SPECIAL TOPIC
Regioselective Hydroformylation–Organocatalytic anti-Mannich Reaction
1315
Yield: 133 mg (0.350 mmol, 98%); colorless oil; 99% ee deter-
mined by chiral HPLC [Chiralpak-AD-H; 25 cm × 4.6 mm ID; n-
51.2 (CH, 1C), 52.0 (CH, 1C), 62.1 (CH -ester, 1C), 67.2 (CH ,
1C), 127.0 (CH, 2C), 127.3 (Ar-C, 1C), 128.1 (Ar-C, 2C), 128.3
2
2
heptane–i-PrOH, 90:10; 1.0 mL/min; λ = 214, 254 nm]: t = 10.8
(Ar-C, 2C), 128.6 (Ar-C, 1C), 156.5 [C(O), 1C], 170.8 [C(O), 1C],
202.4 [C(O), 1C].
R
2
2
(major), 11.6 (minor) min; [α]D +35.6 (c = 0.48, CHCl3).
1
3
+
H NMR (400 MHz, CDCl ): δ = 0.88 (t, J
= 7.2 Hz, 3 H,
MS (CI, NH ): m/z = 91.0 (25), 360.2 (24), 374.2 (100) [M + H].
3
Me–CH2
3
CH ), 1.25 (m , 10 H, CH ), 1.42–1.50 (m, 2 H, CH ), 3.11 (m , 1 H,
+
3
c
2
2
c
HRMS (CI): m/z [M + H] calcd for C H NO : 374.19670; found:
3
21 28
5
CH), 2.75* (m , 1 H, CH), 4.19 (q, J
= 7.2 Hz, 2 H, CH2),
c
CH2–CH3
3
74.19675 (Δ: 0.1 ppm).
3
3
4
.63 (dd, J
= 3.7 Hz, J
= 9.5 Hz, 1 H, CH), 4.74* (dd,
CH–CH
CH–NH
3
3
JCH–CH = 3.9 Hz, J
= 8.4 Hz, 1 H, CH), 5.14 (s, 2 H, CH2),
CH–NH
Ethyl (2S,3R)-2-tert-Butoxycarbonylamino-3-formyl-8-hy-
droxyoctanoate (4e)
Prepared according to the general procedure with hex-5-en-1-ol
(84 μL, 61 mg, 0.54 mmol, 1.5 equiv) and α-amido sulfone 2a
129 mg, 0.360 mmol, 1.0 equiv). Purification was achieved by
flash column chromatography (cyclohexane–EtOAc, 5:1).
5
.52 (d, 3J
= 9.6 Hz, 1 H, NH), 7.14 (m , 5 H, Ar-H), 9.60 (s,
NH–CH c
1
H, CH), 9.69* (s, 1 H, CH). * = diastereomer.
13
C NMR (100 MHz, CDCl ): δ = 14.1 (CH , 1C), 14.2 (CH , 1C),
3
3
3
(
2
5.2 (CH , 1C), 27.5 (CH , 1C), 29.0 (CH , 1C), 29.5 (CH , 1C),
2 2 2 2
3
1.8 (CH , 1C), 49.3 (CH, 1C), 52.7 (CH, 1C), 53.8 (CH, 1C), 54.1
2
(CH, 1C), 62.1 (CH -ester, 1C), 67.3 (CH , 1C), 128.1 (Ph-C, 1C),
Yield: 99 mg (0.30 mmol, 83%); colorless oil; [α] 22 +26.5
2
2
D
1
1
28.2 (Ph-C, 2C), 128.6 (Ph-C, 2C), 136.2 (Ph-C, 1C), 200.8 [C(O),
C], 201.5 [C(O), 1C].
(c = 1.30, CHCl3).
1
3
H NMR (400 MHz, CDCl ): δ = 1.22 (t, J
= 7.2 Hz, 3 H,
Me–CH2
3
Anal. Calcd for C H NO : C, 66.82; H, 8.28; N, 3.71. Found: C,
CH ), 1.42 (s, 3 H, t-Bu), 1.55 (m , 4 H, CH ), 1.65–1.84 (m, 4 H,
2
1
31
5
3
c
2
6
6.86; H, 8.12; N, 3.57.
CH ), 3.05 (m , 0.8 H, CH), 2.75* (m , 0.2 H, CH), 3.60–3.66 (m,
2 c c
3
3
2
H, CH ), 4.17 (q, J
= 7.2 Hz, 2 H, CH ), 4.56 (dd, J
=
2
CH2–CH3
2
CH–CH
Ethyl (2S,3R)-2-(tert-Butoxycarbonylamino)-3-formyl-5,5-di-
methyl-hexanoate (4c)
Prepared according to the general procedure with 3,3-dimethylbut-
3
3.7 Hz, J
= 9.4 Hz, 0.8 H, CH), 4.67* (m , 0.2 H, CH), 5.27
CH–NH
c
3
(
d, J
= 9.2 Hz, 1 H, NH), 9.58 (s, 0.8 H, CHAldehyde), 9.64* (d,
NH–CH
3
JCH–CH = 1.5 Hz, 0.2 H, CHAldehyde). * = diastereomer.
1-ene (77 μL, 45 mg, 0.54 mmol, 1.5 equiv) and α-amido sulfone 2a
13
C NMR (100 MHz, CDCl ): δ = 14.1 (CH , 1C), 25.0 (CH , 1C),
(129 mg, 0.360 mmol, 1.0 equiv). Purification was achieved by
3
3
2
2
1
6
1
5.7 (CH , 1C), 28.3 (CH , t-Bu, 3C), 30.3 (CH , 1C), 32.2 (CH ,
flash column chromatography (cyclohexane–EtOAc, 10:1).
Yield: 79 mg (0.25 mmol, 70%); colorless oil; [α]D22 +6.7 (c = 1.2,
CHCl3).
2 3 2 2
C), 46.3 (CH, 1C), 52.1 (CH, 1C), 53.9 (CH, 1C), 61.9 (CH , 1C),
2
2.6 (CH -ester, 1C), 171.3 (C, 1C), 202.4 [C(O), 1C], 205.2 [C(O),
2
C].
1
H NMR (400 MHz, CDCl ): δ = 0.93 (s, 9 H, t-Bu), 1.25 (t,
MS (APCI, +ve): m/z = 232.1 (96), 257.8 (82), 331.8 (100) [M]+,
3
3
3
3
JMe–CH2 = 7.1 Hz, 3 H, CH ), 1.32 (dd, J
= 7.1 Hz, J
=
3
CHA–CH
CHA–CHB
3
48.8 (72), 654.0 (60).
3
1
5.1 Hz, 1 H, CH ), 1.46 (s, 9 H, t-Bu), 1.70 (dd, J
= 6.8 Hz,
A
CHB–CH
3
Anal. Calcd for C H NO : C, 57.99; H, 8.82; N, 4.23. Found: C,
16 29 6
57.90; H, 8.87; N, 4.06.
JCHB–CHA = 14.5 Hz, 1 H, CH ), 3.08 (m , 0.8 H, CH), 2.80* (m ,
B
c
c
=
3
3
0
.2 H, CH), 4.18 (q, J
= 7.1 Hz, 2 H, CH ), 4.60 (dd, J
CH2–CH3
2
CH–CH
3
4.0 Hz, J
= 8.3 Hz, 0.8 H, CH), 4.50* (m , 0.2 H, CH), 5.33
CH–NH c
3
3
Ethyl (2S,3R)-8-Benzyloxy-2-tert-butoxycarbonylamino-3-for-
myl-octanoate (4f)
(d, J
= 8.3 Hz, 1 H, NH), 9.62 (s, 0.9 H, CH), 9.70* (d, J
=
NH–CH
CH–CH
1.6 Hz, 1 H, CH). * = diastereomer.
Prepared according to the general procedure with 1-[(hex-5-eny-
loxy)methyl]benzene (103 mg, 0.540 mmol, 1.5 equiv) and α-ami-
do sulfone 2a (129 mg, 0.360 mmol, 1.0 equiv). Purification was
achieved by flash column chromatography (cyclohexane–EtOAc,
10:1).
13
C NMR (100 MHz, CDCl ): δ = 14.1 (CH , 1C), 21.8 (CH, 1C),
3
3
2
8.4 (CH , t-Bu, 3C), 29.3 (CH , t-Bu, 3C), 37.2 (CH , 1C), 50.3
3
3
2
(CH, 1C), 54.2 (CH, 1C), 62.0 (CH -ester, 1C), 129.7 [C(O), 1C],
2
129.8 [C(O), 1C], 202.0 [C(O), 1C].
MS (APCI, +ve): m/z = 216.0 (36), 259.8 (51), 276.8 (39), 315.6
Yield: 129 mg (0.310 mmol, 85%); colorless oil; 94% ee deter-
mined by chiral HPLC (Chiralpak-AD-H; 25 cm × 4.6 mm ID; n-
+
(100) [M] , 316.6 (21), 332.6 (44), 374.7 (63).
heptane–i-PrOH, 95:5; 1.0 mL/min; λ = 214 nm): t = 15.6 (major),
R
Ethyl (2S,3R)-2-Benzyloxycarbonylamino-3-formyl-4-(cyclo-
hex-3-enyl)butyrate (4d)
22
1
7.2 (minor) min; [α]D +23.6 (c = 0.48, CHCl3).
1
3
H NMR (400 MHz, CDCl ): δ = 1.18 (t, J
= 7.2 Hz, 3 H,
Prepared according to the general procedure with 4-vinylcyclohex-
3
Me–CH2
CH ), 1.25–1.45 (m, 4 H, CH ), 1.37 (s, 9 H, t-Bu), 1.55 (m , 2 H,
1-ene (58 mg, 0.54 mmol, 1.5 equiv) and α-amido sulfone 2b
3
2
c
CH ), 1.62–1.78 (m, 2 H, CH ), 2.98 (m , 0.7 H, CH), 2.66* (m ,
(
141 mg, 0.360 mmol, 1.0 equiv). Purification was achieved by
2
2
c
c
=
3
3
0
.3 H, CH), 3.40 (t, J
= 6.6 Hz, 2 H, CH ), 4.12 (q, J
flash column chromatography (cyclohexane–EtOAc, 10:1).
CH2–CH2
2
CH2–CH3
7
.2 Hz, 2 H, CH ), 4.42 (s, 0.5 H, CH ), 4.43* (s, 1.5 H, CH ), 4.45
2
2
2
Yield: 88 mg (0.32 mmol, 88%); colorless oil; 94% ee determined
by chiral HPLC (Chiralpak-OJ-H; 25 cm × 4.6 mm ID; n-heptane–
3
3
(
dd, J
= 3.8 Hz, J
= 9.5 Hz, 0.8 H, CH), 4.61* (mc,
CH–CH
CH–NH
3
0.2 H, CH), 5.19 (d, J
= 9.2 Hz, 1 H, NH), 7.20–7.32 (m, 5 H,
NH–CH
EtOH, 200:1; 1.0 mL/min; 40 °C; λ = 210 nm): t = 65.2 (major),
3
R
Ar-H), 9.53 (s, 0.8 H, CH), 9.61* (d, J = 1.1 Hz, 0.2 H, CH).
2
2
CH–CH
7
6.3 (major), 85.1 (minor), 90.8 (minor) min; [α]D +37.5
*
= diastereomer.
(
c = 1.00, CHCl3).
13
C NMR (100 MHz, CDCl ): δ = 14.1 (CH , 1C), 25.1 (CH , 1C),
1
3
3
3
2
H NMR (400 MHz, CDCl ): δ = 1.23 (t, J
= 7.1 Hz, 3 H,
Me–CH2
3
2
2
8.0 (CH , 1C), 28.3 (CH , 1C), 28.4 (t-Bu, 3C), 29.5 (CH , 1C),
2
2
2
CH ), 1.41–1.52 (m, 2 H, CH , CH), 1.70 (m , 4 H, CH, CH ), 2.10
3
2
c
2
9.6 (CH , 1C), 52.3 (CH, 1C), 53.0 (CH , 1C), 53.9 (CH, 1C), 61.9
2
.
(
m , 1 H, CH ), 3.27 (m , 0.8 H, CH), 2.95* (m , 0.2 H, CH), 4.19
c 2 c c
(
1
CH -ester, 1C), 70.2 (CH , 1C), 73.0 (CH , 1C), 127.6 (Ph-C, 1C),
27.7 (Ph-C, 2C), 128.4 (Ph-C, 2C), 138.7 (Ph-C, 1C), 171.2 (t-Bu,
3
3
2
2
2
(
q, J
= 6.0 Hz, 2 H, CH ), 4.62 (dd, J
= 3.2 Hz,
CH–CH
CH2–CH3
2
3
3
3
JCH–NH = 9.0 Hz, 0.8 H, CH), 4.71* (dd, JCH–CH = 3.4 Hz, J
=
CH–NH
= 10.1 Hz,
1C), 201.3 [C(O), 1C], 202.4 [C(O), 1C].
3
8
1
0
.2 Hz, 0.2 H, CH), 5.12 (s, 2 H, CH ), 5.55 (d, J
2
NH–CH
+
MS (APCI, +ve): m/z = 322.1 (52), 421.7 (100) [M] , 438.9 (64),
H, NH), 5.65 (m , 2 H, CH), 7.31–7.46 (m, 5 H, Ar-H), 9.60 (s,
c
4
54.3 (30).
.4 H, CHAldehyde), 9.62 (s, 0.4 H, CHAldehyde), 9.71* (s, 0.1 H,
CHAldehyde), 9.73* (s, 0.1 H, CHAldehyde). * = diastereomer.
+
HRMS (CI): m/z [M + H] calcd for C H NO : 422.25440; found:
2
3
36
6
13
422.25426 (Δ: –0.3 ppm).
C NMR (100 MHz, CDCl ): δ = 14.1 (CH , 1C), 24.9 (CH , 1C),
3
3
2
2
8.3 (CH , 1C), 29.0 (CH , 1C), 30.9 (CH , 1C), 31.0 (CH, 1C),
2 2 2
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1311–1320