Convergent synthesis of stereodefined exo-alkylidene-γ-lactams from β-halo allylic alcohols

Article abstract of DOI:10.1021/ol9022134

"Chemical Equation Presented" A convergent process for the assembly of stereodefined mono- and bicyclic exo-alkylidene-γ-lactams is described that proceeds through the union of β-halo allylic alcohols, aromatic imines, and CO. Overall, reglo- and stereose

Full text of DOI:10.1021/ol9022134

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5402-5405
Convergent Synthesis of Stereodefined
exo-Alkylidene-γ-Lactams from ꢀ-Halo
Allylic Alcohols
Shuhei Umemura, Martin McLaughlin, and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter,
Florida 33458
micalizio@scripps.edu
Received September 24, 2009
ABSTRACT
A convergent process for the assembly of stereodefined mono- and bicyclic exo-alkylidene-γ-lactams is described that proceeds through the
union of ꢀ-halo allylic alcohols, aromatic imines, and CO. Overall, regio- and stereoselective Ti-mediated reductive cross-coupling, followed
by Pd-catalyzed carbonylation, can be performed in a one- or two-pot procedure, defining a highly selective three-component coupling process
for heterocycle synthesis.
Nitrogen-containing heterocycles are ubiquitous structural
motifs in natural products and small molecules of biomedical
relevance.1 Among this class, stereodefined pyrrolidines and
γ-lactams are abundant (Figure 1). A wealth of chemical
pathways are indeed available for the synthesis of these
functionalized heterocycles.2 However, strategic consider-
ations for the preparation of highly substituted and stereo-
defined systems often limit the utility of many available
methods. In a program aimed at defining convergent coupling
reactions for complex molecule synthesis, we have been
investigating the potential of reductive cross-coupling pro-
cesses between imines and alkynes, alkenes, or allenes to
serve as a general foundation for heterocycle synthesis.3
Recently, we set our sights on the development of a
multicomponent coupling reaction suitable for the synthesis
of exo-alkylidene-γ-lactams (Figure 2A). These architectures,
while representing interesting heterocycles in their own right,
possess a rich reactivity profile suitable for diverse elabora-
(1) Fischer, J., Ganellin, C. R., Eds. Analogue-based Drug DiscoVery;
Wiley-VCH: Weinheim, 2002.
(2) For reviews that cover the synthesis of nitrogen heterocycles, see:
(a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127–2198. (b)
Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238. (c) Barluenga,
J.; Santamar´ıa, J.; Toma´s, M. Chem. ReV. 2004, 104, 2259–2283. (d) Zeni,
G.; Larock, R. C. Chem. ReV. 2004, 104, 2285–2309. (e) Royer, J.; Bonin,
M.; Micouin, L. Chem. ReV. 2004, 104, 2311–2352. (f) Mangelinckx, S.;
Giubellina, N.; De Kimpe, N. Chem. ReV. 2004, 104, 2353–2399. (g) Bur,
S. K.; Padwa, A. Chem. ReV. 2004, 104, 2401–2432. (h) Mitchinson, A.;
Nadin, A. J. Chem. Soc., Perkin Trans. 1 1999, 2553–2581. (i) Nadin, A.
J. Chem. Soc., Perkin Trans. 1 1998, 3493–3513l. (j) Harrison, T. Contemp.
Org. Synth. 1995, 2, 209–224.
Figure 1
γ-lactam or pyrrolidine.
. Examples of natural products bearing a substituted
10.1021/ol9022134 CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

syn-elimination (A f B; Figure 3), embraces a boat-like
geometry in the transition state for C-C bond formation to
reflect the presumed mechanistic requirement of preassociating
the allylic alkoxide to the Ti-center of the azametallacyclopro-
pane and the orbital requirements for carbometalation (copla-
narity of the σTi-C and the πCdC). A key factor for stereocontrol
then derives from the minimization of A-1,2 strain in the boat-
like orientation A (minimize steric interaction between R3 and
X). As a consequence, high selectivity is observed for the
formation of products containing a pendant E-alkene. Overall,
the general reactivity pattern is consistent with formal metallo-
[3,3] rearrangement by way of C.4
While having a stereoselective coupling reaction in place for
the synthesis of highly functionalized homoallylic amines, we
were aware of the potential of halogenated homoallylic amines
to participate in Pd-catalyzed carbonylation chemistry.5,6 As
depicted in Figure 4, this was indeed the case. Carbonylation
of vinylbromide 1 and vinyliodide 2 resulted in the produc-
tion of the exo-methylene-γ-lactam 3 in g93% yield.
Figure 2. exo-Alkylidene-γ-lactams.
tion (Figure 2B). Herein, we report the realization of a
synthesis of exo-alkylidene-γ-lactams from the convergent
and stereoselective union of homoallylic alcohols, imines,
and carbon monoxide.
Figure 4. Pd-catalyzed carbonylative cyclization.
With the knowledge gleaned from these initial studies, we
moved on to explore the compatibility of more complex
substrates in this two-step reductive cross-coupling/carbo-
nylation process as a means to access a variety of stereo-
defined γ-lactams (Table 1).7 As depicted in entries 1-3,
the size of the alkyl group at the allylic position plays an
important role in stereoselection. While reductive cross-
coupling of allylic alcohol 5 with imine 4 proceeds in a fairly
unselective manner (E:Z ) 1.5:1), union of imine 4 with
allylic alcohol 7 occurs with increased levels of stereose-
lection and produces the homoallylic amine 8 in 76% yield
(E:Z ) 4:1). Subsequent carbonylation then delivers the
stereodefined unsaturated γ-lactam 9 in 99% yield. As
Figure 3. Imine-allylic alcohol coupling reaction.
Recently, we reported a stereoselective synthesis of homoal-
lylic amines that proceeds by regioselective reductive cross-
coupling of allylic alcohols with aromatic imines.3d Of particular
interest to our goals here, coupling of 2-halo allylic alcohols to
aromatic imines was found to provide stereoselective access to
anti-homoallylic amines that contain a stereodefined vinyl halide
(dr g 20:1; E:Z g 20:1; Figure 3). While the mechanistic details
that result in these high levels of stereoselection remain
undefined, an empirical model has emerged to explain the
patterns of reactivity and selectivity observed. The proposed
model, based on a sequence of directed carbometalation and
(4) For related reductive cross-coupling reactions that appear to proceed
by formal metallo-[3,3] rearrangement, see: (a) Kolundzic, F.; Micalizio,
G. C. J. Am. Chem. Soc. 2007, 129, 15112–15113. (b) Shimp, H. L.; Hare,
A.; McLaughlin, M.; Micalizio, G. C. Tetrahedron 2008, 64, 6831–6837.
(c) Belardi, J. K.; Micalizio, G. C. J. Am. Chem. Soc. 2008, 130, 16870–
16872. (d) Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem.
Soc. 2008, 130, 15997–16002.
(3) For the coupling of homoallylic alcohols to imines, see: (a) Takahashi,
M.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514–7416. For the
coupling of homopropargylic alcohols to imines, see: (b) McLaughlin, M.;
Takahashi, M.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46,
3912–3914. For the coupling of allenic alcohols to imines, see: (c) McLaughlin,
M.; Shimp, H. L.; Navarro, R.; Micalizio, G. C. Synlett 2008, 735–738.
For the coupling of allylic alcohols to imines, see: (d) Takahashi, M.;
McLaughlin, M.; Micalizio, G. C. Angew. Chem., Int. Ed. 2009, 48, 3702–
3706. (e) Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett. 2009, 11, 3132–
3134.
(5) For a review of Pd-catalyzed carbonylation for the synthesis of
lactams and lactones, see: (d) Farina, V.; Magnus, E. Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John
Wiley & Sons, Inc.: Hoboken, NJ, 2002; pp 2351-2375.
(6) For early examples of Pd-catalyzed carbonylation for lactam
synthesis, see: (a) Miwako, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978,
43, 1684–1687. (b) Miwako, M.; Washioka, Y.; Urayama, T.; Yoshiura,
Y.; Chiba, K.; Ban, Y. J. Org. Chem. 1983, 48, 4058–4067. (c) Crisp, G. T.;
Meyer, A. G. Tetrahedron 1995, 51, 5585–5596.
Org. Lett., Vol. 11, No. 23, 2009
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in a highly stereoselective manner to deliver vinyliodides 17
and 20 (dr up to g20:1) These substrates are equally effective
in the Pd-catalyzed carbonylative cyclization and deliver the
bicyclo[4.3.0] and [5.3.0] systems 18 and 21 in 87% and 92%
yield.
Table 1. exo-Alkylidene-γ-lactams via Imine-Allylic Alcohol
Reductive Cross-Coupling
While this two-step procedure is effective for the stereose-
lective convergent synthesis of mono- and bicyclic γ-lactams,
this multicomponent coupling sequence can be streamlined.
Specifically, we have defined a one-pot, three-component cou-
pling reaction that converts 2-halo allylic alcohols, imines, and
carbon monoxide directly to stereodefined exo-alkylidene-γ-
lactams. Aware of the compatibility of Pd-catalyzed coupling
processes with water and base, we speculated that aqueous
quenching of the titanium-mediated reductive cross-coupling
reaction may directly furnish a suitable environment for Pd-
catalyzed carbonylation. This expectation was indeed the case.
Figure 5. One-pot, three-component coupling for heterocycle synthesis.
As depicted in Figure 5, this sequential multicomponent
coupling process for the synthesis of substituted γ-lactams
(7) General experimental procedure for the two-step γ-lactam synthesis
described in Table 1. Synthesis of (S*)-N-benzyl-1-((R*)-2-iodocyclohex-
2-enyl)-1-phenylmethanamine 17: To a solution of imine 4 (563 µL, 586
mg, 3.00 mmol) and ClTi(Oi-Pr)3 (1.0 M in diethyl ether, 3.75 mmol) in
diethyl ether (12 mL) at -70 °C was added c-C5H9MgCl (2.00 M in diethyl
ether, 7.50 mmol) in a dropwise manner with a syringe. The brown solution
was slowly warmed to -40 °C over 30 min and stirred at -40 °C for a
further 1.5 h. A solution of the sodium alkoxide, generated from the
deprotonation of alcohol 16 (1.01 g, 4.50 mmol) with NaH (60% suspension,
225 mg, 5.63 mmol), in THF (15 mL) at 0 °C, was added in a dropwise
manner via Teflon cannula to the brown solution of the imine-Ti complex
at -40 °C. The reaction was allowed to warm to ambient temperature and
stirred overnight. Next, saturated aqueous NH4Cl (5 mL) was added, and
the resulting biphasic mixture was stirred rapidly. The resulting solution
was further diluted with saturated aqueous NaHCO3 (150 mL) and extracted
with ether (3 × 150 mL). The combined organic layers were washed with
brine (50 mL), dried over MgSO4, and concentrated in vacuo. The crude
material was purified by column chromatography on silica gel (1/40f1/30
EtOAc/Hexanes) to yield haloallylic amine 17 as a colorless oil (811 mg,
67%, dr g 20:1). Synthesis of (3S*,3S*)-2-benzyl-3-phenyl-2,3,3a,4,5,6-
hexahydro-1H-isoindol-1-one 18: To a round-bottom flask equipped with
a reflux condenser was sequentially added amine 17 (169 mg, 0.420 mmol),
toluene (4.2 mL), Cl2Pd(PPh3)2 (14 mg, 0.021 mmol), and Et3N (114 µL,
83 mg, 0.820 mmol). The reaction was placed under an atmosphere of CO
by briefly exposing the reaction vessel to vacuum and backfilling with carbon
monoxide from a balloon. The atmosphere of CO was maintained by a
balloon for the remainder of the reaction. The reaction vessel was then
submerged in a preheated oil bath (70 °C) and stirred for 12 h. The reaction
mixture was then allowed to cool to ambient temperature, diluted with
EtOAc, filtered through cotton, and concentrated in vacuo. The crude
material was purified by column chromatography on silica gel (1/10f1/5
EtOAc/Hexanes) to yield γ-lactam 18 as a white solid (111 mg, 87%).
a General reaction conditions for the Ti-mediated coupling: imine,
ClTi(Oi-Pr)3, c-C5H9MgCl, Et2O, or PhMe (-70 to -40 °C), then the
sodium alkoxide of the allylic alcohol was added as a solution in THF.7 b
4
equiv of imine was employed. c The major isomer of 8 was employed in
the carbonylation reaction. d 1.5 equiv of allylic alcohol was used. e Reaction
conditions: Cl2Pd(PPh3)2 (3-5 mol %), Et3N, PhMe, or MeOH (entry 4),
CO (balloon), 70 °C.
depicted in entry 3, branched alkyl substitution on the allylic
alcohol leads to the highest levels of E-selectivity in this
coupling reaction. Here, the homoallylic amine 11 is forged
in 58% yield with greater than 20:1 selectivity for the
formation of the stereodefined E-alkene. Palladium-catalyzed
carbonylation then furnishes γ-lactam 12 in 94% yield.
Moving on to a more highly substituted allylic alcohol, the
conversion of 13 to homoallylic amine 14 proceeds in 53%
yield and delivers the stereodefined anti-product as essentially
a single isomer. Similarly, carbonylation then provides the
highly substituted exo-alkylidene-γ-lactam 15 in 66% yield.
Finally, this two-step, three-component heterocycle synthesis
is useful for the synthesis of stereodefined bicyclic lactams. As
illustrated in entries 5 and 6, reductive cross-coupling of cyclic
allylic alcohols 16 and 17 with imine 4 can be accomplished
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Org. Lett., Vol. 11, No. 23, 2009

can be conducted in a single reaction vessel. Here, union of
imine 4 with allylic alcohol 2 furnishes lactam 3 in 69%
yield. Similarly, union of imine 4 with allylic alcohol 22
provides the stereodefined bicyclic lactam 18 in 73% yield.8
Notably, avoiding the requirement for purification of the
intermediate homoallylic amines substantially improves the
overall yield for this γ-lactam forming annulation process.
Overall, we describe a multicomponent coupling process
for the synthesis of stereodefined exo-alkylidene-γ-lactams.
In short, titanium-mediated regio- and stereoselective cou-
pling of aromatic imines with 2-halo allylic alcohols furnishes
intermediate homoallylic amines that are well-suited for
palladium-catalyzed carbonylation. This two-step process has
been demonstrated with a variety of allylic alcohols and has
defined a convergent and stereoselective pathway to mono-
and bicyclic γ-lactams. Finally, a one-pot procedure has been
developed that enables direct preparation of stereodefined
lactams from allylic alcohols and imines. Given the flexibility
of the titanium-mediated coupling with respect to imine
structure3d and the ability to translate stereochemical infor-
mation from the allylic alcohol to the homoallylic amine
intermediates,3d we anticipate that this heterocycle-forming
annulation will be of utility in medicinal chemistry and
natural product synthesis.
(8) General experimental procedure for the one-pot γ-lactam synthesis
described in Figure 5: Synthesis of (3S*,3aS*)-2-benzyl-3-phenyl-2,3,3a,4,5,6-
hexahydro-1H-isoindol-1-one 18: To a solution of imine 4 (74 µL, 78
mg, 0.400 mmol) and ClTi(Oi-Pr)3 (1.0 M in diethyl ether, 0.500 mmol) in
toluene (1.6 mL) at -70 °C was added c-C5H9MgCl (2.00 M in diethyl
ether, 1.00 mmol) in a dropwise manner with a syringe. The orange-brown
solution was slowly warmed to -40 °C over 30 min and stirred at -40 °C
for a further 1.5 h. A solution of the sodium alkoxide, generated from the
deprotonation of allylic alcohol 22 (106 mg, 0.600 mmol) with NaH (60%
suspension, 30 mg, 0.750 mmol), in THF (1.6 mL) at 0 °C, was added in
a dropwise manner via Teflon cannula to the brown solution of the imine-Ti
complex at -40 °C. The reaction was allowed to warm to ambient
temperature and stirred overnight. The following morning H2O (36 µL, 36
mg, 2.00 mmol) was added and the solution was then rapidly stirred for
2 h at ambient temperature. To the yellow solution of the reaction mixture
was added PdCl2 (1 mg, 0.008 mmol), t-Bu3P (1.0 M toluene, 0.024 mmol),
and Et3N (223 µL, 161 mg, 1.60 mmol). The reaction was placed under
an atmosphere of CO by briefly exposing the reaction vessel to vacuum
and backfilling with carbon monoxide from a balloon. The atmosphere
of CO was maintained by a balloon for the remainder of the reaction.
The reaction vessel was then submerged in a preheated oil bath (70 °C)
and stirred for 12 h. The reaction vessel was then allowed to cool to
ambient temperature. The reaction mixture was diluted with EtOAc (10
mL), and the solids were removed by filtration through celite. The filtrate
was further diluted with EtOAc (75 mL) and washed with 1 M HCl aq.
(75 mL), saturated aqueous NaHCO3 (75 mL), and brine (100 mL). The
organic layer was dried over MgSO4 and concentrated in vacuo. The
crude material was purified by column chromatography on silica gel
(1/10f1/5 EtOAc/Hexanes) to yield γ-lactam 18 as a white solid (89
mg, 73%, dr g 20:1).
Acknowledgment. We gratefully acknowledge financial
support of this work by the Arnold and Mabel Beckman
Foundation, JSPS Research Fellowship for Young Scientists
(to SU), the G-COE in Chemistry from Nagoya University,
and the National Institutes of HealthsNIGMS (GM80266
and GM80266-04S1).
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9022134
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