The use of sodium chlorite in the direct synthesis of glycidic amides: Enantiopure synthesis of both enantiomers of norbalasubramide

Article abstract of DOI:10.1055/s-0032-1316893

Recently, the first direct method for preparing 2,3-epoxyamides (glycidic amides) was disclosed. Now in this letter, the enantiopure synthesis of both enantiomers of norbalasubramide featuring this synthetic method is reported. To this end, chiral N-allyltryptamine 12 was prepared and transformed into an inseparable mixture of diastereomeric epoxyamides 13a/13b, which were submitted to intramolecular cyclization with Cu(OTf)₂ to afford a separable mixture of eight-membered ring lactams 14a and 14b. Finally, after removal of the protective group and the chiral auxiliary an enantiopure synthesis of the title compounds was completed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316893

878▌
LETTER
letter
The Use of Sodium Chlorite in the Direct Synthesis of Glycidic Amides:
Enantiopure Synthesis of Both Enantiomers of Norbalasubramide
Enantiopure Synthesis of Both Enantiomers of Norbalasubramide
Lilia Fuentes, Mireya Hernández-Juarez, Joel L. Terán, Leticia Quintero,* Fernando Sartillo-Piscil*
Centro de Investigación de la Facultad de Ciencias Químicas y Centro de Química del ICUAP, Benemérita Universidad Autónoma de Puebla
(BUAP), 14 Sur Esq. San Claudio, San Manuel 72570, Puebla, México
Fax +52(222)2454972; E-mail: fernando.sartillo@correo.buap.mx
Received: 10.01.2013; Accepted after revision: 17.03.2013
acetamides,4 α-diazo acetamides,5 α-ammonium
Abstract: Recently, the first direct method for preparing 2,3-ep-
acetamides6 with either aldehyde or ketones, or (b)
oxyamides (glycidic amides) was disclosed. Now in this letter, the
through the epoxidation of α,β-unsaturated amides.7
Moreover, recently a third method was reported: (c) selec-
enantiopure synthesis of both enantiomers of norbalasubramide fea-
turing this synthetic method is reported. To this end, chiral N-allyl-
tryptamine 12 was prepared and transformed into an inseparable tive tandem oxidation of tertiary allylic amines with sodi-
um chlorite (Scheme 1).8 Unlike the two methods, in
which at least two steps are involved, the latter represents
mixture of diastereomeric epoxyamides 13a/13b, which were sub-
mitted to intramolecular cyclization with Cu(OTf)2 to afford a sep-
arable mixture of eight-membered ring lactams 14a and 14b.
the first direct method (one step) for preparing glycidic
Finally, after removal of the protective group and the chiral auxilia-
ry an enantiopure synthesis of the title compounds was completed.
amides.
Apparently, the tandem oxidation reaction is initiated by
NaClO2-mediated C–H allylic oxidation of allylamine A
to the corresponding α,β-unsaturated amide B followed by
double bond epoxidation to glycidic amide C by hypo-
chlorite ion, which is formed at the expense of the reduc-
tion of sodium chlorite (Scheme 2). Under this apparent
logical sequence, various tertiary allylamines were trans-
formed into their corresponding 2,3-epoxyamides in few
hours with modest to good yields.8
Key words: 2,3-epoxyamides, glycidic amides, tandem oxidation,
sodium chlorite, balasubramide, norbalasubramide
Glycidic amides (or 2,3-epoxyamides) are very important
organic compounds that are found in nature1 or prepared
in the laboratory for being used in synthesis as versatile
building blocks.2 Until very recently, the glycidic amides
were prepared by only two general methods: (a) via Dar-
zen condensation of α-halo acetamides,3 α-sulfonium
O
R3
R4
O
R3
R4
O
R1
Darzens
condensation
O
R1
epoxidation
R1
X
[O]
+
N
R2
N
R2
+
N
R3
R4
O
R2
2,3-epoxyamides
(glycidic amides)
N2,
N
X = Cl, Br, I,
S
,
R1–R4 = H, alkyl or aryl
tandem
oxidation
R3
R1
R4
+
NaClO2
N
R2
Scheme 1 Synthetic methods for preparing 2,3-epoxyamides (glycidic amides)
O
Cl
O
O
O
R1
R1
R1
NaClO2
N
R2
N
R2
O
N
R2
N
R1
R2
H
ClO
A
B
C
R1, R2 = alkyl, allyl or benzyl
Scheme 2 Proposed tandem oxidation course for the direct synthesis of glycidic amides
SYNLETT 2013, 24, 0878–0882
Advanced online publication: 21.03.2013
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9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316893; Art ID: ST-2013-S0037-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantiopure Synthesis of Both Enantiomers of Norbalasubramide
879
NH
NH
NH
Ph
various
epoxidation
methods
O
O
O
O
OH
(did not work)
N
N
H
N
Ph
Ph
H
H
3
prebalamide
norbalasubramide
2
1
coupling with
tryptamine
(two steps)
(A)
O
O
1. Oxone
2. KOH
OK
OH
O
4
Ph
O
Ph
O
N
NH
N
O
O
NH
O
O
OH
+
OH
N
H
N
N
Ph
Ph
H
N
Ph
H
Ph
H
norbalasubramide
ent-1
6b
6a
(+)-1
Ph
Br
Br
N
C-H oxidation
(B)
tandem oxidation
epoxidation
+
N
H
8
Ph
N
H
Ph
7
Ph
NH2
(S)-9
5
Scheme 3 Kerr’s biomimetic synthesis of norbalasubramide (A) and our retrosynthetic plan (B)
Thus, motivated by these promising results, we focus now original strategy was modified; they decided to follow the
on its application to a specific synthesis of indole alka- traditional two-step synthesis of glycidic amides: first to
loids. We wanted to undertake a synthesis where one of prepare the epoxide 4 and then couple it to tryptamine
the conventional methods failed, and thus showcase some (Scheme 3, A).
of the advantages that this chemical method offers. Going
Having set up this provocative synthetic scenario, we de-
through the literature, we found an elegant biomimetic
cided to apply our tandem oxidation (C–H oxidation/dou-
synthesis of the norbalasubramides (also of the balasub-
ble bond epoxidation) to N-allyltryptamine 5 in order to
ramide) developed by Kerr and co-workers.9 They postu-
prepare, in only one step, the diastereomeric prebalamides
lated to synthesize the norbalasubramide 1 (and also the
6a and 6b, which after Lewis acid mediated epoxide
balasubramide) from natural glycidic prebalamide 2 via a
opening9,10 followed by removing of the chiral auxiliary,
would lead to the enantiopure synthesis of both enantio-
Yb(OTf)3-catalyzed intramolecular epoxide opening, in
which the prebalamide 2 would be prepared by the epoxi-
mers of norbalasubramide in only three steps from 5
dation of unsaturated tryptamide 3. Unfortunately, after
(Scheme 3, B). To this end, both chiral allyltryptamine
(S)-5 and also the N-Boc-allyltryptamine (S)-12 were pre-
pared. The indole protection with tert-butyloxycarbonyl
various attempts for conducting the epoxidation reaction,
they could not obtain the prebalamide 2. Therefore, their
Ph
Br
Ph
Br
NH
+
N
K2CO3
MeCN
K2CO3
MeCN
+
Ph
NH2
N
R
N
R
N
Ph
8
Ph
R
(S)-9
7 (R = H)
7a (R = Boc)
10 (R = H, 65%)
11 (R = Boc, 90%)
5 (R = H, 63%)
12 (R = Boc, 97%)
Scheme 4 Preparation of chiral allyltryptamines 5 and 12
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 878–882

880
L. Fuentes et al.
LETTER
group (Boc) responds to the need for decreasing its reac- 13a/13b was submitted to intramolecular ring opening us-
tivity toward the oxidizing and electrophilic conditions ing ytterbium(III) triflate as catalyst (Kerr’s conditions)
that the NaClO2/NaH2PO4 system provides. Alkylation of obtaining thus the corresponding eight-membered ring
chiral auxiliary (S)-9 with both bromoethyl indole 7 and lactams 14a and 14b in a low yield (entry 1, Table 1). Fur-
its Boc-protected derivative 7a afforded secondary thermore at this stage, both lactams were easily separated
amines 10 and 11 in 65% and 90% yields, respectively; by chromatography. Because of this low yield, it was
then, allylation of 10 and 11 with trans-cinnamyl bromide therefore decided to carry out screening experiments to
(8) gave the N-allyltryptamines 5 and 12 in good and ex- find out a better catalyst that may provide better yields. As
cellent yields, respectively (Scheme 4). It is important to shown in Table 1, p-toluenesulfonic acid (PTSA) gave a
mention that the presence of the Boc-protecting group in modest 50% yield in two days at room temperature (entry
7a increased the yields of the alkylation and allylation re- 2); the other metal triflates catalysts showed decreased ef-
actions; indeed, the sole formation of secondary amine 11 ficiency from less than traces to greater than 42% yield
was observed; however for the alkylation of 7, an undesir- (entries 3–7).
able 28% of tertiary amine (not shown) was formed.
NaClO2
NaH2PO4
With the chiral allylamines 5 and 12 in hand, we proceed-
complex mixture of
by-products
ed to apply our tandem oxidation protocol under the reac-
tion condition that provides the best yields (8 equiv of
NaClO2 and NaH2PO4, 100 equiv of 2-methylbut-2-ene in
a mixture of THF–t-BuOH–H2O solvents with a ratio of
7:3:3).8 For the case of allylamine 5, a complex mixture of
inseparable by-products was obtained; only traces of the
expected glycidic amines were apparently observed. For-
tunately, in the case of the Boc-protected allyltryptamine
12, a gratifying 70% yield of a diastereomeric mixture of
2,3-epoxyamides 13a and 13b (ca. 50:50) was obtained
(Scheme 5).11 Since both epoxyamides had the same re-
tention factor (Rf) in all of the common solvents, we failed
to separate both epoxyamides by chromatography. Conse-
quently, the diastereomeric mixture of epoxyamides
5
2-methylbut-2-ene
THF–t-BuOH–H2O (7:3:3)
Ph
O
Ph
N
N
O
as above
O
12
O
75%
13a/13b = 50:50
+
N
N
Ph
Ph
Boc
Boc
13b
13a
Scheme 5 Synthesis of glycidic amides 13a and 13b via tandem
C–H oxidation and double-bond epoxidation
Table 1 Catalyst Screening for the Intramolecular Cyclization via Epoxide Ring Openinga
Ph
O
Ph
O
Ph
O
Ph
O
N
N
N
N
O
O
catalyst
+
+
OH
OH
N
N
Ph
Ph
N
N
Ph
Ph
Boc
Boc
Boc
Boc
13a
13b
14a
14b
(as an inseparable mixture)
(separable lactams)
Entry
Catalyst
Yield of 14a + 14b (as 1:1 ratio)
Time (h)
1
2
3
4
5
6
7
8
Yb(OTf)3; 20% mol
p-TsOH; 300% mol
In(OTf)3; 20% mol
LiOTf; 20% mol
40%b
50%b
30%b
Trace
Trace
23%b
42%b
82%b
60
48
60
60
72
72
12
0.5
AgOTf; 20% mol
Zn(OTf)2; 20% mol
Sc(OTf)3; 20% mol
Cu(OTf)2; 20% mol
a All reactions were performed in MeCN at r.t.
b Yields obtained after purification.
Synlett 2013, 24, 878–882
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantiopure Synthesis of Both Enantiomers of Norbalasubramide
881
1
and copies of H NMR and 13C NMR spectra for the new com-
A gratifying result was obtained when Cu(OTf)2 was
used; in only 30 minutes at room temperature, lactams 14a
and 14b were obtained in 82% yield (entry 8).12 With the
optically pure eight-membered ring lactams 14a and 14b
in hand, we proceeded to remove the Boc-protective
group and the chiral benzyl group to thus obtain the (+)-
and (–)-norbalasubramides in enantiopure forms. Deprot-
ection of N-Boc proved difficult under classic acidic con-
dition, and decomposition of the starting material was
observed. However, with the use of tetra-n-butylammoni-
um fluoride (TBAF),13 the unprotected indoles 15a and
15b (not shown) were obtained in 77% and 80% yields,
respectively.14 Debenzylation of 15a and 15b with H2 and
Pd/C or Pd(OH)2 did not provide the expected results;
however, under Birch conditions, both enantiomers of
norbalasubramide were obtained.15 Norbalasubramide
(–)-1 exhibited NMR spectral data identical to that report-
ed by Zhao and co-workers,16 as well as similar optical ro-
tation (Scheme 6).
pounds.SupngIopif
omitrSatnuIpofomnipgrairtt
n
References
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(2) (a) Murphree, S. S. Modern Heterocyclic Chemistry; Vol. 1;
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2; Wiley-VCH: Weinheim, 2011. For recent synthetic
applications of 2,3-epoxyamides, see: (b) Sarabia, F.; Vivar-
García, C.; García-Castro, M.; García-Ruiz, C.; Martín-
Gálvez, F.; Sánchez-Ruiz, A.; Chammaa, S. Chem. Eur. J.
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(3) (a) Rosen, T. In Comprehensive Organic Synthesis; Vol. 2;
Trost, B. M.; Fleming, I.; Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991, 409. (b) Tung, C. C.; Speziale, A. J.; Frazier,
H. W. J. Org. Chem. 1963, 28, 1514.
(4) For representative examples, see: (a) Illa, O.; Arshad, M.;
Ros, A.; McGarrigle, E. M.; Aggarwal, V. K. J. Am. Chem.
Soc. 2010, 132, 1828. (b) McGarrigle, E. M.; Myers, E. L.;
Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem.
Rev. 2007, 107, 5841. (c) Aggarwal, V. K.; Hynd, G.;
Picoul, W.; Vasse, J. L. J. Am. Chem. Soc. 2002, 124, 9964.
(d) Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X.; Xia, L. J.; Tang,
M.-H. J. Chem. Soc., Perkin Trans. 1 1999, 77.
Ph
NH
O
N
O
1. TBAF
2. Birch
OH
OH
N
62%
(in two steps)
Ph
H
N
Ph
(–)-1
Boc
[α]D = –3.8 (c 0.5, MeOH)
[α]D = –2.9 (c 0.2, CHCl3)
14b
[α]D = –2.5 (c 0.2, CHCl3)
ref.16
Ph
O
NH
O
N
(5) (a) He, L.; Liu, W. J.; Ren, L.; Lei, T.; Gong, L. Z. Adv.
Synth. Catal. 2010, 352, 1123. (b) Doyle, M. P.; Mckervey,
M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds 1998. (c) López-Herrera,
F. J.; Sarabia-García, F.; Pino-González, M. S. Tetrahedron
Lett. 1994, 35, 2933.
as above
OH
60%
(in two steps)
N
OH
Ph
H
N
Ph
(+)-1
Boc
14a
[α]D = +3.7 (c 0.5, MeOH)
(6) (a) Waser, M.; Herchi, R.; Müller, N. Chem. Commun. 2011,
47, 2170. (b) Herchl, R.; Stiftinger, M.; Waser, M. Org.
Biomol. Chem. 2011, 9, 7021.
Scheme 6 Synthesis of both enantiomers of norbalasubramide, (–)-
1 and (+)-1
(7) (a) Díez, D.; Núñez, M. G.; Antón, A. B.; García, P.; Moro,
R. F.; Garrido, N. M.; Marcos, I. S. Curr. Org. Synth. 2008,
5, 189. (b) Nemoto, T.; Kakei, H.; Gnanadesikda, V.;
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Cabrera, N.; Sartillo-Piscil, F. J. Org. Chem. 2012, 77, 5515.
(9) Johansen, M. B.; Leduc, A. B.; Kerr, M. A. Synlett 2007,
2593.
In summary, we have developed a highly efficient six-step
synthesis of both enantiomers of norbalasubramide fea-
turing our tandem oxidation of allylamines to glycidic am-
ides with sodium chlorite. The application of this
synthetic method clearly demonstrates some advantages
over the conventional two-step synthesis of glycidic
amides.
(10) Yang, L.; Deng, G.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.;
Wang, M.-X. Org. Lett. 2007, 9, 1387.
(11) General Procedure for the Tandem Oxidation of
Allyamines; tert-Butyl-3-[2-{3-phenyl-N-[(S)-1-
Acknowledgment
We gratefully acknowledge the financial support from CONACyT
(Grant: 179074) and the Benemérita Universidad Autónoma de
Puebla (BUAP-VIEP). We also thank Mr. Vladimir Carranza-
Tellez for technical assistance in mass spectroscopy.
phenylethyl]oxirane-2-carboxamido}ethyl]-1H-indole-1-
carboxylate (13a/13b): Allylamine 12 (4.00 g, 8.32 mmol)
and NaH2PO4·2H2O (12.98 g, 83.22 mmol) were dissolved
in a mixture of t-BuOH–THF–H2O (7:3:3; 108 mL), the
reaction mixture was then stirred vigorously at r.t. for 15 min
after which time the solution was cooled to 0 °C followed by
the addition of 2-methylbut-2-ene (58.37 g, 832.22 mmol)
and the sequential addition of NaClO2 (6.02 g, 66.58 mmol)
dissolved in H2O (10 mL). The reaction mixture was stirred
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental procedures for the preparation of allylamines 5 and 12
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 878–882

882
L. Fuentes et al.
LETTER
(7.83 mmol, 1.0 M solution). The reaction mixture was
refluxed for 5 h. Then, the mixture was cooled to r.t., H2O
was added (5 mL), the phases were separated and the
aqueous phase was extracted with EtOAc (2 × 15 mL). The
combined organic phases were dried over Na2SO4 and the
solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel, and
then recrystallized in CH2Cl2–hexane to give the
for 8 h, then phases were separated and the aqueous phase
was extracted with EtOAc (3 × 25 mL). The combined
organic phases were dried over Na2SO4 and the solvent was
removed under reduced pressure. The residue was purified
by column chromatography on silica gel to give an
inseparable mixture of diastereomeric epoxyamides 13a and
13b in a 50:50 ratio as a pale yellow oil (2.97 g, 70%); [α]D
20
–23.9 (c = 1.0, CH2Cl2). NMR data is reported as a mixture
of diastereoisomers and E/Z rotamers. 1H NMR (400 MHz,
CDCl3): δ = 1.60 (d, J = 6.8 Hz), 1.64 (s), 1.66 (d, J = 6.4
Hz), 2.30–2.41 (m), 2.56–2.64 (m), 2.70–2.78 (m), 2.87–
2.99 (m), 3.23–3.35 (m), 3.38–3.61 (m), 3.66 (dd, J = 3.6,
1.6 Hz), 3.79 (dd, J = 6.0, 2.0 Hz), 4.19 (ddd, J = 20.8, 11.6,
1.6 Hz), 5.33 (q, J = 6.8 Hz), 5.39 (q, J = 6.8 Hz), 6.13 (app
quint., J = 7.2 Hz), 6.75 (d, J = 7.8 Hz), 6.88–7.03 (m), 7.18–
7.45 (m), 8.04 (br). 13C NMR (100 MHz, CDCl3): δ = 16.5,
18.3, 18.5, 23.9, 24.2, 26.7, 26.8, 28.1, 28.1, 43.4, 43.5, 44.0,
44.0, 51.8, 51.9, 54.7, 54.9, 57.4, 57.5, 57.9, 58.0, 58.1, 58.3,
83.3, 83.6, 115.0, 115.2, 115.3, 116.4, 117.9, 118.2, 119.3,
119.3, 122.4, 122.4, 123.0, 123.0, 123.1, 124.3, 124.4,
125.5, 125.6, 126.7, 127.1, 127.8, 127.9, 127.9, 128.0,
128.1, 128.6, 128.7, 128.8, 129.6, 130.3, 135.2, 135.3,
135.4, 139.2, 139.8, 140.0, 149.4, 149.7, 166.5, 166.6,
166.7. HRMS (FAB): m/z [M + H]+ calcd for C32H35N2O4:
511.2597; found: 511.2550.
corresponding product. (5S,6R)-5-Hydroxy-6-phenyl-3-
[(S)-1-phenylethyl]-2,3,5,6-tetrahydro-1H-azocino[5,4-
b]indol-4(7H)-one (15a): obtained as a white solid (0.25 g,
79%); mp 231–267 °C (decomp.); [α]D20 –7.1 (c = 1.0,
CH2Cl2). The NMR data is reported as a mixture of rotamers.
1H NMR (400 MHz, CDCl3): δ = 1.47 (d, J = 7.2 Hz), 1. 57
(d, J = 7.2 Hz), 1.99 (br), 2.95 (ddd, J = 16.0, 9.6, 4.0 Hz),
3.11 (dt, J = 16.0, 8.4 Hz), 3.39 (ddd, J = 14.4, 9.6, 8.0 Hz),
3.69 (ddd, J = 14.8, 8.8, 4.0 Hz), 4.28 (d, J = 9.6 Hz), 4.98
(d, J = 9.6 Hz), 5.88 (q, J = 7.2 Hz), 5.94 (q, J = 7.2 Hz), 6.34
(s), 6.53–6.59 (m), 6.82–6.91 (m), 7.04–7.08 (m), 7.15–7.34
(m), 8.40 (br), 8.55 (br). 13C NMR (100 MHz, CDCl3): δ
=16.0, 23.1, 40.3, 42.6, 51.2, 52.4, 53.0, 72.3, 106.5, 110.2,
110.3, 110.7, 117.7, 118.6, 119.0, 121.5, 122.6, 122.9,
127.0, 127.0, 127.2, 127.5, 127.7, 127.8, 128.2, 128.4,
128.4, 128.5, 128.8, 133.8, 134.0, 135.4, 135.5, 135.7,
138.0, 138.2, 139.4, 139.8, 140.2, 169.9, 174.9. HRMS
(FAB): m/z [M + H]+ calcd for C27H27N2O2: 411.2073;
found: 411.2060.
(5R,6S)-5-Hydroxy-6-phenyl-3-[(S)-1-phenylethyl]-
2,3,5,6-tetrahydro-1H-azocino[5,4-b]indol-4(7H)-one
(15b): obtained as a white solid (0.38 g, 80%); mp 147–150
°C; [α]D20 –1.2 (c = 1.0, CH2Cl2). The NMR data is reported
as a mixture of rotamers. 1H NMR (400 MHz, CDCl3): δ =
0.78 (d, J = 6.8 Hz), 1.59 (d, J = 7.2 Hz), 3.03–3.20 (m),
3.20–3.30 (m), 3.39–3.53 (m), 3.87 (d, J = 8.8 Hz), 4.27 (d,
J = 8.8 Hz), 4.95 (t, J = 8.8 Hz, 1 H), 5.83 (q, J = 6.8 Hz, 1
H), 5.99 (q, J = 6.8 Hz), 7.13–7.36 (m), 7.51–7.54 (m), 8.02
(s), 8.20 (s). 13C NMR (100 MHz, CDCl3): δ = 15.6, 23.4,
41.0, 41.3, 51.6, 51.9, 53.5, 72.3, 106.8, 110.7, 110.8, 117.3,
118.7, 119.2, 119.4, 119.5, 121.9, 123.0, 127.3, 127.4,
127.5, 127.5, 127.8, 128.3, 128.5, 128.6, 128.9, 132.9,
134.3, 135.3, 135.7, 137.9, 139.4, 139.9, 140.0, 169.6,
174.7. HRMS (FAB): m/z [M + H]+ calcd for C27H27N2O2:
411.2073; found: 411.2079.
(12) General Procedure for the Intramolecular Ring
Opening: To a solution of 13a/13b (2.00 g, 3.91 mmol) in
anhyd MeCN (45 mL) at r.t. was added Cu(OTf)2 (0.28 g,
0.78 mmol) dissolved in anhyd MeCN (5 mL). The reaction
mixture was stirred for 30 min before H2O (15 mL) was
added. The phases were separated and the aqueous phase
was extracted with EtOAc (3 × 25 mL). The organic phase
was dried over Na2SO4, and the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel or recrystallized with EtOAc–
hexane to give 14a (0.80 g, 40%) and 14b (0.84 g, 42%).
(5S,6R)-tert-Butyl-5-hydroxy-4-oxo-6-phenyl-3-[(S)-1-
phenylethyl]-3,4,5,6-tetrahydro-1H-azocino[5,4-
b]indole-7(2H)-carboxylate (14a): Obtained as a white
solid (0.80 g, 40%); mp 185–186 °C; [α]D20 –32.6 (c = 1.0,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.45 (d, J = 6.8
Hz, 3 H), 1.53 (s, 9 H), 2.98–3.15 (m, 2 H), 3.30 (dt, J = 14.0,
9.6 Hz, 1 H), 3.60 (dd, J = 14.0, 9.6 Hz, 1 H), 3.97 (d, J = 9.2
Hz, 1 H), 4.89 (t, J = 9.6 Hz, 1 H), 5.29 (d, J = 9.6 Hz, 1 H),
5.98 (q, J = 6.8 Hz, 1 H), 6.51–6.60 (m, 3 H), 6.74–6.77 (m,
2 H), 6.96–7.00 (m, 1 H), 7.18–7.30 (m, 7 H), 7.98 (d, J =
8.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 15.9, 23.0,
28.0, 39.5, 51.6, 51.9, 73.1, 84.2, 114.4, 115.5, 117.3, 122.5,
123.8, 126.8, 126.9, 127.0, 127.6, 128.0, 128.7, 129.1,
136.0, 136.5, 138.0, 139.6, 149.9, 174.8. HRMS (FAB): m/z
[M + H]+ calcd for C32H35N2O4: 526.2597; found: 511.2613.
(5R,6S)-tert-Butyl-5-hydroxy-4-oxo-6-phenyl-3-[(S)-1-
phenylethyl]-3,4,5,6-tetrahydro-1H-azocino[5,4-
b]indole-7(2H)-carboxylate (14b): Obtained as a pale
yellow oil (0.84 g, 42%); [α]D20 +17.6 (c = 1.0, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 0.68 (d, J = 6.8 Hz, 3 H), 1.51
(s, 9 H), 2.92–3.43 (m, 4 H), 3.92 (d, J = 9.6 Hz, 1 H), 4.85
(t, J = 9.6 Hz, 1 H), 5.28 (d, J = 9.2 Hz, 1 H), 5.84 (q, J = 6.8
Hz, 1 H), 6.99–7.58 (m, 13 H), 7.94–8.19 (m, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 15.3, 23.1, 28.0, 40.6, 51.4, 51.4,
73.1, 84.4, 114.6, 116.0, 117.2, 122.6, 124.2, 126.8, 127.2,
127.4, 128.1, 128.4, 128.5, 129.1, 136.0, 137.1, 139.5,
140.0, 149.8, 174.6. HRMS (FAB): m/z [M + H]+ calcd for
C32H35N2O4: 526.2597; found: 511.2610.
(15) Birch Debenzylation: A solution of 15b (0.26 g, 0.63
mmol) in anhyd THF (2 mL) was added dropwise to a deep
blue solution of Li (0.030 g, 4.38 mmol) in condensed NH3
(ca. 5 mL) at –78 °C. The reaction mixture was allowed to
stir for 3 h at –78 °C before H2O (3 mL) was added. The
mixture was extracted with EtOAc, dried with Na2SO4 and
evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel, and recrystallized
in CH2Cl2–hexane to afford the corresponding product.
(–)-Norbalasubramide: obtained as a white solid (0.15 g,
79%); mp 251–255 °C (decomp.); [α]D20 –2.9 (c = 0.2,
CHCl3); [α]D20 –3.8 (c = 0.5, MeOH), {[α]D20 –2.5 (c = 0.2,
CHCl3); see ref. 16}. 1H NMR (400 MHz, CDCl3): δ = 3.19–
3.40 (m, 4 H), 3.60–3.71 (m, 1 H), 4.20 (d, J = 9.2 Hz, 1 H),
4.88 (d, J = 9.2 Hz, 1 H), 7.10 (ddd, J = 8.8, 7.2, 1.6 Hz, 2
H), 7.20–7.41 (m, 6 H), 7.44–7.63 (m, 1 H). 13C NMR (100
MHz, CDCl3): δ = 23.8, 40.1, 52.6, 71.9, 106.2, 110.8,
117.2, 119.0, 121.6, 127.2, 128.1, 128.3, 128.5, 134.2,
135.5, 140.0, 176.9. (+)-Norbalasubramide: obtained as a
20
white solid (0.14 g, 76%); mp 251–255 °C (decomp.); [α]D
+3.7 (c = 0.5, MeOH).
(13) Jacquemard, U.; Béneteau, V.; Lefoix, M.; Routier, S.;
Mérour, J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039.
(14) N-Boc Deprotection: To a solution of lactam 14a (0.40 g,
0.78 mmol) in anhyd THF (2 mL) at r.t. was added TBAF
(16) Zheng, C.; Li, Y.; Yang, Y.; Wang, H.; Cui, H.; Zhang, J.;
Zhao, G. Adv. Synth. Catal. 2009, 351, 1685.
Synlett 2013, 24, 878–882
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