Enantio- and diastereoselective tandem zn-promoted brook rearrangement/ene - Allene carbocyclization reaction

Article abstract of DOI:10.1021/ol9004036

The zinc-catalyzed addition of various alkynes to acylsilanes followed by a Zn- Brook rearrangement and either the Zn- ene- allene or Zn- yne- allene cyclization led to the enantio- and diastereoselective formation of carbocycles in a single-pot operation

Full text of DOI:10.1021/ol9004036

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1853-1856
Enantio- and Diastereoselective Tandem
Zn-Promoted Brook Rearrangement/
Ene-Allene Carbocyclization Reaction
Rozalia Unger,† Fritz Weisser,† Nicka Chinkov,† Amnon Stanger,†
Theodore Cohen,‡ and Ilan Marek*,†
Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry, and
the Lise Meitner-MinerVa Center for Computational Quantum Chemistry,
Technion-Israel Institute of Technology, 32 000 Haifa, Israel, and Department of
Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
chilanm@tx.technion.ac.il
Received February 27, 2009
ABSTRACT
The zinc-catalyzed addition of various alkynes to acylsilanes followed by a Zn-Brook rearrangement and either the Zn-ene-allene or
Zn-yne-allene cyclization led to the enantio- and diastereoselective formation of carbocycles in a single-pot operation.
The preparation of enantioenriched tertiary alcohols repre-
sents a stimulating and dynamic area in organic synthesis.
Although effective methods have been described for the
catalytic enantioselective carbon-carbon bond-forming reac-
tions of ketones, they are difficult substrates because of their
low reactivity and the difficulty in controlling facial stereo-
selectivity.1 Therefore, due to the synthetic challenge im-
posed by the difficulties in the creation of such quaternary
stereocenters, most methods usually lead to the creation of
a single carbon-carbon bond per chemical step.2 Over the
past few years, our laboratory has been involved in the
development of alternative and efficient synthetic methodolo-
gies that create several carbon-carbon bonds and stereogenic
centers, including quaternary stereocenters, in a single-pot
operation,3 and we recently questioned whether it might be
possible to develop a simple synthetic solution to the
challenging enantio- and diastereoselective intramolecular
carbometalation reaction on unactivated alkenes4 by using
this principle. Indeed, only very few enantioselective car-
bometalations of alkenes are reported in the literature,4
† Technion-Israel Institute of Technology.
‡ University of Pittsburgh.
(2) For some representative exceptions, see: (a) Marek, I. Chem. Eur.
J. 2008, 14, 7460. (b) Hussain, M. H.; Walsh, P. J. Acc. Chem. Res. 2008,
41, 883.
(1) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b)
Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651. (c) Garcia, C.; La
Rochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970. (d)
DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668.
(e) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895. (f) Stymiest, J. L.;
Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778. (g)
Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873. (h) Shibasaki,
M.; Kanai, M. Chem. ReV. 2008, 108, 2853. (i) Garcia, C.; Larochelle, L. K.;
Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970. (j) Li, H.; Walsh, P. J.
J. Am. Chem. Soc. 2004, 126, 6538. (k) Li, H.; Walsh, P. J. J. Am. Chem.
Soc. 2005, 127, 8355.
(3) (a) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683. (b) Kolodney,
G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew. Chem., Int. Ed.
2007, 119, 9451. (c) Sklute, G.; Marek, I. J. Am. Chem. Soc. 2006, 128,
4642. (d) Sklute, G.; Amsallem, D.; Shibli, A.; Varghese, J. P.; Marek, I.
J. Am. Chem. Soc. 2003, 125, 11776.
(4) For reviews, see: (a) Hogan, A-M. L.; O’Shea, D. E. Chem. Commun.
2008, 38, 3839. (b) Perez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F.
New J. Chem. 2008, 32, 594. (c) Marek, I. J. Chem. Soc. Perkin Trans 1
1999, 535.
10.1021/ol9004036 CCC: $40.75
Published on Web 03/16/2009
2009 American Chemical Society

particularly via asymmetric catalysis.5 In this paper, we
would like to report the first enantio- and diastereoselective
Zn-ene-allene cyclization, via asymmetric catalysis, in
which several carbon-carbon bonds including the challeng-
ing tertiary alcohol stereocenter were created in a single-pot
operation. The intramolecular addition of propargyl/alle-
nylzinc compounds to alkenes and alkynes, called zinc-
ene-allene6 and zinc-yne-allene7 carbocyclization, re-
spectively, leading to the unique formation of carbocycles
in excellent yields as unique diastereoisomers was described
from our research group and was successfully used for the
stereoselective syntheses of polysubstituted tetrahydrofurans8
and pyrrolidines9 as well as for an efficient approach to
angular and linear triquinane skeletons.10
on a model acysilane was reported in the literature,12 and it
has been shown that an enantioenriched silyl alkynol could
be treated with a catalytic amount of n-BuLi to generate
chiral allenyl silylether with minimal erosion of stereochem-
ical information. However, the Brook rearrangement pro-
ceeds only when a catalytic amount of base is utilized, and
the typically rapid and essentially irreversible reaction is by
protonation of the carbanion by the starting alcohol.13
Therefore, transfer of chirality into a metallated allenyl
species through a stoichiometric amount of base for the
Brook rearrangement14 had no precedent, and that drove our
curiosity. We first prepared enantioenriched propargyl silanol
using a tridentate Schiff base ligand 3a as reported by
Scheidt,12a and our results are described in Table 1. We were
This initial approach was further improved when it was
found that a tandem Zn-promoted Brook rearrangement-
carbocyclization reaction also leads to the cyclic product in
similar yields and diastereoselectivities (Scheme 1).11 How-
Table 1. Enantioselective Addition of Alkynes 1a-c to
Acylsilanes 2a-d
Scheme 1. Tandem Zn-Promoted Brook Rearrangement/
Ene-Allene Carbocyclization Reaction
entry
R1
R2
R3
ligand yielda (%)
erb
1
2
3
4
5
6
7
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Hex (1b)
Ph Me (2a)
Ph Ph (2b)
Me t-Bu (2c)
Me Me (2d)
Ph Me (2a)
Ph Me (2a)
3a
3a
3a
3a
3b
3a
3a
94 (4a)
78 (4b)
55 (4c)
96 (4d)
93 (4a)
80 (4e)
87 (4f)
86:14
88:12
53:47
76:24
90:10
84:16
67:33
SiMe3 (1c) Ph Me (2a)
a Isolated yields after column chromatography on silica gel. b Enantiomeric
ratio determined by HPLC on chiral column. c Absolute configuration
determined by comparison of experimentally measured and calculated CD.15
ever,tohaveanenantio-anddiastereoselectiveZn-ene-allene
carbocyclization reaction, we have to address the challenging
in situ preparation and cyclization of enantiomerically
enriched allenylzinc species. The asymmetric alkyne addition
pleased to see that the addition of phenyl acetylene 1a
(R1 ) Ph) to acylsilane 2a (R2 ) Ph, R3 ) Me) proceeds
smoothly to give the expected propargyl silanol 4a in
excellent yield and in fair enantiomeric ratio (94%, er 86:
14, see Table 1, entry 1). Although the same behavior was
found with acylsilane 2b (R2 ) R3 ) Ph, er 88:12, entry 2,
(5) Li chemistry: (a) Majumdar, S.; de Meijere, A.; Marek, I. Synlett
2002, 423. (b) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant,
J. F. Chem.sEur. J. 1999, 5, 2055. (c) Norsikian, S.; Marek, I.; Poisson,
J. F.; Normant, J. F. J. Org. Chem. 1997, 117, 8853. (d) Klein, S.; Marek,
I.; Poisson, J. F.; Normant, J. F. J. Am. Chem. Soc. 1995, 117, 8853. Zn
chemistry: (e) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437.
(f) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122,
978. Zr chemistry: (g) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am.
Chem. Soc. 2006, 128, 2770, and references cited therein. (h) Wipf, P.;
Ribe, S. Org. Lett. 2002, 4, 395. (i) Heron, N. M.; Adams, J. A.; Hoveyda,
A. M. J. Am. Chem. Soc. 1997, 119, 6205.
(12) (a) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2006, 128, 15382. (b) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem.
Soc. 2005, 127, 6170.
(13) For representative examples, see: (a) Reich, H. J.; Eisenhart, E. K.;
Olson, R. E.; Kelly, M. J. J. Am. Chem. Soc. 1986, 108, 7791. (b) Reich,
H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112, 5609.
(14) For recent reports on the Brook rearrangements, see: (a) Smith,
A. B., III.; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int. Ed. 2008, 47,
7082. (b) Smith, A. B., III.; Kim, D. S. J. Org. Chem. 2006, 71, 2547. (c)
Smith, A. B., III.; Kim, D. S. Org. Lett. 2005, 7, 3247. (d) Smith, A. B.,
III.; Kim, D. S. Org. Lett. 2004, 6, 1493. (e) Reynolds, T. E.; Stern, C. A.;
Scheidt, K. A. Org. Lett. 2007, 9, 2581. (f) Tsubouchi, A.; Onishi, K.;
Takeda, T. J. Am. Chem. Soc. 2006, 128, 14268. (g) Linghu, X.; Potnick,
J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070. (h) Nicewicz,
D. A.; Yates, C. M.; Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 2652.
(i) Linghu, X.; Johnson, J. S. Angew. Chem., Int. Ed. 2003, 42, 2534. (j)
Linghu, X.; Nicewicz, D. A.; Johnson, J. S. Org. Lett. 2002, 4, 2957.
(6) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J. F. J. Org.
Chem. 1995, 60, 863.
(7) Meyer, C.; Marek, I.; Normant, J. F.; Platzer, N. Tetrahedron Lett.
1994, 35, 5645.
(8) (a) Lorthiois, E.; Marek, I.; Meyer, C.; Normant, J. F. Tetrahedron
Lett. 1995, 36, 1263. (b) Lorthiois, E.; Marek, I.; Normant, J. F. Bull. Chem.
Soc. Fr. 1997, 134, 5317.
(9) Lorthiois, E.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997, 38,
89.
(10) Meyer, C.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1996, 37,
857.
(11) (a) Unger, R.; Cohen, T.; Marek, I. Org. Lett. 2005, 7, 5313. (b)
Unger, R.; Cohen, T.; Marek, I. Eur. J. Org. Chem. 2009, 0000.
1854
Org. Lett., Vol. 11, No. 8, 2009

Table 1), the more sterically hindered (R2 ) Me, R3 ) t-Bu)
as well as symmetrically substituted (R2 ) R3 ) Me)
acylsilanes 2c,d led to lower enantiomeric ratios (Table 1,
entries 3 and 4, respectively). The enantiomeric ratio could
be slightly improved for the reaction between 1a and 2a by
using ligand 3b instead of 3a (er 90:10, Table 1, entry 5).
In contrast to phenyl acetylene 1a (Table 1, entry 1) and
oct-1-yne 1b (R1 ) Hex, Table 1, entry 6), the enantiomeric
ratio of 4f, resulting from the addition of trimethylsilylacety-
lene 1c to 2a, is only moderate (er 67:33, Table 1, entry 7).
Having in hand propargyl silanol derivatives, we then
investigated the transfer of chirality in the tandem Zn-Brook
rearrangement followed by the Zn-ene--allene carbocy-
clization reaction on the moderately enantioenriched 4d as
described in Scheme 2.
on the stereochemistry of the 1,2-Brook rearrangement was
available, particularly for the formation of a propargylzinc
species. Although more mechanistic investigations are needed
to fully explore this rearrangement, the absolute configuration
of the starting propargyl silanol 4d and the final cyclic
product 5a led us to postulate the following mechanistic
hypothesis: the oxygen atom of the zinc alcoholate 4dZn
first interacts with the silicon atom to form an intermediate
such as 6,19 the zinc countercation occupying the less
sterically hindered face, adjacent to the alkyne (Scheme 3).
Scheme 3. Mechanistic Hypothesis
Scheme 2. Transfer of Chirality in the Sequence Zn-Brook
Rearrangement/Zn-ene-allene Carbocyclization
The zinc-Brook rearrangement would lead to the corre-
sponding propargylzinc derivative 7, with pure retention of
configuration. The second rearrangement in our process, the
metallotropic equilibrium with its allenic counterpart 8,
occurs via a suprafacial migration leading to the correspond-
ing configurationally stable allenylzinc derivative 8 with pure
retention of configuration.20 The latter then undergoes the
last step, a diastereoselective Zn-ene-allene cyclization
reaction in which the allenyl metal moiety plays the role of
the ene moiety and fixes the cis relationships of the two
substituents to give the corresponding alkynyl cyclopentyl
methylzinc derivative 9 (Scheme 3). Clearly, this whole
sequence (three consecutive steps) proceeds with virtually
complete transfer of chirality from 4d with the creation of
two new stereocenters, including the formation of the tertiary
silyl ether as illustrated in 9.
We were pleased to see that when a solution of Et2Zn was
added to enantioenriched 4d (er 76:24) in THF and heated
at 40 °C for 24 h,16 the corresponding cyclic product 5a
was obtained in excellent yield with a similar enantiomeric
ratio (er 74:26) oVer three consecutiVe steps (Zn-Brook
rearrangement, Zn suprafacial migration, and Zn-ene-
allene cyclization, see Scheme 2, path A).17 On the other
hand, when racemic 4d was treated with Et2Zn in the
presence of chiral ligand 3a, only racemic 5a was formed
excluding a possible equilibration of racemic propargyl/
allenylzinc into enantiomerically enriched species via inter-
actions with chiral ligand (Scheme 2, path B). The stereo-
chemical outcome of the first rearrangement, namely the 1,2-
silyl migration, has been occasionally investigated and occurs
with partial inversion of configuration for secondary and
tertiary R-silyl benzyl alcohols, respectively, but with reten-
tion (>97%) of configuration if the phenyl substituent is
replaced by an alkyl group.18 However, silylalkyl anions were
always in situ intercepted rapidly and irreversibly by using
solvents containing water19 or protic source.13a No report
As in the alkynylation of the acylsilane, the Brook
rearrangement and the carbocyclization involve only the zinc
(18) For 1,2-silyl migration with retention of configuration, see: (a)
Simov, B. J.; Wuggenig, F.; Mereiter, K.; Andres, H.; France, J.; Schnelli,
P.; Hammerschmidt, F. J. Am. Chem. Soc. 2005, 127, 13934. (b) Hudrlik,
P. F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem. Soc. 1982, 104, 6809.
(c) Hoffmann, R.; Bru¨ckner, R. Chem. Ber. 1992, 125, 2731. (d) Kapeller,
D. C.; Brecker, L.; Hammerschmidt, F. Chem. Eur. J. 2007, 13, 9582. For
1,2-silyl migration with inversion of configuration, see: (f) Brook, A. G.;
Pascoe, J. D. J. Am. Chem. Soc. 1971, 93, 6224. (g) Biernbaum, M. S.;
Mosher, H. S. J. Am. Chem. Soc. 1971, 93, 6221.
(15) See the experimental part and (a) Masarwa, A.; Stanger, A.; Marek,
I. Angew. Chem., Int. Ed. 2007, 46, 8039. (b) Simaan, S.; Masarwa, A.;
Bertus, P.; Marek, I. Angew. Chem., Int. Ed. 2006, 45, 3963.
(16) When the reaction mixture is warmed at higher temperature, the
diastereoselectivity of the reaction decreases. However, in pure toluene, no
significant Brook rearrangement product could be detected (<5%).
(17) For an easier determination of enantiomeric ratio by chiral HPLC,
the silyl ether is transformed into free alcohol by treatment of the crude
reaction mixture with a solution of tetra-n-butylammonium fluoride.
(19) For theoretical investigations, see: (a) Antoniotti, P.; Tonachini,
G. J. Org. Chem. 1993, 58, 3622. (b) Wang, Y.; Dolg, M. Tetrahedron
1999, 55, 12751. (c) Yu, Y.; Feng, S. J. Phys. Chem. A 2004, 108, 7468.
(20) For configurationally stable allenylzinc derivatives, see: (a) Poisson,
J.-F.; Normant, J. F. J. Am. Chem. Soc. 2001, 123, 4639. (b) Poisson, J.-F.;
Chemla, F.; Normant, J. F. Synlett 2001, 305. (c) Marshall, J. A.; Adams,
N. D. J. Org. Chem. 1998, 63, 3812. (d) Marshall, J. A.; Schaaf, G. M. J.
Org. Chem. 2001, 66, 7825.
Org. Lett., Vol. 11, No. 8, 2009
1855

species; we should therefore be able to perform the entire
sequence in a single-pot operation as described in Table 2
via asymmetric catalysis.
Scheme 4. Enantioselective Zn-Yne-Allene Cyclization
Table 2. Formation of Carbocycles from Acylsilanes and
Alkynes
entry
R1
E-X
yielda (%)
drb
erc,d
Scheme 4). By heating the reaction mixture before hydrolysis
at 40 °C in THF for 24 h, the cyclic product 12, resulting
from the Brook rearrangement followed by suprafacial
migration of the zinc along the carbon chain of the alkyne
and then the Zn-yne-allene carbocyclization, was obtained
in 80% yield with a complete transfer of chirality (er 77:23)
and as a unique geometrical E-isomer.
1
2
3
4
Ph (1a)
H3O+
H3O+
I2
92 (5a)
91 (5b)
65 (5c)
87 (5d)
>99:1
>99:1
>99:1
>99:1
81:19
77:23e
77:23
61:39
Hex (1b)
Hex (1b)
Me3Si (1c)
H3O+
a Isolated yields after column chromatography. b Diastereomeric ratio
determined by chiral HPLC and by 1H NMR. c Enantiomeric ratio
determined by HPLC on chiral column. d Absolute configuration determined
by comparison of experimentally measured and calculated CD.15 e The
enantiomeric ratio of 5b was determined by analogy with 5c (enantiomers
of 5b could not be completely separated by HPLC).
In summary, the catalytic enantioselective alkynylation of
an acylsilane followed by a zinc-promoted Brook rearrange-
ment and finally the ene-allene or yne-allene cyclization
represents a very efficient and powerful entry to enantio-
merically enriched carbocycles with formation of syntheti-
cally challenging quaternary stereocenters, with the formation
of three new bonds in a single-pot operation. One of the
most remarkable features of this sequence is the highly
efficient transfer of chirality in the formation of the orga-
nometallic product during the Zn-Brook rearrangement.
Currently, our efforts are directed toward elucidating the
mechanism of this new asymmetric transformation as well
as improving the enantioselectivity of the alkynylation
reaction.
When acylsilane 2a was added to phenylacetylene 1a in
the presence of Et2Zn and 20 mol % of chiral ligand 3a, as
shown in Table 2, the corresponding cyclopentanol 5a
(E ) H) was obtained in excellent isolated yield as a unique
diastereoisomer with an almost complete transfer of chirality
[from intermediate 4a of er 86:14 (see Table 1, entry 1), to
5a of er 81:19 (Table 2, entry 1)]. The same behavior was
found when acylsilane 2a was treated, under the same
experimental conditions, with oct-1-yne 1b (Table 2, entry
2) or trimethylsilylacetylene 1c (Table 2, entry 4). The
enantiomeric ratio determined after the alkynylation reaction
(Table 1, entries 6 and 7, respectively) is practically the same
as the one obtained for the cyclic products 5b-d. The
formation of a discrete organometallic species after carbocy-
clization was checked by iodinolysis (Table 2, entry 3).
The same principle could be extended to the first enanti-
oselective Zn-yne-allene cyclization as described in Scheme
4. The addition of phenylacetylene 1a to an acylsilane 10
possessing an electrophilic alkynylsilane moiety led to the
corresponding propargylsilanol 11, after hydrolysis, in excel-
lent yield with an enantiomeric ratio of 77:23 (path A,
Acknowledgment. This research was supported by Grant
No. 2005128 from the United States-Israel Binational
Science Foundation (BSF), Jerusalem, Israel. I.M. is holder
of the Sir Michael and Lady Sobell Academic Chair.
Supporting Information Available: Experimental pro-
1
cedure with description of H and 13C NMR data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9004036
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Org. Lett., Vol. 11, No. 8, 2009