Baran Group Meeting Ruben Martinez Creativity From The : Sugar Edition 06/30/14

Disclaimer Molecular Target Categories Cat. 1: Apparent Carbohydrates This group meeting is in no way meant to be The target structure can be broken down into three categories based Usually a lightly modified carbohydrate comprehensive. There is an enormous body on how easily it can be traced back to the chiral carbohydrate pool. appended to a structure via glycosidation. of literature featuring sugar starting Very easy to spot. materials in total synthesis of which this group meeting is only a sample. Any comparison Typical Reaction Channels Cat 2: Partially hidden carbohydrates made between syntheses are for educational One or two chiral centers may have been and discussion purposes only. Working from a feedstock carbohydrate is difficult, time consuming and wasteful. Entry into any reaction channel toward an enantiopure removed. Still contains carb. oxidation building block is mostly limited to chemistry dating back over 100 pattern. Identification likely requires Resources years in the carbohydrate literature. The initial stage always involves squinting. The following books and reviews are excellent the fixation of the sugar in the respective tautomeric form. resources and were very helpful in the Cat. 3: Totally Hidden Carbohydrates preparation of this group meeting. O OH Identification of carb. SM unlikely. Usually OH OH based around application of in-house Total Synthesis of Natural Products: O SEt methodology. The "Chiron Approach" O HO Stephen Hanessian ISBN-10: 0080307159 O OH OH SEt O *These are my simplified definitions based Design and Strategy in Organic Synthesis diacetonide dithioacetal on Hanessians own in depth definitions, Stephen Hanessian ISBN-10: 3527319646 examples and analysis. + Me2CO/ZnCl2 EtSH/H Organic Synthesis with Carbohydrates OH Important Reactions to Keep In Mind Geert-Jan Boons ISBN-10: 1850759138 90% 70% Tracking Treasure Down: HO OH Type I Ferrier reaction Hanessian's "Rule of Five" Natural Abundance OH O L.A. O Nuc Carbohydrates are the single most abundant class of organic 1) Select an sp, sp2, or sp3-hybridized carbon atom in HO O R1 Nuc. R1 compounds associated with living matter. target structure + MeOH/H 1) BzCl R2 R2 ACS Symposium Series 841 2003, 47. 2) Move five bonds away and look for a heteroatom 1) Ac2O 70% 2) Br regardless of functionality in between. These two 2) Br2 2 LG 3) Et NH Is sugar derived right for me? internal reference points correspond to the anomeric 3) Zn/AcOH 2 85% - End differentiated oxidation state C-1 and the C-5 oxygen atoms in the 70% OBz OH OAc - Stereochemical diversity hexapyranose structure BzO OBz Type II Ferrier rearrangement HO OH OAc - Carbon chain length varying between 3-7 carbons 3) Look at only that carbon chain and try to imagine - Strong conformational bias 4 L.A. a suitible chiral sugar SM. O O OR O OH - Ability to introduce other heteroatoms (N, S, X) with inversion MeO O O H2O or retention of configuration OBz An Example: OH - Ability to branch using a C nucleophile OAc R1 R3 R1 R3 glucoside - Excellent conformational bias and stereoelectronic effects OH glucal hydroxyglucal 2 2 HO R R maximize predictive outcomes based on models C5 H H H H C5 OR C1 Arguably the Most Useful Sugar Based "Chiron" for Modern Total Synthesis Why don't we see more syntheses based on chiral sugars? S NH 2 C1 For every one unit of D-mannitol N HO C NH (R)-2,3-O-isopropylideneglyceraldehyde - Overfunctionaliztion with hydroxyl groups that O 2 2 subjected to protection/oxidative have similar or identical reactivity CO H OH OH cleavage two desired aldehydes are 2 2 steps O - Number of chiral centers present on starting formed. The resulting aldehyde is higly thienamycin OH carbohydrate often excessive for the synthetic chemist NH2 HO O O prone to polymerization and hydrolysis. - Lack of suitible functional groups (olefin, carbonyl) OH OH OH Long term storage is not recommended to which modern organic techniques can be applied 25g $53.00 (Oakwood) - Outcome of chemical transformations are unique to For full, indepth explanation C1 C5 D-mannitol For (S)-derivative see: each sugar based on individual with details see pg. 236 in: HO O available in 2 steps from D-mannitol 100g $16 (Oakwood) Org. Syn. 1995, 72, 1. - Development of outstanding asymmetric methodology Design and Strategy in Organic Synthesis OH Org. Syn. 1998, 9, 450. Synlett 2001, 10, 1565. Stephen Hanessian ISBN-10: 3527319646 Some Easily Accessible/Commercial/Useful Sugar Based Chirons Full exploitation of sugar starting materials OH - Retention of the carbon-chain of the sugar OH OH OH OH TsO OH - Reaction sequence should be simple, high yielding with no HO OBz HO Cl N3 Cl HO OH chromatography. Focus on generating crystaline products. Different Representations - Avoid protecting groups or use simple, easy to remove PGs O O - Cost. HO OH MeO MeO MeO O MeO O O OH O HO 5 O HO OH Br OTs Cl OH On practicality: reality vs. raw concept 5 O 3 OAc OH 1 HO 1 5 HO HO There are a huge variety of chiral carbohydrates available in HO 1 OAc HO HO OR OH O O O O principle. However, the pool shrinks immensely when practical 3 3 OH HO O and operational considerations are applied leaving a relatively OH OH OH small number of realistic chiral sugar starting materials. O MeO O O RO O OR α-D-glucopyranose HO Me HO Br MeO OAc OAc Baran Group Meeting Ruben Martinez Creativity From The Chiral Pool: Sugar Edition 06/30/14

OH Total Synthesis of (+)-Ambruticin Total Synthesis of (+)-Ambruticin 5 OH Kende's chiral sugar approach Me Jacobsen's asymmetric catalysis approach

12 15 Jacobsen J. Am. Chem. Soc. 2001, 123, 10772. Kende, A. J. Am. Chem. Soc. 1990, 112 , 9645. O 1) BH3THF then 8 O OTBS 1 OTBS OTBS 30% H O , 3 N NaOH CO2H Me Me Me 24 O 2 2 OTBS Me catalyst 1 (10 mol%) 2) TBSOTf, 2,6-lutidine (+)-Ambruticin (Cat. 1: apparent carbohydrate) + 1) TBDPSCl, Im H OTBDPS 3) Pd/C, H H OBn OBn OBn 1) (COCl) , DMF(cat.) 64% 2 O 2) Im2CS then 1) TBAF 2 O 4) TPAP (cat.), NMO BnO 97% ee O BnO OH Bu SnH BnO 2) PDC then CH2N2 OBn 3 OBn TBDPSO TBDPSO C OH 2) hν Me MeO O MeO O MeO O 53% over OTBDPS O OH two steps OTES catalyst 1 TESO O Me Name rxn? (5 mol%) + OTBS N O 87% OBn Me H OBn OBn Cr 99% ee O 1) Ac2O, H2SO4 (cat.) BnO BnO BnO Cl OTBS Me 2) NaOMe, MeOH O Me Et2NSF3 catalyst 1 1) BH3THF F O 92% HO O MeO O then 10% HCl CO Me CO2Me 2 CO2Me 2) Swern ox. 73:27 β:α CH2CHMgBr 1) Bu SnCu(Bu)CNLi A Me Pd(PPh ) (5 mol%) Me 3 2 Me Me 3 4 MeI, DMPU TMSC(Li)N2 Cl 1) 10% KOH LiTMP (EtOH/H O, 9:1) 2 CO Men 2) I 71% MenO C then MenO2C CO2Men 2) B H /THF 2 O I O 2 O O 2 CO Men Me Br 2 6 O 2 Me Me Me Me Me O Me 45% 3) Swern ox. Men = l-menthyl Me Me as a single see: JACS 1985, 107, 3343. 1) Ph3P, CBr4 Rh(acac)(CO)2 2) DIBAL 73% over (S, R)-BINAPHOS 3) TrCl, DMAP, four steps H2/CO OBn TEA OBn 1) ethyl acrylate OBn 4) n-BuLi Me 1) pTSA(cat.) OBn O Pd(OAc)2 (10 mol%) CrCl2, CHI3 I R Ag CO R 2) DMP 1) DIBAL 2 3 HO O O OTr O O OTr Me 2) DIBAL Me CO2Me 2) A Me Me Me Me CO2Me Me R B Me Name rxn? dr = 96:4 Zn(CH3CHI)2 DME Me L* 1) LiHMDS, DMF/HMPA O Me Me (COCl)2, PPh3, PTSH, DEAD O Me C Tol R DMF (cat.) S then Mo(VI)/H2O2 R HO Me HO O O O H HO C O Me 2 SnMe Me hydroquinone (cat.) 3 O Me Me Me then Me Me 2) chiral [Pd] cat. 1) MeMgBr resolution HMPA 2) Ac2O, DMAP, TEA 3) LDA then TBSCl, HMPA OTBS then acid 1)TBAF OTBS Me 4) CH2N2 2) Pt, O2 H2O/acetone 1) n-BuLi then B Me (+)-Ambruticin SO Tol 1) LDA Me 2) Na(Hg) 2 then PTSF O (+)-Ambruticin O H O 2) (Me) N+-OAc MeO C O OTBDPS Me Me Me 3) LiOH THF/H2O 4 2 Me Me Me HMPA Me 4) Li, NH3 (l), EtOH Me Me Me Baran Group Meeting Ruben Martinez Creativity From The Chiral Pool: Sugar Edition 06/30/14

HO III OH Sm Ph Synthesis of Trehazolin from D-Glucose: MeO OBn BnO HO OH O following a plausible biosynthesis HO N OBn Giese, B. J. Org. Chem. 1998, 63, 5877. N H OBn N O O O SmI2 MeO Trehazolin from trehazolamine is known in the literature OH BnO O N O see J. Org. Chem. 1994, 59, 813. HO H O O OH O Ph O BnO NHOMe Trehazolin HO Ph A speculated biosynthesis OH OH Ph Ph Ph OH O O HO HO O O O +CO2 HO HO O O O O HO Li -2 H O HO HO LAH HO 2 BnO BnO H BnO HO OH O OH N N O Al H C HO NH 1 1 H BnO NHOMe 2 3 BnO NOMe BnO N N OH MeON O 3 HO 5 OH 5 OH OH HO HO The Crimmins' Synthesis of Trehazolin: The and RCM approach J. Org. Chem. 2001, 66, 4012. OH OH 1) TBSOTf TBSO O O 1) LiBH4, MeOH O O OH O O 2) TsNCO O O Bu2BOTf 2,6-lutidine HO HO TEA 2) Grubbs' I N O 3) I2, K2CO3 HO pinacol type HO selective N O N O HO coupling HO oxidation then O 4) DBU 92% for RCM step Bn Bn Bn HN O N O H 63% N OH N OH O OHOH OH OTBS OTBS OTBS Trehazolin OH OAc OAc HO K2CO3 1) DMDO 1) Na naphthalide MeOH HO 2) CSA 2) (Boc) O, TEA, DMAP 2 O Giese's reductive cyclization approach 3) Cs2CO3, MeOH 4) Ac O, TEA, DMAP N Ph Ph Ph O NH 61% over two steps NHBoc 2 Ts O O O O O O SmI (5 equiv.) O O 1) MeONH2•HCl, py 2 1) Ac2O, py, DMAP 2) DMP t-BuOH(2.5 equiv.) BnO 2) Pb(OAc)4 BnO O BnO O OH 84% single diast. BnO OH BnO NHOMe OTBS BnO NOMe OH OTBS TBSO 1)o-NO C H SeCN OH HO 2 6 4 HO n-Bu P HO OsO , NMO 3 4 OH 2) H2O2 O NH O NH O NH Ph Ph OH O BnO OBn O O OH O O O O HO 1) K2CO3, MeOH Na, NH (l) BnO 2) LAH, NaOMe BnO SCN OBn OH 3 OH OAc O AcO OAc HO NH2 BnO NHOMe BnO NOMe AcO 1) 2 N KOH, EtOH HO OAc 2) Ac2O, py, DMAP trehazolamine trehazolin known steps AcO NHAc formal synthesis see J. Org. Chem. 1994, 59, 813. peracylated trehazolamine Baran Group Meeting Ruben Martinez Creativity From The Chiral Pool: Sugar Edition 06/30/14

OH OH O Total Synthesis of (+)-Lycoricidine from D-Glucose Total Synthesis of Echinosporin Ogawa, S. J. Org. Chem. 1993, 58, 4441. Smith III, A. J. Am. Chem. Soc. 1989, 111 , 8039. HO O OH O CONH2 O NH O H O H Lycoricidine (–)-Echinosporin Br O 1) Me CO, Me C(OMe) 1) DIBAL OMOM HO 2 2 2 OH 1) MOMCl 1) Hg(TFA)2 (1 mol %) OMOM O 2) 30% H O (aq.), CaCO 2) MeOH, PPTS O 2) DBU O MsCl, TEA O 2 2 3 O HO O then Pd/C 3) Me2CO, H2SO4 HO O CO2Me MeO OMOM HO OMOM MeO OH HO OH 3) DHP, PPTS O N3 OTHP O N3 N3 4) Me2SO4, NaHCO3 Carbohydr. Res. 1974, 35, 175. L-ascorbic acid

1) LAH then 1)LDA, O O Br O 2)Tf2NPh (72%) 1) Swern ox. H (10 eq.) 3) Pd(OAc)2, PPh3, CO O O 2) NH2NHTs OPMB O OH OPMB O 1) Luche red. TEA, MeOH, DMF (83%) 3) Na, (CH2OH)2 OMOM OMOM OMOM O O 2) PMBCl, NaH O hυ, uranium filter O O Name rxn? H 50% Br OMOM (EtO)2P(O)CN, TEA OMOM OMOM

NMPM 2) MPMCl, NaH N3 N3 O O O CO Me 1) KHMDS, HMPA CO Me 2 CO2Me 2 HO H then Davis oxaziridine HO Pd(DBA) CHCl OPMB OH H H 3• 3 OH O 2) acidic resin OH diallyl carbonate OMOM OH 2 C2 inversion via 90% OH 50% O Pd(OAc) (10 mol%) Mitsunobu O H O 2 O O OH H O H O DPPE, TlOAc (2 equiv) OMOM NH DMF O NMPM deprotection O O 5 steps O Lycoricidine CO Me CO2Me 2 OH HO H HO H Parikh-Doering ox. NH4OH, MeOH CONH2 CONH2 46% 86% O formal anti-elimination? H H OH HO

Br OMPM O H OPMB OPMB Pd OMOM OMOM HO OMOM O H 1) 3.6 N HCl CONH syn-elimination O 2) Bu P, DEAD (28%) 2 Br O OMOM OMOM 3 O Pd OMOM NMPM H O NMPM O NMPM H (–)-Echinosporin O O O O not observed! O Baran Group Meeting Ruben Martinez Creativity From The Chiral Pool: Sugar Edition 06/30/14

Total Synthesis of (–)-Tetracycline Total Synthesis of Fomannosin Tatsuta, K. Chem. Lett. 2000, 647. Paquette, L. Angew. Chem. Int. Ed. 2007, 46, 7817. Tetracycline from a sugar? 1) DBU NO 2) Pd/C, H 1) TBDPSCl 1) 2 MeO C O 2 HO O TBDPSO O 2 O 3) MeOH, acid OMe 2) DIBAL OMe OBn 1) HgCl2 MeO2C OBn 1) TBSCl OBn 4) PMB protect. 3) Swern ox 2) Oxidation SeCN BzN 2) MsCl, TEA O OPMB BzN OH BzN OBn 3) DBU TsO 5) LDA, CH2O OPMB 4) Wittig olefination 3) Wittig PBU3 4) HCl 2) BH •THF then MeO O MeO O 3 MeO O H2O2, NaOH OH OH 3) BnBr 1) O3, Sudan III PPh3 2) I 1) 1) Cp ZrCl , n-BuLi NBz NBz 2 2 Me OH NBz H t-BuLi OTBDPS 2) TBSCl, imid. H OBn OBn OBn LDA OTBS OTBDPS 54% 2 steps 3) PDC PMBO OTBS Me OBn OBn 4) TMSCH Li OBn DBMP 2 2) acidic oxidation PMBO OTBS 5)TsOH O OMe OH O OH O O OH

OMe O 1) HO2CCH2COSEt, EDCI 1) Grubbs II 2) IBX 1) OsO4 2) TBAF OH 3) Pd/C, Et SiH 2) Swern ox. Me OH NMe2 3 O Me NBz H H 4) NaBH , KH PO H OH 4 2 4 SOCl , TEA OBn PMBO OH MeOH/AcOH O 2 23 steps PMBO HO 5) TBSCl OBn NH2 OTBS O OMe OH O OH HO O HO H O O Tetracycline

1) SmI2, t-BuOH O 1) Tf2O O 2) TFA O 2) DBU 3) SOCl2, TEA HO O 3) TBAF O 4) DBU O

O O O HO PMBO HO OH OTBS OTBS Fomannosin

Cp Cp PGO O PGO O Zr OMe Cp2ZrCl2 OMe O Cp Zr OPMB Cp OPMB OPG OPMB

PMBO OPG O ZrL2 PMBO OTBS OPG J. Organomet. Chem. 2006, 691, 2083. Baran Group Meeting Ruben Martinez Creativity From The Chiral Pool: Sugar Edition 06/30/14

Synthesis of DS-8108b: from chiral aux to sugar and back DS-8108b continued Daiichi Sankyo Co. Org. Process Res. Dev. 2013, 17, 1430. Sugars: just a bridesmaid, back to the chiral auxiliary Can your sugar do this? Early-stage synthesis O O 1) NaHMDS O O Shi's catalyst O LHMDS Br O O O O BnO OBn oxone HO O Br O O N HO Br LiH, Cl Br 2) LiOH, H2O2 O NH O N 2 eq O N Bn BnO Ph Ph Ph O O MsCl, TEA O 1) Pd/C, H O 1) MsCl, TEA NsHN 2 AcOiPr 2) NsCl, TEA N3 2) NaN3 O Br N O O O HO A BnO NH2 HMTA O N conc. HCl N N O HCl O N N O O Ph NsHN Ph N 63% O O Cl NH O Br O N O K2CO3 N O NsHN N O O Br NsN 89% from A N NsCl NHNs Br NHNs Cl O N O MsO NaHCO3 O Ph O OH H 1) 1-decanethiol, K2CO3 NsHN N OH 2) fumaric acid OH O H2N O DS-8108b 3) recrystalization O O N OH O N 82% 0.2 eq Py-OH H2N N 0.3 eq TEA NsHN Cl NH cat. 2-hydroxypyridine AcOi-Pr cat. TEA O Cl N So where does the sugar come in? N Avoiding chromatography en route to A 67% 1) Pd/C, cyclohexylamine Cl HCOONH O OH OH 4 O 1) NaIO4, KHCO3, H2O O dicyclohexylamine (DCHA) dr = 67:33 OH O H 1) Decanethiol 2) Ph O CO H 2) acetone slurry NsHN N OH Ph O OH 2 K2CO3, acetone-H2O Ph3P 60% OH O 2) fumaric acid 70% O O 3) NaOH N N

1) MeI, NaHCO3 N3 OMs OH O NaN3, TBAC O 2) MsCl, TEA O Cl OH 64% Ph O CO Me 91% Ph O CO2Me 2 Ph O CO2H H H2N N OH O O O N 1) Pd/C, H2 O - 20% overall yield for the sequence No chromatography 2) NsCl, TEA NsHN - no chromatography 24% overall yield N 3) HCl, MeOH - Sequence cost prohibitive (sugar SM) - Insufficient dr Cl 80% HO DS-8108b Baran Group Meeting Ruben Martinez Creativity From The Chiral Pool: Sugar Edition 06/30/14

Sugars: What are they good for? Process R & D synthetic route: a tale of two protecting groups SGLT2 inhibitors. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes. Type 2 diabetes affects 23 million Americans making this area O O n-BuLi O particularly interesting for the development of novel treatments. O O TMSCl/ NMM TMSO TMSO HO THF/PhMe A OH Me Cl O TMSO OTMS HO OH >90% TMSO OTMS O OTMS >70% OTMS O HO O OH HO S F Et HO OH HO OH OH OH Empagliflozin Canagliflozin limited European approval O O PhMe/Ac O HO 1) MSA/MeOH FDA approved Cl OEt AcO 2 OMe OMe TEA/DMAP 2) NaHCO3 HO O AcO OAc 90% OH 83% HO OAc OH

HO OH Et Et OH Dapagliflozin limited European approval O SGLT2 inhibitors, how do they work? 1) Et SiH/BF OEt /H O AcO O 3 3• 2 2 HO The SGLT family includes the Na/glucose co-transporter SGLT1, which is mainly expressed in the 2) 2,2-dimethoxypropane aq. NaOH/EtOH GI tract and is responsible for glucose absorption from the food intake. SGLT2 is mainly AcO OAc HO expressed in the kidneys. SGLT2 is responsible for ~90% of glucose reabsorption in humans. 3) EtOH OAc OH SGLT2 inhibitors work by blocking the reabsorption of glucose in the kidneys. This prevents the build 74% OH up of glucose in the blood and allows for excess glucose to be eliminated via urination. One of the >20:1 β:α in the crude Et most common side effects is genital infection. crystallization purges the α isomer crystalline final intermediate amorphous API Et For an indepth discussion see: Current Pharmaceutical Design 2014, 20, 3647.

O Development of a large scale synthesis of an SGLT-2 inhibitor HO Bristol-Myers Squibb OPRD 2012, 16, 577. O HO OH HO L-phenylalanine Ph COO OH EtOH/H2O HO OH H2O First-generation synthesis The target Et OH NH3 API Et Et

O OH O O O TEMPO/bleach Br BnO BnO A BnO NaHCO3 OH BnO OBn BnO OBn n-BuLi BnO OBn OBn OBn OBn

Et

O O HO BnO BF •OEt /i-Pr SiH H2, Pd/C 3 2 3 HO OH BnO OBn OH OBn

Et Et