Asymmetric synthesis of acyclic 1,3-amino alcohols by reduction of N-sulfinyl β-amino ketones. Formal synthesis of (-)-pinidinol and (+)- epipinidinol

Article abstract of DOI:10.1021/jo801653c

(Chemical Equation Presented) Stereoselective reduction of acyclic N-sulfinyl β-amino ketones with (LiEt₃BH) and Li(t-BuO) ₃AlH, respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl β-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.

Full text of DOI:10.1021/jo801653c

Asymmetric Synthesis of Acyclic 1,3-Amino Alcohols by Reduction
of N-Sulfinyl ꢀ-Amino Ketones. Formal Synthesis of (-)-Pinidinol
and (+)- Epipinidinol†
Franklin A. Davis,* Paul M. Gaspari, Brad M. Nolt, and Peng Xu
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19096
fdaVis@temple.edu
ReceiVed July 25, 2008
Stereoselective reduction of acyclic N-sulfinyl ꢀ-amino ketones with (LiEt3BH) and Li(t-BuO)3AlH,
respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric
synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl
ꢀ-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel
acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.
Acyclic 1,3-amino alcohols are key structural components
of numerous medicinal compounds as diverse as HIV protease
inhibitors,1 µ-opioid receptor agonists,2 and the potent antibiotic
negamycin.3 This functionality has also been utilized in selective
serotonin reuptake inhibitor antidepressants4 and in the study
of mutagenic deoxyguanosine oligonucleotides.5 Many natural
products such as the sedum alkaloids,6 paliclavine,7 and the
Micronesian marine sponge toxin dysiherbaine8 contain the 1,3-
amino alcohol moiety. Additionally, 1,3-amino alcohols are
useful chiral building blocks in asymmetric synthesis functioning
as chiral ligands and auxiliaries.9
Several racemic syntheses of 1,3-amino alcohols have been
described and include reductions of ꢀ-amino ketones,10 reduc-
tions of ꢀ-hydroxy imines and oximes,11 and the addition of
organometallic reagents to ꢀ-amino aldehydes and ketones.12
Despite the prevalence and importance of 1,3-amino alcohols,
there are few general methods for their asymmetric synthesis,
and many of these are target specific.13,14 Undoubtedly, this is
due to the lack of sources of enantiomerically pure precursors.
Ellman and co-workers reported that the reduction of enan-
tiopure sulfinimine-derived ꢀ-hydroxyl N-sulfinyl imines affords
syn- and anti-1,3-amino alcohols in high diastereomeric ratio.15
† This paper is dedicated to the memory of Albert I. Meyers, a friend and
outstanding scientist, whose pioneering contributions to the art of asymmetric
synthesis continue to inspire.
(1) (a) Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.;
Vasavanonda, 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. (b) 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. (c) 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.
(9) For a review on the use of 1,3-amino alcohols in asymmetric synthesis,
see: (a) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. ReV. 2007, 107, 767.
(10) (a) Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1985, 50, 4052.
(b) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc. Perkin Trans. 1 1990,
1213. (c) Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. J. Org.
Chem. 1992, 57, 1219, and references cited therein. (d) Keck, G. E.; Truong,
A. P. Org. Lett. 2002, 4, 3131.
(11) (a) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. Jpn. 1986,
59, 525. (b) Williams, D. R.; Osterhout, M. H. J. Am. Chem. Soc. 1992, 114,
8750. (c) Veenstra, S. J.; Kinderman, S. S. Synlett 2001, 1109.
(12) Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000, 56, 2665.
(13) For a review see: Tramontini, M. Synthesis 1982, 605.
(14) Reduction of enantiopure ꢀ-amino ketones: (a) Davis, F. A.; Chao, B.
Org. Lett. 2000, 2, 2623. (b) Davis, F. A.; Prasad, K. R.; Nolt, B. M.; Wu, Y.
Org. Lett. 2003, 5, 923. (c) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003,
5, 3855. (d) Kennedy, A.; Nelson, A.; Perry, A. Synlett 2004, 967. (e) Huguenot,
F.; Brigaud, T. J. Org. Chem. 2006, 71, 2159.
(15) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124,
6518.
(2) Shi, Z.; Harrison, B. A.; Verdine, G. L. Org. Lett. 2003, 5, 633.
(3) (a) Kondo, S.; Shibahara, S.; Takahashi, S.; Maeda, K.; Umezawa, H.;
Ohno, M. J. Am. Chem. Soc. 1971, 93, 6305. (b) Raju, B.; Mortell, K.; Anandan,
S.; O’Dowd, H.; Gao, H.; Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.; Yuan,
Z.; White, R.; Trias, J.; Patel, D. V. Bioorg. Med. Chem. Lett. 2003, 13, 2413.
(4) (a) 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.
(5) Nechev, L. V.; Kozedov, I.; Harris, C. M.; Harris, T. M. Chem. Res.
Toxicol. 2001, 14, 1506.
(6) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
(7) Kozikowski, A. P.; Chen, Y.-Y. J. Org. Chem. 1981, 46, 5248.
(8) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc.
1997, 119, 4112.
10.1021/jo801653c CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9619–9626 9619

Davis et al.
SCHEME 1
FIGURE 1. Asymmetric synthesis of ꢀ-amino ketones.
TABLE 1. Synthesis of ꢀ-Amino Ketones by Reaction of ꢀ-Amino
Weinreb Amides with Grignard Reagents at -78 to 0 °C in THF
However, because the ꢀ-hydroxyl N-sulfinyl imines are prepared
by aza-enolate addition to aldehydes this procedure may be
limited.15,16
Weinreb amide
Grignard
reagenta
ꢀ-amino ketone
entry
(R ))
(% isolated yield)
1
2
3
4
5
6
(+)-2a (R ) Me)
(+)-2b (R ) n-C5H11)
(+)-2c (R ) Ph)
(+)-2c (R ) Ph)
(+)-4 (R ) Ph)
PhMgBr
MeMgBr
MeMgBr
PhMgBr
PhMgBr
MeMgBr
(+)-5 (79)
(+)-6 (77)
(+)-7 (92)b
(+)-8 (84)b
(+)-9 (83)
(+)-10 (81%)b
Studies of ꢀ-amino ketone reductions suggest that they offer
the best potential for devising a general method for the
asymmetric synthesis of acyclic syn- and anti-1,3-amino alcohols
from a common precursor.14 The reason why this method has
not found general utility is that diverse enantiopure ꢀ-amino
ketones were lacking. Acyclic enantiopure ꢀ-amino ketones are
now readily available by the addition of methyl ketone enolates
to sulfinimines (N-sulfinyl imines)17,18 or by adding Grignard
reagents to sulfinimine-derived ꢀ-amino Weinreb amides (Fig-
ure 1).14a,b,19,20 N-Sulfinyl ꢀ-amino Weinreb amides, a new
sulfinimine-derived chiral building block,21,22 are prepared by
the addition of Weinreb amide enolates to sulfinimines or by
the reaction of lithium N,O-dimethylhydroxylamine with N-
sulfinyl ꢀ-amino esters.19,20 We describe here a general proce-
dure for the asymmetric synthesis of acyclic syn- and anti-1,3-
amino alcohols via the stereoselective reduction of N-sulfinyl
ꢀ-amino ketones.
(+)-4 (R ) Ph)
a Five equivalents of Grignard reagents used. b Reference 19.
Synthesis of ꢀ-Amino Ketones N-(p-Toluenesulfinyl) Wein-
reb amides (SS,3S)-(+)-2a, (SS,3S)-(+)-2b, and (SS,3R)-(+)-2c
were prepared in 66%, 77%, and 65% yields, respectively, by
addition of the corresponding sulfinimines (S)-(+)-1a-c to the
preformed potassium enolate of N-methoxy-N-methylacetamide
at -78 °C (Scheme 1). While single isomers were isolated for
(+)-2a (R ) Me) and (+)-2b (R ) n-C5H11), Weinreb amide
(+)-2c (R ) Ph) was obtained as a 85:15 mixture.19 As
previously reported, N-(2-methylpropanesulfinyl) Weinreb amide
(SS,3R)-(+)-4 was prepared by the reaction of LiN(OMe)Me
with ꢀ-amino ester (SS,3R)-(-)-3 because the reaction of the
FIGURE 2. Reaction of N-sulfinyl Weinreb amides with Grignard
reagents.
Weinreb amide enolate with the sulfinimine resulted in a 52:48
mixture of diastereoisomers (Scheme 1).19
Treatment of N-sulfinyl ꢀ-amino Weinreb amides 2a-c with
5 equiv of phenyl- or methylmagnesium bromide at -78 to 0
°C gave the corresponding ꢀ-amino ketones. The yields are good
to excellent and are summarized in Table 1 and Figure 2.
Oxidation of (+)-8 with m-CPBA produced (R)-(+)-N-(p-
toluenesulfonyl)-3-amino-1,3-diphenylpropan-1-one (11) in 96%
isolated yield.
(16) Lanter, J. C.; Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905.
(17) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(18) For recent reviews on the chemistry of sulfinimines, see: (a) Morton,
D.; Stockman, R. A. Tetrahedron 2006, 62, 8869. (b) Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichimica. Acta 2005, 38,
93. (c) Zhou, P.; Chem, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (d)
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(19) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.;
Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
(20) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413.
(21) For a review on S-N chemistry, which includes sulfinimines and
sulfinimine-derived chiral building blocks, see: Davis, F. A. J. Org. Chem. 2006,
71, 8993.
(22) For recent reviews on sulfinimine-derived chiral building blocks, see:
(a) Davis, F. A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang, T.;
Burns, D. M.; Rao, A.; Szewczyk, J. M. Heteroatom Chem. 2002, 13, 486. (b)
Davis, F. A.; Yang, B.; Deng, J.; Zhang, J. ARKIVOC 2006, 120.
Reduction of N-Sulfinyl ꢀ-Amino Ketones. Pilli and co-
workers suggested that the anti-selectivity observed in the
reduction of N-aryl ꢀ-amino ketones with Superhydride
(LiEt3BH) resulted from external delivery of hydride to a
N-coordinate boron-amine species.10b With Zn(BH4)2, the syn-
9620 J. Org. Chem. Vol. 73, No. 24, 2008

Formal Synthesis of (-)-Pinidinol and (+)-Epipinidinol
selectivity was observed with lithium tri-tert-butoxyaluminum
hydride [Li(t-BuO)3AlH]. Regardless of whether R1 or R2 in
the N-sulfinyl ꢀ-amino ketone is a large or small group, the
syn/anti selectivity was approximately 4:1 (Table 2, entries 3,
5, 9, and 16). Lithium aluminum hydride (LAH) also gave good
syn-selectivity when R1 in (+)-8 was phenyl (82:18) but lower
syn-selectivity when R1 in (+)-5 was Me (65:35) (Table 2,
entries 21 and 2). Consistent with the cyclic chelated transition
state TS-B (Figure 3), poorer coordinating solvents such as Et2O,
CH2Cl2, and PhMe resulted in improved selectivity as compared
to THF (Table 2: compare entries 9-11 with entry 8). Addition
of LiCl had little effect on the selectivity (Table 1: compare
entries 6, 12, and 17 with 5, 9, and 16). The syn reduction
selectivity for (+)-9 (R1 ) R2 ) Ph) and (+)-10 (R1 Ph, R2 )
Me) having the N-tert-butanesulfinyl group was much better
(Table 1, entries 27 and 29) where single isomers were obtained.
This may reflect steric shielding of the bottom face of the
carbonyl group by the large t-Bu group as in TS-B (Figure 3).
Other reducing reagents such as DIBAL-H and LiBH4 gave
inferior results (Table 2, entries 14, 20, and 23). Interestingly,
Zn(BH4)2, expected to give good syn-selectivity, resulted in
modest anti-selectivity for reduction of (+)-8 (R1, R2 ) Ph)
(Table 2, entries 19 and 24). Here the zinc ion may be
coordinating with the polar sulfinyl group rather than the amino
carbonyl groups. Modest anti-selectivity and poor syn-selectivity
were observed for the reduction of (+)-11 having the N-Ts group
(Table 2, entries 30 and 31). In the latter case, this may reflect
the difficulty in forming the cyclic transition state due to steric
and electronic factors.
The stereochemical configurations of the syn- and anti-1,3-
amino alcohols were assigned analogously to the earlier studies
where LiEt3BH and Li(t-BuO)3AlH preferentially gave the anti-
and syn-1,3-amino alcohols, respectively. Furthermore, as
reported earlier, the C-2(OH) carbon chemical shifts of the anti-
1,3-amino alcohols appear at higher field (lower δ values) as
compared to the syn-alcohols.25 The 13C NMR spectra chemical
shifts for C-2(OH) for anti-13 and 15 appeared at δ 63-65
ppm and for syn-12 and 14 at δ 67-71 ppm. In the single
example where reduction of an N-sulfinyl-1,3-difuryl-ꢀ-amino
ketone with LiEt3BH was reported to give the syn-1,3-amino
alcohol, we believe that the configurational assignment was
incorrect.14d Here, the reported chemical shifts for the C-OH
carbons in the syn- and anti-amino alcohols appeared at δ 64.4
ppm and δ 66.4 ppm, respectively. This is just the opposite of
what has been observed in all other examples.
FIGURE 3. Transition-state structures for reduction of ꢀ-amino
ketones.
SCHEME 2
selectivity arose via external attack of hydride on a cyclic
chelated amino carbonyl species. Similar cyclic chelated
intermediates have been proposed to explain the syn-selectivity
obtained in the reductions of δ-hydroxy-ꢀ-ketoesters,24 ꢀ-hy-
droxy oximes,11a ꢀ-hydroxy imines,11c and ꢀ-hydroxy N-sulfinyl
imines.15 Reduction of several N-sulfinyl ꢀ-amino ketones with
LiEt3BH is reported to give anti-N-sulfinyl 1,3-amino alco-
hols,14b,24 and with Zn(BH4) or Li(t-BuO)3AlH these amino
ketones afforded the syn products.14a,b Although likely to be
more complicated because of the presence of the N-sulfinyl
group, transition-state structures TS-A and TS-B can be evoked
to explain anti/syn-selectivity for metal hydride reductions of
N-sulfinyl ꢀ-amino ketones (Figure 3).
Reduction of N-(p-toluenesulfinyl)-ꢀ-amino ketones (+)-5,
(+)-6, (+)-7, and (+)-8 with (LiEt3BH) at -78 °C in CH2Cl2
in all cases gave the anti-1,3-amino alcohol 13 as the major
isomer and is consistent with TS-A (Scheme 2, Table 2). When
either R1 or R2 in the ketone is phenyl, a single diastereoisomer
was obtained (Table 2, entries 1, 7, and 15). When both R1 and
R2 are small alkyl groups as in (+)-6 (R1 ) n-C5H11 and R2 )
Me) the syn/anti ratio was reduced to 20:80 affording the major
diastereoisomer (+)-13b in 72% isolated yield (Table 2, entry
4). If the nitrogen substituent is a bulky N-(2-methylpropane-
sulfinyl) or N-tosyl group as in (+)-9, (+)-10, and (+)-11, lower
selectivity was observed where the syn/anti ratios were 29:71,
30:70, and 1:9, respectively (Table 2, entries 26, 28, and 30).
This may reflect the difficulty of LiEt3BH to efficiently
coordinate with the nitrogen atom in these compounds resulting
in hydride addition to both Re and Si faces of the carbonyl.
It was more difficult to achieve high syn-selectivity in
reductions of p-tolyl N-sulfinyl ꢀ-amino ketones. The best syn-
Asymmetric Synthesis of (-)-Pinidinol and (+)-Epipin-
dinol. (-)-Pinidinol (18), an alkaloid found in North American
conifers of the Pinaceae family, belongs to the Sedum and
Lobelia species: 2-substituted and 2,6-disubstituted piperidines
with a -CH2CH(OH)R side chain (Scheme 3).5,26 Pinidinol (18)
exhibits antifeedent properties against the Eastern spruce
budworms.27 Other members of this class of alkaloids exhibit
a broad range of biological activities that include memory-
enhancing, antibiotic, anesthetic, and anti-Alzheimer properties.5
Only four asymmetric syntheses of (-)-18 have been de-
scribed,28 three of which are multistep, low overall yield
procedures.28a,b,d Three of these syntheses use nonchiral amine
starting materials,28a,c,d and none of them employ ꢀ-amino
(25) Jager, V.; Buss, V. Liebgs Ann. Chem. 1980, 110.
(26) Strunz, G. M.; Findlay, J. A. Pyridine and Piperidine Alkaloids, The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 26, p 89.
(27) Schneider, M. J.; Montali, J. A.; Hazen, D.; Stanton, C. E. J. Nat. Prod.
1991, 54, 905.
(23) Evans, D. A.; Chapman, K. T.; Carreria, E. M. J. Am. Chem. Soc. 1988,
110, 3560.
(24) Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.;
Stabler, R. S.; Widler, L. HelV. Chem. Acta 1986, 69, 803.
J. Org. Chem. Vol. 73, No. 24, 2008 9621

Davis et al.
% yieldb
TABLE 2. Reduction of ꢀ-Amino Ketones at -78 °C
entry
ꢀ-amino ketone Z, R1, R2
reducing agent (equiv)
solvent
product syn/anti (dr)a
1
2
3
4
5
6
7
8
(+)-5, p-tolyl, Me, Ph
LiEt3BH (5)
LAH (3)
CH2Cl2
Et2O
Et2O
CH2Cl2
Et2O
Et2O
CH2Cl2
THF
Et2O
CH2Cl2
PhMe
Et2O
12a:13a (1:99)
12a:13a (65:35)
12a:13a (9:1)
73
70c
61
72
76
61
87
76c
70
73
62
70
50c
90
68
71
Li(t-BuO)3AlH (3)
LiEt3BH (5)
Li(t-BuO)3AlH (3)
Li(t-BuO)3AlH (3), LiCl (10)
LiEt3BH (5)
(+)-6, p-tolyl, n-C5H11, Me
(+)-7, p-tolyl, Ph, Me
12b:13b (20:80)
12b:13b (81:19)
12b:13b (88:12)
12c:13c (1:99)
12c:13c (66:34)
12c:13c (91:9)
12c:13c (91:9)
12c:13c (89:11)
12c:13c (91:9)
12c:13c (65:35)
12d:13d (1:99)
12d:13d (85:15)
12d:13d (89:11)
12d:13d (55:45)
12d:13d (32:68)
12d:13d (23:77)
12d:13d (82:18)
12d:13d (69:31)
12d:13d (69:31)
12d:13d (17:83)
decomposition
14d:15d (29:71)
14d:15d (1:99)
14d:15d (30:70)
14d:15d (1:99)
16:17 (1:9)
Li(t-BuO)3AlH (3)
9
10
11
12
13
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Li(t-BuO)3AlH (3), LiCl (10)
LAH (3)
LiEt3BH (5)
Li(t-BuO)3AlH (3)
Li(t-BuO)3AlH (3), LiCl (10)
NaBH4 (7)
Zn(BH4)2 (5)
DIBAL-H (5)
LAH (3)
LAH (3)
LiBH4/InCl3
Zn(BH4)2 (5)
Catecholborane (5)
LiEt3BH (5)
Li(t-BuO)3AlH (3), LiCl (10)
LiEt3BH (5)
Li(t-BuO)3AlH (3), LiCl (10)
LiEt3BH (5)
Li(t-BuO)3AlH (3)
LiEt3BH
Li(t-BuO)3AlH (3)
Li(t-BuO)3AlH (3), LiCl (10)
Et2O
CH2Cl2
Et2O
(+)-8, p-tolyl, Ph, Ph
Et2O
MeOH
THFd
THF
Et2O
THF
48b
52c
70c
63c
68c
86
Et2O
Et2Od
THFd
CH2Cl2
Et2O
(+)-9, t-Bu, Ph, Ph
(+)-10, t-Bu, Ph, Me
(+)-11, Ts, Ph, Ph
(-)-25
90c
90
93
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
Et2O
90
47
16:17 (55:45)
27:26 (1:99)
27:26 (54:46)
27:26 (90:10)
72c
90
87c
72
a Determined by 1H NMR on the crude reaction mixture. b Isolated yield of major diastereoisomer unless otherwise noted. c Combined yields of both
diastereoisomers. d Reduction carried out at 0 °C.
SCHEME 3
SCHEME 4
ketones as intermediates.28 The advantage of using a ꢀ-amino
ketone as an intermediate in the synthesis of (-)-18 is that (+)-
epipinidinol (19) would also be available, from a common
precursor, via stereoselective reduction. Furthermore, it will be
possible to test the feasibility of using a tandem or cascade
cyclization reaction to form the piperidine ring from an
N-sulfinyl 1,3-amino alcohol ketal.
Our synthesis begins with masked oxo-sulfinimine (R)-(-)-
22 prepared in 72% yield from aldehyde 20 and (R)-(-)-p-
toluenesulfinamide (21) (Scheme 4). Addition of (-)-22 to the
preformed potassium Weinreb amide enolate 23 gives the
N-sulfinyl ꢀ-amino Weinreb amide (RS,3R)-(-)-24 with a dr
of 22:1 and isolation of the major isomer in 74% yield. Next,
the reaction of (-)-24 with 5 equiv of methylmagnesium
bromide afforded the desired ꢀ-amino ketone ketal (RS,4R)-(-)-
25 in 96% isolated yield (Scheme 4). Reduction of (-)-25 with
LiBEt3H, as expected, gave (RS,2R,4R)-(-)-26 as a single isomer
having the anti-orientation of the amino and hydroxyl groups
(Table 2, entry 32). This assignment is based on our previous
results, its conversion into (-)-pinidinol (18), and the fact the
C-OH 13C NMR chemical shift appears at δ 63.7 ppm. With
Li(t-BuO)3AlH the syn/anti-1,3-amino alcohol ratio was a
disappointing 54:46 (Table 2, entry 33). However, with 10 equiv
of LiCl the syn/anti ratio improved to 90:10 resulting in the
isolation of the (RS,2S,4R)-(-)-27 in 72% yield (Table 2, entry
9622 J. Org. Chem. Vol. 73, No. 24, 2008

Formal Synthesis of (-)-Pinidinol and (+)-Epipinidinol
SCHEME 5
concise formal asymmetric synthesis of (-)-pinidinol (18) and
(+)-epipinidinol (19) in six steps and 42-36% overall yield
from a masked oxo sulfinimine. This procedure employed a
novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl
protected alcohol ketal to prepare the pinidinol piperidine ring.
Experimental Section
Sulfinimines (S)-(+)-N-(acetylidene)-p-toluenesulfinamide (1a)
and (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (1c) were pre-
pared as previously described.29 (SS,3R)-(+)-N-(p-Toluenesulfinyl)-
3-amino-N-methoxy-N-3-phenylpropionamide (2c) and (SS,3R)-(+)-
N-(2-methylpropanesulfinyl)-3-amino-N-methoxy-N-methyl-3-
phenylpropionamide (4) were prepared as previously described.19
ꢀ-Amino ketones (SS,3R)-(+)-N-(p-toluenesulfinyl)-3-amino-1-
methyl-3-phenylpropan-1-one (7),19 (SS,3R)-(+)-N-(p-toluenesul-
finyl)-3-amino-1,3-diphenylpropan-1-one (8),14b and (SS,3R)-(+)-
N-(2-methylpropanesulfinyl)-3-amino-1-methyl-3-phenylpropan-1-
one (10)19 were prepared as previously described.
Typical Procedure for the Preparation of Sulfinimines.19
(S)-(+)-N-(Hexylidene)-p-toluenesulfinamide (1b). In a 250 mL,
flame-dried, single-necked, round-bottomed flask equipped with a
magnetic stirring bar and rubber septum were placed (S)-(+)-p-
toluenesulfinamide19 (1.55 g, 10 mmol) and n-hexanal (1.23 mL,
10 mmol) in CH2Cl2 (62 mL) at 0 °C. To the mixture was added
Ti(OEt)4 (0.114 g, 50 mmol) at 0 °C, and the solution was stirred
for 4 h at rt. At this time, the reaction was quenched with H2O (10
mL) and filtered through a Celite pad, and the Celite was washed
with CH2Cl2 (50 mL). The aqueous phase was extracted with
CH2Cl2 (2 × 10 mL), and the combined organic phases were
combined, dried (MgSO4), and concentrated. Chromatography
34). We speculate that the presence of LiCl promotes formation
of the cyclic transition state TS-B (Figure 3). The C-OH 13C
NMR chemical shifts in (-)-27 appears at 67.6 ppm and
provides further validation for this method of assigning relative
stereochemistry for acyclic 1,3-amino alcohols.
(hexanes/EtOAc, 92:8) gave 1.9 g (80%) of a slightly yellow oil:
1
[R]25 +328.6 (c 0.982, CHCl3); IR, 1597, 1458, 1096 cm-1; H
D
NMR (CDCl3) δ 0.88 (t, J ) 7.2 Hz, 3H), 1.31 (4 overlapping H),
1.61 (m, 2H), 2.41 (s, 3H), 2.49 (m, 2H), 7.30 (d, J ) 8 Hz, 2H),
7.55 (d, J ) 8 Hz, 2H), 8.23 (t, J ) 4.8 Hz, 1H); δ 14.1, 21.7,
22.6, 25.4, 31.6, 36.1, 124.9, 130.1, 141.9, 142.3, 167.6; HRMS
calcd for C13H20NOS (M + H) 238.1272, found 238.1265.
(R)-(-)-N-[5,5-(Ethylenedioxy)hexanylidene]-p-toluenesulfi-
namide (22). This sulfinimine was prepared from (R)-(-)-p-
toluenesulfinamide19 and 5,5-(ethylenedioxy)hexanal.30 Flash chro-
matography (hexanes/EtOAc 8:2) provided 1.06 g (83%) of a
The feasibility of a single-flask, three-step cascade reaction
of an amino alcohol ketal to produce the piperidine heterocycle
was next explored. Acid-catalyzed hydrolysis of (-)-26 is
expected to remove the N-sulfinyl auxiliary, unmasked the oxo
group to give 28 which cyclizes to imine 29 (Scheme 5).
Hydrogenation would give (-)-pinidinol (18). However, hy-
drolysis with 3 N HCl in THF at 0 °C resulted in decomposition.
Considering that the problem may be the free hydroxyl group
in (-)-26, it was protected as the tert-butyldiphenylsilyl ether
to give (RS,2R,4R)-(-)-30, which on reaction with 3 N HCl in
THF afforded imine (2R,2′R)-(+)-31 in 79% yield (Scheme 5).
However, hydrogenation with 10% Pd/C at 1 atm of H2 resulted
in no reaction. Increasing the pressure of H2 to 60 psi gave a
92% isolated yield of the TBDMS-protected pinidinol (-)-32.
Similar methodology gave the TBDMS-protected epipinidinol
(-)-35, but the hydrogenation pressure needed to be increased
to 100 psi for any reaction to occur. Molander and co-workers
had earlier prepared (-)-32 and (-)-35 using a lanthanocene-
catalyzed intramolecular hydroamination reaction.28c This com-
pletes our formal synthesis of (-)-pinidinol (18) and (+)-
epipinidinol (19) from a common N-sulfinyl ꢀ-amino ketone
ketal (-)-25.
In summary, general methodology for the efficient asymmetric
synthesis of syn- and anti-1,3-amino alcohols via the reduction
of enantiopure N-sulfinyl-ꢀ-amino ketones using LiEt3BH and
Li(t-BuO)3AlH, respectively has been devised. These reagents
gave good to excellent syn- and anti-selectivity for reduction
of N-(p-toluenesulfinyl) ꢀ-amino ketones. For reduction of N-(2-
methylpropanesulfinyl) ꢀ-amino ketones, LiEt3BH resulted in
poor anti-selectivity but exhibited excellent syn-selectivity with
Li(t-BuO)3AlH. This new methodology was highlighted in a
colorless oil: [R]20 -279.7 (c 0.52, CHCl3); IR (CH2Cl2) 3051,
D
1
1635, 1214 cm-1; H NMR (CDCl3) δ 1.30 (s, 3H), 1.66 (m, 4
overlapping H), 2.41 (s, 3H), 2.50 (m, 2 overlapping H), 3.92 (m,
4H), 7.32 (d, J ) 8.1 Hz, 2H), 7.57 (d, J ) 7.8 Hz, 2H), 8.23 (t,
J ) 4.8 Hz, 1H); 13C NMR (CDCl3) δ 20.2, 21.7, 24.1, 36.2, 38.7,
65.0, 124.9, 130.1, 142.0, 167.2; HRMS calcd for C15H22NO3S (M
+ H) 296.4051, found 296.4029.
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-me-
thylpropionamide (2a). Typical Procedure. In a two-neck, oven-
dried, 100 mL round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet was placed N-methoxy-N-
methylacetamide (0.16 mL, 1.5 mmol) in THF (20 mL). The
solution was cooled to -78 °C, KHMDS (1.5 mmol, 3 mL of 0.5
M solution in toluene) was added, and the reaction mixture was
stirred at this temperature for 1 h. A solution of (S)-(+)-1a (0.25
g, 1.0 mmol) in THF (10 mL) was added, and the solution was
stirred at this temperature for 2.5 h. At this time, the reaction
(28) (a) Gebauer, J.; Rost, D.; Blechert, S. Heterocycles 2006, 68, 2129. (b)
Fre´ville, S.; Delbecq, P.; Thuy, V. M.; Petit, H.; Ce´le´rier, J. P.; Lhommet, G.
Tetrahedron Lett. 2001, 42, 4609. (c) Molander, G. A.; Dowdy, E. D.; Pack,
S. K. J. Org. Chem. 2001, 66, 4344. (d) Takahata, H.; Yotsui, Y.; Momose, T.
Tetrahedron 1998, 54, 13505.
(29) (a) 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.
Org. Chem. 1997, 62, 2555. (b) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang,
T.; Fanelli, D.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
(30) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 3, 759.
J. Org. Chem. Vol. 73, No. 24, 2008 9623

Davis et al.
mixture was quenched with satd NH4Cl (5 mL), slowly warmed to
rt, and diluted with H2O (10 mL). The solution was extracted with
Et2O (2 × 30 mL), and the organic phases were washed with brine
(25 mL), dried (MgSO4), and concentrated. Chromatography
A cooled -78 °C solution of (S)-(-)-N-(benzylidene-2-methyl-
propane)sulfinamide31 (0.209 g, 1.0 mmol) in THF (10 mL) was
added dropwise via cannula to the enolate solution followed by
THF (5 mL) to rinse the flask. The reaction mixture was stirred at
-78 °C for 2 h and cautiously quenched with satd NH4Cl (4 mL).
The reaction mixture was diluted with H2O (10 mL) and extracted
with EtOAc (2 × 15 mL), and the combined organic phases were
washed with brine (10 mL), dried (MgSO4), and concentrated.
Chromatography (30:70, hexanes/EtOAc) gave 0.273 g (83%) of a
clear oil which solidified on standing: mp 68-70 °C; [R]25D +123.6
(c 0.25, CHCl3); IR (neat) 3270, 3202, 1629; 1H NMR (CDCl3) δ
1.22 (s, 9H), 3.47 (dd, J ) 8.0 Hz, J ) 17.2 Hz, 1H), 3.59 (dd, J
) 17.2 Hz, J ) 4.0 Hz, 1H), 4.81 (d, J ) 4.0 Hz, 1H), 4.96 (m, J
) 4.0 Hz, J ) 8.0 Hz, 1H), 7.35 (m, 7H), 7.55 (m, 1H), 7.91 (m,
2H); 13C NMR (CDCl3) δ 23.0, 46.3, 55.7, 55.9, 127.9, 128.3, 128.5,
129.0, 134.0, 136.9, 141.4, 198.9; HRMS calcd for C19H23NO2SNa
(M + Na) 352.1347, found 352.1348.
(hexanes/EtOAc 1:9) yielded 0.19 g (66%) of a clear oil: [R]25
D
+154.8 (c 2.73, CHCl3); IR (neat) 3482, 3220, 1652 cm-1; 1H NMR
(CDCl3) δ 1.42 (d, J ) 6.6 Hz, 3H), 2.42 (s, 3H), 2.67 (d, J ) 5.5
Hz, 2H), 3.16 (s, 3 H), 3.66 (s, 3H), 3.85 (m, 1H), 5.06 (d, J ) 7.6
Hz, 1H), 7.30 (d, J ) 8.4 Hz, 2H), 7.61 (q, J ) 4.9, 8.2 Hz, 2H);
13C NMR (CDCl3) δ 21.8, 22.7, 32.2, 33.2, 39.7, 40.3, 47.9, 61.6,
126.1, 126.4, 129.9, 141.5, 142.6, 172.5; HRMS calcd for
C13H21O3N2SNa (M + Na) 307.1092, found 307.1090.
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-me-
thyloctanamide (2b). Flash chromatography (hexanes:/EtOAc, 2:3)
gave 1.1 g (77%) of a clear oil: [R]25D +105.7 (c 1.07, CHCl3); IR
1
(thin film) 3019, 1216 cm-1; H NMR (CDCl3) δ 0.91 (t, J ) 6.8
Hz, 3H), 1.4-1.8 (8 overlapping H), 2.41 (s, 3H), 2.78 (m, 2H),
3.16 (s, 3H), 3.67 (s, 3H overlapped with 1H), 4.92 (d, J ) 8.4
Hz, 1H), 7.28 (d, J ) 8.0 Hz, 2H), 7.59 (d, J ) 8.0 Hz, 2H); 13C
NMR (CDCl3) δ 14.4, 21.7, 22.9, 26.3, 31.9, 36.1, 37.9, 53.6, 61.6,
125.9, 129.8, 141.4, 143.3, 173.5; HRMS calcd for C17H29N2O3S
(M + H) 341.1899, found 341.1912.
(R)-(+)-N-(p-Toluenesulfonyl)-3-amino-1,3-diphenylpropan-
1-one (11). In a single-neck, 25-mL round-bottom flask equipped
with magnetic stirring bar, rubber septum, and argon inlet were
placed (SS,3R)-(+)-8 (0.363 g, 1.0 mmol) and CH2Cl2 (15 mL)
under an argon atmosphere. The solution was cooled to 0 °C,
m-CPBA (0.6 g, 3.5 mmol, 77%) was added, and the solution was
stirred at this temperature for 3.5 h. At this time, NaHCO3 (1 N
aqueous solution) was added to the reaction mixture until pH 8
was reached. The solution was extracted with EtOAc (2 × 10 mL),
and the organic phases were washed with brine (5 mL), dried
(MgSO4), and concentrated. Chromatography (hexanes/EtOAc 1:1)
gave 0.364 g (96%) of a clear oil: [R]20D +18.3 (c 1.0, CHCl3)
[lit.31 [R]25D -22.0 (c 1.0, CHCl3) for the S-isomer]; IR (neat)
(RS,3R)-(-)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-meth-
yl-7,7-(ethylenedioxy)octamide (24). Chromatography (hexanes/
EtOAc, 2:3) gave 0.619 g (74%) of a pale yellow oil: [R]25D -44.5
(c 0.951, CHCl3); IR (neat) 3101, 1652, 1215 cm-1 1H NMR
;
(CDCl3) δ 1.31 (s, 3H), 1.63 (m, 6H), 2.38 (s, 3H), 2.76 (m, 2H),
3.13 (s, 3H), 3.64 (s, 3H), 3.68 (m, 1H), 3.92 (m, 4H), 4.94 (d, J
) 8.8 Hz, 1H), 7.25 (d, J ) 8.4 Hz, 2H), 7.57 (d, J ) 8.4 Hz, 2H);
13C NMR (CDCl3) δ 21.0, 21.5, 24.0, 32.1, 36.0, 37.8, 38.9, 53.4,
61.5, 64.9,110.2, 125.8, 129.7, 141.3, 143.0, 172.5; HRMS calcd
for C19H31N2O5S (M + H) 399.1954, found 399.1947.
1
3050, 1629, 1410, 1250 cm-1; H NMR (CDCl3) δ 2.35 (s, 3H),
3.45 (dd, J ) 6.0 Hz, J ) 17.2 Hz, 1H), 3.59 (dd, J ) 6.0 Hz, J
) 17.2 Hz, 1H), 4.87 (dd, J ) 6.4 Hz, J ) 12.8 Hz, 1H), 5.81 (d,
J ) 6.4 Hz, 1H), 7.16 (m, 7H), 7.41 (t, J ) 8.0 Hz, 2H), 7.54 (t,
1H), 7.61 (d, J ) 8 Hz, 2H), 7.80 (dd, J ) 0.8 Hz, J ) 8.0 Hz,
2H); 13C NMR (CDCl3) δ 21.8, 45.1, 54.8, 127.1, 127.6, 128.0,
128.4, 128.9, 129.0, 129.8, 133.9, 136.7, 137.6, 140.3, 143.6, 198.1.
(RS,4R)-(-)-N-(p-Toluenesulfinyl)-4-amino-8,8-(ethylenedioxy)-
nonan-2-one (25). In a flame-dried, 100-mL round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
inlet was placed (-)-24 (0.472 g, 1.18 mmol) in THF (38 mL).
The solution was cooled to -78 °C, and methylmagnesium bromide
(5.9 mmol, 1.97 mL of a 3.0 M solution in Et2O) was added. The
reaction mixture was warmed to 0 °C, stirred for 30 min, and
quenched with satd aqueous NH4Cl (3 mL). At this time, H2O (5
mL) was added, the aqueous layer was extracted with EtOAc (2 ×
10 mL), and the combined organic phases were combined, dried
(MgSO4), and concentrated. Chromatography (hexanes/EtOAc, 2:3)
gave 0.401 g (96%) of a clear oil: [R]25D -78.1 (c 0.547, CHCl3);
IR (thin film) 3210, 1712, 1063 cm-1; 1H NMR (CDCl3) δ 1.32 (s,
3H), 1.4-1.7 (m, 6H), 2.10, (s, 3H), 2.40 (s, 3H), 2.77 (d, J ) 4.8
Hz, 2H), 3.67 (m, 1H), 3.94 (m, 4H), 4.39 (d, J ) 9.6 Hz, 1H with
overlapping 1H), 7.30 (d, J ) 8.0 Hz, 2H), 7.58 (d, J ) 8.0 Hz,
2H); 13C NMR (CDCl3) δ 20.8, 21.4, 23.9, 30.9, 35.9, 38.7, 49.3,
52.6, 64.8, 110.0, 125.6, 129.6, 141.4, 142.7, 207.5; HRMS calcd
for C18H28NO4S (M + H) 354.1739, found 354.1737.
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-1-phenyl-3-meth-
ylpropan-1-one (5). Typical Procedure. In an oven-dried, single-
neck, 50-mL round-bottom flask equipped with a magnetic stirring
bar, a rubber septum, and an argon inlet was placed (SS,R)-(+)-2a
(0.284 g, 1.0 mmol) in THF (20 mL) under an argon atmosphere.
The solution was cooled to -78 °C, PhMgBr (5.0 mmol, 5.0 mL
of 1.0 M solution in THF) was added via syringe, and the reaction
mixture was warmed to rt. After being stirred for 1 h, the solution
was cooled to -78 °C, quenched with satd NH4Cl (6 mL), and
warmed to rt. The solution was diluted with H2O (10 mL) and
extracted with Et2O (3 × 10 mL). The combined organic phases
were washed with brine (5 mL), dried (MgSO4), and concentrated.
Chromatography (hexanes/EtOAc 1:1) gave 0.2567 g (79%) of a
clear oil: [R]25 +75.1 (c 0.8, CHCl3); IR (CHCl3) 3197, 1675,
D
1568 cm-1; 1H NMR (CDCl3) δ 1.36 (d, J ) 6.6 Hz, 3H), 2.33 (s,
3H), 3.09 (dq, J ) 5.4 Hz, J ) 16.8 Hz, 1H), 3.89-3.95 (m, 1H),
4.62 (d, J ) 7.8 Hz, 1H), 7.34 (m, 7H), 7.77 (d, J ) 7.4 Hz, 2H).
13C NMR (CDCl3) δ 21.7, 22.5, 22.9, 46.7, 47.7, 125.8, 128.5,
129.0, 129.9, 133.8, 137.1, 141.6, 142.4, 198; HRMS calcd for
C17H19NO2SNa (M + Na) 324.1034, found 324.1030.
(SS,4S)-(+)-N-(p-Toluenesulfinyl)-4-aminononan-2-one(6).Chro-
matography (hexanes/EtOAc, 7:3) gave 74% of a clear oil: [R]20
+101.6 (c 1.36, CHCl3); IR (CH2Cl2) 3053, 1712, 1265, 1063 cm-1D
;
1H NMR (CDCl3) δ 0.90 (t, J ) 6.8 Hz, 3H), 1.27-1.71 (8
overlapping H), 2.11 (s, 3H), 2.42 (s, 3H), 2.77 (d, J ) 5.2 Hz,
2H), 3.66 (m, 1H), 4.42 (d, J ) 9.2 Hz, 1H), 7.29 (d, J ) 8.0 Hz,
2H), 7.56 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3) δ 14.3, 21.6,
22.8, 26.2, 31.1, 31.8, 36.1, 49.5, 52.9, 125.8, 129.8, 141.5, 143.0,
207.8; HRMS calcd for C16H26N1O2S1 (M + H) 296.1684, found
296.1682.
(SS,1R,3R)-(+)-3-(p-Toluenesulfinylamino)-1,3-diphenylpro-
pan-1-ol (13d). Typical Procedure for the Reduction of ꢀ-Ami-
no Ketones with LiEt3BH To Give anti-1,3-Amino Alcohols. In
a single-neck, oven-dried, 25-mL round-bottom flask equipped with a
magnetic stirring bar, a rubber septum, and an argon inlet was placed
(SS,3R)-(+)-8 (0.036 g, 0.1 mmol) in CH2Cl2 (10 mL) under an argon
atmosphere. The solution was cooled to -78 °C, and LiEt3BH (0.5
mmol, 0.5 mL of 1.0 M solution in THF) was added via syringe. After
being stirred at -78 °C for 2 h, the reaction mixture was cautiously
quenched with satd NH4Cl (1 mL) and warmed to rt. The solution
(SS,3R)-(+)-N-(2-Methylpropanesulfinyl)-3-amino-1,3-diphe-
nylpropan-1-one (9). In a single-neck, oven-dried, 50-mL round-
bottom flask equipped with a magnetic stirring bar, a rubber septum,
and an argon inlet were placed THF (10 mL) and KHMDS (1.8
mmol, 3.6 mL of a 0.5 M solution in THF) under argon atmosphere.
The solution was cooled to -78 °C, acetophenone (0.21 mL, 1.8
mmol) was added via syringe, and the solution was stirred for 1 h.
(31) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 64, 1278.
9624 J. Org. Chem. Vol. 73, No. 24, 2008

Formal Synthesis of (-)-Pinidinol and (+)-Epipinidinol
was diluted with H2O (10 mL) and extracted with CH2Cl2 (3 × 10
mL), and the combined organic phases were washed with brine (5
mL), dried (MgSO4), and concentrated. Chromatography (petroleum
ether/EtOAc 1:1) gave 0.033 g (90%) of a white solid: mp 123-126
7.03 (m, 2H), 7.16 (m, 2H), 7.25 (m, 6H), 7.33 (m, 2H), 7.63 (d,
J ) 8 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 45.7, 55.4, 70.9, 125.7,
126.3, 127.2, 127.4, 127.8, 128.57, 128.60, 129.5, 137.7, 140.5,
143.2, 143.7. A satisfactory HRMS could not be obtained because
of decomposition in the instrument.
°C; [R]20 +130.8 (c 1.0, CHCl3); IR (thin film) 3260, 3030, 1262
D
cm-1; 1H NMR (CDCl3) δ 1.99 (dq, J ) 4.4 Hz, J ) 4.8 Hz, J ) 7.2
Hz, J ) 18.8 Hz, m, 1H), 2.16-2.23 (dq, J ) 4.4 Hz, J ) 4.8 Hz, J
) 7.2 Hz, J ) 18.8 Hz, m, 1H), 2.32 (s, 1H), 3.06 (d, J ) 4.0 Hz,
1H), 4.68-4.73 (m, 2H), 4.76 (d, J ) 6.4 Hz, 1H), 7.15 (m, 1H),
7.22 (m, 7H), 7.29 (d, J ) 4.0 Hz, m, 4H), 7.50 (d, J ) 8.0 Hz, m,
2H); 13C NMR (CDCl3) δ 21.7, 47.4, 56.5, 70.9, 125.9, 126.2, 127.2,
127.85, 127.90, 128.9, 129.1, 130.0, 141.9, 142.6, 143.0, 144.2. Anal.
Calcd for C22H23NO2S: C, 72.30; H, 6.34; N, 3.83. Found: C, 72.46;
H, 6.82; N, 3.89.
(RS,2R,4R)-(-)-N-(p-Toluenesulfinyl)-4-amino-8,8-(ethylene-
dioxy)nonan-2-ol (26). In a flame-dried, 100-mL round-bottom
flask equipped with a magnetic stirring bar, rubber septum, and
argon inlet was placed (-)-25 (0.120 g, 0.34 mmol) in CH2Cl2 (34
mL). The solution was cooled to -78 °C, LiBHEt3 (2.04 mmol,
2.04 mL of a 1.0 M solution in THF) was added dropwise, and the
solution was stirred at this temperature for 2.5 h. At this time, the
reaction mixture was quenched by addition of satd aqueous NH4Cl
(2 mL) and H2O (2 mL). The phases were separated, and the
aqueous phase was saturated with NaCl and extracted with CH2Cl2
(3 × 15 mL). The combined organic phases were dried (MgSO4)
and concentrated. Chromatography (hexanes/EtOAc, 2:3) gave
(SS,1S,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1-phenyl-3-me-
thylpropan-1-ol (13a). Chromatography (petroleum ether/EtOAc,
1:1) provided 73% of a clear oil: [R]25D +88.4 (c 2.6, CHCl3); IR
1
(neat) 3322, 2963, 1248 cm-1; H NMR (CDCl3) δ 1.35 (d, J )
0.102 g (85%) of a clear oil: [R]25 -132.6 (c 0.941, CHCl3); IR
D
6.5 Hz, 3H), 1.80 (m, 1H), 1.89-1.95 (m, 1H), 2.42 (s, 3H), 2.97
(d, J ) 4.5 Hz, 1H), 3.53 (m, 1H), 4.35 (d, J ) 7.5 Hz, 1H), 7.29
(m, 7H), 7.61 (d, J ) 8.5 Hz, 2H); 13C NMR (CDCl3) δ 21.3, 24.0,
47.3, 48.7, 126.0, 127.7, 128.8, 129.9, 141.8, 142.4, 144.9; HRMS
calcd for C17H21NO2SNa (M + Na) 326.1191, found 326.1188.
(SS,2S,4S)-(+)-N-(p-Toluenesulfinyl)-4-aminononan-2-ol (13b).
Chromatography (hexanes/EtOAc, 6:4) gave 72% of a clear oil:
(thin film) 3416, 3240, 1375, 1087 cm-1; 1H NMR (CDCl3) δ 1.18
(d, J ) 6.3 Hz, 3H), 1.33 (s, 3H), 1.57 (m, 8H), 2.40 (s, 3H), 3.23
(d, J ) 5.4 Hz, 1H), 3.61 (m, 1H), 3.95 (m, 4H), 4.05 (d, J ) 8.7
Hz, 1H), 7.31 (d, J ) 7.8 Hz, 2H), 7.64 (d, J ) 7.8 Hz, 2H); 13C
NMR (CDCl3) δ 20.7, 21.5, 23.8, 24.0, 37.7, 39.0, 44.9, 53.7, 63.7,
64.8, 110.2, 125.6, 129.8, 141.7, 142.6; HRMS calcd for
C18H30NO4S (M + H) 356.1895, found 356.1898.
[R]25D +89.6 (c 0.341 CHCl3); IR (CH2Cl2) 3054, 1422, 1265 cm-1
;
(SS,1R,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1-methyl-3-
phenylpropan-1-ol (12c). Typical Procedure for the Reduction
of ꢀ-Amino Ketones with Li(t-Bu)3AlH and LiCl in Et2O To
Give syn-1,3-Amino Alcohols. In a flame-dried, 50-mL round-bottom
flask equipped with a magnetic stirring bar, rubber septum, and argon
inlet were placed (+)-7 (0.054 g, 0.179 mmol) and LiCl (0.076 g, 1.8
mmol) in Et2O (9 mL). The reaction mixture was sonicated for 5-10
min and cooled to -78 °C, and Li(t-BuO)3AlH (0.895 mmol, 0.895
mL of a 1.0 M solution in THF) was added dropwise. The solution
was stirred at this temperature for 2 h and quenched with satd aqueous
NH4Cl (0.5 mL) and H2O (0.5 mL). The organic phases were
separated; the aqueous phase was washed with EtOAc (2 × 1 mL),
and the combined organic phases were dried (MgSO4) and concen-
trated. Chromatography (hexanes/EtOAc, 40:60) gave 0.040 g (70%)
1H NMR (CDCl3) δ (major diastereomer) 0.89 (m, 7 overlapping
H), 1.22 (d, J ) 6.6 Hz, 3H), 1.31-1.78 (m, 6 overlapping H),
2.42 (s, 3H), 3.23 (m, 1H), 3.62 (m, 1H), 3.98-4.03 (m, 2
overlapping H), 4.48 (br s, 1H), 7.33 (d, J ) 8.1 Hz, 2H), 7.61 (d,
J ) 8.1 Hz, 2H); 13C NMR (CDCl3) δ 14.4, 21.7, 23.0, 23.9, 26.1,
32.0, 37.8, 45.1, 54.1, 63.9, 125.7, 129.9, 141.9, 142.7; HRMS calcd
for C16H28NO2S (M + H) 298.4650, found 298.4632.
(SS,1S,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1-methyl-3-
phenylpropan-1-ol (13c). Chromatography (petroleum ether/
EtOAc, 1:1) provided 84% of a clear oil: [R]25 +65.2 (c 1.0,
D
CHCl3); IR (CHCl3) 3339, 3214, 1263 cm-1; 1H NMR (CDCl3) δ
1.15 (d, J ) 6.3 Hz, 3H), 1.73 (m, 1H), 1.88 (m, 1H), 2.34 (s, 3H),
2.86 (d, J ) 4.4 Hz, 1H), 4.65 (d, J ) 6.3 Hz, 1H), 4.74 (m, 1H),
4.88 (br, 1H), 7.25 (m, 7H), 7.53 (d, J ) 5.0 Hz, 2H); 13C NMR
(CDCl3) δ 21.8, 23.8, 45.7, 55.7, 64.7, 126.5, 127.5, 127.7, 128.8,
129.7, 137.9, 141.1, 143.5; HRMS calcd for C17H21NO2S (M +
H) 304.1371, found 304.1368.
of a clear oil: [R]20 +16.6 (c 0.295, CHCl3); IR (thin film) 3054,
D
1422, 1265 cm-1; 1H NMR (CDCl3) δ 1.16 (d, J ) 6 Hz, 3H), 1.85
(m, 2H), 2.40 (s, 3H), 3.45 (d, J ) 4.8 Hz, 1H), 4.01 (m, 1H), 4.74
(m, 1H), 5.51 (d, J ) 2.4 Hz, 1H), 7.24 (d, J ) 8 Hz, 2H), 7.35 (m,
5 overlapping H), 7.54 (d, J ) 8 Hz, 2H); 13C NMR (CDCl3) δ 21.7.
25.0, 47.5, 58.8, 125.6, 127.5, 128.0, 129.1, 129.9, 141.7, 143.1, 143.2;
HRMS calcd for C17H21NO2SNa (M + H) 326.1200, found 326.1199.
(SS,1R,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-3-methyl-1-phe-
nylpropan-1-ol (12a). Chromatography (petroleum ether/EtOAc, 1:1)
(SS,1R,3R)-N-(2-Methylpropanesulfinyl)-3-amino-1-methyl-3-
phenylpropan-1-ol (15c). Mixture of inseparable syn/anti (30:70)
1
isomers: H NMR (CDCl3) δ 1.22 (s, 9H), 1.29 (d, J ) 8.8 Hz,
3H), 1.92 (t, J ) 6.4 Hz, 2H), 3.54 (d, J ) 6.4 Hz, 1H), 4.01 (m,
J ) 6.4 Hz, J ) 14.0 Hz, 1H), 4.61 (d, J ) 7.0 Hz, 1H), 4.73 (dt,
J ) 6.8 Hz, J ) 8.0 Hz, J ) 16.0 Hz, 1H), 7.23-7.28 (m, 1H),
7.30-7.35 (m, 4H).
provided 0.014 g (61%) of a clear oil: [R]25 +76.5 (c 4.5, CHCl3);
D
IR (neat) 3309, 3223, 1270 cm-1; 1H NMR (CDCl3) δ 1.35 (d, J )
6.5 Hz, 3H), 1.74 (m, 1H), 1.88 (m, 1H), 2.41 (s, 3H), 3.71 (m, 1H),
3.84 (d, J ) 3.5 Hz, 1H), 4.79 (m, 1H), 5.03 (d, J ) 4.5 Hz, 1H),
7.26 (m, 9H), 7.61 (m, 2H); 13C NMR (CDCl3) δ 21.9, 24.2, 47.7,
48.9, 50.8, 71.2, 74.2, 126.2, 127.9, 128.1, 129.1, 130.2, 145.3; HRMS
calcd for C17H21NO2SNa (M + Na) 326.1191, found 326.1195.
(SS,2S,4R)-(+)-N-(p-Toluenesulfinyl)-4-aminononan-2-ol (12b).
Chromatography (hexanes/EtOAc, 6:4) gave 61% of a clear oil:
(SS,1R,3R)-(+)-N-(2-Methylpropanesulfinyl)-3-amino-1,3-diphe-
nylpropan-1-ol (15d). Chromatography (CHCl3 satd NH3) gave
51% of the major diastereomer as a white solid: mp 156-160 °C;
[R]D +84.8 (c 1.0, CHCl3); IR (CHCl3) 3233, 1210 cm-1; 1H NMR
(CDCl3) δ 1.22 (s, 9H), 2.17 (m, 1H), 2.29 (m, 1H), 3.33 (br, 1H),
4.37 (d, J ) 5.2 Hz, 1H), 4.66 (dt, J ) 4.4 Hz, J ) 8.2 Hz), 4.85
(q, J ) 4.0 Hz, J ) 8.8 Hz, 1H), 7.26 (m, 5H), 7.33 (m, 5H); 13C
NMR (CDCl3) δ 23.0, 47.2, 56.1, 57.2, 71.5, 126.2, 127.1, 127.7,
128.0, 128.90, 128.92, 143.1, 144.1. Anal. Calcd for C19H25NO2S:
C, 68.85; H, 7.60; N, 4.23. Found: C, 68.94; H, 7.68; N, 3.99.
(1R,3R)-(+)-N-(p-Toluenesulfonyl)-3-amino-1,3-diphenylpro-
pan-1-ol (17). Chromatography (petroleum ether/EtOAc, 1:1)
1
IR (CH2Cl2) 3054, 1422, 1265 cm-1; H NMR (CDCl3) δ 0.92 (t,
J ) 10.4 Hz, 3H), 1.16 (d, J ) 6.4 Hz, 3H), 1.45 (m, 10H), 2.41
(s, 3H), 3.53 (m, 1H), 3.60 (br d, J ) 2.8 Hz, 1H), 4.04 (m, 1H),
4.30 (d, J ) 6.8 Hz, 1H), 7.29 (d, J ) 8 Hz, 2H), 7.59 (d, J ) 8
Hz, 2H); 13C NMR (CDCl3) δ 14.4, 21.7, 22.9, 24.7, 25.5, 32.0,
38.1, 45.5, 56.4, 67.6, 125.6, 129.9, 141.8, 142.8; HRMS calcd for
C16H27NO2S (M + H) 298.1762, found 297.1831.
provided 58% of a colorless oil: IR (thin film) 3600, 3300, 1400,
1
1250 cm-1; [R]20 +110.6 (c 0.15, CHCl3); H NMR (CDCl3) δ
D
(SS,1S,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1,3-diphenyl-
propan-1-ol (12d). Chromatography (hexanes/EtOAc, 65:35) gave
74% of a white solid: mp 46-47 °C; [R]20D +12.1 (c 1.0, CHCl3); IR
2.03 (m, 2H), 2.37 (s, 3H), 2.54 (br, 1H), 4.61 (dt, J ) 4.4 Hz, J
) 8.0 Hz, 1H), 4.82 (t, J ) 5.6 Hz, 1H), 5.66 (d, J ) 8.0 Hz, 1H),
1
(CHCl3) 3268, 1246 cm-1; H NMR (CDCl3) δ 1.95 (m, 1H), 2.14
(32) Zhao, C.-H.; Liu, Li.; Wang, D.; Chen, Y.-J. Eur. J. Org. Chem. 2006,
2977.
(m, 1H), 2.33 (s, 3H), 3.27 (d, J ) 2.8 Hz, 1H), 4.79 (dt, J ) 2.8 Hz,
J. Org. Chem. Vol. 73, No. 24, 2008 9625

Davis et al.
J ) 9.2 Hz, 2H), 5.45 (d, J ) 2.4 Hz, 1H), 7.16 (m, 2H), 7.23 (m,
6H), 7.30 (t, J ) 8 Hz, 2H), 7.37 (t, J ) 8 Hz, 2H), 7.48 (d, J ) 8 Hz,
2H); 13C NMR (CDCl3) δ 21.8, 47.7, 58.7, 125.7, 125.9, 127.7, 128.0,
128.1, 128.9, 129.0, 129.9, 141.7, 142.8, 144.9; HRMS calcd for
C22H23NO2SNa (M + Na) 388.1347, found 388.1345.
-46.8 (c 1.03, CHCl3); IR (CH2Cl2) 3054, 1421, 1265 cm-1; 1H NMR
(CDCl3) δ 0.86 (d, J ) 6.0 Hz, 3H), 1.02 (s, 9H), 1.31 (s, 3H), 1.51
(8 overlapping H), 2.39 (s, 3H), 3.23 (m, 1H), 3.49 (d, J ) 8.0 Hz,
1H), 3.78 (m, 1H), 3.93 (m, 4H), 7.20 (d, J ) 8.4 Hz, 2H), 7.38 (8
overlapping H), 7.68 (4 overlapping H); 13C NMR (CDCl3) δ 19.5,
20.3, 21.6, 23.5, 24.1, 27.3, 37.4, 39.2, 46.1, 52.5, 65.0, 67.4, 110.3,
126.0, 127.8, 128.0, 129.7, 129.9, 130.0, 134.9, 136.3, 141.3, 142.5;
HRMS calcd for C34H47NO4SiSNa (M + Na) 616.2893, found
616.2907.
(SS,1S,3R)-(+)-N-(2-Methylpropanesulinyl)-3-amino-1,3-di-
phenyl-1-ol (14d). Chromatography (hexane/EtOAc, 3:1) gave 90%
of white solid: mp 158-162 °C; [R]25 +66.3 (c 0.3, CHCl3); IR
D
1
(neat) 3231, 1280 cm-1; H NMR (CDCl3) δ 1.22 (s, 9H), 1.98
(dq, J ) 2.4 Hz, J ) 3.2 Hz, J ) 14.4 Hz, 1H), 2.19 (dt, J ) 4.4
Hz, J ) 10.4 Hz, J ) 14.4 Hz, 1H), 4.02 (br, 1H), 4.74 (m, 1H),
5.00 d, J ) 10.4 Hz, 1H), 5.44 (s, 1H), 7.26 (m, 2H), 7.35 (m,
8H); 13C NMR (CDCl3) δ 23.1, 46.3, 55.7, 56.0, 127.9, 128.3, 128.5,
129.0, 134.0, 136.9, 141.4, 198.9; HRMS calcd for C19H25NO2SNa
(M + Na) 354.1504, found 354.1517.
(2R,2′R)-(+)-2′,3′,4′,5′-Tetrahydro-6′-methylpyridinyl-2-(tert-
butyldiphenylsilyloxy)propane (31). In a 50-mL, round-bottom
flask equipped with magnetic stirring bar and rubber septum was
placed (-)-27 (0.244 g, 0.41 mmol) in THF (19 mL). The solution
was cooled to 0 °C, 3 N HCl (1.8 mL) was added, and the reaction
mixture was stirred for 3 h at this temperature. The solution was
neutralized to pH 7.0 by dropwise addition of satd aqueous
NaHCO3. The phases were separated, the aqueous phase was ex-
tracted with Et2O (3 × 2 mL), and the combined organic extracts
were dried (MgSO4) and concentrated. Chromatography (3%
MeOH/CH2Cl2) gave 0.128 g (79%) of a clear oil: [R]25D +12.1 (c
(SS,1S,3R)-(+)-N-(2-Methylpropanesulfinyl)-3-amino-1-meth-
yl-3-phenylpropan-1-ol (14c). Chromatography (EtOAc/hexanes
2:1) gave 90% of a white solid: mp 145-6 °C; [R]20 +181.9 (c
D
0.8, CHCl3); IR (neat) 3100, 1210 cm-1; 1H NMR (CDCl3) δ 1.13
(s, 9H), 1.23 (s, 3H), 1.70 (m, 1H), 1.83 (m, 1H), 2.06 (br, 1H),
4.09 (m, 1H), 4.30 (m, 1H), 4.52 (d, J ) 9.6 Hz, 1H), 5.55 (s, 1H),
7.16 (m, 1H), 7.23 (m, 4H); 13C NMR (CDCl3) δ 23.1, 25.2, 47.1,
55.8, 59.2, 68.8, 127.5, 127.83, 137.84, 143.6; HRMS calcd for
C14H23NSO2 (M + H) 270.1538, found 270.1521.
1.14, CHCl3); IR (thin film) 3070, 3048, 1660, 1427, 1374 cm-1
;
1H NMR (CDCl3) δ 1.05 (s, 9H), 1.12 (d, J ) 6 Hz, 3H), 1.41-1.61
(m, 5 overlapping H), 1.76 (m, 1H), 1.88 (d, J ) 1.6 Hz, 3 H),
2.00 (m, 2H), 3.24 (br m, 1H), 4.14 (m, 1H), 7.39 (m, 5H), 7.72
(m, 5H); 13C NMR (CDCl3) δ 19.0, 19.6, 24.0, 27.4, 27.9, 30.3,
48.1, 55.1, 67.9, 127.7, 129.7, 135.0, 135.4, 136.3, 167.1; HRMS
calcd for C25H35NOSi (M + H) 394.2566, found 394.2555.
(2R,2′R,6′R)-(-)-1-(6′-Methylpiperidin-2′-yl)-2-(tert-butyl-
diphenylsilyloxy)propane (32). In a 2-dram vial equipped with a
loose fitting lid were placed (-)-31 (0.040 g, 0.1 mmol) and 10%
Pd/C (0.001 g) in MeOH (2 mL). The vial was placed in a Parr
bomb and pressurized with H2 (60 psi), and the solution was stirred
for 8 h. The bomb was depressurized, the reaction mixture was
filtered through Celite, and the Celite washed with MeOH (1 mL).
The filtrate was concentrated to give 0.036 g (92%) of a clear oil:
[R]20D -1.5 (c 0.735 CHCl3) [lit.28c [R]27D -1.4 (c 0.55, CHCl3)];
1H NMR (CDCl3) δ 0.96 (d, J ) 6.3 Hz, 3H), 0.99 (m, 1H), 1.07
(m, 12H), 1.28 (m, 1H), 1.51 (m, 5H), 1.70 (m, 2H), 2.46 (m, 1H),
2.73 (m, 1H), 3.95 (m, 1H), 7.37 (m, 6H), 7.67 (m, 4H); 13C NMR
(CDCl3) δ 19.9, 23.2, 24.6, 25.4, 27.7, 33.1, 34.3, 47.1, 53.1, 54.2,
67.5, 128.1, 128.3, 130.2, 130.3, 134.7, 135.3, 136.5, 136.6. Spectral
properties were consistent with literature values.28c
(RS,2S,4R)-(-)-N-(p-Toluenesulfinyl)-4-amino-8,8-(ethylene-
dioxy)nonan-2-ol (27). In a flame-dried, 50-mL round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon inlet
were placed (-)-25 (0.093 g, 0.262 mmol) and LiCl (0.111 g, 2.62
mmol) in Et2O (10 mL). The solution was sonicated for 5-10 min
and cooled to -78 °C. Li(t-BuO)3AlH (0.95 mL, 0.895 mmol of a
1.0 M solution in THF) was added dropwise, and the reaction mixture
was stirred at -78 °C for 2 h. At this time, the reaction was quenched
by addition of satd aqueous NH4Cl (0.5 mL) and H2O (0.5 mL). The
organic phase was separated, and the aqueous phase was extracted
with EtOAc (2 × 1 mL). The combined organic phases were dried
(MgSO4) and concentrated. Chromatography (hexanes/EtOAc, 40:60)
gave 0.049 g (90%) of a clear oil: [R]25D -43.1 (c 0.237, CHCl3); IR
(thin film) 3053, 1421, 1263 cm-1; 1H NMR (CDCl3) δ 1.15 (d, 2H,
J ) 6.4 Hz), 1.34 (s. 3H), 1.510-1.712 (9 overlapping H), 2.40 (s,
3H), 3.55 (m, 1H), 3.70 (m, 1H), 3.96 (m, 4H), 4.05 (m, 1H), 4.39 (d,
1H, 6.8 Hz), 7.27 (d, 2H, J ) 8.8 Hz), 7.59 (d, 2H, J ) 8.8 Hz); 13
C
NMR (CDCl3) δ 20.4, 21.7, 24.1, 24.7, 38.2, 39.2, 45.5, 56.3, 65.0,
67.6, 110.3, 125.6, 129.9, 141.8, 142.7; HRMS calcd for C18H30NO4S
(M + H) 356.1896, found 356.1906.
(2S,2′R,6′R)-(-)-1-(6′-Methylpiperidin-2′-yl)-2-(tert-butyl-
diphenylsilyloxy)propane (35). The same procedure used for the
synthesis of (-)-32 was employed for the preparation of (-)-35
except that the cyclic imine 34 was hydrogenated without purifica-
tion due to its instability. After hydrogenation at 100 psi of H2 in
(Rs,2R,4R)-(-)-N-(p-Toluenesulfinyl)-2-(tert-butyldiphenylsi-
lyloxy)-4-amino-7-(2-methyl-1,3-dioxolan-2-yl)heptane (30). In
a flame-dried 5-mL vial, equipped with a magnetic stirring bar,
rubber septum, and argon inlet were placed (-)-26 (0.030 g, 0.084
mmol) and imidazole (0.014 g, 0.21 mmol) in CH2Cl2 (1 mL). To
the solution was added TBDPSCl (0.025 g, 0.092 mmol) in CH2Cl2
(0.5 mL), and the reaction was stirred for 8 h and quenched by
addition of H2O (0.5 mL). The phases were separated, the aqueous
phase was extracted with CH2Cl2 (3 × 0.5 mL), and the combined
organic phases were dried (MgSO4) and concentrated. Chromatog-
raphy (hexanes/EtOAc, 4:1) gave 0.047 g (90%) of a clear oil:
MeOH for 18 h a clear, viscous oil (84%) was obtained: [R]20
D
-6.5 (c 0.499, CHCl3) [lit.28c [R]27 -6.5 (c 0.51, CHCl3)]; H
1
D
NMR (CDCl3) δ 1.06 (14 overlapping H), 1.25 (m, 2 overlapping
H), 1.42 (d, J ) 6.4 Hz, 3H), 1.64 (m, 4 overlapping H), 2.24 (m,
1H), 2.94 (m, 1H), 3.15 (m, 1H), 3.86 (m, 1H), 7.40 (m, 6
overlapping H), 7.67 (m, 4 overlapping H); 13C NMR (CDCl3) δ
19.4, 19.7, 23.0, 24.4, 27.2, 27.6, 30.9, 42.6, 54.5, 56.0, 66.6, 127.7,
128.0, 129.9, 130.0, 133.7, 134.1, 136.0, 136.1. Spectral properties
were consistent literature values.28c
[R]25D -62.8 (c 1.15, CHCl3); IR (CH2Cl2) 3050, 1415, 1261 cm-1
;
1H NMR (CDCl3) δ 0.83 (s, 9H), 1.07 (d, J ) 6.4 Hz, 3H), 1.33
(s, 3H), 1.68 (m, 8H), 2.37 (s, 3H), 3.64 (m, 1H), 3.92 (m, 4H),
4.04 (m, 1H), 4.94 (d, J ) 4.40 Hz, 1H), 7.44 (m, 14H); 13C NMR
(CDCl3) δ 19.2, 20.3, 21.6, 22.8, 24.1, 27.1, 30.0, 36.1, 39.3, 43.7,
51.9, 65.0, 68.6, 110.3, 125.9, 127.8, 127.9, 129.7, 129.9, 130.0,
133.9, 134.4, 136.2, 141.2, 143.2; HRMS calcd for C34H47NO4SSi
(M + H) 594.3073, found 594.3093.
Acknowledgment. This work was supported by a grant from
the National Institutes of General Medical Sciences (GM 57870).
Supporting Information Available: Experimental proce-
dures and spectroscopic data for all new compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(Rs,2S,4R)-(-)-N-(p-Toluenesulfinyl)-2-(tert-butyldiphenylsi-
lyloxy)-4-amino-7-(2-methyl-1,3-dioxolan-2-yl)heptane (33). Chro-
matography (hexanes/EtOAc, 4:1) gave 85% of a clear oil: [R]20
JO801653C
D
9626 J. Org. Chem. Vol. 73, No. 24, 2008