Synthesis and characterization of novel bi- and tricyclic α-amino acids

Article abstract of DOI:10.1080/00397911.2010.515354

As part of a medicinal chemistry collaboration, a number of novel bi- and tricyclic aamino acids were prepared through various routes and characterized by ¹ H nuclearOverhauser effect difference experiments. The syntheses provide a number of routes to access some highly substituted amino acid derivatives that have not been reported previously. It is envisaged that the chemistry described here could be applied to the synthesis of other unique substrates Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515354

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Synthesis and Characterization of Novel
Bi- and Tricyclic α-Amino Acids
Matthew R. Johnson a , Jolicia F. Gauuan a , Cheng Guo a , Peter
R. Guzzo a , Van-Duc Le a , Rajesh A. Shenoy a , James Hamby b ,
Howard Roark b , Michael Stier b & John E. Mangette a
a Medicinal Chemistry Department , Albany Molecular Research, Inc.
(AMRI) , Albany , New York , USA
b Pfizer, Inc. , Ann Arbor , Michigan , USA
Published online: 29 Jun 2011.
To cite this article: Matthew R. Johnson , Jolicia F. Gauuan , Cheng Guo , Peter R. Guzzo , Van-
Duc Le , Rajesh A. Shenoy , James Hamby , Howard Roark , Michael Stier & John E. Mangette (2011)
Synthesis and Characterization of Novel Bi- and Tricyclic α-Amino Acids, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:18, 2769-2793,
DOI: 10.1080/00397911.2010.515354
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Synthetic Communications1, 41: 2769–2793, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515354
SYNTHESIS AND CHARACTERIZATION OF NOVEL
BI- AND TRICYCLIC a-AMINO ACIDS
Matthew R. Johnson,1 Jolicia F. Gauuan,1 Cheng Guo,1
Peter R. Guzzo,1 Van-Duc Le,1 Rajesh A. Shenoy,1
James Hamby,2 Howard Roark,2 Michael Stier,2 and
John E. Mangette1
1Medicinal Chemistry Department, Albany Molecular Research, Inc.
(AMRI), Albany, New York, USA
2Pfizer, Inc., Ann Arbor, Michigan, USA
GRAPHICAL ABSTRACT
Abstract As part of a medicinal chemistry collaboration, a number of novel bi- and tricyclic a-
amino acids were prepared through various routes and characterized by 1H nuclear Overhauser
effect difference experiments. The syntheses provide a number of routes to access some highly
substituted amino acid derivatives that have not been reported previously. It is envisaged that
the chemistry described here could be applied to the synthesis of other unique substrates.
Keywords Bicyclic amino acids; proline analogs; tricyclic amino acids; unnatural amino
acids
INTRODUCTION
In recent years, significant attention has been focused on the preparation of
unnatural (synthetic) amino acids, particularly as components of systems with thera-
peutic potential.[1] Of the natural amino acids available, proline stands out as unique,
because of its cyclic nature. This amino acid, when incorporated into a peptide or
protein, confers additional stability to enzymatic degradation as well as plays a
key role in determining the secondary structure.[2] Thus, the preparation of substi-
tuted analogs of proline, and in particular analogs that can provide additional rigid-
ity, is highly desirable. The preparation of simple bicyclic proline analogs, which
have been used as components of biologically active systems, has been described
Received May 6, 2010.
Address correspondence to John E. Mangette, Medicinal Chemistry Department, AMRI, Inc., 26
Corporate Circle, P.O. Box 15098, Albany, NY, 12212-5098, USA. E-mail: John.Mangette@
amriglobal.com
2769

2770
M. R. JOHNSON ET AL.
Figure 1. Novel fused bi- and tricyclic proline analogs.
by a number of groups.[3] However, there are relatively few examples of more com-
plex analogs described, the preparation of which would be highly desirable for
exploiting the potential of these proline analogs in biologically active systems.
Herein we describe some selected examples of variously substituted bi- and
tricyclic proline analogs 1–9 (Fig. 1), all having been prepared as single diastereoi-
somers and their structures determined by 1H NMR nuclear Overhause effect
(nOe) experiments. A variety of established chemistries were utilized in the prep-
aration of these compounds, which have not previously been described in the litera-
ture. As reported here, these synthetic strategies leading to unique structures may be
of interest to others pursuing novel proline analogs.
RESULTS AND DISCUSSION
The first examples to be described utilize a reductive cyclization protocol for
accessing bicyclic proline analogs bearing substituents a to the amine and also to
the carboxylic acid. Thus, in the synthesis of compound 1 (Scheme 1), compound
12[4] was afforded as a mixture of diastereomers. After Boc protection of the amide
nitrogen and alkylation a to the carbonyl with lithium diisopropylamide (LDA) and
benzyl bromide, the ring junction was set in the cis configuration. Reduction of the
Boc-amide to the Boc-amino alcohol was followed by Lewis acid–catalyzed forma-
tion of an acyl iminium species; this intermediate then underwent attack by the
nitrile anion exclusively from the b-face, as attack from the a-face is blocked by
the six-membered ring (Fig. 2). Subsequent acidic hydrolysis afforded amino acid
1, with the relative stereochemistry shown, as determined by nOe experiments.
Utilizing a similar protocol, the gem-dimethyl substituted amino acid 2 was
prepared (Scheme 2). In the preparation of 15, the two diastereomers were separable
by silica-gel chromatography. The major diastereomer 15b was then subjected to a
reductive cyclization to afford 16 (determined to be the trans ring junction, based
on final structural assignment), which was then elaborated as described previously
to afford amino acid 2, again as a single diastereomer. In this case, attack by the
nitrile anion on the b face of the acyl iminium species derived from 17 was not
favored, presumably because of the 1,3-diaxial interaction with the axial methyl

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2771
Scheme 1. Reagents and conditions: (i) MeNO2, TBAF, THF, reflux; (ii) Raney Ni, H2, MeOH; (iii)
NaOMe, MeOH, reflux; (iv) (Boc)2O, DMAP, NEt3, THF; (v) LDA, BnBr; (vi) LiBHEt3, THF,
ꢀ78 ꢁC; (vii) TMSCN, BF3(OEt)2, CH2Cl2; (viii) conc. HCl, reflux. The nOe 1H NMR data for 1:
HBn-H1, 0.5%; H6b-HBn, 5.7%; H6b-H5a, 6.5%; H6b-H6a, 29%.
group and also an interaction with the axial hydrogen, resulting in exclusive attack
from the a-face (Fig. 3).
The next series of proline analogs to be described are again a-substituted deri-
vatives, but in this case the ring-forming reaction is a palladium catalyzed intramol-
ecular cyclization (Scheme 3). The preparation of 20 and 22 had previously been
reported by Buchwald et al.[5] In agreement with previously reported related exam-
ples,[6] catalytic hydrogenation of the aromatic rings of 20 and 22 with rhodium on
carbon led to the exclusive formation of single diastereomers, 3 and 4 respectively,
after t-butyl ester removal. For the current cases, the relative stereochemistry was
1
firmly established by H NMR nOe experiments, indicating that hydrogen delivery
occurred from the face opposite the t-butyl ester.
The preparation of a number of substituted [5,5]-bicyclic proline analogs was
also investigated (Schemes 4 and 5). The method used for the preparation of these
analogs utilized a common intermediate 23, which was described previously in the
preparation of kainic acid.[7] This chemistry fixed the relative stereochemistry of
the pyrrolidine ring in the configuration as shown in Scheme 4. The intermediate
was then elaborated to a number of novel targets, two of which are described. Thus,
Figure 2. Cyanation facial selectivity to prepare compound 1.

2772
M. R. JOHNSON ET AL.
Scheme 2. Reagents and conditions: (i) (CH3)2CHNO2, TBAF, THF, reflux; (ii) Raney Ni, H2, MeOH;
(iii) (Boc)2O, DMAP, NEt3, THF; (iv) LiBHEt3, THF, ꢀ78 ꢁC; (v) TMSCN, BF3(OEt)2, CH2Cl2,
ꢀ78 ꢁC; (vi) conc. HCl, reflux. The nOe 1H NMR data for 2: H1-H7a, 3.6%; H7a-CH3b, 4.8%.
ketone 23 was reduced using sodium borohydride as described previously,[7b–d] giv-
ing a 3:1 mixture of epimers at C6. Formation of the n-butyl ether enabled separ-
ation of the epimers, the major one being carried forward through a series of
deprotections to afford amino acid 5 in the configuration shown as determined by
nOe measurements.
The alcohol product 24 was also elaborated to the fluoro derivative 6
(Scheme 5). Thus, as previously reported,[7b,c] treatment of compound 24 with
(diethylamino)sulfur trifluoride (DAST) resulted in the formation of a mixture of
the desired single fluoro derivative 27 and the corresponding olefin, which appears
to be the product of an elimination reaction involving the minor C6 epimer.
Removal of the olefin by-product using silica-gel chromatography was not success-
ful. However, oxidation of the olefin to the cis diol then enabled purification of 27 by
silica-gel chromatography. Again, standard protecting group manipulations
afforded the amino acid 6 in the configuration shown.
The next class of analogs to be prepared was the tricyclic proline analogs 7 and
8, accessible via Diels–Alder cycloaddition chemistry (Scheme 6 and 7). Thus in the
preparation of 7, reaction of cyclohexadiene with maleimide gave imide 31, which
Figure 3. Cyanation facial selectivity to prepare compound 2.

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2773
Scheme 3. Reagents and conditions: (i) Pd2(dba)3, (20-diphenylphosphanylbiphenyl-2-yl)dimethylamine,
LiOtBu; (ii) 5% Rh=C, H2, EtOH, 60 psi, 60 ꢁC; (iii) 20% aqueous HCl, reflux. The nOe 1H NMR data
for 3: H3a-H7a, 4.5%; H3a-CH3, 5.4%; H7a-CH3, 3.5%; H3b-H3a, 2.7%; H3b-CH3, 1.2%. The nOe 1H
NMR data for 4: H7a-H9b, 1.4%; H3a-H7a, 2.8%; H3b-H3a, 2.6%; H3a-H3a, 1.3%, H3a-H11a, 1.3%.
was then successively reduced, first with lithium aluminum hydride and then by
hydrogenation, to afford the tricyclic amine 32. The introduction of a carboxylic acid
moiety a to the amine was achieved by oxidation of 32 to a nitrone,[8] followed by
cyanide addition to give 33. Hydrolysis of the nitrile gave 34 and reduction of the
hydroxylamine of 34 afforded the amino acid 35. For convenient purification pur-
poses, the amino acid 35 was Boc protected to facilitate chromatography and then
the Boc group was subsequently removed. Compound 35 was then subjected to a
reductive amination protocol to provide 7. In this particular example, the final struc-
tural assignment based on nOe experiments determined that the nitrile attack
occurred from the b-face (Figure 4). However, NMR data of intermediates did
Scheme 4. Reagents and conditions: (i) NaBH4, THF, H2O; (ii) NaH, n-BuI, DMF; (iii) LiOH, THF,
H2O; (iv) H2, Pd=C, EtOH, H2O. The nOe 1H NMR data for 5: H1a-H3a, 2.5%; H3b-H3a, 2.6%;
H
1a-H6a, 4.0%; H6a-H1a, 0.9%; H6b-H6a, 3.0%; H6b-H4, 3.2%; H4-H3a, 4.5%.

2774
M. R. JOHNSON ET AL.
Scheme 5. Reagents and conditions: (i) DAST; (ii) K2OsO4, NMO, acetone, water; (iii) LiOH, THF, H2O;
(iv) H2, Pd=C, EtOH, H2O. The nOe 1H NMR data for 6: H1a-H3a, 1.9%, H3a-H4, 2.8%.
suggest the presence of trace amounts of the other stereoisomer, which were removed
by silica-gel chromatography following N-methylation. Figure 4 demonstrates the
concave nature of the tricyclic ring system and a rationale for b-face attack.
In the preparation of 8, a slightly different route was required (Scheme 7).
Diels–Alder reaction of succinic anhydride and furan gave the cyclic anhydride
38.[9] Hydrogenation followed by treatment with benzylamine afforded the corre-
sponding imide 39, which upon lithium aluminum hydride reduction and hydrogen-
ation afforded amine 40. Further elaboration provided amino acid 8 via the
oxidation and a-cyanation chemistry previously described. In this example, the
stereochemistry of the ring junction was set during the Diels–Alder reaction, which
is known to give the exo product.[9] This then gives a very rigid structure, which
forces the nitrile anion to attack from the lower face, affording the product with
the relative stereochemistry as depicted. Only one diastereomer was observed
throughout the synthetic sequence.
The final example to be described differs from the previous examples in that the
amino acid is a perhydroindole derivative; in this case, a cyclopropyl group was
incorporated at the 2,3-position (Scheme 8). Thus, commencing from commercially
available enantiomerically pure octahydroindole-2-carboxylic acid 44, formation of
the carbamate followed by esterification gave 45. The corresponding enolate was
formed using potassium bis(trimethylsilyl)amide (KHMDS), which was then trapped
with phenyl disulfide to give 46. Subsequent oxidation to the sulfoxide followed by a
Scheme 6. Reagents and conditions: (i) toluene, reflux; (ii) LiAlH4, THF, diethyl ether, reflux; (iii) H2, Pd=
C, MeOH; (iv) Na2WO4, H2O2, MeOH; (v) KCN, HCl, MeOH, H2O; (vi) conc. HCl; (vii) (Boc)2O,
Na2CO3, 1,4-dioxane, H2O; (viii) 4 N HCl, 1,4-dioxane; (ix) formalin, NaBH4, THF, Na2CO3; (x) 2 N
HCl, ether. The nOe 1H NMR data for 7: H1-H3a, 3.5%; H3a-H3b, 17.4%; H3b-H3a, 4.2%.

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2775
Scheme 7. Reagents and conditions: (i) ether; (ii) H2, Pd=C, THF; (iii) benzylamine, toluene, reflux; (iv)
LiAlH4, THF, reflux; (v) H2, Pd=C, MeOH; (vi) Na2WO4, H2O2, MeOH; (vii) TMSCN, CH2Cl2; (viii)
6 N HCl, reflux; (ix) (Boc)2O, Na2CO3, 1,4-dioxane, H2O; (x) 2 N HCl, ether. The nOe 1H NMR data
for 8: H1-H6b, 1.2%; H1-H1a, 1.0%; H1-H2, 3.0%; H2-H1a, 1.3%; H5-H5a, 1.2%; H5-H6b, 2.2%; H5a-H6b
0.4%; H6a-H6b, 12.0%; H6a-H5a, 3.5%.
,
Figure 4. Cyanation facial selectivity to prepare compound 7.
Scheme 8. Reagents and conditions: (i) MeOCOCl, Na2CO3, CH2Cl2; (ii) SOCl2, reflux; (iii) MeOH,
CH2Cl2; (iv) KHMDS, THF, ꢀ78 ꢁC; (v) (PhS)2, ꢀ78 ꢁC to rt; (vi) m-CPBA, CH2Cl2, ꢀ40 ꢁC; (vii) tolu-
ene, reflux; (viii) trimethyl sulfoxonium iodide, NaH, DMSO; (ix) 4 N HCl, reflux; (x) (Boc)2O, 1 N
NaOH, 1,4-dioxane; (xi) HCl, ether, 1,4-dioxane. The nOe 1H NMR data for 9: H2a-H6a, 4.0%; H6a
-
H
10, 1.4%; H2a-H10, 5.9%.

2776
M. R. JOHNSON ET AL.
Figure 5. Cyclopropanation facial selectivity to prepare compound 9.
thermal elimination afforded the a,b-unsaturated ester 47. Cyclopropanation was
then achieved using the sulfur ylide generated from trimethylsulfoxonium iodide.
Subsequent deprotection gave the tricyclic proline analog 9 as a single enantiomer
and in the configuration shown, as determined by nOe experiments. This stereoselec-
tivity can be rationalized from the conformation adopted by the alkene (Fig. 5). In
this case, the cyclohexane ring precludes attack from the b-face of the molecule and
forces the incoming sulfur ylide to attack from the a-face, resulting in the observed
stereoisomer.
CONCLUSION
A number of different strategies for synthesizing bi- and tricyclic proline ana-
logs have been described. The syntheses provide a number of routes to access some
highly substituted amino acid derivatives that have not previously been reported. It
is envisaged that the range of chemistry described could be applied to the synthesis of
other unique substrates.
EXPERIMENTAL
Unless otherwise noted, reagents and solvents were used as received from com-
mercial suppliers. Proton nuclear magnetic resonance spectra were obtained on a Bru-
ker Avance 300 spectrometer at 300 MHz or on a Bruker Avance 500 spectrometer at
500 MHz. Spectra are given in parts per million (d), and coupling constants, J values,
are reported in hertz. Tetramethylsilane (TMS) was used as an internal standard.
Infrared (IR) spectra were obtained on a Nicolet Nexus 470 (ATR) spectrometer.
Mass spectra were obtained on a Perkin-Elmer Sciex 100 atmospheric pressure ioniza-
tion (APCI) mass spectrometer or a Finnigan LCQ Duo liquid Chromatagrapy–mass
spectroscopy (LCMS) ion trap electrospray ionization (ESI) mass spectrometer.
Thin-layer chromatography (TLC) was performed using Analtech silica-gel plates
and visualized by ultraviolet (UV) light or iodine. Elemental analyses were performed
by Quantitative Technologies, Inc. (Whitehouse, NJ).
2-(Nitromethyl)cyclohexanecarboxylic Acid Methyl Ester (11)
A solution of methyl 1-cyclohexene-1-carboxylate 10 (23.0 g, 164 mmol), nitro-
methane (19.9 g, 328 mmol), and tetrabutylammonium fluoride [1.0 N solution in

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2777
tetrahydrofuran (THF), 246 mL, 246 mmol] in THF (200 mL) was heated at 70 ꢁC
for 17 h. The reaction mixture was cooled to room temperature and concentrated.
The residue was diluted with ethyl acetate (800 mL) and washed with 2 N HCl
(200 mL) and brine (2 ꢂ 300 mL). The organic layer was dried over magnesium sul-
fate and concentrated. Purification by flash chromatography (silica, hexanes, then
hexanes=ethyl acetate 20:1 to 9:1) afforded a mixture of isomeric nitro adducts
11a and 11b (1:1.5 ratio) as yellow oils (25.2 g, 76%). The mixture of isomers was
used in the following steps without separation. A portion of pure 11a and 11b were
isolated for characterization purposes. For 11a (Rf 0.46, 9:1 hexanes=ethyl acetate):
1H NMR (300 MHz, CDCl3) d 1.41–1.76 (m, 6H), 1.92–1.98 (m, 2H), 2.58 (m, 1H),
2.75 (dd, J ¼ 9.9, 4.6 Hz, 1H), 3.69 (s, 3H), 4.48 (dd, J ¼ 11.5, 7.9 Hz, 1H), 4.57 (dd,
J ¼ 12.5, 6.6 Hz, 1H). For 11b (Rf 0.37, 9:1 hexanes=ethyl acetate) 1H NMR
(300 MHz, CDCl3) d 1.11–1.57 (m, 4H), 1.77–1.88 (m, 3H), 2.23 (td, J ¼ 11.5,
3.7 Hz, 1H), 2.41 (m, 1H), 3.70 (s, 3H), 4.26 (dd, J ¼ 11.9, 7.6 Hz, 1H), 4.42 (dd,
J ¼ 11.9, 4.3 Hz, 1H); MS (APCI) m=z 202 [M þ H]þ.
Octahydroisoindol-1-one (12)
A mixture of 11a and 11b (25.0 g, 124 mmol) and Raney nickel (6.0 mL) in
methanol (550 mL) was hydrogenated (40 psi) at room temperature for 25.5 h, and
then the reaction mixture was filtered through diatomaceous earth. Sodium methox-
ide (25 wt% in MeOH, 60 mL) was added to the filtrate and the solution was heated
at reflux for 44 h. The reaction mixture was cooled to room temperature and then
concentrated. The residue was diluted with methylene chloride (300 mL) and neutra-
lized with 2 N HCl. The aqueous layer was extracted with methylene chloride
(3 ꢂ 100 mL). The combined organic layers were washed with brine, dried over
sodium sulfate, filtered, and concentrated. Purification by flash chromatography (sil-
ica, methylene chloride, then 2 to 5% methanol=methylene chloride) provided lactam
1
12 (15.0 g, 86%) as an off-white solid: H NMR (300 MHz, CDCl3) d 1.20–1.38 (m,
3H), 1.46–1.59 (m, 3H), 1.71 (m, 1H), 2.00 (m, 1H), 2.42 (m, 2H), 2.94 (dd, J ¼ 9.4,
1.6 Hz, 1H), 3.37 (dd, J ¼ 9.5, 5.7 Hz, 1H), 6.49 (br s, 1H); MS (APCI) m=z 140
[M þ H]þ, 279 [2M þ H]þ.
7a-Benzyl-1-hydroxyoctahydroisoindole-2-carboxylic Acid tert-Butyl
Ester (13)
Step 1. A solution of lactam 12 (15.0 g, 108 mmol), Boc2O (35.3 g, 162 mmol),
Et3N (21.9 g, 216 mmol), and dimethylaminopyridine (DMAP) (2.60 g, 21.6 mmol) in
THF (600 mL) was stirred at room temperature for 15.5 h, and then the reaction mix-
ture was concentrated. The residue was diluted with methylene chloride (500 mL),
washed with 0.05 N HCl and brine, dried over sodium sulfate, filtered, and concen-
trated. Purification by flash chromatography (silica, methylene chloride, then 1–2%
methanol=methylene chloride) provided the Boc-protected lactam as a yellow oil
1
(21.0 g, 81%), which solidified on standing: H NMR (300 MHz, CDCl3) d 1.18–
1.32 (m, 3H), 1.54 (s, 9H), 1.46–1.67 (m, 3H), 1.74 (m, 1H), 2.10 (m, 1H), 2.28
(m, 1H), 2.59 (m, 2H), 3.42 (dd, J ¼ 10.7, 1.9 Hz, 1H), 3.62 (dd, J ¼ 10.7, 6.0 Hz,
1H); MS (APCI) m=z 184 [M – CH2 ¼ C(CH3)2 þ H]þ, 140 [M – Boc þ H]þ.

2778
M. R. JOHNSON ET AL.
Step 2. To a stirred solution of lithium diisopropylamide (1.8 N solution in
heptane=THF=ethylbenzene, 37.2 mL, 66.9 mmol) and THF (300 mL) at ꢀ78 ꢁC was
added dropwise a solution of the Boc protected lactam (8.0 g, 34 mmol) in THF
(100 mL). After stirring the mixture for 1 h at ꢀ78 ꢁC, benzyl bromide (15.9 mL,
134 mmol) was added dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for
3.5 h, and water (10 mL) was added. The organic solvent was evaporated under vac-
uum, and the aqueous layer was extracted with methylene chloride (3 ꢂ 150 mL).
The combined organic layers were washed with 0.05 N HCl and brine, dried over
sodium sulfate, filtered, and concentrated. Purification by flash chromatography (sil-
ica, methylene chloride, then 1–2% methanol=methylene chloride) provided the alky-
1
lated compound (6.80 g, 62%) as a greenish yellow viscous oil: H NMR (300 MHz,
CDCl3) d 1.26–1.60 (m, 6H), 1.52 (s, 9H), 1.65–1.81 (m, 2H), 1.99–2.05 (m, 1H),
2.76 (d, J ¼ 13.7 Hz, 1H), 3.07 (d, J ¼ 13.6 Hz, 1H), 3.32 (dd, J ¼ 10.7, 7.1 Hz, 1H),
3.42 (dd, J ¼ 10.7, 7.4 Hz, 1H), 7.17–7.30 (m, 5H); MS (ESI) m=z 681 [2M þ Na]þ.
Step 3. Lithium triethylborohydride (1 N in THF, 23.7 mL, 23.7 mmol) was
added dropwise to a stirred solution of the benzyl alkylated compound (6.80 g,
20.6 mmol) in THF (125 mL) at ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ
78 ꢁC for 2 h, quenched with saturated aqueous sodium bicarbonate (60 mL), and
then warmed to 0 ꢁC. Hydrogen peroxide (35%, 6 mL) was added, and the mixture
was stirred at 0 ꢁC for 30 min. The organic solvent was evaporated under vacuum,
and the aqueous layer was extracted with methylene chloride (3 ꢂ 120 mL). The com-
bined organic layers were dried over sodium sulfate, filtered, and concentrated to
provide alcohol 13 (6.60 g, 96%, mixture of rotamers) as a pale yellow syrup. Com-
pound 13 was used in the next step without further purification: 1H NMR (300 MHz,
CDCl3) d 1.07, 1.09 (two s, 3H), 1.47 & 1.49 (two s, 9H), 1.25–1.64 (m, 8H),
1.76–1.85 (m, 1H), 3.25–3.45 (m, 1H), 4.22 & 4.96 (two d, J ¼ 1.6 Hz, 1H); MS
(ESI) m=z 238 [M – Boc – H2O þ Na]þ.
7a-Benzyl-1-cyano-octahydro-isoindole-2-carboxylic Acid tert-Butyl
Ester (14)
Boron trifluoride diethyl etherate (5.8 mL, 46 mmol) was added dropwise to a
stirred solution of 13 (6.60 g, 25.8 mmol) and trimethylsilyl cyanide (4.10 g, 41.3 mmol)
in methylene chloride (300 mL) at ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ78 ꢁC
for 4 h, then quenched with saturated aqueous sodium bicarbonate (30 mL), and
extracted with methylene chloride (3 ꢂ 100 mL). The combined organic layers were
dried over sodium sulfate, filtered, and concentrated. Purification by flash chromato-
graphy (silica, methylene chloride, then 1% methanol=methylene chloride) afforded 14
(3.92 g, 47%, mixture of rotamers) as a pale yellow foamy solid: 1H NMR (300 MHz,
CDCl3) d 1.13–1.73 (m, 8H), 1.47 & 1.49 (two s, 9H), 2.33–2.41 (m, 1H), 2.95 & 2.98
(two d, J ¼ 14.4 Hz, 1H), 3.14 & 3.16 (two d, J ¼ 14.4 Hz, 1H), 3.34–3.62 (m, 2H), 3.99
& 4.18 (two s, 1H), 7.23–7.37 (m, 5H); MS (ESI) m=z 341 [M þ H]þ.
7a-Benzyl-octahydro-isoindole-1-carboxylic Acid (1)
Cyano compound 14 (3.90 g, 11.4 mmol) was dissolved in concentrated HCl
(220 mL) and heated at reflux for 16.5 h. The reaction mixture was cooled to room

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2779
temperature, washed with diethyl ether (3 ꢂ 50 mL), and concentrated. Purification
by flash chromatography (silica, methylene chloride=methanol=concentrated
ammonium hydroxide 14:4:1 to 6:3:1) provided 1 (2.36 g, 70%) as off-white needles
1
after recrystallization from water: H NMR (300 MHz, D2O) d 0.87 (q, J ¼ 11.8 Hz,
1H), 1.17 (q, J ¼ 12.4 Hz, 1H), 1.41 (q, J ¼ 12.3 Hz, 1H), 1.55–1.67 (m, 4H), 2.00 (d,
J ¼ 14.2 Hz, 1H), 2.20 (quintet, J ¼ 5.9 Hz, 1H), 2.45 (d, J ¼ 13.6 Hz, 1H), 2.76 (d,
J ¼ 13.6 Hz, 1H), 3.12 (d, J ¼ 12.1 Hz, 1H), 3.88 (dd, J ¼ 12.1, 5.8 Hz, 1H), 4.46
(s, 1H), 7.24–7.42 (m, 5H); 13C NMR (75 MHz, D2O) d 22.1, 25.7, 29.1, 29.4,
40.5, 40.9, 51.1, 64.3, 128.5, 129.8, 132.4, 137.2, 170.5; MS (ESI) m=z 260 [M þ H]þ,
, 282 [M þ Na]þ, 519 [2M þ H]þ. Anal. calcd. for C16H21NO2 ꢃ 0.1 NH3 ꢃ 0.75 H2O:
C, 69.99; H, 8.37; N, 5.61. Found: C, 69.67; H, 8.34; N, 5.46.
2-(1-Methyl-1-nitroethyl)cyclohexanecarboxylic Acid Methyl Eester
(15a/15b)
A
stirred mixture of methyl-1-cyclohexene-1-carboxylate (10, 24.8 g,
176.9 mmol), 2-nitropropane (31.7 g, 357 mmol), and 1 N TBAF in THF (265 mL,
265 mmol) was heated at 80 ꢁC under nitrogen for 4 d. The reaction mixture was
cooled to room temperature and then diluted with ethyl acetate (200 mL). The mixture
was washed with 2 N HCl (100 mL) and brine (200 mL), dried over sodium sulfate, fil-
tered, and concentrated. Purification by flash chromatography (silica, 14:1 hexanes=
diethyl ether) provided the nitro adducts 15a (2.56 g, 6%, other mixed fractions con-
1
taining 15a were not purified) and 15b (15.14 g, 37%) as oils. For 15a: H NMR
(300 MHz, CD3OD) d 1.24–1.40 (m, 3H), 1.48 (s, 3H), 1.55 (s, 3H), 1.61–1.76 (m,
2H), 1.86–2.03 (m, 3H), 2.24–2.31 (m, 1H), 2.76–2.84 (m, 1H), 3.66 (s, 3H); IR
(ATR) 2942, 1735, 1540, 1349, 1257, 632 cmꢀ1. For 15b: 1H NMR (300 MHz,
CD3OD) d 1.02–1.43 (m, 4H), 1.51 (d, 3H), 1.52 (s, 3H), 1.54–1.65 (m, 1H),
1.74–1.83 (m, 2H), 1.89–1.95 (m, 1H), 2.31 (dt, J ¼ 3.6, 11.4 Hz, 1H), 2.51 (dt,
J ¼ 3.4, 11.7 Hz, 1H), 3.65 (s, 3H); IR (ATR) 2942, 1735, 1540, 1349, 1257, 632 cmꢀ1
.
1,1-Dimethyl-3-oxo-octahydro-isoindole-2-carboxylic Acid tert-Butyl
Ester (16)
Step 1. A solution of nitro adduct 15b (15.1 g, 66.0 mmol) in MeOH (420 mL)
was hydrogenated (60 psi) over Raney nickel (4 mL) for 4 d at room temperature.
The reaction mixture was filtered through a pad of diatomaceous earth to remove
the catalyst, and the filtrate was evaporated under reduced pressure. The lactam
(9.94 g, 90%) was obtained as a white solid after trituration with hexanes=diethyl
1
ether: mp 182–186 ꢁC; H NMR (300 MHz, DMSO-d6) d 1.10 (s, 3H), 1.14 (s, 3H),
1.11–1.21 (m, 1H), 1.33–1.41 (m, 1H), 1.67–1.75 (m, 3H), 1.83–1.93 (m, 2H), 7.52 (br
s, 1H); IR (ATR) 2938, 2917, 2851, 2568, 1602, 1526, 1379, 1284, 895, 764, 704 cmꢀ1
;
MS (ESI) m=z 168 [M þ H]þ, 335 [2M þ H]þ.
Step 2. To a stirred solution of the lactam (892 mg, 5.33 mmol), triethylamine
(0.65 g mL, 6.5 mmol) and dimethylaminopyridine (0.66 g, 5.4 mmol) in methylene
chloride (25 mL) was added di-tert-butyl dicarbonate (3.66 g, 16.8 mmol) under
nitrogen. The reaction mixture was stirred overnight and then diluted with ethyl
acetate (75 mL). The organic layer was washed with 0.25 N HCl (46 mL, 12 mmol),

2780
M. R. JOHNSON ET AL.
water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concen-
trated. Purification by flash chromatography (silica, 3:1 hexanes=diethyl ether) pro-
1
vided compound 16 (1.24 g, 87%) as a white solid: H NMR (300 MHz, CDCl3) d
1.17–1.24 (m, 3H), 1.27 (s, 3H), 1.27–1.61 (m, 2H), 1.45 (s, 3H), 1.53 (s, 9H),
1.75–1.80 (m, 1H), 1.86–2.02 (m, 3H), 2.15–2.19 (m, 1H); IR (ATR) 2986, 2930,
2857, 1774, 1687, 1307, 1295, 1157, 1126, 943, 770 cmꢀ1; MS (ESI) m=z 557
[2M þ Na]þ.
3-Hydroxy-1,1-dimethyloctahydro-isoindole-2-carboxylic Acid tert-
Butyl Ester (17)
Lithium triethylborohydride (1.0 M solution in THF, 4.6 mL, 4.6 mmol) was
added to a stirred solution of lactam 16 (1.0 g, 3.8 mmol) in THF (95 mL) at
ꢀ78 ꢁC under nitrogen. After 2 h, saturated aqueous sodium bicarbonate (10 mL)
was added, and the reaction mixture was warmed to 0 ꢁC. Hydrogen peroxide
(35% aq., 40 drops) was added and the reaction was stirred for an additional
30 min. The THF was evaporated and the residue was dissolved in methylene chlor-
ide (30 mL). Additional saturated aqueous sodium bicarbonate (20 mL) was added
to facilitate extraction of the aqueous solution with methylene chloride (2 ꢂ 25 mL).
The combined organic extracts were washed with brine (30 mL), dried over sodium
sulfate, filtered, and concentrated to afford alcohol 17 (1.02 g, 98% crude) as a solid
1
that was used in the next step without further purification: H NMR (300 MHz,
CDCl3) d 1.07–1.26 (m, 3H), 1.14 (s, 3H), 1.32 (s, 3H), 1.50 (s, 9H), 1.52–1.58 (m,
1H), 1.64–1.69 (m, 1H), 1.78–1.86 (m, 3H), 2.08–2.13 (m, 2H), 4.85 (d,
J ¼ 1.7, 1H), 4.94 (dd, J ¼ 7.5, 1.7 Hz, 1H); IR (ATR) 3464, 2973, 2926, 2855,
1650, 1405, 1361, 1328, 1122, 882, 764 cmꢀ1; MS (ESI) m=z 561 [2M þ Na]þ.
3-Cyano-1,1-dimethyloctahydro-isoindole-2-carboxylic Acid tert-
Butyl Ester (18)
Trimethylsilyl cyanide (0.59 g, 6.0 mmol) was added to a stirred solution of
alcohol 17 (1.01 g, 3.75 mmol) in methylene chloride (42 mL) at ꢀ78 ꢁC followed
by boron trifluoride diethyl etherate (0.80 mL, 6.3 mmol). After 4 h, the reaction mix-
ture was quenched with saturated aqueous sodium bicarbonate (10 mL). The layers
were separated, and the organic layer was washed with brine, dried over sodium sul-
fate, filtered, and concentrated. Purification by flash chromatography (silica, 1.25%
methanol=methylene chloride) provided a mixture of rotamers (observed by 1H
NMR spectroscopy) of nitrile 18 (602 mg, 57%) as a white solid: 1H NMR
(300 MHz, CDCl3) d1.10 (s, 3H), 1.15 (s, 3H), 1.18–1.46 (m, 3H), 1.42 (s, 2H),
1.49, 1.51 (2 s, 9H), 1.53–1.97 (m, 6H), 4.48 (d, J ¼ 7.2 Hz, 0.6 H), 4.58 (d, J ¼ 6.9 Hz,
0.4 H); IR (ATR) 2974, 2930, 2860, 1686, 1380, 1354, 1174, 1122 cmꢀ1; MS (ESI)
m=z 279 [M þ H]þ, 579 [2M þ Na]þ.
3,3-Dimethyloctahydroisoindole-1-carboxylic Acid Hydrochloride (2)
A solution of nitrile 18 (0.60 g, 2.1 mmol) in concentrated HCl (30 mL) was
heated at reflux overnight. The reaction mixture was cooled to room temperature

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2781
and then extracted with diethyl ether (2 ꢂ 50 mL). The aqueous layer was separated
and evaporated under reduced pressure. Purification by flash chromatography (sil-
ica, 40:33.3:20:6.7 ethyl acetate=chloroform=methanol=concentrated ammonium
hydroxide) provided the zwitterionic form of the amino acid that was then stirred
in 2 N HCl in diethyl ether (30 mL) overnight. The solids were collected by filtration
and dried under vacuum at 60 ꢁC to provide 2 (408 mg, 81%) as a white solid: mp
220–224 ꢁC; 1H NMR (300 MHz, CD3OD) d 1.10–1.28 (m, 4H), 1.30 (s, 3H),
1.48–1.60 (m, 1H), 1.57 (s, 3H), 1.78–1.88 (m, 3H), 2.08–2.12 (m, 1H), 2.24–3.32
(m, 1H), 4.33 (d, J ¼ 8.91 Hz, 1H); IR (ATR) 2930, 2859, 2742, 2494, 1724, 1547,
1377, 1202, 883, 829, 779 cmꢀ1 13C NMR (75 MHz, CD3OD) d 22.2, 26.0, 26.3,
;
26.4, 26.6, 29.1, 45.4, 52.1, 62.5, 69.3, 170.9; MS (ESI) m=z 198 [M þ H]þ. Anal.
calcd. for C11H19NO2 ꢃ HCl: C, 56.52; H, 8.62; N, 5.99; Cl, 15.17. Found: C,
56.09; H, 8.45; N, 5.72; Cl, 14.89.
1-Methyloctahydroisoindole-1-carboxylic Acid Hydrochloride (3)
Step 1. Methanol (50 mL) was added to a Parr bottle containing 5% Rh=C
(0.45 g) under an atmosphere of nitrogen. The mixture was shaken with hydrogen
(40 psi) for 20 min to prereduce the catalyst. A solution of compound 20[5] (1.30 g,
3.05 mmol) in methanol (100 mL) was then added to the prereduced catalyst and
the reaction mixture was shaken at 60 ꢁC for 24 h under hydrogen (60 psi). The mix-
ture was filtered through a pad of diatomaceous earth and concentrated. Purification
by flash chromatography (silica, 9:1 hexanes=ethyl acetate) afforded the aliphatic
tert-butyl ester (0.4 g, 56%) as a colorless oil: 1H NMR (300 MHz, CD3OD) d
1.09–1.26 (m, 4H), 1.34 (s, 3H), 1.47 (s, 9H), 1.51–1.68 (m, 4H), 1.84–1.91 (m,
1H), 2.62–2.64 (m, 1H), 2.87 (dd, J ¼ 10.2, 8.4 Hz, 1H), 3.05 (t, J ¼ 10.7 Hz, 1H);
13C NMR (75 MHz, CD3OD) d 21.8, 24.7, 25.7, 26.4, 28.3, 37.7, 47.7, 48.4, 71.5,
82.8, 175.1; MS (ESI) m=z 240 [M þ H]þ.
Step 2. A mixture of the aliphatic tert-butyl ester (1.65 g, 6.89 mmol) and 20%
aqueous HCl (60 mL) was heated at reflux for 4 h. The reaction mixture was allowed
to cool to room temperature, and the solvent was removed under vacuum. The white
solid obtained was stirred in diethyl ether (20 mL) for 3 h and then filtered to afford 3
(1.3 g, 87%) as a white solid: mp 237–240 ꢁC; 1H NMR (300 MHz, CD3OD) d
1.23–1.31 (m, 3H), 1.54–1.60 (m, 1H), 1.68–1.74 (m, 7H), 2.21 (ddd, J ¼ 17.4, 11.6,
5.6 Hz, 1H), 2.93–2.94 (m, 1H), 3.31–3.32 (m, 1H), 3.45 (dd, J ¼ 11.8, 9.3 Hz, 1H);
13C NMR (75 MHz, CD3OD) d 21.0, 22.3, 24.2, 24.8, 24.9, 36.2, 46.7, 46.8, 74.6,
172.7; MS (APCI) m=z 184 [M þ H]þ. Anal. calcd. for C10H17NO2 ꢃ HCl ꢃ 0.1 H2O:
C, 54.22; H, 8.28; N, 6.32; Cl, 16.00. Found: C, 53.87; H, 8.27; N, 6.30; Cl, 16.08.
Octahydropyrrolo[2,1-a]isoindole-9b-carboxylic Acid
Hydrochloride (4)
Step 1. Ethanol (50 mL) was added to a Parr bottle containing 5% Rh=C (0.4 g)
under an atmosphere of nitrogen. The mixture was shaken with hydrogen (40 psi) for
20 min to prereduce the catalyst. A solution of compound 22[5] (2.00 g, 7.72 mmol) in
ethanol (130 mL) was added to the prereduced catalyst, and the reaction mixture was
shaken at 60 ꢁC for 3 days under hydrogen (60 psi). The mixture was filtered through

2782
M. R. JOHNSON ET AL.
a pad of diatomaceous earth and concentrated. Purification by flash chromato-
graphy (silica, 1:1 hexanes=ethyl acetate) afforded the aliphatic tert-butyl ester
1
(0.6 g, 30%) as a colorless oil: H NMR (300 MHz, CD3OD) d 1.20–1.46 (m, 4H),
1.50 (s, 9H), 1.63–1.75 (m, 5H), 1.99–2.04 (m, 2H), 2.27–2.29 (m, 1H), 2.36–2.38
(m, 1H), 2.68–2.70 (m, 1H), 2.88 (dd, J ¼ 11.7, 8.0 Hz, 1H), 3.06–3.12 (m, 1H),
3.45–3.58 (m, 2H); MS (ESI) m=z 266 [M þ H]þ;
Step 2. A mixture of the aliphatic tert-butyl ester (0.6 g, 2.26 mmol) and 20%
aqueous HCl (20 mL) was heated at reflux for 2 h. The reaction mixture was allowed
to cool to room temperature and concentrated to dryness. The resulting white solid
was stirred in diethyl ether (20 mL) and acetonitrile (2 mL) for 3 h, and the product 4
was collected by filtration and dried (0.4 g, 72%): mp 250–255 ꢁC; 1H NMR
(300 MHz, CD3OD) d 1.24–1.34 (m, 3H), 1.54–1.55 (m, 1H), 1.69–1.78 (m, 4H),
1.93–1.94 (m, 1H), 2.15–2.26 (m, 2H), 2.44–2.45 (m, 1H), 2.61–2.66 (m, 1H),
2.90–2.91 (m, 1H), 3.22 (dd, J ¼ 18.6, 11.0 Hz, 1H), 3.34–3.36 (m, 1H), 3.70
(t, J ¼ 12.1 Hz, 1H), 3.76–3.77 (m, 1H); 13C NMR (75 MHz, CD3OD) d 21.1, 24.3,
24.5, 25.0, 25.3, 36.5, 36.8, 46.1, 57.3, 58.7, 87.9, 172.4; MS (ESI) m=z 210 [M þ H]þ.
. Anal. calcd. for C12H19NO2 ꢃ 1.05 HCl ꢃ 0.3 H2O: C, 56.97; H, 8.23; N, 5.54; Cl,
14.72. Found: C, 57.12; H, 8.12; N, 5.50; Cl, 14.52.
Ethyl N-(Benzyloxycarbonyl)-3-aza-6-hydroxybicyclo[3.3.0]octane-2-
carboxylate (24)
Sodium borohydride (689 mg, 18.2 mmol) was added to a solution of 23 (8.70 g,
26.3 mmol) in THF (157 mL) and water (7 mL) at 0 ꢁC portion wise such that the
reaction temperature was maintained at 5–10 ꢁC. After stirring at 0–5 ꢁC for 2 h,
TLC analysis indicated that the starting material was consumed. Saturated aqueous
ammonium chloride (100 mL) was added over 30 min at a rate such that the tempera-
ture was maintained at 5–10 ꢁC. After an additional 30 min, the layers were sepa-
rated, and the aqueous layer was extracted with ethyl acetate (2 ꢂ 100 mL). The
organic layers were combined, dried over sodium sulfate, filtered, and concentrated
under vacuum. Purification by flash chromatography (silica, 1:1 hexanes=ethyl acet-
1
ate) afforded 24 (3:1 ratio of C6 epimers, 7.6 g, 87%) as a colorless oil: H NMR
(300 MHz, CDCl3) d 1.10–1.30 (m, 3H), 1.52–2.03 (m, 3.75H), 2.21–2.31 (m,
0.25H), 2.59–2.81 (m, 2.75H), 2.84–2.90 (m, 0.25H), 3.32–3.43 (m, 0.25H), 3.56–
3.65 (m, 0.75H), 3.74–3.82 (m, 0.25H), 3.86–3.95 (m, 0.75H), 3.97–4.29 (m, 4H),
5.11, 5.16 (s and AB q, J ¼ 12.4 Hz, 2H), 7.28–7.37 (m, 5H).
Ethyl N-(Benzyloxycarbonyl)-3-aza-6-n-butoxybicyclo[3.3.0]octane-
2-carboxylate (25)
Sodium hydride (60% in mineral oil, 485 mg, 12.1 mmol) was added in small
portions to a stirred solution of 24 (4.10 g, 12.3 mmol) and 1-iodobutane (22.2 g,
120 mmol) in DMF (75 mL) cooled to 0 ꢁC over 15 min. After stirring for 1.5 h,
0.5 N KHSO4 (15 mL) was added portionwise, and the mixture was stirred for
5 min. The solvent was removed under vacuum and the residue was partitioned
between diethyl ether and water. The aqueous layer was extracted with diethyl ether
(3 ꢂ 100 mL), and the combined organic extracts were dried over sodium sulfate,

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2783
filtered, and concentrated under vacuum. Purification by flash chromatography (sil-
ica, 85:15 hexanes=ethyl acetate) afforded the desired product as two separate C6
epimers, 25a (0.92 g, 19%) as a colorless oil and 25b (0.25 g, 5%) as a colorless oil.
1
For 25a, H NMR (300 MHz, CDCl3) d 0.85–0.91 (m, 3H), 1.12–1.37 (m, 5H),
1.46–1.55 (m, 2H), 1.59–1.98 (m, 4H), 2.68–2.72 (m, 1H), 2.74–2.86 (m, 1H), 3.27–
3.43 (m, 2H), 3.58 (td, J ¼ 14.2, 9.2 Hz, 1H), 3.74–3.88 (m, 2H), 4.00–4.22 (2 m,
3H), 5.11 and 5.15 (s, AB q, J ¼ 12.4 Hz, 2H), 7.26–7.61 (m, 5H); MS (ESI) m=z
390 [M þ H]þ. For 25b, 1H NMR (300 MHz, CDCl3) d0.90 (t, J ¼ 7.2 Hz, 3H),
1.15–1.26 (m, 3H), 1.34 (sextet, J ¼ 7.4 Hz, 2H), 1.47–1.61 (m, 3H), 1.64–1.75 (m,
1H), 1.86–1.98 (m, 1H), 2.11–2.20 (m, 1H), 2.68–2.77 (m, 1H), 2.76–2.84 (m, 1H),
3.32–3.44 (m, 3H), 3.64–3.71 (m, 1H), 3.81 (td, J ¼ 10.1, 1.9 Hz, 1H), 4.01–4.23
(m, 3H), 5.10 and 5.14 (s, AB q, J ¼ 12.5 Hz, 2H), 7.28–7.37 (m, 5H); MS (ESI)
m=z 390 [M þ H]þ.
N-(Benzyloxycarbonyl)-3-aza-6-n-butoxybicyclo[3.3.0]octane-2-
carboxylic Acid (26)
A solution of 25a (2.11 g, 5.40 mmol) and lithium hydroxide monohydrate
(0.52 g, 12.5 mmol) in THF (35 mL) and water (17 mL) was stirred at room tempera-
ture. After 18 h, TLC analysis indicated that the starting material was consumed.
Diethyl ether (20 mL) was added, and the layers were separated. The aqueous layer
was extracted with diethyl ether (2 ꢂ 10 mL) and acidified to pH 4 with 1 N HCl. The
product was extracted into diethyl ether (3 ꢂ 20 mL). The combined organic extracts
were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated
1
under vacuum to afford 26 (1.85 g, 94%) as a colorless oil: H NMR (300 MHz,
CDCl3) d 0.88 (t, J ¼ 7.2 Hz, 3H), 1.22–1.37 (m, 2H), 1.39–1.50 (m, 2H), 1.55–1.72
(m, 1H), 1.74–1.88 (m, 2H), 1.93–2.02 (m, 1H), 2.70–2.99 (m, 2H), 3.22–3.65 (m,
3H), 3.69–4.16 (m, 2H), 4.20–4.24 (m, 1H), 5.01–5.18 (m, 2H), 7.31–7.61 (m, 5H);
MS (ESI) m=z 362 [M þ H]þ.
3-Aza-6-n-butoxybicyclo[3.3.0]octane-2-carboxylic Acid (5)
Palladium on carbon (10%, wet, 0.6 g) was added to a solution of 26 (1.85 g,
5.1 mmol) in ethanol (150 mL) and water (14 mL). The suspension was hydrogenated
at 35 psi for 1.5 h, at which time TLC analysis indicated that the starting material
was consumed. The mixture was filtered through diatomaceous earth, and the filter
cake was rinsed with ethanol (3 ꢂ 20 mL). The filtrate was concentrated under vac-
uum, and the residue obtained was redissolved in water and filtered through diato-
maceous earth. The filtrate was concentrated under vacuum to afford 5 (0.99 g, 85%)
as a white solid: mp 180–184 ꢁC (dec); 1H NMR (300 MHz, D2O) d 0.77 (t,
J ¼ 7.3 Hz, 3H), 1.16–1.35 (m, 2H), 1.36–1.55 (m, 2H), 1.56–1.90 (m, 4H), 2.76
(qd, J ¼ 8.2, 2.6 Hz, 1H), 2.96 (tt, J ¼ 8.7, 7.3 Hz, 1H), 3.21 (dd, J ¼ 12.1, 7.2 Hz,
1H), 3.26–3.46 (m, 3H), 3.63 (d, J ¼ 7.0 Hz, 1H), 3.91 (dt, J ¼ 7.1, 5.6 Hz, 1H); 13C
NMR (75 MHz, D2O) d 13.4, 19.1, 27.5, 29.3, 31.4, 44.0, 45.3, 45.7, 68.3, 70.0,
81.0, 174.3; MS (ESI) m=z 228 [M þ H]þ. Anal. calcd. for C12H21NO3: C, 63.41;
H, 9.31; N, 6.16. Found: C, 63.21; H, 9.36; N, 6.08.

2784
M. R. JOHNSON ET AL.
Ethyl N-(Benzyloxycarbonyl)-3-aza-6-fluorobicyclo[3.3.0]octane-2-
carboxylate (27)
A solution of 24 (5.90 g, 17.7 mmol) in methylene chloride (100 mL) was added
dropwise to a stirred solution of (diethylamino)sulfur trifluoride (3.01 g, 18.7 mmol)
in methylene chloride (400 mL) at ꢀ5 ꢁC over 30 min. After stirring for 30 min at
0 ꢁC, the solution was transferred to a separatory funnel and washed with water
(75 mL), saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The
organic layer was dried over sodium sulfate, filtered and concentrated under vac-
uum. Purification by flash chromatography (silica, 85:15 hexanes=ethyl acetate)
afforded a 3:2 mixture of the desired fluoro derivative and the corresponding alkene,
an elimination by-product (4.47 g), as a yellow oil. The alkene byproduct was
removed by a dihydroxylation reaction and subsequent chromatography. Thus, N-
methyl morpholine-N-oxide (0.87 g, 7.4 mmol) and potassium osmate (0.008 g,
0.02 mmol) were added to a solution of the mixture of alkene and fluoro derivative
(4.47 g) in acetone (85 mL) and water (15 mL) at 0 ꢁC. The mixture was allowed to
warm to room temperature and stirred overnight. The solution was then cooled to
0 ꢁC, and 3% aqueous sodium bisulfite (50 mL) was added. After warming to room
temperature, ethyl acetate (50 mL) was added, and the layers separated. The aqueous
layer was extracted with ethyl acetate (50 mL), and the combined organic layers were
dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by
flash chromatography (silica, methylene chloride to 93:7 methylene chloride=meth-
1
anol) afforded 27 (2.94 g, 50%) as a yellow oil: H NMR (300 MHz, CDCl3) d
1.17–1.27 (m, 3H), 1.60–2.05 (m, 3H), 2.19–2.32 (m, 1H), 2.83–3.01 (m, 2H), 3.26–
3.38 (m, 1H), 3.82 (t, J ¼ 10.3 Hz, 1H), 4.03–4.26 (m, 3H), 4.78–4.85 and 4.96–5.01
(m, 1H), 5.11 and 5.15 (s, AB q, J ¼ 12.4 Hz, 2H), 7.28–7.35 (m, 5H); MS (ESI)
m=z 336 [M þ H]þ.
N-(Benzyloxycarbonyl)-3-aza-6-fluoro[3.3.0]octane-2-carboxylic
Acid (28)
A solution of 27 (1.90 g, 5.7 mmol) and lithium hydroxide monohydrate (0.56 g,
13.3 mmol) in THF (37 mL) and water (18 mL) was stirred at room temperature.
After 18 h, TLC analysis indicated that the starting material was consumed. Diethyl
ether (20 mL) was added, and the layers were separated. The aqueous layer was
extracted with diethyl ether (2 ꢂ 10 mL) and acidified to pH 4 with 1 N HCl. The pro-
duct was extracted into diethyl ether (3 ꢂ 20 mL). The combined organic extracts were
washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated
1
under vacuum to afford 28 (1.70 g, 98%) as a colorless oil. H NMR (300 MHz,
CDCl3) d 1.65–1.74 (m, 1H), 1.80–2.05 (m, 2H), 2.22–2.35 (m, 1H), 2.84–3.06 (m,
2H), 3.28–3.40 (m, 1H), 3.75–3.84 (m, 1H), 4.28 (d, J ¼ 16.3 Hz, 1H), 4.82–5.05 (m,
1H), 5.12–5.16 (m, 2H), 7.30–7.61 (m, 5H); MS (ESI) m=z 308 [M þ H]þ.
3-Aza-6-fluorobicyclo[3.3.0]octane-2-carboxylic Acid (6)
Palladium on carbon (10%, wet, 0.6 g) was added to a solution of 28 (1.70 g,
5.5 mmol) in ethanol (150 mL) and water (15 mL). The suspension was hydrogenated

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2785
at 35 psi for 1.5 h, at which time TLC analysis indicated that the starting material
was consumed. The mixture was filtered through diatomaceous earth, the filter cake
was then rinsed with ethanol (3 ꢂ 20 mL), and the filtrate was concentrated under
vacuum. The residue obtained was redissolved in water and filtered through diato-
maceous earth, and the filtrate was concentrated under vacuum. Recrystallization
of the crude product from 2-propanol and water afforded 6 (0.56 g, 58%) as a white
1
solid: mp 197–225 ꢁC (dec); H NMR (300 MHz, D2O) d 1.73–2.14 (m, 4H), 2.77–
2.91 (m, 1H), 2.93–3.10 (m, 2H), 3.56–3.67 (m, 2H), 4.94 (dd, J ¼ 7.8, 2.9 Hz, 1H);
13C NMR (75 MHz, D2O) d28.4, 30.6 (d, J ¼ 21 Hz), 45.9, 47.0, 47.2, 49.0, 49.3,
99.4 (d, J ¼ 171 Hz), 174.0; 19F NMR (282 MHz, D2O) d –173.2; MS (ESI) m=z
174 [M þ H]þ. Anal. calcd. for C8H12FNO2 ꢃ 0.4H2O: C, 53.27; H, 7.15; N, 7.76;
F, 10.53. Found: C, 53.49; H, 6.99; N, 7.61; F, 10.21.
4-Aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione (31)
1,3-cyclohexadiene 29 (15.0 mL, 160 mmol) was added to a solution of malei-
mide 30 (7.80 g, 80.4 mmol) in toluene (100 mL). The reaction mixture was heated
to reflux for 16 h, then cooled to room temperature. The resulting solid was collected
by filtration and dried to give the product 31 (13.9 g, 98%) as a white solid: 1H NMR
(300 MHz, CDCl3) d 1.20–1.22 (m, 2H), 1.55–1.57 (m, 2H), 2.85 (s, 2H), 2.90 (s, 2H),
6.15–6.18 (m, 2H); MS (ESI) m=z 178 [M þ H]þ.
4-Aza-tricyclo[5.2.2.02,6]undecane (32)
Step 1. A solution of imide 31 (13.2 g, 74.6 mmol) in anhydrous tetrahydro-
furan (200 mL) was added to a solution of lithium aluminum hydride (11.3 g,
298 mmol) in anhydrous diethyl ether (300 mL). The reaction mixture was heated
to reflux overnight, then cooled to 0 ꢁC. Water (11 mL) was added dropwise, fol-
lowed by sodium sulfate. The solids present were removed by filtration through a
pad of diatomaceous earth, and the filtrate was concentrated under vacuum to give
1
the desired amine (11.1 g, 94%) as a semisolid: H NMR (300 MHz, CDCl3) d 1.20–
1.24 (m, 2H), 1.44–1.49 (m, 2H), 2.25 (br s, 2H), 2.45–2.54 (m, 4H), 2.95 (dd,
J ¼ 11.4, 7.1 Hz, 2H), 6.19 (dd, J ¼ 4.4, 3.3 Hz, 2H); MS (ESI) m=z 150 [M þ H]þ.
Step 2. Methanol (50 mL) was added to a Parr bottle containing 10% Pd=C
(0.67 g) under an atmosphere of nitrogen. The mixture was shaken with hydrogen
(40 psi) for 20 min to prereduce the catalyst. A solution of the amine (6.70 g,
45.0 mmol) in methanol (100 mL) was added to the prereduced catalyst, and the reac-
tion mixture was shaken for 16 h under hydrogen (60 psi). The mixture was filtered
through a pad of diatomaceous earth and concentrated to afford the desired product
1
32 (6.0 g, 85%) as a colorless oil: H NMR (300 MHz, CDCl3) d 1.31–1.33 (m, 2H),
1.50–1.54 (m, 4H), 1.59–1.66 (m, 4H), 2.13 (br s, 2H), 2.80 (dd, J ¼ 11.5, 5.6 Hz, 2H),
3.03–3.09 (m, 2H), 3.58 (br s, 1H); MS (ESI) m=z 152 [M þ H]þ.
4-Hydroxy-4-aza-tricyclo[5.2.2.02,6]undecane-3-carbonitrile (33)
Step 1. Na2WO4 ꢃ 2H2O (0.26 g, 0.77 mmol) was added to a solution of amine
32 (2.90 g, 19.2 mmol) in methanol (30 mL) at 0 ꢁC followed by the dropwise addition

2786
M. R. JOHNSON ET AL.
of 35% aqueous hydrogen peroxide solution (5.0 mL, 57.6 mmol) over 15 min. The
reaction mixture was stirred at 0 ꢁC for 4 h and then diluted with water (20 mL)
and methylene chloride (50 mL). The organic layer was separated, and the aqueous
phase was extracted with methylene chloride (3 ꢂ 50 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated under vacuum to
give a yellow oil. Purification by flash chromatography (silica, 9:1 methylene
1
chloride=methanol) afforded the desired nitrone (2.5 g, 80%) as a white solid: H
NMR (300 MHz, CDCl3) d 1.44–1.47 (m, 1H), 1.59–1.74 (m, 8H), 1.83 (s, 1H),
2.68–2.69 (m, 1H), 3.13 (d, J ¼ 10.4 Hz, 1H), 3.83–3.89 (m, 1H), 4.18 (dd, J ¼ 14.1,
11.8 Hz, 1H), 6.87 (d, J ¼ 1.2 Hz, 1H); MS (ESI) m=z 166 [M þ H]þ.
Step 2. Potassium cyanide (2.20 g, 35.2 mmol) and 4 N HCl (7 mL) were added
to a solution of the nitrone (2.90 g, 17.6 mmol) in methanol (40 mL). The reaction
mixture was stirred at 0 ꢁC for 4 h and then quenched with 10% aqueous sodium
hydrogen sulfite (10 mL). The aqueous phase was made alkaline to pH 10 with
2 N NaOH and extracted with methylene chloride (3 ꢂ 100 mL). The combined
organic layers were dried over sodium sulfate and concentrated under vacuum. Puri-
fication by flash chromatography (silica, 1:1 hexanes=ethyl acetate) afforded the
1
desired nitrile 33 (2.0 g, 59%) as a thick oil: H NMR (300 MHz, CDCl3) d 1.44–
1.51 (m, 5H), 1.64–1.70 (m, 5H), 2.36–2.38 (m, 1H), 2.50–2.53 (m, 1H), 2.91–2.92
(m, 1H), 3.41 (t, J ¼ 8.3 Hz, 1H), 3.72–3.74 (m 1H), 7.02 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 19.6, 20.0, 25.0, 25.6, 25.7, 25.8, 36.5, 43.5, 59.6, 60.7, 119.1;
MS (ESI) m=z 193 [M þ H]þ.
4-Hydroxy-4-aza-tricyclo[5.2.2.02,6]undecane-3-carboxylic Acid (34)
A solution of nitrile 33 (1.0 g, 5.1 mmol) in concentrated hydrochloric acid
(10 mL) was heated at 50 ꢁC overnight and then cooled to room temperature, and
the solvent was removed under vacuum to afford the acid 34 (1.0 g, 91%) as a white
1
solid: H NMR (300 MHz, CD3OD) d 1.54–1.82 (m, 10H), 2.44–2.57 (m, 2H), 3.53
(t, J ¼ 10.7 Hz, 1H), 3.98 (dd, J ¼ 11.3, 7.9 Hz, 1H), 4.40 (d, J ¼ 10.6 Hz, 1H); MS
(ESI) m=z 212 [M þ H]þ.
4-Aza-tricyclo[5.2.2.02,6]undecane-3-carboxylic Acid
Hydrochloride (35)
Methanol (30 mL) was added to a Parr bottle containing 10% Pd=C (0.1 g)
under an atmosphere of nitrogen. The mixture was shaken with hydrogen (40 psi)
for 20 min to prereduce the catalyst. A solution of compound 34 (1.0 g, 4.7 mmol)
in methanol (30 mL) was added to the prereduced catalyst, and the reaction mixture
was shaken for 3 h under hydrogen (60 psi). The mixture was filtered through a pad
of diatomaceous earth, and the filtrate was concentrated to afford the crude amino
acid (1.0 g, 99%) as a colorless oil: MS (ESI) m=z 196 [M þ H]þ. A solution of
sodium carbonate (0.54 g, 5.1 mmol) in water (10 mL) was added to a solution of
the amino acid (1.0 g, 5.1 mmol) in 1,4-dioxane (10 mL) followed by a solution
of di-tert-butyldicarbonate (1.7 g, 7.7 mmol) in 1,4-dioxane (5 mL), and the reac-
tion mixture was stirred at room temperature for 4 h. The reaction mixture was then
diluted with ethyl acetate (50 mL) and aqueous 1 N HCl (10 mL). The organic layer

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2787
was separated, and the aqueous phase was extracted with ethyl acetate (2 ꢂ 50 mL).
The combined organic layers were washed with brine, dried over sodium sulfate, fil-
tered, and concentrated. Purification by flash chromatography (silica, 1:9 hexanes=
1
ethyl acetate) afforded the desired acid (1.2 g, 79%) as a colorless foam. H NMR
(300 MHz, CDCl3) d 1.44 (s, 9H), 1.47–1.63 (m, 10H), 2.37–2.50 (m, 2H), 3.51–
3.71 (m, 2H), 4.22–4.37 (m, 1H), 11.3 (br s, 1H); MS (ESI) m=z 296 [M þ H]þ,
196 [M – Boc þH]þ. A solution of the acid (1.2 g, 4.1 mmol) in 2 N HCl in diethyl
ether (20 ml) was stirred at room temperature overnight. The precipitate that formed
was collected, washed with diethyl ether, and dried to give the product 35 (0.72 g,
1
77%) as a white solid: mp 260–265 ꢁC; H NMR (300 MHz, CD3OD) d 1.51–1.75
(m, 9H), 1.87–1.88 (m, 1H), 2.38–2.45 (m, 1H), 2.53–2.56 (m, 1H), 3.15 (t, J ¼ 9.9 Hz,
Hz, 1H), 3.53 (dd, J ¼ 11.8, 8.4 Hz, 1H), 4.19 (d, J ¼ 9.9 Hz, 1H); 13C NMR
(75 MHz, CD3OD) d 20.0, 20.3, 26.3, 26.5, 40.1, 44.9, 48.3, 62.9, 170.9; MS (ESI)
m=z 196 [M þ H]þ. Anal. calcd. for C11H17NO2 ꢃ HCl: C, 57.02; H, 7.83; N, 6.04;
Cl, 15.30. Found: C, 56.70; H, 7.79; N, 6.00; Cl, 15.40.
4-Methyl-4-aza-tricyclo[5.2.2.02,6]undecane-3-carboxylic Acid
Hhydrochloride (7)
Sodium carbonate (0.75 g, 6.9 mmol) was added to a suspension of 35 (1.6 g,
6.9 mmol) in water (16 mL), followed by formalin (2.5 mL, 37% solution, 34 mmol).
After stirring for 10 min, the mixture was added dropwise to a stirred solution of
sodium borohydride (0.65 g, 17.3 mmol) in THF (30 mL). The reaction mixture
was stirred overnight at room temperature and then concentrated to dryness. The
crude residue was dissolved in methanol, reduced in volume to approximately
5 mL, and applied directly to a silica-gel column (eluant methylene chloride=
methanol=ammonium hydroxide 90:10:2) to afford 0.8 g of a white solid. This white
solid was stirred in 2 N HCl in diethyl ether (20 mL) for 3 h and the solid was col-
1
lected by filtration and dried to afford 7 (0.9 g, 62%): mp 262–263 ꢁC; H NMR
(300 MHz, CD3OD) d 1.53–1.61 (m, 5H), 1.74–1.86 (m, 5H), 2.46–2.54 (m, 2H),
3.06 (s, 3H), 3.16 (t, J ¼ 9.9 Hz, 1H), 3.70–3.72 (m, 1H), 4.11 (d, J ¼ 9.7 Hz, 1H);
13C NMR (75 MHz, CD3OD) d 20.0, 20.2, 26.2, 26.3, 26.5, 26.6, 39.0, 39.8, 46.2,
58.9, 70.5, 170.4; MS (ESI) m=z 210 [M þ H]þ.
4,10-Dioxa-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (38)
Furan 36 (72.0 mL, 995 mmol) was added to a solution of maleic anhydride 37
(48.8 g, 498 mmol) in dry diethyl ether (500 mL). The reaction mixture was stirred at
room temperature overnight. The white precipitate that formed was collected and
1
dried to give anhydride 38 (30.0 g, 37%) as a white solid: H NMR (300 MHz,
DMSO-d6) d 3.31 (s, 2H), 5.34 (s, 2H), 6.58 (s, 2H); MS (ESI) m=z 167 [M þ H]þ.
4-Benzyl-10-oxa-4-aza-tricyclo[5.2.1.02,6]decane-3,5-dione (39)
Step 1. THF (50 mL) was added to a Parr bottle containing 10% Pd=C (1.0 g)
under an atmosphere of nitrogen. The mixture was shaken with hydrogen (40 psi) for
5 min to prereduce the catalyst. A solution of compound 38 (16.6 g, 100 mmol) in

2788
M. R. JOHNSON ET AL.
THF (100 mL) was added to the prereduced catalyst, and the reaction mixture was
shaken for 1 h under hydrogen (15 psi). The mixture was filtered through a pad of
diatomaceous earth, and the filtrate was concentrated to afford the reduced anhy-
1
dride (17 g, 99%) as a white solid. H NMR (300 MHz, DMSO-d6) d 1.62–1.68 (m,
4H), 3.40 (s, 2H), 4.86 (t, J ¼ 1.5 Hz, 2H); MS (ESI) m=z 169 [M þ H]þ.
Step 2. Benzylamine (10.5 mL, 97.1 mmol) was added to a solution of the
reduced anhydride (13.6 g, 81.0 mmol) in toluene (360 mL). The reaction mixture
was heated at reflux overnight and then cooled to room temperature and concen-
trated. The residue was triturated with hexanes, and subsequent filtration afforded
the desired product 39 (21.0 g, 81%) as a white solid: 1H NMR (300 MHz,
DMSO-d6) d 1.62–1.68 (m, 4H), 3.10 (s, 2H), 4.54 (s, 2H), 4.73 (d, J ¼ 1.8 Hz,
2H), 7.08–7.34 (m, 5H); MS (ESI) m=z 258 [M þ H]þ.
10-Oxa-4-aza-tricyclo[5.2.1.02,6]decane (40)
Step 1. A solution of imide 39 (21.3 g, 82.9 mmol) in tetrahydrofuran (200 mL)
was added to a solution of lithium aluminum hydride (12.6 g, 332 mmol) in anhy-
drous tetrahydrofuran (200 mL). The reaction mixture was heated to reflux for 2 h
and then cooled to 0 ꢁC. Water (15 mL) was added dropwise, followed by sodium
sulfate. The solid was removed by filtration through a pad of diatomaceous earth,
and the filtrate was concentrated under vacuum to give the intermediate benzylamine
1
(17 g, 91%) as a white soli. H NMR (300 MHz, DMSO-d6) d 1.30–1.36 (m, 2H),
1.47–1.53 (m, 2H), 1.75–1.77 (m, 2H), 2.20–2.29 (m, 2H), 2.93–2.95 (m, 2H), 3.44
(s, 2H), 4.16 (t, J ¼ 2.6 Hz, 2H), 7.19–7.33 (m, 5H); MS (ESI) m=z 230 [M þ H]þ.
Step 2. Methanol (80 mL) was added to a Parr bottle containing 10% Pd=C
(2.0 g) under an atmosphere of nitrogen. The mixture was shaken with hydrogen
(40 psi) for 15 min to prereduce the catalyst. A solution of the amine (16.6 g,
72.5 mmol) in methanol (120 mL) was added to the prereduced catalyst, and the reac-
tion mixture was shaken for 16 h under hydrogen (50 psi). The mixture was filtered
through a pad of diatomaceous earth and concentrated to afford 40 (9.0 g, 87%)
1
as a white solid: H NMR (300 MHz, CDCl3) d 1.40–1.46 (m, 2H), 1.61–1.66 (m,
2H), 2.25–2.33 (m, 2H), 2.72 (dd, J ¼ 11.5, 3.4 Hz, 2H), 2.92–2.98 (m, 2H), 3.05
(br s, 1H), 4.31 (dd, J ¼ 3.1, 2.3 Hz, 2H); MS (ESI) m=z 140 [M þ H]þ.
4-Trimethylsilanyloxy-10-oxa-4-aza-tricyclo[5.2.1.02,6]decane-3-
carbonitrile (41) and 4-Hydroxy-10-oxa-4-aza-
tricyclo[5.2.1.02,6]decane-3-carbonitrile (42)
Step 1. Na2WO4 ꢃ 2H2O (0.47 g, 1.4 mmol) was added to a solution of amine
40 (4.0 g, 29 mmol) in methanol (60 mL) at 0 ꢁC, followed by the dropwise addition
of 35% aqueous hydrogen peroxide solution (6.0 mL, 65 mmol) over 15 min. The reac-
tion mixture was stirred at 0 ꢁC for 6 h and then diluted with water (50 mL) and meth-
ylene chloride (150 mL). The organic layer was separated, and the aqueous phase was
extracted with methylene chloride (3 ꢂ 150 mL). The combined organic layers were
dried over sodium sulfate, filtered, and concentrated under vacuum to give a yellow
oil. Purification by flash chromatography (silica, 9:1 methylene chloride=methanol)
afforded the desired nitrone (3.0 g, 69%) as a low-melting solid: 1H NMR

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2789
(300 MHz, CDCl3) d 1.53–1.58 (m, 2H), 1.75–1.79 (m, 2H), 2.72–2.76 (m, 1H), 3.13–
3.16 (m, 1H), 3.78–3.83 (m, 1H), 4.06–4.09 (m, 1H), 4.44 (d, J ¼ 4.7 Hz, 1H), 4.50 (d,
J ¼ 4.7 Hz, 1H), 6.82 (d, J ¼ 1.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 27.6, 28.3,
41.5, 52.3, 66.6, 77.7, 80.8, 135.0; MS (ESI) m=z 154 [M þ H]þ.
Step 2. To a solution of the nitrone (3.0 g, 20 mmol) in methylene chloride
(40 mL) was added trimethylsilyl cyanide (7.7 mL, 58 mmol). The reaction mixture
was stirred at room temperature overnight and then diluted with water (50 mL)
and methylene chloride (100 mL). The organic layer was separated, and the aqueous
phase was extracted with methylene chloride (3 ꢂ 100 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated under vacuum to
give a mixture of two products. These products were separated by flash chromato-
graphy (silica, 9:1 hexanes=ethyl acetate) to give the nitrile 41 (2.7 g, 55%) as a
1
semisolid: H NMR (300 MHz, CDCl3) d ꢀ0.04 (s, 9H), 1.20–1.24 (m, 2H), 1.50–
1.58 (m, 2H), 2.10–2.28 (m, 2H), 2.50–2.70 (m, 1H), 3.05–3.18 (m, 2H), 4.04–4.05
(m, 1H), 4.20–4.21 (m, 1H); MS (ESI) m=z 253 [M þ H]þ; and the hydroxylamine
1
42 (0.5 g, 14%) as a white solid: H NMR (300 MHz, CDCl3) d 1.45–1.51 (m, 2H),
1.71–1.83 (m, 2H), 2.62–2.63 (m, 3H), 3.50 (dd, J ¼ 10.1, 7.8 Hz, 2H), 4.31
(d, J ¼ 4.7 Hz, 1H), 4.45 (d, J ¼ 4.9 Hz, 1H), 7.14 (br s, 1H); MS (ESI) m=z 181
[M þ H]þ.
10-Oxa-4-aza-tricyclo[5.2.1.02,6]decane-3-carboxylic Acid 4-tert-Butyl
Ester (43)
A mixture of nitrile 41 (2.7 g, 10.7 mmol) and 6 N HCl (100 mL) was heated at
reflux for 6 h. The reaction mixture was allowed to cool to room temperature, and
diethyl ether (40 mL) was added. The organic layer was separated, and the aqueous
phase was concentrated under vacuum to give the crude acid (1.5 g, 94%) as a foam:
MS (ESI) m=z 200 [M þ H]þ. Methanol (80 mL) was added to a Parr bottle con-
taining 10% Pd=C (0.4 g) under an atmosphere of nitrogen. The mixture was shaken
with hydrogen (40 psi) for 15 min to prereduce the catalyst. A solution of the acid
(1.5 g) in methanol (80 mL) was added to the prereduced catalyst, and the reaction
mixture shaken for 24 h under hydrogen (50 psi). The mixture was filtered through a
pad of diatomaceous earth, and the filtrate was concentrated to give crude amino
acid (1.0 g, 72%) as a colorless foam: MS (ESI) m=z 184 [M þ H]þ. A solution of
sodium carbonate (2.3 g, 4.0 mmol) in water (50 mL) was added to this amino acid
(1.0 g, 5.4 mmol) in 1,4-dioxane (10 mL), followed by a solution of di-tert-butyldi-
carbonate (2.4 g, 11 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was
stirred at room temperature overnight. The reaction mixture was then diluted with
ethyl acetate (150 mL) and aqueous 1 N HCl (20 mL). The organic layer was sepa-
rated, and the aqueous phase was extracted with ethyl acetate (2 ꢂ 100 mL). The
combined organic layers were washed with brine, dried over sodium sulfate, and
concentrated. Purification by flash chromatography (silica, 9:1 methylene
chloride=methanol) afforded the desired acid 43 (0.9 g, 32%) as a colorless foam.
1H NMR (300 MHz, CDCl3) d 1.43 (s, 9H), 1.44–1.46 (m, 2H), 1.62–1.69 (m,
2H), 2.52–2.62 (m, 2H), 3.53–3.55 (m, 1H), 3.67–3.69 (m, 1H), 4.18–4.26 (m,
1H), 4.40–4.42 (m, 1H), 4.56 (d, J ¼ 4.1 Hz, 1H), 7.84 (br s, 1H); MS (ESI) m=z
284 [M þ H]þ.

2790
M. R. JOHNSON ET AL.
10-Oxa-4-aza-tricyclo[5.2.1.02,6]decane-3-carboxylic Acid (8)
A solution of the acid 43 (0.9 g, 3.2 mmol) in 2 N HCl in diethyl ether (10 ml)
was stirred at room temperature overnight. The precipitate was collected, washed
with diethyl ether and dried to give the product (0.65 g) as a hygroscopic solid. Puri-
fication by flash chromatography (silica, 6:3:1 methylene chloride=methanol=
concentrated ammonium hydroxide) afforded the amino acid 8 (0.35 g, 60%) as a
1
pale yellow solid: mp 188–190 ꢁC; H NMR (300 MHz, CD3OD) d 1.52–1.55 (m,
2H), 1.66–1.70 (m, 2H), 2.64–2.69 (m, 2H), 3.03 (dd, J ¼ 12.1, 5.4 Hz, 1H), 3.52
(dd, J ¼ 12.1, 8.0 Hz, 1H), 3.73 (d, J ¼ 5.2 Hz, 1H), 4.42 (d, J ¼ 4.5 Hz, 1H), 4.58
(d, J ¼ 4.7 Hz, 1H); 13C NMR (75 MHz, CD3OD) d 28.8, 48.4, 50.6, 53.6, 67.9,
81.8, 82.2, 173.0; MS (ESI) m=z 184 [M þ H]þ.
(S,S,S)-Octahydroindole-1,2-dicarboxylic Acid Dimethyl Ester (45)
Methyl chloroformate (5.0 mL, 65 mmol) was added dropwise at a rate suf-
ficient to maintain a gentle reflux to a stirred mixture of 44 (10.0 g, 59.1 mmol)
and sodium carbonate (11.9 g, 112 mmol) in methylene chloride (40 mL). The reac-
tion mixture was stirred for 16 h and then diluted with methylene chloride
(100 mL) and water (100 mL). The organic layer was removed and extracted with
water (2 ꢂ 50 mL). The combined aqueous layers were then acidified to pH 3 using
3 N HCl and extracted with methylene chloride (2 ꢂ 100 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated. The residue was
then dissolved in thionyl chloride (25 mL), heated to reflux for 45 min, cooled to
room temperature, and then co-evaporated with toluene (2 ꢂ 30 mL). The residue
was then dissolved in anhydrous methylene chloride and methanol (10 mL) was
added. The mixture was stirred for 45 min and then concentrated to dryness. The
residue obtained was dissolved in methylene chloride (50 mL); washed successively
with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and
brine (50 mL); dried over sodium sulfate; filtered; and concentrated. Purification
by flash chromatography (silica 80:20 to 50:50 hexanes=ethyl acetate) afforded 45
1
(9.1 g, 64%) as a light orange oil: H NMR (300 MHz, CDCl3) d 1.12–1.74 (m,
8H), 1.93–2.36 (m, 3H), 3.64–3.75 (m, 6H), 3.71–3.98 (m, 1H), 4.22–4.34 (m, 1H);
MS (ESI) m=z 242 [M þ H]þ.
(3aS,7aS)-2-Phenylsulfanyloctahydroindole-1,2-dicarboxylic Acid
Dimethyl Ester (46)
Potassium hexamethyldisilazane (0.5 N in toluene, 80 mL, 40 mmol), was
added dropwise to a stirred solution of 45 (9.1 g, 38 mmol) in anhydrous THF
(200 mL) at ꢀ78 ꢁC and the mixture was stirred for 1 h. A solution of diphenyl dis-
ulfide (9.1 g, 42 mmol) in THF (200 mL) was then added, and the mixture was
allowed to gradually warm to room temperature over 16 h. The reaction mixture
was then diluted with ethyl acetate (300 mL); washed with 1 N HCl (2 ꢂ 150 mL)
and saturated sodium bicarbonate (150 mL); dried over sodium sulfate; filtered;
and concentrated. Purification by flash chromatography (silica, 1:1 hexanes=ethyl
1
acetate) afforded 46 (8.5 g, 64%) as a yellow solid. H NMR (300 MHz, CDCl3) d

NOVEL BI- AND TRICYCLIC a-AMINO ACIDS
2791
0.94–1.67 (m, 8H), 1.88–2.57 (m, 3H), 3.49–3.86 (m, 7H), 7.29–7.40 (m, 3H), 7.58–
7.61 (m, 2H); MS (ESI) m=z 372 [M þ Na]þ.
(3aS,7aS)-3a,4,5,6,7,7a-Hexahydroindole-1,2-dicarboxylic Acid
Dimethyl Ester (47)
A solution of m-chloroperbenzoic acid (77%, 6.6 g, 29 mmol) in methylene
chloride (70 mL) was added to a stirred solution of 46 (8.5 g, 24 mmol) in methylene
chloride at ꢀ40 ꢁC. After stirring for 5 min, a white precipitate was observed, and the
reaction was stirred for an additional hour, maintaining the temperature at ꢀ40 ꢁC.
The reaction mixture was poured into saturated aqueous sodium bicarbonate
(200 mL). The organic layer was removed, and the aqueous layer was extracted with
methylene chloride (100 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated. The crude sulfoxide was then dissolved in toluene
(120 mL) and heated at reflux for 3 h. The solvents were evaporated, and the residue
was purified by flash chromatography (silica 3:1 hexanes=ethyl acetate) to afford 47,
(1.9 g, 33%) as a pale yellow oil. Unreacted sulfoxide was also recovered (3.5 g),
which was resubjected to the reaction conditions for 24 h and after workup and puri-
1
fication afforded an additional 1.2 g, 21% of 47, to give an overall yield of 54%. H
NMR (300 MHz, CDCl3) d 1.10–2.01 (m, 8H), 3.27–3.35 (m, 1H), 3.72 (s, 3H), 3.80
(s, 3H), 4.28–4.37 (m, 1H), 5.83 (d, J ¼ 2.1 Hz, 1H); MS (ESI) m=z 240 [M þ H]þ.
(1aS,5aS)-Octahydro-6-azacyclopropa[a]indenedicarboxylic Acid
Dimethyl Ester (48)
Anhydrous dimethylsulfoxide (30 mL) was added to a round-bottomed flask
containing sodium hydride (60% dispersion in mineral oil, 0.85 g, 21 mmol and tri-
methylsulfoxonium iodide (5.15 g, 23.4 mmol). The mixture was stirred for 1.5 h,
allowing for complete cessation of the evolution of hydrogen. A solution of 47
(2.24 g, 9.37 mmol) in anhydrous dimethylsulfoxide (30 mL) was added dropwise
to the reaction mixture, which was then immediately heated to 50 ꢁC and stirred
for 16 h. The reaction mixture was then cooled to room temperature, diluted with
ethyl acetate (100 mL), washed with water (2 ꢂ 100 mL), dried over sodium sulfate,
filtered, and concentrated. Purification by flash chromatography (silica 3:1
hexanes=ethyl acetate) afforded the desired product 48 (0.95 g, 40%) as a colorless
1
oil: H NMR (300 MHz, CDCl3) d 1.10–2.15 (m, 12H), 3.69 (s, 3H), 3.73 (s, 3H),
3.99–4.06 (m, 1H); 13C NMR (75 MHz, CDCl3) d 21.1, 22.5, 26.7, 27.6, 31.2, 35.3,
42.3, 46.9, 52.3, 52.5, 65.6, 155.7, 172.1; MS (ESI) m=z 254 [M þ H]þ.
(1aS,5aS)-Octahydro-6-azacyclopropa[a]indene-6a-carboxylic Acid
Hydrochloride (9)
A stirred suspension of 48 (0.95 g, 3.7 mmol) in 4 N HCl (45 mL) was heated at
reflux for 13 h, at which time the reaction was complete as determined by mass spec-
troscopic analysis. The solvents were evaporated, and the residue was co-evaporated
with toluene (5 ꢂ 10 mL), methanol (10 mL), and diethyl ether (10 mL) to afford
crude product (0.85 g, >100%). To assist in purification, the crude amino acid was

2792
M. R. JOHNSON ET AL.
Boc protected. Sodium hydroxide (0.38 g, 4.7 mmol) and di-tert-butyl dicarbonate
(1.1 g, 5.1 mmol) were added to a stirred solution of the amino acid in 1,4-dioxane
(20 mL) and water (10 mL). After stirring for 16 h, the reaction mixture was diluted
with diethyl ether (30 mL) and water (30 mL). The organic layer was separated and
extracted with water (30 mL). The combined aqueous layers were diluted with meth-
ylene chloride (50 mL), and the mixture was stirred vigorously while adjusting to pH
2 with 2 N HCl. The aqueous layer was separated and extracted with methylene
chloride (2 ꢂ 50 mL). The combined organic layers were dried over sodium sulfate,
filtered, concentrated and purified by flash chromatography (silica, 95:5 methylene
chloride=methanol) to afford the Boc-protected amino acid (0.65 g). The Boc group
was then cleaved by dissolving the compound in 1,4-dioxane (15 mL) and stirring
with 2 N HCl in diethyl ether (15 mL) for 16 h. The solvents were evaporated to yield
a sticky gum, which was then purified by flash chromatography (silica, 80:20:5 meth-
ylene chloride=methanol=concentrated ammonium hydroxide) to afford 9 (0.36 g,
25
53%) as an off-white solid: mp 155–159 ꢁC; ½aꢄD ꢀ20.2ꢁ (c 1.00, methanol); 1H
NMR (300 MHz, CD3OD) d 1.06–1.35 (m, 2H), 1.44 (t, J ¼ 5.7 Hz, 1H), 1.51–1.99
(m, 8H), 2.18–2.26 (m, 1H), 3.42–3.47 (m, 1H); MS (ESI) m=z 182 [M þ H]þ.
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