Stereoselective intermolecular formal [3+3] cycloaddition reaction of cyclic enamines and enones

Article abstract of DOI:10.1002/anie.200603302

(Chemical Equation Presented) A convergent strategy for the synthesis of tricyclic imino alcohols was partly inspired by a postulated biosynthesis of galbulimima alkaloids. In this sequential α,α′ alkylation of unsymmetrical ketoimines, at least three ste

Full text of DOI:10.1002/anie.200603302

Angewandte
Chemie
DOI: 10.1002/anie.200603302
Cascade Reactions
Stereoselective Intermolecular Formal [3+3] Cycloaddition Reaction
of Cyclic Enamines and Enones**
Mohammad Movassaghi* and Bin Chen
À
The development of new tandem C C bond-forming reac-
tions with control of stereochemistry is of fundamental
interest in organic synthesis.[1] Important discoveries in
conjugate-addition chemistry have resulted in a variety of
valuable catalytic and asymmetric methodologies for fine-
chemical synthesis.[2] Herein we report a new highly diaste-
reoselective reaction involving cyclic enamines and enones
that provides rapid access to tricyclic imino alcohols and
derivatives thereof (Scheme 1). Additionally, we discuss our
findings in the development of catalytic and asymmetric
variants of this formal [3+3] cycloaddition reaction.
We postulated that the conjugate addition of the organo-
cuprate reagent[8] derived from the readily available iminium
chloride 5a to cyclopent-2-enone (6a) would afford the imino
ketone 7a, which might spontaneously undergo tautomeriza-
tion and addition to the carbonyl group to give the tricyclic
imino alcohol 10a (Scheme 3).[9,10] Gratifyingly, the addition
Scheme 1. Formal [3+3] cycloaddition reaction.
Scheme 3. Rapid synthesis of the CDE ring system of class II and III
galbulimima alkaloids.
Enamines and metalloenamines have served as powerful
nucleophiles in a wide range of bond-forming reactions,[3,4]
including many cycloaddition reactions.[5] Motivated by the
efficiency of the transient-d-imino ketone strategy that we
employed[6] for the introduction of the CDE ring system of
class II and class III galbulimima alkaloids[7] (Scheme 2), we
sought to develop a new formal [3+3] cycloaddition reaction.
of enone 6a to a cold solution of the homocuprate
(1.5 equiv),[9,11] followed by warming of the mixture, gave
the corresponding tricyclic imino alcohol 10a as a single
diastereomer in 82% yield. The addition of thiophenol
(1.5 equiv) and strict exclusion of dioxygen during workup
were critical in the isolation of this sensitive product.[9]
Reduction of the imine with sodium borohydride gave the
tricyclic amino alcohol 11a, which constitutes the CDE
tricyclic substructure of class II and III galbulimima alkaloids
(Scheme 2).[12] The relative configuration of the four stereo-
centers in amino alcohol 11a was confirmed by X-ray
crystallographic analysis[9] and is consistent with the chairlike
transition-state structure 9a for the intramolecular addition to
the carbonyl group.[13]
Scheme 2. Representative galbulimima alkaloids. Bz=benzoyl.
The reaction of iminium chloride 5a with enones 6b–d
under the optimal reaction conditions described above
afforded the corresponding tricyclic imino alcohols in a
single step (Table 1, entries 1–3). As the imino alcohols 10c
and 10d proved highly sensitive toward oxidation by air, they
were converted into tricycles 11c and 11d, respectively, for
ease of isolation (Table 1, entries 2–3). The configuration at
C12[9] of amino alcohol 11c, which has five contiguous
stereocenters, is consistent with transient formation of imino
ketone 7c, followed by intramolecular addition of the
enamine to the carbonyl group. The stereoselective formation
of tricycles 11a–c via the corresponding imino ketones 7a–c is
consistent with our proposed biogenesis of this substructure in
the galbulimima alkaloids.[6] The use of iminium chloride 5b[9]
[*] Prof. Dr. M. Movassaghi, Dr. B. Chen
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139 (USA)
E-mail: movassag@mit.edu
Homepage: http://web.mit.edu/movassag/www/index.html
[**] M.M. is a Dale F. and Betty Ann Frey Damon Runyon Scholar
supported by the Damon Runyon Cancer Research Foundation
(DRS-39-04). M.M. is a Firmenich Assistant Professor of Chemistry.
We acknowledge financial support by NIH-NIGMS (GM074825),
Amgen Inc., and Boehringer Ingelheim Pharmaceutical Inc.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Highly diastereoselective sequential 1,4- and 1,2-addition of cyclic imines to cyclic enones.[a]
Entry
1
Iminium chloride
Enone
1,4-Adduct
Yield [%][b]
Imino alcohol
Yield [%][b]
72
Amino alcohol
Yield [%][b]
91
–
2
3
–
–
–
–
55[c]
50
4
5
88
67
85
91
93
87
6
70
82
88
[a] The optimized reaction conditions were used uniformly.[9] [b] Yield of the isolated product as a single diastereomer. [c] Yield of the isolated product
as a mixture of diastereomers at C12 (8:1); major isomer shown.[9] Cbz=benzyloxycarbonyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
under the same reaction conditions resulted in the stable
imino ketones 7e–g (Table 1, entries 4–6). The isolation and
greater stability of these imino ketones is probably a result of
slower imine/enamine tautomerization (see below). Treat-
ment of the isolated imino ketones 7e–g with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in ethanol provided
the desired tricyclic imino alcohols 10e–g as single diastereo-
mers. Reduction of the imine proceeded with complete
diastereoselectivity to give the corresponding amino alcohols
(Table 1, entries 4–6). Similarly, 1,2-addition of allylmagne-
sium chloride to a derivative of imine 10e gave the
corresponding tertiary amine as a single diastereomer.[14]
The resistance of cyclic imines toward hydrolysis makes
them more effective substrates than acyclic imines for this
chemistry. The use of the acyclic imine 5c and enone 6a under
the optimal reaction conditions described above provided the
desired imino alcohol 10h (52%), along with the product of
competitive hydrolysis 12 [28%, Eq. (1); Bn = benzyl].[15] No
products of sequential addition were observed when acyclic
D2O (3:2, 0.5 mm) revealed greater than 90% deuterium
À
incorporation at C3 and C2 Me within 10 min and 9 h,
respectively (Scheme 4).[9] However, the five-membered-ring
imine 13b required 96 h before 90% deuterium incorporation
À
at C2 Me was observed, at which time less than 25%
deuterium incorporation at C3 was detected.
These observations revealed the favored enamine tauto-
mers and prompted us to explore the direct utilization of the
=
=
enones (e.g., PhCH CHCOPh or PhCH CHCOMe) were
used under the standard reaction conditions.
Interestingly, incomplete double deprotonation of imi-
nium ion 5a prior to cuprate formation led to equilibration
between the isomeric metalloenamines. Monitoring of a
solution of the six-membered-ring imine 13a in [D6]DMSO–
Scheme 4. Equilibration of enamine tautomers.[9]
566
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Angewandte
Chemie
enamines in place of the corresponding metalloenamine
derivatives as nucleophiles in this formal [3+3] cycloaddition.
Inspired by the recent advances in organocatalytic trans-
formations,[16] we envisaged the activation of the enone in the
form of an unsaturated iminium ion to facilitate the conjugate
addition of the enamines. Various catalysts and solvents were
screened, and proline[17] proved particularly effective as the
catalyst in a mixture of trifluoroethanol (TFE) and water.[9]
When a solution of imine 13a and enone 6a in TFE–water
(10:1) was heated at 508C, the desired tricyclic imino alcohol
10i was isolated in 91% yield as a single diastereomer
(Table 2, entry 1).[18] The relative stereochemistry of imino
Intrigued by the above results, we explored the extension
of this chemistry to catalytic asymmetric synthesis. The use of
chloroform as the solvent in place of TFE–water led to a
modest level of enantioselectivity in the conjugate addition of
imine 13b to enone 6a (Scheme 5).[9] Warming of a solution of
Scheme 5. Catalytic asymmetric synthesis of (À)-10e: a) l-proline
(20 mol%), CHCl3, 458C, 48 h (50%); DBU, EtOH, 788C (80%).
Table 2: Single-step catalytic diastereoselective intermolecular formal
[3+3] cycloaddition reaction.[a]
Entry 13
6
1,4-adduct
Product
Yield [%][b]
imine 13b and enone 6a in chloroform provided the initial
1,4-conjugate-addition product, which was converted upon
treatment with DBU into the desired tricyclic imino alcohol
(À)-10e with 52% ee. The optical purity was increased to
90% ee through a single recrystallization from n-pentane–
diethyl ether (1:1).[9] The absolute stereochemistry of the
imino alcohol (À)-10e was determined by X-ray crystallo-
graphic analysis of the corresponding amino alcohol cocrys-
tallized with l-tartaric acid (1 equiv).[9]
The chemistry described herein relies on the sequential
Ca and Ca’ alkylation of unsymmetrical ketoimines and
allows rapid generation of molecular complexity with excel-
lent stereochemical control. This new formal [3+3] cyclo-
addition reaction provides a practical solution to the synthesis
of fused tricyclic imino alcohol derivatives.[19] We envisage the
further development of this methodology and its application
to target-oriented synthesis by building on advances in
catalyst- and substrate-controlled conjugate-addition chemis-
try.[2,16,20] The complementary copper-promoted and proline-
catalyzed variants of this reaction enable the highly selective
and rapid introduction of at least three stereocenters in a
convergent assembly of these tricyclic products and offer a
valuable addendum to methodologies for the synthesis of
complex molecules.
1[c]
2[c]
3[f]
4[f]
13a 6a
13a 6d
13b 6a
13b 6d
91, 90[d]
78[e]
40, 21[g]
56
[a] Reaction conditions: L-proline (10 mol%), TFE–water (10:1), 16 h.[9]
[b] Yield of the isolated product as a single diastereomer. [c] T=508C.
[d] Yield of the corresponding amino alcohol upon the treatment of 10i
with NaBH4 and EtOH at 08C. [e] Yield after reduction of the imine and
N protection. [f] T=808C. [g] Yield of 7e.
Received: August 11, 2006
Published online: December 5, 2006
alcohol 10i was established by X-ray crystallography.[9] The
tricyclic imino alcohol 10i is isomeric with the product
obtained with the cuprate chemistry (imino alcohol 10a,
Scheme 3), and its formation is consistent with the interme-
diacy of the preferred six-membered-ring enamine with an
endocyclic double bond (Scheme 4). The exclusion of water as
a cosolvent led to a decrease in the yield of the desired
tricyclic imino alcohol products. The use of the free-base
imines 13a–b in place of the corresponding iminium chloride
derivatives 5a–b was found to give generally better results. In
only one case was the intermediate 1,4-addition product
isolated along with the desired tricyclic imino alcohol
(Table 2, entry 3). The use of the protic solvent system and
higher temperatures allowed direct conversion of recalcitrant
intermediates (that is, imino ketones 7e and 7g) into the
corresponding tricyclic imino alcohols.
Keywords: conjugate addition · diastereoselectivity · enamines ·
enones · imines
.
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[17] The suggested mode of catalysis is based on prior reports on
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[18] The use of TFE–water as the solvent mixture led to products
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[9] See Supporting Information for details.
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