Metal-catalyzed cycloisomerization reactions of cis-4-hydroxy-5- alkynylpyrrolidinones and cis-5-hydroxy-6-alkynylpiperidinones: Synthesis of furo[3,2-b]pyrroles and furo[3,2-b]pyridines

Article abstract of DOI:10.1021/jo9007942

(Chemical Equation Presented) Furo[3,2-b]pyrroles and furo[3,2-b]pyridines can be conveniently prepared in good yields from the cycloisomerization reactions of cis-4-hydroxy-5-alkynylpyrrolidinones and cis-5-hydroxy-6- alkynylpiperidinones, respectively,

Full text of DOI:10.1021/jo9007942

pubs.acs.org/joc
Metal-Catalyzed Cycloisomerization Reactions of cis-4-Hydroxy-
5-alkynylpyrrolidinones and cis-5-Hydroxy-6-alkynylpiperidinones:
Synthesis of Furo[3,2-b]pyrroles and Furo[3,2-b]pyridines
Jasmine C. Jury,† Nalivela Kumara Swamy,† Arife Yazici,† Anthony C. Willis,‡ and
Stephen G. Pyne*,†
†School of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia, and
‡Research School of Chemistry, Australian National University, Canberra, ACT, 0200, Australia
spyne@uow.edu.au
Received April 16, 2009
Furo[3,2-b]pyrroles and furo[3,2-b]pyridines can be conveniently prepared in good yields from the
cycloisomerization reactions of cis-4-hydroxy-5-alkynylpyrrolidinones and cis-5-hydroxy-6-alky-
nylpiperidinones, respectively, using Ag(I), Pd(II)/Cu(I), or Au(I) catalysis. In one case, the
cycloisomerization product was unstable and produced a furan derivative by a ring-opening reaction.
Introduction
The synthesis of unsaturated five-membered ring hetero-
cycles in general, via metal-catalyzed cycloisomerization
reactions of homopropargylic alcohols, amines (and their
N-derivatives), and thiols and related ortho-alkynyl phenols,
anilines, and arylthiols, is well-established.5 In the case
of homopropargylic alcohols, Pd(II),6 (Et3N)Mo(CO)5,7
Au(I),8 and Pt(II)9 have been employed as catalysts in the
The furo[3,2-b]pyrrole nucleus 1 (X=O) is a key structural
feature of the bioactive fungal metabolites lucilactaene,1 a
cell-cycle inhibitor in p53-transfected cancer cells, 13R-luci-
lactaene,2 the structurally related alkaloids fusarins A and
D,3 and the telomerase inhibitors UCS1025A and B
(Figure 1).4 A general and versatile synthesis of this hetero-
cyclic ring system and its furo[3,2-b]pyridine homologue 2
would thus provide valuable scaffolds for new drug discov-
ery programs (Scheme 1). Bicyclic heterocyclic systems 1 and
2 could in principle be prepared via a metal-catalyzed
cycloisomerization of the heterocyclic cis-β-hydroxy alkynes
4 (n = 1, 2) followed by reduction of the resulting unsatu-
rated bicyclic heterocyclic system 3 (Scheme 1).
(5) For reviews on metal-catalyzed cyclization reactions, see: (a) Nakamura,
I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198. (b) Zeni, G.; Larock, R. C.
Chem. Rev. 2006, 106, 4644–4680. (c) Hashmi, A. S. K.; Hutchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896–7936. (d) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180–3211. (e) Fuerstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410–3449. (f) Shen, H. C. Tetrahedron 2008, 64, 3885–3903. (g) Shen, H. C.
Tetrahedron 2008, 64, 7847–7870. (h) Alvarez-Corral, M.; Munoz-Dorado, M.;
Roderiguez-Garcia, I. Chem. Rev. 2008, 108, 3174–3198. (i) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442. (j) Gorin, D. J.; Sherry, B.
D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–3378. (k) Arcadi, A. Chem. Rev.
2008, 108, 3266–3325. (l) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–
3265.
(1) Kakeya, H.; Kageyama, S.-I.; Nie, L.; Onose, R.; Okada, G.; Beppu,
T.; Norbury, C. J.; Osada, H. J. Antibiot. 2001, 54, 850–854.
(2) Bashyal, B. P.; Faeth, S. H.; Gunatilaka, A. A. L. Nat. Prod.
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4, 4387–4390.
(8) (a) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489–4492. (b) The
system Au(Ph3P)Cl/AgBF4 was used in the published work, ref 8a, but only
Au(Ph3P)Cl was used in our study.
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DOI: 10.1021/jo9007942
r
Published on Web 06/04/2009
J. Org. Chem. 2009, 74, 5523–5527 5523
2009 American Chemical Society

Jury et al.
JOCArticle
SCHEME 2
FIGURE 1. Furo[3,2-b]pyrrole-based natural products.
SCHEME 1
Results and Discussion
The cis-hydroxy alkyne substrates 7a-c were prepared via
the BF3 Et2O-catalyzed reactions between the hemiaminals
3
5a-c17,18 and the potassium alkynyltrifluoroborates 6a,b
(Scheme 2 and Table 1). We17 and Batey et al.18 have
previously reported the successful reactions of 5b,c with vinyl
and arylboronic acids. Under similar reaction conditions
that we have developed earlier,17 the reactions of 1-benzyl-
4S-hydroxy-5-methoxypyrrolidin-2-one 5a with the potas-
sium 1-alkynyltrifluoroborates 6a,b gave the 4,5-cis-adducts
7a and 7b, respectively, with high cis-diastereoselectivity
and in moderate to good yields, respectively (Table 1, entries
1 and 2). In contrast, the reaction of racemic N-Cbz-
4,5-dihydroxypyrrolidine5bwith6bgavethe racemichydroxy
alkyne 7c in 89% yield as a 73:27 mixture of diastereomeric
adducts that could be separated (Table 1, entry 3).
The six-membered ring hemiaminal (5S)-5c gave the cor-
responding 5,6-cis-adducts 7d, 7e, and 7f with high diaster-
eoselectivity but in modest yields (Table 1, entries 4-6).
These yields were low due to formation of the known Ritter
reaction product A, comprising 18-30% of the product
yields, formed between the in situ generated cyclic N-acyli-
minium ion and acetonitrile.19 The use of alternative solvents
such as nitromethane did not improve the yields of 7d-f. To
assist in the stereochemical assignments of these adducts,
these reactions were repeated on the 4-O- and 5-O-protected
analogues 8a-c of the substrates 5a-c, respectively
(Scheme 3). The reactions were highly trans-diastereoselec-
tive and proceeded in generally higher yields (Table 2). This
was due in part to the better solubility properties of the
substrates in the nonparticipating solvent dichloromethane.
The 4,5-cis-stereochemistry of products 7a and 7b was
based on the magnitude of J4,5 (5.0 and 5.1 Hz, respectively)
for these compounds. Their related trans-isomers 9a
(R3 = Ac, Bn, and TBPDS) and trans-7b that was prepared
from O-TBS deprotection of 9c (Supporting Information)
had J4,5 values of 0-2 Hz. In related literature examples, J4,5
key C-O bond forming reaction. Reactions involving the
latter two metal catalysts have been performed in alcohol
solvent, resulting in conversion of the initially formed 1,2-
dihydrofuran to a 2-alkoxytetrahydrofuran.8,9 In the case of
homopropargylic alcohol itself, cycloisomerization with
Ag2CO3 was not successful and only starting material was
recovered.10 Bis-homopropargylic alcohols (4-alkyn-1-ols)
undergo cycloisomerization reactions with Pd(II),6 Ag(I),11
Au(I),8,12 Pt(II),9 Ir(I),13 Ru(I),14 and (Et3N)Mo(CO)5,15 to
give 5-exo7,9,11-13 and/or 6-endo14,15 cyclic enol ether pro-
ducts. 5-Alkyn-1-ols often give 6-exo products;9,12,13 how-
ever, under (Et3N)Mo(CO)5 catalysis, seven-membered ring
glycals have been formed.15 While the cycloisomerization
reactions of acyclic homopropargylic alcohols are well-
documented, we are not aware of such studies on saturated
cyclic cis-β-hydroxy alkynes, either carbocyclic (2-alkynyl-
1-cycloalkanols) or heterocyclic analogues related to 4, to
give bicyclic systems incorporating a dihydrofuran moiety.
The lack of ready accessibility of these cyclic cis-β-hydroxy
alkyne substrates may be a major reason for this.
We report here a direct method for the synthesis of the
novel heterocyclic cis-hydroxy alkynes 7a-c, via cis-diaster-
eoselective reactions of cyclic N-acyliminium ions16 with
potassium 1-alkynyltrifluoroborates and the synthesis of
novel furo[3,2-b]pyrrole and furo[3,2-b]pyridine derivatives
from the metal-promoted cycloisomerization of these sub-
strates under Ag(I), Pd(II)/Cu(I), or Au(I) catalysis.
(10) Pale, P.; Chuche, J. Eur. J. Org. Chem. 2000, 1019–1025.
(11) Dalla, V.; Pale, P. New J. Chem. 1999, 23, 803–805.
(12) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2007, 48, 1439–
1442.
(13) Genin, E.; Antoniotti, S.; Michelet, V.; Genet, J.-P. Angew. Chem.,
Int. Ed. 2005, 44, 4949–4953.
(14) Trost, B. M.; Rhee, Y. H. Org. Lett. 2004, 6, 4311–4313.
(15) Alczar, E.; Pietcher, J. M.; McDonald, F. E. Org. Lett. 2004, 6,
3877–3880.
(17) Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409–
1419.
(16) For reviews on N-acyliminium ions, see: (a) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856. (b) Maryanoff, B. E.;
Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004,
1431–1628. (c) Yazici, A.; Pyne, S. G. Synthesis 2009, 339–368. (d) Yazici, A.;
Pyne, S. G. Synthesis 2009, 513–541.
(18) (a) Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. Am. Chem.
Soc. 1999, 121, 5075–5076. (b) Batey, R. A.; MacKay, D. B. Tetrahedron
Lett. 2000, 41, 9935–9938.
(19) Morgan, I. R.; Yazici, A.; Pyne, S. G.; Skelton, B. W. J. Org. Chem.
2008, 73, 2943–2946.
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Jury et al.
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TABLE 1. Synthesis of cis-β-Hydroxy alkynes 7a-f
entry
substrate
boronate
temp (°C) /time (h)
solvent
product (yield (%))
cis/trans
1
2
3
4
5
5a
5a
5b
5c
5c
6a
6b
6b
6a
6a
0/1 then rt/12
0/1 then rt/4
0/2
0/1 then rt/16
0/1 then rt/16
MeNO2
MeCN
MeCN
MeCN
MeCN
7aa (41)
7b (70)
7c (89)
7da (31)b
7d (33)
7ec (4)
95:5
100:0
73:27
100:0
100:0
6
5c
6b
0/1 then rt/16
MeCN
7f (36)b
91:9
a After treatment of the reaction mixture with aqueous LiOH solution, rt, 1 h. b The known Ritter reaction product A19 was also isolated (entry 4, 18%
and entry 6, 30%). c This reaction did not include treatment with LiOH, consequently compound 7e was isolated along with the major product 7d.
SCHEME 3
modified literature procedures. Consequently, compounds
7b and 7f (both bearing a phenyl alkynyl moiety) were
cycloisomerized into the corresponding dihydrofurans 10b
and 10e in good to excellent yields using all three of the
chosen catalyst systems in DMF as solvent (Table 3, entries
2-5 and 14-16). While substrates 7b and 7f required reac-
tion temperatures of 60-70 °C, the substrate 7c underwent
reaction at rt with all three catalysts in DMF (not shown in
Table 1) or MeOH (Table 1, entries 6-8). These reactions
gave not the expected product 10c but the furan derivative 11
(Scheme 4). The structure of 11 was clear from NMR
analysis that showed resonances for two vicinally coupled
furan methines (δH 6.54 (d, J=3.5 Hz), δc 105.7 (H-4/C-4),
and δH 6.13 (d, J = 3.5 Hz), δc 108.7 (H-3/C-3)) and a
carbamate NH (δH 4.99-4.87 (br s)). This compound clearly
arises from a ring-opening reaction of the desired product
10c, surprisingly at rt and in the absence of a strong base or
acid catalyst. Notably, the N-Boc analogue of 10c, but
lacking the 5-phenyl substituent, is a known compound that
was stable to distillation at low pressure.23
It was also observed that 30 mol % of AgF (DMF, 65-
70 °C, 2.5 h) and Ag2O (MeOH, rt, 5 h) could be used in the
silver-catalyzed reactions of 7b (70% yield of 10b) and 7c
(77% yield of 11), respectively. Compounds 7a and 7d, each
bearing a terminal alkyne, were cycloisomerized using
AgNO3 to their respective dihydrofurans 10a and 10d
(Table 3, entries 1 and 9); however, all attempts to cycloi-
somerize compound 7d using either the Au(I) or Pd(II)/Cu(I)
catalyst systems were unsuccessful, leading only to the
recovery of the starting material. The AgNO3-mediated
cyclization of compound 7e, bearing the trimethylsilylethy-
nyl moiety, led to the formation of 10d, with the associated
loss of the TMS group (Table 3, entry 10). The order of
catalyst reactivity in these reactions proved to be AgNO3 >
PdCl2(Ph3P)2/CuI>Au(Ph3P)Cl. Catalyst loadings of PdCl2-
(Ph3P)2 were low (4 mol %), while the higher loading
used for Au(Ph3P)Cl (10-30 mol %) reflected the slower
observed rates of reaction when using this catalyst. AgNO3
and Au(Ph3P)Cl could be used in amounts as low as 5-10
mol % (Table 3, entry 11 and footnotes a-c); however, this
resulted in slower reaction times and slightly decreased
yields. The corresponding trans-β-hydroxyl alkyne 9 (n =
1, R2 = H, X = O) did not undergo a cycloisomerization
reaction with any of the aforementioned catalysts.
TABLE 2. Synthesis of trans-β-Hydroxy alkynes 9a-e
temp
entry substrate (°C)/time (h)
product
solvent (yield (%)) trans/cisa
1
2
3
4
5
8a
8b
8c
8d
8e
0/1 then rt/12 CH2Cl2
0/1 then rt/12 CH2Cl2
0/1 then rt/12 CH2Cl2
0/1 then rt/16 CH2Cl2
0/1 then rt/16 CH3CN
9a (68)b
9b (89)
9c (71)
9d (77)
9e (86)
90:10
100:0
100:0
100:0
84:16
aRatio from 1H NMR analysis of crude reaction mixture. bRatio of
trans/cis = 96:4 after purification by column chromatography.
is typically 0-2.5 Hz for trans-isomers and 6.0-7.5 Hz
for the corresponding cis-isomers.17 For compound 9d, J4,5
was <1 Hz, consistent with its relative 4,5-trans-configura-
tion; however, J4,5 for its corresponding cis-isomer, 7d, could
not be determined due to peak broadening. The cis-stereo-
chemistry of 7e was established by a single-crystal X-ray
analysis (see Supporting Information).
The BF3 Et2O-catalyzed reactions between N-benzyl-
3
3,4,5-triacetoxy-2-pyrrolidinone and potassium 1-alkynyl-
trifluoroborates have previously been shown to be 4,5-
cis-diastereoselective (4,5-cis/4,5-trans = 70-90:30-10).20
The stereochemical outcomes of these reactions, however,
were thought to be due to neighboring group participation of
the 3-acetoxy group; this group is absent in our substrate 5a.
The cis-diastereoselectivity observed in the products 7a-c,
therefore, arises via a different reaction mechanism, presum-
ably via a boronate intermediate involving the free hydroxyl
group of substrates 5a-c.17
Initial studies on the cycloisomerization reactions of the
cis-β-hydroxy alkynes 7a-e involved their reactions with
AgNO3,21 Au(Ph3P)Cl,8a,b or PdCl2(Ph3P)2/CuI,22 using
In order to further explore the synthetic potential of metal-
catalyzed cycloisomerizations of cis-β-hydroxy alkynes of
the type 7, the sequential palladium-catalyzed cycloisome-
rization/cross-coupling reactions of 7b,c were examined
(20) Vieira, A. S.; Ferreira, F. P.; Fiorante, P. F.; Guadagnin, R. C.;
Stefani, H. A. Tetrahedron 2008, 64, 3306–3314.
(21) Barange, D. K.;Nishad,T. C.;Swamy, N. K.;Bandameedi, V.;Kumar,
D.; Sreekanth, B. R.; Vyas, K.; Pal, M. J. Org. Chem. 2007, 72, 8547–8550.
(22) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am.
Chem. Soc. 2001, 123, 1878–1889.
(23) Paolucci, C.; Venturelli, F.; Fava, A. Tetrahedron Lett. 1995, 36,
8127–8128.
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TABLE 3. Cycloisomerization Reactions of Substrates 7a-f
entry
substrate
catalyst (mol %)
temp (°C)
time (h)
solvent
product (yield (%))
1
2
3
5
6
7
8
9
10
11
12
13
7a
7b
7b
7b
7c
7c
7c
7d
7e
7f
AgNO3 (26)
AgNO3 (12)
65-70
65-70
65-70
65-70
rt
1.5
1.5
24
1.5
2
8
DMF
DMF
EtOH
DMF
MeOH
MeOH
MeOH
DMF
DMF
DMF
EtOH
DMF
10a (68)
10b (77)
10b (72)
10b (70)
11 (82)
Au(Ph3P)Cl (22)
PdCl2(Ph3P)2 (4) CuI (10)
AgNO3 (25)a
Au(Ph3P)Cl (30)b
PdCl2(Ph3P)2 (4) CuI (5)
AgNO3 (10)c
rt
rt
11 (87)
11 (69)
8
60-65
60 then rt
60-65
60-65
60-65
4
2 then 16
4
5 d
16
10d (60)
10d (66)
10e (75)
10e (79)
10e (63)
AgNO3 (22)
AgNO3 (18)
Au(Ph3P)Cl (17)
PdCl2(Ph3P)2 (4) CuI (7)
7f
7f
a10 mol % of AgNO3 (rt, 10 h) gave 75% of 11. b10 mol % of Au(Ph3P)Cl (rt, 21 h) gave 74% of 11. c5 mol % of AgNO3 (60-65 °C, 8 h) gave 54% of
10d.
of this same or analogous Pd(II) complex, respectively.
Interestingly, compound 12b was stable under the reaction
conditions and did not produce the corresponding ring-
opened furan derivative.
SCHEME 4
In conclusion, furo[3,2-b]pyrroles and furo[3,2-b]pyri-
dines can be conveniently prepared in good yields from the
cycloisomerization reactions of cis-4-hydroxy-5-alkynylpyr-
rolidinones and cis-5-hydroxy-6-alkynylpiperidinones, re-
spectively, using Ag(I), Pd(II)/Cu(I), or Au(I) catalysis.
The N-Cbz substrate 7c gave an unexpected furan product
(11). These β-hydroxy alkyne substrates are readily prepared
from the BF3 Et2O-catalyzed reactions between in situ
3
formed N-acyliminium ions and potassium 1-alkynyltri-
fluoroborates. AgNO3 proved to be the most effective cata-
lyst for these cycloisomerization reactions in terms of
substrate versatility, rate of reaction, and catalyst loading
(down to 5-10 mol %).
Experimental Section
(4S,5S)-1-Benzyl-5-ethynyl-4-hydroxypyrrolidin-2-one (7a). To
a stirred solution of 5a (60 mg, 0.27 mmol) and potassium
trimethylsilylacetylenetrifluoroborate 6b25 (166 mg, 0.81 mmol)
in MeNO2 (1.3 mL) maintained at 0 °C under a nitrogen
atmosphere was added BF3 Et2O (0.154 g, 1.08 mmol). The
3
SCHEME 5
resulting mixture was stirred for 1 h before warming to rt and
stirring for a further 12 h. The reaction mixture was then diluted
with EtOAc (8 mL) and washed with NaHCO3 (8 mL of a 10%
aqueous solution). The separated organic phase was dried then
concentrated under reduced pressure. The resulting residue
was dissolved in THF (5 mL) then treated with LiOH (2 mL
of a saturated aqueous solution), and the resulting mixture
was stirred for 1 h before being diluted with EtOAc (8 mL).
The separated organic layer was dried and the solvent removed
in vacuo. The resulting crude product (present only as the
1
cis-diastereomer, as judged by H NMR analysis) was purified
by column chromatography (silica, 2:1 v/v EtOAc/petrol +
0.5% MeOH). Concentration of the relevant fractions (Rf 0.5 in
2:1 v/v EtOAc/petrol+0.5% MeOH) gave the title compound 7a
(24 mg, 41%) as a pale yellow solid: mp 74-76 °C; [R]2D5 -17.1
(c 2.1, CHCl3); υmax 3314, 2929, 2371, 1673, 1439, 1414, 1291,
1072, and 708 cm-1; δH 7.33-7.27 (5H, complex m), 5.10
(1H, d, J = 14.7 Hz), 4.37 (1H, m), 4.23 (1H, dd, J = 2.0
and 5.0 Hz), 4.02 (1H, d, J=14.9 Hz), 2.64 (1H, dd, J=17.1
and 6.6 Hz), 2.63 (1H, d, J=2.0 Hz), 2.51 (1H, dd, J=17.1 and
3.5 Hz); δC 172.0, 136.0, 128.7, 128.4, 127.8, 78.1, 76.3,
using iodobenzene.24 These reactions gave moderate yields
of the arylated products 12a (45%) and 12b (38%), respec-
tively, along with significant amounts of the previously
observed products 10b (23%) and 11 (19%), respectively
(Scheme 5). We assume that compound 10b arises via
protonation of a 3-PhPd(II)-furo[3,2-b]pyrrole interme-
diate, while products 12a,b are from reductive elimination
(24) Hu, Y.; Nawoschik, Y. L.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem.
2004, 69, 2235–2239.
(25) Molander, G. A.; Katona, B. W.; Machrouchi, F. J. Org. Chem.
2002, 67, 8416–8423.
5526 J. Org. Chem. Vol. 74, No. 15, 2009

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JOCArticle
65.4, 55.3, 44.4, 39.1; MS (ESI+) m/z 216 [(MH)+, 100%];
HRMS (ESI+) found 216.1018, C13H14NO2 requires (MH)+,
216.1025.
product was subjected to column chromatography as described
above to give the title compound 10b (21 mg, 70%) as a colorless
gum. The spectral data of the purified product were in good
agreement with those obtained from the sample of compound
10b prepared by Method A.
Method C (Au(PPh3)Cl): To a stirred solution of 7b (10 mg,
0.046 mmol) in EtOH (0.6 mL) maintained at rt under a nitro-
gen atmosphere was added Au(PPh3)Cl (5 mg, 0.01 mmol).
The resulting mixture was heated at 65-70 °C for 24 h before
being cooled and diluted with water (2 mL). The resulting
mixture was extracted, and the crude product was subjected to
column chromatography as described above to give the title
compound 10b (7 mg, 72%) as a colorless gum. The spectral data
of the purified product were in good agreement with those
obtained from the sample of compound 10b prepared by
Method A.
(3aS,6aS)-4-Benzyl-2,3-diphenyl-6,6a-dihydro-3aH-furo[3,2-
b]pyrrol-5(4H)-one (12a). A solution of iodobenzene (49 mg,
0.24 mmol) and K2CO3 (66 mg, 0.48 mmol) in acetonitrile
(1.5 mL) maintained at 50 °C under a nitrogen atmosphere
was treated with Pd(dba)2 (7 mg, 7.2 μmol). The resulting
mixture was stirred for 30 min before adding a solution of 7b
(35 mg, 0.12 mmol) in acetonitrile (1.5 mL), and stirring was
continued for a further 12 h. The reaction solvent was then
removed in vacuo, and the resulting residue was filtered through
a short plug of silica gel using EtOAc. The filtrate was concen-
trated under reduced pressure, and the resulting crude material
was purified using flash column chromatography (1:3 v/v
EtOAc/petrol) to furnish three fractions, A, B, and C. Concen-
tration of the fraction A (Rf 0.5 in 1:4 v/v EtOAc/petrol) gave
compound 10b (8 mg, 23%) as a colorless gum. The spectro-
scopic data of this material were in good agreement with those
obtained from the sample of compound 10b prepared pre-
viously. Concentration of the fraction B (Rf 0.5 in 1:3 v/v
EtOAc/petrol) gave compound 12a (20 mg, 45%) as a white
solid: mp 144-146 °C; [R]2D3+44.0 (c 1.0, CHCl3); υmax
1682, 1433, 1227, 911, and 765 cm-1; δH 7.36-6.73 (15H,
complex m), 5.21-5.17 (1H, m), 5.13 (1H, d, J=7.8 Hz), 4.96
(1H, d, J=15.2 Hz), 3.40 (1H, d, J=15.2 Hz), 3.04-2.96 (2H, m);
δC 172.4, 154.1, 135.9, 134.0, 130.3, 129.2, 129.1, 128.9, 128.4,
128.1, 127.95, 127.5, 127.4, 127.3, 111.0, 75.8, 68.5, 44.5,
38.2; MS (ESI+) m/z 368 [(M+H)+, 100%]; HRMS (EI+) found
367.1572, C25H21NO2 requires M+, 367.1565. Concentration of
fraction C (Rf 0.5 in 2:1 v/v EtOAc/petrol+1% MeOH) gave
unreacted 7b (10 mg) as a colorless solid.
(4S,5R)-1-Benzyl-4-(acetyloxy)-5-(phenylethynyl)pyrrolidin-2-one
(9a). To a stirred solution of 8a3 (100 mg, 0.34 mmol) and
potassium phenylacetylenetrifluoroborate 6b (92 mg, 0.44
mmol) in CH2Cl2 (1.5 mL) maintained at 0 °C under a nitrogen
atmosphere was added dropwise BF3 Et2O (0.20 g, 1.37 mmol).
3
The resulting mixture was stirred for 1 h before being warmed to
rt and stirred for a further 12 h. The reaction mixture was diluted
with CH2Cl2 (10 mL) and washed with NaHCO3 (8 mL of a
saturated aqueous solution). The separated organic layer was
dried and then concentrated under reduced pressure. The crude
product (90:10 ratio of trans/cis) was purified by column
chromatography (silica, 1:3 v/v EtOAc/petrol), and concentra-
tion of the relevant fractions (Rf 0.55 in 1:3 EtOAc/petrol)
afforded the title compound 9a (78 mg, 68%, 96:4 trans/cis
mixture) as a light brown gum: [R]2D2 -65.3 (c 3.0, CHCl3); υmax
1744, 1700, 1490, 1408, 1231, 1036, and 703 cm-1; δH (major
trans-diastereomer) 7.40-7.26 (10H, complex m), 5.34 (1H, d,
J=6.5 Hz), 5.14 (1H, d, J=15.2 Hz), 4.27 (1H, s), 4.11 (1H, d,
J=15.2 Hz), 3.05 (1H, dd, J=17.9 and 6.6 Hz), 2.53 (1H, d,
J =17.9 Hz), 2.03 (3H, s); minor cis-diastereomer 7.40-7.26
(10H, complex m), 5.90 (1H, s), 5.06 (d, J=15.0 Hz), 4.17 (1H, s),
4.15 (1H, d, J=15.0 Hz), 2.80 (1H, dd, J=17.0 and 7.0 Hz), 2.70
(1H, dd, J=17.0 and 2.5 Hz); δC (major trans-diastereomer)
171.4, 170.0, 135.5, 131.8, 128.9, 128.7, 128.3, 128.2, 127.7,
121.6, 87.2, 82.4, 72.0, 55.5, 44.5, 36.9, 20.8; MS (ESI+)
m/z 334 [(MH)+, 100%]; HRMS (ESI+) found 334.1450,
C21H20NO3 requires (MH)+, 334.1443.
(3aS,6aS)-4-Benzyl-2-phenyl-6,6a-dihydro-3aH-furo[3,2-b]pyrrol-
5(4H)-one (10b). Method A (AgNO3): A magnetically stirred
solution of 7b (30 mg, 0.10 mmol) in DMF (1 mL) maintained
at rt under a nitrogen atmosphere was treated with AgNO3
(2 mg, 0.012 mmol). The reaction mixture was then heated
at 65-70 °C for 1.5 h, before being cooled and diluted
with water (3 mL). The resulting mixture was extracted with
EtOAc (2 Â 10 mL). The combined extracts were dried, and the
solvent was removed in vacuo. The crude product was subjected
to column chromatography (silica, 1:4 v/v EtOAc/petrol), and
concentration of the relevant fractions (Rf 0.5 in 1:4 v/v EtOAc/
petrol) gave the title compound 10b (23 mg, 77%) as a colorless
gum: [R]2D4 -9.3 (c 1.6, CHCl3); υmax 1669, 1438, 1248, 1020, and
756 cm-1; δH 7.53-7.28 (10H, complex m), 5.38 (1H, d, J = 2.4
Hz), 5.17 (1H, app t, J = 7 Hz), 4.92 (1H, d, J = 14.8 Hz),
4.71 (1H, dd, J=7.8, 2.2 Hz), 4.07 (1H, d, J=14.8 Hz), 2.97
(1H, dd, J=18.0 and 7.1 Hz), 2.88 (1H, d, J=18.0 Hz); δC 171.7,
160.4, 136.2, 129.6, 129.5, 128.7, 128.4, 128.3, 127.7, 125.7, 93.5,
77.4, 65.5, 44.7, 38.3 MS (ESI+) m/z 292 [(MH)+, 100%];
HRMS (ESI+) found 292.1356, C19H18NO2 requires (MH)+,
292.1338.
Acknowledgment. We thank the Australian Research
Council and the University of Wollongong for financial
support.
Method B (Pd(PPh3)2Cl2/CuI): To a stirred solution of 7b
(30 mg, 0.10 mmol) in DMF (1 mL) maintained at rt under a
nitrogen atmosphere were added Pd(PPh3)2Cl2 (3 mg, 4.0 μmol)
and CuI (2 mg, 0.01 mmol). The resulting mixture was heated
at 65-70 °C for 1.5 h, before being cooled and diluted with
water (3 mL). The resulting mixture was extracted, and the crude
Supporting Information Available: General experimental pro-
cedures and full experimental procedures and characterization data
as well as copies of the 1H NMR and 13C NMR spectra of all new
compounds. Crystal/refinement data and ORTEP plot of com-
pound 7e (CCDC 724111). This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 15, 2009 5527