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!"#$ %$&'()*$&')+,-./-0+0+
Enantioselective Synthesis of AzameroneMatthew L. Landry, Grace M. McKenna, and Noah Z. Burns*Department of Chemistry, Stanford University, Stanford, California 94305, United States
*S Supporting Information
ABSTRACT: A concise and selective synthesis of thedichlorinated meroterpenoid azamerone is described. Thepaucity of tactics for the synthesis of natural-product-relevant chiral organochlorides motivated the develop-ment of unique strategies for accessing these motifs inenantioenriched forms. The route features a novelenantioselective chloroetheri!cation reaction, a Pd-cata-lyzed cross-coupling between a quinone diazide and aboronic hemiester, and a late-stage tetrazine [4+2]-cycloaddition/oxidation cascade.
The napyradiomycins are a diverse class of halogenatedmeroterpenoids that have been isolated from terrestrial
and marine actinomycetes (Figure 1A).1 Initial isolation e"ortswere driven by a desire to identify novel antibiotic sca"olds; thenapyradiomycins have since demonstrated potent inhibition ofgastric (H+-K+)-ATPase, nonsteroidal estrogen antagonism,cancer cell cytotoxicities, and activity against Gram-positivebacteria.1c!f Of the over 40 members within this class, onlynapyradiomycin A1 has succumbed to chemical synthesis (2,Figure 1A).2 Syntheses of more highly oxidized members of thenapyradiomycins (e.g., 1 and 3, Figure 1A), which featuredensely functionalized, chiral halocycle appendages, remainelusive, representing an exciting arena for synthetic develop-ment.Azamerone is structurally unique among the napyradiomy-
cins. It is the lone example of a phthalazinone-containing naturalproduct.3 Moore has postulated that this nitrogen!nitrogenbond-containing heterocycle arises from oxidative rearrange-ment of SF2415A1 (5) via intermediate 6 (Figure 1B).3a,b Inaddition to its unusual hetereocycle, azamerone’s highlyoxidized structure, diversity of heteroatoms, two stereogenictertiary alcohols, and two distinct chlorine-bearing stereogeniccenters pose signi!cant synthetic challenges. We envisaged thatazamerone could be retrosynthetically traced to a chlorobenzo-pyran, tetrazine, and chlorocyclohexane of general forms 7, 8,and 9 (Figure 1C). A challenging enantioselective chloroether-i!cation on prenyl-containing hydroxyquinone 10 (a reactionwith no enantioselective variants, Figure 1D), a hinderedcarbon!carbon bond formation between 9 and 7, and anelectronically mismatched late-stage tetrazine Diels!Alderreaction were thus identi!ed as key challenges for this chemicalsynthesis.Our synthetic approach !rst required the assembly of
enantioenriched chlorocycles 7 and 9. Biosynthetically, thechlorocycle motifs found in 7 and 9 are proposed to derive fromchloronium-initiated cyclizations of the prenyl and geranylfragments within 5 (Figure 1B,C).4 Neither of these trans-
formations have enantioselective, synthetic parallels (Figure1D).5 In fact, the use of enantioselective halogenation in naturalproduct synthesis has been limited thus far to the enantiose-lective bromochlorination and dichlorination of ole!ns.2b,6
Cognizant of these methodological gaps and the challenge ofchiral organochloride synthesis in general, we set out to developa new method for enantioselective chloroetheri!cation toproduce a benzochloropyran akin to 7 and to discover ameans for resolving the enantiomers of chlorocycle 9, which waspreviously made in racemic form (9, X = OAc, Figure 1C).9a
De novo development of an enantioselective chloroether-i!cation required the identi!cation of a substrate that not onlywas amenable to asymmetric halogenation but also could beparlayed into a synthesis of azamerone. Although considerableadvances have been made in the area of intramolecular catalytic,enantioselective chlorolactonization and chloroetheri!cation,high selectivity has been achieved only for styrenyl substrates;use of nonstabilized ole!ns is accompanied by a precipitous dropin enantioselectivity.5,7 After extensive investigation of potentialsubstrate structures and chiral catalysts, we discovered thatprenylated hydroxyquinone 11 could be chlorocyclized to abenzochloropyran by a TADDOL-ligated titanium complex andtert-butyl hypochlorite in modest yield and 10% ee (entry 1,Table 1). Application of other common systems forenantioselective chlorofunctionalization, including cinchonaalkaloids, returned racemic product.7 Unexpectedly, under theconditions of entry 1, ortho-quinone 12 was formed as the majorproduct. Signi!cant enol chlorination was observed withformation of a racemic !-chlorinated triketone byproduct.Initial formation of intermediate 13 is proposed, as this isconsistent with our hypothesis in a related dihalogenationsystem that a coordinatively saturated octahedral titaniumcomplex is necessary for high selectivity.6d Chloroether 12 likelyarises via trapping of the chloronium by the vinylogouscarboxylate carbonyl oxygen in 14; however, titanium is notnecessary for such regioselectivity, as the racemic product couldbe produced in 52% yield solely by the action of tert-butylhypochlorite (see Supporting Information). We anticipated that12 could be leveraged as a precursor to a para-quinoneintermediate for the synthesis of azamerone and, therefore,pursued optimization of this chloroetheri!cation.A survey of chiral ligands a"orded optimal TADDOL ligand
B,8 which produced chloropyran 11 in increased yield but withsimilarly low enantioselectivity (entry 2, Table 1). Althoughcomparable to ligand A under the conditions of entries 1 and 2,acyclic ligand B proved to be more selective and higher yieldingacross a broader range of conditions and was selected for further
Received: November 22, 2018Published: February 1, 2019
Communication
pubs.acs.org/JACSCite This: J. Am. Chem. Soc. 2019, 141, 2867!2871
© 2019 American Chemical Society 2867 DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
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racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Why amazerone?
• Highly oxidized structure• Diversity of heteroatoms• Two stereogenic tertiary alcohols• Two chlorine in the structure• 5 chiral center
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
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2869
optimization e!orts. Screening of reaction solvents revealed that2-methyltetrahydrofuran increased the selectivity of thechloroetheri"cation to 57% ee (entries 3!8, Table 1). Use ofother electrophilic chlorine sources led to a reduction in theyield or enantioselectivity of the process (entries 9!11, Table1). Hypothesizing that adventitious acid could be promoting aracemic background reaction, we found that inclusion ofheterocyclic base additives, such as pyridine and quinoline,increased the enantioselectivity of chlorocyclization (entries 12,13, Table 1); the precise role of these additives is unclear, butthey could serve as general bases, activating agents for transfer ofelectrophilic chlorine, or ligands on titanium. Employing astoichiometric amount of titanium and chiral ligand deliveredonly amodest increase in selectivity but a dramatic improvementin yield (entry 14, Table 1). Increasing the amount of tert-butylhypochlorite to 1.3 equiv provided an improvement in yieldwhen using 25 mol % titanium and ligand (entry 15, Table 1).
Gratifyingly, performing the reaction on 4 g scale under theseconditions resulted in an isolated 40% yield (entry 16, Table 1),which was deemed su#cient for completing the synthesis.With an enantioselective chloroetheri"cation in hand, we
commenced our synthesis of azamerone. Prenylquinone 11,which can be made in two steps from commercially availablematerials, was cyclized to chloropyran 12 using our optimizedconditions (Scheme 1). Treatment of this ortho-quinone withaqueous acid induced hydrolysis and isomerization to anintermediate 2-hydroxy-para-quinone, which was smoothlyconverted to its corresponding ortho-chloro-para-quinone 15with oxalyl chloride and dimethylformamide (DMF). Pyrano-quinone 15 is embedded within nearly all members of thenapyradiomycins (e.g., 1!4, Figure 1).Our synthesis of the chlorocyclohexane of azamerone focused
on "rst establishing a means to resolve racemic 16 (Scheme 1).In 2010, the Snyder group reported the direct chlorocyclizationof geranyl acetate with chlorodiethylsulfonium hexachloroan-timonate (see Scheme S2 in the Supporting Information).9a
This reaction provides the primary acetate of diol 16 in racemicform. Important recent work by Gulder,9b along with a protocolused here by Snyder9c on a mercury-based two-step mimic forhalopolyene cyclizations, provided strategies for accessing
Figure 1. (A) Representative napyradiomycin meroterpenoids. (B)Proposed biosynthesis of azamerone. (C) Retrosynthetic analysis ofazamerone. (D) Methodological gap.
Table 1. Enantioselective Chloroetheri!cation Optimization
aReactions were conducted on a 0.035!0.176 mmol scale, and 1HNMR yields are reported based on 1,4-dinitrobenzene as internalstandard. b100 mol % ClTi(Oi-Pr)3, 100 mol % B. c1.3 equiv of t-BuOCl. dReaction conducted on 4.0 g of 11. eIsolated yield.
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DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
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racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
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S4
3. Azamerone Synthesis Scheme
Scheme S1. Full synthesis of azamerone
PhOO
OO
MeMeCl
aq. HClO477%
O
OO
Cl
MeMe
Cl
O MeMe
ClO
N2
ClTf2Othen DBU
80%
BH3ŎSMe2
71%
BOOH
Me
MeMe
Cl
MeMe
Cl
OHMe
MeMe
Cl
OHMe OH
90% ee
O
OH
MeMe
ClCl
MeHO
MeMe
Cl
+
SPhos-Pd G3
K3PO4
NN
O
O
MeMe
Cl
MeO
Me
MeMe
Cl
H
TBSO OH
H H
H
O
O
MeMe
Cl
MeTBSO
MeMe
Cl
OH
H
SPhos-Pd G3K2CO3, i-PrOH
56%
34%overall
TsNHNH2then NaOH
46%
12
15
ClTi(Oi-Pr)3 (25 mol %)lig. B (25 mol %)
t-BuOCl (1.3 equiv)
quinoline (1.0 equiv)2-Me-THF, -78 ˚C
40%, 84% ee[4 grams]11
17(–)-16 18
19
2021
1-TBS
OH
OPhO
OOMe
OH
OMe
PhOO
O
(COCl)293%
S4
S1S3
OHHORef. 1
OMeOMe
BBr3;
air, CuSO496%
Proton Sponge®
64%I
Me
Me
S2
PhMgBr
99%
MeMe
Cl
OHMe O
H
OPh
OMe
MeMe
Cl
OHMe OAc
H
MeMe
HgCl
OHMe OAc
H
MeMe
Me OAc
Cl2, LiCl64%
S5
S6
MeMe
Cl
OHMe OH
H
(±)-16
K2CO3MeOH
82%
(+)-S7
Cl
OPh
OMe
HO
OPh
OMe
pyridine33%
K2CO3MeOH
95%
S9
O
OH
MeMe
Cl
MeHO
MeMe
Cl
H
S8
PhI(OTFA)242%
TBSOTf;NaOH87%
O
OH
MeMe
Cl
MeTBSO
MeMe
Cl
H
NN N
N
MeHO
MeOMe
NH•HCl
OHNH•HOAcH2N
1. H2NNH2•H2O
2.
3. NaNO2, HCl 5%22
BBMe
Me
NN
23
110 ˚C
NN
O
O
MeMe
Cl
MeO
Me
MeMe
Cl
H
HO OH
1: azamerone
NN
O
O
MeMe
Cl
MeHO
Me
MeMe
Cl
H
TBSO OH
S10
O
OO
Cl
MeMe
HOPhO
O
OOH
Me
Me
HCl
commercially availableHg(OTFA)2then NaCl
(COCl)2DMF
commercially available
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Starting materials:
Chem. Ber. 1968, 101, 3744-3752.
OH
OH
MeOH, MeONa O
O
MeO
MeOS2
Br92.4 mmol
NaI(1.1 equiv)
Iacetone, air
O
O
OH
Ar Ar
OH
Ar
Ar + ClTi(Oi-Pr)3O
O
O
Ar Ar
O
Ar
Ar Ti O-iPrO-iPr
3.52 mmol
hexane, 10 min0.25 equiv
O
NH
OHH Cl H2N NH2
H O H+
1 equiv2.5 equiv
MeOH, 0 oC, 1 h
NHH2NO
OH2.5 equiv
rt, 2 h
NN N
N
HO
22
NaNO28 equiv
0 oC, 30 min5%
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Step 1:
OH
OH
MeOH, MeONa O
O
MeO
MeOS2
356 mmol
THF, -78oC
Br
2.5 equivMg
2.6 equivTHF, -78oC, 1h
rt, 12hOMe
OMe
OHPhO
S199%
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Proposed mechanism:
OH
OH
MeOH, MeONa
O2
O
OH
O O O
OHO-O
O
O
OMe
MeO O
O
O O O
O
MeOH
MeO O
O
O
O
MeO
MeOS2
356 mmol
OMeOMe
OHPhO
S199%
MgBr
OMeOMe
OMgBrPhO
Step 2:
OMeOMe
OHPhO
S1353 mmol
DCM, -78oC, 30 min
BBr32.2 equiv
rt, 1h
OHO
OPhO
S396%
CuSO4
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Proposed mechanism:
OMeOMe
OHPhO
S1353 mmol
DCM, -78oC, 30 min
BBr3
rt, 1hOMeBBr3
OMe
OHPhO
MeBrOBBr2
OMe
OHPhO
+
OBBr2OBBr2
OHPhO CuSO4
OHO
OPhO
Step 3, 4:
OHO
OPhO
S323.1 mmol
dioxane, rt, until dissolved
Proton SpongeI
(2 equiv)
24 h OHO
OPhO
1164%
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Step 5, 6:
OHO
OPhO
1114.07 mmol
OTi
OO-iPrO-iPr
ArAr
Ar Ar
O
O
2-Me-THF, rt, 10 min
(0.25 equiv)
N(1 equiv)
OO
OPhO
1240%, 80%ee
Cl
t-butyl-hypochlorite(1.3 equiv)
hexane, -78oC, 16 hrt, 1 h
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
OCl
Proposed mechanism:
J. Org. Chem. 1995, 60, 6847-6851
optimization e!orts. Screening of reaction solvents revealed that2-methyltetrahydrofuran increased the selectivity of thechloroetheri"cation to 57% ee (entries 3!8, Table 1). Use ofother electrophilic chlorine sources led to a reduction in theyield or enantioselectivity of the process (entries 9!11, Table1). Hypothesizing that adventitious acid could be promoting aracemic background reaction, we found that inclusion ofheterocyclic base additives, such as pyridine and quinoline,increased the enantioselectivity of chlorocyclization (entries 12,13, Table 1); the precise role of these additives is unclear, butthey could serve as general bases, activating agents for transfer ofelectrophilic chlorine, or ligands on titanium. Employing astoichiometric amount of titanium and chiral ligand deliveredonly amodest increase in selectivity but a dramatic improvementin yield (entry 14, Table 1). Increasing the amount of tert-butylhypochlorite to 1.3 equiv provided an improvement in yieldwhen using 25 mol % titanium and ligand (entry 15, Table 1).
Gratifyingly, performing the reaction on 4 g scale under theseconditions resulted in an isolated 40% yield (entry 16, Table 1),which was deemed su#cient for completing the synthesis.With an enantioselective chloroetheri"cation in hand, we
commenced our synthesis of azamerone. Prenylquinone 11,which can be made in two steps from commercially availablematerials, was cyclized to chloropyran 12 using our optimizedconditions (Scheme 1). Treatment of this ortho-quinone withaqueous acid induced hydrolysis and isomerization to anintermediate 2-hydroxy-para-quinone, which was smoothlyconverted to its corresponding ortho-chloro-para-quinone 15with oxalyl chloride and dimethylformamide (DMF). Pyrano-quinone 15 is embedded within nearly all members of thenapyradiomycins (e.g., 1!4, Figure 1).Our synthesis of the chlorocyclohexane of azamerone focused
on "rst establishing a means to resolve racemic 16 (Scheme 1).In 2010, the Snyder group reported the direct chlorocyclizationof geranyl acetate with chlorodiethylsulfonium hexachloroan-timonate (see Scheme S2 in the Supporting Information).9a
This reaction provides the primary acetate of diol 16 in racemicform. Important recent work by Gulder,9b along with a protocolused here by Snyder9c on a mercury-based two-step mimic forhalopolyene cyclizations, provided strategies for accessing
Figure 1. (A) Representative napyradiomycin meroterpenoids. (B)Proposed biosynthesis of azamerone. (C) Retrosynthetic analysis ofazamerone. (D) Methodological gap.
Table 1. Enantioselective Chloroetheri!cation Optimization
aReactions were conducted on a 0.035!0.176 mmol scale, and 1HNMR yields are reported based on 1,4-dinitrobenzene as internalstandard. b100 mol % ClTi(Oi-Pr)3, 100 mol % B. c1.3 equiv of t-BuOCl. dReaction conducted on 4.0 g of 11. eIsolated yield.
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Step 7, 8:
O Cl
OO
PhO
122.98 mmol
Et2O, rt, 1 h
HClO4(1.3 equiv)
O Cl
O
O
S477%
OH
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
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O Cl
O
O
1593%
ClDMF
(1.4 equiv)
+Cl
Cl
O
O(1.1 equiv)
acetonitrile, 0oC, 10 min
O Cl
O
O
S4 OH
DCM
Step 9-11:
Hg(CF3COO)2
O
O+
1.1 equiv 1 equiv MeNO2, -15 oC, 3 hOAc
HgCl
HHO
OAc
HgCl
HHO
S5
S567 g crude mass
LiCl3 equivCl2, Ar
Pyridine, -40 oC
OAc
Cl
HHO
S664%
K2CO32 equiv
92 mmol
MeOH, 50 oC, 30 min
OH
Cl
HHO
(+)1682%
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
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Step 12, 13:
DMF
(1.4 equiv)
+Cl
Cl
O
O(1.1 equiv)
acetonirle, 0oC, 10 min
O OH
O
Cl
OPh
OMe
OH
Cl
HHO
(+)1653 mmol
pyridine, 20 min
O
Cl
HHO
(+)S733%
OPh
OMe
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
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Step 14:
O
Cl
HHO
(+)S714 mmol
OPh
OMe
K2CO3(2 equiv)
MeOH, 50 oCOH
Cl
HHO
(-)1695%, 90%ee
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
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Step 15-18:
OH
Cl
HHO
(-)1626.1 mmol
N
(1.2 equiv)
DCM, -78 oC
(1.05 equiv)
DCM, -78 oC
Tf2O DBU(2.5 equiv)rt, 12 h
Cl
HO
1780%
Cl
HO
174.36 mmol
(1.4 equiv)
THF, 0 oC, 5 min
BH3.SMe2
rt, 18 h
O
Cl1871%
BOH
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
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Step 19, 20:
O Cl
O
O
150.126 mmol
Cl
S O
O NHNH2
(1.1 equiv)
MeOH, rt, 30 min O
O
N2
Cl Cl
19
NaOH
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Step 21:
O
O
N2
Cl Cl
19
O
Cl181.1 equiv
BOH
+
crude
(SPhos)Pd-G30.1 equivK3PO4
1.3 equivDioxane, 60 oC, 30 min
OH
Cl
O
OHCl
Cl
2046%
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
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Step 22, 23:
OH
Cl
O
OHCl
Cl
20
0.36 mmol
(SPhos)Pd-G30.1 equivK2CO3
2 equiv
90 oC, 50 min
i-Propanol
OH
Cl
O
OH
Cl
56%S8
OH
Cl
O
OH
Cl
0.2 mmolS8
TBSOTf3 equiv
i-Pr2NEt4 equiv
DCM, rt, 18 h
NaOHOSBT
Cl
O
OH
Cl
87%S9
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
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Step 24:
OSBT
Cl
O
OH
Cl
0.027 equivS9
CH3CN/H2O(10:3), 30 s
PhI(OTFA)21.1 equiv OSBT
Cl
O
OH
Cl
42%21
OH
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
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Step 25:
O
NH
OHH Cl H2N NH2
H O H+
1 equiv2.5 equiv
MeOH, 0 oC, 1 h
NHH2NO
OH2.5 equiv
rt, 2 h
NN N
N
HO
22
NaNO28 equiv
0 oC, 30 min5%
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
Proposed mechanism:
ON
O
HHO
NO
HH2O
NO N O
O
NH2
OHH2N NH2
+
NH2H2N
ONH2
OHH2N
NH2
NH
NH
OH
NH2
HNHN
OH
NH2H2N NH2
HNH2N
OH
NH2HN NH2
H2N NH2
HNH2N
OH
NH2HN NH2
NH2NH2
NN N
N
HONO
Step 26, 27:
NN N
N
HO
225 equiv
OSBT
Cl
O
OH
Cl
0.018 mmol21
OH+ +
NN
HS
S
23 CF3Ph, 110 oC, 2 d
NN
O
OHO
Cl
TBSO
Cl
101 equiv
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
NN N
N
HO
225 equiv
++NN
HS
S
23 1 equiv CF3Ph, 110 oC, 2 d
NN
O
OO
Cl
TBSO
Cl
1-TBS
NN
O
OHO
Cl
TBSO
Cl
10 34%
Step 28:
racemic chlorocycle 16 (Scheme 1). Attempts to catalyticallyresolve diol 16 by either chemical or enzymatic means were metwith limited success. Investigations into resolution by chiralderivatization revealed the (S)-!-methoxyphenylacetic ester ofdiol 16 to be uniquely competent in providing chromatographicresolution of diastereomers on silica gel.10 This result isnoteworthy given the challenges associated with resolvingprimary alcohols,11 and we anticipate that access toenantioenriched diol 16 will enable syntheses of otherchlorinated natural products. Using this approach, multigramquantities of racemic diol 16 can be separated into itsconstituent enantiomers.We next investigated the coupling of quinone 15 and an
appropriate derivative of chlorocyclohexane (!)-16. Initialstudies attempted to unite these pieces through a 1,2-addition ofgeneralized organometallic 9 (X = metal, Figure 1C) into themore electrophilic carbonyl of 15. These e!orts were hampereddue to Grob-type fragmentation of organometallic 9, whichoccurs at temperatures above !78 °C, and due to preferentialreduction of the quinone by organometallic reagents. Owing tothese obstacles, a cross-coupling approach was adopted for theunion of these fragments (Scheme 1). Chemoselectivedehydration of the primary alcohol in 16 with tri"ic anhydrideand diazabicycloundecene (DBU) provided ole#n 17, whichwas hydroborated to form boronic hemiester 18 in good yieldand diastereoselectivity. Boronic hemiester 18 is stable tocolumn chromatography, allowing for facile removal of a minor
diastereomer; X-ray crystallographic analysis of racemic 18unambiguously veri#ed its relative con#guration. This cross-coupling partner has precedent in the synthesis of sclareolidederivatives and was chosen to attenuate Grob-type fragmenta-tion.12
Quinone 15 was joined with boronic hemiester 18 through aquinone diazide-based coupling strategy (Scheme 1). Chemo-selective condensation of tosyl hydrazide with quinone 15followed by treatment with base provided intermediate quinonediazide 19, which was directly used as a cross-couplingelectrophile without puri#cation. Screening of conditionsrevealed that SPhos-ligated palladium was able to catalyzeCsp
3!Csp2 bond formation between sterically hindered boronic
hemiester 18 and quinone diazide 19, providing phenol 20 in46% overall yield from 15. Quinone diazide 19 was completelyconsumed in this reaction, and no elimination of either alkylchloride was observed. The structure and relative con#gurationof phenol 20 was con#rmed via X-ray crystallography of itsacetate. Small amounts of another diastereomer were produceddue to the presence of minor enantiomers of each substrate.Limited precedent exists for Suzuki reactions with quinonediazides, and to the best of our knowledge, this represents the#rst example of this reaction type with a Csp
3 nucleophile.13
Subsequent dechlorination, silylation, and hypervalent iodine-mediated para oxidation14 of phenol 20 provided the desiredstereoisomer of para-quinol 21 as the major product in 42%yield (Scheme 1). Protection of the tertiary alcohol of 21 was
Scheme 1. Short Enantioselective Synthesis of Azameronea
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-THF, !78 °C, 40%,84% ee; (b) HClO4(aq) (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN, 0 °C, 93%; (d) Hg(OTFA)2 (1.1equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 °C, 52% overall; (f) Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU(2.5 equiv), DCM, !78 °C to RT, 80%; (g) BH3·SMe2 (2.0 equiv), THF, 0 °C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1 MNaOH(aq), DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2!-amino-1,1!-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv),dioxane, 60 °C, 46% over 2 steps, 10:1 dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 °C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv), DCM then 3 M NaOH(aq) (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.8b12566J. Am. Chem. Soc. 2019, 141, 2867!2871
2869
NN
O
OO
Cl
TBSO
Cl
1-TBS
0.0072 mmol
HCl (12 M)
MeOH/DCM, 5 h
NN
O
OO
Cl
HO
Cl
Azamerone
84%