9
00
Synthesis
M. Jasiński et al.
Paper
1
1
H NMR (600 MHz, CDCl ): δ = 1.03 (s, 9 H, t-Bu), 3.48 (s, 3 H, OMe),
H NMR (600 MHz, CDCl ): δ = 1.84 (ddd, J = 5.8, 12.9, 14.7 Hz, 1 H, 4-
3
3
3
.76 (br d, J ≈ 3.4 Hz, 1 H, 3-H), 3.86–3.90 (m, 2 H, NCH Ph, 4′-H),
H), 2.00 (br d, J ≈ 14.7 Hz, 1 H, 4-H), 2.99 (d, J = 9.1 Hz, 1 H, 9a-H), 3.26
(s, 3 H, OMe), 3.49–3.55 (m, 2 H, 6-H, 8-H), 3.61–3.68 (m, 2 H, 6-H, 7-
H), 3.77 (br dd, J ≈ 5.5, 11.1 Hz, 1 H, 3-H), 3.93–3.98 (m, 2 H, 3-H, 9-H),
2
3.97 (dd, J = 3.7, 10.9 Hz, 1 H, 4′-H), 4.04–4.11 (m, 3 H, NCH Ph, 2′-H,
2
3
′-H), 4.19 (dd, J = 3.4, 6.4 Hz, 1 H, 1′-H), 4.23 (br dd, J ≈ 1.7, 14.5 Hz, 1
H, 6-H), 4.30 (br d, J ≈ 14.5 Hz, 1 H, 6-H), 4.49 (AB system, JAB = 11.4
Hz, 1 H, OCH Ph), 4.65, 4.66 (AB system, J = 11.5 Hz, 2 H, OCH Ph),
4.18, 4.59 (AB system, JAB = 14.9 Hz, 2 H, NCH Ph), 4.63, 4.71 (AB sys-
2
tem, JAB = 14.9 Hz, 2 H, OCH Ph), 4.82, 5.00 (AB system, J = 10.2 Hz, 2
2
AB
2
2
AB
4.69 (br t, J ≈ 2.8 Hz, 1 H, 5-H), 4.696, 4.704 (AB system, JAB = 12.5 Hz, 2
H, OCH Ph), 4.83, 5.02 (AB system, J = 10.8 Hz, 2 H, OCH Ph), 7.19–
2
A
B
2
H, OCH Ph), 4.74 (AB system, J = 11.4 Hz, 1 H, OCH Ph), 7.18–7.39,
7.22, 7.25–7.33, 7.39–7.41 (3 m, 1 H, 17 H, 2 H, 4 Ph).
2
AB
2
7
.61–7.67 (2 m, 26 H, 4 H, 6 Ph).
13
C NMR (151 MHz, CDCl ): δ = 28.3 (t, C-4), 48.0 (q, OMe), 57.6 (t, C-
3
13
C NMR (151 MHz, CDCl ): δ = 19.2, 26.9 (s, q, t-Bu), 54.1 (q, OMe),
6), 59.6 (t, NCH Ph), 64.4 (t, C-3), 67.3 (d, C-9a), 73.7, 75.8, 76.3 (3 t, 3
3
2
5
8.2 (t, NCH Ph), 63.4 (t, C-6), 63.6 (d, C-3), 64.7 (t, C-4′), 72.8, 72.9,
OCH Ph), 79.9 (d, C-9), 80.5 (d, C-7), 88.8 (d, C-8), 98.3 (s, C-4a), 126.7,
2
2
7
3.1 (3 t, 3 OCH Ph), 79.1 (d, C-1′) 79.9, 81.0 (2 d, C-2′, C-3′), 91.3 (d,
127.36, 127.37, 127.7*, 127.8, 128.0, 128.18, 128.23, 128.3, 128.4,
128.5, 138.3, 138.8, 139.1, 139.6 (11 d, 4 s, 4 Ph); * higher intensity.
2
C-5), 126.9, 127.0, 127.07, 127.14, 127.5*, 127.67, 127.68, 128.0,
1
1
28.06*, 128.07, 128.1, 128.4*, 129.4, 133.7, 133.8, 135.7*, 138.0,
38.9, 139.0, 139.3 (13 d, 2 s, d, 4 s, 6 Ph), 152.8 (s, C-4); * higher in-
+
+
ESI-MS: m/z (%) = 618 (73) [M + Na] , 596 (100) [M + H] .
Anal. Calcd for C37H41NO (595.3): C, 74.60; H, 6.94; N, 2.35. Found: C,
6
tensity.
74.61; H, 6.93; N, 2.39.
+
+
ESI-MS: m/z (%) = 857 (29) [M + Na] , 835 (100) [M + H] .
Anal. Calcd for C53H59NO Si (834.4): C, 76.32; H, 7.13; N, 1.68. Found:
C, 76.49; H, 6.99; N, 1.54.
6
trans-17a
1
H NMR (600 MHz, CDCl ): δ (selected signals) = 1.81 (ddd, J = 5.3,
3
1
3
8
3.2, 14.1 Hz, 1 H, 4-H), 2.19 (br dt, J ≈ 2.3, 14.1 Hz, 1 H, 4-H), 3.34 (s,
H, OMe), 3.70 (ddd, J = 1.4, 5.3, 12.0 Hz, 1 H, 3-H), 4.49 (dd, J = 8.1,
Cyclization of 1,2-Oxazine Derivatives rac-11 and syn-15a–c; Gen-
eral Procedure
.9 Hz, 1 H), 4.84 (d, J = 11.3 Hz, 1 H, CH Ph).
2
A solution of 1,2-oxazine derivative rac-11 (257 mg, 0.50 mmol) or
syn-15a–c (417 mg, 0.50 mmol) in ca. 0.3% HCl in MeOH (25 mL) was
stirred at r.t. for the required time. The resulting mixture was treated
with an excess of solid NaHCO , diluted with CH Cl (50 mL), and fil-
tered through a short pad of Celite. The crude mixture was pre-puri-
fied by filtration through a short pad of silica gel (PE–EtOAc, 6:1) to
give a mixture of cis- and trans-products. The major cis-fused diaste-
reomers were isolated by additional column chromatography.
13
C NMR (151 MHz, CDCl ): δ (selected signals) = 32.1 (t, C-4), 48.0 (q,
3
OMe), 96.4 (s, C-4a).
3
2
2
(4aS,7S,8R,9S,9aS)-1-Benzyl-7,8,9-tris(benzyloxy)-4a-methoxyoxe-
pano[3,2-c][1,2]oxazine (cis-17b)
Reaction time 5 d; partially purified 17b (259 mg, 87%, cis/trans
84:16) was subjected to column chromatography (silica gel, hexane–
EtOAc, 5:1) to yield the major cis isomer as thick colorless oil.
Y
i
e
l
d
:
2
0
3
m
g
(
6
8
%
)
;
[
α
]
2
2
+
9
.
3
(
c
0
.
7
7
,
C
H
C
l
)
.
cis-1-Benzyl-4a-methoxyoxepano[3,2-c][1,2]oxazine (rac-12)
Reaction time 3 d; partially purified product (126 mg, 91%, cis/trans
D
3
IR (KBr): 3090–2830 (=C–H, C–H), 1455, 1350, 1115, 1075, 1030
–
1
>
99:1) was subjected to column chromatography (silica gel, PE–
(C–O) cm .
EtOAc, 6:1) to yield rac-12 as thick colorless oil; yield: 108 mg (78%).
1
H NMR (600 MHz, CDCl ): δ = 1.92 (ddd, J = 5.6, 12.0, 14.5 Hz, 1 H, 4-
3
IR (neat): 3070–2855 (=C–H, C–H), 1590, 1430, 1110 (C–O) cm–1
.
H), 1.97 (br d, J ≈ 14.5 Hz, 1 H, 4-H), 2.80 (d, J = 9.2 Hz, 1 H, 9a-H),
3.19 (s, 3 H, OMe), 3.60–3.67 (m, 3 H, 6-H, 7-H, 8-H), 3.69 (br ddd, J ≈
1
td, J ≈ 3.4, 11.5 Hz, 1 H, 3-H), 4.08 (AB system, JAB = 14.9 Hz, 1 H,
NCH Ph), 4.16 (dd, J = 5.2, 9.2 Hz, 1 H, 9-H), 4.30 (AB system, J = 14.9
Hz, 1 H, NCH Ph), 4.52, 4.55 (AB system, J = 12.2 Hz, 2 H, OCH Ph),
1
H NMR (600 MHz, CDCl ): δ = 1.18–1.26 (m, 1 H, 8-H), 1.61–1.71 (m,
3
.2, 5.2, 10.9 Hz, 1 H, 3-H), 3.77 (dd, J = 3.3, 12.7 Hz, 1 H, 6-H), 3.88 (br
3
H, 7-H , 9-H), 1.80 (ddd, J = 5.7, 12.4, 14.4 Hz, 1 H, 4-H), 1.89–1.95
2
(m, 2 H, 4-H, 8-H), 2.05 (ddd, J = 2.6, 5.8, 14.2 Hz, 1 H, 9-H), 2.88 (d,
2
AB
J = 9.7 Hz, 1 H, 9a-H), 3.27 (s, 3 H, OMe), 3.57 (dtd, J ≈ 1.6, 3.2, 12.7 Hz,
H, 6-H), 3.70 (AB system, JAB = 14.0 Hz, 1 H, CH Ph), 3.70–3.77 (m, 2
2
AB
2
1
2
4
.57 (AB system, JAB = 10.7 Hz, 1 H, OCH Ph), 4.65 (AB system,
2
H, 3-H, 6-H), 3.88 (ddd, J = 3.0, 11.2, 12.3 Hz, 1 H, 3-H), 4.09 (AB sys-
JAB = 12.3 Hz, 1 H, OCH Ph), 4.72 (AB system, J = 10.7 Hz, 1 H,
OCH Ph), 4.73 (AB system, J = 12.3 Hz, 1 H, OCH Ph), 7.10–7.14,
7
2
AB
tem, JAB = 14.0 Hz, 1 H, CH Ph), 7.22–7.25, 7.29–7.32, 7.37–7.40 (3 m,
2
2
AB
2
1
H, 2 H, 2 H, Ph).
.17–7.28, 7.29–7.32 (3 m, 1 H, 17 H, 2 H, 4 Ph).
13
C NMR (151 MHz, CDCl ): δ = 22.1 (t, C-9), 27.0 (t, C-8), 28.5 (t, C-4),
3
13
C NMR (151 MHz, CDCl ): δ = 28.9 (t, C-4), 48.0 (q, OMe), 59.5 (t,
3
2
9.9 (t, C-7), 48.0 (q, OMe), 58.5 (t, CH Ph), 60.9 (t, C-6), 66.0 (t, C-3),
2
NCH Ph), 60.4 (t, C-6), 63.9 (t, C-3), 70.5 (d, C-9a), 71.7, 73.7, 74.2 (3 t,
3
1
2
71.0 (d, C-9a), 99.9 (s, C-4a), 126.9, 128.1, 128.5, 138.0 (3 d, s, Ph).
OCH Ph), 75.5 (d, C-7), 78.2 (d, C-9), 83.1 (d, C-8), 97.8 (s, C-4a),
2
+
+
ESI-MS: m/z (%) = 278 (62) [M + H] , 246 (100) [M – OMe] .
26.6, 127.4, 127.49, 127.51, 127.7, 127.98, 127.99, 128.19, 128.21,
+
HRMS (EI): m/z [M] calcd for C16H23NO : 277.1678; found: 277.1678.
128.28, 128.29, 128.33, 138.5, 138.7, 138.9, 139.6 (12 d, 4 s, 4 Ph).
3
+
+
ESI-MS: m/z (%) = 618 (100) [M + Na] , 596 (13) [M + H] .
(
4aS,7R,8R,9S,9aS)-1-Benzyl-7,8,9-tris(benzyloxy)-4a-methoxy-
Anal. Calcd for C37H41NO (595.3): C, 74.60; H, 6.94; N, 2.35. Found: C,
6
oxepano[3,2-c][1,2]oxazine (cis-17a)
74.45; H, 6.92; N, 2.37.
Reaction time 5 d; partially purified 17a (223 mg, 75%, cis/trans
8
8:12) was subjected to column chromatography (silica gel, hexane–
trans-17b
1H NMR (600 MHz, CDCl
EtOAc, 6:1) to yield the major cis-isomer as thick colorless oil; yield:
22
3
): δ (selected signals) = 1.89 (br d, J ≈ 14.2
164 mg (55%); [α]D +34.1 (c 0.67, CHCl3).
Hz, 1 H, 4-H), 2.15 (br ddd, J = 5.9, 13.5, 14.2 Hz, 1 H, 4-H), 3.26 (s,
H, OMe), 4.34 (d, J = 12.1 Hz, 1 H, CH Ph), 4.77 (d, J = 11.8 Hz, 1 H,
IR (KBr): 3090–2830 (=C–H, C–H), 1455, 1355, 1125, 1075 (C–O) cm–1
.
3
2
CH Ph).
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 893–905