Synthesis of a new chiral amine: (S)-5,5-dimethyl-2-methoxymethyl-pyrrolidine

Article abstract of DOI:10.1081/SCC-100103258

The title compound, a potential 'quat' auxiliary,was prepared from (S)-glutamic acid derivatives like (S)-N-Benzyl-5-methoxymethyl-2-pyrrolidinone 1. Other routes starting from (S)-pyroglutamic acid in an attempt to bypass N-Aryl compounds like 1 were also tested, but have not rendered the expected results yet.

Full text of DOI:10.1081/SCC-100103258

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SYNTHESIS OF A NEW CHIRAL
AMINE:(S)-5,5-DIMETHYL-2-
METHOXYMETHYL-
PYRROLIDINE
Leonardo J. Breña-Valle a , Raymundo Cruz-
Almanza a & F. Oscar Guadarrama-Morales a
a Instituto de Química, UNAM, Circuito Exterior,
Ciudad Universitaria , Coyoacán, México, D.F.,
04510
Published online: 16 Aug 2006.
To cite this article: Leonardo J. Breña-Valle , Raymundo Cruz-Almanza & F.
Oscar Guadarrama-Morales (2001) SYNTHESIS OF A NEW CHIRAL AMINE:(S)-5,5-
DIMETHYL-2-METHOXYMETHYL-PYRROLIDINE, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:5, 697-706, DOI: 10.1081/SCC-100103258
To link to this article: http://dx.doi.org/10.1081/SCC-100103258
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SYNTHETIC COMMUNICATIONS, 31(5), 697–706 (2001)
SYNTHESIS OF A NEW CHIRAL AMINE:
(S)-5,5-DIMETHYL-2-METHOXYMETHYL-
PYRROLIDINE
Leonardo J. Brena-Valle,* Raymundo Cruz-Almanza, and
F. Oscar Guadarrama-Morales
Instituto de Quımica, UNAM, Circuito Exterior, Ciudad
Universitaria, Coyoacan, 04510, Mexico, D.F.
ABSTRACT
The title compound, a potential ‘quat’ auxiliary,was pre-
pared from (S)-glutamic acid derivatives like (S)-N-Benzyl-5-
methoxymethyl-2-pyrrolidinone 1. Other routes starting from
(S)-pyroglutamic acid in an attempt to bypass N-Aryl com-
pounds like 1 were also tested, but have not rendered the
expected results yet.
Pyrrolidines, like SMP, have been early on a mainstay in the development
of asymmetric synthesis.1 In the twenty or more years since the SMP-
derived hydrazine SAMP was first synthesized, it has shown its value as a
chirality inducer in hydrazone-based synthetic methodology to form C-C
bonds.2,3 However, in the enantio-selective ‘true’ aldol condensation, results
in stereoselectivity have not always matched those obtained in other reac-
tions.2b A detailed picture of the conformation that the pyrrolidine ring of
SAMP takes in while acting as auxiliary is available.4 Taking this picture
into account, it may be inferred that a more sterically congested ring would
* Corresponding author.
697
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

698
BRENA-VALLE ET AL.
block even further one of the sides of the reacting aza-enolate, and could
thereby enhance the inducing power of this hydrazine. To test this hypo-
thesis, a modified hydrazine, itself easily obtainable from the corresponding
amine 7, could be used. The racemic amine has been synthesized already and
7 separated by resolution from its enantiomer.5 Here we wish to outline our
synthetic efforts towards the elusive amine 7 via a route involving the chiral
imine 6, a compound not previously known.
Scheme 1. Reagents: (a) 4 eq. Li (NH3-THF-H2O); (a0) CAN (CH3CN-H2O);
(b) (BOC)2O DMAP (CH3CN); (c) CH3MgBr (THF/Et2O); (d) CF3COOH
(CH2Cl2); (e) CH3MgBr-CeCl3 (THF/Et2O).
Initially, our plan called for the introduction of alkyl groups at the
carbonyl position of pyrrolidinone 1, available from previous work.6 Yet,
the N-benzyl group did not activate the carbonyl moiety in the desired
mode. Thus it had to be changed for another group. Although the deben-
zylation to produce derivative 3 did not take place under catalytic hydro-
genation conditions like those usually employed for pyrrolidines, it could be
achieved with Li in liquid ammonia.7,8 Key compound 4 did react in the
Grignard addition to produce the ring-opened derivative 5 as shown
in Scheme 1, in agreement with other findings.9–12 No N-BOC splitting
was detected in this reaction. This is in contrast to those cases where the
addition has been done on similar molecules carrying the N-Cbz group,
whose carbonyl moiety did react sometimes to give this kind of scission.13
In fact, the Grignard addition in the presence of th BOC group is of such a

(S)-5,5-DIMETHYL-2-METHOXYMETHYL-PYRROLIDINE
699
selective nature, that even a relatively unhindered ester moiety in pyroglu-
tamates remains unaffected.14 Removal of the N-protecting group in
methylketone 5 with excess trifluoroacetic acid in CH2Cl2 gave pyrroline 6
in 14% overall yield from (S)-glutamic acid.15 Introduction of the second
methyl group (step e) required the addition of an organometallic reagent to
the C ¼¼ N bond. Reviews about such reactions published during the course
of this work, confirmed that additions to ketimines are not commonly
successful due to side-reactions.16,17 Nevertheless, we decided to try the
organometallic reagents considered most suitable according to literature
precedents, including the organocopper and the Grignard reagent, both in
the presence of a Lewis acid, as well as the Cerium compound. We could
obtain compound 7 in small amount (up to 15% yield) with the Cerium
transmetallated Grignard reagent.18 Unfortunately, this was not invariably
the case and imine 6 could always be recovered to some extent.
Scheme 2. Reagents: (a) (BOC)2O DMAP (CH3CN); (b) 1) NaBH4 (DME-MeOH);
2) AcOH (H2O); (c) 1) LiBH4 (THF); 2) AcOH (H2O).
While trying to scale up the procedure, we found that the removal of
the benzylic group in 1 (step (a); Scheme 1) was not easily manageable due
to the large amount of ammonia required.19 As the preparation of com-
pound 1 itself involved several steps, we sought a shorter way that would
allow bypassing this pyrrolidinone to arrive at key intermediate 4 starting
from (S)-pyroglutamic acid.20 Its esterification to 8 and N-protection
afforded compound 9 (see Scheme 2). Our previous experience with N-
benzylpyroglutamates suggested that we could carry out the reduction of
the ester moiety in derivative 9 in a selective manner, but this time over-
reduction to 10 took place.6 Then we tried to obtain 12 reversing the order

700
BRENA-VALLE ET AL.
of the protection-reduction protocol, that is, via (S)-pyroglutaminol 11.21 In
this case, however, we observed lack of selectivity during the N-protection
step, which yielded in fair amount compound 12a instead. We did consider
the selective hydrolysis of the carbonate in compound 12a, but judged it
impractical since it meant another step in the process and anyway, pursuing
the synthesis along this path would be wasteful of valuable BOC2O.
Compound 12, precursor to intermediate 4, remained thus rather intangible
by any of these routes. Hence, we had to turn back to the original plan in
order to obtain key derivative 4. This time we prepared pyrrolidinone 2,
using anisaldehyde instead of benzaldehyde and performed an oxidative
removal of the protecting group.22 This change allowed a slight increase
in the yield of 3, so that pyrroline 6 could be obtained in 38% yield from
compound 2 (17% overall). But more importantly, we were able to carry
out the synthesis at a larger scale.
In conclusion, this is the first synthesis of amine 7 by means of a
nonracemic pathway. This route allows the creation of pyrrolidines with a
chiral quaternary center vicinal to nitrogen. We continue exploring ways to
shorten the synthetic sequence to 7 in order to obtain it in larger quantities
and be able to test it routinely as a chiral ‘quat’ auxiliary.23
EXPERIMENTAL
Commercial THF was distilled under an inert atmosphere from sodium
benzophenone ketyl prior to use. Other reagents and solvents were pur-
chased and used without further purification unless stated otherwise.
Work up as usual means separating the organic phase, drying over
Na2SO4 and concentrating on a rotary evaporator. Melting points were
taken on a Fisher-Johns apparatus and are uncorrected.
1H-NMR and 13C-NMR data were recorded on a Varian Gemini 200
(200 MHz) and Varian Unity Plus (300 MHz) and are given as ꢀ ppm
displacements from TMS as internal standard; coupling constants (J) are
expressed in Hertz. IR spectra were obtained on a Nicolet 55-XFT and a
Perkin Elmer 283B. Low (EIþ mode) and HRMS were determined on JEOL
instruments, JMS-AX505HA (EIþ mode) and JMS-SX102A (FABþ
mode). Optical rotations were taken at r.t. on a Jasco DIP-60 polarimeter.
Analytical TLC was done on Macherey-Nagel aluminum foils coated with
F254 silica gel cut in 7 Â 2–3 cm pieces and viewed with UV light and/or
ethanolic 10% phosphomolybdic acid solution. Column chromatography
was carried out using 70–230 mesh silica gel from Merck.
(S)-1-(40-Methoxybenzyl)-5-methoxymethyl-pyrrolidin-2-one. 2. This
compound, a yellow oil, was obtained according to the published procedure

(S)-5,5-DIMETHYL-2-METHOXYMETHYL-PYRROLIDINE
701
for the preparation of 1, using 4-methoxy-benzaldehyde instead.6 Overall
yield: 45% (5 steps from (S)-glutamic acid). [ꢁ]D ¼ þ81.9ꢀ (c ¼ 1.00; CHCl3);
lit.24 [ꢁ]D ¼ þ85.5ꢀ (c ¼ 1.2 CHCl3). IR (film, cmꢁ1): 2930, 1686, 1612, 1513,
1246, 1119. H-NMR (CDCl3): 7.19 (AA0BB0, 2H, J ¼ 7.6), 6.84 (AA0BB0,
1
2H, J ¼ 7.6), 4.85 (d, HA, J ¼ 14.8), 4.11 (d, HB, J ¼ 14.8), 3.78 (s, 3H), 3.64–
3.53 (m, 1H), 3.42–3.28 (m, 2H), 3.26 (s, 3H), 2.61–2.45 (ddd, 1H, J ¼ 16.8,
9.6, 3.1), 2.44–2.25 (ddd, 1H, J ¼ 16.8, 9.6, 3.1), 2.13–1.97 (m, 1H), 1.89–1.72
(m, 1H). 13C-NMR (CDCl3): 175.2, 158.8, 129.2, 128.5, 113.7, 73.6, 58.9,
56.6, 55.1, 44.1, 30.1, 21.5. MS m/z (%): 249 (Mþ, 35), 204 (40), 121 (100),
91 (6), 78 (9), 55 (5). EI-HRMS calcd for C14H19NO3 (Mþ) 249.1365,
found 249.1363.
(S)-5-Methoxymethyl-pyrrolidin-2-one
3
by reductive cleavage.8
In a 500 ml three-necked round bottom flask compound 16 (4.5 g;
20.54 mmol) was dissolved in 55 ml THF and 4.5 ml water. The flask,
fitted with a glass stopper and a dry ice filled cold finger connected to a
dry ice cooled trap, was placed in a dry ice/acetone bath. Liquid ammonia
(ꢂ220 ml), collected from a cylinder in a dry ice cooled trap, was distilled
into the flask connecting the trap to the reaction flask by means of a rubber
hose and a glass fitting and gently warming it with a water/methanol bath.
Stirring was started next and Lithium (2.76 g; ꢂ4 eq.) cut into small pieces,
washed in hexane and immersed briefly in methanol to turn it shiny, was
added as quickly as possible. The reaction mixture turned blue and the next
piece was not added until the color had disappeared; pieces were added until
the color did not vanish immediately. Cooling bath and cold finger were
removed next and the mixture left overnight in a hood for ammonia
to evaporate. Solvents were then removed in vacuo, the solid residue
suspended in THF, filtered and the solution worked up as usual. Yield:
2.2 g (84.6%) of a light yellow oil used without further purification.
[ꢀ]D ¼ þ61.44ꢀ (c ¼ 1.04; CHCl3).
By oxidative cleavage:22. To compound 2 (5.5 g; 22 mmol) dissolved in
20 ml CH3CN in a 250 ml round bottom flask were added, ammonium
cerium (IV) nitrate (CAN) (48.5 g; 4 eq.), 0.4 ml water and another 20 ml
CH3CN (to keep a 1:100 water/CH3CN ratio). The mixture was stirred 2 h,
then 60 ml CH2Cl2 were added and stirring was continued a further 30 min.
Solids were next filtered off and the reaction mixture was concentrated in
vacuo at r.t. The residue was taken up in 100 ml ethyl ether and solid
NaHCO3 was added until the brown precipitate turned deep yellow. After
separation of the solids the mixture was worked up as usual. The residue
was purified by silica gel column chromatography; elution: hexane/ethyl
acetate 9:1. Yield: 2.8 g (97.9%) of a colorless oil.
[ꢁ]D ¼þ 60.5ꢀ (c ¼ 1.0; CHCl3). IR (film, cmꢁ1): 3269, 1691, 1267,
1
1124. H-NMR (CDCl3): 7.01 (br, s, 1H), 3.88–3.80 (m, 1H), 3.41 (dd, HA,

702
BRENA-VALLE ET AL.
J ¼ 9.6, 4.2), 3.37 (s, 3H), 3.29 (dd, HB, J ¼ 9.6, 7.2), 2.35 (ddd, 1H, J ¼ 7.2,
3.3, 0.3), 2.32 (ddd, 1H, J ¼ 7.2, 4.5 0.3), 2.27–2.13 (m, 1H). 13C-NMR
(CDCl3): 178.3, 76.0, 58.8, 53.6, 29.54, 22.9. MS m/z (%): 129 (Mþ, 15),
84 (100), 56 (24), 41 (46). EI-HRMS calcd for C6H12NO2 (Mþ1)þ 130.0868,
found 130.0866.
Introduction of the amino protecting group (General procedure). The
substrate was dissolved in CH3CN. Next, DMAP (0.1 eq.) was added, fol-
lowed by solid BOC2O (1.2 eq), added in small portions. The mixture in the
flask, stoppered with a glass valve that allowed the relief of pressure buildup
(CO2 generation), monitored by TLC, was stirred 24 h; upon reaction com-
pletion it was concentrated in vacuo at r.t. The residue was dissolved in ether
and worked up as described elswhere.25
(S)-1-(tert-Butoxycarbonyl)-5-methoxymethyl-pyrrolidin-2-one 4 Pre-
pared as described above dissolving compound 3 (6.11 g; 47.36 mmol)
in 50 ml CH3CN, adding DMAP (0.584 g) and BOC2O (12.44 g). Yield:
813 g (75%) of a yellow oil. [ꢁ]D ¼ꢁ 75.31ꢀ (c ¼ 1.04; CHCl3); lit.26
[ꢁ]D ¼ꢁ 58.8ꢀ (c ¼ 1.0; CHCl3).
IR (film, cmꢁ1): 2981, 1787, 1710, 1313, 1154, 1023. 1H-NMR
(CDCl3): 4.28–4.22 (m, 1H), 3.58 (dd, 1H, J ¼ 9.6, 4.8), 3.51 (dd, 1H,
J ¼ 9.6, 3.0), 3.35 (s, 3H), 2.69 (ddd, 1H, J ¼ 1.77, 10.2, 1.2), 2.37 (ddd,
1H, J ¼ 17.7, 10.2, 2.7), 2.18–2.05 (m, 1H), 2.04–1.93 (m, 1H), 1.54
(s, 9H). 13C-NMR (CDCl3): 174.6, 149.8, 82.6, 73.3, 59.1, 57.1, 31.8, 27.9,
21.1. MS m/z (%): 230 (Mþ1, 10), 184 (21), 156 (32), 130 (44), 84 (100),
57 (93).
(S)-5-tert-Butoxycarbonylamino-6-methoxy-hexan-2-one 5 In a dry
100 ml round bottom flask provided with stirring bar, septum and under
Argon atmosphere, pyrrolidone 4 (8 g; 34.93 mmol) was dissolved in 15 ml
anhydrous THF. The flask was cooled in a dry ice/acetone bath kept at
ꢁ60ꢀ to ꢁ40ꢀC and under stirring, an ethereal solution of 3M methyl mag-
nesium bromide (20 ml; 1.7 eq.) was added dropwise via syringe. The bath
was next removed and the resulting milky, slightly yellow mixture was
stirred 1 h at r.t., cooled to ꢁ20ꢀC and quenched with 30 ml of a NH4Cl
saturated aqueous solution. After phase separation, the aqueous was
extracted with ethyl ether (3Â30 ml), the extracts combined with the organic
phase and worked up as usual. The product was crystallized from an ethyl
ether-hexane mixture. Yield: 6.5 g (75.8%) of a slightly yellow crystalline
compound; m.p. 42ꢀC. [ꢁ]D ¼ꢁ 13.5ꢀ (c ¼ 1.0; CHCl3). IR (film, cmꢁ1):
1
2976, 1714, 1525, 1455, 1366, 1171. H-NMR (CDCl3): 4.75 (br. s. 1H),
3.7–3.66 (m, 1H), 3.36–3.33 (m, 2H), 3.33 (s, 3H), 2.52 (dt, 2H, J ¼ 7.3,
2.1), 2.14 (s, 3H), 1.86–1.71 (m, 2H), 1.44 (s, 9H). 13C-NMR (CDCl3):
208.2, 155.6, 79.1, 74.7, 58.9, 49.7, 40.3, 29.8, 28.3, 26.2. MS m/z
(%): 245 (Mþ, 23), 190 (49), 172 (21), 144 (71), 128 (34), 100 (95), 83 (44),

(S)-5,5-DIMETHYL-2-METHOXYMETHYL-PYRROLIDINE
703
57 (100). EI-HRMS calcd for C12H24NO4 (Mþ1)þ 246.1705, found
246.1699.
(S)-5-Methoxymethyl-2-methyl-Á1-pyrroline 6. In a 250 ml round
bottom flask, trifluoroacetic acid (17.3 ml; 10 eq.) was added dropwise by
means of an addition funnel to compound 5 (5.5 g; 22.44 mmol) dissolved in
100 ml CH2Cl2. The reaction was stirred 5 h at r.t. and then quenched by
careful addition of 30 ml of NaHCO3 saturated aqueous solution. The aqu-
eous phase was extracted with CH2Cl2 (2Â10 ml), the extracts were mixed
with the organic phase and worked up as usual to give a brown liquid
purified by distillation. Yield: 1.93 g (67.71%) of a colorless volatile oil
that was kept away from light in the refrigerator under Argon atmosphere;
b.p. (Kugelrohr) 50ꢀC (0.1 mmHg). [ꢁ]D ¼þ 131.36ꢀ (c ¼ 1.02; CHCl3). IR
(film, cmꢁ1): 2923, 1650, 1197, 1124. 1H-NMR (CDCl3): 4.17–4.11 (m, 1H),
3.53 (dd, 1H, J ¼ 9.0, 5.1), 3.44 (dd, 1H, J ¼ 9.0, 6.0), 3.38 (s, 3H), 2.61–2.42
(m, 2H), 2.04 (d, 3H, J ¼ 3), 2.07–1.95 (m, 1H), 1.75–1.6 (m, 1H). 13C-NMR
(CDCl3): 175.6, 75.8, 72.1, 59.0, 38.8, 25.7, 19.6 MS m/z (%): 128 (Mþ1,
98), 97 (36), 82 (100), 55 (26). FAB-HRMS calcd for C7H14NO (Mþ1)þ
128.1075, found 128.1078.
(S)-5,5-Dimethyl-2-methoxymethyl-pyrrolidine 7. Finely ground
CeCl3 Â 7H2O (4.55 g; 12.21 mmol) was dried under high vacuum in a
100 ml round bottom flask placed in an oil bath at 135–140ꢀC for at least
2 h. The hot flask was then purged with Argon until cool, capped with a
septum and put in an ice bath to add 50 ml of anhydrous THF via syringe.
The mixture was stirred for another 2 h at r.t., the flask cooled again to 0ꢀC
and an ethereal solution of 2 M methyl magnesium bromide (6 ml; 12 mmol)
was added dropwise via syringe. After 112 h stirring at 0ꢀC, cooling to ꢁ78ꢀC,
adding vial syring pyrroline 6 (0.19 g; 1.49 mmol) dissolved in a little THF,
the mixture was monitored by TLC and stirred another 3 h at ꢁ25ꢀ to 0ꢀC.
Since TLC did not show further change, the reaction was quenched with
10 ml of a NH4Cl saturated aqueous solution, phases were separated, the
aqueous extracted with ethyl ether (2Â10 ml), the extracts and organic phase
combined and worked up as usual. The residue was purified by silica gel
column chromatography; elution: CH2Cl2/CH3OH 95:5. Yield: 10 mg
(15%). [ꢁ]D ¼ þ0.66ꢀ (c ¼ 0.3; CHCl3). IR (film, cmꢁ1): 3412, 2928, 1633,
1
1380. H-NMR (CDCl3): 8.01 (br. s, 1H), 4.18–4.09 (m, 1H), 3.73 (d, 2H,
J ¼ 45), 3.44 (s, 3H) 2.19–1.99 (m, 2H), 1.94–1.88 (m, 2H), 1.64 (s, 3H), 1.63
(s, 3H). 13C-NMR (CDCl3): 70.2, 65.8, 59.1, 58.5, 38.4, 25.9, 25.8, 25.6. MS
m/z (%): 144 (Mþ,7), 129 (10), 98 (62), 83 (100), 45 (42). Anal. calcd for
C8H17NO C, 67.09 H, 11.96 N, 9.78. Found: C, 66.95 H, 11.90 N, 9.67%.
Methyl (S)-pyroglutamate 8. To (S)-pyroglutamic acid (64.5 g;
500 mmol) dissolved in 500 ml absolute methanol in a 1 l round bottom
flask, SOCl2 (54 ml; 739.22 mmol) was slowly added at 0ꢀC. The mixture

704
BRENA-VALLE ET AL.
was next refluxed for 30 min, then concentrated in vacuo at r.t., trapping
acid fumes with solid KOH. The residue was taken up in 500 ml CH2Cl2 and
neutralized with Et3N. The precipitate was filtered and washed with Et2O.
The combined organic phases were evaporated, the residue redissolved in
ether for additional salt precipitation, filtered if necessary and worked up as
usual. Yield: 71g (99.3%) of a light yellow oil whose physical data were in
accordance with those reported.27,28
(S)-1-tert-Butoxycarbonyl-5-methoxycarbonyl-pyrrolidin-2-one 9. Pre-
pared as indicated in the general procedure above, dissolving methyl (S)-
pyroglutamate 8 (70 g; 489.5 mmol) in 200 ml CH3CN, adding DMAP (6 g)
and BOC2O (100 g). The crystalline compound obtained was recrystallized
from ethyl ether/CH2Cl2. Yield: 81.74 g (68.7%); m.p. 83–84ꢀC.
[ꢁ]D ¼ ꢁ32.4ꢀ (c ¼ 1.01; CHCl3); lit.28 m.p. 72.5–73.5ꢀC (hexane/ethyl acet-
ate). [ꢁ]D ¼ ꢁ30.4ꢀ (c ¼ 1.0; CHCl3). IR (film, cmꢁ1): 2980, 1794, 1750, 1716,
1371, 1312, 1154. 1H-NMR (CDCl3): 4.62 (dd, 1H, J ¼ 9.6, 3.0), 3.78 (s, 3H),
2.69–2.57 (dt, 1H, J ¼ 17.4, 9.9), 2.54–2.38 (ddd, 1H, J ¼ 17.4, 9.9, 4.2), 2.4–
2.26 (dddd, 1H, J ¼ 12.9, 9.9, 4.2, 0.9), 2.085–1.98 (dddd, 1H, J ¼ 12.9, 6.6,
3.0, 0.9), 1.49 (s, 9H). 13C-NMR (CDCl3): 173.1, 171.7, 149.2, 83.48, 58.7,
52.4, 31.1, 27.79, 21.39. MS m/z (%): 243 (Mþ, 1), 228 (4), 184 (23), 170
(12), 144 (28), 84 (100) 57 (96), 41 (27).
(S)-2-tert-Butoxycarbonylamino-1,5-dihydroxypentane 10. In a 1 l
round bottom flask pyroglutamate 9 (81.77 g; 336 mmol) was dissolved in
350 ml DME and 17.5 ml methanol. Stirring was started, the flask cooled in
an ice bath and NaBH4 (25.42 g, 2 eq.) was added. The mixture was then
stirred at r.t. for 112 days and adjusted to pH ¼ 6 by the addition of aqueous
20% AcOH. The aqueous phase was extracted with CH2Cl2 (2Â100 ml). The
combined organic phases were worked up as usual and the residue crystal-
lized in an ethyl acetate/hexane mixture. Yield: 50 g (73.9%) of crystalline
white solid; m.p. ¼ 55ꢀC. [ꢁ]D ¼ ꢁ48.2ꢀ (c ¼ 0.99; CHCl3). IR (film, cmꢁ1):
1
3349, 2985, 1682, 1533, 1170. H-NMR (CDCl3): 5.1 (br, s, 1H), 3.65–3.62
(m, 2H), 3.6 (m, 2H), 3.58 (m, 1H), 1.66–1.56 (m, 4H), 1.43 (s, 9H).
13C-NMR (CDCl3): 156.5, 79.52, 64.94, 62.11, 52.27, 28.68, 28.37, 27.91,
MS m/z (%): 188 (Mþ, 6), 146 (15), 132 (94), 88 (32), 71 (35), 57 (100), 41
(21), Anal. calcd for C10H21NO4 C, 54.77 H, 9.65 N, 6.39. Found: C, 54.69
H, 9.71 N, 6.29%.
(S)-1-tert-Butoxycarbonyl-5-tert-butoxycarbonyloxymethyl-pyrroli-
din-2-one 12a. Prepared as indicated in the general procedure above, dissol-
ving pyroglutaminol 11 (4.88 g; 42.43 mmol) in 20 ml CH3CN and
40 ml CH2Cl2, adding DMAP (0.518 g) and BOC2O (18.52 g; 2 eq.). In
this case however, the first eq. Of BOC2O was added and the reaction
monitored by TLC, but since starting material did not disappear completely,
the rest was added in portions. After work up, the product was purified by

(S)-5,5-DIMETHYL-2-METHOXYMETHYL-PYRROLIDINE
705
recrystallization from ether/hexane. Yield: 8.2 g (61.3%) of a white solid;
m.p. 52ꢀC. [ꢁ]D ¼ ꢁ59.14ꢀ (c ¼ 1.0; CHCl3). IR (film, cmꢁ1): 2980, 1790,
1784, 1716, 1285. 1H-NMR (CDCl3): 4.41–4.33 (m, 2H), 4.17–4.11 (m,
1H), 2.68 (ddd, 1H, J ¼ 17.7, 11.1, 9.6), 4.42 (ddd, 1H, J ¼ 17.7, 9.6, 2.4),
2.24–2.07 (m, 1H), 2.03–1.94 (m, 1H), 1.54 (s, 9H), 1.47 (s, 9H). 13C-NMR
(CDCl3): 173.8, 153.1, 149.2, 83.2, 82.5, 66.6, 56.2, 31.5, 27.8, 27.6, 20.8. MS
m/z (%): 316 (Mþ1, 2), 204 (7), 160 (17), 142 (20), 97 (57), 84 (100), 57 (93).
FAB-HRMS calcd for C15H26NO6 (Mþ1)þ 316.1760, found 316.1755.
ACKNOWLEDGMENTS
We want to thank R. Patino for taking IR spectra and measuring
optical rotations, B. Quiroz, H. Rıos and W. Matus for obtaining the
NMR data, L. Velasco and F. J. Perez-Flores for measuring mass spectra.
Financial support from CONACYT (2619P-E9509) is also acknowledged.
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Received in the U.S.A. June 10, 2000