One-pot enantioselective formation of eight-membered rings from alkenyl fischer carbene complexes and ketone enolates

Article abstract of DOI:10.1021/ja0264551

Eight-membered carbocycles with up to five new stereogenic centers are enantioselectively obtained following a one-pot procedure that involves the coupling of three components: an alkenyl Fischer carbene complex, a ketone enolate, and allyl lithium. Copyr

Full text of DOI:10.1021/ja0264551

Published on Web 07/12/2002
One-Pot Enantioselective Formation of Eight-Membered Rings from Alkenyl
Fischer Carbene Complexes and Ketone Enolates
Jose´ Barluenga,* Alejandro Die´guez, Fe´lix Rodr´ıguez, Josefa Flo´rez, and Francisco J. Fan˜ana´s
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, Unidad Asociada al C.S.I.C.,
UniVersidad de OViedo, Julia´n ClaVer´ıa, 8, E-33071 OViedo, Spain
Received April 8, 2002
Modern organic chemistry demands new strategies and technolo-
gies to obtain new compounds in a fast, clean, and efficient way.
Among these procedures, sequential reactions (domino or consecu-
tive) offer the opportunity to build up complex molecules, frequently
with high stereoselectivity, from simple and easily available
substrates.1 On the other hand, the importance of eight-membered
rings in organic chemistry is due to its presence in the structural
core of a large number of natural targets with promising biological
activities.2 As a consequence, the search for new strategies for the
Figure 1. Retrosynthetic analysis.
Scheme 1. Eight-Membered Carbocycles from Alkenyl
Boroxycarbene Complexes (Yield and Ee when (-)-Sparteine Is
Used as Cosolvent (See Text) Are Given in Parentheses)a
stereoselective construction of this type of rings is clearly a field
of great significance in synthesis.3 The use of metal-based methods
to obtain medium-size rings has seen a considerable increase in
the past decade4 due to the advantage of these metal-promoted inter-
and intramolecular cyclizations over other methodologies in the
gain of entropy, reactivity, and stereoselectivity.5 As part of a
program concerned with the development of new methods for the
synthesis of medium-size rings mediated by Fischer carbene
complexes,6 herein we report an easy and enantioselective “one-
pot” synthesis of eight-membered carbocycles from alkenyl Fischer
carbene complexes following two different approaches: by the use
of chiral boroxycarbene complexes and achiral enolates, and by
the use of methoxycarbene complexes and chiral ketone enolates.
We argued that eight-membered rings such as 1 could be obtained
from 2 by a selective cyclopropane ring expansion (Figure 1). Due
to the ability of Fischer carbene complexes to give cyclopropanation
reactions with olefins,7 we believed that tricyclic compounds 2 could
be derived from carbene complex 3, obtained from alkenyl carbene
complexes 4 and enolates derived from ketones 5. In this context,
we have previously reported the racemic synthesis of tricyclic ethers
2;8 however, the chiral version of this reaction using alkenylcarbene
complexes 4, where the methoxy group was substituted by a (-)-
8-phenylmenthyloxy group, failed, and open-chain products were
obtained instead of the corresponding cyclic compounds 2 and/or
3.9 These studies indicated that small alkoxy groups in 4 were
necessary to obtain cyclic compounds. Taking into account this
limitation, two different approaches could be devised in order to
obtain the corresponding cyclic compounds in an enantioselective
way: (i) by the use of a chiral oxy group, easily transformed into
a methoxy group, at the alkenyl Fischer carbene complex 4, and
(ii) by the use of a chiral enolate derived from ketone 5. Thus,
first, we carried out the sequence of reactions shown in Scheme 1.
Alkenyl boroxycarbene complex 6, derived from (-)-chlorodiiso-
pinocampheylborane,10 was treated with lithium enolate 7, derived
from cyclohexanone, from -100 °C to room temperature. The
reaction was followed by IR, indicating total transformation of the
starting alkenyl carbene complex 6 into a new acyltungstenate-
type complex. This kind of compounds are known to react with
a Reagents and conditions: (i) cyclohexanone, LDA, Et2O, -30 °C, 15
min, then 6, Et2O, -100 °C; (ii) MeOTf, 0 °C; (iii) 2 equiv of
CH2CHCH2MgBr, Et2O, -50 °C; (iv) THF, 90 °C; (v) HCl, acetone, RT.
alkylating agents to give conventional Fischer carbene complexes.
So, treatment of the reaction crude with excess of methyl triflate
gave rise to the new carbene complex 8 in 45% yield and 40%
ee.11,12 Some improvements on the yield and enantioselectivity were
reached by the use of (-)-sparteine13 as cosolvent of the reaction.
Under these conditions, a match situation between both chiral
substrates led to complex 8 in 55% yield and 55% ee.11,14 Despite
the moderate enantioselectivity of the reaction, it is important to
remark that this is the first example of an enantioselective reaction
using a dialkylborane as the chiral auxiliary on a Fischer carbene
complex.
To investigate the feasibility of our strategy to obtain eight-
membered carbocycles, we decided to try the remaining steps of
our synthetic plan. Thus, addition of allylmagnesium bromide (2
equiv) to 8 gave the new cyclic carbene complex 9 (tungsten
complex analogous to 3) in 64% yield as a single diastereoisomer.
Warming of this complex in THF at 90 °C in a sealed tube led to
the tetracyclic compound 2a, again, as a single diastereoisomer in
75% yield. Further treatment of this compound with hydrochloric
acid in acetone resulted in the diastereoselective expansion of the
cyclopropane ring to give eight-membered hemiacetal 1a (90%
yield, 55% ee for the product obtained from compound 8 using
(-)-sparteine as cosolvent).11
* Address correspondence to this author. E-mail:
sauron.quimica.uniovi.es.
barluenga@
9
9056
J. AM. CHEM. SOC. 2002, 124, 9056-9057
10.1021/ja0264551 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Enantioselective Synthesis of Eight-Membered
compound. It is important to note that the “one-pot” procedure was
much more efficient (76% yield for 1b) than the multistep process
(37% global yield for 1b).
Carbocycles from Chiral Silyl Enol Ethersa
In summary, we have developed a new route to the enantiose-
lective synthesis of eight-membered carbocycles from alkenylcar-
bene complexes. For the first time, chiral auxiliaries derived from
dialkylboranes and attached to the carbene complex were used in
an enantioselective reaction. Moreover, the use of chiral ketone
enolates allowed the efficient one-pot synthesis of eight-membered
rings with up to five stereogenic centers in a sequence involving
the coupling of three components in very high ee. Further studies
on this subject are underway in our laboratories and will be
published shortly.14,17
a Reagents and conditions: (i) 10a, BuLi, THF, 0 °C, 30 min, then 4a,
THF, -78 °C; (ii) 3 equiv of CH2CHCH2Li, THF, -78 °C to RT; then
SiO2; (iii) THF, 90 °C; (iv) HCl, acetone, RT.
Acknowledgment. We gratefully acknowledge financial support
from the DGICYT (PB97-1271), FICYT (grant to A.D.) and the
EU (Marie Curie fellowship to F.R.).
Scheme 3. One-Pot, Enantioselective Synthesis of
Eight-Membered Carbocyclesa
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at htpp://pubs.acs.org.
References
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a Reagents and conditions: (i) 10, BuLi, THF, 0 °C, 30 min, then 4,
THF, -78 °C; (ii) CH2CHCH2Li, THF, -78 °C to RT; (iii) H3PO4; (iv)
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(10) Boroxycarbene complexes are stable compounds only at low temperature,
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(11) The ee was determined by HPLC analysis on a chiral support.
(12) The absolute configuration of 8 was not determined yet.
(13) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
(14) The influence of different chiral boroxycarbene complexes and chiral
cosolvents on the yield and enantioselective outcome of the reaction will
be published in a full paper shortly.
At this point, the viability of the method to obtain eight-
membered rings had clearly been demonstrated; however, some
improvements on the enantioselectivity of the process were desir-
able. For this reason, we decided to investigate the reaction between
chiral enolates and alkenyl methoxycarbene complexes. Taking
advantage of some recent and excellent works about the catalytic
enantioselective synthesis of ketones from enones,15 we carried out
the enantioselective synthesis of silyl enol ether 10a.16
Thus, reaction of 10a (98% ee), easily obtained from 2-cyclo-
hexenone, with butyllithium in THF generated the corresponding
lithium enolate, which reacted with chromium alkenyl carbene
complex 4a to give product 11 as a single diastereoisomer (Scheme
2). Further reaction with allyllithium (3 equiv) diastereoselectively
led to the new cyclic carbene complex 3a (>98% ee).11 Warming
a solution of this complex in THF at 90 °C in a sealed tube gave
tetracyclic compound 2b as a single diastereoisomer (>98% ee).11
Finally, treatment of cyclopropyl derivative 2b with hydrochloric
acid in acetone afforded eight-membered hemiketal 1b as a single
diastereoisomer (>98% ee).11 The structure of compound 1b was
unequivocally determined by X-ray structure analysis.17
(15) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Degrado, S. J.;
Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755. (c) Reetz,
M.; Gosberg, A.; Moulin, D. Tetrahedron Lett. 2002, 43, 1189.
(16) Silylenol ethers 10 were obtained following the procedure described by
Feringa: Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620.
Attracted by the possibility of performing the sequence of
reactions described in Scheme 2 following a “one pot” procedure,
we decided to carry out the sequential transformation of silyl enol
ethers 10a-c15 into eight-membered hemiacetals 1b-g without the
isolation of any intermediate, as depicted in Scheme 3. Following
this strategy, compounds 1b-g were obtained, each as a single
diastereoisomer in high yield and as an enantiomerically pure
(17) Detailed data concerning the X-ray structure elucidation will be given
separately.
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