Development and application of a new general method for the asymmetric synthesis of syn- and anti-1,3-amino alcohols

Article abstract of DOI:10.1021/ja0363462

A general method is described for asymmetric synthesis of both syn- and anti-1,3-amino alcohols. The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes. The reduction of the product β-hydroxy N-sulfinyl imines 2 with catecholborane and LiBHEt₃ provides syn- and anti-1,3-amino alcohols with very high diastereomeric ratios. This method was found to be effective for a variety of substrates incorporating either aromatic or various aliphatic substituents. The convergent and efficient asymmetric syntheses of the two natural products, (-)-8-epihalosaline and (-)-halosaline, were also accomplished.

Full text of DOI:10.1021/ja0363462

Published on Web 08/23/2003
Development and Application of a New General Method for
the Asymmetric Synthesis of syn- and anti-1,3-Amino
Alcohols
Takuya Kochi, Tony P. Tang, and Jonathan A. Ellman*
Contribution from the Center for New Directions in Organic Synthesis, Department of
Chemistry, UniVersity of California, Berkeley, California 94720
Received May 26, 2003; E-mail: jellman@uclink.berkeley.edu
Abstract: A general method is described for asymmetric synthesis of both syn- and anti-1,3-amino alcohols.
The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly
diastereoselective addition to aldehydes. The reduction of the product â-hydroxy N-sulfinyl imines 2 with
catecholborane and LiBHEt3 provides syn- and anti-1,3-amino alcohols with very high diastereomeric ratios.
This method was found to be effective for a variety of substrates incorporating either aromatic or various
aliphatic substituents. The convergent and efficient asymmetric syntheses of the two natural products,
(-)-8-epihalosaline and (-)-halosaline, were also accomplished.
Scheme 1
Introduction
1,3-Amino alcohols are found in many natural products1 and
potent drugs,2 including a number of nucleoside antibiotics1a-d
and the HIV protease inhibitors, ritonavir and lopinavir.2a-d They
have also been used as ligands for asymmetric catalysts and as
synthetic intermediates.3 However, despite the importance of
1,3-amino alcohols, there are relatively few methods for their
stereoselective synthesis.4
Recently, we published a preliminary communication on a
new, straightforward method for the asymmetric synthesis of
(1) (a) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. J. Am.
Chem. Soc. 1972, 94, 4, 4353-4354. (b) Kozikowski, A. P.; Chen, Y.-Y.
J. Org. Chem. 1981, 46, 6, 5248-5250. (c) Wang, Y.-F.; Izawa, T.;
Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104, 4, 6465-6466. (d)
Hashiguchi, S.; Kawada, A.; Natsugari, H. J. Chem. Soc., Perkin Trans. 1
1991, 2435-2444. (e) Knapp, S. Chem. ReV. 1995, 95, 5, 1859-1876. (f)
Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc.
1997, 119, 9, 4112-4116.
(2) (a) Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasa-
vanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong,
X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.;
Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck,
D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488. (b) Sham, H.
L.; Kempf, D. J.; Molla, A.; Marsh, K. C.; Kumar, G. N.; Chen, C.-M.;
Kati, W.; Stewart, K.; Lal, R.; Hsu, A.; Betebenner, D.; Korneyeva, M.;
Vasavanonda, S.; McDonald, E.; Saldivar, A.; Wideburg, N.; Chen, X.;
Niu, P.; Park, C.; Jayanti, V.; Grabowski, B.; Granneman, G. R.; Sun, E.;
Japour, A. J.; Leonard, J. M.; Plattner, J. J.; Norbeck, D. W. Antimicrob.
Agents Chemother. 1998, 42, 3218-3224. (c) Haight, A. R.; Stuk, T. L.;
Allen, M. S.; Bhagavatula, L.; Fitzgerald, M.; Hannick, S. M.; Kerdesky,
F. A. J.; Menzia, J. A.; Parekh, S. I.; Robbins, T. A.; Scarpetti, D.; Tien,
J.-H. J. Org. Process Res. DeV. 1999, 3, 94-100. (d) Sham, H. L.; Zhao,
C.; Li, L.; Betebenner, D. A.; Saldivar, A.; Vasavanonda, S.; Kempf, D.
J.; Plattner, J. J.; Norbeck, D. W. Bioorg. Med. Chem. Lett. 2002, 12, 3101-
3103. (e) Carlier, P. R.; Lo, M. M.-C.; Lo, P. C -K.; Richelson, E.; Tatsumi,
M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med. Chem. Lett. 1998, 8, 487-
492.
(3) (a) Hulst, R.; Heres, H.; Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron:
Asymmetry 1996, 7, 1373-1384. (b) Li, X.; Yeung, C.-H.; Chan, A. S. C.;
Yang, T.-K. Tetrahedron: Asymmetry 1999, 10, 759-763. (c) Evans, P.
A.; Holmes, A. B.; McGeary, R. P.; Nadin, A.; Russell, K.; O’Hanlon, P.
J.; Pearson, N. D. J. Chem. Soc., Perkin Trans. 1 1996, 123-138.
(4) Asymmetric synthesis of 1,3-amino alcohols: (a) Yamamoto, Y.; Komatsu,
T.; Maruyama, K. J. Chem. Soc., Chem. Commun. 1985, 814-815. (b)
Barluenga, J.; Fernandez-Mar´ı, F.; Viado, A. L.; Aguilar, E.; Olano, B. J.
Org. Chem. 1996, 61, 5659-5662. (c) Toujas, J.-L.; Toupet, L.; Vaultier,
M. Tetrahedron 2000, 56, 2665-2672. See also refs 1-3.
both syn- and anti-1,3-amino alcohols.5 The metalloenamine
derived from the tert-butanesulfinyl imine of acetophenone was
added to a range of aldehydes with high diastereoselectivities.
Stereoselective methods were then identified for the reduction
of the â-hydroxy N-sulfinyl imine products to provide both the
syn- and anti-1,3-amino alcohols with high diastereoselectivities
and yields (Scheme 1). This sequence represents the first
efficient and general approach to access both the syn- and anti-
stereoisomers from a common precursor.
In the preliminary communication, the N-sulfinyl imine of
acetophenone was the only substrate to be reported. Herein, we
report greatly expanded substrate scope, with tert-butanesulfinyl
imines derived from structurally diverse methyl ketones serving
as suitable substrates. For the large majority of N-sulfinyl imine
and aldehyde coupling partners, good yields and high diaste-
(5) Kochi, T.; Tang, T. P.; Ellman J. A. J. Am. Chem. Soc. 2002, 124, 6518-
6519.
9
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J. AM. CHEM. SOC. 2003, 125, 11276-11282
10.1021/ja0363462 CCC: $25.00 © 2003 American Chemical Society

Asymmetric Synthesis of 1,3-Amino Alcohols
A R T I C L E S
Table 2. Addition of N-Sulfinyl Metalloenamines to Aldehydes
Table 1. Optimization of the Addition of an N-Sulfinyl
Metalloenamine to Aldehydes
entry
substrate
R
product
dra
yield (%)b
entry
R
product
solvent
additive
dra
yield (%)b
1
2
3
1a (R′ ) Ph)
t-Bu
i-Pr
i-Bu
Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
98:2
98:2
96:4
96:4
92:8
99:1
99:1
98:2
90:10
99:1
97:3
91:9
77:23
98:2
92:8
80:20
60:40
64
88
75
84
79
92
80
84
76
85
81
73
75
70
65
51
50
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Ph
Ph
Ph
2d
2d
2d
2d
2d
2e
2e
2e
THF
Et2O
toluene
THF
THF
THF
THF
THF
-
86:14
81:19
73:23
96:4
80
nd
nd
84
62
64
56
79
1a
1a
1a
1a
-
-
4
5c
6
Ph
MgBr2
ZnBr2
-
93:7
1b (R′ ) t-Bu)
t-Bu
i-Pr
Et
73:27
76:24
92:8
7
8
1b
1b
1b
MgBr2
ZnBr2
9d
10
11
12
13d
14
15
16
17d
Ph
1c (R′ ) i-Pr)
t-Bu
i-Pr
Et
a Diastereomeric ratio. b Isolated yield of diastereomerically pure material.
1c
1c
1c
Ph
reoselectivities are observed for both the metalloenamine
addition step and the reduction steps to provide both the syn-
and anti-1,3-amino alcohol products. Experiments are also
described that contribute to an understanding of the high
diastereoselectivity observed in both steps. Finally, the utility
of the method is demonstrated by the convergent and efficient
asymmetric syntheses of (-)-halosaline (anti-10) and (-)-8-
epihalosaline (syn-10).
1d (R′ ) Et)
t-Bu
i-Pr
Et
1d
1d
1d
Ph
a Diastereomeric ratio. b Isolated yield of diastereomerically pure material.
c ZnBr2 was used as an additive instead of MgBr2. d Reaction with aldehyde
was carried out for 1 h instead of 3 h.
group. Treatment of 1a with LDA at -78 °C in THF, followed
by reaction of the resulting metalloenamine with propionalde-
hyde afforded the desired â-hydroxy sulfinyl imine 2d in 80%
yield and 86:14 dr (entry 1). A similar reaction with benz-
aldehyde afforded the corresponding product 2e in 64% yield
and 73:27 dr (entry 6).
Results and Discussion
A. Asymmetric Additions of N-Sulfinyl Metalloenamines
to Aldehydes. The addition of nucleophiles to N-sulfinyl imines
has become an important and extensively used method for the
asymmetric synthesis of a wide range of amine-containing
compounds.6,7 In contrast, the chemistry of metalloenamines8
derived from sulfinyl imines has not been explored. We
envisioned that the addition of N-sulfinyl metalloenamines to
different electrophiles could provide access to diverse N-sulfinyl
imine products, which could then serve as versatile intermediates
in the asymmetric synthesis of amines. The addition of N-
sulfinyl metalloenamines to aldehydes would be particularly
useful because the â-hydroxy N-sulfinyl imine products could
serve as convenient intermediates to the important class of 1,3-
amino alcohols.
The reaction conditions for the metalloenamine addition were
optimized to improve the diastereomeric ratios. First, solvent
effects were examined. When toluene and ether were used
instead of THF, lower diastereoselectivities were observed
(entries 2, 3). However, addition of metal salts resulted in a
dramatic increase in diastereoselectivity. For the reaction with
propionaldehyde, the addition of 2.0 equiv of MgBr2 (entry 4)
and ZnBr2 (entry 5) afforded 2d with 96:4 and 93:7 ratios,
respectively, with the addition of MgBr2 providing the highest
yield. In this reaction, the use of 2 equiv of MgBr2 was found
to give a higher diastereoselectivity than 1.0 or 0.5 equivalents
(92:8 and 88:12, respectively). Notably, addition of the metal-
loenamine of 1 to benzaldehyde proceeded with highest ste-
reoselectivity when ZnBr2 (entry 8) rather than when MgBr2
(entry 7) was added.
A.1. Optimization Studies for the Addition of N-Sulfinyl
Metalloenamines to Aldehydes (Table 1). In the initial studies,
the (R)-tert-butanesulfinyl imine of acetophenone, 1a, was
chosen because deprotonation would only occur on the R-methyl
(6) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13-18.
(7) (a) Ellman, J. A.; Owens, T. D.; Tang. T. P. Acc. Chem. Res. 2002, 35,
984-995. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39-46. (c) Liu,
G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913-
9914. (d) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12-13. (e)
Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268-269. (f)
Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278-1284. (g) Cogan, D. A.; Liu, G.; Ellman, J. A.
Tetrahedron 1999, 55, 8883-8904. (h) Borg, G.; Cogan, D. A.; Ellman, J.
A. Tetrahedron Lett. 1999, 40, 6709-6712. (i) Borg, G.; Chino, M.; Ellman,
J. A. Tetrahedron Lett. 2001, 42, 1433-1436. (j) Dragoli, D. R.; Burdett,
M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 10127-10128. (k) Lee,
A.; Ellman, J. A. Org. Lett. 2001, 3, 3707-3709. (l) Tang, T. P.; Volkman,
S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772-8778. (m) Tang, T. P.;
Ellman, J. A. J. Org. Chem. 2002, 67, 7819-7832.
(8) (a) Martin, D. Metalloenamines. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 475-502.
(b) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 95, 517-536. (c)
Bergbreiter, D. E.; Newcomb, M. Alkylation of Imine and Enamine Salts.
In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando,
FL, 1984; Vol. 2, pp 243-273.
A.2. Reaction Scope for the Addition of N-Sulfinyl
Metalloenamines to Aldehydes (Table 2). With these promis-
ing results, the addition of the metalloenamine derived from
1a to a variety of aldehydes was investigated. With MgBr2, the
addition to the R,R-dibranched aldehyde, pivaldehyde (entry 1),
the â-branched aldehyde, isovaleraldehyde (entry 2), and the
R-branched aldehyde, isobutyraldehyde (entry 3), each exhibited
excellent diastereoselectivities and afforded the desired products
2a, 2b, and 2c in good yields. In all the cases, the reaction with
no additive resulted in poorer diastereoselectivity (77:23, 97:3
and 84:16 dr, respectively).
The additions of metalloenamines derived from aliphatic
N-sulfinyl imines were next investigated to greatly expand the
scope of the reaction. The reactions of 1b, in which deproto-
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A R T I C L E S
Kochi et al.
SdO bond is 30°, which is larger than usual. The short S-N
bond (1.66 Å) also indicates a strong interaction between the
sulfinyl group and the CdN group, such as nN-σ*S-O inter-
actions.10 The distance between the oxygen atom of the hydroxyl
group and that of the sulfinyl group is 2.75 Å and indicates a
hydrogen-bond interaction between the alcohol hydrogen and
the oxygen atom of the sulfinyl group.
Although N-sulfinyl imines exhibit a rapid equilibrium
between E and Z isomers,11 the barrier to isomerization is
sufficiently high that the individual isomers can readily be
observed by NMR at room temperature.7f For most of the
â-hydroxy N-sulfinyl imines (2a-m) only one out of the two
1
possible geometric isomers was present as determined by H
NMR, while for those N-sulfinyl imines that have ethyl
substitution on the CdN bond (2n-q), only a small amount of
the minor geometric isomer (<10% compared to the major
isomer) was present. NOESY experiments for â-hydroxy
N-sulfinyl imines 2e and 2q suggested that the sulfinyl groups
are proximal to the â-hydroxyl groups in the major isomer
present in solution. While the occurrence of this isomer can be
argued on purely steric grounds for imines 2a-m, steric
interactions cannot explain the preponderance of this isomer
for imines 2n-q. For these and the other imines the isomer
preference is likely enforced by a hydrogen-bonding interaction
between the sulfinyl oxygen and the hydrogen of the hydroxyl
group as is observed in the crystal structure for 2e (Scheme 2).
Figure 1. Structure of 2e.
nation can only occur at the R-methyl group, with aliphatic
aldehydes proceeded with excellent diastereoselectivities and
afforded the desired â-hydroxy sulfinyl imines in high yields
(> 98:2 dr, >80% yield) (entries 6-8). N-Sulfinyl imines 1c
and 1d have two possible deprotonation sites potentially
resulting in the formation of two metalloenamine regioisomers.
However, products resulting from deprotonation at the more
hindered site were not observed (entries 10-12, 14-16). The
diastereoselectivities for the metalloenamine addition reaction
of 1c and 1d with aliphatic aldehydes exceeded 90:10 in most
cases, and the major diastereomers were isolated in good yields.
Scheme 2
When benzaldehyde was used as an electrophile in the
additions of metalloenamines derived from aliphatic N-sulfinyl
imines, diastereoselectivities were not as high as those for the
reactions with aliphatic aldehydes (entries 9, 13, 17). Upon
reexamining the effects of additives for the reaction of 1c,
MgBr2 provided higher stereoselectivity (77:23) than ZnBr2 or
in the case where no additive was used (72:28 and 68:32 dr,
respectively). Therefore, the reactions of the other N-sulfinyl
imines were carried out with MgBr2. Using these conditions
the reaction of 1b with benzaldehyde proceeded with 90:10 dr
(entry 9), but the reaction of 1d proceeded with only 60:40 dr
(entry 17).
A.4. A Stereochemical Model for the Aldol-Type Reaction.
Although the source of diastereocontrol is unclear, the stereo-
chemistry of the products can be explained with a stereochemical
model (Figure 2). First, the use of smaller and more covalently
bonded metals generally resulted in higher diastereoselectivities.
Therefore, the reaction may occur via a closed transition state.
There is no direct information about structures of metalated
sulfinyl imines or sulfinamides, but a M-O bond may be
expected to be formed in the ground state, as seen in lithium
sulfoxides.12 If we assume that the M-N interaction arises
during the reaction, the stereoselectivity observed can be
explained by using a Zimmerman-Traxler-type transition-state
model.13
A.3. Structures of â-Hydroxy N-Sulfinyl Imines. The
crystal structure of â-hydroxy sulfinyl imine 2e is shown in
Figure 1. The N-sulfinyl imine group adopts an approximate
synperiplanar structure as observed for most crystal structures
of N-sulfinyl imines9 and as predicted in theoretical studies,10
although the dihedral angle between the CdN bond and the
The reaction may proceed via A instead of B, because the
large tert-butyl group can hinder the attack of an aldehyde.
Given the preference of A over B, the stereoselectivity of the
reaction is consistent with a simple Zimmerman-Traxler-type
transition state, favoring C over D, in which a 1,3-diaxial
interaction arises. If the reaction proceeds via B, the opposite
stereoselectivity may be observed according to the Zimmer-
man-Traxler-type transition-state model. That is, the steric
repulsion between the tert-butyl group and the approaching
aldehydes may play a very important role in the diastereo-
(9) (a) Robinson, P. D.; Hua, D. H.; Chen, J. S.; Saha, S. Acta Crystallogr.,
Sect. C 1991, 47, 594-596. (b) Davis, F. A.; Reddy, R. E.; Szewczyk, J.
M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.;
Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555-2563. (c) Owens,
T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 1539-1540. (d) Owens, T. D.; Souers, A. J.; Ellman, J. A. J.
Org. Chem. 2003, 68, 3-10. (e) Schenkel, L. B.; Ellman, J. A. Org. Lett.
2003, 5, 545-548. See also ref 9a.
(10) (a) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998, 1629, 9-1637.
(b) Bharatam, P. V.; Uppal, P.; Amita; Kaur, D. J. Chem. Soc., Perkin
Trans. 2 2000, 43-50. (c) Bharatam, P. V.; Amita; Uppal, P.; Kaur, D.
Ind. J. Chem. B 2001, 40, 181-186.
(11) Davis, F. A.; Kluger, E. W. J. Am. Chem. Soc. 1976, 98, 302-303.
(12) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277-297.
(13) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-
1923.
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Asymmetric Synthesis of 1,3-Amino Alcohols
A R T I C L E S
Scheme 4
determined by comparison of the optical rotations to the
literature values,15 confirming that the sense of induction is the
same for additions to both aliphatic and aromatic aldehydes.
(R)-tert-Butanesulfinamide 4 was also recovered in the hydroly-
sis of 3c, and the chiral auxiliary was isolated in 99% yield
and without racemization (>99% ee).
C. Diastereoselective Reductions of â-Hydroxy Sulfinyl
Imines. C.1. Optimization Studies. The reduction of â-hy-
droxy-N-sulfinyl imines 2 was next examined. Several strategies
have been reported to convert â-hydroxy imines to either syn-
or anti-1,3-amino alcohols by choosing an appropriate protecting
group on the nitrogen atom or geometry of the imines.16
However, general methods have not been reported for the
stereoselective reduction of a single â-hydroxy imine to either
the syn- or anti-1,3-amino alcohol through the use of different
reagents and reaction conditions. In contrast, the stereoselective
reduction of â-hydroxy ketones to either the syn- or anti-1,3-
diol can be accomplished through appropriate choice of the
reducing agent.17 Therefore, our goal for this reduction step was
to identify general conditions to selectively access both the syn-
and anti-1,3-amino alcohols.
The reduction of 2b with a number of reducing agents was
initially investigated (Scheme 4). The reaction with NaBH4 was
slightly anti-selective (∼2:1), and N-sulfinyl 1,3-amino alcohol
anti-5b was isolated in 45% yield after chromatography. While
NaBH(OAc)3 is well documented to stereoselectively reduce
â-hydroxy ketones to deliver anti-1,3-diols,17 the NaBH(OAc)3
reduction of 2b under various conditions afforded only trace
amounts of the desired product with low selectivity (<2:1 anti/
syn). Interestingly, the reduction of 2b with NaCNBH3 in THF/
AcOH proceeded with 83:17 syn selectivity, and syn-5b was
isolated in 78% yield. Among the reducing agents we examined,
catecholborane reduced 2b to afford syn-5b with the highest
syn selectivity and the diastereomerically pure material was
isolated in 84% yield. On the other hand, complete anti
selectivity was observed for the reduction of 2b with LiBHEt3
at -78 °C and provided the pure anti product 5b in 83% isolated
yield. Reduction of 2b with LiBH(s-Bu)3 provided a result
similar to that observed for LiBHEt3 (83% yield, >99:1 anti/
syn).
Figure 2. Stereoselective addition of N-sulfinyl metalloenamines to
aldehydes.
Scheme 3
selection. A similar transition-state model was indicated by
Narasaka for the aldol-type reaction of chiral stannous aza-
enolates.14
B. Hydrolysis of â-Hydroxy Sulfinyl Imines (Scheme 3).
The hydrolysis of the â-hydroxy-N-sulfinyl imines was next
investigated. Aqueous HCl hydrolyzed 2e completely in 20 h,
but the R,â-unsaturated ketone was formed as a byproduct.
When the reaction with aqueous AcOH was carried out at room
temperature, imine starting material was still observed at 20 h.
However, upon heating to 40 °C, complete hydrolysis was
achieved, and â-hydroxy ketone 3e was isolated in quantitative
yield with <2% racemization. Hydrolysis of 2c similarly
proceeded to afford 3c in quantitative yield with <2% racem-
ization. The absolute configurations for 3c and 3e were
C.2. syn-Selective Reduction with Catecholborane (Table
3). The reduction of a variety of â-hydroxy-N-sulfinyl imines
2 with catecholborane was investigated to determine the
generality of this reaction. The reductions of aromatic N-sulfinyl
imines 2a-e generally proceeded with 95:5 to 96:4 dr, and the
corresponding N-sulfinyl 1,3-amino alcohols syn-5a-e were
isolated in higher than 84% yields (entries 1-5). When aliphatic
(15) Loh, T.-P.; Li, X.-R. Tetrahedron 1999, 55, 10789-10802.
(16) (a) Narasaka, K.; Ukaji, Y. 1984, 147-150. (b) Narasaka, K.; Yamazaki,
S.; Ukaji, Y. 1984, 2065-2068. (c) Williams, D. R.; Osterhout, M. H. J.
Am. Chem. Soc. 1992, 114, 8750-8751. (d) Haddad, M.; Dorbais, J.;
Larcheveque, M. Tetrahedron Lett. 1997, 38, 5981-5984.
(17) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370.
(14) Narasaka, K.; Miwa, T.; Hayashi, H.; Ohta, M. Chem. Lett. 1984, 1399-
1402.
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A R T I C L E S
Kochi et al.
Table 3. syn-Selective Reduction of â-Hydroxy Sulfinyl Imines
with Catecholborane
entry
substrate
R′
R
product
dra
yield (%)b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
Ph
Ph
Ph
Ph
t-Bu
i-Pr
i-Bu
Et
syn-5a
syn-5b
syn-5c
syn-5d
syn-5e
syn-5f
syn-5g
syn-5h
syn-5i
syn-5j
syn-5k
syn-5l
syn-5m
syn-5n
syn-5o
syn-5p
syn-5q
96:4
96:4
96:4
95:5
96:4
95:5
96:4
95:5
98:2
95:5
96:4
95:5
90:10
92:8
97:3
94:6
76:24
89
88
84
94
84
79
91
81
77
93
82
82
81
82
91
76
69
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
i-Pr
i-Pr
i-Pr
Et
t-Bu
i-Pr
Et
9
Ph
10
11
12
13
14
15
16
17
t-Bu
i-Pr
Et
Ph
t-Bu
i-Pr
Et
Figure 3. Structure of syn-5e.
Et
Et
Et
Ph
a Diastereomeric ratio. b Isolated yield of diastereomerically pure material.
Table 4. anti-Selective Reduction of â-Hydroxy Sulfinyl Imines
with LiBHEt3
entry
substrate
R′
R
product
dra
yield (%)b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
Ph
Ph
Ph
Ph
t-Bu
i-Pr
i-Bu
Et
anti-5a
anti-5b
anti-5c
anti-5d
anti-5e
anti-5f
anti-5g
anti-5h
anti-5i
anti-5j
anti-5k
anti-5l
anti-5m
anti-5n
anti-5o
anti-5p
anti-5q
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
99:1
98:2
92:8
97:3
95:5
93:7
88:12
91
83
85
69
73
83
96
96
95
96
94
94
85
90
94
78
80
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
i-Pr
i-Pr
i-Pr
Et
t-Bu
i-Pr
Et
Figure 4. Strucuture of anti-5h.
9
Ph
10
11
12
13
14
15
16
17
t-Bu
i-Pr
Et
was next investigated.18 Reductions of substrates 2f to 2i (R )
tert-butyl) also proceeded with >99:1 diastereoselectivity, and
the pure anti-isomers were isolated in >83% yields (entries
6-9). â-Hydroxy-N-sulfinyl imines 2j-q were also reduced to
afford anti-1,3-amino alcohol derivatives with good to high
selectivity (>88:12 to 99:1 dr), and in all cases the pure anti-
isomers were isolated in good yields (entry 10-17).
Ph
t-Bu
i-Pr
Et
Et
Et
Et
Ph
a Diastereomeric ratio. b Isolated yield of diastereomerically pure material.
C.4. Determination of the Sense of Induction for the
Preparation of N-Sulfinyl-1,3-amino Alcohols. The crystal
structures of N-sulfinyl-1,3-amino alcohols syn-5e and anti-5h
were obtained (Figures 3, 4). In the structure of syn-5e, the
nitrogen and the oxygen of the hydroxyl group are separated
by a short distance (2.74 Å), and the amine hydrogen is located
at a reasonable position for an intramolecular hydrogen bond
with the oxygen atom. On the other hand, the crystal structure
of anti-5h shows that the oxygen of the hydroxy group is in
close contact with the oxygen of the sulfinyl group (2.78 Å)
and the alcohol hydrogen is located at the position for an
imines were subjected to the same reaction conditions, excellent
diastereoselectivities were achieved for almost all of the
reactions, and pure syn-1,3-amino alcohol products were isolated
in good yields (>76%). Only for the reduction of 2q (R′ )
ethyl and R ) phenyl) was poor selectivity observed (entry 17).
C.3. anti-Selective Reduction with LiBHEt3 (Table 4). The
generality of the reaction with LiBHEt3 was also examined with
various â-hydroxy-N-sulfinyl imines 2. The reduction of
aromatic sulfinyl imines 2a-e was first examined (entries 1-5).
All five substrates afforded the anti-1,3-amino alcohols anti-
5a-e exclusively, and the diastereomerically pure products were
isolated in good yields. The reduction of the aliphatic imines
(18) Reduction of 2n with LiBH(s-Bu)3 resulted in a slight decrease in
diastereoselectivity (95:5 anti/syn).
9
11280 J. AM. CHEM. SOC. VOL. 125, NO. 37, 2003

Asymmetric Synthesis of 1,3-Amino Alcohols
A R T I C L E S
Scheme 5
intramolecular hydrogen bond with the sulfinyl group. Although
the solution-state conformations for syn-5 and anti-5 could
certainly be different from the observed solid-state structures,
the distinct conformations and hydrogen-bonding patterns
observed for syn-5e and anti-5h could explain the consistent
elution order and very large chromatographic separations that
are consistently observed for the syn- and anti-isomers (the
separability factors19 of the two diastereomers by HPLC range
from 1.78 to 6.65 and are averaged at 3.18).
Figure 5. Stereoselective reduction of N-sulfinyl imines 2.
Scheme 6. Total Synthesis of (-)-Halosaline and
(-)-8-Epihalosalinea
Furthermore, these crystal structures established the sense of
induction for the catecholborane and LiBHEt3 reductions to give
syn- and anti-5e and 5h, respectively. The relative stereochem-
istry of N-sulfinyl-1,3-amino alcohols, syn- and anti-5b and 5e
were also determined by NMR analysis of the corresponding
cyclic carbamates, which were prepared by the two-step
sequence of sulfinyl group cleavage followed by reaction with
phosgene.20
C.5. Stereochemical Models for the Diastereoselective
Reductions. To understand the origin of the reduction stereo-
selectivities, the reduction of the C-3 epimer of 2e was
investigated. Reduction with catecholborane provided the anti-
1,3-amino alcohol product with 86:14 diastereoselectivity, while
reduction with LiBHEt3 provided the syn-1,3-amino alcohol with
90:10 diastereoselectivity (Scheme 5). Clearly, the selectivity
of the reduction is primarily controlled by the stereochemistry
of the N-sulfinyl group rather than by the stereochemistry of
the alcohol.21 The opposite diastereoselectivity for the reduction
with catecholborane versus LiBHEt3 can be rationalized by
considering the geometry of the N-sulfinyl imine during the
reduction step (Figure 5). The E-geometry of â-hydroxy
N-sulfinyl imine 2 is based upon the X-ray crystal structure of
2e and NMR analysis of 2e and 2q (see Section A.3). The
addition of LiBHEt3 is unlikely to change the N-sulfinyl imine
geometry. In contrast, addition of catecholborane may provide
the stable six-membered ring intermediate H in analogy to the
stereoselective reduction of â-hydroxy ketones reported by
Evans and Hoveyda.22 Boron chelation clearly plays a significant
role in the reduction because less than 10% reduction was
observed upon reaction of the N-sulfinyl imine derived from
a Reaction Conditions: (a) Ti(OEt)4, THF, 75 °C, 15 h; (b) i) LDA,
THF, - 78 °C, 45 min; ii) MgBr2, - 78 °C, 45 min; iii) butyraldehyde,
THF, - 78 °C, 20 min; (c) catecholborane, THF, - 48 °C, 3 h; (d) LiBHEt3,
THF, - 78 °C, 3 h; (e) H2 gas (1 atm), PtO2 (10 mol %), TFA/EtOH/H2O
(1:5:5), rt, 15 h.
acetophenone with catecholborane under the standard conditions.
Isomerization from the E- to the Z-imine would presumably
result in the observed reversal in the stereoselectivity for the
catecholborane reduction.
D. Total Synthesis of (-)-Halosaline and (-)-8-Epiha-
losaline (Scheme 6). More than 10 2-(2-hydroxyalkyl)piperidine
alkaloid natural products have been isolated (Figure 6). The
natural products differ in the structure and length of the R2
substituents, the substitution on nitrogen, and the occurrence
of all four possible stereoisomers. To demonstrate the versatility
of the reported 1,3-amino alcohol synthesis methods we sought
(19) Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1983, 48, 2520-2527.
(20) See Supporting Information of ref 8.
(21) Reduction of the N-sulfinyl imine derived from acetophenone with LiBHEt3
proceeds with 96: 4 dr and with the same relative stereochemistry as
observed for the reductions of 2 with LiBHEt3. In contrast, reduction with
catecholborane proceeds in very poor yield (<10%) and with poor
selectivity (<2:1).
(22) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5, 5190-5192.
9
J. AM. CHEM. SOC. VOL. 125, NO. 37, 2003 11281

A R T I C L E S
Kochi et al.
reduction, thereby enabling the final product to be obtained in
a single step. Indeed, hydrogenation of syn-9 and anti-9 with
PtO2 in the presence of TFA was performed cleanly, and (-)-
8-epihalosaline (syn-10) and (-)-halosaline (anti-10) were
isolated after column chromatography in 73 and 81% yield,
respectively.
Figure 6. 2-(2-Hydroxyalkyl)piperidine alkaloids.
to carry out the asymmetric syntheses of two members of this
family, (-)-halosaline (anti-10)23 and (-)-8-epihalosaline (syn-
10).24 A convergent route to these two natural products was
specifically designed such that it also could be employed to
prepare any other member of this family of natural products.
First, protected ketone 6 was prepared according to the
procedure of Grigg and co-workers25 in two steps from the
inexpensive starting materials, ethyl acetoacetate and 2-(2-
bromoethyl)-1,3-dioxolane. Condensation of (R)-tert-butane-
sulfinamide with ketone 6 then provided N-sulfinyl imine 7 in
82% yield. Formation of the metalloenamine of 7 followed by
addition of butyraldehyde under standard conditions provided
â-hydroxy N-sulfinyl imine 8 with 82:18 dr. Column chroma-
tography delivered the pure major isomer in 51% yield. The
catecholborane reduction of 8 at the standard temperature of
-10 °C resulted in significant product decomposition due to
the lability of the acetal under the reaction conditions. Fortu-
nately, when the catecholborane reduction was performed at
-48 °C the reaction proceeded to completion within 3 h and
with 93:7 dr. After column chromatography, diastereomerically
pure syn-9 was isolated in 72% yield. The reaction of 8 with
LiBHEt3 was performed at -78 °C for 3 h and proceeded with
high diastereoselectivity (91:9) to provide diastereomerically
pure anti-9 in 75% yield after column chromatography. We
envisioned that the acidic conditions necessary to remove the
sulfinyl group and cleave the acetal present in syn-9 or anti-9
could also be appropriate for cyclization to the imine and its
Conclusions
A general method is described for asymmetric synthesis of
both syn- and anti-1,3 amino alcohols. The first application of
metalloenamines derived from N-sulfinyl imines is reported for
the highly diastereoselective addition to aldehydes. The reduc-
tion of the product â-hydroxy N-sulfinyl imines 2 with cat-
echolborane and LiBHEt3 provides syn- and anti-1,3-amino
alcohols with very high diastereomeric ratios. This method was
found to be effective for a variety of substrates incorporating
either aromatic or various aliphatic substituents. Finally, the
convergent and efficient asymmetric syntheses of the two natural
products, (-)-8-epihalosaline and (-)-halosaline, were ac-
complished.
Acknowledgment. This work was supported by the NSF
CHE0139468. Dr. Fred J. Hollander and Dr. Allen G. Oliver
are gratefully acknowledged for solving all of the X-ray crystal
structures reported in this contribution. Dr. Herman van Hal-
beek’s assistance in determining the solution structures of 2e
and 2q is greatly appreciated. The Center for New Directions
in Organic Synthesis is supported by Bristol-Myers Squibb as
a sponsoring member and Novartis as a supporting member.
Supporting Information Available: Experimental details,
including synthetic procedures and characterization, and X-ray
crystallographic data of anti-5h (PDF/CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(23) (a) Michel, K.-H.; Sandberg, F.; Haglid, F.; Norin, T. Acta Pharm. Suec.
1967, 4, 97-116. (b) Michel, K.-H.; Sandberg, F.; Haglid, F.; Norin, T.;
Chan, R. P. K.; Craig, J. C. Acta Chem. Scand. 1969, 23, 3479-3481.
(24) Mill, S.; Hootele, C. J. Nat. Prod. 2000, 63, 762-764.
(25) Grigg, R.; Markandu, J.; Perrior, T.; Surendrakumar, S.; Warnock, W. J.
Tetrahedron 1992, 48, 6929-6952.
JA0363462
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11282 J. AM. CHEM. SOC. VOL. 125, NO. 37, 2003