Diastereoselectivities realized in the amino acid catalyzed aldol cyclizations of triketo acetonides of differing ring size

Article abstract of DOI:10.1021/jo0486084

(Chemical Equation Presented) A study designed to assess the diastereoselectivity of the intramolecular aldol reaction of two differently sized monocyclic 1,3-diketones bearing a chiral, oxygenated side chain has been undertaken. The cyclizations were bro

Full text of DOI:10.1021/jo0486084

Diastereoselectivities Realized in the Amino Acid Catalyzed Aldol
Cyclizations of Triketo Acetonides of Differing Ring Size
Kohei Inomata,† Matthieu Barrague´,‡ and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received August 10, 2004
A study designed to assess the diastereoselectivity of the intramolecular aldol reaction of two
differently sized monocyclic 1,3-diketones bearing a chiral, oxygenated side chain has been
undertaken. The cyclizations were brought about under catalysis by pyrrolidine, a series of D- and
L-amino acids including proline, and several proline derivatives. The levels of selectivity were found
to be consistently higher with the six-membered ring system than its cycloheptane counterpart.
In the mid-to-early 1970s, the capability of L-(-)-
proline to promote the intramolecular aldolization of
prochiral triketones 1 in a highly enantioselective man-
ner gained considerable recognition.1,2 Progression from
these discoveries saw the Hajos-Parrish ketone (2a)3 and
the Wieland-Miescher homologue 2b4 adopted as enan-
tioenriched starting materials for numerous targeted
syntheses. Beyond this, catalysis of the Robinson annu-
lation by D-(+)-proline has been implemented as war-
ranted.5 Also to come under intense scrutiny were the
mechanistic details of this asymmetric transformation.
Presently, enamine intermediates are recognized to be
involved,6 with C-C bond formation serving as the rate-
determining step.7
Bicyclic ketones related to 2b but carrying an oxygen-
ated angular methyl group have been elaborated by
means of related protocols. These include the ester 38 as
well as the masked hydroxymethyl derivatives 4a-c.9-11
† Permanent address: Tohoku Pharmaceutical University, 4-4-1,
Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
‡ Present address: Aventis Pharmaceuticals, Inc., 1041 U.S. Route
202/206, P.O. Box 6800, Bridgewater, NJ 08807-0800.
(4) (a) Ling, T.; Chowdury, C.; Kramer, B. A.; Vong, B. G.; Palladino,
M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843. (b) Katoh, T.;
Nakatani, M.; Shikita, S.; Sampe, R.; Ishiwata, A.; Ohmori, O.;
Nakamura, M.; Terashima, S. Org. Lett. 2001, 3, 2701. (c) Yajima, A.;
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Palladino, M. A.; Theodorakis, E. A. Org. Lett. 2000, 2, 2073. (e)
Kende, A. S.; Rustenhoven, J. J.; Zimmermann, K. Tetrahedron
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1999, 55, 11001. (g) Paquette, L. A.; Backhaus, D.; Braun, R.;
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Stork, G.; West, F.; Lee, H. Y.; Isaacs, R. C. A., Manabe, S. J. Am.
Chem. Soc. 1996, 118, 10660. (j) Paquette, L. A.; Wang, H.-L. J. Org.
Chem. 1996, 61, 5352. (k) Dzierba, C. D.; Zandi, K. S.; Moellers, T.;
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1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38,
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Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland, L. A.;
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(3) For recent examples, consult: (a) Di Filippo, M.; Izzo, I.; Vece,
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Lajunen, M.; Koskinen, A. J. Chem. Soc., Perkin Trans. 1 2000, 1439.
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10.1021/jo0486084 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/17/2004
J. Org. Chem. 2005, 70, 533-539
533

Inomata et al.
In connection with an ongoing synthetic project, we had
need to prepare quantities of the enantiomerically pure
diketo acetonides 6a and 6b. The presence of a stereo-
defined stereogenic center in 5 allowed for examination
of the contribution of this quite remote site on product
diastereoselection as defined by the ratio of 6/7. Our
FIGURE 1. Amino acids screened as catalysts.
FIGURE 2. Proline derivatives involved in this study.
SCHEME 1
expectation was that contributions from the acetonide
moiety to partitioning between the two competing cy-
clization events would be low. On the other hand,
catalysis studies involving amino acids of varying type
(Figure 1) and substituted proline derivatives (Figure
2)12,13 were expected to shed light on the potential for
diastereocontrol of the ring formation. Pyrrolidine-like
secondary amines such as 20-23 are recognized to be
capable of acting as serviceable catalysts in asymmetric
aldol reactions.14,15 The recent example of efficient enan-
tioselective cyclization of 8 as promoted by the L-proline
derivative 20 has been reported by Iwabuchi16 (Scheme
1). The remarkable effect of p-toluenesulfonic acid as a
co-additive for production of the R-substituted Wieland-
Miescher ketone 11 also prompted us to explore Shiba-
saki’s conditions.17
Results and Discussion
Knoevenagel-type condensation of commercially avail-
able 24a or 1,3-cycloheptanedione (24b)18 with enan-
tiopure D-glyceraldehyde acetonide19 in the presence of
silica gel and an excess of thiophenol in dichloromethane
or benzene furnished diketones 25a and 25b, respec-
tively, in good yield (Scheme 2). The thiophenol was
necessary to thwart 2-fold addition of the 1,3-diketones
to aldehyde 19.20 NMR data showed evidence of good
(6) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
12911. (b) Gathergood, N. Austr. J. Chem. 2002, 55, 615. (c) Agami,
C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987, 358. (d) Agami,
C.; Puchot, C. J. Mol. Catal. 1986, 38, 341. (e) Agami, C. Bull. Soc.
Chim. Fr. 1998, 499. (f) Agami, C.; Sevestre, H. J. Chem. Soc., Chem.
Commun. 1984, 1385. (g) Agami, C.; Puchot, C.; Sevestre, H. Tetra-
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D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 29,
3108.
(7) (a) Reymond, J. L. J. Mol. Catal. B 1998, 5, 331. (b) Clemente,
F. R.; Houk, K. N. Angew. Chem., Int. Ed. 2004, 43, 5766.
(8) Lavalee, J. F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslongchamps,
P. Can. J. Chem. 1992, 70, 1406.
(9) Tamai, T.; Mizutani, Y.; Hagiwara, H.; Uda, H.; Harada, N. J.
Chem. Res., Synop. 1985, 148; J. Chem. Res., Miniprint 1985, 1746.
(10) Hamilton, R. J.; Mander, L. N.; Sethi, S. P. Tetrahedron 1986,
42, 2881.
(11) Hanselmann, R.; Benn, M. Synth. Commun. 1996, 26, 945.
(12) Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem. 1991, 5, 2787.
(13) Ohtake, H.; Imada, Y.; Murahashi, S. Bull. Chem. Soc. Jpn.
1999, 72, 2737.
(14) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395.
(15) Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951.
(16) Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. 2nd
Synposium on Organic Chemistry - The Next Generation, Tokyo,
Japan, June 25-26, 2004, Abstracts, pp 30-31.
(17) Shigehisa, K.; Mizutani, S.; Honzawa, S.; Tozaki, S.; Ohshima,
T.; Shibasaki, M. 124th Annual Meeting of the Pharmaceutical Society
of Japan, Osaka, Japan, March 29-31, 2004. See Abstracts Vol. 2, p
55.
(18) Ragan, J. A.; Makowski, T. W.; Ende, D. J.; Clifford, P. J.;
Young, J. R.; Conrad, A. K.; Eisenbeis, S. A. Org. Proc. Res. Dev. 1998,
2, 379.
(19) Schmid, C. R.; Bryant, J. D. Organic Syntheses; Wiley: New
York, 1998; Collect. Vol. IX, p 450.
534 J. Org. Chem., Vol. 70, No. 2, 2005

Amino Acid Catalyzed Aldol Cyclizations of Triketo Acetonides
SCHEME 2
SCHEME 3
diastereoselectivity in this step, but this issue was not
investigated further. Following the desulfurization of
diketones 25 with Raney nickel, formation of the qua-
ternary center was realized by 1,4-addition to methyl
vinyl ketone in the presence of Triton B.21 The pyrroli-
dine-mediated intramolecular cyclization of 26a and 26b
afforded diastereomeric mixtures of 6 and 7, the composi-
tion of which was ascertained by integration of high-field
1H NMR spectra recorded on CDCl3 solutions of unpu-
rified products. The relevant signals of the olefinic
protons appear at the following chemical shifts: 6a, δ
5.90; 6b, δ 6.06; 7a, δ 5.88; 7b, δ 6.16.
Both diastereomeric pairs proved to be readily sepa-
rated by chromatography on silica gel. The controlled
lithium aluminum hydride reduction of 6b gave rise to
the highly crystalline keto alcohol 27, thus allowing for
unequivocal assignment of absolute configuration by
means of X-ray crystallography. The a and b series were
intercorrelated by chemical means involving expansion
of the saturated ring in 6a. This ketone lent itself
conveniently to the regioselective and stereoselective
addition of trimethylsilyl cyanide22 in the presence of
KCN and 18-crown-623 (Scheme 3). When 28 was subse-
quently reduced with lithium aluminum hydride in THF,
the amino diol 29 was formed (30%) alongside diol 30
(52%). The latter product was obviously generated by
retrogession back to 6a under the reaction conditions
followed by in situ reduction at two sites. An investigation
of conditions that would give rise to heightened levels of
29 was not undertaken. However, the oxidation of 30
with manganese dioxide to furnish exclusively 31 estab-
lished that its diastereomeric composition was due to
nonstereoselective hydride transfer to ring A and not to
ring B.
Diazotization of 29 with sodium nitrite in aqueous
acetic acid24 resulted in the generation of a number of
products. Direct oxidation of the allylic alcohol function-
ality simplified matters to the three-component level.
Following chromatographic separation, it became clear
that 1,2-migration of the quaternary carbon is the
dominant reaction pathway (58% of 32) after generation
of the diazonium ion.25 Epoxide generation as in 33 (19%)
is somewhat less prevalent. Despite the low percent
conversion to 6b, adequate amounts were made available
to link 6a structurally to 6b, thereby confirming all
stereochemical assignments.
The results obtained during the pyrrolidine-induced
aldol cyclizations of 5a and 5b in methanol provided the
first indication that this pair of homologues might well
exhibit distinguishably different chemical responses.
Thus, 5a was transformed under these conditions into a
complex product mixture (entry 1, Table 1). In the second
(20) Paquette, L. A.; Fuchs, K. J. Org. Chem. 1994, 59, 528.
(21) Rajamannar, T.; Palani, N.; Balasubramanian, K. Synth. Com-
mun. 1993, 23, 3095.
(22) (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. Chem.
Commun. 1973, 55; J. Org. Chem. 1974, 39, 914. (b) Lidy, W.;
Sundermeyer, W. Chem. Ber. 1973, 106, 587.
(24) Di Mayo, G.; Tardello, P. A. Tetrahedron 1966, 22, 2069.
(25) Gutsche, C. D.; Redmore, D. Carbocyclic Ring Expansion
Reactions, Academic Press: New York, N. Y. 1968.
(23) Greenlee, W. J.; Hangauer, D. G. Tetrahedron Lett. 1983, 24,
4559.
J. Org. Chem, Vol. 70, No. 2, 2005 535

Inomata et al.
TABLE 1. Asymmetric Aldol Reactions of 5a Involving
Catalysis by Proline Derivative
TABLE 3. Diastereoselective Aldol Reactions of 5b
Involving Catalysis by Pyrrolidine and Select Amino
Acids
catalyst
(equiv)
solvent/
time,
h
yield,a
%
ratio de,c
6a/7ab
%
additive
(equiv)
time, yield,a ratio de,c
entry
1
T (°C)
entry
proline
solvent
h
%
6b/7bb
%
pyrrolidine MeOH/rt
(1:1)
16 complex
mixture
48 34
24 20 (1.1)
25 ent-20 (1.1)
26 21 (1.1)
27 22 (1.1)
28 23 (1.1)
29 ent-23 (1.1)
30 20 (1.1)
31 20 (1.1)
32 20 (1.1)
33 20 (1.1)
34 20 (1.1)
35 20 (1.1)
36 20 (0.2)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
DMF
2.5
1.5
1.5
3.0
2.5
4.0
9.5
5.5
75
71
64
79
66
83
30
60
62
58:42
16
39:62 -22
2
3
4
5
6
7
8
9
13 (0.1)
13 (0.2)
13 (0.2)
20 (0.2)
20 (0.2)
20 (0.2)
20 (0.2)
DMSO/rt
7:93 -86
8:92 -84
10:90 -80
10:90 -80
10:90 -80
8:92 -84
23:77 -54
50:50
53:47
47:53
0
6
-6
DMSO/50 °C 21 52d
MeCN/rt
DMSO/rt
48 8d
48 51
37:63 -26
DMSO/50 °C 16 76
MeCN/rt
DMF/rt
59:41
51:49
50:50
47:53
50:50
50:50
52:48
18
2
0
-6
0
0
4
48 55d
48 66d
48 40
DMSO 1.0
ent-20 (0.2) DMSO/rt
76:24
80:20
52
60
i-PrOH 1.0
PPTS (0.50) DMSO 5.0
PPTS (0.50) MeOH
MeOH
10 ent-20 (0.2) DMSO/50 °C 23 61
53d
17d
71
4.0
7.0
a Isolated yield. b The 6a/7a ratios were determined from the
1H NMR spectra at 300 MHz of the crude products by integration
of the signals due to the olefinic process. c Opposite diastereose-
lection is assigned as minus. d Percent conversion.
a Isolated yield. b The 6b/7b ratios were determined from the
1H NMR spectra at 300 MHz of the crude products by integration
of the signals due to the olefinic process. c Opposite diastereose-
lection is assigned as minus. d Percent conversion.
TABLE 2. Diastereoselective Aldol Reactions of 5b
Involving Catalysis by Pyrrolidine and Select Amino
Acids
pointingly, the associated range of results proved not to
be broadly observed. The data compiled in Table 3
hovered most often around 50:50, on occasion rising to
60:40 (entries 24-33). Close examination of the product
mixtures involving the use of pyridinium p-toluenesul-
fonate as a co-catalyst did not provide any sign of im-
provement.
amino
acids
time, yield,a
ratio
de,c
%
entry
solvent
h
%
6b/7bb
11
12
13
14
15
16
17
18
19
20
21
22
23
pyrrolidine benzene
pyrrolidine MeOH
12
ent-12
ent-12
13
ent-13
14
2.5
0.5
9.0
7.5
60
56
79
75
34
77
51
66
28
75
88
39d
3d
43:57
41:59
38:62
39:61
39:61
47:53
45:55
43:57
31:69
34:66
35:65
27:63
38:62
-14
-18
-24
-22
-22
-6
-10
-14
-38
-32
-30
-46
-24
MeOH
MeOH
DMSO
MeOH
DMF
MeOH
DMSO
MeOH
MeOH
MeOH
MeOH
10
1.5
3.0
8.5
In no cyclization involving 5b could the proportion of
7b be pushed above the 66% mark. For 5a, the aldol
product 7a was often present at a level of 90% or above.
This comparative analysis argues in favor of advancing
to 6b by the highly diastereoselective cyclization of 5a.
If this route is selected, then an improved means for
regiodirected ring expansion requires development. Al-
ternatively, the choice of beginning a campaign to arrive
at 6b from 5b clearly would be facilitated by the discovery
of a superior asymmetric catalyst system suited to
improved transformation into this bicyclic enedione.
Although the proposed mechanism of the title reaction
has enthusiastic supporters,6,26-28 it is not at all apparent
that a direct kinetic link between diastereoselectivity and
ring size can be formulated. In the present examples as
in their simpler structural counterparts, the use of
S-proline directs reaction toward the Si face of the
prochiral carbonyl. Beyond that, while the involvement
of enamines is well supported, the exact nature of the
ensuing chemical events has proven to be more elusive.
Is the inability of a seven-membered ring to adopt a chair
conformation akin to cyclohexyl systems responsible?
Why is the small increase in energy associated with this
ent-14
15
10
6.0
14.5
36
16
17
18
36
a Isolated yield. b The 6b/7b ratios were determined from the
1H NMR spectra at 300 MHz of the crude products by integration
of the signals due to the olefinic process. c Opposite diastereose-
lection is assigned as minus. d Percent conversion.
instance, ring closure occurred with modest efficiency to
deliver a 41:59 mixture of 6b/7b (entry 12, Table 2). The
product distribution remains unaltered in benzene as
solvent (entry 11, Table 2), thereby indicating that the
acetonide subunit is not capable in its own right to
engage in a reasonably useful level of stereochemical
control. However, heightened levels of diastereomeric
bias were noted when the aldol reaction of 5a was
promoted with L-proline (13). Recourse to this cata-
lyst resulted in the observation of 6a/7a ratios of 10:90
in either DMSO or acetonitrile as reaction medium
(entries 2-4). Annulation of the seven-membered ring
as in the case of 6b/7b was not comparably effective
(∼45:55, entries 16 and 17). Recourse to other amino
acids including D- and L-serine, D- and L-phenylala-
nine, L-homoserine, L-histidine, N-methyl-L-serine, and
R-methyl-L-proline did not give evidence of comparable
or superior diastereomeric ratios (Table 1).
(26) (a) List, B.; Hoang, L.; Martin, H. J. Proc. Nat. Acad. Sci. U.S.A.
2004, 101, 5839. (b) List, B. Tetrahedron 2002, 58, 5572. (c) List, B. J.
Am. Chem. Soc. 2000, 122, 9336. (d) List, B.; Pojarliev, P.; Martin, H.
J. Org. Lett. 2001, 3, 2423. (e) List, B. J. Am. Chem. Soc. 2002, 124,
5656. (f) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.,
Int. Ed. 2003, 42, 2785. (g) Vignola, N.; List, B. J. Am. Chem. Soc.
2004, 126, 450.
As this study was extended to include the proline
derivatives 20-23, it was found that the maximum
10:90 diastereomeric ratio earlier observed for 5a could
be matched by 20 in DMSO at 50 °C, in tandem with a
useful increase in yield to the 76% level (entry 6). By
analogy, it was expected that 5b would exhibit a similar
enhancement in its diastereoselectivity profile. Disap-
(27) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
9922. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273. (c) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.
Chem. Soc. 2003, 125, 2475. (d) Hoang, L.; Bahmanyar, S.; Houk, K.
N. J. Am. Chem. Soc. 2003, 125, 16.
(28) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245.
(b) Jung, M. E. Tetrahedron 1976, 32, 3. (c) Puchot, C.; Samuel, O.;
Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986,
108, 2353.
536 J. Org. Chem., Vol. 70, No. 2, 2005

Amino Acid Catalyzed Aldol Cyclizations of Triketo Acetonides
δ 5.90 (s, 1H), 4.19-3.97 (m, 2H), 3.51-3.35 (m, 1H) 2.84-
2.38 (m, 6H), 2.24-1.89 (m, 4H), 1.81-1.51 (m, 2H), 1.36 (s,
3H), 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 210.4, 198.5,
165.4, 126.6, 109,5, 72.0, 69.6, 53.3, 39.7, 38.3, 33.7, 32.2, 27.5,
26.7, 25.6, 23.1; ES HRMS m/z (C16H22O4+) calcd 278.1513,
phenomenon so disruptive of the preferred operation of
one dominant pathway? A different option is that the
charge stabilization associated with hydrogen bonding of
the carboxylic acid proton to the developing alkoxide
center is less easily attained for minor structural reasons.
This feature of intermolecular aldol reactions and the
geometry of the ensuing proton transfer could act in
unison to impede the attainment of high quality stereo-
selectivity control.
obsd 278.1501; [R]21 -57.7 (c 1.54, benzene).
D
For 7a: colorless needles; mp 117-117.5 °C (from ether/
hexanes); IR (film, cm-1) 1709, 1662; 1H NMR (300 MHz,
CDCl3) δ 5.88 (d, J ) 1.7 Hz, 1H), 4.12-4.04 (m, 2H), 3.51-
3.44 (m, 1H), 2.91-2.75 (m, 2H), 2.55-2.25 (m, 5H), 2.23-
2.10 (m, 3H), 1.96 (dd, J ) 2.7, 14.7 Hz, 1H), 1.78-1.58 (m,
1H), 1.38 (s, 3H), 1.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
209.6, 197.7, 165.3, 126.5, 109.5, 71.6, 69.5, 53.3, 39.3, 38.7,
33.2, 31.8, 26.6, 26.0, 25.2, 23.8; ES HRMS m/z (C16H22O4Na+)
Experimental Section
Compound 25a. To a stirred suspension of 1,3-cyclohex-
anedione (12.9 g, 0.12 mol), thiophenol (118 mL, 1.15 mol),
and silica gel (19.35 g) in CH2Cl2 (400 mL) was added
D-glyceraldehyde acetonide (22.5 g, 0.17 mol) at rt over 5 min.
After being stirred for 48 h at the same temperature, the
mixture was filtered through a Celite pad and the filtrate was
evaporated under reduced pressure. The residue was chro-
matographed on silica gel (hexane/ethyl acetate) to afford a
diastereomeric mixture (ca. 9:1) of 25a (27.22 g, 68%) as a
white solid. The major isomer was purified by recrystallization
from ethyl acetate/hexanes to supply spectra. The mixture was
used in the next reaction without further purification. For the
pure major isomer of 25a: colorless needles; mp 123-123.5
calcd 301.1410, obsd 301.1408; [R]21 -0.53 (c 1.5, benzene).
D
Compound 25b. A solution of 24b18 (1.0 g, 7.9 mmol),
D-glyceraldehyde acetonide19 (1.7 g, 13 mmol), and thiophenol
(8 mL) in 50 mL of benzene was heated at reflux in the
presence of 10 g of silica gel for 5 h. The reaction mixture was
allowed to cool to rt and filtered. The solvent was removed,
and the resulting oil was chromatographed on silica gel (ether/
hexanes) to afford 2.57 g (93%) of 25b as a pale yellow oil: IR
1
(film, cm-1) 1724, 1695; H NMR (300 MHz, CDCl3) δ 7.51-
7.10 (m, 5H), 4.60-3.40 (m, 4H), 2.67 (m, 4H), 1.93 (m, 4H),
1.50-1.10 (series of m, 7H); 13C NMR (75 MHz, CDCl3) δ 207.6,
107.2, 136.1, 129.4 (2C), 129.2 (2C), 77.8, 68.4, 66.2, 52.2, 44.6,
44.0, 26.8, 25.2, 24.9; ES HRMS m/z (C19H24O4SNa+) calcd
371.1295, obsd 371.1288. Anal. Calcd for C19H24O4S: C, 65.49;
H, 6.95. Found: C, 65.25; H, 6.83.
1
°C; IR (film, cm-1) 1603; H NMR (300 MHz, CDCl3) δ 7.45-
7.20 (m, 5H), 5.13 (d, J ) 2.6 Hz, 1H), 4.53 (dt, J ) 2.7, 7.5
Hz, 1H), 3.99 (dd, J ) 6.7, 8.4 Hz, 1H), 3.40 (t, J ) 8.4 Hz,
1H), 2.52-2.10 (m, 4H), 1.92-1.78 (m, 1H), 1.69-1.51 (m, 1H),
1.45 (s, 3H), 1.46-1.38 (m, 1H), 1.38 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 197.4, 176.2, 133.2, 132.9, 128.72, 128.68, 127.6,
110.2, 110.0, 77.3, 66.9, 42.5, 36.0, 29.8, 25.4, 24.6, 20.1; ES
HRMS m/z (C18H22O4SNa+) calcd 357.1131, obsd 357.1125;
Compound 26b. Diketone 25b (2.6 g, 7.5 mmol) was added
to a large excess of Raney nickel (2 g) in 10 mL of ethanol.
The mixture was stirred at rt for 1 h and filtered through
Celite. The solvent was removed, and the resulting oil was
chromatographed on silica gel (ether/hexanes) to afford 1.3 g
(76%) of 26b as a colorless oil: IR (film, cm-1) 1724, 1697; 1H
NMR (300 MHz, CDCl3) δ 4.12 (m, 1H), 3.96 (m, 2H), 3.47 (m,
1H), 2.66 (m, 2H), 2.48 (m, 2H), 2.15 (m, 3H), 1.58 (m, 3H),
1.35 (s, 3H), 1.22 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 205.8,
205.3, 109.0, 73.4, 69.3, 62.9, 44.4, 43.9, 30.1, 26.8, 25.5, 25.0,
24.8; ES HRMS m/z (C13H20O4SNa+) calcd 263.1259, obsd
[R]21 +88.7 (c 1.52, benzene).
D
Compound 5a. To a stirred solution of 25a (27 g, 80.8
mmol) in ethanol (300 mL) was added Raney nickel (67.5 mL,
wet volume; 2.5 mL/1 g of substrate) suspended in ethanol (50
mL) at 0 °C over 10 min. After further stirring for 2 h at rt,
the mixture was filtered and the filtrate was evaporated under
reduced pressure. The residue was chromatographed on silica
gel (hexane/ethyl acetate) to afford 26a (15.7 g) as a colorless
oil containing trace impurities. Without further purification,
a solution of 26a (15.7 g), methyl vinyl ketone (14.5 mL, 0.17
mol), and benzyltrimethylammonium hydroxide (Triton B, 40%
in methanol, 2.9 mL, 6.95 mmol) in methanol (150 mL) was
stirred at rt for 19 h. The mixture was evaporated under
reduced pressure, and the residue was chromatographed on
silica gel (hexane/ethyl acetate) to afford 5a (8.11 g, 35%
over two steps) as colorless prisms: mp 50-51 °C (from
ether/hexane); IR (film, cm-1) 1718, 1693; 1H NMR (300 MHz,
CDCl3) δ 4.03-3.97 (m, 2H), 3.49-3.42 (m, 1H), 2.73-2.60 (m,
4H), 2.42-2.35 (m, 2H), 2.26-2.18 (m, 1H), 2.09 (s, 3H),
2.06-1.89 (m, 5H), 1.25 (s, 3H), 1.23 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 211.0, 210.1, 206.9, 109.2, 72.0, 69.8, 63.9, 39.2,
38.5, 38.3, 38.0, 30.5, 29.9, 26.0, 25.5, 17.0; ES HRMS m/z
263.1259; [R]21 -24.0 (c 1.25, benzene).
D
Compound 5b. A solution of 26b (7.39 g, 30.8 mmol),
methyl vinyl ketone (5.1 mL, 61.6 mmol), and Triton B (1.3
mL, 3.08 mmol) in methanol (70 mL) was heated at reflux for
1 h. The solvent was removed under reduced pressure. The
residue was diluted with ether, and the mixture was washed
with water, saturated NaHCO3 solution, and brine. The
organic phase was dried, and the solvent was removed under
reduced pressure. The residue was chromatographed on silica
gel (ether/hexanes) to afford 5b (8.11 g, 85%): colorless
needles; mp 79-82 °C; IR (film, cm-1) 1716, 1694; 1H NMR
(300 MHz, CDCl3) δ 3.86 (m, 2H), 3.35 (t, J ) 3.3 Hz, 1H),
2.45-1.70 (series of m, 17H), 1.20 (d, J ) 2.0 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 211.7, 211.6, 206.7, 109.2, 71.2, 69.5, 65.8,
41.8, 41.4, 37.3, 35.0, 29.8, 28.0, 27.9, 26.5, 25.3, 23.9; ES
HRMS m/z (C17H26O5Na+) calcd 310.1780, obsd 310.1768. Anal.
Calcd for C17H26O5: C, 65.77; H, 8.47. Found: C, 65.55; H,
8.46.
Ring Closure of 5b Promoted by Pyrrolidine. A solution
of 5b (3.00 g, 12.9 mmol) in 50 mL of benzene was heated at
reflux in the presence of pyrrolidine (1.00 mL, 12.9 mmol) for
1 h. Water was removed from the system via a Dean-Stark
trap. The reaction mixture was concentrated and chromato-
graphed on silica gel (ether/hexanes, 1/5) to afford 1.62 g of
7b, 1.44 g of 6b, and 0.456 g of a mixture (total of 93%) as an
orange oil.
(C16H24O5Na+) calcd 319.1516, obsd 319.1510; [R]21 -43.1 (c
D
1.67, benzene).
Typical Aldol Condensation Protocol Involving 5a
and Proline Derivatives. A solution of 5a (3.0 g, 10.1 mmol)
in dimethyl sulfoxide (30 mL) was degassed under vacuum at
rt for 10 min. After addition of proline derivative 20 (748 mg,
2.03 mmol), the mixture was heated at 50 °C with stirring for
16 h. After cooling, the mixture was poured into water and
extracted with ethyl acetate. The combined organic layers
were washed with water, saturated NaHCO3 solution, and
brine. The organic phase was dried, and the solvent was
removed under reduced pressure. The residue was chromato-
graphed on silica gel (ether/hexanes) to afford 7a (1.60 g), a
mixture of 6a and 7a (0.519 g), and pure 6a (36 mg, total 2.155
g, 76%).
For 6b: IR (CCl4, cm-1) 1706, 1667; 1H NMR (300 MHz,
CDCl3) δ 6.06 (s, 1H), 4.51-4.42 (m, 1H), 4.20 (dd, J ) 8.0,
6.0 Hz, 1H), 3.50 (t, J ) 7.9 Hz, 1H), 2.85-2.65 (m, 2H), 2.53-
2.42 (m, 2H); 2.39-1.83 (m, 6H), 1.75 (dd, J ) 8.3, 14.8 Hz,
1H), 1.36 (s, 3H), 1.31 (s, 3H), 1.19-1.06 (m, 3H); 13C NMR
(75 MHz, CDCl3) δ 213.4, 198.2, 166.4, 129.3, 109.3, 75.4, 70.3,
For 6a: colorless needles; mp 59-60 °C (from ether hex-
anes); IR (film, cm-1) 1710, 1670; 1H NMR (300 MHz, CDCl3)
J. Org. Chem, Vol. 70, No. 2, 2005 537

Inomata et al.
54.8, 40.4, 37.8, 35.3, 30.1, 31.5, 29.3, 27.7, 26.8, 25.8; ES
Hydride Reduction of 28. To a stirred suspension of
lithium aluminum hydride (242 mg, 6.38 mmol) in THF (10
mL) was added 28 (601 mg, 1.59 mmol) dissolved in THF (5
mL) at 0 °C. After 10 min of stirring, the mixture was heated
at reflux for 2.5 h, water was carefully introduced, and stirring
was resumed for 2 h at rt. The mixture was filtered through
a Celite pad, and the filtrate was extracted with ethyl acetate.
The combined organic layers were dried and the solvent was
removed under reduced pressure. The residue was chromato-
graphed on silica gel (methanol/ethyl acetate/NH4OH) to afford
a diastereomeric mixture of 29 (146 mg, 30%) and diol 30 (233
mg, 52%), both as colorless oils. Amine 29 and diol 30 were
used in subsequent reactions without further purification of
diastereomers.
HRMS m/z (C17H24O4Na+) calcd 292.1675, obsd 292.1720; [R]21
D
-60.0 (c 0.35, benzene).
For 7b: IR (CCl4, cm-1) 1708, 1676; 1H NMR (300 MHz,
CDCl3) δ 6.16 (s, 1H), 4.09-3.99 (m, 2H), 3.52-3.44 (m, 1H),
2.81 (ddd, J ) 5.9, 13.3, 17.8 Hz, 1H), 2.74-2.65 (m, 1H), 2.57
(dd, J ) 4.7, 12.7 Hz, 1H), 2.47-2.35 (m, 2H), 2.30-1.83 (m,
7H), 1.72-1.49 (m, 2H), 1.34 (s, 3H), 1.27 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 211.8, 197.9, 164.7, 130.4, 109.2, 72.2, 70.1,
54.8, 40.5, 37.8, 36.48, 32.6, 31.86, 31.5, 27.1, 26.8, 25.8; ES
HRMS m/z (C17H24O4Na+) calcd 292.1674, obsd 292.1800; [R]21
-40.0 (c 0.35, benzene).
D
Typical Aldol Condensation Protocol Involving 5b
and Proline Derivatives. A solution of 5b (1.04 g, 3.35 mmol)
and 20 (1.36, 3.69 mmol) in methanol (20 mL) was heated to
reflux for 2.5 h. The solvent was removed under reduced
pressure, and the residue was diluted with ether. The mixture
was washed with saturated NaHCO3 solution and brine. The
organic phase was dried and the solvent was removed under
reduced pressure. The residue was chromatographed on silica
gel (ether/hexanes) to afford 6b (426 mg, 44%) as a colorless
oil and 7b (307 mg, 31%) as colorless crystals.
Controlled Hydride Reduction of 6b. A solution of 6b
(1.547 g, 5.3 mmol) in 10 mL of THF was added to a slurry of
lithium aluminum hydride (0.442 g, 11.65 mmol) in 20 mL of
THF at 0 °C. The mixture was stirred at rt for 1 h and 5 mL
of water was carefully introduced. The mixture was added to
10 mL of ether and washed twice with 2 mL of brine. The
organic layer was dried and the solvent was removed under
reduced pressure. The resulting oil was treated with manga-
nese dioxide (4.5 g, 51.8 mmol) at rt for 5 h. The mixture was
filtered through Celite and the solvent was removed under
reduced pressure. The resulting oil was chromatographed on
silica gel (ether/hexanes, 1/1) to furnish 1.053 g (68%) of 27
as a white solid and 0.110 g (7%) of unreacted starting
material.
Ring Expansion of 29. To a stirred suspension of 29 (146
mg, 0.47 mmol) in glacial acetic acid (2 mL) and water (2 mL)
was added sodium nitrite (100 mg, 1.41 mmol) at 0 °C. After
being stirred for 2 h, the mixture was poured into water and
extracted with ethyl acetate. The combined organic layers were
washed with saturated NaHCO3 solution and brine. The
organic phase was dried, and the solvent was removed under
reduced pressure. The residue was dissolved in CH2Cl2 (5 mL),
and manganese dioxide (366 mg, 4.22 mmol) was added at rt.
After 1.5 h of stirring at this temperature, the mixture was
chromatographed on silica gel (ether/hexanes) to afford 6b (3
mg, 2%), 32 (71 mg, 58%), and 33 (24 mg, 19%). The spectra
of 6b were identical to those recorded for the material prepared
from 5b.
1
For 32: colorless oil; IR (film, cm-1) 1702, 1668; H NMR
(300 MHz, CDCl3) δ 5.87 (s, 1H), 4.25-4.12 (m, 1H), 4.08 (dd,
J ) 6.0, 7.8 Hz, 1H), 3.44 (t, J ) 7.7 Hz, 1H), 3.03 (d, J ) 12.0
Hz, 1H), 2.69-2.33 (m, 7H), 2.29-1.96 (m, 3H), 1.88-1.60
(m, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 210.3, 198.8, 169.3, 128.4, 109.4, 72.1, 69.9, 50.1, 43.8,
40.7, 39.6, 33.7, 33.5, 32.4, 26.7, 25.7, 24.7; ES HRMS m/z
(C17H24O4Na+) calcd 315.1567, obsd 315.1578; [R]21 -113.8
D
(c 1.12, benzene).
For 27: mp 116-118 °C; IR (CCl4, cm-1) 3450, 1668; 1H
NMR (300 MHz, CDCl3) δ 5.82 (s, 1H), 4.50 (m, 1H), 4.25 (m,
1H), 3.85 (dd, J ) 6.3, 7.4 Hz, 1H), 3.49 (t, J ) 7.4 Hz, 1H),
2.64 (m, 2H), 2.43 (dt, J ) 5.5, 17 Hz, 1H), 2.34-1.40 (series
of m, 12H), 1.40 (s, 3H), 1.31 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 199.4, 172.6, 128.8, 109.2, 73.2, 73.0, 70.5, 46.1, 36.2,
33.9, 33.6, 31.4, 31.2, 29.7, 26.8, 25.9, 21.4; ES HRMS m/z
For 33: colorless oil; IR (film, cm-1) 1670; 1H NMR (300
MHz, CDCl3) δ 5.84 (d, J ) 1.7, 1H), 4.47 (ddd, J ) 3.6, 7.5,
13.6 Hz, 1H), 4.15 (dd, J ) 6.0, 8.0 Hz, 1H), 3.51 (t, J ) 7.9
Hz, 1H), 2.98 (dd, J ) 2.2, 4.1 Hz, 1H), 2.62-2.49 (m, 2H),
2.42-1.91 (m, 8H), 1.75-1.50 (m, 3H), 1.37 (s, 3H), 1.33 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 199.0, 167.0, 126.2, 109.0,
72.6, 70.3, 63.4, 50.1, 42.1, 38.1, 34.1, 32.1, 31.4, 26.9, 26.0,
25.6, 23.8; ES HRMS m/z (C17H24O4Na+) calcd 315.1567, obsd
(C17H26O4Na+) calcd 317.1723, obsd 317.1726; [R]20 -74.0 (c
D
0.35, benzene).
315.1554; [R]21 -80.1 (c 1.10, benzene).
D
Silylated Cyanohydrin 28. To a stirred solution of 6a (773
mg, 2.78 mmol) in CH2Cl2 (10 mL) were added potassium
cyanide (27 mg, 0.42 mmol), 18-crown-6 as the CH3CN complex
(34 mg, 0.11 mmol), and trimethylsilyl cyanide (0.44 mL, 3.34
mmol) at 0 °C. After being stirred for 0.5 h at this temperature,
the mixture was washed with saturated NaHCO3 solution and
brine. The organic layer was dried, and the solvent was
removed under reduced pressure. The residue was chromato-
graphed on silica gel (ether/hexanes) to afford 28 (601 mg, 57%)
as colorless needles: mp 106-107 °C (from ether/hexanes); IR
For the â-epimer of 32: 63% yield; colorless prisms; mp
120-121 °C (from ether); IR (film, cm-1) 1699, 1670; 1H NMR
(300 MHz, CDCl3) δ 5.86 (s, 1H), 4.22-4.13 (m, 1H), 4.06 (dd,
J ) 5.9, 7.8 Hz, 1H), 3.45 (t, J ) 7.8 Hz, 1H), 3.06 (d, J ) 12.4
Hz, 1H), 2.68-2.32 (m, 7 H), 2.28-2.10 (m, 2H), 1.98 (dt, J )
4.6, 14.1 Hz, 1H), 1.92-1.76 (m, 2H), 1.73-1.51 (m, 1H), 1.38
(s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 210.2, 197.9,
169.2, 128.3, 109.3, 72.0, 69.8, 50.9, 43.5, 41.2, 38.8, 33.4, 32.7,
31.1, 26.7, 25.6, 25.3; ES HRMS m/z (C17H24O4Na+) calcd
315.1567, obsd 315.1578; [R]21 +141.6 (c 1.67, benzene).
1
(film, cm-1) 1669; H NMR (300 MHz, CDCl3) δ 5.97 (s, 1H),
D
For the â-epimer of 33: 13% yield; colorless oil; IR (film,
cm-1) 1672; 1H NMR (300 MHz, CDCl3) δ 5.89 (d, J ) 1.8 Hz,
1H), 4.34-4.25 (m, 1H), 4.10 (dd, J ) 5.8, 7.8 Hz, 1H), 3.45 (t,
J ) 7.9 Hz, 1H), 2.95 (dd, J ) 2.0, 4.1 Hz, 1H), 2.97-2.20 (m,
7H), 2.04-1.94 (m, 2H), 1.91-1.69 (m, 2H), 1.68-1.50 (m, 1H),
1.37 (s, 3H), 1.34 (s, 3H), 1.42-1.30 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 198.3, 165.7, 126.7, 108.4, 72.4, 70.0, 63.1, 50.7,
41.9, 37.2, 33.8, 31.8, 30.7, 26.7, 26.0, 25.8, 23.7; ES HRMS
m/z (C17H24O4Na+) calcd 315.1567, obsd 315.1587; [R]21D +87.3
(c 1.72, benzene).
For 6b: 2% yield; all of the spectra proved identical to those
recorded for the keto alcohol prepared from 5b.
Compound 31. To a stirred suspension of 30 (56 mg, 0.20
mmol) in CH2Cl2 (3 mL) was added manganese dioxide (173
mg, 2.0 mmol) at rt. After 1.5 h of stirring at this temperature,
the mixture was filtered through a Celite pad and the filtrate
4.42-4.32 (m, 1H), 4.06 (dd, J ) 6.1, 7.9 Hz, 1H), 3.45 (t, J )
7.7 Hz, 1H), 2.69-2.21 (m, 6H), 2.20-1.79 (m, 6H), 1.35 (s,
3H), 1.28 (s, 3H), 0.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
198.4, 161.9, 128.4, 120.1, 109.3, 80.0, 72.9, 70.5, 46.7, 36.6,
34.5 (2C), 30.7, 28.9, 26.8, 25.5, 21.9, 1.2 (3C); ES HRMS m/z
(C20H31NO4SiNa+) calcd 400.1915, obsd 400.1902; [R]21D -65.2
(c 1.62, benzene).
For the â-epimer of 28: yield 75%; colorless needles; mp
1
108-108.5 °C (from ether/hexanes); IR (film, cm-1) 1673; H
NMR (300 MHz, CDCl3) δ 6.07 (s, 1H), 4.10-3.98 (m, 2H), 3.45
(t, J ) 7.3 H, 1H), 2.76 (ddd, J ) 7.0, 11.9, 17.3 Hz, 1H), 2.60-
2.20 (m, 5H), 2.15-1.80 (m, 6H), 1.39 (s, 3H), 1.28 (s, 3H), 0.27
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.5, 159.6, 130.0, 120.2,
109.3, 80.2, 72.1, 70.3, 47.1, 35.6, 34.3, 34.2, 30.8, 29.4, 26.9,
25.9, 22.0, 1.2 (3C); ES HRMS m/z (C20H31NO4SiNa+) calcd
400.1915, obsd 400.1910; [R]21 +3.0 (c 1.67, benzene).
D
538 J. Org. Chem., Vol. 70, No. 2, 2005

Amino Acid Catalyzed Aldol Cyclizations of Triketo Acetonides
was evaporated under reduced pressure. The residue was
chromatographed on silica gel (hexanes/ethyl acetate) to afford
31 (41 mg, 74%).
(75 MHz, CDCl3) δ 198.8, 168.0, 125.6, 110.2, 78.0, 72.0, 70.2,
44.6, 34.6, 33.5, 31.8, 30.1, 29.7, 26.8, 25.8, 24.1; ES HRMS
m/z (C16H24O4Na+) calcd 303.1567, obsd 303.1575; [R]21D +74.0
(c 0.50, benzene).
1
For 31: colorless oil; IR (film, cm-1) 3347, 1652; H NMR
(300 MHz, CDCl3) δ 5.84 (d, J ) 1.3 Hz, 1H), 4.41(quint, J )
7.0 Hz, 1H), 4.09 (dd, J ) 6.0, 7.9 Hz, 1H), 3.53 (dd, J )
5.2, 10.7 Hz, 1H), 3.49 (t, J ) 8.0 Hz, 1H), 2.63-2.33 (m, 4H),
2.18-2.16 (m, 1H), 2.08-1.70 (m, 7H), 1.36 (s, 3H), 1.30 (s,
3H), 1.50-1.20 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 199.8,
167.8, 126.2, 109.1, 78.5, 73.4, 70.7, 44.0, 35.7, 34.0, 32.5, 31.4,
30.1, 26.8, 25.6, 23.9; ES HRMS m/z (C16H24O4Na+) calcd
Acknowledgment. We thank Dr. Judith Gallucci
of our department for the X-ray diffraction studies.
Supporting Information Available: ORTEP diagrams
and tables of X-ray crystal data, atomic coordinates, both
lengths and angles, equivalent isotropic and anisotropic
displacement parameters, and intramolecular hydrogen bonds
303.1567, obsd 303.1565; [R]21 -120.5 (c 0.80, benzene).
D
For the â-epimer of 31: 84% yield; colorless oil; IR (film,
1
for 27. High-field H and 13C NMR spectra for all compounds
1
cm-1) 3442, 1661; H NMR (300 MHz, CDCl3) δ 5.80 (d, J )
described herein. This material is available free of charge via
the Internet at http://pubs.acs.org.
1.7 Hz, 1H), 4.38-4.29 (m, 1H), 4.13 (dd, J ) 6.0, 8.2 Hz,
1H), 3.54 (t, J ) 8.0 Hz, 1H), 3.35 (dd, J ) 4.0, 10.9 Hz, 1H),
2.51-2.11 (m, 7H), 2.07-1.73 (m, 4H), 1.65 (dd, J ) 0.7, 15.2
Hz, 1H), 1.58-1.35 (m, 1H), 1.46 (s, 3H), 1.38 (s, 3H); 13C NMR
JO0486084
J. Org. Chem, Vol. 70, No. 2, 2005 539