Chiral auxiliary induced diastereoselective synthesis of (R,R)-N,N′-Di(tert-butoxycarbonyl) cyclohex-4-ene-1,2-diamine

Article abstract of DOI:10.1002/ejoc.201403058

The synthesis of optically pure N,N′-di(tert-butoxycarbonyl)-trans-cyclohex-4-ene-1,2-diamine was accomplished from the diimine, which was obtained by condensation of glyoxal and (R)-1-(4-methoxyphenyl)ethanamine. The synthetic sequence involved the highl

Full text of DOI:10.1002/ejoc.201403058

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403058
Chiral Auxiliary Induced Diastereoselective Synthesis of (R,R)-N,NЈ-Di(tert-
butoxycarbonyl)cyclohex-4-ene-1,2-diamine
Davide Balestri,[a] Stefano Grilli,[a] Ciro Romano,[a] and Diego Savoia*[a]
Keywords: Asymmetric synthesis / Metathesis / Diastereoselectivity / Chiral auxiliaries / Amines
The synthesis of optically pure N,NЈ-di(tert-butoxycarbonyl)-
trans-cyclohex-4-ene-1,2-diamine was accomplished from
the diimine, which was obtained by condensation of glyoxal
and (R)-1-(4-methoxyphenyl)ethanamine. The synthetic se-
quence involved the highly diastereoselective addition of all-
ylzinc bromide to the diimine to give the N,NЈ-disubstituted
octa-1,7-diene-4,5-diamine, followed by removal of the N-
substituents by using an excess amount of boron trichloride,
routine conversion to the di(N-tert-butoxycarbonyl) deriva-
tive, and final ring-closing metathesis by using Grubbs Ru
catalyst. The sequence of the two latter steps could be in-
verted. Removal of the chiral auxiliaries with trifluoroacetic
acid or hydrochloric acid gave less satisfactory results. More-
over, N,NЈ-dibenzoylocta-1,7-diene-4,5-diamine was simi-
larly prepared.
sis (RCM)[7] of hepta-1,7-diene-4,5-diamine or N,NЈ-disub-
stituted derivative 3, which can be diastereoselectively pre-
pared by the auxiliary-induced double allylmetalation of
chiral glyoxal diimine 4 (Scheme 1). As a matter of fact,
compound 3 was obtained with 85% diastereoselectivity by
the Barbier-type double allylzincation of glyoxal diimine 4
derived from (R)-tert-butylsulfinamide. Then, the chiral
auxiliary could be removed by acidic hydrolysis.[6] This re-
port constitutes a formal total synthesis of cyclohex-4-ene-
1,2-diamine (1), although the required RCM reactions were
not performed.
Introduction
Optically pure cyclohex-4-ene-1,2-diamine, for example,
(R,R)-1, is a valuable chiral synthon that has found use in
a variety of applications. For example, (R,R)-1 has been em-
ployed as a building block for the preparation of large chi-
ral cages by dynamic imine reaction with tris(4-formyl-
phenyl)amine,[1] tetraazamacrocycles useful as magnetic res-
onance contrast agents in hepatobiliary systems.[2] More-
over, the preparation of antitumoral platinum complexes[3]
from 1 has been reported in several patents.[3] Therein, op-
tically pure 1 was obtained by exploiting resolution pro-
cesses of rac-1, which was synthesized from trans-cyclohex-
4-ene-1,2-dicarboxylic acid by sequential formation of the
di(carbonyl hydrazide) and di(carbonyl azide) and final
Curtius rearrangement. On the other hand, only two asym-
metric syntheses of a di(N-tert-butoxycarbonyl) [di(N-Boc)]
derivative of 1, see 9 in Scheme 2, have been reported, and
both required a long sequence of steps. Then, 9 was con-
verted into Oseltamivir phosphate (Tamiflu). One of these
routes involved the ring-opening desymmetrization of meso-
N-(3,5-dinitrobenzoyl)cyclohexa-1,4-diene-substituted azir-
idine,[4] whereas the other route exploited the chemoenzym-
atic resolution of trans-N,N-diallylcyclohex-4-ene-1,2-di-
amine and its precursor trans-6-(diallylamino)cyclohex-3-
enol.[5]
Scheme 1. Retrosynthetic routes to optically pure trans-cyclohex-4-
ene-1,2-diamines.
As an alternative, we envisioned that optically pure 1
could be synthesized by exploiting the ring-closing metathe-
On the other hand, we described the preparation of
N,NЈ-disubstituted 1, as well as ring-disubstituted cyclohex-
4-ene-1,2-diamine derivatives, by RCM reactions of the 4,5-
diaminoocta-1,7-dienes, for example, 3, obtained by ad-
dition of (substituted)allylzinc reagents to glyoxal diimine 4
derived from (S)-1-phenylethylamine.[8] However, unsatu-
[a] Dipartimento di Chimica “G. Ciamician”, Università di
Bologna,
via Selmi 2, 40126 Bologna, Italy
E-mail: diego.savoia@unibo.it
http://www.unibo.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403058.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Balestri, S. Grilli, C. Romano, D. Savoia
SHORT COMMUNICATION
rated primary diamine 1 could not be prepared by that perature, although any of the three diastereomers could be
route because the hydrogenolysis conditions that are re- isolated by column chromatography of the enriched reac-
quired to remove the N-(1-phenylethyl) substituent are not tion mixtures (see the Supporting Information).
tolerant of the alkene double bond. Consequently, the chi-
Cleavage of the N,NЈ-substituents in 6 was then ac-
ral auxiliaries could be removed only after functionalization complished by treatment with BCl3,[10a] which promoted
reactions of the C=C bond.[9]
the heterolytic cleavage of the N–C benzyl bond to form
the relatively stable p-MeO-benzylic carbenium ion interme-
diate and the primary diamine–BCl3 complex. This was im-
mediately converted into di(N-Boc) derivative 7a in 71%
yield by routine treatment with base and (Boc)2O. Then,
Results and Discussion
We considered that NH2-free diamine 1 has a larger po- RCM by using the second-generation Grubbs catalyst
tential of synthetic transformations with respect to the (Grubbs II, 5 mol-%, r.t., 12 h) in CH2Cl2 afforded pro-
N,NЈ-disubstituted derivatives. For example, 1 can be easily tected cyclohex-4-ene-1,2-diamine 9 in 67% yield.
converted into symmetrical and unsymmetrical diamides,
An alternative approach to compound 9 from 6 was pos-
upon which electrophile-promoted cyclizations and C=C sible by inverting the previously described steps. In fact, the
bond oxidation reactions, for example, should be easily per- RCM reaction of diamine dihydrochloride 6·2HCl by using
formed, whereas the double acylation of diamines 3, e.g. 6, the Grubbs II catalyst (4 mol-%, r.t., 12 h) gave cyclized di-
is often incomplete (unpublished results from our labora- amine 8 in 94% yield, in consequence of the precipitation
tory). For this reason, with the aim of preparing target of 8·2HCl in the reaction medium, filtration, and then basic
compound 1, we looked for another chiral auxiliary to be treatment. The RCM reaction was repeated by using 0.5
used as an alternative to tert-butyl sulfinamide, which is and 1 mol-% of the same catalyst at room temperature, but
commercially available although relatively expensive; it can incomplete conversions of 50 and 84%, respectively, were
also be prepared by a tedious procedure, and copper sulfate observed after 24 h. Moreover, a run performed with a cata-
must be added to the reaction to obtain moderately efficient lyst loading of 0.5 mol-% at reflux in CH2Cl2 for 7 h gave
condensation with aqueous glyoxal solution to give the cor- 78% conversion, but unidentified byproducts were also
responding diimine in 71% yield.
formed (18%). Surprisingly, the cheaper first-generation
Among the commercially available chiral primary ruthenium catalyst was poorly effective in the same reac-
amines, we chose 1-(4-methoxyphenyl)ethylamine because tion. Finally, removal of the chiral auxiliaries by treatment
the N-substituent can be removed from the derived second-
ary amines either oxidatively[10] or by the action of Lewis[11]
or Brønsted acids.[12] Although this chiral auxiliary was
never been employed for the organometallic addition to de-
rived imines, we supposed that it would provide a level of
diastereoselectivity close to that previously obtained in the
double allylation of the glyoxal bisimine derived from 1-
phenylethylamine (93% diastereoselectivity.[13]
Bisimine 5 was efficiently prepared by heating glyoxal tri-
mer dihydrate and (S)-1-(4-methoxyphenyl)ethylamine in
absolute ethanol at reflux for 20 min. The crude diimine
was obtained as a yellow-orange sticky solid and appeared
almost pure by analysis by 1H NMR spectroscopy, so it was
directly used in the successive allylmetalation step. We were
delighted to find that the double addition of freshly
prepared allylzinc bromide to a solution of diimine 5 in
anhydrous THF at –78 °C occurred cleanly to afford desired
diaminodiene 6 in 93% yield with high diastereoselectivity
(dr = 96.8:3:0.2 according to the order of elution in GC–
MS analysis). Column chromatography afforded the main
diastereomer of 6 in 60% yield as a pure compound. Several
attempts to obtain pure crystals from different solvents
were unsuccessful. The (R,R) configuration of the main dia-
stereomer was assigned on the basis of our previous report
by considering that the sense of asymmetric induction
should not be reversed by the presence of the p-methoxy
substituent in the phenyl group of the chiral auxiliary. On
the other hand, the addition of allylmagnesium chloride to
the same diimine occurred with an unsatisfactory level of
diastereoselectivity; the dr was highly affected by the tem- and cyclohex-4-ene-1,2-diamine derivatives.
Scheme 2. Stereoselective synthesis of octa-1,7-diene-4,5-diamine
2
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Synthesis of (R,R)-N,NЈ-Di(Boc)-cyclohex-4-ene-1,2-diamine
CDCl3, 25 °C): δ = 160.4, 158.7, 135.6, 127.7, 113.9, 68.9, 55.2,
23.7 ppm. MS (ESI): m/z = 325 [M + H]+.
of 8 with BCl3 and protection of the amine groups gave
desired 9 in overall 71% yield (two steps).
We also removed the benzylic substituents of diaminodi-
ene 6 by heating a trifluoroacetic acid (TFA) solution at
reflux for 24 h according to a reported procedure.[12b] In
this way, salt 10·2TFA was obtained as a pure solid in 60%
yield (Scheme 2). Moreover, cleavage of the auxiliaries was
performed by heating 6 with 3 m HCl at reflux, but the reac-
tion was incomplete after 24 h; on the other hand, heating
with 6 m HCl resulted in the complete consumption of the
starting material, but the isolated cyclohex-4-ene-1,2-di-
amine dihydrochloride was accompanied by unidentified
impurities and could not be satisfactorily purified. Cleavage
of the auxiliaries in protic acid is advantageous with respect
to the Lewis acid procedure, because in certain applications
the free diamine can be liberated in situ from its salt by
treatment with triethylamine.
Activation of Zinc Dust: Zinc dust was suspended in 2 m HCl and
vigorously stirred for 2 min. After filtration, the dust was washed
with plenty of water, then with ethanol, and lastly with diethyl
ether. The moist zinc was transferred into a round-bottomed flask
and flamed under vacuum until a fine powder was obtained.
Allylzinc Bromide (ca. 1
M in THF): Under a nitrogen atmosphere,
a 100 mL, three-necked, round-bottomed flask equipped with a
dropping funnel and containing activated zinc (3.92 g, 60 mmol)
was flamed for 5 min. When cooled, anhydrous THF (40 mL) was
added; then allyl bromide (5.44 g, 45 mmol) was slowly added
dropwise, and the mixture was stirred at room temperature for
1.5 h.
(4R,5R)-N,NЈ-Bis[(S)-1-(4-methoxyphenyl)ethyl]octa-1,7-diene-4,5-
diamine [(R,R)-6]: Diimine 5 (3.1 g, 9.6 mmol) was dissolved in dry
THF (30 mL) under a N2 atmosphere, and the solution was cooled
to –78 °C. Then, allylzinc bromide (1 m in THF, 30 mmol, 30 mL),
freshly prepared from allyl bromide and zinc dust, was added drop-
wise over 1 h. The mixture was stirred overnight while the tempera-
ture was slowly raised to 20 °C. The reaction was quenched by the
addition of 33% NH4OH/saturated aqueous NH4Cl (1:1, 50 mL),
and the organic material was extracted with Et2O (3ϫ 30 mL). The
collected layers were combined, dried (Na2SO4), and concentrated
to leave a brownish sticky solid (3.65 g, 93%). Column chromatog-
raphy allowed separation of the main diastereomer in high purity.
Yellow-orange sticky solid, yield 2.35 g (60%). [α]2D0 = –135.1 (c =
Conclusions
(S)-1-(4-Methoxyphenyl)ethanamine proved to be a con-
venient chiral auxiliary for the preparation of 1,2-diamines
from glyoxal through the corresponding 1,2-diimine. Com-
pared to optically pure tert-butyl sulfinamide, this commer-
cially available benzylic amine is less expensive and the 1-(4-
methoxyphenyl)ethyl substituent can be removed from the
derived secondary amines by treatment with boron trichlor-
ide. Moreover, it provides a high level of asymmetric induc-
tion, comparable to that offered by the more commonly
used 1-phenylethanamine, which cannot be applied to the
asymmetric synthesis of unsaturated primary amines be-
cause it can be removed by secondary amines exclusively
by hydrogenolysis protocols that are incompatible with the
presence of unsaturation.
1
1.11, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.21 (d, J
= 8.8 Hz, 4 H), 6.84 (d, J = 8.8 Hz, 4 H), 5.50–5.40 (m, 2 H), 4.84
(dd, J = 2.0, 10.0 Hz, 2 H), 4.74 (d, J = 17.2 Hz, 2 H), 3.79 (s, 6
H), 3.71 (q, J = 6.0 Hz, 2 H), 2.23–2.15 (m, 4 H), 2.10–2.02 (m, 2
H), 1.25 (d, J = 6.0 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 158.4, 138.4, 136.4, 128.0, 116.3, 113.6, 56.4, 55.3, 55.2,
34.9, 25.2 ppm. MS (ESI): m/z = 409 [M + H]+. MS (EI, 70 eV):
m/z (%) = 204 (12), 135 (100),105 (12).
N,NЈ-Di(Boc)-Octa-1,7-diene-4,5-diamine (7a): Diamine (R,R)-6
(110 mg, 0.27 mmol) was dissolved in CH2Cl2 (10 mL) and a solu-
tion of BCl3 (1 m in CH2Cl2, 1.35 mL, 1.35 mmol) was added. The
solution was stirred at room temperature for 24 h; it slowly turned
purple in color. Then, 1 m NaOH (10 mL) was added, and the mix-
ture was stirred for 1 h, after which time (Boc)2O (290 mg,
The choice of this chiral auxiliary allowed us to achieve
the asymmetric syntheses of N,NЈ-unsubstituted octa-1,7-
diene-4,5-diamine, cyclohex-4-ene-1,2-diamine, and their N-
protected derivatives. Noteworthy, N,NЈ-di(Boc)-cyclohex-
4-ene-1,2-diamine 9, which is a valuable building block and, 1.35 mmol) dissolved in CH2Cl2 (2 mL) was added. After vigorous
stirring for 12 h, the organic phase was separated, and the organic
material was further extracted with CH2Cl2 (3ϫ 15 mL). The col-
lected organic layers were concentrated under reduced pressure,
and then a mixture CH2Cl2/THF (1:1, 20 mL) was added. The sol-
vents were evaporated under reduced pressure. This operation was
repeated four times to obtain a slightly brown solid residue (81 mg).
Column chromatography (SiO2; cyclohexane/ethyl acetate, 95:5)
gave compound 7a as a white sticky solid, yield 65.2 mg (71%).
[α]2D0 = +4.1 (c = 0.12, CHCl3). 1H NMR (400 MHz, CDCl3,
25 °C): δ = 5.82–5.72 (m, 2 H), 5.12–5.08 (m, 4 H), 4.69 (br., 2 H),
3.64 (br., 2 H), 2.40–2.25 (br., 2 H), 2.18–2.13 (m, 2 H), 1.42 (s, 18
H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 156.2, 133.9,
118.0, 79.1, 53.2, 37.1, 28.4 ppm. MS (ESI): m/z = 341 [M + H]+.
MS (EI, 70 eV): m/z (%) = 243 (6), 170 (8), 143(7), 114 (32), 57
(100).
importantly, a precursor of Oseltamivir, was prepared from
the glyoxal diimine by a three-step sequence involving a
ring-closing metathesis step, which should be further opti-
mized by examining the activity of other recently developed
ruthenium catalysts.
Experimental Section
(1S,1ЈS)-N,NЈ-(Ethane-1,2-diylidene)bis[1-(4-methoxyphenyl)ethan-
amine] (5): Glyoxal trimer dihydrate (240 mg, 3.42 mmol) was
added to a solution of (S)-1-(4-methoxyphenyl)ethylamine (900 μL,
6 mmol) in EtOH (12 mL). The mixture was heated at reflux for
20 min and then cooled; it was filtered through a Celite pad and
washed with dichloromethane (2ϫ 10 mL). After cooling, the sol-
vent was removed under reduced pressure to leave diimine 5 as an
orange-yellow sticky solid (933 mg, 96%): [α]2D0 = –198 (c = 0.99,
N,NЈ-Dibenzoylocta-1,7-diene-4,5-diamine (7b): BCl3 (1 m in
CH2Cl2, 1 mL, 1.0 mmol) was slowly added to a stirred solution of
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.04 (s, 2 H), 6 (41 mg, 0.1 mmol) in CH2Cl2 (2.5 mL) under a N2 atmosphere.
7.29–7.26 (m, 4 H), 6.91–6.88 (m, 4 H), 4.50 (q, J = 6.4 Hz, 2 H), The purple mixture was stirred for 24 h, after which time the disap-
3.80 (s, 6 H), 1.58 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz,
pearance of the starting material was observed by TLC analysis
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D. Balestri, S. Grilli, C. Romano, D. Savoia
SHORT COMMUNICATION
(cyclohexane/EtOAc, 7:3). CH2Cl2 (2.5 mL) and then Bu4NF
(262 mg, 1.0 mmol), followed by Et3N (4 mmol, 0.558 mL) were
Preparation of 10: Diamine 6 (156 mg, 0.38 mmol) was dissolved in
trifluoroacetic acid (6 mL), and the solution was heated at reflux
added. After stirring the colorless mixture for 30 min, benzoyl for 24 h; then, TFA was coevaporated with CH2Cl2 (4ϫ 10 mL).
chloride (56 mg, 0.4 mmol) was added and stirring was continued
overnight. The reaction was quenched with saturated aqueous
The brownish sticky solid residue was triturated and washed with
CH2Cl2 (2ϫ 5 mL) and then with cyclohexane (3 mL) to give 10
NaHCO3 (5 mL), and the organic material was extracted with as a white sticky solid, yield 85 mg (60%). [α]2D0 = +10.9 (c = 0.63,
1
CH2Cl2 (3ϫ 20 mL). The collected organic layers were dried with
Na2SO4, and then the solvent was removed under vacuum. Product
7b was recovered as a white solid after chromatography of the resi-
due on a silica gel column (cyclohexane/EtOAc, 8:2), yield 17.5 mg
(50%), m.p. 177–185 °C. [α]2D0 = –12.8 (c = 1.75 in CHCl3). 1H
MeOH). H NMR (400 MHz, CD3OD, 25 °C): δ = 5.90–5.75 (m,
2 H), 5.42–5.30 (m, 4 H), 3.70–3.60 (m, 2 H), 2.65–2.55 (m, 2 H),
2.50–2.38 (m, 2 H) ppm. 13C NMR (100 MHz, CD3OD, 25 °C): δ
= 163.2 (q, J = 40.3 Hz), 132.2, 121.8, 118.1 (q, J = 290.0 Hz),
53.0, 33.3 ppm. 19F NMR (377 MHz, CD3OD, 25 °C): δ = –77.06
NMR (400 MHz, CDCl3, 25 °C): δ = 2.48 (m, 4 H), 2.56 (br., 2 (s) ppm. MS (ESI): m/z = 141 [M – CF3COOH – CF3COO–]+.
H), 4.24 (br., 2 H), 5.14–5.18 (dd, J = 1.6, 9.6 Hz, 4 H), 5.88 (m,
Supporting Information (see footnote on the first page of this arti-
2 H), 7.36 (t, J = 8.0 Hz, 4 H), 7.42 (d, J = 7.2 Hz, 2 H), 7.70 (d,
cle): NMR spectra of all the isolated intermediates and products;
J = 7.6 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
procedures for the addition of allylmagnesium chloride to the di-
36.2, 52.8, 118.7, 126.9, 128.5, 131.5, 133.5, 134.1, 168.2 ppm. MS
imine; analytical data of diastereoisomers (S,S)-6 and (R,S)-6.
(ESI): m/z = 348 [M + H]+. MS (EI, 70 eV): m/z (%) = 307 (8), 175
(22), 105 (100), 77 (36).
Acknowledgments
(1R,2R)-N,NЈ-Bis[(S)-1-(4-methoxyphenyl)ethyl]cyclohex-4-ene-1,2-
diamine (8): Salt 6·2HCl (350 mg, 0.73 mmol), prepared by the ad-
This work was supported by the Ministero dell’Istruzione, dell’Uni-
dition of HCl (2 m in Et2O) to diamine (R,R)-6, was dissolved in
versità e della Ricerca (MIUR), Roma and was performed in the
dry CH2Cl2 (7 mL) under an argon atmosphere. The solution was
context of the PRIN program: “Sintesi e stereocontrollo di molec-
ole organiche mediante metodologie innovative”.
deaerated for 5 min, and then the second-generation Grubbs cata-
lyst (25 mg, 0.029 mmol) was added. The mixture was stirred for
12 h, and 8·2HCl precipitated as a white solid. Then, Et2O (60 mL)
was added and 8·2HCl was filtered under vacuum, yield 315 mg
(95%). Free base 8 was obtained after basification with 5% aq.
NaHCO3 (10 mL) and extraction with CH2Cl2 (3ϫ 8 mL). White
sticky solid, yield 261 mg (94%). [α]2D0 = +66.7 (c = 2.1, CHCl3).
1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.22 (d, J = 8.4 Hz, 4 H),
6.87 (d, J = 8.8 Hz, 4 H), 5.50–5.45 (m, 2 H), 3.84 (q overlapped,
J = 6.4 Hz, 2 H), 3.80 (s, 6 H), 2.50–2.40 (m, 2 H), 2.35–2.27 (m,
2 H), 1.71–1.65 (m, 2 H), 1.33 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 158.3, 13 7.6, 127.5, 113.8, 55.1,
53.9, 53.7, 31.7, 25.5 ppm. MS (ESI): m/z = 381 [M + H]+. MS
(EI, 70 eV): m/z (%) = 245 (7), 150 (10), 135 (100), 105 (25).
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Chem. 1999, 1523–1526; b) S. Grilli, G. Martelli, D. Savoia, C.
Zazzetta, Adv. Synth. Catal. 2002, 344, 1068–1072; c) C. Boga,
C. Fiorelli, D. Savoia, Synthesis 2006, 285–292.
[9] a) D. Savoia, S. Grilli, A. Gualandi, Org. Lett. 2010, 12, 4964–
4967; b) D. Savoia, D. Balestri, S. Grilli, M. Monari, Eur. J.
Org. Chem. 2014, 1907–1914.
[10] a) J. Podlech, S. Steurer, Synthesis 1999, 650–654; b) B. A. R.
Prasad, A. Bisai, V. K. Singh, Tetrahedron Lett. 2004, 45, 9565–
9567.
From 8: A solution of BCl3 (1 m in CH2Cl2, 2.83 mL, 2.83 mmol)
was added to a stirred solution of diamine 7 (185 mg, 0.49 mmol)
in dry CH2Cl2 (5 mL). After 24 h, 1 m NaOH (10 mL) was added,
and the mixture was stirred for 3 h. Then a solution of (Boc)2O
(617 mg, 2.83 mmol) in dry CH2Cl2 (6 mL) was added, and the
resulting mixture was stirred for 12 h. The organic material was
extracted with CH2Cl2 (3ϫ 20 mL) and the solvent was coevapo-
rated with Et2O (2ϫ 10 mL). Column chromatography of the resi-
due (SiO2; cyclohexane/EtOAc, 95:5) gave 9 as a white sticky solid,
yield 108 mg (71%). [α]2D0 = +28.9 (c = 0.93, CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 5.60–5.50 (m, 2 H), 4.91 (br., 2 H),
3.70–3.60 (m, 2 H), 2.55–2.40 (m, 2 H), 2.05–1.90 (m, 2 H), 1.41
(s, 18 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 156.5,
125.0, 79.2, 51.3, 32.8, 28.4 ppm. MS (ESI): m/z = 313 [M + H]+.
MS (EI, 70 eV): m/z (%) = 195 (7), 139 (55),95 (21), 82 (39), 57
(100).
[11] a) S. D. Boggs, J. D. Cobb, K. S. Gudmundsson, L. A. Jones,
R. T. Matsuoka, A. Millar, D. E. Patterson, V. Samano, M. D.
Trone, S. Xie, X. Zhou, Org. Process Res. Dev. 2007, 11, 539–
545; the BCl3–SMe2 complex was previously used to cleave
4
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Job/Unit: O43058
/KAP1
Date: 20-11-14 13:16:38
Pages: 6
Synthesis of (R,R)-N,NЈ-Di(Boc)-cyclohex-4-ene-1,2-diamine
benzyl ethers, see: b) M. S. Congreve, E. C. Davidson,
M. A. M. Fuhry, A. B. Holmes, A. N. Payne, R. A. Robinson,
S. E. Ward, Synlett 1993, 663–664; c) A. Scheurer, P. Mosset,
R. W. Saalfrank, Tetrahedron: Asymmetry 1997, 8, 1243–1251.
[12] a) J. G. Catalano, K. S. Gudmundsson, A. Svolto, S. D. Boggs,
J. F. Miller, A. Spaltenstein, M. Thomson, P. Wheelan, D. J.
Minich, D. P. Phelps, Bioorg. Med. Chem. Lett. 2010, 20, 2186–
2190; b) G. Martelli, M. Orena, S. Rinaldi, Eur. J. Org. Chem.
2011, 7199–7206; c) S. Sashikant, V. Raju, S. Somajah, P. S.
Rao, K. V. Reddy, Synthesis 2013, 45, 621–624.
[13]
Optically pure 1-(2-methoxyphenyl)- and 1-(2,n-dimethoxy)-
phenylethanamine (n = 3–6) were previously used as chiral aux-
iliaries in organometallic addition to derived imines: a) Y.
Hashimoto, N. Kobayashi, A. Kai, K. Saigo, Synlett 1995,
961–962; b) T. Kohara, Y. Hashimoto, K. Saigo, Tetrahedron
1999, 55, 6453–6464. Hence, they might be applied to the
double allylmetalation of the corresponding glyoxal bisimines.
Received: August 8, 2014
Published Online: ᭿
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Job/Unit: O43058
/KAP1
Date: 20-11-14 13:16:38
Pages: 6
D. Balestri, S. Grilli, C. Romano, D. Savoia
SHORT COMMUNICATION
Asymmetric Synthesis
D. Balestri, S. Grilli, C. Romano,
D. Savoia* ......................................... 1–6
Chiral Auxiliary Induced Diastereoselec-
tive Synthesis of (R,R)-N,NЈ-Di(tert-but-
oxycarbonyl)cyclohex-4-ene-1,2-diamine
Keywords: Asymmetric synthesis / Metath-
esis / Diastereoselectivity / Chiral auxiliar-
ies / Amines
(R,R)-N,NЈ-Di(tert-butoxycarbonyl)cyclo-
hex-4-ene-1,2-diamine is synthesized from
the glyoxal diimine, which is prepared by
using a chiral auxiliary. Double allylation
to the diimine proceeds with excellent dia-
stereoselectivity; then, removal of the N-
substituents followed by ring-closing met-
athesis (RCM) of the diene moiety affords
the protected cyclohex-4-ene-1,3-diamine
in satisfactory overall yield.
6
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