Short enantioselective syntheses of trans-5-alkylprolines from new functionalized amino alcohols

Article abstract of DOI:10.1021/jo8014243

(Chemical Equation Presented) Amino alcohols, having an enol ether function, cyclized in acidic medium to give quantitatively diastereosomerically pure bicyclic compounds that were transformed in five steps in enantiopure trans-5-alkylproline derivatives.

Full text of DOI:10.1021/jo8014243

compounds.6 As a matter of fact, such amino acids possessing
alkyl substituents have emerged as an important tool for
governing peptide conformation; thus, the stereoselective syn-
thesis of substituted proline derivatives remains a challenging
task.
Short Enantioselective Syntheses of
trans-5-Alkylprolines from New Functionalized
Amino Alcohols
Jeanne Alladoum, Sylvain Roland, Emmanuel Vrancken,
Pierre Mangeney,* and Catherine Kadouri-Puchot*
In the course of our research on the enantioselective synthesis
of substituted aminoacids from functionalized ꢀ-amino-alco-
hols,7 we have recently developed a diastereoselective synthesis
of enantiomerically enriched enol ethers 3, by addition of the
lithium derivative of the methylallylether to oxazolidines (or
imines) 2 derived from phenylglycinol.8 According as that 3
are direct precursors of 4, we decided to study the possibility
of using these compounds for the development of straightfor-
ward syntheses of enantiopure trans-5-alkyl-proline derivatives
as shown in Scheme 1. As a matter of fact, among the several
routes already described for the selective synthesis of trans 2,5-
substituted pyrrolidines 5, which can be potential precursors of
5-alkylprolines 1, we turned our attention on their preparations
reported by Higashiyama9 and Katritzky10 by addition of
Grignard reagents to bicyclic oxazolidines 4.11
UniVersite´ Pierre et Marie Curie-Paris 6, Laboratoire de
Chimie Organique UMR 7611, Institut de Chimie
Mole´culaire FR 2769, 4 place Jussieu, case courrier 47,
75005 Paris, France
cathy.kadouri-puchot@upmc.fr; pierre.mangeney@upmc.fr
ReceiVed July 15, 2008
As expected, the synthesis of the ꢀ-aminoalcohols 3a-d from
oxazolidines 2a-c and imine 2d, and their subsequent cycliza-
Amino alcohols, having an enol ether function, cyclized in
acidic medium to give quantitatively diastereosomerically
pure bicyclic compounds that were transformed in five steps
in enantiopure trans-5-alkylproline derivatives.
(4) For some examples, see: (a) Aubry, C.; Oulyadi, H.; Dutheuil, G.;
Leprince, J.; Vaudry, H.; Pannecoucke, X.; Quirion, J.-C. J. Peptide Sci. 2006,
12, 154–160. (b) An, S. S. A.; Lester, C. C.; Peng, J.-L.; Li, Y.-J.; Rothwarf,
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H. A. J. Am. Chem. Soc. 1999, 121, 11558–11566. (c) Trabocchi, A.; Rolla, M.;
Menchi, G.; Gurna, A. Tetrahedron Lett. 2005, 46, 7813–7816. (d) Tong, Y.;
Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65,
2484–2493. (e) Arasappan, A.; Chen, K. X.; Njooroge, G.; Parekh, T., N.;
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R. K.; Jonhson, R. L. J. Med. Chem. 1993, 36, 3481–3483. (g) Duan, S.; Moeller,
K. D. Tetrahedron 2001, 57, 6407–6415. (h) Belvisi, L.; Colombo, L.; Colombo,
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2001, 57, 6463–6473. (i) Bittermann, H.; Gmeiner, P. J. Org. Chem. 2006, 71,
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Among the 20 proteinogenic amino acids, proline with its
cyclic nature and its secondary amine plays a specific role in
peptides and proteins secondary structure formation.1 Due to
their major role in chemistry and biology, this R-amino acid
and its derivatives remain synthetic targets of great interest. The
ever growing number of reactions involving these compounds
as chiral organocatalysts2,3 or scaffolds for the construction of
peptidomimetics4 is a good reason for developing new methods
for their preparation.5 In these fields, 5-alkylprolines 1 bearing
a bulky substituent constitute a particularly interesting class of
(5) For review on the synthesis of substituted prolines, see: Karoyan, P.;
Sagan, S.; Lequin, O.; Quancard, J.; Lavielle, S.; Chassaing, G. Targets
Heterocycl. Syst. 2004, 8, 216–273.
(6) For the synthesis of 5-alkyl proline derivatives, see: (a) Manfre´, F.; Kern,
J.-M.; Biellmann, J.-F. J. Org. Chem. 1992, 57, 2060–2065. (b) Halab, L.; Be´lec,
L.; Lubell, W. D. Tetrahedron 2001, 57, 6349–6446. (c) Beausoleil, E.;
L’Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell, W. D. J. Org. Chem. 1996,
61, 9447–9454. (d) Pyne, S. G.; Javidan, A.; Skelton, B. W.; White, A. H.
Tetrahedron 1995, 51, 5157–5168. (e) Davis, F. A.; Zhang, H.; Seung, H. L.
Org. Lett. 2001, 3, 759–762. (f) Brun, M.-P.; Martin, A.-S.; Garbay, C.; Bishoff,
L. Tetrahedron Lett. 2003, 44, 7011–7013. (g) Van Esseveldt, B. C. J.; Vervoot,
P. W. H.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791–
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(i) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229–1239. (j) Hussaini,
S. R.; Moloney, M. G. Tetrahedron Lett. 2004, 45, 1125–1127. (k) Gu, Y. G.;
Xu, Y.; Krueger, A. C.; Madigan, D.; Sham, H. L. Tetrahedron Lett. 2002, 43,
955–957. (l) Walle´n, E. A. A.; Christiaans, J. A. M.; Gynther, J.; Vepsa¨la¨inen,
J. Tetrahedron Lett. 2003, 44, 2081–2082. (m) Walle`n, E. A. A.; Christiaans,
J. A. M.; Saarinen, T. J.; Jarho, E. M.; Forsberg, M. M.; Vena¨la¨inen, J. I.;
Ma¨nnisto¨, P. T.; Gynther, J. Bioorg. Med. Chem. 2003, 11, 3611–3619. (n) Davis,
F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147–5152. (o) Agami, C.;
Comesse, S.; Guesne´, S.; Kadouri-Puchot, C.; Martinon, L. Synlett 2003, 1058,
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67, 1496–1500. (b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem.
2002, 67, 2424–2428. (c) Guesne´, S.; Comesse, S.; Kadouri-Puchot, C. Lett Org.
Chem. 2006, 3, 318–319.
(8) Alladoum, J.; Roland, S.; Vrancken, E.; Kadouri-Puchot, C.; Mangeney,
P. Synlett 2006, 1855, 1858.
(9) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50, 1083–
1092.
(10) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999,
64, 1979–1985.
(1) For a review, see: (a) Yaron, A.; Naider, F. Crit. ReV. Biochem. Mol.
Biol. 1993, 28, 31. For some selected examples, see: (b) Halab, L.; Gosselin, F.;
Lubell, W. D. Biopolymers 2000, 55, 101–122. (c) Beausoleil, E.; Lubell, W. D.
J. Am. Chem. Soc. 1996, 118, 12902–12908. (d) Che, Y.; Marshall, G. R.
Biopolymers 2006, 81, 392–406. (e) Williams, K. A.; Deber, C. M. Biochemistry
1991, 30, 8919. (f) Walle´n, E. A. A.; Christiaans, J. A. M.; Saarinen, T. J.;
Jarho, E. M.; Forsberg, M. M.; Vena¨la¨inen, J. I.; Ma¨nnisto¨, P. T.; Gynther, J.
Bioorg. Med. Chem. 2003, 11, 3611–3619.
(2) For some selected reviews, see: (a) List, B. Tetrahedron 2002, 58, 5573–
5590. (b) List, B. Acc. Chem. Res. 2004, 37, 548–557. (c) Dalko, P. I.; Moisan,
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(3) For some selected recent examples of proline organocatalysis, see: (a)
Rodr´ıguez, B.; Bruckmann, A.; Bolm, C. Chem.-Eur. J. 2007, 13, 4710–4722.
(b) Mitchell, C. E. T.; Brenner, S. E.; Garc´ıa-Fortanet, J.; Ley, S. V. Org. Biomol.
Chem. 2006, 4, 2039–2049. (c) Puleo, G. L.; Masi, M.; Iuliano, A. Tetrahedron:
Asymmetry 2007, 18, 1364–1375. (d) Chi, Y.; Gellman, S. H. J. Am. Chem.
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Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285–9289.
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2593–2595. (i) Enders, D.; Gasperi, T. Chem. Commun. 2007, 88, 90. (j) Chen,
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10.1021/jo8014243 CCC: $40.75
Published on Web 10/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9771–9774 9771

SCHEME 1
SCHEME 4
TABLE 1. Selectivity of Compounds
exp
SM
R
R′
Pdt
yield (%)
dra 8/8′
1
2
3
4
5
6
7
8
4b
4b
4b
4b
4c
4c
4c
4d
4b
4c
4d
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
Ph
MeLi
MeMgBr
n-BuLi
n-BuMgCl
MeMgBr
n-BuLi
n-BuMgCl
PhMgCl
8a
8a
8b
8b
8c
8d
8d
8e
8f
67
75
72
quant
68
48
quant
89
quant
quant
75
>95/5
>95/5
>95/5
>95/5
>95/5
>90/10
>90/10
>90/10
>95/5
>95/5
90/10
SCHEME 2
9
10
11
i-Pr
t-Bu
Ph
C2H3MgBr
C2H3MgBr
C2H3MgBr
8g
8h
a Diastereoisomeric ratios were determined by 1H NMR analysis of
the crude mixture.
SCHEME 3
FIGURE 1. Attack of the Grignard reagent on the iminium intermediate.
tion by H2SO4 4N gave spontaneously and quantitatively the
bicyclic oxazolidines 4a-d in a totally diastereoselective
manner, as shown in Scheme 2.12
With the aim of synthesizing proline derivatives, we first
tested the addition of trimethylsilylcyanide (Scheme 3).13,14
Whereas these reactions occurred quantitatively to give the
corresponding cyanopyrrolidines, only the tert-butyl derivative
4c afforded the diastereoisomerically pure cyanopyrrolidine 6.
In contrast, the i-Pr and the phenyl derivatives, respectively 4b
and 4d, were found to be less selective and gave an inseparable
mixture of two diastereoisomers 6 and 6′.
So, to propose a more general route toward 5-alkyl prolines,
we investigated the reactivity of vinyl Grignard reagent. As
reported above, the addition of Grignard reagents on bicyclic
compounds 4 has already been described. An excellent stereo-
control was observed by Higashiyama9 by addition of aryl
magnesium reagents to 4 (R ) Aryl). In contrast, the selectivity
obtained by Katritzky10 in additions of several Grignard reagents
to compounds 4 (when R ) allyl) was found to be dependent
on the nature of this reagent. We decided therefore to reexamine
this reaction on the more sterically hindered 4 (R ) i-Pr and
t-Bu). Additionally, the possibility of using lithium derivatives
was also tested (Scheme 4).
of the R (i-Pr or t-Bu) substituent. In all cases, an excellent
stereocontrol was observed resulting in the formation of the same
diastereomer with organolithium or Grignard reagents. However,
the best yields of 5-alkyl pyrrolidines 8 (R′ ) alk) were achieved
when Grignard reagents were used (see entries 2, 4, 5, and 7).
Therefore, only the addition of vinyl Grignard reagent was
attempted giving rise to the totally stereoselective formation of
8, which was obtained in excellent yield (entries 9, 10).
Additionally, addition of this reagent to compound 4d was also
studied (entry 11). In this case, a decrease in selectivity and
yield was observed. The configuration of the new stereogenic
center in 8 was confirmed by comparison of the NMR data of
pyrrolidine 8e and those reported in the literature9 and, a
posteriori, by comparison of NMR data of the compound 7a
(R ) i-Pr) obtained from 8f (see below). As reported, these
additions were found to occur with a trans-stereoselectivity
relatively to the R substituent, such stereocontrol being attributed
to the nucleophilic attack of the organometallic reagent on the
less hindered face of an iminium intermediate resulting of an
opening of the oxazolidine ring (Figure 1).
As shown in Table 1, the selectivity was found to be
insensitive to the nature of the organometallic (R′Li or R′MgX)
reagents (Table 1, entries 1-7) as well as the steric hindrance
The next step in the synthesis of the proline derivatives was
the oxidation of the double bond of the 2-vinylpyrrolidines 8f-g.
Initial attempts were performed onto the hydrochloride of 8f,
to protect the nitrogen atom from oxidation. But, on ozonolysis
(O3, then Me2S or NEt315), this hydrochloride gave mainly the
bicyclic compound 4b accompanied by only a small amount of
the desired hemiacetal 9a (Scheme 5). The unexpected formation
of 4b can be explained as a result of a nitrogen assisted
elimination reaction occurred in the intermediate ozonide, upon
treatment with triethylamine, with the loss of vinyl group and
(11) For the synthesis of 2,5-pyrrolidines by opening bicyclic oxazolidines,
see also: (a) Huang, P. Q.; Arsenyadis, S.; Husson, H.-P. Tetrahedron Lett. 1987,
28, 547–550. (b) Arsenyadis, S.; Huang, P. Q.; Piveteau, D.; Husson, H.-P.
Tetrahedron 1988, 44, 2457–2470. (c) Katritzky, A. R.; Cui, X.-L.; Yang, B.;
Steel, P. J. Tetrahedron Lett. 1998, 39, 1697–1700.
(12) The stereochemistry of compound 4d was determined by comparing its
NMR spectra and [R]D with those reported in the literature: ref 10.
(13) Warmuth, R.; Munsch, T. E.; Stalker, R. A.; Li, B.; Beatty, A.
Tetrahedron 2001, 57, 6383–6397.
(14) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995,
51, 9179–9190.
(15) Hon, Y.-S.; Lin, S.-W.; Chen, Y.-J. Tetrahedron 1995, 51, 5019–5034.
9772 J. Org. Chem. Vol. 73, No. 24, 2008

SCHEME 5
SCHEME 6a
[3S,5R,7aR]-3-Phenyl-5-propylhexahydropyrrolo[2,1-b]ox-
azole (4a). Oil. (Et2O/Pentane: 10/90). Yield: quant. [R]D20: +45
(c 1.5, CHCl3). 1H NMR (CDCl3): 7.42-7.24 (m, 5H), 5.04 (dd, J
) 5.4, 2.4 Hz, 1H), 4.39 (dd, J ) 8.3, 7.1 Hz, 1H), 4.20 (t, J ) 6.7
Hz, 1H), 3.65 (dd, J ) 8.3, 6.3 Hz, 1H), 2.92-2.89 (m, 1H),
2.24-2.08 (m, 2H), 1.97-1.91 (m, 1H), 1.60-1.51 (m, 2H),
1.34-1.26 (m, 3H), 0.89 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3):
143.1, 128.4, 126.9, 126.5, 98.9, 72.8, 68.0, 66.6, 38.4, 30.6, 30.1,
19.7, 14.4. Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05.
Found: C, 77.26; H, 8.89; N, 5.85.
[3S,5S,7aR]-5-Isopropyl-3-phenyl-hexahydro-pyrrolo[2,1-b]ox-
azole (4b). Oil. (Et2O/Pentane: 10/90). Yield: quant. [R]D20: + 58
(c 1.2, CHCl3). 1H NMR (CDCl3): 7.42-7.24 (m, 5H), 5.03 (dd, J
) 5.2, 1.9 Hz, 1H), 4.35 (dd, J ) 8.3, 7.1 Hz, 1H), 4.22 (t, J ) 6.4
Hz, 1H), 3.63 (dd, J ) 8.3, 6.1 Hz, 1H), 2.83 (dd, J ) 7.1, 5.6 Hz,
1H), 2.20-2.12 (m, 1H), 2.04-1.91 (m, 2H), 1.74-1.61 (m, 2H),
0.88 (d, J ) 6.8 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H). 13C NMR
(CDCl3): 143.4, 128.4, 126.8, 126.6, 99.2, 72.9, 72.6, 69.1, 32.0,
30.2, 25.7, 19.9, 17.6. HRMS: Calcd for C15H21NO (M + H+) m/z
) 232.16959, obsd m/z ) 232.16942.
[3S,5S,7aR]-5-tert-Butyl-3-phenyl-hexahydro-pyrrolo[2,1-b]ox-
azole (4c). Oil. (Et2O/Pentane: 10/90). Yield: quant. [R]D20: +44
(c 1.2, CHCl3). 1H NMR (CDCl3): 7.42-7.24 (m, 5H), 4.96 (dd, J
) 3.3, 1.8 Hz, 1H), 4.33-4.24 (m, 2H), 3.63 (dd, J ) 7.8, 4.5 Hz,
1H), 2.75-2.72 (m, 1H), 2.11-1.99 (m, 3H), 1.76-1.71 (m, 1H),
0.83 (s, 9H). 13C NMR (CDCl3): 143.7, 128.3, 126.6, 126.5, 99.5,
77.2, 72.3, 71.3, 35.4, 31.0, 26.5, 24.4. IR (CHCl3): 3448, 2951,
1603, 1360, 1037, 700 cm-1. Anal. Calcd for C16H23NO: C, 78.32;
H, 9.45; N, 6.52. Found: C, 78.01; H, 9.54; N, 6.44.
a Reaction conditions: (a) O3, TFA/CH2Cl2, -78 °C, then DMS; then
NaOH 5N, (b) TPAP, NMO, CH3CN, rt, 80% for 7a and 92% for 7b (two
steps); (c) H2, MeOH/H2O/TFA, Pd(OH)2, 95% for 1a, 73% for 1b.
the concomitant departure of formic acid and formaldehyde.
Hemiacetals 9a-b were obtained quantitatively when ozonolysis
was performed in a mixture of TFA/methylene chloride.16
Oxidation of 9a-b with TPAP17 afforded lactones 7a-b in a
diastereoisomerically pure form (Scheme 6). The stereochem-
istry of lactone 7a was determined by an X-ray radiocrystal-
lographic analysis and found to be 4S,6S,8aS.18 Structural data
of lactone 7b (R ) t-Bu) revealed it to be identical to those
obtained after hydrolysis of the cyano derivative 6 (R ) t-Bu)
in Scheme 3. This correlation showed that the addition of the
nitrile ion occurred also on the less hindered face of the iminium
ion obtained by opening of the oxazolidine ring.
[3S,5S,7aR]-3,5-Diphenylhexahydropyrrolo[2,1-b]oxazole (4d).
20
Solid. (Et2O/Pentane: 10/90). Yield: quant. Mp: 47-49 °C. [R]D
:
Finally, hydrogenolysis of the two lactones 7a and 7b with
Pearlman’s catalyst in the presence of one equivalent of TFA
led to the enantiomerically pure 5-alkyl proline derivatives
1a-b.19 It is noteworthy that all the steps involved in the
transformation of the vinyl pyrrolidines 8 into the proline
derivatives 1 need no purification of the intermediates.
In conclusion, we have shown that the ꢀ-amino alcohols 3,
easily obtained by diastereoselective addition of methoxypro-
pene-derived lithium reagent onto oxazolidines (or imines) of
phenylglycinol, are valuable synthons for the stereoselective
synthesis of bicyclic intermediates that are precursors of
diastereoisomerically pure 5-alkylated pyrrolidines. Finally, in
three steps from the 5-vinyl-pyrrolidines 8, we have synthesized
5-alkylated proline derivatives 1 in an enantiomerically pure
form.
1
+38 (c 0.6, EtOH). H NMR (CDCl3): 7.41-7.19 (m, 10H), 5.18
(dd, J ) 5.6, 2.0 Hz, 1H), 4.42 (dd, J ) 8.3, 7.1 Hz, 1H), 4.22 (t,
J ) 6.1 Hz, 1H), 4.05 (dd, J ) 9.7, 5.7 Hz, 1H), 3.75 (dd, J ) 8.3,
5.3 Hz, 1H), 2.60-2.27 (m, 2H), 2.06-1.98 (m, 1H), 1.87-1.77
(m, 1H). 13C NMR (CDCl3): 143.1, 142.8, 128.4, 128.3, 127.1,
127.0, 126.8, 126.4, 98.3, 72.0, 69.5, 66.6, 35.2, 30.4. Anal. Calcd
for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.34; H,
7.35; N, 5.27.
General Procedure for the Synthesis of the Pyrrolidines
(8f-h). To a solution of bicycle 4 (4.3 mmol) in THF (30 mL) at
0 °C was added a solution of vinyl Grignard reagent in THF (13
mmol). The reaction was then allowed to warm up and was stirred
for 2 h at room temperature. When the reaction was complete, the
solution was hydrolyzed carefully with NH4Cl. The aqueous layer
was extracted with Et2O, and the organic layers were dried over
MgSO4 and evaporated to give the corresponding vinylated
pyrrolidine.
[2S,2(2S,5S)]-2-(2-Isopropyl-5-vinylpyrrolidin-1-yl)2-phenyl-
ethanol (8f). Oil. Yield: quant. [R]D20: +130 (c 1, CHCl3). 1H NMR
(CDCl3): 7.30-7.15 (m, 5H), 5.85 (ddd, J ) 17, 10, 9.4 Hz, 1H),
5.13-5.03 (m, 2H), 4.04 (dd, J ) 7.7, 6.5 Hz, 1H), 3.79 (dd, J )
10.2, 7.7, 1H), 3.71-3.62 (m, 2H), 2.88 (dt, J ) 9.25, 3.5 Hz,
1H), 1.89-1.75 (m, 1H), 1.70-1.36 (m, 4H), 0.71 (d, J ) 6.75
Hz, 3H), 0.61 (d, J ) 6.75 Hz, 3H). 13C NMR (CDCl3): 140.7,
139.5, 129.7, 128.3, 127.5, 115.8, 67.3, 63.5, 62.8, 31.6, 31.1, 23.6,
20.3, 15.4. HRMS Calcd for C17H25NO (M + H+) m/z ) 260.20089,
obsd m/z ) 260.20053.
Experimental Section
General Procedure for the Syntheses of Bicyclic Compounds
(4a-d). A solution of amino alcohol 3a-d (10 mmol) in ether (40
mL) was washed several times with a solution of sulfuric acid 4N
(40 mL) until the entire product passed in the aqueous layer. This
aqueous layer was then separated from the organic one, neutralized
with a solution of NaOH 2 M, and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4, and the solvent
was evaporated to give corresponding bicyclic compounds 4a-d
in quantitative yield.
[2S,2(2S,5S)]-2-(2-tert-Butyl-5-vinylpyrrolidin-1-yl)-2-phenyl-
ethanol (8g). Solid. Yield: quant. Mp: 69 °C. [R]D20: +32 (c 1.7,
1
(16) (a) Carretero, J. C.; Arraya`s, R. G. J. Org. Chem. 1998, 63, 2993–
3005. (b) Dieter, R. K.; Watson, R. Tetrahedron Lett. 2002, 43, 7725–7728.
(17) Dauban, P.; Dubois, L.; Dau, M. E. T.; Dodd, R. H. J. Org. Chem.
1995, 60, 2035–2043.
(18) Atomic coordinates, bond lengths and angles, and thermal parameters
of compound 7a have been deposited at the Cambridge Crystallographical Data
Center with the deposition number CCDC 661332.
(19) The trans stereochemistry of the proline derivatives was ascertained on
the basis of the NMR analysis: the 1H NMR spectra of compounds 1a-b showed
an apparent triplet for the R proton, a feature for the trans diastereoisomer (see
ref 6c).
CHCl3). H NMR (CDCl3): 7.24-7.19 (m, 5H), 6.17 (ddd, J )
16.6, 10.5, 5.5 Hz, 1H), 5.20 (dt, J ) 10.5, 1.6 Hz, 1H), 5.08 (dt,
J ) 17.2, 1.6 Hz, 1H), 4.14 (dd, J ) 9.75, 5.5 Hz, 1H), 3.75 (t, J
) 10 Hz, 1H), 3.68-3.62 (m, 1H), 3.50 (dd, J ) 10.25, 5.5 Hz,
1H), 3.02 (dd, J ) 8.9, 4.1 Hz, 1H), 1.71-1.60 (m, 1H), 1.48-1.05
(m, 3H), 0.85 (s, 9H). 13C NMR (CDCl3): 140.4, 138.6, 129.3,
128.2, 127.5, 116.8, 67.9, 66.9, 62.5, 62.3, 35.5, 30.6, 27.7, 25.5.
IR (CHCl3): 3416, 2958, 1470, 1215, 1027, 756 cm-1. HRMS Calcd
for C18H27NO (M + H+) m/z ) 274.21654, obsd m/z ) 274.21627.
J. Org. Chem. Vol. 73, No. 24, 2008 9773

[2S,(2S,5S)]-2-Phenyl-2-(2-phenyl-5-vinylpyrrolidin-1-yl)etha-
nol (8h). Oil (Et2O/pentane: 15/85). Yield: 75%. [R]D20: +37 (c
cm-1. Anal. Calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12.
Found: C, 74.56; H, 8.85; N, 4.77.
1
Lactone 7b was also obtained from the cyano derivative 6
(R ) t-Bu) by treatment with a solution of HCl (1 M in Et2O, 10
equiv) in MeOH during 1 night. A saturated solution of NaHCO3
was added and the mixture was extracted with dichloromethane.
The organic layers were dried over MgSO4, then evaporated to give
the crude product. Flash chromatography afforded the lactone 7b
(yield: 80%), which was totally identical to the compound obtained
previously.
1.4, CHCl3). H NMR (CDCl3): 7.17-6.96 (m, 10H), 5.88 (td, J
) 17, 9, 8 Hz), 5.16-5.04 (m, 2H), 4.03-3.88 (m, 3H), 3.52 (d,
J ) 7 Hz, 2H), 2.35-2.17 (m, 3H), 1.63-1.49 (m, 2H). 13C NMR
(CDCl3): 47.7, 140.6, 138.7, 129.9, 128.3, 127.9, 127.4, 126.8,
126.6, 116.0, 67.0, 63.8, 63.2, 62.9, 34.1, 31.3. Anal. Calcd for
C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found: C, 81.48; H, 7.97;
N, 4.44.
General Procedure for the Synthesis of Lactones (7a) and
(7b). A solution of pyrrolidine 8f or 8g (0.74 mmol) in TFA (20
mL) and CH2Cl2 (10 mL) was ozonolyzed at -20 °C for 1 h. Then
DMS (7.4 mmol) was added and the solution was stirred at room
temperature overnight. The solvent and TFA were evaporated. The
residue was dissolved in CH2Cl2 (20 mL), and washed with a
solution of NaOH 2M. The organic layer was dried over MgSO4
and the solvent was evaporated to give the hemiketal as an oil which
was used without purification in the oxidation step. The hemiketal
(0.85 mmol) was dissolved in acetonitrile (20 mL). Molecular sieves
(500 mg) was introduced and then, TPAP (0.025 mmol) and
N-methylmorpholine (1.7 mmol) were rapidly added to the solution.
The reaction was stirred for about 2-3 h. When the reaction was
complete, the solvent was evaporated and the crude product was
dissolved in AcOEt and filtered through a short pad of silica gel.
The solvent was evaporated to give the corresponding lactones.
General Procedure for Hydrogenolysis of Bicyclic Lactones.
Compounds 7a or 7b (0.15 mmol) were dissolved in aqueous
methanol (20:1, MeOH:H2O, 3 mL). Trifluoroacetic acid (0.15
mmol) and Pearlman’s catalyst (1 equiv by mass) were added to
the mixture, which was degassed and was stirred under hydrogen
for 1 night. The suspension was then filtered under a pad of Celite.
After evaporation, amino acids 1a or 1b were purified by trituration
with diethyl ether.
[2S,5S]-5-Isopropylpyrrolidine-2-carboxylic acid (1a). Yield
95%. [R]D20: -34 (c 0.3, HCl 1.2M). H NMR (CD3OD): 3.86 (t,
1
J ) 9.1 Hz, 1H), 3.23-3.12 (m, 1H), 2.16-2.02 (m, 1H),
1.89-1.28 (m, 4H), 0.62 (d, J ) 7.4 Hz, 3H), 0.53 (d, J ) 7.7 Hz,
3H). 13C NMR (CD3OD): 68.3, 32.2, 30.0, 20.5, 19.5. HRMS: Calcd
for C8H16NO2 (M + H+) m/z ) 158.11756, obsd m/z ) 158.11747.
[2S,5S]-5-tert-Butylpyrrolidine-2-carboxylic acid (1b). Yield
73%. [R]D20: -30 (c 0.3, HCl 1.2M). H NMR (CD3OD): 3.96 (t,
1
[4S,6S,8aS]-6-Isopropyl-4-phenylhexahydropyrrolo[2,1-c][1,4]-
oxazin-1-one (7a). Solid. Yield: 80%. Mp: 132 °C. [R]D20: -76 (c
1.0, CHCl3).1H NMR (CDCl3): 7.36-7.19 (m, 5H), 4.17-4.13 (m,
2H), 4.06 (dd, J ) 7.75, 3.75 Hz, 1H), 3.81 (dd, J ) 9.4, 6.1 Hz,
1H), 2.70-2.62 (m, 1H), 2.38-2.27 (m, 1H), 2.07-1.92 (m, 1H),
1.78-1.63 (m, 1H), 1.57-1.51 (m, 1H), 1.50-1.29 (m, 1H), 0.63
(d, J ) 7 Hz, 3H), 0.53 (d, J ) 6.75 Hz, 3H). 13C NMR (CDCl3):
173.3, 139.8, 128.7, 128.1, 127.6, 72.7, 71.3, 63.6, 59.8, 29.8, 25.8,
22.9, 20.2, 15.1. Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N,
5.40. Found: C, 73.55; H, 8.37; N, 5.35.
J ) 7.7 Hz, 1H), 3.53 (dd, J ) 10.3, 6.7 Hz, 1H), 2.41-2.30 (m,
1H), 2.13-1.81 (m, 3H), 1.03 (s, 9H). 13C NMR (CD3OD): 71.2,
63.0, 33.4, 30.1, 27.1, 26.4. HRMS: Calcd for C9H18NO2 (M +
H+) m/z ) 172.13321, obsd m/z ) 172.13318.
Acknowledgment. We thank Dr. Herson for X-ray analysis
of lactone 7a. MENESR is acknowledged for a Ph D fellowship
for J.A. We thank DSM Deretil for a generous gift of (L)-R-
phenyl glycine which is the precursor of (S)-phenylglycinol.
Supporting Information Available: General procedure to
obtain compounds 3a-d and 8a-e, product characterization
for all new compounds synthesized and X-ray data for lactone
[4S,6S,8aS]-6-tert-Butyl-4-phenylhexahydropyrrolo[2,1-c]-
[1,4]oxazin-1-one (7b). Solid. Yield: 92%. Mp: 103-104 °C.
[R]D20: -22 (c 1, CHCl3). .1H NMR (CDCl3): 7.36-7.19 (m, 5H),
4.40 (dd, J ) 11.75, 4.5 Hz, 1H), 4.26 (dd, J ) 11.75, 7.75 Hz,
1H), 4.09-3.91 (m, 2H), 2.72 (dd, J ) 8.75, 4.75 Hz, 1H),
2.25-1.85 (m, 3H), 1.71-1.61 (m, 1H), 0.66 (s, 9H).13C NMR
(CDCl3): 172.3, 139.8, 128.6, 127.6, 127.4, 75.3, 69.8, 62.1, 61.0,
35.4, 28.8, 26.9, 25.7. IR (CHCl3): 3020, 1741, 1215, 1170, 756
1
7a. H and 13C spectra of compounds 1a-b, 3a-c, 4a-c, 6,
7a-b, 8f-h. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8014243
9774 J. Org. Chem. Vol. 73, No. 24, 2008