A divergent strategy for synthesis of the tetrahydroisoquinoline alkaloids renieramycin G and a lemonomycin analog

Article abstract of DOI:10.1016/j.tet.2012.02.043

A divergent synthesis to the tetrahydroisoquinoline alkaloids (±)-renieramycin G and (±)-lemonomycinone amide is reported. A strategy was developed that allowed access to both the diazabicyclo[3.3.1]nonane and diazabicyclo[3.2.1]octane ring systems of the respective targets from a common advanced intermediate. The high diastereoselectivity observed throughout the synthesis is controlled by the first stereocenter formed from alkylation of an unactivated isoquinoline. Key findings include the synthesis of isoquinolines under palladium-free Larock conditions, diastereoselective ionic hydrogenation conditions to set the 1,3-cis-tetrahydroisoquinoline architecture, a highly diastereoselective reprotonation, and a thiophilic Lewis acid-catalyzed 5-endo-trig N-acyl iminium ion silyl enol ether cyclization. This divergent approach to the tetrahydroisoquinoline alkaloids offers an alternative strategy to further structural diversity in this family of natural products.

Full text of DOI:10.1016/j.tet.2012.02.043

Tetrahedron 68 (2012) 6343e6360
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A divergent strategy for synthesis of the tetrahydroisoquinoline alkaloids
renieramycin G and a lemonomycin analog
*
Philip Magnus , Kenneth S. Matthews
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 January 2012
Received in revised form 15 February 2012
Accepted 16 February 2012
Available online 22 February 2012
A divergent synthesis to the tetrahydroisoquinoline alkaloids (ꢀ)-renieramycin G and (ꢀ)-lemon-
omycinone amide is reported. A strategy was developed that allowed access to both the diazabicyclo
[3.3.1]nonane and diazabicyclo[3.2.1]octane ring systems of the respective targets from a common ad-
vanced intermediate. The high diastereoselectivity observed throughout the synthesis is controlled by
the first stereocenter formed from alkylation of an unactivated isoquinoline. Key findings include the
synthesis of isoquinolines under palladium-free Larock conditions, diastereoselective ionic hydrogena-
tion conditions to set the 1,3-cis-tetrahydroisoquinoline architecture, a highly diastereoselective re-
protonation, and a thiophilic Lewis acid-catalyzed 5-endo-trig N-acyl iminium ion silyl enol ether
cyclization. This divergent approach to the tetrahydroisoquinoline alkaloids offers an alternative strategy
to further structural diversity in this family of natural products.
Keywords:
Tetrahydroisoquinoline alkaloids
Lemonomycin
Renieramycin
N-Acyl iminium ion cyclization
Ionic hydrogenation
Isoquinoline synthesis
Diastereoselective reprotonation
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
was the first to be synthesized in 1982 by Fukuyama.5 One of the
most synthetically challenging structures, Et-743 (2), has inspired
The tetrahydroisoquinoline alkaloids are a broad family of nat-
ural products with nearly 60 isolated members and over a hundred
analogs.1 They have been found in a variety of environments from
Easter Island soil samples, naphthyridinomycin (4, Fig. 1),2a to Fijian
sea sponges, renieramycin G (3),2b to Caribbean sea squirts, ectei-
nascidin 743 (Et-743, 2)2c and numerous cultures of Streptomyces
strains, lemonomycin (6),2c saframycin B (1),2d and quinoncarcin
(5).2e Their broad range of biological activity as potent cytotoxic
agents exhibiting antitumor, antibiotic, and antimicrobial activity
has made them attractive targets as potential therapeutics. The
only commercially available tetrahydroisoquinoline alkaloid ther-
apeutic, Et-743 (Trabectedin, Yondelis), has received considerable
attention due to its potent in vivo activity. It shows greater anti-
proliferative activity than taxol,1j and is currently marketed in
Europe and South Korea for the treatment of soft-tissue sarcoma,
and is in Phase II/III clinical trials for the treatment of other
cancers.3
a variety of elegant syntheses,6 yet the commercial synthesis is
a semisynthetic route from cyanosafracin B, obtained from the
fermentation of the bacteria Pseudomonas fluorescens.7 Lemon-
omycin (6), whose structure was not elucidated until 2000,8 ex-
emplifies the architectural variance in the tetrahydroisoquinoline
alkaloids. It is the only member to have a carbohydrate appendage
in addition to the unusual aldehyde hydrate.
These structurally diverse alkaloids can be divided into mono-
tetrahydroisoquinolines 9 (MTHI) and bis-tetrahydroisoquinolines
10 (BTHI) (Scheme 1). Naphthyridinomycin, quinocarcin, and lem-
onomycin share the same diazabicyclo[3.2.1]octane framework that
is common to the MTHI core, while saframycin,ecteinascidin, and
renieramycin share the diazabicyclo[3.3.1]nonane ring system
common to the BTHI core. Although numerous strategies have been
employed to synthesize these alkaloids, a divergent strategy that
allows access to both families of tetrahydroisoquinoline alkaloids
from a common advanced intermediate has not been reported.9
Fukuyama has developed an excellent convergent approach to
both MTHI and BTHI using an efficient Ugi four-component con-
For over three decades these natural products have been the
focus of numerous synthetic efforts not only because of their bi-
ological significance, but also because of their diverse and chal-
lenging architecture. Naphthyridinomycin (4) was the first
structure elucidated in 19744 by X-ray analysis. Saframycin B (1)
densation.6b,10a Myers reported the synthesis of saframycin using
a-
aminoaldehydes as key components.10b Danishefsky’s convergent
‘lynchpin Mannich’ strategy has been demonstrated with BTHI’s Et-
743 and saframycin11 but met with limited success for the MTHI
quinoncarcin.12
* Corresponding author. E-mail address: p.magnus@mail.utexas.edu (P. Magnus).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.043

6344
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
Fig. 1. Representatives of the tetrahydroisoquinoline alkaloids.
OMe
accessible from a 1,3-cis-substituted tetrahydroisoquinoline 12. A
two-step process from electron-rich isoquinoline14, employing an
alkylation at the C1 position and diastereoselective reduction of
the resulting 1,2-dihydroisoquinoline 13, would afford the 1,3-
cis relationship. A challenge faced in syntheses of the tetrahy-
droisoquinoline alkaloids is efficient and selective formation of the
1,3-cis substituted tetrahydroisoquinoline core. Many strategies use
a late stage PicteteSpengler or Mannich reaction to form either the
C1 or C3 stereocenters, which often result in formation of some
unwanted 1,3-trans isomer.13
O
H
Me
O
HO
O
O
OH
H
O
O
H
Me
15
11
H
N
Me
H 3
Me
11
NH
N
H 3
13 H
Me
MeO
1
N
13
MeO
O
1
17
Y
O
X
OR
O
H
7, Lemonomycinone (R = H, X = OH, Y = H)
8, Lemonomycinone amide (R = H, X,Y = O)
Me
3, Renieramycin G
2. Results and discussion
2
R
2
H
H
R
H
H
We previously reported the C-1 alkylation of electron-rich iso-
quinolines with organolithium nucleophiles as an efficient method
to form 1,2-dihydroisoquinolines.14 Treatment of isoquinoline with
an organolithium results in alkylation at C1 generating the 1,2-
dihydroisoquinoline intermediate 15 (Scheme 2), which readily
rearomatizes via air oxidation, but on quenching with methyl
chloroformate the stable 1,2-dihydroisoquinoline 16 can be iso-
lated. Research by the Alexakis group demonstrated modest
enantioselectivity could be achieved from alkylation of isoquinoline
with MeLi and in the presence of (ꢁ)-sparteine.15 We explored this
11
11
N
Me
NH
H 3
H 3
N
N
13 H
13
1
1
H
1
1
R
R
Y
Y
X
X
9, mono-tetrahydroisoquinoline core
10, bis-tetrahydroisoquinoline core
bicyclo[3.2.1]octane
bicyclo[3.3.1]nonane
OMe
Me
Z
H
2
11
NR
H 3
N
13
MeO
1
1
R O
O
X
11
R-Li, (
−)-sparteine
N
N
−
78 °C, toluene
Li
OMe
Z
OMe
Z
2
15
OMe
Z
H
R
Me
3
Me
3
Me
ClCO Me
2
H 3
H
N
NH
NR
N
CO Me
MeO
2
1
MeO
1
MeO
1
1
16
1
R
R O
1
OR
OR
X
X
12
13
14
Scheme 1. Retrosynthetic analysis.
R
Yield
80%
ee
Me
60%
To demonstrate our divergent approach to tetrahydroisoquino-
line alkaloids we targeted a lemonomycin analog 7 (Scheme 1) and
renieramycin G (3), which share the same substitution on the
quinone group. As shown in the retrosynthetic analysis, their
structures can be simplified to bridged ring systems 9 and 10, re-
spectively. These could be constructed late in the synthesis from
a common advanced piperazine 11. The intermediate 11 should be
17 PhSCH2-
91%
0%
18 PhOCH2- 66%
33%
Scheme 2. Model system.

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6345
i) n-BuLi (3 equiv), THF
78 °C, 10 min.
chemistry with isoquinoline and more functionalized nucleophiles
O
SnBu
phenyl thiomethyllithium 1716 and benzyl oxymethyllithium 18
(BOM-Li).17 Under no conditions did we observe enantioselectivity
for alkylations using the sulfur nucleophile 17, while the BOM-Li 18
gave only modest ee. Alkylation with BOM-Li allowed the C1 sub-
stituent to be installed for both renieramycin G and lemon-
omycinone amide. The fully substituted, electron-rich isoquinoline
would have to be synthesized in order to test the enantioselectivity
of this alkylation on the real system.
−
3
ii) 25 (1 equiv), THF
iii) ClCO Me
2
26, 4 equiv.
OMe
OMe
Me
Me
OTIPS
OTIPS
CO Me
+
N
N
MeO
CO Me
2
MeO
2
OBn
BnO nBu
28, <5%
OBn
A modification of Larock’s isoquinoline methodology18 was
employed for the synthesis of isoquinoline 25 from aryl-iodide 1914
(Scheme 3). The initial Sonogashira conditions for the reaction of
electron-rich imine 19 and alkyne 20 gave incomplete coupling.
The alkyne insertion proved slow and precipitation of palladium(0)
was apparent. To circumvent this challenge aryl-iodide 19 and al-
kyne 23 were coupled using CastroeStevens conditions.19 The
coupled product 24 was cleanly formed by stirring 19 and 20 at
25 ꢂC for 24 h with a stoichiometric amount of CuI. The activation of
the coupling reaction required the presence of the ortho-imine.
When aldehyde 21 was treated to analogous room temperature
coupling conditions only unreacted starting material was obtained.
The coupled product 24 (after removal of Et3NHCl, in the work-up)
was converted into the isoquinoline 25 by heating in DMF with
catalytic CuI. Heating the reaction to promote the copper catalyzed
cyclization in the presence of Et3NHCl resulted in removal of the
TIPS group, and gave a significant increase in the formation of by-
products.20
27, 79% yield
Scheme 4. Installation of the C1 substituent.
reduction of the 3,4-olefin of enecarbamates21 to afford exclusively
the 1,3-cis isomer, presumably due to the axial orientation of the C-
1 substituent during reduction of the iminium intermediate. It was
expected that the reduction of 1,2-dihydroisoquinoline 27 with TFA
and Et3SiH would form the TIPS deprotected alcohol 30 followed by
reduction to the 1,3-cis isomer 29. Upon addition of TFA rapid loss
of the TIPS group was observed followed by reduction to the 3-
methyl product 33 (Scheme 5).22 The formation of 33 maybe ra-
tionalized by acid catalyzed elimination of 31 to give 32, which
upon reduction leads to 33. Although a number of alternative re-
duction conditions were attempted, the tri-substituted cyclic olefin
proved difficult to reduce without decomposition or by-product
formation.
Larock Isoquinoline Conditions:
i)
20
OBn
2
OMe
OBn
OMe
OBn
OMe
2% PdCl (PPh ) ,
3 2
Me
I
Me
Me
I
1% CuI, Et N,
3
OBn
+
55 °C, 3 h
t
N
NBu
MeO
CHO
MeO
MeO
ii) 10% CuI, DMF
100 °C, 5 h
OBn
19
21, 41% yield
OTIPS
22, 33% yield
Optimized conditions:
OTIPS
19
OMe
OMe
OTIPS
Me
Me
CuI (0.2 eq), DMF
100 °C, 1 h
23
t
CuI (1.2 eq), Et N
3
NBu
24
N
MeO
MeO
25 °C, 24 h
76% yield
two steps
OBn
OBn
25
Scheme 3. Isoquinoline synthesis.
We next turned our attention to C-1 alkylation of the electron-
rich isoquinoline 25. Treating isoquinoline 25 with 1 equiv of
BOM-Li in the presence of (ꢁ)-sparteine, generated from stannane
26 by trans-metalation with n-BuLi at ꢁ78 ꢂC resulted in slow and
incomplete alkylation (Scheme 4). The nucleophile proved to be
unstable above ꢁ30 ꢂC. Excess BOM-Li was needed for efficient
conversion; 4 equiv of stannane 26 and 3 equiv of n-BuLi gave the
alkylated product 27 in 79% yield. Interestingly, when equimolar
amounts of stannane 26 and n-BuLi were used the n-butyl alkylated
product 28 was isolated in 33% yield as the major by-product. Any
attempt to effect an enantioselective alkylation with (ꢁ)-sparteine
was unsuccessful. At this time no alternative enantioselective al-
kylation methodology was pursued, and we continued our di-
vergent approach to the tetrahydroisoquinolines in racemic form.
Efficient and selective formation of the 1,3-cis substituted tet-
rahydroisoquinoline core could be achieved using ionic hydroge-
nation conditions, which proved very successful in our previous
work.14 Ionic hydrogenation has shown very high selectivity for the
It was found that treatment of 30 with NaBH4 yielded the
cyclized product 34, which under ionic hydrogenation conditions
was selectively reduced to the 1,3-cis-tetrahydroisoquinoline 36 in
95% yield. The process was optimized by conversion of 27 into
oxazolidinone 34, followed by reduction (TFAeEt3SiH) and hydro-
lysis with hydrazine and KOH to give 40 in 86% yield (Scheme 6).
The 1,3-cis stereochemistry of 40 was confirmed by X-ray
analysis. The absence of any observable by-products was surprising
because a degradation pathway forming eliminated 38 and de-
carboxylation to 39 is conceivable (Scheme 5). The poor overlap
between the CeO antibonding orbital and the
p system presumably
prevents this pathway.
To complete the synthesis of the common intermediate the in-
stallation of piperazine ring was required. To this end, Boc-glycine
was coupled with the sterically hindered secondary amine 40
(Scheme 7). Treating amino alcohol 40 with 1 equiv of PyBOPÒ and
BocGlyOH did not give the amide product 43, instead only the ester
product 41 was isolated. Attempts to rearrange the ester to the

6346
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
First Attempt to Form the 1,3-cis-tetrahydroisoquinoline
OMe
OMe
OBn
H
N
Me
Me
OTIPS
CO2Me
OBn
OH
TFA, Et3SiH, CH2Cl2
10 °C to 25 °C, 1 h
H
N
MeO
MeO
CO2Me
OBn
OBn
27
29
-TIPS
OMe
OBn
OMe
OMe
OMe
OBn
H
N
Me
Me
H
Me
Me
MeO
H
Me
H
OH
OMe
O
H
H
H2
CO2Me
N
N
N
MeO
MeO
MeO
CO2Me
CO2Me
O
OBn
32
OBn
31
OBn
OBn
OBn
33
OBn
30
Successful Diastereoselective Reduction
OMe
Me
OMe
OBn
OMe
OMe
OBn
H
N
Me
Me
Me
NaOMe
OH
TFA
Et3SiH
H
O
O
H
O
N
25 °C, 15 h
86% yield
N
N
MeO
CO2Me
MeO
MeO
MeO
O
O
O
OBn
30
OBn
35
OBn
OBn
OBn
OBn
34
36, 95% yield
H
OMe
OMe
OMe
Me
Me
MeO
Me
MeO
-CO2
O
N
N
O
NH
MeO
O
OBn
H
OBn
38
OH
OBn
OBn
39
OBn
OBn
37
Scheme 5. Synthesizing the 1,3-cis-substituted tetrahydroisoquinoline 36.
OMe
OBn
OMe
OMe
H
1) TFA, Et SiH
3
Me
MeO
Me
Me
MeO
TBAF, THF
OTIPS
−
10 °C to 25 °C, 2 h
OH
3
O
H
N
2) H NNH H O, KOH
NH
N
−
10 °C to 25 °C
2
2
2
CO Me
2
MeO
1
ethylene glycol
150 °C, 3 h
O
OBn
34
OBn
91% yield
OBn
OBn
OBn
40, X-ray
27
86% yield
Scheme 6. Optimized synthesis of 1,3-cis-substituted tetrahydroisoquinoline 40.
The second route utilized the in situ protection of the C-3
hydroxymethyl as a TMS ether. Addition of TMS-Cl and triethyl-
amine to a solution of amino alcohol 40 readily formed the pro-
tected intermediate, which was added, after filtration to remove
triethylamine hydrochloride, to tert-butyl mixed anhydride 44
(Scheme 8). After acidic work-up the coupled product was isolated
as the deprotected alcohol 43. Addition of the silylated
OMe
OBn
1.0 equiv. PyBOP®
1.0 equiv. Boc-GlyOH
OMe
O
H
H
Me
Me
NHBoc
OH
O
H
H
Hünig's base, CH Cl
2
2
NH
NH
MeO
MeO
0 °C to 25 °C, 4 h
OBn
41
82% yield
OBn
OBn
40
dichlorobenzene
150 °C
3.0 equiv. PyBOP®
3.0 equiv. Boc-GlyOH
or
Hünig's base, CH Cl
2
2
thiopyridone
PhMe, 100 °C
0 °C to 25 °C, 15 h
OMe
OMe
H
1) TMSCl, Et N, THF
3
H
N
Me
Me
0 °C to 25 °C, 3 h
OH
OH
NHBoc
OMe
O
H
H
OMe
OBn
H
N
O
O
2)
NH
OBn
44
H
Me
NHBoc
MeO
NHBoc
MeO
Me
O
NaOH
O
OH
H
OBn
OBn
O
H
N
MeO
NHBoc
THF,
−
55 °C to 25 °C, 12 h
82% yield
OBn
43
MeO
NHBoc
51% yield
from 40
40
OBn
42
O
O
OBn
OBn
43
Scheme 7. First approach to amide 43.
OMe
OH
H
N
Me
MeO
11
Swern ox.
87% yield
NBoc
H
amide were unsuccessful. Amide 43 was synthesized by using ex-
cess coupling reagent and Boc-glycine to form the di-coupled
product 42 followed by hydrolysis of the ester. Although this was
a viable route to the product, an alternative approach was needed
to significantly improve throughput and yield.
OBn
O
OBn
45
3:2 mixture at C11
Scheme 8. Optimized coupling conditions.

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6347
intermediate at warmer temperatures (>ꢁ20 ꢂC) gave higher
OMe
OBn
SPh
H
N
i) LiHMDS, THF
Me
amounts of the tert-butyl amide by-product. Oxidation of alcohol
43 using Swern conditions led to piperazine formation, and affor-
ded hemi-aminal 45, as a 3/2 mixture of diastereomers at the C11
stereocenter.23
11
−
78 °C, 15 min.
NBoc
46
H
ii)
Br
13
MeO
O
70% yield
OBn
47, X-ray
Intermediate 45 represented a point of divergence for our syn-
thesis of the tetrahydroisoquinoline alkaloids as either bridged ring
system could be installed. The first approach focused on forming
the diazabicyclo[3.2.1] octane ring system present in the MTHI
lemonomycin. To this end, we investigated alkylation at the C-11
position via acid catalyzed N-acyliminium methodology.24 Un-
fortunately, treatment of hemi-aminal 45 with a Lewis acid only
elimination products and loss of benzyl and/or Boc protecting
groups was observed. In order to form the N-acyliminium in-
termediate under more selective conditions the hemi-aminal was
converted to a thioaminal. A high yielding two-step process gave
thioaminal 46 from Swern oxidation of 43 followed by reaction
with thiophenol and p-TSA (Scheme 9). Interestingly, the thio-
aminal formed as a single diastereomer, which upon crystallization
and X-ray analysis proved to be the cis isomer (Fig. 2). The Boc
protecting group exhibited strong amide resonance as evidenced in
1H NMR, imparting considerable double bond character across the
N-12 and Boc carbonyl carbon. This situated the tert-butoxy group
in an equatorial position and the thiophenol group pseudo-axial,
even in the presence of the C-1 axial substituent. Efforts to in-
termolecularly alkylate at the C11 via N-acyliminium chemistry
proved unsuccessful.
OMe
SPh
i) 2.4 equiv. t-BuLi, THF
78 °C, 30 sec.
H
Me
−
11
NBoc
H
ii) BHT
79% yield
N
13
MeO
OBn
O
OBn
48
Scheme 10. Diastereoselective alkylation and stereo-center inversion.
OMe
OMe
SPh
H
N
H
N
Me
Me
1) Swern ox.
OH
NHBoc
11
NBoc
H
H
2) PhSH, pTSA
0 °C, 1.5 h
MeO
13
MeO
OBn
O
OBn
O
OBn
OBn
46, X-ray
86% yield
Fig. 3. X-ray structure of 47.
43
Scheme 9. Formation of thioaminal 46.
X-ray structure of 47 showed poor
p-overlap of the C13 hydrogen
and C14 carbonyl suggesting a significantly decreased acidity. In
addition, formation of the enolate intermediate would require
overcoming the steric strain of the allyl side-chain and the Boc
group being positioned in the same plane. Optimized conditions
required treatment of 47 with t-BuLi (2.0 equiv)/ꢁ78 ꢂC followed by
quenching with a hindered proton source, BHT, to give only the
epimeric product 48 (protonation from the least hindered face).
Quenching with a less hindered proton source like MeOH gave a 5/1
mixture of cisetrans diastereomers. Efforts to further elaborate the
allyl side-chain to the diazabicyclo[3.2.1]octane ring system were
unsuccessful.
Using an alternative side-chain, thioaminal 46 was alkylated
with iodide 49 after enolization with KHMDS (Scheme 11). Alkyl-
ation methods using LiHMDS or the bromo analog of 49 gave in-
ferior results. It proved necessary to deoxygenate the starting
solution in order to optimize the yield. The product was isolated as
one diastereomer, presumed to be the trans isomer 50. Inversion of
the C13 stereocenter and TIPS deprotection (TBDMS, TES proved
unstable to t-BuLi) gave alcohol 51. Swern oxidation followed by
silyl enol ether formation gave the cyclization precursor 52.
It was anticipated that the silyl enol ether 52 would react upon
N-acyliminium ion formation to form the diazabicyclo[3.2.1]oc-
tane ring system. Such intramolecular cyclizations are well pre-
cedented in the literature,26 and specifically the N-acyliminium
intramolecular cyclization of a silyl enol ether to a five-membered
ring has been reported (Scheme 12).27 Both Fukuyama10 and
Myers28 have used allyl silane-iminium cyclizations to form the
diazabicyclo[3.2.1] framework of lemonomycin. Fukuyama also
demonstrated formation of the ring system in his total synthesis
Fig. 2. X-ray structure of 46.
Our second strategy investigated building the bridged ring
system from alkylation at the C-13 position. Thioaminal 46 was
alkylated after enolate formation and addition of allyl bromide to
give only one diastereomer 47 (Scheme 10). The expected trans
isomer (least hindered face) was confirmed by X-ray analysis
(Fig. 3). Although this was not the required stereochemistry we
anticipated the stereocenter could be readily epimerized. Depro-
tonation of 47 under thermodynamic conditions with t-BuOKet-
BuOH at 55 ꢂC gave 47 and 48 in a 1/1 ratio. A diastereoselective
reprotonation strategy25 would have to rely on complete deproto-
nation of the C-13 hydrogen, which proved more difficult than
initially expected. Treatment of 47 with LiHMDS, KHMDS, or LDA at
ꢁ78 ꢂC did not lead to deprotonation, while at elevated tempera-
tures only degradation products were observed. Examination of the

6348
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
OMe
SPh
OMe
OBn
SPh
H
N
i) KHMDS, THF
78 °C, 5 min.
H
N
Me
Me
−
NBoc
NBoc
H
H
ii)
MeO
MeO
I
OTIPS
49
OBn
O
OTIPS
O
OBn
50
OBn
78% yield
46
1) i) 2.2 equiv. t-BuLi, THF
OMe
SPh
H
OMe
SPh
−
78 °C, 10 sec.
H
N
Me
Me
MeO
ii) BHT, THF
NBoc
1) Swern ox.
2) TIPSOTf, Et N,
Et O, 25 °C, 16 h
2
NBoc
H
H
N
2) 48% aq. HF, CH CN
3
0 °C, 30 min.
OTIPS
3
MeO
OBn
O
OBn
52
O
OBn
83% yield
88% yield
OBn
51
OH
Scheme 11. C13 side-chain installation.
Hiemstra/Speckamp
TIPSO
Treatment of 52 with Hg(O2CCF3)2 in THF did not afford the
cyclized product, nor did Speckamp’s conditions, BF3$Et2O. Al-
ternative methods such as simply heating the derived sulfoxide
from 52, or radical formation (n-Bu3SnH, AIBN) failed to yield
cyclized product.
Bn
O
Bn
N
O
BF OEt
3
2
N
Me
Bn
O
H
CH Cl , 20°C
2 2
Me
OEt
N
OTIPS
NBoc
O
Me
From reaction observations we concluded that the iminium ion
was rapidly formed upon treatment with a thiophilic Lewis acid,
but a non-basic counter ion was needed to avoid formation of
elimination products. Although reaction intermediates were never
identified it is likely that the iminium ion 54 rapidly cyclizes to form
the triisopropylsilyloxonium ion 55, which remains in equilibrium
until cleavage of the TIPS group. Without removal of the TIPS group
the intermediate is susceptible to formation of elimination by-
products. The loss of the TIPS is likely to controlled by THF. The
THF acts as either a direct participant in the removal of TIPS or it
assists in the release of a fluoride anion by complexation with BF4
and then the released fluoride removes the TIPS. Small amounts of
THF polymer were observed in the crude product mixture poten-
tially generated from silyloxonium ion 56 or trifluoroborate oxo-
nium ion 57.
Fukuyama; Lemonomycin
TMS
OAc
N
TMS
Boc
BF OEt
3
2
NBoc
N
Ar
N
CH Cl , −78°C
Ar
2
2
Ar
N
O
O
O
OAc
OAc
OAc
Fukuyama; Quinocarcin
O
Cbz
OH
HgCl , CSA
SPh
2
Ar
NCbz
Ar
N
CH CN, H O, 40°C
3
2
HN
HN
O
O
Scheme 12. Literature examples of N-acyl iminium ion cyclization to bridged ring
systems.
The cyclization product 53 was formed as a single diastereomer
at C-15. It was anticipated that the desired exo stereochemistry
would be preferred due to steric strain over the tetrahy-
droisoquinoline core imparted by the axial orientation of the C-1-
substituent as observed in structures 40, 43, and 47. The aldehyde
53 was converted to the oxime 58 as a 1/1 mixture of cis and trans
isomers (Scheme 14). After chromatographic separation, the more
polar fraction was crystallized as a 4/1 cisetrans mixture, and X-ray
analysis (Fig. 4) revealed the desired orientation at the C-15
stereocenter.
of quinoncarcin from the N-acyliminium cyclization of a vinyl
sulfide.29
Intramolecular N-acyliminium cyclization of 52 to give dia-
zabicyclo[3.2.1]octane 53 was successfully achieved by treatment
of 52 with AgBF4 in THF (Scheme 13). The N-acyliminium ion
formation was rapid as evidenced by the immediate precipitation
of AgSPh, but product formation proceeded slowly over 4 h. The
product was not observed when AgBF4 was used in diethyl ether
or chlorobenzene. The starting material was consumed, but only
elimination by-products or decomposition were observed.
O
H
OMe
OBn
SPh
H
N
OMe
15
Me
H
Boc
NBoc
AgBF /THF
4
Me
11
H
N
H 3
OTIPS
MeO
N
25 °C, 4h
13
MeO
1
O
OBn
O
OBn
52
OBn
53
BF
O
TIPS
O
fast
slow
3
AgSPh
BF
4
or
TIPS
O
OMe
OMe
OBn
56
57
H
N
H
N
BF
4
Boc
Me
Me
NBoc
N
H
H
OTIPS
MeO
MeO
OBn
O
O
OBn
OBn
54
55
Scheme 13. N-Acyliminium cyclization.

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6349
N
first required installation of the requisite side-chain as the di-
vergence between the lemonomycin and the renieramycin G routes
occurs from thioaminal 46. Our strategy would take advantage of
the well precedented PicteteSpengler cyclization employed in the
synthesis of a variety of tetrahydroisoquinoline alkaloids.1 To this
end we used benzyl halide 63 (Scheme 16), which has a trityl
protecting group that would be stable to the alkylation and dia-
stereoselective reprotonation conditions, but readily cleaved prior
to N-acyliminium ion cyclization. Benzyl halide 63 was synthesized
from the same benzaldehyde 61 used to build aryl-iodide 19 in
the construction of the left-hand tetrahydroisoquinoline. Chlor-
omethylation of benzaldehyde 61 followed by BaeyereVilliger ox-
idation afforded the formate ester 62. Reduction with LiBH4
generated an unstable phenol that was immediately protected with
a trityl group to give benzyl chloride 63.
HO
H
H
OMe
OBn
15
HONH2 HCl
Boc
Me
53
11
N
KOAc, EtOH
25 °C, 2 h
H
N
13
MeO
O
OBn
58
83% yield, 1:1 cis:trans
crystallized as 4:1 cis:trans, X-ray
Scheme 14. Confirmation of C15 stereochemistry.
OMe
OMe
1) 40% aq. formalin
ZnCl , HCl, reflux
Me
Me
Cl
2
2) MCPBA, CH Cl
2
0 °C to 25 °C
2
MeO
MeO
O
H
O
H
70% yield
61
62
O
OMe
OTrt
Me
1) LiBH , THF, 0 °C
4
Cl
2) TrtCl, TEA, CH Cl
2
2
MeO
49% yield
63
Scheme 16. Benzyl chloride formation.
Fig. 4. X-ray structure of cis-58.
The alkylation conditions used in our approach to lemon-
omycinone amide (8) were unsuccessful when applied to benzyl
chloride 63. Only unreacted starting material was observed fol-
lowing treatment of thioaminal 46 with KHMDS and benzyl
chloride. Enolate formation was not in doubt so the lack of re-
activity suggested either O-alkylation or poor benzyl chloride
reactivity. Successful alkylation was accomplished by the addition
of 18-crown-6. The optimized conditions required deoxygenation
of a solution of 46, benzyl chloride 63, and 18-crown-6 in THF,
followed by addition of KHMDS, which resulted in rapid forma-
tion of product 64 in near quantitative yield as a single di-
astereomer (Scheme 17). The same conditions were used for
inversion of the C13-stereocenter, but, presumably due to the
steric bulk of benzyl substituent, complete inversion was not
observed. A 6/1 mixture of the desired epimeric product and
starting material was isolated. At this stage separation of the di-
astereomers was difficult, but after removal of the trityl group the
diastereomers were readily separated by chromatography. The
PicteteSpengler precursor phenol 65 could be isolated in 73%
yield from alkylated product 64.
The AgBF4-catalyzed N-acyliminium ion cyclization condi-
tions used for silyl enol ether 52 were not ideal for the cycli-
zation of phenol 65. Treatment of a solution of phenol 65 in THF
with AgBF4 gave a significant amount of polymerized THF
leading to incomplete cyclization and poor product isolation. It
was deduced that the polymer formation was catalyzed by HBF4,
a known catalyst for THF polymerization reactions.30 HBF4 is not
formed in the mechanism of cyclization of silyl enol ether 52 as
it did not involve a deprotonation step. To eliminate the po-
tential for polymerization the solvent was changed to chloro-
benzene, and upon treatment with AgBF4 the cyclization
product 66 was rapidly formed along with cleavage of the acid
sensitive Boc group (Scheme 18). The crude amine product un-
derwent reductive amination conditions to give the N-methyl
product 67 in 65% yield over the two steps.
Hydrogenolysis of the benzylethers gave diol 59 in 79% yield
from the silyl enol ether 52 (Scheme 15). It was noted that the
cyclized product 53 and diol 59 only existed in aldehyde form,
while the natural product was found as the aldehyde hydrate. The
aldehyde hydrate was not formed until after removal of the Boc
protecting group with 3 N HCl. The stability of the aldehyde hydrate
60 is likely to come from internal hydrogen bonding between the
hydroxyl and the bridge nitrogen. Under optimized conditions diol
59 was treated with aqueous HCl in MeOH then concentrated and
oxidized with aqueous ammonium cerium (IV) nitrate to yield
lemonomycinone amide (8) after purification by HPLC. Spectro-
scopic data were consistent with similar functionality of lemon-
omycin, and the stereochemistry at the C-15 center remained
unepimerized over the final three steps.
CHO
OMe
H
H
N
Boc
Me
1) AgBF , THF, 25 °C, 4 h
4
3N HCl
N
52
H
2) Pd(OH) , MeOH
2
1 atm H , 25 °C, 4 h
2
1:1 MeOH:H O
2
25 °C, 3 h
MeO
H
OH
O
79% yield
OH
59
HO
HO
16
OH
OH
15
O
O
H
15
OMe
H
H
N
H
N
(NH4)2Ce(NO3)6
Me
Me
MeO
NH
H
NH
H
HCl
H
H
H O, 25 °C, 4 h
2
MeO
O
OH
O
35% yield
two steps
OH
OH
60
( )-lemonomycinone amide (8)
Scheme 15. Lemonomycinone amide.
Having demonstrated the ring construction of the diazabicyclo
[3.2.1]octane ring system our efforts focused on forming the dia-
zabicyclo[3.3.1]nonane framework of the BTHI renieramycin G. This

6350
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
OTrt
OMe
OMe
SPh
OMe
OBn
SPh
H
N
H
N
OMe
Me
Me
Me
11
NBoc
11
NBoc
63, 18-crown-6, KHMDS
THF, 78 °C, 20 min
98% yield
H
13
H
−
MeO
13
MeO
H
OBn
OH
O
O
OBn
OBn
64
46
SPh
OMe
i) t-BuLi (2.2 eq), THF,
−
78 °C
H
N
Me
MeO
OMe
10 sec. then BHT in THF
11
NBoc
13
ii) HCl in Et O, 0 °C, 1 h
2
Me
H
73% yield
OBn
O
OMe
OBn
65
Scheme 17. Benzyl side-chain installation.
OMe
SPh
OMe
OBn
OH
H
N
HO
Me
Me
OMe
AgBF /PhCl
4
NBoc
OMe
OBn
H
H
25 °C, 10 min
Me
OMe
MeO
Me
NH
H
H
O
OMe
N
MeO
OBn
H
65
O
OBn
66
OMe
HO
H
Me
OMe
NaBH CN, AcOH,
3
OMe
OBn
47% aq. formaldehyde
MeOH, 25 °C, 1h
H
Me
N
Me
H
N
65% yield
two steps
MeO
H
O
OBn
67
Scheme 18. Cyclization to the diazabicyclo[3.3.1]nonane ring system.
Although NMR data indicated the correct product, the structure
the construction of diazabicyclo[3.3.1]nonane ring system. The
oxidation to diquinone 70 was accomplished with ceric (IV) am-
monium nitrate. The final step of the synthesis required in-
stallation of the angelate ester. This was left as the last step
was further confirmed by X-ray analysis of diol 68 (Scheme 19 and
Fig. 5). Incomplete hydrogenolysis gave diol 68, which was more
readily crystallized than triol 69. The X-ray structure confirmed
OMe
OMe
OMe
HO
Me
HO
H
Me
O
H
Me
O
OMe
OH
H
OMe
OBn
O
O
H
N
H
(NH ) Ce(NO )
Pd(OH) , MeOH
2
4 2
3 6
H
N
Me
OMe
Me
OMe
Me
N
Me
N
Me
CH CN, H O
N
Me
1 atm H , 6 h
2
94% yield
H
H
3
2
H
N
−
5 °C, 10 min.
55% yield
MeO
MeO
H
H
MeO
H
O
O
O
OH
OBn
69
67
OH
70
Pd(OH) , MeOH
2
O
1 atm H , 1 h
2
Cl
Me
H
85% yield
CH Cl
74% yield
2
2
Me
OMe
HO
Me
OMe
OMe
OH
H
O
H
Me
H
Me
OMe
O
N
Me
H
N
H
Me
O
N
N
Me
MeO
H
H
O
O
MeO
H
OBn
68, X-ray
O
O
O
Me
H
Me
( )-renieramycin G (3)
Scheme 19. Synthesis of renieramycin G (3).

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6351
because angelate esters are known to readily isomerize to the
more stable trans isomer.31 The successful procedure for formation
of the angelate ester32 involved simply stirring diquinone 70 with
angeloyl chloride33 in CH2Cl2 for 24 h, concentrating, and after
purification by HPLC (ꢀ)-renieramycin G (3) was isolated in 74%
yield. All characterization was consistent with literature data, but
an authentic sample was not available for direct comparison.
obtained on a VG ZAB2E or a Finnigan TSQ70. Routine monitoring of
reactions was performed using Merck 60 F254 silica gel, aluminum-
backed TLC plates. Flash column chromatography was performed
using EMD silica gel (particle size 0.040e0.063 mm). Reverse-phase
HPLC purification was done with a WATERS 1525 Binary HPLC
Pump and WATERS 2996 Photoiodide Array Detector using C18
packed analytical (VYDAC, 10
preparatory (WATERS,
Bondapak, 7.8ꢃ300 mm), and/or pre-
paratory column (VYDAC, 10
mm packing, 4.6ꢃ250 mm), semi-
m
m
m packing, 22ꢃ250 mm). Solvents
and commercial reagents were purified in accordance with Perrin
and Armarego34 or used without further purification.
4.1.1. 1,2-Dihydroisoquinoline 16 (R¼SPh). To a stirred solution of
thioanisole (60
m
L, 0.51 mmol) and (ꢁ)-sparteine (117
mL,
0.51 mmol) in THF (1.0 mL) at 0 ꢂC was added n-BuLi (1.45 M in
hexanes, 350 mL, 0.51 mmol) dropwise within 10 min. The cloudy
yellow solution was allowed to warm to 25 ꢂC and was stirred for
1 h. The solution of phenylthiomethyllithium and (ꢁ)-sparteine was
added dropwise over 10 min to a degassed solution of isoquinoline
(50
m
L, 0.43 mmol) in toluene (3.5 mL) at ꢁ78 ꢂC under an atmo-
sphere of argon. The resulting orange solution was stirred for 5 min
at ꢁ78 ꢂC. The solution was warmed to 25 ꢂC and stirred for 1.5 h.
The orange/brown solution was quenched with methyl chlor-
oformate (100 mL, 1.28 mmol) and the color of the clear solution
changed to canary yellow. The solution stirred for 15 min and was
then cooled to 0 ꢂC, and diluted with 1.5 mL of satd aq NaHCO3. The
reaction warmed to room temperature and the aqueous layer was
extracted with toluene (3ꢃ5 mL). The organic extracts were com-
bined, dried (Na2SO4), filtered, and concentrated under vacuum.
The crude yellow oil was purified by flash column chromatography
(SiO2, 3e7% EtOAc in hexanes) to provide 16 (121 mg, 91% yield) as
a colorless oil: Rf¼0.37 (20% EtOAc in hexanes); IR (thin film) 2947,
Fig. 5. X-ray structure of 68.
3. Summary
The divergent strategy to the tetrahydroisoquinolines demon-
strates an alternative approach to building structural diversity to
this family of natural products. A common intermediate to both
the mono- and bis-tetrahydroisoquinolines is readily accessed
from ortho-iodo aryl imines in approximately 10 steps and 32%
yield. The synthesis of the common core constructs the central
1,3-cis substituted tetrahydroisoquinoline early with a highly
diastereoselective ionic hydrogenation reaction. Subsequent dia-
stereoselectivity was achieved after converting a hemiaminal to
a thioaminal, which allowed diastereoselective alkylation and
reprotonation of the side chain. The diazabicyclo[3.2.1]octane ring
system was formed from the silyl enol ether cyclization of imi-
nium ion in the presence of THF where triisopropylsilyloxonium
cleavage appears to be the rate determining step. The C-15 alde-
hyde formed as one diastereomer and converted to the aldehyde
hydrate upon formation of (ꢀ)-lemonomycinone amide. The dia-
zabicylco[3.3.1]nonane ring system could be readily formed after
diastereoselective alkylation of the benzyl side chain from known
electrophilic aromatic cyclization methods leading to the com-
pletion of (ꢀ)-renieramycin G (3).
1716, 1635, 1456, 1439, 1354, 1330, 1232 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) 7.36e7.04 (9H, m), 6.91 (0.5H, d, J¼7.7 Hz), 6.69 (0.5H, d,
J¼7.7 Hz), 5.95 (0.5H, d, J¼7.8 Hz), 5.85 (0.5H, d, J¼7.8 Hz), 5.52
(0.5H, t, J¼7.0 Hz), 5.32 (0.5H, t, J¼7.0 Hz), 3.79 (2H, s), 3.71 (1H, s),
1
3.27e3.02 (2H, m) ppm; H NMR (500 MHz, DMSO-d6, 120 ꢂC)
7.33e7.16 (8H, m), 7.12 (1H, d, J¼7.7 Hz), 6.78 (1H, d, J¼7.7 Hz), 5.97
(1H, d, J¼7.8 Hz), 5.44 (1H, t, J¼6.7 Hz), 3.72 (3H, s), 3.18 (1H, dd,
J¼13.7, 6.8 Hz), 3.13 (1H, dd, J¼13.7, 6.7 Hz) ppm; 13C NMR
(500 MHz, DMSO-d6, 120 ꢂC) 152.5, 135.3, 130.0, 129.4, 128.2, 128.1,
127.4, 126.2, 126.0, 125.3, 123.9, 123.8, 108.0, 53.7, 52.4, 36.9 ppm;
HRMS calcd for C18H18NO2S (MHþ) 312.1058 Da. Found 312.1049 Da.
HPLC conditions for separation of enantiomers using analytical
column Chiracel OD: loaded 15 mL of 0.5 mg/mL sample in 1% iso-
propanolehexanes, gradient 2e5% over 15 min, enantiomers elute
at 11.9 min and 13.9 min in a ratio of 1/1.
4.1.2. 1,2-Dihydroisoquinoline 16 (R¼OBn). To a stirred solution of
35
4. Experimental
BnOCH2SnBu3 (0.35 g, 0.85 mmol) and (ꢁ)-sparteine (0.32 mL,
1.41 mmol) in toluene (6.0 mL) at ꢁ78 ꢂC was added n-butyllithium
(2.1 M in hexanes, 0.40 mL, 0.85 mmol) dropwise within 5 min. The
brown solution was stirred for 10 min at ꢁ78 ꢂC, and isoquinoline
(0.10 mL, 0.71 mmol) was added as a solution in THF (0.10 mL). The
brown solution was allowed to warm to 25 ꢂC and stirred for
15 min. The reaction was quenched with ClCO2Me (0.16 mL,
2.12 mmol) and the solution became colorless. The solution was
cooled to 0 ꢂC, diluted with satd aq NaHCO3 (5 mL), and extracted
with EtOAc (3ꢃ15 mL). The extracts were combined and washed
with satd aq NaCl (15 mL), dried (Na2SO4), filtered, and concen-
trated under vacuum. The resulting residue was purified by flash
column chromatography (SiO2, 10e20% EtOAc in hexanes) to pro-
vide 1,2-dihydroisoquinoline 16c (144 mg, 66% yield) as a colorless
oil: Rf¼0.30 (20% EtOAc in hexanes); IR (thin film): 3063, 3028,
2953, 2856, 1716, 1632, 1456, 1441, 1416, 1354, 1330, 1292, 1235,
4.1. General procedures
All reactions were setup under an atmosphere of argon and only
degassed when specified. Melting points were taken on a Thomas-
Hoover capillary tube apparatus and are uncorrected. Infrared
spectra were recorded on a Nicolet FTIR spectrophotometer neat
unless otherwise indicated. 1H NMR spectra were recorded on ei-
ther a General Electric QE-300 spectrometer at 300 MHz or a Varian
spectrometer at 500 MHz in the indicated solvent and are reported
in parts per million relative to tetramethylsilane and referenced
internally to the residually protonated solvent. 13C NMR spectra
were recorded on a General Electric QE-300 at 75 MHz or a Varian
spectrometer at 125 MHz in the solvent indicated and are reported
in parts per million relative to tetramethylsilane and referenced
internally to the residually protonated solvent. Mass spectra were
1196, 1125 cmꢁ1 1H NMR (300 MHz, C6D6): 7.21e6.68 (10H, m),
;

6352
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
5.79 (0.6H, t, J¼6.6 Hz), 5.54 (0.4H, d, J¼7.8 Hz), 5.49 (0.6H, d,
J¼7.8 Hz), 5.40 (0.4H, t, J¼6.8 Hz), 4.34 (0.6H, d, J¼12.1 Hz), 4.19
(0.6H, d,12.2 Hz), 4.15 (0.4H, d, J¼12.4 Hz), 4.07 (0.4H, d, J¼12.3 Hz),
3.54 (0.6H, dd, J¼9.9, 7.5 Hz), 3.45e3.29 (4H, m), 3.14 (0.4H, dd,
J¼9.7, 5.9 Hz) ppm; 13C NMR (75 MHz, C6D6): 153.6, 152.8, 138.4,
138.2, 130.9, 130.6, 129.8, 129.5, 127.9, 127.0, 126.9, 126.8, 126.7,
126.4, 126.0, 125.4, 124.4, 124.2, 107.8, 72.2, 70.2, 55.2, 54.3,
for 24 h, then treated with satd aq NaHCO3 (200 mL). The solution
was extracted with EtOAc (3ꢃ200 mL), combined extracts, washed
with satd aq NaHCO3 (75 mL) until aqueous layer was no longer blue,
washed with satd aq NaCl (100 mL), dried (Na2SO4), filtered, and
concentrated under vacuum to a pale orange solid. The coupled
product was dissolved in dry DMF (260 mL) and degassed (argon
bubbling for 3 h). CuI (0.989 g, 5.19 mmol) was added. The reaction
flask was sealed and heated to 100 ꢂC, and the clear solution was
stirred for 2 h. The reaction was cooled to 25 ꢂC, treated with satd aq
NH4Cl (300 mL), and extracted with EtOAc (3ꢃ300 mL). The com-
bined extracts were washed with satd aq NH4Cl (200 mL), satd aq
NaCl (200 mL), dried (Na2SO4), filtered, and concentrated under
vacuum. The resulting brown oil was purified by flash column
chromatography (SiO2, 5e10% EtOAcehexane) to afford isoquinoline
25 (10.8 g, 76% yield) as a yellow oil: Rf¼0.21 (10% EtOAc in hexanes);
IR (thin film): 2942, 2865, 1623, 1591, 1456, 1394, 1363, 1315, 1121,
1106, 1082, 1014, 883 cmꢁ1; 1H NMR (300 MHz, CDCl3): 9.38 (1H, s),
8.05 (1H, s), 7.54 (2H, d, J¼7.0 Hz), 7.41e7.37 (3H, m), 5.18 (2H, s), 5.10
(2H, s), 4.0 (3H, s), 3.90 (3H, s), 2.43 (3H, s), 1.29e1.20 (3H, m), 1.15
(18H, d, J¼5.5 Hz) ppm; 13C NMR (75 MHz, CDCl3): 154.4, 149.3,
148.6,146.6,146.4,143.2,137.0,128.8,128.6,128.4,128.3,122.2,109.5,
75.9, 66.1, 61.3, 60.7, 18.0, 12.0, 10.1 ppm; HRMS calcd for
C29H42NO4Si (MHþ) 496.2883 Da. Found 496.2887 Da.
1
52.3 ppm; H NMR (500 MHz, toluene-d8, 100 ꢂC): 7.07e6.85 (9H,
m), 6.79 (1H, d, J¼7.5 Hz), 5.55 (1H, d, J¼7.7 Hz), 5.54 (1H, br s), 4.29
(1H, d, J¼12.2 Hz), 4.22 (1H, d, J¼12.1 Hz), 4.30e4.20 (2H, br s), 3.53
(1H, dd, J¼9.9, 7.1 Hz), 3.49 (3H, s), 3.36 (1H, dd, J¼9.7, 6.0 Hz) ppm;
13C NMR (125 MHz, toluene-d8, 100 ꢂC): 154.0, 139.3, 131.7, 130.9,
129.2, 129.0, 128.8, 128.3, 128.1, 127.9, 127.6, 126.9, 125.8, 125.5,
125.3, 108.4, 73.5, 71.1, 56.1, 52.8 ppm; HRMS calcd for C19H20NO3
(MHþ) 310.1443 Da. Found 310.1444 Da. HPLC conditions: loaded
15 mL of 0.50 mg/mL sample solution in 1% isopropanol in hexanes,
gradient¼2e5% isopropanol in hexanes, enantiomers elute at
12.85 min and 16.47 min in a ratio of 2/1, 33% ee.
4.1.3. Isoquinoline 22. To
a degassed solution of 19 (1.45 g,
3.10 mmol) and progargyl benzyl ether (0.543 g, 3.72 mmol) in
triethylamine (12.4 mL) at 25 ꢂC under argon were added
PdCl2(PPh3)2 (44 mg, 0.062 mmol) and CuI (6 mg, 0.031 mmol). The
reaction flask was sealed under argon, heated to 55 ꢂC, and stirred
for 3 h. The solution became black in color and a precipitate formed.
The mixture was cooled to 25 ꢂC, filtered through CeliteÒ, and
concentrated filtrate under vacuum. The resulting residue was
dissolved in anhydrous DMF (30 mL), and to this solution was
added CuI (50 mg, 0.30 mmol). The reaction flask was flushed with
argon, sealed, heated to 100 ꢂC, and stirred for 5 h. The reaction was
cooled to 25 ꢂC, diluted with satd aq NH4Cl (30 mL), and extracted
with Et2O (2ꢃ50 mL). The combined extracts were dried (Na2SO4),
filtered, and concentrated under vacuum. The resulting residue
was purified by flash column chromatography (SiO2, 10e40%
EtOAcehexane) to afford aldehyde 219 (0.524 g, 41% yield) and
isoquinoline 22 (0.440, 33% yield): Rf¼0.43 (40% EtOAc in hexanes);
IR (thin film) 2936, 2857, 1589, 1454, 1394, 1359, 1317, 1079, 1004,
735, 698 cmꢁ1; 1H NMR (300 MHz, CDCl3) 9.45 (1H, s), 7.91 (1H, s),
7.54 (2H, d, J¼8.01 Hz), 7.46e7.31 (8H, m), 5.18 (2H, s), 4.84 (2H, s),
4.73 (2H, s), 4.01 (3H, s), 3.90 (3H, s), 2.43 (3H, s) ppm; 13C NMR
(75 MHz, CDCl3) 150.8, 149.2, 148.9, 147.0, 143.0, 138.0, 136.7,
128.8, 128.4, 128.3, 128.2, 127.7, 127.3, 126.7, 122.3, 111.6, 75.8, 73.0,
72.6, 61.4, 60.6, 10.0 ppm; HRMS calcd for C27H28NO4 (MHþ)
430.2018 Da. Found 430.2027 Da.
4.1.6. 1,2-Dihydroisoquinoline 27. To a degassed (argon bubbling)
and stirred solution of BnOCH2SnBu3 (9.0 g, 21.9 mmol) in THF
(109 mL) at ꢁ78 ꢂC was added n-BuLi (2.10 M in hexanes, 7.81 mL,
16.4 mmol) within 8 min. The solution became yellow in color and
was stirred for 5 min, then a degassed (argon bubbling) solution of
isoquinoline 25 (2.71 g, 5.47 mmol) in THF (5.0 mL) was added
dropwise within 10 min. The reaction solution became deep red/
brown in color. The solution was stirred for 2 h at ꢁ78 ꢂC, then
quenched rapidly with ClCO2Me (2.1 mL, 27.4 mmol). The dark color
of the solution faded to pale yellow. The reaction was diluted with
satd aq NaHCO3 (150 mL) and extracted with EtOAc (2ꢃ250 mL). The
combined extracts were washed with satd aq NaCl (100 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The resulting
yellow oil was purified by flash column chromatography (SiO2,
5e10% EtOAcehexane) to afford 1,2-dihydroisoquinoline 27 (3.22 g,
79% yield) as a colorless oil, and n-butyl adduct 28 (84 mg, 3% yield)
as a colorless oil. Compound 28: Rf¼0.26 (10% EtOAc in hexanes); 1H
NMR (300 MHz, CDCl3): 7.56e7.52 (2H, m), 7.46e7.34 (3H, m), 6.68
(1H, s), 5.70 (1H, br s), 5.07 (1H, d, J¼10.7 Hz), 4.97 (1H, d, J¼10.7 Hz),
4.95 (1H, br s), 4.57 (1H, d, J¼14.0 Hz), 3.85 (3H, s), 3.73 (3H, s), 3.72
(3H, s), 2.22 (3H, s), 1.71e1.63 (2H, m), 1.32e0.77 (28H, m) ppm; 1H
NMR (500 MHz, toluene-d8, 100 ꢂC): 7.46e7.44 (2H, m), 7.20e7.17
(3H, m), 6.88 (1H, t, J¼1.5 Hz), 5.92 (1H, dd, J¼9.4, 4.7 Hz), 5.05 (1H,
dd, J¼14.0, 1.3 Hz), 5.05 (1H, d, J¼11.3 Hz), 4.93 (1H, d, J¼11.2 Hz),
4.79 (1H, dd, J¼13.9, 1.5 Hz), 3.64 (3H, s), 3.55 (3H, s), 3.46 (3H, s),
2.20 (3H, s),1.85e1.80 (1H, m),1.55e1.49 (1H, m),1.47e1.40 (2H, m),
1.32e1.23 (2H, m),1.18e1.14 (21H, m), 0.81 (3H, t, J¼3.9 Hz) ppm; 13C
NMR (125 MHz, toluene-d8, 100 ꢂC): 155.1, 152.0, 151.5, 144.4, 138.9,
138.1, 128.8, 128.7, 128.2, 124.3, 121.0, 109.1, 76.0, 65.0, 60.9, 60.2,
52.9, 52.4, 33.3, 28.4, 22.9, 18.5, 14.1, 13.1, 9.5 ppm. Compound 27:
Rf¼0.21 (10% EtOAc in hexanes); IR (thin film): 2943, 2865, 1714,
4.1.4. Acetylene 23. To a stirred solution of propargyl alcohol
(2.08 mL, 35.7 mmol) and imidazole (2.67 g, 39.3 mmol) in DMF
(16 mL) at 0 ꢂC was added TIPS-Cl (8.83 mL, 41.0 mmol). The re-
action was warmed to 25 ꢂC and stirred for 16 h. The reaction
mixture was partitioned between hexanes (125 mL) and satd aq
NaHCO3 (75 mL). The organic layer was washed with satd aq
NaHCO3 (50 mL), satd aq NaCl (50 mL), dried (Na2SO4), filtered,
and concentrated under vacuum. The resulting colorless liquid
was purified by flash column chromatography (SiO2, 2e4%
EtOAcehexane) then by distillation (110 ꢂC, 20 mmHg) to afford 23
(3.8 g, 54% yield) as a colorless liquid: Rf¼0.35 (2% EtOAc in hex-
anes); IR (neat): 3313, 2944, 2867, 1464, 1370, 1263, 1101, 1001, 883,
1456, 1321, 1128, 1090, 1067 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
7.54e7.51 (2H, m), 7.45e7.29 (6H, m), 7.21e7.17 (2H, m), 6.74 (1H, s),
6.05 (1H, br s), 5.10 (1H, br s), 5.09 (1H, d, J¼10.8 Hz), 4.98 (1H, d,
J¼10.8 Hz), 4.50 (2H, m), 4.38 (1H, d, J¼12.2 Hz), 3.82 (3H, s), 3.73
(3H, s), 3.71 (3H, s), 3.56 (1H, t, J¼10.3), 3.27 (1H, dd, J¼10.6, 4.3 Hz),
2.21 (3H, s), 1.21e1.08 (21H, m) ppm; 13C NMR (75 MHz, CDCl3):
150.0, 144.2, 138.6, 137.7, 128.6, 128.2, 127.4, 125.0, 121.2, 107.1, 95.1,
75.4, 73.5, 72.4, 68.4, 67.2, 63.4, 61.3, 60.5, 53.1, 51.0, 18.2, 12.2,
9.4 ppm; 1H NMR (500 MHz, toluene-d8,100 ꢂC): 7.46e7.44 (2H, m),
7.25e6.96 (8H, m), 6.91 (1H, t, J¼1.5 Hz), 6.28 (1H, dd, J¼8.8, 4.7 Hz),
5.20 (1H, dd, J¼14.5, 1.5 Hz), 5.05 (1H, d, J¼11.1 Hz), 4.95 (1H, d,
774 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 4.38 (2H, d, J¼2.2 Hz), 2.39
(1H, t, J¼2.3 Hz), 1.16e1.05 (21H, m) ppm; 13C NMR (75 MHz,
CDCl3): 82.2, 72.4, 51.5, 17.6, 11.7 ppm; HRMS calcd for C12H23OSi
(MꢁHþ) 211.1518 Da. Found 211.1515 Da.
4.1.5. Isoquinoline 25. To a stirred solution of o-iodoimine 19
(12.1 g, 26.0 mmol) and acetylene 23 (5.61 g, 28.6 mmol) in trie-
thylamine (130 mL) was added CuI (6.09 g, 31.2 mmol) in small
portions over 20 min. The reaction was stirred under argon at 25 ꢂC

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6353
J¼11.2 Hz), 4.76 (1H, dd, J¼14.5,1.6 Hz), 4.42 (1H, d, J¼12.2 Hz), 4.31
(1H, d, J¼12.2 Hz), 3.71 (1H, dd, J¼10.6, 8.8 Hz), 3.61 (3H, s), 3.56 (3H,
s), 3.45 (3H, s), 3.41 (1H, dd, J¼10.6, 4.8 Hz), 2.20 (3H, s), 1.16e1.14
(21H, m) ppm; 13C NMR (125 MHz, toluene-d8, 100 ꢂC): 155.0, 151.9,
151.4,145.0,138.8,137.9,137.5,129.3,128.7,128.4,128.3,127.8,127.5,
122.0,108.1, 76.0, 73.7, 73.1, 69.9, 67.9, 64.6, 61.0, 60.2, 52.3,18.5,13.1,
9.5 ppm; HRMS calcd for C39H54NO7Si (MHþ) 676.3591 Da. Found
676.3601 Da.
to a yellow oil. A small portion was purified for characterization and
the rest used crude in the next step. The yellow oil was purified by
flash column chromatography (SiO2, 20e40% EtOAcehexane) to
afford the tetrahydroisoquinoline 36 as a yellow oil: Rf¼0.16 (40%
EtOAc in hexanes); IR (thin film): 2936, 1751, 1456, 1411, 1117,
1030 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.36e7.28 (5H, m),
7.19e7.16 (3H, m), 7.00e6.96 (2H, m), 5.01 (C1, 1H, t, J¼2.2 Hz), 4.96
(C16,1H, d, J¼11.3 Hz), 4.92 (C16,1H, d, J¼11.3 Hz), 4.37 (C11-Hb,1H,
t, J¼7.6 Hz), 4.40 (C15, 1H, d, J¼12.2 Hz), 4.29 (C14, 1H, dd, J¼9.8,
2.8 Hz), 4.22 (C15, 1H, d, J¼12.2 Hz), 3.94 (C11-Ha, 1H, dd, J¼10.8,
8.2 Hz), 3.78 (C7-OMe, 3H, s), 3.77e3.71 (C3, 1H, m), 3.64 (C5-OMe,
3H, s), 3.52 (C14, 1H, dd, J¼9.8, 2.0 Hz), 3.14 (C4-Hb, 1H, dd, J¼14.1,
3.0 Hz), 2.61 (C4-Ha, 1H, dd, J¼14.0, 1.6 Hz), 2.24 (C6-Me, 3H, s)
ppm; 13C NMR (75 MHz, CDCl3): 156.5, 151.6, 150.5, 144.8, 138.7,
137.1, 128.5, 128.1, 128.0, 127.3, 127.1, 126.8, 124.6, 124.3, 74.4 (C16),
72.9 (C15), 70.0 (C14), 68.6 (C11), 60.7 (C5), 60.3 (C7), 53.9 (C3), 50.9
(C1), 27.7 (C4), 9.5 (C6) ppm; HRMS calcd for C29H32NO6 (MHþ)
490.2230 Da. Found 490.2216 Da.
4.1.7. Alcohol 30. To a stirred solution of 27 (22 mg, 0.033 mmol) in
CH2Cl2 (0.33 mL) at 0 ꢂC was added TFA dropwise with reaction
monitoring until all starting materials were consumed. The re-
action was diluted with satd aq NaHCO3 (15 mL) and extracted with
EtOAc (2ꢃ20 mL). The combined extracts were washed with satd aq
NaCl (10 mL), dried (Na2SO4), filtered, and concentrated under
vacuum. The residue was purified by flash column chromatography
(SiO2, 25e40% EtOAcehexane) to afford 30 (15 mg, 88% yield) as
a colorless oil: Rf¼0.28 (50% EtOAc in hexanes); IR (thin film): 3462,
2938, 2862, 1699, 1456, 1414, 1395, 1346, 1331, 1290, 1251, 1114,
1064, 1008 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.51e7.19 (10H, m),
4.1.11. Amino alcohol 40. The crude tetrahydroisoquinoline 36 was
dissolved in ethylene glycol (144 mL) then KOH (21 g, 373 mmol)
and hydrazine monohydrate (3.48 mL, 72.0 mmol) were added at
25 ꢂC. The reaction mixture was warmed to 150 ꢂC and became
homogeneous, then stirred for 3 h. The heat was removed and
solution cooled to 25 ꢂC. The mixture was made homogeneous by
the addition of CH2Cl2 and minimal amounts of MeOH, then pu-
rified by flash column chromatography (SiO2 pre-treated with TEA,
100% CH2Cl2) to afford amino alcohol 40 (5.7 g, 86% yield) as
a brown solid: recrystallized from EtOAc and hexanes; X-ray
(CCDC 288713); mp 84e89 ꢂC; Rf¼0.19 (100% EtOAc); IR (thin
6.44 (1H, s), 5.98 (1H, s), 5.10 (1H, d, J¼11.1 Hz), 4.99 (1H, d,
J¼11.1 Hz), 4.54 (2H, m), 4.31 (2H, m), 3.83 (3H, s), 3.76 (3H, s), 3.71
(3H, s), 3.47 (1H, t, J¼10.2 Hz), 3.20 (1H, m), 2.21 (3H, s) ppm; 13C
NMR (75 MHz, CDCl3): 154.1, 143.8, 137.2, 128.2, 128.0, 127.3, 127.2,
125.1, 120.3, 111.2, 95.1, 75.2, 72.1, 67.6, 63.8, 61.3, 60.2, 53.1, 20.6,
14.0, 9.1 ppm; HRMS calcd for C30H33NO7 (MHþ) 519.2257 Da.
Found 519.2253 Da.
4.1.8. Oxazolidinone 34. To
a stirred solution of 30 (15 mg,
0.029 mmol) in MeOH (0.33 mL) at 25 ꢂC was added NaOMe (31 mg,
0.813 mmol). The reaction was stirred for 15 h at 25 ꢂC, quenched
withH2O(0.5 mL), dilutedwithsatdaqNaHCO3 (5 mL), and extracted
with EtOAc (2ꢃ10 mL). The combined extracts were washed with
satd aq NaCl (10 mL), dried (Na2SO4), filtered, and concentrated un-
der vacuum. The residue was purified by flash column chromatog-
raphy (SiO2, 10e30% EtOAcehexane) to afford oxazolidinone 34
(12 mg, 86% yield) as a colorless oil: Rf¼0.23 (30% EtOAc in hexanes);
IR (thin film): 2937, 2862, 1773, 1675, 1457, 1364, 1228, 1119, 1049,
1008 cmꢁ1; 1H NMR (300 MHz, CDCl3): 7.45e7.35 (5H, m), 7.24e7.21
(3H, m), 7.18e7.15 (2H, m), 5.77(1H, t, J¼2.0 Hz), 5.57(1H, t, J¼3.9 Hz),
5.03e4.99 (4H, m), 4.60 (1H, d, J¼12.0 Hz), 4.24 (1H, d, J¼11.9 Hz),
3.79 (3H, s), 3.62 (3H, s), 3.62e3.58 (2H, m), 2.23 (3H, s) ppm;
HRMS calcd for C29H30NO6 (MHþ) 488.2073 Da. Found 488.2051 Da.
film): 3333, 2935, 2864, 1455, 1410, 1336, 1113, 1060, 1026 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.38e7.29 (5H, m), 7.27e7.19 (5H, m),
5.02 (C15, 1H, d, J¼11.3 Hz), 4.85 (C15, 1H, d, J¼11.2 Hz), 4.43 (C14,
1H, d, J¼12.1 Hz), 4.38 (C14, 1H, d, J¼12.0 Hz), 4.35 (C1, 1H, dd,
J¼8.0, 2.6 Hz), 4.03 (C12, 1H, dd, J¼9.3, 3.2 Hz), 3.80 (C7-OMe, 3H,
s), 3.72 (C11, 1H, dd, J¼10.9, 3.4 Hz), 3.67 (C5-OMe, 3H, s), 3.61
(C12, 1H, dd, J¼9.2, 7.4 Hz), 3.52 (C11, 1H, dd, J¼11.0, 6.6 Hz),
2.83e2.78 (C3, C4-Hb, 2H, m), 2.75 (NH, OH, 2H, br s), 2.32 (C4-Ha,
1H, dd, J¼15.9, 11.6 Hz), 2.21 (C6-Me, 3H, s) ppm; 13C NMR
(75 MHz, CDCl3): 152.3 (C5), 149.9 (C7), 145.4 (C8), 138.5 (C14Ph-
ipso), 137.7 (C15Ph-ipso), 128.4, 128.2, 128.0, 127.9, 127.6 (C9), 127.5,
127.4, 125.8 (C10), 123.5 (C6), 74.5 (C15), 74.1 (C12), 72.9 (C14),
65.9 (C11), 60.3 (C7-OMe), 60.2 (C5-OMe), 53.6 (C3), 53.5 (C1),
26.5 (C4), 9.3 (C6) ppm; HRMS calcd for C28H34NO5 (MHþ)
464.2437 Da. Found 464.2423 Da.
4.1.9. Oxazolidinone 34. To
a
stirred solution of 1,2-
dihydroisoquinoline 27 (11.2 g, 16.6 mmol) in THF (110 mL) at
ꢁ10 ꢂC was added TBAF (1.0 M in THF, 16.6 mL, 16.6 mmol) drop-
wise within 5 min. The yellow solution was stirred for 15 min at
ꢁ10 ꢂC, warmed to 0 ꢂC and stirred 30 min, warmed further to
25 ꢂC and stirred for 10 min. The reaction was quenched with satd
aq NaHCO3 (200 mL) and extracted with EtOAc (3ꢃ200 mL). The
combined extracts were washed with satd aq NaCl (200 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The resulting
yellow oil was purified by flash column chromatography (SiO2,
20e30% EtOAcehexane) to afford oxazolidinone 35 (7.3 g, 91%
yield), characterized as above.
4.1.12. Ester 41. To a stirred solution of 40 (100 mg, 0.216 mmol)
and Boc-Gly-OH (40 mg, 0.227 mmol) in CH2Cl2 (1.1 mL) at 0 ꢂC was
added Py-BOPÒ (118 mg, 0.227 mmol), and after 5 min Hunig’s base
€
(0.12 mL, 0.681 mmol) was added. After stirring at 0 ꢂC for 1 h the
solution was warmed to 25 ꢂC and stirred 3 h. The reaction was
treated with H2O (5 mL) and extracted with EtOAc (2ꢃ15 mL). The
combined extracts were washed with 5% aq NaHSO4 (15 mL), satd
aq NaHCO3 (15 mL), satd aq NaCl (15 mL), dried (Na2SO4), filtered,
and concentrated under vacuum. The residue was purified by flash
column chromatography (SiO2, 20e40% EtOAcehexane) to afford
ester 41 (110 mg, 82% yield) as a pale yellow oil: Rf¼0.26 (30% EtOAc
in hexanes); IR (thin film): 3421, 3357, 1754, 1716, 1455, 1366, 1165,
4.1.10. 1,3-cis-Tetrahydroisoquinoline 36. To a stirred solution of
oxazolidinone 34 (7.0 g, 14.4 mmol) and Et3SiH (34 mL, 215 mmol)
in CH2Cl2 (72 mL) at ꢁ10 ꢂC was added TFA (pre-cooled to ꢁ10 ꢂC,
16.7 mL, 215 mmol). The yellow solution was stirred for 45 min at
ꢁ10 ꢂC to 0 ꢂC, then warmed to 25 ꢂC and stirred for 2 h. The re-
action was cooled to 0 ꢂC and slowly quenched with 10% aq Na2CO3
until the aqueous layer was basic, and extracted with CH2Cl2
(3ꢃ150 mL). The combined extracts were washed with satd aq NaCl
(100 mL), dried (Na2SO4), filtered, and concentrated under vacuum
1058 cmꢁ1
;
1H NMR (500 MHz, CDCl3): 7.38e7.30 (5H, m),
7.29e7.19 (5H, m), 5.03 (C22, 1H, d, J¼11.1 Hz), 5.00 (BocNH, 1H, br
s), 4.82 (C22, 1H, d, J¼11.1 Hz), 4.43 (C21, 1H, d, J¼12.3 Hz), 4.40
(C21, 1H, d, J¼12.1), 4.38 (C1, 1H, m), 4.30 (C11, 1H, dd, J¼10.9,
4.4 Hz), 4.14 (C11, 1H, dd, J¼11.0, 7.2 Hz), 4.12 (C20, 1H, dd, J¼9.2,
3.0 Hz), 3.93 (C14, 2H, br s), 3.79 (C7-OMe, 3H, s), 3.67 (C5-OMe, 3H,
s), 3.54 (C20, 1H, dd, J¼9.0, 7.4 Hz), 2.98e2.93 (C3, 1H, m), 2.85 (C4-
Hb, dd, J¼15.4, 2.2 Hz), 2.30 (C4-Ha, dd, J¼15.1, 11.0 Hz), 2.20 (C6-

6354
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
Me, 3H, s), 1.43 (Boc, 9H, s) ppm; 13C NMR (125 MHz, CDCl3): 170.4
(C13), 155.7 (C16), 152.3 (C5), 150.2 (C7), 145.6 (C8), 138.6 (C21Ph-
ipso),137.7 (C22Ph-ipso),128.4,128.3,128.0, 127.9,127.5,127.4,127.2
(C9), 125.1 (C10), 123.6 (C6), 80.0 (C18), 74.6 (C22), 74.4 (C20), 73.0
(C21), 68.9 (C11), 60.4 (C7-OMe), 60.2 (C5-OMe), 53.9 (C1), 51.0
(C3), 42.4 (C14), 28.3 (C19), 27.4 (C4), 9.3 (C6-Me) ppm; HRMS calcd
for C35H45N2O8 (MHþ) 621.3176 Da. Found 621.3186 Da.
5.43 (1H, br s), 4.98 (1H, d, J¼11.1 Hz), 4.91 (1H, d, J¼11.2 Hz),
4.28e4.20 (4H, m), 3.99 (1H, d, J¼14.4 Hz), 3.80 (1H, br s), 3.59
(3H, s), 3.53e3.43 (3H, m), 3.39 (3H, s), 2.98 (1H, br s), 2.66e2.61
(2H, m), 2.19 (3H, s), 1.41 (9H, s) ppm; HRMS calcd for C35H45N2O8
(MHþ) 621.3176 Da. Found 621.3170 Da.
4.1.15. Hemi-aminal 45. To a stirred solution of oxalyl chloride
(1.32 mL, 15.1 mmol) in CH2Cl2 (66 mL) at ꢁ78 ꢂC was added DMSO
(2.14 mL, 30.2 mmol). The mixture was stirred for 10 min and am-
ide 43 (7.2 g, 11.6 mmol) was added as a solution in CH2Cl2 (15 mL)
within 10 min. After 8 min triethylamine (4.85 mL, 34.8 mmol) was
added dropwise. The reaction was stirred at ꢁ78 ꢂC for 10 min and
the solution was allowed to warm for 8 min (when the reaction
mixture was allowed to completely warm to 25 ꢂC and stir for more
than 15e30 min, degradation was observed). The reaction mixture
was diluted with H2O (100 mL) and extracted with CH2Cl2
(3ꢃ150 mL). The combined extracts were washed with satd aq NaCl
(100 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The product was used directly for thioaminal formation.
4.1.13. Di-coupled 42. To a stirred solution of amino alcohol 40
(75 mg, 0.162 mmol) and Boc-Gly-OH (85 mg, 0.485 mmol) in
CH2Cl2 (0.81 mL) at 0 ꢂC was added Py-BOPÒ (252 mg,
€
0.485 mmol), and after 5 min Hunig’s base (0.260 mL, 1.45 mmol)
was added. After 1 h stirring at 0 ꢂC the solution was warmed to
25 ꢂC and stirred 15 h. The reaction was treated with H2O (5 mL)
and extracted with EtOAc (2ꢃ15 mL) The combined extracts were
washed with aq 1 N HCl (15 mL), satd aq NaHCO3 (15 mL), satd aq
NaCl (15 mL), dried (Na2SO4), filtered, and concentrated under
vacuum. The residue was purified by flash column chromatography
(SiO2, 20e40% EtOAcehexane) to afford 42 (107 mg, 85% yield) as
a pale yellow oil: Rf¼0.33 (50% EtOAc in hexanes); IR (thin film):
3419, 3362, 2977, 2936, 1716, 1652, 1498, 155, 1417, 1366, 1249, 1166,
For identification purposes some material was purified by flash
column chromatography (SiO2, 20e40% EtOAcehexane) to afford
hemi-aminal 45 as a pale yellow oil and a 3:2 mixture of di-
astereomers: Rf¼0.23/0.18 (40% EtOAc in hexanes); IR (thin film):
3400, 2976, 2936, 2869, 1700, 1653. 1455, 1413, 1393, 1367, 1339,
1055 cmꢁ1 1H NMR (300 MHz, CDCl3): 7.51e7.12 (10H, m), 5.36
;
(1H, br s), 5.23 (1H, dd, J¼9.1, 4.1 Hz), 5.12e5.04 (3H, m), 4.56 (1H,
br s), 4.45e4.34 (3H, m), 4.29e4.13 (3H, m), 3.90e3.82 (2H, m), 3.81
(3H, s), 3.67 (3H, s), 3.46 (1H, t, J¼9.6 Hz), 3.32 (1H, br s), 3.21 (1H,
dd, J¼16.4, 7.5 Hz), 2.61 (1H, dd, J¼16.2, 9.7 Hz), 2.23 (3H, s), 1.46
(9H, s), 1.44 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): 169.8, 169.5,
155.5, 151.7, 149.8, 144.0,137.3, 137.1, 128.5, 128.3, 128.2, 128.1, 128.0,
127.6, 127.5, 127.3, 125.5, 125.3, 121.6, 79.7, 79.0, 74.8, 72.8, 70.8,
65.6, 60.6, 60.2, 60.0, 50.5, 49.1, 42.7, 42.2, 28.1, 22.6, 9.3 ppm;
HRMS calcd for C42H56N3O11 (MHþ) 778.3915 Da. Found
778.3924 Da.
1164, 1115, 1061 cmꢁ1 1H NMR (300 MHz, CDCl3, only listed sig-
;
nals for dominant isomer): 7.44e7.28 (5H, m), 7.25e7.19 (3H, m),
7.15e7.05 (2H, m), 5.94 (1H, t, J¼4.9 Hz), 5.59 (0.6H, br s), 5.47
(0.4H, br s), 4.98 (2H, s), 4.52e4.38 (2H, m), 4.23e4.18 (1H, m),
3.95 (1H, d, J¼6.6 Hz), 3.88 (1H, d, J¼17.5 Hz), 3.81 (3H, s),
3.80e3.70 (1H, m), 3.69 (3H, s), 3.59e3.38 (2H, m), 3.19e3.01 (2H,
m), 2.26 (3H, s), 1.50 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): 171.0,
165.9, 153.8, 151.3, 150.3, 144.5, 137.6, 137.0, 128.4, 128.3, 128.2,
128.0, 127.8, 127.5, 127.3, 127.2, 126.4, 124.8, 122.9, 81.2, 75.2, 74.6,
72.6, 71.7, 64.2, 60.7, 60.1, 55.5, 47.7, 46.0, 28.1, 23.7, 9.2 ppm;
HRMS calcd for C35H43N2O8 (MHþ) 619.3019 Da. Found
619.3016 Da.
4.1.14. Amide 43. To a stirred solution of amino alcohol 40 (6.6 g,
14.2 mmol) in THF (71 mL) at 0 ꢂC was added triethylamine
(5.95 mL, 42.7 mmol) then freshly distilled TMS-Cl (3.70 mL,
29.2 mmol) dropwise within 10 min. A white precipitate formed.
The reaction was warmed to 25 ꢂC and stirred for 3 h. To a stirred
solution of Boc-Gly-OH (2.74 g, 15.7 mmol) and triethylamine
(6.0 mL, 42.7 mmol) in THF (78 mL) at ꢁ20 ꢂC was added pivaloyl
chloride (1.93 mL, 15.7 mmol) dropwise within 10 min. The re-
action was stirred for 2.5 h, then cooled to ꢁ65 ꢂC. The above
solution of 40 was added with filtration (cotton plug) within
30 min. The reaction was stirred at ꢁ65 ꢂC to ꢁ10 ꢂC for 3 h,
warmed to 25 ꢂC and stirred for 10 h. The reaction was treated
with aq 1 N HCl (100 mL), stirred vigorously for 1 min and
extracted with EtOAc (3ꢃ150 mL). The combined extracts were
washed with aq 1 N HCl (100 mL), H2O (150 mL), aq satd NaHCO3
(150 mL), satd aq NaCl (150 mL), dried (Na2SO4), filtered, and
concentrated under vacuum. The resulting pale yellow oil was
purified by flash column chromatography (SiO2, 30e60%
EtOAcehexane) to afford amide 43 (7.2 g, 82% yield) as a colorless
oil: Rf¼0.42 (75% EtOAc in hexanes); IR (thin film): 3420, 2975,
2935, 1714, 1656, 1455, 1415, 1366, 1251, 1168, 1054 cmꢁ1; 1H NMR
(300 MHz, CDCl3, signals from minor, ca. 20%, carbamate reso-
nance isomer not reported): 7.53e7.17 (10H, m), 6.38e6.34 (0.3H,
m), 5.56 (0.3H, br s), 5.37 (0.7H, br s), 5.24 (0.7H, dd, J¼10.3,
4.6 Hz), 5.17e5.04 (1.7H, m), 4.88 (0.3H, d, J¼10.4 Hz), 4.66 (0.3H,
d, J¼11.8 Hz), 4.42 (0.7H, d, J¼11.6 Hz), 4.37e3.91 (5H, m), 3.82
(3H, s), 3.68 (3H, s), 3.61e3.39 (2H, m), 3.21e2.97 (3H, m),
2.83e2.73 (1H, m), 2.06 (3H, s), 1.47 (9H, s) ppm; 13C NMR
(75 MHz, CDCl3): 170.0, 155.5, 151.8, 149.6, 143.8, 137.1, 136.8,
128.6, 128.4, 128.3, 128.2, 128.0, 127.8, 127.6, 125.6, 125.0, 124.8,
122.8, 79.1, 74.9, 73.0, 70.1, 64.4, 60.6, 60.0, 54.0, 53.0, 42.8, 28.2,
22.2, 9.2 ppm; 1H NMR (500 MHz, toluene-d8, 100 ꢂC): 7.40 (2H, d,
J¼7.6 Hz), 7.25 (2H, d, J¼7.6 Hz), 7.13e7.96 (6H, m), 5.60 (1H, br s),
4.1.16. Thioaminal 46. To a stirred solution of the crude product
mixture of hemi-aminal 45 (11.6 mmol) in CH2Cl2 (60 mL) at 0 ꢂC
was added thiophenol (6.0 mL, 58.0 mmol) and p-toluenesulfonic
acid monohydrate (2.65 g, 13.9 mmol). The reaction was stirred for
1.5 h at 0e5 ꢂC, quenched with satd aq NaHCO3 (100 mL), and
extracted with CH2Cl2 (3ꢃ150 mL). The combined extracts were
washed with satd aq NaCl (150 mL), dried (Na2SO4), filtered, and
concentrated under vacuum. The resulting yellow oil was purified
by flash column chromatography (SiO2, 10e30% EtOAcehexane) to
afford thioaminal 46 (7.1 g, 86% yield over two steps) as a white
solid: recrystallized from EtOAc and hexanes; X-ray (CCDC 28814);
mp 162e164 ꢂC; Rf¼0.26 (30% EtOAc in hexanes); IR (thin film):
2977, 2936, 2864, 1702, 1658, 1455, 1415, 1391, 1368, 1305, 1163,
;
1118, cmꢁ1 1H NMR (300 MHz, CDCl3): 7.57e7.52 (2H, m),
7.42e7.24 (8H, m), 7.20e7.12 (5H, m), 5.98 (0.5H, d, J¼2.5 Hz),
5.81e5.75 (1H, m), 5.65 (0.5H, d, J¼2.5 Hz), 5.06e4.96 (2H, m),
4.53e4.40 (2H, m), 4.20e4.05 (2H, m), 3.84 (1.5H, s), 3.83 (1.5H, s),
3.82e3.77 (1H, m), 3.72 (1.5H, s), 3.67 (1.5H, s), 3.70e3.55 (2H, m),
3.14e3.06 (2H, m), 2.28 (1.5H, s), 2.26 (1.5H, s), 1.26 (4.5H, s), 1.15
1
(4.5H, s) ppm; H NMR (500 MHz, DMSO-d6, 130 ꢂC, signals were
still significantly broad at 90 ꢂC): 7.56e7.54 (2H, m), 7.39e7.27 (8H,
m), 7.22e7.18 (3H, m), 7.13e7.12 (2H, m), 5.87 (1H, br s), 5.76 (1H, t,
J¼4.4 Hz), 5.02 (1H, d, J¼11.4 Hz), 4.95 (1H, d, J¼11.2 Hz), 4.41 (1H,
d, J¼12.0 Hz), 4.36 (1H, d, J¼12.2 Hz), 4.13 (1H, d, J¼17.8 Hz), 3.91
(1H, d, J¼17.8 Hz), 3.77 (3H, s), 3.73 (1H, d, J¼12.2 Hz), 3.69e3.63
(2H, m), 3.65 (3H, s), 3.15 (1H, dd, J¼14.8, 3.3 Hz), 2.99 (1H, t,
J¼14.5 Hz), 2.20 (3H, s), 1.25 (9H, s) ppm; 13C NMR (125 MHz,
DMSO-d6, 130 ꢂC): 163.7, 150.7, 149.5, 143.8, 137.9, 136.8, 133.2,
128.3, 127.5, 127.3, 127.2, 127.0, 126.4, 126.3, 125.8, 123.2, 122.9, 79.9,

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6355
13
73.8, 71.7, 59.9, 59.3, 56.3, 48.2, 27.1, 25.4, 8.5 ppm; HRMS calcd. For
C41H47N2O7S (MHþ) 711.3104 Da. Found 711.3113 Da.
s), 1.32 (C24, 9H, s) ppm; C NMR (125 MHz, toluene-d8, 100 ꢂC):
167.8, 153.6, 152.4, 151.5, 145.7, 139.7, 138.3, 137.9, 137.5, 135.3, 132.7
(C16), 129.3, 128.9, 128.6, 128.4, 128.0, 127.7, 127.4, 125.5, 124.8,
124.7, 116.1 (C17), 81.3 (C23), 75.5 (C20), 73.9 (C18), 73.6 (C19), 60.6
(C5-OMe), 60.2 (C7-OMe), 58.6 (C3), 57.8 (C13), 50.6 (C1), 41.2
(C15), 28.5 (C24), 28.2 (C4), 9.6 (C6-Me) ppm; HRMS calcd for
C44H51N2O7S (MHþ) 751.3417 Da. Found 751.3419 Da.
4.2. Synthesis of ( )-lemonomycinone amide (8)
4.2.1. Allyl alkylated product 47. To a stirred solution of thioaminal
46 (30 mg, 0.042 mmol) in THF (0.33 mL) at ꢁ78 ꢂC was added
LiHMDS (0.57 M in THF, 86 mL, 0.049 mmol) dropwise within
5 min. The yellow solution was stirred for 15 min at ꢁ78 ꢂC, and
allyl bromide (4.1 mL, 0.049 mmol) added. After 20 min the re-
action was quenched with satd aq NH4Cl (5 mL) and extracted with
EtOAc (2ꢃ10 mL). The combined extracts were washed with satd aq
NaCl (5 mL), dried (Na2SO4), filtered, and concentrated under vac-
uum. The resulting pale yellow oil was purified by flash column
chromatography (SiO2, 10e30% EtOAcehexane) to afford product
47 (22 mg, 70% yield) as a white solid: recrystallized from benzene
and hexanes; X-ray (CCDC 28815); mp 119e122 ꢂC; Rf¼0.38 (30%
EtOAc in hexanes); IR (thin film): 2976, 2935, 2865, 1703, 1661,
4.2.3. Alkylated product 50. To a stirred solution of thioaminal 46
(3.04 g, 4.28 mmol) in THF (21 mL) at ꢁ78 ꢂC was added KHMDS
(0.5 M in toluene, 10.3 mL, 5.14 mmol) dropwise within 5 min. The
pale orange clear solution was stirred for 5 min and iodide 49 (1.9 g,
5.56 mmol) was added dropwise. No color change was observed.
The reaction appeared complete by TLC analysis after 10 min. The
reaction was quenched with water (10 mL), diluted with satd aq
NH4Cl (75 mL), and extracted with EtOAc (3ꢃ150 mL). The com-
bined extracts were washed with satd aq NaCl (100 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The resulting
pale yellow oil was purified by flash column chromatography (SiO2,
5e10% EtOAcehexane) to afford alkylated product 51 (3.10 g, 78%
yield) as a colorless oil and starting material 46 (0.31 g, 10% yield).
Compound 50: Rf¼0.34 (20% EtOAc in hexanes); IR (thin film):
2940, 2865, 1701, 1663, 1457, 1414, 1367, 1337, 1304, 1164,
1455, 1414, 1368, 1338, 1289, 1163, 1115 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): 7.57e7.15 (15H, m), 5.92 (1H, t, J¼5.2 Hz), 5.73e5.54 (2H,
m), 5.06e4.92 (4H, m), 4.53e4.36 (3H, m), 3.85e3.77 (6H, m),
3.71e3.52 (4H, m), 3.26e3.10 (1H, m), 3.05e2.85 (1H, m), 2.66 (1H,
br s), 2.25 (3H, s), 1.41 (4.5H, s), 1.14 (4.5H, s) ppm; 1H NMR
(500 MHz, toluene-d8, 100 ꢂC): 7.55 (PhS-ortho, 2H, d, J¼6.7 Hz),
7.10e6.94 (13H, m), 6.23 (C1, 1H, t, J¼5.2 Hz), 5.79e5.71 (C11, C16,
2H, m), 5.07 (C20, 1H, d, J¼11.0 Hz), 4.99 (C20, 1H, d, J¼11.0 Hz),
4.98e4.95 (C17-Ha, 1H, m), 4.83e4.80 (C17-Hb, 1H, m), 4.59 (C13,
1H, br s), 4.41 (C19, 1H, d, J¼12.0 Hz), 4.34 (C19, 1H, d, J¼12.1 Hz),
4.03 (C18, 2H, d, J¼5.0 Hz), 3.85e3.80 (C3, 1H, m), 3.61 (C7-OMe,
3H, s), 3.40e3.34 (C4-Ha, 1H, m), 3.36 (C5-OMe, 3H, s), 2.98 (C4-Hb,
1H, dd, J¼14.7, 3.4 Hz), 2.80e2.73 (C15, 2H, m), 2.23 (C6-Me, 3H, s),
1106 cmꢁ1 1H NMR (300 MHz, CDCl3): 7.60e7.15 (15H, m), 5.98
;
(1H, t, J¼5.3 Hz), 5.71 (1H, br s), 5.03 (2H, s), 4.51 (2.5H, br s), 4.30
(0.5H, br s), 3.95e3.84 (2H, m), 3.82 (3H, s), 3.64e3.54 (6H, m),
3.23e3.14 (1.5H, m), 3.02e2.90 (0.5H, m), 2.27 (3H, s), 2.05e1.95
(1H, m), 1.80e1.48 (3H, m), 1.42 (6H, br s), 1.16 (3H, br s), 1.06e0.99
(21H, m) ppm; 13C NMR (75 MHz, CDCl3): 168.3, 151.1, 150.2, 145.3,
138.3, 137.4, 134.6, 133.1, 128.9, 128.8, 128.4, 128.2, 128.1, 128.0,
127.8, 127.7, 127.3, 127.2, 126.9, 124.6, 122.8, 81.1, 74.7, 72.4, 62.9,
60.7, 60.0, 55.7, 48.4, 28.1, 27.9,17.8,17.5,13.5,11.7, 9.2 ppm; 1H NMR
(500 MHz, DMSO-d6, 90 ꢂC): 7.52 (2H, d, J¼7.6 Hz), 7.43 (2H, d,
J¼7.2 Hz), 7.39e7.27 (6H, m), 7.19e7.16 (3H, m), 7.11e7.09 (2H, m),
5.83 (1H, t, J¼5.4 Hz), 5.79 (1H, s), 4.99 (1H, d, J¼10.9 Hz), 4.91 (1H,
d, J¼10.9 Hz), 4.42 (1H, d, J¼12.3 Hz), 4.39 (1H, d, J¼12.1 Hz), 4.14
(1H, dd, J¼7.5, 4.2 Hz), 3.95 (1H, ddd, J¼11.9, 4.0, 1.6 Hz), 3.78e3.74
(1H, m), 3.76 (3H, s), 3.64 (1H, dd, J¼9.4, 6.9 Hz), 3.61e3.59 (2H, m),
3.60 (3H, s), 3.19 (1H, br s), 3.05e2.99 (1H, m), 2.18 (3H, s),
1.90e1.78 (2H, m),1.61e1.54 (1H, m),1.48e1.39 (1H, m),1.27 (9H, s),
1.01e0.91 (21H, m) ppm; HRMS calcd for C53H73N2O8SiS (MHþ)
925.4857 Da. Found 925.4833 Da.
13
1.24 (C24, 9H, s) ppm; C NMR (125 MHz, toluene-d8, 100 ꢂC):
168.2, 153.5, 151.5, 146.1, 139.8, 138.5, 137.9, 137.5, 135.2, 134.8, 134.4
(C16), 129.3, 128.9, 128.6, 128.4, 128.0, 127.7, 127.3, 125.5, 124.8,
124.1, 118.1 (C17), 81.2 (C23), 75.8 (C20), 73.7 (C18), 73.4 (C19), 69.5
(C11), 60.5 (C5-OMe), 60.1 (C7-OMe), 59.1 (C13), 56.9 (C3), 50.3
(C1), 38.9 (C15), 28.4 (C24), 9.6 (C6-Me) ppm; HRMS calcd for
C44H51N2O7S (MHþ) 751.3417 Da. Found 751.3410 Da.
4.2.2. Epimer product 48. To a solution of 47 (75 mg, 0.10 mmol) in
THF (1.2 mL) at ꢁ78 ꢂC was added t-BuLi (0.9 M in pentane,
0.28 mL, 0.25 mmol). Upon addition of t-BuLi the solution became
orange in color. Within 10 s of complete t-BuLi addition the reaction
was quenched with a solution of butylated hydroxytoluene (0.110 g,
0.50 mmol) in THF (0.5 mL) and the solution became pale yellow in
color. The solution was diluted with H2O (10 mL) and extracted
with EtOAc (3ꢃ10 mL). The extracts were combined, washed with
satd aq NaCl (15 mL), dried (Na2SO4), filtered, and concentrated
under vacuum. The residue was purified by flash column chroma-
tography (SiO2, 10e20% EtOAcehexane) to yield 48 (0.145 g, 73%
yield) as a colorless oil: Rf¼0.41 (30% EtOAc in hexanes); IR (thin
film): 2977, 2935, 2863, 1696, 1653, 1455, 1413, 1382, 1316, 1162,
4.2.4. epi-50. To
a stirred, degassed solution of 50 (0.20 g,
0.22 mmol) in THF (2.2 mL) at ꢁ78 ꢂC was added t-BuLi (1.2 M in
pentane, 0.40 mL, 0.48 mmol). Upon addition of t-BuLi the solution
became brown/orange in color. Within 10 s of complete t-BuLi ad-
dition the reaction was quenched with a solution of butylated
hydroxytoluene (0.19 g, 0.86 mmol) in THF (0.5 mL) and the solu-
tion became pale yellow in color. The solution was diluted with H2O
(15 mL) and extracted with EtOAc (3ꢃ15 mL). The extracts were
combined, washed with satd aq NaCl (15 mL), dried (Na2SO4), fil-
tered, and concentrated under vacuum. The residue was purified by
flash column chromatography (SiO2, very slow gradient of
5e10e20% EtOAcehexane) to yield epi-50 (0.145 g, 73% yield) as
a colorless oil: Rf¼0.38 (20% EtOAc in hexanes); IR (thin film): 2941,
1117 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.47e7.45 (2H, m),
7.35e7.23 (8H, m), 7.22e7.15 (5H, m), 6.17 (0.5H, s), 6.08e5.94
(0.5H, m), 5.93e5.73 (2H, m), 5.01e4.93 (3H, m), 4.91e4.79 (1H, m),
4.56e4.51 (0.5H, m), 4.47 (2H, s), 4.44e4.40 (0.5H, m), 3.81 (3H, s),
3.76 (1.0H, d, J¼5.2 Hz), 3.68 (1.0H, d, J¼3.9 Hz), 3.65e3.45 (4H, m),
3.20e2.91 (3H, m), 2.80e2.61 (1H, m), 2.22 (3H, s), 1.40 (6H, s), 1.27
2865, 1698, 1653, 1456, 1414, 1384, 1367, 1310, 1163, 1116 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): 7.52e7.47 (2H, m), 7.37e7.19 (13H, m), 6.17
(0.5H, s), 5.85e5.79 (1.5H, m), 5.06e4.96 (2H, m), 4.50e4.45 (2.5H,
m), 4.34e4.30 (0.5H, m), 3.83 (3H, s), 3.79e3.48 (8H, m), 3.20e2.97
(2H, m), 2.38e2.10 (2H, m), 2.25 (3H, s), 2.05e1.84 (2H, m),1.43 (6H,
br s), 1.27 (3H, br s), 1.07e0.94 (21H, m) ppm; 13C NMR (75 MHz,
CDCl3): 168.3, 153.3, 151.0, 150.2, 144.6, 138.5, 137.1, 133.3, 131.2,
128.8, 128.7, 128.5, 128.3, 128.1, 127.8, 127.7, 127.2, 126.9, 126.8,
124.4, 123.8, 81.3, 74.4, 72.7, 72.3, 63.3, 62.2, 60.8, 60.2, 57.7, 56.7,
49.4, 33.1, 31.8, 31.4, 27.9, 27.7, 26.8, 17.9, 11.8, 9.2 ppm; 1H NMR
1
(3H, s) ppm; H NMR (500 MHz, toluene-d8, 100 ꢂC): 7.52 (PhS-or-
tho, 2H, d, J¼7.7 Hz), 7.09e6.95 (13H, m), 6.26 (C16, 1H, br s), 6.12
(C1, 1H, t, J¼4.8 Hz), 6.08 (C11, 1H, br s), 5.08 (C17-Ha, 1H, d,
J¼16.5 Hz), 5.03 (C20, 2H, s), 4.99 (C17-Hb, 1H, d, J¼9.4 Hz), 4.50
(C13, 1H, br s), 4.40 (C19, 1H, d, J¼12.0 Hz), 4.30 (C19, 1H, d,
J¼12.1 Hz), 3.98 (C18, 1H, dd, J¼9.9, 5.3 Hz), 3.83 (C18, 1H, dd, J¼9.8,
4.0 Hz), 3.66 (C7-OMe, 3H, s), 3.36 (C5-OMe, 3H, s), 3.35e3.29 (C15,
C3, C4-Ha, 3H, m), 2.97e2.87 (C15, C4-Hb, 2H, m), 2.25 (C6-Me, 3H,

6356
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
(500 MHz, DMSO-d6, 120 ꢂC): 7.53e7.51 (2H, m), 7.38e7.27 (8H, m),
7.23e7.18 (3H, m), 7.16e7.14 (2H, m), 6.01 (1H, s), 5.78 (1H, t,
J¼5.2 Hz), 4.99 (1H, d, J¼11.1 Hz), 4.95 (1H, d, J¼11.0 Hz), 4.42 (1H,
d, J¼12.2 Hz), 4.37 (1H, d, J¼12.3 Hz), 4.27 (1H, t, J¼5.4 Hz), 3.77
(3H, s), 3.69e3.59 (5H, m), 3.61 (3H, s), 3.03 (2H, d, J¼7.5 Hz),
2.28e2.22 (1H, m), 2.19 (3H, s), 1.98e1.88 (2H, m), 1.67e1.62 (1H,
m), 1.34 (9H, s), 1.11e1.01 (21H, m) ppm; 13C NMR (125 MHz,
DMSO-d6, 120 ꢂC): 167.2, 150.7, 149.5, 143.8, 138.0, 136.8, 131.3,
128.3, 127.6, 127.4, 127.2, 127.1, 126.6, 126.5, 126.4, 125.9, 123.2,
123.1, 80.1, 73.8, 72.0, 71.8, 62.7, 60.0, 59.4, 56.8, 48.3, 32.0, 30.7,
27.2, 26.1, 17.2, 17.1, 11.1, 8.6 ppm; HRMS calcd for C53H73N2O8SiS
(MHþ) 925.4857 Da. Found 925.4824 Da.
1368, 1336, 1291, 1162, 1117, 1078 cmꢁ1; 1H NMR (300 MHz, CDCl3,
pronounced carbamate resonance led to two aldehyde signals for
CHO): 9.74 (0.5H, s), 9.65 (0.5H, s), 7.50e7.42 (2H, m), 7.34e7.10
(13H, m), 6.21 (0.5H, s), 5.82e5.75 (1.5H, m), 5.01 (2H, s), 4.48 (2H,
s), 4.40e4.25 (1H, m), 3.83 (3H, s), 3.78e3.45 (6H, m), 3.18e2.98
(2H, m), 2.96e2.64 (2H, m), 2.60e2.21 (2H, m), 2.26 (3H, s), 1.28
(4H, s), 1.09 (5H, s) ppm; 13C NMR (75 MHz, CDCl3): 201.9, 201.4,
167.8, 167.5, 153.1, 152.3, 150.8, 150.3, 144.6, 138.4, 137.0, 136.8,
133.1, 132.6, 132.5, 131.1, 129.6, 128.9, 128.5, 128.3, 128.2, 128.1,
128.0, 127.8, 127.7, 127.6, 127.2, 127.0, 126.6, 126.2, 124.4, 123.6, 81.8,
81.4, 74.4, 72.2, 65.0, 61.7, 61.0, 60.8, 60.2, 57.5, 55.1, 53.2, 49.5, 42.3,
28.0, 27.8, 26.6, 14.0, 9.2 ppm; 1H NMR (500 MHz, DMSO-d6,
100 ꢂC): 9.64 (1H, s), 7.53 (2H, d, J¼7.0 Hz), 7.38e7.28 (8H, m),
7.23e7.19 (3H, m), 7.16e7.14 (2H, m), 6.04 (1H, s), 5.76 (1H, t,
J¼5.1 Hz), 5.00 (1H, d, J¼11.1 Hz), 4.95 (1H, d, J¼11.0 Hz), 4.43 (1H,
d, J¼12.2 Hz), 4.38 (1H, d, J¼12.2 Hz), 4.29 (1H, t, J¼6.8 Hz), 3.77
(3H, s), 3.70e3.59 (3H, m), 3.63 (3H, s), 3.12e3.08 (1H, m),
3.05e3.01 (1H, m), 2.72e2.66 (1H, m), 2.55e2.40 (2H, m), 2.19 (3H,
s), 2.14e2.08 (1H, m), 1.32 (9H, s) ppm; 13C NMR (125 MHz, DMSO-
d6, 100 ꢂC): 201.6, 166.9, 150.7, 150.0, 143.9, 138.0, 136.8, 132.5,
131.6, 128.5, 127.7, 127.4, 127.2, 126.9, 126.6, 126.5, 125.9, 123.4,
123.1, 80.5, 73.8, 71.9, 71.8, 60.1, 59.5, 56.7, 54.9, 48.4, 41.0, 27.4,
27.3, 25.9, 8.7 ppm; HRMS calcd for C44H51N2O8S (MHþ)
767.3366 Da. Found 767.3366 Da.
4.2.5. Alcohol 51. To a stirred solution of 50 (1.37 g, 1.48 mmol) in
THF (15 mL) at ꢁ78 ꢂC was added t-BuLi (1.2 M in pentane, 2.71 mL,
3.26 mmol) within 30 s. After 10 s the orange solution was
quenched with a solution of butylated hydroxytoluene (1.31 g,
5.92 mmol) in THF (3.0 mL). The pale yellow solution was diluted
with H2O (75 mL) and extracted with EtOAc (3ꢃ100 mL). The
combined extracts were washed with satd aq NaCl (75 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The residue
was dissolved in CH3CN (15 mL), cooled to 0 ꢂC, and 48% aq HF
(1.5 mL) added dropwise. The solution became dark orange in color.
After stirring for 30 min at 0 ꢂC, the reaction was quenched with
satd aq NaHCO3 (100 mL) and extracted with EtOAc (3ꢃ100 mL).
The combined extracts were washed with satd aq NaCl (75 mL),
dried (Na2SO4), filtered, and concentrated under vacuum. The
resulting yellow residue was purified by flash column chromatog-
raphy (SiO2, 30e50% EtOAcehexane) to afford alcohol 51 (0.829 g,
83% yield) as a colorless oil: Rf¼0.28 (50% EtOAc in hexanes); IR
(thin film): 3472, 2936, 2866, 1696, 1652, 1454, 1414, 1388, 1368,
4.2.7. Silyl enol ether 52. To a stirred solution of oxalyl chloride
(0.139 mL, 1.60 mmol) in CH2Cl2 (7.0 mL) at ꢁ78 ꢂC was added
DMSO (0.227 mL, 3.20 mmol). The reaction was stirred for 10 min
then alcohol 51 (0.95 g, 1.23 mmol) as a solution in CH2Cl2
(1.5 mL) within 5 min. The solution became dark orange and
a
precipitate formed. After 10 min triethylamine (0.514 mL,
1336, 1262, 1162, 1117, 1059 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
3.69 mmol) was added dropwise. The solution was stirred at
ꢁ78 ꢂC for 5 min and allowed to warm for 9 min. The reaction was
quenched with H2O (25 mL) and extracted with CH2Cl2
(3ꢃ40 mL). The combined extracts were washed with satd aq NaCl
(50 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The residue was dissolved in Et2O (12.3 mL) and triethylamine
(0.343 mL, 2.46 mmol), cooled to 0 ꢂC, and freshly distilled TIP-
SOTf (0.495 mL, 1.85 mmol) added dropwise. The solution was
warmed to 25 ꢂC and stirred for 16 h. The reaction was quenched
with satd aq NaHCO3 (50 mL) and extracted with EtOAc
(3ꢃ75 mL). The combined extracts were washed with satd aq NaCl
(75 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The resulting yellow residue was purified by flash column chro-
matography (SiO2, 5e10e20% EtOAcehexane) to afford silyl enol
ether 52 (1.01 g, 88% yield) as a colorless foam: Rf¼0.33 (20%
EtOAc in hexanes); IR (thin film): 2943, 2866, 1695, 1653, 1456,
7.53e7.42 (2H, m), 7.33e7.17 (13H, m), 6.19 (0.5H, s), 5.76e5.73
(1.5H, s), 5.05e4.98 (2H, m), 4.49 (2H, s), 4.43e4.35 (1H, s), 3.84
(3H, s), 3.81e3.45 (8H, m), 3.25e2.97 (2H, m), 2.61e2.57 (0.5H, m),
2.41e2.37 (0.5H, m), 2.25 (3H, s), 1.95e1.85 (2.5H, m), 1.64e1.61
(0.5H, m), 1.43 (3H, br s), 1.24 (6H, br s) ppm; 13C NMR (75 MHz,
CDCl3): 168.9, 152.3, 150.8, 150.3, 144.6, 144.5, 138.4, 136.8, 133.7,
132.4, 130.9, 129.6, 128.9, 128.7, 128.5, 128.1, 127.8, 127.7, 127.6,
128.2, 126.8, 126.7, 124.4, 123.4, 81.5, 74.5, 72.6, 72.1, 65.6, 62.1, 61.0,
60.7, 60.2, 57.5, 56.2, 54.1, 49.6, 33.3, 32.6, 31.4, 30.6, 28.1, 27.7, 26.8,
1
26.5, 9.2 ppm; H NMR (500 MHz, DMSO-d6, 120 ꢂC): 7.54e7.53
(2H, m), 7.39e7.27 (8H, m), 7.27e7.18 (3H, m), 7.16e7.14 (2H, m),
6.01 (1H, s), 5.78 (1H, t, J¼5.2 Hz), 5.01 (1H, d, J¼11.2 Hz), 4.95 (1H,
d, J¼11.1 Hz), 4.42 (1H, d, J¼12.3 Hz), 4.38 (1H, d, J¼12.3 Hz), 4.27
(1H, t, J¼6.2 Hz), 3.90 (1H, br s), 3.77 (3H, s), 3.67e3.60 (3H, m),
3.61 (3H, s), 3.43e3.40 (2H, m), 3.04e3.00 (2H, m), 2.28e2.20 (1H,
m), 2.19 (3H, s), 1.92e1.75 (2H, m), 1.59e1.54 (1H, m), 1.35 (9H, s)
ppm; HRMS calcd for C44H53N2O8S (MHþ) 769.3523 Da. Found
769.3525 Da.
1414, 1384, 1330, 1166, 1118 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
7.51e7.48 (2H, m), 7.39e7.16 (13H, m), 6.39e6.11 (2H, m),
5.85e5.76 (1H, m), 5.06e4.84 (3H, m), 4.50 (2H, s), 4.46e4.42 (1H,
m), 3.83 (3H, s), 3.77e3.48 (6H, m), 3.21e2.82 (3H, m), 2.76e2.58
(1H, m), 2.23 (3H, s), 1.46 (6H, s), 1.39e1.26 (3H), 1.05e0.85 (21H,
m) ppm; 13C NMR (75 MHz, CDCl3): 167.6, 153.4, 151.1, 150.3,
144.5, 141.6, 138.5, 137.0, 134.0, 132.6, 131.9, 130.5, 128.9, 128.7,
128.5, 128.3, 128.1, 127.8, 127.6, 127.2, 126.9, 126.5, 124.3, 123.8,
107.9, 81.3, 74.5, 72.7, 72.3, 62.2, 60.7, 60.1, 58.1, 57.5, 49.5, 33.5,
27.9, 26.8, 17.6, 11.7, 9.2 ppm; HRMS calcd for C53H71N2O8SiS
(MHþ) 923.4700 Da. Found 923.4702 Da.
4.2.6. Aldehyde 51b. To a solution of oxalyl chloride (0.139 mL,
1.60 mmol) in CH2Cl2 (7.0 mL) at ꢁ78 ꢂC was added DMSO
(0.227 mL, 3.20 mmol). The reaction was stirred 10 min and added
alcohol 51 (0.95 g, 1.23 mmol) as a solution in CH2Cl2 (1.5 mL)
within 5 min. The solution became dark orange and a precipitate
formed. After 10 min triethylamine (0.514 mL, 3.69 mmol) was
added dropwise. The reaction was stirred at ꢁ78 ꢂC for 5 min and
allowed to warm for 9 min. The reaction was quenched with H2O
(25 mL) and extracted with CH2Cl2 (3ꢃ40 mL). The combined ex-
tracts were washed with satd aq NaCl (50 mL), dried (Na2SO4),
filtered, and concentrated under vacuum. A small portion of
product was purified, for the purposes of characterization, by flash
column chromatography (SiO2, 20e30% EtOAcehexane) to afford
51b as a colorless oil: Rf¼0.19 (30% EtOAc in hexanes); IR (thin
film): 2976, 2937, 2863, 2721, 1722, 1694, 1651, 1454, 1415, 1385,
4.2.8. Aldehyde 53. To a stirred solution of silyl enol ether 52
(0.22 g, 0.238 mmol) in THF (7.0 mL) at 15 ꢂC was added AgBF4 as
a solution in THF (1.7 mL from 1.0 g AgBF4 in 20 mL THF). A pre-
cipitate immediately formed. After 15 min at 15 ꢂC the reaction was
warmed to 25 ꢂC and stirred for another 4 h. The reaction was
quenched with satd aq NaHCO3 (7 mL) and extracted with EtOAc
(3ꢃ15 mL). The combined extracts were washed with satd aq NaCl

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6357
(15 mL), dried (Na2SO4), filtered through a plug of silica gel, and
concentrated under vacuum. The resulting residue was carried to
hydrogenolysis without further purification. For the purpose of
characterization some of the residue was purified by flash column
chromatography (SiO2, 20e60% EtOAcehexane) to afford pure al-
dehyde 53 as a colorless oil: Rf¼0.46 (60% EtOAc in hexanes); IR
(thin film): 2975, 2936, 2868, 1726, 1700, 1663, 1456, 1412, 1368,
H2OeMeOH, 1.0 mL). The solution was warmed to 25 ꢂC, stirred for
3 h, and the solvents removed under vacuum to give 60. The white
residue was used directly for oxidation to the quinone. For the
purpose of characterization some of the residues were purified
by reverse phase HPLC (preparatory column, rate¼8 mL/min,
gradient¼100e70% H2O with 0.1% TFA in CH3CN with 0.1% TFA
over 20 min, injection volume¼1 mL, product elution from 17 to
19 min) and lyophilized to a white powder: IR (thin film): 3350,
2944, 1668, 1466, 1417, 1286, 1258, 1201, 1136, 1056 cmꢁ1; 1H NMR
(500 MHz, D2O): 5.31 (C1, 1H, t, J¼3.0 Hz), 5.12 (C16, 1H, d,
J¼4.6 Hz), 4.37 (C11, 1H, s), 4.28 (C13, 1H, d, J¼6.4 Hz), 3.90 (C18,
1H, dd, J¼11.8, 4.0 Hz), 3.79 (C3, 1H, dt, J¼12.2, 2.4 Hz), 3.66 (C7-
OMe, 3H, s), 3.61 (C5-OMe, 3H, s), 3.58 (C18, 1H, dd, J¼11.7,
2.8 Hz), 2.98 (C4-Hb, 1H, dd, J¼15.3, 2.6 Hz), 2.86e2.82 (C15, 1H,
m), 2.76 (C4-Ha, 1H, dd, J¼15.1, 12.3 Hz), 2.44 (C14-Ha, 1H, dd,
J¼14.1, 9.1 Hz), 2.25 (C14-Hb, 1H, dt, J¼14.2, 6.6 Hz), 2.13 (C6-Me,
3H, s) ppm; 13C NMR (125 MHz, D2O, carbon signals for C6-10 are
inferred by chemical shift and analogous compounds): 167.4 (C17),
147.6 (C5), 144.8 (C7), 142.3 (C8), 124.9 (C9/10), 124.6 (C9/10), 118.6
(C6), 90.0 (C16), 62.1 (C18), 61.3 (C5-OMe), 60.8 (C7-OMe), 59.5
(C13), 59.1 (C11), 56.4 (C3), 52.3 (C1), 41.4 (C15), 31.6 (C14), 24.5
(C4), 9.0 (C6-Me) ppm; HRMS calcd for C19H27N2O (MHþ)
395.1818 Da. Found 395.1825 Da.
1317, 1161, 1114 cmꢁ1 1H NMR (300 MHz, CDCl3): 9.56 (1H, s),
;
7.38e7.27 (5H, m), 7.22e7.19 (3H, m), 7.05e7.02 (2H, m), 5.43 (1H,
s), 5.02e4.95 (2H, m), 4.63 (1H, br s), 4.57 (1H, br s), 4.29 (1H, d,
J¼11.8 Hz), 4.24 (1H, d, J¼11.7 Hz), 4.15e4.09 (1H, m), 3.81 (3H, s),
3.69 (3H, s), 3.66e3.57 (1H, m), 3.34 (1H, dd, J¼9.4, 1.9 Hz), 3.08
(1H, t, J¼7.9 Hz), 2.92 (1H, dd, J¼14.3, 2.5 Hz), 2.71 (1H, t,
J¼12.9 Hz), 2.42e2.32 (1H, m), 2.27 (3H, s), 2.07e1.99 (1H, m), 1.43
(9H, s) ppm; 13C NMR (75 MHz, CDCl3): 198.9, 167.9, 150.9, 150.3,
144.2, 138.1, 136.9, 128.4, 128.2, 128.1, 127.8, 127.4, 126.4, 124.6,
124.3, 81.0, 74.4, 72.9, 71.4, 60.7, 60.1, 57.5, 56.8, 49.9, 48.5, 32.2,
28.0, 25.2, 9.3 ppm; HRMS calcd for C38H45N2O8 (MHþ)
657.3176 Da. Found 657.3201 Da.
4.2.9. Oxime 58. To a solution of hydroxylamine hydrochloride
(12 mg, 0.165 mmol) in H2O (0.10 mL) at 0 ꢂC was added KOAc
(40 mg, 0.411 mmol) then aldehyde 53 (90 mg, 0.137 mmol) as
a solution in EtOH (1.0 mL). The reaction was warmed to 25 ꢂC and
stirred for 2 h. The reaction mixture was extracted with Et2O
(3ꢃ15 mL). The combined extracts were washed with satd aq NaCl
(15 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
The resulting residue was purified by flash column chromatography
(SiO2, 20e40% EtOAcehexane) to afford two fractions, each with
predominantly one isomer: the trans oxime (50 mg, 45% yield) with
Rf¼0.32 (50% EtOAc in hexanes) as a 1/4 mixture of cisetrans oxime
and cis oxime 58 (44 mg, 38% yield) as a white solid in 4/1 mixture
of cisetrans oxime: recrystallized from benzene and hexanes; X-ray
(CCDC 28816); mp 168e169 ꢂC; Rf¼0.30 (50% EtOAc in hexanes); IR
(thin film): 3334, 2930, 2857, 1702, 1666, 1455, 1412, 1368, 1318,
4.2.12. (ꢀ)-Lemonomycinone amide 8. To a stirred solution of
amine 60 (0.084 mmol) in H2O (1.0 mL) at 25 ꢂC was added am-
monium cerium(IV) nitrate (0.138 g, 0.252 mmol) in one portion.
The reaction was monitored by reverse phase HPLC and after 4 h no
starting material remained. The reaction solution was then purified
without concentration on reverse phase HPLC (semi-preparatory
column, rate¼1.5 mL/min, gradient¼98e60% H2O with 0.1% TFA in
CH3CN with 0.1% TFA over 50 min, injection volume¼0.3 mL,
product elution from 25 to 26 min) and lyophilized to afford
(ꢀ)-lemonomycinone amide 8 (14 mg, 35% yield) as an orange
residue: 1H NMR (500 MHz, D2O): 5.13 (C16, 1H, d, J¼4.7 Hz), 5.04
(C1, 1H, br s), 4.38 (C11, 1H, br s), 4.31 (C13, 1H, d, J¼6.3 Hz), 4.09
(C18, 1H, dd, J¼12.1, 3.4 Hz), 3.84 (C3, 1H, dt, J¼11.5, 2.9 Hz), 3.84
(C7-OMe, 3H, s), 3.51 (C18, 1H, dd, J¼12.2, 2.1 Hz), 2.93 (C4-Hb, 1H,
dd, J¼16.5, 2.8 Hz), 2.81e2.77 (C15, 1H, m), 2.48e2.43 (C4-Ha, C14-
Ha, 2H, m), 2.26 (C14-Hb , 1H, dt, J¼14.4, 6.5 Hz), 1.92 (C6-Me, 3H, s)
ppm; 13C NMR (125 MHz, D2O, carbon signals for C6-10 are inferred
by chemical shift and comparison with analogous compounds, no
long-range carbonehydrogen correlation was conducted): 187.0
(C5), 181.5 (C8), 167.3 (C17), 155.8 (C7), 142.7 (C10), 136.5 (C9), 131.2
(C6), 89.9 (C16), 61.5 (C7-OMe), 61.0 (C18), 59.6 (C13), 58.7 (C11),
55.1 (C3), 52.2 (C1), 41.6 (C15), 31.6 (C14), 23.5 (C4), 8.7 (C6-Me)
ppm; HRMS calcd for C18H23N2O7 (MHþ) 379.1505 Da. Found
379.1535 Da.
1290, 1162, 1114 cmꢁ1 1H NMR (300 MHz, CDCl3): 7.37e7.31 (5H,
;
m), 7.27e7.18 (3H, m), 7.06e7.01 (2H, m), 6.78 (1H, br s), 5.45 (1H,
br s), 5.00e4.94 (2H, m), 4.57e4.44 (2H, m), 4.34e4.26 (2H, m),
4.08e4.03 (1H, m), 3.80 (3H, s), 3.67 (3H, s), 3.57 (1H, br s),
3.38e3.25 (2H, m), 2.94e2.78 (2H, m), 2.38e2.25 (1H, m), 2.26 (3H,
s), 2.19e1.95 (1H, m), 1.46 (9H, s) ppm; 13C NMR (75 MHz, CDCl3):
168.0, 152.2, 150.9, 150.1, 144.3, 138.2, 128.2, 128.0, 127.9, 127.8,
127.3,127.1,125.3, 125.0, 124.2, 124.1, 80.9, 74.4, 72.7, 71.2, 60.7, 60.2,
49.9, 29.5, 28.1, 25.4, 9.2 ppm; HRMS calcd for C38H46N3O8 (MHþ)
672.3285 Da. Found 672.3298 Da.
4.2.10. Diol 59. To a stirred solution of crude aldehyde 53 (156 mg,
0.238 mmol) in MeOH (5 mL) at 25 ꢂC was added Pd(OH)2 (moist,
Pd content 20%, 64 mg) and the reaction stirred under an atmo-
sphere of H2 (balloon pressure) for 4 h. The reaction mixture was
filtered through a plug of Celite, washed with MeOH, and concen-
trated under vacuum. The residue was purified by flash column
chromatography (SiO2, 50e100% EtOAcehexane, then 5% MeOH
in EtOAc) to afford diol 59 (64 mg, 79% yield from cyclization) as
a colorless foam: Rf¼0.20 (100% EtOAc in hexanes); IR (thin
film): 3384, 2937, 1700, 1684, 1653, 1472, 1417, 1368, 1162, 1115,
1055 cmꢁ1; 1H NMR (300 MHz, CDCl3): 9.74 (1H, s), 5.93 (1H, br s),
5.63 (1H, t, J¼4.3 Hz), 4.74 (1H, s), 4.67 (1H, br s), 3.97 (1H, dd,
J¼11.1, 3.6 Hz), 3.78 (3H, s), 3.68 (3H, s), 3.66e3.60 (1H, m), 3.33
(1H, t, J¼8.0 Hz), 3.07 (1H, dd, J¼14.7, 2.2 Hz), 2.61 (1H, dd, J¼14.4,
6.8 Hz), 2.57e2.47 (1H, m), 2.41e2.37 (1H, m), 2.24 (3H, s), 2.21 (1H,
m), 1.43 (9H, s) ppm; HRMS calcd for C24H33N2O8 (MHþ)
477.2237 Da. Found 477.2219 Da.
4.3. Synthesis of ( )-renieramycin G 3
4.3.1. Benzyl chloride 62. To a refluxing suspension of commercially
available 2,4-dimethoxy-3-methylbenzaldehyde 61 (11.6 g,
64.5 mmol) and zinc chloride (9.3 g, 68.2 mmol) in 37% aq form-
aldehyde (26 mL) was bubbled HCl gas for 90 min. The reaction
solution became homogeneous and dark orange in color. The re-
action was cooled to 25 ꢂC, poured over ice, and extracted with
Et2O (3ꢃ100 mL). The organic extracts were combined, washed
with aq NaHCO3 (3ꢃ50 mL), satd aq NaCl (100 mL), dried (Na2SO4),
filtered, and concentrated under vacuum. The resulting brown
oil was purified by flash column chromatography (SiO2, 5e15%
EtOAcehexane) to afford the benzyl chloride (10.8 g, 73% yield) as
a white solid: Rf¼0.41 (20% EtOAc in hexanes); mp 67e68 ꢂC; IR
(thin film): 2946, 2854, 1682, 1595, 1472, 1472, 1417, 1390, 1307,
1268, 1244, 1187, 1112,1001 cmꢁ1; 1H NMR (300 MHz, CDCl3): 10.29
(1H, s), 7.79 (1H, s), 4.63 (2H, s), 3.92 (3H, s), 3.90 (3H, s), 2.28 (3H,
4.2.11. Amine 60. To
a stirred solution of diol 59 (40 mg,
0.084 mmol) in MeOH (1.0 mL) at 0 ꢂC was added 6 M HCl (1/1

6358
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
s) ppm; 13C NMR (75 MHz, CDCl3): 188.7, 163.1, 128.4, 127.7, 125.9,
125.5, 63.1, 61.3, 40.6, 9.26 ppm; HRMS calcd for C11H14O3Cl (MHþ)
229.0631 Da. Found 229.0637 Da.
2936, 1701, 1668, 1479, 1449, 1368, 1306, 1162, 1064, 1011, 907,
733 cmꢁ1 1H NMR (300 MHz, CDCl3), pronounced carbamate res-
;
onance was observed giving sharp signals in ratio of 1/2 (high
temperature NMR [100 ꢂC] led to decomposition): 7.66e7.53 (4H,
m), 7.44e7.06 (26H, m), 6.20 (0.3H, s), 6.11 (0.7H, s), 6.02 (0.3H, t,
J¼6.2 Hz), 5.97 (0.7H, t, J¼6.2 Hz) 5.26 (0.3H, s), 5.17 (0.3H, s), 5.13
(1.4H, s), 5.06 (1H, t, J¼5.2 Hz), 4.53e4.46 (2.3H, m), 4.37 (0.7H, m),
3.86e3.65 (2.0H, m), 3.80 (2.3H, s), 3.76 (0.7H, s), 3.59 (2.3H, s), 3.54
(0.7H, s), 3.48 (0.7H, s), 3.42 (2.3H, s), 3.36 (3H, s), 3.06e2.76 (3H,
m), 2.55e2.25 (2H, m), 2.22 (0.7H, s), 2.20 (2.3H, s), 1.53 (0.7H, s),
1.49 (2.3H, s), 1.31 (6.3H, s), 1.17 (2.7H, s) ppm; 13C NMR (75 MHz,
CDCl3): 167.9, 153.2, 152.5, 152.2, 150.9, 150.6, 150.0, 145.1, 144.1,
138.6, 137.7, 134.5, 131.4, 129.5, 129.0, 128.8, 128.6, 128.3, 128.1,
128.0, 127.7, 127.4, 127.3, 127.1, 126.8, 126.7, 123.9, 123.2, 122.7,
122.3, 91.3, 81.0, 80.7, 74.3, 72.3, 72.2, 72.0, 69.0, 68.7, 60.5, 60.4,
60.3, 60.2, 60.1, 60.0, 59.0, 58.6, 54.8, 54.7, 48.3, 33.3, 32.3, 28.1, 27.6,
24.9, 24.2, 9.1, 8.9 ppm; HRMS calcd for C70H73N2O10S (MHþ)
1133.4986 Da. Found 1133.4980 Da.
4.3.2. Formate ester 62. To a stirred solution of the above benzyl
chloride (4.0 g, 17.5 mmol) in CH2Cl2 (35 mL) at 0 ꢂC was added m-
CPBA (77% max, 6.6 g, 29.7 mmol max) in small portions. The re-
action was warmed to 25 ꢂC and stirred for 3 h. The reaction was
treated with satd aq NaHCO3 and extracted with CH2Cl2 (3ꢃ40 mL).
The combined organic extracts were dried (Na2SO4), filtered, and
concentrated under vacuum to afford the formate ester 62 (4.1 g,
96% yield) as a yellow oil: Rf¼0.44 (20% EtOAc in hexanes); IR (thin
film): 2944, 2831, 1747, 1484, 1457, 1417, 1319, 1243, 1218, 1100,
1005 cmꢁ1 1H NMR (300 MHz, CDCl3): 8.27 (1H, s), 7.04 (1H, s),
;
4.60 (2H, s), 3.82 (3H, s), 3.75 (3H, s), 2.25 (3H, s) ppm; 13C NMR
(75 MHz, CDCl3): 159.0, 155.4, 139.1, 126.8, 126.6, 121.3, 61.3, 60.5,
40.4, 9.7 ppm; HRMS calcd for C11H14O4Cl (MHþ) 245.0581 Da.
Found 245.0575 Da.
4.3.3. Trityl ether 63. To a stirred solution of the formate ester 62
(4.1 g, 16.7 mmol) in THF (94 mL) at 0 ꢂC was added LiBH4 (0.36 g,
16.7 mmol) in small portions. After 10 min analysis by TLC showed
that starting material was consumed. The reaction was treated with
aq 1 N HCl (50 mL) and extracted with EtOAc (1ꢃ150 mL, 2ꢃ50 mL).
The combined extracts were washed with satd aq NaCl (50 mL),
dried (Na2SO4), filtered, and concentrated under vacuum to afford
the phenol as an unstable orange oil. Rf¼0.22 (20% EtOAc in hex-
anes); IR (thin film): 3405, 2942, 2834, 1596, 1485, 1457, 1418, 1346,
1307, 1248, 1197, 1114, 1049, 1005 cmꢁ1; 1H NMR (300 MHz, CDCl3):
6.85 (1H, s), 5.58 (1H, br s), 4.60 (2H, s), 3.80 (3H, s), 3.79 (3H, s),
2.26 (3H, s) ppm; 13C NMR (75 MHz, CDCl3): 150.2, 146.1, 145.2,
129.5, 127.7, 126.7, 113.9, 61.4, 60.6, 41.1, 9.6 ppm; HRMS calcd for
C10H14O3Cl (MHþ) 217.0631 Da. Found 217.0629 Da.
4.3.5. Phenol 65. To a degassed solution (freeze/pump/thaw) of 64
(0.09 g, 0.080 mmol) in THF (1.2 mL) at ꢁ78 ꢂC was added t-BuLi
(1.1 M in pentane, 0.18 mL, 0.20 mmol). Upon complete addition the
solution became deep orange/brown in color. After 10 s a degassed
solution (freeze/pump/thaw) of butylated hydroxytoluene (0.103 g,
0.466 mmol) in THF was added in one portion. The brown color
faded to pale yellow. To the reaction mixture was added anhydrous
HCl (1.0 M in Et2O, 1.0 mL). The solution was warmed to 0 ꢂC and
added HCl in small portions over 1 h until the trityl ether could not
be detected by TLC. The solution was diluted with satd aq NaHCO3
(10 mL) and extracted with EtOAc (2ꢃ15 mL). The combined ex-
tracts were washed with satd aq NaCl (15 mL), dried (Na2SO4), fil-
tered, and concentrated under vacuum. The resulting yellow
residue was purified by flash column chromatography (SiO2, slow
gradient, 10e25% EtOAcehexane) to afford phenol 65 (0.052 g, 73%
yield) as a colorless oil: Rf¼0.26 (30% EtOAc in hexanes); IR (thin
film): 3395, 2936, 2863, 1686, 1653, 1456, 1417, 1385, 1334, 1255,
1162, 1115, 1009, 735 cmꢁ1; 1H NMR (300 MHz, CDCl3): 7.56 (2H, d,
J¼7.6 Hz), 7.40e7.17 (13H, m), 6.64 (0.2H, s), 6.34 (0.8H, s), 6.04 (0.8,
s), 5.86 (0.2H, s), 5.86e5.81 (1H, m), 5.03 (2H, s), 5.01e4.93 (1H, m),
4.80 (1H, dd, J¼8.8, 3.4 Hz), 4.54 (2H, s), 3.90e3.45 (4H, m), 3.84
(3H, s), 3.74 (6H, s), 3.63 (3H, s), 3.21e3.00 (3H, m), 2.26 (3H, s), 2.22
(3H, s), 1.28 (2.3H, s), 1.12 (6.7H, s) ppm; 13C NMR (75 MHz, CDCl3):
167.4, 153.5, 151.0, 150.5, 150.3, 144.5, 144.4, 143.9, 138.5, 137.0,
134.0, 131.9, 129.6, 129.1, 128.9, 128.6, 128.4, 128.3, 128.1, 127.8,
127.7, 127.5, 127.2, 127.0, 126.6, 124.4, 123.8, 123.7, 123.5, 114.7, 114.2,
81.1, 74.4, 72.3, 65.2, 61.3, 60.8, 60.3, 60.2, 58.0, 57.5, 56.3, 49.9,
49.5, 35.3, 34.7, 27.7, 27.4, 26.8, 9.6, 9.2 ppm; HRMS calcd for
C51H59N2O10S (MHþ) 891.3890 Da. Found 891.3887 Da.
To solution of the phenol (3.8 g, 16.7 mmol) and triethylamine
(7.0 mL, 50.1 mmol) in CH2Cl2 (90 mL) at 25 ꢂC was added trityl-
chloride (4.7 g, 16.7 mmol). The reaction was stirred for 2 h then
quenched with satd aq NaHCO3 (100 mL) and extracted with EtOAc
(1ꢃ150 mL, 2ꢃ50 mL). The combined extracts were washed with
satd aq NaCl (50 mL), dried (Na2SO4), filtered, and concentrated
under vacuum. The brown residue was purified by flash column
chromatography (SiO2, slow gradient 0e10% EtOAcehexane) to
afford benzyl chloride 63 (3.89 g, 51% yield over three steps) as
a white solid. Approximately 20% decomposition was observed
when stored under argon in the dark at room temperature for 2
weeks. Rf¼0.46 (20% EtOAc in hexanes); recrystallized from
EtOAcehexanes, mp 136e140 ꢂC; IR (thin film): 3059, 3024, 2932,
2853, 1596, 1483, 1448, 1418, 1230, 1116, 1064, 1010, 905, 701 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.48 (6H, d, J¼6.9 Hz), 7.31e7.20 (9H,
m), 6.35 (1H, s), 4.26 (2H, s), 3.87 (3H, s), 3.68 (3H, s), 2.13 (3H, s)
ppm; 13C NMR (75 MHz, CDCl3): 150.8, 145.3, 143.7, 128.6, 127.5,
127.0, 125.0, 124.0, 120.1, 90.9, 61.2, 60.3, 41.2, 9.4 ppm; HRMS calcd
for C29H26O3Cl (MꢁHþ) 457.1570 Da. Found 457.1569 Da.
4.3.6. Methylamine 67. To a stirred solution of phenol 65 (0.20 g,
0.224 mmol) in dry chlorobenzene (7.5 mL) at 25 ꢂC was added
AgBF4 (0.93 mL of a solution of 1.0 g AgBF4 in 2.8 mL of PhCl). A
precipitate formed and the solution remained pale yellow in color.
The reaction was complete upon first TLC analysis (within 5 min).
After 10 min the reaction mixture was diluted with 20% aq
Rochelle’s salt (25 mL) and extracted with EtOAc (3ꢃ20 mL). The
combined extracts were washed with satd aq NaCl (20 mL), dried
(Na2SO4), filtered, and concentrated under vacuum to give crude
66. The yellow crude residue of 66 was dissolved in MeOH (16 mL),
37% aq formaldehyde (1.2 mL), sodium cyanoborohydride (0.282 g,
4.48 mmol), and acetic acid (4.0 mL) were added. The yellow so-
lution became colorless. After 40 min the solution was concen-
trated under vacuum, the resultant residue treated with satd aq
NaHCO3 (25 mL) and extracted with EtOAc (3ꢃ25 mL). The com-
bined extracts were washed with satd aq NaCl (20 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The pale yellow
4.3.4. Alkylated product 64. To a degassed solution (freeze/pump/
thaw) of thioaminal 46 (0.38 g, 0.54 mmol), benzyl chloride 63
(0.30 g, 0.65 mmol), and 18-crown-6 (0.16 g, 0.59 mmol) in THF
(4.15 mL) at ꢁ78 ꢂC was added KHMDS (0.5 M in toluene, 1.3 mL,
0.65 mmol) dropwise within 2 min. The reaction became orange
and remained clear. After 20 min no starting material was observed
by TLC analysis. The reaction was quenched with satd aq NaHCO3
(25 mL) and extracted with EtOAc (3ꢃ25 mL). The combined ex-
tracts were washed with satd aq NaCl (25 mL), dried (Na2SO4),
filtered, and concentrated under vacuum. The yellow oil was pu-
rified by flash column chromatography (SiO2, 15e25%
EtOAcehexane) to afford alkylated product 64 (0.595 g, 98% yield)
as a colorless foam: Rf¼0.35 (30% EtOAc in hexanes); IR (thin film):

P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
6359
residue was purified by flash column chromatography (SiO2 treated
with triethylamine, 50e100% EtOAc in hexanes) to afford methyl-
amine 67 (0.101 g, 65% yield over two steps) as a pale yellow oil:
Rf¼0.27 (100% EtOAc in hexanes); IR (thin film): 3319, 2986, 2937,
added ammonium cerium(IV) nitrate (0.369 g, 0.674 mmol) as
a solution in water (0.2 mL), pre-cooled to 0 ꢂC. The orange/brown
solution was stirred for 15 min as the temperature rose to ꢁ5 ꢂC.
The solution was diluted with CHCl3 (15 mL) and 5% aq NaHCO3
(5 mL), aqueous layer extracted with CHCl3 (2ꢃ10 mL). The com-
bined organic extracts were washed with satd aq NaCl (5 mL),
dried (Na2SO4), filtered, and concentrated under vacuum. The
brown residue was purified by flash column chromatography (SiO2
treated with triethylamine, 50e100% EtOAc in hexanes) to afford
bisisquinolinequinone 70 (0.036 g, 55% yield) as a burnt orange
residue; Rf¼0.35 (5% MeOH in EtOAc); IR (thin film): 3365, 2925,
2869,1635,1455,1412,1361,1302,1257,1109,1058,1008, 753 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 7.44e7.27 (5H, m), 7.11e7.08 (3H, m),
6.80e6.77 (2H, m), 5.92 (1H, ArOH, s), 5.75 (1H, t, J¼3.1 Hz), 5.06
(1H, d, J¼11.0 Hz), 4.97 (1H, d, J¼11.0 Hz), 4.31 (1H, d, J¼3.0 Hz),
4.04 (1H, d, J¼12.1 Hz), 3.98 (1H, d, J¼12.2 Hz), 3.91e3.83 (1H, m),
3.80 (3H, s), 3.72e3.67 (2H, m), 3.64 (3H, s), 3.59 (3H, s), 3.58 (3H,
s), 3.43e3.38 (2H, m), 3.14 (1H, dd, J¼6.7, 18.1 Hz), 2.98 (1H, d,
J¼18.0 Hz), 2.46 (3H, s), 2.33 (1H, dd, J¼12.9, 15.0 Hz), 2.23 (3H, s),
2.15 (3H, s) ppm; 13C NMR (75 MHz, CDCl3): 170.4, 151.0, 149.9,
149.3, 144.6, 143.4, 142.9, 138.4, 137.2, 128.2, 128.0, 127.8, 127.7,
127.6, 126.6, 126.5, 126.2, 126.1, 123.8, 122.7, 116.4, 74.4, 72.5, 71.9,
60.5, 60.1, 59.8, 59.2, 57.0, 55.0, 49.6, 40.1, 25.8, 24.6, 9.4, 9.2 ppm;
HRMS calcd for C41H47N2O8 (MHþ) 695.3332 Da. Found
695.3337 Da.
2853, 1653, 1617, 1429, 1307, 1232, 1150 cmꢁ1 1H NMR (500 MHz,
;
CD2Cl2): 5.23 (C1,1H, dd, J¼4.0, 1.4 Hz), 4.14 (C11,1H, br s), 3.98 (C7/
17-OMe, 3H, s), 3.97 (C7/17-OMe, 3H, s), 3.89 (C3, 1H, br d,
J¼11.4 Hz), 3.73 (C22, 1H, dd, J¼11.0, 3.5 Hz), 3.68 (C13, 1H, d,
J¼6.7 Hz), 3.43 (C22, 1H, dd, J¼11.2, 4.1 Hz), 3.05 (C4-Hb, 1H, dd,
J¼16.4, 2.6 Hz), 2.88 (C14-Hb, 1H, dd, J¼20.7, 6.8 Hz), 2.66 (C14-Ha,
1H, br d, J¼20.6 Hz), 2.65 (OH, 1H, br s), 2.00 (NMe, 3H, s), 1.95 (C6/
16-Me, 3H, s), 1.94 (C6/16-Me, 3H, s), 1.68 (C4-Ha, 1H, ddd, J¼16.3,
12.3, 1.3 Hz) ppm; 13C NMR (125 MHz, CD2Cl2): 186.8 (C15), 185.7
(C5), 182.7 (C18), 181.2 (C8), 171.2 (C21), 156.0 (C17), 155.9 (C7),
142.3 (C20/10), 142.2 (C20/10), 137.1 (C9), 135.2 (C19), 129.7 (C6/
C16), 129.2 (C6/C16), 65.6 (C22), 61.3 (C7 and C17-OMe), 59.2 (C13),
57.0 (C3), 53.4 (C11), 52.4 (C1), 39.9 (NMe), 25.8 (C4), 24.3 (C14), 8.9
(C6 and C16-Me) ppm; HRMS calcd for C25H27N2O8 (MHþ)
483.1767 Da. Found 483.1786 Da.
4.3.7. Monobenzylether 68. To
a solution of methylamine 67
(0.31 g, 0.446 mmol) in MeOH (9.0 mL) at 25 ꢂC was added Pd(OH)2
(moist, Pd content 20%, 62 mg) and the reaction was stirred under
an atmosphere of H2 (balloon pressure) for 1 h. The reaction mix-
ture was filtered through a plug of Celite, washed with MeOH, and
concentrated under vacuum. The pale yellow residue was purified
by flash column chromatography (SiO2 treated with triethylamine,
75e100% EtOAc in hexanes then 2% MeOH in EtOAc) to afford
monobenzylether 68 (0.229 g, 85% yield) as a fine white solid:
recrystallized from MeOH with slow diffusion of EtOAc; X-ray
(CCDC 288717); mp 209e211 ꢂC (dec); Rf¼0.45 (6% MeOH in
EtOAc); IR (thin film): 3326, 2938, 2870, 1635, 1464, 1414, 1362,
4.3.10. (ꢀ)-Renieramycin G 3. To a solution of alcohol 70 (6 mg,
0.012 mmol) in CH2Cl2 (0.30 mL) at 25 ꢂC was added angeloyl
chloride33 (approx. 15
mL, 0.120 mmol) and the solution was
allowed to stand for 24 h at 25 ꢂC in the dark. The solution was
concentrated under vacuum then purified by reverse phase HPLC
(preparatory column, rate¼8.0 mL/min, gradient¼65e30% H2O
without TFA in CH3CN without TFA over 20 min, then to 0% H2O
over next 10 min, injection volume¼1.0 mL, product elution from
23 to 24 min) and lyophilized to afford (ꢀ)-renieramycin G 3
(5 mg, 74% yield) as an orange residue: Rf¼0.25 (100% EtOAc); IR
(thin film): 2929, 2854, 1717, 1655, 1616, 1420, 1373, 1351, 1307,
1263, 1229, 1149, 1120 cmꢁ1; Renieramcyin G was originally
characterized in CD2Cl2, however trace amounts of CH2Cl2 and
water made NMR interpretation difficult. C6D6 proved to be
a better solvent for analysis of all signals without overlap or dis-
tortion. 1H NMR (500 MHz, C6D6): 5.56 (C1, 1H, d, J¼2.2 Hz), 5.34
(C26, 1H, q of q, J¼7.3, 1.4 Hz), 4.92 (C22, 1H, dd, J¼11.6, 2.4 Hz),
4.52 (C22, 1H, dd, J¼11.7, 2.3 Hz), 3.82 (C11, 1H, d, J¼3.5 Hz), 3.79
(C7-OMe, 3H, s), 3.62 (C17-OMe, 3H, s), 3.47 (C13, 1H, d, J¼7.2 Hz),
3.36 (C3, ddd, J¼12.3, 3.2, 3.0 Hz), 3.10 (C4-Hb, 1H, dd, J¼16.5,
2.7 Hz), 2.87 (C14-Ha, 1H, d, J¼20.9 Hz), 2.59 (C14-Hb, 1H, dd,
J¼20.5, 7.0 Hz), 1.90 (C6-Me, 3H, s), 1.87 (C16-Me, 3H, s), 1.80
(NMe, 3H, s), 1.55 (C26-Me, 3H, dq, J¼7.3, 1.5 Hz), 1.51 (C4-Ha, 1H,
ddd, J¼16.7, 12.2, 2.0 Hz), 1.37 (C25-Me, 3H, dq, J¼1.6, 1.4 Hz) ppm;
13C NMR (125 MHz, C6D6): 185.9 (C15), 185.0 (C5), 182.7 (C18),
180.4 (C8), 169.9 (21), 166.8 (C24), 156.4 (C7), 155.5 (C17), 142.2
(C20), 141.1 (C10), 139.1 (C26), 136.3 (C9), 135.1 (C19), 128.8 (C16),
127.4 (C6), 126.9 (C25), 62.8 (C22), 60.6 (C7-OMe), 60.5 (C17-OMe),
59.3 (C13), 56.0 (C3), 53.3 (C11), 50.8 (C1), 39.3 (NMe), 25.9 (C4),
23.6 (C14), 20.3 (C25-Me), 15.3 (C26-Me), 8.6 (C16-Me and C6-Me)
ppm; HRMS calcd for C30H33N2O9 (MHþ) 565.2186 Da. Found
565.2203 Da.
1302, 1273, 1193, 1109, 1059, 1006, 910 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): 7.19e7.12 (3H, m), 6.91e6.88 (2H, m), 6.04 (1H, s), 5.77 (2H,
br s), 4.33 (1H, s), 4.20 (1H, d, J¼12.1 Hz), 4.11 (1H, d, J¼12.1 Hz),
4.01e3.96 (1H, m), 3.76 (3H, s), 3.74e3.68 (1H, m), 3.64e3.58 (1H,
m), 3.63 (3H, s), 3.62 (3H, s), 3.59 (3H, s), 3.49e3.40 (1H, m), 3.14
(1H, dd, J¼18.1, 6.8 Hz), 2.99 (1H, d, J¼18.0 Hz), 2.48 (3H, s),
2.27e2.20 (1H, m), 2.22 (3H, s), 2.17 (3H, s) ppm; 13C NMR (75 MHz,
CDCl3): 149.3, 148.1, 144.4, 143.4, 142.9, 142.1, 138.0, 127.8, 126.9,
126.6, 125.3, 122.6, 119.6, 77.0, 72.8, 71.7, 60.6, 60.5, 59.8, 59.3, 57.1,
55.0, 49.4, 40.0, 25.6, 24.5, 9.4 ppm; HRMS calcd for C34H41N2O8
(MHþ) 605.2863 Da. Found 605.2864 Da.
4.3.8. Triol 69. To
a
solution of methylamine 67 (0.10 g,
0.144 mmol) in MeOH (2.9 mL) at 25 ꢂC was added Pd(OH)2 (moist,
Pd content 20%, 45 mg), and the reaction was stirred under an at-
mosphere of H2 (balloon pressure) for 6 h. The reaction mixture
was filtered through a plug of Celite, washed with MeOH, and
concentrated under vacuum. The pale yellow residue was purified
by flash column chromatography (SiO2 treated with triethylamine,
75e100% EtOAc in hexanes then 5% MeOH in EtOAc) to afford the
triol 69 (0.073 g, 94% yield) as a fine white solid: Rf¼0.36 (6% MeOH
in EtOAc); IR (thin film): 3333, 2937, 1634, 1463, 1413, 1362, 1302,
1272, 1192, 1110, 1060, 1005 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
;
8.74 (1H, s), 8.48 (1H, s), 5.45 (1H, t, J¼4.9 Hz), 4.26 (1H, br s), 4.19
(1H, d, J¼3.2 Hz), 3.71 (1H, dt, J¼12.7, 2.7 Hz), 3.58 (6H, s), 3.54 (3H,
s), 3.53 (3H, s), 3.53e3.51 (1H, m), 3.28 (1H, d, J¼15.3 Hz), 3.17 (1H,
m), 2.96 (2H, m), 2.63 (1H, d, J¼17.6 Hz), 2.28 (3H, s), 2.09 (3H, s),
2.08 (3H, s), 2.01 (1H, dd, J¼15.0, 13.0 Hz) ppm; 13C NMR (75 MHz,
DMSO-d6): 170.7, 148.3, 147.4, 144.7, 144.1, 144.0, 143.2, 125.7, 122.5,
122.3, 122.1, 120.4, 117.6, 63.7, 60.8, 60.2, 59.7, 59.0, 57.8, 54.8, 50.5,
39.0, 25.6, 24.2, 9.6 ppm; HRMS calcd for C27H35N2O8 (MHþ)
515.2393 Da. Found 515.2394 Da.
Acknowledgements
The National Institutes of Health (GM 32721) and the Welch
Chair (F-0018) are thanked for their support of this research. Vince
Lynch is thanked (University of Texas, Austin) for X-ray structure
determinations.
4.3.9. Bis-isoquinolinequinone 70. To a solution of the triol 69
(73 mg, 0.135 mmol) in dry acetonitrile (5.0 mL) at ꢁ15 ꢂC was

6360
P. Magnus, K.S. Matthews / Tetrahedron 68 (2012) 6343e6360
13. (a) Quinoncarcin: Danishefsky, S. J.; Harrison, P. J.; Webb, R. R., II; O’Neill, B. T. J.
References and notes
Am. Chem. Soc. 1985, 107, 1421; (b) Renieramycin: Williams, R. M.; Lane, J. W.;
Chen, Y. J. Am. Chem. Soc. 2005, 127, 12684; (c) Saframycin: Kubo, A.; Saito, N.;
Yamato, H.; Masubuchi, K.; Nakamura, M. J. Org. Chem. 1988, 53, 4295.
14. Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181.
15. Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 2117; For more details
on the enantioselective alkylation of isoquinolines and quinolines see: Amiot, F.
Ph.D. Thesis #3366, University of Geneva, Geneva, Switzerland.
16. Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097.
1. The chemistry and biology of tetrahydroisoquinoline alkaloids has been exten-
sively reviewed in following: (a) Williams, R. M.; Scott, J. D. Chem. Rev. 2002, 102,
1669; (b) Kubo, A.; Arai, T. In The Alkaloids; Brossi, A., Ed.; Academic: New York,
NY, 1983; Vol. 21, p 55; (c) Remers, W. A. The Chemistry of Antitumor Antibiotics;
Wiley: New York, NY, 1988; Vol. 2; p 93; (d) Remers, W. A. The Chemistry of An-
titumor Antibiotics; Wiley: New York, NY, 1988; Vol. 2; p 120; (e) Arai, T. In Journal
of Chromatography Library: Natural Product Isolation; Wagman, G. H., Cooper, R.,
Eds.; Elsevier: New York, NY, 1989; Vol. 43, p 191; (f) Kubo, A.; Saito, N. Studies in
Natural Products Chemistry; Elsevier: New York, NY, 1992; Vol. 10; p 77; (g) Fu-
kuyama, T. Adv. Heterocycl. Nat. Prod. Synth. 1992, 2, 189; (h) Katoh, T.; Terashima,
S. Studies in Natural Products Chemistry; Elseveir: New York, NY, 1997; Vol. 19; p
289; (i) Ozturk, T. In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 2000;
Vol. 53, p 119; (j) Rinehart, K. L. Med. Res. Rev. 2000, 20, 1.
17. Kaufman, T. S. Synlett 1997, 6464.
18. Larock, R. C.; Roesch, K. R. J. Org. Chem. 2002, 67, 86.
19. Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313; Castro, C. E.; Havlin, R.;
Honwad, V. K.; Malte, A. M.; Moje, S. W. J. Am. Chem. Soc. 1969, 91, 6464.
20. Larock reported that 3-hydroxymethylisoquinoline could not be synthesized
using his isoquinoline conditions when propargyl alcohol was used (Table 3,
entry 5 in Ref. 18).
21. For more information about reductions of enecarbamates using TFAeEt3SiH
see: Molinski, T. F.; Masuno, M. N. Tetrahedron Lett. 2001, 42, 8263 These con-
ditions were not successful in the reduction of eneamides.
22. A similar 3-methyl by-product was observed in the ionic hydrogenation per-
formed in Ref. 14.
23. Fukumoto, K.; Sukegawa, Y.; Kametani, T.; Shishido, K. Heterocycles 1986, 24,
641; Hu, L.; Yu, C. Tetrahedron Lett. 2001, 42, 5167.
2. (a) Kluepfel, D.; Baker, H. A.; Piattoni, G.; Sehgal, S. N.; Sidorowicz, A.; Singh, K.;
ꢀ
Vezina, C. J. Antibiot. 1975, 28, 497; (b) Davidson, B. S. Tetrahedron Lett. 1992, 33,
3721; (c) Original isolation: Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.;
Kieffer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512;
Structural revision: Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Kieffer,
P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1991, 56, 1676; (d) Arai, T.;
Takahashi, K.; Kubo, A. J. Antibiot. 1977, 30, 1015; (e) Tomita, F.; Takahashi, K.;
Shimizu, K. J. Antibiot. 1983, 36, 463.
24. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431; Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817.
€
3. (a) Schoffski, P.; Wolter, P.; Clement, P.; Sciot, R.; Wever, I. D.; Wozniak, A.;
Stefan, C.; Dumez, H. Future Oncol. 2007, 3, 381; (b) Carter, N. J.; Keam, S. J.
Drugs 2007, 67, 2257.
25. Davies, S. G.; Bull, S. D.; Epstein, S. W.; Ouzman, J. V. A. Tetrahedron: Asymmetry
1998, 9, 2795; Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566.
26. Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311; Hiemstra, H.;
Veerman, J. J. N.; Bon, R. S.; Hue, B. T. B.; Girones, D.; Rutjes, F. P. J. T.; van
Maarseveen, J. H. J. Org. Chem. 2003, 68, 4486 and references therein.
27. Speckamp, W. N.; Hiemstra, H.; Vijn, R. J. J. Org. Chem. 1988, 53, 3882.
28. Myers, A. G.; Kwon, S. J. Am. Chem. Soc. 2005, 127, 16796.
29. Fukuyama, T.; Nunes, J. J. J. Am. Chem. Soc. 1988, 110, 5196.
30. Morschel, H.; Lohmar, W. (Farbenfabriken Bayer A.G.) 1961, DE 1120139,
19611221.
4. Sygusch, J.; Brisse, F.; Hanessian, S.; Kluepfel, D. Tetrahedron Lett. 1974, 15, 4021.
5. Fukuyama, T.; Schleben, R. A. J. Am. Chem. Soc. 1982, 104, 4975.
6. (a) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202; (b) Endo,
A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc.
2002, 124, 6552; (c) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc.
2006, 128, 87.
ꢀ
7. Echavarren, A. M.; Ceballos, P. A.; Cuevas, C.; Perez, M.; Francesch, A.; Man-
zanares, I. Eur. J. Org. Chem. 2006, 8, 1926 and references therein.
8. He, H.; Shen, B.; Carter, G. T. Tetrahedron Lett. 2000, 41, 2067.
9. This work was first published as a communication: Magnus, P.; Matthews, K. S.
J. Am. Chem. Soc. 2005, 127, 12476.
10. (a) Fukuyama, T.; Rikimaru, K.; Mori, K.; Kan, T. Chem. Commun. 2005, 394; (b)
Myers, A. G.; Kung, D. W. J. Am. Chem. Soc. 1999, 121, 10828.
11. (a) Danishefsky, S. J.; Guo, J.; Zhou, B. Tetrahedron Lett. 2000, 41, 2043; (b)
Danishefsky, S. J.; Chan, C.; Zheng, S.; Zhou, B.; Guo, J.; Heid, R. M.; Wright, B. J.
D. Angew. Chem., Int. Ed. 2006, 45, 1749.
ꢀ
31. Greene, A. E.; Hartmann, B.; Kanazawa, A. M.; Depres, J.-P. Tetrahedron Lett.
1991, 32, 5077.
32. Joseph-Nathan, P.; Torres-Valencia, J. M.; Cerda-Garcia-Rojas, C. M. Tetrahedron:
Asymmetry 1998, 9, 757.
33. Beeby, P. J. Tetrahedron Lett. 1977, 38, 3379.
34. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.;
Pergamon: New York, NY, 1993.
12. Danishefsky, S. J.; Harrison, P. J.; Webb, R. R., II; O’Neill, B. T. J. Am. Chem. Soc.
1985, 107, 1421.
35. Kaufman, T. S. Synlett 1997, 1377; Lett 1992, 33, 3721.