N-Tritylprolinal: An Efficient Building Block for the Stereoselective Synthesis of Proline-Derived Amino Alcohols

Article abstract of DOI:10.1021/jo034976g

N-Tritylprolinal (prepared in four steps from L-proline) shows a very high Felkin diastereoselectivity in its reaction with various nucleophiles, leading to a straightforward and highly stereoselective access to syn-proline-derived amino alcohols.

Full text of DOI:10.1021/jo034976g

N-Tr itylp r olin a l: An Efficien t Bu ild in g Block for th e
Ster eoselective Syn th esis of P r olin e-Der ived Am in o Alcoh ols
J oseph Bejjani, Fabrice Chemla,* and Max Audouin
Laboratoire de Chimie Organique, UMR 7611, Universite´ Pierre et Marie Curie, Tour 44 - 45 2e`me e´tage,
4 Place J ussieu, 75252 Paris Cedex 05, France
fchemla@ccr.jussieu.fr
Received J uly 7, 2003
N-Tritylprolinal (prepared in four steps from L-proline) shows a very high Felkin diastereoselectivity
in its reaction with various nucleophiles, leading to a straightforward and highly stereoselective
access to syn-proline-derived amino alcohols.
SCHEME 1
In tr od u ction
1,2-Amino alcohols constitute a large class of structures
which have been widely used in organic synthesis and
catalysis. Among these, prolinol derivatives 1 have
received considerable interest due to their efficiency as
ligands in organometallic chemistry1 as well as structural
targets in several biologically interesting molecules such
as dolastatine,2 detoxins,3 and serine protease inhibitors.4
These prolinol derivatives are generally prepared by
nucleophilic addition to N-protected prolinals such as
2a -d bearing a benzyl or a carbalkoxy protecting group
on the nitrogen atom (Scheme 1).
SCHEME 2
However, the addition of organometallic nucleophiles
on the aldehyde 2a usually shows5 a low diastereoselec-
tivity. The same behavior is observed with aldehydes
2b,3,4,6 2c,3,7 and 2d .8 However, good stereoselectivities
can be achieved by means of double diastereoselection.9
The syn adduct 3 (Scheme 2) is obtained generally as the
major diastereomer, but some examples are reported
where the anti adduct 4 is mainly obtained.
SCHEME 3
We report here our results concerning the synthesis
of enantiomerically pure N-tritylprolinal 2e10 and its
reactions with various nucleophiles.
Resu lts
ing the four-step sequence depicted in the Scheme 3. All
attempts to reduce directly the ester 5 into 2e (DIBAL-H
in various solvents) were unsuccessful.
The aldehyde 2e was prepared on a large scale and in
a good overall yield (80%) starting from L-proline follow-
Aldehyde 2e was obtained as an amorphous powder.
Its enantiomeric purity was ascertained by its reaction
with the two enantiomerically pure diamines 7a and 7b
(Scheme 4).11 The two corresponding aminals 8a and 8b
were obtained as a single product (based on 1H NMR),
showing that the enantiomeric purity of the aldehyde 2e
is >95% ee. This enantiomeric purity is remarkably
stable in time, as no racemization was detected after 15
days at room temperature.12
* To whom correspondence should be addressed. Tel: (+33) 1 44
27 55 71. Fax: (+33) 1 44 27 75 67.
(1) See, for example: Soai K.; Ookawa, A.; Ogawa, K.; Kaba, T. J .
Chem. Soc., Chem. Commun. 1987, 467-468. Fehr, C.; Galindo, J .
Angew. Chem., Int. Ed. 2000, 39, 769-573. Pu, L.; Yu, H.-B. Chem.
Rev. 2001, 101, 757-824.
(2) Pettit, G. R.; Kamano, Y.; Herald, C. L.; Fujii, Y.; Kizu, H.; Boyd,
M. R.; Boettner, F. E.; Doubek, D. L.; Schmidt, J . M.; Chapuis, J .-C.;
Michel, C. Tetrahedron 1993, 49, 9151-9170.
(3) Harris, B. D.; Bhat, K. L.; J oullie´, M. M. Heterocycles 1986, 24,
1045-1060 and ref. cit.
(4) Reed, P. E.; Katzenellenbogen, J . A. J . Org. Chem. 1991, 56,
2624-2634.
Having in hand an efficient synthesis of aldehyde 2e,
we turned then to its reactions with organometallic
nucleophiles. Our results are reported in Table 1.
(5) Andre´s, J . M.; Pedrosa, R.; Pe´rez, A.; Pe´rez-Encabo, A. Tetra-
hedron 2001, 57, 8521-8530. Ma, D.; Pan, Q.; Han, F. Tetrahedron
Lett. 2002, 43, 9401-9403.
10.1021/jo034976g CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/18/2003
J . Org. Chem. 2003, 68, 9747-9752
9747

Bejjani et al.
SCHEME 4
TABLE 1. Rea ction of N-Tr itylp r olin a l 2e w ith Va r iou s
Nu cleop h iles
SCHEME 5
T
yielda
(°C) product (%)
SCHEME 6
entry
R-M
n-BuLi
n-BuLi
n-BuLi
n-BuMgBr
MeMgCl
iPrMgBr
vinylMgCl
solvent
Et2O
THF
THF
Et2O
Et2O
Et2O
Et2O
drb
1
2
3
4
5
-80
-80
-30
-80
-80
-80
-80
-80
-80
9a
9a
9a
9a
9b
9c
9d
9e
9f
65
93/7
86/14
70/30
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
63/37
50/50
n.d.c
n.d.c
78
90
76
94
88
6
7
8
9
10
11
12
TMS-CC-Li Et2O
PhMgBr
Et2O
90
could be overcome by using the Sakurai reaction,13 as
depicted in Scheme 5. The compound 9g was obtained
as only one diastereomer.
PhMgCl
AllylMgBr
AllylMgBr
Et2O/THFd -80
Et2O
THF
9f
9g
9g
88
-80
-80
85e
92e
a
Isolated yield in the major product after flash chromatography.
b Diastereomeric ratio measured by 1H NMR on the crude material.
One of the main interests of this methodology is the
ease in removing the trityl protecting group. In our case,
a simple treatment with aqueous HCl (6 N) gave, after
neutralization, the corresponding amino alcohols 10-13
(Scheme 6) in good yields without any detectable dehy-
c Not determined. Et2O/THF 10/1. e Isolated yield in the diaste-
d
reomer mixture.
dration product. Physical data (mp, [R]24D, and H NMR)
As can be seen in Table 1, the diastereoselectivity is
excellent in most cases when the reaction is conducted
in ether at low temperature. Only one diastereomer could
1
for compound 10 were found to be identical to those
reported in the litterature,14 thus confirming the relative
and absolute configurations in 9b. 1H NMR data for
compound 12 were found also to be identical to literature
data.8c
1
be detected by H NMR, except in the case of of n-BuLi
(entry 1), where the diastereoselectivity is slightly lower,
and in the case of allylMgBr which showed a low
stereoselectivity (entry 11). The reasons for this drop in
diastereoselectivity are still unclear, but this problem
The relative configurations were ascertained for com-
pounds 9a , 9f, and 9g as described in Scheme 7. Com-
(6) See, for example: Hanson, G. J .; Baran, J . S.; Lindberg, T.
Tetrahedron Lett. 1986, 27, 3577-3580. Pettit, G. R.; Singh, S. B.;
Hogan, F.; Lloyd Williams, P.; Herald, D. L.; Burkett, D. D.; Clewlow,
P. J . J . Am. Chem. Soc. 1989, 111, 5463-5465. Vara Prasad, J . V. N.;
Rich, D. H. Tetrahedron Lett. 1990, 31, 1803-1806. Tomioka, T.; Kanai,
M.; Koga, K. Tetrahedron Lett. 1991, 32, 2395-2398. Koskinen, A. M.
P.; Paul, J . M. Tetrahedron Lett. 1992, 33, 6853-6856. Ibuka, T.; Taga,
T.; Habashita, H.; Nakai, K.; Tamamura, H.; Fujii, N. J . Org. Chem.
1993, 58, 1207-1214. Drewes, S. E.; Khan, A. A.; Rowland, K. Synth.
Commun. 1993, 23, 183-188. Tourwe´, D.; Piron, J .; Defreyn, P.; Van
Binst, G. Tetrahedron Lett. 1993, 34, 5499-5502. Roux, F.; Maugras,
I.; Poncet, J .; Niel, G.; J ouin, P. Tetrahedron 1994, 50, 5345-5360.
Niel, G.; Roux, F.; Maisonnasse, Y.; Maugras, I.; Poncet, J .; J ouin, P.
J . Chem. Soc., Perkin Trans. 1 1994, 1275-1280.Ito, H.; Ikeuchi, Y.;
Taguchi, T.; Hanzawa, Y. J . Am. Chem. Soc. 1994, 116, 5469-5470.
Tsutsumi, S.; Okonogi, T.; Shibahara, S.; Ohuchi, S.; Hatsuchiba, E.;
Patchett, A. A.; Christensen, B. G. J . Med. Chem. 1994, 37, 3492-
3502. Shalem, H.; Shatzmiller, S.; Feit, B. A. Liebigs Ann. 1995, 433-
436. Miyazaki, K.; Kobayashi, M.; Natsume, T.; Gondo, M.; Mikami,
T.; Sakakibara, K.; Tsukagoshi, S. Chem. Pharm. Bull. 1995, 43, 1706-
1718. Mahboobi, S.; Popp, A.; Burgemeister, T.; Schollmeyer, D.
Tetrahedron: Asymmetry 1998, 9, 2369-2376. For examples with a
high diastereoselectivity, see: Bigi, F.; Casnati, G. Sartori, G.; Araldi,
G.; Bocelli, G. Tetrahedron Lett. 1989, 30, 1121-1124. Shono, T.; Kise,
N.; Tanabe, T. J . Org. Chem. 1988, 53, 1364-1367.
(8) (a) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J . Am. Chem. Soc.
1987, 109, 7111-7115. (b) Klein, G.; Pandiaraju, S.; Reiser, O.
Tetrahedron Lett. 2002, 43, 7503-7506. (c) Soai, K.; Ookawa, A. J .
Chem. Soc., Chem. Commun. 1986, 412-413.
(9) Beckett, R. P.; Davies, S. G. J . Chem. Soc., Chem. Commun.
1988, 160-161. Hamada, Y.; Hayashi, K.; Shioiri, T. Tetrahedron Lett.
1991, 32, 931-934. Hayashi, K.; Hamada, Y.; Shioiri, T. Tetrahedron
Lett. 1991, 32, 7287-7290. Beckett, R. P.; Davies, S. G.; Mortlock, A.
A. Tetrahedron: Asymmetry 1992, 3, 123-136. Shioiri, T.; Hayashi,
K.; Hamada, Y. Tetrahedron 1993, 49, 1913-1924. Pettit, G. R.; Singh,
S. B.; Hogan, F.; Lloyd Williams, P.; Herald, D. L.; Burkett, D. D.;
Clewlow, P. J . J . Org. Chem. 1994, 59, 6287-6295. Pettit, G. R.;
Burkett, D. D.; Barkoczy, J .; Breneman, G. L.; Pettit, W. E. Synthesis
1996, 719-725. Pettit, G. R.; Grealish, M. P. J . Org. Chem. 2001, 66,
8640-8642. Marquez, F.; Montoro, R.; Llebaria, A.; Lago, E.; Molins,
E.; Delgado, A. J . Org. Chem. 2002, 67, 308-311.
(10) The synthesis of aldehyde 2e in a racemic form has already
been reported: De Koning, H.; Springer-Fidder, A.; Moolemaar, M. J .;
Huisman, H. O. Recl. Trav. Chim. Pays-Bas 1973, 92, 237-244. Vedejs,
E.; Hagen, J . P.; Roach, B. L.; Spear, K. L. J . Org. Chem. 1978, 43,
1185-1190.
(11) Mangeney, P.; Alexakis, A.; Normant, J . F. Tetrahedron Lett.
1988, 29, 2677-2680.
(12) N-Tritylamino aldehydes have been reported to be of high
configurational stability: Dellaria, J . F., J r.; Maki, R. J .; Stein, H. H.;
Cohen, J .; Whittern, D.; Marsh, K.; Hoffman, D. J .; Plattner, J . J .;
Perun, T. J . J . Med. Chem. 1990, 33, 534-542. Thaisrivongs, S.; Pals,
D. T.; Kroll, L. T.; Turner, S. R.; Han, F.-S. J . Med. Chem. 1987, 30,
976-982.
(7) See, for example: (a) Kiyooka, S.; Nakano, M.; Shiota, F.;
Fujiyama, R. J . Org. Chem. 1989, 54, 5409-5411. (b) StDenis, Y.;
Chan, T. H. J . Org. Chem. 1992, 57, 3078-3085. (c) Barrett, A. G. M.;
Damiani, F. J . Org. Chem. 1999, 64, 1410-1411. (d) Konradi, A. W.;
Kemp, S. J .; Pedersen, S. F. J . Am. Chem. Soc. 1994, 116, 1316-1323.
9748 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of Proline-Derived Amino Alcohols
SCHEME 7
SCHEME 8
pound 9f gave the amino alcohol 14 in 55% overall yield
upon detritylation and N-methylation. Comparison of its
1
spectral data ([R]24 and H NMR) with those reported
D
in the literature15 confirmed the relative and absolute
configurations (ee > 98%) of 9f. Compounds 9a and 9g
were transformed into the corresponding oxazolidinones
15 and 16 by detritylation, reaction with methylchloro-
formate, and ring closure. NMR experiments (coupling
constants measurements and NOE effects) showed un-
ambiguously the cis relationship between the two vicinal
protons and then the relative configurations of the
starting materials.
confirmed by PM3 calculations18 which show also that
the trityl group adopts a position trans to the carbonyl
moiety (Scheme 8).
In such a conformation, two possible reactive conform-
ers can be involved. The first one (C1 in the Scheme 8)
presents the carbonyl group lying over the five-membered
ring. In such a conformation, the Si face is masked by
the trityl group, and a nucleophilic attack (TS1q in
Scheme 8) on the Re face gives the observed major
product. This transition state is slightly different from a
Felkin-Anh classical transition state (the dihedral angle
of carbonyl and amino groups is not ca. 90°), but
resembles merely to the transition states proposed in the
reductions of R-N-tritylamino ketones.16 The other pos-
sible conformation with the pseudoaxial carbonyl moiety
lying out of the five-membered ring (C2 in Scheme 8)
leads to an attack of the organometallic species hindered
by the five-membered ring. The transition state (TS2q in
Scheme 8) obtained from this conformer is then higher
in energy and the corresponding product is not or little
observed.
In conclusion, we have disclosed a high stereoselective
synthesis of substituted prolinols by using the (2S)-N-
tritylprolinal. This aldehyde has been prepared from
L-proline in three steps with a 80% overall yield. It shows
a remarkable stability toward epimerization as well as
an efficient stereocontrol in its reactions with various
organometallic species. Further advances in this field as
well as applications in organic synthesis will be reported
in due course.
Discu ssion
It has been shown recently16 that in the reduction of
aminoketones the presence of a trityl group on nitrogen
atom prevents any chelation due to important steric
crowd. However, in the case of N-tritylaziridinyl alde-
hydes, an organometallic chelation to nitrogen bearing
a sterically hindered trityl group has been reported.17 In
our case, the fact that the reaction of 2e with allylsilane
in the presence of BF3‚Et2O (monodentate Lewis acid)
shows the same stereoselectivity as the reactions with
lithium or Grignard reagents provides a good indica-
tion of a general nonchelate transition state. Examina-
tion of the 1H NMR spectrum for the aldehyde 2e
shows nontypical coupling constants between the proton
Hb (R to the carbonyl moiety) and the two vicinal protons
Hc and Hd (Scheme 7); the pseudoaxial position of the
carbonyl group was evidenced by NOE effects between
Ha and Hc, He and Hf. This pseudoaxial position was
(13) Sakurai, H. Pure Appl. Chem. 1982, 54, 1-22. Fleming, I. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2, pp 567-572. Fleming, I.;
Dunogues, J .; Smithers, R. Org. React. (N.Y.) 1989, 37, 57-575.
Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207-2293.
(14) (a) Schwerdtfelder, J .; Hoppe, D. Angew. Chem., Int. Ed. Engl.
1992, 31, 1505-1507. (b) Ganguly, A. K.; Szmuliewicz, S.; Sarre, O.
Z.; Greeves, D.; Morton, J .; McGlotten, J . J . Chem. Soc., Chem.
Commun. 1974, 395-396.
(15) Compound 14 and its OH-epimer are reported; see ref 8a.
(16) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J . Org. Chem.
2002, 67, 1045-1056.
(17) Utsunomiya, I.; Fuji, M.; Sato, T.; Natsume, M. Chem. Pharm.
Bull. 1993, 41, 854-860. Nayak, S. K.; Thijs, L.; Zwanenburg, B.
Synlett 1998, 1187-1188.
Exp er im en ta l Section
(2S)-1-Tr ip h en ylm eth yl-2-p yr r olid in eca r boxylic Acid
Meth yl Ester 5. To a solution of l-proline (11.51 g, 100 mmol)
in methanol (100 mL) was added thionyl chloride (23.80 g,
14.50 mL, 200 mmol) at -10 °C. After addition, the reaction
mixture was allowed to warm to room temperature. After 18
h stirring, the solvent and other volatile compounds were
(18) PM3 calculations were conducted using CS ChemBats3D Pro
v5.0 (CambridgeSoft Corp.).
J . Org. Chem, Vol. 68, No. 25, 2003 9749

Bejjani et al.
removed in vacuo. The resulting intermediate was dissolved
in CHCl3 (120 mL), and Et3N (41.85 mL, 300 mmol) was added,
followed by trityl chloride (27.92 g, 100 mmol) in CHCl3 (50
mL). The reaction mixture was stirred for 18 h at room
temperature and hydrolyzed with a 2:1 mixture of saturated
aqueous NH4Cl solution and NH3 (28% in water). After the
layers were separated, the aqueous one was extracted twice
with CH2Cl2. The combined organic layers were dried over
anhydrous MgSO4 and concentrated in vacuo. Recrystallization
from Et2O afforded the title compound (33.46 g, 90%) as a
white solid. Mp: 119-120 °C. [R]20D ) -42.0 (c ) 2.70, CHCl3).
IR (CHCl3) cm-1: 3040, 2930, 2850, 2240, 1950, 1890, 1810,
1710, 1585, 1480, 1440, 1270, 1150, 900, 695. 1H NMR (CDCl3,
400 MHz): δ 0.89-1.08 (m, 2H), 1.48-1.66 (m, 2H), 2.86 (dt,
68.5, 77.0, 126.5, 127.8, 129.5, 144.5, 204.4. Anal. Calcd for
C24H23NO (MW 341.45): C, 84.42; H, 6.79; N, 4.10. Found: C,
84.41; H, 6.87; N, 4.12.
(2S,4′R,5′R)-2-(1,3-Dim eth yl-4,5-d ip h en ylim id a zolid in -
2-yl)-N-tr itylp yr r olid in e 8a . The aldehyde 2e (50 mg, 0.146
mmol) was kept reacting with the (R,R)-N,N′-dimethyl-1,2-
diphenylethylenediamine 7a (35 mg, 0.146 mmol) in CH2Cl2
(3 mL) in the presence of 4 Å molecular sieves. After 20 h of
stirring at room temperature, the reaction mixture was filtered
and the solvent evaporated under reduced pressure to afford
quantitatively the aminal 8a as a white solid. 1H NMR (CDCl3,
400 MHz): δ 0.23-0.34 (m, 1H), 1.06-1.20 (m, 1H), 1.47-
1.69 (m, 1H), 1.75-1.85 (m, 1H), 1.88 (s, 3H), 2.85 (s, 3H), 3.10
3
(t, J ) 9.7 Hz, 1H), 3.35-3.43 (m, 1H), 3.58 (d, J ) 8.6 Hz,
3
2
3
2J ) 11.2 Hz, J ) 7.1 Hz, 1H), 3.43 (ddd, J ) 11.2 Hz, J )
3
3
1H), 3.76 (d, J ) 8.3 Hz, 1H), 3.85 (d, J ) 8.3 Hz, 1H), 4.62
(bs, 1H), 7.03-7.33 (m, 19H), 7.62 (d, 3J ) 7.6 Hz, 6H). 13C
NMR (CDCl3, 100 MHz): δ 25.7, 27.8, 33.2, 42.3, 51.9, 65.3,
75.7, 78.9, 79.5, 86.9, 126.2, 127.2, 127.5, 127.7, 127.7, 128.1,
128.2, 128.6, 128.0, 140.0, 140.2, 145.8.
3
8.1, 5.1 Hz, 1H), 3.69 (s, 3H), 3.92 (dd, J ) 8.6, 2.0 Hz, 1H),
3
3
3
7.16 (t, J ) 7.4 Hz, 3H), 7.26 (t, J ) 7.6 Hz, 6H), 7.59 (d, J
) 6.8 Hz, 6H). 13C NMR (CDCl3, 50 MHz): δ 24.4, 31.3, 44.0,
51.7, 62.8, 77.5, 126.2, 127.7, 129.3, 144.76, 177.3. Anal. Calcd
for C25H25NO2 (MW 371.47): C, 80.83; H, 6.78; N, 3.77.
Found: C, 80.49; H, 6.78; N, 3.59.
(2S,4′S,5′S)-2-(1,3-Dim eth yl-4,5-d ip h en ylim id a zolid in -
2-yl)-N-tr itylp yr r olid in e 8b. The aminal 8b was prepared
quantitatively by the same procedure described for 8a using
(S,S)-N,N′-dimethyl-1,2-diphenylethylenediamine 7b as a white
solid. 1H NMR (CDCl3, 400 MHz): δ 0.26-0.39 (m, 1H), 1.06-
1.21 (m, 1H), 1.42-1.54 (m, 1H), 1.93 (s, 3H), 1.89-2.04 (m,
1H), 2.46 (s, 3H), 3.00 (t, J ) 9.7 Hz, 1H), 3.16-3.39 (m, 1H),
(2S)-1-Tr ip h en ylm eth yl-2-p yr r olid in em eth a n ol 6. Es-
ter 5 (14.84 g, 40 mmol) dissolved in dry THF (50 mL) was
added dropwise under an argon atmosphere to a suspension
of LiAlH4 (1.21 g, 32 mmol) in dry THF (30 mL) at room
temperature. The reaction course was monitored by TLC, and
once all the starting material was consumed (2 h at room
temperature), the mixture was quenched dropwise under
vigorous stirring with an aqueous solution of sodium potas-
sium tartrate (50 mL, 1 M). Et2O (50 mL) was added, the
layers were separated, and the aqueous layer was extracted
twice with CH2Cl2. The combined organic phases were dried
over anhydrous MgSO4. Removal of solvents in vacuo yielded
the title compound as a white foam (13.39 g, 97%) which was
used without further purification. For analytical purposes, 6
was purified by flash column chromatography on silica gel
3
3
3.70 (d, J ) 9.6 Hz, 1H), 3.68-3.75 (m, 1H), 3.90 (d, J ) 1.5
3
Hz, 1H), 4.15 (d, J ) 9.4 Hz, 1H), 7.10-7.36 (m, 19H), 7.61
(d, 3J ) 7.6 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 25.6, 27.0,
38.6, 40.0, 51.5, 64.0, 73.0, 75.2, 78.6, 93.0, 126.1, 127.3, 127.5,
127.6, 128.0, 128.1, 128.3, 130.0, 130.4, 136.8, 140.3, 145.8.
Gen er a l P r oced u r e for Com p ou n d s 9a -f. To the alde-
hyde 2e (0.341 g, 1 mmol) in dry Et2O (10 mL) under argon
was added the organometallic solution (2 mmol) at -80 °C.
The reaction was followed by TLC. After 5 h of stirring, the
reaction was hydrolyzed at -80 °C with a 2:1 mixture of a
saturated aqueous NH4Cl solution and NH3 (28% in water).
The layers were separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organic phases
were dried over anhydrous MgSO4 and the solvents removed
in vacuo. The resulting solid was purified by flash column
chromatography on silica gel (cyclohexane/EtOAc/Et3N, 9/1/
0.2) to afford compounds 9a -f.
(cyclohexane/EtOAc/Et3N, 9/1/0.2). Mp: 55-56 °C. [R]20
)
D
+44.0 (c ) 2.20, CHCl3). IR (CHCl3) cm-1: 3400, 3060, 2960,
1
2870, 1950, 1820, 1590, 1490, 1450, 1020, 900, 700. H NMR
(CDCl3, 400 MHz): δ 0.54-0.65 (m, 1H), 0.92-1.93 (m, 1H),
2
3
1.37-1.47 (m, 2H), 2.36 (bs, 1H), 3.00 (ddd, J ) 12.5 Hz, J
) 4.1, 8.4 Hz, 1H), 3.17-3.24 (m, 1H), 3.47-3.52 (m, 1H), 3.56
2
3
2
3
(dd, J ) 10.0 Hz, J ) 7.3 Hz, 1H), 3.66 (dd, J ) 9.9 Hz, J
3
3
) 3.8 Hz, 1H), 7.19 (t, J ) 7.6 Hz, 3H), 7.27 (t, J ) 7.6 Hz,
(RR,2S)-R-(1-Bu t yl)-1-t r ip h en ylm et h yl-2-p yr r olid in e-
m eth a n ol 9a . Prepared from n-BuMgCl (2 mmol, 1.35 mL,
6H), 7.62 (d, J ) 7.6 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ
3
1.48M in ether) in 78% yield (0.307 g). Mp: 86-87 °C. [R]20
24.2, 29.2, 51.0, 61.3, 65.9, 77.7, 126.3, 127.7, 129.7, 145.2.
D
HRMS: calcd for C24H26NO (MH+) 344.2014, found 344.2018.
) -7.8 (c ) 2.08, CHCl3). IR (CHCl3) cm-1: 3420, 3050, 3000,
2930, 2860, 1950, 1815, 1710, 1590, 1485, 1445, 1075, 1030,
(2S)-1-Tr ip h en ylm eth yl-2-p yr r olid in em eth a n a l 2e. To
a solution of (COCl)2 (3.5 mL, 40 mmol) in dry CH2Cl2 (35 mL)
under argon was added dropwise at -80 °C a solution of
DMSO (5.7 mL, 80 mmol) in CH2Cl2 (15 mL). After 10 min,
the alcohol 6 (13.39 g, 38.9 mmol) dissolved in CH2Cl2 (35 mL)
was added dropwise at -80 °C. After 1.5 h stirring at this
temperature, Et3N (22.5 mL, 160 mmol) was added. After 1.5
h stirring at -80 °C, the reaction was hydrolyzed with a 2:1
mixture of a saturated aqueous NH4Cl solution and NH3 (28%
in water). The layers were separated, and the aqueous layer
was extracted twice with CH2Cl2. The combined organic phases
were dried over anhydrous MgSO4 and the volatile compounds
removed in vacuo. The solid obtained was dissolved in THF
and filtered, and the solvent removed under reduced pressure
to give, after recrystallization from ether, the title compound
1
2
1000, 900, 705. H NMR (CDCl3, 400 MHz): δ 0.16 (dquin, J
3
2
) 11.9 Hz, J ) 8.6 Hz, 1H), 1.08-1.41 (m, 8H), 1.62 (ddt, J
) 12.5 Hz, 3J ) 8.6, 5.9 Hz, 1H), 0.83 (t, 3J ) 6.9 Hz, 3H,),
2
3
2.87 (bs, 1H), 3.02 (ddd, J ) 11.7 Hz, J ) 8.1, 3.3 Hz, 1H),
2
3
3
3.16 (ddd, J ) 11.9 Hz, J ) 7.0, 9.4 Hz, 1H), 3.38 (ddd, J )
3
8.6, 5.6, 3.1 Hz, 1H), 3.92-3.88 (m, 1H), 7.18 (t, J ) 7.4 Hz,
3H), 7.26 (t, J ) 7.6 Hz, 6H), 7.55 (d, J ) 7.1 Hz, 6H). 13C
NMR (CDCl3, 100 MHz): δ 14.1, 22.7, 25.1, 25.2, 28.5, 33.0,
53.3, 64.2, 74.3, 78.2, 126.3, 127.6, 130.0, 144.8. Anal. Calcd
for C28H33NO (MW 399.57): C, 84.17; H, 8.32; N, 3.51. Found:
C, 84.14; H, 8.42; N, 3.51.
3
3
(RR,2S)-R-Meth yl-1-tr iph en ylm eth yl-2-pyr r olidin em eth -
a n ol 9b. Prepared from CH3MgCl (2 mmol, 0.66 mL, 3.0 M in
THF) in 90% yield (0.323 g). Mp: 52-53 °C. [R]20 ) +24.4 (c
D
(12.59 g, 92%) as a white solid. Mp: 140-141 °C dec. [R]20
)
) 2.25, CHCl3). IR (CHCl3) cm-1: 3400, 3060, 2960, 2860, 1590,
1490, 1445, 900, 700. 1H NMR (CDCl3, 400 MHz): δ 0.11
(dquin, 2J ) 11.8 Hz, 3J ) 8.9 Hz, 1H), 1.08 (ddt, 2J ) 12.9
D
-15.2 (c ) 2.54, CHCl3). IR (CHCl3) cm-1: 3060, 2960, 2860,
2800, 2700, 1960, 1900, 1815, 1715, 1595, 1490, 1450, 900, 705.
1H NMR (CDCl3, 400 MHz): δ 0.76-0.86 (m, 1H), 1.14 (ddd,
3
2
Hz, J ) 8.6, 4.2 Hz, 1H), 1.20-1.28 (m, 1H), 1.60 (ddt, J )
3
2J ) 16.8 Hz, J ) 12.7, 8.7 Hz, 1H), 1.39-1.49 (m, 1H), 1.62
3
3
12.7 Hz, J ) 8.6, 5.8 Hz, 1H), 0.91 (d, J ) 6.4 Hz, 3H), 2.90
2
3
2
2
3
(ddd, J ) 16.8 Hz, J ) 8.2, 4.1 Hz, 1H), 2.94 (ddd, J ) 11.7
(bs, 1H), 2.99 (ddd, J ) 12.0 Hz, J ) 8.4, 3.1 Hz, 1H), 3.13
3
2
3
2
3
3
Hz, J ) 7.1, 4.1 Hz, 1H), 3.31 (dt, J ) 11.7 Hz, J ) 7.1 Hz,
(ddd, J ) 11.9 Hz, J ) 9.4, 6.9 Hz, 1H), 3.30 (ddd, J ) 8.9,
3 3
3
3
1H), 3.79 (dt, J ) 9.1, 3.3 Hz, 1H), 7.20 (t, J ) 7.4 Hz, 3H),
6.1, 3.0 Hz, 1H), 4.06 (dq, J ) 3.1, 6.4 Hz, 1H), 7.13 (t, J )
6.6 Hz, 3H), 7.22 (t, 3J ) 7.6 Hz, 6H), 7.52 (d, 3J ) 8.1 Hz,
6H). 13C NMR (CDCl3, 100 MHz): δ 18.8, 24.9, 25.0, 53.2, 65.1,
3
3
3
7.30 (t, J ) 7.6 Hz, 6H), 7.59 (d, J ) 7.6 Hz, 6H), 9.88 (d, J
) 2.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 24.4, 28.1, 50.7,
9750 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of Proline-Derived Amino Alcohols
69.8, 78.2, 126.3, 127.6, 129.9, 144.8. Anal. Calcd for C25H27
NO (MW 357.49): C, 83.99; H, 7.61; N, 3.92. Found: C, 83.90;
H, 7.78; N, 3.79.
-
(RR ,2S )-R-(2-P r op e n yl)-1-t r ip h e n ylm e t h yl-2-p yr r o-
lid in em eth a n ol 9g. To the aldehyde (0.511 g, 1.5 mmol) in
dry CH2Cl2 (15 mL) under argon was added allyltrimethylsi-
lane (3 mmol, 0.48 mL) followed by BF3‚Et2O (1.5 mmol, 0.19
mL) at -80 °C. The reaction was followed by TLC. After 5 h
of stirring at the same temperature, the reaction was hydro-
lyzed with a 2:1 mixture of a saturated aqueous NH4Cl solution
and NH3 (28% in water). The layers were separated, and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic phases were dried over anhydrous MgSO4 and the
solvents removed in vacuo. The solid obtained was purified
by flash column chromatography on silica gel (cyclohexane/
EtOAc/Et3N, 9/1/0.2) to afford the title product (0.364 g, 63%)
as white solid. Mp: 40-41 °C. [R]20D ) -7.8 (c ) 1.50, CHCl3).
IR (CHCl3) cm-1: 3400, 3040, 2930, 2860, 1940, 1810, 1710,
1630, 1590, 1480, 1440, 1200, 1000, 900, 710. 1H NMR (CDCl3,
400 MHz): δ 0.15 (dquin, 2J ) 11.7 Hz, 3J ) 8.8 Hz, 1H), 1.09
(RR,2S)-R-(1-Meth yleth yl)-1-tr ip h en ylm eth yl-2-p yr r o-
lid in em eth a n ol 9c. Prepared from i-PrMgCl (2 mmol, 1.29
mL, 1.55 M in ether) in 76% yield (0.292 g). Mp: 124-125 °C.
[R]20 ) -1.7 (c ) 2.06, CHCl3). IR (CHCl3) cm-1: 3400, 3060,
D
1
2960, 2860, 1950, 1590, 1490, 1470, 1445, 1000, 900, 710. H
NMR (CDCl3, 400 MHz): δ 0.18 (sext, J ) 9.2 Hz, 1H), 1.16-
1.32 (m, 2H), 1.43-1.52 (m, 1H), 1.59-1.68 (m, 1H), 0.57 (d,
3J ) 6.6 Hz, 3H), 0.97 (d, 3J ) 6.6 Hz, 3H), 3.00-3.06 (bs,
2
3
1H), 3.03 (ddd, J ) 11.9 Hz, J ) 7.4, 2.6 Hz, 1H), 3.17 (ddd,
2J ) 12.0 Hz, J ) 9.7, 6.6 Hz, 1H), 3.45 (dd, J ) 9.4, 2.8 Hz,
3
3
3
3
1H), 3.58 (ddd, J ) 8.6, 5.8, 2.8 Hz, 1H), 7.18 (t, J ) 7.4 Hz,
3H), 7.26 (t, J ) 7.6 Hz, 6H), 7.55 (d, J ) 7.1 Hz, 6H). 13C
NMR (CDCl3, 100 MHz): δ 18.5, 20.5, 25.0, 25.1, 31.0, 53.4,
62.6, 78.3, 80.3, 126.3, 127.6, 130.0, 144.7. Anal. Calcd for
3
3
2
3
(ddt, J ) 12.9 Hz, J ) 8.6, 4.2 Hz, 1H), 1.21-1.30 (m, 1H),
C
27H31NO (MW 385.54): C, 84.11; H, 8.10; N, 3.63. Found: C,
2
3
2
1.59 (ddt, J ) 12.2 Hz, J ) 8.6, 5.6 Hz, 1H), 1.89 (ddd, J )
84.22; H, 8.15; N, 3.49.
3
2
3
12.7 Hz, J ) 6.6, 5.6 Hz, 1H), 2.10 (ddd, J ) 12.7 Hz, J )
(RR,2S)-R-E t h en yl-1-t r ip h en ylm et h yl-2-p yr r olid in e-
m eth a n ol 9d . Prepared from vinylMgCl (2 mmol, 1.19 mL,
2
3
8.2, 7.1 Hz, 1H), 2.78 (bs, 1H), 2.98 (ddd, J ) 12.2 Hz, J )
7.9, 2.8 Hz, 1H), 3.15 (ddd, 2J ) 12.2 Hz, 3J ) 9.7, 7.1 Hz,
1.8 M in THF) in 94% yield (0.348 g). Mp: 50-51 °C. [R]20
)
3
3
D
1H), 3.38 (ddd, J ) 8.4, 5.6, 2.8 Hz, 1H), 3.98 (ddd, J ) 8.3,
-20.5 (c ) 2.09, CHCl3). IR (CHCl3) cm-1: 3400, 3040, 2960,
3
3
5.5, 2.9 Hz, 1H), 4.93 (d, J ) 12.2 Hz, 1H), 4.94 (d, J ) 15.2
2860, 1950, 1590, 1490, 1445, 1000, 925, 900, 710. 1H NMR
3
Hz, 1H), 5.56-5.66 (m, 1H), 7.13 (t, J ) 7.4 Hz, 3H), 7.22 (t,
2
3
(CDCl3, 400 MHz): δ 0.19 (dquin, J ) 11.8 Hz, J ) 8.9 Hz,
3J ) 7.1 Hz, 6H), 7.51 (d, J ) 7.6 Hz, 6H). 13C NMR (CDCl3,
3
1H), 1.06-1.14 (m, 1H), 1.25-1.33 (m, 1H), 1.55-1.64 (m, 1H),
100 MHz): δ 25.0, 25.2, 38.2, 53.1, 63.8, 73.8, 78.2, 116.7,
126.3, 127.6, 129.9, 135.4, 144.8. Anal. Calcd for C27H29NO
(MW 383.53): C, 84.55; H, 7.62; N, 3.65. Found: C, 84.26; H,
7.62; N, 3.37.
2
3
2
3.03 (ddd, J ) 11.7 Hz, J ) 7.9, 3.6 Hz, 1H), 3.20 (ddd, J )
3
3
12.2 Hz, J ) 9.3, 7.0 Hz, 1H), 3.16 (bs, 1H), 3.50 (ddd, J )
8.9, 5.6, 3.4 Hz, 1H), 4.44-4.47 (m, 1H), 5.06 (dt, 2J ) J )
4
1.5, 2.0 Hz, J ) 10.7 Hz, 1H), 5.18 (dt, J ) 4J ) 1.5, 2.0 Hz,
3J ) 17.3 Hz, 1H), 5.65 (ddd, 3J ) 17.3, 10.7, 5.1 Hz, 1H), 7.19
(t, 3J ) 7.1 Hz, 3H), 7.27 (t, 3J ) 7.6 Hz, 6H), 7.57 (d, 3J ) 7.1
Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 24.9, 26.2, 53.2, 64.2,
75.1, 78.3, 114.7, 126.4, 127.7, 130.0, 138.2, 144.7. Anal. Calcd
for C26H27NO (MW 369.50): C, 84.51; H, 7.37; N, 3.79. Found:
C, 84.51; H, 7.38; N, 3.56.
3
2
(RR,2S)-R-Meth yl-2-pyr r olidin em eth an ol 10. To 9b (0.388
g, 1.085 mmol) in Et2O (5 mL) was added HCl (5 N aqueous
solution, 5 mL). After 3 h of vigorous stirring, the two phases
were separated, and the aqueous phase washed three times
with Et2O (3 × 5 mL). The aqueous phase was cooled and made
alkaline with concentrated aqueous NaOH followed by the
extraction with chloroform (5 × 5 mL). The extract was dried
(Na2SO4) and evaporated in vacuo to afford the title compound
(0.082 g, 66%). Mp: 83-85 °C. [R]20D ) -36.6 (c ) 1.07, MeOH)
(lit.14a [R]20D ) -36.4 (c ) 1.0, MeOH)). IR (CHCl3) cm-1: 3269,
2971, 2875, 1621, 1539, 1412, 1379, 1217, 769, 751, 665. 1H
(RR,2S)-R-(2-Tr im eth ylsilyleth yn yl)-1-tr iph en ylm eth yl-
2-p yr r olid in em eth a n ol 9e. Prepared from aldehyde 5e (1,-
02 g, 3 mmol) in ether (30 mL) and lithium trimethylsilyl-
acetylide (9 mmol, 0.58 M in THF) in 88% yield (1.165 g).
Lithium trimethylsilylacetylide was obtained from trimethyl-
silylacetylene (1.12 g, 11.4 mmol) in THF (12 mL) and n-BuLi
(9 mmol, 3.6 mL of a 2.5 M solution in hexane). Mp: 70-71
3
NMR (CDCl3, 400 MHz): δ 1.13 (d, J ) 6.3 Hz, 3 H), 1.55-
3
1.80 (m, 4 H), 2.48 (bs, 2 H), 2.86-2.99 (m, 2 H), 3.06 (dt, J
) 7.5 Hz, d, 3J ) 3.6 Hz, 1 H), 3.75 (dq, 3J ) 6.3, 3.6 Hz, 1 H).
°C. [R]20 ) -69.5 (c ) 2.05, CHCl3). IR (CHCl3) cm-1: 3400,
D
13C NMR (CDCl3, 100 MHz): δ 19.4, 24.2, 25.9, 47.0, 63.5, 68.1.
3060, 2950, 2160, 1945, 1590, 1485, 1440, 1245, 1000, 900, 845,
(RR,2S)-R-(1-Met h ylet h yl)-2-p yr r olid in em et h a n ol 11.
To 9c (0.107 g, 0.278 mmol) in Et2O (4 mL) was added HCl (5
N aqueous solution, 4 mL). After 3 h of vigorous stirring, the
two phases were separated, and the aqueous layer washed
three times with Et2O (3 × 5 mL). The aqueous phase was
cooled and made alkaline with concentrated aqueous NaOH
followed by extraction with chloroform (5 × 5 mL). The extract
was dried (Na2SO4) and evaporated in vacuo to afford the title
705. 1H NMR (CDCl3, 400 MHz): δ 0.15 (s, 9H), 0.20-0.31
2
(m, 1H), 1.31-1.42 (m, 2H), 1.90-1.99 (m, 1H), 3.05 (ddd, J
3
2
3
) 11.8 Hz, J ) 8.3, 3.4 Hz, 1H), 3.24 (ddd, J ) 11.8 Hz, J
3
) 9.0, 6.7 Hz, 1H), 3.38 (bs, 1H), 3.64 (ddd, J ) 8.4, 4.6, 4.1
3
3
Hz, 1H), 4.61 (d, J ) 4.1 Hz, 1H), 7.19 (t, J ) 7.1 Hz, 3H),
7.28 (t, J ) 7.9 Hz, 6H), 7.54 (d, J ) 8.1 Hz, 6H). 13C NMR
3
3
(CDCl3, 100 MHz): δ -0.0, 24.8, 28.1, 53.4, 64.0, 66.1, 78.2,
compound (0.033 g, 82%). Mp: 65-67 °C. [R]20 ) -39.2 (c )
91.1, 105.3, 126.5, 127.8, 129.8, 144.5. Anal. Calcd for C29H33
-
D
0.82, MeOH). IR (CHCl3) cm-1: 3282, 2958, 2872, 1621, 1539,
1470, 1417, 1385, 1365, 1336, 1216, 1066, 1001, 912, 752, 664.
NOSi (MW 439.66): C, 79.22; H, 7.57; N, 3.19. Found: C,
79.03; H, 7.74; N, 3.18.
3
1H NMR (CDCl3, 400 MHz): δ 0.86 (d, J ) 6.6 Hz, 3 H), 1.01
(RR,2S)-R-P h en yl-1-tr iph en ylm eth yl-2-pyr r olidin em eth -
a n ol 9f. Prepared from C6H5MgBr (2 mmol, 1.21 mL, 1.65 M
in ether) in 90% yield (0.378 g). Mp: 71-72 °C. [R]20D ) -77.8
(c ) 2.29, CHCl3). IR (CHCl3) cm-1: 3400, 3060, 2940, 2860,
1945, 1810, 1590, 1480, 1440, 1315, 1170, 1080, 1000, 900, 700.
1H NMR (CDCl3, 400 MHz): δ 0.26 (dquin, 2J ) 11.7 Hz, 3J )
3
(d, J ) 6.6 Hz, 3 H), 1.55-1.80 (m, 5 H), 2.75-2.92 (m, 3 H),
2.95-3.02 (m, 1 H), 3.18-3.27 (m, 2 H). 13C NMR (CDCl3, 100
MHz): δ 18.8, 19.9, 23.7, 25.9, 31.58, 46.60, 60.33, 77.06.
HRMS: calcd for C8H18NO (MH+) 144.1388, found 144.1391.
(RR,2S)-R-P h en yl-2-p yr r olid in em eth a n ol 12. To 9f (1.85
g, 4.4 mmol) in Et2O (10 mL) was added HCl (5 N aqueous
solution, 10 mL). After 3 h of vigorous stirring, the two phases
were separated, and the aqueous layer was washed three times
with Et2O (3 × 5 mL). The aqueous phase was cooled and made
alkaline with concentrated aqueous NaOH followed by extrac-
tion with CHCl3 (3 × 10 mL). The extract was dried (Na2SO4),
and the solvents were evaporated under vacuum to afford the
2
3
8.6 Hz, 1H), 0.084 (ddt, J ) 13.2 Hz, J ) 8.6, 4.6 Hz, 1H),
2
3
1.32-1.40 (m, 1H), 1.49 (ddt, J ) 12.7 Hz, J ) 8.1, 5.1 Hz,
2
3
1H), 3.09 (ddd, J ) 11.7 Hz, J ) 8.1, 3.6 Hz, 1H), 3.34 (ddd,
2J ) 12.2 Hz, J ) 8.9, 6.9 Hz, 1H), 3.34 (bs, 1H), 3.78 (ddd,
3
3J ) 8.7, 5.1, 3.6 Hz, 1H), 5.17 (d, 3J ) 3.6 Hz, 1H), 7.14 (d, 3J
3
) 7.1 Hz, 2H), 7.18-7.34 (m, 12H), 7.65 (d, J ) 7.6 Hz, 6H).
13C NMR (CDCl3, 100 MHz): δ 24.9, 25.8, 53.4, 66.1, 75.7, 78.3,
125.5, 128.1, 126.5, 126.6, 127.7, 130.0, 142.3, 144.7. Anal.
Calcd for C30H29NO (MW 419.56): C, 85.88; H, 6.97; N, 3.34.
Found: C, 85.70; H, 7.09; N, 3.18.
1
title compound (0.673 g, 86%). H NMR (CDCl3, 400 MHz): δ
1.40-1.50 (m, 1H), 1.58-1.77 (m, 3H), 2.80 (bs, 2H), 2.86-
2.93 (m, 1H), 2.97-3.03 (m, 1H), 3.34-3.41 (m, 1H), 4.70 (d,
J . Org. Chem, Vol. 68, No. 25, 2003 9751

Bejjani et al.
3
3
3J ) 4.3 Hz, 1H), 7.24 (t, J ) 6.8 Hz, 1H), 7.33 (t, J ) 7.1,
added. After 20 h of stirring at room temperature, NaH (16
mg, 0.68 mmol) was added, and the reaction mixture was
allowed to stir for an additional 20 h before being quenched
with aqueous NaHCO3. The two phases were separated, the
organic phase was dried (Na2SO4), and the solvents were
evaporated in vacuo. Purification by flash chromatography
over silica gel with AcOEt-cyclohexane (1:2) gave 19 mg (30%
yield) of the title compound. 1H NMR (CDCl3, 400 MHz): δ
0.92 (t, 3J ) 7.1 Hz, 3H), 1.30-1.66 (m, 6H), 1.69-1.93 (m,
3H), 2.01-2.12 (m, 1H), 3.17 (ddd, J ) 11.4 Hz, J ) 9.8, 3.5
Hz, 1H), 3.64 (dt, 2J ) 11.4 Hz, 3J ) 8.1, 8.4 Hz, 1H), 3.78
(ddd, 3J ) 10.9, 7.1, 5.4 Hz, 1H), 4.62 (dt, 3J ) 7.8, 5.4 Hz,
1H). 13C NMR (CDCl3, 100 MHz): δ 14.0, 22.6, 25.0, 25.2, 28.2,
30.3, 45.9, 63.5, 75.5, 162.0.
7.8 Hz, 2H), 7.38 (d, J ) 7.7 Hz, 2H). 13C NMR (CDCl3, 100
MHz): δ 25.10, 25.61, 46.94, 64.04, 74.29, 125.99, 128.32,
127.24, 142.43.
3
(RR,2S)-R-(2-P r op en yl)-2-p yr r olid in em et h a n ol 13. To
9g (0.437 g, 1.139 mmol) in Et2O (10 mL) was added HCl (5 N
aqueous solution, 10 mL). After 3 h of vigorous stirring, the
two phases were separated, and the aqueous layer was washed
three times with Et2O (3 × 5 mL). The aqueous phase was
cooled and made alkaline with concentrated aqueous NaOH
followed by the extraction with chloroform (4 × 5 mL). The
extract was dried (Na2SO4) and evaporated in vacuo to afford
the amino alcohol (0.130 g, 81%). Mp: 81-83 °C. [R]20D ) -18.0
(c ) 0.80, MeOH). IR (CHCl3) cm-1: 3269, 3076, 2970, 2875,
1640, 1540, 1413, 1366, 1339, 1212, 915, 771, 751, 665. 1H
NMR (CDCl3, 400 MHz): δ 1.62 (m, 4 H), 2.18-2.28 (m, 2 H),
2.38 (bs, 2 H), 2.88-3.02 (m, 2 H), 3.18-3.19 (m, 1 H), 3.63-
3.70 (m, 1 H), 5.06-5.17 (m, 2 H), 5.80-5.92 (m, 1 H).13C NMR
(CDCl3, 100 MHz): δ 24.5, 25.9, 38.8, 46.9, 62.0, 71.6, 117.4,
135.2. HRMS: calcd for C8H16NO (MH+) 142.1232, found
142.1230.
2
3
(1R,7S)-Tetr a h yd r o-1-(2-p r op en yl)-1H,3H-p yr r olo[1,2-
c]oxa zol-3-on e 16. To 9g (0.364 g, 0.949 mmol) in Et2O (10
mL) was added HCl (5 N aqueous solution, 10 mL). After 3 h
of vigorous stirring, the two phases were separated, and the
aqueous phase was washed three times with Et2O (3 × 3 mL).
The aqueous phase was cooled and made alkaline with
concentrated aqueous NaOH followed by extracting the amino
alcohol with CHCl3 (3 × 5 mL). The extract was dried (Na2-
SO4) and the solventd evaporated under vacuum. The obtained
crude amino alcohol was dissolved in anhydrous CH2Cl2 (8
mL). Et3N (0.61 mL, 3,75 mmol) and methyl chloroformate (76
µL, 1 mmol) were added. After 20 h of stirring at room
temperature, NaH (72 mg, 3 mmol) was added, and the
reaction mixture was allowed to stir for an additional 20 h
before being quenched with aqueous NaHCO3. The two phases
were separated, the organic phase was dried (Na2SO4), and
the solvents were evaporated under vacuum. Purification by
flash chromatography over silica gel with AcOEt-cyclohexane
(rR,2S)-1-Meth yl-R-p h en yl-2-p yr r olid in em eth a n ol 14.
The amino alcohol 12 (0.673 g, 3.8 mmol) was dissolved in
water (2 mL), and formic acid (98%, 1 mL) and formaldehyde
(37% aqueous solution, 1.5 mL) were added. The reaction
mixture was stirred for 10 h at refluxing temperature and then
cooled and made alkaline with concentrated aqueous NaOH,
followed by extraction with CH2Cl2. The extract was dried (Na2-
SO4) and the solvent evaporated under vacuum. The residue
was filtered over silica gel (AcOEt) to afford the title compound
(0.460 g, 63%) as slightly yellow oil. [R]20 ) -60.7 (c ) 0.72,
D
CHCl3) (lit.8a [R]20 ) -59.0 (c ) 0.73, CHCl3)). 1H NMR
D
1
(CDCl3, 400 MHz): δ 1.21-1.33 (m, 1H), 1.56-1.77 (m, 3H),
(1:2) gave 52 mg (32% yield) of the title compound. H NMR
2.34 (dt, J ) 9.3, 7.6 Hz, 1H), 2.46 (s, 3H), 2.52 (ddd, 3J ) 9.2,
(CDCl3, 400 MHz): δ 1.42-1.53 (m, 1H), 1.72-1.78 (m, 1H),
1.80-1.90 (m, 1H), 2.01-2.09 (m, 1H), 2.34-2.38 (m, 1H),
2.52-2.60 (m, 1H), 3.11-3.18 (m, 1H), 3.57-3.64 (m, 1H),
3.75-3.81 (m, 1H), 4.68 (q, 3J ) 7.3 Hz, 1H), 5.11-5.19 (m,
2H), 5.72-5.83 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ 25.0,
25.2, 34.9, 45.7, 63.2, 75.4, 118.7, 132.3, 161.6.
3
6.6, 3.0 Hz, 1H), 3.11-3.17 (m, 1H), 3.54 (bs, 1H), 4.87 (d, J
3
3
) 3.0 Hz, 1H), 7.23 (t, J ) 7.1 Hz, 1H), 7.33 (t, J ) 7.8, 7.3
Hz, 2H), 7.38 (d, 3J ) 7.1 Hz, 2H). 13C NMR (CDCl3, 100
MHz): δ 23.0, 23.9, 40.1, 57.7, 69.8, 71.0, 125.6, 128.2, 126.8,
141.8.
(1R,7S)-Tetr ah ydr o-1-bu tyl-1H,3H-pyr r olo[1,2-c]oxazol-
3-on e 15. To 9a (136 mg, 0.34 mmol) in Et2O (5 mL) was added
HCl (5 N aqueous solution, 3 mL). After 5 h of vigorous
stirring, the two phases were separated and the aqueous one
washed three times with Et2O (3 × 3 mL). The aqueous phase
was cooled and made alkaline with concentrated aqueous
NaOH followed by extracting the amino alcohol with CHCl3
(3 × 5 mL). The extract was dried (Na2SO4) and the solvent
evaporated under vacuum. The obtained crude amino alcohol
was dissolved in anhydrous CH2Cl2 (5 mL). Et3N (0.15 mL,
0.94 mmol) and methyl chloroformate (32 µL, 0.41 mmol) were
Ack n ow led gm en t. Thanks are due to Dr. Franck
Ferreira for helpful discussions and to the Lebanese
National Council for Scientific Research for a grant (to
J .B.).
Su p p or tin g In for m a tion Ava ila ble: Spectral data for 2e,
5, 6, 8a ,b, 9a -g, and 10-16. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034976G
9752 J . Org. Chem., Vol. 68, No. 25, 2003