Diastereoselective zinco-cyclopropanation of chiral allylic alcohols with gem-dizinc carbenoids

Article abstract of DOI:10.1021/ja054328+

The highly diastereoselective zinco-cyclopropanation of chiral allylic alcohols using gem-dizinc carbenoids is described. The reaction produces three contiguous stereogenic centers, and the resulting chiral cyclopropylzinc derivatives can be trapped with

Full text of DOI:10.1021/ja054328+

Published on Web 09/02/2005
Diastereoselective Zinco-Cyclopropanation of Chiral Allylic Alcohols with
gem-Dizinc Carbenoids
Jean-Franc¸ois Fournier, Simon Mathieu, and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al (Que´bec) Canada H3C 3J7
Received June 30, 2005; E-mail: andre.charette@umontreal.ca
1,2,3-Substituted cyclopropanes are important subunits in natural
products and other biologically active molecules.1 Our interest in
developing stereoselective methods for their synthesis using zinc
carbenoids2 prompted us to look at novel organometallic species
that would complement existing methods. Recently, an approach
relying on the synthesis and reactivity of gem-dizinc carbenoids3
prepared from Et2Zn and iodoform was developed.4 The reaction
proceeds via a cyclopropylzinc intermediate 3, which could then
be further functionalized upon treatment with a suitable electrophile
or undergo palladium-catalyzed cross-coupling reactions. The scope
of the reaction could be significantly enhanced by using gem-dizinc
carbenoid 2a prepared from EtZnI and CHI3. Herein, we report
that the directed zinco-cyclopropanation of chiral acyclic allylic
Figure 1. Two possible diastereomeric zinc complexes.
alcohols using gem-dizinc carbenoids (such as 2a) is highly
stereoselective, yielding either to syn or anti cyclopropanes,
Scheme 1
depending on the substitution pattern of the alkenes. This is quite
remarkable given the overall instability of reagent 2a.4 The reaction
provides an expedient route to chiral, nonracemic 1,2,3-substituted
cyclopropanes.
It is well-established that proximal basic groups of chiral acyclic
allylic alcohols, ethers, or zinc alkoxides can direct the cyclopro-
panation reaction of simple zinc and samarium carbenoids (MCH2X),
leading to one predominant diastereomer.5 On the basis of this
precedent, we were intrigued by the possibility of using gem-dizinc
carbenoid reagents in a directed process. Since both iodozinc groups
in 2a are enantiotopic, complexation of this reagent to a zinc
alkoxide derived from a chiral allylic alcohol can lead to many
diastereomeric complexes since up to three additional stereocenters
could be formed upon complexation (O, ZnI, and C1′ in Figure 1).
Since the transition structure of the cyclopropanation reaction of
zinc carbenoids is assumed to proceed in a well-defined manner
via precomplexation of the basic group with the Lewis acidic
reagent, good diastereocontrol for this reaction can only be achieved
if the equilibrium between the diastereomeric complexes is faster
than the zinco-cyclopropanation. Alternatively, it is also possible
but highly unlikely that the various possible diastereomeric com-
plexes could lead to a highly diastereoselective transfer. A simple
model indicates that among the many possible diastereomeric com-
plexes, two potential complexes A and B that minimize the A-1,3
strain could lead to two diastereomeric cyclopropylzinc derivatives.
The Z-alkene 5 was chosen as the test substrate since Z-
substituted chiral allylic alcohols provide excellent diastereomeric
ratios with samarium and zinc carbenoids. The optimization of the
reaction conditions involved the deprotonation of alcohol 5 with
1.2 equiv of ethylzinc iodide. The zinc alkoxide was then added to
2.0 equiv of the gem-dizinc carbenoid prepared by mixing 2 equiv
of iodoform with 4 equiv of ethylzinc iodide (leading theoretically
to 2 equiv of the gem-dizinc carbenoid 2a) at 0 °C. We were very
pleased to observe that, under these conditions, 6a could be isolated
in 76% yield and as a single diastereomer (out of four possible
diastereomeric cyclopropanes) upon quenching with D2O (eq 1).
The yield and the efficiency of the process could be improved
if 0.5 equiv of ZnI2 was added to the reaction mixture (Table 1,
entry 1).6 Under these conditions, the amount of 2a could be
decreased to 1.5 equiv and the reaction time to 20 min. Although
the exact role of ZnI2 is not known, it is believed to either stabilize
2a (by avoiding its premature decomposition) or to lower the
transition state energy of the zinco-cyclopropanation reaction.
Equally high isolated yields were observed if the cyclopropylzinc
intermediate was quenched with D2O or with iodine.
9
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J. AM. CHEM. SOC. 2005, 127, 13140-13141
10.1021/ja054328+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Diastereoselective Zinco-Cyclopropanation of cis-Allylic
Alcohols and Ethers
syn:anti ratio; however, the trans-cyclopropylzinc was now the
major product, indicating that the benzyl ether became a better
directing group than the more sterically hindered zinc alkoxide
(entry 2).10 A cis-selective reaction could be achieved by replacing
the benzyl protecting group by a triisopropylsilyl (entry 3).
This level of diastereocontrol could be increased by using a TMS-
substituted allylic alcohol.11,12 Introducing a TMS substituent at
either the R1 or the R2 position led to the exclusive formation of
the anti,cis or of the syn,trans diastereomer.13
Access to enantiomerically pure orthogonally protected 1,2,3-
cis-substituted cyclopropane is easily accomplished starting from
enantioenriched 14, which is readily available using Carreira’s
catalytic asymmetric alkynylation of aldehydes, and when followed
by reduction led to 16.14,15 Treatment of alcohol 16 with Dess-
Martin periodinane afforded ketone 36 that underwent Baeyer-
Villiger oxidation to afford 37 (overall, five steps from pivaldehyde).
dr
yield (%)
(E D)
yield (%)
(E I)
entry
R (PG)
(a:(b
+
c
+
d))
)
)
1
2
3
4
5
6
Me (H) (5)
Et (H) (8)
i-Pr (H) (11)
t-Bu (H) (14)
Ph (H) (17)
Me (Bn) (20)
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
82 (6)
85 (9)
86 (12)
91 (15)
62 (18)
86 (21)
75 (7)
84 (10)
87 (13)
91 (16)
58 (19)
77 (22)
Table 2. Diastereoselective Zinco-Cyclopropanation of
Trisubstituted Allylic Alcoholsa
In conclusion, the directed zinco-cyclopropanation reaction of
gem-dizinc carbenoid of chiral allylic alcohols provides an expedient
entry into the 1,2,3-substituted cyclopropane motif.16 Further studies
are in progress to extend the scope of the reaction and for its
application in natural product synthesis.
Acknowledgment. This work was supported by NSERC and
the Universite´ de Montre´al. J.-F.F. is grateful to NSERC (PGF B)
and F.C.A.R. (B2) for postgraduate fellowships. S.M. thanks
NSERC for a postgraduate fellowship (PGS M) and the Universite´
de Montre´al for a S. Hanessian fellowship.
Supporting Information Available: Experimental procedures for
the preparation of all the compounds and characterization data for each
reaction and detailed structural assignment. This material is available
free of charge via the Internet at http://pubs.acs.org.
dr
dr
entry
PG
R
R1
R2
(syn:anti)
(cis:trans)
yield (%)
1
2
3
4
5
6
7
H
H
Me
t-Bu
H
H (23)
H (24)
H (25)
TMS (26)
TMS (27)
60:40
94:6
>95:5
<5:95 >95:5
<5:95 >95:5
>95:5
>95:5
85 (29)b
H
H
H
H
28:72 73 (30)b
75:25 64 (31)b
TIPS t-Bu
H
H
H
H
Me
t-Bu
68 (32c)
77 (33c)
References
(1) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. ReV. 2003, 103,
t-Bu TMS H (28)
t-Bu TMS H (28)
<5:95 84 (34b)
<5:95 81 (35b)
1625-1648.
(2) For reviews on zinc carbenoids, see: (a) Lebel, H.; Marcoux, J. F.;
Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977-1050. (b)
Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1-415. (c)
Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M. Org.
React. 1973, 20, 1-131.
a In entries 2-6, cyclopropylzinc was quenched with D2O (E ) D). I2
was used in entries 2 and 7 (E ) I). H2O was used in entry 1. b Combined
yield of the diastereomers.
(3) For reviews on gem-dimetallic compounds, see: (a) Marek, I. Chem. ReV.
2000, 100, 2887-2900. (b) Matsubara, S.; Oshima, K.; Utimoto, K. J.
Organomet. Chem. 2001, 617-618, 39-46.
These conditions were then applied to the zinco-cyclopropanation
of several cis-disubstituted allylic alcohols bearing various sterically
demanding substituents at the allylic position (Table 1). High
diastereomeric ratios were observed with a wide range of substit-
uents (entries 2-5). The facial selectivity for the attack of the gem-
zinc carbenoid on the alkene was excellent and is consistent with
an alkoxy-directed reaction involving the A1,3 minimized conformer.
In all the cases, the resulting cyclopropylzinc had a cis-relationship
with the other substituents on the ring as determined by trapping
with a suitable electrophile. High diastereoselectivity leading to the
cis,syn-isomer was also observed using a protected allylic alcohol
(entry 6). It is also possible to trap the intermediate cyclopropylzinc
in a copper-mediated allylation reaction.7,8
The zinco-cyclopropanation of the corresponding trans-isomer
leads to a mixture of stereoisomers (Table 2, entry 1). This is not
surprising since the cyclopropanation of this substrate with unsub-
stituted zinc carbenoids proceeds with poor diastereocontrol.
Treatment of 23a with 5 equiv of Et2Zn and 5 equiv of CH2I2 led
to a 57:43 syn:anti ratio.9 As expected, increasing the size of the R
group in the zinco-cyclopropanation led to an improvement in the
(4) Charette, A. B.; Gagnon, A.; Fournier, J. F. J. Am. Chem. Soc. 2002,
124, 386-387.
(5) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370. (b) Molander, G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525-
3532.
(6) Fournier, J. F.; Charette, A. B. Eur. J. Org. Chem. 2004, 1401-1404.
(7) Sekiya, K.; Nakamura, E. Tetrahedron Lett. 1988, 29, 5155-5156. See
Supporting Information for experimental details.
(8) Cyclopropylzinc species have been reported to be useful synthetic
intermediates that could be used in copper-catalyzed processes as well as
in Ni- and Pd-coupling reactions: (a) Piers, E.; Coish, P. D. G. Synthesis
2001, 251-261. (b) de Lang, R.-J.; Brandsma, L. Synth. Commun. 1998,
28, 225-232. (c) See also ref 4.
(9) Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966-2967.
(10) For a systematic study of the directing group ability of ethers versus zinc
alkoxides, see: Charette, A. B.; Marcoux, J. F. Synlett 1995, 1197-1207.
(11) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1992, 57, 798-800.
(12) For an alternative approach, see: Takai, K.; Hirano, M.; Toshikawa, S.
Synlett 2004, 1347-1350.
(13) For synthetic applications of silyl-substituted cyclopropane derivatives,
see: Paquette, L. A. Chem. ReV. 1986, 86, 733-750.
(14) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688.
(15) See Supporting Information for the preparation of enantiomerically
enriched 16.
(16) Allylic ethers bearing only one directing group could not be zinco-
cyclopropanated using this protocol.
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