Enantioselective direct aldol reaction: the blossoming of modern organocatalysis

45 Pages·2007·0.77 MB·English

Available online at www.sciencedirect.com
Tetrahedron:Asymmetry18(2007)2249–2293
Tetrahedron: Asymmetry report number 97
Enantioselective direct aldol reaction: the blossoming
of modern organocatalysis
Gabriela Guillena,* Carmen Na´jera* and Diego J. Ramo´n*
Instituto deSı´ntesis Orga´nica(ISO) andDepartamentodeQuı´mica Orga´nica, FacultaddeCiencias,
Universidad deAlicante, Apdo.99, E-03080Alicante, Spain
Received16August2007;accepted24September2007
DedicatedtoProfessorMiguelYusontheoccasionofhis60thbirthday
Abstract—Theuseofsimple(S)-prolineascatalystfortheintermoleculardirectaldolreactionatthebeginningofthiscenturybecamea
truemilestoneinthegrowthoforganocatalysisasausefulsyntheticstrategy.Sincethen,aplethoraofneworganocatalyticsystemshave
beendevelopedallowingtoreachextraordinarylevelsofefficiencies,wideningthescopeofsubstratesused.Severalmodificationshave
beenintroducedtoovercomesomeoftheinitialdrawbacks,suchaslongreactiontimes,highcatalystloading,excessofreagents,etc.,
improvingtheexpectationsfortheiruseinlargescalesynthesis.Alltheseachievementswouldnotbepossiblewithoutapartialunder-
standingoftheinvolvedmechanism.Theacquiredknowledgeinthisareahasallowedtheapplicationofthisstrategytobeusedinthe
synthesis of natural products.Withinthis review,a comprehensivelook of alltheseaspects will bediscussed.
(cid:2)2007Elsevier Ltd. Allrights reserved.
Contents
1. Introduction. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2250
2. Prolineas organocatalyst. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2251
2.1. Intramolecular reactions.. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2251
2.2. Intermolecularreactions.. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2252
2.2.1. Ketones assource of nucleophile.. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2252
2.2.2. Aldehydes as sourceof nucleophile .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2257
3. Prolinederivatives as organocatalysts. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2259
3.1. Prolinamide derivatives .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2259
3.1.1. Ketones assource of nucleophile.. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2259
3.1.2. Aldehydes as sourceof nucleophile .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2264
3.2. Prolinamine derivatives .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2264
3.2.1. Ketones assource of nucleophile.. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2264
3.2.2. Aldehydes as sourceof nucleophile .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2264
3.3. Prolinesulfonimide derivatives . . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2265
3.3.1. Aldehydes as electrophiles. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2265
3.3.2. Ketones aselectrophiles .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2266
3.4. Heteroaromatic pyrrolidine derivatives .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2266
3.5. 4-Hydroxyproline derivatives .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . . 2266
3.5.1. Intramolecular reactions .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2266
3.5.2. Intermolecular reactions .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 2267
*Correspondingauthors.Tel./fax:[phone];e-mailaddresses:[email protected];[email protected];[email protected]
0957-4166/$-seefrontmatter (cid:2)2007ElsevierLtd.Allrightsreserved.
doi:10.1016/j.tetasy.2007.09.025
2250 G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293
3.6. Prolinepeptide derivatives .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2268
3.6.1. Aldehydes aselectrophiles. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2268
3.6.2. Ketones aselectrophiles .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2269
3.7. Otherpyrrolidine derivatives. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2270
3.7.1. Intramolecular reactions .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2270
3.7.2. Intermolecular reactions .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2270
4. Otherorganocatalysts. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2271
4.1. Intramolecular reactions.. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2271
4.2. Intermolecularreactions.. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2273
4.2.1. Ketones assource of nucleophile.. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2273
4.2.2. Aldehydes assource of nucleophile .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2275
4.2.3. Ketenesas source ofnucleophile .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2276
5. Supportedorganocatalysts.. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2276
6. Phase-transfercatalysis.. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2279
7. Mechanisticstudies. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2280
7.1. Intramolecular reactions.. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2280
7.2. Intermolecularreactions.. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2282
8. Applications tothe synthesis of biologically active products.. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2283
8.1. Intramolecular reactions.. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2283
8.2. Intermolecularreactions.. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 2285
8.2.1. Ketones assource of nucleophile.. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2285
8.2.2. Aldehydes assource of nucleophile .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2286
9. Conclusionsand outlook. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2287
References.. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 2287
1. Introduction thegenerationofasilylenolether(orchemicalequivalent)
iscompulsory,requiringtheuseofstoichiometricamounts
Thealdolreaction1,2isoneofthemostvenerablereactions of bases and silylating reagents and therefore having low
inorganicchemistry,firstlydiscoveredbyWurtzin1872,1b atom efficiencies. In order to enhance the global efficiency
although Kane previously described the prevently known oftheprocess,anefforthasbeenmadetodevelopenantio-
aldol condensation.1a This useful transformation allows selectivedirectaldolreactions,9wheretheuseofperformed
the formation of a C–C bond by reaction of an enolizable enolates (or their equivalents) is avoided.
carbonyl compound acting as a source of nucleophile with
itself or another carbonyl compound acting as an electro- A remarkable success has been achieved on the substrate
phile to give a b-hydroxy carbonyl compound known as scopeandreactionselectivitiesbytheuseofso-calledenan-
aldol. When the aldol product suffers a subsequent dehy- tioselective organocatalytic direct aldol processes. The
dration step to give the related a,b-unsaturated carbonyl adjective organocatalytic is applied to processes in which
compound, the process is called aldol condensation. The reagents and catalysts are all small organic molecules con-
reaction could be catalyzed by either basic or acidic com- tainingonlyC,H,O,N,S,P,andhalogenatoms.10There-
pounds. Besides the new C–C bond formed, one or more fore, processes in which a metal (including boron and
stereogeniccenterscanalsobecreated.Forthisreason,this siliconatom)isinvolvedshouldbeexcludedinstrictsense.
transformation has been chosen historically as a chemical- Furthermore, those processes involving high molecular
test to prove the efficiency of new methodology, especially weight organic compounds such as enzymes, antibodies,
asymmetric ones.3 Although diastereoselective approaches even polymers, and dendrimers, should be excluded.
make the synthesis of all possible stereoisomers possible, Althoughaccordingtotheabovestrictdefinition,reactions
the additional steps required to introduce and remove the involving silicon atoms, polymers, and inorganic materials
chiral auxiliaries suppose a great disadvantage for this should be excluded. We considered that processes where
strategy.4 thesilylgrouphasonlyastericrole(orincreasethesolubil-
ity)shouldbeincludedaswellascasesinwhichthecatalyst
Without any doubt, catalytic enantioselective methods are isimmobilizedinapolymer,dendrimer,orinorganicmate-
the most attractive alternative for providing chiral com- rial, since in these cases the matrix does not play any rele-
poundswithhighselectivityandatomefficiency.5Biochemi- vant role in the reaction, and is only important in the
cal methods based on the use of aldolase enzymes6 and recovery of catalysts.
antibodies7 have shown their usefulness to perform this
task, with the scope of substrates being very narrow. In The enantioselective organocatalytic aldol reaction has
searchofawidersubstratescope,differentenantioselective been profusely revised.11 However, many of these reviews
chemical methods have been extensively developed in are strongly focused on proline as catalyst as well as on
recent years, especially after the introduction of the theauthor’sresults,butnoneofthemfocusedonacompre-
Mukaiyama-aldol version of this reaction.8 In this case, hensive list of catalysts and results, as well as conditions,
G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293 2251
while in only a few of them are new data and perspectives isolationofalcohol3(entry3inTable1).Theuseofother
onthefieldgiven.Withthisreview,wewouldliketofillthis solventsallowedadecreasetheamountofcatalyst1,isolat-
gap, giving a comprehensive overview of the catalyst, ingthea,b-unsaturatedketone4oralcohol3dependingon
providing an easy way for comparison between different nature of solvent, isopropanol or DMF, respectively (en-
catalysts, protocols and results, as well as the possible tries 4 and 5 in Table 1). The change of the substituent R
drawbacks of this methodology. All these facts would in 2 did not have any important impact on the enantio-
allow us to find the best choice for a given problem, as selectivity, but did decrease the isolated chemical yield of
well as to discover new niches and possibilities that are compound 3.15e The low enantiomeric excess could be
currently unexplored. The final aim of this review will be enhanced up to >99% by recrystallization of the
to reach these goals. corresponding tert-butyl ether obtained by reduction of
non-conjugated carbonyl group in compound 4 and alkyl-
ation (entries 6 and 7 in Table 1).15f
2. Proline as organocatalyst
The long reaction time required for this intramolecular
aldol process could be decreased by employing microwave
(S)-Proline1,knownasthesimplestenzyme,11disacorner-
heating(114W)inconjunctionwithsimultaneousair-cool-
stone in the field of organocatalysis due to the fact that it
ing at 35(cid:3)C,16 affording the corresponding napththalene-
has been used as a catalyst in a wide range of asymmetric
dione 4 (n=2, R=Me) with similar results but in only
reactions with excellent results in many cases, its high effi-
15min (69%, 70% ee).
ciency being clearly demonstrated in the enantioselective
direct aldol reaction.
Insteadofusingthetriketonederivative2asthestartingre-
agent, methyl vinyl ketone 5 and methylcyclohexane-1,3-
2.1. Intramolecular reactions dione 6a could be used. In this case, proline first catalyzes
the Michael-type addition and then the aforementioned
The use of proline in the enantioselective intramolecular annulation process obtaining the expected compound 4b
aldol reaction (Robinson-type annulation) was a crucial (R=Me, n=1) in 49% yield and 76% ee (compare with
event in the history of organocatalytic processes,12 with it entry 2 in Table 1).17
beingoneofthefirstexampleswherethepotentialofenan-
tioselective reactions for the synthesis of natural products, This 6-(enolendo)-exo-trig process has been expanded
even at large scale was demonstrated.13 The 6-(enolendo)- to the enantioselective desymmetrization of simple
exo-trig14 Robinson annulation (Table 1)15 was indepen- acyclic diketones 7 (Scheme 1).18 The results were highly
dently discovered by two industrial groups at Schering12a dependent upon the bulkiness of the R group, with the
and at Hoffmann-La Roche12b almost simultaneously. best results being obtained for the smallest methyl
The differences between both procedures relied on the use group.
of perchloric acid as a co-catalyst, which led to the final
compound4,byaninsitudehydrationofproduct3.Under
theseconditions15a(presenceofHClO ),thecorresponding R R
4 THF, 25 °C, 2 d
indanone derivative 4 (n=1, R=Me) could be isolated
with a better yield and enantioselectivity than the related
O O O O
naphthalendione 4 (n=2, R=Me; compare entries 1 N
and 2 in Table 1). The yield could be improved upon by 7 H OH 8
(52-75%, 12-43% ee)
1 (20 mol%)
using stoichiometric amounts of catalyst 1 at 20(cid:3)C.15b
However, the absence of an inorganic acid permitted the Scheme1.
Table1. Robinson-typeannulation
O R O R O
O R
O n O O OH n O n
N
2 H 3 4
OH
1
Entry R n 1(mol%) Reactionconditions Yield(%) ee(%)
1 Me 1 50 MeCN,1d,80(cid:3)C,HClO 84 84
4
2 Me 2 50 MeCN,1d,80(cid:3)C,HClO 71 72
4
3 Me 1 100 MeCN,6d,20(cid:3)C 97a 86
4 Me 1 10 PriOH,4d,20(cid:3)C 75 61
5 Me 1 3 DMF,1h,20(cid:3)C 100a 93
6 SPh 1 5 DMF,6d,17(cid:3)C 64a 95
7 SPh 2 5 DMF,6d,17(cid:3)C 27a 95
aCompound3wasisolated.
2252 G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293
The preparation of highly substituted hydroxycyclohexa- rotationsofknowncompounds(Scheme4).22Thepresence
nones 10 seems to be more successful with regards to the of two substitutents on the starting aldehyde 13 was deci-
enantioselectivity (Scheme 2).19 The reaction of different sive in reaching these results, since the presence of only a
1,3-diketones 9 with methyl vinyl ketone 5 in N-methyl-2- single substituent at any position on the chain showed a
pyrrolidone (NMP) at room temperature gave cylohexa- veryimportantdetrimentaleffect,notonlyonthediastereo-
none derivatives 10 with moderate enantioselectivities and selectivity, but also on the enantioselectivity.
asonlyonediastereoisomer.Thetandemprocess20involves
aninitialMichael-typeadditiontoformthecorresponding
triketone intermediate, which finally suffers the 6-(enolen-
do)-exo-trig annulation. The chemical yields are affected O R1 O R3 OHO
by the substituents on the aromatic ring of compound 9, R3 R1 H CH2Cl2, 25 ºC, 16 h R1 H
R1
the more the electron-withdrawing character of the substi-
tuent the higher the yields obtained. In the case of using R2 R2 N O R2 R2
unsymmetricalsubstitutedcompounds9highregioselectiv- 13 H OH 14
ity was found, with the more electrophilic carbonyl group R1, R2, R3 = H, Me 1 (10 mol%) (75-95%, 97-99% ee)
being the electrophilic partner in the cyclization.
Scheme4.
The above methodology has also been successfully applied
O to a 5-(enolexo)-exo-trig process (Scheme 5). Thus, the
N O
Ar1 O H OH proline-catalyzed reaction of compound 15 gave the
O 1(20 mol%) cyclic derivative 16 with a diastereomeric excess ranging
+ HO from 71% to 99%.23 While the substituent on the aromatic
O NMP Ar1 ring had a negligible effect, the R2-substituent had a very
Ar2 25 ºC, 3 d O Ar2 important effect, with the increase of hindrance from
9 5
10 methyl to ethyl group providing lower yields and enanti-
(39-93%, 43-80% ee)
oselectivities.Itshouldbepointedoutthatrecrystallization
Scheme2. increased the diastereomeric and enantiomeric excesses up
to 99%.
As an extension of this annulation process, (S)-proline 1
hasbeenusedtoperformthekineticresolutionofdifferent
racemicdiketones.So,thereactionofracemica,a-disubsti- O HO R1
tuted cyclohexanone 11 (R=Me) gave the cyclic product R1 DMF, 25 ºC, 7-72 h O
12 with 43% ee and the chiral starting diketone 11 (ee O R2 O R2
not determined). However, when the reaction was per- R3 O N O R3
formed with the related a-monosubstituted cyclohexanone 15 H OH 16
11 (R=H) under similar reaction conditions and at 50% R1 = H, Me 1 (30 mol%) (74-96%, 73-87% ee)
R2 = Me, Et
conversion, product 12 (R=H) was obtained with 46%
ee but with the opposite configuration at the stereogenic Scheme5.
center.Similarresultswereobtainedinthecaseofb-mono-
substituted cyclohexanone derivatives21 (Scheme 3).
2.2. Intermolecular reactions
Withoutdoubt,thesuccessfuluseof(S)-proline1asacat-
alyst in the intermolecular direct aldol reaction was a high
O R O
R DMF, 65 ºC, 1 h R pointintheexplosionoforganocatalysisasanewdifferent
+ researchfield.Thissectionwillbedividedaccordingtothe
O O O O combination of the possible nature of the nucleophilic and
rac-11 NH OH 12 11 electrophilic partner used.
1(65mol%)
2.2.1. Ketones as source of nucleophile
Scheme3.
2.2.1.1. Aldehydes as electrophiles. Inspired by the
action of class I aldolases, proline was tested in the aldol
According to Baldwin’s rules not only 6-(enolendo)-exo- reaction between ketones 18 and aldehydes 17, especially
trig but also 6-(enolexo)-exo-trig processes are permitted. a-substituted ones, affording compounds 19 (Table 2),
Theselastcyclizationprocesseshaveonlyrecentlybeenre- which proved to be excellent catalysts.24 A large excess of
ported. The intramolecular reaction of compound 13 gave ketone 18 was employed in all of these reactions in order
product14withmoderatetoexcellentdiastereoselectivities to prevent several side reactions such as self-condensation
(50!98% de) and excellent enantioselectivities, with the of the aldehyde, or the formation of the oxazolidinone de-
absolute configurations being assigned from the specific rived from proline and the aldehyde.
G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293 2253
Table2. Enantioselectivealdolreactioncatalyzedbyproline1usingketonesasasourceofnucleophile
O O 25 °C OH O OH O
R1 + R3 H R3 R1 + R3 R1
R2 O R2 R2
N
18 17 H OH anti-19 syn-19
1
Entry R1 R2 R3 18(equiv) 1(mol%) Reactionconditions Yield(%) de(%) eea(%)
1 Me H 4-ONCH 27.3 30 DMSO/MeCO(4:1,v:v),4h 68 — 76
2 6 4 2
2 Me H Pri 27.3 30 DMSO/MeCO(4:1,v:v),2–8h 97 — 96
2
3 Me H CH(CH) 68.2 10 MeCO,7d 35b — 73
3 25 2
4 –(CH) – 4-ONCH 22.6 20 DMSO/(CH) CO(4:1,v:v),1–2d 73 63 69
23 2 6 4 24
5 –(CH) – 4-ONCH 19.3 20 DMSO/(CH) CO(4:1,v:v),1–2d 65 63 86
24 2 6 4 25
6 Et H 4-ONCH 22.3 20 DMSO/EtCOMe(4:1,v:v),1–2d 65 — 77
2 6 4
aForthemajordiastereoisomer.
bThecorrespondingenonewasisolatedin40%yield.
Moreover, since the whole process is a series of equilibria, mentioned reaction, allowing the synthesis of b-hydroxy-
the high amount of one of the reagents drives the process. b-perfluoroalkyl ketones.28 In this case, the ketone used
Notwithstanding this, when the reaction was performed asasourceofthenucleophilewasalsothereactionsolvent,
using linear aldehydes, significant amounts of the side- providing the expected products 19 with good diastereo-
product enone were obtained, arising from the aldol con- selectivities for cyclic ketones (88–98% de) and moderate
densation process (entry 3 in Table 2). For the use of sim- to good enantioselectivities (37–93% ee).
ple and volatile ketones, their use in a large amount is not
an important problem, neither economical nor practical, The use of the more complex 1-(phenylsulfanyl)cyclo-
but when more sophisticated ketones are employed, this alkane-carboxaldehydes as electrophiles in proline 1
largeexcess,whichisrequiredcouldbeaseveredrawback. (20mol%) catalyzed aldol reaction with a large excess of
The use of cyclic ketones such as cyclohexanone 18c and aliphatic ketones in DMSO led to the corresponding aldol
cyclopentanone, as a source of nucleophile gave modest products 19 with yields ranging from 21% to 80% and
diastereoselectivities(ca.60%)andsimilarenantioselectivi- excellent enantiomeric excesses (up to 99%). The chiral
ties, with anti-isomer 19 being the main diastereoisomer aldols obtained were further transformed into the
(Table 2, entries 4 and 5). For butanone the reaction took corresponding cis-fused spirocyclic tetrahydrofurans and
placeatthelesssubstitutedposition.Otherdialkylketones cyclopentanones, after carbonyl reduction and an acid-
such as 3-pentanone, acetylcyclohexane, isopropylmethyl catalyzed cyclization process.29
ketone, 3-methyl-2-butanone, and cyclopropylmethyl
ketone were not reactive toward the aldol reaction with The diastereoselective aldol reaction catalyzed by
p-nitrobenzaldehyde under the aforementioned reaction (S)-prolineanddifferentchiralaldehydes,suchasprotected
conditions.24c sugars,30a protected a-aminoaldehydes,30b 4-formyl-2,2-
dimethyloxazolidine (Garner’s aldehyde),30c and 4-oxo-
Instead of using acetone 18a 4-methyl-4-hydroxy-2-penta- azetidine-2-carboxaldehydes30d have been used in order to
none (diacetone alcohol) can be used as a source of the prepare possible biologically active compounds.
nucleophile.25 The reaction of 2equiv of this reagent with
different aldehydes gave the expected compounds 19 A multicomponent reaction10u,31 between acetone 18a,
(R2=H) with lower enantioselectivities (48–86% ee). benzyl azodicarboxylate 21 and enolizable aldehydes 20
catalyzed by substoichiometric amounts of (S)-proline 1
In order to increase the enantioselectivities achieved for yielded ca. 1:1 mixture of the corresponding diastereoiso-
the b-hydroxy ketones 19 (R2=H) a tandem organo- mers 22 (Scheme 6).32 The success of the reaction can be
and biocatalytic process has been designed.26 Thus, after attributedtothehigherreactivityasasourceofthenucleo-
the proline-catalyzed reaction, the resulting mixture was phile of aldehydes over acetone (about 100-fold) toward
kineticallyresolvedbyacylationcatalyzedbyPseudomonas the azodicarboxylate under proline-catalyzed conditions.
cepacia lipase (Amano I). In this manner, an a-amino aldehyde derivative is created
in situ, which is, in turn, the electrophilic partner for the
The scope of aldehydes as electrophiles has been further further aldol reaction. The disappointing diastereomeric
extended for these simple ketones. Aqueous formaldehyde ratio was attributed to the easy and fast racemization of
was reacted with cyclic ketones catalyzed by 1 (10mol%), the initially formed a-amino aldehyde, compared to its
togivetheexpectedproductswithmoderateyield(25–45%) reaction with acetone. This strategy has been used in the
and high enantioselectivity (95–99%) in only 1h and using synthesis of a rennin inhibitor, despite the disappointing
only 2equiv of cyclic ketone.27 diastereoselectivity.
Remarkably, perfluoroalkyl aldehyde ethyl hemiacetals The use of a-functionalized ketones as a nucleophilic
could be used as a source of the electrophile in the afore- source has permitted access to chiral compounds of high
2254 G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293
O aldehydeswereusedaselectrophiles,themajorproductob-
O
O tainedwasacompoundoftypeiso-25withvariableenanti-
BnO N
+ H + oselectivities (10–95% ee).
N OBn
R
O Theuseofanionicliquidallowsareductionintheamount
18a 20 21
of ketones used. The reaction of a-hydroxyacetone 23a
(27.2 equiv.)
(R1=H),aswellasa-methoxyacetone23c(R1=Me)with
O p–(trifluoromethyl)benzaldehyde derivatives gave a mix-
N
MeCN, 25 °C, 4 d H OH tureofthreepossibleisomersoftype24and25withmedi-
1 ocre diastereoselectivities (no enantioselectivities were
(20 mol%) reported) when 1-ethyl-3-methyl-1H-imidozolium trifluoro-
methane-sulfonate ([emim][OTf]) was used.35 a-Fluoro
CbzHN OH O CbzHN OH O anda-chloroacetone26werealsousedasasourceofnucleo-
CbzN CbzN phile (Scheme 8), giving a mixture of two isomers 27 (60%
+
de). The mixture of isomers 27b (X=Cl) could be easily
R R
transformed in the corresponding (3R,4S)-trans-epoxides
anti-22 syn-22
(22-65%, 98-99% ee) (12-50%, 28-85%ee) by treatment with triethylamine with yields from 69% to
83% and enantioselectivities around 70%, with the related
Scheme6.
cis-epoxides not being detected.
interest. Thus, the use of an excess of a-hydroxyacetone
23a (R1=H) allows the synthesis of chiral diols (Scheme O O
7). Excellent regio-, diastereo-, and enantioselectivities +
R H
(up to 99%) were obtained when a-substituted aliphatic X
aldehydes were used as electrophiles, with the anti-24 iso- 26 17
merbeingthemain/onlyisolatedproduct.Whenaromatic, (2 equiv.)
linear aliphatic aldehydes, and chiral (R)-glyceraldehyde
O
derivatives were used the results were significantly lower, [emim][OTf] N
H
with diastereoselectivities ranging from 0% to 75% and 25 °C, 2 d 1OH
enantiomeric excesses from 67% to 97%. The iso-isomer
(50 mol%)
25wasonlydetectedwhenaromaticcarboxaldehydeswere
used,althoughinlowyields(ca.4%).Theuseof(R)-2,3-O- OH O OH O OH O
(isopropylidene)glyceraldehyde gave anti-24 compound as + +
R R R
the main diastereoisomer (40%, 66% de, >97% ee), which
X X X
is a known DD-tagatose derivative.24c,33 anti-27 syn-27 iso-28
Scheme8.
O
O
+
R2 H Sincethecorrespondingproducts19arisingfromthedirect
OR1
aldol reaction of 3-pentanone with aldehydes are not suit-
23a : R1= H 17 able for the proline-catalyzed reaction, an indirect alterna-
(29.2 equiv.)
tive has been introduced. The reaction of tetrahydro-4H-
thiopyran-4-one29withaldehydesgavetheexpectedprod-
DMSO:MeCOCH2OH O ucts 30 (Scheme 9). The reductive desulfurization using
(4:1, v:v) N Raney nickel (W-2) gave the corresponding 5-hydroxy-4-
H
OH
methylpentanone derivatives, impossible to prepare by a
1
25°C, 1-3 d (20-30 mol%) direct pathway. As in the previous cases, the main diaste-
reoisomer was the corresponding anti-30 (up to 95% de)
and the enantiomeric excess ranged from 76% to 98%.
OH O OH O OH O
+ +
R2 R2 R2
OR1 OR1 OR1
anti-24 syn-24 iso-25 O
N
H
OH
Scheme7.
O O 1 OH O OH O
(50 mol%)
+ R + R
Followingthesameprocedureandunderthesamereaction R H DMSO
conditions, tert-butyl(dimethyl)silyloxy]acetone 23b (R1= S or S S
TBS) reacted with aromatic carboxaldehydes affording a 29 17 DMF (aq.) anti-30 syn-30
(3 equiv.) 25 °C, 1-4 d
product of type anti-24 with enantioselectivities from 28%
to95%.34Surprisingly,whena-substituted-a,b-unsaturated Scheme9.
G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293 2255
The best results for aromatic aldehydes were obtained in oxan-5-one or 1,5-dioxaspiro[5.5]undecan-3-one gave low-
aqueousDMF,whereasdryDMSOwasgenerallysuperior er results, compared with those of using dioxanone 31.39
with aliphatic aldehydes.36
Followingtheaforementionedstrategy,differentazasugars
Theproline-catalyzedaldolreactionbetween2,2-dimethyl- (iminocyclitols) have been successfully prepared. The dia-
1,3-dioxan-5-one31andaldehydesisanexcellentapproach stereoselective aldol reaction between ketone 31 and chiral
to the enantioselective synthesis of carbohydrates, since protected 3-amino-2,4-dihydroxypentanal catalyzed by
compound31isasyntheticequivalentofdihydroxyacetone proline1gavetheexpectedcompounds,whichaftersimple
(Table 3). When the reaction was performed in DMF at manipulation,suchasdeprotectionandreductioncouldbe
2(cid:3)C using only 1equiv of compound 31 (Table 3, entries transformed into iminocyclitols.40
1–5),37goodyields,diastereo-andenantioselectivitieswere
obtained with aliphatic a-branched aldehydes. However, As was been previously mentioned, some of the general
thechemicalyieldwaslowerfora-unsubstitutedaldehydes drawbacks of the enantioselective aldol reaction catalyzed
(see for instance entry 2 in Table 3), as well as the dia- by proline are: (a) the high catalyst loading usually
stereo- and enantioselectivity for benzaldehyde (entry 3 in required, (b) the huge excess of starting ketone needed,
Table 3). Surprisingly, the related diastereoselective reac- and (c) the long reaction timesrequired for completion. In
tion using (S)-proline 1 and either (R)-2,3-O-(isopropylid- order to avoid some of these inconveniences several modi-
ene)glyceraldehyde (entry 4) or (S)-Garner’s aldehyde ficationsof the standard protocols have been introduced.
(entry 5 in Table 3) gave in both cases excellent results,
with catalyst 1 and chiral aldehydes being the match pair The influence of additives in the reaction media was first
for both cases. The reaction using sterically demanding explored. Early studies revealed that the proline-catalyzed
ora,b-unsaturatedaldehydes,aswellasaqueousformalde- aldol reaction between an excess of ketone and aldehydes
hyde,failed.Thereactionofketone31witha,a-dimethoxy- waspossibleinaqueousmedia41(foracompletediscussion
acetaldehyde allowed the synthesis of partly orthogonally on the problem of water in organic solvents see Section
protected aldopentoses and derivatives.37c 3.2.1.1). As a result, when (S)-proline (20mol%) was used
as a catalyst in the standard aldol reaction (see Table 2),
Table3. Enantioselectivealdolreactionusingdioxane31 using as reaction media a 0.01M phosphate buffer
(pH=7.4) in the presence of sodium dodecyl sulfate
O (0.1equiv) at 25(cid:3)C, the expected aldol product 19 was
N obtained as a nearly racemic mixture in a shorter reaction
H
OH
time (16–24h) compared with that registered in only an
O O (30m1ol%) OH O OH O organic medium (1–2 days). However, the aldol product
+ R H DMF, 2 °C R + R could be obtained enantioselectively by performing the
O O O O O O reaction in aqueous organic solvents. For instance, the
or
31 17 DMSO (aq.), 25 °C anti-32 syn-32 reactionofacetonewithp-nitrobenzaldehydegaveproduct
1-4 d 19a with 40% ee when the reaction was performed in
Entry 17 Solvent Yield(%) de(%) eea(%) DMSO/H2O (9:1, v:v), with 35% ee in DMF/H2O (10:1,
v:v), and with 63% ee in 1,4-dioxane/H O (10:1, v:v).
1 PriCHO DMF 97 96 97 2
2 BnOCHCHO DMF 40 96 90
3 PhCHO2 DMF 57 60 76b This acceleration of the reaction rate by the addition of
water allowed a reduction in the excess of ketone to a
O stoichiometric amount. The addition of 100–500mol%
4 O H DMF 76 >96 >98 of water to dry DMF provided the aldol products 19
O using only stoichiometric amount of all reagents 17 and
18, affecting neither the diastereoselectively nor the
O
enantioselectivity.42
5 O H DMF 80 >96 >96
NCbz The use of Brønsted/Lewis acids in the aforementioned
reaction has also been evaluated. Thus, the reaction using
6 BnOCHCHO DMSO 85 95 98
2 chiral camphorsulfonic acid (10mol%) and proline
7 PhCHO DMSO 80 0 97
(20mol%) in a mixture of acetone/water (4:1, v:v;
O
54.4equivof18a)withp-nitrobenzaldehydeaselectrophile
8 O H DMSO 74 95 >98 gave the expected aldol product 19a (R2=H) with 74%
O yield and 61% ee in only 1 day (compare with entry 1 in
Table2).Thesameprotocolwasalsoemployedwithcyclic
aeeoftheanti-32. ketones obtaining the corresponding products with good
b49%eeforthesyn-32. enantioselectivities (44–99% ee).43 The use of other acids,
such as pyridinium p-toluenesulfonate (100mol%) or lith-
SimilarresultswereobtainedunderaqueousDMSOcondi- ium chloride (150mol%) had also an important effect in
tionsat25(cid:3)Candusing2equivoftheexpensiveketone31 the reaction of ketone 31 and aldehydes increasing some
(seeforexamplesentries6–8inTable3).38However,other eevaluesfrom66%to92%.44Onthecontrary,thepresence
synthetic equivalents of dihydroxyacetone, such as 1,3-di- of either acids, such as acetic and trifluoroacetic acid, or
2256 G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293
bases,suchasDBUortriethylamine,didnothaveanysig- This strategy has also been used to perform the dynamic
nificant beneficial effect when the reaction was performed kineticresolutionofracemic1,4-dioxa-8-thia-spiro[4.5]dec-
using acetone 18a (27.3equiv) in DMF.45 However, under ane-6-carboxaldehyde 33 using ketone 29 as the source of
these conditions, the addition of water (100–500mol%) the nucleophile with an excellent enantioselectivity
speeded up the reaction, increasing slightly the enantio- (Scheme10).53Theprotocolhasbeensuccessfullyextended
selectivities, especially for cyclic ketones.45 to the related 6,10-dicarboxaldehyde, as a mixture of race-
mic and meso-compounds.
Thepresenceofchiraldiolsseemstohaveabeneficialeffect
on the aldol reaction.46 Thus, the reaction of acetone 18a
(8.18equiv)withbenzaldehydeinDMSOat0(cid:3)Ccatalyzed
O
by (S)-proline (30mol%) gave the expected product 19 N
(R2=H) with 72% ee, which was increased up to 96% H OH
when the same reaction was performed in the presence of O O O O 1 O O OH O
(50 mol%)
(R)-BINOL (0.5mol%). Although the reason for this + H
enhancement is not clear, the authors suggested a possible DMSO
template effect of the chiral diol, activating and ordering S S H2O (800 mol%) S S
29 rac-33 25 ºC, 2 d 34
the aldehyde and enamine nucleophile.
(6 equiv.) (56%, >98% ee)
The negative activation volume of the proline-catalyzed Scheme10.
aldolreactionanticipatedthepossiblebeneficialuseofhigh
pressure conditions. Thus, when the reaction was per-
2.2.1.2. Ketones as electrophiles. Although ketones are
formed using acetone 18a as a source of the nucleophile
poorelectrophilesand therefore are considereda non-suit-
and solvent and p-nitrobenzaldehyde in the presence of
ablepartnerforthealdolreaction,thistransformationhas
proline 1 (30mol%) at 25(cid:3)C and pressures of 0.2GPa,
been achieved in certain cases using very high active non-
the only effect was suppression of the condensation by-
enolizable ketones, leading to chiral compounds bearing
product. However, for other aldehydes, a slight increase
tertiary alcohols.54
of the enantioselectivity was produced.47a Similar results
were found when the high pressure (0.2GPa) was induced
The reaction of 1-aryl-2,2,2-trifluoroethanones 35 with a
by water freezing conditions at (cid:2)20(cid:3)C.47b
large excess of alkyl methyl ketones 18, acting at the same
time asthe source of thenucleophileand assolvent,in the
Animportantaccelerationeffectwasobservedwhentheal-
presence of substoichiometric amounts of (S)-proline 1
dol reaction was performed under microwave conditions
gave the expected trifluoromethyl aldol products 36 with
(15W) with external cooling, providing the aldol products
modestenantioselectivities(Scheme11).Thenatureofsub-
18 with similar results (see Table 2) but in very short reac-
stitutiononthearomaticringof35determinedthesuccess
tion times (15–60min).48
ofthereactions.Thus,thepresenceofanelectron-donating
group at the para-position causes the reaction to fail,
Although the previous protocol modifications had some
whereas electron-withdrawing groups facilitate it.55
beneficial effect, perhaps the best modifications was the
introductionofsolvent-freeconditions(donotbeconfused
with the use of a large excess of ketone as a source of
nucleophile and solvent at the same time). The use of a O O -20 °C, 1-24 h F3C OH O
+
ball-milling technique facilitated the aldol reaction using R Ar CF3 Ar R
only 1equiv of ketone 18, 10mol% of (S)-proline, reduc- 18 35 N O 36
ing the reaction time from days to hours and increasing (50.5 equiv.) H OH (45-99%, 18-64% ee)
in some cases the enantioselectivity.49 The reaction can be 1
(10 mol%)
performed under conventional magnetic stirring using an
excess of ketone 18 (5equiv) and 30mol% of catalyst 1, Scheme11.
affording the expectedaldolproducts 19in longer reaction
times but with similar enantioselectivities. The addition of
a-Ketocarbonylcompoundsarealsoreactiveenoughtobe
a small amount of water (up to 5equiv) had a beneficial
used as an electrophilic partner in this transformation
effectonthediastereo-andenantioselectivities(forexample
(Scheme 12). Although the reaction of acyclic a-keto ester
from75%deand84%eewithoutwaterto93%deand97%
ee with 500mol% of water).50
Finally,(S)-proline has shown itsefficiency asacatalystin O O R2 OH O
doyfnraamceicmkicinaettircopreissoomluetiroicn Npr,oNc-edsisiesso.p51roTphyel-2a-ldfoorlmryealbcetinozn- R1 + R2 R3 O R1
amide derivatives with an excess of acetone (18a, O O R3
27.3equiv) in DMSO at room temperature gave mixtures 18 37 NH OH 38
(53-89%, 14-99% ee)
of diastereoisomers depending on the nature of the benz- 1
(10-50 mol%)
amidesubstituentsfrom36%to78%de,andthemajordia-
stereoisomer reaching up to 95% ee.52 Scheme12.
G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293 2257
derivatives gave very low enantioselectivities, the results never higher than 60%. In all the cases tested, the syn-42
were increased up to 81% ee when the reaction was per- wasthemayordiastereoisomerinhighee,withtheabsolute
formed using alkyl methyl ketones 18 (67equiv) as the configuration being determined by X-ray. These results
source of the nucleophile (and as solvent) and a-oxolac- were independent of the nature of the substitution on the
tones of type 37.56a Better results were obtained when aryl group, as well as on the ester group.58
1,2-diketonederivatives37wereusedaselectrophilesusing
DMSOassolvent,givingenantioselectivitiesupto99%.56b 2.2.2. Aldehydes as source of nucleophile. Although the
organocatalytic intermolecular aldol reaction was initially
Acetone 18a was reacted with a-keto phosphonates 39 to developed using only ketones as the source of the nucleo-
give the corresponding a-hydroxy phosphonates 40 with phile, two years later the use of aldehydes as a source of
excellent enantioselectivities (Scheme 13). The results nucleophiles was introduced.
seemed to be practically independent of the nature of
ketonesubstituentR1,andonlythesizeoftheestermoiety
2.2.2.1. Aldehydes as electrophiles. Two possible gen-
R2 had a marginal effect, with the best results being
eral transformations can arise from the intermolecular
obtained for isopropyl derivatives.57
aldol reaction using aldehydes. The first one is the auto-
aldoldimerizationprocessofasinglealdehyde.Thesecond
O O OR2 R1 OH O general transformation is the cross-aldol process between
-30 °C
+ R1 P OR2 O P two different aldehydes. The latter case is a really more
O O R2O OR2 challenging problem, since there are two possible auto-
18a 39 N 40 aldol dimerization processes to be avoided, and two possi-
(54 equiv.) H OH (32-94%, 71-99% ee) ble cross-aldol processes to be discriminated.
1
(20 mol%)
However,boththeauto-aldolandthecross-aldolreactions
Scheme13. have been successfully achieved using (S)-proline 1 as cat-
alyst(Table4).Thus,theauto-aldolprocessusingpropion-
The dynamic kinetic resolution of 2-oxo-3-arylsuccinate aldehyde (R1=Me in 20 and R2=Et in 17) gave the
derivatives 41 by reaction with acetone 18a (17equiv) in expected b-hydroxyaldehyde 43 as a mixture of anti- and
acetonitrile has been described (Scheme 14). The reaction syn-diastereoisomers with an excellent enantioselectivity
gave a mixture of products with diastereomeric excess for the major anti-43 isomer (entry 1 in Table 4).
Moreover, the cross-aldol reaction has been performed
RO2C OH O under similar reaction conditions, and for example using
ROC
2
propionaldehyde 20 as the source of the nucleophile
N O H Ar (R1=Me)otherdifferentaliphaticandaromaticaldehydes
RO H OH syn-42 could be used as electrophilic partners yielding in all cases
O O 1(20mol%) (36-68%, 89-99% ee) tested the anti-43 isomer as the main diastereoisomer
+ Ar +
O MeCN, -30 °C ROC OH O (entries 2–4 in Table 4).59 This behavior was attributed to
18a O OR RO2C2 thhyedesste(rRic2h=inBdurainince17in) atsheweclalsaesotfheb,kbi-ndeitsiucbisntaitcucteesdsibaillditey-
(17equiv.) Ar H
of the hydrogen in a,a-disubstituted aldehydes
41 anti-42 [R2=(CH ) CH or Pri in 17], making in both cases the
(21-10%, 12-95% ee) 2 5
corresponding nucleophilic enamine intermediate thermo-
Scheme14. dynamically unstable (see Section 7.2).
Table4. Enantioselectivealdolreactioncatalyzedbyproline1usingaldehydesasasourceofnucleophile
O O OH O OH O
H + R2 H R2 H + R2 H
R1 O R1 R1
N
20 17 H OH anti-43 syn-43
1
(10 mol%)
Entry R1 R2 Reagent(equiv) Reactionconditions Yielda(%) de(%) ee(%)
1 Me Et — DMF,4(cid:3)C,10h 80 80 99
2 Me Bui 20(2) DMF,4(cid:3)C,16h 88 75 97
3 Me (CH) CH 17(2) DMF,4(cid:3)C,20h 87 94 99
25
4 Me Ph 17(10) DMF,4(cid:3)C,16h 81 75 99
5 Bun Pri 17(3) DMF,25(cid:3)C,24h 80 96 98
6 PhCH S(CH)SCH 17(2) DMF,25(cid:3)C,46h 73 97 97
2 23
7 Pri H 20(2) DMF,25(cid:3)C,16h 52 — 99
aResultsfortheanti-diastereoisomer.
2258 G.Guillenaetal./Tetrahedron:Asymmetry18(2007)2249–2293
The great success obtained in the cross-aldol reaction has Othera-functionalizedaldehydeshavebeenusedassources
beenfurtherexpandedtootherelectrophilicaldehydessuch of nucleophile. Thus, the reaction of glycine aldehyde
as 1,3-dithianyl-2-carboxaldehyde60 and aqueous formal- derivative48withanexcess ofdifferentaldehydes17gave,
dehyde27 (entries 6 and 7 in Table 4, respectively). as the main product, the corresponding anti-b-hydroxy-a-
amino aldehyde anti-49, with excellent results (Scheme
Aldehydes anti-43 can be easily transformed into 1,2-diols 16). The subsequent oxidation of aldehydes 49 provided a
byanallylationreactionmediatedbyindium.Thereaction new entry to the synthesis of the corresponding amino
gave modest diastereoselectivities, except for the prenyl- acids.67
ation process.61 It is possible to obtain different d-lactone
derivatives by Horner–Wittig–Emmons reaction of alde-
hydes anti-43 with methyl 2-(diethoxyphosphoryl)acetate
O O OH O
followed by dihydroxylation using osmium tetraoxide N
and final cyclization.62 H H OH R1 H
O
O N O 1(10 mol%) O N O
+
A careful study of the reaction conditions showed that the R1 H NMP, 4 °C, 16-48 h
cross-aldol reaction can be performed using an excess of
aldehyde20(500mol%),whichisthesourceofnucleophile
and solvent at the same time, with the presence of water 48 17 anti-49
(62-93%, 88-99% ee)
(300mol%) increasing the obtained enantiomeric excess.50
Scheme16.
The use of a-alkoxyacetaldehydes 44 allowed access to
polyol architectures. The nature of the protecting group
is crucial in order to forecast the possible role of this (S)-Proline1wasabletocatalyzetheauto-aldolreactionto
aldehyde. Thus, when the protecting group is either an obtain dimers as well as trimers, affording directly poly-
alkyl or silyl, the corresponding aldehyde 44 could play ketide derivatives. Thus, the trimerization of acetaldehyde
eithertheroleofthesourceofthenucleophile,inreactions can be achieved in a THF/acetaldehyde mixture (4:1) at
with a,a-disubstituted aldehydes, or the role of an electro- 0(cid:3)C, giving (5S)-hydroxy-2-hexenal in low yield (12%)
phile, in reactions with simple aliphatic aldehydes. In but with high ee (84%).68 This result could be improved
both cases, products were obtained with good yields (33– by the slow addition of acetaldehyde to the in situ formed
84%), high diastereoselectivities (60–78%) and excellent dimer of type anti-43. For instance, the trimerization of
enantioselectivities (94–99%).63 The auto-aldol reaction of propionaldehyde (R1=Me, R2=Et in Scheme 17) cata-
a-(triisopropylsilyloxy)acetaldehyde 44 (R=SiPri) gave lyzed by (S)-proline 1 (10mol%) in DMF afforded after
the corresponding aldehyde anti-45 with 75% diastereo- 3 days, a mixture of diastereoisomers 50 and 51 (78% de)
selectivity, which after reaction with silyl enol ether 46 in in 53% yield (Scheme 17).69
the presence of titanium tetrachloride64 yielded the corre-
sponding allose 47 (Scheme 15).65
O O DMF, 4 °C, 1-4 d OH O
O DMSO, 25 °C, 1-2 d OH O H + R2 H R2 H
R1 O R1
H H N
OR O OR OR 20 17 H OH anti-43
N (5 equiv.) 1
44 H OH anti-45 (10 mol%)
1 (R = SiPri3, 92%, 95% ee)
(10 mol%)
OSiMe3 R2 O OH R2 O OH 25 °C, 1-3 d
+
Pri3SiO O OH TiCl4 OAc R1 R1 R1 R1 O
Pri3SiO OAc CH2Cl2, -78 to -40 ºC 46 OH OH H
OH 51 50 R1
(12-42%, 99% ee) (32-78%, 12-99% ee) 20
47 (4 equiv.)
(97%, 95% ee)
Scheme17.
Scheme15.
TheuseofMgBr asaLewisacidforthelastMukaiyama- Theuseofadifferentelectrophilicaldehyde,suchasisobu-
2
aldol reaction gave the diastereomeric mannose derivative tyraldehyde(R2=Priin17)ledtotheformationofasingle
with similar results. A positive non-linear effect was de- diastereoisomer 50 (R1=Me) but with low yields and
tectedintheaboveauto-aldolreaction,66whichwasattrib- enantioselectivity, the last fact being attributed to the mis-
uted to the different reaction rates of both enantiomers of matched pair of intermediate anti-43 and (S)-proline. The
prolinewithanti-45(R=Bn)toformtheinactiveimidazol- enantioselectivity of the process could be improved up to
idinone derivative, resulting in a kinetic resolution of pro- 99% by carrying out the reaction in a stepwise manner,
line by the final product. using(S)-prolineforthefirstaldolprocess,and(R)-proline