Journal of the American Chemical Society
Article
assigned to the methyl groups at δ 0.92 (major) and δ 0.82
(minor) ppm; >99% ee and 92% ee, respectively). H NMR
methanol) to yield the product as a glassy, colorless film (267
mg, 71% yield). 1H NMR (400 MHz, CDCl3): δ 7.07 (bs, 1H),
6.93 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 9.9 Hz, 1H), 6.57 (d, J = 7.9
Hz, 1H), 6.05 (t, J = 3.9 Hz, 1H), 5.73 (d, J = 9.9 Hz, 1H), 5.23
(d, J = 11.4 Hz, 1H), 5.03 (d, J = 11.4 Hz, 1H), 3.91 (s, 1H), 3.41
(s, 3H), 3.23 (d, J = 11.5 Hz, 1H), 3.15−3.08 (m, 2H), 3.00−2.94
(m, 1H), 2.48 (d, J = 15.1 Hz, 1H), 2.24−2.17 (m, 2H), 2.12 (d, J
= 15.1 Hz, 1H), 2.02−1.81 (m, 2H), 1.47 (s, 3H), 1.41 (s, 3H),
1.32 (s, 3H), 0.96 (s, 3H). 13C NMR (125 MHz, CD2Cl2): δ
183.2, 160.9, 154.9, 139.4, 136.5, 132.1, 125.7, 118.8, 117.9,
117.8, 111.4, 109.3, 108.4, 75.8, 72.9, 60.7, 59.5, 58.7, 56.9, 51.4,
50.5, 49.3, 47.0, 28.0, 27.2, 23.0, 22.7, 21.8. IR (thin film): 3361,
1
(major diastereomer only, 400 MHz, CDCl3): δ 6.98 (d, J = 7.8
Hz, 1H), 6.93 (d, J = 9.8 Hz, 1H), 6.57 (d, J = 7.8 Hz, 1H), 5.72
(d, J = 9.8 Hz, 1H), 5.48 (s, 1H), 5.25−5.21 (m, 2H), 5.02 (d, J =
11.7 Hz, 1H), 4.59 (s, 1H), 3.41 (s, 3H), 2.80 (s, 2H), 1.47 (s,
3H), 1.41 (s, 3H), 1.24 (s, 3H), 0.97 (s, 3H). 13C NMR (major
diastereomer only, 100 MHz, CDCl3): δ 182.5, 154.4, 142.4,
139.1, 131.6, 125.6, 119.8, 119.0, 117.9, 111.6, 111.2, 107.9, 75.5,
72.5, 58.0, 56.8, 48.4, 45.9, 39.1, 28.2, 27.4, 22.3, 21.4. IR (thin
film): 2974, 2230, 1713, 1635, 1608, 1461 cm−1. [α]24D = −67.0
(c 1.15, CHCl3). Chiral HPLC: Chiralpak OD-H, 0.8 mL/min,
1% i-PrOH in heptane, λ = 254 nm; MAJOR: tR,major = 14.7 min,
tR,minor = 17.5 min; MINOR: tR,minor = 21.8 min, tR,major = 29.3 min.
HRMS: calcd for (M + Na+) C23H26N2O3Na 401.1836. Found
401.1820.
D
2933, 1702, 1674, 1629, 1451 cm−1. [α]25 = −9.0 (c 0.94,
CH2Cl2, 89% ee). HRMS: calcd for (M + H+) C29H35N4O4
503.2653. Found 503.2647.
Primary Alcohol (83). (i) To a solution of nitrile 81 (210
mg, 0.42 mmol, dried from 3 × 4 mL benzene) in dichloro-
methane (10.5 mL) at 0 °C was added triethylaluminum (0.42
mL, 1 M in heptane, 0.42 mmol), and the pale pink solution was
stirred for 90 min at 0 °C. It was then cooled to −78 °C, and
DIBAL (1.04 mL, 1.2 M in toluene, 1.04 mmol) was added. The
solution was stirred for 60 min at −78 °C and quenched by the
addition of methanol (125 μL). The cooling bath was removed,
sat. aq Rochelle’s salt (10 mL) was added, and the mixture was
stirred for 1 h before it was extracted with ethyl acetate (3 × 10
mL). The combined organic layers were washed with brine (10
mL), dried over MgSO4, concentrated, and purified by
chromatography (2−3% methanol in dichloromethane) to
yield a mixture of the nitrile and the desired aldehyde that was
carried on directly to the next step. 1H NMR (aldehyde only, 600
MHz, CDCl3): δ 9.85 (d, J = 4.0 Hz, 1H), 7.08 (bs, 1H), 6.92 (d, J
= 7.6 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H),
6.08 (t, J = 4.3 Hz, 1H), 5.71 (d, J = 7.6 Hz, 1H), 5.23 (d, J = 11.0
Hz, 1H), 5.01 (d, J = 11.0 Hz, 1H), 3.62 (d, J = 4.0 Hz, 1H), 3.41
(s, 3H), 3.28−3.09 (m, 4H), 2.45 (d, J = 14.8 Hz, 1H), 2.23−2.16
(m, 2H), 2.07 (d, J = 14.8 Hz, 1H), 1.99−1.83 (m, 2H), 1.47 (s,
3H), 1.41 (s, 3H), 1.30 (s, 3H), 0.85 (s, 3H). (ii) The mixture
was dissolved in dichloromethane and methanol (30 mL, 4:1)
and cooled to 0 °C. Sodium borohydride (79.0 mg, 2.09 mmol)
was added, and the reaction was stirred for 4 h at 0 °C. It was then
carefully quenched by the addition of 1 M NaHSO4 (2 mL) and
extracted with ethyl acetate (2 × 100 mL). The combined
organic layers were dried over MgSO4, concentrated, and
purified by chromatography (2.0−3.5% methanol in dichloro-
methane) to yield recovered starting material (44 mg) followed
by the desired product (98 mg, 46% yield, 58% yield brsm) as a
white film. 1H NMR (400 MHz, CDCl3): δ 7.60 (bs, 1H), 6.93
(d, J = 9.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 8.1 Hz,
1H), 6.27 (t, J = 4.3 Hz, 1H), 5.71 (d, J = 9.9 Hz, 1H), 5.26 (d, J =
10.3 Hz, 1H), 5.01 (d, J = 10.3 Hz, 1H), 4.19 (d, J = 10.5 Hz, 1H),
3.87 (t, J = 11.5 Hz, 1H), 3.68−3.60 (m, 1H), 3.42 (s, 3H), 3.28
(d, J = 12.0 Hz, 1H), 3.25−3.19 (m, 1H), 3.08 (dd, J = 3.4, 10.5
Hz, 1H), 2.94 (d, J = 11.5 Hz, 1H), 2.77 (dt, J = 3.7, 11.3 Hz, 1H),
2.27−2.20 (m, 3H), 2.04 (d, J = 14.6 Hz, 1H), 1.97−1.89 (m,
(R)-4-(Hydroxymethyl)-1′-(methoxymethyl)-2,2,7′,7′-
tetramethyl-2′-oxo-2′,7′-dihydro-1′H-spiro[cyclopent-
[3]ene-1,3′-pyrano[2,3-g]indole]-3-carbonitrile (78e). (i)
To an argon-purged vial of oxindole 76 (1.0 g, 3.34 mmol),
ligand L10 (35.0 mg, 0.067 mmol), and Pd(dba)2 (19.2 mg,
0.033 mmol) was added toluene (8 mL), and the solution was
stirred for 2−3 min at room temperature before cooling to 4 °C.
1-Cyano-2-((trimethylsilyl)methyl)allyl acetate (1.06 g, 5.0
mmol) was added, and the reaction was stirred for 18 h at 4
°C, then purified directly by flash chromatography (7% ethyl
acetate in hexanes) to yield the product as a white foam (∼1.3 g).
(ii) This foam was dissolved in dry THF (24 mL) and cooled to
−78 °C. To this flask was then added 7.8 mL of a 0.30 M LiOt-
Bu/0.60 M n-BuLi solution (2.34 and 4.7 mmol, respectively) in
THF. The resultant yellow solution was stirred at −78 °C for 45
min, and then a −78 °C solution of oxaziridine (1.83 g, 7.0
mmol) in THF (8 mL) was added as quickly as possible using a
thick cannula. After 30 min at −78 °C, the reaction was warmed
to room temperature over 30 min, quenched with 1 M NaHSO4
(50 mL), and extracted with ethyl acetate (100 mL). The organic
phase was washed with sat. NaHCO3 (2 × 50 mL) and brine (50
mL), dried over MgSO4, concentrated, and purified by flash
chromatography (40% ethyl acetate in hexanes) to yield the
product as a faint yellow foam (785 mg, 60% yield over 2 steps,
89% ee). The product is sometimes contaminated by a small
amount of benzenesulfonamide, which can be removed by
washing an ethyl acetate solution with 2−3 portions of 1 M
NaOH. 1H NMR (400 MHz, CDCl3): δ 7.01 (d, J = 8.3 Hz, 1H),
6.92 (d, J = 10.2 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 5.72 (d, J =
10.2 Hz, 1H), 5.26 (d, J = 11.0 Hz, 1H), 5.00 (d, J = 11.0 Hz, 1H),
4.52 (d, J = 14.9 Hz, 1H), 4.45 (d, J = 14.9 Hz, 1H), 3.39 (s, 3H),
2.99 (d, J = 18.1 Hz, 1H), 2.88 (d, J = 18.1 Hz, 1H), 1.48 (s, 3H),
1.40 (s, 3H), 1.19 (s, 3H), 1.12 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 180.9, 158.9, 154.3, 138.5, 131.6, 124.9, 121.2, 117.9,
117.6, 115.0, 111.3, 107.9, 75.5, 72.5, 60.6, 58.7, 56.6, 53.0, 41.8,
28.2, 27.2, 25.1, 22.6. IR (thin film): 3425 (br), 2969, 2933, 2216,
1722, 1609, 1461 cm−1. [α]23D = −41.0 (c 0.88, CHCl3, 89% ee).
Chiral HPLC: Chiralpak IA, 0.8 mL/min, 5% i-PrOH in heptane,
λ = 254 nm; tR,minor = 16.6 min, tR,major = 20.2 min. HRMS: calcd
for (M + Na+) C23H26N2O4Na 417.1785. Found 417.1779.
Michael Adduct (81). A solution of unsaturated nitrile 80
(376 mg, 0.75 mmol, concentrated thrice from toluene (4 mL) in
THF (24 mL) was cooled to 0 °C. Lithium tert-butoxide solution
(1.82 mL, 0.41 M in 4.5:1 THF/hexanes, 0.75 mmol) was added
by syringe pump over 60 min, and the resulting solution was
stirred at 0 °C for an addition 2 h. It was then concentrated and
purified by flash chromatography (70:1 dichloromethane/
2H), 1.47 (s, 3H), 1.40 (s, 3H), 0.90 (s, 3H), 0.85 (s, 3H). 13
C
NMR (100 MHz, C6D6): δ 183.4, 160.3, 154.4, 139.8, 137.4,
130.9, 125.7, 120.4, 118.5, 110.8, 110.7, 107.8, 75.1, 72.4, 61.2,
60.1, 59.7, 58.8, 57.7, 56.4, 50.8, 48.3, 48.1, 28.1, 27.0, 23.7, 22.8,
22.2, 20.6. IR (thin film): 3353, 2971, 2934, 1703, 1668, 1626
cm−1. [α]24D = −14.8 (c 0.96, CH2Cl2, 89% ee). HRMS: calcd for
(M + H+) C29H38N3O5 508.2806. Found 508.2802.
Unsaturated Bicyclo[2.2.2]diazaoctane (85). In a round-
bottom flask equipped with a reflux condenser, a solution of
N
dx.doi.org/10.1021/ja409013m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX