Intramolecular ene reaction of a chiral bicyclic lactam

Article abstract of DOI:10.1021/jo801696r

(Chemical Equation Presented) The preparation of bicylic lactam 2 is described, employing an acetoacetate-based synthesis of 1,4-ketoacid 3. The lactam 2 was shown to undergo a thermal ene reaction at 280-300°C to afford tricycle 7. Reduction of the ene product followed by removal of the chiral auxiliary fragment provided the unusual lactam system 9 in highly enantioenriched form.

Full text of DOI:10.1021/jo801696r

SCHEME 1
Intramolecular Ene Reaction of a Chiral Bicyclic
Lactam1
James E. Resek*,†
Department of Chemistry, Colorado State UniVersity, Fort
Collins, Colorado 80503
resek_j@ricerca.com
ReceiVed August 12, 2008
SCHEME 2
The preparation of bicylic lactam 2 is described, employing
an acetoacetate-based synthesis of 1,4-ketoacid 3. The lactam
2 was shown to undergo a thermal ene reaction at 280-300
°C to afford tricycle 7. Reduction of the ene product followed
by removal of the chiral auxiliary fragment provided the
unusual lactam system 9 in highly enantioenriched form.
made as shown in Scheme 1.4 Thus, formation of the dianion
derived from methyl acetoacetate by sequential treatment with
NaH and n-BuLi5 followed by addition of 3-methyl-1-bromo-
2-butene gave the elaborated ketoester 4 in 100% crude yield.
Treatment of 4 with NaH and methyl bromoaceate provided
5in 48% yield. Saponification followed by acidification resulted
in decarboxylation to give the desired 1,4-ketoacid 3 in about
70% yield.6
The requisite saturated bicyclic lactam 6 was prepared in 80%
yield by heating an equimolar mixture of ketoacid 3 and (R)-
phenylglycinol in toluene with azeotropic removal of water
(Scheme 2). Oxidation of this lactam to the corresponding R,ꢀ-
unsaturated lactam Via the selenoxide was somewhat capricious,
providing yields of 29-65%. The yield and reproducibility of
this transformation were significantly improved by treatment
Intramolecular pericyclic reactions are a powerful method for
the construction of carbocycles and heterocycles. As part of the
Meyers research program directed toward elucidation of the
chemistry of chiral bicyclic lactams of type 1,2 the possibility
of performing an intramolecular ene reaction3 on an ap-
propriately substituted framework was investigated. In the
envisioned system the C-C double bond of the unsaturated
lactam 2 would act as the eneophile, being activated by the
carbonyl; and the ene component (CH2CdCMe2) would be
appended onto the angular position, R1. Herein the successful
execution of such an ene process is described, thus serving to
expand the portfolio of highly enantioenriched products available
from the bicyclic lactam template.
(1) Dedicated to the memory of Professor Albert I. Meyers.
(2) Reviews: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503. (b)
Meyers, A. I. Stereocontrolled Org. Synth. 1994, 145–175. More recent work: (c)
Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 1413–1419.
(d) Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.; McLaughlin,
M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999, 55, 8931–8952. (e) Lemieux,
R. M.; Devine, P. N.; Mechelke, M. F.; Meyers, A. I. J. Org. Chem. 1999, 64,
3585–3591. (f) Groaning, M. D.; Brengel, G. P.; Meyers, A. I. J. Org. Chem.
1998, 63, 5517–5522. (g) Schwarz, J. B.; Meyers, A. I. J. Org. Chem. 1998, 63,
1619–1629. (h) Fray, A. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 3362–3374.
(i) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084–7085.
(3) For a general ene reaction review, see: (a) Mikami, K.; Shimizu, M. Chem.
ReV. 1992, 92, 1021–1050. Reviews focusing on intramolecular ene reactions: (b)
Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476–486.
(c) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1–19. (d) Taber, D. F.
Intramolecular Diels-Alder and Alder Ene Reactions; Springer Verlag: Berlin,
1984.
The most common method employed for the synthesis of
saturated lactams of type 1 is a simple cyclodehydration reaction
between a 1,4-ketoacid and the appropriate chiral nonracemic
aminoalcohol.2a When desired, unsaturated lactam rings can be
prepared subsequently by common carbonyl dehydrogenation
techniques. As such, synthesis of the target ene-substrate lactam
2 required the preparation of the ketoacid 3, and the latter was
(4) Brown, E.; Guilmet, E.; Touet, J. Tetrahedron 1973, 29, 2589–2596.
(5) Hucklin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 1082–1087.
(6) The mass yield obtained was 84%, but the product clearly contained
ethanol and diethyl ether impurities. The material was estimated to have ca.
85% weight purity by 1H NMR. The presence of the solvents does not affect
the subsequent reaction, and they were not rigorously removed.
† Current Address: Ricerca Biosciences LLC, 7258 Auburn Road, Concord,
OH 44077.
9792 J. Org. Chem. 2008, 73, 9792–9794
10.1021/jo801696r CCC: $40.75 2008 American Chemical Society
Published on Web 11/01/2008

SCHEME 3
The relative stereochemistry in the lactam 9 was determined
by measurement of NOE enhancements between the protons
on the stereogenic carbon atoms. This analysis indicated an all-
cis relationship between the protons on the stereogenic carbon
atoms, as shown. Given the rigidity of the bicyclic lactam
system, this would be the expected stereochemical outcome if
the ene reaction follows the thermal pericyclic pathway.3a
The present work serves as yet another example of a
potentially useful extension of the chiral bicyclic lactam
methodology, that being exploitation of an intramolecular
cycloaddition process on an angularly functionalized lactam
template.
of 6 with potassium hydride and methyl phenylsulfinate followed
by thermal elimination of the resulting mixture of diastereomeric
sulfoxide substituted lactams.7 This reaction provided the desired
unsaturated lactam 2 in 88% yield. Analysis of both compounds
6 and 2 by 1H and 13C NMR indicated the presence of a single
diastereomeric form, which is the normal result when [3.3.0]
fused bicyclic lactams of this type are prepared.2a
The thermal ene reaction of 2 was executed in toluene solution
in a sealed tube. The reaction proceeded smoothly at 280-300
°C (bath temperature) to provide the expected tricyclic product
7 in 99% yield. The reaction did in fact proceed at lower
temperatures (190-250 °C), but the rate was impractically low.
As might be expected in a reaction performed under such
conditions, we observed a strong qualitative correlation between
the purity of the starting material and the success of the reaction.
Thus, in cases where pure and colorless 2 was employed, the
product was analytically pure after simple concentration of the
reaction solution. Starting material of lower purity and with more
color tended to undergo higher levels of decomposition.
Experimental Section
6-Isopropenyl-3-phenylhexahydro-1-oxa-3a-azacyclo-penta[c]-
pentalen-4-one (7). A solution of 2 (305 mg, 0.16 mmol) in toluene
(20 mL) was sealed in a thick-walled glass tube and heated in a
280-300 °C oil bath for 12 h. The solution was cooled and analyzed
by TLC (2/1 hexanes/EtOAc) to confirm completion of the reaction.
The solution was concentrated by rotary evaporation to provide
lactam 7 (302 mg, 99%) as a tan solid. mp 175-177 °C. [R]D
)
-200.0° (c ) 0.85 in CHCl3). 1H NMR (CDCl3) δ 1.60-1.74 (m,
2H), 1.70 (s, 3H), 1.84 (m, 1H), 2.05 (m, 1H), 2.51 (m, 2H), 2.71
(m, 1H), 2.89 (m, 1H), 4.02 (dd, J ) 8.6, 7.4 Hz, 1H), 4.59 (t, J )
8.2 Hz, 1H), 4.73 (s, 1H), 4.90 (q, J ) 1.3 Hz, 1H), 5.16 (t, J )
7.6 Hz, 1H), 7.13-7.35 (m, 5H); 13C NMR (CDCl3) δ 22.8, 26.5,
34.3, 43.6, 47.7, 57.5, 73.2, 109.6, 111.6, 125.6, 127.4, 128.7, 139.6,
144.3, 179.8. Anal. calcd for C18H21NO2: C, 76.30; H, 7.47. Found:
C, 76.15; H, 7.44.
1-(2-Hydroxy-1-phenylethyl)-4-isopropenylhexahydro-cyclo-
penta[b]pyrrol-2-one (8). To a CH2Cl2 (2 mL) solution of the
tricyclic lactam 7 (51 mg, 0.18 mmol) and triethylsilane (67 mg,
92 µL, 0.58 mmol, 3.2 equiv) at -78 °C was added TiCl4 (75 mg,
43 µL, 0.40 mmol, 2.2 equiv). The resulting yellow solution was
stirred at -78 °C for 1 h and allowed to warm to 0 °C over 2 h
(Note: extended stirring or higher temperatures resulted in apparent
migration of the double bond). The reaction was quenched by
addition of saturated NH4Cl (20 mL) and diluted with CH2Cl2 (10
mL). The mixture was stirred for 10 min and the layers were
separated. The aqueous portion was extracted with CH2Cl2 (3 ×
20 mL), and the combined organic solutions were washed with
saturated NaCl (20 mL), dried (Na2SO4), and concentrated. The
crude product was purified by flash chromatography (1/1 hexane/
EtOAc) to give 8 (37 mg, 72%). 1H NMR (CDCl3) δ 1.4-1.8 (m,
4H), 1.67 (s, 3H), 2.28 (dd, J ) 18.3, 6.7 Hz, 1H), 2.40 (m, 1H),
2.41 (dd, J ) 10.7, 18.3 Hz, 1H), 2.90 (m, 1H), 3.96 (m, 2H), 4.27
(m, 1H), 4.42 (dd, J ) 7.8, 3.5 Hz), 4.60 (br, 1H), 4.71 (s, 1H),
4.88 (s, 1H), 7.20-7.36 (m, 5H); 13C NMR (CDCl3) δ 22.9, 25.7,
30.6, 32.8, 36.5, 49.9, 62.9, 64.1, 64.4, 111.7, 127.4, 127.9, 128.7,
137.3, 144.0, 176.6. GC/MS: 285(1, M+), 254(100), 212(13),
166(24), 91(48).
4-Isopropenylhexahydrocyclopenta[b]pyrrol-2-one (9). To a flask
containing a glass-covered magnetic stirbar was charged a THF (3
mL) solution of lactam 8 (68 mg, 0.238 mmol). The flask was fitted
with a dry ice-acetone cooled coldfinger condenser and liquid
ammonia (ca. 20 mL) was condensed into the flask. To the solution
was added ethanol (0.1 mL) followed by a freshly cut piece of
lithium metal (20 mg). After a few minutes the solution became
dark blue in color, and stirring was continued under ammonia reflux
(-33 °C) for 4 min. The reaction was quenched by addition of
solid ammonium chloride (vigorous bubbling/foaming was ob-
served). The ammonia was allowed to evaporate and water (10 mL)
was added. The mixture was extracted with CH2Cl2 (4 × 15 mL),
and the combined organic solutions were washed with saturated
NaCl (20 mL), dried (Na2SO4), and concentrated. The residue was
purified by flash chromatography (EtOAc) to give 9 (36 mg, 91%)
as a colorless solid. [R]D ) -34.2° (c ) 0.65 in CHCl3). 1H NMR
Attempts were made to promote this reaction with Lewis acids
(TiCl4, MeAlCl2, Me2AlCl), but in all cases decomposition of
the lactam 2 was competitive with product formation and
product mixtures were obtained.
Cleavage of the chiral auxiliary from lactam 7 was ac-
complished as shown in Scheme 3. The process began with the
triethylsilane-TiCl4 reduction reported by Burgess and Meyers.8
Treatment of lactam 7 with these reagents resulted in smooth
reduction of the angular center to provide the expected bicyclic
lactam 8 in 72% yield. Analysis of the crude mixture showed
a single diastereomeric product. In previous work on this
transformation, retention of configuration at the reduction center
was the consistent result.8 To the extent the transition state is
product-like, the present case favors retention of configuration
to an even greater degree, as inversion would lead to a
significantly more strained trans-fused [3.3.0] ring system.9 The
stereochemical result of this reaction was confirmed after
removal of the phenethanol fragment in the final step of the
sequence. This was accomplished by treatment with lithium
metal in liquid ammonia, which furnished the unusual bicyclic
lactam 9 in 91% yield.10
(7) Resek, J. E.; Meyers, A. I. Tetrahedron Lett. 1995, 7051–7054.
(8) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656.
(9) See, for example: Lautens, M.; Ren, Y. J. Am. Chem. Soc. 1996, 118,
10668–10669, and references cited therein.
J. Org. Chem. Vol. 73, No. 24, 2008 9793

(CDCl3) δ 1.55-1.70 (m, 4H), 1.66 (s, 3H), 2.06 (dd, J ) 18.2,
5.6 Hz, 1H), 2.20 (dd, J ) 18.2, 10.6 Hz, 1H), 2.41 (br m, 1H),
2.97 (m, 1H), 4.13 (m, 1H), 4.69 (s, 1H), 4.86 (s, 1H), 6.70 (br,
1H); 13C NMR (CDCl3) δ 22.9, 25.5, 31.2, 33.8, 38.5, 50.4, 58.6,
111.7, 144.4, 178.6. IR (film) cm-1 3395, 3181, 1661, 1329, 1290,
897. GC/MS 165(97, M+), 150(12), 136 (27), 122 (38), 108 (59),
96 (100), 83 (66), 55 (76). Anal. calcd for C10H15NO: C, 72.69; H,
9.15. Found: C, 72.50; H, 9.11.
Supporting Information Available: Experimental proce-
1
dures for compounds 2-6, and H and 13C NMR spectra for
compounds 2-9. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO801696R
Acknowledgment. This work was supported by the National
Institutes of Health.
(10) For related compounds: Bartmann, W.; Rupp, H.; Beck, G.; Knolle, J.
German Patent DE2947493, 1981.
9794 J. Org. Chem. Vol. 73, No. 24, 2008