Protecting Groups Are Attacked by the by Attacked Are Groups Protecting -Troc -Phthalimido), Benzylidene and Isopropyl- O N CO 2

Home , Diene, List of reagents, Protecting group

REVIEW 4005 2 OMe O Cl OMe O 2 (Scheme 3). 3 3 OAc OAc NO 3 2 O O OMe MeONa (1 mmol) (in MeOH, 1 ml, 1 M) MeOH-CH (50 ml, 9:1), rt O O 2 NH (5 mmol) 4 3 / Table of Contents for this issue this for Contents of Table / G/GHNO N N 2 2 G = guanidine H H , 1998, 4005–4037 OH 6 steps HO R = COCH R = H OTES O 7 OR O 5 6 TBSO O O ) required a mild method for the a mild method for ) required 11 82% Scheme 2 Scheme 1 O OTBS O OTES OTBS O / Journal Homepage Journal / OMe H OMe H (6 ml) HO 3 Perkin Trans. 1 Trans. Perkin 4 rt, 15 min 0.1 mmol scale AcO , MeOH ., SEt 3 H O H O NH HO 94% O NH TESO O CCl View Online View OBn R = Ac R = H O J. Chem. Soc J. 1 2 HO O RO RO The penultimate step in a recent synthesis of the antitumour step in a recent The penultimate macrolides cryptophycin 1 ( cryptophycin macrolides ring in the side chain of the epoxide introduction 3 -Troc -acetyl N O The goal 1 , 454 4 obtained by the obtained by [ ected the . ) 5 ﬀ solution of a mix- 2 4 , 1997, Cl 2 MeONa in MeOH; NH e.g. , Scheme 2), Evans and co- , Scheme 2), Evans O) also a ( 2 7 1 ) with 0.2 equivalents of sodium ) with 0.2 equivalents SiO but tetrachlorophthalimido, SiO but t 3 -glycosides are stable under the stable are -glycosides O Bu 2 - and S in MeOH–H Contemp. Org. Synth. Org. Contemp. 3 -Troc protecting groups are attacked by the by attacked are groups protecting -Troc -phthalimido), benzylidene and isopropyl- O N CO 2 . Both ] exploited the higher base lability of methoxyacetates the higher base lability exploited 2 nally achieved with a MeOH–CH achieved nally ﬁ In the closing stages of an impressive synthesis of the marine of an impressive In the closing stages -Fmoc, and

12 Introduction 2.1 groups protecting Hydroxy Esters 2.2 ethers Silyl 2.3 ethers Alkyl 2.4 ethers Alkoxyalkyl 34 Thiol groups protecting 5 groups Diol protecting 6 groups protecting Carboxy 7 groups Phosphate protecting 8 groups protecting Carbonyl 9 groups Amino protecting groups Miscellaneous protecting

reaction of guanidine nitrate ( of guanidine nitrate reaction groups protecting some standard conditions as are reaction NPhth ( like and Ph BnO, idene acetals, methoxide ture of guanidine and guanidine nitrate ( nitrate of guanidine and guanidine ture (2,2,2-trichloroethoxycarbonyl) group (Scheme 1). group (2,2,2-trichloroethoxycarbonyl) in MeOH; K 2 groups protecting Hydroxy 2.1 Esters the to cleave basic reagents Attempts to use standard in aminosugar derivative groups 1 Introduction in protecting developments new covers review The following our previ- in 1997. As with appeared which methodology group is a personal selection of our coverage review, ous annual of the or useful. Many deemed interesting we methods which Index a Science Citation through selected were references and cleavage; protect block, words based on the root search facets of protecting unearthed many casual reading however, the pale of a typical key- beyond are which chemistry group in areas omits whole reading our casual Inevitably search. word cannot claim comprehensive so we and lack expertise we which to according is organised The review of the literature. coverage with emphasis being placed on protected the functional groups on combin- review annual A separate conditions. deprotection incorporates which this year earlier chemistry appeared atorial chemistry. subject of solid phase linker the related 1011 Reviews References Department of Chemistry, University of Glasgow, Glasgow, UK G12 8QQ Glasgow, of Glasgow, University of Chemistry, Department 1997 Covering: review: Previous Krzysztof Jarowicki and Philip Kocienski and Philip Jarowicki Krzysztof Protecting groups Protecting to achieve a selective deprotection in the presence of two in the presence deprotection selective a to achieve functions in intermediate secondary acetate N reagent. guanidine–guanidine nitrate C ( altohyrtin antitumour agent workers was was

Published on 01 January 1998 on http://pubs.rsc.org | doi:10.1039/A803688H | http://pubs.rsc.org on 1998 January 01 on Published Downloaded by San Francisco State University on 14 September 2012 September 14 on University State Francisco San by Downloaded View Online

OH Ph O O Ph O OH OOHN Cl N3(CH2)3C(OMe)3 MeO O OOHN Cl

Me3SiCl 63% O HN O OMe O HN O OMe

N3 O O

8 9

–Me3SiOMe Cl O O O Ph Ph (a) Ph P, H O (63%) OOHN Cl 3 2 O O OOHN Cl

(b) K2CO3, Me2C=O (98%) O HN O OMe O HN O OMe

O N3 O

11 10 Scheme 3

A variant of a direct method for the conversion of diols to 3-yloxycarbonyl (Doc) group can be used for protecting the epoxides developed by Sharpless 4 was cleverly adapted to the hydroxy group of tyrosine.6 The protection is achieved in the case at hand. Thus diol 8 was treated with the 4-azido-1,1,1- reaction of tyrosine derivative 14 with 2,4-dimethylpentan-3-yl trimethoxybutane in the presence of chlorotrimethylsilane chloroformate and ethyldiisopropylamine (Scheme 5). The Doc to give the cyclic orthoester 9 which decomposed under the group is 1000-fold more stable towards nucleophilic piperidine

reaction conditions with loss of Me3SiOMe to give the chloro- than the commonly used 2-bromobenzyloxycarbonyl (2-BrCbz) hydrin ester 10 (inversion). Selective reduction of the azide group and it is completely cleaved by hydrogen ﬂuoride. How- under Staudinger conditions produced an intermediate amino ever the 2-BrCbz group is superior in terms of acid stability (the ester which underwent intramolecular lactamisation to release loss of protection after 20 min in 50% triﬂuoroacetic acid–

a hydroxy group. In the last step, the resultant chlorohydrin CH2Cl2 is 0.01% for 2-BrCbz group and 0.04% for Doc group). was converted to the cryptophycin 1 (11) on treatment with base. The Hasan group 5 tested o-nitrobenzyloxycarbonyl (NBOC) O OH and related groups as photolabile protectors of nucleoside i (a) Pr 2CHOC(O)Cl O O 5Ј-hydroxy groups (Scheme 4). Generally the rates of photo- i EtNPr 2 removal of 2-(o-nitrophenyl)ethoxycarbonyl (NPEOC) deriv- MeCN

Downloaded by San Francisco State University on 14 September 2012 atives (12, n = 1) were faster than the corresponding NBOC- Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H = (b) Pd/H2 protected compounds (12, n 0). Also substitution at the COOBn α-carbon had an enhancing eﬀect. The most reactive com- COOH = pound had a methyl group and ethyl chain (t1/2 0.66 min) and NHBoc = NHBoc the order of reactivity of 12 was found to be: R Me, 14 n = 1>R= o-nitrophenyl, n = 1>R= o-nitrophenyl, n = 0. 15 Unden and co-workers reported that the 2,4-dimethylpentan- Scheme 5

NO2 R 2.2 Silyl ethers NH In the ﬁnal steps of an elegant synthesis of dynemicin A (19, (CH2)nO O N O Scheme 6), Myers and co-workers 7 needed to deprotect the O O hydroquinone in Diels–Alder adduct 18 before cleavage of the sensitive bicyclic acetal followed by in situ oxidation to the 12 HO anthraquinone in the target. This required the use of an iso-

hν (365 nm, 200 W Hg lamp) benzofuran (16) with highly labile protecting groups for which MeOH-H2O (1:1) the trimethylsilyl ether was ideally suited. Thus, brief treatment of Diels–Alder adduct 18 with excess activated manganese fl O dioxide and triethylamine trihydro uoride (1:1 molar ratio, ca. 70 equiv.) led to cleavage of the three trimethylsilyl ethers NH together with the triisopropylsilyl ester and the resultant ff HO product oxidised in situ to a ord dynemicin A (19) in 53% yield. N O N-Silylpyridinium triflates are powerful silylating agents O which have been used in the preparation of enol silanes and for the silylation of carboxylic acids.8 Olah and Klumpp report a HO new method for their preparation as well as their use in the 13 silylation of alcohols 9 (Scheme 7). The salts 21a–c were pre- Scheme 4 pared by reaction of an allylsilane 20 with triflic acid followed

4006 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online

O O– +PPh Br PPh3 (1.5 mmol) 3 Br Br MeCN (3 ml) Br Br i CO2Si(Pr )3 TMSO N CaCO3 (0.9 mmol) O 0 °C Br Br OMe 23 Br O + H 1.5 mmol 24 R OTMS TMSO O OTBDPS 16 17

75% THF, –20 → 55 °C, 5 min 25 R = OTES 24, THF (1 ml), rt, 6 h 75% (0.5 mmol scale) 26 R = Br Scheme 8

butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS) ethers. i CO2Si(Pr )3 TMSO N This allows the selective bromination of 25 to give 26 in 75% O yield. OMe Maiti and Roy 12 reported a selective method for deprotection O H of primary allylic, benzylic, homoallylic and aryl TBS ethers using aqueous DMSO at 90 ЊC (Scheme 9). All other TBS- TMSOO O protected groups as well as THP ethers, methylenedioxy ethers, TMS 18 benzyl ethers, methyl ethers and aldehyde functionalities remain unaﬀected. Also a benzyl TBS ether can be selectively MnO2, Et3N•3HF 53% THF, 23 °C, 9 min deprotected in the presence of an aryl TBS ether.

OTBS

27 R = TBS CO2H DMSO (10 ml) OH O HN 82% H O (2 ml), 90 °C, 8 h O RO 28 R = H 2 OMe OMe H Scheme 9

OH OOH Full details of Fraser-Reid’s synthesis of the bacterial nodu- 19 lation factor 30 NodRf-III (C18:2, MeFuc) have been pub- Scheme 6 lished.13 The ﬁnal step of the synthesis required removal of three TBS ethers, one of which was protecting the anomeric

(a) CF3SO3H (1 equiv.) position in 29 (Scheme 10). Anomeric deprotections using CH2Cl2, 0 °C, 2 h TBAF are complicated by Lobry de Bruyn–Alberda van SiR3 – (b) pyridine (1 equiv.) CF3SO3 Eckenstein rearrangements and other base catalysed degrad- rt, 2 h N 20 ations and mildly acidic methods (e.g. PPTS in MeOH at 55 ЊC) Downloaded by San Francisco State University on 14 September 2012 SiR3 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H were fruitless even after extended reaction times. However buff- 21a R = Me ering the TBAF with AcOH gave the desired target 30 in 83% 21b R = Ph fl TMSO OTMS i yield. The problems associated with the basicity of uoride are 21c R = Pr underscored by another recent example taken from Boger’s syn- TMSO glucose thesis of the vancomycin CD and DE ring systems.14 Attempted O removal of the TBS group from 31 was accompanied by retro- 70% TMSO aldolisation of the resultant β-hydroxyphenylalanine subunit to TMSO 22 give 33 in 61% yield. Here again, buffering the reaction mixture Scheme 7 with AcOH suppressed the unwanted side reaction and gave the desired deprotected product 32 in 60% yield. by addition of pyridine. They were obtained in nearly quanti- Full details of the use of a non-ionic superbase 34 (Scheme tative yield as crystalline solids which were stable indefinitely 11) as a catalyst for the silylation of alcohols using tert- at room temperature in an inert atmosphere. However, the butyldimethylsilyl chloride or tert-butyldiphenylsilyl chloride reagents are more conveniently prepared in situ and used has been reported.15 The reactions are carried out in acetonitrile immediately as silylation reagents. No aqueous workup is at 24–40 ЊC though DMF at 24–80 ЊC may be needed for required to isolate the silyl ethers: the product mixture is simply hindered systems. The catalyst, which is commercially available diluted with pentane to complete the precipitation of the pyrid- from Strem, is compatible with aldehydes, ketones, esters, inium triflate. Filtration of the product through a plug of silica nitriles and skipped dienes. The catalyst is expensive but it can gel returns the pure silyl ether. be easily recycled. The catalytic effect of 34 was attributed to Phosphonium salt 24 (formed in the reaction of 2,4,4,6- the formation of a transannular stabilised loose ion pair 35. tetrabromocyclohexa-2,5-dienone 23 with triphenylphosphine, A new synthesis of protected phenolic ethers has been 16 Ј Scheme 8) has been reported recently to transform primary and reported in which Ni(cyclooctadiene)2 and 1,1 -bis(diphenyl- secondary alcohols and THP ethers into the corresponding phosphino)ferrocene mediates the reaction of electron deficient bromides.10 It can also directly convert 11 silyl ethers (e.g. 25) aryl halides (e.g. 36a,b) with sodium tert-butyldimethylsiloxide into bromides. The reagent 24 is not isolated but is immediately (Scheme 12). The reaction fails with the corresponding tri- treated with the corresponding silyl ether. The reaction works methylsilyl, triethylsilyl and triphenylsilyl derivatives. tert-Butyl well with trimethylsilyl (TMS), triethylsilyl (TES) and tert- ethers of phenols can also be prepared using sodium tert- butyldimethylsilyl (TBS) ethers but is very slow with tert- butoxide.

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4007 View Online

OH S O OH N OMe H OR OR O OO OH O O O HO O O 38 R = SiPh3 OR HF•pyr HO HO HO 92% NH pyr, THF, rt NHAc NHAc 39 R = H O OR OTBS 29 R = TBS TBAF, AcOH MeOH-THF, rt 83% Scheme 13 30 R = H sisyl ethers are prepared by treatment of a primary or secondary alcohol with tris(trimethylsilyl)silyl chloride (derived in one

OMe step from commercial (Me3Si)3SiH and carbon tetrachloride) NO2 OOH and dimethylaminopyridine (DMAP) (Scheme 14). Tertiary and hindered secondary alcohols fail to give the corresponding RO ether presumably due to steric interactions. Sisyl ethers are O H stable to a variety of synthetic protocols like organometallic re- N agents (MeMgBr, Ph P᎐CH ), oxidation (Jones reagent), acidic MeO2CN NHBoc 3 2 H conditions (PTSA; 0.2 M HCl) and some ﬂuoride reagents (KF O and 18-crown-6; CsF). However, they are unstable in the pres- TBAF 61% THF, rt, 2 h ence of butyllithium, LiAlH4 (giving a mixture of products) Br and tetrabutylammonium ﬂuoride. The deprotection can be OMe cleanly performed by photolysis using a medium pressure TBAF (5 equiv.) 31 R = TBS mercury lamp (a Hanovia lamp and a Pyrex immersion well). AcOH (6 equiv.) 60% MeOH-THF, rt 32 R = H NO2 OMe H H OHC OOH H

O H H H N RO MeO2CN NHBoc H O 40 R = H (Me3Si)3SiCl (1.2 mmol) DMAP (1.2 mmol) 79% CH Cl (1.2 M solution) Br 2 2 rt, overnight, 1 mmol scale OMe 33 41 R = Si(SiMe3)3 hν (medium pressure mercury lamp) 87% Scheme 10 MeOH–CH2Cl2 (0.01 M solution) 10 °C, 30 min, 40 R = H Downloaded by San Francisco State University on 14 September 2012

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H Scheme 14 R Me Si R 2.3 Alkyl ethers Me P N N Me δ Me N Me + N The nucleophilic cleavage of aryl alkyl ethers by alkanethiol- N P Me N ates 19 or trimethylsilanethiolate 20 typically requires an excess Cl– δ+ of the reagent at high temperature. A recent improvement in N N the procedure 21 (Scheme 15) allows the use of only one equiv- 34 35 (R = Me, Ph) alent of thiophenol in 1-methyl-2-pyrrolidone (NMP) using a Scheme 11 catalytic amount (2–5 mol%) of potassium carbonate as the base. The reactions are complete in 10–30 min at 190 ЊC. A Br OTBS noteworthy feature of the procedure is the preservation of Ni(COD)2 (15 mol%) aromatic nitro and chloro substituents which are displaced with t Bu Me2SiONa α β 37a R = CHO (98%) stoichiometric thiolates. Moreover, , -unsaturated carbonyl PhMe, 95 °C, 2 h 37b R = CN (96%) compounds do not undergo Michael addition of thiolate under these conditions. R R OMe OH 36a,b PhSH (1.0 equiv.) K CO (2-5 mol%) Scheme 12 2 3 NMP, 190 °C, 10-30 min

Triphenylsilyl ethers are the poor relations of the silyl ether 68% (R = NO2) family of protecting groups but their easy cleavage in the pres- R 83% (R = COCH=CHPh(E)) R ﬀ ence of TBS ethers o ered a welcome degree of orthogonality Scheme 15 which Danishefsky et al. exploited in syntheses of the epothil- ones (Scheme 13).17 The triphenylsilyl group is introduced via Hwu and co-workers reported sodium bis(trimethylsilyl)-

the chloride in DMF using imidazole as base. amide [NaN(SiMe3)2] and lithium diisopropylamide (LDA) as The Brook group used the tris(trimethylsilyl)silyl (sisyl) eﬃcient agents for demethylation and debenzylation of alkyl group as a new photolabile protecting group for alcohols.18 The ethers of phenol.22 However, the deprotection requires quite

4008 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online harsh conditions (heating at 185 ЊC for 12 h) which might cause Discodermolide is a polyhydroxylated lactone exhibiting decomposition of more sensitive molecules. In the case of potent microtubule stabilising activity similar to that of taxol. dimethoxybenzenes (e.g. 42) the selective mono-O-demethyl- In a recent synthesis of (Ϫ)-discodermolide, Myles and co- ation can be achieved (Scheme 16). LDA—but not sodium workers 29 selectively cleaved the terminal benzyl ether in inter- bis(trimethylsilyl)amide—can also selectively deprotect a mediate 50 (Scheme 20) using Raney nickel and hydrogen in benzyl ether such as 43 in the presence of a methoxy group. ethanol. Reductive cleavage of the terminal p-methoxybenzyl PMB ether was minimised under these conditions

OMe NaN(SiMe3)2 OH OBn and the trisubstituted alkene survived unscathed. Several (2.5 equiv.) LDA (2.5 equiv.) steps later, diﬃculty was encountered removing the MOM DMEU (0.5 ml) DMEU (0.5 ml) ether from intermediate 52. After extensive experimentation, the recalcitrant MOM ether was cleaved in 60% yield with 1 185 °C, 12 h 185 °C, 12 h 96% (0.95 mmol) 87% (0.55 mmol) equiv. of chlorocatecholborane and 0.5 equiv. of water in OMe OMe OMe dichloromethane. 42 43 DMEU = 1,3-dimethylimidazolidin-2-one RO OTIPS TIPS Scheme 16 O OMOM

Alkali metals in liquid ammonia are well known reagents OPMB for deprotecting benzyl ethers.23 It is not then surprising that lithium naphthalenide (prepared from lithium and 1.33 equivalents of naphthalene) also proved successful in this transform- 50 R = Bn ation (Scheme 17).24 The reagent seems rather harsh; however, Ra/Ni, H2, EtOH 71% a wide range of functionalities survive the reaction conditions 51 R = H

like alcohols, carbon–carbon double bonds, benzene rings, and 5 steps THP, silyl and methoxymethyl ethers. A ketone group can also be present but its prior conversion to an enolate is necessary. OTIPS TIPS OH OOR I 44 R = Bn Lithium naphthalenide (6 equiv.) 94% THF, –25 °C, 80 min H 45 R = H 52 R = MOM OR chlorocatecholborane (1 equiv.) 60% H O (0.5 equiv.), CH Cl Scheme 17 2 2 2 53 R = H Scheme 20 A similar transformation, but with a catalytic amount of naphthalene, has been reported by Yus and co-workers.25 Hirota and co-workers 30 reported that Pd/C catalysed Although allyl ethers are also cleaved by the procedure, the hydrogenolysis of PMB protected phenols can be selectively selective deprotection of benzyl groups is possible (Scheme 18). inhibited by pyridine. This allows the selective removal of other Dimethylphenylsilyloxy (but not diphenyl-tert-butylsilyloxy) groups like benzyl and Cbz, as well as reduction of alkenes and

Downloaded by San Francisco State University on 14 September 2012 groups can also be removed by this methodology.

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H nitro groups in the presence of a PMB group (Scheme 21).

OR 46 R = Bn Li (powder, 14 mmol) naphthalene (0.08 mmol) OR THF (7 ml) 97% –78 → –10 °C, 5 h OPMB (1 mmol scale) 47 R = H O Scheme 18 N COOMe ﬁ H The nal step in a synthesis of the serine/threonine phos- BocHN phatase inhibitor okadaic acid 26 (49) required the reductive cleavage of three benzyl ethers in the precursor 48 (Scheme 19). 54 R = Bn Previous experience had shown that over-reduction occurs H2, 5% Pd/C (10%, w/w) MeOH-dioxane (1:1) or DMF (20 ml) readily upon debenzylation using lithium in liquid ammonia Pyridine (0.5 mmol), rt, 24 h 27 containing ethanol. However, over-reduction was avoided 96 % (1 mmol scale) using lithium 4,4Ј-di-tert-butylbiphenylide (LiDBB).28 55 R = H Scheme 21

fi O OR Staurosporine, the rst member of the glycosylated indolo- H O O carbazoles to reveal potent protein kinase C activity, has been HO HO O O O investigated for its potential for the treatment of cancer, H H OR OO Alzheimer’s disease, and other neurodegenerative disorders. H H H 31 OR Wood et al. have published full details of their efficient and general route to staurosporine and other members of this family of compounds including (Ϫ)-K252a, (ϩ)-RK286c, 48 R = Bn (ϩ)-MLR-52 and (Ϫ)-TAN-1030a. The final step in the 70% LiDBB, THF, –78 °C synthesis of (Ϫ)-TAN-1030a (57, Scheme 22), cleavage of an 49 R = H O-benzyl bond from an oxime, was accomplished with a large Scheme 19 excess of iodotrimethylsilane, albeit in poor yield (24%).

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4009 View Online

H N O O O RO

N N 62 R = PMB, Z/E = 12.6/1 MgBr •OEt (3 equiv.) O 2 2 64% Me2S (10 equiv.) 56 R = Bn Me3SiI (0.3 ml) 63 R = H, Z/E = 8.4/1 CH2Cl2, rt, 20 h CDCl3 (3 ml), rt, 48 h 24% (0.02 mmol scale) (8% recovery of 62) MeO 57 R = H N Scheme 25 RO Scheme 22

Iodine is a weak Lewis acid which promotes the peracetyl- O O ation of unprotected sugars. However, acetylation of O-benzyl 64 R = PMB SnCl4•2H2O (0.3 equiv.) protected derivatives may be accompanied by cleavage of the O OBn 80% 65 R = H EtSH (4 equiv.), rt, 3 h benzyl protecting group. Thus treatment of the glucosamine H derivative 58 with iodine (100 mg gϪ1 sugar) in acetic anhydride BnO resulted in acetylation of the hydroxy group at C4 together with selective cleavage of the primary O-benzyl group and its OR replacement by acetate to give the 4,6-di-O-acetyl derivative 59 Scheme 26 in >95% yield (Scheme 23).32 4-Azido-3-chlorobenzyl (Cl-Azb) ethers are prepared by alkyl- OBn OAc ation of hydroxy groups with 4-azido-3-chlorobenzyl bromide, I2, Ac2O available in two steps from commercial 2-chloro-4-methyl- HO O AcO O OEt rt, 24 h OEt 37 BnO >95% BnO aniline. Cl-Azb ethers are more stable than the parent NPhth NPhth 4-azidobenzyl (Azb) ether. Cl-Azb ethers were inert towards 58 59 DDQ but were cleaved smoothly after conversion to the corre- Scheme 23 sponding iminophosphorane (Scheme 27).

N The O-benzylation of alcohols with benzyl trichloro- 3 N PPh3 acetimidate is usually accomplished using triﬂic acid as a Cl Cl catalyst. However, in a concise synthesis of the cellular mes- senger -α-phosphitidyl--myo-inositol 3,4-bisphosphate,33 trityl cation promoted benzylation of the C5 and C6 hydroxy functions was used instead (Scheme 24).34 BnO O BnO O

BnO PPh3, THF BnO OR O rt, 1 h O (BnO)2OPO OR BnO BnO OMe 66 OMe (BnO)2OPO O 67

Downloaded by San Francisco State University on 14 September 2012 O Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H NaH, DMF 94% ArCH2Br

60 R = H BnO OH PhCH2O—C(=NH)CCl3 BnO Ph3CBF4 (5 mol%) >73% DDQ, H2O, AcOH (95%) Et O, 24 °C, 32 h 2 61 R = Bn O DDQ, silica gel, rt, 1.5 h (90%) BnO Scheme 24 OMe Magnesium bromide–dimethyl sulfide is a mild reagent for 68 deprotecting p-methoxybenzyl (PMB) ethers to the correspond- Scheme 27 ing alcohols.35 The method is specially suitable for molecules containing a 1,3-diene moiety (e.g. 62, Scheme 25) because 6-O-Trityl monosaccharides are central to a strategy for the other PMB-deprotecting reagents (DDQ, CAN) are unsuccess- synthesis of oligosaccharides based on thioglycoside activation. ful in these cases. However, some isomerisation of the diene is Thus the trityl group in thioglycoside 69 (Scheme 28) was observed. Other protective groups like TBS, benzyl, benzoyl robust enough to withstand the arming of the thioglycoside and acetonide also remain intact. On the other hand the acceptor using N-iodosuccinimide (NIS) in the presence of a fl ؒ MgBr2 OEt2–SMe2 system fails when the PMB group is accom- catalytic amount of tri ic acid followed by reaction with the panied by a methoxymethyl (MOM) or benzyloxymethyl donor 70 to give the disaccharide 71 in 62% yield.38 The pre- (BOM) protecting group. ponderance of the α-anomer was attributed to the steric effect A p-methoxybenzyl (PMB) group can also be removed from of the trityl group. In a subsequent step, the trityl ether in 71

alcohols and phenols using a catalytic amount of AlCl3 or was cleaved and the freed hydroxy group acted as a donor when 36 ؒ SnCl2 2H2O in the presence of EtSH at room temperature. the thioglycoside 72 was armed with NIS in the presence of one Under these mild conditions other protecting groups such as equivalent of TMSOTf, whereupon the trisaccharide 73 was methyl, benzyl and TBDPS ethers, p-nitrobenzoyl esters, iso- formed in 70% yield, again with modest α-selectivity. propylidene acetals and glycosydic moieties (Scheme 26) 4-Dimethylamino-N-triphenylmethylpyridinium chloride remain unchanged. EtSH, by trapping PMB cations, is essential (75, Scheme 29) is a stable isolable salt which can be used for a to obtain the product free from impurities. clean triphenylmethylation of a primary alcohol over a second-

4010 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online

OTr OTr α:β = 6:1 NIS O TfOH (cat.) O O BnO BnO O SEt OBn BnO BnO BnO BnO O 79 R = allyl O O NaBH4, I2 69 OR 87% BnO THF, 0 °C, 30 min BnO 80 R = H OMe 71 (62%) OR OBn MeO O HO Scheme 31 BnO BnO OMe OBn ethers are cleaved without detriment to cyano, ester, nitro, 70 O acetonide and tetrahydropyranyl groups. BnO 44 BnO SEt Miura and co-workers reported a new method for the OBn α:β = 3:1 BnO etheriﬁcation of phenols by using allyl alcohols and catalytic 72 amounts of palladium() acetate and titanium() isopropoxide O BnO (Scheme 32). The reaction is quite general; however, it fails BnO NIS, TMSOTf (1 equiv.) BnO CH2Cl2-Et2O (1:1) 70% in the case of 3,5-dimethoxyphenol because of the exclusive O rt, 15 min formation of a C-allylated product.

BnO O OBn BnO CH2=CHCH2OH (4 mmol) BnO O O OH Pd(OAc)2 (0.01 mmol) O BnO PPh3 (0.04 mmol) 73 BnO Ti(OPri) (0.25 mmol) OMe 4

MS (4Å, 200 mg) Scheme 28 O PhH (5 ml), 50 °C, 4-20 h O O 67% (1 mmol scale) NMe O NMe2 2 Ph CCl (0.1 mmol) 3 Scheme 32 CH2Cl2 (200 ml)

20-25 °C, 3 h N Benzyltriethylammonium tetrathiomolybdate deprotects N Cl– 96% (0.1 mol scale) propargyl ethers and esters in acetonitrile at room temperature CPh 74 3 (Scheme 33).45 Allyl ethers, nitro compounds, aldehydes and 75 ketones are not affected though alkyl halides are converted to Scheme 29 sulfides, and azides and thiocyanates are reduced. ary one.39 Recently Hernandez and co-workers published in O Organic Syntheses 40 a detailed large scale procedure for this OH 41 reagent, slightly modifying their original method. [PhCH2NEt3]2MoS4 (1 equiv.) In order to protect the hydroxy function of serine and threo- MeCN, 36 h, rt nine, temporary protection of α-amino and α-carboxy groups is OMe 87% OMe 42 necessary. Recently a new methodology has been developed CHO CHO in which boron trifluoride–diethyl ether is used for the simul- Downloaded by San Francisco State University on 14 September 2012

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H taneous protection of these two groups as a 2,2-diﬂuoro-1,3,2- Scheme 33 oxazaborolidin-5-one derivative (e.g. 77, Scheme 30). Reaction of 77 with isobutylene in acidic conditions aﬀorded selectively Electroreductive cleavage of propargylic aryl ethers and protected derivative 78. In similar fashion benzyl trichloro- esters to the corresponding phenols and carboxylic acids occurs in good yield (77–99%) using NiII–bipyridine complex acetimidate converts 77 into the corresponding O-benzyl 46 derivative. as catalyst. Ester, cyano and, most interestingly, aryl ketone functionalities (Scheme 34) are stable under the reaction condi- O tions. However, in the case of o-bromo and o-iodo derivatives, the halogen is quantitatively replaced with hydrogen, whereas HO OLi an o-chloro atom is only partially reduced (20%).

NH2 O O 76 –3 Bu4NBF4 (10 M) BF3•OEt2 (6 ml) Ni(bipy)3(BF4)2 (0.3 mmol) THF (15 ml) O OH rt, 6 h; 40-45 °C, 2 h DMF (40 ml), E = 5-10 V, 60 mA 100% (10 mmol scale) 90% (3 mmol scale)

O O (a) dioxane (30 ml) 81 82 HO rt, 15 min O ButOOH Scheme 34 H N 2 (b) H3PO4 (0.4 ml) B NH2 F2 rt, 15 min 2.4 Alkoxyalkyl ethers 77 (c) isobutylene (20 ml) 78 –20 °C→rt, 2-2.5 h Methoxymethyl (MOM) protecting groups are quite robust and (10 mmol scale) their removal is often incompatible with many functional Scheme 30 groups. A further complication is the formation of formal derivatives on deprotection of MOM-protected 1,3-diols. Never- 47 Diborane generated in situ by reaction of NaBH4 with iodine theless, Ghosh and Liu were able to remove two MOM groups in THF at 0 ЊC accomplishes the deprotection of allyl ethers protecting a 1,3-diol in the ﬁnal step of their synthesis of under mild conditions (Scheme 31).43 Both aryl and alkyl allyl the streptogramin antibiotic madumycin II (84, Scheme

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4011 View Online 35). The successful method employed tetrabutylammonium MeO2C MeO2C bromide (2 equiv.) and an excess of dichlorodimethylsilane in O OMe O Br dichloromethane at 0 ЊC for 6 h. H Me2BBr (3.5 equiv.) H

EtNPri (0.1 equiv.) O O 2 H CH2Cl2, –78 °C, 20 min N O FmocHN FmocHN 90 91 ON EtSH (3 equiv.) O i EtNPr 2 (2.0 equiv.) 60% HN O CH2Cl2, –78 °C, 3 h NH

OTMS MeO2C N O MeO2C RO OR O N O SEt

83 R = MOM N OTMS Bu4NBr (2 equiv.), Me2SiCl2 (excess) H H 47% (5.0 equiv.) CH Cl , 4Å MS, 0 °C, 6 h 2 2 84 R = H I2 (1.0 equiv.) Scheme 35 THF, rt, 48 h FmocHN 58% FmocHN fi The nal step in a synthesis of the Annonaceous acetogenin 93 92 (ϩ)-4-deoxygigantecin 48 entailed the cleavage of two MOM Scheme 38 ؒ ether groups using BF3 OEt2 in the presence of SMe2 (Scheme 49 36). Macrosphelide A (96) strongly inhibits adhesion of human leukaemia HL-60 cells to human umbilical vein endothelial HO HH O cells by inhibiting the binding of sialyl Lewis x to E-selectin. C12H25 O O It is also orally active against lung metastasis of B16/BL6 HH RO OR O melanoma in mice and it appears to be a lipoxygenase inhibitor as well. The closing steps in a recent synthesis of macrosphelide fi 85 R = MOM A required the stepwise release rst of a hydroxy and carboxy BF •OEt 3 2 57% function as a prelude to macrolactonisation and then two SMe2 86 R = H hydroxy groups protected as their (2-methoxyethoxy)methyl (MEM) ethers—all this without detriment to the three lactone Scheme 36 functions.52 The first deprotection was accomplished with a During a synthesis of the diterpene epoxydictymene, the mixture of trifluoroacetic acid (TFA, 5 parts) and thioanisole Paquette group found that easy elimination took place during (1 part) in dichloromethane (5 parts) (Scheme 39). The final the cleavage of the MOM ether in intermediate 87 (Scheme deprotection of the 2 MEM groups (95→96) was accomplished 37).50 When 1 equiv. of bromocatecholborane in dichloro- in good yield with trifluoroacetic acid in dichloromethane methane was used, the desired cleavage took place to give the (1:1). requisite alcohol 88 in quantitative yield. However, when less than 1 equiv. was used, the dimeric species 89 was generated. O OMEM O H Downloaded by San Francisco State University on 14 September 2012 MEMO Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H O t CO2Bu RO O OTBS H 94

88 R = H (a) TFA-thioanisole-CH2Cl2 (5:1:5) (64%) bromocatecholborane (1 equiv.) (b) 2,4,6-trichlorobenzoyl chloride, NEt , DMAP (91%) 100% 3 CH2Cl2, –78 °C 87 R = MOM O bromocatecholborane (< 1 equiv.) OR CH2Cl2, –78 °C O 95 R = MEM RO 90% TFA-CH Cl (1:1) O 2 2 H 96 R = H

O O O

O Scheme 39 H H O A concise synthesis of zaragozic acid 53—an inhibitor of squalene synthase—required the deprotection of a MEM ether in the presence of two dioxolane rings. This was accomplished H 89 (Scheme 40) using iodotrimethylsilane generated in situ by reaction of chlorotrimethylsilane and sodium iodide.54 ؒ Scheme 37 In 1993 a Cambridge group showed that BCl3 SMe2 select- Synthetic analogues of natural oligonucleotides have ively cleaved benzyl ethers in the presence of acetate and tert- attracted interest for their promising applications in antisense butyldiphenylsilyl groups.55 On the other hand trityl ethers are chemotherapy.51 In a synthesis of the thymidine acyclonucleo- rapidly cleaved in the presence of benzyl ethers. The same side analogue 93 (Scheme 38), the MOM group in 90, normally group 56 applied the method twice in a synthesis of the marine used as a hydroxy protecting group was converted to the ethyl- oxocin derivative laurencin as shown in Scheme 41. Early on the thiomethyl ether intermediate 92 which was then used as a benzyloxymethyl (BOM) ether 97 was cleaved in good yield and functional group to append thymine. the resultant hydroxy group converted to silyl ether 98 and later

4012 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online

OR O O O O O HO HO n-C5H11 ( )3 OO ( )11 OMEM OH H H H H OR OR O EtO2C EtO2C Me3SiCl, NaI MeO2C MeO2C OH OH 103 R = SEM O O PPTS (13.3 equiv.) MeCN, 0 °C, 1 h 80% O O EtOH, ∆, 16 h 88% 104 R = H Scheme 43 Scheme 40 Me Cl N Cl– R Me Cl RO 105 R = OTHP O 106 (1.05 equiv.) 106 t 78% O OSiPh2Bu CH Cl , 0 °C 107 R = Cl 2 2 97 R = BOM (a) BCl3•SMe2 (2 equiv.), CH2Cl2, rt, 1 min Scheme 44 75% (b) TMSCl, NEt , THF 98 R = SiMe 3 3 (4.4 mmol scale) ammonium bromide. The reaction works well with primary alcohols. With secondary alcohols the formation of elimination by-product is observed (which is the main product in the case of tertiary alcohols). RO O Solvent free tetrahydropyranylation of alcohols and phenols OAc SiMe3 over HSZ zeolites as reusable catalysts has been reported by an Italian group.60 99 R = PMB Selective protection of the hydroperoxy function in 108 BCl3•SMe2 (5 equiv.), CH2Cl2, rt, 5 min 75% (Scheme 45) using 2-methoxypropene enabled subsequent oxid- (19.9 mmol scale) 100 R = H ation of the remaining allylic alcohol function.61 The product Scheme 41 109 was converted to the marine cyclic peroxide plakorin.

the p-methoxybenzyl ether 99 was cleaved selectively in the H33C16 H C presence of the sensitive enyne. 33 16 O OH Mycobactins are a family of siderophores produced by myco- (a) MeC(OMe)=CH , PPTS bacteria to promote growth via iron uptake processes. Hu and 2 57 Miller reported a synthesis of mycobactin S (102, Scheme 42) (b) PDC O O which was a potent growth inhibitor of Mycobacterium tubercu- 67% overall (2 steps) O HO losis. The use of a 2-(trimethylsilyl)ethoxymethyl (SEM) group OTIPS OTIPS to protect the hydroxamic acid residue in the N α-Cbz-N ε- OMe ε hydroxy-N -palmitoyl--lysine fragment 101 was crucial in the 108 109 construction of the ester linkage. Both the SEM and tert- Scheme 45 butyldiphenylsilyl (TBDPS) groups were cleaved in the ﬁnal Downloaded by San Francisco State University on 14 September 2012

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H ﬂ step using tri uoroacetic acid. Acetal derivatives prepared from N-substituted 4-methoxy- 1,2,5,6-tetrahydropyridine (e.g. 111) have been used by the O 62,63 Ј OO Reese group for the protection of the 2 -hydroxy function H in an automated solid phase synthesis of oligoribonucleotides. N N N ONOR2 The drawback of this methodology was the ﬁve steps required H OH O O to make 111 (and related compounds). Recently the same group reported a much shorter procedure consisting of only two steps (Scheme 46).64

CH3(CH2)14 N (a) OR1 ArNH2 (0.20 mol) TsOH·H2O (0.22 mol) O MeOH (200 ml), ∆, 2h OMe O (b) 101 R1 = SEM, R2 = TBDPS HC(OMe)3 (0.6 mol) CF3CO2H-CH2Cl2 (1:1) ∆, 1 h 68% rt, 1 h 102 R1 = R2 = H (c) Et3N (0.33 mol) N Cl Cl i Scheme 42 (d) EtNPr 2 (0.48 mol) Ar 110 BF3•OEt2 (0.40 mol) A mild method for the deprotection of SEM ethers was dis- CH2Cl2 (300 ml), 0 °C, 3 h 111 covered by Marshall and Chen 58 during their synthesis of the 83% (0.22 mol scale) Ar = o-fluorophenyl cytotoxic acetogenins aciminocin and asiminecin (104). In the Scheme 46 example shown (Scheme 43), the three SEM ethers were simul- taneously cleaved from 103 by heating with pyridinium tosylate (PPTS) in ethanol to give asiminecin (104) in 80% yield. 3 Thiol protecting groups Mioskowski and co-workers 59 described the direct conver- Hypusine (Hpu) is an unusual amino acid uniquely found in sion of THP-protected alcohols into the corresponding chlor- eLF-5A, a protein which serves as an initiation factor in all ides using dichlorophosgeniminium chloride 106 (Scheme 44). growing eukaryotic cells and which plays a critical role in The corresponding bromides can also be obtained if the reac- the replication of human immunodeﬁciency virus-1 (HIV-1). tion is carried out in the presence of 2 equivalents of tetrabutyl- Bergeron and co-workers 65 synthesised the hypusine-containing

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4013 View Online

pentapeptide 113 found in eIF-5A capped at its N-terminus NH2 with -cysteine (i.e. Cys-Thr-Gly-Hpu-His-Gly, Scheme 47) as a means of covalently linking this peptidic hapten to a carrier CO2H protein for ultimate use in raising antibodies specific to S hypusine-containing epitopes. The Cbz group used to protect L-cysteine R the cysteine thiol group was robust enough to survive aqueous TFA-DME (1:50) 25 °C, 30 min sodium carbonate in DMF and typical peptide coupling condi- O tions; however, in the final step, it was cleaved together with fl 115a R = H seven other acid-labile protecting groups, using neat re uxing OH 115b R = OMe trifluoroacetic acid containing phenol as a scavenger. R Fmoc–OSu NEt , MeCN-H O, rt, 3 h NHCbz 3 2 CbzN O OTHP 114a R = H NHFmoc 114b R = OMe H t OBu Fmoc-L-cysteine CO2H O O O TFA (1 equiv.) H H S t CbzHN N N OBu CH2Cl2, rt, 30 min N N N R H H H O O O Su = Succinimide CbzS N–Boc O 112 N 116a R = H 24% phenol (50 µmol) 116b R = OMe 7.2 µmol scale CF3COOH (5 ml), ∆, 90 min

88% 97% 114a 115a 114b 115b NH2 HN 81% 83% OH 90% 83% H 116a 116b OH O O O H H Scheme 48 H2N N N OH N N N H H H O O O AcCl (0.352 mmol) HS OO ZnCl (0.5 mmol) AcO O Cl NH 2 Hpu N 113 Et2O (200 ml) 117 rt, 3 h Scheme 47 MeOH (1.11 mol) 77-91% EtNPri (0.350 mol) (0.294 mol scale) 2 S-9H-Xanthen-9-yl (Xan) and 2-methoxy-9H-xanthen-9-yl Et2O (60 ml) → (2-Moxan) are new S-protecting groups for cysteine which are 0 °C rt, 1 h α compatible with the base-labile N -ﬂuoren-9-ylmethoxycarb- K2CO3 (0.253 mol) onyl (N α-Fmoc) group currently used in solid phase peptide Me MeOH (100 ml) HO O O H O (50 ml) AcO O OMe synthesis.66 Both groups are introduced onto sulfhydryl func- 2 Downloaded by San Francisco State University on 14 September 2012

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H tions by S-alkylation reactions involving the corresponding rt, 2 h 89-92% xanthydrols 114a,b under acid catalysis (Scheme 48). Selective 119 118 removal of S-Xan or S-2-Moxan groups is best accomplished (0.1 mmol scale)

with TFA–CH2Cl2–Et3SiH (1:98.5:0.5) at room temperature. Scheme 49 Alternatively, oxidative deprotection of S-Xan or S-2-Moxan groups with iodine (10–20 equiv.) or thallium() tris(trifluoro- OH OH fi O O acetate) (1–3 equiv.) provides the corresponding disul des. Both HO O groups are more labile towards acidolysis and more readily POCl3, DMSO oxidised than S-acetamidomethyl (Acm), S-trityl and S-2,4,6- O 65 °C, 2 h O HO 85% O trimethoxybenzyl (Tmob) protecting groups. O OMe OMe 4 Diol protecting groups Scheme 50 A detailed large scale Organic Syntheses procedure has formation of a group stable in acidic conditions into another appeared for the selective MOM-protection of 1,3-diols via stable in basic conditions.70 The sequence, exemplified in regioselective cleavage of methylene acetals (Scheme 49) 67 first Scheme 51, begins with the formation of thiocarbonate 121 by communicated in 1995.68 reaction of diol 120 with 1,1Ј-thiocarbonyldiimidazole (TCDI). Despite the relatively harsh conditions required for their The thiocarbonate moiety in 121 is stable under acidic condi- removal (2 M HCl in acetone, 50 ЊC), methylene acetals are tions as illustrated by selective hydrolysis of the isopropylidene occasionally used in synthesis. An Italian group 69 has added moiety to give 123 in quantitative yield, but the thiocarbonate

POCl3 and SOCl2 in DMSO to the list of reagents which con- reverts to the starting diol 120 by basic hydrolysis. Easy trans- vert diols to methylene acetals. Whilst syn-1,2- and -1,3-diols formation of thiocarbonate 121 into methylene acetal 122 in give the corresponding 1,3-dioxolane and 1,3-dioxane deriv- one step by radical desulfurisation with triphenyltin hydride in atives respectively, anti-1,2-diols or syn-1,2-diols in sterically the presence of AIBN gives a protecting group which is highly crowded environments give the corresponding 1,3,5-trioxepane stable in alkaline medium while it is labile towards acid. derivatives as illustrated in Scheme 50. The method does not Tricolorin A is an unusual tetrasaccharide macrolactone work well with simple monohydric alcohols. isolated from Ipomoea tricolor, a plant used in Mexican tradi- A new protecting group strategy for diols allows easy trans- tional agriculture as a weed controller. Two syntheses of tri-

4014 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online S O

HO OH Ph3SnH (2 mmol) O O O O H MCPBA (5 equiv.) Ph O TCDI (2 mmol) AIBN (10 mg) O OMe BPCC (2 equiv.) MeCN PhMe (25 ml) O CH2Cl2 (5 ml) O OMe rt, 36 h, 70% OO rt, 2-3 days ∆ OO (0.64 mmol scale) OO , 2-4 h, 91% Ph O OMe 90% (1 mmol scale) H HO OMe (1 mmol scale) OMe OMe 120 121 122

Amberlite 15(H+) BPCC = 2,2'-bipyridinium chlorochromate 100% MeOH, rt, 30 min MCPBA = m-chloroperbenzoic acid Scheme 53 S

O O TrO OH O (a) KOBut, THF, 0 °C OMe N (b) PhCHO, 0 °C HO OH Me 126 123 Ph Scheme 51 TrO OOK O 71 colorin A have been reported recently by the groups of Hui OMe 72 N and Heathcock. The closing stages of the Hui synthesis Ph entailed the simultaneous deprotection of a benzylidene acetal 127 Me and an isopropylidene acetal (Scheme 52) using DDQ in reﬂux- TrO OO O ing aqueous acetonitrile. The last step, hydrogenolysis of the OMe three benzyl ether functions in 124 gave tricolorin A (125). N 128 Me H O Scheme 54

O The oxidative cyclisation of mono-PMB ethers of 1,3-diols O ff fi O O to a ord the corresponding p-methoxyphenyl acetals was rst Ph O 75 O O reported by Yonemitsu and co-workers in 1982. Myles and co- O 76 O workers have shown that oxidative cyclisation can be used to O differentiate the end groups in 1,3,5-triol systems having pseudo O C2-symmetry as shown in Scheme 55. O Ferric chloride (either anhydrous or hexahydrate) absorbed O 77,78 O O on silica gel is known to promote the cleavage of acetals. Sen 79 O and co-workers have recently reported that the reaction is BnO ؒ O BnO faster when non-absorbed FeCl3 6H2O in dichloromethane is BnO 124 used. Depending on the number of equivalents, the selective deprotection of either one or both acetal groups can be (a) DDQ (3 equiv.) achieved (Scheme 56). In both cases, the TBS ether remains Downloaded by San Francisco State University on 14 September 2012 70% MeCN-H2O (9:1), ∆, 4 h Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H (b) H2, Pd/C, EtOH intact. H Ley has used the butane-2,3-diacetal protecting group in an O expedient synthesis of several rare 6-deoxy sugars starting from 80 OH cheap galactose and mannose. The general procedure is illustrated in Scheme 57 by the synthesis of methyl-α--rhamno- O HO O pyranoside (135, unnatural rhamnose configuration). Selective HO α HO O O protection of the two equatorial hydroxy functions in methyl- - O -mannopyranoside (132) occurred in a single step by treat- O ment with butane-2,3-dione and trimethyl orthoformate in the O presence of catalytic camphorsulfonic acid. Alternatively, the O requisite protection can be accomplished using BF ؒOEt as O 3 2 O O the catalyst. The final deprotection to give 135 was effected by O fl HO hydrolysis using tri uoroacetic acid containing 10% water. O HO A detailed procedure for the large scale preparation of HO 125 1,1,2,2-tetramethoxycyclohexane 137 and its use in the pro- Scheme 52 tection of methyl α--mannopyranoside 138 has been described in Organic Syntheses (Scheme 58).81 The paper summarised the Benzylidene acetals can be cleaved to hydroxy esters using results obtained when 137 was used for the selective protection 2,2Ј-bipyridinium chlorochromate (BPCC) and m-chloro- of the trans-hydroxy groups in a range of sugars. Further perbenzoic acid (MCPBA).73 The selectivity of the cleavage experimental details of the methodology 82,83 and its application favours the product having primary ester and secondary alcohol in oligosaccharide assembly 84,85 have also been published. functionality, as shown in Scheme 53. O-Allyl and O-benzyl The simultaneous and selective protection of the two groups do not tolerate the reaction conditions, presumably equatorial hydroxy groups in methyl dihydroquinate (140, because they undergo competitive oxidation. Scheme 59) as the butane-2,3-diacetal was a key strategic The base-induced intramolecular heteroconjugate addition feature in a synthesis of inhibitors of 3-dehydroquinate syn- of the hemiacetal 127 (Scheme 54) derived from reaction thase.86 Later in the synthesis, deprotection of intermediate 142 of alcohol 126 with benzaldehyde was used to generate the required three steps: (a) hydrolysis of the TMS ether and the benzylidene-protected 1,3-diol derivative 128 in 83% yield.74 butane-2,3-diacetal with trifluoroacetic acid; (b) cleavage of

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4015 View Online

CO2Et OH OH butane-2,3-dione OMe HO OH cat. CSA, HC(OMe)3 OH OMe MeOH, ∆ (95%) OH HO O O O HO or butane-2,3-dione O cat. BF3•OEt2, HC(OMe)3 O DDQ, 4Å MS OMe MeOH, rt (99%) OMe OMe 132 133 CH2Cl2, –30 °C OH 91% (a) I2, PPh3, imidazole, PhMe (85%) HO (b) H2, Pd/C, Et2NH, MeOH (86%) CO2Et

OMe CO2Et CO2Et OH OH TFA-H O (9:1) O HO HO HO O 2 O HO O O OH OMe OMe OMe OMe 135 O O 134 + OMe Scheme 57 OH O HO 99:1 HO OMe O CH(OMe) (1.46 mol) CO Et 3 OMe CO2Et 2 H2SO4 (conc., ~32 drops)

MeOH (100 ml), ∆, 5 h OMe O 73% (0.4 mol scale) OMe OMe 136 137 OH DDQ, 4Å MS HO HO CH Cl , –30 °C 137 (0.29 mol) O 2 2 HC(OMe) (0.15 mol) MeO 93% OH 3 OH MeOH (300 ml) O HO O O O OH HO CSA (0.015 mol) ∆, 16 h, 41-46% OMe (0.15 mmol scale) MeO OMe 138 139 O OH Scheme 58 OMe O O + HO CO Me OMe 2 82:18 OH O HO CO2Me Scheme 55 2,2,3,3-tetramethoxybutane HO O (MeO) CH, MeOH, CSA, ∆ OMe 3 O HO OH HO OH 87% OH OMe O O FeCl3•6H2O (3.5 equiv.) 140 O OTBS CH2Cl2, rt, 10 min 141 77% H Downloaded by San Francisco State University on 14 September 2012 O Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H OTBS HO H OH O 130 HO CO2H TMSO CO2Me O (a) TFA, H2O (20:1) (b) TMSBr, NEt3, CH2Cl2

129 O O OH (c) 0.2 M NaOH O (d) Dowex 50 (H+) OMe PriO P O FeCl3•6H2O (0.1 equiv.) HO P OH >58% overall O O O PriO CH Cl , rt, 10 min OTBS HO 2 2 OMe 70% (by GLC) H 143 142 HO Scheme 59 OH 131 NH2 Scheme 56

O the isopropyl phosphonate with TMSBr; and (c) hydrolysis of H N the methyl ester with aqueous NaOH. N O H O CO2R N 5 Carboxy protecting groups H

Radiosumin is isolated from the freshwater blue-green alga 144 R = Me Plectonema radiosum. It is a highly potent inhibitor of trypsin (Bu3Sn)2O, PhH 26% (44% conversion) 145 R = H and a moderately active inhibitor of plasmin and thrombin. In the last step of their synthesis of radiosumin (Scheme 60), Scheme 60 Shioiri and co-workers 87 required an ester hydrolysis (144→ 145) which did not epimerise the two amino acid residues. The The classical method for the preparation of tert-butyl esters desired transformation was accomplished under neutral condi- is the reaction of an acid with isobutylene in the presence of an tions through the agency of bis(tri-n-butyltin) oxide.88 acidic catalyst.23 Wright and co-workers 89 reported a modiﬁed

4016 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online procedure in which, instead of isobutylene, tert-butyl alcohol recycling 149, the enal and allylic alcohol functions were is used in the presence of a heterogeneous acid catalyst— obtained in 16 and 62% yields respectively. Conversion of the concentrated sulfuric acid dispersed on powdered anhydrous allylic alcohol to the enal by Swern oxidation followed by a magnesium sulfate. No internal pressure is developed during Horner–Wadsworth–Emmons reaction then gave the dienoate the reaction and the method is successful for various aromatic, ester 150. Simultaneous deprotection of the nascent 2-(tri- aliphatic, olefinic, heteroaromatic and protected amino acids methylsilyl)ethyl ester and the 2-(trimethylsilyl)ethoxycarbonyl (Scheme 61). Also primary and secondary alcohols can be con- group with tris(dimethylamino)sulfonium difluorotrimethyl- verted into the corresponding tert-butyl ethers using essentially silicate (TASF) returned an amino acid which macrolactamised the same procedure (with the exception of alcohols particularly on treatment with N-methyl-2-chloropyridinium iodide to give prone to carbonium ion formation, e.g. 4-methoxybenzyl macrolactam 151 in 76% yield for the two steps. Selective alcohol). hydrolysis of the MOM group adjacent to the naphthalene amide occurred together with the acetonide to yield a triol 152 from which the allyl ether and allyl ester functions were H2SO4 conc. (10 mmol) O MgSO4 anh. (40 mmol) O removed by treatment with catalytic (Ph3P)4Pd and Bu3SnH in ButOH (50 mmol) toluene containing HOAc.93 Next, the two acetate functions OH OBut fi CH2Cl2, 25 °C, 18 h were hydrolysed with LiOH and the carboxylic acid esteri ed NHCbz 87% (10 mmol scale) NHCbz with trimethylsilyldiazomethane. To complete the synthesis, the remaining two MOM groups were hydrolysed with aqueous Scheme 61 TFA and the resultant diol oxidised in air to give damavaricin D (153). 2-(Trimethylsilyl)ethoxymethyl (SEM) esters are usually fi fi fl A P zer process development group showed that sul nic cleaved with HF in acetonitrile or with uoride ion—conditions acids or the corresponding salts, in the presence of a catalytic which are incompatible with acid sensitive TBS ethers and Boc amount of Pd(PPh ) , efficiently cleave the C–O bond of allyl groups or fluoride sensitive Fmoc groups. Joullié and co- 3 4 90 esters and ethers as well as the C–N bond of N-allyl amines in workers have explored the virtues of SEM esters for the dichloromethane or methanolic THF at room temperature.94 protection of the C-terminus of peptides and found that many The reaction works equally well with but-2-enyl, cinnamyl, of the previous incompatibilities can be reconciled by using 91 2-chloroprop-2-enyl and 2-methylprop-2-enyl esters. Most of magnesium bromide–diethyl ether for the deprotection. the 19 examples reported used toluene-p-sulfinic acid or its Protecting groups typically encountered in peptide chemistry sodium salt, but other sulfinates worked equally well such as including Boc, Cbz, Fmoc and Troc carbamates are retained. fi ffi sodium thiophene-2-sul nate, sodium 4-chloro-3-nitrobenzene- The procedure is illustrated by the e cient and selective sulfinate, sodium tert-butylsulfinate, monosodium p-sulfino- deprotection of the didemnin tetrapeptide 146 shown in benzoate and sodium formaldehyde sulfoxylate (Rongalit). To Scheme 62. demonstrate the power of the method, various allylic esters (154a–e, Scheme 64) of the highly sensitive penem system were OMe ffi fi NHCbz removed e ciently with sodium toluene-p-sul nate, whereas other allyl scavengers such as carboxylic acids, morpholine, N dimedone and N,NЈ-dimethylbarbituric acid led to poor results. O O A major problem in the synthesis of serine or threonine O N phosphopeptides is the selective removal of N- or C-terminal Me O protecting groups without causing β-elimination of the phosphate moiety—a transformation that occurs at pH > 8. O Sebastian and Waldmann showed that heptyl esters were Downloaded by San Francisco State University on 14 September 2012 NHBoc

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H enzyme-labile carboxy protecting groups that could be cleaved OR under conditions mild enough to preserve phosphate residues.95

146 R = CH2OCH2CH2SiMe3 A synthesis of phosphopentapeptide 158 representing a con- MgBr2•OEt2 (3 equiv.) 100% CH2Cl2, –20 °C → rt sensus sequence of the Raf-1 kinase (Scheme 65) illustrates 147 R = H the value of both the enzyme deprotection technique as well Scheme 62 as the use of Pd0-catalysed deprotection of allyl phosphates, carbamates and carboxylates. Damavaricin D (153), a biosynthetic precursor and degrad- The carbamoylmethyl (CAM) group developed by Mar- ation product of streptovaricin D, inhibits RNA-directed DNA tinez 96 was employed as a carboxy protecting group in the polymerase. Roush et al. recently accomplished a synthesis of construction of the Cys-Thr-Gly fragment 160 of the eIF-5A damavaricin D which is a salutary lesson in the frustrations hapten 65 (vide supra). The synthesis began with N-Boc-Gly- attending model studies.92 Success in the synthesis was very CAM ester from which the tripeptide 159 was constructed using dependent upon a carefully wrought protecting group strategy standard methodology. The CAM ester was removed with which had been thoroughly evaluated in closely related models. sodium carbonate in aqueous DMF to give the desired frag- However, the preliminary studies were largely useless in the real ment 160 in 77% yield (Scheme 66). Note the survival of the system. For our present purposes we will join the synthesis S-Cbz function under these conditions. at intermediate 148 (Scheme 63) and consider the selective The Givens group 97 have reported the use of the p-hydroxy- manipulation of the five ester functions leading to the final phenacyl group as a new photoactivated protecting group for product. Cleavage of the 2-(trimethylsilyl)ethyl ester with carboxy functions. Irradiation of buffered solutions of the ester TBAF followed by a Curtius rearrangement on the resultant 161 at room temperature led to rapid release of γ-aminobutyric carboxylic acid returned an isocyanate intermediate which was acid (162) with the concomitant formation of p-hydroxyphenyl- trapped with 2-(trimethylsilyl)ethanol to give the 2-(trimethyl- acetic acid (164, Scheme 67). silyl)ethyl carbamate 149. Selective reduction of the (Z)-enoate The 3Ј,5Ј-dimethoxybenzoin (DMB) system can photo- of 149 required careful control of the reaction conditions in release a variety of functional groups with ca. 350 nm irradi- order to avoid competing reduction on the two acetate esters. ation. A recent study 98 of the mechanism of the reaction using Treatment of 149 with 5 equiv. of DIBAL-H in THF at Ϫ100 to nanosecond laser flash photolysis led to the suggestion that the Ϫ78 ЊC for 1.5 h provided the (Z)-enal (14%), the correspond- primary step in the photorelease is a charge transfer interaction ing allylic alcohol (33%) and recovered 149 (49%). After of the electron-rich dimethoxybenzene ring with the electron-

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4017 View Online

MOM MOM O O O O O H SiMe3 N O O (a) TBAF, DMF SiMe3 O MOMO (b) Ph2PON3, NEt3, MOMO OMOM Me3SiCH2CH2OH, THF OMOM O OAc OAc O O 66% (2 steps) O OAc OAc O O

CO2Me CO2Me OO OO 148 149 (a) DIBAL-H (5 equiv.), THF, –100 → –78 °C, 1.5 h (b) Swern oxidation (67% 2 steps)

MOM MOM O O O O H H N N O SiMe3

OO O MOMO (a) TASF, DMF MOMO OMOM O OMOM O (b) N-methyl-2-chloropyridinium iodide O OAc OAc O O NEt , CH Cl O 3 2 2 76% (2 steps)

OAcOAc O OO 151 150 OO 1 M HCl–THF (7:9), 23 °C, 14 h (54%)

SiMe3 MOM O O OH O H H N N (a) (Ph P) Pd, Bu SnH, HOAc OHO 3 4 3 (b) LiOH, THF–MeOH–H2O (2:2:1) OHO HO HO (c) Me3SiCHN2 (50%, 3 steps) OMOM HO (d) TFA-H O (9:1), then O (70%) O HO O 2 2 O O OMe

OAcOAc O OHOH O Downloaded by San Francisco State University on 14 September 2012

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H 152 153 Scheme 63

– 99 O O– antibiotic enopeptin B, Schmidt and co-workers required an acid labile protecting group that could be removed in the pres- S S OH OH ence of a tert-butyl ester and a sensitive pentenedioyl system. H H H H S S The task was accomplished using a tert-butyldiphenylsilyl ester S which was removed from the fragment 169 using aqueous HF in Pd(PPh ) (5 mol%) S N 3 4 N acetonitrile–THF (Scheme 69). O O OR TolSO2Na (1.0 equiv.) An alternative synthesis of Corey’s OBO group has been OH 100 O THF–MeOH, rt O reported by Charette and Chua (Scheme 70). Imino and 154 iminium triﬂates derived from secondary and tertiary amides RTime (min) Yield respectively, react with 2,2-bis(hydroxymethyl)propan-1-ol in

a CH2C(Cl)=CH2 105 97% the presence of pyridine to give the orthoester. Primary amides b CH2C(CH3)=CH2 130 94% cannot be used as substrates because they dehydrate to the c CH2CH=CHCH3 35 91% nitrile under the reaction conditions. d CH2CH=CHPh 30 94% A new method for the protection of polyfunctionalised carb- e CH CH=CH 25 87% 2 2 oxylic acids involves a zirconocene-catalysed epoxy ester–ortho Scheme 64 ester rearrangement.101 A synthesis of a γ-hydroxyleucine derivative 174 illustrates the method (Scheme 71). The epoxy deﬁcient oxygen of the n,π* singlet excited acetophenone, to ester 172 prepared from (2S)-2-(benzyloxycarbonylamino)- form an intramolecular exciplex 166 which can return to 165 or succinic acid 4-methyl ester 171 was treated with zirconocene react to give cation 167 (Scheme 68). This mechanism accounts dichloride in the presence of silver() perchlorate to give the for the high eﬃciency of the substitution pattern of the 2,7,8-trioxabicyclo[3.2.1]octane (ABO) derivative 173 in 99% methoxy groups as well as the absence of solvent-substitution yield. Reaction of the remaining ester function with excess or radical-derived products in 3Ј,5Ј-dimethoxybenzoin photo- methylmagnesium bromide followed by hydrolysis gave the chemistry. target molecule 174. The ABO ortho ester derivatives of a During a synthesis of the challenging cyclodepsipeptide number of amino acids were prepared in 90–100% yield by this

4018 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online OAll OAll O P OAll O P OAll lipase from Aspergillus niger O OH O OH O O 0.2 M phosphate buffer/acetone (95:5) O O H H N O pH 7, 37 °C N OH AllO N N AllO N N H H 68% H H O O O O OH OH

155 156

H-Thr-Pro-OAll 71% EDC, HOBt, CH2Cl2 OH OAll O P OH O P OAll O OH O OH O O O CO H O O O OAll H H 2 H H N N (Ph3P)4Pd(0) N N H2N N N AllO N N N H HCO2H, BuNH2 H H O O 73% O O OH OH OH OH 158 157 Scheme 65

H OMe OMe * OBut O O H O O CbzHN N N O–CH2–CONH2 H OMe OMe O CbzS CAM X X 159 166 165 (a) Na CO (2.72 mmol) 77% 2 3 X = OCOR, OPO(OR)2 1.36 mmol scale DMF-H2O (7:4, 22 ml), rt, 5 min OCONHR, OCO2R (b) add citric acid (0.5 M) to pH 6

H MeO MeO OBut O O H H OMe CbzHN N O OMe –HX O N OH H O CbzS X– 160 168 167 Scheme 66 Scheme 68 Downloaded by San Francisco State University on 14 September 2012 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H NH3X

NH3X 162 O – OO ButO OR N H OO + O O O O CO2H t 169 R = Si(Bu )Ph2 HF, THF-H O-MeCN 2 85% hν rt, 1 h H2O 170 R = H buffer r.t. Scheme 69

OH O OH

161 163 164 O NEt2 (a) Tf2O (1.3 equiv.) Scheme 67 pyr (3.0 equiv.) OOO

CH2Cl2, –40 → 0 °C, 4 h procedure. A potentially useful feature of the new ABO protecting group is its greater stability towards mild acid hydrolysis (b) MeC(CH2OH)2CH2OH (1.5 equiv.) than the 2,6,7-trioxabicyclo[2.2.2]octane (OBO) ortho ester.102 EtOH, MeCN Thus, OBO groups hydrolyse in 2 min with pyridinium tosylate 88% in aqueous methanol whereas the corresponding ABO group requires 22 h. Scheme 70 A synthesis of α-hydroxy-β-homoarginine derivative 177 (Scheme 72) was accomplished 103 by the addition of [tris- (methylthio)methyl]lithium 104 to the aldehyde 175 followed by 6 Phosphate protecting groups Hg2ϩ-catalysed methanolysis of the resultant orthothioester The (N-triﬂuoroacetylamino)butyl and (N-triﬂuoroacetyl- 176. amino)pentyl groups have been reported as alternatives to

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4019 View Online

O ODMTr ODMTr O O (a) HO(CH ) C(CH )=CH Thy Thy CO2Me 2 2 3 2 DCC, DMAP, CH2Cl2 CO2H MeO C O 2 •• O O NH (b) mcpba, CH2Cl2 NH3 aq. (conc.) 2 NHCbz O OP O(CH ) NHCOCF OOP 55% (2 steps) 2 4 3 2 h, 25 °C NHCbz 171 O O O O 172 Thy Thy

Cp2ZrCl2 (10 mol%), AgClO4 (5 mol%) 99% CH Cl , 22 °C, 1 h 2 2 HO HO 179 178

(a) MeMgBr (excess) Thy = thymine O MeO2C O (b) 1 M HCl O O O ODMTr (c) LiOH, H2O-THF O NHCbz 48% (3 steps) NHCbz Thy 174 173 H N O Scheme 71 – OOP NH4 O O BocN NHBoc BocN NHBoc Thy

HN HN (MeS)3CLi (ca. 52 mmol) HO 180 THF (182 ml), –65 °C, 5 h 54% (11.5 mmol scale) Scheme 73 OH CbzHN CbzHN OTBS OH O C(SMe)3 175 176 OPO(OPh)2 OPO(OH)2

O H2, PtO2 O BocN NHBoc O O O O P EtOH, rt O O P HN O 96% O HgCl2 (20.8 mmol) Cl3CCH2O Cl3CCH2O HgO (7.82 mmol) 181 182

MeOH (118 ml), H2O (8.5 ml) 9:1 TPSCl, tetrazole OH rt, 72 h 46% CbzHN pyr, rt, 48 h 79% (6.2 mmol scale) CO2Me O OH O OH 177 P P O O O Zn-Cu O O O Scheme 72 DMF

Downloaded by San Francisco State University on 14 September 2012 O 50 °C O Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H the traditional 2-cyanoethyl phosphate protecting group in O O O O P 96% P the solid phase synthesis of nucleosides.105 They can be HO O Cl3CCH2O O removed from oligonucleotides (e.g. 178) by treatment with 184 conc. aqueous ammonia at ambient temperature (Scheme 73). 183 Note that cleavage of 2-cyanoethyl phosphates is usually Scheme 74 carried out in non-nucleophilic basic conditions using DBU.

The deprotection kinetics, examined in the case of dimer 178, InsP5) and related bis-pyrophosphates which have an unusually showed that the initial rate-limiting cleavage of the N-trifluoro- high metabolic turnover consistent with the speculation that acetyl group was followed by a rapid cyclodeesterification of they act as phosphate donors for unidentified kinases. The the intermediate 179. Complete conversion occurred within 2 h Falck group 107 have described a stereocontrolled synthesis of Њ  at 25 C producing phosphodiester 180 and innocuous pyrrol- 5-PP- -myo-InsP5 (191) outlined in Scheme 75 which illustrates idine. By comparison, deprotection of a 2-cyanoethyl group how a single phosphate residue in a hexakisphosphate deriv- releases acrylonitrile which can form an addition by-product ative can be transformed selectively to a pyrophosphate. The with nucleobases. readily available myo-inositol bis-disilanoxylidene 185 was

The C2-symmetric cyclic bis(phosphate) 184, a potent phosphorylated selectively at the less hindered equatorial C5 inhibitor of oligonucleotide processing enzymes including hydroxy group. Desilylation of 186 required carefully con- RNA integrase, was synthesised from 2-deoxy--ribose in 18% trolled conditions as more basic or acidic reagents such as overall yield.106 The synthesis required two orthogonal phos- TBAF, HF or TFA aﬀorded a complex mixture. The desilyl- -phate protecting groups (Scheme 74). In the closing stages of ation was best achieved using HFؒpyridine complex where the synthesis the diphenyl phosphate ester 181 was hydrogen- upon the desired pentaol 187 was produced in 68% yield. olysed to generate the free acid, which promoted concomitant Phosphorylation of the liberated hydroxy groups gave hexa- cleavage of the TBS ether. Cyclisation of 182 was accomplished kisphosphate 188. Then conversion of the C5 phosphate to the with 2,4,6-triisopropylbenzenesulfonyl chloride (TPSCl) giving corresponding pyrophosphate was initiated by speciﬁc cleavage 183 in a 46% yield. Finally, reductive cleavage of the trichloro- of the phosphate methyl ester using one equivalent of lithium ethyl group with zinc–copper alloy returned the target in 96% cyanide at room temperature. The resultant lithium salt 189 yield. was coupled immediately with dibenzyl chlorophosphonate to Recent studies on the myo-inositol cycle have revealed a give the protected pyrophosphate derivative 190. Finally the family of pyrophosphoryl myo-inositol pentaphosphates (PP- sequence was completed by hydrogenolysis of the benzyl phos-

4020 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online

OMe OMe O P OBn O P OBn OR O O i (a) Pr 2N–P(OBn)2 (1 equiv.) (BnO) OPO OPO(OBn) Si O O Si HO OH 2 2 HF•pyr, THF (1:2.5), rt, 3 h 1H-tetrazole (2 equiv.) O O 68% → Si Si CH2Cl2, 0 23 °C, 3 h O O HO OH (BnO)2OPO OPO(OBn)2 (b) MCPBA, –78 °C, 15 min OH OH OPO(OBn)2 78% 187 188

185 R = H i (a) Pr 2N–P(OMe)(OBn) (1 equiv.) 92% 1H-tetrazole (2 equiv.), CH Cl , 0 °C, 3 h 2 2 LiCN (1 equiv.) 186 R = PO(OMe)(OBn) (b) MCPBA, –78 °C, 15 min DMF, rt, 12 h

ONa O OBn O OLi

OP O P(ONa)2 O P O P(OBn)2 O P OBn O O O Pd, H (50 psi) 2 (BnO) POCl (NaO)2OPO OPO(ONa)2 (BnO)2OPO OPO(OBn)2 2 (BnO)2OPO OPO(OBn)2 NaHCO3 NEt3, CH2Cl2 → t 0 23 °C, 2 h Bu OH-H2O (6:1) 56% (2 steps) (NaO)2OPO OPO(ONa)2 70% (BnO)2OPO OPO(OBn)2 (BnO)2OPO OPO(OBn)2 OPO(ONa)2 OPO(OBn)2 OPO(OBn)2

191 190 189 Scheme 75

O O OH

RO O PACLev–O O ∆ PACLev–O OH TFA, MeOH, CH2Cl2 80% aq. HOAc,

95% 79% O OR RO O–PACLev (FmO)2P(O)O O–PACLev

O RO (FmO)2P(O)O

i 194 R = H (FmO)2PNPr 2, 1H-tetrazole 196 followed by MCPBA 93% 195 R = (FmO)2P(O) O2CC17H33 192 R = H pyr•HBr3 PACLev–OH O2CC17H33 2,6-lutidine 100% DCC, DMAP OP(OMe)2 90% 193 R = PACLev

O2CC17H33 O2CC17H33

Downloaded by San Francisco State University on 14 September 2012 OH O O2CC17H33 OH O O2CC17H33 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H (a) NaI, acetone, ∆ (84%) HO O P O PACLev–O O P O (b) Et3N, MeCN-EtCN (3:1), ∆ (86%) O– OMe (c) NH NH , pyr, HOAc (100%) –HO P(O)O 3K+ 2 2 (FmO) P(O)O O–PAC 2 OH (d) ButOK (100%) 2 Lev – HO2P(O)O (FmO)2P(O)O 198 197

CO2H O PACLev = Fm = CH2 C17H33 = O O

Scheme 76

phate esters in the presence of sodium hydrogen carbonate to ate with m-chloroperoxybenzoic acid. Subsequent regioselective give the target 191. A similar sequence was used to prepare phosphorylation of the 1-hydroxy function in diol 196 gave the  2-PP- -myo-InsP5. triphosphate 197 which completed the assembly of the com- A recent synthesis of a -1,2-di-O-oleoyl-sn-glyceryl phos- ponents of the target. The deprotection regime began with the phate analogue of phosphatidylinositol 4,5-bisphosphate 198 1-phosphate group (NaI) followed by the fluorenylmethyl (Scheme 76) incorporated fluoren-9-ylmethyl (Fm) esters as phosphates at the 4- and 5-positions using triethylamine. The protecting groups for phosphate.108 The synthesis began with first Fm group in each phosphate was removed at room tem- the protection of the 3,6-dihydroxy functions in the inositol perature and the mixture then heated to remove the second Fm

derivative 192 as their 2-[2-(levulinoyloxy)ethyl]benzoyl group. Finally, the PAVLev esters were removed by reaction with 109 (PACLev) esters. Phosphorylation of the 4,5-diol functions hydrazine in pyridine and acetic acid and the resultant hydroxy- with difluorenylmethyl phosphoramidite gave the fluoren-9- ethylbenzoates were treated with KOBut to afford the final ylmethyl diester 195 after oxidation of the phosphite intermedi- product 198.

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4021 View Online Photoactivated protective groups play an important role in Lee and Cheng 112 reported that acetals and ketals can be the study of biochemical mechanisms, allowing the rapid deprotected to the corresponding carbonyl compounds using a and eﬃcient release of bioactive compounds in the tested catalytic amount of carbon tetrabromide in acetonitrile–water environment. Recently Park and Givens 110 demonstrated that mixture under either ultrasound or thermal (reﬂux) conditions p-hydroxyphenacyl groups can be used to trigger the photo- (Scheme 79). Ultrasound conditions are milder; e.g. acetals release of adenosine 5Ј-triphosphate (ATP, 200) from the pro- containing strong electronegative substituents (like p-nitro- tected nucleotide 199 when irradiated at wavelengths between benzaldehyde derivatives) remain intact. 300–350 nm (Scheme 77). p-Hydroxyphenacyl phototrigger

compares favourably with other photoactivated protecting CBr4 (0.2 mmol) groups (e.g. desyl) because it has no chiral centres and has a MeCN (1 ml), H2O (2 ml) better aqueous buﬀer solubility. Also, the by-product of the O ultrasound H photolysis—p-hydroxyphenylacetic acid 201—does not com- O (Crest 575-D, 39 kHz) O O O pete for the incident radiation in the 300–400 nm region, which ~40 °C, 2 h improves the yield of the photolysis. 81% (1 mmol scale)

Scheme 79 NH2 N N A method for the cleavage of acetals and ketals to the corresponding carbonyl compounds using lithium chloride and O OOO N N water in DMSO at elevated temperatures (90–130 ЊC) has been O P OPOPO described.113 The method is limited to systems which give O α β OOO , -unsaturated aldehydes and ketones. Diaryl and saturated compounds remain intact allowing selective deprotection, as HO NH4 NH4 NH4 OH OH illustrated in Scheme 80. 199

OH hν (300 nm irradiation) TRIS buffer (5 ml, 0.05 M, pH 7.3) O O H O O (0.125 mmol scale) LiCl (10 mmol) HO H2O (2 ml) 201 NH2 DMSO (15 ml) N N 90 °C, 6 h O 91% (2 mmol scale) O OOO N N O O O P OPOPO O Scheme 80 OOO

NH4 NH4 NH4 OH OH Ferric chloride hexahydrate in dichloromethane is a mild 200 reagent for deprotecting acetals (Scheme 81) and the method is compatible with some acid sensitive groups.79 For example, 205 TRIS = tris(hydroxymethyl)aminomethane was inert to oleﬁn isomerisation under the conditions even after Scheme 77 long reaction times.

O O Downloaded by San Francisco State University on 14 September 2012 7 Carbonyl protecting groups

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H FeCl •6H O (2.8 equiv.) 111 3 2 Lipshutz and co-workers devised a new carbonyl protecting OEt OEt group which involves the formation of ‘cyclo-SEM’ derivatives CH Cl , ∆, 20 min O 2 2 (e.g. 204, Scheme 78) in the reaction with 2-trimethylsilyl- 77% propane-1,3-diol (202). The deprotection is achieved with O O lithium tetrafluoroborate in THF which also allows the select- 206 ive unmasking of one carbonyl group in 204 (only 2–3% 205 of the corresponding diketone is observed). The choice of Scheme 81 solvent can affect the selectivity of the deprotection; e.g. in MeCN the cyclo-SEM group as well as standard 1,3-dioxane 1,3-Dioxolanes are cleaved 114 in good yield using 1.5 equiv- and 1,3-dioxolane derivatives are removed. alents of CeCl3–7H2O in acetonitrile at room temperature. The deprotection can be hastened by adding a catalytic amount of sodium iodide and/or by heating to reflux. It is not possible to 202 (5.4 equiv.) O O ascertain from the 13 examples cited whether these new condi- O O 4Å MS, CSA (0.25 equiv.) tions offer tangible benefits over the traditional aqueous acidic O conditions. CH2Cl2, rt, 12 h One step conversion of acetals to esters can be achieved with 85% O O H hydrogen peroxide and hydrochloric acid in alcohols (Scheme H Me Si 3 82).115 The reaction works well with saturated compounds but 203 204 with α,β-unsaturated acetals the yield is low due to competitive fi LiBF4 (0.5 M in THF) addition of HCl to the ole n.

66 °C, 3 h HCl (12 M, 0.25 ml, 3 mmol) SiMe3 >80% H2O2 (34% in H2O, 3.0 mmol) MeO OMe MeOH (4 ml) O OMe

C9H19 C H HO OH CSA = camphorsulfonic acid 0 °C, 30 min → 40 °C, 3 h 9 19 202 96% (2 mmol scale) Scheme 78 Scheme 82

4022 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online α β Acetalisation of , -unsaturated carbonyl compounds is Ph Ph O O often diﬃcult with conventional acid catalysts. In 1992 Otera MeReO3 (1 mol%) 116 O Re Me and co-workers reported that distannoxanes (e.g. 209, CHCl3, rt, 2-5 days) Scheme 83) are extremely active catalysts for acetalisation. The Ph O O Ph reaction proceeds under almost neutral conditions and thus is 214 recommended for sensitive compounds like enones and enals. 213 (1.1 equiv.) Recently Malacria and co-workers 117 successfully used 209 for cyclopentanone (1 equiv.) the protection of unsaturated aldehyde 208.

Ph O O O (a) DIBAL-H, CH2Cl2 O → Ph –78 0 °C H OEt 215 (87%) (b) Swern oxidation Scheme 86 208 207 can also be formed from the analogous reaction of oxiranes ∆ 209, (HOCH2)2, PhH, with ketenes and aldimines respectively. 83% (overall) Cyclic ketals of acetophenone can be prepared directly by the reaction of aryl triﬂates, bromides or iodides (e.g. 216, Scheme NCS Bu Bu Bu O 87) with hydroxyalkyl vinyl ethers (e.g. 217) in the presence of a Sn O Sn OH catalytic amount of palladium() acetate and 1,3-bis(diphenyl- Bu Bu O 121 HO Sn O Sn phosphino)propane (DPPP). The example illustrated in Bu Bu Bu NCS Scheme 87 is especially noteworthy since the protected methyl ketone was introduced in the presence of a reactive aldehyde 209 functionality. 210

Scheme 83 O OH (217) O O OHC OTf The classical ketalisation of the Wieland–Miescher ketone (10 mmol) OHC 211 (ethylene glycol, benzene, PTSA, reﬂux) (Scheme 84) is

capricious. It results in moderate yields of 212 due to the form- Pd(OAc)2 (0.15 mmol) DPPP (0.30 mmol) ation of the corresponding bisketal and also because of the 216 218 presence of unreacted 211 in the reaction mixture. However, Et3N (7.5 mmol) DMF (15 ml), 80 °C, 24 h selective ketalisation of 211 can be achieved in high yield using 76% (5.0 mmol scale) ethylene glycol as solvent and a stoichiometric amount of PTSA.118 Scheme 87

Acetals are susceptible to oxidation by ozone and dioxolane O O derivatives are especially reactive giving 2-hydroxyethyl esters at HOCH2CH2OH (730 ml) O 122 PTSA (1 equiv.) a rate comparable with the oxidation of alkenes. Frigerio and co-workers 123 recently showed that dimethyldioxirane (DMD) 4Å MS, rt, 23 min ﬀ Downloaded by San Francisco State University on 14 September 2012 O O also e ects the oxidation of dioxolanes in good yield. In the Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H 90% (146 mmol scale) single example illustrated in Scheme 88, the secondary alcohol 211 212 function is also oxidised to a ketone. Scheme 84

Solvent free acetalisation of aldehydes and ketones under O O OH microwave irradiation has been described by Hamelin and co- O O 119 workers. Methyl or ethyl orthoformates, ethylene glycol or DMD / acetone 2,2-dimethyl-1,3-dioxolane can be used as reagents and PTSA rt or montmorillonite clay KSF as a catalyst (Scheme 85). 100% OH OH HO O O

O Scheme 88 O O (3 equiv.) O KSF (10 mmol) H Deprotection of thioacetals using clay supported ammonium H nitrate 124–126 and zirconium sulfophenyl phosphonate 127 has MW (120 °C, 15 min) also been reported recently. 85% (10 mmol scale) Yamamoto and co-workers 128 reported a new protecting Scheme 85 group for aldehydes and ketones which is based on the reaction of a carbonyl compound (e.g. 220, Scheme 89) with lithiocar- A new synthesis of dioxolanes from oxiranes and carbonyl borane (formed by treatment of o-carborane 219 with n-butyl- compounds has been reported 120 which is catalysed by methyl- lithium). The addition product 221, unlike acetals, is stable rhenium trioxide. The stereochemistry of the starting oxirane is under aqueous protic acid and Lewis acid conditions. The retained in the ﬁnal product owing to two inversions in the adduct can be easily converted back into the corresponding sequence depicted in Scheme 86. Aldehydes and cyclic ketones carbonyl compound under basic conditions using a catalytic give good yields but acyclic ketones such as pentan-3-one and amount of KOH in aqueous THF. The practical application cyclic conjugated enones such as cyclohexenone give poor to of the methodology is illustrated in Scheme 89. Reduction of modest yields. In some cases the bis(alkoxy)rhenium() com- the ester group in 221 by lithium aluminium hydride gave alco- plexes 214 could be detected. Ketene acetals and oxazolidines hol 222 which, after deprotection of the carbonyl function,

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4023 View Online 129 (a) BuLi (5 mmol) (N-Dts) and azido functionalities has been investigated. By OH –78 °C, 30 min use of propane-1,3-dithiol (PDT) in the presence of diiso- MeO2C B10H10 propylethylamine (DIPEA), it is possible to reduce selectively (b) 220 (5.5 mmol) the N-Dts group of 227 (Scheme 91) without affecting the azido 219 –78 °C, 1 h then rt 221 B10H10 95% (5 mmol scale) group. On the other hand, the more reactive dithiothreitol LiAlH4 (DTT)–DIPEA reduced both groups affording 229 in 96% yield 95% THF, ∆ after acetylation. KOH (0.15 equiv.) OH THF-H2O (100:1) CHO OAc rt, 2 days HO HO 77% (a) PDT, EtNPri , CH Cl 222 2 2 2 O 223 B10H10 AcO N3 (b) Ac2O-pyr (1:2) AcO NHAc 94% 228 SnBu3 OAc MeO C CHO 2 O B10H10 AcO i (a) DTT, EtNPr 2, CH2Cl2 OAc AcO N3 220 224 N O OO(b) Ac2O-pyr (1:2) AcO Scheme 89 96% AcO NHAc SS NHAc yielded hydroxy aldehyde 223. Chemoselective protection of an 227 229 aldehyde in the presence of a ketone can also be accomplished Scheme 91 using o-carboranyltributylstannane 224 and a catalytic amount . of Pd dba ؒCHCl 2 3 3 During their synthesis of disaccharide 234 bearing an eth- anolamine phosphate group (PEA), van Boom and co- 8 Amino protecting groups workers 130 reported the first example of immobilised penicillin- A key element in Fraser-Reid’s synthesis of nodulation factor G acylase mediated deblocking of an N-phenylacyl-protected NodRf-III (C18:1, MeFuc) was the use of a tetrachloro- PEA moiety. The introduction of the protected phosphate phthaloyl (TCP) group to provide N-differentiation of the group was achieved in the reaction of disaccharide 230 linear glucosamine backbone.13 Thus installation of the (Z)- (Scheme 92) with phosphoramidite 232. Oxidation of the octadec-11-enoyl group on the terminal glucosamine began by intermediate phosphite triester with tert-butyl hydroperoxide selective deprotection of the TCP group in tetrasaccharide 225 and triethylamine was accompanied by the simultaneous de- (Scheme 90) using only 5 equivalents of ethylenediamine. After protection of the 2-cyanoethyl group. The resulting protected amide bond formation and esterification of any deprotected phosphodiester 231 was subjected to hydrogenation (to cleave acetates, the two remaining phthalimide (Phth) groups were the Cbz and benzyl groups) followed by treatment with removed by heating 226 in EtOH at 90 ЊC for 34 h with 500 immobilised penicillin-G acylase (Seperase G) to remove the equivalents of ethylenediamine. N-phenylacetyl group from the PEA moiety. A similar application of penicillin-G acylase for the de- OBz protection of N-phenylacetyl-protected nucleobases in oligo- 131 O nucleotides has been reported by the Waldmann group. OBz The use of a picolinoyl group as an electrochemically remov- OMe able protecting group for amines in peptide synthesis has been OTBS OTBS O reported.132 The protection step is carried out by treating an Downloaded by San Francisco State University on 14 September 2012 O Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H O AcO O O O amino acid ester or peptide (e.g. 235, Scheme 93) with pipe- OTBS AcO AcO HO colinic acid (Pic-OH), 1-hydroxybenzotriazole (HOBT), N PhthN OO PhthN N-methylmorpholine (NMM) and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC). The picolinoyl Cl Cl protecting group is then removed from the tripeptide 237 by 225 electrolysis at E = Ϫ1300 mV vs. saturated calomel electrode Cl Cl (SCE). The deprotection can be performed selectively in the presence of tosyl, benzyloxycarbonyl, O-benzyl, tert-butoxy- (a) ethylenediamine (5 equiv.) carbonyl and O-tert-butyl groups. However, two groups turned MeCN-THF (3:1), 60 °C 25% (3 steps) (b) 2-chloro-N-methylpyridinium iodide (2.5 equiv.) out to be incompatible: trichloroethoxycarbonyl (Troc) (prob-

MeCN, NEt3, (Z)-octadec-11-enoic acid, 40 °C ably because of competitive cleavage of the C–Cl bond) and (c) Ac2O, NEt3, CH2Cl2, rt fluoren-9-ylmethoxycarbonyl (solubility problems). OBz The pent-4-enoyl group 133 has been used for protection of an O α-amino function during the synthesis of aminoacylated trans- OBz fer RNA’s (Scheme 94).134 The protection step is carried out by OMe OTBS OTBS O treating the methyl ester of (S)-valine 239 with pent-4-enoic anhydride. The product 240 was then attached to a nucleotide O O AcO O O O ff OTBS to give 241. Deblocking was then e ected by treatment with AcO AcO AcO NH PhthN PhthN iodine. O Stannic chloride in ethyl acetate is a new reagent for the deprotection of bis-Boc substituted guanidines 135 (e.g. 243, Scheme 95). The reagent is milder than the trifluoroacetic acid 226 typically used and gives good yields of the corresponding solid Scheme 90 guanidinium chlorides 244 whereas trifluoroacetate salts are difficult to crystallise. In the course of studies concerning the development of During a synthesis of the serine protease inhibitor cyclo- orthogonal protecting group schemes for glycopeptide syn- theonamide B, a Dutch group 103 found that under many acidic thesis, the selectivity between the reduction of N-dithiasuccinyl conditions, the O-(tert-butyl)tyrosine in the dipeptide 245

4024 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online

OBn O

OBn OMe N H NH2 P CN BnO N O O O OBn OBn H 235 RO O OBn Pic-OH (2 mmol), HOBT (2 mmol) HN OBn H Ph O NMM (2 mmol), EDC (2.2 mmol) O BnO CH2Cl2 (90 ml), 0 °C, 2 h; 20 °C, 2 h O 232 O NHCbz

230 R = H OMe (a) 232 (1.5 equiv.) NH 1H-tetrazole (1.9 equiv.) 84% N H N CH2Cl2–MeCN (2:1), rt, 45 min (0.14 mmol scale) O t (b) Bu OOH, Et3N, 0 °C, 16h O 231 R = 236 PO(CH2)2NHC(O)Bn – + O Et3HN H2 (35 psi), Pd(OH)2 (10%, 0.3 g) (a) Basic hydrolysis i Pr OH–H2O–AcOH (3:1:1), 20 ml (b) Peptide coupling rt, 16 h, 61% (0.12 mmol scale) O H OH NCO2Bn N H OH NH O H N Ph HO H N O OH O OH O O OH 237 O P O OH H O O HO H SO , NaHSO (pH 2) 84% 2 4 4 MeOH, 25 °C ONH2 (0.6 mmol scale) E = –1300 mV vs. SCE R 233 R = NHC(O)Bn O Separase G (150 U g–1, 18 g mmol–1) H H2O (5 ml), NaOH (0.01 M), pH = 7.5 93% NCO2Bn N rt, 16 h (0.036 mmol scale) + H 234 R = NH3 NH2 O N Ph Scheme 92 H 238 Scheme 93 (Scheme 96) cleaved more rapidly than the N-Boc group. Fortunately, using the conditions of Ohfune and co- NH2 workers,136,137 the N-Boc group could be cleaved selectively O using TMSOTf followed by aqueous workup. The extreme O OOP N Downloaded by San Francisco State University on 14 September 2012 H Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H sensitivity of an O-(tert-butyl)tyrosine derivative towards careful N 3 steps O treatment with HCl in ethyl acetate (1 M, 500 mol%) was also OMe N O recently established in a study aimed at selective cleavage of O O N-Boc groups in the presence of other acid-labile protecting NH2 groups such as tert-butyl esters, aliphatic tert-butyl ethers, 240 O 138 N S-Boc groups and S-trityl ethers. O P O N (H2C=CH(CH2)2CO)2O, During the early stages of Myers’ synthesis of dynemicin 73% O Et3N, 0 °C, 2 h A,7 deprotection of the Boc group in 247 (Scheme 97) was N N O required in order to effect internal amidation for the prepar- O O ation of the quinolone 248. Initial experiments confirmed that H N 2 O OH the enol ether function in 247 was too labile to the acidic condi- OMe tions usually associated with Boc deprotection (e.g. trifluoro- RHN acetic acid in dichloromethane). However, by heating 247 in the 239 weakly acidic 4-chlorophenol (180 ЊC, 30 min) the Boc group was cleaved while preserving the enol ether function to give the 241 R = C(O)(CH2)2CH=CH2 quinolone 248 in 84% yield. 4-Chlorophenol was the optimal I2, THF-H2O, 25 °C, 5 min 242 R = H solvent for the deprotection/amidation since aprotic solvents such as diphenyl ether gave very slow reaction and phenol itself Scheme 94 was slower and gave a messy reaction with by-products derived

from reaction with the phenol. HN Boc NH2•HCl The azinomycins are antitumour antibiotics isolated from HN HN the culture broth of strain Streptomyces griseofuscus S42227. N Boc NH During a study directed towards the synthesis of the aziridine SnCl4 (4 equiv.) core of the azinomycins, Coleman and Carpenter 139 had encountered diﬃculties in removing the benzyloxycarbonyl AcOEt, rt, 3 h NHCOCF3 88% NHCOCF3 (Cbz) group from the aziridine 249 (Scheme 98). For example, hydrogenolysis using various palladium catalysts [Pd–C, Pd- 243 244

(OH)2, Pd black, Pd–Al2O3] was incompatible with the bromo- Scheme 95

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4025 View Online

NHR (a) MeONa (1 equiv.) O OAll MeOH, 10 min, (b) PNZ-Cl (1 equiv.) OAc H OH Et N (1 equiv.) N 3 0 → 20 °C AcO O HN HO O AcO OAc O HO OH (c) Ac O, pyr, 16 h HN O NH2•HCl 2 78% (overall) PNZ OBut 255 256 NO TMSOTf (8 mmol) 245 R = Boc 2 (a) BnNH2 (1.1 equiv) 2,6-lutidine (10 mmol) THF, 16 h 100% CH2Cl2 (4 ml), rt, 95 min (b) CCl3CN (10 equiv.) 2 mmol scale 246 R = H O K2CO3, CH2Cl2, 7 h 75% (overall) Scheme 96 OCl PNZ-Cl OAc O HO AcO O BnO O MeO2C AcO 4-ClPhOH HN BnO HN O CCl 180 °C BnO PNZ 3 MeO OMe OMe OMe 258 30 min 257 NH 84% (a) 257 (0.375 mmol) NHBoc 4 Å MS (250 mg), CH2Cl2 (0.75 ml) OMe –30 °C, 10 min 247 248 (b) BF3•Et2O (0.125 mmol) Scheme 97 CH2Cl2 (0.75 ml), <0 °C, 2 h 91% (0.25 mmol scale)

MeO CHN CO Me MeO CHN CO Me OAc 2 2 DABCO 2 2 AcO O CDCl3 O AcO AcO AcO Br N HN BnO O 50 °C, 1 h PNZ BnO N R (41% overall) TBSO BnO TBSO 259 OMe 251 (a) MeONa, MeOH, 2.5 h 249 R = Cbz Et3SiH (23 equiv.), PdCl2 (1.0 equiv.) 93% 57% NEt3 (2.0 equiv.), 25 °C, 2 h (b) H2, 10% Pd/C 250 R = H MeOH, 76% Scheme 98 OH HO O alkene. Success was eventually achieved using the conditions of HO O 140 Њ O Birkofer: PdCl2, Et3SiH, NEt3, 25 C. H2N HO Peptide nucleic acid (PNA) analogues of DNA have attracted HO 260 HO interest as potential regulators of gene expression owing to OMe their ability to invade duplex DNA, thereby forming PNA: Scheme 100

Downloaded by San Francisco State University on 14 September 2012 DNA heteroduplexes. During a synthesis of the requisite Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H α-amino acids harbouring the four DNA bases in the side chain, difficulty was encountered protecting the N 6-amino sequent acetylation gave the protected amino-sugar 256 in 81% group of the adenine in compound 252 as its Cbz derivative.141 overall yield. The trichloroacetamide 257 was formed by regio- Treatment with benzyl chloroformate under all the usual con- selective deacetylation with benzylamine followed by treatment ditions did not give clean or efficient acylation. However, with Cl3CCN in the presence of potassium carbonate. Glyco- when 1-(benzyloxycarbonyl)-3-ethylimidazolium tetrafluoro- sidation of 258 with the glycosyl donor 257 was carried out fl borate (253, Rapoport’s reagent 142) was used instead, the using boron tri uoride–diethyl ether as a promoter to give the desired acylation was both clean and efficient (Scheme 99). disaccharide 259 in 91% yield. This result indicates that the combination of the PNZ moiety with anomeric trichloro- β – acetimidate activation achieves -glycosidation in high yield BF4 NH with high stereoselectivity. Finally the PNZ group was removed 2 + CO2Bn NHCbz Et N N by hydrogenolysis along with O-benzyl ethers to give 260 in N N N N 76% yield. Alternatively the PNZ group can be deprotected 253 (6 equiv.) selectively by sodium dithionite under neutral conditions where N N N N CH2Cl2, rt, 12 h benzyl ethers and carboxylate esters remain intact. Since 82% O-acetyl groups can be removed by treatment with MeONa– MeOH in the presence of the PNZ group, this makes the PNZ ff BocHN CO2Me BocHN CO2Me group e ectively an orthogonal protecting group in oligo- 252 saccharide synthesis. 254 A German group 144 has introduced the [(2-{[5-(dimethyl- Scheme 99 amino)-1-naphthyl]sulfonyl}ethoxy)carbonyl] group (Dnseoc) for protection of amino function in nucleobases during oligo- The p-nitrobenzyloxycarbonyl (PNZ) N-protecting group nucleotide synthesis (Scheme 101). The nucleoside (e.g. 261) has been reported as a participating group in the stereoselective could be protected directly in the reaction with Dnseoc-Cl formation of 2-amino-β-glucosides (Scheme 100).143 The pro- (263) and N-methyl-1H-imidazole. However a better result was tection was carried out in the reaction of glucosamine hydro- obtained when the two hydroxy groups were temporarily trans- chloride 255 with sodium methoxide in methanol followed by formed into TMS ethers followed by reaction with 263 and p-nitrobenzyl chloroformate (PNZ-Cl) and triethylamine. Sub- desilylation. The crude product 262 was then treated with 4,4Ј-

4026 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online dimethoxytrityl chloride to afford protected nucleoside 264 in to its ability to cross-link DNA. In studies directed towards the 81% overall yield from 261. Deprotection of the nucleobase was synthesis of FR 900482, Rollins and Williams 145 were unable to achieved by reaction with excess 1,8-diazabicyclo[5.4.0]undec- deprotect the TBS ether in intermediate 266 (Scheme 102) 7-ene (DBU). Kinetic experiments showed that the rate of without prior deprotection of the adjacent aziridine. Simul- deprotection was much faster than the previously used [2-(4- taneous N-deprotection and reduction of the ester function was nitrophenyl)ethoxy]carbonyl (Npeoc) group. In most cases accomplished in 61% yield using DIBAL-H without compet- complete deprotection occurred within 30 min. ing reduction of the 6-nitroveratryloxycarbonyl (Nvoc) group. FR 900482 isolated from the fermentation broth of Strepto- Cleavage of the TBS ether with TBAF followed by restoration myces sandaensis shows promising anti-tumour activity owing of the methoxycarbonyl group using N-(methoxycarbonyl- oxy)succinimide gave 269 in 89% yield for the two steps. After NHR 261 R = H Dess–Martin oxidation to the keto aldehyde 270, the Nvoc (a) Me3SiCl (21.4 mmol) group was removed photochemically to give the target mitosene N pyr (15 ml), rt, 2 h (b) 263 (4.2 mmol) derivative 271 in 38% yield. HO N O rt, 2.5 h Carpino et al. have invented a new base-sensitive amino pro- (c) H O (30 ml), rt, 30 min O 262 R = Dnseoc 2 tecting group which is more labile than the ubiquitous Fmoc group.146 The 1,1-dioxobenzo[b]thiophene-2-methoxycarbonyl (Bsmoc) group is introduced via its chloroformate or N-hydroxy- HO (a) (MeO)2TrCl (5.67 mmol) pyr (20 ml), rt, 2 h succinimide derivative and it is stable to peptide coupling in (b) (MeO)2TrCl (1.89 mmol), rt, 30 min solution or solid phase using acyl fluorides or in situ activation 81% (overall, 3.8 mmol scale) via ammonium or phosphonium salts. The Bsmoc group is stable towards tertiary amines (pyridine, diisopropylethyl- NMe2 NHR amine) for 24 h but deblocking occurs (via nucleophilic addition followed by β-elimination) within 3–5 min using piperidine or N tris(2-aminoethyl)amine (TAEA). In Fmoc chemistry the deblocking event generates dibenzofulvene which is sub- (MeO)2TrO SO2 N O sequently scavenged—an event which may not be very efficient O OC(O)Cl on solid phases. However, a particular advantage of the Bsmoc 263 (Dnseoc-Cl) group is that the deblocking and scavenging reactions are iden- HO tical as illustrated in Scheme 103. The intermediate 273 decays fi 264 R = Dnseoc DBU (20 equiv) over 8–10 min to give the nal stable deblocking product 274. MeCN (1 ml) A synthesis of Bsmoc-(Leu)3-OFm illustrates the selective rt, half-life = 27 s fl (0.01 mmol scale) deblocking of the N-Bsmoc in the presence of a uoren-9- 265 R = H ylmethyl (Fm) ester. Thus, treatment of Bsmoc-Leu-OFm Scheme 101 with 2% TAEA in dichloromethane followed by coupling with

OMOM OTBS OMOM OTBS OMOM OH H H H DIBAL-H TBAF NCO2Me NH NH → CH2Cl2, –78 °C THF, 0 °C rt MeO2C N N N H 61% H H O OH O OH O Downloaded by San Francisco State University on 14 September 2012 O O

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H O

O N O2N O 2 O O2N O

O O O 266 267 268

pyr, rt N O–CO2Me 89% from 267 O

OMOM OMOM O OMOM OH H H Dess-Martin OH 350 nm NCO2Me NCO2Me N MeCN-H O, rt 83% 2 N 38% N H H NHCO Me O 2 O O OH O 271 O O

O N O2N O 2 O

O O 270 269 Scheme 102

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4027 View Online Cl

Cl Br Br N

+ NH2 O2NNHO2S + HN SO2 NO2 O NH O N O O S piperidine (2 equiv.) N Boc 2 O2S 279 CHCl3, rt, 3–5 min 50% (6.2 mmol scale) Cs2CO3, DMF, rt, 24 h 272 273

N N RN NR

S O O2 274 N Boc Scheme 103 280 R = 2-nitrophenylsulfonyl PhSH, K2CO3 Bsmoc-Leu-F and subsequent repetition of the procedure pro- DMF, rt, 2 h 97% duced the target tripeptide. However, selective cleavage of the 281 R = H ﬂ uoren-9-ylmethyl ester could be accomplished using 10% Scheme 106 N-methylcyclohexylamine or diisopropylamine in dichloromethane. from which the arylsulfonyl groups were removed selectively Magnesium in anhydrous methanol has been reported as a using benzenethiol in the presence of potassium carbonate. reagent for the removal of arylsulfonyl groups from N-aryl- 4-Nitrobenzenesulfonamides, which are cleaved under similar sulfonylcarbamates and N-acylsulfonamides 147 (Scheme 104). mild conditions, have been used to alkylate amino acids.150 The deprotection is carried out under ultrasonic conditions The 2- and 4-nitrophenylsulfonamide derivatives of amino and is compatible with other nitrogen protecting groups like acids are useful substrates for mono-N-alkylation using only N-benzyl, N-benzyloxycarbonyl (N-Cbz) and N-tert-butoxy- caesium carbonate as the base (Scheme 107).151 The sulf-

carbonyl (N-Boc). However an N-2,2,2-trichloroethoxycarb- onamide can then be easily cleaved in high yield by SNAr onyl (N-Troc) group undergoes a known alkyl halide reduction reaction between the N-alkylated sulfonamide and potassium giving rise to the N-2,2-dichloroethoxycarbonyl (N-Doc) phenylthiolate in acetonitrile to give the N-alkylated α-amino derivative. Furthermore, transesteriﬁcation takes place when esters without racemisation. the protected esters of amino acids are used.

O 275 R = Ts Downloaded by San Francisco State University on 14 September 2012 O Ph Mg powder (10 equiv.)

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H MeOH H N N 100% NCOMe sonication 2 H2C=CH–(CH2)3Br NCO2Me R O rt, 35 min Cs CO (1 equiv.) 276 R = H O2S 2 3 O2S O Ph DMF, 60 °C, 6 h Scheme 104 O2N 72% O2N The use of excess lithium powder and a catalytic amount of naphthalene to cleave toluene-p-sulfonamides has been reported.25 The procedure is chemoselective in so far as benzylic ff K2CO3 (3.1 equiv.) derivative 277 a ords the amine 278 without any cleavage of the PhSH (1.1 equiv.) benzylic moiety (Scheme 105). Deprotection of the correspond- MeCN, rt, 12 h ing mesyl (methanesulfonyl) derivatives fails but it works well NCO2Me 54% in the case of N,N-disubstituted sulfonamides. The removal of H tosyl, mesyl and benzyl groups from disubstituted carbox- Scheme 107 amides can also be achieved by the reported methodology. Hydrazine 282 harbouring three orthogonal protecting NHR groups has been prepared (two steps from H N-NHCbz, 277 R = Ts Li (powder, 14 mmol) 2 naphthalene (0.08 mmol) 87%) and used for the stepwise synthesis of tetrasubstituted 81% THF (7 ml), –78 °C, 2 h 152 (1 mmol scale) hydrazine derivatives as illustrated in Scheme 108. Mitsu- 278 R = H nobu alkylation of 282 gave 283 from which the 4-cyanophenyl- sulfonyl group was removed by reduction and the resultant Scheme 105 product then alkylated under phase transfer conditions to give 284. Cleavage of the Boc group with dilute TFA allowed the Scheme 106 shows the synthesis of one of three scaffolds introduction of the third group, a benzoyl. Finally cleavage of used in a solution phase combinatorial search for poly- the Cbz group in refluxing neat TFA and acetylation returned azapyridinophanes with potent antibacterial activity.148 Alkyl- the tetrasubstituted hydrazine derivative 285 in 98% overall ation of the bis-2-nitrobenzenesulfonyl-protected 149 derivative yield. 279 with 2,6-di(bromomethyl)pyridine gave the macrocycle 280 A sequence for the glycosidation of glycals with concomitant

4028 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online acetamidation previously developed by Danishefsky et al.153 has derivative 287, which was then treated with tetrabutyl- now been extended to a synthesis of a model glycopeptide in the ammonium azide to give the glycosyl azide 289 via the form of an asparagine-linked pentasaccharide 154 (Scheme 109). N-sulfonylaziridine intermediate 288. After acetylation of the We join the synthesis at the pentasaccharide stage when the sulfonamide, the 9-anthrylsulfonyl group was removed under final iodoanthracenesulfonamidation is initiated using iodo- very mild conditions using thiophenol in the presence of base. nium bis(collidine) perchlorate to give the iodosulfonamide Earlier in the same synthesis, benzenesulfonamide was used as the nucleophilic partner in which case the phenylsulfonyl group CN CN was removed using sodium naphthalenide. Weinreb et al. have reported the use of the tert-butylsulfonyl (Bus) group as a new protecting group for amines.155 The Bus group is introduced (Scheme 110) by reaction of the amine with 4-ClC6H4CH2OH tert-butylsulfinyl chloride followed by oxidation of the sulfin- O2S Boc Ph3P, DEAD O2S Boc amide with dimethyldioxirane, m-chloroperbenzoic acid, or N N RuCl (cat.)/NaIO . This two-step procedure is a consequence N N 3 4 H Cbz Cbz of the instability of tert-butylsulfonyl chloride; indeed, tert- butylsulfinyl chloride itself is also unstable though it can be C6H4Cl 282 stored neat in a freezer indefinitely. The Bus group is stable 283 towards strong alkyllithium and Grignard reagents, 0.1 M HCl in MeOH (20 ЊC, 1 h), 0.1 M TFA in dichloromethane (20 ЊC, (a) Al(Hg), CO2, aq. Et2O Њ (b) MeI, K2CO3-NaOH, Bu4NHSO4 1 h), or pyrolysis at 180 C. However, Bus-protected secondary amines can be cleaved with 0.1 M triflic acid in dichloromethane containing anisole as a cation scavenger at 0 ЊC for 15– Me COPh (a) TFA, CH Cl Me Boc N 2 2 N 30 min whilst primary amines are released more slowly at room (b) BzCl, pyr N N temperature. It is also possible to cleave Bus-protected second- Cbz Ac (c) TFA, reflux ary amines with neat TFA in anisole at room temperature over-

C6H4Cl (d) Ac2O C6H4Cl night whereas the corresponding primary sulfonamides are unscathed under the same conditions. 285 (98% overall) 284 Trimethylsilylethanesulfonyl chloride (SES-Cl) is a reagent Scheme 108 used to protect amines as their corresponding sulfonamides.23

OAc BnO O BnO OBn BnO I O I(coll) ClO , AnthrSO NH O BnO OAc 2 4 2 2 O BnO O OBn BnO PMB OAc 4Å MS, THF, 0 °C, 3 h BnO O OBn HN O O SO2 O O BnO OO BnO NHAc

286

287 Downloaded by San Francisco State University on 14 September 2012 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H Bu4NN3 THF, rt, 30 min

OBn OBn OBn Ac O 2 O O O O O O N N3 BnO 3 BnO BnO NEt3 NAc NH 86% N SO2 SO2 SO2

290 289 (67% overall) 288

Pri NEt PhSH 2 60%

OBn

O O BnO N3 NHAc

291 Scheme 109

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4029 View Online

t amide derivative 301 (Scheme 113). Treatment of 301 with NH2 NHSO2Bu TBAF in DMPU at 45 ЊC returned the α-hydroxy amide 302 in t (a) Bu SOCl, NEt3 excellent yield as a 3:1 mixture of diastereoisomers. Whilst the CH Cl , 0 °C 2 2 nature of the reducing agent is unknown, the authors specu- NH NSO But (b) MCPBA, CH2Cl2 2 late that it must have been triggered by a reagent of the type rt, 45 min N-CH2-O- or F-CH2-O- derived from cleavage of the SEM 72% group. The reduction was a welcome and useful surprise since 293 292 the nascent hydroxy group is present in the natural product. TfOH (0.1 M), anisole

CH Cl , rt, 2.5 h 2 2 MeO O TBAF•3H2O 67% TfOH (0.1 M) anisole DMPU, 45 °C NHSO But 86% N O 2 CH2Cl2, 0 °C O H 87% 25 min O O MeO O

NH N O O H H SiMe3 OH

294 301 302 Scheme 110 Scheme 113

Recently an improved large scale preparation of this reagent The SEM group can also be used for the regioselective has been published in Organic Syntheses (Scheme 111).81 In the protection of the N1 position of uracil allowing the selective first step sodium bisulfite was added to trimethylvinylsilane alkylation of the nitrogen at the 3-position.158 (295) in the presence of a catalytic amount of tert-butyl per- Protection of the imidazole nucleus of histidine derivatives benzoate. The resulting crude sodium sulfonate 296 was then (e.g. 303, R = H, Scheme 114) during peptide synthesis is highly treated with thionyl chloride and a catalytic amount of DMF recommended to avoid racemisation at the α-carbon of the cor- to afford the corresponding sulfonyl chloride 297 in 53–66% responding acid-activated species. Guibé and co-workers 159 overall yield. reported that the allyl group at the Nπ position could be used for this purpose. The regioselective protection of the imidazole τ t PhCO3Bu (3.6 mmol) nucleus was achieved in two steps starting from N -trityl deriv- NaHSO3 (347 mmol) ative 303 by (a) reaction with the excess of allyl bromide and MeOH (70 ml), H2O (70 ml) (b) removal of the trityl group from the resulting ammonium 50 °C, 48 h SO2R salt with silver acetate in acetic acid. Basic hydrolysis of 304 Me3Si Me3Si 295 (181 mmol scale) (aqueous 1 M NaOH–methanol) followed by DCC mediated peptide coupling of the corresponding acid occurred with good 296 (R = ONa) SOCl2 (1.10 mol), DMF (5.2 mmol) 53-66% (97%) conservation of enantiomeric purity. Selective removal → 0 °C, 20 min 20 °C, overnight overall 297 (R = Cl) of the allyl group was then achieved by treatment with a catalytic amount of tetrakis(triphenylphosphine)palladium(0) either in Scheme 111 Ј the presence of N,N -dimethylbarbituric acid or PhSiH3 and acetic acid. Neat acetic acid at 50–80 ЊC cleaved the aminal protecting

Downloaded by San Francisco State University on 14 September 2012 group in 298 (Scheme 112) selectively without harm to the acid (a)

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H CH =CHCH Br 156 2 2 labile N-Boc group. Lactonisation of the open chain inter- (20 mmol) BocHN CO Me BocHN CO Me mediate 299 occurred under these conditions whereas most 2 MeCN (50 ml) 2 40 °C, 72 h other methods produced mixtures of the desired lactone π 300 together with varying amounts of the hydroxy ester 299. N 90% (4 mmol scale) N Lactone 300 was used in a synthesis of deoxy aminohexoses. Nτ (b) AcOAg/AcOH N 52% R 304

303 (R = Tr) NDMBA AcOH O HO Pd(PPh3)4 (cat) ∆ N CO2Me CH2Cl2, , 3 h 50-80 °C HN CO2Me Boc Boc Tr = triphenylmethyl 68% NDMBA = N,N ′-dimethylbarbituric acid 303 (R = H) 298 299 Scheme 114

During their synthesis of a potential inhibitor of glucosyl- O ceramide synthase Rayner and co-workers 160 encountered dif- ﬁ O culties in deprotecting the amino group in intermediate 307 (Scheme 115). Under conditions previously successful for this

transformation—(Ph3P)3RhCl–MeCN–H2O—only very low NHBoc yields of the desired product 308 were obtained. The problem was finally overcome by modifying the previously published 300 161 procedure of Picq and co-workers (Pd/C, MeSO3H and Scheme 112 water) to afford 308 in 82% yield. In the closing stages of a recent synthesis of narciclasine, During model studies directed towards the synthesis of the Rigby and Mateo 162 encountered difficulties removing the marine antitumour agent mycalamide, Hoffmann and co- PMB group protecting the amide nitrogen in intermediate 309 workers 157 discovered a reduction reaction which accompanied (Scheme 116). The usual oxidative methods were to no avail but the deprotection of an N-SEM [2-(trimethylsilyl)ethoxymethyl] an old desperate method of Williams 163 eventually succeeded.

4030 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online O O O (allyl)2NH DMB O DMB O HN N OC13H27 KI, DMF N OC13H27 HN HN TsO O CF CO H O 305 81% 306 3 2 H H H PhMe, ∆ H 2 steps 89%

N N O O F3C F3C O O Pd/C (0.11 g) N OH N OH MeSO3H (1.6 mmol) 311 312

∆ (a) H2, Pd/C H2O (10 ml), , 12 h 100% (b) o-N3C6H4COCl 82% (0.8 mmol scale) N OC13H27 NH2 OC13H27

308 307 N H O DMB N N Scheme 115 N N O (a) CAN (67%) O H N O H OH O 3 H H (b) Bu3P (63%) O (a) BuLi, THF, O2 H N O (b) TsOH N O F C F3C 3 ca. 37% OH N O O O PNB OH OH O 314 313 H O OH Scheme 117 309 NH O MeO OMe

OH O 310 N Scheme 116 O TFA (1.4 ml) CH2Cl2 (1.4 ml) Thus treatment of the diol 309 with excess BuLi in THF whilst thioanisole (50 equiv.) bubbling oxygen through the solution cleaved the PMB group 83% and the natural product 310 was obtained by acid hydrolysis N N H of the acetonide. The yield was low but no doubt welcome O N nevertheless. O The fumiquinazolines are moderately cytotoxic metabolites MeO C isolated from fungi isolated from fish. In the synthesis of fumi- 2 OH Downloaded by San Francisco State University on 14 September 2012 164 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H quinazoline G (Scheme 117), He and Snider used a 2,4- 315 dimethoxybenzyl group (DMB) to protect an amide nitrogen in N N two important steps: the cyclisation of 311 to 312 and acylation O step (b) in the conversion of 312 to 313. Note that the DMB group is inert to the hydrogenation conditions. The DMB group MeO2C OH was finally removed with CAN prior to closure of the quinazol- H ine ring, which completes the skeleton of the target. N O 316 [(–)-K252a] After Raphael et al.165 had encountered problems in the OMe cleavage of an N-benzyl group protecting the indole pyrrolidone ring system Wood et al.166 elected to use the acid labile 2,4-dimethoxybenzyl group which was successfully cleaved in N N OMe the final step of their synthesis of the indolocarbazole (Ϫ)- O K252a (Scheme 118) using trifluoroacetic acid (TFA). In the absence of the thioanisole scavenger, an appreciable amount of 317 MeO C 317 was formed. 2 OH The di(p-anisyl)methyl group is a useful protector for Scheme 118 the amino function during a synthesis of arylglycines via a Mannich reaction between an aldimine of glyoxylic acid and The Ddm group, together with the Boc group, were removed an arylboronic acid (Scheme 119).167 The di(p-anisyl)methyl by treatment of 318 with trifluoroacetic acid to give the desired protector is easily removed with hot 70% aqueous acetic acid. product. In this preliminary communication the yield of the Orienticin C is a member of the vancomycin family of anti- final three steps is not specified. biotics used for the treatment of methicillin resistant Staphylo- The trityl group is well established for the N-protection coccus aureus infections. The Evans synthesis 168 of orienticin C of amino acids and other primary amine derivatives but the exploited the 4,4Ј-dimethoxydiphenylmethyl (Ddm) protecting more labile methoxy-substituted trityl derivatives have received group for the asparagine unit; because it survived the synthesis scant attention. Golding et al. recently reported the use fi Ј fl ϩ Ϫ intact until the nal step (shown in Scheme 120), it helped of 4,4 -dimethoxytrityl tetra uoroborate (DMT BF4 ) and Ј Љ fl ϩ Ϫ minimise epimerisation during peptide coupling, and it sup- 4,4 ,4 -trimethoxytrityl tetra uoroborate (TMT BF4 ) as use- pressed the vexatious aspartate–isoaspartate rearrangement.169 ful reagents for the protection of primary and some secondary

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4031 View Online

(p-MeOC6H4)2CH–NH2 ing anti-cancer pro-drugs using monoclonal antibodies that are + specifically internalised by the tumour cells.171 The pro-drugs HO2C–CHO•H2O CH(C6H4OMe)2 + are then released by cathepsin B cleavage of a maleimido- HN CO2H H2NCO2H caproyl Phe-Lys linker attached through a self-immolative B(OH)2 p-aminobenzyloxycarbonyl spacer. One of the synthetic chal- S S lenges in the synthesis of the pro-drug is its sensitivity to S PhMe HOAc-H O (7:3) 2 common deprotection regimes used for amino groups such as r.t., 22 h 80 °C, 40 min 80% (2 steps) TFA in dichloromethane (Boc), hydrogenation (Cbz), Pd (allyloxycarbonyl, Alloc) and secondary amines (Fmoc). A particularly vexing problem was the protection of the terminal Scheme 119 amino group of lysine. The problem was solved by using a monomethoxytrityl (MMT) group which was introduced as OH shown in Scheme 121. Lys(MMT) (323) was prepared from O O Fmoc-Lys (320) by a one-pot tritylation procedure in which HO both the amino and carboxy groups are temporarily silylated O OH with TMSCl followed by removal of the Fmoc group with O 2 N H O R diethylamine. The Lys(MMT) (323) was then incorporated into H N H NMe pro-drugs harbouring doxorubicin, taxol and mitomycin C as N N O H H the warheads. In the case of the doxorubicin pro-drug 324, the O O H NH MMT group was cleaved from the lysine using dichloroacetic O HO C acid in the presence of anisole at room temperature. Under 2 HN OH these conditions the lysine was protonated, thereby preventing R1 HO OH addition of the amino group to the maleimide residue leading to the formation of polymeric products. 1 2 fl ff 318 R = Boc, R = CH(C6H4OMe)2 The 9-phenyl uoren-9-yl (Pf) protecting group o ers steric TFA, SMe2 CH2Cl2, rt protection to functional groups in its periphery. A Spanish 319 R1 = R2 = H group 172 has shown that the certain chiral N-(9-phenylfluoren- Scheme 120 9-yl)-α-amido esters react with organolithium reagents to give the corresponding enantiomerically pure ketones in good yield. amines.170 The latter reagent is stable indefinitely in air. Pro- For example, the imidazolidinone 327 (Scheme 122) reacted ϩ Ϫ tected amines are obtained either by reaction of DMT BF4 or with chloromethyllithium to give ketone 328 in quantitative ϩ Ϫ TMT BF4 with the amine or by alkylating DMT- or TMT- yield. The protecting group was later removed from intermedi- ϩ Ϫ ϩ Ϫ amine (available from DMT BF4 and TMT BF4 by treat- ate 329 by acidolysis to give 330, a core structure of the ment with ammonia). Alkylation of DMT- or TMT-amines streptothricin antibiotics. stops after monoalkylation. The DMT and TMT amines are far The [2ϩ2] cycloaddition of ketenes generated from acid more stable than their corresponding ethers and require rela- chlorides and a tertiary organic base with imines (the tively strongly acidic conditions even for the TMT group. For Staudinger reaction) is an important reaction in the commercial example, DMT amines are cleaved with 2 M HCl in THF (1:1) synthesis of the azetidin-2-one ring system. Unfortunately, the at room temperature whereas the TMT derivatives are cleaved reaction has hitherto been limited mostly to imines prepared with 0.05–0.5 M HCl under similar conditions. from non-enolisable aldehydes. Palomo and co-workers 173 have Bristol-Myers Squibb have developed a technique for target- shown that N-[bis(trimethylsilyl)methyl]imines of enolisable Downloaded by San Francisco State University on 14 September 2012

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H OMe OMe

NH2 NHTMS

∆ (a) TMSCl, CH2Cl2, , 1 h MMT-Cl Et2NH NH NH i (b) EtN(Pr )2, 0 °C → rt rt, 18 h DMF, rt, 1 h 91% 100% HN CO2H HN CO2TMS Fmoc Fmoc

320 321 HN CO2TMS H2NCO2H Fmoc 322 323

O OH O N H 7 steps O OO H N N N OOOH OMe H H O O 324 R = NHMMT Cl2CHCO2H, anisole H CH Cl , rt, 1 h 57% 2 2 + – N 325 R = NH3 Cl2CHCO2 HO AG® 2-X8 resin (Cl–) 57% O OH MeOH + – R O OH O 326 R = NH3 Cl Scheme 121

4032 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online been hampered by lack of a suitable N-protecting group. For O example, previous attempts to convert various 1-protected O ClCH2Li 2,4,5-tribromoimidazoles to the thieno[2,3-d]imidazole 342 (2 equiv.) Bn Pf N N Bn (Scheme 124) failed owing to the instability of the product to N N THF the acidic or basic conditions required for N-deprotection. Ph 174 –78 °C, 75 min O CO2Me Hartley and Iddon have shown that the vinyl group survives MeO2CCO2Me 100% Cl the three halogen metal exchange reactions used to convert 327 1-vinyl-2,4,5-tribromoimidazole (340) to the thienoimidazole 328 341. Oxidative cleavage of the vinyl group in 341 using ozone in methanol (dimethyl sulﬁde workup) or potassium permangan- ate in reﬂuxing acetone gave the desired parent thieno[2,3-d]- imidazole 342 in excellent yield. O O

Bn Bn Pf Br ∆ Br N NH N N N (a) BrCH2CH2Br, NEt3, N TFA Br Br H H H H N (b) 10% aq. NaOH, ∆ N HO O CH2Cl2 HO O Br Br H 80% NH 84% NH 339 340 330 329 6 steps Scheme 122

S N S N aldehydes (e.g. 334, Scheme 123) are stable and isolable reagents KMnO4 ﬃ ϩ which undergo easy and e cient [2 2] cycloaddition with N acetone, ∆ N homochiral aminoketene 332. The mild deprotection of the 99% H bis(trimethylsilyl)methyl and phenyloxazolidinone N-protecting groups was accomplished with cerium() ammonium 342 341

nitrate (CAN) and hydrogen/Pd(OH)2 respectively. Alter- Scheme 124 natively, the latter protecting group can be cleaved with lithium in liquid ammonia. A French group 175 have shown that N,N-dibenzylformamidine derivatives serve as useful protecting groups for the protec- O tion of the primary amino function of guanine and adenine O groups in nucleotide synthesis. The N,N-dibenzylformamidine N H2N SiMe3 derivatives are prepared (Scheme 125) by reaction of the primary amino function with dibenzylformamide dimethyl acetal Ph SiMe3 prepared in situ by reaction of dimethylformamide dimethyl OCl ﬂ 331 333 acetal with dibenzylamine (3 equiv.) in re uxing acetonitrile for 20 h. N,N-Dibenzylformamidines are cleaved by hydrogenolysis CH3CHO, 4Å MS t NEt3, 4Å MS, CHCl3 CH Cl , rt using Pd(OH)2 (0.5–5.0 equiv.) in Bu OH–H2O (1:1) at 70 psi. 0 °C → ∆, 12 h 2 2 90% (E:Z = 94:6)

O NH2 N NBn2

Downloaded by San Francisco State University on 14 September 2012 O H3C

Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H N N N N H N Bn2N-CH(OMe)2 (2.5 equiv.) N SiMe3 MeCN, rt (87%) N N N Ph • N SiMe3 332 O O O Pd(OH)2/C, H2 (70 psi) O O 334 t Bu OH-H2O (1:1), rt (99%) 70% O O OH OH O O H H Scheme 125 H H H2 (60 psi) BocHN CH3 N CH Pd(OH)2 3 176 N SiMe3 The process research group at Schering-Plough have (Boc) O, EtOAc, rt Ph N SiMe3 2 O devised an asymmetric synthesis of the broad spectrum anti- O 79% SiMe fl 336 3 biotic orfenicol (348, Scheme 126) which made good strategic SiMe3 use of a (dichloromethyl)oxazoline group as a protecting group 335 CAN (4 equiv.) cis:trans = 4:1 MeOH, 60 °C, 3 h which is eventually incorporated in the final product after transformation to a dichloroacetamide. Treatment of the homo- H H chiral epoxy alcohol 343 with sodium hydride followed by zinc H H BocHN CH3 chloride gave a zinc alkoxide, which reacted with dichloro- BocHN CH3 78% (2 steps) acetonitrile to introduce the (dichloromethyl)oxazoline moiety. NH The zinc chloride was added to suppress the Payne rearrange- NH O O O ment. After conversion of the hydroxy function in 344 to its 338 337 ethanesulfonate, the oxazoline was hydrolysed to the dichloro- Scheme 123 acetamide derivative 345. Intramolecular displacement of the ethanesulfonate group (inversion) regenerated the oxazoline The bromine atoms in 1-protected 2,4,5-tribromoimidazole ring which protected the hydroxy and amino functions during can be sequentially replaced through selective Br→Li (or the conversion of the free hydroxy group in 346 to the fluoro MgBr) exchange strategies. However, application of this derivative 347. Finally, hydrolysis of the oxazoline ring at pH strategy to the synthesis of polyfunctionalised imidazoles has 5.0 gave the crystalline florfenicol (348).

J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4033 View Online

OH NH O Cl 2 O O O O H OH (a) PhH, ∆, 1-2 h N (a) NaH, THF, 5 °C, 30 min H H N Cl O (b) add ZnCl (1.0 equiv.) 2 H (b) AcCl (11 ml), ∆, 1 h 92% (3.9 mmol scale) (c) add Cl2CHCN (1.2 equiv.) Br O 55 °C, 16 h 4.1 mmol 65% (128 mmol scale) 349 Br SO2Me SO2Me 350 343 344 TIPSOTf (4.27 mmol) (a) EtSO2Cl, pyr, NEt3, 5 °C Et3N (6.21 mmol) (b) pH 2.0 (3.0 M H2SO4) CH Cl (8 ml), rt, 2 h Cl 2 2 90% (1.94 mmol scale) Cl OH N O H EtSO2O OTIPS O H Cl (a) HCl (0.5 M, 1.09 mmol) TIPSO N N THF (7 ml), rt, 10 min H H H OH Cl pH 12.0 (50% NaOH) (b) N2H4•H2O (2.74 mmol) EtOH, ∆, 20 h 50% overall from 344 82% (0.55 mmol scale) Br SO2Me SO2Me 351 346 345 Scheme 127 CF3CHFCF2NEt2 CH2Cl2, 100 °C, 3 h

Cl Cl Cl relatively mild conditions. It turned out that neopentyl (2,2- Cl dimethylpropyl) esters (e.g. 359, Scheme 129) served this purpose well, withstanding such reagents as tert-butyllithium, N HN O H i vinylmagnesium bromide, CrO3, NBS/benzoyl peroxide, H2/ O Pr OH-H2O HO RaNi, DIBAL-H, NaI, HONH2, NaH, aq. HBr or NaOH. H KOAc, ∆, 3 h F F Deprotection could be easy accomplished by heating the ester ca 90% with excess tetramethylammonium chloride in DMF. Sulfate monoesters in carbohydrates can be protected as their trifluoroethyl ester.180 The protected sulfates were prepared by SO2Me SO2Me treatment of the carbohydrate (e.g. 361, Scheme 130) with sul- fur trioxide–pyridine complex followed by reaction of the crude 347 348 monosulfate with trifluorodiazoethane. The resulting 2,2,2- Scheme 126 trifluoroethyl ester 362 was stable to sodium methoxide in methanol, which allowed selective acetate methanolysis to give 363. The removal of the sulfate protecting group was achieved Primary amines can be protected as their 2,5-bis[(triiso- with potassium tert-butoxide in tert-butyl alcohol. Apart from 177 propylsilyl)oxy]pyrrole (Bipsop) derivatives. The two step sodium methoxide, 2,2,2-trifluoroethyl sulfates were also stable fi protection sequence is shown in Scheme 127. In the rst step the to tetrabutylammonium fluoride, trifluoroacetic acid in ethanol Downloaded by San Francisco State University on 14 September 2012 amine (e.g. 349) is transformed into the corresponding imide Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H and catalytic hydrogenation, but not to dilute sulfuric acid (the 350 by reaction with succinic anhydride followed by cyclodehy- entire sulfate moiety was cleaved). dration of the intermediate amide acid with acetyl chloride. In the second step the imide 350 is treated with triisopropylsilyl 10 Reviews triflate (TIPSOTf) in the presence of triethylamine to give the ‘Recent developments in solid-phase organic synthesis’, R. desired pyrrole derivative 351. The bis[(triisopropylsilyl)oxy]- Brown, J. Chem. Soc., Perkin Trans. 1, 1998, 3293. pyrrole ring is stable to strong bases such as organolithium ‘Solid Phase Synthesis’, R. Brown, Contemp. Org. Synth., 1997, reagents (Ϫ78 to 20 ЊC), heating at temperatures up to 150 ЊC, 4, 216. and chromatography on neutral alumina. Removal of the ‘Protecting Groups’, K. Jarowicki and P. Kocienski, Contemp. Bipsop protecting group can be accomplished under mild con- Org. Synth., 1997, 4, 454. ditions by sequential reaction first with dilute acid followed by ‘Allylic protecting groups and their use in a complete environ- refluxing the intermediate succinimide with hydrazine in ment. 1. Allylic protection of alcohols’, F. Guibé, Tetra- ethanol. hedron, 1997, 53, 13 509. The first total synthesis of haliclamine A (357, Scheme 128) ‘Enzymatic Synthesis of Peptide Conjugates: Tools for the was achieved by stepwise inter- and intra-molecular N-alkyl- Study of Biological Signal Transduction’, T. Kappies and ations of 3-alkylpyridine derivatives.178 To avoid polymerisation H. Waldmann, Liebigs Ann., 1997, 803. or intramolecular N-alkylation of 353 during coupling of 352 ‘Recent Advances in N-Protection for Amino Sugar Synthesis’, and 353, the nucleophilic nitrogen in 352 was protected as its J. Debenham, R. Rodebaugh and B. Fraser-Reid, Liebigs N-oxide. Mesylation of the alcohol function in 354 resulted in Ann., 1997, 791. expedient deoxygenation of the N-oxide whence macrocyclis- ‘Esterifications, Transesterifications, and Deesterifications ation of intermediate 355 gave the bispyridinium salt 356. Mediated by Organotin Oxides, Hydroxides, and Alkoxides’, Reduction with sodium borohydride completed the synthesis. O. A. Mascaretti and R. L. E. Furlan, Aldrichim. Acta, 1997, 3, 55. 9 Miscellaneous protecting groups A new and practical removal of allyl and allyloxy-carbonyl Roberts and co-workers 179 were looking for a protecting group groups promoted by water-soluble Pd(0) catalysts, S. Lemaire- for arenesulfonic acids which, on the one hand, would be Audoire, M. Savignac, J. P. Genet and J. M. Bernard, in Roots compatible with a wide range of standard organic synthesis of Organic Development, ed. J. R. Desmurs and S. Ratton, methodologies, but on the other hand, could be removed under 1996, Elsevier, Amsterdam, p. 416.

4034 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online

Br Br OMs HO N 352 pyr O– N SO Cl 95% SO OR + 2 2

358 359 R = CH2C(Me)3 Me4NCl (4-5 equiv.) DMF,160 °C, 16 h 100% 360 R = H Scheme 129 HO 353 OR 67% KI, MeCN, ∆, 4 d O AcO OAc AcO N OAc

N 361 (R = H) (a) SO3•pyr (1-5 equiv.) – O MeCN, 80 °C, 1-2 h 93% (overall) (b) CF3CHN2 (~10 equiv.) 354 MeCN, 5 min 362 (R = SO OCH CF ) HO 2 2 3

64% MsCl, NEt3, CH2Cl2, 0 °C, 1 h MeONa, MeOH 2 h, 66%

OR N O N HO OH HO OH

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