Synthesis of enantiomerically pure functionalized cis- and trans-2-aminocyclohexaneearboxylic acid derivatives

Full text of DOI:10.1021/jo981511v

10052
J . Org. Chem. 1998, 63, 10052-10056
Syn th esis of En a n tiom er ica lly P u r e
F u n ction a lized cis- a n d
tr a n s-2-Am in ocycloh exa n eca r boxylic Acid
Der iva tives
J ose´ Barluenga,* Fernando Aznar, Cristina Ribas, and
Carlos Valde´s
Instituto Universitario de Quı´mica Organometa´lica
“Enrique Moles”, Unidad asociada al C.S.I.C., Universidad
de Oviedo, 33071 Oviedo, Spain
F igu r e 1.
Received J uly 30, 1998
Sch em e 1
In tr od u ction
The enantioselective synthesis of â-amino acids has
always attracted considerable attention,1 because this
substructure is present in many natural products2,3 and
biologically active peptides,4 as well as in other bioactive
compounds,5 and they are useful starting materials in
the synthesis of â-lactam antibiotics.6 Moreover, the
â-amino acid moiety is currently gaining increasing
importance as a result of the recent advances in the
chemistry of â-peptides (oligomers of â-amino acids),
which have been reported to adopt predictable and
reproducible folding patterns7,8 and to form self-as-
sembling transmembrane ion channels.9
On the other hand, in the recent years we have been
exploring some of the synthetic applications of com-
pounds derived from chiral 2-amino-1,3-butadienes.10 In
a previous paper, we demonstrated that functionalized
4-nitrocyclohexanones can be prepared with very high
enantiomeric excesses from the reaction of chiral 2-ami-
nodienes with conjugated nitroalkenes bearing aryl or
alkyl substituents (Scheme 1).11
would lead to the carboxylic functionality. The apparently
simple sequence required for those transformations
together with the increasing interest of â-amino acids
prompted us to develop a synthetic route to these
compounds starting from 4-nitrocyclohexanones 1. As an
extension of our previous work,11c in this paper we report
our studies toward the synthesis of functionalized enan-
tiomerically pure cis- and trans-2-ACHC derivatives from
4-nitrocyclohexanones 1.
Resu lts a n d Discu ssion
Nitro compounds 1 may be regarded as precursors of
enantiomerically pure cis- and trans-2-aminocyclohex-
anecarboxylic acid (ACHC) derivatives I and II (Figure
1): reduction of the nitro group would afford the amino
function, and oxidation of either the C3 or C5 substituent
Syn th esis of cis-â-Am in o Acid Der iva tives I. Two
different approaches can be designed for the synthesis
of cis-â-amino acid derivatives I from nitrocyclohexanones
1 depending on the sequence chosen for the synthetic
transformations (reduction of the nitro group and oxida-
tion of the hydroxy substituent). Both strategies were
explored independently, to find out that the sequence that
involved the oxidation of the hydroxy group in first place
required less number of steps and provided higher overall
yield.12 The synthetic sequence applied is depicted in
Scheme 2. First of all, the hydroxy group of 1a (protected
as a TBDMS ether in the starting cyclohexanone) was
deprotected under acidic conditions leading to nitro
hydroxy ketone 2a along with its intramolecular hemiket-
al 3a (ratio 2a /3a , 1:3). Nevertheless, oxidation of the
mixture with J ones reagent went to completion, and after
diazomethane esterification of the crude, the desired nitro
ester 4a was isolated as a single compound in good yield.
Finally, hydrogenation of the nitro group in the presence
of Raney nickel13 proceeded smoothly to obtain the cis-
â-amino ester 5a in 80% overall yield (4 steps).
(1) For a review on recent stereoselective synthetic approaches to
â-amino acids, see: Cole, D. C. Tetrahedron 1994, 32, 9517-9582.
(2) Goto, T.; Toya, Y.; Ohgi, T.; Kondo, T. Tetrahedron Lett. 1982,
23, 1271.
(3) Katayama, N.; Nozaki, Y.; Tsubotani, S.; Kondo, M.; Harada,
S.; Ono, H. J . Antibiot. 1990, 43, 10.
(4) Drey, C. N. C. In Chemistry and Biochemistry of the Amino acids;
Barret, G. C., Ed.; Chapman and Hall: New York, 1985; Chapter 3.
(5) For the applications of â-amino acids as peptidomimetics, see:
Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-
1267.
(6) For a review in the field of â-lactam antibiotics, see: Du¨rckhe-
imer, W.; Blumbach, J .; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180-202.
(7) Seebach, D.; Matthews, J . L. Chem. Commun. 1997, 2015-2022.
(8) Apella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.;
Huang, X.; Barchi, J r. J . J .; Gellman, S. H. Nature 1997, 387, 381-
384.
(9) Clark, T. D.; Buehler, L. K.; Ghadiri, M. R. J . Am. Chem. Soc.
1998, 120, 651-656.
(10) (a) Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C.; Ferna´ndez,
M.; Cabal, M. P.; Trujillo, J . Chem. Eur. J . 1996, 2, 805-811. (b)
Enders, D.; Meyer, O.; Raabe, G. Liebigs Ann. 1996, 1023-1035 and
references therein.
The same strategy was applied to 4-nitrocyclohexanone
1b (Scheme 2). This time, upon desilylation with aqueous
(11) (a) Barluenga, J .; Aznar, F.; Valde´s, C.; Mart´ın, A.; Garc´ıa-
Granda, S.; Mart´ın, E. J . Am. Chem. Soc. 1993, 115, 4403-4404. (b)
Enders, D.; Meyer, O.; Raabe, G. Synthesis 1992, 1242-1244. (c)
Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C. J . Org. Chem. 1997, 62,
6746-6753.
(12) Spectroscopic data for the alternative approach are included
as Supporting Information.
(13) Moffett, R. B. Organic Syntheses; Rabjohn, N., Ed.; J ohn
Wiley: New York; Collect. Vol. IV, p 1963, 357-359.
10.1021/jo981511v CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/03/1998

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10053
Sch em e 2
Sch em e 3
Sch em e 4
HCl, a small amount of the C3 epimer 2′b was observed
along with nitrohydroxyketone 2b and its intramolecular
hemiketal 3b, (ratio 2b/3b/2′b, 1:3:0.3). Again, oxidation
of the mixture with J ones reagent and subsequent
treatment of the crude acid with diazomethane afforded
nitro ester 4b, which was easily separated from the minor
C3 epimer 4′b by column chromatography. The tertiary
nitro group could then be cleanly reduced by hydrogena-
tion with Raney nickel employing longer reaction times
(14 h), leading to cis-â-amino ester 5b with 85% overall
yield. It is worth pointing out that amino ester 5b
features a very rigid structure, as a result of the amino
group being positioned in a tertiary carbon atom, which
may be of interest in the design of â-peptides with
predefined conformations.
indicates the equatorial arrangement of the amino group.
Under the acidic conditions required for the hydrolysis
of the silyl group, the benzoyl carbamate was cleanly
cleaved, leading to diol 8 as the unique reaction product.
Oxidation of 8 with J ones reagent then afforded bicyclic
lactone 9, the lactonization process being favored by the
cis diaxial arrangement of both substituents at C1 and
C3. Finally, hydrogenation of the Cbz protecting group
gave amine 10 with 37% overall yield based on nitrocy-
clohexanone 1a . It is worth noting that amino lactone
10 is a conformationally rigid nitrogenated analogue of
trans-2-phenylcyclohexanol, a chiral auxiliary widely
used in asymmetric synthesis. Therefore, this simple
approach would be useful in the preparation of a new
class of rigid chiral auxiliaries.
Syn th esis of tr a n s-â-Am in o Acid Der iva tives II.
Once we had completed the synthesis of cis-ACHC esters,
we turned our attention to the trans derivatives. The
conversion of the substituent at C5 of 4-nitrocyclohex-
anones 1 into a carboxylic group would give â-amino
esters with trans relative configuration. To accomplish
this chemical transformation, compound 1c, derived from
â-(3-furyl)nitroethylene, was used as starting material.
The furan ring was oxidized employing the Sharpless
procedure,17 followed by esterification with diazometane
to obtain â-nitro ester 11 in very high yield (Scheme 4).
Catalytic hydrogenation of the nitro group then afforded
trans-â-amino ester 12 with 99% yield (91% overall yield
Interestingly, bicyclic lactone 10, a different â-amino
acid derivative, was prepared when the sequence of
synthetic transformations was inverted and the reduction
of the nitro group was carried out applying Ganem’s
reduction procedure (Scheme 3).14 Thus, when (()-1a was
treated with NiCl2 and NaBH4 in methanol, amino
alcohol 6 was obtained as a single diastereoisomer.15 The
amino group was protected by treatment of crude 6 with
excess benzyl chloroformate to produce the benzoylation
of both the amino and hydroxy groups to furnish car-
1
bamate 7.16 At this point, the analysis of the H NMR
spectrum revealed that the reduction step had taken
place with no epimerization: CH-NH appears as a ddd
(J H4-H5 ) 12.5 Hz, J H3-H4 ) 6.9 Hz, J H4-NH ) 6.9 Hz),
where the large coupling constant J H4-H5 ) 12.5 Hz
(14) Osby, J . O.; Ganem, B. Tetrahedron Lett. 1985, 26, 6413-6416.
(15) This synthetic study was carried out on racemic 1, obtained by
cycloaddition of â-nitrostyrene with the appropriate 2-morpholino-1,3-
butadiene.
(16) Under the reaction conditions studied, it was not possible to
protect exclusively the amino group in the presence of the secondary
alcohol, although the monoprotected compound could be isolated with
low yields when the reaction was carried out in the presence of smaller
amounts of CbzCl.
(17) Carlsen, P. H. J .; Katsuki, T.; Mart´ın, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.

10054 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
1.18 (d, J ) 6.8 Hz, 3H, 2b), 1.09 (d, J ) 7.0 Hz, 3H, 3b) ppm;
13C NMR (50 MHz, CDCl3) δ 209.9 (2b), 105.7 (3b), 95.1 (2b),
94.6 (3b), 66.1 (3b), 58.9 (2b), 53.0 (3b), 52.9 (2b), 42.3 (2b),
42.2 (2b), 41.0 (3b), 40.6 (3b), 34.9 (2b), 32.1 (3b), 30.7 (2b),
30.3 (3b), 26.5 (2b), 25.8 (3b), 22.3 (2b), 22.0 (3b), 20.3 (3b),
18.8 (2b), 11.8 (2b), 11.6 (3b) ppm. Anal. Calcd for C12H19NO4:
C, 59.73; H, 7.94; N, 5.81. Found: C, 59.73; H, 7.96; N, 5.73.
Oxid a tion of th e Mixtu r e of 2 a n d 3. Syn th esis of Nitr o
Ester s 4. The mixture of compounds 2 and 3 (0.53 mmol) was
dissolved in 8 mL of acetone and cooled to 0 °C. A solution of
J ones reagent was then added dropwise with stirring until the
orange color of the CrO3 solution remained. The stirring was
then continued for 30 min, and ethanol was added dropwise until
the solution turned colorless. The solution was separated from
the viscous green residue and filtered through Celite, and the
green residue and the Celite were washed with additional
acetone. The filtrates were combined and concentrated under
reduced pressure. The resulting oil was redissolved in EtOAc,
(20 mL) and washed with brine. The aqueous layer was extracted
with EtOAc and the combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The crude
acid obtained was dissolved in 10 mL of Et2O and treated with
a solution of freshly prepared diazomethane in Et2O. After 15
min, the excess of diazomethane was destroyed by the addition
of acetic acid until the yellow color due to diazomethane
disappeared. The mixture was washed with brine, the aqueous
layer was extracted with Et2O (2 × 20 mL), and the combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure to afford a solid that was purified by flash
chromatography. The following compounds were prepared with
this method:
for the three steps). Again, no epimerization was observed
during the process, as deduced by the analysis of the
coupling constants in the H NMR spectrum. Thus, the
1
signal assigned to H1 (CH-COOMe) appears as a triplet
of doublets at 4.18 ppm (J H1-H6ax ) J H1-H2 ) 12.0 Hz,
J H1-H6eq ) 6.2 Hz); the presence of a large coupling
constant between H1 and H2 (CH-NH2) clearly indicates
the equatorial-equatorial trans arrangement of both the
amino and carboxylate substituents.
In conclusion, we have described some very simple
syntheses of enantiomerically pure substituted cis- and
trans-2-aminocyclohexanecarboxylic esters from 4-nitro-
cyclohexanones derived from the asymmetric cycloaddi-
tion of 2-aminodienes and nitroolefins. It is interesting
to note that these compounds present the â-amino ester
moiety in a conformationally restricted environment,
which is an important feature to be employed in the fields
of peptidomimetics and â-peptides. Furthermore, given
the wide scope of the cycloaddition reaction, the method
presented herein would allow for the preparation of a
large variety of cyclic â-amino acid derivatives with
different substituents.
Exp er im en ta l Section
Gen er a l. The same experimental techniques were used as
reported previously (see ref 11c). Nitrocyclohexanones 1 were
prepared as described in ref 11c.
(+)-Meth yl (1S,2R,5R,6R)-2-Meth yl-6-n itr o-3-oxo-5-p h en -
ylcycloh exa n e-1-ca r boxyla te (4a ). A mixture of 2a and 3a
(140 mg) afforded 124 mg of 4a as a white solidin 80% yield: Rf
Desilyla tion of 1. Syn th esis of th e Mixtu r e of Nitr o
Alcoh ols 2 a n d Hem ik eta ls 3. To a solution of nitroketone 1
(0.55 mmol) in 20 mL of THF were added 15 mL of 3 N aqueous
HCl, and the mixture was vigorously stirred for 90 min at room
temperature. Brine (15 mL) and EtOAc (30 mL) were then added
to the reaction mixture. The layers were separated, and the
aqueous layer was extracted with additional EtOAc (3 × 20 mL).
The organic layers were combined, washed with brine (15 mL),
dried over Na2SO4, and concentrated under reduced pressure.
The resulting oil was purified by flash chromatography (SiO2,
hexane/EtOAc, 1:1) to obtain a mixture of compounds 2 and 3
which was employed for the next step. The following were
prepared with this procedure:
) 0.37 (SiO2, hexane/EtOAc 2:1); mp ) 143-144 °C; [R]15
)
D
+157.0 (c 0.8, CH2Cl2); ee > 99%; 1H NMR (200 MHz, CDCl3) δ
7.41-7.24 (m, 5H), 5.37 (dd, J ) 12.3, 4.6 Hz, 1H), 4.22 (td, J )
12.3, 5.5 Hz, 1H), 3.77 (s, 3H), 3.70 (t, J ) 4.6 Hz, 1H), 2.89 (dd,
J ) 15.6, 5.5 Hz, 1H), 2.78 (qdd, J ) 6.7, 4.6, 0.9 Hz, 1H), 2.60
(ddd, J ) 15.6, 12.3, 0.9 Hz, 1H), 1.17 (d, J ) 6.7 Hz, 3H) ppm;
13C NMR (50 MHz, CDCl3) δ 204.4, 170.1, 137.7, 129.0, 128.0,
127.0, 88.8, 52.5, 51.2, 45.5, 43.9, 42.7, 11.5 ppm. Anal. Calcd
for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.48; H,
6.17; N, 4.96.
(+)-Meth yl (1S,2R,9R,10S)-2-Meth yl-9-n itr o-3-oxobicycle-
[4.4.0]d eca n e-1-ca r boxyla te (4b). A mixture of 2b, 3b, and
2′b (118 mg) afforded 107 mg of 4b as a white solid in 81%
yield: Rf ) 0.19 (SiO2, hexane/EtOAc 4:1); mp ) 147-148 °C;
(2R,3S,4R,5R)-3-(Hydroxymethyl)-2-methyl-4-nitro-5-phen-
ylcycloh exa n on e (2a ) a n d (1S,3R,4R,5S,8R)-1-Hyd r oxy-8-
m eth yl-4-n itr o-3-p h en ylbicyclo[3.2.1]octa n -7-on e (3a ). Ni-
tro compound 1a (208 mg) was employed to obtain 144 mg of a
white solid existing as a 3:1 mixture of compounds 2a and 3a
in 99% yield: Rf ) 0.23 (SiO2, hexane/EtOAc 2:1); mp ) 169-
[R]15 ) +58.3 (c 1.1, CH2Cl2); ee > 99%; 1H NMR (200 MHz,
D
CDCl3) δ 3.65 (s, 3H), 3.54-3.40 (m, 1H), 3.27 (d, J ) 6.8 Hz,
1H), 2.66 (quint, J ) 6.8 Hz, 1H), 2.60-2.50 (m, 3H), 2.22 (ddd,
J ) 14.5, 12.7, 4.1 Hz, 1H), 1.88-1.26 (m, 6H), 1.07 (d, J ) 6.8
Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ 206.1, 169.8, 92.4,
58.9, 52.5, 42.3, 41.6, 33.7, 29.4, 26.1, 22.0, 18.2, 11.8 ppm. Anal.
Calcd for C13H19NO5: C, 57.98; H, 7.11; N, 5.20. Found: C, 57.60;
H, 6.75; N, 5.02.
170 °C; [R]15 ) +9.5 (c 0.4, MeOH); ee > 99%; 1H NMR (300
D
MHz, CDCl3) δ 7.35-7.24 (m, 5H) × 2, 5.43 (dd, J ) 12.3, 4.1
Hz, 1H, 2a ), 4.89 (dd, J ) 11.7, 1.2 Hz, 1H, 3a ), 4.37 (td, J )
12.3, 6.0 Hz, 1H, 2a ), 4.28 (d, J ) 9.4 Hz, 1H, 3a ), 4.10 (dd, J )
9.4, 4.1 Hz, 1H, 3a ), 3.91-3.60 (m, 2H, 2a ), 3.91-3.82 (m, 1H,
3a ), 2.82-2.66 (m, 3H, 2a ), 2.82-2.66 (m, 1H, 3a ), 2.47 (dd, J
) 15.8, 12.3 Hz, 1H, 2a ), 2.27 (dd, J ) 12.9, 7.0 Hz, 1H, 3a ),
2.08 (q, J ) 7.0 Hz, 1H, 3a ), 2.00 (t, J ) 12.9 Hz, 1H, 3a ), 1.22
(d, J ) 6.5 Hz, 3H, 2a ), 1.15 (d, J ) 7.0 Hz, 3H, 3a ) ppm; 13C
NMR (50 MHz, CDCl3) δ 207.9 (2a ), 141.0 (2a ), 139.7 (3a ), 129.7
(3a ), 129.6 (2a ), 128.4 (2a ), 128.3 (3a ), 127.8 × 2, 106.1 (3a ),
92.1 (3a ), 91.8 (2a ), 66.1 (3a ), 58.2 (2a ), 48.5 (3a ), 47.4 (2a ), 47.3
(2a ), 46.2 (3a ), 45.3 (2a ), 44.7 (3a ), 43.9 (2a ), 42.7 (3a ), 12.2 (2a ),
12.0 (3a ) ppm. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N,
5.32. Found: C, 63.77; H, 6.38; N, 5.06.
Hyd r ogen a t ion of t h e Nit r o Gr ou p of Nit r o E st er s 4.
Syn th esis of Am in o Ester s 5. A mixture of nitro compound 4
(0.40 mmol) and Raney nickel (120 mg) in 50 mL of absolute
EtOH was hydrogenated at a pressure of 90 atm and 60 °C for
6 h. The mixture was then cooled to room temperature and
filtered through Celite, and the catalyst and the Celite were
washed with additional EtOH (3 × 5 mL). The combined filtrates
were concentrated under reduced pressure, and the residue was
redissolved in CH2Cl2 (20 mL) and filtered again through Celite.
The solvent was removed under reduced pressure to afford amino
ester 5 as a white solid. The following compounds were preapred
with this procedure:
(1S,3S,8R,9S,12R)-1-Hyd r oxy-12-m eth yl-8-n itr otr icyclo-
[7.2.1.03,8]d od eca n -11-on e (3b) a n d (3R,4S,5R,10S)-4-(Hy-
d r oxym eth yl)-3-m eth yl-5-n itr o-2-d eca lon e (2b). Nitro com-
pound 1b (196 mg) was employed to obtain 128 mg of a white
solid consisting in a 3:1 mixture of compounds 2b and 3b in 97%
yield: Rf ) 0.24 (SiO2, hexane/EtOAc, 2:1); mp ) 126-128 °C;
(+)-Meth yl (2R,1S,6R,5R)-6-Am in o-2-m eth yl-3-oxo-5-ph en -
ylcycloh exa n e-1-ca r boxyla te (5a ). Hydrogenation of 117 mg
of nitro ester 4a afforded 104 mg of amino ester 5a as a white
solid with a reaction time of 6 h in 100% yield: Rf ) 0.40 (SiO2,
[R]15 ) -31.4 (c 1.0, CH2Cl2); ee > 99%; 1H NMR (300 MHz,
CH2Cl2/MeOH 20:1); mp ) 136 °C (dec); [R]15 ) +66.9 (c 1.4,
D
D
CDCl3) δ 3.99 (dd, J ) 9.4, 4.6 Hz, 1H, 3b), 3.80 (dd, J ) 12.3,
3.5 Hz, 1H, 2b), 3.67 (d, J ) 9.4 Hz, 1H, 3b), 3.63-3.52 (m, 1H,
2b), 3.37 (d, J ) 12.3 Hz, 1H, 2b), 3.15-3.02 (m, 1H, 3b), 2.76
(quint, J ) 7.0 Hz, 1H, 3b), 2.58-1.21 (m, 12H, 2b; 11H 3b),
CH2Cl2); ee > 99%; 1H NMR (200 MHz, CDCl3) δ 7.38-7.20 (m,
5H), 3.72 (s, 3H), 3.70 (dd, J ) 12.0, 5.6 Hz, 1H), 3.35 (td, J )
12.0, 5.6 Hz, 1H), 3.28 (t, J ) 5.6 Hz, 1H), 2.75 (qd, J ) 6.8, 5.6
Hz, 1H), 2.64 (dd, J ) 15.0, 5.6 Hz, 1H), 2.53 (ddd, J ) 15.0,

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10055
12.0, 0.9 Hz, 1H), 1.07 (d, J ) 6.8 Hz, 3H) ppm; 13C NMR (50
MHz, CDCl3) δ 207.8, 172.5, 141.3, 128.9, 127.4, 127.2, 55.4, 54.9,
51.6, 47.3, 46.4, 44.2, 11.9 ppm. Anal. Calcd for C15H19NO3: C,
68.95; H, 7.33; N, 5.36. Found: C, 68.85; H, 7.69; N, 5.46.
(-)-Meth yl (1S,2R,9R,10S)-9-Am in o-2-m eth yl-3-oxobicy-
cle[4.4.0]d eca n e-1-ca r boxyla te (5b). Hydrogenation of 94 mg
of nitroester 4b using 100 mg of Raney nickel afforded 80 mg of
amino ester 5b as a white solid with a reaction time of 14 h in
96% yield: Rf ) 0.21 (SiO2, CH2Cl2/MeOH 40:1); mp ) 105-
Rf ) 0.16 (SiO2, hexane/EtOAc 1:1); 1H NMR (300 MHz, CDCl3)
δ 7.27-7.03 (m, 10H), 5.28 (d, br, J ) 9.0 Hz, 1H), 4.87 (s, 2H),
4.15-4.02 (m, 1H), 3.83 (dd, J ) 12.5, 1.7 Hz, 1H), 3.81-3.70
(m, 1H), 3.75 (d, J ) 12.5 Hz, 1H), 3.24 (td, J ) 12.8, 3.4 Hz,
1H), 2.21-2.09 (m, 2H), 2.05 (dt, J ) 12.8, 3.4 Hz, 1H), 1.73 (td,
J ) 12.8, 2.6 Hz, 1H), 1.13 (d, J ) 6.4 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ 155.9, 142.9, 136.4, 128.5, 128.3, 127.7, 127.4,
127.3, 126.5, 68.4, 66.1, 56.7, 55.5, 43.0, 42.4, 40.5, 37.2, 15.8
ppm; HRMS (EI) calcd for C22H27NO4 369.1940, found 369.1940.
Oxid a t ion of Diol 7. Syn t h esis of (()-(1S*,2R*,3R*,
5S*,8R*)-2-(Ben zyloxyca r b on yla m in o)-8-m et h yl-6-oxa -3-
p h en ylbicyclo[3.2.1]octa -7-on e (9). The procedure is identical
to that described above for the oxidation of nitro alcohols 2 but
employing 92 mg of 8 (0.25 mmol). The reaction crude was
purified by flash chromatography (SiO2, hexane/EtOAc 2:1) and
afforded 92 mg of lactone 9 as a white solid in 51% yield: mp )
145-154 °C; Rf ) 0.25 (SiO2, hexane/EtOAc 2:1); 1H NMR (200
MHz, CDCl3) δ 7.39-7.17 (m, 10H), 5.09 (d, br, J ) 9.1 Hz, 1H),
4.96 (s, 2H), 4.54 (d, J ) 4.4 Hz, 1H), 4.24 (ddd, J ) 12.3, 9.1,
2.6 Hz, 1H), 2.81 (td, J ) 12.3, 6.7 Hz, 1H), 2.78 (d, J ) 2.6 Hz,
1H), 2.41 (ddd, J ) 14.1, 6.7, 4.4 Hz, 1H), 2.32 (q, J ) 6.8 Hz,
1H), 1.79 (dd, J ) 14.1, 12.3 Hz, 1H), 1.19 (d, J ) 6.8 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 176.5, 155.5, 139.6, 135.9,
128.7, 128.3, 127.9, 127.7, 127.6, 127.3, 82.1, 66.6, 53.8, 51.6,
43.5, 42.4, 37.7, 16.2 ppm. Anal. Calcd for C22H23NO4: C, 72.31;
H, 6.34; N, 3.83. Found: C, 71.91; H, 6.05; N, 3.68.
107 °C; [R]15 ) -17.2 (c 1.0, CH2Cl2); ee > 99%; 1H NMR (200
D
MHz, CDCl3) δ 3.66 (s, 3H), 2.78 (d, J ) 6.5 Hz, 1H), 2.66 (quint,
J ) 6.5 Hz, 1H), 2.54-2.05 (m, 4H), 1.88-1.24 (m, 7H), 0.98 (d,
J ) 6.5 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ 210.3, 172.8,
62.8, 51.9, 51.3, 42.1, 41.8, 38.6, 33.4, 25.9, 21.0, 19.3, 12.1 ppm.
Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84; N, 5.85. Found:
C, 64.85; H, 8.49; N, 5.63.
Red u ction of th e Nitr o Gr ou p of 1a w ith Ni2B. Syn th esis
of (()-(1S*,2R*,3S*,4R*,5R*)-4-Am in o-3-(ter t-bu tyld im eth -
ylsilyloxym eth yl)-2-m eth yl-5-p h en ylcycloh exa n ol (6). A
suspension of NiCl2 (33 mg, 0.28 mmol) in 10 mL of MeOH was
sonicated for 15 min followed by the addition of NaBH4 (29 mg,
0.84 mmol), and the sonication was maintained for 30 min. A
solution of nitro compound 1a (190 mg, 0.5 mmol) in 5 mL of
MeOH was then added to the mixture. Ten minutes later the
sonicator was turned off, and the mixture was stirred at room
temperature. NaBH4 was then added in four portions (4 × 190
mg, 4 × 5 mmol) distributed in a period of 6 h. Finally, the
solvent was removed under reduced pressure and the black
slurry was redissolved in H2O (10 mL) and EtOAc (10 mL). The
layers were separated, and the aqueous layer was extracted with
more EtOAc (3 × 15 mL). The organics were combined, washed
with brine, dried under Na2SO4, and concentrated under reduced
pressure. The crude amino alcohol was then purified by flash
chromatography (SiO2, CH2Cl2/MeOH 20:1) to obtain 166 mg of
6 as a white solid in 95% yield: mp ) 90-94 °C; Rf ) 0.29 (SiO2,
CH2Cl2/MeOH 19:1); 1H NMR (300 MHz, CDCl3) δ 7.32-7.14
(m, 5H), 4.08 (dd, J ) 11.2, 2.6 Hz, 1H), 3.75 (dd, J ) 11.2, 2.2
Hz, 1H), 3.66 (q, J ) 3.0 Hz, 1H), 3.05-2.95 (m, 2H), 2.12
(quintd, J ) 7.3, 3.0 Hz, 1H), 2.01 (dt, J ) 14.2, 3.0 Hz, 1H),
1.94-1.90 (m, 1H), 1.72-1.62 (m, 1H), 1.15 (d, J ) 7.3 Hz, 3H),
0.99 (s, 9H), 0.20 (s, 3H), 0.18 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 144.3, 128.6, 127.6, 126.3, 68.6, 57.7, 56.4, 45.4, 44.1,
42.2, 38.3, 25.7, 18.0, 15.9, -5.6, -6.0 ppm. Anal. Calcd for
C20H35NO2Si: C, 63.29; H, 8.76; N, 3.69. Found: C, 63.33; H,
8.86; N, 3.82.
P r otection of Am in o a lcoh ol 8 w ith Cbz. Syn th esis of
(()-(1S*,2R*,3S*,4R*,5R*)-4-(N-Ben zyloxyca r bon yla m in o)-
1-(b en zyloxyca r b on yloxy)-3-(ter t-b u t yld im et h ylsilyloxy-
m eth yl)-2-m eth yl-5-p h en ylcycloh exa n e (7). Benzyl chloro-
formate (0.22 mL, 1.56 mmol) was added to a solution of 136
mg (0.39 mmol) of amino alcohol 6 in 10 mL of CH3CN and 5
mL of saturated aqueous solution of K2CO3, and the mixture
was stirred vigorously at room temperature for 14 h. The
reaction was diluted with 20 mL of EtOAc, the layers were
separated, and the aqueous layer was extracted with EtOAc (2
× 10 mL). The organic layers were combined, washed with brine,
dried over Na2SO4, and concentrated in a vacuum. The resulting
oil was purified by column chromatography (SiO2, hexane/EtOAc
4:1) affording 200 mg of 7 as a colorless oil in 83% yield: Rf )
0.35 (SiO2, hexane/EtOAc 2:1); 1H NMR (300 MHz, CDCl3) δ
7.38-7.15 (m, 15H), 5.00 (d, J ) 12.7 Hz, 1H), 4.94 (d, J ) 12.7
Hz, 1H), 4.58 (d, J ) 6.9 Hz, 1H), 4.51 (d, J ) 10.8 Hz, 1H), 4.06
(dt, J ) 12.5, 6.9 Hz, 1H), 3.88 (dd, J ) 11.2, 2.8 Hz, 1H), 3.79
(dd, J ) 11.2, 2.4 Hz, 1H), 3.72-3.64 (m, 1H), 3.18 (td, J ) 12.5,
3.4 Hz, 1H), 2.35-2.29 (m, 1H), 2.23-2.14 (m, 1H), 2.09 (dt, J
) 13.8, 3.4 Hz, 1H), 1.72 (td, J ) 13.8, 12.6 Hz, 1H), 1.16 (d, J
) 6.9 Hz, 3H), 1.00 (s, 9H), 0.17 (s, 6H) ppm; 13C NMR (75 MHz,
CDCl3) 155.3 (×2), 142.4, 141.1, 136.2, 128.2, 128.1, 127.9, 127.8,
127.3, 127.0, 126.7, 126.3, 126.2, 68.0, 65.7, 64.1, 58.3, 55.6, 42.7,
42.5, 39.7, 36.9, 25.4, 17.6, 15.4, -6.0, -6.3 ppm.
Dep r otection of th e Cbz Gr ou p of 9. Syn th esis of
(()-(1S*,2R*,3R*,5S*,8R*)-2-Am in o-8-m eth yl-6-oxa -3-p h en -
ylbicyclo[3.2.1]octa -7-on e (10). A flask containing lactone 11
(40 mg, 0.11 mmol) and Pd/C 10% (43 mg, 0.04 mmol) and
capped with a rubber septum was evacuated and filled with
nitrogen with a needle and a balloon. Absolute EtOH (10 mL)
was added with a syringe, and the mixture was stirred vigor-
ously at room temperature overnight. The reaction was filtered
through Celite, and the Celite washed with EtOH (2 × 5 mL).
The solvents were removed under reduced pressure to afford 23
mg of pure amino lactone 10 after filtration through a short flash
chromatographic column (SiO2, hexane/EtOAc 2:1) (yield 91%):
Rf ) 0.24 (SiO2, CH2Cl2/EtOAc 1:2); 1H NMR (200 MHz, DMSO-
d6) δ 7.56-7.34 (m, 5H), 4.70 (d, J ) 4.1 Hz, 1H), 3.85 (dd, J )
11.5, 2.0 Hz, 1H), 3.00 (d, J ) 2.0 Hz, 1H), 2.96 (td, J ) 11.5,
6.2 Hz, 1H), 2.72 (q, J ) 6.9 Hz, 1H), 2.28 (ddd, J ) 13.5, 6.2,
4.1 Hz, 1H), 1.95 (dd, J ) 13.5, 11.5 Hz, 1H), 1.16 (d, J ) 6.9
Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 175.1, 139.3,
128.8, 128.6, 127.5, 82.1, 53.1, 49.6, 42.6, 41.0, 36.7, 16.1 ppm;
HRMS (EI) calcd for C14H17NO2 231.1259, found 231.1259.
Oxid a tion of th e F u r a n Rin g of 1c. Syn th esis of Nitr o
Ester (+)-Meth yl (1S,2S,3S,4R)-3-(ter t-Bu tyld im eth ylsilyl-
oxymethyl)-4-methyl-2-nitro-5-oxocyclohexane-1-carboxylate
(11). To a solution of nitrocyclohexanone 1c (202 mg, 0.55 mmol)
in CH3CN (4 mL) were added 4 mL of CCl4, 6 mL of H2O, and
1.75 g (8.19 mmol) of NaIO4. The biphasic mixture was vigor-
ously stirred, and 11 mg of RuCl3‚xH2O was added in one portion.
After 15 min the mixture was diluted with 25 mL of EtOAc, and
the supernatant organic layer was decanted carefully; this
operation was repeated three times. The combined organic layers
were treated with Na2SO4 and charcoal, filtered through Celite,
and concentrated under reduced pressure. The residue was
dissolved in 15 mL of Et2O and treated with a solution of freshly
prepared diazomethane in Et2O. After 15 min, the excess of
diazomethane was destroyed by the addition of acetic acid until
the yellow color of diazomethane disappeared. The mixture was
washed with brine, the aqueous layer was extracted with Et2O
(2 × 20 mL), and the combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The solid was
purified by flash chromatography (SiO2, hexane/EtOAc 2:1) to
afford 180 mg of nitro ester 11 as a pale yellow solid in 91%
yield: Rf ) 0.53 (SiO2, hexane/EtOAc 2:1); mp ) 74-76 °C; [R]15
D
1
) +14.7 (c 1.3, CH2Cl2); ee > 99%. H NMR (200 MHz, CDCl3)
δ 5.32 (dd, J ) 12.0, 4.7 Hz, 1H), 4.18 (td, J ) 12.0, 6.2 Hz, 1H),
3.77 (dd, J ) 11.5, 3.2 Hz, 1H), 3.76 (s, 3H), 3.47 (dd, J ) 11.5,
0.9 Hz, 1H), 2.90-2.82 (m, 1H), 2.82 (dd, J ) 15.6, 6.2 Hz, 1H),
2.60 (q, J ) 6.8 Hz, 1H), 2.32 (dd, J ) 15.6, 12.0 Hz, 1H), 1.21
(d, J ) 6.8 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H) ppm;
13C NMR (50 MHz, CDCl3) δ 203.7, 172.4, 85.7, 57.9, 52.5, 45.4,
43.7, 41.8, 39.9, 25.4, 17.9, 11.4, -6.3, -6.4 ppm; HRMS (EI)
calcd for C15H26NO6Si (M - CH3) 344.1529, found 344.1529.
Dep r otection of 6. Syn th esis of Diol (()-(1S*,2R*,3S*,
4R*,5R*)-4-(N-Ben zyloxyca r bon yla m in o)-3-(h yd r oxym eth -
yl)-2-m eth yl-5-p h en ylcycloh exa n ol (8). The procedure is
identical to that described for the deprotection of silyl ethers 1
employing compound 7 (173 mg, 0.28 mmol). The residue was
purified by a short flash chromatography (SiO2, hexane/EtOAc
1:1) to obtain 103 mg of diol 8 as a colorless oil in 100% yield:

10056 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
Ca ta lytic Hyd r ogen a tion of th e Nitr o Gr ou p of Ester
11. Syn t h esis (+)-Met h yl (1S,2S,3S,4R)-3-(ter t-Bu t yld i-
m eth ylsilyloxym eth yl)-2-am in o-4-m eth yl-5-oxocycloh exan e-
1-ca r boxyla te (12). The procedure is identical to that described
above for nitro compound 1a , but applied to 165 mg (0.46 mmol)
of nitro ester 11 with 160 mg of Raney nickel. The resulting
yellowish oil consisted in essentially pure amino ester 12 that
was filtered through a short chromatographic column (SiO2, CH2-
Cl2/MeOH 20:1) to obtain 150 mg (yield 99%): Rf ) 0.23 (SiO2,
-6.1, -6.2 ppm; HRMS (EI) calcd for C16H31NO4Si 329.2022,
found 329.2019.
Ack n ow led gm en t. Financial support of this work
was provided by Direccio´n General de Investigacio´n
Cient´ıfica y Te´cnica DGICYT of Spain (PB-92 1005). A
FICYT predoctoral fellowship from the Regional Gov-
ernment of Principado de Asturias to C.R. is gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
and DEPT 3 spectra of selected compounds (3 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
CH2Cl2/MeOH 20:1); [R]18 ) +12.3 (c 1.1, CH2Cl2); ee > 99%;
D
1H NMR (200 MHz, CDCl3) 4.00 (dd, J ) 10.9, 0.9 Hz, 1H), 3.74
(s, 3H), 3.70 (dd, J ) 10.9, 3.8 Hz, 1H), 3.67-3.54 (m, 1H), 3.27
(td, J ) 12.0, 6.2 Hz, 1H), 2.56 (dd, J ) 15.8, 6.2 Hz, 1H), 2.53
(quint, d, J ) 6.8 Hz, 1H), 2.43 (ddd, J ) 15.8, 12.0, 0.9 Hz,
1H), 2.10-2.01 (m, 1H), 1.14 (d, J ) 6.8 Hz, 3H), 0.88 (s, 9H),
0.07 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 207.1,
174.5, 57.2, 53.1, 51.9, 48.4, 47.8, 44.9, 41.1, 25.5, 17.9, 11.6,
J O981511V