. 3, 2004

the resulting vinyl aluminum species obtained before acidic
hydrolysis undergoes a ring fragmentation into polysubsti-
tuted diene.17 The cyclopropenylcarbinol can also bear three
alkyl substituents as in 1e (R2 ) H, Table 1, entry 5) or be
substituted by a secondary alkyl group (1f, R3 ) cyclohexyl,
Table 1, entry 6) without altering the diastereoselectivity of
the reduction.
Considering that the deprotonation of the alcohol precedes
the reduction and assuming that the reaction occurs intra-
molecularly inducing the hydroalumination reaction on the
same face as the oxygen atom, the anti-diastereofacial
selectivity in the hydroalumination reaction of cyclopro-
penylcarbinol derivatives involved a transition state with the
smallest substituent at the preexisting stereogenic center
(hydrogen) oriented “inside” over the face of the transition
state ring.
Minimization of the A-1,3 strain20 is therefore the main
controlling element for the good diastereocontrol and then
the oxygen atom is oriented “outside” slightly (Houk’s
transition state model)21 as described in Scheme 5.
As the heat of hydrogenation for the conversion of
cyclopropene to cyclopropane is ca. 54 kcal/mol and is
considerably larger than that for the conversion of ethylene
to ethane,18 the chemoselective reduction of the cyclopro-
penylcarbinol containing a (E) double bond such as in 1g
(Table 1, entry 7) has been investigated. The expected anti-
cyclopropylcarbinol 2g was obtained in good yield as a
unique isomer without any reduction of the external (E)
double bond. Finally, the silyl cyclopropenylcarbinol 1h,
treated under our experimental conditions, leads to the
expected adduct with an anti relationship between the
cyclopropyl and the secondary alcohol moieties but as a
mixture of trans and cis isomers on the silyl-cyclopropane
ring itself (trans/cis 60/40). The presence of these two
isomers came from the remarkably facile configurational
isomerization of 1-silyl-1-aluminocyclopropyl derivatives.19
The regioselectivity of the hydroalumination reaction on
the cyclopropenyl ring has been mapped out by deuterium
labeling experiments. When LiAlD4 was used as reducing
agent followed by acid hydrolysis, 1c and 1e led to the
deuteriocyclopropanes 2c(d1) and 2e(d1), respectively, as
unique isomers in good chemical yields as shown in Scheme
4. On the other hand, when 1c was treated with LiAlH4
Scheme 5
Moreover, the presence of the geminal dimethyl group on
the upper carbon of the cyclopropenyl moiety also has an
effect on the diastereoselectivity of the reduction (compare
entries 2 and 3, Table 1). Due to the short bond lengths of
the carbon-carbon bonds in the cyclopropene ring,22 syn-
pentane interactions (between the R substituent at the
preexisting stereogenic center and the methyl groups) have
an important effect on the diastereoselectivity. In conclusion,
the diastereoselective reduction of polysubstituted cyclopro-
penylcarbinol with LiAlH4 in Et2O allows an easy and
straightforward preparation of trans-cyclopropylcarbinol as
a single isomer.
Scheme 4
Acknowledgment. This research was supported by the
Israel Science Foundation administrated by the Israel Acad-
emy of Sciences and Humanities (79/01-1) and by Technion
Research & Development.
followed by deuterio methanolysis, 2c(d2) is obtained as the
unique isomer. Therefore, both deuteriocyclopropylcarbinols
can be selectively prepared.
Supporting Information Available: Experimental pro-
1
cedures with a description of H and 13C NMR data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) The stereospecific formation of diene will be reported in due course.
(18) (a) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and
Organometallic Compounds; Academic Press: New York, 1970. (b) Gloss,
G. AdV. Alicyclic Chem. 1966, 1, 53.
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S. Chem. Lett. 1986, 177. (c) Negishi, E.; Takahashi, T. J. Am. Chem. Soc.
1986, 108, 3402.
OL036143I
(20) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(21) Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J. T.; Paddon-Row,
M. N. Tetrahedron 1984, 40, 2257.
(22) Carter, F. L.; Frampton, V. L. Chem. ReV. 1964, 64, 497.
Org. Lett., Vol. 6, No. 3, 2004
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