Nonracemic bicyclic lactam lactones via regio- and cis-diastereocontrolled C-H insertion. Asymmetric synthesis of (8S,8aS)-octahydroindolizidin-8-ol and (1S,8aS)-octahydroindolizidin-1-ol

Article abstract of DOI:10.1021/jo901790g

(Chemical Equation Presented) The Rh₂(MPPIM)₄- catalyzed intramolecular C-H insertion reaction of (S)- and (R)-1-benzyl-5-(R- diazoacetoxy)piperidin-2-one and (S)-1-benzyl-4-(α-diazoacetoxy) pyrrolidin-2-one proceeds with high regios

Full text of DOI:10.1021/jo901790g

pubs.acs.org/joc
Nonracemic Bicyclic Lactam Lactones via Regio- and cis-
Diastereocontrolled C-H Insertion. Asymmetric Synthesis of (8S,8aS)-
Octahydroindolizidin-8-ol and (1S,8aS)-Octahydroindolizidin-1-ol
Andrew G. H. Wee,* Gao-Jun Fan, and Hypolite M. Bayirinoba
Department of Chemistry and Biochemistry, University of Regina, Regina Saskatchewan, S4S 0A2, Canada
andrew.wee@uregina.ca
Received August 18, 2009
The Rh2(MPPIM)4-catalyzed intramolecular C-H insertion reaction of (S)- and (R)-1-benzyl-
5-(R-diazoacetoxy)piperidin-2-one and (S)-1-benzyl-4-(R-diazoacetoxy)pyrrolidin-2-one proceeds
with high regioselectivity and cis-diastereoselectivity to give good yields of chiral nonracemic bicyclic
lactam lactones (BLLs). For (S)- and (R)-1-benzyl-5-(R-diazoacetoxy)piperidin-2-one, the regio
selectivity of the C-H insertion is catalyst-dependent; for example, (S)-1-benzyl-5-(R-diazoace-
toxy)piperidin-2-one undergoes C-H insertion at C-6 preferentially when Rh2(5S-MPPIM)4 is used,
but with Rh2(5R-MPPIM)4, C-H insertion occurs preferentially at C-4. This effect is not observed in
the reaction of (S)-1-benzyl-4-(R-diazoacetoxy)pyrrolidin-2-one. The utility of the BLLs as chiral
building blocks in alkaloid synthesis is exemplified by the synthesis of (8S,8aS)-octahydroindoli-
zidin-8-ol and (1S,8aS)-octahydroindolizidin-1-ol.
Introduction
N-acyliminium ion cyclization,4 intramolecular cyclization
reactions (SN2,5 reductive amination,1b,3 carboamination6),
imino Diels-Alder7 and 1,3-dipolar nitrone8 cycloaddition,
ring closing metathesis,9 and the use of N-heterocyclic inter-
mediates10 are the most widely studied. In spite of the
The piperidine and pyrrolidine moieties are found as core
structures or as subfeatures in many structurally diverse and
stereochemically interesting alkaloids isolated from marine
and terrestrial plants and animals.1 Many of the alkaloids
also possess potent and therapeutically interesting biological
activities, which has led to their use as drug candidates or as
lead compounds in new drug designs.2 A wide range of
synthetic methods for the stereoselective construction of
functionalized piperidine and pyrrolidine derivatives have
been developed.1a,b,3 Among these, methods based on
(4) (a) Yazici, A.; Pyne, S. G. Synthesis 2009, 339. (b) Maryanoff, B. E.;
Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004,
104, 1431. (c) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311.
(d) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
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2007, 5105. (b) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367.
(7) (a) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721. (b) Caballero, E.;
Figueroa, J.; Puebla, P.; Pelaez, R.; Tome, F.; Medarde, M. Eur. J. Org.
Chem. 2008, 4004.
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J.; Stork, T. C.; Warner, J. A. Pure Appl. Chem. 1997, 69, 531. (b) Li, X. L.;
Zhu, Z. G.; Duan, K. F.; Chen, H.; Li, Z. W.; Li, Z.; Zhang, P. Z. Tetrahedron
2009, 65, 2322. (c) Stecko, S.; Solecka, J.; Chmielewski, M. Carbohydr. Res.
2009, 344, 167.
(9) (a) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (b)
Pavlyuk, O.; Teller, H.; McMills, M. C. Tetrahedron Lett. 2009, 50, 2716. (c)
Muroni, D.; Mucedda, M.; Saba, A. Tetrahedron Lett. 2008, 49, 2373.
(10) (a) Toyooka, N.; Nemoto, H. Studies in Natural Products Chemistry:
Bioactive Natural Products (Part J); Atta-ur-Rahman, Ed.; Elsevier: New York,
2003; Vol. 29, p 419. (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56,
9843. (c) Husson, H. P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383.
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (b) Liddell, J. R. Nat.
Prod. Rep. 2002, 19, 773. (c) Garraffo, H. M.; Caceres, J.; Daly, J. W.;
Spande, T. F.; Andriamaharavo, N. R.; Andriantsiferana, M. J. Nat. Prod.
1993, 56, 1016. (d) Attygalle, A. B.; Morgan, E. D. Chem. Soc. Rev. 1984, 13,
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(2) (a) Kishore, N.; Mishra, B. B.; Tripathi, V.; Tiwari, V. K. Fitoterapia
2009, 80, 149. (b) Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.;
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DOI: 10.1021/jo901790g
r
Published on Web 10/07/2009
J. Org. Chem. 2009, 74, 8261–8271 8261
2009 American Chemical Society

Wee et al.
SCHEME 1. Preparation of Diazoacetates (S)-4 and (R)-4
JOCArticle
progress achieved to date, versatile and stereoselective routes
are still highly desired.
The Rh(II)-catalyzed intramolecular carbon-hydrogen
insertion reaction continues to attract considerable attention
due to the high levels of regio-, chemo-, and diastereoselec-
tivity that can be achieved.11 Over a decade ago, Doyle and
co-workers reported12 the intramolecular C-H insertion
reactions of chiral nonracemic alkyl-substituted cyclohexyl
diazoacetates catalyzed by chiral dirhodium(II) carboxami-
dates. The catalysts showed matched/mismatched relation-
ship to the diazo substrates; Rh2(MEPY)4 and Rh2(MEOX)4
emerged as effective catalysts, which promoted highly regio-
selective C-H insertion into equatorial secondary and ter-
tiary C-H bonds to give lactone products. The regioselecti-
vity in Rh2(MPPIM)4-catalyzed reactions, however, was
found to be substrate-dependent.12 On the other hand, the
regio- and diastereoselectivities of C-H insertion in equiva-
lent heterocyclic diazoacetates have not been extensively
examined. Previously, we showed13 that the Rh(II)-carbox-
amidate-catalyzed C-H insertion of 3-(N-Cbz-pyrrolidi-
nyl)diazoacetate did not exhibit a matched/mismatched
relationship and also demonstrated the use of the method
in the synthesis of the necine base, (-)-turneforcidine.
In keeping with our ongoing interest in the asymmetric
synthesis of piperidine and pyrrolidine-containing alkal-
oids,14 we needed access to functionalized, nonracemic
building blocks that would permit the facile assembly of
the wide variety of substituents and stereochemical diversity
around the pyrrolidine and piperidine framework. We have
investigated the rhodium(II)-catalyzed diazo decomposition
of γ- and δ-lactam diazoacetates as a method for accessing
functionalized nonracemic compounds and, herein, report
the details of our study.14a We found that the C-H insertion
reactions in both the γ- and δ-lactam diazoacetates were
efficiently catalyzed by Rh2(MPPIM)4 catalysts to give
bicyclic lactam lactones (BLLs) with high regioselectivity
and excellent cis-diastereoselectivity. For the δ-lactam dia-
zoacetate system, the regioselectivity of the C-H insertion
exhibited a unique matched/mismatched relationship with
Rh2(MPPIM)4, which was not observed for the γ-lactam
diazoacetate system. We have demonstrated the synthetic
utility of the functionalized BLLs in the synthesis of select
alkaloids, and in this report, we also detail the synthesis of
two indolizidine alkaloids, (8S,8aS)-octahydroindolizidin-
8-ol and (1S,8aS)-octahydroindolizidin-1-ol.
SCHEME 2. Preparation of Diazoacetate (S)-8
obtain (S)-3 in 77% yield over two steps (Scheme 1). The
second route involved N,O-dibenzylation15b of (S)-1 to pro-
vide (S)-2b, which was then selectively O-debenzylated under
catalytic transfer hydrogenation conditions16 to give (S)-3 in
67% overall yield. Inversion of configuration at C-5 in (S)-3
via Mitsunobu reaction17 (ClCH2CO2H, DEAD, Ph3P) gave
the corresponding chloroacetate, which was hydrolyzed to
afford the enantiomeric alcohol (R)-3. Treatment of (S)-3
and (R)-3 with the House-Blankley reagent [TsNHNdCHC-
(O)Cl]18 provided the diazoacetates (S)-4 and (R)-4.
Informed by the preparation of (S)-4, we prepared
γ-lactam diazoacetate (S)-8 starting from commercially
available (S)-519a (Scheme 2) via O-silylation and N-benzy-
lation to obtain (S)-619b followed by O-desilylation under
acidic conditions to afford the alcohol (S)-719b-d in 82%
overall yield. Subsequent treatment with House-Blankley
Results and Discussion
reagent18 proceeded efficiently to give the diazoacetate (S)-8.
Rh(II)-Catalyzed C-H Insertion Studies. The diazoace-
Preparation of δ- and γ-Lactam Diazoacetates: (S)-4, (R)-
4, and (S)-8. The known15a lactam alcohol (S)-1 was con-
verted to (S)-3 using two different routes. The first, higher
yielding route involved silylation (TBSCl) and N-benzyla-
tion to give (S)-2a followed by acid-mediated desilylation to
tate, (S)-4, was used to delineate optimal reaction conditions
for C-H insertion reaction and to determine product dis-
tribution. In (S)-4, there are two likely sites, C-4 and C-6, at
which Rh(II)-carbenoid C-H insertion can occur. It was
reasoned that the C-4 methylene hydrogens would be elec-
tronically deactivated toward Rh(II)-carbenoid insertion
(11) Wee, A. G. H. Curr. Org. Synth. 2006, 3, 499.
(12) (a) Doyle, M. P.; Dyatkin, A. B.; Autry, C. I. J. Chem. Soc., Perkin
Trans. 1 1995, 619. (b) Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.; Canas,
F.; Pierson, D. A.; Vanbasten, A.; Muller, P.; Polleux, P. J. Am. Chem. Soc.
1994, 116, 4507.
(13) (a) Wee, A. G. H. Tetrahedron Lett. 2000, 41, 9025. (b) Wee, A. G. H.
J. Org. Chem. 2001, 66, 8513.
(14) (a) Fan, G. J.; Wang, Z. Y.; Wee, A. G. H. Chem. Commun. 2006,
3732. (b) Wee, A. G. H.; Fan, G. J. Org. Lett. 2008, 10, 3869.
(15) (a) Olsen, R. K.; Bhat, K. L.; Wardle, R. B.; Hennen, W. J.; Kini,
G. D. J. Org. Chem. 1985, 50, 896. (b) N,O-Dibenzylation of rac-1, see: Herdeis,
C. Arch. Pharm. 1983, 316, 719.
(16) Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis 1981, 396.
(17) (a) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340. (b) Hughes,
D. L. Org. Prep. Proced. Int. 1996, 28, 127.
(18) (a) House, H. O.; Blankley, C. J. J. Org. Chem. 1968, 33, 53. (b)
Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559.
(19) (a) Purchased from Sigma Aldrich Chemical Co., USA. (b) Chang, D. L.;
Witholt, B.; Li, Z. Org. Lett. 2000, 2, 3949. (c) Huang, P. Q.; Zheng, X. A.; Wang,
S. L.; Ye, J. L.; Jin, L. R.; Chen, Z. Tetrahedron: Asymmetry 1999, 10, 3309. (d)
Inagaki, S.; Shitara, H.; Hirose, T.; Nohira, H. Enantiomer 1998, 3, 187.
8262 J. Org. Chem. Vol. 74, No. 21, 2009

Wee et al.
JOCArticle
TABLE 1. Rh(II)-Catalyzed Reaction of Diazoacetates (S)-4 and (R)-4
a
entry
diazo
Rh2L4
b
yield (%)c
relative yield (%) 9a/b:10a/b
% 11d (E:Z)e
% 12a/bd
1
2
3
4
5
6
7
8
9
10
11
12
13
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(S)-4
(R)-4
(R)-4
Rh2(OAc)4
Rh2(OAc)4
0
6
28
5
11
45
14
44
39
87
86
84
85
0
20 (1:2.5)
14 (1:1)
11 (1:3)
50 (1:2.4)
64 (1:3)
28 (1:3.1)
12 (1:3)
28 (1:3.1)
0
0
0
0
0
0
21
0
21
23
13
3
9
12
3
100:0
100:0
100:0
100:0
100:0
100:0
100:0
42:58
100:0
17:83
20:80
100:0
Rh2(S-PTTL)4
Rh2(cap)4
Rh2(cap)4
b
Rh2(5S-MEPY)4
Rh2(5R-MEPY)4
Rh2(4S-MEOX)4
Rh2(4R-MEOX)4
Rh2(4S-MPPIM)4
Rh2(4R-MPPIM)4
Rh2(4S-MPPIM)4
Rh2(4R-MPPIM)4
10
14
4
aReaction conducted under argon in refluxing CH2Cl2, unless otherwise stated, using 2 mol % of Rh(II) catalyst. bReaction conducted at 25 °C.
cCombined isolated yields of 9a; 10a or 9b; 10b. dBased on isolated yields of (S,S)-11 or 12a,b. eRatio of Z:E isomers was based on the integration of the
singlets due to the olefinic hydrogens centered at δ 6.12 (Z) and δ 6.64 (E).
because they are located β to the amide carbonyl group,20
whereas the C-6 methylene hydrogens are activated by the
amide nitrogen21 and metallocarbenoid insertion at C-6 to
give 9a should be favored. Another potential Rh(II)-carben-
oid insertion site is at the C-5-methine to give a β-lactone
product; however, we considered this would represent a very
minor pathway, if it were to occur, because of ring strain. We
examined the reaction of (S)-4 with both achiral and chiral
Rh(II) carboxylate and carboxamidate catalysts,22a and the
results are collected in Table 1.
In general, it was found that chiral Rh(II) catalysts were
better than achiral ones at promoting C-H insertion reac-
tion. Carbon-hydrogen insertion was inefficient with
Rh2(OAc)4 as catalyst; at rt, neither 9a nor 10a was detected.
When the reaction was conducted at reflux, a very low yield
(6%) of 9a was obtained. The main products formed were the
olefin dimers 11 and the ether product 12a, arising from
interception of the Rh(II)-carbenoid by adventitious water
(entries 1 and 2). The use of the chiral Rh(II) carboxylate,
Rh2(S-PTTL)4, gave a 28% yield of 9a, which was an
improvement over that achieved with Rh2(OAc)4. The di-
mers 11 were still formed, but ether 12a was not detected
(entry 3). In all of the cases examined, the regioisomeric
C-H insertion product 10a and the β-lactone product were
not detected.
(20) Stork, G.; Nakatani, K. Tetrahedron Lett. 1988, 29, 2283.
(21) Wee, A. G. H.; Duncan, S. C. J. Org. Chem. 2005, 70, 8372.
(22) (a) Rh2(S-PTTL)4: Dirhodium(II) tetrakis[(S)-N-phthaloyl-tert-leuci-
nate]; for the full names of the Rh(II) carboxamidates, see ref 13b. (b) At this
time, it appears that the N-benzyl protecting group is optimal for efficient C-H
insertion. We have examined the C-H insertion of the N-(R-methyl)benzyl and
N-allyl lactams Aa,b catalyzed by Rh2(5S-MPPIM)4 under identical conditions
(slow addition, refluxing (CH2Cl)2) to that used for (S)-8. We found that the yields
of the C-H insertion products Ba,b are markedly lower, and ether products Ca,b
were also obtained. The dimer Db was also formed in the reaction of Ab but was
not detected in the reaction of Aa.
The use of the less electrophilic Rh2(cap)4 either at rt or
reflux did not favor the C-H insertion pathway, and low
yields of 9a were obtained (entries 5 and 6). The preferred
reaction pathway was dimerization of the Rh(II)-carbenoid
to form 11, and this was also accompanied by the formation
of 12a. We next evaluated the effectiveness of three enantio-
meric pairs of Rh(II) carboxamidates to catalyze the C-H
insertion of (S)-4. With Rh2(5S-MEPY)4, a modest but
Other effects of the influence of azacyclic N-protecting group on the
efficiency of reactions have been noted. See for example: Wood, J. L.;
Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc.
1997, 119, 9641.
J. Org. Chem. Vol. 74, No. 21, 2009 8263

Wee et al.
JOCArticle
encouraging 45% yield of only 9a was obtained, although the
dimers 11 were still formed in appreciable amounts along
with 12a (entry 6). The enantiomeric Rh2(5R-MEPY)4 gave a
significantly lower yield of 9a (14%), and again, 10a was not
detected (entry 7). The yield of 9a was comparable to that
achieved using Rh2(cap)4 (compare entries 5 and 7), but the
yields of the dimer and ether products were substantially
lower.
TABLE 2. Rh(II)-Catalyzed Reaction of (S)-8
The results from the reactions catalyzed by the enantio-
meric sets of Rh2(MEOX)4 and Rh2(MPPIM)4 were espe-
cially interesting and displayed important differences from
those obtained from the previous two chiral catalysts, Rh2-
(S-PTTL)4 and Rh2(5R or 5S-MEPY)4. Although the results
obtained for Rh2(4S-MEOX)4 mirrored that of Rh2(5S-
MEPY)4 (compare entries 6 and 8), the reaction catalyzed
by Rh2(4R-MEOX)4 gave a 1:1.1 ratio of 9a/10a (entry 9)
and in a combined yield of 39%. Further, olefin dimers 11
were not observed.
The use of the hindered Rh2(4S-MPPIM)4 resulted in a
high yield (87%) of 9a, without dimer formation (entry 10).
More importantly, the regioisomer 10a was not detected.
With Rh2(4R-MPPIM)4, the yield of 9a depreciated signifi-
cantly (entry 11), and the regioisomeric 10a was now ob-
tained as the major product in synthetically good yield
(71%). This outcome was confirmed by the Rh2(MPPIM)4-
catalyzed reaction of (R)-4. Thus, Rh2(4R-MPPIM)4 gave a
high yield (85%) of only 9b (entry 13), whereas with Rh2(4S-
MPPIM)4, a 17% yield of 9b was realized and the yield of the
regioisomer 10b was 68% (entry 12). In these reactions,
dimer formation was not observed and formation of the
ethers 12a,b was a minor pathway.
The overall results show that the optimal catalyst for
achieving high regioselectivity in the formation of bicyclic
lactam lactones 9 is the use of Rh2(MPPIM)4; (S)-4/Rh2-
(4S-MPPIM)4 and (R)-4/Rh2(4R-MPPIM)4 represent the
matched pairs for regioselective C-H insertion reaction. It
is also interesting to note that the regioisomeric 10a,b are
also useful chiral nonracemic synthetic intermediates and are
readily accessible via the use of the mismatched sets, that is,
(S)-4/Rh2(4R-MPPIM)4 and (R)-4/Rh2(4S-MPPIM)4.
It is also evident from the results above that dimer forma-
tion is very competitive with C-H insertion. There is also a
preference for the formation of the (Z)-11 over the (E)-11
(entries 1, 3-8). The interception of the metallocarbenoid by
adventitious water is a minor pathway, and interestingly, the
yields of ether 12a (or 12b) obtained for each of the enantio-
meric sets of chiral Rh(II) carboxamidates were found to be
invariable between sets. Also, in the matched reactions, the
yields of ether 12a,b were lower than those in the mismatched
reactions (compare entries 10 and 13 with 11 and 12,
respectively).
Next, the effect of a smaller ring size on the efficiency and
regioselectivity of C-H insertion reaction (Table 2) was
investigated using the γ-lactam diazoacetate, (S)-8,22b and
the enantiomeric sets of Rh2(MEOX)4 and Rh2(MPPIM)4. It
is clear from Table 2 that the C-H insertion reaction also
proceeded with excellent cis-diastereoselectivity and high
regioselectivity. Further, reaction temperature has a definite
influence on the efficiency of the reaction; in refluxing
CH2Cl2, which was found to be effective in the δ-lactam
case (vide supra), poor to moderate yields of the C-H
insertion product 13 were obtained. For the S-configurated
solvent,
temp °C
% 14a
entry
Rh2L4
% 13a
(E:Z)b
% 15a
1
2
3
4
5
6
Rh2(4S-MEOX)4 CH2Cl2, 45
Rh2(4R-MEOX)4 CH2Cl2, 45
Rh2(4S-MPPIM)4 CH2Cl2, 45
Rh2(4R-MPPIM)4 CH2Cl2, 45
Rh2(4S-MPPIM)4 (CH2Cl)2, 83
Rh2(4R-MPPIM)4 (CH2Cl)2, 83
17
6
51
0
70
0
20 (1:11)
11 (1:33)
20 (2.4:1)
30 (1.5:1)
7 (E only)
0
21
13
28
37
11
19
aIsolated yields of 13, 14, and 15. For entry 6, the remaining material
balance consisted of intractable polar mixtures. bRatio of Z:E isomers
was based on the integration of the singlets for the olefinic hydrogens
centered at δ 6.23 (Z) and δ 6.78 (E).
catalysts, Rh2(4S-MEOX)4 and especially Rh2(4S-MPPIM)4
(entries 1 and 3), better yields of 13 were obtained, whereas
the corresponding R-catalysts (entries 2 and 4) led either to a
poor yield of 13 or no formation of product. A significantly
higher yield (70%) of 13 was realized when the Rh2(4S-
MPPIM)4-catalyzed reaction of (S)-8 was conducted in
refluxing dichloroethane (compare entries 3 and 5). Unlike
the δ-lactam system, (S)-4 (vide supra), the Rh2(4R-
MPPIM)4-catalyzed reaction of (S)-8 did not give the regioi-
somer 16; a modest yield of the ether 15 was formed along
with major amounts of uncharacterizable mixture of pro-
ducts.
The data from entries 1-5 (Table 2) indicated that the
formation of dimer 14 and ether 15 was very competitive with
the desired C-H insertion to form 13. Moreover, it is
interesting to note that, with Rh2(MEOX)4, there was a
strong preference for (Z)-14 over (E)-14 (entries 1 and 2),
whereas for the Rh2(MPPIM)4 catalysts, (E)-14 was pre-
ferred over (Z)-14 (entries 3 and 4).
Reaction Conformers and Product Formation. To under-
stand the formation of the BLL-9 and its regioisomer 10, we will
use the Rh2(4S and 4R-MPPIM)4-catalyzed reaction of (S)-4 as
an example. We envisioned the formation of the bicyclic
δ-lactam lactones 9a and 10a to proceed via the rapidly inter-
converting reaction conformers,23 A, A0 and B, B0, depicted in
Figure 1. In the half-chair conformers A and B0, the Rh(II)-
carbenoid moiety is oreinted in the pseudoaxial position, and in
B and A0, the Rh(II)-carbenoid unit is pseudoequatorial.
The generally accepted view for C-H insertion reaction is
that the Rh(II)-carbenoid intermediate has to adopt an
(23) The minimum energy conformation about the Rh(II)-carbene car-
bon bond is based on: Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.;
Lynch, V.; Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968. (b)
AM1 calculations (PC Spartan Pro, v.6.0.6) were performed on the δ-lactams with
a pseudoaxial and pseudoequatorial diazoacetyl unit: ΔHf (axial)=-31.822 kcal/
mol, ΔHf (equatorial)=-32.164 kcal/mol.
8264 J. Org. Chem. Vol. 74, No. 21, 2009

Wee et al.
JOCArticle
FIGURE 2. C-H insertion reaction conformers of Rh2(MPPIM)4-
carbenoid derived from (S)-8.
properly aligned for insertion reaction to occur to provide
10a as the major product; insertion into C-Ha, as was with
C-Hb in A, is geometrically disfavored.
In the reaction of (S)-8, catalyzed by Rh2(4S-MPPIM)4,
C-H insertion is envisaged to occur via an envelope-like
reaction conformer, C (Figure 2). The amide N-activated
C-Ha bond has the correct alignment to the Rh(II)-carbe-
noid bond, and C-H insertion results in the formation of the
BLL-13. With Rh2(4R-MPPIM)4, the reaction conformer D
is envisioned. Although C-Hb and the Rh(II)-carbenoid
bond in D have the proper alignment for insertion, the
C-Hb bond is deactivated toward metallocarbenoid C-H
insertion by the amide carbonyl group. Consequently, the
regiosiomer 16 was not formed. This outcome taken in
context with the result from the Rh2(4R-MPPIM)4-catalyzed
reaction of (S)-4 to form 10a indicated that C-H bonds
located R to an amide carbonyl group are more deactivated
compared to those that are located β to the amide carbonyl
unit. This observation is in accord with those made by Stork
regarding the deactivating influence of the ester group on
C-H bonds located R and β to the ester group.20 It is also
clear that, in the reaction of the γ-lactam diazoacetate (S)-8,
the matched/mismatched relationship that was observed in
the δ-lactam diazoacetate (S)-4 [or (R)-4] does not apply.
Synthesis of (8S,8aS)-Octahydroindolizidin-8-ol (17) and
(1S,8aS)-Octahydroindolizidin-1-ol (22). The nonracemic
BLLs have several attributes that are particularly advanta-
geous for their application in alkaloid synthesis. The inher-
ent functionalities of the BLLs facilitate the ready
modification of their carbon framework and for the installa-
tion of additional substituents. Further, their cis-fused bi-
cyclic structures afford practical stereocontrol over reactions
conducted on the BLLs. To demonstrate the utility of BLLs,
9a and 13, we detail below the syntheses of (8S,8aS)-octahy-
droindolizidin-8-ol (17) and (1S,8aS)-octahydroindolizidin-
1-ol (22). The successful syntheses of alkaloids 17 and 22 also
serves to confirm the absolute configuration of C-3a, C-7a in
9a and of C-3a, C-6a in 13.
FIGURE 1. C-H insertion reaction conformers of Rh2(MPPIM)4-
carbenoid derived from (S)-4.
arrangement wherein the Rh(II)-carbenoid bond and the
target C-H σ-bond are aligned parallel to each other.24 This
would allow for the proper trajectory required for the
interaction of the vacant p-orbital of the carbenoid carbon
with the σ-orbital of the C-H bond. Further, the degree of
interaction depends on the “electron-richness” of the C-H
bond. For a less electron-rich C-H bond, the interaction
occurs farther along the reaction coordinate, which would
involve a more compact transition state (TS). On the other
hand, for a more electron-rich C-H bond, the interaction
occurs earlier along the reaction coordinate, which would
involve in a less compact (open) TS.21
For the matched Rh2(4S-MPPIM)4-catalyzed reaction,
the two reactive conformers, A and A0, are involved. In A,
metallocarbenoid insertion into C-Ha is geometrically
favored and is also facilitated by the greater nucleophilicity
of the σ-bond (early TS) due to the activating influence of the
amide nitrogen atom. However, insertion of the metallocar-
benoid into C-Hb is prevented from occurring because the
C-Hb σ-bond and the Rh(II)-carbenoid bond cannot adopt
the proper alignment. Reactive conformer A0 is destabilized
by the close interaction of the pseudoaxial C-Ha and C-Hb
σ-bonds with the ligand wall of the Rh(II) catalyst and
especially between C-Hb and the NR moiety [NRdNC-
(O)(CH2)2Ph)] of the ligand. Therefore, preferential C-H
insertion occurs via A to give the observed 9a.
In the mismatched Rh2(4R-MPPIM)4-catalyzed reaction,
reactive conformer B is destabilized by the interaction of the
pseudoaxial C-Ha and C-Hb with the ligand wall and
especially between C-Ha and the NR unit. However, be-
cause C-Ha is activated by the amide nitrogen, its interac-
tion with the vacant p-orbital of the Rh(II)-carbenoid
carbon can occur at a greater distance (early TS), resulting
in the formation of the minor product, 9a. On the other hand,
in B0, the metallocarbenoid bond and the C-Hb bond are
Indolizidine (17). Several reports have described the syn-
thesis of (()-17,25a-d and to date, only one25e asymmetric syn-
thesis of (8S,8aS)-17 has been reported. Our retrosynthetic
(24) Trajectory for C-H insertion: (a) Taber, D. F.; You, K. K.;
Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 547. (b) Doyle, M. P.; Westrum,
L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson,
M. M. J. Am. Chem. Soc. 1993, 115, 958. (c) Yoshikai, N.; Nakamura, E. Adv.
Synth. Catal. 2003, 345, 1159. (d) Nakamura, E.; Yoshikai, N.; Yamanaka, M.
J. Am. Chem. Soc. 2002, 124, 7181.
(25) (a) Barton, D. H. R.; Pereira, M.; Taylor, D. K. Tetrahedron Lett.
1994, 35, 9157. (b) Bond, T. J.; Jenkins, R.; Ridley, A. C.; Taylor, P. C. J.
Chem. Soc., Perkin Trans. 1 1993, 2241. (c) Shono, T.; Matsumura, Y.;
Tsubata, K.; Inoue, K.; Nishida, R. Chem. Lett. 1983, 21. (d) Rader, C. P.;
Young, R. L.; Aaron, H. S. J. Org. Chem. 1965, 30, 1536. (e) Lee, H. K.;
Chun, J. S.; Pak, C. S. J. Org. Chem. 2003, 68, 2471.
J. Org. Chem. Vol. 74, No. 21, 2009 8265

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SCHEME 3. Retrosynthesis of Indolizidine 17
SCHEME 5. Retrosynthesis of Indolizidine 22
SCHEME 4. Synthesis of Indolizidine (8S,8aS)-17
involved in the biosynthesis of hydroxylated indolizidines
such as swainsonine and slaframine.27 Four asymmetric
syntheses28 and one involving resolution of racemic 2227
have been reported. The retrosynthetic analysis of the in-
dolizidine 22 (Scheme 5) suggested the unsaturated bicycle 23
as the precursor, which can be assembled via a ring closing
metathesis (RCM) reaction of the diallyl γ-lactam 24 that
can be obtained from BLL-13.
An obvious starting point is to use the γ-lactone moiety in
13 to install the C-4 hydroxy and C-5 allyl units, which is
modeled along the chemistry that we have developed for the
conversion of 9a to 20 (Scheme 4). We found, however, that
although reduction of BLL-13 with Red-Al proceeded to
give a good yield (70%) of the corresponding lactol the
subsequent Wittig olefination using methylenetriphenylpho-
sphorane was unsuccessful under a variety of reaction con-
ditions examined. To circumvent this unexpected difficulty,
an alternative approach based on Julia-Lythgoe-type29
chemistry was investigated.
BLL-13 was treated with methyl phenyl sulfone anion
(Scheme 6) to afford an 80% yield of an inseparable mixture
of diastereomeric lactols, which was reduced with NaBH4 to
the corresponding diol followed by diacetylation (Ac2O,
DMAP) to obtain 25. The conversion of the β-acetoxy
sulfone 25 to alkene 26a was examined. Attempted reductive
elimination using Mg/EtOH30 in the presence of a catalytic
amount of HgCl2 did not yield the desired olefin 26a, and
only starting material was recovered.
analysis of 17 (Scheme 3) suggested that the indolizidine
framework can be formed via the precursor 18, which in turn
can be derived from the bicyclic lactol 19; compound 19 is to
be prepared from BLL-9a.
Our synthesis began with the chemoselective reduction of
9a with Red-Al to provide an excellent yield of the bicyclic
lactam lactol 19 (Scheme 4). Wittig olefination using (metho-
xymethylene)triphenylphosphorane followed by MOM pro-
tection of the secondary alcohol gave the ether 20. N-
Debenzylation (Na, NH3) was followed by selective acid
hydrolysis of the enol ether and sodium borohydride reduc-
tion to give the primary alcohol 18 in an overall yield of 76%.
Tosylation of 18 and subsequent treatment of the primary
tosylate with sodium hydride resulted in intramolecular
cyclization to afford the bicyclic lactam 21a in 86% yield.
Deprotection of the MOM ether in 21a followed by reduc-
With SmI2 (0.1 M SmI2/HMPA)31 as the reductant, a 60%
yield of 26a was obtained as well as a minor amount (10%) of
the vinylic sulfone 26b.32 It is useful to note that reductive
(27) (a) Harris, C. M.; Harris, T. M. Tetrahedron Lett. 1987, 28, 2559. (b)
Harris, T. M.; Harris, C. M.; Hill, J. E.; Ungemach, F. S.; Broquist, H. P.;
Wickwire, B. M. J. Org. Chem. 1987, 52, 3094.
(28) (a) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A. E.
J. Org. Chem. 2000, 65, 6966. (b) Sibi, M. P.; Christensen, J. W. J. Org. Chem.
1999, 64, 6434. (c) Green, D. L. C.; Kiddle, J. J.; Thompson, C. M.
Tetrahedron 1995, 51, 2865. (d) Takahata, H.; Banba, Y.; Momose, T.
Tetrahedron: Asymmetry 1990, 1, 763.
(29) (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833. (b) Kociens-
ki, P. J.; Lythgoe, B.; Waterhouse, I. J. Chem. Soc., Perkin Trans. 1 1980,
1045.
(30) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S.
Tetrahedron Lett. 1995, 36, 5607.
tion of the lactam group using excess BH3 SMe2 initially
3
gave a very stable, nonpolar 17-borane complex as a white
solid.26 The volatile indolizidine 17 was obtained only after
refluxing the 17-borane complex in 95% ethanol for 24 h.
Compound (8S,8aS)-17 was purified (Dowex 50x2-400,
H+ form) and characterized as its hydrochloride salt
([R]22D +12.5 (c 0.60, CH3OH).
(31) (a) Concellon, J. M.; Rodriguez-Solla, H. Chem. Soc. Rev. 2004, 33,
599. (b) Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K.
Tetrahedron 1995, 51, 9873.
Indolizidine (22). Interest in the synthesis of compound
22 stems from it being one of the intermediates that is
(32) Compound 26b showed the following data: IR νmax 1740, 1695, 1584
cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.78-7.90 (m, 2 H), 7.52-7.68 (m, 3 H),
7.15-7.35 (m, 5 H), 6.78 (ddd, J=15.1, 7.2, 7.2 Hz, 1 H), 6.25 (d, J=15.1 Hz, 1
H), 5.27-5.31 (m, 1 H), 4.88 (d, J=15.0 Hz, 1 H), 4.02 (d, J=15.2 Hz, 1 H),
3.78-3.86 (m, 1 H), 2.78 (dd, J=17.4, 7.5 Hz, 1 H), 2.50 (dd, J=17.7, 5.4 Hz, 1
H), 1.95-2.12 (m, 2 H),1.93 (s, 3 H). The characteristic resonances of the
hydrogens of the vinylic sulfone occurred at δ 6.25 (d, J=15.1 Hz, 1 H) and δ
6.78 (ddd, J=15.1, 7.2, 7.2 Hz, 1 H).
(26) This white solid product was reported (ref 25e) as the indolizidine 17.
However, the spectral data of the compound we obtained following the
literature procedure indicated that this solid was in fact the indolizidine
17 borane complex; its IR spectrum showed the following characteristic
3
absorptions at νmax (B-H): 2367 and 2320 cm-1. 1H NMR of this complex is
identical to that reported (see Supporting Information).
8266 J. Org. Chem. Vol. 74, No. 21, 2009

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SCHEME 6. Synthesis of Indolizidine (1S,8aS)-22
Conclusions
Rh2(MPPIM)4 was found to be the best catalyst for
effecting the intramolecular C-H insertion reaction of chiral
nonracemic δ-lactam diazoacetate, (S)- and (R)-4, and the
γ-lactam diazoacetate (S)-8. The C-H insertion proceeded
efficiently, with excellent regioselectivity and cis-diastereos-
electivity to give bicyclic lactam lactones (BLLs). The regio-
selectivity of the reaction in the δ-lactam diazoacetate was
also found to be dependent on the chirality of the Rh2-
(MPPIM)4 catalyst; however, this effect was not observed in
the γ-lactam diazoacetate. Reaction conformer models were
proposed to explain the observed regioselectivity of the C-H
insertion reaction. The use of BLL-9a and BLL-13 in the
synthesis of (8S,8aS)-octahydroindolizidin-8-ol (17, 9 steps,
34% overall yield) and (1S,8aS)-octahydroindolizidin-1-ol
(22, 11 steps, 14.4% overall yield) nicely demonstrates the
utility of the BLLs as chiral building blocks in alkaloid
synthesis. Further studies in this area are in progress.
Experimental Section
General: Only diagnostic absorptions in the infrared spec-
trum are reported. Reported melting points are uncorrected. 1H
(200 or 300 MHz) and 13C (50 or 75 MHz) NMR spectra were
recorded in CDCl3 unless stated otherwise. The residual CHCl3
singlet at δH=7.24 and the CDCl3 triplet centered at δC=77.0
were used as internal references for 1H and 13C NMR spectra,
respectively. Where applicable, the positions of the signals of
minor diastereomers are given within square brackets. High-
resolution electron impact (70 eV) and chemical ionization mass
spectral analyses were performed at the Chemistry Department,
University of Saskatchewan, Canada. Optical rotations were
recorded at the NaD line using an Optical Activity (AA5)
polarimeter. Reaction progress was monitored by thin-layer
chromatography on Merck silica gel 60F254 precoated
(0.25 mm) on aluminum-backed sheets. Air- and moisture-
sensitive reactions were conducted under a static pressure of
argon. All organic extracts were dried over anhydrous Na2SO4.
Chromatographic purification implies flash column chroma-
tography, which was performed on SiliaFlash 60 (230-
400 mesh). Dichloromethane, 1,2-dichloroethane, dimethoxy
ethane, chloroform, N,N-(diisopropyl)ethylamine, and acetoni-
trile were dried by distillation from calcium hydride. THF and
diethyl ether were dried by distillation from sodium using
sodium benzophenone ketyl as indicator.
elimination did not occur when DMPU33 was used instead
of HMPA as the additive. Compounds 26a and 26b were
readily separated, but vinylic sulfone 26b was found to be
contaminated by an uncharacterizable impurity that was
difficult to remove in spite of repeated chromatography.
Next, the plan was to replace the acetyl group in 26a with
the MOM ether group, which would be more stable under
the reducing (Na, NH3) conditions for N-debenzylation.
Thus, base hydrolysis of the acetate gave the corresponding
secondary alcohol, which was then treated with MOMCl to
obtain 26c (80% over two steps). Birch reduction of 26c gave
the debenzylated γ-lactam, which was N-allylated to obtain
the RCM precursor 24 in good overall yield (64% over two
steps). Cyclization of 24 catalyzed by Grubbs II34a-d (28a)
proceeded efficiently in refluxing CH2Cl2 and was complete
within 1 h to give 23 in 90% yield; in comparison, the use of
Grubbs I34e,f (28b) required 6 h for completion, but the yield
of 23 was 95%.
General Procedure for Rh(II)-Catalyzed Reaction of (S)-4,
(R)-4, and (S)-8. The appropriate Rh(II) catalyst (2 mol %) was
dried under vacuum at 80 °C for 1 h and then cooled to rt. Dry
CH2Cl2 (2 mL) was added, and the mixture was heated (oil bath)
to reflux. A solution of the appropriate lactam diazoacetate
(0.2 mmol) in dry CH2Cl2 (2 mL) was added dropwise, via
syringe pump, over a period of 1 h. After addition was complete,
the mixture was refluxed for an additional 1 h and then cooled to
rt. The solvent was removed under reduced pressure, and the
crude product was purified by chromatography: For the
δ-lactam diazoacetates, (S)-4 and (R)-4: EtOAc/MeOH 10:1
and then 5:1 EtOAc/MeOH gave compounds 9a,b, 10a,b, 11,
and 12a,b. For the γ-lactam diazoacetate (S)-8: 1:1 petroleum
ether/EtOAc, EtOAc and then 10:1 EtOAc/MeOH gave subse-
quently compounds 13, 14, and 15. See Tables 1 and 2 for details.
(3aS,7aS)-4-Benzyltetrahydrofuro[3,2-b]pyridine-2,5(3H,6H)-
The double bond in 23 was then hydrogenated (10% Pd/C,
2 atm H2) in a Parr apparatus to afford 27a in 88% yield. Acid
hydrolysis of the MOM group in 27a gave the hydroxy lactam
27b, whose spectral and physical properties were in agreement
with those reported by Greene et al.28a The alkaloid 22 was
obtained after the reduction of the lactam carbonyl unit in27b
with BH3 SMe2 complex. This compound was identical in
3
D
all respects to the properties reported for 22 {[R]26 þ19.2
(c 0.13, CHCl3); lit.28a [R]22D þ17.4 (c 0.4, CHCl3)}.
(33) Pospisil, J.; Pospisil, T.; Marko, I. E. Org. Lett. 2005, 7, 2373.
(34) (a) Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153. (b) Scholl,
M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (c) Weskamp,
T.; Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem.,
Int. Ed. 1999, 38, 2416. (d) Huang, J. K.; Stevens, E. D.; Nolan, S. P.;
Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674. (e) Sanford, M. S.; Love, J.
A.; Grubbs, R. H. Organometallics 2001, 20, 5314. (f) Nguyen, S. T.;
Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114,
3974.
dione (9a): light yellow needles; mp 131-132 °C; [R]22 þ50.0
D
(c 1.90, CHCl3); IR νmax 1778, 1642, 1202, 1166 cm-1; 1H NMR
(300 MHz) δ 7.18-7.38 (m, 5 H), 5.28 (d, J=15.0 Hz, 1 H), 4.84
(ddd, J=3.7, 3.7, 7.0 Hz, 1 H), 4.11 (ddd, J=3.4, 7.4, 7.4 Hz,
1 H), 3.97 (d, J=15.0 Hz, 1 H), 2.75 (dd, J=7.7, 18.1 Hz, 1 H),
J. Org. Chem. Vol. 74, No. 21, 2009 8267

Wee et al.
JOCArticle
2.45-2.68 (m, 3 H), 2.32 (ddd, J=4.6, 9.1, 18.9 Hz, 1 H), 2.00
(dddd, J=3.2, 5.0, 11.8, 14.8 Hz, 1 H); 13C NMR (50 MHz) δ
173.9, 169.1, 135.9, 128.9, 128.0, 127.9, 75.6, 54.7, 47.5, 35.7,
26.5, 24.0; HRMS calcd for C14H15NO3 245.1052, found
245.1047.
24.8; δ (minor diastereomer) 171.1, 136.7, 128.3, 128.0, 127.4,
97.6, 75.3, 57.5, 47.3, 39.0, 27.1, 24.5; HRMS calcd for
C14H17NO3 247.1208, found 247.1208.
(5S,6S)-1-Benzyl-6-(3-methoxyallyl)-5-(methoxymethoxy)-
piperidin-2-one (20):. Ph3PþCH2OMeCl- (1.67 g, 4.86 mmol)
was suspended in dry THF (20 mL) and cooled to -60 °C. BuLi
(2.2 mL, 4.45 mmol, 2 M in hexane) was added, dropwise, to the
suspension. After addition was complete, the resulting red
solution was gradually warmed (∼40 min) to -20 °C and then
recooled to -40 °C. A solution of 19 (500 mg, 2.0 mmol) in dry
THF (4 mL) was added via cannula, and after addition was
complete, the reaction temperature was gradually increased to rt
(2 h). Saturated aqueous NH4Cl (10 mL) was added, and the
organic layer separated, and the aqueous layer back-extracted
with EtOAc. The combined organic layers were dried, filtered,
and concentrated. The crude product was purified by chroma-
tography (1:1 then 1:3 petroleum ether/EtOAc and finally
EtOAc) to afford a 5.5:1 ratio of Z:E diastereomeric mixture
of the enol ether (407 mg, 74%): IR νmax 3366 (br), 2931, 1613
(3aR,7aR)-4-Benzyltetrahydrofuro[3,2-b]pyridine-2,5(3H,6H)-
dione (9b): light yellow oil, [R]22D -48.4 (c 1.60, CHCl3); IR νmax
1778, 1642, 1449, 1202, 1167 cm-1 1H NMR (300 MHz) δ
;
7.18-7.38 (m, 5 H), 5.28 (d, J=15.0 Hz, 1 H), 4.84 (ddd, J=3.7,
3.7, 7.0 Hz, 1 H), 4.11 (ddd, J=3.4, 7.4, 7.4 Hz, 1 H), 3.97 (d, J=
15.0 Hz, 1 H), 2.75 (dd, J=7.7, 18.1 Hz, 1 H), 2.45-2.68 (m, 3
H), 2.32 (ddd, J=4.6, 9.1, 18.9 Hz, 1 H), 2.00 (dddd, J=3.2, 5.0,
11.8, 14.8 Hz, 1 H); 13C NMR (50 MHz) δ 173.9, 169.0, 135.9,
128.9, 128.0, 127.9, 75.5, 54.7, 47.5, 35.6, 26.4, 24.0; HRMS
calcd for C14H15NO3 245.1052, found 245.1059.
(3aR,7aS)-6-Benzyltetrahydrofuro[2,3-c]pyridine-2,5(3H,6H)-
dione (10a): [R]22 -44.2 (c 1.30, CHCl3); IR νmax 1754, 1649,
D
1472, 1437, 1178 cm-1; 1H NMR (300 MHz) δ 7.19-7.38 (m, 5
H), 4.80-4.86 (m, 1 H), 4.83 (d, J=14.4 Hz, 1 H), 4.36 (d, J=
14.6 Hz, 1 H), 3.44 (d, J=3.2 Hz, 2 H), 3.06-3.19 (m, 1 H), 2.83
(dd, J=10.9, 18.7 Hz, 1 H), 2.54 (dd, J=5.6, 15.4 Hz, 1 H), 2.47
1
cm-1; H NMR (200 MHz) δ (E-diastereomer) 7.10-7.30 (m,
5 H), 6.22 (d, J=12.6 Hz, 1 H), 5.20 (d, J=15.1 Hz, 1 H), 4.62 (dt,
J = 8.0, 15.1 Hz, 1 H), 3.70-4.10 (m, 2 H), 3.40 (s, 3 H),
3.12-3.30 (m, 1 H), 1.50-2.60 (m, 6 H); δ (Z-diastereomer)
7.10-7.30 (m, 5 H), 5.88 (d, J=6.2 Hz, 1 H), 5.16 (d, J=15.3 Hz,
1 H), 4.30 (dd, J=7.8, 14.2 Hz, 1 H), 3.70-4.10 (m, 2 H), 3.50 (s,
3 H), 3.12-3.30 (m, 1 H), 1.50-2.60 (m, 6 H); 13C NMR
(50 MHz) δ (E-diastereomer) 169.9, 148.4, 136.8, 128.2, 127.2,
(dd, J=4.4, 15.4 Hz, 1 H), 2.36 (dd, J=6.0, 18.7 Hz, 1 H); 13
C
NMR (50 MHz) δ 175.0, 169.6, 136.2, 128.7, 128.1, 127.7, 76.6,
50.0, 49.0, 36.0, 33.5, 30.6; HRMS calcd for C14H15NO3
245.1052, found 245.1060.
(3aS,7aR)-6-Benzyltetrahydrofuro[2,3-c]pyridine-2,5(3H,6H)-
dione (10b): [R]22 þ36.4 (c 1.10, CHCl3); IR νmax 1778, 1654,
D
1178 cm-1
;
1H NMR (300 MHz) δ 7.19-7.38 (m, 5 H),
126.9, 99.0, 66.0, 59.4, 55.6, 48.4, 28.3, 27.0, 25.0; δ
4.80-4.86 (m, 1 H), 4.83 (d, J = 14.4 Hz, 1 H), 4.36 (d, J =
14.6 Hz, 1 H), 3.44 (d, J=3.2 Hz, 2 H), 3.06-3.19 (m, 1 H), 2.83
(dd, J=10.9, 18.7 Hz, 1 H), 2.54 (dd, J=5.6, 15.4 Hz, 1 H), 2.47
(Z-diastereomer) 170.1, 147.7, 137.0, 128.1, 127.1, 126.8,
102.2, 65.8, 60.1, 55.6, 47.4, 28.0, 25.1, 23.2; HRMS calcd for
C16H21NO3 275.1521, found 275.1526.
(dd, J=4.4, 15.4 Hz, 1 H), 2.36 (dd, J=6.0, 18.7 Hz, 1 H); 13
C
A solution of the secondary alcohol (370 mg, 1.34 mmol) in
dry 1,2-dichloroethane (20 mL) containing Bu4NI (5 mg) was
cooled to 0 °C, and i-Pr2NEt (0.94 mL, 5.36 mmol) and MOMCl
(0.2 mL, 2.7 mmol) were added. Then the solution was refluxed
overnight. The reaction mixture was cooled to rt and then at
0 °C. Saturated aqueous Na2CO3 (1 mL) and brine (5 mL) were
added to the reaction mixture, and the organic layer was
separated and dried. After the solvent was removed, the result-
ing oil was purified by chromatography (1:1 and then 1:2
petroleum ether/EtOAc) to give a Z:E mixture (3:1 based on
the integration of the methyl group of the enol ether unit) of the
NMR (50 MHz) δ 174.9, 169.7, 136.2, 128.7, 128.0, 127.7, 76.6,
50.1, 49.0, 36.0, 33.5, 30.6; HRMS calcd for C14H15NO3
245.1052, found 245.1058.
(3aS,6aS)-4-Benzyltetrahydro-2H-furo[3,2-b]pyrrole-2,5(3H)-
dione (13): light yellow powder; mp 114-116 °C; [R]22D -38.9 (c
1
0.90, CHCl3); IR νmax 1782, 1692, 1399, 1159 cm-1; H NMR
(300 MHz) δ 7.17-7.38 (m, 5 H), 5.03 (ddd, J=3.9, 3.9, 5.6 Hz,
1 H), 4.97 (d, J=15.0 Hz, 1 H), 4.19 (ddd, J=2.0, 5.9, 5.9 Hz,
1 H), 4.02 (d, J=15.0 Hz, 1 H), 2.81 (d, J=3.9 Hz, 2 H), 2.69 (dd,
J=2.0, 18.4 Hz, 1 H), 2.60 (dd, J=6.0, 18.4 Hz, 1 H); 13C NMR
(50 MHz) δ 173.7, 171.2, 135.0, 129.0, 128.1, 128.0, 75.5, 57.3,
44.6, 37.1, 32.6; HRMS calcd for C13H13NO3 231.0895, found
231.0895.
MOM ether 20 as a colorless oil (381 mg, 89%): [R]23 -36.9
D
(c 1.10, CH2Cl2); IR νmax 2931, 1637 cm-1; 1H NMR (200 MHz)
δ (Z-diastereomer) 7.16-7.38 (m, 5 H), 5.97 (d, J=6.2 Hz, 1 H),
5.46 (d, J=14.7 Hz, 1 H), 4.48-4.64 (m, 2 H), 4.32-4.48 (m,
1 H), 4.00 (d, J=15.0 Hz, 1 H), 3.72-3.88 (m, 1 H), 3.61 (s, 3 H),
3.30-3.48 (m, 1 H), 3.32 (s, 3 H), 1.85-2.75 (m, 6 H); δ (E-
diastereomer) 7.16-7.38 (m, 5 H), 6.31 (d, J=12.6 Hz, 1 H), 5.40
(d, J=14.3 Hz, 1 H), 4.66-4.80 (m, 1 H), 4.48-4.64 (m, 2 H),
4.02 (d, J=15.0 Hz, 1 H), 3.72-3.88 (m, 1 H), 3.53 (s, 3 H),
3.30-3.48 (m, 1 H), 3.32 (s, 3 H), 1.85-2.75 (m, 6 H); 13C NMR
(75 MHz) δ (Z-diastereomer) 168.8, 147.3, 137.0, 127.8, 127.2,
126.5, 102.0, 94.8, 72.1, 58.8, 57.4, 54.8, 47.6, 28.2, 23.0, 22.8; δ
(E-diastereomer) 168.7, 148.3, 136.8, 127.9, 127.1, 126.6, 98.4,
94.9, 72.1, 58.5, 55.2, 54.9, 48.2, 28.1, 27.0, 22.7; HRMS calcd
for C18H26NO4 (M þ 1) 320.1862, found 320.1864.
(3aS,7aS)-4-Benzyl-2-hydroxyhexahydrofuro[3,2-b]pyridin-
5(6H)-one (19): Red-Al (0.25 mL, 65 wt % in toluene) was
dissolved in dry toluene (5 mL). This solution (4.3 mL,
0.68 mmol) was added, dropwise, to a solution of lactone 9a
(240 mg, 0.98 mmol) in dry THF (20 mL) at -78 °C under argon.
The mixture was stirred at -78 °C for 4 h, at which time
methanol (1.0 mL) and then saturated aqueous NH4Cl (8 mL)
were added. The reaction mixture was allowed to warm slowly
to rt. The organic layer was separated, and the aqueous layer
was back-extracted with ethyl acetate. The combined organic
layers were dried, filtered, and evaporated. The residue was
purified by chromatography (2:1 CH2Cl2/acetone) to give un-
reacted 9a (19 mg) and a diastereomeric mixture of lactol 17 (209
mg, 86%; 94% based on recovered starting material) as a
(5S,6S-6-(3-Hydroxypropyl)-5-(methoxymethoxy)piperidine-
2-one (18): Sodium metal (166 mg, 7.2 mmol) was added to
liquid NH3 (20 mL) at -78 °C under argon. The mixture was
stirred for 10 min, and a solution of the diastereomeric mixture
of N-benzyl lactam 20 (380 mg, 1.2 mmol) in THF (2 mL) was
added, dropwise, via cannula. The solution was stirred at
-78 °C for 3 h, and then solid NH4Cl (250 mg) was added.
The solution was gradually warmed to rt, and the residue was
extracted with CH2Cl2. The combined organic extracts were
dried, filtered, and concentrated. The crude product was pur-
ified by chromatography (2:1 CH2Cl2/acetone) to give the
colorless oil: IR νmax 3354 (br), 2931, 1625 cm-1 1H NMR
;
(300 MHz) δ (major diastereomer) 7.12-7.30 (m, 5 H), 5.50 (d,
J=4.8 Hz, 1 H), 5.08 (d, J=14.8 Hz, 1 H), 4.40-4.48 (m, 1 H),
3.98 (q, J=7.6 Hz, 1 H), 3.94 (d, J=15.0 Hz, 1 H), 1.60-2.45 (m,
6 H); δ (minor diastereomer) 7.12-7.30 (m, 5 H), 5.44 (t, J=3.6,
3.4 Hz, 1 H), 5.34 (d, J=15.0 Hz, 1 H), 4.22-4.30 (m, 1 H), 3.80
(d, J=15.0 Hz, 1 H), 3.71 (q, J=5.3 Hz, 1H), 2.62-2.76 (m, 1 H),
1.60-2.45 (m, 5 H); 13C NMR (50 MHz) δ (major diastereomer)
171.2, 136.8, 128.6, 128.1, 127.5, 97.0, 72.5, 57.6, 48.1, 41.6, 27.5,
8268 J. Org. Chem. Vol. 74, No. 21, 2009

Wee et al.
JOCArticle
debenzylated lactam (272 mg, 100%) as a colorless oil: [R]22
95.0, 68.6, 62.1, 55.8, 45.1, 27.5, 26.6, 25.5, 22.0; HRMS calcd
for C10H17NO3 199.1208, found 199.1207.
D
þ11.1 (c 0.50, CHCl3); IR νmax 3200, 2931, 1660 cm-1; 1H NMR
(200 MHz) δ (E-diastereomer) 6.58 (s, 1H), 6.16 (d, J=12.6 Hz,
1H), 4.50 (d, J=7.3 Hz, 1H), 4.40 (d, J=7.3 Hz, 1H), 4.30-4.50
(m, 1H), 3.60-3.70 (m, 1H), 3.29 (s, 3H), 3.16 (s, 3H), 3.05-3.25
(m, 1H), 1.70-2.40 (m, 5H), 1.40-1.60 (m, 1H); δ (Z-
diastereomer) 6.35 (s, 1 H), 5.80 (d, J=6.2 Hz, 1 H), 4.49 (d,
J=7.3 Hz, 1H), 4.40 (d, J=7.3 Hz, 1H), 4.08 (q, J=7.3 Hz, 1H),
3.60-3.70 (m, 1H), 3.36 (s, 3H), 3.16 (s, 3H), 3.05-3.25 (m, 1H),
1.70-2.40 (m, 5H), 1.40-1.60 (m, 1H); 13C NMR (75 MHz) δ
(E-diastereomer) 171.2, 149.6, 96.8, 95.0, 69.5, 56.4, 55.5, 55.4,
26.3, 26.2, 24.3; δ (Z-diastereomer) 171.1, 148.6, 100.1, 95.1,
69.7, 59.2, 56.1, 55.3, 29.8, 26.1, 24.4; HRMS calcd for
C11H20NO4 (MHþ) 230.1392, found 230.1401.
(8S,8aS)-Octahydroindolizidin-8-ol (17): MOM ether 21a (80
mg, 0.40 mmol) was dissolved in 1 M methanolic HCl (5 mL),
and the mixture was heated at 60-65 °C (oil bath) for 100 min.
The reaction mixture was cooled to rt, solid Na2CO3 was added,
and the reaction mixture was concentrated. The residue was
extracted with MeOH, and the methanol extract was filtered
through a pad of Celite. The filtrate was concentrated, and the
crude alcohol was purified by chromatography (10:1 EtOAc/
MeOH) to afford the bicyclic lactam alcohol 21b (59 mg, 95%)
as a white solid: mp 104-105 °C, lit.25e mp 98-100 °C; [R]22
D
-44.4 (c 2.70, CHCl3), lit.25e [R]22 -30.6 (c 2.0, CHCl3); IR
D
1
νmax 3378 (br), 1601, 1478 cm-1; H NMR (300 MHz) δ 4.13
The debenzylated lactam (270 mg, 1.18 mmol) was dissolved
in THF (8 mL), and aqueous 1 M HCl (4 mL) was added. The
mixture was stirred at rt for 3 h, and then solid Na2CO3 was
added. The organic layer was separated, and aqueous layer was
back-extracted with CH2Cl2. The combined organic layers were
dried, filtered, and concentrated. The crude product was dis-
solved in 95% EtOH (10 mL) and treated with NaBH4 (90 mg,
2.38 mmol). After 3 h, the mixture was quenched with saturated
aqueous NH4Cl (1 mL). The mixture was evaporated and then
extracted with CH2Cl2. The combined organic layers were dried,
filtered, and concentrated. The residue was purified by chroma-
tography (5:1 EtOAc/MeOH) to give recovered debenzylated
(ddd, J=2.2, 2.2, 4.1 Hz, 1 H), 3.40-3.58 (m, 3 H), 2.91 (s, 1 H),
2.51 (ddd, J=7.4, 11.8, 18.5 Hz, 1 H), 2.33 (br dd, J=7.4, 17.9
Hz, 1 H), 2.08 (dddd, J=1.7, 3.9, 7.3, 14.1 Hz, 1 H), 1.64-2.02
(m, 5 H); 13C NMR (75 MHz) δ 169.3, 63.2, 62.6, 45.2, 28.3,
27.5, 26.1, 22.0; HRMS calcd for C8H13NO2 155.0946, found
155.0946.
The alcohol 21b (17 mg, 0.11 mmol) was dissolved in dry THF
(2 mL) and cooled to 0 °C. BH3 SMe2 in ether (0.35 mL, 5 M)
3
was added dropwise to the solution, and the mixture was stirred
at 0 °C for 30 min and then at rt for 22 h. The reaction mixture
was cooled to 0 °C, and then EtOH (4 mL) was carefully added.
The reaction mixture was concentrated, and the resulting white
solid was redissolved in EtOH (8 mL) and refluxed for 24 h. The
mixture was cooled to rt, and five drops of concentrated HCl
was added. EtOH was removed under reduced pressure, and the
resulting white solid was dissolved in distilled water (5 mL) and
washed with CH2Cl2. The aqueous solution was concentrated,
and the residue was purified using ion exchange chromatogra-
phy (Dowex 50x2-400 ion-exchange resin, 200-400 mesh,
eluent: water and then 5% NH4OH solution). The combined
fractions containing 17 were concentrated by fractional distilla-
tion using a vigreux column. The remaining aqueous mixture
was treated with three drops of concentrated HCl and then
lactam (10 mg) and primary alcohol 18 (188 mg, 76%): [R]23
D
þ23.0 (c 0.65, CHCl3); IR νmax 3284 (br), 2930, 1651 cm-1; 1H
NMR (200 MHz) δ 6.97 (br s, 1 H), 4.73 (d, J=7.0 Hz, 1 H), 4.62
(d, J=7.0 Hz, 1 H), 3.84-3.94 (m, 1 H), 3.68-3.76 (m, 2 H),
3.40-3.50 (m, 1 H), 3.39 (s, 3 H), 2.50-2.00 (m, 3 H), 1.80-1.60
(m, 5 H); 13C NMR (50 MHz) δ 172.1, 95.2, 70.2, 62.1, 56.4,
56.0, 28.6, 28.5, 26.7, 24.4; HRMS calcd for C10H19NO4
217.1314, found 217.1323.
(8S,8aS)-8-(Methoxymethoxy)hexahydroindolizin-5(1H)-one
(21a): A solution of 18 (185 mg, 0.85 mmol), tosyl chloride
(243 mg, 1.3 mmol), Et3N (0.23 mL, 1.7 mmol), and DMAP
(10 mg) in dry CH2Cl2 (10 mL) was stirred at rt for 20 h under
argon. The reaction mixture was washed with saturated aqu-
eous NH4Cl, and the organic layer was separated and dried,
filtered, and concentrated. The residue was purified by chro-
matography (2:3 CH2Cl2/acetone) to give the correspond-
evaporated under reduced pressure to afford 17 HCl (20 mg,
3
88%) as a white solid: mp 128-130 °C; [R]22 þ12.5 (c 0.60,
D
CH3OH); IR νmax 3354 (br) cm-1; 1H NMR (D2O, 300 MHz) δ
4.30 (s, 1 H), 3.540-3.70 (m, 2 H), 3.22-3.36 (m, 1 H),
2.90-3.12 (m, 2 H), 1.66-2.24 (m, 8 H); 13C NMR (CD3OD,
75 MHz) δ 70.5, 64.0, 54.1, 53.0, 30.8, 24.8, 20.4, 19.1; HRMS
calcd for C8H16NO (MHþ) 142.1232, found 142.1229.
ing tosylate (286 mg, 91%) as a colorless oil: [R]23 þ18.8
D
(c 0.80, CHCl3); IR νmax 1658 cm-1 1H NMR (200 MHz)
;
δ 7.77 (d, J=8.3 Hz, 2 H), 7.34 (d, J=8.0 Hz, 2 H), 6.26 (br s,
1 H), 4.70 (d, J=7.0 Hz, 1 H), 4.58 (d, J=7.0 Hz, 1 H), 4.04
(t, J=6.0 Hz, 2 H), 3.78-3.90 (m, 1 H), 3.30-3.38 (m, 1H), 3.35
(s, 3 H), 2.44 (s, 3 H), 2.05-2.60 (m, 3 H), 1.64-1.88 (m, 4 H),
1.38-1.56 (m, 1 H); 13C NMR (50 MHz) δ 171.6, 144.8, 132.8,
129.8, 127.8, 95.2, 69.8, 69.5, 56.0, 55.9, 27.8, 26.8, 24.9, 24.2,
21.6; HRMS calcd for C17H26NO6S (M þ 1) 372.1481, found
372.1491.
Hexane-washed NaH (56 mg, 60% dispersion in oil) was
suspended in dry THF (7 mL), and a solution of the above
tosylate (263 mg, 0.70 mmol) in dry THF (3 mL) was added via
cannula. The mixture was stirred at rt, and the reaction was
monitored by TLC. After the starting material was consumed,
the mixture was cooled in ice-water bath and saturated aqueous
NH4Cl (5 mL) was carefully added. The organic layer was
separated, and aqueous layer was back-extracted with CH2Cl2.
The combined organic layers were dried, filtered, and concen-
trated. The crude residue was purified by chromatography (2:3
CH2Cl2/acetone) to give the indolizidinone 21a (134 mg, 95%)
as a colorless oil: [R]22D þ1.88 (c 4.0, CHCl3); IR νmax 1631, 1455
cm-1; 1H NMR (300 MHz) δ 4.73 (d, J=6.9 Hz, 1 H), 4.62 (d, J=
6.9 Hz, 1 H), 4.01 (ddd, J=2.1, 2.1, 4.0 Hz, 1 H), 3.40-3.62 (m, 3
H), 3.39 (s, 3 H), 2.28-2.52 (m, 2 H), 2.20 (dddd, J=2.2, 4.0, 8.7,
14.2 Hz, 1 H), 1.64-2.02 (m, 5 H); 13C NMR (75 MHz) δ 168.7,
(4S,5S)-4-Acetoxy-5-(2-acetoxy-3-phenylsulfonylpropyl)-1-ben-
zylpyrrolidin-2-one (25): A solution of methyl phenyl sulfone
(70.8 mg, 0.453 mmol) in dry THF (1 mL) was cooled to -78 °C,
and n-BuLi (0.25 mL of 1.79 M in hexanes, 0.450 mmol) was
added dropwise, resulting in a clear, bright yellow solution,
which was stirred for 2 h, and then warmed to -40 °C. The
bicyclic γ-lactam lactone 13 (80.5 mg, 0.350 mmol) in dry THF
(1 mL) was added dropwise via cannula, and then the cannula
was rinsed with 0.5 mL of dry THF. The mixture was stirred at
-40 °C for 1.5 h and at 0 °C for 1.5 h, by which time reaction was
judged to be complete by TLC. The reaction mixture was cooled
to -40 °C, quenched with saturated NH4Cl (2 mL), and then
diluted with CH2Cl2 (2 mL). The aqueous layer was saturated
with NaCl and brine; the resulting mixture was stirred for 30 min
and then extracted with CH2Cl2. The combined organic extracts
were dried, concentrated, and the crude product was purified by
chromatography (5:1 CH2Cl2/acetone) to give an inseparable
mixture of lactols (107 mg, 80%) as a colorless oil: [R]26D þ6.6
(c 0.38, CHCl3); IR νmax 3500-3125, 3050, 1687, 1667, 1600,
1512 cm-1 1H NMR (300 MHz) (major diastereomer) δ
.
7.85-7.92 (m, 2 H), 7.59-7.68 (m, 1 H), 7.47-7.57 (m, 2 H),
7.12-7.35 (m, 5 H), 4.78 (d, J=14.7 Hz, 1 H), 4.61-4.71 (m, 1
H), 3.99-4.08 (m, 1 H), 3.90 (d, J = 14.7 Hz, 1 H), 3.48 (d,
J=14.8 Hz, 1 H), 3.41 (d, J=14.6 Hz, 1 H), 2.52 (dd, J=6.9,
J. Org. Chem. Vol. 74, No. 21, 2009 8269

Wee et al.
JOCArticle
18.1 Hz, 1 H), 2.25 (dd, J=7.3, 13.7 Hz, 1 H), 2.04 (d, J=18.1
Hz, 1 H), 1.83 (dd, J=3.5, 13.7 Hz, 1 H); discernible signals of
minor diastereomer δ 5.05 (d, J=15 Hz, 1 H), 4.61-4.67 (m, 1
H), 3.91 (d, J=15 Hz, 1H), 3.54 (d, J=14.9 Hz, 1 H), 2.70 (dd, J=
6.2, 18.2 Hz, 1 H), 2.63 (dd, J=9.2, 18.2 Hz, 1 H), 2.46 (d, J=
13.9 Hz, 1 H), 1.85 (dd, J=3.5, 13.7 Hz, 1 H); 13C NMR (75
MHz) δ 172.2, 172.0, 140.2, 140.0, 135.6, 133.9, 133.7, 128.9,
128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.6,
103.6, 103.2, 74.6, 63.0, 62.7, 61.3, 61.0, 44.7, 42.9, 40.2, 39.6,
36.8. HRMS calcd for C20H21NO5S for 387.1140, found
387.1143.
and 0.5 M aqueous NaOH (1 mL) were added to the residue. The
mixture was stirred at rt for 5 min and then extracted with
EtOAc and CH2Cl2. The organic extracts were combined, dried,
filtered, and concentrated under reduced pressure. Purification
by means of flash column chromatography (8:1 CH2Cl2/
acetone) afforded the desired 26a (11.8 mg, 61%; 72% based
on recovered starting material) as a colorless oil, unreacted 25
(5.1 mg) and a small amount of impure 26b (2.1 mg, 7%).
Further attempts to purify 26b were unsuccessful. Compound
26a: [R]23 -19.5 (c 0.77, CHCl3); IR νmax 3050, 3025, 3000,
D
1738, 1694 1687, 1612, 1512 cm-1 1H NMR (300 MHz) δ
;
The ratio of the diastereomeric lactols was 1:2 and was based
on the integration of the one of the benzylic methylene protons
at δ 4.78 and 5.05.
7.09-7.39 (m, 5 H), 5.55-5.72 (m, 1 H), 5.26-5.34 (m, 1 H),
5.04-5.13 (m, 2 H), 5.04 (d, J=15.3 Hz, 1 H), 4.02 (d, J=15.2
Hz, 1 H), 3.66-3.76 (m, 1 H), 2.75 (dd, J=7.0, 17.3 Hz, 1H),
2.53 (dd, J=4.2, 17.4 Hz, 1 H), 2.38 (t, J=6.7 Hz, 2 H), 2.06
(s, 3 H); 13C NMR (75 MHz) δ 171.9, 170.1, 135.9, 132.6,
128.6, 127.7, 127.6, 118.5, 68.1, 58.9, 44.0, 37.4, 31.7, 20.7;
(CI-NH3)-HRMS calcd for C16H20NO3 (M þ 1) 274.1443,
found 274.1434.
NaBH4 (192 mg, 5.09 mmol) was added to a solution of
bicyclic phenylsulfone lactol (148 mg, 0.380 mmol) in ethanol
(5 mL) at 0 °C. The mixture was stirred at rt for 1 h and then
quenched with three drops of acetic acid at 0 °C, after which
the EtOH was removed under reduced pressure to give a white
slurry residue. CH2Cl2 (15 mL) was added to the residue, and
the resulting suspension was suction filtered through a pad of
Celite washing the residue with CH2Cl2 (40 mL) in the process.
The filtrate was concentrated, and the residual thick oil was
dried under high vacuum. The dihydroxy sulfone was used in the
next step without further purification.
(4S,5S)-5-Allyl-1-benzyl-4-(methoxymethoxy)pyrrolidin-2-one
(26c): K2CO3 (477 mg, 3.46 mmol) was added to a solution of
26a (282 mg, 1.03 mmol) in methanol (10 mL), and the mixture
was stirred at rt for 1 h. Methanol was removed under reduced
pressure, and to the resulting residue was added CH2Cl2
(20 mL), and then the solution was filtered through a pad of
Celite. The filtrate was concentrated, and the residue was
purified by chromatography (1:1 petroleum ether/EtOAc) to
afford the secondary alcohol (214 mg, 90%) as white crystals:
To a mixture of dihydroxy sulfone (124 mg, 0.320 mmol) and
DMAP (3.90 mg, 0.0320 mmol) was added dry CH2Cl2 (5 mL).
After cooling the resulting solution to 0 °C, Ac2O (0.12 mL, 1.27
mmol) was added and the mixture was stirred at the same
temperature for 15 min before Et3N (0.18 mL, 1.27 mmol) was
added dropwise to the mixture. The reaction was stirred at rt for
5 h, by which time reaction was complete as indicated by TLC
analysis. The reaction mixture was washed with 0.5 M aqueous
HCl solution, saturated aqueous NaHCO3 solution and finally
with water. The organic extract was dried, filtered, and concen-
trated. The crude product was purified by chromatography (4:1
CH2Cl2/acetone) to afford inseparable, diastereomeric dia-
cetates 25 (136 mg, 85% over 2 steps) as a white foam. The
diastereomeric ratio was 1:2 and is based on the integration of
the signals of the methyl protons of the acetate at δ 1.63 and
mp 64-65 °C; [R]23 -47.9 (c 0.365, CHCl3); IR νmax
D
3500-3175, 3050, 1670, 1500 cm-1 1H NMR (300 MHz) δ
;
7.13-7.35 (m, 5H), 5.68-5.86 (m, 1 H), 5.06-5.20 (m, 2 H), 4.96
(d, J=15.2 Hz, 1 H), 4.39 (ddd, J=3.4, 5.3, 6.5 Hz, 1 H), 4.07 (d,
J=15.2 Hz, 1 H), 3.51 (ddd, J=5.4, 5.4, 8.4 Hz, 1 H), 2.67 (dd,
J=6.6, 17.2 Hz, 1 H), 2.48 (dd, J=1.3, 16.5 Hz, 1 H), 2.35-2.48
(m, 2 H), 2.18 (br s, 1 H); 13C NMR (75 MHz) δ 173.1, 136.3,
133.7, 128.6, 127.6, 127.4, 118.3, 66.3, 60.9, 43.9, 40.1, 31.5;
HRMS calcd for C14H17NO2 231.1259, found 231.1256.
To a solution of the above-described secondary alcohol (214
mg, 0.93 mmol) in dry CH2Cl2 (10 mL) was added MOMCl
(1.86 mmol, 0.14 mL), under Ar, at 0 °C. The mixture was
1.77: [R]25 -7.4 (c 1.01, CHCl3); IR νmax 3075, 3050, 1736,
stirred, Pr2NEt (1.86 mmol, 0.32 mL) was added, and the
i
D
1689, 1625, 1500 cm-1
.
1H NMR (300 MHz) (major
reaction mixture was stirred at rt overnight. The solvents were
removed in vacuo, the residue was taken into EtOAc, and the
organic phase was washed with water, dried, filtered, and
concentrated. The residue was purified by chromatography
(1:1 petroleum ether/EtOAc) to afford 26c (227 mg, 89%) as a
pale yellow oil: [R]26D -50 (c 0.35, CHCl3); IR νmax 3050, 3025,
1694, 1662, 1600, 1512 cm-1; 1H NMR (300 MHz) δ 7.16-7.39
(m, 5 H), 5.69-5.86 (m, 1 H), 5.06-5.15 (m, 2 H), 5.06 (d, J=
15.4 Hz, 1 H), 4.65 (d, J=6.9 Hz, 1 H), 4.61 (d, J=6.9 Hz, 1 H),
4.22-4.32 (m, 1 H), 3.98 (d, J=15.2 Hz, 1 H), 3.39 (ddd, J=3.2,
4.7, 6.3 Hz, 1 H), 3.36 (s, 3 H), 2.64 (dd, J=6.9, 16.8 Hz, 1 H),
2.56 (dd, J=5.6, 16.8 Hz, 1 H), 2.47 (dd, J=7.1, 14.9 Hz, 1 H),
2.37 (dd, J=6.0, 14.1 Hz, 1 H); 13C NMR (75 MHz) δ 172.2,
136.1,133.5, 128.3, 127.5, 127.2, 117.9, 95.8, 71.4, 59.6, 55.6,
43.7, 37.4, 31.4; (CI-NH3)-HRMS calcd for C16H22NO3 (M þ 1)
276.1599, found 276.1598.
(4S,5S)-1,5-Diallyl-4-(methoxymethoxy)pyrrolidin-2-one
(24): To liquid NH3 (50 mL) at -78 °C was added sodium metal
(41.1 mg, 1.80 mmol). The resulting deep blue-black solution
was stirred at the same temperature for 30 min, after which
a solution of the N-benzyl amide 26c (33.0 mg, 0.120 mmol) in
dry THF (3 mL) was transferred via cannula (rinsed with with
1 mL of dry THF). The reaction mixture was allowed to stir
at -78 °C for 3 h . The reaction mixture was quenched at -78 °C
with excess solid NH4Cl and then allowed to warm slowly
to rt, by which time all the NH3 had evaporated. The resi-
due was extracted with CH2Cl2, the combined extracts were
diastereomer) δ 7.77-7.87 (m, 2 H), 7.61-7.69 (m, 1 H),
7.50-7.59 (m, 2 H), 7.14-7.36 (m, 5 H), 5.14-5.27 (m, 1 H),
5.04-5.27 (m, 1 H), 5.04 (d, J=15.3 Hz, 1 H), 3.99 (d, J=15.4
Hz, 1 H), 3.51-3.60 (m, 1 H), 3.27 (dd, J=8.9, 14.6 Hz, 1 H),
3.04 (dd, J=9.0, 14.5 Hz, 1 H), 2.74 (dd, J=6.7, 17.5 Hz, 1 H),
2.51 (dd, J=3.2, 17.5 Hz, 1 H), 1.97-2.21 (m, 2 H), 2.09 (s, 3 H),
1.77 (s, 3 H, Me); discernible signals of minor diastereomer δ
5.27-5.35 (m, 1 H), 5.01 (d, J=15.5 Hz, 1 H), 3.91 (d, J=15.4
Hz, 1 H), 3.41-3.46 (m, 1 H), 3.35 (dd, J=8.9, 14.6 Hz, 1 H),
3.11 (dd, J=9.0, 14.9 Hz, 1 H), 2.80 (dd, J=6.7, 17.5 Hz, 1 H),
1.63 (s, 3 H), 2.01 (s, 3 H); 13C NMR (75 MHz) δ 171.9, 170.1,
169.6, 139.1, 135.5, 134.0, 133.9, 129.3, 129.0, 128.8, 128.7,
128.6, 128.0, 127.9, 127.8, 127.7, 127.6, 127.4, 67.8, 67.6, 66.0,
64.7, 59.4, 58.7, 56.9, 55.5, 43.9, 43.8, 43.5, 37.7, 31.4, 30.4, 20.8,
20.7, 20.5, 20.3. HRMS calcd for C24H27NO7S for 473.1508,
found 473.1502.
(4S,5S)-4-Acetoxy-5-allyl-1-benzylpyrrolidin-2-one (26a): To
a stirred mixture of SmI2 (3.5 mL, 0.350 mmol, 0.1 M in THF)
and HMPA (0.18 mL, 1.06 mmol) was added a solution of
lactam diacetate 25 (33.4 mg, 0.070 mmol) in THF (1 mL) via
cannula transfer at rt. The reaction mixture was stirred at the
same temperature for 10 min, by which time the deep purple
color of the reaction mixture had discharged and the reaction
was judged to be complete by TLC analysis. The reaction
mixture was cooled to 0 °C and then quenched with three drops
of saturated NH4Cl solution. THF was removed, and then brine
8270 J. Org. Chem. Vol. 74, No. 21, 2009

Wee et al.
JOCArticle
concentrated under reduced pressure, and the residue was
purified by chromatography (2:1 CH2Cl2/acetone) to afford
the N-debenzylated γ-lactam (16 mg, 73%) as a colorless oil:
(d, J = 6.8 Hz, 1 H), 4.28 (ddd, J = 2.9, 3.6, 9.7 Hz, 1 H),
4.09 (br d, J=13.2 Hz, 1 H), 3.43-3.53 (m, 1 H), 3.32 (s, 3 H),
2.50-2.64 (m, 2 H), 2.38 (dd, J=2.8, 17.2 Hz, 1 H), 1.88-1.97
(m, 1 H), 1.51-1.72 (m, 3 H), 1.28-1.46 (m, 2 H).
1
IR νmax 3231, 3075, 1698, 1650 cm-1; H NMR (300 MHz) δ
5.60-5.84 (m, 2 H), 5.09-5.19 (m, 2 H), 4.65 (d, J=6.9 Hz, 1 H),
4.60 (d, J=6.9 Hz, 1 H), 4.31-4.40 (m, 1 H), 3.76 (ddd, J=5.8,
5.8, 10.2 Hz, 1 H), 3.35 (s, 3 H), 2.55 (dd, J=6.4, 16.5 Hz, 1 H),
2.39 (dd, J=4.3, 16.5 Hz, 1 H), 2.37-2.47 (m, 1 H), 2.27 (ddd, J=
9.2, 9.2, 14.2 Hz, 1 H); 13C NMR (75 MHz) δ 175.0, 134.4, 118.7,
96.1, 73.7, 57.6, 56.1, 38.0, 34.4; (CI-NH3)-HRMS calcd for
C9H16NO3 (M þ 1) 186.1130, found 186.1126.
Indolizidinone 27a (20 mg, 0.10 mmol) was dissolved in a
mixture of aqueous 1 M HCl and MeOH (1:1 v/v, 5 mL), and the
mixture was heated at 60-65 °C with stirring for 100 min. The
mixture was cooled to rt, and the reaction was quenched with
solid Na2CO3. The solvent was removed under reduced pres-
sure, and the residual solid was extracted with MeOH. To the
residual solid were added brine and solid NaCl, and the mixture
was stirred vigorously and then was extracted thoroughly with
CH2Cl2. The combined MeOH and CH2Cl2 phases were dried,
filtered, concentrated, and then purified by chromatography
(15:1 EtOAc/MeOH) to afford the lactam alcohol 27b (13 mg,
84%) as colorless crystals: mp 147-150 °C, lit.28a 149-157 °C;
[R]26D þ27.8 (c 0.18, acetone); lit.28a [R]20D þ26.9 (c 1.5, acetone);
The N-debenzylated γ-lactam (14.0 mg, 0.080 mmol) together
with a few crystals of 2,20-bipyridine was dissolved in dry THF
(3 mL), and the solution was cooled to -15 °C. BuLi (0.07 mL,
0.080 mmol, 1.15 M) was then added to the cooled solution
dropwise, resulting in a deep red colored solution which was
stirred for 10 min before dry DMF (0.5 mL) was added. After
stirring the mixture for another 10 min, allylbromide (0.01 mL,
0.120 mmol) was added to the reaction mixture, resulting in an
instant discharge of the red color to yellow. The reaction mixture
was stirred at -15 °C for 20 min and then allowed to warm
gradually to rt, by which time the reaction was complete as
indicated on TLC analysis. The reaction mixture was diluted
with EtOAc (10 mL) and then washed with brine. The organic
layer was dried, filtered, and concentrated. The crude product
was purified by chromatography (8:1 CH2Cl2/acetone) to afford
the diallyl product 24 (16.5 mg, 97% yield) as a pale yellow
IR νmax 3500-3125, 3001, 2390, 1688 1557 cm-1 1H NMR
;
(300 MHz) δ 4.30-4.38 (m, 1 H), 4.05 (m, 1 H), 3.67 (ddd, J=
6.0, 6.0, 11.3 Hz, 1 H), 2.51-2.67 (m, 2 H), 2.30 (dd, J=1.3, 17.4
Hz, 1 H), 2.23 (br d, J = 5.7 Hz, 1 H), 1.88-1.98 (m, 1 H),
1.50-1.71 (m, 3 H), 1.25-1.46 (m, 2 H); 13C NMR (75 MHz)
δ 171.9, 66.3, 61.5, 40.9, 40.1, 24.5, 23.9, 23.1. HRMS calcd for
C8H13NO2 155.0946, found 155.0949.
(þ)-(1S,8aS)-Octahydroindolizidin-1-ol (22): A solution of
lactam alcohol 27b (10.0 mg 0.065 mmol) in THF (1.5 mL)
was added dropwise to BH3 SMe2 in ether (0.35 mL, 5 M). The
3
nonviscous oil: [R]26 -41.7 (c 0.24, CHCl3); IR νmax 3060,
mixture was refluxed at 80 °C for 1 h, and then stirred at rt
temperature overnight. The reaction mixture was cooled to 0 °C
and then quenched with ethanol (2 mL). The solvent was
removed under reduced pressure, and to the residue was added
95% ethanol (5 mL), and the mixture was refluxed for 5 h, after
which time the less polar 27-borane complex was completely
converted to a polar compound. The reaction mixture was
cooled to rt and then treated with concentrated HCl (6 drops).
Ethanol was evaporated off, and the white solid was dissolved in
distilled water (5 mL) and then washed with CH2Cl2. The
aqueous solution was concentrated under reduced pressure,
and the residue was subjected to ion exchange chromatography
(Dowex 50x2-400 ion-exchange resin, 200-400 mesh) eluting
with water and then 5% NH4OH solution as eluent. The
fractions were combined and concentrated under reduced pres-
sure. The residue was redissolved in CH2Cl2 (5 mL), dried,
filtered, and evaporated to afford the indolizidine 22 (7 mg,
D
1689, 1650, 1587, 1550 cm-1; 1H NMR (300 MHz) δ 5.60-5.88
(m, 2 H), 5.04-5.21 (m, 4 H), 4.64 (d, J=6.9 Hz, 1 H), 4.60 (d, J=
6.9 Hz, 1 H), 4.33 (dd, J=4.5, 15.3 Hz, 1 H), 4.28 (dd, J=6.3,
12.8 Hz, 1 H), 3.69-3.77 (m, 1 H), 3.50 (dd, J=7.2, 15.7 Hz, 1
H), 3.35 (s, 3 H), 2.56 (dd, J=6.8, 16.1 Hz, 1 H), 2.47 (dd, J=2.3,
16.1 Hz, 1 H), 2.32-2.46 (m, 2 H); 13C NMR (75 MHz) δ 172.4,
134.1, 132.6, 118.4, 117.9, 96.3, 71.9, 60.6, 56.1, 43.1, 37.9, 31.9;
(CI-NH3)-HRMS calcd for C12H20NO3 (M þ 1) 226.1443,
found 226.1440.
(1S,8aS)-1-(Methoxymethoxy)-1,2,8,8a-tetrahydroindolizin-
3(5H)-one (23): To a solution of diallyl γ-lactam 24 (25.0 mg,
0.11 mmol) in dry CH2Cl2 (3 mL) at reflux was added via
cannula transfer a solution of Grubbs (II) catalyst (4.7 mg,
6.0 ꢀ 10-3 mmol) in dry CH2Cl2 (2 mL). The reaction was
refluxed for 1 h, by which time the reaction was judged to be
complete by TLC analysis. The reaction was cooled to rt, and
the solvent was evaporated and the crude oil purified by
chromatography (8:1 CH2Cl2/acetone) to give 23 (18.5 mg,
78%) as a clear light yellow oil: [R]26 þ19.2 (c 0.13, CHCl3),
D
lit.28a [R]22 þ17.4 (c 0.4, CHCl3); IR νmax 3525-3100, 1737
D
90%) as an amber colored oil: [R]26 -72.9 (c 0.24, CHCl3);
cm-1; 1H NMR (300 MHz) δ 3.97-4.06 (m, 1 H), 3.01-3.14 (m,
2 H), 2.06-2.20 (m, 2 H), 1.76-2.01 (m, 3 H), 1.37-1.73 (m, 6
H), 1.10-1.31 (m, 1 H); 13C NMR (75 MHz) δ 72.8, 68.7, 53.4,
52.6, 30.0, 25.1, 24.9, 23.7; HRMS calcd for C8H15NO 141.1154,
found 141.1157.
D
IR νmax 3025, 1689, 1648 cm-1 1H NMR (300 MHz) δ
;
5.79-5.88 (m, 1 H), 5.62-5.71 (m, 1 H), 4.65 (d, J=6.8 Hz,
1 H), 4.59 (d, J=6.8 Hz, 1 H), 4.41 (ddd, J=4.4, 6.7, 6.7 Hz, 1 H),
4.25 (dddd, J=3.9, 3.9, 3.9, 17.5 Hz, 1 H), 3.72 (ddd, J=4.8, 5.9,
10.7 Hz, 1 H), 3.51 (br d, J=17.5 Hz, 1 H), 3.34 (s, 3 H), 2.63 (dd,
J=7.2, 17.3 Hz, 1 H), 2.42-2.54 (m, 1 H), 2.42 (dd, J=4.2, 17.5
Hz, 1 H), 2.00-2.13 (m, 1 H); 13C NMR (75 MHz) δ 171.8,
124.2, 122.7, 95.8, 70.8, 56.2, 55.6, 40.1, 37.5, 24.2.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council, Canada, and the University
of Regina for financial support.
(1S,8aS)-1-Hydroxyhexahydroindolizin-3(5H)-one (27b): To
a solution of alkene 23 (30 mg, 0.15 mmol) in methanol (4 mL)
was added 10 wt % Pd-C (3 mg). The mixture was then
subjected to hydrogen pressure of 2 atm on a Parr hydrogenator
for 1 h. The methanol was removed under reduced pressure, and
the residue was filtered through a short pad of silica gel (2:1
CH2Cl2/acetone) to afford indolizidinone 27a (26 mg, 88%)
Supporting Information Available: Preparation and char-
acterization of 2a,b, (S)-3, (R)-3, (S)-4, (R)-4, (S)-6, (S)-7, (S)-8;
data for (S,S)-11, 12a,b, (S,S)-14, 15; spectral data for com-
pounds 2a, (S)-4, (R)-4, (S)-2b, (S)-3, (R)-3, (S)-6, (S)-7, (S)-8,
9a, 10a, (S,S)-11, 12a(5S), 9b, 10b, 12b(5R), 13, 15, 14E, 14Z, 19,
20(Z/E), 18, 21a, 21b, 17 BH3, 17 HCl, 25, 26a, 26c, 24, 23, 27a,
3
3
as a colorless oil: [R]26 þ37.9 (c 0.33, CHCl3); IR νmax 1766,
27b, 22. This material is available free of charge via the Internet
at http://pubs.acs.org.
D
1684 cm-1; 1H NMR (300 MHz) δ 4.63 (d, J=6.8 Hz, 1 H), 4.57
J. Org. Chem. Vol. 74, No. 21, 2009 8271