Highly diastereoselective addition of Grignard reagents to aliphatic, enolizable N-alkylketimines and 2,2-disubstituted 1,3-oxazolidines. Asymmetric synthesis of the antidepressant cericlamine

Article abstract of DOI:10.1021/jo982222+

Grignard reagents were added to 2,2-disubstituted 1,3-oxazolidines and enolizable ketimines prepared from hydroxyacetone and phenylglycinol derivatives, with high to excellent diastereoselectivity, to yield 2,2- disubstituted 1,2-amino alcohol derivatives. Lewis acids had considerable influence on the yield and diastereoselectivity of the addition. This method was applied to the first asymmetric synthesis of the 5-HT reuptake inhibitor Cericlamine.

Full text of DOI:10.1021/jo982222+

2406
J . Org. Chem. 1999, 64, 2406-2410
High ly Dia ster eoselective Ad d ition of Gr ign a r d Rea gen ts to
Alip h a tic, En oliza ble N-Alk ylk etim in es a n d 2,2-Disu bstitu ted
1,3-Oxa zolid in es. Asym m etr ic Syn th esis of th e An tid ep r essa n t
Cer icla m in e
Arno G. Steinig and Denice M. Spero*
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road,
P.O. Box 368, Ridgefield, Connecticut 06877-0368
Received November 6, 1998
Grignard reagents were added to 2,2-disubstituted 1,3-oxazolidines and enolizable ketimines
prepared from hydroxyacetone and phenylglycinol derivatives, with high to excellent diastereo-
selectivity, to yield 2,2-disubstituted 1,2-amino alcohol derivatives. Lewis acids had considerable
influence on the yield and diastereoselectivity of the addition. This method was applied to the first
asymmetric synthesis of the 5-HT reuptake inhibitor Cericlamine.
Sch em e 1. P r ep a r a tion of th e Sta r tin g Ma ter ia ls
Although the asymmetric synthesis of amines by
addition of organometallic reagents to aldimines and
2-monosubstituted 1,3-oxazolidines has gained much
interest in recent years,1 the corresponding reactions with
ketimines and 2,2-disubstituted 1,3-oxazolidines remain
largely unexplored. This is due to their poorer reactivity
toward nucleophilic addition and their propensity to
enolize on addition of Grignard reagents.2 Hua et al.
observed that addition of allylmagnesium bromide to
N-sulfinylketimines, which have one potential site for
enolization, occurred in 47-98% yields, but more basic
Grignard reagents gave only enolization.3 We recently
showed4 that a broad variety of Grignard reagents could
be added in a highly diastereoselective manner to (2-
heteroaryl)alkylimines with phenylglycinol derivatives as
chiral auxiliaries,5 the key feature being chelate forma-
tion of MgBr2 with the imine nitrogen and the heteroatom
of the arene. The chelate activated the imine toward
nucleophilic attack and “locked” it into the (E) configu-
ration. After demonstrating the first example of an
asymmetric addition of a Grignard reagent to a phenyl-
glycinol-derived ketimine, we set out to broaden the scope
of the methodology. We report here the unprecedented
addition of Grignard reagents to imines and oxazolidines
prepared from hydroxyacetone and phenylglycinol de-
rivatives. In this work, we demonstrate that the chelating
substituent on the imine can be extended to include not
only aromatic heterocycles but also an aliphatic CH2OR
group. These substrates have two potential sites for
enolization; therefore, the addition of Grignard reagents
to them represents a significant synthetic challenge.
In this study, we have focused on two types of sub-
strates, the oxazolidine 3 and the O-TBDMS-protected
imine 4. The oxazolidine 3 was prepared from (S)-
phenylglycinol (1) and methoxyacetone (2) by stirring
with MgSO4 in CH2Cl2.6 The imine 4 was prepared from
(S)-O-TBDMS-phenylglycinol (TBDMS-1) and 2 with
MgSO4 in benzene (Scheme 1). The configuration of the
double bond in 4 and the configuration at C-2 of 3 were
determined by NOESY experiments in CD2Cl2.
With the starting materials in hand, we investigated
the feasibility of the addition of Grignard reagents. The
reactions were carried out in CH2Cl2 instead of the more
commonly used THF to increase the coordination of Lewis
acids to the substrates.4 We were gratified to find that
Grignard reagents could indeed be added with high
selectivity. We optimized the addition of Grignard re-
agents to 3 and 4 using benzylmagnesium halides by
(1) Reviews: (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895-1946. (b) Pridgen, L. N. Adv. Asymm. Synth. 1997, 2,
55-117. (c) Risch, N.; Arend, M. In Methods of Organic Chemistry
(Houben-Weyl): Stereoselective Synthesis; Helmchen, G., Hoffmann, R.
W., Mulzer, J ., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart,
1995; Vol. E 21b, 1833-1893. (d) Volkmann, R. A. In Comprehensive
Organic Synthesis, Additions to C-X π Bonds, Part 1; Schreiber, S.
L., Ed.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter 1.12. (e)
Kleinmann, E. F.; Volkmann, R. A. In Comprehensive Organic Syn-
thesis, Additions to C-X π Bonds, Part 2; Heathcock, C. H., Ed.;
Pergamon Press: Oxford, 1991; Vol. 2, Chapter 4.3.
(2) Stork, G.; Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178-2180.
(3) (a) Hua, D. H.; Miao, S. W.; Chen, J . S.; Iguchi, S. J . Org. Chem.
1991, 56, 4-6. (b) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J .
Tetrahedron: Asymmetry 1995, 6, 349-352.
(4) Spero, D. M.; Kapadia, S. R. J . Org. Chem. 1997, 62, 5537-5541.
(5) The pioneering work by Takahashi et al. on the use of phenyl-
glycinol as chiral auxiliary for additions to imines and 1,3-oxazolidines
was later explored widely by Pridgen et al.; see ref 1 and (a) Takahashi,
H.; Chida, Y.; Higashiyama, K.; Onishi, H. Chem. Pharm. Bull. 1985,
33, 4662-4670. (b) Poerwono, H.; Higashiyama, K.; Takahashi, H. J .
Org. Chem. 1998, 63, 2711-2714 and references therein. (c) Wu, M.-
J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340-1344. (d) Mokhallalati,
M. K.; Wu, M.-J .; Pridgen, L. N. Tetrahedron Lett. 1993, 34, 47-50.
(e) Pridgen, L. N.; Mokhallalati, M. K.; McGuire, M. A. Tetrahedron
Lett. 1997, 38, 1275-1278 and references therein.
(6) It is interesting to note that oxazolidine 3 does not exist as a
mixture of the open-chain hydroxyimine and the cyclized oxazolidines,
as was observed in our earlier work with the corresponding pyridyl-
substituted compounds.
10.1021/jo982222+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/06/1999

Asymmetric Synthesis of the Antidepressant Cericlamine
J . Org. Chem., Vol. 64, No. 7, 1999 2407
Ta ble 1. Ad d ition of RMgX to Oxa zolid in es 3 a n d Im in e 4
entry
substrate
RMgX
BnMgCl
BnMgCl
BnMgCl
Bn MgBr
BnMgCl
BnMgCl
Lewis acid
product
yield (%)
de (eea) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(S)-3
(S)-3b
(S)-3
(S)-3
(S)-4
(S)-4
(S)-4
(S)-4
(S)-3
(S)-4
(S)-4
(S)-3
(S)-4
(S)-4
-
5a
5a
5a
5a
29
28
34
38
56
71
49
87
80
73
50
54
59
67
92
94
24
99.5
93
98.4
92
98.8
96
96
95
MgBr2
EtAlCl2
MgBr 2
-
MgBr2
EtAlCl2
MgBr 2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr 2
TBDMS-5a
TBDMS-5a
TBDMS-5a
TBDMS-5a
5b
TBDMS-5b
TBDMS-5c
5eb
BnMgCl
Bn MgBr
AllylMgBr
AllylMgBr
PhMgBr
AllenylMgBr
ArCH2MgClc
Ar CH2MgBr c
98
89
95
TBDMS-5d
TBDMS-5d
a
b
ee of 6a and 6d , determined by HPLC.10 Homopropargylamine 5e:allenylamine 8 g 99:1. c Ar ) (3,4-diCl)Ph.
Sch em e 2. Ad d ition of RMgX to 3 a n d 4 a n d
Rem ova l of th e Au xilia r ya
Sch em e 3
is the first highly diastereo- and chemoselective addition
of this Grignard reagent to a 1,3-oxazolidine.
The auxiliary was efficiently removed from 5 by
Pb(OAc)4 oxidation10 to give the 2,2-disubstituted 1,2-
amino alcohol derivatives 6.11 This reaction requires an
unprotected 1,2-amino alcohol moiety, so the compounds
TBDMS-5 had to be desilylated. Both acidic and TBAF/
THF deprotection worked in good yield. We found that
the desilylation of TBDMS-5 and also the hydrolysis of
the intermediate benzaldimine generated from 5 by Pb-
(OAc)4 could be performed very conveniently by using
disposable syringe barrel columns containing a bonded
silica support functionalized with ethylbenzenesulfonic
acid (SCX), designed for solid-phase extraction.12 To our
knowledge, these are the first examples of performing
synthetic reactions on these columns. Additionally, from
both TBDMS-5a and 5a , the auxiliary could be removed
by transfer hydrogenation (NH4HCO2, 10% Pd/C, MeOH,
reflux).13 The methyl ether of 6a and 6c was cleaved with
BBr3 in good yield to give the 1,2-amino alcohols 7a and
7c (Scheme 2).
a
Conditions: (A) RMgX, Lewis acid, CH2Cl2; (B) Pb(OAc)4,
MeOH/CH2Cl2; (C) NH4HCO2, 10% Pd/C, MeOH, reflux, overnight.
varying the Lewis acids and the halide (Table 1, entries
1-87,8). Selectivity was highest with MgBr2 and BnMgBr
(entries 4 and 8). Addition of BnMgBr to the oxazolidine
3 afforded the amine 5a in 38% yield with a 99.5% de.
The yield could be improved by the addition of BnMgBr
to the O-TBDMS-protected imine 4. In this case, an 87%
yield of amine product was realized with a 98.8% de.
This method can be extended to a variety of Grignard
reagents. For example, under the optimized conditions,
allylmagnesium bromide was added to 3 and 4 in 80%
and 73% yield, respectively (entries 9 and 10). Even
phenylmagnesium bromide could be added to 4 (entry 11,
50% yield), despite the considerably higher basicity of this
Grignard reagent and the fact that the substrate has two
sites for enolization.9 In all of the above cases, the de was
g95%. The addition of allenylmagnesium bromide (entry
12) to 3 deserves special comment. It proceeded with 98%
de and a ratio of homopropargylamine 5e:allenylamine
8 of g99:1 (Scheme 3). To the best of our knowledge, this
Both the oxazolidine 3 and the imine 4 gave predomi-
nantly the same diastereomer of the addition product.
On the basis of the sign of optical rotation of the known
amino alcohols 7a ,14 7c,15 and 10,14 the (S) configuration
of the auxiliary leads to the (S) configuration at the newly
formed stereocenter. A possible transition structure is
(10) Mokhallalati, M. K.; Pridgen, L. N. Synth. Commun. 1993, 23,
2055-2064.
(11) 6a : Chiralcel OD column eluting with hexanes/iPrOH/NEt3
3873:90:1 at 0.5 mL/min, UV detection at 254 nm; tR (S,R) 18.3 min,
(S,S) 20.3 min. 6d : Chiralcel OD column eluting with hexanes/EtOH/
HNEt2 960:30:1 at 0.5 mL/min, UV detection at 254 nm; tR (S,R) 15.5
min, (S,S) 18.4 min. The ee of 6a and 6d determined under these
conditions were in accord with the de of the addition products 5a ,d
and TBDMS-5a ,d determined by 1H NMR.
(7) Other Lewis acids such as BF3‚OEt2, CuI/BF3‚OEt2, CeCl3,
Yb(OTf)3, ZnI2, and TMSOTf gave inferior results.
(8) We observed that the yields for the addition of BnMgCl in the
presence of MgBr2 to imine 4 increased from 53% and 66% to 71%
with 3, 4, and 5 equiv of this Grignard reagent, respectively. The
selectivity dropped slightly (98.7%, 98.5%, 98.4% ee, respectively). With
oxazolidine 3 and BnMgCl, the yields did not change; however, the
selectivity increased (83% and 92% ee with 3 and 5 equiv, respectively).
(9) We also tried to add ethylmagnesium bromide (as an example
for very basic alkyl Grignard reagents) but obtained only poor yields
of the desired addition product.
(12) See, for example: Lawrence, R. M.; Biller, S. A.; Fryszman, O.
M.; Poss, M. A. Synthesis 1997, 553-558.
(13) With 5d and TBDMS-5d , the 3,4-dichlorophenyl ring was
dechlorinated prior to cleavage of the auxiliary, giving 6a instead of
6d .
(14) Kaptein, B.; Moody, H. M.; Broxterman, Q. B.; Kamphuis, J .
J . Chem. Soc., Perkin Trans. 1 1994, 1495-1498.
(15) Terashima, S.; Yamada, S.-I. Chem. Pharm. Bull. 1968, 16,
1953-1971.

2408 J . Org. Chem., Vol. 64, No. 7, 1999
Steinig and Spero
(67% vs 59%), as was observed with the simple BnMgCl
and BnMgBr.22
Scheme 4 shows our final synthesis. After addition of
3,4-dichlorobenzylmagnesium bromide to ketimine 4, the
phenylglycinol auxiliary was desilylated and removed by
oxidative cleavage with Pb(OAc)4 (73% for desilylation
and removal of auxiliary). Dimethylation of 6d with
formic acid/formaldehyde gave the amine 9 in high yield
(89%). Cleavage of the methyl ether with BBr3 (67%)
yielded (S)-Cericlamine (10).
F igu r e 1. Possible transition structure.
In summary, we have developed an unprecedented,
asymmetric synthesis of 2,2-disubstituted 1,2-amino al-
cohols23 via a highly diastereoselective addition of Grig-
nard reagents to ketimines and 2,2-disubstituted 1,2-
oxazolidines. We applied this to the first asymmetric
synthesis of the 5-HT reuptake inhibitor Cericlamine. In
the course of that work, we used solid-phase extraction
SCX columns for cleaving TBDMS ethers and hydrolysis
of benzaldimines.
Sch em e 4. Syn th esis of (S)-Cer icla m in e [(S)-10]
Exp er im en ta l Section
Gen er a l P r oced u r es. Proton NMR spectra were recorded
at 270 or 400 MHz in CDCl3 using TMS (δ 0.00) or CHCl3 (δ
7.26) as the internal standard. 13C NMR spectra were recorded
at 100.6 MHz in CDCl3 using CDCl3 (δ 77.00) as the internal
standard. Multiplicities were determined by the DEPT se-
quence and are given as follows: (+) CH or CH3, (-) CH2,
(Cquat) C. Commercially available chemicals were used as
received. Column chromatography was carried out on silica
gel 60 (E. Merck, 230-400 or 60-230 mesh). Solid-phase
extraction SCX columns were obtained from Varian Sample
Preparation Products.
shown in Figure 1. We postulate that the stereochemistry
can be explained by A1,3 strain, which favors the confor-
mation shown. The phenyl group blocks the re face, and
the delivery of the nucleophile occurs from the less
hindered si face.16 The MgBr2 seems to activate the imine
through complexation.17 In addition, the methoxyl oxygen
could also participate in coordination with magnesium.18
This transition structure is analogous to the one we
previously reported.4
To demonstrate the utility of this methodology, we
have synthesized the serotonin reuptake inhibitor Ceri-
clamine (10)19 which is in clinical trials as an antidepres-
sant.20 The patented synthesis of enantiopure 10 starts
from the corresponding amino acid that has been resolved
by crystallization with tyrosine hydrazide.21 An enzy-
matic resolution of the amino acid amide has also been
published.14
(S)-O-TBDMS-p h en ylglycin ol (TBDMS-1).4 To a solution
of (S)-1 (5.00 g, 36.4 mmol) and TBDMSCl (6.03 g, 40.0 mmol)
in dry CH2Cl2 (50 mL) were added NEt3 (10.15 mL, 7.367 g,
72.8 mmol) and DMAP (178 mg, 1.5 mmol). After the mixture
was stirred at room temperature for 21 h, saturated NH4Cl
solution (25 mL) was added; the crude product was extracted
with CH2Cl2, dried over solid Na2SO4, and distilled (bp 120
°C/0.5 Torr) to give TBDMS-1 (7.62 g, 83%) as a colorless oil,
[R]25.2D ) +15.6° (c 1.94, EtOH). MS (ES+) m/z 252 (83) [MH+],
235 (84) [MH+ - NH3], 220 (35), 156 (100); 1H NMR (270 MHz,
CDCl3) δ 0.03 (s, 6 H), 0.90 (s, 9 H), 1.8 (br s, 2 H), 3.51 (dd,
The key step is the addition of 3,4-dichlorobenzylmag-
nesium halides to imine 4 (see Table 1, entries 13 and
14). Both 3,4-dichlorobenzylmagnesium halides gave high
selectivities (89% and 95% de). The bromide was more
selective than the chloride and also gave a higher yield
3
2
3
2J ) 9.8, J ) 8.4 Hz, 1 H), 3.72 (dd, J ) 9.8, J ) 4.0 Hz, 1
3
3
H), 4.07 (dd, J ) 8.4, J ) 4.0 Hz, 1 H), 7.25-7.40 (m, 5 H);
13C NMR (100 MHz, CDCl3) δ -5.47 (+, 2 C), 18.25 (Cquat),
25.85 (+, 3 C), 57.57 (+), 69.52 (-), 126.86 (+, 2 C), 127.21
(+), 128.22 (+, 2 C), 142.63 (Cquat).
2-Meth oxym eth yl-2-m eth yl-4S-p h en yloxa zolid in e (3).
A mixture of phenylglycinol [(S)-1] (1.37 g, 10.0 mmol),
methoxyacetone (2) (969 mg, 11.0 mmol), and MgSO4 (2.5 g)
in CH2Cl2 (20 mL) was stirred at room temperature for 3 h.
Filtration and evaporation of the solvent gave 3 (1.97 g, 95%)
as a yellow oil, (2S/2R) ) 1.5:1. The compound was used
without further purification. IR (neat) ν 3329, 1445, 1102,
1040, 753, 679 cm-1; MS (ES+) m/z 208 (100) [MH+], 162 (45)
(16) When R ) MgX, as would occur upon treatment of 3 with a
Grignard reagent, the oxygen of the auxiliary might also participate
in chelation with the Mg.
(17) In a related case, Corey et al. recently observed the superiority
of MgI2 over MgBr2 in the addition of a silyl enol ether to an
R-aminoaldehyde in terms of yield and reactivity. This was explained
by the more facile dissociation of the iodide: Corey, E. J .; Weidong,
L.; Reichard, G. A. J . Am. Chem. Soc. 1998, 120, 2330-2336.
(18) For examples of additions of Grignard reagents to aliphatic
aldimines with an oxygen atom as coordination site R to CdN, see:
(a) Kobayashi, Y.; Matsumoto, T.; Takemoto, Y.; Nakatani, K.; Ito, Y.;
Kamijo, T.; Harada, H.; Terashima, S. Chem. Pharm. Bull. 1991, 39,
2550-2555. (b) Beresford, K. J . M.; Howe, G. P.; Procter, G. Tetrahe-
dron Lett. 1992, 33, 3355-3358. (c) Franz, T.; Hein, M.; Veith, U.;
J a¨ger, V.; Peters, E.-M.; Peters, K.; von Schnering, H. G. Angew. Chem.
1994, 106, 1308; Angew. Chem., Int. Ed. Engl. 1994, 33, 1298-1301.
(19) Aubard, G.; Bure, J .; Calvet, A. P.; Gouret, C.; Grouhel, A. G.;
J unien, J .-L. Eur. Pat. 0237366, 1987.
1
[MH+ - MeOMe]. Ma jor isom er (2S): H NMR (400 MHz,
CDCl3) δ 1.37 (s, 3 H), 2.6 (br s, 1 H), 3.44 (s, 3 H), 3.48 and
2
3
2
3.50 (AB, J ) 10.4 Hz, 2 H), 3.61 (dd, J ) 8.9, J ) 7.7 Hz,
2
3
3
1 H), 4.25 (dd, J ) 7.7, J ) 6.8 Hz, 1 H), 4.49 (dd, J ) 8.9,
3J ) 6.8 Hz, 1 H), 7.25-7.39 (m, 5 H); 13C NMR (100 MHz,
CDCl3) δ 23.42 (+), 59.32 (+), 61.18 (+), 72.37 (-), 76.00 (-),
96.49 (Cquat), 126.57 (+, 2 C), 127.54 (+), 128.52 (+, 2 C), 139.30
(20) (a) Wettstein, J . G.; Gouret, C. J .; J unien, J .-L. Eur. J .
Pharmacol. 1990, 183, 1477. (b) Gouret, C. J .; Wettstein, J . G.; Porsolt,
R. D.; Puech, A.; J unien, J .-L. Eur. J . Pharmacol. 1990, 183, 1478. (c)
Gouret, C. J .; Porsolt, R.; Wettstein, J . G.; Puech, A.; Pascaud, X.;
J unien, J .-L. Arzneim.-Forsch. 1990, 40, 633-640. (d) Drugs Future
1991, 16, 301-304. (e) Drugs Future 1992, 17, 319-320. (f) Drugs
Future 1993, 18, 365-366. (g) Drugs Future 1995, 20, 410.
(21) Dimsdale, M. J . Fr. Demande 2378746, 1977.
(22) The addition of 3,4-dichlorobenzylmagnesium bromide to N-
Me-3 gave an excellent yield (82%) but poor selectivity (38% de).
(23) We also prepared the compounds corresponding to 3 and 4 with
a methylthio or dimethylamino substituent in place of the methoxy
group, aiming at 1,2-aminothiols and 1,2-diamines, respectively.
However, only poor yields were obtained. This may be explained in
the methylthio case by the enhanced acidity of the adjacent methylene
protons, leading to deprotonation instead of addition.

Asymmetric Synthesis of the Antidepressant Cericlamine
J . Org. Chem., Vol. 64, No. 7, 1999 2409
(Cquat). Min or isom er (2R): 1H NMR (400 MHz, CDCl3) δ 1.45
Chromatography on silica gel eluting with hexanes/EtOAc
2
(s, 3 H), 2.6 (br s, 1 H), 3.37 and 3.42 (AB, J ) 9.8 Hz, 2 H),
(40:1 f 2:1) gave TBDMS-5b (136 mg, 73%) as a colorless oil,
3
2
2
1
3.44 (s, 3 H), 3.70 (dd, J ) J ) 8.0 Hz, 1 H), 4.28 (dd, J )
de 96%. H NMR (270 MHz, CDCl3) δ 0.00 (s, 3 H), 0.01 (s, 3
3
3
3
8.0, J ) 6.9 Hz, 1 H), 4.51 (dd, J ) 8.0, J ) 6.9 Hz, 1 H),
7.25-7.39 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 23.69 (+),
59.36 (+), 61.60 (+), 71.95 (-), 76.69 (-), 96.02 (Cquat), 126.49
(+, 2 C), 127.44 (+), 128.49 (+, 2 C), 140.19 (Cquat).
H), 0.82 (s, 3 H), 0.88 (s, 9 H), 2.10-2.30 (m, 3 H), 2.93 and
3.01 (AB, 2J ) 9.0 Hz, 2 H), 3.15 (s, 3 H), 3.42 (dd, 3J ) 9.0, 2J
3
2
) 9.8 Hz, 1 H), 3.52 (dd, J ) 4.7, J ) 9.8 Hz, 1 H), 3.94 (dd,
3J ) 4.7, 3J ) 9.0 Hz, 1 H), 5.01-5.07 (m, 2 H), 5.75-5.90 (m,
1 H), 7.17-7.31 (m, 3 H), 7.37-7.42 (m, 2 H); 13C NMR (100
MHz, CDCl3) δ -5.51 (+), -5.44 (+), 18.19 (Cquat), 22.45 (+),
25.83 (+, 3 C), 42.03 (-), 55.93 (Cquat), 58.72 (+), 58.85 (+),
68.72 (-), 78.90 (-), 117.45 (-), 126.85 (+), 127.65 (+, 2 C),
127.94 (+, 2 C), 134.95 (+), 144.21 (Cquat); MS (ES+), m/z: 364
(100) [MH+].
(S)-[2-(ter t-Bu tyld im eth ylsilyloxy)-1-p h en yleth yl]-(2-
m eth oxy-1-m eth yleth ylid en e)-a m in e (4). A mixture of (S)-
TBDMS-1 (1.26 g, 5.01 mmol), 2 (493 mg, 5.60 mmol), and
MgSO4 (2 g) in C6H6 (10 mL) was stirred at room temperature
for 3 h. Filtration and evaporation of the solvent gave 4 (1.53
g, 95%) as a yellow oil. The compound was used without
further purification. IR (neat) ν 1688, 1252, 1103, 832, 775,
699 cm-1; 1H NMR (270 MHz, CDCl3) δ -0.05 (s, 6 H), 0.83 (s,
9 H), 1.89 (s, 3 H), 3.34 (s, 3 H), 3.83-3.86 (m, 2 H), 4.00 (s, 2
(S,S)-2-(1-Meth oxym eth yl-1-m eth yl-3-bu ten yla m in o)-
2-p h en yleth a n ol (5b). Meth od A. As described for 5a ,
allylMgBr in Et2O (1.0 M, 2.5 mL, 2.5 mmol) was reacted with
3 (108 mg, 0.521 mmol) and MgBr2 (193 mg, 1.05 mmol) in
CH2Cl2 (6.5 mL) for 21 h. Chromatography on silica gel eluting
with hexanes/EtOAc (5:1 f 2:1) gave 5b (104 mg, 80%) as a
3
3
H), 4.65 (dd, J ) J ) 6.7 Hz, 1 H), 7.18-7.42 (m, 5 H); 13C
NMR (100 MHz, CDCl3) δ -5.51(+), -5.46 (+), 15.21 (+), 18.22
(Cquat), 25.81 (+, 3 C), 58.23 (+), 66.31 (+), 69.08 (-), 78.75
(-), 127.00 (+), 127.60 (+, 2 C), 128.17 (+, 2 C), 141.37 (Cquat),
168.17 (Cquat).
1
colorless oil, de 96%. H NMR (270 MHz, CDCl3) δ 0.98 (s, 3
3
3
H), 1.8-2.1 (br s, 2 H), 2.11 and 2.16 (AB of ABX, J ) 7.1, J
2
2
(S,S)-(1-Ben zyl-2-m eth oxy-1-m eth yleth yl)-[2-(ter t-bu -
tyld im eth ylsilyloxy)-1-p h en yleth yl]-a m in e (TBDMS-5a ).
A suspension of MgBr2 (183 mg, 0.994 mmol) and the imine 4
(160 mg, 0.498 mmol) in CH2Cl2 (6 mL) was stirred for 20 min
at room temperature. BnMgBr (0.9 M in Et2O, 2.8 mL, 2.5
mmol) was added, and stirring was continued overnight. The
reaction was quenched with a saturated solution of NH4Cl (10
mL), the mixture was extracted with CH2Cl2, and the CH2Cl2
extract was dried over solid Na2SO4 and concentrated. The
crude product was chromatographed on silica gel eluting with
hexanes/EtOAc (100:0 f 2:1) to give TBDMS-5a (179 mg,
) 7.7, J ) 13.8 Hz, 2 H), 2.82 and 3.06 (AB, J ) 9.0 Hz, 2
3 2
H), 3.21 (s, 3 H), 3.28 (dd, J ) 9.7, J ) 10.4 Hz, 1 H), 3.52
3
2
3
3
(dd, J ) 4.7, J ) 10.4 Hz, 1 H), 3.85 (dd, J ) 4.7, J ) 9.7
Hz, 1 H), 4.98-5.08 (m, 2 H), 5.75 (ddt, 3J ) 7.4, 3J ) 10.2, 3J
) 16.9 Hz, 1 H), 7.21-7.34 (m, 5 H); 13C NMR (100 MHz,
CDCl3) δ 22.12 (+), 43.41 (-), 55.85 (Cquat), 58.15 (+), 58.42
(+), 67.25 (-), 77.71 (-), 117.88 (-), 126.73 (+, 2 C), 127.10
(+), 128.35 (+, 2 C), 134.17 (+), 143.39 (Cquat); MS (ES+), m/z:
250 (100) [MH+]. Meth od B. Desilylation of TBDMS-5b was
carried out as described for TBDMS-5a (80% yield).
(S,S)-[2-(ter t-Bu tyld im eth ylsilyloxy)-1-p h en yleth yl]-(2-
m eth oxy-1-m eth yl-1-p h en yleth yl)-a m in e (TBDMS-5c). As
described for TBDMS-5a , PhMgBr (3.0 M in Et2O, 1.0 mL,
3.0 mmol) was reacted with 4 (161 mg, 0.501 mmol) and MgBr2
(184 mg, 1.00 mmol) in CH2Cl2 (6 mL) for 27 h. Chromato-
graphy on silica gel eluting with hexanes/EtOAc (100:0 f 2:1)
gave TBDMS-5c (100 mg, 50%) as a pale yellow oil, de 95%.
1H NMR (270 MHz, CDCl3) δ 0.00 (s, 3 H), 0.02 (s, 3 H), 0.92
(s, 9 H), 1.09 (s, 3 H), 3.23 (s, 3 H), 3.30 and 3.36 (AB, 2J ) 8.8
1
87%) as a colorless oil, de 98.8%. H NMR (270 MHz, CDCl3)
δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.76 (s, 3 H), 0.88 (s, 9 H), 2.2 (br
2
s, 1 H), 2.79 (B of AB, J ) 13.0 Hz, 1 H), 2.84-2.94 (m, 3 H),
3
2
3
3.17 (s, 3 H), 3.46 (dd, J ) 9.0, J ) 9.9 Hz, 1 H), 3.57 (dd, J
2
3
3
) 4.7, J ) 9.9 Hz, 1 H), 4.05 (dd, J ) 4.7, J ) 9.0 Hz, 1 H),
7.16-7.33 (m, 8 H), 7.43-7.47 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ -5.53 (+), -5.44 (+), 18.17 (Cquat), 21.72 (+), 25.81
(+, 3 C), 43.61 (-), 56.73 (Cquat), 58.30 (+), 58.84 (+), 68.72
(-), 77.70 (-), 125.82 (+), 126.82 (+), 127.65 (+, 2 C), 127.79
(+, 2 C), 127.92 (+, 2 C), 130.63 (+, 2 C), 138.79 (Cquat), 144.32
(Cquat); MS (ES+) m/z 414 (100) [MH+].
3
Hz, 2 H), 3.47 (d, J ) 6.5 Hz, 2 H), 3.64 (dd, J ) 3J ) 6.9 Hz,
1 H), 7.18-7.36 (m, 8 H), 7.49-7.53 (m, 2 H); 13C NMR (100
MHz, CDCl3) δ -5.60 (+), -5.47 (+), 18.25 (Cquat), 23.84 (+),
25.85 (+, 3 C), 59.23 (+), 59.40 (+), 59.62 (Cquat), 68.66 (-),
82.87 (-), 126.36 (+), 126.81 (+), 127.33 (+, 2 C), 127.72 (+, 2
C), 127.75 (+, 2 C), 127.90 (+, 2 C), 144.30 (Cquat), 144.80
(Cquat); MS (PB-NH3-CI) m/z 400 (100) [MH+].
(S,S)-2-(1-Ben zyl-2-m et h oxy-1-m et h ylet h yla m in o)-2-
p h en ylet h a n ol (5a ). Met h od A (a d d it ion of Gr ign a r d
r ea gen t). A suspension of MgBr2 (188 mg, 1.02 mmol) and
the oxazolidine 3 (106 mg, 0.511 mmol) in CH2Cl2 (6.5 mL)
was stirred for 20 min at room temperature. BnMgBr (0.9 M
in Et2O, 2.8 mL, 2.5 mmol) was added, and stirring was
continued overnight. The reaction was quenched with 2 N HCl
(10 mL), and the mixture was extracted with Et2O. Disodium
EDTA (2 g) and 25% NH3 (to adjust pH to 9-10) were added,
and the crude product was extracted with CH2Cl2, dried over
Na2SO4, and concentrated. Chromatography on silica gel
eluting with hexanes/EtOAc (5:1 f 2:1) gave 5a (58 mg, 38%)
as a colorless oil, de 99.5%. 1H NMR (270 MHz, CDCl3) δ 0.94
(S,S)-2-(2-Met h oxy-1-m et h yl-1-p h en ylet h yla m in o)-2-
p h en yleth a n ol (5c). TBDMS-5c (69 mg, 0.17 mmol) was
stirred at room temperature in 2% HCl/EtOH (4 mL) for 4 h.
After evaporation of solvent and addition of 2 N HCl, the
mixture was extracted with Et2O. The aqueous layer was
basified (2 N NaOH) and extracted with CH2Cl2. The CH2Cl2
extract was dried over Na2SO4 and concentrated to give 5c
1
(35 mg, 72%) as a colorless oil. H NMR (270 MHz, CDCl3) δ
2
1.26 (s, 3 H), 2.77 (br s, 2 H), 3.21 (d, J ) 8.9 Hz, 1 H), 3.24
2
3
2
3
(s, 3 H), 2.4 (br s, 2 H), 2.71 and 2.73 (AB, J ) 13.0 Hz, 2 H),
(s, 3 H), 3.37 (dd, J ) 9.0, J ) 10.7 Hz, 1 H), 3.43 (dd, J )
2 2 3
2.65 and 2.89 (AB, 2J ) 9.0 Hz, 2 H), 2.95 (s, 3 H), 3.30 (dd, 3J
5.0, J ) 10.7 Hz, 1 H), 3.55 (d, J ) 8.9 Hz, 1 H), 3.59 (dd, J
2
3
2
3
) 9.7, J ) 10.4 Hz, 1 H), 3.52 (dd, J ) 4.8, J ) 10.4 Hz, 1
) 9.0, J ) 5.0 Hz, 1 H), 7.16-7.34 (m, 8 H), 7.46-7.48 (m, 2
3
3
H), 3.87 (dd, J ) 4.8, J ) 9.7 Hz, 1 H), 7.15-7.38 (m, 10 H);
13C NMR (100 MHz, CDCl3) δ 21.12 (+), 45.55 (-), 56.66 (Cquat),
58.00 (+), 58.29 (+), 67.09 (-), 76.38 (-), 126.21 (+), 126.77
(+, 2 C), 127.21 (+), 127.89 (+, 2 C), 128.40 (+, 2 C), 130.67
(+, 2 C), 137.83 (Cquat), 143.21 (Cquat); MS (PB-NH3-CI) m/z
300 (100) [MH+]. Meth od B (d esilyla tion of TBDMS-5a on
SCX colu m n ). A solution of TBDMS-5a (32 mg, 0.077 mmol)
in CH2Cl2 (1 mL) was loaded on a SCX column (500 mg of
sorbent). The column was washed with MeOH (2 × 2.5 mL)
and eluted with 1:1 CH2Cl2/2 N NH3 in MeOH to give 5a (19
mg, 82%).
H); 13C NMR (100 MHz, CDCl3) δ 24.18 (+), 58.84 (+), 59.00
(+), 59.58 (Cquat), 67.40 (-), 81.12 (-), 126.73 (+, 2 C), 126.87
(+, 2 C), 126.98 (+), 127.05 (+), 128.15 (+, 2 C), 128.35 (+, 2
C), 143.48 (Cquat), 144.26 (Cquat); MS (ES+), m/z: 286 (38)
[MH+], 149 (62) [MH+ - 1‚H+], 138 (100) [1‚H+].
(S,S)-[2-(ter t-Bu t yld im et h ylsilyloxy)-1-p h en ylet h yl]-
[1-(3,4-d ich lor oben zyl)-2-m eth oxy-1-m eth yleth yl)-a m in e
(TBDMS-5d ). As described for TBDMS-5a , 3,4-dichloroben-
zylmagnesium bromide (0.9 M in Et2O, 2.9 mL, 2.6 mmol) was
reacted with 4 (162 mg, 0.504 mmol) and MgBr2 (190 mg, 1.03
mmol) in CH2Cl2 (7 mL) for 22 h. Chromatography on silica
gel eluting with hexanes/EtOAc (100:0 f 20:1 f 2:1) gave
TBDMS-5d (163 mg, 67%) as a colorless oil, de 95%. 1H NMR
(270 MHz, CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.76 (s, 3 H),
(S,S)-[2-(ter t-Bu tyld im eth ylsilyloxy)-1-p h en yleth yl]-(1-
m eth oxym eth yl-1-m eth yl-3-bu ten yl)-a m in e (TBDMS-5b).
As described for TBDMS-5a , allylMgBr in Et2O (1.0 M, 2.6
mL, 2.6 mmol) was reacted with 4 (164 mg, 0.510 mmol) and
MgBr2 (190 mg, 1.03 mmol) in CH2Cl2 (6 mL) for 26 h.
2
0.88 (s, 9 H), 2.74 and 2.80 (AB, J ) 12.9 Hz, 2 H), 2.83 (s, 2
H), 3.16 (s, 3 H), 3.43 (dd, 3J ) 9.1, 2J ) 9.9 Hz, 1 H), 3.56

2410 J . Org. Chem., Vol. 64, No. 7, 1999
Steinig and Spero
(dd, 3J ) 4.5, 2J ) 9.9 Hz, 1 H), 4.00 (dd, 3J ) 4.5, 3J ) 9.1
(m, 2 H), 7.49-7.52 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ
27.88 (+), 55.40 (Cquat), 59.33 (+), 82.52 (-), 125.40 (+, 2 C),
126.54 (+), 128.15 (+, 2 C), 146.67 (Cquat); MS (ES+) m/z 166
(5) [MH+], 149 (100) [MH+ - NH3].
3
4
Hz, 1 H), 7.04 (dd, J ) 8.2, J ) 2.0 Hz, 1 H), 7.20-7.33 (m,
5 H), 7.40-7.44 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ -5.55
(+), -5.44 (+), 18.14 (Cquat), 21.71 (+), 25.77 (+, 3 C), 42.81
(-), 56.72 (Cquat), 58.32 (+), 58.86 (+), 68.58 (-), 77.64 (-),
126.98 (+), 127.58 (+, 2 C), 128.01 (+, 2 C), 129.64 (+), 129.88
(Cquat), 130.01 (+), 131.66 (Cquat), 132.39 (+), 139.18 (Cquat),
143.99 (Cquat); MS (ES+) m/z 486/484/482 (14/75/100) [MH+].
(S,S)-2-[1-(3,4-Dich lor ob en zyl)-2-m et h oxy-1-m et h yl-
eth yla m in o]-2-p h en yleth a n ol (5d ). TBDMS-5d (143 mg,
0.296 mmol) was stirred at room temperature in 2% HCl/EtOH
(4 mL) for 3 h. After evaporation of solvent and addition of 2
N NaOH, the product was extracted with CH2Cl2, dried over
Na2SO4 and concentrated. The crude 5d (106 mg, 97%) was
used without further purification. 1H NMR (270 MHz, CDCl3)
δ 0.91 (s, 3 H), 2.60-2.71 (m, 5 H), 2.81 (A of AB, 2J ) 9.2 Hz,
(S)-1-(3,4-Dich lor ob en zyl)-2-m et h oxy-1-m et h ylet h yl-
a m in e [(S)-6d ]. Oxidative cleavage of 5d (106 mg, 0.288
mmol) with Pb(OAc)4 (166 mg, 0.374 mmol) as described above
for the preparation of 6c gave (S)-6d (53.5 mg, 75%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.02 (s, 3 H), 1.4
(br s, 2 H), 2.66 (s, 2 H,), 3.02 and 3.06 (AB, 2J ) 8.8 Hz, 2 H),
3
4
4
3.38 (s, 3 H), 7.03 (dd, J ) 8.2, J ) 1.9 Hz, 1 H), 7.29 (d, J
) 1.9 Hz, 1 H), 7.35 (d, 3J ) 8.2 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 24.98 (+), 45.00 (-), 52.64 (Cquat), 58.94 (+), 80.20
(-), 129.83 (+), 129.87 (Cquat), 130.31 (+), 131.91 (Cquat), 132.21
(+), 138.40 (Cquat); MS (CI, NH3) m/z 252/250/248 (13/70/100)
[MH+].
3
2
1 H), 2.94 (s, 3 H), 3.33 (dd, J ) 9.6, J ) 10.5 Hz, 1 H), 3.53
(S)-2-Am in o-2-m eth yl-3-p h en ylp r op a n -1-ol [(S)-7a ].14
To a solution of the methyl ether (S)-6a (27 mg, 0.15 mmol) in
dry CH2Cl2 (1.5 mL) was added at 0 °C BBr3 (57 µL, 150 mg,
0.60 mmol). After 30 min, the cooling bath was removed, and
stirring at room temperature was continued for 2 h. The
mixture was poured into 2 N HCl (4 mL) and extracted with
Et2O, and the aqueous layer was refluxed for 1.5 h. After
basification (6 N NaOH), the product was extracted with
CHCl3, dried over Na2SO4, and concentrated. (S)-7a was
obtained in 79% yield. The characterization data were in
accord with the literature values.14
3
2
3
3
(dd, J ) 4.7, J ) 10.5 Hz, 1 H), 3.86 (dd, J ) 4.7, J ) 9.6
3
4
Hz, 1 H), 6.99 (dd, J ) 8.2, J ) 1.8 Hz, 1 H), 7.23-7.38 (m,
7 H); 13C NMR (100 MHz, CDCl3) δ 20.94 (+), 44.46 (-), 56.71
(Cquat), 57.96 (+), 58.44 (+), 67.10 (-), 76.02 (-), 126.76 (+, 2
C), 127.35 (+), 128.46 (+, 2 C), 129.72 (+), 130.01 (+), 130.26
(Cquat), 131.79 (Cquat), 132.40 (+), 138.19 (Cquat), 142.91 (Cquat);
MS (ES+) m/z 372/370/368 (11/68/100) [MH+].
(S,S)-2-(1-Meth oxym eth yl-1-m eth yl-3-bu tyn yla m in o)-
2-p h en yleth a n ol (5e). As described for 5a , allenylMgBr (1.1
M in Et2O, 2.5 mL, 2.8 mmol) was reacted with 3 (110 mg,
0.531 mmol) and MgBr2 (195 mg, 1.06 mmol) in CH2Cl2 (6.5
mL) for 20 h. Chromatography on silica gel eluting with
hexanes/EtOAc (5:1 f 2:1) gave 5e (70 mg, 54%) as a colorless
(S)-r-Meth ylph en ylglycin ol [(S)-7c].15 As described above
for 7a , (S)-6c (18 mg, 0.11 mmol) was reacted with BBr3 (47
µL, 125 mg, 0.50 mmol) to give (S)-7c (10.4 mg, 63% yield) as
1
oil, de 98%. IR (neat) ν 3294, 2115, 634 cm-1; H NMR (270
a colorless oil, [R]25 ) +16° (c 0.535, EtOH) [ref 15 [R]23
)
4
D
D
MHz, CDCl3) δ 1.08 (s, 3 H), 1.8-2.3 (br s, 2 H), 2.01 (t, J )
+14.3° (c 0.978, EtOH)]. NMR data are not reported in ref 15.
4
2
2.6 Hz, 1 H), 2.93 (d, J ) 2.6 Hz, 2 H), 2.93 and 3.19 (AB, J
1H NMR (400 MHz, CDCl3) δ 1.45 (s, 3 H), 1.9 (br s, 3 H), 3.58
3
2
) 8.9 Hz, 2 H), 3.10 (s, 3 H), 3.29 (dd, J ) 9.7, J ) 10.5 Hz,
2
and 3.63 (AB, J ) 10.7 Hz, 2 H), 7.23-7.28 (m, 1 H), 7.34-
3
2
3
1 H), 3.54 (dd, J ) 4.6, J ) 10.5 Hz, 1 H), 3.86 (dd, J ) 4.6,
3J ) 9.7 Hz, 1 H), 7.20-7.35 (m, 5 H); 13C NMR (100 MHz,
CDCl3) δ 22.07 (+), 29.03 (-), 55.79 (Cquat), 58.44 (+), 58.66
(+), 67.28 (-), 70.64 (+), 77.19 (-), 81.30 (Cquat), 126.65 (+, 2
C), 127.25 (+), 128.44 (+, 2 C), 142.94 (Cquat); MS (ES+), m/z:
248 (100) [MH+].
7.38 (m, 2 H), 7.44-7.46 (m, 2 H); 13C NMR (100 MHz, CDCl3)
δ 27.11 (+), 56.27 (Cquat), 71.74 (-), 125.24 (+, 2 C), 126.78
(+), 128.43 (+, 2 C), 146.40 (Cquat); MS (ES+) m/z 152 (6)
[MH+], 135 (100) [MH+ - NH3].
(S)-[1-(3,4-Dich lor oben zyl)-2-m eth oxy-1-m eth yleth yl]-
d im eth yla m in e [(S)-9]. A mixture of (S)-6d (53.5 mg, 0.215
mmol), formic acid (372 mg, 8.08 mmol) and aqueous formal-
dehyde (37%, 200 mg, 2.46 mmol) was heated at 105 °C for 3
(S)-3-P h en yl-2-m eth yl-2-am in o-1-m eth oxypr opan e [(S)-
6a ]. A mixture of TBDMS-5a (130 mg, 0.314 mmol), NH4HCO2
(208 mg, 3.3 mmol) and 10% Pd/C (51 mg) in MeOH (4 mL)
was refluxed overnight. Then Pd/C was filtered off, the solvent
was evaporated, the residue was dissolved in 2 N HCl (2.5 mL)
and extracted with Et2O (3 × 6 mL), and the aqueous layer
was basified (6 N NaOH) and extracted with CH2Cl2 (5 × 5
mL). The CH2Cl2 extract was dried over Na2SO4 and concen-
trated to give amine (S)-6a (53 mg, 90%), bp 20 °C/0.5 Torr
h
and stirred at room temperature overnight. After the
addition of 2 N NaOH (5 mL) and extraction with CH2Cl2 (5
× 2 mL), the combined extracts were loaded on a SCX column
(500 mg of sorbent). The column was washed with MeOH (2
× 2.5 mL) and eluted with 1:1 CH2Cl2/2 N NH3 in MeOH to
give (S)-9 (53 mg, 89%) as a clear oil. 1H NMR (270 MHz,
2
(Kugelrohr distillation), colorless oil, [R]25.2 ) +2.50° (c 2.04,
CDCl3) δ 0.85 (s, 3 H), 2.34 (s, 6 H), 2.69 and 2.89 (AB, J )
D
2
EtOH). Starting from 5a , the yield was 83%. 1H NMR (270
MHz, CDCl3) δ 1.04 (s, 3 H), 1.5 (br s, 2 H), 2.71 (s, 2 H), 3.08
13.0 Hz, 2 H), 2.90 and 3.12 (AB, J ) 9.9 Hz, 2 H), 3.31 (s, 3
3
4
4
H), 7.04 (dd, J ) 8.2, J ) 2.1 Hz, 1 H), 7.31 (d, J ) 2.1 Hz,
3
1 H), 7.33 (d, J ) 8.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
2
and 3.09 (AB, J ) 8.7 Hz, 2 H), 3.39 (s, 3 H), 7.16-7.33 (m,
5 H); 13C NMR (100 MHz, CDCl3) δ 25.12 (+), 45.98 (-), 52.64
(Cquat), 58.99 (+), 80.52 (-), 126.23 (+), 128.02 (+, 2 C), 130.50
(+, 2 C), 137.95 (Cquat); MS (PB-NH3-CI), m/z 180 (100) [MH+].
(S)-2-Am in o-2-p h en yl-1-m eth oxyp r op a n e [(S)-6c]. Re-
moval of the auxiliary of 5c (35 mg, 0.12 mmol) by Pb(OAc)4
(69 mg, 0.16 mmol) was done following the procedure by
Pridgen et al.10 Instead of hydrolyzing the intermediate
benzaldimine by aqueous HCl in EtOH as described in ref 10
the hydrolysis was performed on a SCX column. A solution of
the benzaldimine (29 mg, 95%) in CH2Cl2 (1 mL) was loaded
on a SCX column (500 mg of sorbent, prewet with CH2Cl2).
The column was then washed with MeOH (2 × 2.5 mL), and
1:1 CH2Cl2/2 N NH3 in MeOH (2.5 mL) eluted the amine (S)-
6c (18 mg, 91% from 5c) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 1.45 (s, 3 H), 1.74 (br s, 2 H), 3.35 (s, 3 H), 3.43 and
3.47 (AB, 2J ) 8.9 Hz, 2 H), 7.21-7.25 (m, 1 H), 7.32-7.36
15.48 (+), 38.59 (+, 2 C), 39.34 (-), 58.52 (+), 59.54 (Cquat),
74.91 (-), 129.63 (+), 129.93 (Cquat), 130.05 (+), 131.65 (Cquat),
132.41 (+), 139.32 (Cquat).
(S)-3-(3,4-Dich lor oph en yl)-2-(dim eth ylam in o)-2-m eth yl-
p r op a n -1-ol (Cer icla m in e) [(S)-10].14 (S)-9 (52 mg, 0.19
mmol) was reacted for 6 h with BBr3 (72 µL, 190 mg, 0.76
mmol) as described above for 7a to give (S)-10 (33 mg, 67%).
The characterization data are in accord with the literature
values.14
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for the (S,R) isomers of 5 and for 8 and proton and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O982222+