Synthetic studies on lemonomycin: Construction of the tetracyclic core

Article abstract of DOI:10.1016/j.tet.2013.05.009

A substrate-induced stereocontrol strategy was used to gain access to the tetracyclic core of (-)-lemonomycin. An advanced intermediate was prepared from a known substituted tyrosinol through a 16-step sequence, which involved a Pictet-Spengler reaction, a [3+2] dipolar cycloaddition and an enamide hydrogenation.

Full text of DOI:10.1016/j.tet.2013.05.009

Tetrahedron 69 (2013) 7505e7512
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies on lemonomycin: construction of the tetracyclic
core
a
a,b,
*
ꢀ
Alberto Jimenez-Somarribas , Robert M. Williams
a Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872, United States
b University of Colorado Cancer Center, Aurora, CO 80045, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A
substrate-induced stereocontrol strategy was used to gain access to the tetracyclic core of
Received 9 December 2012
Received in revised form 4 May 2013
Accepted 6 May 2013
(ꢀ)-lemonomycin. An advanced intermediate was prepared from a known substituted tyrosinol
through a 16-step sequence, which involved a PicteteSpengler reaction, a [3þ2] dipolar cycloaddition
and an enamide hydrogenation.
Available online 10 May 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
(ꢀ)-Lemonomycin
Tetrahydroisoquinoline antitumor
antibiotics
PicteteSpengler reaction
[3þ2] Dipolar cycloaddition
1. Introduction
aldehyde 5 via azomethine ylide 4, using a [3þ2] dipolar cycload-
dition approach previously developed by our group.20 This key
Lemonomycin (1) is a member of the tetrahydroisoquinoline
(THIQ) family of antitumor antibiotics.1 It was isolated from the
fermentation broth of Streptomyces candidus (LL-AP191) in 1964,2
and its structure was reported by He and co-workers in 2000.4
This compound showed significant in vitro antimicrobial activi-
ties against both gram-negative and gram-positive bacteria, in-
cluding antibiotic-resistant strains, as well as against the human
colon tumor cell line HCT116.2,4 Structurally, the compound con-
tains the tetracyclic core found in quinocarcin5 and tetrazomine,6
which includes a 3,8-diazabicyclo ring system and a rare bis-
desoxy aminosugar portion, which has only been found in a few
natural products.7e11 The structural complexity and biological ac-
tivities of this substance have made lemonomycin an attractive
target for the synthetic community. To date, there are two total
syntheses by Stoltz12 and Fukuyama13 and synthetic studies by
Magnus,14,15 Zhu,16e18 Mulzer,19 and our laboratory.20
reaction was also used for the construction of the [3,8]-diazabicyclo
ring system in our total syntheses of (ꢀ)-tetrazomine21 and
(ꢁ)-quinocarcinamide.22 The tetrahydroisoquinoline system of 5
could be formed through a PicteteSpengler reaction involving
a derivative of compound 6, which is a known compound.23
As shown in Scheme 1, we envisioned that the final steps in the
synthesis of lemonomycin (1) would involve a late-stage glycosyl-
ation reaction, and the formation of the quinone, hemiaminal, and
aldehyde hydrate functional groups. Compound
2 could be
accessed through the epimerization of the southern benzylic po-
sition and the reduction of the enamide double bond found in
tetracycle 3. This key intermediate could be prepared from
* Corresponding author. Tel.: þ1 970 491 6747; fax: þ1 970 491 3944; e-mail
Scheme 1. Retrosynthetic analysis.
address: rmw@lamar.colostate.edu (R.M. Williams).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.05.009

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A. Jimenez-Somarribas, R.M. Williams / Tetrahedron 69 (2013) 7505e7512
7506
2. Results and discussion
Our synthetic sequence starts with substituted tyrosinol 6,
which can be prepared from commercially available -tyrosine
L
methyl ester according to the procedure described by Liao.23 We
initially attempted to perform the direct conversion of 6 into bis-
silyl ether 8 using 2 equiv of TBS-Cl, but the yields were in-
consistent and low (<30%).24,25 By increasing the relative amount
of TBS-Cl to 6 equiv, compound 6 was converted into the tris-
silylated compound 7. Unexpectedly, the hydrolysis of the silyl-
amine function required
a prolonged vigorous stirring with
aq NH4Cl at rt (w2 h) to form the bis-silyl ether 8 in 90% yield. The
phenolic silyl ether was selectively cleaved with 1 equiv of TBAF at
0
ꢂC,26 to afford compound 9 in 98% yield (Scheme 2).
Scheme 3. Preparation of aldehyde 15.
Scheme 2. Tetrahydroisoquinoline ring formation.
The next step entailed the formation of the trans-tetrahy-
droisoquinoline ring via a PicteteSpengler reaction between 9 and
ethyl glyoxalate. Previously, our group reported a similar trans-
formation, which was performed by stirring a solution of the
starting materials in acetonitrile for 3.5 days at 50 ꢂC, which
afforded the trans-product stereospecifically.27 A similar report by
Zhu and co-workers involved the use of LiCl, hexafluoroisopropanol
and molecular sieves, and stirring the suspension in toluene at
rt for 48 h. Since none of these mild conditions led to the formation
of the desired tetrahydroisoquinoline ring system, we decided to
adapt the reaction conditions that were originally described by
Zhu28,29 to our substrate. The amount of acetic acid was reduced
from 2.5 equiv to 0.2 equiv to prevent cleavage of the O-TBS ether
due to the prolonged exposure to the acid. In the present system,
treatment of a solution of compound 9 and ethyl glyoxylate with
Scheme 4. Formation of cycloadducts 20a and 20b.
The deacetylation of the 20a/20b mixture under standard
methanolysis conditions provided a 5:1 mixture of 21a and 21b in
70% yield (Scheme 5). We suggest that 21b decomposes under the
reaction conditions at a higher rate than 21a, which provides an
explanation for both the moderate yield and the change in the di-
astereomeric ratio. The chemoselective reduction of the ethyl esters
with 1 equiv of LiAlH4 at ꢀ10 ꢂC, afforded a 3:1 mixture of alde-
hydes 22a and 22b in 55% yield.36 We submit that the partial
ꢁ
CF3CH2OH, AcOH (0.2 equiv), and 4 A MS afforded an 8:1 mixture of
10a and 10b in 82% yield. These two diastereomers were separated
via flash chromatography and 10a was subjected to selective acet-
ylation,30 followed by hydrogenolysis of the CeBr bond23 to afford
compound 12 (Scheme 3).
Following the conditions described in our previous report,20 we
converted THIQ 12 into the [3þ2] dipolar cycloaddition adducts 20a
and 20b. Thus, THIQ 12 and N-Boc-N-Bn-Gly were coupled using
EDCI, and the resulting amide was treated with TBAF to cleave the
O-TBS ether, followed by a Swern oxidation31 to afford aldehyde 15
(Scheme 3).
As illustrated in Scheme 4, aldehyde 15 was dissolved in CHCl3
and treated under aerobic conditions with TFA32e34 (50 equiv) and
TEMPO (0.1 equiv), to generate iminium ion 16, which tautomerizes
to form ammonium ion 17. This intermediate is autoxidized in situ
to afford conjugated iminium ion 18, which was concentrated to
dryness and taken up in CHCl3. Addition of triethylamine induces
the formation of azomethine ylide 19, which is trapped in situ by
tert-butyl acrylate to give a 2.4:1 mixture of tetracycles 20a and 20b
in a combined 59% yield.35
Scheme 5. Synthesis of aldehydes 23a and 23b.

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7507
epimerization seen in this step is promoted by the slightly basic
workup conditions. Treatment with BnBr and Na2CO3 formed the
phenolic benzyl ethers and induced additional epimerization of the
electrospray (ESI) and atmospheric pressure chemical ionization
(APCI). Optical rotations were recorded on a Rudolph Research
Autopol polarimeter, at a wavelength of 589 nm.
aldehyde’s
a
carbon, to provide a 2.2:1 mixture of 23a and 23b,37
which was then reacted with DBN in THF to invert the epimeric
4.2. (S)-1-(2-Bromo-5-((tert-butyldimethylsilyl)oxy)-4-
methoxy-3-methylphenyl)-3-((tert-butyldimethylsilyl)oxy)
propan-2-amine (8)
ratio.21,22
The 1:2.2 mixture of aldehydes 23a and 23b was then treated
with sodium borohydride to afford a mixture of alcohols 24a and
24b, which were separated via flash chromatography to afford 24b
in 65% yield (Scheme 6). The sequence used to transform the 20a/
20b mixture into 24b not only provided the desired configuration
in the benzylic position but also furnished an unhindered substrate
for the N-debenzylation of the piperazinone amine. Thus, hydro-
genolysis of 24b in glacial acetic acid (10% Pd/C, 1 atm) effected the
bis-debenzylation to afford 25 in 92% yield. Similarly, the removal
of the N-benzyl group also provided an unhindered substrate for
the hydrogenation of the enamide double bond from the Re face of
C-3 (lemonomycin numbering). Gratifyingly, the hydrogenation of
25 with RaneyÒ nickel at 100 psi21 provided compound 26 in 73%
yield.
To a stirred solution of compound 6 (1.55 g, 5.36 mmol, 1 equiv)
(6) in CH2Cl2 (90 mL, 0.06 M), were added DMAP (327 mg,
2.68 mmol, 0.5 equiv), Et3N (4.48 mL, 32.2 mmol, 6.00 equiv), and
TBS-Cl (4.86 g, 32.2 mmol, 6 equiv). The reaction was stirred under
Ar for 3 h at rt, and then satd aq NH4Cl (50 mL) was added and the
mixture was stirred for 2 h. The phases were separated, the aqueous
layer was extracted with CH2Cl2 (2ꢃ50 mL) and the combined or-
ganic layers were rinsed with brine (50 mL), dried (Na2SO4), fil-
tered, and concentrated under vacuum. The crude material was
purified by flash chromatography (silica gel, hexane/EtOAc 5:1) to
give the title compound 8 (2.50 g, 90%) as a colorless oil. 1H NMR
(400 MHz; CDCl3):
d
6.65 (s, 1H), 3.72 (s, 3H), 3.61 (1/2 ABX, J¼9.7,
4.1 Hz, 1H), 3.47 (1/2 ABX, J¼9.7, 6.5 Hz, 1H), 3.20e3.14 (m, 1H), 2.87
(1/2 ABX, J¼13.4, 5.4 Hz,1H), 2.57 (1/2 ABX, J¼13.4, 8.0 Hz, 1H), 2.35
(s, 3H), 1.00 (s, 9H), 0.91 (s, 9H), 0.17 (s, 6H), 0.07 (s, 3H), 0.06 (s,
3H); 13C NMR (101 MHz, CDCl3):
d 148.8, 147.6, 134.6, 133.1, 121.3,
119.4, 67.6, 60.2, 52.9, 41.3, 26.1, 25.8, 18.4, 18.4, 17.2, ꢀ4.4, ꢀ5.2; Rf
(SiO2, 2:1 hexanes/EtOAc) 0.35; [
a]
25 þ0.9 (c 0.35, CHCl3); IR (film,
D
CH2Cl2), nmax 2996, 2930, 2858, 2471, 839 cmꢀ1; HRMS (MHþ),
found 520.2103. C23H45BrNO3Si2 requires 520.2101.
4.3. (S)-5-(2-Amino-3-((tert-butyldimethylsilyl)oxy)propyl)-
4-bromo-2-methoxy-3-methylphenol (9)
To a stirred solution of compound 8 (1.59 g, 3.05 mmol, 1 equiv)
in THF (100 mL, 0.03 M), under Ar, at 0 ꢂC, was added a 1.0 solution
M of TBAF in THF (3.05 mL, 3.05 mmol, 1 equiv). The reaction was
stirred for 25 min and quenched with satd aq NH4Cl (50 mL). The
phases were allowed to warm to rt, the aqueous phase was
extracted with EtOAc (2ꢃ50 mL) and the combined organic layers
were rinsed with brine (50 mL), dried (Na2SO4), filtered, and con-
centrated under vacuum. The crude material was purified by flash
chromatography (silica gel, CHCl3/MeOH 10:1) to give the title
compound 9 (1.23 g, 98%) as a colorless oil. 1H NMR (400 MHz;
Scheme 6. Synthesis of compound 26.
3. Conclusion
In summary, we have accomplished the construction of the
tetracyclic core of (ꢀ)-lemonomycin. Compound 26 was prepared
from known bromotyrosinol 6 in 16 steps. Efforts to gain access to
(ꢀ)-lemonomycin through this advanced intermediate are cur-
rently under investigation.
CDCl3): d 6.77 (s, 1H), 3.73 (s, 3H), 3.71e3.66 (m, 1H), 3.56e3.50 (m,
1H), 3.27e3.24 (m, 1H), 2.92 (1/2 ABX, J¼13.5, 4.6 Hz, 1H), 2.62 (1/2
ABX, J¼13.5, 9.0 Hz, 1H), 2.34 (s, 3H), 0.92 (s, 9H), 0.09 (s, 3H), 0.08
(s, 3H); 13C NMR (101 MHz, CDCl3):
d 148.4,145.0, 134.6, 132.2, 117.2,
4. Experimental section
4.1. General methods
116.1, 67.1, 60.8, 52.9, 52.7, 40.5, 26.1, 18.4, 17.2, ꢀ5.2, ꢀ5.2. Rf (SiO2,
CH2Cl2/MeOH 10:1) 0.4; [
a
]
25 þ8.3 (c 0.41, CHCl3); IR (film, CH2Cl2),
D
nmax 3263 (br), 2954, 2928, 2856, 1578, 1471, 1092 cmꢀ1; HRMS
(MHþ), found 406.1233. C17H31BrNO3Si requires 406.1236.
Unless otherwise noted, all materials were obtained from
commercial sources and used without purification. All reactions
requiring anhydrous conditions were performed under a positive
pressure of argon using flame-dried glassware. Organic solvents
were degassed with argon and dried through a solvent purification
system (Pure Process Technology). Flash chromatography was
performed on silica gel grade 60 (230ꢃ400 mesh) from Sorbent
Technologies. Thin layer chromatography was performed on glass
4.4. (1S,3S)-Ethyl 5-bromo-3-(((tert-butyldimethylsilyl)oxy)-
methyl)-8-hydroxy-7-methoxy-6-methyl-1,2,3,4-
tetrahydroisoquinoline-1-carboxylate (10a) and (1R,3S)-ethyl
5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-8-hydroxy-
7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxylate (10b)
plates coated with silica gel grade 60, from Merck. 1H NMR and 13
C
To a stirred solution of compound 9 (5.43 g, 13.4 mmol,
1.0 equiv) in CH2Cl2 (134 mL, 0.10 M), under Ar, were added, 4 A
ꢁ
NMR spectra were recorded on Varian 300 or 400 MHz spectrom-
eters as indicated. Proton spectra in CDCl3 were referenced to re-
sidual CHCl3 at 7.26 ppm. Carbon spectra in CDCl3 were referenced
to 77.16 ppm. Proton spectra in DMSO-d6 were referenced to re-
sidual CD3SOCD2H at 2.50 ppm. Infrared spectra were recorded on
a Bruker Tensor FT-IR spectrometer. High-resolution mass spectra
were obtained using a TOF spectrometer using simultaneous
molecular sieves (2.72 g), CF3CH2OH (13.4 mL), AcOH (153
mL,
2.68 mmol, 0.20 equiv), and ethyl glyoxalate (50% solution in
PhCH3, 2.93 mL, 14.8 mmol, 1.1 equiv). The reaction was stirred
overnight, diluted with CH2Cl2 (50 mL), filtered through CeliteÒ,
and concentrated under vacuum. The crude material was purified
by flash chromatography (silica gel, hexanes/EtOAc 5:1) to give

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A. Jimenez-Somarribas, R.M. Williams / Tetrahedron 69 (2013) 7505e7512
7508
compound 10a (4.78 g, 73%) as a white solid and compound 10b
(610 mg, 9%) as a white solid. Compound 10a: 1H NMR (400 MHz;
by flash chromatography (silica gel, hexanes/EtOAc 5:1, 4:1 and
3:1) to give the title compound 12 (2.25 g, 91%) as a colorless oil.
CDCl3):
d
6.25 (br s, 1H), 4.89 (s, 1H), 4.26e4.18 (m, 2H), 3.82 (1/2
1H NMR (400 MHz; CDCl3):
d 6.85 (s, 1H), 4.65 (s, 1H), 4.17 (q,
ABX, J¼9.8, 3.5 Hz, 1H), 3.76 (s, 3H), 3.54 (1/2 ABX, J¼9.8, 8.5 Hz,
1H), 3.13e3.07 (m, 1H), 2.71 (1/2 ABX, J¼16.9, 4.1 Hz, 1H), 2.35 (s,
3H), 2.27 (1/2 ABX, J¼16.9,11.3 Hz, 1H),1.29 (t, J¼7.1 Hz, 3H), 0.93 (s,
J¼7.1 Hz, 2H), 3.73 (1/2 ABX, J¼9.8, 3.7 Hz, 1H), 3.70 (s, 3H), 3.52
(1/2 ABX, J¼9.8, 7.2 Hz, 1H), 3.28e3.22 (m, 1H), 2.59 (1/2 ABX,
J¼16.1, 4.2 Hz, 1H), 2.50 (1/2 ABX, J¼16.1, 10.7 Hz, 1H), 2.28 (s, 3H),
2.27 (s, 3H), 1.26 (t, J¼7.1 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s,
9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (101 MHz, CDCl3):
d 172.9,
145.6, 144.3, 130.8, 130.7, 120.0, 118.4, 66.9, 61.7, 61.2, 55.6, 51.6,
2H). 13C NMR (101 MHz, CDCl3):
d 172.2, 168.3, 148.2, 141.6, 131.5,
32.7, 26.0, 18.4, 17.0, 16.9, 14.4, 14.4, ꢀ5.1, ꢀ5.2, ꢀ5.2, ꢀ5.3;
131.1, 129.2, 124.0, 66.7, 61.3, 60.6, 55.6, 50.7, 30.2, 26.0, 20.6, 18.4,
mp¼47 ꢂC; Rf (SiO2, hexanes/EtOAc 4:1) 0.40; [
a]
25 ꢀ24.3 (c 0.885,
16.0, 14.4, ꢀ5.2, ꢀ5.3. Rf (SiO2, hexanes/EtOAc 4:1) 0.42; [
a
]
25 ꢀ17
D
D
CHCl3); IR (film, CH2Cl2), nmax 3284 (br), 2955, 2931, 2857, 1739,
1462, 1178 cmꢀ1; HRMS (MHþ), found 490.1446. C21H35BrNO5Si
requires 490.1447. Compound 10b: 1H NMR (400 MHz; CDCl3):
(c 0.42, CHCl3); IR (film, CH2Cl2), nmax 2954, 2929, 2857, 1775,
1737, 1197 cmꢀ1; HRMS (MHþ), found 452.244. C23H38NO6Si re-
quires 452.2468.
d
5.86 (br s, 1H), 4.78 (s, 1H), 4.30e4.15 (m, 2H), 3.80 (1/2 ABX,
J¼9.9, 4.1 Hz, 1H), 3.74 (s, 3H), 3.68 (1/2 ABX, J¼9.9, 6.6 Hz, 1H),
2.95e2.89 (m, 1H), 2.77 (1/2 ABX, J¼16.6, 3.1 Hz, 1H), 2.44 (1/2 ABX,
J¼16.6, 8.5 Hz, 2H), 2.36 (s, 3H), 1.27 (t, J¼7.1 Hz, 3H), 0.92 (s, 9H),
4.7. (1S,3S)-Ethyl 8-acetoxy-2-(2-(benzyl(tert-butox-
ycarbonyl)-amino)acetyl)-3-(((tert-butyldimethylsilyl)oxy)
methyl)-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-
1-carboxylate (13)
0.09 (s, 6H); 13C NMR (101 MHz, CDCl3):
d 172.8, 145.1, 143.9, 132.0,
130.4, 120.3, 118.4, 66.7, 61.5, 61.4, 58.4, 54.5, 33.0, 26.1, 26.0, 18.5,
17.0, 14.2, ꢀ5.1, ꢀ5.2; mp¼95 ꢂC; Rf (SiO2, hexanes/EtOAc 4:1) 0.37;
A solution of compound 12 (2.20 g, 4.87 mmol, 1.0 equiv), N-
Bn-N-Boc-glycine (2.58 g, 9.74 mmol, 2.0 equiv), and EDCI (1.40 g,
7.31 mmol, 1.5 equiv) in CH2Cl2 (2.5 mL, 2 M), under Ar, was
stirred for 2.5 days. The reaction was diluted with EtOAc
(200 mL), and the solution was extracted with water (100 mL),
satd aq NaHCO3 (2ꢃ100 mL) and brine (100 mL), dried (Na2SO4),
filtered, and concentrated under vacuum. The crude material was
purified by flash chromatography (silica gel, hexanes/EtOAc 4:1,
3:1 and 2:1) to give the title compound 13 (3.15 g, 93%) as a col-
orless oil. 1H NMR (300 MHz; DMSO-d6, 393 K, mixture of
[
a]
25 ꢀ36.7 (c 0.600, CHCl3); IR (film, CH2Cl2), nmax 3314 (br), 2955,
D
2931, 2858, 1738, 1463, 1257 cmꢀ1; HRMS (MHþ), found 490.1456.
C21H35BrNO5Si requires 490.1447.
4.5. (1S,3S)-Ethyl 8-acetoxy-5-bromo-3-(((tert-butyldime-
thylsilyl)oxy)methyl)-7-methoxy-6-methyl-1,2,3,4-
tetrahydroisoquinoline-1-carboxylate (11)
To a stirred solution of compound 10a (840 mg, 1.72 mmol,
1.0 equiv) in acetone (34 mL, 0.05 M), under Ar, were added K2CO3
rotamers): d 7.36e7.24 (m, 5H), 6.94 (s, 1H), 6.88 (s, 1H, minor
(1.20 g, 8.64 mmol, 5.0 equiv) and acetic anhydride (162
m
L,
rotamer), 5.48 (s, 1H), 4.49 (1/2 AB, J¼15.6 Hz, 1H), 4.39 (1/2 AB,
J¼15.6.0 Hz, 1H), 4.33e4.27 (m, 2H), 4.13e3.87 (m, 3H), 3.69 (s,
3H), 3.66 (s, 1H, minor rotamer), 3.34e3.10 (br m, 2H), 3.07e2.91
(br m, 2H), 2.33 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H, minor rotamer),
2.23 (s, 1H, minor rotamer), 1.41 (s, 9H), 1.21 (t, J¼7.0 Hz, 3H,
minor rotamer), 1.12 (t, J¼7.1 Hz, 3H), 0.92 (d, J¼0.6 Hz, 2H), 0.79
(s, 9H), 0.08 (s, 3H, minor rotamer), 0.04 (s, 3H, minor rotamer),
0.03 (m, 3H, minor rotamer), ꢀ0.11 (s, 3H), ꢀ0.14 (s, 3H). 13C NMR
1.72 mmol, 1.0 equiv). The suspension was stirred overnight, the
solvent was evaporated, and the residue was partitioned between
water (25 mL) and EtOAc (25 mL). The aqueous phase was extracted
with EtOAc (2ꢃ25 mL) and the combined organic layers were
rinsed with brine (50 mL), dried (Na2SO4), filtered, and concen-
trated under vacuum. The crude material was purified by flash
chromatography (silica gel, hexanes/EtOAc 5:1) to give the title
compound 11 (800 mg, 88%) as a colorless oil. 1H NMR (400 MHz;
(101 MHz, CDCl3, mixture of rotamers): d 170.1, 169.7, 168.1, 168.0,
CDCl3):
d
4.66 (s, 1H), 4.18 (q, J¼7.1 Hz, 2H), 3.81 (1/2 ABX, J¼9.8,
156.1, 149.6, 129.2, 129.1, 128.7, 128.4, 127.8, 127.5, 127.5, 127.4,
121.6, 80.5, 80.4, 71.6, 61.9, 61.3, 60.7, 53.6, 53.6, 53.5, 53.0, 53.0,
52.9, 52.9, 50.9, 47.7, 29.5, 28.5, 28.4, 26.0, 26.0, 25.9, 20.9, 18.3,
3.5 Hz, 1H), 3.70 (s, 3H), 3.55 (1/2 ABX, J¼9.8, 7.6 Hz, 1H), 3.22e3.16
(m, 1H), 2.74 (1/2 ABX, J¼16.9, 4.1 Hz, 2H), 2.38 (s, 3H), 2.37e2.33
(m, 1H), 2.29 (s, 3H), 1.27 (t, J¼7.1 Hz, 3H), 0.921 (s, 9H), 0.10 (s, 3H),
16.1, 16.0, 14.0, 13.9, ꢀ5.3, ꢀ5.4, ꢀ5.4, ꢀ5.7. Rf (SiO2, hexanes/
25
0.07 (s, 3H); 13C NMR (101 MHz, CDCl3):
d
171.8, 167.9, 148.6, 141.0,
EtOAc 3:1) 0.30; [
a
]
þ26.8 (c 0.995, CHCl3); IR (film, CH2Cl2),
D
132.5, 131.5, 125.9, 125.8, 66.7, 61.5, 61.1, 55.8, 51.0, 32.6, 26.0, 20.6,
nmax 2956, 2931, 2857, 1781, 1743, 1703, 1668, 1199 cmꢀ1; HRMS
18.4, 17.1, 14.4, ꢀ5.2, ꢀ5.3. Rf (SiO2, hexanes/EtOAc 4:1) 0.45;
(MHþ), found 699.3666. C37H55N2O9Si requires 699.3677.
[
a]
25 ꢀ21.1 (c 1.10, CHCl3); IR (film, CH2Cl2), nmax 2956, 2932, 2856,
D
1780, 1737, 1462, 1192 cmꢀ1; HRMS (MHþ), found 532.1561.
C23H37BrNO6Si requires 530.1574.
4.8. (1S,3S)-Ethyl 2-(2-(benzyl(tert-butoxycarbonyl)amino)
acetyl)-8-hydroxy-3-(hydroxymethyl)-7-methoxy-6-methyl-
1,2,3,4-tetrahydroisoquinoline-1-carboxylate (14)
4.6. (1S,3S)-Ethyl 8-acetoxy-3-(((tert-butyldimethylsilyl)oxy)-
methyl)-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-
1-carboxylate (12)
To a solution of compound 13 (765 mg, 1.09 mmol, 1.0 equiv) in
THF (10 mL, 0.11 M), under Ar, were added MeOH (625 mL) and TBAF
(1.0 M solution in THF, 2.18 mL, 2.0 equiv). The reaction was stirred
overnight and quenched with satd aq NH4Cl (50 mL) and then di-
luted with EtOAc (100 mL). The phases were separated, the aqueous
phase was extracted with EtOAc (2ꢃ25 mL) and the combined or-
ganic layers were rinsed with brine (50 mL), dried (Na2SO4), fil-
tered, and concentrated under vacuum. The crude material was
dissolved in the minimal amount of CH2Cl2 and purified by flash
chromatography (silica gel, hexanes/EtOAc 2:1, then 1:1) to give the
title compound 14 (525 mg, 82%) as a white amorphous solid. 1H
A solution of compound 11 (2.90 g, 5.46 mmol) in MeOH
(110 mL, 0.05 M), and Pearlman’s catalyst (20% Pd(OH)2/C,
580 mg) were placed in a FisherePorter bottle, under Ar. The
mixture was sparged with Ar for 5 min and the vessel was filled
with hydrogen gas at 50 psi. The reaction was vigorously stirred
overnight and then filtered through CeliteÒ and the vessel was
rinsed with MeOH (50 mL) and EtOAc (50 mL). The solution was
concentrated under vacuum to dryness and partitioned between
satd aq NaHCO3 (75 mL) and EtOAc (75 mL). The aqueous phase
was extracted with EtOAc (2ꢃ75 mL) and the combined organic
layers were rinsed with brine (50 mL), dried (Na2SO4), filtered,
and concentrated under vacuum. The crude material was purified
NMR (300 MHz; DMSO-d6, 393 K): d 7.36e7.26 (m, 5H), 6.96 (s, 1H),
5.50 (s, 1H), 4.49e4.40 (br m, 2H), 4.27e4.17 (br m, 2H), 4.07e3.89
(m, 3H), 3.70 (s, 3H), 3.19e3.03 (br m, 2H), 2.94e2.81 (m, 2H,
overlapped with H2O signal), 2.34 (s, 3H), 2.25 (s, 3H), 1.41 (s, 9H),

ꢀ
A. Jimenez-Somarribas, R.M. Williams / Tetrahedron 69 (2013) 7505e7512
7509
1.13 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3, mixture of
56.6 mmol, 20 equiv) and triethylamine (3.95 mL, 28.3 mmol,
10 equiv) were added. The reaction was allowed to warm to rt and
stirred overnight. The solution was diluted with EtOAc (200 mL),
rinsed with satd aq NH4Cl (50 mL) and brine (50 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The crude
material was purified by flash chromatography (silica gel, hexanes/
EtOAc 4:1, 3:1) to afford a 2.4:1 mixture of the title compounds 20a
and 20b (985 mg, 59%) as a yellow oil, which was used in the next
step without further purification. 1H NMR (400 MHz; CDCl3):
rotamers):
d 170.2, 170.1, 168.0, 168.0, 156.4, 154.8, 152.8, 149.7,
145.0, 141.7, 141.5, 138.1, 138.1, 138.0, 132.9, 132.8, 130.2, 130.0, 128.7,
128.5, 128.4, 128.3, 128.1, 127.8, 127.8, 127.7, 127.5, 127.5, 127.1, 124.2,
121.2, 80.9, 80.4, 65.1, 63.8, 62.0, 60.6, 53.7, 53.5, 52.7, 52.0, 51.0,
47.9, 30.6, 30.0, 29.5, 28.5, 28.4, 20.9, 16.2, 13.8; mp 80 ꢂC; Rf (SiO2,
hexanes/EtOAc 1:1) 0.35; [
a
]
25 þ78 (c 0.44, CHCl3); IR (film, CH2Cl2),
D
nmax 3455 (br), 2977, 2935, 1780, 1742, 1698, 1663, 1200 cmꢀ1
;
HRMS (MHþ), found 585.2816. C31H41N2O9 requires 585.2812.
d
7.41e7.22 (m, 5H), 6.74 (s, 1H, minor diastereomer), 6.73 (s, 1H),
4.9. (1S,3S)-Ethyl 2-(2-(benzyl(tert-butoxycarbonyl)amino)-
acetyl)-3-formyl-8-hydroxy-7-methoxy-6-methyl-1,2,3,4-
tetrahydroisoquinoline-1-carboxylate (15)
6.36 (s, 1H, minor diastereomer), 6.27 (s, 1H), 5.51 (s, 1H, minor
diastereomer), 5.50 (s, 1H), 4.28e3.96 (m, 6H), 3.89e3.71 (m, 2H),
3.75 (s, 3H, minor diastereomer), 3.72 (s, 3H), 2.80e2.67 (m, 2H),
2.45 (dd, J¼13.0, 9.8 Hz, 1H, minor diastereomer), 2.40 (s, 3H), 2.39
(s, 3H, minor diastereomer), 2.28 (s, 3H, minor diastereomer), 2.26
(s, 3H), 2.13 (dd, J¼13.3, 9.5 Hz, 1H), 1.46 (s, 9H, minor di-
astereomer), 1.42 (s, 9H), 1.24 (t, J¼7.1 Hz, 3H), 1.20 (t, J¼7.2 Hz, 3H,
A solution of oxalyl chloride (825 mL, 9.75 mmol, 3.0 equiv) in
CH2Cl2 (22.5 mL), under Ar, was cooled to ꢀ78 ꢂC, and DMSO
(921 mL, 13.0 mmol, 4.0 equiv) was added dropwise. The resulting
mixture was stirred an additional 30 min at ꢀ78 ꢂC. A solution of
compound 14 (1.90 mg, 3.25 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at
rt was then added slowly by cannula, and the mixture continued
to stir at ꢀ78 ꢂC for 30 min. Triethylamine (4.50 mL, 32.5 mmol,
10 equiv) was then added dropwise, and the solution was stirred
for 15 min at ꢀ78 ꢂC and an additional 30 min at 0 ꢂC. The re-
action was quenched with satd aq NH4Cl (50 mL) and allowed to
warm to rt. The layers were separated, the aqueous phase was
extracted with CH2Cl2 (3ꢃ50 mL) and the combined organic
layers were rinsed with brine (50 mL), dried (Na2SO4), filtered,
and concentrated under vacuum. The crude material was purified
by flash chromatography (silica gel, hexanes/EtOAc 2:1, then 1:1)
to give the title compound 15 (1.65 g, 87%) as a colorless oil,
which solidifies upon standing to afford a colorless amorphous
solid. 1H NMR (300 MHz; DMSO-d6, 373 K, mixture of rotamers):
minor diastereomer); 13C NMR (101 MHz, CDCl3):
d 172.4, 171.7,
168.7,167.9,149.9,141.6,133.1,129.0,128.6,128.4,128.4,127.4,127.3,
126.6, 125.0, 124.8, 117.3, 116.7, 104.6, 103.1, 81.4, 81.3, 65.1, 64.1,
63.1, 62.6, 62.4, 62.3, 60.7, 60.6, 52.7, 51.8, 51.3, 50.7, 50.0, 48.0, 34.3,
31.9, 31.7, 28.2, 22.8, 21.0, 16.1, 14.2, 14.0; Rf (SiO2, hexanes/EtOAc
3:1) 0.5; [
a
]
25 ꢀ65.0 (c 0.320, CH2Cl2); IR (film, CH2Cl2), nmax 2980,
D
2936, 1781, 1741, 1693, 1651 cmꢀ1; HRMS (MHþ), found 591.2712.
C33H39N2O8 requires 591.2706.
4.11. (5S,8S,10R,11S)-10-tert-Butyl 5-ethyl 13-benzyl-4-
hydroxy-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-5,10-dicarboxylate
(21a) and (5R,8S,10R,11S)-10-tert-butyl 5-ethyl 13-benzyl-4-
hydroxy-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-5,10-dicarboxylate
(21b)
d
9.54 (s, 1H, minor rotamer), 9.28 (s, 1H), 7.35e7.23 (m, 5H), 7.08
(s, 1H, minor rotamer), 7.01 (s, 1H), 6.94 (s, 1H, minor rotamer),
6.91 (s, 1H, minor rotamer), 5.70 (s, 1H), 5.10e4.88 (m, 1H),
4.52e4.28 (m, 3H), 4.26e4.14 (m, 1H), 4.13e3.98 (m, 2H),
3.97e3.86 (m, 1H), 3.69 (s, 3H, minor rotamer), 3.68 (s, 3H, minor
rotamer), 3.67 (s, 3H), 3.38e3.27 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H,
minor rotamer), 2.25 (s, 3H, minor rotamer), 2.24 (s, 3H, minor
rotamer), 2.22 (s, 3H), 1.41 (s, 9H, minor rotamer), 1.40 (s, 9H),
1.36 (s, 9H, minor rotamer), 1.34 (s, 9H, minor rotamer), 1.12 (t,
J¼7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3, mixture of rotamers):
To a stirred solution of a 2.6:1 mixture of compounds 20a and
20b (410 mg, 0.695 mmol, 1.0 equiv) in THF/MeOH 1:1 (14 mL,
0.05 M), under Ar, was added K2CO3 (192 mg, 1.39 mmol,
2.0 equiv). The suspension was stirred for 2.5 h, the solvent was
evaporated and the residue was partitioned between phosphate
buffer (0.1 M, pH¼7.5, 50 mL) and EtOAc (33 mL). The aqueous
phase was extracted with EtOAc (2ꢃ33 mL) and the combined
organic layers were rinsed with brine (50 mL), dried (Na2SO4),
filtered, and concentrated under vacuum. The crude material was
purified by flash chromatography (silica gel, hexanes/EtOAc 4:1)
to afford a 5:1 mixture of the title compounds 21a and 21b
(255 mg, 67%) as a pale yellow oil, which was used in the next
step without further purification. 1H NMR (400 MHz; CDCl3):
d
201.2, 199.6, 199.2, 169.9, 167.8, 155.9, 155.8, 150.2, 149.7, 141.5,
141.0, 137.6, 137.5, 137.5, 133.6, 133.3, 128.6, 128.6, 128.5, 128.5,
128.4, 128.1, 128.0, 127.9, 122.6, 122.1, 81.0, 80.8, 62.7, 62.2, 60.9,
60.6, 60.6, 60.2, 53.7, 53.5, 53.3, 50.9, 47.8, 47.6, 47.1, 29.6, 28.5,
28.5, 28.4, 28.2, 20.9, 16.2, 13.8; mp 78 ꢂC; Rf (SiO2, hexanes/EtOAc
25
1:1) 0.40; [
a
]
þ35 (c 0.23, CHCl3); IR (film, CH2Cl2), nmax 2978,
d 7.38e7.24 (m, 5H), 6.76 (s, 1H), 6.63 (s, 1H, minor diastereomer),
D
2937, 1780, 1742, 1699, 1673, 1200 cmꢀ1; HRMS (MHþ), found
583.2654. C31H39N2O9 requires 583.2656.
6.49 (s, 1H, minor diastereomer), 6.43 (s, 1H, minor di-
astereomer), 6.42 (s, 1H), 6.39 (s, 5H), 5.46 (s, 1H, minor di-
astereomer), 5.45 (s, 1H. minor diastereomer), 4.24 (q, J¼7.1 Hz,
2H), 4.19e3.9 (m, 5H), 4.07 (s, 1H), 3.86 (d, J¼7.5 Hz, 1H), 3.84 (s,
1H, minor diastereomer), 3.82 (s, 3H), 3.31 (dd, J¼9.8, 6.0 Hz, 1H,
minor diastereomer), 2.79 (dd, J¼9.5, 4.6 Hz, 1H), 2.74e2.66 (m,
1H), 2.46 (dd, J¼13.0, 9.9 Hz, 1H, minor diastereomer), 2.26 (s, 3H,
minor diastereomer), 2.24 (s, 3H), 2.13 (dd, J¼13.4, 9.6 Hz, 6H),
1.46 (s, 9H, minor diastereomer), 1.42 (s, 9H), 1.27 (t, J¼7.1 Hz,
3H), 1.24 (t, J¼7.2 Hz, 3H, minor diastereomer); 13C NMR
4.10. (5S,8S,10R,11S)-10-tert-Butyl 5-ethyl 4-acetoxy-13-
benzyl-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-5,10-dicarboxylate
(20a) and (5R,8S,10R,11S)-10-tert-butyl 5-ethyl 4-acetoxy-13-
benzyl-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-5,10-dicarboxylate
(20b)
(101 MHz, CDCl3):
d 172.4, 171.9, 170.7, 170.6, 170.4, 168.9, 146.9,
To solution of compound 15 (1.65 g, 2.83 mmol, 1.0 equiv) in
CHCl3 (28 mL, 0.1 M), under air, were added TEMPO (44 mg,
0.28 mmol, 0.10 equiv), and trifluoroacetic acid (10.8 mL, 142 mmol,
50 equiv) and the flask was loosely capped with a TeflonÒ stopper.
The solution was stirred for 4 h, the solvent was evaporated to
dryness under vacuum and the residue was taken up in CHCl3. The
solution was cooled to 0 ꢂC and then tert-butyl acrylate (8.20 mL,
146.8, 146.2, 138.5, 138.0, 136.1, 134.2, 131.9, 131.7, 128.5, 127.4,
127.3, 126.6, 126.0, 119.1, 119.1, 110.8, 103.4, 81.3, 64.3, 62.7, 62.6,
60.8, 60.8, 52.2, 52.2, 52.1, 51.5, 50.8, 48.2, 32.1, 28.2, 28.1, 22.8,
15.9, 14.3; Rf (SiO2, hexanes/EtOAc 2:1) 0.45; [
a
]
25 ꢀ73.6 (c 0.282,
D
CH2Cl2); IR (film, CH2Cl2), nmax 3374 (br), 2980, 2938, 1736, 1689,
1647, 1154 cmꢀ1; HRMS (MHþ), found 549.2606. C31H37N2O7
requires 549.2601.

ꢀ
A. Jimenez-Somarribas, R.M. Williams / Tetrahedron 69 (2013) 7505e7512
7510
4.12. (5S,8S,10R,11S)-tert-Butyl 13-benzyl-5-formyl-4-
hydroxy-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-10-carboxylate (22a)
and (5R,8S,10R,11S)-tert-butyl 13-benzyl-5-formyl-4-hydroxy-
3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-8,11-
epiminoazepino[1,2-b]isoquinoline-10-carboxylate (22b)
diastereomer), 6.36 (s, 1H), 5.37 (s, 1H), 5.36 (s, minor di-
astereomer), 5.28 (1/2 AB, J¼11.1 Hz, 1H, minor diastereomer), 5.26
(1/2 AB, J¼11.1 Hz, 2H), 5.20 (1/2 AB, J¼11.1 Hz, 1H, minor di-
astereomer), 5.14 (1/2 AB, J¼11.1 Hz, 1H), 4.20 (1/2 AB, J¼13.5 Hz,
1H), 4.14 (1/2 AB, J¼13.5 Hz, 1H), 4.05 (s, 1H), 3.97 (s, 1H, minor
diastereomer), 3.86 (s, 3H, minor diastereomer), 3.84 (s, 3H), 3.80
(1/2 AB, J¼13.5 Hz, 1H) 3.79 (d, J¼7.4 Hz, 1H), 3.75 (d, J¼6.9 Hz,
minor diastereomer), 3.68 (1/2 AB, J¼13.5 Hz, 1H, minor di-
astereomer), 3.37 (dd, J¼9.7, 6.1 Hz, 1H, minor diastereomer), 2.78
(dd, J¼9.6, 4.7 Hz, 1H), 2.71e2.64 (m, 2H), 2.53 (1/2 ABX, J¼13.1,
9.9 Hz, 1H, minor diastereomer), 2.28 (s, 3H, minor diastereomer),
2.26 (s, 3H), 2.10 (dd, J¼13.3, 9.7 Hz, 1H), 1.45 (s, 9H minor di-
A solution of LiAlH4 in THF (1.0 M, 447 mL, 0.447 mmol, 1.0 equiv)
was added dropwise to a solution of a 5:1 mixture of compounds
21a and 21b (245 mg, 0.447 mmol, 1.0 equiv) in THF (9 mL, 0.05 M),
under Ar, at ꢀ10 ꢂC. The solution was stirred for 10 min at this
temperature, quenched with EtOAc (12 mL) and satd aq Rochelle’s
salt (12 mL) and allowed to warm to rt. The flask was covered with
aluminum foil and stirred overnight under a stream of Ar. The so-
lution was diluted with phosphate buffer (0.1 M, pH¼7.5, 50 mL), the
phases were separated and aqueous phase was extracted with EtOAc
(3ꢃ33 mL) and the combined organic layers were rinsed with brine
(25 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified by flash chromatography (silica gel,
hexanes/EtOAc 4:1) to afford a 3:1 mixture of the title compounds
22a and 22b (124 mg, 55%) as a pale yellow oil, which was used in
the next step without further purification. 1H NMR (400 MHz;
astereomer), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3):
d 192.5, 191.7,
171.9, 169.8, 168.8, 150.4, 150.3, 148.3, 148.1, 138.6, 138.1, 136.9,
136.9, 136.6, 135.3, 133.7, 128.9, 128.8, 128.8, 128.6, 128.6, 128.5,
128.5, 128.4, 128.3, 127.4, 127.2, 126.9, 123.1, 122.8, 115.0, 114.6,
103.9, 102.5, 81.4, 81.2, 75.0, 75.0, 65.0, 63.9, 63.1, 62.8, 60.5, 58.8,
57.3, 52.8, 51.6, 48.8, 34.7, 32.2, 28.2, 16.0, 16.0; Rf (SiO2, hexanes/
25
EtOAc 4:1) 0.45; [
a
]
ꢀ64 (c 0.32, CH2Cl2); IR (film, CH2Cl2), nmax
D
3030, 2976, 2934, 1733, 1688, 1646, 1154 cmꢀ1; HRMS (MHþ), found
595.2801. C36H39N2O6 requires 595.2808.
To a stirred solution of a 2.2:1 mixture of compounds 23a and
23b (88 mg, 0.15 mmol, 1.0 equiv) in THF (2 mL, 0.08 M), under Ar,
CDCl3): d 9.48 (s, 1H), 9.38 (s,1H, minor diastereomer), 7.41e7.23 (m,
5H), 6.58 (s, 1H), 6.57 (s, 1H, minor diastereomer), 6.43 (s, 1H, minor
diastereomer), 6.41 (s, 1H), 6.18 (s, 1H, minor diastereomer), 6.17 (s,
1H, minor diastereomer), 4.25 (1/2 AB, J¼13.5 Hz, 1H), 4.18 (1/2 AB,
J¼13.5 Hz, 1H), 4.07 (s, 1H), 4.00 (s, 1H, minor diastereomer), 3.83 (s,
3H, minor diastereomer), 3.81 (s, 3H, minor diastereomer), 3.40 (dd,
J¼9.7, 6.0 Hz, 1H, minor diastereomer), 2.81 (dd, J¼9.5, 4.7 Hz, 1H),
2.73e2.67 (m,1H), 2.59 (dd, J¼13.0, 9.8 Hz,1H, minor diastereomer),
2.28 (s, 3H, minor diastereomer), 2.26 (s, 3H), 2.15 (dd, J¼13.4,
9.6 Hz, 1H), 1.48 (s, 9H, minor diastereomer), 1.46 (s, 9H); 13C NMR
was added DBN (19 mL, 0.15 mmol, 1.0 equiv). The mixture was
stirred for 30 min and then diluted with phosphate buffer (0.1 M,
pH¼7.5, 50 mL) and water (50 mL). The aqueous phase was
extracted with EtOAc (3ꢃ33 mL) and the combined organic layers
were rinsed with brine (25 mL), dried (Na2SO4), filtered, and con-
centrated under vacuum. The crude material was dissolved in the
minimal amount of EtOAc purified by flash chromatography (silica
gel, hexanes/EtOAc 4:1) to afford a 1:2.2 mixture of compounds 23a
and 23b (64 mg, 72%) as a pale yellow oil, which was used in the
next step without further purification. 1H NMR (400 MHz; CDCl3):
(101 MHz, CDCl3): d 192.1,191.3,172.5,171.9,170.1,145.7,144.6,138.6,
138.0, 136.6, 135.3, 131.5, 128.8, 128.4, 127.5, 127.2, 119.4, 119.2, 107.3,
104.0, 102.7, 102.6, 81.4, 64.1, 64.0, 62.9, 62.8, 61.2, 61.1, 58.6, 58.5,
d 9.32 (s, 1H, minor diastereomer), 9.19 (s, 1H), 7.48e7.24 (m, 10H),
6.63 (s, 1H), 6.62 (s, 1H, minor diastereomer), 6.38 (s, 1H), 6.36 (s,
1H, minor diastereomer), 5.37 (s, 1H, minor diastereomer), 5.36 (s,
1H), 5.28 (1/2 AB, J¼11.1 Hz, 1H), 5.26 (1/2 AB, J¼11.1 Hz, 1H, minor
diastereomer), 5.19 (1/2 AB, J¼11.1 Hz, 1H), 5.13 (1/2 AB, J¼11.2 Hz,
2H, minor diastereomer), 4.20 (1/2 AB, J¼13.4 Hz, 1H, minor di-
astereomer), 4.14 (1/2 AB, J¼13.5 Hz, 1H minor diastereomer), 4.05
(s, 1H, minor diastereomer), 3.97 (s, 1H), 3.86 (s, 3H, minor di-
astereomer), 3.84 (s, 3H, minor diastereomer), 3.81 (1/2 AB,
J¼13.6 Hz,1H), 3.79 (d, J¼6.2 Hz, 4H), 3.75 (d, J¼6.6 Hz, 3H), 3.68 (1/
2 AB, J¼13.4 Hz, 3H), 3.37 (dd, J¼9.8, 6.0 Hz, 1H), 2.78 (dd, J¼9.5,
4.7 Hz, 1H, minor diastereomer), 2.71e2.65 (m, 2H), 2.53 (1/2 ABX,
J¼13.0, 9.9 Hz, 3H), 2.28 (s, 3H), 2.26 (s, 3H, minor diastereomer),
2.10 (dd, J¼13.4, 9.5 Hz, 1H, minor diastereomer), 1.45 (s, 9H), 1.44
51.6, 50.8, 48.8, 34.7, 32.4, 31.7, 29.8, 28.1, 22.8, 16.0, 14.3; Rf (SiO2,
25
hexanes/EtOAc 2:1) 0.42; [
a
]
ꢀ64.8 (c 0.250, CH2Cl2); IR (film,
D
CH2Cl2), nmax 3331 (br), 2977, 2935, 1733, 1679, 1642, 1154 cmꢀ1
;
HRMS (MHþ), found 505.2345. C29H33N2O6 requires 505.2339.
4.13. (5S,8S,10R,11S)-tert-Butyl 13-benzyl-4-(benzyloxy)-5-
formyl-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-10-carboxylate (23a)
and (5R,8S,10R,11S)-tert-butyl 13-benzyl-4-(benzyloxy)-5-
formyl-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-
8,11-epiminoazepino[1,2-b]isoquinoline-10-carboxylate
(5R,8S,10R,11S)-tert-butyl 13-benzyl-4-(benzyloxy)-5-formyl-
3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-hexahydro-8,11-
epiminoazepino[1,2-b]isoquinoline-10-carboxylate (23b)
(s, 9H, minor diastereomer); 13C NMR (101 MHz, CDCl3):
d 192.5,
191.7,172.5,171.9,168.8, 150.4, 148.1,138.0, 136.9, 135.3, 133.7, 128.9,
128.8, 128.8, 128.6, 128.5, 128.4, 128.3, 127.4, 127.2, 126.9, 123.1,
122.8, 115.0, 114.6, 103.9, 102.5, 81.4, 81.2, 75.0, 75.0, 65.0, 63.9, 63.1,
To a stirred solution of a 3:1 mixture of compounds 22a and 22b
(115 mg, 0.228 mmol, 1.0 equiv) and benzyl bromide (108 L,
m
62.7, 60.4, 58.8, 57.3, 52.7, 51.6, 50.9, 48.8, 34.7, 32.2, 28.2, 28.1, 16.0,
25
0.912 mmol, 4.0 equiv) in DMF (7.6 mL, 0.03 M), under Ar, were
added tetrabutylammonium iodide (9.0 mg, 0.023 mmol,
0.10 equiv) and finely ground anhydrous Na2CO3 (241 mg,
2.28 mmol, 10 equiv). The mixture was vigorously stirred for 2 h
and diluted with water (25 mL) and phosphate buffer (0.1 M,
pH¼7.5, 25 mL). The aqueous phase was extracted with EtOAc
(3ꢃ33 mL) and the combined organic layers were rinsed with brine
(25 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified by flash chromatography (silica gel,
hexanes/EtOAc 6:1, 4:1) to afford a 2.2:1 mixture of compounds 23a
and 23b (88 mg, 65%) as a pale yellow oil, which was used in the
next step without further purification. 1H NMR (400 MHz; CDCl3):
16.0; Rf (SiO2, hexanes/EtOAc); [
a
]
D
þ27 (c 0.22, CHCl3); IR (film,
CH2Cl2), nmax 3029, 2969, 2935, 1732, 1688, 1647, 1154 cmꢀ1; HRMS
(MHþ), 595.2789. C36H39N2O6 requires 595.2808.
4.14. (5S,8S,10R,11S)-tert-Butyl 13-benzyl-4-(benzyloxy)-5-
(hydroxymethyl)-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-
hexahydro-8,11-epiminoazepino[1,2-b]isoquinoline-10-
carboxylate (24a) and (5R,8S,10R,11S)-tert-butyl 13-benzyl-4-
(benzyloxy)-5-(hydroxymethyl)-3-methoxy-2-methyl-7-oxo-
5,7,8,9,10,11-hexahydro-8,11-epiminoazepino[1,2-b]isoquino-
line-10-carboxylate (24b)
d
9.32 (s, 1H), 9.19 (s, 1H minor diastereomer), 7.48e7.22 (m, 10H),
To a stirred solution of a mixture of compounds 23a and 23b
6.63 (s, 1H, minor diastereomer), 6.62 (s, 1H), 6.38 (s, 1H, minor
(60 mg, 0.10 mmol) in EtOH (5 mL, 0.20 M), at 0 ꢂC, under Ar, was

ꢀ
A. Jimenez-Somarribas, R.M. Williams / Tetrahedron 69 (2013) 7505e7512
7511
added NaBH4 (30 mg, 0.80 mmol 8.0 equiv). The reaction was
4.16. (5R,8S,10R,11S,11aS)-tert-Butyl 4-hydroxy-5-(hydrox-
ymethyl)-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11,11a, 12-
octahydro-8,11-epiminoazepino[1,2-b]isoquinoline-10-
carboxylate (26)
stirred at rt for 2 h, quenched with 1 N HCl (2.4 mL, 2.40 mmol,
24 equiv) and diluted with phosphate buffer (0.1 M, pH¼7.5,
50 mL). The aqueous phase was extracted with EtOAc (3ꢃ25 mL)
and the combined organic layers were rinsed with brine (25 mL),
dried (Na2SO4), filtered, and concentrated under vacuum. The
crude material was purified by flash chromatography (silica gel,
hexanes/EtOAc 4:1) to afford compounds 23a (18 mg, 30%) as
a colorless oil and compound 23b (38 mg, 65%) as a colorless oil.
To a solution of compound 25 (4.6 mg, 0.011 mmol) in EtOH
(1 mL) in a 5 mL vial, was added a slurry of RaneyÒ nickel 2800
(500 mL of commercially available water slurry, washed with EtOH
(3ꢃ1 mL) and suspended in EtOH (1 mL)). The vial was placed in
a FisherePorter bottle, under Ar, the suspension was sparged with
Ar for 5 min and the vessel was filled with hydrogen gas at 100 psi.
The reaction was vigorously stirred overnight, diluted with EtOAc
(10 mL) and satd aq Rochelle’s salt (10 mL), and stirred vigorously
for 2 h. The biphasic suspension was filtered through CeliteÒ, the
phases separated and the aqueous phase extracted with EtOAc
(3ꢃ10 mL). The combined organic phases were rinsed with brine
(25 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified by flash chromatography (silica gel,
CHCl3/MeOH 97:3) to afford compound 26 (3.4 mg, 74%) as a col-
Compound 23a: 1H NMR (400 MHz; CDCl3):
d 7.50e7.22 (m, 10H),
6.62 (s, 1H), 6.14 (t, J¼6.1 Hz, 1H), 5.48 (s, 1H), 5.18 (1/2 AB,
J¼11.1 Hz, 1H), 5.09 (1/2 AB, J¼11.1 Hz, 1H), 4.10 (s, 1H), 3.97 (1/2
AB, J¼13.3 Hz, 1H), 3.87 (1/2 AB, J¼13.3 Hz, 1H), 3.79 (d, J¼7.7 Hz,
1H), 3.73 (s, 1H), 2.69 (ddt, J¼27.0, 9.0, 4.6 Hz, 2H), 2.25 (s, 3H),
2.06 (dd, J¼13.3, 9.5 Hz, 1H), 1.90 (br t, 6.0 Hz, 1H), 1.44 (s, 9H); 13C
NMR (101 MHz, CDCl3):
d 171.9, 171.7, 150.5, 148.2, 138.3, 137.2,
135.6, 132.6, 128.7, 128.5, 128.4, 128.4, 127.6, 127.3, 122.1, 120.1,
103.7, 81.3, 75.1, 65.4, 64.2, 62.7, 60.4, 51.7, 51.3, 50.7, 31.6, 28.1,
25
28.1, 15.9, 14.3; Rf (SiO2, hexanes/EtOAc 4:1) 0.12; [
a
]
ꢀ60.0 (c
D
0.895, CHCl3); IR (film, CH2Cl2), nmax 3447 (br), 3063, 3030, 2934,
2870, 1730, 1676, 1636, 1154 cmꢀ1; HRMS (MHþ), found 597.2971.
C36H41N2O6 requires 597.2965. Compound 24b: 1H NMR
orless oil. 1H NMR (400 MHz; CDCl3):
d
6.51 (s, 1H), 5.59 (dd, J¼5.6,
3.4 Hz, 1H), 3.96 (d, J¼6.1 Hz, 1H), 3.88 (dd, J¼10.9, 3.2 Hz, 1H), 3.78
(s, 3H), 3.77e3.76 (m, 1H), 3.67 (dt, J¼12.4, 2.6 Hz, 1H), 3.61 (dd,
J¼11.1, 5.8 Hz, 1H), 3.16 (dd, J¼9.0, 6.4 Hz, 1H), 2.84 (t, J¼13.5 Hz,
1H), 2.54 (dd, J¼14.7, 2.2 Hz, 1H), 2.50 (dd, J¼13.2, 9.0 Hz, 1H), 2.27
(s, 3H), 2.18 (dt, J¼13.2, 6.6 Hz, 1H), 1.53e1.45 (m, 9H); 13C NMR
(400 MHz; CDCl3):
d
6.62 (s, 1H), 6.09 (dd, J¼8.4, 4.4 Hz, 1H), 5.45
(s, 1H), 5.17 (1/2 AB, J¼11.1 Hz, 1H), 5.14 (1/2 AB, J¼11.1 Hz, 1H),
3.95 (s, 1H), 3.83 (s, 3H), 3.78 (d, J¼13.5 Hz, 1H), 3.73 (d, J¼6.6 Hz,
1H), 3.63 (d, J¼13.4 Hz, 1H), 3.63e3.50 (m, 1H), 3.15 (dd, J¼9.8,
6.1 Hz, 1H), 2.63 (dt, J¼12.8, 6.5 Hz, 1H), 2.45 (dd, J¼13.0, 9.8 Hz,
1H), 1.77e1.74 (br m, 1H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3):
(101 MHz, CDCl3):
d 174.4, 172.4, 145.7, 132.0, 129.7, 121.2, 120.2,
118.0, 81.5, 67.8, 63.0, 62.2, 61.0, 60.8, 52.6, 42.8, 38.8, 32.1, 29.9,
25
28.2, 15.9; Rf (SiO2, CHCl3/MeOH 95:5) 0.20; [
a
]
ꢀ36 (c 0.080,
D
d
172.3, 170.4, 150.6, 147.9, 138.1, 137.2, 134.0, 132.5, 128.7, 128.7,
CHCl3); IR (film, CH2Cl2), nmax 3286 (br), 2958, 2925, 2855, 1729,
1652, 1456 cmꢀ1; HRMS (MHþ), found 419.2174. C22H31N2O6 re-
quires 419.2182.
128.6, 128.6, 128.5, 128.5, 128.4, 128.4, 127.3, 126.5, 122.8, 122.7,
120.6, 105.3, 105.3, 81.3, 75.0, 65.5, 65.5, 63.1, 63.0, 60.4, 52.7,
49.4, 49.4, 48.4, 34.8, 28.2, 16.0, 16.0; Rf (SiO2, hexanes/EtOAc 4:1)
25
0.10; [
a
]
þ64 (c 0.31, CHCl3); IR (film, CH2Cl2), nmax 3444 (br),
Acknowledgements
D
3062, 3029, 2970, 2927, 1729, 1682, 1639, 1154 cmꢀ1; HRMS
(MHþ), found 597.2974. C36H41N2O6 requires 597.2965.
We gratefully acknowledge financial support from the National
Institutes of Health (Grant RO1CA085419) and Bristol Myers Squibb
Co (doctoral fellowship to A.J.).
4.15. (5R,8S,10R,11S)-tert-Butyl 4-hydroxy-5-(hydrox-
ymethyl)-3-methoxy-2-methyl-7-oxo-5,7,8,9,10,11-
hexahydro-8,11-epiminoazepino[1,2-b]isoquinoline-10-
carboxylate (25)
Supplementary data
1H and 13C NMR spectra of all compounds. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.05.009.
A solution of compound 24b (7.0 mg, 0.012 mmol) in glacial
acetic acid (1 mL) and 10% Pd/C (7 mg) were placed in round
bottom flask and sparged with Ar for 5 min. The vessel was
evacuated and filled with hydrogen three times. The reaction was
vigorously stirred overnight under hydrogen (1 atm). The sus-
pension was diluted with CH2Cl2 (25 mL) and then filtered
through CeliteÒ and the flask was rinsed with CH2Cl2 (3ꢃ5 mL).
The solution was extracted with satd aq NaHCO3 (3ꢃ15 mL). The
combined aqueous layers were diluted with phosphate buffer
(0.1 M, pH¼7.5, 25 mL) and extracted with CH2Cl2 (3ꢃ15 mL). The
combined organic layers were rinsed with brine (50 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The crude
material was purified by flash chromatography (silica gel, CHCl3/
MeOH 97:3) to afford compound 25 (4.6 mg, 92%) as a colorless
References and notes
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oil. 1H NMR (400 MHz; CDCl3):
d
6.40 (s, 1H), 6.05 (dd, J¼7.9,
4.1 Hz, 1H), 5.53 (s, 1H), 4.30 (s, 1H), 4.09 (d, J¼6.7 Hz, 1H),
3.78e3.74 (m, 2H), 3.76 (s, 3H), 3.65e3.60 (m, 1H), 3.17 (dd, J¼9.3,
6.2 Hz, 1H), 2.61 (dd, J¼13.1, 9.4 Hz, 1H), 2.32 (dt, J¼13.2, 6.6 Hz,
10. Sasaki, T.; Otani, T.; Matsumoto, H.; Unemi, N.; Hamada, M.; Takeuchi, T.; Hori,
M. J. Antibiot. 1998, 51, 715e721.
1H) 2.24 (s, 3H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3):
d 173.4,
11. Zhang, C. W.; Herath, K.; Jayasuriya, H.; Ondeyka, J. G.; Zink, D. L.; Occi, J.;
Birdsall, G.; Venugopal, J.; Ushio, M.; Burgess, B.; Masurekar, P.; Barrett, J. F.;
Singh, S. B. J. Nat. Prod. 2009, 72, 841e847.
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13. Yoshida, A.; Akaiwa, M.; Asakawa, T.; Hamashima, Y.; Yokoshima, S.; Fukuyama,
T.; Kan, T. Chem.dEur. J. 2012, 18, 11192e11195.
14. Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476e12477.
15. Magnus, P.; Matthews, K. S. Tetrahedron 2012, 68, 6343e6360.
16. Couturier, C.; Schlama, T.; Zhu, J. P. Synlett 2006, 1691e1694.
171.1, 145.2, 144.7, 144.7, 136.9, 136.8, 130.3, 127.1, 119.1, 112.9,
112.9, 102.7, 81.6, 65.1, 62.4, 61.8, 61.0, 49.5, 48.1, 37.0, 29.8, 29.8,
25
28.2, 15.9; Rf (SiO2, CHCl3/MeOH 95:5) 0.17; [
a
]
þ4.3 (c 0.23,
D
CHCl3); IR (film, CH2Cl2), nmax 3262 (br), 2969, 2925, 2854,
1719, 1683, 1646, 1154 cmꢀ1; HRMS (MHþ), found 417.2033.
C22H29N2O6 requires 417.2026.

ꢀ
A. Jimenez-Somarribas, R.M. Williams / Tetrahedron 69 (2013) 7505e7512
7512
17. Wu, Y. C.; Bernadat, G.; Masson, G.; Couturier, C.; Schlama, T.; Zhu, J. P. J. Org.
Chem. 2009, 74, 2046e2052.
29. Zhu’s conditions were also used by Liao (Ref. 22) to convert compound 6 into
a trans-THIQ system, using 2-benzyloxyacetaldehyde.
18. Bernadat, G.; George, N.; Couturier, C.; Masson, G.; Schlama, T.; Zhu, J. P. Synlett
30. Fukuyama, T.; Nunes, J. J. J. Am. Chem. Soc. 1988, 110, 5196e5198.
31. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480e2482.
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80, 176e180.
33. Vishnetskaya, M. V.; Yakimova, I. Y.; Sidorenkova, I. A. Russ. J. Phys. Chem. 2006,
80, 173e175.
2011, 576e578.
19. Siengalewicz, P.; Brecker, L.; Mulzer, J. Synlett 2008, 2443e2446.
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24. The lack of reactivity of the primary hydroxyl of 7 is consistent with the re-
gioselectivity observed in the reaction between TBS-Cl and diols bearing
35. As illustrated in Scheme 4, we propose that the dipolarophile adds from the Re
face of the iminium ion carbon to form 20a, which epimerizes under the re-
action conditions to form 20b.
a b-aminoalcohol motif (Ref. 24). We concur with the explanation provided by
the authors, which stated that the nucleophilicity of the primary hydroxyl is
reduced by internal hydrogen bonding to the neighboring amino group.
25. Sales, M.; Charette, A. B. Org. Lett. 2005, 7, 5773e5776.
26. Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009, 11, 5394e5397.
27. Lane, J. W.; Chen, Y. Y.; Williams, R. M. J. Am. Chem. Soc. 2005, 127, 12684e12690.
28. Chen, J.C.;Chen, X. C.; Bois-Choussy, M.;Zhu,J.P. J. Am. Chem. Soc. 2006,128, 87e89.
36. We propose that the observed chemoselectivity can be explained by the initial
formation of a phenoxyaluminum hydride species, which upon delivery of one
hydride to the ester, forms a stable seven-membered ring alkoxy(phenoxy)
aluminum hydride species.
37. Compounds 23a and 23b are unstable to silica gel. Consequently, we did not
attempt their separation for the purpose of recycling of 23a.