Diastereoselective synthesis of 1,3- Syn -oxazines via a tandem hemiaminalization and Tsuji-Trost reaction

Article abstract of DOI:10.1055/s-0032-1318300

A novel domino sequence for the rapid assembly of 1,3-syn-substituted oxazines is reported. Mechanistically, the one-pot procedure is based on a three-step sequential process involving a hemiaminalization and Tsuji-Trost reaction. The process generates up

Full text of DOI:10.1055/s-0032-1318300

LETTER
▌625
lDettierastereoselective Synthesis of 1,3-syn-Oxazines via a Tandem Hemiaminali-
zation and Tsuji–Trost Reaction
Diastereoselective Synthesis of 1,3-syn-Oxazines
Bin Tang,a Liang Wang,a,1 Dirk Menche*b
a
Ruprecht-Karls-Universität Heidelberg, Institut für Organische Chemie, INF 270, 69120 Heidelberg, Germany
b
Rheinische Friedrich-Wilhelms-Universität Bonn, Institut für Organische Chemie und Biochemie, Gerhard-Domagk-Str 1, 53121 Bonn,
Germany
Fax +49(228)735813; E-mail: dirk.menche@uni-bonn.de
Received: 03.12.2012; Accept after revision: 31.01.2013
ple starting materials. A related sequence, as reported by
Abstract: A novel domino sequence for the rapid assembly of 1,3-
the groups of Campagne and Robiette,4l relies on the addi-
syn-substituted oxazines is reported. Mechanistically, the one-pot
tion of homoallylic alcohols to tosyl isocyanate giving the
corresponding cyclic carbamates. Using their approach
procedure is based on a three-step sequential process involving a
hemiaminalization and Tsuji–Trost reaction. The process generates
up to two new stereogenic centers in a concise and convergent fash- the trans diastereomers may be obtained in useful yields,
ion from simple and readily available starting materials.
in contrast to the results discussed herein giving access to
the syn diastereomers. The group of Hiemstra had report-
ed the attack of an hemiaminal derived from a sulfon-
amide and a glyoxylate to a double bond activated by
Pd(II) giving an allylic N,O-acetal.7
Key words: synthetic methodology, tandem reaction, catalysis, al-
lylic substitution, oxazines
As exemplified by the potent alkaloids sedamine (1a) and
pyrrolsedamine (1b, Scheme 1),2 the 1,3-hydroxylamine
functionality presents a prevalent structural feature in a
wide variety of biologically active natural products and
bioactive agents,3 which renders the development of effi-
cient synthetic procedures for their assembly an important
research goal from the perspective of medicinal chemistry
and drug discovery. Consequently, a wide variety of
methods have been reported to access this structural fea-
ture.4 Inspired by present targets in our group in combina-
tion with certain limitations of these existing methods, in
particular with respect to convergence and conciseness,
we desired a more direct and convergent procedure, rely-
ing on a readily available chiral alcohol functionality.
Herein, we report a novel process for the concise con-
struction of protected 1,3-syn-amino alcohols from readi-
ly available starting materials, based on a relay sequence
involving a tandem hemiaminalization and an intramolec-
ular allylic substitution reaction.
Me
OH
Me
OH
N
N
(+)-sedamine (1a)
(+)-pyrrolsedamine (1b)
3 step relay process
R2
(1)
R2
*
R2
*
NTs
(2)
5
(3)
NTs
NTs
O
O
*
+
OH
*
*
R1
R1
R1
OR
*
MLn
2
3
MLn
4
Scheme 1
To test our concept, readily available homoallylic alcohol
68 was treated with various tosylated aldimines9 in the
presence of allylpalladium(II) chloride dimer [{Pd(al-
lyl)Cl}2], triphenylphosphine and LHMDS as base (1.5
equiv) in accordance with similar conditions previously
developed in our group for related transformations (en-
tries 1–6).4
Inspired by previous sequential processes developed in
our group,5 our synthetic approach to access the protected
1,3-amino alcohol functionality was based on a three-step
sequential process, involving a hemiaminalization6 and
subsequent allylic substitution. As shown in Scheme 1,
homoallylic alcohol 4 would first add to a suitable imine
(5). Secondly, a π-allyl complex 3 would be generated,
which would be finally trapped in an intramolecular fash-
ion by an allylic substitution reaction, generating the de-
sired oxazine motif in a highly direct fashion. Along this
process, two new stereogenic centers are formed, demon-
strating a high increase in structural complexity from sim-
Gratifyingly, as shown in Table 1, the reaction worked in-
deed within expectation in good diastereoselectivities al-
beit low yield under these conditions (Table 1, entry 3).
During further optimization studies (entries 7–11) it was
then found that the amount of base was crucial for the pro-
cess. Considering that the tert-butoxide anion formed dur-
ing the Tsuji–Trost process10 may itself act as a base and
may then deprotonate the starting alcohol, we evaluated
whether the desired transformation could also be effectu-
ated with only catalytic amount of base (entries 7–11).
Furthermore, based on the excellent selectivities obtained
SYNLETT 2013, 24, 0625–0629
Advanced online publication: 18.02.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318300; Art ID: ST-2012-B1033-L
© Georg Thieme Verlag Stuttgart · New York

626
B. Tang et al.
LETTER
with acetaldimine (entry 3), a variety of aldimines were nylphosphine as ligand and 10 mol% load of {Pd(al-
evaluated. It was found that the overall results of N-nosyl- lyl)Cl}2 as catalyst dissolved in toluene adding the base
protected phenyl aldimine were not improved (entry 7). (KHMDS, 10 mol%) at –78 °C and 15 minutes after addi-
Furthermore, no reaction occurred by utilizing N-Boc- tion warming the reaction mixture to room tempera-
protected phenyl aldimine (entry 8). Improved yields were ture.13,14
observed by using N-tosyl-protected acetaldimine, how-
As shown in Figure 1, this protocol was readily applicable
ever at the expense of diastereoselectivity (entries 9 and
for the synthesis of diverse 1,3-oxazines with good selec-
11).
tivities considering the stereochemical complexity of the
As shown in Table 2, this reaction was then further evalu- process. As compared to aliphatic substrates better stereo-
ated with different catalysts and ligands. Low degrees of selectivities were obtained with electron-rich aromatic
conversion could also be observed in the complete ab- homoallylic substrates and were up to 10.1:1.0:2.7:2.8
sence of base, suggesting that the alcohol itself might be (viz. 12) which confirms the preparative utility of the pro-
nucleophilic enough to initiate this sequential process.12 cess. The 1,3-syn diastereomer was preferentially ob-
Best yields were obtained with KHMDS as a base, toluene tained.
as solvent while a similar result was observed with tetra-
As demonstrated in Scheme 2 for the conversion of 11, the
hydrofuran as solvent. In contrast to related cyclizations
aminal tether can be readily cleaved with activated mag-
previously studied in our group,5b only a minor influence
nesium powder,5b to deliver the N-benzyl-protected 1,3-
of the solvent on the stereochemical outcome of the reac-
tion was observed. In a parallel fashion a variety of differ-
amino alcohol 19, demonstrating the usefulness of our ap-
proach for the synthesis of 1,3-syn-amino alcohols. Inter-
ent palladium sources and ligands were also evaluated
estingly, this transformation led to an increased
(entries 9–14); however, the overall efficiency of this
diastereomeric purity, possibly by a kinetic effect with the
syn isomer reacting faster.
process could not be further increased. The best reagent
combination (entry 5) involved 30 mol% of triphe-
Table 1 Tandem Hemiaminalization–Tsuji–Trost Reaction11
{Pd(allyl)Cl}2 (10 mol%)
PPh3 (30 mol%), base
NR2
OH
+
R1
Ar
OBoc
solvent, –78 °C to r.t.
7
6
R1
R1
R1
R1
O
NR2
O
NR2
O
NR2
O
NR2
+
+
+
Ar
Ar
Ar
Ar
8a
8b
8c
8d
Entry
Ar
R1
Et
R2
Base
Solvent
Yield (%)
dr (a/b/c/d)
1
2
Ph
Ph
Ts
Ns
Ts
Ts
Ts
Ts
Ns
Boc
Ts
Ts
Ts
t-BuOKa
LHMDSa
LHMDSa
LHMDSa
LHMDSa
LHMDSa
KHMDSc
KHMDSc
KHMDSc
THF
15
9
–
2-MeOC6H4
THF
–
3
4-Tol
4-Tol
4-Tol
4-Tol
Me
Et
THF
8
17.8:3.6:1.0:–f
9.2:1.0: 2.1:–f
1.0:1.5:4.8:0.3
–
4
THF
10
16b
n.r.
39
n.r.
64
13
41
5
Ph
THF
6
i-Pr
Ph
THF
7
4-MeOC6H4
4-MeOC6H4
Ph
toluene
toluene
toluene
THF
2.6:1.4:2.4:1.0
–
8
Ph
9
Me
Me
Me
4.9:1.4:1.0:5.4
d
d
10
11
4-MeOC6H4
4-MeOC6H4
–
–
LHMDSe
THF
5.0:1.0:1.0:6.3
a The amount of base used was 1.5 equiv.
b One of two fractions in which the mixtures of isomers were partially separated by chromatography.
c The amount of base used was 10 mol%.
d No base was used.
e Pd2dba3·CHCl3/P(i-PrO)3 was used as catalyst.
f Diastereomer d could not be detected by NMR of the crude product.
Synlett 2013, 24, 625–629
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Synthesis of 1,3-syn-Oxazines
627
Table 2 Optimization of Reaction Conditions11
OH
Ph
Ph
Ph
Ph
Pd source (10 mol%)
ligands (30 mol%)
KHMDS (10 mol%)
4-Tol
OBoc
9
O
NTs
O
NTs
O
NTs
O
NTs
+
+
+
+
solvent, –78 °C to r.t.
4-Tol
4-Tol
4-Tol
4-Tol
NTs
11a
11b
11c
11d
Ph
10
Entry
Pd catalyst/ligand
Base, solvent
Yield (%)
dr (11a/11b/11c/11d)
1
2
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(allyl)Cl}2/PPh3
{Pd(dppf)Cl}2/dppf
[Pd2(dba)3]·CHCl3/PPh3
Pd(PPh3)4/–
NaH, THF
n.r.
31
60
29
67
59
31
35
12
48
39
38
n.r.
46
–
LiHMDS, THF
KHMDS, THF
2.8:1.0:1.6:1.5
3.9:1.0:2.0:1.5
1.2:1.0:1.1:1.3
3.9:1.0:2.7:1.5
2.5:1.0:3.0:1.2
3.9:1.0:2.3:2.6
3.5:1.0:2.6:2.0
1.1:1.0:1.6:0.6
2.7:1.0:1.8:0.1
0.9:1.0:1.1:0.2
0.7:1.0:2.0:–
–
3
4
KHMDS, CH2Cl2
KHMDS, toluene
DBU, toluene
5
6
7
Cs2CO3, toluene
KOtBu, toluene
KHMDS, toluene
KHMDS, toluene
KHMDS, toluene
KHMDS, toluene
KHMDS, toluene
KHMDS, toluene
8
9
10
11
12
13
14
{Pd(allyl)Cl}2/dppe
{Pd(allyl)Cl}2/PCy3
{Pd(allyl)Cl}2/P(i-PrO)3
0.9:1.0:2.0:0.6
In accordance with related cyclizations,5 the observed ste-
reoselectivity may arise from a Zimmerman–Traxler-type
transition state (20a, Scheme 3) giving 11a with all sub-
stituents in equatorial positions, in agreement with the ob-
served stereochemical outcome. Alternatively, attack
from the opposite side of the π-allyl system via 20c may
lead to the less favored isomer 11c with two of the three
substituents residing in equatorial positions.15
Ph
Ts
OH HN
Ph
O
N
Mg
MeOH, reflux
8 h, 64%
19
11
syn/anti = 1.3:1
syn/anti = 2.6:1
Scheme 2
In summary, we have devised a novel method for the ste-
reoselective synthesis of 1,3-syn-oxazines. Mechanisti-
cally, the one-pot procedure is based on a tandem
hemiaminalization with Tsuji–Trost reaction and it en-
ables a rapid and highly convergent access to these hetero-
cycles from very simple and readily available starting
materials. 1,3-syn Diastereomers are obtained in good
yields and selectivities, considering the stereochemical
complexity of the process. The diastereomeric induction
is purely based on substrate-control, which adds to the ef-
fectiveness of the process. These results may find useful
applications in natural product synthesis or scaffold prep-
aration in medicinal chemistry.
9 + 10
PdLn
base
Ph
Ph
N
N
O
O
Ts
Ts
Ar
Ar
PdLn
PdLn
20a
20c
Ph
Ph
N
O
O
N
Ts
Ts
Ar
Ar
11a
11c
Scheme 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 625–629

628
B. Tang et al.
LETTER
J.-P. Angew. Chem. Int. Ed. 1991, 30, 1702. (d) Boyd, S. A.;
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Dias, L. C. J. Chem. Soc., Chem. Commun. 1987, 1053.
(b) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc.,
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Norbedo, S. J. Org. Chem. 2002, 67, 8635. (g) Wabnitz, T.
C.; Spencer, J. B. Org. Lett. 2003, 5, 2141. (h) Kochi, T.;
Tang, T.; Ellman, J. J. Am. Chem. Soc. 2003, 125, 11276.
(i) Kennedy, A.; Nelson, A.; Perry, A. Synlett 2004, 967.
(j) Adamo, I.; Benedetti, F.; Berti, F.; Campaner, P. Org.
Lett. 2006, 8, 51. (k) Menche, D.; Arikan, F.; Li, J.; Rudolph,
S. Org. Lett. 2007, 9, 267. (l) Broustal, G.; Ariza, X.;
Campagne, J.-M.; Garcia, J.; Georges, Y.; Marinetti, A.;
Robiette, R. Eur. J. Org. Chem. 2007, 4293. (m) Ghorai, M.;
Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48, 4373.
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1231. (o) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008,
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Feringa, B. L. J. Am. Chem. Soc. 2009, 131, 9473. (q) Rice,
G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707.
(r) Paradine, S. M.; White, M. C. J. Am. Chem. Soc. 2012,
134, 2036.
Ph
Ph
6
O
NTs
O
NTs
2
4
15
11
dr 7.4:1.0:2.5:3.3a (57%)b
dr 3.9:1.0:2.7:1.5a (67%)b
(2,4-syn/anti = 2.2:1)
(2,4-syn/anti = 1.2:1)
Ph
Ph
O
NTs
OMe
O
NTs
12
16
dr 10.1:1.0:2.7:2.8a (62%)b
dr 9.8:2.1:3.9:1.0a (63%)b
(2,4-syn/anti = 2.1:1)
(2,4-syn/anti = 2.4:1)
Ph
Ph
O
NTs
O
NTs
MeO
17
13
dr 5.2:1.0:1.1:1.1a (51%)b
dr 8.0:1.7:4.5:1.0a (69%)b
(2,4-syn/anti = 2.8:1)
(2,4-syn/anti = 1.7:1)
Ph
Ph
O
NTs
O
NTs
18
14
dr 5.2:1.0:1.5:2.2a (55%)b
dr 1.9:1.5:2.7:1.0a (53%)b
(2,4-syn/anti = 1.7:1)
(2,4-syn/anti = 0.9:1)
(5) (a) Wang, L.; Li, P.; Menche, D. Angew. Chem. Int. Ed.
2010, 49, 9270. (b) Morgen, M.; Bretzke, S.; Li, P.; Menche,
D. Org. Lett. 2010, 12, 4494. (c) Wang, L.; Menche, D.
Angew. Chem. Int. Ed. 2012, 51, 9425. (d) Wang, L.;
Menche, D. J. Org. Chem. 2012, 77, 10811.
a dr for (6-epi)-, (4-epi)- and (4-epi, 6-epi)-isomer given
b combined yield
Figure 1
(6) For a domino reaction involving a hemiaminalization, see:
Urushima, T.; Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2010, 12, 4588.
Acknowledgment
(7) van Benthem, R. A. T. M.; Hiemstra, H.; Michels, J. J.;
Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 357.
(8) All required homoallylic substrates were readily prepared by
allylation of the respective aldehyde and subsequent cross-
metathesis, as previously described; see ref. 4.
Generous financial support by the Deutsche Forschungsgemein-
schaft (SFB 623 ‘Molekulare Katalysatoren: Struktur und Funk-
tionsdesign’) and the Chinese Scholarship Council (CSC,
scholarship to B.T.) is gratefully acknowledged. Furthermore, we
thank Andreas J. Schneider for HPLC support.
(9) N-Arenesulfonyl aldimines were readily prepared from
aliphatic and aromatic aldehydes in a two-step
transformation. See: Chemla, F.; Hebbe, V.; Normant, J.-F.
Synthesis 2000, 75.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(10) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(11) In all cases, stereochemical assignment was based on NMR
methods. Scheme 4 shows an example.
References and Notes
(1) Present address: University of Basel, Switzerland.
(2) (a) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491. (b) Plunkett,
A. O. Nat. Prod. Rep. 1994, 11, 581. (c) Cossy, J.; Willis, C.;
Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982.
(d) Fustero, S.; Jimenéz, D.; Moscardó, J.; Catalán, S.; Pozo,
C. Org. Lett. 2007, 9, 5283.
Ph
Ph
3
Ts
Ha
O
N
O
NTs
H
2
=
1
Ar
H
Hb
H
H
(3) For examples of bioactive 1,3-amino alcohols, see:
(a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am.
Chem. Soc. 1982, 104, 6465. (b) Colau, B.; Hootelk, C. Can.
J. Chem. 1983, 61, 470. (c) Benz, G.; Henning, R.; Stasch,
11a
: NOE
correlation
Scheme 4
Synlett 2013, 24, 625–629
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Synthesis of 1,3-syn-Oxazines
629
(12) A yield of 56% was obtained in the absence of base for the
analogous reaction described in entry 5 (Table 2).
10.4, 7.7 Hz, 1 H), 5.02 (d, J = 17.3 Hz, 1 H), 4.96 (d, J =
10.3 Hz, 1 H), 4.40 (ddd, J = 8.5, 8.2, 7.7 Hz, 1 H), 3.86 (dd,
J = 10.2, 4.7 Hz, 1 H), 2.50 (s, 3 H), 2.35 (s, 3 H), 1.93 (ddd,
J = 13.7, 10.2, 8.2 Hz, 1 H), 1.54 (ddd, J = 13.7, 8.5, 4.7 Hz,
1 H). 13C NMR (125.76 MHz, CDCl3): δ = 143.93, 141.52,
139.12, 137.74, 137.48, 137.36, 129.78, 129.19, 129.14,
128.27, 128.02, 127.82, 127.63, 127.29, 126.81, 126.17,
125.71, 115.73, 83.83, 73.15, 56.10, 33.62, 21.58, 21.08.
HRMS (ESI): m/z [M + H]+ calcd for C26H28NO3S:
434.17844; found: 434.17839. Oxazine 12a: 1H NMR
(500.13 MHz, CDCl3): δ = 7.91–7.96 (m, 4 H), 7.71 (d, J =
7.7 Hz, 2 H), 7.50 (d, J = 7.7 Hz, 2 H), 7.32–7.40 (m, 5 H),
6.73 (s, 1 H), 5.78 (ddd, J = 17.3, 10.4, 6.6 Hz, 1 H), 5.02 (d,
J = 17.3 Hz, 1 H), 4.94 (d, J = 10.4 Hz, 1 H), 4.50 (ddd, J =
8.2, 8.0, 6.6 Hz, 1 H), 4.34 (dd, J = 11.5, 2.2 Hz, 1 H), 3.71
(s, 3 H), 2.48 (s, 3 H), 2.07 (ddd, J = 13.7, 8.0, 2.2 Hz, 1 H),
1.82 (ddd, J = 13.7, 11.5, 8.0 Hz, 1 H). 13C NMR (125.77
MHz, CDCl3): δ = 155.85, 143.35, 141.45, 139.34, 131.19,
129.72, 129.06, 128.57, 128.00, 127.90, 127.65, 126.89,
126.29, 120.62, 115.46, 110.29, 84.36, 68.03, 55.78, 55.09,
33.19, 21.54. HRMS (ESI): m/z [M + K]+ calcd for
C26H27NO4SK: 488.12924; found: 488.12948.
(13) Experimental Procedure: Under an argon atmosphere,
imine 10 (62.2 mg, 0.24 mmol), allylpalladium(II) chloride
dimer (7.3 mg, 10 mol%) and triphenylphosphine (15.8 mg,
30 mol%) were added to a well-dried Schlenk flask. Then, a
solution of the respective carbonate (0.2 mmol) in anhyd
toluene (0.33 M, 0.61 mL) was added to the flask and stirred
until all solids were dissolved. After cooling to –78 °C, the
potassium bis(trimethylsilyl)amide solution (0.5 M in
toluene) was added dropwise (40 μL, 10 mol%). After 15
min the reaction mixture was warmed to r.t. and stirred at
this temperature until complete conversion. After addition of
a sat. aq solution of NH4Cl (2 mL), the mixture was extracted
with EtOAc (3 ×), washed with H2O and brine and dried over
Na2SO4. The solvent was removed in vacuo and the residue
was purified by column chromatography on silica gel with
EtOAc–hexane (1:16) as eluent to afford the oxazines with
the indicated yields and selectivities.
(14) All new compounds had spectroscopic data in support of the
assigned structures. Oxazine 11a: 1H NMR (500.13 MHz,
CDCl3): δ = 7.97 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1
H) 7.63 (d, J = 8.2 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 7.29–
7.42 (m, 5 H), 7.12–7.19 (m, 2 H), 7.07 (d, J = 7.9 Hz, 1 H),
7.00 (d, J = 7.9 Hz, 1 H), 6.75 (s, 1 H), 5.78 (ddd, J = 17.3,
(15) For a more detailed mechanistic discussion of a related
cyclization, see ref. 4d.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 625–629

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