Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids via Copper-Catalyzed Thiolane Assembly

Article abstract of DOI:10.1021/jacs.7b07685

An asymmetric total synthesis of (+)-6-hydroxythiobinupharidine (1b) and (-)-6-hydroxythionuphlutine (2b), a set of hemiaminal containing dimeric sesquiterpenes isolated from yellow water lilies of the Nuphar genus, is described. The central bis-spirocyclic tetrahydrothiophene ring was forged through the Stevens rearrangement of a sulfonium ylide, generated in situ from the coupling of a copper-carbene with a spirocyclic thietane. This strategy diverges both from the proposed biosynthesis1 and previous syntheses of this family of alkaloids,2,3 all of which employ dimerization of symmetric monomers to form the aforementioned thiaspirane. The coupling of unsymmetrical monomers allowed access to the unsymmetrically oxidized product 2b for the first time.

Full text of DOI:10.1021/jacs.7b07685

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Communication
Total Synthesis of Unsymmetrically Oxidized Nuphar
Thioalkaloids via Copper-Catalyzed Thiolane Assembly
Jacob J. Lacharity, Jeremy Fournier, Ping Lu, Artur K. Mailyan, Aaron T Herrmann, and Armen Zakarian
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07685 • Publication Date (Web): 15 Sep 2017
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Total Synthesis of Unsymmetrically Oxidized Nuphar Thio-
alkaloids via Copper-Catalyzed Thiolane Assembly
Jacob J. Lacharity, Jeremy Fournier, Ping Lu,# Artur K. Mailyan, Aaron T. Herrmann,† Armen Zakarian
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§
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,‡
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
Supporting Information Placeholder
(2b) strongly inhibited nuclear factor κB (NFκB).13 Additionally, these
ABSTRACT: An asymmetric total synthesis of (+)-6-
extracts were shown to work synergistically with cisplatin and etopo-
side, demonstrating a potential for Nuphar alkaloids to act as sensitizers
in chemotherapy.
hydroxythiobinupharidine (1b) and (−)-6-Hydroxythionuphlutine
(2b), a set of hemi-aminal containing dimeric sesquiterpenes isolated
from yellow water lilies of the Nuphar genus, is described. The central
bis-spirocyclic tetrahydrothiophene ring was forged through the Ste-
vens rearrangement of a sulfonium ylide, generated in-situ from the
coupling of a copper-carbene with a spirocyclic thietane. This strategy
diverges both from the proposed biosynthesis1 and previous syntheses
of this family of alkaloids,2,3 all of which employ dimerization of sym-
metric monomers to form the aforementioned thiaspirane. The cou-
pling of unsymmetrical monomers allowed access to the unsymmetri-
cally oxidized product 2b for the first time.
Nupharidine Series
Nuphlutine Series
O
O
O
X
S
Y
H
X
N
H
6
N
S
6'
6'
N
N
H
6
Y
H
O
X,Y = OH:
X,Y = OH:
(+)-6,6'-dihydroxythiobinupharidine (1a)
(−)-6,6'-dihydroxythionuphlutine (2a)
X = OH, Y = H:
X = OH, Y = H:
The unusual bis(spirothiolane) structural signature of Nuphar alka-
loids has incited innovative synthetic studies over the past two dec-
ades.4 This series of dimeric sesquiterpenes was first isolated from the
yellow water lily Nuphar lutea by Achmatowicz in 1964,5 and the struc-
ture of neothiobinupharidine (3c) was determined by Birnbaum in
1965 using X-ray crystallography.6 Over the following decade, exten-
sive structural studies by LaLonde conclusively characterized a number
of alkaloids belonging to the thiobinupharidine, thionuphlutine, and
neothiobinupharidine series, particularly those containing hemiaminal
groups (Figure 1).7 Early investigations of the antifungal and antibac-
terial activity of these compounds were somewhat disappointing.8
However, recent reports by Yoshikawa in the early 2000s rekindled
interest in the biological activity of these natural products. Seminal
publications showed that (+)-6,6´-dihydroxythiobinupharidine (1a),
(+)-6-hydroxythiobinupharidine (1b), (−)-6-hydroxythionuphlutine
(2b), and (+)-6´-hydroxythionuphlutine (2d) displayed significant
immunosuppressive activity in mouse splenocytes at 1 µM concentra-
tion.9,10 Remarkably, the mono-hydroxylated alkaloids 1b, 2b, and 2d
were not cytotoxic at this concentration, while (+)-6,6´-
dihydroxythiobinupharidine (1a) showed minor cytotoxicity. Further
studies by the same group demonstrated that (+)-6,6´-
dihydroxythiobinupharidine (1a), (+)-6-hydroxythiobinupharidine
(1b), and (−)-6-hydroxythionuphlutine (2b) inhibited invasion of
B16 melanoma cells across collagen-coated filters with an IC50 value of
29−360 nM in vitro.11 These same compounds also exhibited substan-
tial cytotoxicity at a concentration of 10 µM against U937, B16F10,
and HT1080 cell lines, with 1b inducing apoptosis in cell line U937
within 1 h.12 Dimeric alkaloids lacking a hydroxyl group or possessing
only a 6´- rather than 6-hydroxyl group showed weak activity, leading
the authors to conclude that the 6-hydroxyl moiety is essential to the
observed apoptotic and anti-metastatic activity. Recently it was dis-
covered that semi-purified extracts of Nuphar lutea containing (+)-6-
hydroxythiobinupharidine (1b) and (−)-6-hydroxythionuphlutine
(+)-6-hydroxythiobinupharidine (1b)
(−)-6-hydroxythionuphlutine (2b)
X,Y = H:
X,Y = H:
(−)-thiobinupharidine (1c)
(−)-thionuphlutine (2c)
X = H, Y = OH:
X = H, Y = OH:
(+)-6'-hydroxythiobinupharidine (1d)
(+)-6'-hydroxythionuphlutine (2d)
O
O
O
X
Y
S
H
X
N
S
N
H
6
6'
6'
N
N
H
6
Y
H
O
X,Y = OH:
X,Y = OH:
∗
∗
(−)-6,6'-dihydroxyneothiobinupharidine (3a)
(+)-6,6'-dihydroxyneothionuphlutine (4a)
X = OH, Y = H:
X = OH, Y = H:
∗
6-hydroxyneothionuphlutine (4b)
6-hydroxyneothiobinupharidine (3b)
X,Y = H:
X,Y = H:
∗
(+)-neothionuphlutine (4c)
(−)-neothiobinupharidine (3c)
X = H, Y = OH:
X = H, Y = OH:
∗
6'-hydroxyneothiobinupharidine (1d)
6'-hydroxyneothionuphlutine (4d)
∗
have not been isolated from natural sources
Figure 1. Nuphar sesquiterpene thioalkaloids.
Despite being known since the 1960s, the first total synthesis of a
dimeric Nuphar alkaloid was not reported until Shenvi’s pioneering
synthesis of (−)-neothiobinupharidine (3c) in 2013.2 Wu and co-
workers later expanded upon this work and completed syntheses of five
hydroxylated Nuphar alkaloids (1a, 1b, 2a, 3a, and 4a), along with
their unnatural enantiomers.3 Biological evaluation of these synthetic
products showed that both natural and unnatural enantiomers exhibit-
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Scheme 1. Synthesis Plan.
ed nearly the same activity against human cell line U937. In a subse-
quent study, Wu prepared a library of simplified monomeric analogues
and analyzed their ability to induce apoptosis.14 These monomers were
found to possess comparable or slightly more potent activity compared
to the dimeric alkaloids. Monomers corresponding to both the natural
and unnatural configurations displayed cytotoxicity, but greater poten-
cy was seen in the unnatural antipodes. It also appears that the C1
methyl group is not essential to the biological activity, as analogues
lacking a C1 methyl group or with an epimeric configuration at C1
maintained activity.15 Furthermore, an anti relationship between the 6-
hydroxyl group and the adjacent sulfide substituent (corresponding to
the configurations of 2a-b and 3a-b) was found to produce more po-
tent cytotoxicity than a syn-relationship (corresponding to the configu-
rations of 1a-b and 4a-b).
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Shenvi and co-workers have proposed that the apoptotic activity of
6,6´-dihydroxy Nuphar alkaloids arises from a retro-dimerization
event, triggered by nucleophilic attack of sulfur, to form an electro-
philic ene-iminium species.16 To test this hypothesis, simplified mon-
omeric and dimeric thiaspirane iminium analogues were prepared.
The thioether moiety was indeed shown to be electrophilic, as treat-
ment of these analogues with nucleophilic thiols resulted in disulfide
formation.17 The dimeric analogues also proved to be cytotoxic against
Jurkat and HT29 cells, whereas their monomeric counterparts exhibit-
ed no activity. However, as noted by the authors, this hypothesis can-
not account for the apoptotic activity of 6-hydroxy Nuphar alkaloids
nor the monomeric analogues prepared by Wu, neither of which can
undergo retro-dimerization. Given that all 6-hydroxy containing dia-
stereomeric members of the natural Nuphar alkaloids, in addition to
their enantiomers and Wu’s monomeric analogues, possess similar
apoptotic activity, it is likely that a common mechanism is at hand. It is
unclear, however, what the exact mechanism is, or whether this mecha-
nism can also account for the observed immunosuppressive activity,
anti-metastic activity, or the inhibition of NFκB.
In accordance with this plan, the enantioselective synthesis of (3R)-
1-iodo-3-methyl-4-pentene 11 was accomplished in 4 steps from 2-
methylene-γ-butyrolactone 12 in 71% overall yield, 96% ee as shown in
Scheme 2. Direct asymmetric alkylation of 3-furanacetic acid with 11
was accomplished in the presence of the dilithium amide of 13 by a
protocol developed previously in our group, delivering 14 in 70% yield
and >20:1 dr on >3g scale.19 Curtius rearrangement performed directly
on the alkylation product 14 followed by exposure of the intermediate
isocyanate to 2,2,2-trichloroethanol afforded carbamate 9 in 94% yield
with full retention of configuration. A cross-metathesis of 9 with acrole-
in diethylacetal20 followed by Wittig homologation of enal 15 gave
conjugated dienyl ester 16. Removal of Troc using conditions devel-
oped by Ciufolini and co-workers21 led directly to intramolecular 1,6-
addition to form piperidine 17 in 65% yield along with its C10 epimer.
Attempts to recycle the epimer to the more thermodynamically stable
isomer 17 led mostly to double bound migration and formation of only
minor amounts of 17. The final step in the synthesis of amino ester 8
was a seemingly trivial olefin hydrogenation. Unfortunately, subjection
of 8 to numerous conditions using classic Pd hydrogenation catalysts
(including deactivated catalysts such as Lindlar’s) led to competitive
hydrogenation of the 3-substituted furan. A literature survey revealed
that we were not the first to experience this issue in the synthesis of
Nuphar alkaloids. A similar problem was reported by Bates and co-
workers during the synthesis of nupharamine, which they resolved
The elegant syntheses put forth both by Shenvi and Wu have paved
the way for future biological investigations on the Nuphar alkaloids.
Yet, a critical challenge that has remained unmet is the selective synthe-
sis of several of the unsymmetrically oxidized, or 6-hydroxy, congeners.
Wu and co-workers were able to access one such compound, (+)-6-
hydroxythiobinupharidine (1b), through a reduction of (+)-6,6´-
dihydroxythiobinupuharidine (1a) based on innate selectivity. Howev-
er, attempts to perform similar reductions on other 6,6´-dihydroxy
members were met with little success,3 and as a result, 2b, 3b, and 4b
have remained inaccessible. Our interest was piqued by one compound
in particular, namely (−)-6-hyroxythiobinupharidine (2b), which rep-
resents a particularly attractive synthetic target given the intriguing
results observed in the biological assays described above. In addition
to developing a general strategy for the synthesis of all Nuphar thioalka-
loids, the goal of our synthesis was to gain access to 2b and provide a
platform for further exploration of its biological activity.
Scheme 2. Synthesis of piperidine intermediate 8.
1. (PhH)((S)-BINAP)RuCl2
HN
NH
H2, CH2Cl2
2. i-Bu2AlH, CH2Cl2, −78 o
N
N
O
Ph Ph
13
C
3. Ph3P=CH2
O
4. I2, Ph3P, ImH
I
O
n-BuLi, THF, −78 °C, 24 h
CO2H
+
O
71% yield over
4 steps, 96% ee
70% yield, dr > 20:1
CO2H
10
14
11
12
OEt
OEt
The basis of our synthesis design was the advanced fragment cou-
pling by a stereodivergent metallocarbene insertion into the thietane
C–S bond forming the central spirothiolane ring system of the alka-
loids (6+7, Scheme 1). We envisaged this taking place through a sul-
fonium-ylide intermediate 5 which could undergo a Stevens-type ring
expansion.18 In the latest iteration of the synthesis plan, we opted to use
an acyclic diazo ester for the fragment coupling, as attempts to utilize a
cyclic diazo lactam intermediate during thiolane formation were un-
successful. It was thought that both the diazo ester and thietane com-
ponents could be synthesized from a common piperidine intermediate
8, for which we determined carbamate 9 to be a suitable precursor. In
the forward sense, we imagined that direct, asymmetric alkylation of 3-
furanacetic acid 10 with (3R)-1-iodo-3-methyl-4-pentene 11 would
provide access to the requisite Troc carbamate 9.
O
O
i-Pr2NEt, (PhO)2P(O)N3
2,2,2-trichloroethanol
PhH, 80 °C, 11 h
Ph3P=CHCO2Me
CH2Cl2, 40 °C, 6 h
HGII (5 mol %), CH2Cl2
40 °C, 20 h
NHTroc
15
NHTroc
97% yield
94% yield
74% yield
O
E:Z 5:1
E:Z 10:1
9
RhCl(PPh3)3 (5 mol %)
O
O
O
Cd- Pb Couple
THF- 1 M NH4OAc
23 °C, 24 h
H2 (300 psi)
PhMe, 23 °C, 24 h
NH
H
NH
H
NHTroc
16
10
88%
CO2Me
CO2Me
CO2Me
65% yield
yield
(+ 32% C10 epimer)
8
17
all reactions performed on >1g scale.
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Scheme 3. Convergent fragment coupling by Cu-mediated Stevens-type ring expansion to install the central thiolane.
1
O
2
O
O
O
S
H
MeO2
C
3
4
5
6
7
8
9
AllocCl, i-Pr2NEt , THF
KN(SiMe3)2, PhCO2Me
(4-NO2C6H4)SO2N3, DBU
CH2Cl2, 23 °C, 1 h
N
H
66 °C, 36 h
THF, −78 to 0 °C, 2.5 h
NAlloc
NAlloc
H
NAlloc
CO2Me
CO2Me
Ph
CO2Me
90% yield
90% yield
AllocN
87% yield
H
H
N2
O
O
O
18
19
24
29% yield
20
Cu(hfacac)2 (5 mol %)
CH2Cl2, 100 °C (µW), 3 h
NH
CO2Me
55% yield
(+ 27%
O
1. MsCl, i-Pr2NEt
CH2Cl2, 0 °C
2. Na2S•9H2O
n-Bu4NI
H
8
1. LDA, 4-MeOC6H4OCOCl
THF, −78 °C (53% yield)
2. NaBH4, MeOH
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S
H
MeO2
C
recovered 7)
AcOH, PhMe
110 °C, 24 h
i-Bu2AlH, PhMe
N
O
HO
HO
O
O
S
S
0 °C, 30 min
DMF, 50 °C
23 °C (81% yield)
N
N
H
N
H
N
H
H
AllocN
90% yield
91% yield
81% yield
H
O
25
26% yield
21
22
23
7
through the use of Wilkinson’s catalyst.22 Gratifyingly, hydrogenation
of 17 in an autoclave at a pressure of 300 psi in the presence of Wil-
kinson’s catalyst afforded the desired reduction product 8 in 88% yield.
NMR analysis of the crude reaction mixture and after isolation by col-
umn chromatography. We believe the striking selectivity of this reac-
tion can be rationalized through a mechanism that involves anchimeric
assistance from the 5’ nitrogen (Scheme 4). After formation of sul-
fonium ylide i, the axially oriented nitrogen lone pair25 can open the
thietane ring through an SN2 displacement at the axial carbon. The final
carbon-carbon bond of the thiolane ring is then formed through an
enolate ring opening of the intermediate azetidinium species ii, which
occurs exclusively from the bottom face in order to avoid a developing
twist boat-like product conformation in the disfavored transition state.
Given the approximately 1:1 dr observed at C7, there appears to be no
facial bias with respect to the enolate.
The diazo ester (20) and thietane (7) coupling partners were then
prepared from piperidine 8 in three and six steps, respectively (Scheme
3). After initial N-allyloxycarbonylation, enolization of ester 8 with
KN(SiMe3)2 followed by acylation with methyl benzoate provided keto
ester 19. The use of LDA as a base in the acylation step led to rapid
decomposition of the substrate, presumably due to competitive lithia-
tion of the allyloxycarbonyl group. Keto ester 19 was converted to
diazo ester 20 with 4-nitrobenzenesulfonyl azide in the presence of
DBU in 87% yield.23 A direct diazo transfer to ester 8 proved to be
inefficient. For the synthesis of thietane 7, piperidine 8 was first cy-
clized through treatment with acetic acid in refluxing toluene to give
lactam 21. A series of transformations involving bisacylation, reduction
to a diol, mesylate formation, and displacement with sodium sulfide
successfully installed the thietane ring. Quinolizidinone 23 was then
reduced with i-Bu2AlH to give spirocyclic thietane 7 in 90% yield.
Scheme 5. Completion of the total synthesis.
O
O
S
H
MeO2C
RN
S
H
MeO2C
RN
N
H
N
H
O
Scheme 4. Mechanistic hypothesis for selective thiolane synthesis.
O
Pd(PPh3)4
PhSiH3
Pd(PPh3)4
PhSiH3
24, R = Alloc
26, R = H
25, R = Alloc
27, R = H
O
R
CO2Me
R
N
87% yield
98% yield
Me
S
[CuII
]
5'
N
i-Bu2AlH, CH2Cl2
−89 °C, 1 h
S
i-Bu2AlH, CH2Cl2
−89 °C, 30 min
O
MeO2
C
H
R
i
O
7
O
R
S
CO2Me
OH
N
S
H
O
R
N
OH
Me
Me
N
S
N
N
H
S
MeO2
C
7
H
R
H
N
H
Me
7'
R
disfavored
N
7'
O
R
N
S
R
(−)-6-hydroxythionuphlutine (2b)
(+)-6-hydroxythiobinupharidine (1b)
7
ii
MeO2C
60% yield
38% yield
+
S
+
O
N
O
R
MeO2C
O
favored
S
H
N
H
S
N
Having gained access to sufficient quantities of coupling partners 7
N
H
H
and 20, the stage was now set to assemble the central thiolane ring.
Extensive screening using Rh2(OAc)4, Rh2(O2CC3F7)4, Rh2(PTAD)4,
Rh2(esp)2, Cu(CH3CN)4BF4, Cu(tfacac)2, and Cu(hfacac)2 catalysts24
revealed that a combination of Cu(hfacac)2 and microwave irradiation
was the most effective for 7 and 20, and that the reaction was sensitive
to seemingly minor structural variations of both coupling partners.
Under optimized conditions, 7 and 20 were heated to 100 °C using
microwave irradiation in the presence of Cu(hfacac)2 to give two prod-
ucts corresponding to the configurations of thiobinupharidine (24)
and thionuphlutine (25). While this reaction has the potential to pro-
O
(−)-thionuphlutine (2c)
(−)-thiobinupharidine (1c)
10% yield
6% yield
To complete the synthesis, the allyloxycarbonyl groups were first
removed using 5 mol % of Pd(PPh3)4 in the presence of phenylsilane to
form 26 and 27 in 87% and 98% yields, respectively. Our initial plan
called for lactamization of these amino esters and a reduction of the
corresponding quinolizidinones to access the hemiaminal natural
products. However, these substrates proved to be surprisingly resistant
to lactamization under a variety of acidic or basic conditions, including
treatment with acetic acid, sulfuric acid, trimethyl aluminum, DBU,
1
duce four diastereomeric products, only two are observed both by H
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(3) Korotkov, A.K.; Li, H.; Chapman, C.W.; Xue, H.; MacMillan, J.B.; East-
man, A.; Wu, J. Angew. Chem. Int. Ed. 2015, 54, 10604.
and sodium methoxide. We reasoned that perhaps reversing the order
of these steps could circumvent this obstacle. It was thought that care-
ful reduction of the ester moiety would produce an intermediate ami-
no-aldehyde, which should tautomerize to a hemiaminal.26 Reduction
of amino ester 26 with i-Bu2AlH at −89 °C afforded hemiaminal (+)-6-
hydroxythiobinupharidine (1b) in 38% isolated yield, along with 6% of
the fully reduced product (−)-thiobinupharidine (1c). Shortening the
reaction time and decreasing the amount of i-Bu2AlH did not lead to an
increase in yield. To our delight, submission of amino ester 27 to anal-
ogous conditions resulted in the formation of (−)-6-
hydroxythionuphlutine (2b) in 60% yield, along with a 10% yield of
(−)-thionuphlutine (2c). The thiaspirane stereochemistry in the prod-
1
2
3
4
5
6
7
8
(4) (a) Lu, P.; Herrmann, A.T.; Zakarian, A. J. Org. Chem. 2015, 80, 7581.
(b) Goodenough, K.M.; Moran, W.J.; Raubo, P.; Harrity, J.P.A. J. Org. Chem.
2005, 70, 207. (c) Moran, W.J.; Goodenough, K.M.; Raubo, P.; Harrity, J.P.A.
Org. Lett. 2003, 5, 3427. (d) Katoh, M.; Mizutani, H.; Honda, T. Heterocycles
2006, 69, 193. (e) Barluenga, J.; Anzar, F.; Ribas, C.; Valdes, C. J. Org. Chem.
1999, 64, 3736.
(5) Initial isolation of monomeric nuphar alkaloids was first reported in
1962: (a) Achamatowicz, O.; Bellen, Z. Tetrahedron Lett. 1962, 3,1121. The
isolation of the dimeric alkaloids was reported later in 1964: (b) Achamatowicz,
O.; Wróbel, J.T. Tetrahedron Lett. 1964, 5, 129. (c) Achamatowicz, O.;
Banaszek, H.; Spiteller, G.; Wróbel, J.T. Tetrahedron Lett. 1964, 5, 927.
(6) Birnbaum, J. Tetrahedron Lett. 1965, 6, 4149.
(7) LaLonde, R.T.; Wong, C. Pure Appl. Chem. 1977, 49, 169 and references
therein.
(8) (a) Cullen, W.P.; Lalonde, R.T.; Wang, C.J.; Wong, C.F. J. Pharm. Sci.
1973, 62, 826. For a more recent report on the antibiotic activity of dimeric
nuphar alkaloids, see: (b) Okamura, S.; Nishiyama, E.; Yamazaki, T.; Otsuka,
N.; Taniguchi, S.; Ogawa, W.; Hatano, T.; Tsuchiya, T.; Kuroda, T. Biochim.
Biohpys. Acta, Gen. Subj. 2015, 1850, 1245.
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1
13
ucts was determined by correlation of the H NMR and C NMR data
obtained for 1b, 1c and 2c to those reported by Lalonde27 and by Wu,3
all of which were in full agreement.
In summary, an asymmetric total synthesis of two hemiaminal
containing Nuphar thioalkaloids, (+)-6-hydroxythiobinupharidine 1b
and (−)-6-hydroxythionuphlutine 2b has been accomplished. The
essential feature of the synthesis was assembly of the central bis-
spirocyclic through a copper-catalyzed coupling of unsymmetric mon-
omers. This bio-divergent strategy was successful in providing
chemoselective access to unsymmetrically oxidized hemiaminal alka-
loids 1b and 2b, with 2b being synthesized for the first time.
(9) Yamahara, J.; Shimoda, H.; Matsuda, H.; Yoshikawa, M. Biol. Pharm.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization and spectral data for all
compounds (PDF). The Supporting Information is available free of
charge on the ACS Publications website.
(15) Li, H.; Cooke, T. J.; Korotkov, A.; Chapman, C.W.; Eastman, A.; Wu, J.
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(17) As noted in the previous reference, the electrophilic sulfur hypothesis
can also account for the equilibration observed by Yoshikawa between 1b and
2b in hot chloroform: Yoshikawa, M.; Murakami, T.; Wakao, S.; Ishikado, A.;
Murakami, N.; Yamahara, J.; Matsuda, H. Heterocycles 1997, 45, 1815.
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133, 11936.
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R.H. Tetrahedron Lett. 1999, 40, 1091.
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Int. Ed. 1997, 36, 2821.
(24) For a review on the formation of rhodium and copper carbenoids, see:
(a) Gillingham, D.; Fei, N. Chem. Soc. Rev. 2013, 42, 4918. For select examples
of the use of the aforementioned catalysts in metal-carbenoid chemistry, see (b)
See ref. 17(c) Brown, D.S.; Elliot, M.C.; Moody C.J.; Mowlem, T.J.; Marino,
J.P. Jr.; Padwa, A. J. Org. Chem. 1994, 59, 2447. (d) Reddy, R.P.; Lee, G.H.;
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5144.
(25) The fixed axial orientation of the nitrogen lone-pair is confirmed by the
presence of Bohlman bands in the IR spectra of nuphar alkaloids. See ref. 7.
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AUTHOR INFORMATION
Corresponding Author
*zakarian@chem.ucsb.edu
Present Addresses
‡Arcus Biosciences, 3928 Point Eden Way, Hayward, California 94545,
United States
# Research Center for Molecular Recognition and Synthesis, Depart-
ment of Chemistry, Fudan University, 220 Handan Lu, Shanghai
200433, P.R.China
†Janssen Research & Development, LLC, 3210 Merryfield Row, San
Diego, California 92121, United States.
Author Contributions
§ J.J.L. and J.F. contributed equally.
ACKNOWLEDGMENT
We thank Dr. Matthew Beaver and Dr. Matthew Bio of Amgen for the
donation of > 3 kg of tetraamine 13. We are grateful to Materia, Inc. for
a generous donation of HGII catalyst. Dr. Hongjun Zhou is acknowl-
edged for assistance with NMR spectroscopy, and Rachel Behrens and
the UCSB MRL mass spectroscopy facility (supported by the MRSEC
Program of the NSF, under award NSF DMR 1121053) are thanked
for assistance with mass spectral analysis. J.J.L. was supported by a
UCSB Chancellor’s fellowship. This work was supported by NIH
(NIGMS R01 077379).
REFERENCES
(1) Wong, C.F.; LaLonde, R.T. Experientia 1975, 31, 15.
(2) Jansen, D.J.; Shenvi, R.A. J. Am. Chem. Soc. 2013, 135, 1209.
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129, 9631. (c) Lee, Y.S.; Cho, D.J.; Kim, S.N.; Choi, J.H.; Park. H. J. Org. Chem.
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(27) (a) LaLonde, R.T.; Donvito, T.N.; Tsai, A.I.M. Can. J. Chem. 1975 53,
1714. (b) LaLonde, R.T.; Wong, C.F.; Das, K.C. J. Org. Chem. 1974, 39, 2892.
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TOC graphic:
O
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(−)-6-hydroxythionuphlutine
(+)-6-hydroxythiobinupharidine
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