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Expedient Synthesis of (+)-Lycopalhine A
N N H
OH
O
H H
H
Benjamin M. Williams and Dirk Trauner
Angew. Chem. Int. Ed., 2016, 128, 2231-2234
1 Step McCabe @ Wipf Group Page 1 of 15 6/19/2016
Lycopodium alkaloids
2
obscurinineO
H
N
H
N
H
N
OH O
HH
Fawcettimine-type
N
O
lycopodine-type
HN
N
lycodine-type
HN
NH
miscellaneous
Lycopodiumalkaloids
H2N
NHO
HN
N
N HN
MeH H
complanadine Astimulates nerve
growth factor (NGF)production in human glial cells
N
O
N
fastigiatine
huperzine Areversible inhibitor of
AChe
N N H
OH
O
H H
H
lycopalhine A
NMe
HN
O
HH
H lyconadin A * cytotoxic to murine lymphoma cells (IC50 = 0.46 µg/mL)
& human epidermoid carcinoma KB cells (IC50 = 1.7 µg/mL)* stimulates NGF production in human glial cells
NMe
HH
H
HN
nankakurine A
phlegmarine
N
HN
O
CO2H
huperzine G
H
Step McCabe @ Wipf Group Page 2 of 15 6/19/2016
• Isolated in Guizhou Province, China from Palhinhaea cernua along with it’s proposed biosynthetic precursor obscurinine Structure & absolute configuration determined through spectroscopic/computational methods • Complex hexacyclic ring system containing
• 1x6 + 2x5 membered carbocycles, 1x piperidine ring & 1x hexahydropyrimidine ring on a highly substituted pyrrolidine core • Sensitive aminal functionality + strained aldol moiety • 9 stereogenic centres, 8 of which are contiguous
• Weak butyrylcholinesterase (BuChe) inhibitory activity
• (31.4% at 50 µM) compared to Tacrine (87.8% at 33 µM, + control )
Palhinhaea cernua
Isolation/ Characterization
3
O
H
obscurinine(10 mg)
N
H
N
HN N H
OH
O
H H
H
lycopalhine A(1.5 mg)
Chem. Commun., 2012, 48, 9038
Step McCabe @ Wipf Group Page 3 of 15 6/19/2016
Biosynthesis
4
• The biosynthesis of lycopodium alkaloids is not well established due to difficulty cultivating lycopodium species in the lab.
• Current insight is largely based on feeding experiments with radiolabeled precursors
NH2
H2NO
OH
lysine
NN
H
N
O
lycopodine
HOrearrangement
N
OH O
HH
Fawcettimine
N
O[O]
obscurinineO
H
N
H
N
H
H2NH2Ncadaverine
NH
OCO2H
NH
O
-CO2-CO2
NN
HO
HO
HO2C
lycodane skeleton
N HN
N
OH
41312
13 12 4H N N H
OH
O
H H
H
lycopalhine A
H2O
Step McCabe @ Wipf Group Page 4 of 15 6/19/2016
Proposed Biosynthesis
O
H
obscurinine
N
H
N
H
O
H
N
H
N
H
H
O
O
HN
H
N
H OH
H
O
HN
H
HN
H OH
HO H
O
HN
H
HN
H OH
H
N N H
OH
O
H H
H
[O]aldol
condensation
[O][H]
cyclization
Polonovski-typereaction
N HN H
OH
O
H
H
lycopalhine A
[H]
5 Step McCabe @ Wipf Group Page 5 of 15 6/19/2016
6
• Trauner group – published 8th January 2016 • Fukuyama group – 7th March 2016
• 2 total syntheses of (+)-Lycopalhine to date:
N N H
OH
O
H
H
aminal condensation
biomimeticaldolH
N N H
OH
O
H
aminal condensation
biomimeticaldol
H
Michael addition
cyclopropanationorganocatalyzedintramolecular
Mannich reaction
Pauson-Khand
Step McCabe @ Wipf Group Page 6 of 15 6/19/2016
7
Fukuyama’s Retrosynthesis
Org. Lett., 2016, 18 (6),1494–1496
O O
OEtN2
OPMP
H
O
CO2Et
OPMP
H
O
O
NH
H
H
NHMe
H
O
N
H
H
HO
NMe
H
(+)-lycopalhine A
OHC O
O
OPMP
O OH
aminalformation
aldol
cyclopropanationcyclopropanecleavage/Michael addition
Johnson-Claisen
rearrangement
Step McCabe @ Wipf Group Page 7 of 15 6/19/2016
Fukuyama’s Approach
8
OHO
OH
N2
OO
N
ClO2C
NHSO2Tol
N
N
OCuN
OtBu
tBu
Tetrahedron Lett., 1984, 25, 3559E. J. Corey and Andrew G. Myers
bis-(N-t-butylsalicylaldiminato) copper (II) catalyst
- soluble catalyst --> higher yields on scale compared to
heterogenous Cu powder
PhMe, reflux
NHNSO2Tol
ClO2C
Et3NN
HC•
O
N STol
O O
O
O S Tol
O
N2
ROHO
ORN2
RO S Tol
Oor
weak base preventedbasic side reaction observed with NEt3
OPMPTBSO
OH
OAcTBSO
11 steps
O O
OEtNN
N3 PF6
Et3N, MeCN, THF, rt
TBSO
O O
OEtN2
OPMP
PhMe, reflux, 55%H
TBSO
O
CO2Et H
HO
O
OPMP OPMP
O
NH
SO2Ar
Ar = C6H4-p-CF3
R
O O
OEtH N
NN
MeN NMe
Synlett, 2009, 2009, 2943Synthesis, 2011, 7, 1037
N
O CuN
OtBu
tBu
3 steps
synthesized 26.1 g scale
mild diazo transfer for 1,3-dicarbonylswater soluble guanidine byproduct
2 steps(lit. procedure)
Step McCabe @ Wipf Group Page 8 of 15 6/19/2016
Fukuyama’s Approach
9
H
O
OPMP
NBocOHC
H
H
NNsMe
15 stepsKOH, MeOH
0 °C to rt, 98% H
O
OPMP
NBoc
H
H
NNsMeHO
6 steps H
O
N
H
H
HO
NMe
H H
O
N
H
H
OH
NMe
H+
lycopalhine A epi-lycopalhine A
DMP, pyridineCH2Cl2, rt to 40 °C
H
O
O
OPMP
O
NHSO2Ar H
O
O
OPMP
NSO2Ar
O
Ar = C6H4-p-CF3
H
HO
O
OPMP
O
NH
SO2Ar
synthesized on 490 mg scale
H
80%
Step McCabe @ Wipf Group Page 9 of 15 6/19/2016
Retrosynthesis
10
Angew. Chem. Int. Ed., 2016, 128, 2231-2234
N N H
OH
O
H
H
aminal condensation
biomimeticaldol
BocN HN
O
H
H
OH
O
Mannich cyclization O
H
H2N
OHNBoc
CHO
conjugate addition
OH
H2N
OTBSPauson-Khand
reaction NHOTBS
Boc
NH2
O
OH
O
HO
diastereoselectiveallylation
L-glutamic acid
H
Step McCabe @ Wipf Group Page 10 of 15 6/19/2016
Synthesis of Core Bicycle
11
MeO2C
NHBoc
CO2Me
LiHMDS, THF, - 78 °C
90%Br
OHO
BocHN
DIBAL (5 equiv.)THF, PhMe, -78 °C
83%NH
CO2MeMeO2C
Boc
1. K2CO3, MeOH
2. TBSCl, imidazoleCH2Cl2
61% (2 steps)
NH OTBSBoc
OPMeO
MeON2
O
Co2(CO)8PhMe, 70 °C
72% NHBocOTBS
H
Co2(CO)8
O
H
BocHN OTBS
dr C(3) 10:1
H
nOe
O
H
BocHN
OTBS
H
MgBr
CuBr•SMe2TMSCl, HMPA,
78%
AcClMeOH92%
O
H
H2N
OH
H
gram quantities(up to 1.3 grams 1 batch)
3
7
Ohira-Bestmann reagent
Pauson-Khand reaction
anti diastereoselectivity
dr C(3) 10:1
3
chlorosilane accelerated
conjugate addition
Step McCabe @ Wipf Group Page 11 of 15 6/19/2016
propargylic carbamate 11. This intermediate would ultimatelybe derived from l-glutamic acid.
Our actual synthesis of lycopalhine A, guided by theseconsiderations, is presented in Scheme 2. To begin, dimethylester 12, prepared from l-glutamic acid on a decagram scalein a one-pot procedure (see the Supporting Information),[7]
was allylated with high anti diastereoselectivity in a proceduredescribed by Hanessian and co-workers.[8] Chemoselectivereduction of 13 by controlled addition of diisobutylaluminumhydride (DIBAL) afforded lactol 14 as a 1:1 mixture ofdiastereomers (C1). Alkynylation of 14 was complicated bythe epimerization of the neighboring amine stereocenterunder the basic conditions required to open the six-memberedlactol. Optimized conditions using Ohira–Bestmann reagent15[9] and silyl protection of the resulting alcohol affordedalkyne 11 and its C3 epimer as an inseparable 10:1 mixture.[10]
The ensuing Pauson–Khand reaction proceeded under ther-mal conditions and afforded enone 10 with the desired C7stereoselectivity, confirmed by nuclear Overhauser effect(NOE) analysis, as a 10:1 mixture with the cyclized C3epimer. The diastereoselectivity of related intramolecularPauson–Khand reactions in the context of Lycopodiumalkaloid synthesis has previously been explored by thegroups of Zard,[11] Takayama,[2d] and Mukai.[2i] The authorspropose that chair-like conformations of intermediate 16translate to the desired configuration of the bicyclo-[4.3.0]nonenone.[12] TMSCl-promoted conjugate addition ofbutenylmagnesium bromide to the enone[13] and cleavage ofthe resulting silyl enol ether with acetic acid afforded 17,featuring the sole quaternary stereocenter of the molecule, asa single diastereomer upon purification. The first six steps of
the synthesis were easily scalable and provided gram quanti-ties of advanced intermediate 17. Global deprotection withacetyl chloride in methanol then produced free aminoketone8.
The intramolecular 5-endo-trig Mannich cyclizationproved to be a challenging transformation. Acidic conditionsresulted mainly in self-condensation of the aldehyde. How-ever, mixing amine 8 and aldehyde 9 with triethylaminefollowed by concentration under reduced pressure granted
Scheme 2. Total synthesis of lycopalhine A. a) LiHMDS, THF, ˇ78 88C, then allyl bromide; b) DIBAL (5.0 equiv), THF/PhMe, ˇ78 88C; c) dimethyl(1-diazo-2-oxopropyl)phosphonate 15, K2CO3, MeOH, 0 88C!RT; d) TBSCl, imidazole, CH2Cl2, 0 88C!RT; e) Co2(CO)8, PhMe, 70 88C; f) 3-butenylmagnesium bromide (4.5 equiv), CuBr·SMe2 (20 mol %), TMSCl, HMPA, THF, ˇ78 88C!ˇ30 88C, then AcOH, RT; g) AcCl (10 equiv),MeOH, 45 88C; h) 9 (1.1 equiv), Et3N, CH2Cl2, then l-proline, DMF, RT; i) Boc2O, CH2Cl2, RT, 72 h; j) IBX, EtOAc, 80 88C; k) K2CO3, MeOH, RT,l) OsO4, NaIO4, 2,6-lutidine, dioxane/H2O (3:1 v/v), RT, then TFA, CH2Cl2, 0 88C!RT. Boc = tert-butyloxycarbonyl, DIBAL= diisobutylaluminumhydride, DMF=dimethylformamide, HMPA= hexamethylphosphoramide, IBX =2-iodoxybenzoic acid, LiHMDS = lithium bis(trimethylsilyl)amide,TBS = tert-butyldimethylsilyl, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMS= trimethylsilyl.
Table 1: Conditions for the intramolecular Mannich cyclization.
Entry[a] Additives (equiv) Solvent T [88C] Yield[b] [%]
1 Yb(OTf)3 (1.0) MeCN 0–RT –2 TiCl4 (2.0)/ Et3N (4.0) CH2Cl2 ˇ30–RT –3 K2CO3 (3.0) MeOH RT –4[c] Et3N (3.0) PhMe RT–80 –5 pyrrolidine (1.0) DMF RT 116 pyrrolidine (1.0)/
AcOH (1.0)DMF RT 10
7 d-proline (1.0) DMF RT 208 l-proline (1.0) DMF RT 609[c] l-proline (0.5) DMF RT 3910 l-phenylalanine (1.0) MeCN RT 30
[a] Reactions conducted under nitrogen atmosphere for 18–24 h.[b] Yield of isolated product. [c] Reaction performed without preforma-tion of imine by treatment with Et3N.
AngewandteChemieZuschriften
2232 www.angewandte.de ⌫ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2016, 128, 2231 –2234
5-endo-trig Mannich reaction
12
O
H
H2N
OH
H
BocN O
H BocN N
O
H
H
OHconditionsEt3N, CH2Cl2
BocN HN
O
H
H
OH7
HN
O
H
H
OH7
HN
Boc
(not observed)
Step McCabe @ Wipf Group Page 12 of 15 6/19/2016
Completion of the Synthesis via a biomimetic aldol reaction
13
N HN
O
H
H
OH BocN N
O
H
H
OH
BocN N H
OH
O
H
H
Boc
BocN N H
OH
O
H
HN N H
OH
O
H
H
1. OsO4 (0.1 equiv.) NaIO4 (10 equiv.)2,6-lutidine, dioxane/ H2O
Lemieux-Johnson oxidation
2. TFA, CH2Cl2, 0 °C to rt56% (2 steps)
+
Boc2O, CH2Cl272 h, 93%
Boc1. IBX, EtOAc, 80 °C
2. K2CO3, MeOH98% (2 steps)
biomimetic aldol
1616
dr C(16) 5.5: 1
H H H
HN HN H
OH
O
H
H
O H
Step McCabe @ Wipf Group Page 13 of 15 6/19/2016
14
Expedient Synthesis of (+)-Lycopalhine A – Supporting Information
S41
6. Deuterium exchange studies of lycopalhine A
Figure S7. Deuterium exchange studies of lycopalhine A and epi-lycopalhine A
Note: No additional deuterium exchange was observed after stirring for >24 h in MeOD with K2CO3 or after repeating the experiment over 3Å molecular sieves.
b. 1 and epi-1 (pyridine-d5, 600 MHz) after stirring in MeOD with K2CO3 at rt for 2h
a. 1 and epi-1 (pyridine-d5, 600 MHz) before treatment with MeOD/K2CO3
H-1a H-6
H-6‘
H-15 H-4
H-4 H-8a
H-1a
H-6
H-6‘
H-15 H-14a
H-8a H-14a
H-7
H-7
Deuterium Study
• Deuterium exchange between C6/C15 under basic conditions + the existence of both epimers in the experimental and isolated samples suggests equilibration with a thermodynamic preference for closed aldol product.
N N H
OH
O
H
HN N H
OH
O
H
H+ 1616
H H
MeOD, K2CO3
15
6
Step McCabe @ Wipf Group Page 14 of 15 6/19/2016
Conclusions
• First total synthesis of lycopalhine A • First asymmetric synthesis utilizing a chiral pool approach
• Key steps:
• Comparison of synthetic routes
• Application of P-K/ organocatalytic Mannich approach to other lycopodium alkaloids
Synthesis Steps Overall Yield (mixture of C(16)
epimers)
Quantity
Fukuyama 41 ~2% 13.0 mg
Trauner 13 ~5.7% 4.0 mg
15
NH2
O
OMe
O
MeON N H
OH
O
H
H
N N H
OH
O
H
H
biomimeticaldol
Pauson-Khand
reaction
5-endo-trigorganocatalytic
Mannich cyclization
16
Step McCabe @ Wipf Group Page 15 of 15 6/19/2016