Asymmetric synthesis of α-substituted β-amino ketones from sulfinimines (N-sulfinyl imines). Synthesis of the indolizidine alkaloid (-)-223A

Article abstract of DOI:10.1021/ja051452k

Of the possible four stereoisomers, addition of the lithium enolate of 4-heptanone to sulfinimines resulted in only the syn- and anti-α- substituted β-amino ketones. The formation of the major syn-β-amino ketone was rationalized in terms of addition of th

Full text of DOI:10.1021/ja051452k

Published on Web 05/21/2005
Asymmetric Synthesis of r-Substituted â-Amino Ketones
from Sulfinimines (N-Sulfinyl Imines). Synthesis of the
Indolizidine Alkaloid (-)-223A
Franklin A. Davis* and Bin Yang
Contribution from the Department of Chemistry, Temple UniVersity,
Philadelphia, PennsylVania 19122
Received March 7, 2005; E-mail: fdavis@temple.edu
Abstract: Of the possible four stereoisomers, addition of the lithium enolate of 4-heptanone to sulfinimines
resulted in only the syn- and anti-R-substituted â-amino ketones. The formation of the major syn-â-amino
ketone was rationalized in terms of addition of the E-enolate to the C-N double bond of the sulfinimine via
a six-member chelated chairlike transition state. The enolates of 4-heptanone were generated using LiHMDS
in THF where a 1:2.5 E:Z enolate ratio was noted. In diethyl ether the E:Z ratio was 15:1 in favor of the
E-enolate and explained in terms of Ireland’s transition state model. Here increased steric interactions
between the ethyl group and the carbonyl-LiN(TMS)2 moiety destabilize the transition state leading to the
Z-enolate in the poorly coordinating diethyl ether solvent. This new synthesis of syn-R-substituted-â-amino
ketones was applied to the concise enantioselective total synthesis of indolizidine (-)-223A, a 5,6,8-
trisubstituted alkaloid isolated from the skin of the dendrobatide frog.
Scheme 1
Substituted piperidines represent a common structural motif
in numerous alkaloid natural products, bioactive compounds,
drugs, and drug candidates. Although many methods have been
devised to prepare this ring system, the continuing challenge is
to develop concise procedures for establishing the piperidine
ring stereocenters.1 Our recent studies have demonstrated that
the intramolecular Mannich reaction of aldehydes with the free
Sulfinimine-derived N-sulfinyl â-amino ketones 3 provided
amino group derived from N-sulfinyl δ-amino â-ketoesters is
a general solution to the difficulty of preparing â-amino ketone
ketals 4 in enantiomerically pure form. We found that treatment
of 3 with p-toluenesulfinic acid (TsOH) and 1,3-propane diol
an important one-pot strategy for the stereoselective assembly
of substituted piperidines in enantiopure form.2,3 In previous
work we applied this methodology to the concise asymmetric
resulted in N-sulfinyl deprotection and protection of the carbonyl
synthesis of the frog skin toxin (+)-241D,4 a 2,4,6-trisubstituted
group all in one pot (Scheme 2).7 For example, this new
piperidine, and the quinolizidine alkaloid (-)-epimyrtine.5
Using the intramolecular Mannich protocol, Troin and co-
methodology resulted in the synthesis of (S)-(+)-1 in better than
72% yield. The â-amino ketones 3 were readily prepared by
workers reported that the ketal of enantiopure 4-amino-2-
reaction of the potassium enolates of methyl ketones with
pentanone (S)-(+)-1 reacts with various aldehydes in the
sulfinimine 57 or by treatment of the N-sulfinyl â-amino
presence of acid to give cis-2,6-disubstituted piperidines 2
Weinreb amide 6 with Grignard reagents.8 Significantly this new
(Scheme 1).6 However, the multistep synthesis of (+)-1 requires
way of preparing â-amino ketone ketals means that, along with
either a classical resolution or a microbiological reduction as a
the intramolecular Mannich protocol, it will be possible to
key step and did not provide easy access to substituted
derivatives.6a,e
prepare diverse 2,3,4,6-tetrasubstituted piperidines in an efficient
and highly stereoselective manner. Previously, we illustrated
(1) For reviews on the asymmetric synthesis of piperidines, see: (a) Laschat,
S.; Dickner, T. Synthesis 2000, 1781. (b) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693. (c) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953. (d) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701.
(2) For a review of the application of the Mannich reaction in alkaloid synthesis,
see: Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044.
(3) For a review on sulfinimine chemistry that includes a discussion of
N-sulfinyl δ-amino â-ketoesters, see: Zhou, P.; Chen, B.-C.; Davis, F.
Tetrahedron 2004, 60, 8030.
(4) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
(5) Davis, F. A.; Zhang, Y.; Anilkumar, G. J. Org. Chem. 2003, 68, 8061.
(6) (a) Ripoche, I.; Canet, J.; Gelas, J.; Troin, Y. Tetrahedron: Asymmetry
1999, 10, 2213. (b) Ciblat, S.; Besse, P.; Canet, J.; Troin, Y.; Veschambre,
H.; Gelas J. Tetrahedron: Asymmetry 1999, 10, 2225. (c) Besse, P.; Ciblat,
S.; Canet, J.; Troin, Y.; Veschambre H. Tetrahederon: Asymmetry 2000,
11, 2211. (d) Glasson, S. R.; Canet, J.-L.; Troin, Y. Tetrahedron Lett. 2000,
41, 9797. (e) Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem. Soc.,
Perkin Trans. 1 2000, 353. (f) Carbonnel, S.; Troin, Y. Heterocycles 2002,
57, 1807. (g) Lamazzi, C.; Carbonnel, S.; Calinaud, P.; Troin, Y.
Heterocycles 2003, 60, 1447.
(7) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(8) (a) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5,
925. (b) Davis, F. A.; Nolt, B. M.; Wu, Y.; Prasad, K. R.; Li, D.; Yang,
B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
9
8398
J. AM. CHEM. SOC. 2005, 127, 8398-8407
10.1021/ja051452k CCC: $30.25 © 2005 American Chemical Society

R
-Substituted
â-Amino Ketones from Sulfinimines
A R T I C L E S
Scheme 2
Scheme 4
Asymmetric Synthesis of syn-r-Substituted â-Amino Ke-
tones. It appears that methods for the asymmetric synthesis of
R-substituted â-amino ketones, where the amino group is
attached to the stereogenic center, have not been previously
described.14,15 Among the procedures considered was the
R-alkylation of â-amino ketones or â-amino ester enolates, but
this would provide the anti-isomers.14,16 Conversion of syn-R-
substituted â-amino esters is another possibility but necessitates
conversion into the ketone.12b,17,18 Our recent success in the
asymmetric synthesis of syn- and anti-R,â-diamino esters by
addition of protected glycine enolates to sulfinimines (N-sulfinyl
imines) encouraged us to devise a more direct method for the
preparation of syn-R-ethyl â-amino ketone 10.19 This procedure
involved the addition of the metal enolate derived from
4-heptanone (12) to sulfinimines 11 (Scheme 4).
In a typical experiment (S)-(+)-N-(benzylidine)-p-toluene-
sulfinamide (11a) was added to 1.5 equiv of the preformed
sodium enolate of 12 at -78 °C. In this reaction the formation
of four isomeric R-substituted â-amino ketones is possible.
Significantly, the only two detected were the syn-13a and anti-
14a isomers, isolated by flash chromatography in 66 and 24%
yield, respectively (Table 1, entry 1). The best selectivities were
observed for the lithium enolate generated using lithium bis-
(trimethylsilyl)amide (LiHMDS) in diethyl ether with the syn:
anti ratios being dependent on the number of equivalents of
the enolate (Table 1, entries 9 and 10). With 1.5 and 3.0 equiv
of the lithium enolate of 12 the ratios of 13a and 14a were 9:1
and 18:1, respectively (Table 1, entries 9 and 10). These same
trends were noted for the reaction of the lithium enolate of 12
with sulfinimines (S)-(+)-N-(2-furylmethylidene)-p-toluene-
sulfinamide (11b) and in particular (S)-(+)-N-(butylidene)-p-
toluenesulfinamide (11c) necessary for the preparation of 223A
(9). The major syn isomers 13b and 13c were isolated in 64
and 67% yields, respectively (Table 1, entries 13 and 15). An
Scheme 3
the potential of this methodology with a concise asymmetric
synthesis of (-)-indolizidine 209B (8), an alkaloid isolated from
the skin of the toxic dendrobatide frog, from the ketal of â-amino
ketone (-)-7 (Scheme 2).
The indolizidine alkaloid (-)-223A (9), like 209B (8), was
isolated from the skin of the dendrobatide frog by Daly and
co-workers (Scheme 3).9 Indeed more than 500 alkaloids
(pyrrolidines, piperidines, indolizidines, and quinolizidines) have
been detected in the skin extracts of poisonous frogs and toads
worldwide.10 Many of these alkaloids exhibit interesting biologi-
cal activity, including noncompetitive blockers for nicotinic
channels.11 However, due to the scarcity of the majority of these
materials, their biological activities remain largely unexplored.
While most of the isolated indolizidine alkaloids have the 3,5-
or 5,8-disubstituted structure, e.g., 8, (-)-223A (9) was the first
trisubstituted indolizidine alkaloid to have been isolated from
the dendrobatid frogs.9 To prepare 223A (9) using the intramo-
lecular Mannich protocol requires access to (5S,6R)-6-amino-
5-ethylnonan-4-one (10), a syn-R-substituted â-amino ketone
(Scheme 3). Described below are studies aimed at the asym-
metric synthesis of syn-R-substituted â-amino ketones, which
is highlighted in a concise asymmetric synthesis of (-)-indoli-
zidine 223A (9).12,13 In addition we report a novel and apparently
not well-recognized effect of ether solvents on the stereoselec-
tivity of aliphatic acyclic ketone E- and Z-enolate formation.
(14) For a recent review on the asymmetric synthesis of â-amino acids: see:
Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(15) For other asymmetric syntheses of R-substituted â-amino ketones, see: (a)
Enders, D.; Adam, J.; Oberborsch, S.; Ward, D. Synthesis 2002, 2737. (b)
Bartoli, G.; Bartolacci, M.; Cortese, M.; Marcantoni, E.; Massaccesi, M.;
Pela, R.; Sambri, L. Eur. J. Org. Chem. 2004, 2359.
(16) (a) McNeil A. J.; Toombes, G. E. S.; Gruner, S. M.; Lobkovsky, E.; Collum,
D. B.; Chandramouli, S. V.; Vanasse, B. J.; Ayers, T. A. J. Am. Chem.
Soc. 2004, 126, 16559. (b) Wang, J.; Hou, Y.; Wu, P.; Qu, Z.; Chan, A. S.
C. Tetrahedron: Asymmetry 1999, 10, 4553.
(17) (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819. (b) Langenhan,
J. M.; Gellman, S. H. J. Org. Chem. 2003, 68, 6640. (c) Ikemoto, N.;
Tellers, D. M.; Dreher, S. D.; Liu, J.; Huang, A.; Rivera, N. R.; Njolito,
E.; Hsiao, Y.; McWilliams, J. C.; Williams, J. M.; Armstrong, J. D., III;
Sun, Y.; Mathre, D. J.; Grabowski, E. J. J.; Tillyer, R. D. J. Am. Chem.
Soc. 2004, 126, 3048.
(9) Garraffo, H. M.; Spande, J. T. F.; Daly, J. W. J. Nat. Prod. 1997, 60, 2.
(10) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon Press: New York,
1999; Vol. 13, pp 1-161.
(11) Daly, J. W. J. Med. Chem. 2003, 46, 445.
(12) For earlier asymmetric syntheses of 223A, see: (a) Toyooka, N.; Fukutome,
A.; Nemoto, H.; Daly, J. W.; Spande, T. F.; Garraffo, H. M.; Kaneto, T.
Org. Lett. 2002, 4, 1715. (b) Pu, X.; Ma, D. J. Org. Chem. 2003, 68, 4400.
(c) Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Tetrahedron 2004,
60, 6197. (d) Zhu, W.; Dong, D.; Puy, X.; Ma, D. Org. Lett. 2005, 7, 705.
(13) For a racemic synthesis of 223A, see: (a) Harris, J. M.; Padwa, A. J. Org.
Chem. 2003, 68, 4371. See also: Kumareswaran R.; Gallucci, J.; Rajan-
Babu, T. V. J. Org. Chem. 2004, 69, 9151.
(18) Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org.
Lett. 2000, 2, 2177. (b) Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem.
2003, 68, 5735.
(19) (a) Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789. (b) Davis, F. A.; Deng,
J. Org. Lett. 2005, 7, 621.
9
J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005 8399

A R T I C L E S
Davis and Yang
Table 1. Addition of the Enolate of 4-Heptanone to Sulfinimines at -78 °Ca
products
syn:antic,e (% isolated yield)f
sulfinimine
enolate
E:Zb,c 15 (equiv)d
entry
11 (R
))
base
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
11a (Ph)
NaHMDS
Et2O
Et2Og
Et2O
Et2Oh
THF
Et2O
THF
PhMe
Et2O
Et2Oi
THF
Et2O
Et2O
Et2O
Et2O
Et2Oj
THF
3.5:1 (1.5)
13a:14a
3:1 (66):(21)
3:1 (55):(18)
3:1 (36)
1:1 (44):(44)
2:1 (55):(24)
2:3 (34):(50)
6:5 (52):(40)
2:1 (48)
9:1 (35)
18:1 (71)
6:1 (21)
3:1 (62):(20)
15:1 (64)
3.5:1 (0.9)
(1.5)
1:45 (1.5)
4:1 (1.5)
1:2.5 (1.5)
(1.5)
15:1 (1.5)
12:1 (3.0)
1:2.5 (1.5)
3.5:1 (1.5)
15:1 (3.0)
3.5:1 (1.5)
15:1 (3.0)
15:1 (3.0)
1:2.5 (1.5)
KHMDS
LiHMDS
11b (2-furyl)
11c (n-Pr)
NaHMDS
LiHMDS
NaHMDS
LiHMDS
LiHMDS
LiHMDS
13b:14b
13c:14c
3:1 (65):(21)
12:1 (67)
10:1 (78):(8)
4:1 (20)
a Sulfinimine transferred to the enolate unless otherwise noted. b E:Z ratio of the enolate was determined by trapping experiments. c The % THF, from the
LiHMDS solution, in diethyl ether was approximately the same. d Equivalents of enolate. e Determined by 1H NMR on the crude reaction mixtures. f Isolated
yields of major and minor isomers. g 4-Heptanone was added to 11a and the base. h HMPA, 1.5 equiv added. i The % THF in Et2O was approximately 3
times greater. j The preformed enolate added to the sulfinimine.
Scheme 5
alternative procedure involved adding the enolate to the sulfin-
imine 11c, and while this increased the yield of the major
product, syn-13c, to 78%, it resulted in decreased selectivity
(Table 1, entry 16).
Assignment of the absolute stereochemisty for the syn-13
(major) and anti-14 (minor) â-amino ketones was ultimately
determined by the conversion of the enantiomer of syn-13c to
(-)-223A (9) (see below). However, chemical shifts of the NH
protons for the minor anti isomers 14 appeared about 0.6 to
0.9 ppm downfield from the major syn isomers 13. There was
no useful diagnostic correlation of the coupling constants for
13 and 14. Interestingly, on TLC the minor isomers had higher
Rf values compared to the major syn isomers.
lithium and potassium enolates were much lower, i.e., 1:2.5
(Table 1, entries 7, 11, and 17). Earlier studies by Munchhof
and Heathcock, which used LDA and THF to generate the
enolate of 12, also revealed a preference for the Z-enolate.23
However, these workers observed that as the polarity of the
solvent increased (hexane in THF), the portion of the Z-enolate
decreased. Enhanced E:Z ketone enolate selectivity (50:1) has
also been reported by Collum and others using hindered lithium
bases and added lithium salts.24 For ketone enolization the
LiHMDS/THF base system usually results in the formation of
the kinetic Z-enolate.20,22,23,25 These results have generally been
interpreted in terms of Ireland’s transition model invoking steric
and electronic effects (see below).
Significantly, in diethyl ether we observed a dramatic increase
in selectivity for formation of the E-enolate (E-15) that has not
previously been noted (Table 1). The highest E:Z ratio, 15:1,
was observed for the lithium enolates generated using LiHMDS
(Table 1, entries 9, 10, 13, 15, and 16). With one exception,
the sodium, potassium, and lithium enolates of 12, on addition
to sulfinimines (S)-11, preferentially formed the syn-â-amino
R-ethyl â-amino ketones 13. The syn:anti 13:14 ratios were 2:1
for the sodium enolates in THF, whereas the enolate 15 had a
Enolate Geometries. Pioneering studies by Heathcock and
others on the aldol reaction have demonstrated that there is a
strong correlation between the enolate geometry and the
stereochemistry of the aldol product.20 In our studies, the
geometries of the acyclic enolates of 4-heptanone (12), generated
using LiHMDS, NaHMDS, and KHMDS, were determined by
trapping with trimethylsilyl chloride (TMS-Cl) at -78 °C to
give the corresponding E- and Z-enol silanes 16 as previously
described (Scheme 5).20-22 The ratios of the E- and Z-enol
silanes 16 were determined by integration of the characteristic
1
triplets of the vinyl proton resonances on C-3 in the H NMR
of 16.21 In E-16 the vinyl proton appears at δ 4.62 ppm and in
Z-16 it appears at δ 4.31 ppm in accordance with earlier studies.
The enolate geometries thus determined are summarized in
Table 1.
In all cases examined the Z-enolate, Z-15, was favored in
THF solvent (Table 1). For example the sodium enolate gave a
1:45 E:Z ratio (Table 1, entry 5), whereas the E:Z ratios for the
(20) (a) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: London, 1984; Vol. 3, p 111. (b) Evans, D. A.; Vogel,
E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120. (c) Hirama, M.;
Masamune, S. Tetradedron Lett. 1979, 2225. (d) Dubois, J. E.; Fellman,
P. Tetrahedron Lett. 1975, 1225.
(21) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J.
E.; Lampe, J. J. Org. Chem. 1980, 45, 1066, and references therein.
(22) (a) House, H. O.; Kramar, V. J. Org. Chem. 1963, 28, 3362. (b) Bohlmann,
F.; Arndt, C.; Starnick, J. Tetrahedron Lett. 1963, 1605. (c) House, H. O.;
Gall, C. M.; Olmstead, H. D. J. Org. Chem. 1969, 34, 2324.
(23) Munchhof, M. J.; Heathcock, C. J. Tetrahedron Lett. 1992, 33, 8005.
(24) For leading references see: Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J.
Am. Chem. Soc. 1991, 113, 9571.
(25) Xie, L.; Isenberger, K. M.; Held, G.; Dahl, L. M. J. Org. Chem. 1997, 62,
7516.
9
8400 J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005

R
-Substituted
â-Amino Ketones from Sulfinimines
A R T I C L E S
Scheme 6
amino esters.17a The enolate geometry is presumed to be E. The
addition of the E- and Z-enolate of 12 to sulfinimines (S)-11
results in exclusive re face addition, which affords the syn-13
and anti-14 â-amino ketones via transition states TS-3 and TS-
4, respectively (Scheme 6). The fact that syn-13 is favored in
nearly all cases suggests that the E-enolate E-15 is more reactive
and more selective toward addition to the sulfinimine than is
the Z-enolate. Consistent with this idea is the observation that
the E:Z-enolate ratio of 12 is lower than the syn:anti selectivity,
particularly at higher concentrations of the enolate. Here the
E-enolate E-15 reacts at a faster rate with sulfinimine 13 and
favors the syn-13 product. However, the possibility that the
Z-enolate could also give some of the syn product via boatlike
transition state TS-5 cannot be ruled out at this time. Indeed if
this were correct, it could explain the unusually high yield of
syn-11a (55%) despite the fact that the E:Z ratio is 1:45 (Table
1, entry 5).
Asymmetric Synthesis of (-)-223A. To prepare alkaloid
(-)-223A (9) using the intramolecular Mannich protocol
requires the enantiomer of syn-13c, (RS,5S,6R)-(-)-19, which
was readily prepared from sulfinimine (R)-(-)-17 as outlined
in Scheme 7. The N-sulfinyl â-amino ketone (-)-19 was
deprotected with TFA/MeOH, and the product was passed
through a short pad of silica gel and treated with E-4-
benzyloxybut-2-enal in the presence of anhydrous MgSO4 to
give the crude imine 20 in ca. 88%. Attempted isolation of the
imine by chromatography resulted in decomposition. However,
the intramolecular Mannich cyclization, which involves stirring
the crude imine in benzene with 2 equiv of TsOH for 40 h,
resulted in only a 15% yield of the desired 2,3,5,6-tetrasubsti-
tuted piperidin-4-one (+)-21. Considerable decomposition was
noted under these conditions, and we speculated that this might
be due to the liability of the benzyloxy group under the acidic
conditions. To affect the cyclization of (+)-21 to (+)-22, the
former was hydrogenated (H2/Pd) and the intermediate alcohol
(not shown) was subjected to cyclization with CBr4/Ph3P/Et3N,
affording the indolizidine (+)-22 in 71% yield for the three steps
(Scheme 7).7
Figure 1. Ireland transition state models for the formation of E- and
Z-enolates.
1:45 E:Z ratio (Table 1, entry 5). Only the potassium enolate
of 12 in diethyl ether afforded more anti product 14a on addition
to 11a (Table 1, entry 6). Importantly, the syn:anti ratios
improved from 9:1 to 18:1 for the lithium enolates in diethyl
ether (Table 1, entries 10, 13, 15, and 16).
Mechanism. Particularly intriguing is why the E-enolate of
12 (E-15) is so dramatically favored in LiHMDS/diethyl ether
(E:Z, 15:1) compared to this base in THF (E:Z, 1:2.5). The well-
known Ireland transition model for formation of E- and
Z-enolates, applied to the deprotonation of 4-heptanone (12),
may offer an explanation (Figure 1).26 In Ireland’s transition
state model the formation of E- and Z-enolates is determined
by the energy differences between transition state TS-1 and TS-2
and dependent on steric and electronic factors within these
structures. A more demanding steric interaction between the Et
group and the carbonyl-LiN(TMS)2 moiety in TS-2 is expected
to result in an increase in the formation of the E-enolate. Because
ethyl ether is a poorer coordinating solvent than THF, this could
result in a tighter transition state and greater interaction between
the Et group and the carbonyl-LiN(TMS)2 moiety, which could
destabilize TS-2 and favor TS-1.27 Collum and co-workers have
reported that, in the formation of ketone enolates, LiHMDS acts
as a dimer in ether solvents and a monomer in THF,28,29 which
has even greater impact on the stability of TS-2 vs TS-1. Thus
the effective size of the carbonyl-Li group should be much larger
in diethyl ether than in THF, which further destabilizes TS-2
(Figure 1).
The absolute stereochemistry for the product of addition of
enolates to sulfinimines is controlled by the N-sulfinyl group
and predicted by a six-membered chairlike transition state.3 For
the addition of R-substituted ester enolates to tert-butyl sulfin-
imines Ellman evoked a six-member chairlike transition state
to explain the preferred formation of the syn-R-substituted-â-
In an effort to circumvent the poor yields in the Mannich
cyclization step when using imine 20, a ring-closing meta-
thesis strategy was next explored to install the indolizidine
structure. Here (-)-19, after removal of the N-sulfinyl group,
was treated with crotonaldehyde to give the crude imine 23 in
better than 93% yield (Scheme 8). Treatment of 23 with TsOH
for 40 h resulted in two piperidines, (2S,3S,5S,6R)-(+)-24 and
(2R,3S,5S,6R)-(+)-25, in 58 and 18% isolated yields, respec-
tively (Scheme 8). Importantly, no epimerization was noted at
C-5 during the acid-catalyzed Mannich cyclization.
(26) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976,
98, 2868. (b) Moreland, D. W.; Dauben, W. G. J. Am. Chem. Soc. 1985,
107, 2264. (c) Narula, A. S. Tetrahedron Lett. 1981, 22, 4119. (d) Fataftah,
Z. A.; Kopka, I. E.; Rathke, M. W. J. Am. Chem. Soc. 1980, 102, 3959.
(27) Lucht, B. L.; Collum, D. B. Acc. Chem. Res. 1999, 1035, 5.
(28) (a) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008. (b) Zhao,
P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411. (c) Zhao, P.; Lucht,
B. L.; Kenkre, S. L.; Collum, D. B. J. Am. Chem. Soc. 2004, 126, 242. (d)
Zhao, P.; Condo, A.; Keresztes, I.; Collum, D. B. J. Am. Chem. Soc. 2004,
126, 3113.
The stereochemistry features of (+)-24 and (+)-25 were based
on 1D NOE studies and ultimately the conversion of (+)-24
(29) See also: Sun, C.; Williard, P. G. J. Am. Chem. Soc. 2000, 122, 7829.
9
J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005 8401

A R T I C L E S
Scheme 7
Davis and Yang
Scheme 8
into (-)-223A (9) (see below). In 24, the observed NOE
between the C-2 and C-6 methine protons indicates a cis
orientation for the 6-propyl and 2-propenyl groups. Another
NOE was observed between the C-3 methine proton and the
HR of the propenyl group, which indicates the trans relationship
between the propenyl group on C-2 and the ethyl group on C-3.
In (+)-25 the 1D NOE revealed an interaction between the
methine proton at C-6 and the HR of the propenyl group at C-2,
which signifies the trans relationship between the groups on
C-2 and C-6. No NOE was observed between the two methine
protons on C-2 and C-6 and provides additional evidence for
the trans relationship of these groups. The observed NOE
between the C-3 methine proton and the methylene protons in
the ethyl group on C-5 suggests that the C-3 ethyl group has a
trans relationship with the C-5 substituent. Again no NOE was
detected between the C-3 methine proton and the HR on the
2-propenyl group, which provides further evidence for the cis
relationship between the groups on C-2 and C-3 (Scheme 8).
the E-imine 23 isomerizes to the Z-imine under the acidic
reaction conditions.30
Applying the intramolecular Mannich protocol to the minor
anti isomer (SS,5R,6R)-(-)-18 resulted in the formation of two
piperidin-4-ones, (2S,3S,5R,6R)-(+)-26 and (2R,3R,5R,6R)-(-
)-27, in 65 and 18% yields, respectively, for the three-step
sequence (Scheme 9). Considering the axial alignment of the
C-5 ethyl group in (2S,3S,SR,6R)-24, we anticipated that base-
induced epimerization at C-5 would result in (2S,3S,5R,6R)-
(+)-26. Indeed, refluxing (+)-24 in the presence of sodium
methoxide in MeOH for 24 h afforded (+)-26 in 55% yield
(Scheme 9). This transformation provides further support for
the stereochemistry of (+)-26. The structure of (-)-27 is
supported by NOE studies.
With the requisite tetrasubstituted piperidin-4-one (+)-24 in
hand we found heating 24 with allyl bromide/Na2CO3 afforded
diene (+)-28 in 91% yield (Scheme 10). Ring-closing metathesis
using 5 mol % of the Grubbs “first generation” catalyst,31
followed by hydrogenation (Pd/H2), gave indolizidine (+)-22
in 72% yield for two steps (Scheme 10). All that remains is to
remove the 7-oxo group in (+)-22 and our target indolizidine
(-)-223A (9) would be in hand. However, attempts to form
the thioketal of (+)-22 using ethanedithiol/BF3, as we had
previously found successful in our synthesis of indolizidine
209B (8),7 resulted in extensive decomposition. A Clemenson
reduction with Zn/HCl resulted in no reaction. Reduction of
The formation of the major product (2S,3S,5S,6R)-(+)-24 can
be rationalized by a six-member chairlike transition state TS-6
(Scheme 8). Here the 2-(1-propenyl), 3-ethyl, and 6-propyl all
occupy equatorial positions, while the 5-ethyl is forced into an
axial orientation. As shown in TS-6, the enol is assumed to
have the Z configuration and is similar to transition state models
proposed by Troin et al. in their syntheses of cis-2,6-disubsti-
tuted piperidin-4-ones from â-amino ketal (S)-(+)-1.6 A boatlike
transition state TS-7 can be used to rationalize the formation
of the minor product (2R,3S,5S,6R)-(+)-25, where the ethyl
group at C-5 and the propyl group at C-6 both assume
pseudoaxial positions. The 1-propenyl group on C-2 and the
ethyl group on C-3 both have pseudoequatorial orientations.
Another possibility that cannot be ruled out at this time is that
(30) Jennings, W. B.; Boyd, D. R. J. Am. Chem. Soc. 1972, 94, 7187.
(31) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1999, 54, 4413. (b) Chatterjee,
A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751.
9
8402 J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005

R
-Substituted
â-Amino Ketones from Sulfinimines
A R T I C L E S
Scheme 9
Scheme 10
Scheme 11
11).34 Reaction of tri-n-butyltin hydride and AIBN in benzene
with (-)-31 furnished indolizidine (-)-223A (9) in 74% yield
with properties consistent with literature values.12
Summary and Conclusions. Of four possible stereoisomers,
addition of the lithium enolate of 4-heptanone (12) to sulfin-
imines (S)-11 results in only the syn-13 and anti-14 R-ethyl
â-amino ketone isomers being formed. These results were
interpreted in terms of the E-enolate of 12, E-15, adding to the
re face of the sulfinimine C-N double bond via six-member
chelated transition state TS-3, affording syn-13 as the major
product. Trapping of the enolate of 12, generated using
LiHMDS, with TMS-Cl revealed an unexpected effect of solvent
on the enolate geometry. In THF the E:Z ratio of enolates
generated using this base was 1:2.5, as observed by a number
of others. However, in diethyl ether the enolate geometry
dramatically changes to 15:1 in favor of the E-enolate. These
results were rationalized in terms of Ireland’s transition state
model wherein increased steric interaction between the Et group
and the carbonyl-LiN(TMS)2 moiety results in destabilized of
TS-2 (Z-enolate formation) relative to TS-1 (E-enolate forma-
tion) (Figure 1). The increased interaction between the Et group
and the carbonyl-LiN(TMS)2 was suggested to result from a
tighter transition state and the dimeric nature of LiHMDS in
the poorly coordinating diethyl ether solvent compared to THF.
This new methodology for R-substituted â-amino ketone
synthesis was applied in a concise asymmetric synthesis of
indolizidine 223A (9), a 5,6,8-trisubstituted indolizidine. The
key step in this synthesis was the intramolecular Mannich
cyclization of the crotonaldehyde imine of syn-R-ethyl â-amino
ketone 10 to give 2,3,5,6-tetrasubstituted piperidine (+)-24 in
58% yield. The synthesis of (-)-223A (9) was accomplished
in approximately nine steps (9.3% overall yield) from sulfin-
imine (R)-(-)-17 and represents the most concise synthesis of
this alkaloid to date.
(+)-22 with NaBH4 gave a 90% yield of alcohol (+)-29 as a
single isomer. The two vicinal diaxial coupling constants of 10.5
Hz between the C-7 proton and the C-8 methine protons in (+)-
29 support the equatorial orientation for the hydroxy group and
are consistent with approach of hydride from the least hindered
axial position; so the next plan was to convert (+)-29 into its
mesylate (+)-30 followed by a reductive deoxygenation as
previously reported.32 Unfortunately, reduction of the mesylate
with Li/NH3 simply regenerated the alcohol (Scheme 10).
Attempts to convert the alcohol into the corresponding diethyl
phosphonate or N,N,N′N′-tetramethylphosphoradiamidates for
reductive deoxygenation, as described by Ireland,33 was also
unsuccessful. Our inability to remove the 7-oxy/hydroxy groups
in these transformations is likely the result of steric congestion
in the regions of these moieties in (+)-22 and (+)-29,
respectively.
A radical deoxygenation protocol proved to be successful.
Treatment of indolizidine alcohol (+)-29 with phenylthion-
ochloroformate and pyridine in dichloromethane afforded the
phenylthionocarbonate (-)-31 in 55% isolated yield (Scheme
(32) Turos, E.; Audia, J. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
8231.
(34) (a) Berninger, J.; Krauss, R.; Weinig, H.; Koert, U.; Ziemer, B.; Harms,
K. Eur. J. Org. Chem. 1999, 875. (b) Martin, S. F.; Dappen, M. S.; Dupre,
B.; Murphy, C. J.; Colapret, J. A. J. Org. Chem. 1989, 54, 2209.
(33) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J. Am. Chem. Soc. 1972,
94, 5098.
9
J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005 8403

A R T I C L E S
Davis and Yang
210.0952, found 210.0949. Spectral properties were identical to (S)-
(+)-N-(butylidene)-p-toluenesulfinamide (11a).35
Experimental Section
General Procedures. Column chromatography was performed on
silica gel, Merck grade 60 (230-400 mesh). TLC plates were visualized
with UV, in an iodine chamber, or with phosphomolybdic acid. Melting
points were recorded on a Mel-Temp apparatus and were uncorrected.
Optical rotations were measured on a Perkin-Elmer 341 polarimeter,
and IR spectra were recorded, using NaCl plates, on a Mattson 4020
FTIR. 1H NMR and 13C NMR spectra were recorded on a Bruker 400,
operating at 400 and 100 MHz, respectively. HRMS were performed
in the Department of Chemistry, Drexel University, Philadelphia, PA,
using a Fissions ZAB HF double-focusing mass spectrometer.
Anhydrous and oxygen-free dichloromethane, toluene, Et2O, and
THF were obtained from a Schlenk manifold with purification columns
packed with activated alumina and supported copper catalyst (Glass
Contour, Irvine, CA). Unless stated otherwise, all reagents were
purchased from commercial sources and used without additional
purification. Sulfinimines (S)-(+)-N-(benzylidene)-p-toluenesulfinamide
(11a), (S)-(+)-N-(2-furylmethylidene)-p-toluenesulfinamide (11b), and
(S)-(+)-N-(butylidene)-p-toluenesulfinamide (11c) were prepared as
previously decribed.35
Determination of the Enolate Geometry of 4-Heptanone. General
Procedure for Trapping the Enolate with Trimethylsilyl Chloride.21
In a 50 mL, one-necked, round-bottomed flask equipped with a
magnetic stirring bar and argon balloon was placed 2.89 mmol of the
appropriate base (LiHMDS, NaHMDS, 1 M solution in THF, KHMDS,
0.5 M solution in toluene) in 30 mL of the specified solvent (diethyl
ether or THF) at -78 °C. To the solution was slowly added 4-heptanone
(12) (0.37 mL, 2.63 mmol) via syringe. The reaction was kept stirring
at -78 °C for 1 h, and 0.33 mL (2.63 mmol) of chlorotrimethylsilane
was added dropwise via syringe. The reaction was allowed to warm to
room temperature over 0.5 h, and after stirring for an additional 0.5 h,
the reaction mixture was partitioned between hexane and saturated
NaHCO3, The organic phase was dried (Na2SO4) and concentrated.
Inspection of the 1H and 13C NMR spectra of the crude reaction mixture
was used to determine the ratio of E/Z silyl enol ethers 16. Integrations
of the vinyl protons at δ 4.62 and 4.31 ppm in the 1H NMR were used
to determined the E:Z ratios, respectively.
Typical Procedure of the Addition of the Enolate of 4-Heptanone
(12) to Sulfinimines. In a 50 mL, one-necked, round-bottomed flask
equipped with a magnetic stirring bar and argon balloon was placed
0.48 mL (0.48 mmol) of NaHMDS (1.0 M solution in THF) in diethyl
ether (5 mL). The % of THF in the diethyl ether was approximately
the same as that used in the enolate trapping experiments. The solution
was cooled to -78 °C, and 0.063 mL (0.45 mmol) of 4-heptanone
(12) was added dropwise via syringe. The reaction was stirred for 1 h
at this temperature, and 0.3 mmol of appropriate sulfinimine, 11a, 11b,
or 11c, in ether (1 mL) was added dropwise via cannula. After 0.5 h
the reaction mixture was quenched at -78 °C by addition of saturated
NH4Cl solution (1.5 mL), and H2O (6 mL) was added. The solution
was extracted with EtOAc (2 × 10 mL), and the combined organic
phases were dried (Na2SO4) and concentrated. Column chromatography
(20% EtOAc/hexane) was used to purify the products. The first to elute
was anti-14, followed by syn-13.
syn-(SS,1R,2R)-(+)-N-(p-Toluenesulfinyl)-1-amino-2-ethyl-1-phe-
nylhexan-3-one (13a). Purification (20% EtOAc/hexane) afforded 0.072
g (66%) of a white solid: mp 90-91 °C; [R]20D +33.8 (c 0.8, CHCl3);
1
IR (neat) 3195, 2963, 1709 cm-1; H NMR (CDCl3) δ 0.71 (dt, J )
7.5, 1.0 Hz, 3 H), 0.78 (t, J ) 7.5 Hz, 3 H), 1.36 (m, 2 H), 1.62 (m,
1 H), 1.68 (m, 1 H), 2.04 (dt, J ) 18.0, 7.5 Hz, 1 H), 2.16 (dt, 18.0,
7.5 Hz, 1 H), 2.41 (s, 3 H), 2.81 (m, 1 H), 4.57 (d, J ) 3.5 Hz, 1 H),
4.62 (dd, J ) 7.5, 3.5 Hz, 1 H), 7.30 (m, 3 H), 7.36 (m, 4 H), 7.55 (d,
J ) 7.5 Hz, 2 H); 13C NMR (CDCl3) δ 11.2, 12.9, 15.7, 20.5, 20.8,
46.4, 58.2, 59.0, 124.8, 127.4, 127.5, 128.1, 129.1, 139.3, 141.0, 141.8,
212.2; HRMS calcd for C21H27NO2S (M + H) 358.1841, found
358.1851.
anti-(SS,1R,2S)-(+)-N-(p-Toluenesulfinyl)-1-amino-2-ethyl-1-phe-
nylhexan-3-one (14a). Purification (20% EtOAc/hexane) afforded 0.023
g (21%) of a white solid: mp 83-84 °C; [R]20D +135.3 (c 0.53, CHCl3);
IR (neat) 3197, 2963, 1701 cm-1; 1H NMR δ (CDCl3) 0.70 (t, J ) 7.5
Hz, 3 H), 0.82 (t, J ) 7.5 Hz, 3 H), 1.34 (m, 2 H), 1.55 (m, 1 H), 1.65
(m, 1 H), 1.86 (dt, J ) 22.0, 9.0 Hz, 1 H), 2.16 (dt, J ) 10.0, 22.0 Hz,
1 H), 2.39 (s, 3 H), 2.80 (m, 1 H), 4.58 (t, J ) 7.5 Hz, 1 H), 5.36 (d,
J ) 8.0 Hz, 1 H), 7.24-7.35 (m, 7 H), 7.52 (d, J ) 9.0 Hz, 2 H); 13
C
((E)-Hept-3-en-4-yloxy)trimethylsilane (E-16): 1H NMR (CDCl3)
δ 0.17 (s, 9 H), 0.90 (t, J ) 7.6 Hz, 3 H), 0.93 (t, J ) 7.5 Hz, 3 H),
1.47 (m, 2 H), 1.94 (t, J ) 7.6 Hz, 2 H), 2.02 (t, J ) 7.2 Hz, 2 H),
4.62 (t, J ) 7.4 Hz, 1 H); 13C NMR (CDCl3) δ 0.6, 13.9, 15.6, 20.4,
20.5, 33.3, 109.4, 150.4.
((Z)-Hept-3-en-4-yloxy)trimethylsilane (Z-16): 1H NMR (CDCl3)
δ 0.05 (s, 9 H), 0.78 (m, 6 H), 1.34 (m, 2 H), 1.85 (m, 4 H), 4.31 (t,
J ) 7.0 Hz, 1 H); 13C NMR (CDCl3) δ 0.8, 13.9, 14.7, 18.8, 20.4,
38.8, 110.5, 150.0.
NMR (CDCl3) δ 12.1, 13.9, 16.6, 21.8, 23.7, 47.2, 59.5, 59.7, 125.9,
127.4, 128.0, 129.0, 129.9, 141.7, 141.8, 142.6, 215.2; HRMS calcd
for C21H27NO2S (M + H) 358.1841, found 358.1842.
syn-(SS,1R,2R)-(+)-N-(p-Toluenesulfinyl)-1-amino-2-ethyl-1-(2-fu-
ryl)hexan-3-one (13b). Purification (20% EtOAc/hexane) afforded
0.065 g (62%) a colorless oil: [R]20D +76.3 (c 1.74, CHCl3); IR (neat)
3192, 2964, 1709 cm-1 1H NMR δ (CDCl3) 0.78 (t, J ) 7.5 Hz,
;
6 H), 1.42 (m, 2 H), 1.61 (m, 2 H), 2.09 (dt, J ) 6.8, 17.8 Hz, 1 H),
2.20 (dt, J ) 7.2, 17.8 Hz, 1 H), 2.40 (s, 3 H), 2.88 (dt, J ) 8.0, 5.6
Hz, 1 H), 4.59 (t, J ) 7.4 Hz, 1 H), 4.64 (d, J ) 7.4 Hz, 1 H), 6.25
(d, J ) 3.1 Hz, 1 H), 6.32 (dd, J ) 2.0, 3.1 Hz, 1 H), 7.29 (d, J ) 7.8
Hz, 2 H), 7.37 (d, J ) 2.0 Hz, 1 H), 7.53 (d, J ) 7.8 Hz, 2 H); 13C
NMR (CDCl3) δ 11.7, 13.6, 16.4, 21.4, 21.6, 45.9, 52.4, 57.2, 108.3,
110.6, 125.6, 129.6, 141.6, 141.8, 142.1, 153.1, 212.2; HRMS calcd
for C19H25NO3S (M + Na) 370.1453, found 370.1449.
(R)-(-)-N-(Butylidene)-p-toluenesulfinamide (17). In a 250 mL,
one-necked, round-bottomed flask equipped with magnetic stirring bar
and argon balloon was placed 3.0 g (19.3 mmol) of (R)-(-)-p-
toluenesulfinamide (Aldrich) in dichloromethane (100 mL). To this
solution were added 1.73 mL (19.3 mmol) of butyraldehyde and 20.3
mL (96.6 mmol) of titanium tetraethoxide at room temperature. The
reaction mixture was stirred for 3 h and poured into a 500 mL beaker
containing 80 mL of an ice-water mixture, and the solution was
vigorously stirred for 10 min. At this time dichloromethane (50 mL)
was added and the solution was extracted with dichloromethane (2 ×
50 mL). The combined organic phases were dried (Na2SO4) and
anti-(SS,1R,2S)-(+)-N-(p-Toluenesulfinyl)-1-amino-2-ethyl-1-(2-
furyl)hexan-3-one (14b). Purification (20% EtOAc/hexane) afforded
0.021 g (20%) of a colorless oil: [R]20 +94.6 (c 1.14, CHCl3); IR
D
1
(neat) 3192, 2964, 1709 cm-1; H NMR (CDCl3) δ 0.79 (t, J ) 7.5
Hz, 3 H), 0.80 (t, J ) 7.5 Hz, 3 H), 1.46 (m, 3 H), 1.59 (m, 1 H), 2.16
(dt, J ) 17.6, 7.1 Hz, 1 H), 2.28 (dt, J ) 17.6, 7.3 Hz, 1 H), 2.41 (s,
3 H), 2.95 (dt, J ) 7.6, 6.0 Hz, 1 H), 4.57 (dd, J ) 6.0, 7.7 Hz, 1 H),
5.27 (d, J ) 7.7 Hz, 1 H), 6.28 (d, J ) 3.3 Hz, 1 H), 6.34 (dd, J ) 1.8,
3.3 Hz, 1 H), 7.30 (d, J ) 8.0 Hz, 2 H), 7.37 (d, J ) 1.8 Hz, 1 H),
7.56 (d, J ) 8.0 Hz, 2 H); 13C NMR (CDCl3) δ 11.7, 13.6, 16.5, 21.4,
22.6, 46.3, 53.0, 55.9, 108.0, 110.6, 125.7, 129.6, 141.4, 141.8, 142.0,
154.0, 214.1; HRMS calcd for C19H25NO3S (M + Na) 370.1452, found
370.1454.
concentrated under vacuum to give 3.4 g (84%) of a colorless oil: [R]20
D
-385.4 (c 0.6, CHCl3); IR (neat) 2961, 2873, 1620 cm-1; H NMR
1
(CDCl3) δ 0.94 (t, J ) 7.6 Hz, 3 H), 1.64 (m, 2 H), 2.39 (s, 3 H), 2.46
(m, 2 H), 7.30 (d, J ) 7.6 Hz, 2 H), 7.56 (d, J ) 7.6 Hz, 2 H), 8.22
(t, J ) 4.9 Hz, 1 H); 13C NMR (CDCl3) δ 13.8, 19.0, 21.6, 38.0, 124.7,
130.0, 141.8, 142.1, 167.3; HRMS calcd for C11H15NOS (M + H)
(35) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang,
H. J. Org. Chem. 1999, 64, 1403.
9
8404 J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005

R-Substituted
â-Amino Ketones from Sulfinimines
A R T I C L E S
(SS,5R,6R)-(+)-N-(p-Toluenesulfinyl)-6-amino-5-ethylnonan-4-
washed with saturated NaHCO3 (2 × 5 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic phases were dried (Na2SO4) and
concentrated. Column chromatography (10% EtOAc/hexane, 1% Et3N)
one (13c). Purification (20% EtOAc/hexane) afforded 0.063 g (65%)
of a colorless oil: [R]20D +63.7 (c 0.67, CHCl3); IR (neat) 3214, 2960,
1702 cm-1; 1H NMR (CDCl3) δ 0.83 (t, J ) 7.5 Hz, 3 H), 0.88 (t, J )
7.5 Hz, 3 H), 0.95 (t, J ) 7.5 Hz, 3 H), 1.37 (m, 1 H), 1.48-1.71 (m,
7 H), 2.35 (m, 2 H), 2.41 (s, 3 H), 2.63 (dt, J ) 9.0, 5.0 Hz, 1 H), 3.48
(m, 1 H), 4.13 (d, J ) 7.5 Hz, 1 H), 7.30 (d, J ) 7.8 Hz, 2 H), 7.57
(d, J ) 7.8 Hz, 2 H); 13C NMR (CDCl3) δ 12.2, 13.9, 14.0, 16.9, 19.8,
21.2, 21.6, 35.1, 46.0, 55.8, 57.7, 125.7, 129.7, 141.5, 142.7, 213.6;
HRMS calcd for C18H29NO2S (M + Na) 346.1816, found 346.1821.
(SS,5R,6R)-(+)-N-(p-Toluenesulfinyl)-6-amino-5-ethylnonan-4-
one (14c). Purification (20% EtOAc/hexane) afforded 0.026 g (21%)
of a colorless oil: [R]20D +107.7 (c 0.96, CHCl3); IR (neat) 3214, 2963,
1704 cm-1; 1H NMR (CDCl3) δ 0.83 (t, J ) 7.1 Hz, 3 H), 0.87 (t, J )
7.6 Hz, 3 H), 0.92 (t, J ) 7.4 Hz, 3 H), 1.33-1.57 (m, 7 H), 1.66 (m,
1 H), 2.35 (m, 2 H), 2.41 (s, 3 H), 2.55 (m, 1 H), 3.41 (m, 1 H), 5.05
(d, J ) 8.6 Hz, 1 H), 7.29 (d, J ) 8.2 Hz, 2 H), 7.60 (d, J ) 8.2 Hz,
2 H); 13C NMR (CDCl3) δ 12.4, 13.7, 13.9, 16.7, 19.8, 21.4, 21.8,
37.6, 46.8, 55.8, 56.4, 125.7, 129.5, 141.2, 142.6, 215.0; HRMS calcd
for C18H29NO2S (M + Na) 346.1816, found 346.1821.
afforded 0.041 g (15%) of a pale brown oil: [R]20 +65.6 (c 0.6,
D
CHCl3); IR (neat), 2956, 1705 cm-1; 1H NMR (CDCl3) δ 0.81 (t, J )
7.6 Hz, 3 H), 0.88 (t, J ) 7.4 Hz, 3 H), 0.91 (t, J ) 7.4 Hz, 3 H),
1.24-1.37 (m, 3 H), 1.43 (m, 2 H), 1.61 (m, 3 H), 1.85 (m, 1 H), 2.25
(m, 2 H), 2.90 (m, 1 H), 3.05 (dd, J ) 8.1, 10.6 Hz, 1 H), 4.03 (d, J
) 5.3 Hz, 2 H), 4.53 (m, 2 H), 5.70-5.82 (m, 2 H), 7.25-7.39 (m, 5
H); 13C NMR (CDCl3) δ 11.5, 12.5, 14.3, 18.0, 18.2, 19.4, 35.0, 53.5,
57.2, 59.7, 64.9, 70.3, 72.6, 127.8, 127.9, 128.6, 130.0, 134.0, 138.3,
213.6; HRMS calcd for C22H33NO2 (M + H) 344.2589, found 344.2594.
(5R,6S,8S,8aS)-(+)-6,8-Diethyl-hexahydro-5-propylindolizin-7(1H)-
one (22). In a 50 mL, one-necked, round-bottomed flask equipped with
magnetic stirring bar was placed 0.030 g (0.09 mmol) of 21 in
anhydrous methanol (5 mL). Wet 10% Pd/C (0.05 g) was slowly added
to the solution, the reaction vessel was evacuated, and an H2 balloon
was attached. After stirring at room temperature for 8 h, the solution
was filtered through a pad of Celite, and the filter cake was washed
with methanol (2 × 5 mL). The filtrate was concentrated to give 0.020
g of the crude alcohol. The alcohol was dissolved in dichloromethane
(5 mL) and transferred into a 25 mL, one-necked, round-bottom flask
equipped with a magnetic stirring bar. The solution was cooled to 0
°C, and 0.039 g (0.12 mmol) of CBr4 and 0.041 g (0.16 mmol) of
triphenyl phosphine were added. The reaction mixture was warmed to
room temperature and stirred for 2 h, and 0.033 mL (0.24 mmol) of
triethylamine was added. The reaction mixture was stirred for 0.5 h,
washed with aqueous saturated NaHCO3 (5 mL), and extracted with
dichloromethane (2 × 5 mL). The combined organic phases were dried
(Na2SO4) and concentrated. Chromatography (10% EtOAc/0.5% Et3N/
(RS,5S,6R)-(-)-N-(p-Toluenesulfinyl)-6-amino-5-ethylnonan-4-
one (19). In a 500 mL, one-necked, round-bottomed flask equipped
with a magnetic stirring bar and argon balloon was placed diethyl ether
(150 mL), the solution was cooled to -78 °C, and 23.6 mL (23.6 mmol)
of LiHMDS (1.0 M solution in THF) was added. After 10 min 3.0 mL
(21.5 mmol) of 12 was added via syringe and the reaction mixture
was stirred for 1 h. In a separate 500 mL, one-necked, round-bottomed
flask equipped with magnetic stirring bar and argon balloon was placed
1.50 g (7.16 mmol) of sulfinimine (R)-(-)-17 in diethyl ether (40 mL),
and the solution was cooled to -78 °C. At this time the preformed
lithium enolate was added via cannula to the sulfinimine over 30 min,
the solution was stirred for 1 h, and then the reaction was quenched
at this temperature by addition of saturated NH4Cl (30 mL) and H2O
(60 mL). The solution was extracted with EtOAc (2 × 50 mL), and
the combined organic phases were dried (Na2SO4) and concentrated.
On chromatography (8%, EtOAc/hexane), the first to elute was
hexane) gave 0.015 g (71%) of a colorless oil: [R]20 +10.5 (c 0.56,
D
1
CHCl3); IR (neat) 2960, 1711 cm-1; H NMR (CDCl3) δ 0.78 (t, J )
7.7 Hz, 3 H), 0.91 (t, J ) 7.2 Hz, 3 H), 0.92 (t, J ) 7.1 Hz, 3 H), 1.16
(m, 1 H), 1.29 (m, 2 H), 1.47-1.72 (m, 6 H), 1.81-2.03 (m, 5 H),
2.22 (m, 1 H), 2.27 (br, 1 H), 2.38 (m, 1 H), 3.17 (m, 1 H); 13C NMR
δ (CDCl3) 11.3, 12.5, 14.4, 18.6, 18.8, 18.9, 21.4, 30.2, 33.0, 50.8,
54.2, 54.6, 64.8, 70.1, 217.5; HRMS calcd for C15H27NO (M + H)
238.2171, found 238.2169.
(RS,5R,6R)-(-)-18, 0.19 g (21%) of a colorless oil: [R]20 -110.3 (c
D
0.66, CHCl3). Spectral properties were identical to (+)-14. HRMS:
calcd for C18H29NO2S (M + H) 324.2000, found 324.2000.
(5S,6R,6E)-(-)-6-((E)-But-2-enylideneamino)-5-ethylnonan-4-
one (23). In a 100 mL, one-necked, round-bottomed flask equipped
with a magnetic stirring bar and argon balloon was placed 1.75 g (5.4
mmol) of (-)-19 in anhydrous methanol (50 mL). The solution was
cooled to 0 °C, 1.67 mL (21.6 mmol) of TFA was added via syringe,
and the solution was warmed to room temperature and stirred for 2 h.
At this time the solution was concentrated and the crude produce was
subjected to a short silica gel pad elution with 30% EtOAc/hexane to
remove the p-toluenesulfinyl byproducts. Elution with methanol gave
the ammonium triflate salt, which was concentrated and placed in a
100 mL, one-necked, round-bottomed flask equipped with a magnetic
stirring bar and argon balloon. To the flask were added dichloromethane
(50 mL), 1.5 g of anhydrous MgSO4, and 2.24 mL (27.1 mmol) of
crotonaldehyde via syringe. The reaction was mixture stirred at room
temperature for 2 h, the solution concentrated, and the residue washed
with saturated NaHCO3 (20 mL). At this time the solution was extracted
with EtOAc (3 × 20 mL), dried (Na2SO4), and concentrated. Chro-
matography gave 0.45 g (35%) of a colorless oil: [R]20D -38.9 (c 0.62,
CHCl3); IR (neat) 2961, 1707, 1655 cm-1; 1H NMR (CDCl3) δ 0.76 (t,
J ) 7.5 Hz, 3 H), 0.81 (t, J ) 7.3 Hz, 3 H), 0.83 (m, 1 H), 0.92 (t, J
) 7.5 Hz, 3 H), 1.01 (m, 1 H), 1.17 (m, 1 H), 1.31 (m, 1 H), 1.37-
1.49 (m, 3 H), 1.59 (m, 2 H), 1.88 (d, J ) 5.0 Hz, 3 H), 3.37-2.51
(m, 2 H), 3.04 (dt, J ) 2.5, 9.4 Hz, 1 H), 6.22 (m, 2 H), 7.73 (m, 1 H);
13C NMR (CDCl3) δ 11.5, 13.7, 13.8, 16.6, 18.4, 19.7, 23.1, 36.1, 47.6,
58.5, 72.0, 131.7, 141.0, 162.5, 214.4; HRMS calcd for C15H27NO (M
+ H) 238.2171, found 238.2168.
The second to elute was syn-19, 1.81 g (78%) as a colorless oil:
[R]20D -64.9 (c 0.67, CHCl3). Spectra properties were identical to (+)-
13c. HRMS: calcd for C18H29NO2S (M + Na) 346.1817, found
346.1826.
(2S,3S,5S,6R)-(+)-2-((E)-3-(Benzyloxy)prop-1-enyl)-3,5-diethyl-
6-propylpiperidin-4-one (21). In a 50 mL, one-necked, round-bottomed
flask equipped with a magnetic stirring bar and argon balloon was
placed 0.29 g (0.9 mmol) of (-)-19 in of anhydrous methanol (15 mL).
The solution was cooled to 0 °C, and 0.28 mL of TFA (3.6 mmol) was
added via syringe. After warming to room temperature the solution
was stirred for 2 h, the solution concentrated, and the crude mixture
passed through a short silica gel pad eluting with 30% EtOAc/hexane
to remove the p-toluenesulfinyl byproducts. Elution with methanol gave
the crude ammonium triflate salt, which was concentrated and placed
in a 50 mL, one-necked, round-bottomed flask equipped with a magnetic
stirring bar and argon balloon. Dichloromethane (15 mL) was added
at room temperature followed by addition of 0.16 g (0.9 mmol) of
4-benzyloxylbutenal via syringe, and then 0.5 g of anhydrous MgSO4
was added. The reaction mixture was stirred at room temperature for
2 h, concentrated, and washed with saturated NaHCO3 (8 mL). The
solution was extracted with EtOAc (3 × 5 mL), dried (Na2SO4), and
concentrated to give 0.27 g (88%) of an oil. In a separate 50 mL, one-
necked, round-bottomed flask equipped with a magnetic stirring bar
and argon balloon was placed 0.27 g (0.8 mmol) of the crude imine
and anhydrous benzene (20 mL) was added, followed by 0.33 g (1.6
mmol) of p-toluenesulfonic acid monohydrate. After stirring at room
temperature for 40 h, the solvent was concentrated and the residue was
(2S,3S,5S,6R)-(+)-3,5-Diethyl-2-((E)-prop-1-enyl)-6-propylpiperi-
din-4-one (24). In a 250 mL, one-necked, round-bottomed flask
9
J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005 8405

A R T I C L E S
Davis and Yang
equipped with a magnetic stirring bar and argon balloon was placed
1.28 g (5.41 mmol) of crude imine 23. Anhydrous benzene (120 mL)
and 2.06 g (10.8 mmol) of p-toluenesulfonic acid monohydrate were
added. After stirring for 40 h, the solution was concentrated, and the
residue was washed with saturated NaHCO3 solution. The solution was
next extracted with EtOAc (3 × 20 mL), and the combined organic
phases were dried (Na2SO4) and concentrated. Column chromatography
(10% EtOAc/hexane, 1% Et3N) afforded 0.74 g (58% from (-)-19) of
) 6.5, 1.4 Hz, 3 H), 1.82 (m, 1 H), 2.09 (ddd, J ) 4.7, 6.1, 9.0 Hz, 1
H), 2.20 (dt, J ) 3.5, 8.5 Hz, 1 H), 3.01 (dt, J ) 4.0, 8.5 Hz, 1 H),
3.26 (t, J ) 8.2 Hz, 1 H), 5.44 (m, 1 H), 5.59 (dq, J ) 6.5, 15.1 Hz,
1 H); 13C (CDCl3) NMR δ 12.0, 12.2, 14.0, 17.8, 19.3, 19.4, 23.7,
35.3, 54.3, 57.2, 57.5, 59.2, 128.1, 132.7, 213.7; HRMS calcd for
C15H27NO (M + H) 238.2171, found 238.2180.
(2S,3S,5R,6R)-(+)-3,5-Diethyl-2-((E)-prop-1-enyl)-6-propylpiperi-
din-4-one (26) from (+)-24. In a 50 mL, one-necked, round-bottomed
flask equipped with a magnetic stirring bar was placed 0.12 g of sodium
(previously washed with hexane), and anhydrous MeOH (6 mL) was
slowly added. The solution was stirred at room temperature for 1 h,
and 0.10 g of (+)-24 (0.42 mmol) was added. The solution was stirred
at 65 °C for 24 h and concentrated, and the residue was treated with
H2O (2 mL). The solution was extracted with EtOAc (3 × 3 mL), and
the combined organic phases were dried (Na2SO4) and concentrated.
Chromatography (10% EtOAc/hexane, 1% Et3N) afforded 0.055 g
(55%) of a colorless oil identical in all respects to (+)-26 prepared
previously (see above).
a colorless oil: [R]20 +54.8 (c 0.73, CHCl3); IR (neat) 3332, 2960,
D
1706 cm-1; 1H NMR δ (CDCl3) 0.79 (t, J ) 7.5 Hz, 3 H), 0.86 (t, J )
7.5 Hz, 3 H), 0.90 (t, J ) 7.5 Hz, 3 H), 1.23-1.35 (m, 4 H), 1.42 (m,
2 H), 1.59 (m, 2 H), 1.69 (dd, J ) 6.5, 1.7 Hz, 3 H), 1.82 (m, 1 H),
2.21 (m, 2 H), 2.86 (dt, J ) 3.2, 6.8 Hz, 1 H), 2.95 (dd, J ) 8.4, 10.3
Hz, 1 H), 5.42 (m, 1 H), 5.62 (dq, J ) 6.5, 15.1 Hz, 1 H); 13C NMR
(CDCl3) δ 11.4, 12.5, 14.2, 17.8, 18.11, 18.13, 19.4, 35.0, 53.7, 57.2,
59.5, 65.5, 128.8, 132.5, 213.9; HRMS calcd for C15H27NO (M + H)
238.2171, found 238.2170.
(2R,3S,5S,6R)-(+)-3,5-Diethyl-2-((E)-prop-1-enyl)-6-propylpiperi-
din-4-one (25). This compound was second to elute; 0.19 g (18% from
(2S,3S,5S,6R)-(+)-1-Allyl-3,5-diethyl-2-((E)-prop-1-enyl)-6-pro-
pylpiperidin-4-one (28). In a 100 mL, one-necked, round-bottomed
flask equipped with a magnetic stirring bar and condenser was placed
0.42 g (1.76 mmol) of (+)-24 in anhydrous EtOH (30 mL). To the
reaction mixture were added allyl bromide (1.53 mL) and anhydrous
solid Na2CO3 (2.8 g), and the reaction mixture was refluxed for 6 h.
At this time the solution was cooled to room temperature, filtered, and
concentrated. Water (10 mL) was added to the residue, and the solution
was extracted with dichloromethane (3 × 15 mL). The combined
organic phases were dried (Na2SO4) and concentrated. Chromatography
(-)-19) of a colorless oil: [R]20 +62.7 (c 1.31, CHCl3); IR (neat)
D
3336, 2960, 1705 cm-1; 1H NMR (CDCl3) δ 0.85-1.00 (m, 9 H), 1.20-
1.92 (m, 12 H), 2.47 (dt, J ) 5.3, 4.6 Hz, 1 H), 2.60 (dt, J ) 8.4, 5.8
Hz, 1 H), 3.31 (m, 1 H), 3.78 (d, J ) 5.5, 8.1 Hz, 1 H), 5.52 (m, 1 H),
5.67 (dq, J ) 15.2, 6.2 Hz, 1 H); 13C (CDCl3) NMR δ 11.70, 11.73,
14.1, 18.0, 18.4, 19.1, 19.2, 32.7, 54.2, 55.5, 55.6, 59.8, 128.4, 128.8,
214.6; HRMS calcd for C15H27NO (M + H) 238.2170, found 238.2181.
(2S,3S,5R,6R)-(+)-3,5-Diethyl-2-((E)-prop-1-enyl)-6-propylpiperi-
din-4-one (26). In a 100 mL, one-necked, round-bottomed flask
equipped with a magnetic stirring bar and argon balloon was placed
0.38 g (1.2 mmol) of (-)-18 in anhydrous methanol (20 mL). The
solution was cooled to 0 °C, and 0.36 mL of TFA (4.7 mmol) was
added via syringe. After warming to room temperature the reaction
mixture was stirred for 2 h, the solution was concentrated, and the
crude product was passed through a short silica gel pad eluting with
30% EtOAc/hexane to remove the p-toluenesulfinyl byproducts. Elution
with methanol gave the ammonium triflate salt, which was concentrated
and placed in a 100 mL, one-necked, round-bottomed flask equipped
with a magnetic stirring bar and argon balloon. Dichloromethane (20
mL) was added at room temperature followed by the addition of 0.46
mL (5.7 mmol) of crotonaldehyde via syringe. Anhydrous MgSO4, 1.5
g was added, and the reaction mixture was stirred at room temperature
for 2 h, concentrated, and washed with saturated NaHCO3 (15 mL).
The solution was extracted with EtOAc (3 × 10 mL), dried (Na2SO4),
and concentrated to give 0.26 g (93%) of the crude imine as a colorless
oil. In a separate 100 mL, one-necked, round-bottomed flask equipped
with a magnetic stirring bar and argon balloon was place the crude
imine, and anhydrous benzene (40 mL) was added, followed by 0.39
g (2.31 mmol) of p-toluenesulfonic acid monohydrate. After stirring
at room temperature for 40 h, the solvent was concentrated, the residue
was washed with saturated NaHCO3 (2 × 8 mL), and the organic phase
was extracted with EtOAc (3 × 8 mL). The combined organic phases
were dried (Na2SO4) and concentrated. Column chromatography (10%
EtOAx/hexane, 1% Et3N) afford 0.18 g (65%, from (-)-18) of a
colorless oil: [R]20D +19.4 (c 2.28, CHCl3); IR (neat) 3334, 2959, 1708
(6% EtOAc/hexane) afforded 0.44 g (91%) of a colorless oil: [R]20
D
+85.4 (c 0.56, CHCl3); IR (neat) 2961, 1715 cm-1; 1H NMR (CDCl3)
δ 0.81 (t, J ) 7.4 Hz, 3 H), 0.85 (t, J ) 7.5 Hz, 3 H), 0.87 (t, J ) 7.3
Hz, 3 H), 1.21-1.38 (m, 5 H), 1.53 (m, 1 H), 1.65 (m, 1 H), 1.72 (dd,
J ) 6.5, 1.5 Hz, 3 H), 1.86 (m, 1 H), 2.17 (ddd, J ) 4.0, 7.2, 10.0 Hz,
1 H), 2.47 (ddd, J ) 4.8, 5.8, 10.5 Hz, 1 H), 2.90 (m, 1 H), 3.18 (t, J
) 9.3, 1 H), 3.36 (m, 2 H), 5.11-5.24 (m, 3 H), 5.51 (dq, J ) 15.4,
6.5 Hz, 1 H), 5.84-5.92 (m, 1 H); 13C NMR (CDCl3) δ 11.1, 11.8,
14.4, 17.7, 18.7, 19.6, 20.6, 34.5, 52.7, 53.3, 54.5, 59.9, 65.3, 117.8,
128.2, 132.9, 134.3, 214.2; HRMS calcd for C18H31NO (M + H)
278.2484, found 278.2476.
(5R,6S,8S,8aS)-(+)-6,8-Diethylhexahydro-5-propylindolizin-7(1H)-
one (22) via RCM. In a 100 mL, one-necked, round-bottomed flask
equipped with a magnetic stirring bar and argon balloon were placed
0.22 g of (+)-28 and dichloromethane (30 mL). To the solution was
added 0.032 g (5 mol %) of the Grubbs “first generation” catalyst, and
the solution was refluxed for 2 h. At this time the solution was
concentrated, anhydrous methanol (20 mL) was added, followed by
0.050 g of 10% Pd/C, and the argon balloon was replaced by a
hydrogen-filled balloon. The reaction mixture was stirred at room
temperature for 4 h, the solution was filtered through a Celite pad, and
the pad was washed with methanol (3 × 10 mL). The solution was
concentrated, and the residue was purified by column chromatography
(1% Et3N, 15% EtOAc/hexane) to afford 0.135 g (71%) of a colorless
oil identical in all respects to (+)-22 prepared previously (see above).
(5R,6S,7S,8S,8aS)-(+)-6,8-Diethyloctahydro-5-propylindolizin-7-
ol (29). In a 50 mL, one-necked, round-bottomed flask equipped with
a magnetic stirring bar and argon balloon was placed 0.10 g (0.42 mmol)
of (+)-22 in anhydrous MeOH (20 mL). The solution was cooled to
-78 °C, and 0.024 g (0.63 mmol) of NaBH4 was added. After 2 h the
reaction mixture was warmed to room temperature and concentrated.
To the residue was added water (10 mL), the solution was extracted
with dichloromethane (3 × 15 mL), and the combined organic phases
were dried (Na2SO4) and concentrated. Chromatography (1% Et3N, 30%
EtOAc/hexane) afforded 0.9 g (90%) of a white solid: mp 121-122
°C; [R]20D +56.5 (c 0.69, CHCl3); IR (neat) 3331, 2951 cm-1; 1H NMR
(CDCl3) δ 0.85 (t, J ) 7.3 Hz, 6 H), 0.94 (t, J ) 7.6 Hz, 3 H), 1.12
(m, 1 H), 1.28-1.85 (m, 16 H), 1.91 (b, 1 H), 3.03 (m, 1 H), 3.47 (dd,
1
cm-1; H NMR (CDCl3) δ 0.86 (t, J ) 7.2 Hz, 3 H), 0.89 (t, J ) 7.3
Hz, 3 H), 0.93 (t, J ) 7.4 Hz, 3 H), 1.29-1.68 (m, 9 H), 1.71 (dd, J
) 1.4, 6.4 Hz, 3 H), 2.12 (m, 2 H), 2.63 (m, 1 H), 3.00 (dd, J ) 8.6,
10.3 Hz, 1 H), 5.43 (m, 1 H), 5.62 (dq, J ) 6.4, 15.4 Hz, 1 H); 13C
NMR δ (CDCl3) 12.1, 12.3, 14.2, 17.7, 17.8, 18.5, 18.7, 36.4, 57.6,
57.7, 60.6, 65.2, 128.7, 132.5, 211.1; HRMS calcd for C15H27NO (M
+ H) 238.2171, found 238.2163.
(2R,3R,5R,6R)-(-)-3,5-Diethyl-2-((E)-prop-1-enyl)-6-propylpip-
eridin-4-one (27). Second to elute, 0.5 g (18% from (-)-18) of a
colorless oil; [R]20D -57.6 (c 1.06, CHCl3); IR (neat) 3334, 2960, 1704
1
cm-1; H NMR (CDCl3) δ 0.86 (t, J ) 7.2 Hz, 3 H), 0.87 (t, J ) 7.3
Hz, 3 H), 0.91 (t, J ) 7.1 Hz, 3 H), 1.24-1.67 (m, 8 H), 1.69 (dd, J
9
8406 J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005

R-Substituted
â-Amino Ketones from Sulfinimines
A R T I C L E S
J ) 4.9, 10.5 Hz, 1 H); 13C NMR (CDCl3) δ 10.6, 14.8, 17.1, 17.6,
20.1, 21.2, 21.5, 29.3, 33.6, 44.3, 45.5, 51.6, 65.8, 68.0, 76.6; HRMS
calcd for C15H29NO (M + H) 238.2171, found 238.2166.
and extracted with dichloromethane (3 × 10 mL), and the combined
organic phases were dried (Na2SO4) and concentrated. Chromatography
afforded 0.057 g (55%) of a pale yellow oil: [R]20 -3.6 (c 0.88,
D
(5R,6S,7S,8S,8aS)-(+)-6,8-Diethyloctahydro-5-propylindolizin-7-
yl Methanesulfonate (30). In a 25 mL, one-necked, round-bottomed
flask equipped with a magnetic stirring bar and argon balloon was
placed 0.024 g (0.1 mmol) of (+)-29 in dichloromethane (5 mL). To
the solution were added 0.031 mL (0.4 mmol) of methanesulfonyl
chloride and 0.055 mL (0.4 mmol) of triethylamine, and the reaction
mixture was stirred at room temperature for 4 h. At this time the reaction
was quenched by addition of saturated NaHCO3 (1 mL) and water (5
mL). The solution was extracted with dichloromethane (2 × 3 mL),
and the organic phases were combined, dried (Na2SO4), and concen-
trated. Chromatography (1% Et3N, 15% EtOAc/hexane) afforded 0.021
CHCl3); IR (neat) 2959, 1255, 1201 cm-1; 1H NMR (CDCl3) δ 0.91-
1.05 (m, 9 H), 1.20-1.99 (m, 15 H), 2.10 (br, 1 H), 2.28 (br, 1 H),
3.11 (br, 1 H), 5.21 (dd, J ) 5.0, 11.1 Hz, 1 H), 7.08-7.47 (m, 5 H);
13C NMR (CDCl3) δ 10.3, 14.4, 15.8, 17.6, 19.6, 21.06, 21.09, 28.9,
33.2, 40.2, 41.8, 51.1, 64.5, 67.5, 89.4, 122.1, 126.5, 129.5, 153.4, 194.7;
HRMS calcd for C22H33NO2S (M - H) 374.2154, found 374.2161.
Alkaloid (-)-223A (9) DCl Salt. In a 50 mL, two-necked, round-
bottomed flask equipped with a magnetic stirring bar and condenser
was placed 0.04 g (0.11 mmol) of (-)-31 in benzene (25 mL). Argon
was bubbled through the solution for 10 min, and 0.085 mL (0.53 mmol)
of tributyltinhydride and 0.005 g of AIBN were added to the solution.
The reaction mixture was refluxed for 4 h and concentrated, and the
residue was treated with 5 mL of 2 N potassium fluoride in dichlo-
romethane (10 mL). After stirring for 20 min the mixture was extracted
with dichloromethane (3 × 5 mL), and the combined organic phases
were dried (Na2SO4) and concentrated. Chromatography (3% Et3N, 15%
EtOAc/hexane) afforded 0.018 g (74%) of a colorless volatile oil. To
the oil was added 1 mL of DCl in diethyl ether solution (1.0 N), and
the solution was shaken and concentrated to give 0.02 g (74%) of a
colorless oil: [R]20D -36.8 (c 0.45, CHCl3) [lit.12a [R]25D -40.9 (c 0.25,
CHCl3); lit.12b [R]15D -38.4 (c 0.3, CHCl3)]; 1H NMR (CDCl3) δ 0.82-
0.89 (m, 9 H), 1.10-1.21 (m, 4 H), 1.30-1.73 (m, 7 H), 1.82-2.00
(m, 3 H), 2.06 (dd, J ) 13.2, 2.5 Hz, 1 H), 2.28 (m, 1 H), 2.84 (dt, J
) 18.0, 6.2 Hz, 1 H), 2.95 (q, J ) 9.0 Hz, 1 H), 3.15 (dt, J ) 15.0, 3.8
Hz, 1 H), 3.58 (m, 1 H); 13C NMR (D2O) δ 9.5, 11.2, 12.8, 16.6, 17.5,
18.3, 24.4, 26.5, 29.6, 29.8, 35.2, 35.3, 51.2, 66.4, 72.0. The 1H NMR
and 13C NMR spectra data were consistent with the literature values.12
g (67%) of a colorless oil: [R]20 +17.9 (c 0.56, CHCl3); IR (neat)
D
2962, 2875, 1458 cm-1; 1H NMR (CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3 H),
0.93 (t, J ) 7.8 Hz, 3 H), 1.02 (t, J ) 7.3 Hz, 3 H), 1.17-2.12 (m, 17
H), 3.04 (s, 3 H), 3.09 (m, 1 H), 4.61 (dd, J ) 5.0, 10.9 Hz, 1 H); 13
C
NMR (CDCl3) δ 10.1, 14.6, 16.1, 17.6, 19.9, 21.0, 21.2, 29.1, 33.3,
39.1, 42.4, 42.5, 43.8, 51.1, 65.0, 67.6; HRMS calcd for C16H31NO3S
(M - H) 316.1946, found 316.1939.
Lithium Ammonia Reduction of (5R,6S,7S,8S,8aS)-(+)-30. In a
50 mL, two-necked, round-bottomed flask equipped with a magnetic
stirring bar, argon balloon, and ammonia dry ice condenser cooled to
-78 °C in a dry ice/acetone bath was collected about 5 mL of liquid
ammonia. Approximately 0.10 g (14 mmol) of lithium wire cut into
pieces was added to the solution, and the mixture was stirred until the
lithium was completely dissolved (15 min). Mesylate (+)-30 (0.010 g,
0.03 mmol) in THF (0.5 mL) was added dropwise, and the solution
was stirred at -78 °C for 30 min. At this time the reaction mixture
was quenched by addition of 0.002 g of solid NH4Cl. After evaporation
of the ammonia, the mixture was partitioned between saturated NaHCO3
(5 mL) and ether (5 mL), and the aqueous phase was extracted with
ether (2 × 5 mL). The combined organic phases were dried (Na2SO4)
and concentrated. Chromatography (20% EtOAc/hexane) afforded 0.05
g (71%) of alcohol (+)-29.
O-(5R,6S,7S,8S,8aS)-(-)-Indolizidine Carbonothioate (31). In a
50 mL, one-necked, round-bottomed flask equipped with a magnetic
stirring bar and argon balloon was placed 0.072 g (0.30 mmol) of (+)-
29 in dichloromethane (20 mL). To the solution was added 0.20 mL
(1.8 mmol) of pyridine, and the solution was cooled to 0 °C. To the
solution was added 0.20 mL (1.5 mmol) of phenyl chlorothionoformate,
and the reaction was warmed to room temperature and stirred for 24 h.
At this time the reaction was quenched by addition of water (15 mL)
Acknowledgment. We thank Professor David B. Collum,
Cornell University, for meaningful discussions on enolate
chemistry and Dr. Charles DeBrosse, Director of NMR facilities,
for aid in running NMR experiments. This work was support
by a grant from the National Institute of General Medical
Sciences (NIH GM 51982).
Supporting Information Available: Compound characteriza-
1
tion data and H and 13C NMR data available for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA051452K
9
J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005 8407