Efficient and Expeditious Protocols for the Synthesis of Racemic and Enantiomerically Pure Endocyclic Enecarbamates from N-Acyl Lactams and N-Acyl Pyrrolidines

Article abstract of DOI:10.1021/jo9903297

A mild, practical, and straightforward protocol for the construction of endocyclic enecarbamates starting from N-acyl lactams and N-acyl pyrrolidines is presented. Lactams were reduced to the corresponding α-hydroxycarbamates in good to excellent yields using DIBAL-H, SuperHydride, or NaBH₄ followed by β-elimination (dehydration) promoted by trifluoroacetic anhydride in the presence of hindered nitrogenated bases such as 2,6-lutidine, diisopropylethylamine, or triethylamine. Small variations of this protocol permitted the preparation of several endocyclic enecarbamates (12 examples) in good to excellent overall yields (56-96%). The protocol was demonstrated to be applicable to several ring sizes, compatible with different protecting groups, and to be mild enough to prevent racemization of racemization-prone stereocenters. The efficacy of the procedure in the preparation of enantiomerically pure endocyclic enecarbamates was also demonstrated and compared to the commonly used Shono's protocol, which in our hands led to partial racemization of the endocyclic enecarbamate 18c.

Full text of DOI:10.1021/jo9903297

6646
J . Org. Chem. 1999, 64, 6646-6652
Efficien t a n d Exp ed itiou s P r otocols for th e Syn th esis of Ra cem ic
a n d En a n tiom er ica lly P u r e En d ocyclic En eca r ba m a tes fr om
N-Acyl La cta m s a n d N-Acyl P yr r olid in es
Denilson F. Oliveira,† Paulo C. M. L. Miranda, and Carlos R. D. Correia*
Instituto de Quı´mica, Universidade Estadual de Campinas, P.O. Box 6154, Campinas,
13083-970 Sa˜o Paulo, Brazil
Received February 22, 1999
A mild, practical, and straightforward protocol for the construction of endocyclic enecarbamates
starting from N-acyl lactams and N-acyl pyrrolidines is presented. Lactams were reduced to the
corresponding R-hydroxycarbamates in good to excellent yields using DIBAL-H, SuperHydride, or
NaBH4 followed by â-elimination (dehydration) promoted by trifluoroacetic anhydride in the presence
of hindered nitrogenated bases such as 2,6-lutidine, diisopropylethylamine, or triethylamine. Small
variations of this protocol permitted the preparation of several endocyclic enecarbamates (12
examples) in good to excellent overall yields (56-96%). The protocol was demonstrated to be
applicable to several ring sizes, compatible with different protecting groups, and to be mild enough
to prevent racemization of racemization-prone stereocenters. The efficacy of the procedure in the
preparation of enantiomerically pure endocyclic enecarbamates was also demonstrated and
compared to the commonly used Shono’s protocol, which in our hands led to partial racemization
of the endocyclic enecarbamate 18c.
In tr od u ction
In the past few years we have focused on a general
protocol for the preparation of enantiomerically pure
enecarbamates in conjunction with some ongoing syn-
thetic programs.4 We then sought to develop general
methodology for the preparation of endocyclic enecar-
bamates under mild conditions with consistently good
yields.
Endocyclic enecarbamates are heterocyclic compounds
whose structural motif, a deactivated enamine group,
makes them useful building blocks for the synthesis of
nitrogen-containing heterocycles of biological signifi-
cance.1 Despite the fact that these valuable compounds
have been known for quite some time, there is a renewed
interest in them as can be perceived from the recent
increasing number of publications on the subject.2 Of the
methodologies available for their preparation,3 only a few
are applicable to the construction of more complex
endocyclic enecarbamates, especially the five-membered
ones. This has probably functioned as a limiting factor
for a more extensive use of these moderately reactive
N-acyl enamines in organic synthesis.
Shono’s protocol,3e,f probably the most used one for the
synthesis of enecarbamates, involves methanol elimina-
tion from R-methoxycarbamates and has been considered
the methodology of choice. Recently, two efficient proce-
dures for the synthesis of endocyclic enecarbamates from
lactams were reported.3a,c Although Dieter’s procedure3c
is efficient, it uses HMPA, a toxic and expensive solvent,
under rather harsh conditions (160-190 °C for 2-4 h).
An attractive alternative reported by Cossy3a employs
catalytic amounts of the weakly acidic quinolinium
camphorsulfonate to promote dehydration of R-hydroxy-
carbamates. However, some enecarbamates are unstable
under these conditions, which might explain some of the
low yields obtained in a few cases as well as the rather
short reaction periods enecarbamates can be exposed to
under these conditions. Prompted by these two rather
recent publications, we report herein our results on the
development of a general and mild protocol for the
preparation of endocyclic enecarbamates from lactams,
which we have been using routinely for quite some time
in our laboratories. This protocol produces the desired
enecarbamates in good to excellent overall yields, and is
compatible with a number of protecting groups and with
racemization-prone stereogenic centers.
* To whom correspondence should be addressed. Phone: +55 19
7883086. FAX: +55 19 7883023. E-mail: roque@iqm.unicamp.br.
† Present address: Departamento de Qu´ımica, Universidade Federal
de Lavras, CEP 37200, CP 37, Lavras, Mg, Brazil.
(1) For reviews, see: (a) Campbell, A. L.; Lenz, G. R. Synthesis 1987,
421. (b) Lenz, G. R. Synthesis 1978, 489. Although these reviews
focused on enamides, the authors use the term enamide in a rather
broad sense including enecarbamates.
(2) For some selected examples, see: (a) Bueno, A. B.; Hegedus, L.
S. J . Org. Chem. 1998, 63, 684. (b) Bach, T.; Brummerhop, H. Angew.
Chem., Int. Ed. Engl. 1998, 37, 3400. (c) Cossy, J .; Cases, M.; Pardo,
D. G. Synlett 1998, 507. (d) Wolf, L. B.; Tjen, K. C. M. F.; Rutjes, F. P.
T.; Hiemstra, H.; Schoemaker, H. E. Tetrahedron Lett. 1998, 39, 5081.
(e) Paquette, L. A.; Tae, J . Tetrahedron Lett. 1997, 38, 3151. (f)
Matsumura, Y.; Yoshimoto, Y.; Horikawa, C.; Maki, T.; Watanabe, M.
Tetrahedron Lett. 1996, 37, 5715. (g) Foti, C. J .; Comins, D. L. J . Org.
Chem. 1995, 60, 2656. (h) Rawal, V. H.; Michoud, C.; Monestel, R. F.
J . Am. Chem. Soc. 1993, 115, 3030. (i) Martin, S. F.; Rein, T.; Liao, Y.
Tetrahedron Lett. 1991, 32, 6481.
(3) In addition to refs 1 and 2, for specific references on the synthesis
of enecarbamates consult the following: (a) Cossy, J .; Cases, M.; Pardo,
D. G. Synth. Commun. 1997, 27, 2769. (b) McDonald, F. E.; Chatterjee,
A. K. Tetrahedron Lett. 1997, 38, 7687. (c) Dieter, R. K.; Sharma, R.
R. J . Org. Chem. 1996, 61, 4180. (d) Brown, D. S.; Charreau, P.;
Hansson, T.; Ley, S. V. Tetrahedron 1991, 47, 1311. (e) Shono T.
Tetrahedron 1984, 40, 811. (f) Shono, T.; Matsumura, Y.; Tsubata, K.;
Sugihara, Y.; Yamane, S.; Kanazawa, T.; Aoki, T. J . Am. Chem. Soc.
1982, 104, 6697. (g) Kraus, G. A.; Neuenschwander, K. J . Org. Chem.
1981, 46, 4791.
(4) (a) Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron
Lett. 1999, 40, 2083. (b) Pohlit, A. M.; Correia, C. R. D. Heterocycles
1997, 45, 2321. (c) Carpes, M. J . S.; Miranda, P. C. M. L.; Correia, C.
R. D. Tetrahedron Lett. 1997, 38, 1869. (d) Correia, C. R. D.; Faria, A.
R.; Carvalho, E. S. Tetrahedron Lett. 1995, 36, 5109. (e) Faria, A. R.;
Matos, C. R.; Correia, C. R. D. Tetrahedron Lett. 1993, 34, 27.
10.1021/jo9903297 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/11/1999

Synthesis of Endocyclic Enecarbamates
J . Org. Chem., Vol. 64, No. 18, 1999 6647
Sch em e 1
Besides, attempts to generate enecarbamate 3a or 3b
directly from R-methoxycarbamate 2c (derived from 2a
with MeOH/PPTS) employing Shono’s conditions (NH4Cl,
100 °C, ∼25 Torr)3f led to decomposition (eq 1). However,
when we reacted hydroxycarbamate 2a with (CF3CO)2O
(∼2 equiv) at 0 °C, in the presence of i-Pr2EtN, the 3-acyl
enecarbamate 28 was obtained as the main reaction
product (eq 2) in moderate yields (∼48% yield).
Resu lts a n d Discu ssion
The strategy for the synthesis of enecarbamates in-
volves reduction of N-acyl lactams to R-hydroxycarbam-
ates followed by dehydration promoted by trifluoroacetic
anhydride (TFAA) and a hindered base: 2,6-lutidine,
triethylamine (TEA), or diisopropylethylamine (DIPEA).
Special attention was placed on the preparation of
enantiomerically pure endocyclic enecarbamates (Scheme
1).
(1)
R-Hydroxycarbamates (also termed hemiaminals or
lactamols) were readily obtained from N-acyl lactams by
reduction employing DIBAL-H,5 SuperHydride (LiEt3-
BH),6 or NaBH4.7 Use of DIBAL-H and LiEt3BH led to
R-hydroxycarbamates in high yields (80-97%), whereas
NaBH4 provided the corresponding R-hydroxycarbamates
in slightly lower yields (50-80%). As pointed out by
Dieter, this latter process requires more stringent control
of the reaction conditions than does reduction with
DIBAL-H and LiEt3BH to prevent formation of byprod-
ucts resulting from over-reduction.7c For this reason,
reduction of N-acyl lactams using NaBH4 was used here
only on a few occasions, but was preferred in multigram
scale reactions for economic reasons. Alternatively, R-hy-
droxycarbamates can be obtained by mild acetic acid
hydrolysis of R-methoxycarbamates,8 which in turn can
be readily obtained through anodic oxidation of the
corresponding carbamate according to Shono’s protocol.3e,f
That was the specific case for the preparation of R-hy-
droxycarbamate 17c as shown in Scheme 2. All N-acyl
lactams used as starting materials in this study were
prepared by coupling the lactams with the correspond-
ing chloroformate or with an acyl imidazole derivative
(generated from the precursor alcohols) under standard
conditions (see the Supporting Information for details),
or by oxidation of the carbamate precursor with
Ru(VIII).9 This latter procedure was found advantageous
when preparing enecarbamates derived from L-proline
(compounds 18b and 18c; Scheme 2) which bear a
stereocenter susceptible to racemization.
(2)
We thus changed reaction conditions to ensure stoi-
chiometric formation of the trifluoroacetate intermediate
(1 equiv of TFAA, -78 °C, 7 h), followed by elimination
with i-Pr2EtN (20 equiv, -78 °C to room temperature).
Gratifyingly, these conditions provided reasonable yields
(65-69%) of the corresponding endocyclic enecarbamate
3a (Table 1, entry 1, procedure B). This protocol was later
refined, resulting in five slightly different procedures,
applicable to a broad range of R-hydroxycarbamates as
described in Table 1 below. All R-hydroxycarbamates
examined afforded the corresponding endocyclic enecar-
bamate in good to excellent yields in a scale ranging from
30 mg to 2 g.
These procedures were compatible with a number of
nitrogen protecting groups and also allowed the prepara-
tion of enecarbamates of different ring sizes (entries 1,
2, 3, and 4; Table 1). Several enantiomerically pure
enecarbamates were also prepared without noticeable
racemization (entries 5, 6, 7, and 9; Table 1). As described
in Table 1, procedures B, D, and E allowed the prepara-
tion of enecarbamates at room temperature, thus making
it an appropriate procedure for the preparation of ther-
molabile enecarbamates. However, in several occasions
yields were somewhat lower when using i-Pr2EtN (pro-
cedure B) or Et3N (procedure D) with a concomitant
increase in the amounts of side products.10
Similarly to the results obtained by other research
groups,3c attempts to perform dehydration of the R-hy-
droxycarbamates employing some of the available meth-
odologies proved more difficult than anticipated. For
example, attempts to obtain five-membered enecarbam-
ates 3a /3b from 2a /2b (see Table 1) using MsCl/Et3N/
CH2Cl2, Tf2O/pyr/CH2Cl2, refluxing in toluene, CuSO4/
SiO2, and FeCl3/SiO2 failed completely or provided the
desired enecarbamates in very low yields (5-10%).
Procedure A was found to be the most reliable one in
preparing endocyclic enecarbamates. It is worth men-
tioning that enecarbamates are rather unstable under
acidic conditions. Nevertheless, the slightly acidic luti-
dinium trifluoroacetate salt formed as a byproduct in the
reaction medium did not cause any noticeable decomposi-
(10) Use of Et3N or i-Pr2EtN seems very effective in promoting
elimination, yielding the corresponding enecarbamates even at 0 °C
as detected by TLC. 2,6-Lutidine, on the other hand, promotes
elimination of the trifluoroacetates only after heating. Despite this
higher effectiveness, use of Et3N and i-Pr2EtN frequently led to the
formation of side products in variable yields.
(5) (a) Adapted from Langlois, N.; Rojas, A. Tetrahedron 1993, 49,
77. (b) See also ref 3c.
(6) Adapted from the work of Choi, J . K.; Ha, D. C.; Hart, D. L.;
Lee, C. S.; Ramesh, S.; Wu, S. J . Org. Chem. 1989, 54, 279. See also
ref 3c.
(7) Adapted from the following: (a) Altman, K. W. Tetrahedron
Lett.1993, 34, 7721. (b) Chamberlin, A. R.; Nguyen, H. D.; Chung, J .
Y. L. J . Org. Chem. 1984, 49, 1682. (c) Hubert, J . C.; Wijnberg, J . B.
P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437.
(8) Procedure adapted from the work of Nagasaka, T.; Tamano, H.;
Maekawa, T.; Hamaguchi, F. Heterocycles 1987, 26 (3), 617.
(9) Yoshifuji, S.; Tanaka, K.; Kawai, T.; Nitta, Y. Chem. Pharm. Bull.
1986, 34, 3873.

6648 J . Org. Chem., Vol. 64, No. 18, 1999
Oliveira et al.
Sch em e 2a
a
Reagents and Conditions: (a) preparation of 30b, (i) SOCl2, MeOH (86%); (ii) Boc2O, Et3N, THF (82%); (b) preparation of 30c, MeCO2Cl,
MeOH, K2CO3 (93%); (c) MeOH, Et4NOTs (75%); (d) NH4Cl, 150 °C, 1-2 h (61%); (e) H2, Pd/C 10%, 40 psi (78-95%); (f) H2O/HOAc (83%);
(g) (i) TFAA (1 equiv), toluene, 0 °C; (ii) 2,6-lutidine, 0 °C to rt; (iii) reflux, 20 min (78% for 18b and 46% for 18c); (h) RuCl3 (cat.), NaIO4,
AcOEt (78-82%); (i) (i) SOCl2, MeOH (85%); (ii) Boc2O, Et3N, DMAP, CH2Cl2 (89%); (j) DIBAL-H, toluene, -78 °C or LiEt3BH (72-89%).
tion. Actually most of the endocyclic enecarbamates
prepared in this work can be refluxed in the presence of
lutidinium trifluoroacetate for a period of 2 h without
significant reduction in yields. Interestingly, procedure
D was found more suitable for the synthesis of five-
membered enecarbamate than for the preparation of six-
membered enecarbamates. For instance, when procedure
D was applied to R-hydroxycarbamate 8, the “dimeric”
enecarbamate 29 was obtained in 90% isolated yield (eq
3).11 Apparently, the six-membered enecarbamate un-
En a n tiom er ic P u r ity of th e Ch ir a l En d ocyclic
En eca r ba m a tes 18b a n d 18c. To confirm that the
TFAA/2,6-lutidine protocol causes no racemization, the
endocyclic enecarbamates 18b and 18c were converted
to the known chiral proline derivatives 30b and 30c
according to Scheme 2. Furthermore, a comparison
between our protocol and Shono’s protocol for preparing
enantiomerically pure enecarbamates was also carried
out. Along the way interesting observations were made
and some important conclusions obtained.
This comparative study was found necessary because
enecarbamate 18bsobtained by the sequence L-pyro-
glutamic acid f 16b f 17b f 18b (Scheme 2)shad a
specific rotation value of -64.7, which was ∼60% of the
value reported in the literature ([R]D ) -108).9 In
addition, enecarbamate 18c, used by us in previous
work4c (sequence L-proline f 30c f 31 f 18c; Scheme
2) was found to be only 80-90% enantiomerically pure
by chiral phase HPLC, as well as by comparing specific
rotations after conversion of 18c to 30c.12
In the case of Shono’s protocol (30c f 31 f 18c;
Scheme 2), it was critical to determine which was the
racemization step in the process: the anodic oxidation,
the methanol elimination, or both. Thus, with the objec-
tive of determining the racemization step, proline deriva-
tive 30c was oxidized to methoxy proline 31 (75% yield)
and immediately converted into enecarbamate 18c by
methanol elimination (NH4Cl, 150 °C, 2-3 h; 61%).
Catalytic hydrogenation afforded proline derivative 30c
possessing a [R]D value of -55, meaning an estimated
10% racemization along the sequence of reactions. On the
other hand, catalytic hydrogenation of enecarbamate 18c
obtained from R-hydroxycarbamate 17c8 provided the
proline derivative 30c with a [R]D value of -69, identical
to that measured for 30c used as starting material. These
(3)
dergoes self-condensation promoted by CF3CO2Et3NH
generated in the reaction medium. This type of self-
condensation is largely suppressed when 2,6-lutidine is
used as base (e.g., procedure A).
Overall yields of the endocyclic enecarbamates were
consistently good, ranging from 56 to 96%. The only
exception was entry 6 for enecarbamate 18c. This lower
overall yield for 18c was credited to the volatility of the
compound. Of the several chiral, nonracemic, enecar-
bamates depicted in Table 1 (entries 5, 6, 7, and 9) special
mention is made of enecarbamates 18b and 18c, bearing
a potentially racemizable stereocenter, which were ob-
tained in enantiomerically pure form.
The procedures developed employ conditions that are
essentially neutral or slightly acidic, and the option of
choosing between toluene and CH2Cl2 (in which trifluo-
roacetic anhydride is more soluble at -78 °C) as reaction
solvent also extends the potential applicability of this
methodology.
(12) Although Shono’s protocol calls for a 30 min heating at 150 °C
in the presence of NH4Cl, in our hands this procedure led to low
conversion of the R-methoxycarbamate, resulting in low overall yields
of the corresponding enecarbamate. To ensure higher conversions, it
was necessary to heat the reaction mixture for 1-2 h. It is conceivable
that the longer reaction times were responsible for the degree of
racemization observed, in the range of 5-10%.
(11) This dimeric compound contains the basic skeleton of the
bispiperidine alkaloid ammodendrine (see: Pinder, A. R. Nat. Prod.
Rep. 1989, 515) and also the enamine form of tetrahydroanabasine
(see: Koomen, G.-J .; Wanner, M. J . J . Org. Chem. 1996, 61, 5581).

Synthesis of Endocyclic Enecarbamates
J . Org. Chem., Vol. 64, No. 18, 1999 6649
Ta ble 1. Con ver sion of N-Acyl La cta m s in to En d ocyclic En eca r ba m a tes
a
b
Yields refer to isolated compounds. Letter a after the number of the compound indicates R ) CBz; b, R ) Boc; and c, R ) CO2Me.
c Procedures; A, (i) TFAA, toluene, 2,6-lutidine; (ii) reflux; B, (i) TFAA, toluene; (ii) DIPEA; C, (i) TFAA, toluene; (ii) 2,6-lutidine, reflux;
D, (i) TFAA, CH2Cl2; (ii) TEA; E, (i) TFAA, CH2Cl2, 2,6-lutidine; see Experimental Section for details. This lower yield is due to the
d
higher volatility of 18c when compared to 18b.
results permitted the conclusion that partial racemization
was occurring exclusively during methanol elimination
in Shono’s protocol. It was also clear that the presence
of the racemization-prone C-2 stereocenter of L-proline
was fully compatible with the (CF3CO)2O/2,6-lutidine
protocol.
Unequivocal confirmation that no significant racemiza-
tion was occurring was obtained when 18b was catalyti-
cally hydrogenated to 30b, which showed specific rotation
([R]D ) -69.0) almost identical to that measured for the
proline derivative we started with ([R]D) -69.4).14 Thus,
to obtain enantiomerically pure endocyclic enecarbamates
of type 18b (R ) Boc), the longer route starting from
In the case of enecarbamate 18b (R ) Boc) obtained
from L-pyroglutamic acid ([R]D ) -64.7), it was assumed
that partial racemization was taking place during instal-
lation of the Boc protecting group (Et3N, DMAP, Boc2O).
To circumvent this problem and also to demonstrate that
racemization was indeed occurring at the stage of Boc
installation, enecarbamate 18b was synthesized through
the sequence 30b f 16b f 17b f 18b (Scheme 2). This
time, the specific rotation value observed for 18b ([R]D)
-102) was very close to that reported in the literature.13
(13) (a) Dormoy, J .-R. Synthesis 1982, 753. [R]20 ) -108 (c 0.71,
D
MeOH) for compound 18b. (b) Cossy, J . (see ref 3a). [R]20D ) -101.1 (c
1.22, EtOH) for an ethyl analogue of 18b. (c) Schumacher, K. K.; J iang,
J .; J oullie´, M. M. Tetrahedron: Asymmetry 1998, 9, 47. [R]20D ) -98.0
(c 0.89, CHCl3)
(14) The [R]D values obtained for compounds 30b and 30c were very
similar. The literature value for compound 30b is -69.4 (see ref 9).
Since the [R]D value for 30c is not reported in the recent literature,
we checked its enantiomeric excess (ee) by chiral phase GC. The ee
found for 30c was >98%.

6650 J . Org. Chem., Vol. 64, No. 18, 1999
Oliveira et al.
P r oced u r e D. The same as described in C, but using
CH2Cl2 and Et3N instead of toluene and 2,6-lutidine, respec-
tively. The major difference between procedure C and proce-
dure D is the fact that reflux of the reaction is not necessary
to carry out elimination of the intermediate trifluoroacetate.
P r oced u r e E. Used for the conversion of lactamol 5 into
enecarbamate 6. To a solution of lactamol 5 (307 mg, 1.5 mmol)
in 6 mL of CH2Cl2 at -78 °C were added successively
2,6-lutidine (0.27 mL, 2.3 mmol) and trifluoroacetic anhydride
(0.21 mL, 1.5 mmol, dissolved in 2 mL of CH2Cl2) over a period
of 15 min. The mixture was slowly warmed to room temper-
ature and stirred for a total of 12 h. The reaction was quenched
with 3 mL of a saturated solution of NaHCO3 and stirred for
15 min. After extraction with CH2Cl2 the combined organic
layer was washed with brine and dried over anhydrous
Na2SO4. The solvent was evaporated in vacuo to provide a
colorless liquid that was flash chromatographed (SiO2, 10%
EtOAc in hexane) to give 239 mg (84% yield) of colorless
enecarbamate 6, whose spectroscopic data were in full agree-
ment with those described.3c
L-proline was preferred over the one starting from
pyroglutamic acid.15
Con clu sion
An efficient and inexpensive protocol was developed
for the synthesis of racemic and enantiomerically pure
endocyclic enecarbamates in good to excellent overall
yields starting from N-acyl lactams. The N-acyl lactams
were reduced to the corresponding R-hydroxycarbamates
in excellent yields using DIBAL-H and SuperHydride or
with NaBH4 in slightly lower yields. Conversion of the
R-hydroxycarbamates into the desired endocyclic enecar-
bamates was accomplished in good to excellent overall
yields using stoichiometric amounts of trifluoroacetic
anhydride in the presence of triethylamine, diisopropyl-
ethylamine, or 2,6-lutidine. The conditions employed
were very mild and essentially neutral and should prove
suitable to a considerable number of synthetic applica-
tions.
Note. Although 2,6-lutidine was routinely used in proce-
dures A and C, it can be effectively replaced by 2,4-lutidine.
Also, on several occasions the amount of 2,6-lutidine was
reduced from 20 equiv to 5-10 equiv without any noticeable
changes in yields.
Exp er im en ta l Section
1-(Ben zyloxyca r bon yl)-2-p yr r olin e (3a ).3g A 68.2 mg
sample of 2a afforded 33.3 mg (69% yield) of 3a as a clear
liquid by procedure B. When procedure C was employed, 70.8
mg of 2a afforded 46.2 g (69% yield) of 3a . Rf ) 0.33 (EtOAc/
For general experimental details, see the Supplementary
Information.
Gen er a l P r oced u r es for th e Syn th esis of En d ocyclic
N-Ca r b a m oyl E n a m in es (E n d ocyclic E n eca r b a m a t es).
P r oced u r e A. To a stirred solution of the lactamol, 2,6-
lutidine, and toluene (in a 1 mmol:20 mmol:20.5 mL ratio), at
0 °C under N2, was added 1 equiv of (CF3CO)2O. After being
stirred for approximately 7 h at 0 °C, the reaction mixture
was slowly warmed to room temperature overnight. The
mixture was refluxed for 20 min, cooled to room temperature,
and, after addition of saturated NaHCO3 (22 mL/mmol of
lactamol), stirred for 1 h. The toluene layer was separated and
the aqueous layer extracted with toluene or hexane. The
combined toluene/hexane extract was dried over anhydrous
Na2SO4 and concentrated in vacuo, and the residue obtained
purified by silica gel flash chromatography (hexane/EtOAc).
P r oced u r e B. To a solution of 1 mmol of lactamol in 20
mL of toluene cooled to -78 °C was added 1 equiv of (CF3-
CO)2O under N2. After 7 h, 4 equiv of i-Pr2NEt was added and
the resulting solution stirred overnight, during which time it
slowly warmed to room temperature. Saturated NaHCO3 (22
mL/mmol of lactamol) was then added, and the reaction
mixture was stirred for 1 h. The toluene layer was separated
and the aqueous layer extracted with toluene. The organic
extracts were combined and concentrated in vacuo (1 Torr) to
afford a residue that was purified by silica gel flash chroma-
tography (hexane/EtOAc).
P r oced u r e C. To a solution of 1 mmol of lactamol in 20
mL of toluene cooled to -78 °C was added 1 equiv of (CF3-
CO)2O under N2. After 7 h, 2,6-lutidine (20 equiv) was added,
and the resulting solution was stirred overnight, during which
time it slowly warmed to room temperature. The reaction
mixture was refluxed for 20 min and then cooled to room
temperature, followed by addition of saturated NaHCO3 (22
mL/mmol of lactamol). After the resulting mixture was stirred
for 1 h, the toluene layer was separated and the aqueous layer
extracted with hexane. The combined toluene and hexane
extracts were washed with water, dried over anhydrous
Na2SO4, concentrated in vacuo (water pump), and purified by
silica gel flash chromatography (hexane/EtOAc).
1
hexane, 1:4). H NMR (CCl4, 80 MHz) (mixture of rotamers):
δ 2.6 (dd, J ) 9. 9 Hz, 2H), 3.8 (dd, J ) 9. 9 Hz, 2H), 5.1 (br
s, 1H), 5.2 (s, 2H), 6.6 (br s, 1H), 7.3 (s, 5H). MS: m/z (rel
intens) 203(4) [M•+], 159 (7), 92 (9), 91 (100), 65 (8), 41 (18).
1-(ter t-Bu toxyca r bon yl)-2-p yr r olin e (3b).3c Employing
procedure D, 0.152 g (0.9 mmol) of 2b yielded 0.112 g (81%
yield) of 3b. When procedure C was used, 0.150 g (0.80 mmol)
of 2b provided 0.073 g (54% yield) of 3b. Rf ) 0.32 (EtOAc/
1
hexane, 1:10). FTIR (neat): 1704, 1410, 1365, 1134 cm-1. H
NMR (CCl4, 80 MHz) (rotamers): δ 1.4 (s, 9H), 2.6 (m, 2H),
3.6 (d, J ) 13 Hz, 1H), 3,7 (d, J ) 13 Hz,1H), 4.9 (br s, 1H),
6.4 (br s, 1H, H). MS: m/z (rel intens): 169(8) [M•+], 113 (26),
96 (16), 69 (38), 68 (60), 57 (100), 41(88).
(5S)-1-(Ben zyloxyca r bon yl)-5-[(ter t-bu tyldiph en ylsilyl-
oxy)m eth yl]-2-p yr r olid in on e (13a ). To a solution of i-Pr2NH
(0.53 mL, 3.7 mmol) in 4 mL of THF at -78 °C was slowly
added 2.86 mL of 1.3 N BuLi (3.7 mmol). After 15 min, a
solution of (S)-5-[(tert-butyldiphenylsilyloxy)methyl]-2-pyrrol-
idinone16 (1.200 g, 3.4 mmol) in 6.8 mL of THF was added to
the LDA solution, followed by addition of benzyl chloroformate
(0.66 mL, 3.7 mmol) 30 min later. After 2 h at -78 °C,
saturated NH4Cl (12 mL) was added to the reaction mixture
and the cooling bath removed. Once at room temperature, the
reaction mixture was extracted with EtOAc (3 × 5 mL). The
combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo to provide an oily residue that was
purified by flash column chromatography (SiO2, EtOAc/hexane,
1:2) to afford 1.40 g (85% yield) of the carbobenzyloxy deriva-
tive 13a as a viscous liquid. TLC: Rf ) 0.49 (EtOAc/hexane,
1:2). FTIR (neat): 1789, 1751, 1716, 1294,1110, 702 cm-1
;
1
[R]20 ) -18.4 (c 2.08, EtOAc). H NMR (CDCl3, 300 MHz): δ
D
1.00 (s, 9H), 2.02-2.20 (m, 2H), 2.42 (ddd, 1H, J ) 3.6, 8.3,
17.8 Hz), 2.79 (ddd, 1H, J ) 10.4, 10.4, 17.8 Hz), 3.67 (dd, 1H,
J ) 2.5, 10.6 Hz), 3.86 (dd, 1H, J ) 4.0, 10.6 Hz), 4.22 (m,
1H), 5.09 (d, 1H, J ) 12.3 Hz), 5.16 (d, 1H, J ) 12.3 Hz), 7.36
(m, 11H), 7.57 (m, 4H).
(5S)-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-(m eth oxy-
ca r bon yl)-2-p yr r olid in on e (13c). Prepared according to the
procedure described above, using methyl chloroformate instead
(15) We adopted Grieco’s procedure to attach the Boc protecting
group (Boc2O, DMAP, Et3N CH2Cl2); see: Flynn, D. L.; Zelle, R. E.;
Grieco, P. A. J . Org. Chem. 1983, 48, 2424. Under these conditions
the agent causing partial racemization is most probably Et3N. Near
the conclusion of this study we learned of another procedure to
introduce the Boc group on pyroglutamic acid without racemization
(Boc2O, DMAP, CH3CN): Coudert, E.; Acher, F.; Azerad, R. Synthesis
1997, 863.
(16) (S)-Pyroglutamic acid was converted to (S)-5-(hydroxymethyl)-
2-pyrrolidinone according to the procedure described in Saijo, S.; Wada,
M.; Ishida, A.; Himizu, J .-I. Chem. Pharm. Bull. 1980, 28, 1449. The
hydroxy group was then protected by standard procedures as described
in Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic
Press: London, 1988.

Synthesis of Endocyclic Enecarbamates
J . Org. Chem., Vol. 64, No. 18, 1999 6651
of benzyl chloroformate. After flash column chromatography
(SiO2, EtOAc/hexane, 1:1), the carbomethoxy derivative 13c
was obtained in 86% yield as a white solid. Mp ) 125-127
and 0.35 for the diastereomers).3c IR (neat): 3454, 1744, 1700
cm-1 1H NMR (CCl4, 80 MHz) (mixture of diastereoisomers
.
and rotamers): δ 1.4 (s, 9H), 1.8-2.4 (m, 4H), 3.6-3.8 (m, 3H),
°C. TLC: Rf ) 0.36 (EtOAc/hexane, 1:1). FTIR (KBr): 1753,
3.8-4.3 (m, 2H), 5.5 (br s, 1H).
1
1715, 1305, 1103, 700 cm-1. [R]20 ) -25.0 (1.28, EtOAc). H
(2S,5RS)-1,2-Dim eth yl-5-h yd r oxyp yr r olid in e-1,2-d ica r -
boxyla te (17c). TLC: Rf ) 0.30 (30% EtOAc in hexane). IR
D
NMR (CDCl3, 300 MHz): δ 1.05 (s, 9H), 2.14 (m, 2H), 2.47
(ddd, 1H, J ) 3.5, 8.6, 17.8 Hz), 2.83 (ddd, 1H, J ) 10.4, 10.4,
17.8 Hz), 3.73 (dd, 1H, J ) 2.4, 10.8 Hz), 3.98 (dd, 1H, J )
3.8, 10.8 Hz), 4.27 (m, 1H), 7.41 (m, 6H), 7.62 (m, 4H). MS:
m/z (rel intens) 354 (96) [M•+ - t-Bu•], 213 (100), 183 (24), 135
(12), 105 (14), 91 (7), 77 (5).
(film): 3465, 1747, 1709, 1456, 1379, 1201, 1128, 1011 cm-1
.
1H NMR (CDCl3) (mixture of diastereomers plus rotamers): δ
set of several closed signals at 5.68 (dd, J ) 2.7 and 5.6 Hz),
5.60 (br d, J ) 5.1 Hz), 5.56 (br d, J ) 5.4 Hz), 5.49 (br d, J )
5.3 Hz) all integrating for 1H, two triplets at 4.44 (J ) 14.2
Hz), and 4.41 (J ) 13.8 Hz) integrating for 1H, a set of eight
singlets at 3.77, 3.76, 3.73, 3.72, 3.71, 3.69, 3.67, and 3.66
Typ ica l P r oced u r es for t h e R ed u ct ion of t h e N-
Acylp yr r olid in on es Em p loyin g DIBAL-H to th e Cor r e-
sp on d in g N-Acyl-2-h yd r oxyp yr r olid in es. Illustrated for
the preparation of compounds 14a .5a To a solution of 13a (0.884
g, 1.8 mmol) in 5.2 mL of THF at -78 °C was slowly added
DIBAL-H (1 M solution in hexanes, 2.5 mL, 2.5 mmol). After
the solution was stirred for 1 h, saturated NH4Cl (6.5 mL) was
added and the reaction warmed to room temperature. The
mixture was then treated with 10% Na2CO3 (4.5 mL) and more
15 mL CH2Cl2 added. After 10 min the organic layer was
separated and the aqueous layer extracted with CH2Cl2 (4 ×
10 mL). The combined organic extract was dried over anhy-
drous Na2SO4 and concentrated in vacuo. Flash column
chromatography (SiO2, Et2O) of the residue afforded 0.858 g
(97% yield) of 14a as a homogeneous material by TLC (mixture
of diastereomers). TLC: Rf ) 0.27 (EtOAc/hexane, 1:3). FTIR
integrating for 6H, 2.58-2.29 (m, 1H), 2.17-1.82 (m, 3H). 13
C
NMR (CDCl3): δ 173.1 (C), 173.0 (C), 155.7 (C), 155.0 (C), 89.1
(CH), 88.9 (CH), 88.8 (CH), 82.6 (CH), 81.7 (CH), 59.2 (CH),
59.0 (CH), 58.9 (CH), 58.8 (CH), 58.7 (CH), 52.7 (CH3), 52.5
(CH3), 52.2 (CH3), 52.1 (CH3), 31.9 (CH2), 31.8 (CH2), 30.7
(CH2), 30.3 (CH2), 27.8 (CH2), 26.7 (CH2).
(5S)-N-(ter t-Bu toxyca r bon yl)-5-(m eth oxyca r bon yl)-2-
p yr r olin e (18b).3c Starting from (S)-pyroglutamic acid, and
employing procedure A, 0.158 g of 17b yielded 0.115 g (78%
yield) of 18b as a viscous liquid. Rf ) 0.34 (EtOAc/hexane, 1:5).
[R]20D ) -64.7 (c ) 0.79, MeOH). Lit.13 [R]20D ) -108 (c ) 0.71,
MeOH). Optical rotation for 18b prepared as described in
Scheme 2; [R]20 ) -102.0 (c ) 0.89, CDCl3). FTIR (neat):
D
1759, 1700, 1402, 1129 cm-1
.
1H NMR (CDCl3, 300 MHz)
1
(neat): 3494, 1687, 1423, 1113, 703 cm-1. H NMR (CCl4, 300
(mixture of rotamers): δ 1.43 (s, 5H), 1.48 (s, 4H), 2.62 (br d,
J ) 14.6 Hz and 0.5H), 2.68 (br d, J ) 14.3 Hz, 0.5H), 3.01 (br
d, J ) 14.3 Hz, 0.5H), 3.10 (br d, J ) 14.6 Hz, 0.5H), 4.58 (dd,
J ) 5.5 and 12.1 Hz, 0.5H), 4.66 (dd, J ) 5.3 and 11.9 Hz,
0.5H), 4.91 (br s, 0.5H), 4.95 (br s, 0.5H), 6.51 (br s, 0.5H),
6.65 (br s, 0.5H). MS: m/z (rel intens): 227 (4), 127 (12), 68
(100), 57 (84), 41 (58). HRMS (EI): calcd for C11H17O4N [M+]
227.1157, found: 227.1159.
MHz) (rotamers + diastereoisomers): δ 1.03 (s, 9H), 1.72-
2.06 (m, 3H), 2.10-2.30 (m, 1H), 3.12 (br s, 0.2H), 3.40-3.50
(m, 0.2H), 3.50-3.80 (m, 1.6H), 3.80-4.00 (m, 2H), 4.81-4.98
(m, 1.5H), 5.09 (br s, 0.5H), 5.34-5.50 (m, 1H), 7.0-7.4 (m,
11H), 7.56 (m, 4H).
(2S)-1-(Ben zyloxyca r bon yl)-2-[(ter t-bu tyld ip h en ylsilyl-
oxy)m eth yl]-4-p yr r olin e (15a ). Using procedure A, 0.862 g
of 14a afforded 0.821 g (99% yield) of 15a as a viscous liquid.
Rf ) 0.36 (EtOAc/hexane, 1:7). Chiral HPLC was performed
on a Chiralcel OD column from Daicel Chemical Industries:
retention time tr ) 12.20 min (0.2% 2-propanol in hexane)
corresponding to an ee > 98%. Racemic 15a was used as
standard to give the following tr: (S) 12.20 min; (R) 14.62 min.
(5S)-N-(Meth oxyca r bon yl)-5-(m eth oxyca r bon yl)-2-p yr -
r olin e (18c).3f [R]20D ) -180.6 (c 1.0, acetone). IR (film): 3114,
1
1755, 1712, 1624, 1454, 881, 762, 771 cm-1. H NMR (CDCl3,
300 MHz): δ 6.69 and 6.56 (two br s, 1H), 5.02 and 4.99 (two
br s, 1H), 4.68 (dt, J ) 5.0, 12.5 Hz, 1H), 3.77 and 3.72 (two s,
6H), 3.20-3.02 (m, 1H), 2.69 (br t, J ) 12.5 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): δ 172.3, 153.0, 130.2, 129.4, 106.3, 106.0,
57.9, 52.7, 52.3, 35.4, 34.0. MS: (m/z) (rel intens) 185 (51) [M+],
[R]20 ) -26.8 (c 0.71, hexane). IR (neat): 1707, 1417, 1113
D
1
cm-1. H NMR (CDCl3, 300 MHz) (rotamers): δ 1.09 (s, 9H),
2.81 (br s, 0.7H), 2.86 (br s, 1.3H), 3.70-4.00 (m, 2H), 4.30 (br
s, 0.5H), 4.39 (br s, 0.5H), 4.95-5.23 (m, 3H), 6.57 (br s, 0.5H),
6.65 (br s, 0.5H), 7.15-7.50 (m, 11H), 7.65-7.75 (m, 4H). 13C
NMR (CDCl3): δ 19.2 (C), 26.7 (CH3), 32.1 (CH2), 33.2 (CH2),
57.8 (CH), 58.3 (CH), 63.5 (CH2), 64.0 (CH2), 66.8 (CH2), 108.0
(CH), 127.7 (CH), 127.9 (CH), 128.0 (CH), 128.5 (CH), 129.1
(CH), 129.7 (CH), 133.5 (C), 133.7 (C), 135.6 (CH), 135.7 (CH),
136.4 (C), 136.6 (C), 152.2 (C), 152.8 (C). MS: m/z (rel
intens): 414 (20), 370 (40), 270 (10), 202 (25), 135 (10), 91 (100).
Anal. Calcd for C29H33NO3Si: C, 73.85; H, 7.06; N, 2.97.
Found: C, 74.09; H, 7.05; N, 2.98.
126 (100), 59 (37), 67 (38), 59 (37). HRMS (EI): calcd for C8H11
-
NO4 [M+] 185.0688, found 185.0590.
P r ep a r a tion of (1R)-1-(2,4,6-Tr iisop r op ylp h en yl)eth yl-
2-oxo-1-p yr r olid in eca r boxyla te (19). A solution of (1R)-1-
(2,4,6-triisopropylphenyl)ethyl-1H-1-imidazolecarboxylate (see
preparation in the Supporting Information) in 3 mL of 2-pyr-
rolidinone was heated at 85 °C under nitrogen for 52 h. After
this period the reaction mixture was cooled to room temper-
ature followed by addition of 10 mL of ether and 5 mL of water.
The resulting heterogeneous system was then stirred vigor-
ously. Next, the phases were separated, and the organic layer
was washed twice with water (2 × 2 mL). The organic layer
was dried over MgSO4 and the solvent evaporated in vacuo to
give a residue which was flash chromatographed (10% EtOAc/
hexane) to afford 168 mg (55% yield) of an oil corresponding
to N-acyl lactam 19 and 73 mg (35%) of the starting carbonyl-
imidazole. TLC: Rf ) 0.25 (10% EtOAc/hexanes). [R]D ) 48.2
(c 1.1, EtOAc). FTIR (film, NaCl): 2960, 2931, 2870, 1790,
(2S)-[(ter t-Bu tyld ip h en ylsilyloxy)m eth yl]-1-(m eth oxy-
ca r bon yl)-4-p yr r olin e (15c). Applying procedure A, 0.775 g
of 14c provided 0.711 g (95% yield) of 15c as a viscous liquid.
Rf ) 0.30 (EtOAc/hexane, 1:6). [R]20 ) -74.6 (c ) 0.80,
D
hexane). FTIR (neat): 1708, 1450, 1394, 1112 cm-1. H NMR
1
(CCl4, 300 MHz) (mixture of rotamers): δ 1.03 (s, 9H), 2.74
(br s, 0.9H), 2.79 (br s, 1.1H), 3.46 (br s, 1.3H), 3.63 (br s, 2.5H),
3.80 (br s, 2H), 4.15 (br s, 0.4H), 4.24 (br s, 0.6H), 4.90 (br s,
0.7H), 4.93 (br s, 0.3H), 6.38 (br s, 0.6H), 6.51 (br s, 0.4H),
7.30-7.35 (m, 6H), 7.52-7.63 (m, 4H). 13C NMR (CCl4)
(mixture of rotamers): δ 19.2 (C), 26.8 (CH3), 32.2 (CH2), 33.3
(CH2), 51.9 (CH3), 57.7 (CH), 58.1 (CH), 63.6 (CH2), 64.1 (CH2),
106.4 (CH), 106.8 (CH), 127.8 (CH), 129.8 (CH), 130.7 (CH),
133.7 (C), 135.7 (CH), 135.8 (CH), 152.0 (C). MS: m/z (rel
intens) 338 (100), 213 (60), 183 (25), 135 (5), 105 (5). Anal.
Calcd for C23H29NO3Si: C, 69.84; H, 7.39; N, 3.54. Found: C,
69.64; H, 7.22; N, 3.48.
1759, 1712, 1608 cm-1 1H NMR (CDCl3): δ 7.02 (br s, 2H),
.
6.61 (q, J ) 6.8 Hz, 1H), 3.81 (t, J ) 7.1 Hz, 2H), 3.60 (br s,
2H), 2.86 (sept, J ) 7.0 Hz, 1H), 2.51 (t, J ) 8.2 Hz, 2H), 2.02
(quint, J ) 7.6 Hz, 2H), 1.70 (d, J ) 7.0 Hz, 3H), 1.30 (d, J )
7.0 Hz, 6H), 1.23 (t, J ) 6.6 Hz, 12H). 13C NMR (CDCl3): δ
174.4 (C), 151.3 (C), 148.6 (C), 146.2 (C), 131.6 (C), 123.1 (CH),
121.4 (CH), 70.7 (CH), 46.2 (CH2), 33.9 (CH), 32.6 (CH2), 29.0
(CH), 24.7 (CH3), 23.7 (CH3), 23.6 (CH3), 22.0 (CH3), 17.4 (CH2).
(1R,2RS)-1-(2,4,6-Tr iisop r op ylp h en yl)eth yl-2-h yd r oxy-
1-p yr r olid in eca r boxyla te (20). FTIR (film, NaCl): 3440,
2956, 1684, 1606, 1417, 1384 cm-1. 1H NMR (CDCl3) (mixture
of epimers and rotamers): δ 7.03 (s, 2H), 6.52 (q, J ) 6.8 Hz,
1H), 5,54 and 5,48 (two br s, 1H), 3.75-3.49 (m, 2H), 3.47-
3.26 (m, 2H), 2.90-2.80 (m, 1H), 2.18-1.83 (m, 4H), 1.69-
(2S,5RS)-1-(ter t-Bu t oxyca r b on yl)-5-h yd r oxy-2-(m et h -
oxyca r bon yl)p yr r olid in e (17b). A 0.416 g sample of 34b
afforded 0.354 g (84% yield) of 35b as a viscous liquid after
column chromatography (SiO2, EtOAc/hexane, 1:2, Rf ) 0.28

6652 J . Org. Chem., Vol. 64, No. 18, 1999
Oliveira et al.
1.53 (m, 3H), 1.31 (d, J ) 6.6 Hz, 6H), 1.26-1.14 (m, 12H).
13C NMR (CDCl3): δ 155.6 (C), 154.1 (C), 148.2 (C), 132.6 (C),
132.4 (C), 129.0 (C), 123.1 (CH), 121.3 (CH), 82.1 (CH), 82.0
(CH), 81.1 (CH), 69.6, 69.3, 69.1, 46.0 (CH2), 45.5 (CH2), 33.9
((CH), 33.5 (CH), 32.4 (CH), 29.1 (CH3), 29.0 (CH3), 24.6 (CH2),
23.7 (CH2).
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cyclo-
h exyl-2-h ydr oxy-1-pyr r olidin ecar boxylate (26). FTIR (film,
1
NaCl): 3435, 2954, 1693, 1599, 1415 cm-1. H NMR (CDCl3)
(mixture of rotamers and epimers): δ 7.35-7.21 (m, 4H), 7.17-
7.11 (m, 1H), 5.40-5.03 (two s, 1H), 4.94-4.75 (m, 1H), 3.77;
3.65; 3.53 (three br s) together with 3.45-3.41 (m) integrating
for 1H, 3.18-2.78 (m, 1H), 2.39-2.32 (m, 1H), 2.13-1.99 (m,
1H), 1.94-1.78 (m, 3H), 1.76-1.41 (m, 3H), 1.37 (s, 3H), 1.32-
0.94 (m) overlapping with three s at 1.23, 1.22, and 1.19 for a
total of 8H, 0.90-0.85 (m, 3H). 13C NMR (CDCl3) (mixture of
rotamers and epimers): δ 154.6 (C), 153.0 (C), 152.7 (C), 152.2
(C), 128.0 (CH), 127.8 (CH), 127.7 (CH), 125.3 (CH), 125.2
(CH), 124.8 (CH), 124.7 (CH), 82.0 (CH), 81.9 (CH), 80.2 (CH),
74.9 (CH), 74.7 (CH), 50.9 (CH); 50.7 (CH), 45.7 (CH2), 44.8
(CH2), 44.7 (CH2), 42.6 (CH2), 42.5 (CH2), 42.4 (CH2), 39.6 (C),
39.4, 34.6 (CH2), 33.0 (CH2), 32.5 (CH2), 32.4 (CH2), 31.3 (CH),
30.2 (CH2), 29.7 (CH3), 29.4 (CH3), 28.7 (CH3), 28.4 (CH3), 26.6
(CH2), 26.5 (CH2), 26.3 (CH2), 24.6 (CH3), 24.1 (CH3), 22.6
(CH2), 22.4 (CH2), 21.9 (CH3), 21.8 (CH3).
(1R)-1-(2,4,6-Tr iisop r op ylp h en yl)eth yl-2,3-d ih yd r o-1H-
1-p yr r oleca r boxyla te (21). [R]20D ) 2.8 (c 1.3, hexanes). FTIR
(film, NaCl): 2958, 2929, 2868, 1705, 1616 cm-1 1H NMR
.
(CDCl3): δ 6.87 (s, 2H), 6.55-6.47 (m, 1H), 6.44-6.36 (m, 1H),
4.92 and 4.89 (two br s, 1H), 3.82-3.60 (m, 2H), 3.52 (br s,
2H), 2.79 (quint, J ) 7,0 Hz, 1H), 2.69-2.52 (m, 2H), 1.58 and
1.50 (two close d, J ) 7.0 Hz, 3H), 1.27 (d, J ) 6.6 Hz, 6H),
1.21 and 1.13 (two d, J ) 7.0 Hz, 12H). 13C NMR (CDCl3): δ
151.6 (C), 150.9 (C), 147.5 (C), 132.5 (C), 130.9 (CH), 129.6
(CH), 122.0 (CH), 106.8 (CH), 106.3 (CH), 76.8 (CH), 68.2 (CH),
45.1 (CH2), 44.8 (CH2), 44.5 (CH2), 33.8 (CH), 32.0 (CH), 29.4
(CH2), 28.7 (CH), 28.1 (CH2), 24.5 (CH3), 24.1 (CH3), 23.8 (CH3),
23.7 (CH3), 22.1 (CH3). MS: m/z (rel intens) 343 (6) [M•+], 231
(100), 230 (79), 215 (37), 147 (9). HRMS (EI): calcd for C22H33
-
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cyclo-
NO2 [M+] 343.2511, found 343.2514.
h exyl-2,3-d ih yd r o-1H-1-p yr r oleca r boxyla te (27). [R]20
)
D
(1RS,2SR)-2-P h en ylcycloh exyl-2-oxo-1-p yr r olid in eca r -
boxyla te (22). FTIR (film, NaCl): 2933, 1786, 1753, 1711,
1603, 1282 cm-1. 1H NMR (CDCl3): δ 7.30-7.16 (m, 5H), 4.95
(dt, J ) 4.4; 10.6 Hz, 1H), 3.62-3.54 (m, 1H), 3.38-3.30 (m,
1H), 2.74 (dt, J ) 3.5; 11.6 Hz, 1H), 2.40 (t, J ) 8.1 Hz, 2H),
2.30 (br s, 1H), 1.93-1.72 (m, 5H), 1.67-1.30 (m, 4H). 13C NMR
(CDCl3): δ 174.4 (C), 150.9 (C), 143.0 (C), 128.4 (CH), 127.7
(CH), 126.7 (CH), 78.8 (CH), 49.5 (CH), 45.9 (CH2), 33.4 (CH2),
32.3 (CH2), 32.0 (CH2), 25.5 (CH2), 24.4 (CH2), 17.0 (CH2).
(1RS,2SR)-2-P h en ylcycloh exyl-2-h yd r oxy-1-p yr r oli-
d in eca r boxyla te (23). FTIR (film, NaCl): 3435, 2933, 1693,
- 25.4 (c 1.1, hexanes). FTIR (film, NaCl):2954, 2922, 1699,
1620, 1599, 1417 cm-1. 1H NMR (CDCl3): δ 7.36-7.20 (m, 4H),
7.19-7.05 (m, 1H), 6.52 and 5.58 (two br s, 1H), 5.42-4.94
(m, 1H), 4.90-4.74 (m, 1H), 3.66-3.30 (m, 1H), 3.22-2.78 (m,
1H), 2.54-2.42 (m, 1H), 2.40-2.16 (m, 1H), 2.04-1.57 (m, 6H),
1.55-1.43 (m, 1H), 1.42-1.30 (m, 3H), 1.22 (br s, 3H), 1.18-
0.94 (m, 2H), 1.02-0.82 (m, 3H). 13C NMR (CDCl3): δ 152.2
(C), 151.9 (C), 130.9 (C), 130.0 (C), 128.1 (CH), 128.0 (CH),
127.9 (CH), 125.5 (CH), 125.3 (CH), 125.1 (CH), 124.8 (CH),
106.1 (CH), 82.8 (CH), 74.1 (CH), 74.0 (CH), 73.7 (CH), 50.9
(CH), 44.5 (CH2), 42.7 (CH2), 43.3 (CH2), 39.7 (C), 39.6 (C),
34.7 (CH2), 31.3 (CH), 31.2 (CH), 28.7 (CH3), 26.7 (CH3), 26.6
(CH3), 26.5 (CH3), 22.0 (CH3), 21.9 (CH3). MS: m/z (rel intens)
327 (8) [M•+], 199 (6), 119 (69), 105 (100), 91 (42).
1603, 1417 cm-1 1H NMR (CDCl3) (mixture of epimers and
.
rotamers): δ 7.37-7.14 (m, 5H), 5.33 and 5.23 (two br s, 1H),
4.86-4.71(m, 1H), 3.54-3.09 (m, 2H), 2.94-2.63 (m, 2H),
2.43-2.05 (m, 1H), 1.96-1.69 (m, 6H), 1.62-1.26 (m, 5H). 13
C
(RS)-1-(ter t-bu toxycar bon yl)-3-[1′-(ter t-bu toxycar bon yl)-
2′-p ip er id in yl]-4,5,6,1-tetr a h yd r op yr id in e (29). Using pro-
cedure D for the synthesis of endocyclic enecarbamates, 207
mg of the lactamol 8 afforded 171 mg (90% yield) of 29 after
purification by flash column chromatography. TLC: Rf ) 0.32
(EtOAc/hexane, 1:5). FTIR (neat): 1705, 1653, 1373, 1170,
NMR (CDCl3): δ 155.4 (C), 153.8 (C), 143.8 (C), 143.4 (C), 129.3
(CH), 128.4 (CH), 127.7 (CH), 127.2 (CH), 126.6 (CH), 126.4
(CH), 81.9 (CH), 81.7 (CH), 81.1 (CH), 80.7 (CH), 50.3 (CH),
50.1 (CH), 49.9 (CH), 45.7 (CH2), 45.4 (CH2), 45.1 (CH2), 34.0
(CH2), 33.7 (CH2), 33.1 (CH2), 32.8 (CH2), 32.2 (CH2), 25.7
(CH2), 25.6 (CH2), 24.6 (CH2), 24.4 (CH2), 22.3 (CH2), 21.6
(CH2).
1
1115 cm-1. H NMR (CDCl3, 300 MHz) (mixture of rotamers):
δ 6.80 (br s, 0.5H, H2), 6.60 (br s, 0.5H, H2), 4.74 (br s, 0.5H),
4.70 (br s, 0.5H), 3.96 (br s, 0.5H), 3.92 (br s, 0.5H), 3.51 (br
m, 0.6H), 3.47 (br s, 1.4H), 2.76 (br d, J ) 13.2 Hz, 0.5H), 2.67
(br d, J ) 13.7 Hz, 0.5H), 2.08-1.72 (br m, 4H), 1.71-1.52
(m, 2H), 1.48 (s. 9.4H), 1.45 (s. 9.6H), 1.27 (br s, 1H), 0.86 (m,
2H). MS: m/z (rel intens) 366 (5) [M•+], 209 (61), 165 (20), 84
(20), 57 (100), 41 (88).
(1RS,2SR)-2-P h en ylcycloh exyl-2,3-dih ydr oxy-1H-1-pyr -
r oleca r boxyla te (24). FTIR (film, NaCl): 3028, 2936, 2859,
1705, 1618 cm-1. 1H NMR (CDCl3): δ 7.23-7.03 (m, 5H), 6.38
and 6.14 (two br s, 1H), 4.82 (sl) and 4.74 (dt, J ) 4.2, 10.6
Hz) integrating for 2H, 3.59-3.48 (m) and 3.15-3.12 (m)
integrating for 2H, 2.64-2.49 (m, 3H), 2.27-2.24 (m, 1H),
1.94-1.77 (m, 3H), 1.62-1.48 (m, 2H), 1.41-1.28 (m, 2H). 13
C
NMR (CDCl3): δ 151.7 (C), 143.5 (C), 130.9 (CH), 129.8 (CH),
128.5 (CH), 127.5 (CH), 126.5 (CH), 106.6 (CH), 106.4 (CH),
76.5 (CH), 50.0 (CH), 44.8 (CH2), 44.4 (CH2), 34.2 (CH2), 32.8
(CH2), 29.4 (CH2), 28.3 (CH2), 25.9 (CH2), 24.7 (CH2). MS: m/z
(rel intens) 271 (53) [M•+], 227 (6), 159 (54), 117 (33), 91 (100).
HRMS (EI): calcd for C17H21NO2 [M+] 271.1572, found 271.1581.
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cyclo-
h exyl-2-oxo-1-p yr r olid in eca r boxyla te (25). [R]20D ) -51.6
(c 2.3, EtOAc). FTIR (film, NaCl): 2956, 2922, 1786, 1755,
1707, 1599, 1298 cm-1. 1H NMR (CDCl3): δ 7.32-7.22 (m, 4H),
7.20-7.09 (m, 1H), 4.94 (dt, J ) 4.5; 10,8 Hz, 1H), 3.19 (dt, J
) 7,8; 11,5 Hz, 1H), 2.55-2,47 (m, 1H), 2.35 (t, J ) 8.1 Hz,
2H), 2.09 (dt, J ) 3.5, 11.4 Hz, 1H), 1.92-1.81 (m, 2H), 1.79-
1.67 (m, 3H), 1.51-1.42 (m, 1H), 1.35 (s, 3H), 1.28-0.82 (m,
3H), 1.19 (s, 3H), 0.88 (d, J ) 6,6 Hz, 3H). 13C NMR (CDCl3):
δ 174.4 (C), 152.4 (C), 150.2 (C), 128.0 (CH), 125.6 (CH), 124.8
(CH), 75.7 (CH), 50.4 (CH), 45.3 (CH2), 41.8 (CH2), 39.3 (C),
34.2 (CH2), 32.4 (CH2), 31.0 (CH), 29.5 (CH3), 26.0 (CH2), 22.6
(CH3), 21.5 (CH3), 16.9 (CH2).
Ack n ow led gm en t. The support of this research by
a grant from the Research Supporting Foundation of the
State of Sa˜o Paulo (FAPESP) is gratefully acknowl-
edged. We also thank CNPq, CAPES, and FAPESP for
fellowships, and Dr. Andrew E. Greene from J oseph
Fourier University, Grenoble, France, for a gift of (1R)-
1-(2,4,6-triisopropylphenyl)ethanol.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of compounds 2a /b, 8, 9, 11, 12, and 16b/c, experimental
procedures for the synthesis of 14a /c (with NaBH4), 17c
(hydrolysis of 31), 22, 25, 28, and 31, and copies of 1H and 13C
NMR spectra of compounds 3a /b, 6, 9, 12, 13a /c, 15a /c, 17c,
18b/c, 19, 21, 22, 24, 25, 27-29, and 31. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9903297