Chem. Rev. 1994, 94, 2483-2547 2483

Catalytic Asymmetric Dihydroxylation

Hartmuth C. Kolb,t Michael S. VanNieuwenhze,* and K. Barry Sharpless*

Department of Chemistry, The Scripps Research Institute, 10666 North Torfey Pines Road, La Jolla, California 92037

Received Ju/y 28, 1994 (Revised Manuscript Received September 14, 1994)

Contents 3.1.4. Differentiation of the Hydroxyl Groups by 2524 Selective, Intramolecular Trapping 1. Introduction and General Principles 2483 3.1.5. Miscellaneous Transformations 2525 2. Enantioselective Preparation of Chiral 1,2-Diols 2489 3.2. Preparation of Chiral Building Blocks 2527 from Olefins 3.2.1. Electrophilic Building Blocks 2527 2.1. Preparation of Ligands, Choice of Ligand, 2489 Scope, and Limitations 3.2.2. Chiral Diol and Polyol Building Blocks 2529 2.1.1. Preparation of the Ligands 2490 3.2.3. Chiral Monohydroxy Compounds Derived 2529 from Diols 2.1 -2. Ligand Choice and Enantioselectivity Data 2490 3.2.4. 5- and 6-Membered Heterocycles 2530 2.1.3. Limitations 2491 3.3. Preparation of Chiral Auxiliaries for Other 2530 2.2. Reaction Conditions 2493 Asymmetric Transformations 2.2.1. Asymmetric Dihydroxylation of the 2493 3.3.1. Preparation of 2530 “Standard Substrates” (1 R,2S)-trans-2-phenylcyclohexanol 2.2.2. Asymmetric Dihydroxylation of 2496 3.3.2. Optically Pure Hydrobenzoin (Stilbenediol) 2531 Tetrasubstituted Olefins, Including Enol and Derivatives Ethers 4. Recent Applications: A Case Study 2536 2.2.3. Asymmetric Dihydroxylation of 2496 Electron-Deficient Olefins 5. Conclusion 2538 2.2.4. Chemoselectivity in the AD of Olefins 2497 6. References and Footnotes 2542 Containing Sulfur 2.3. Double Diastereoselection and Kinetic 2497 1. Introduction and General Principles Resolution 2.3.1. Double Diastereoselection 2497 During the last decade a number of powerful 2.3.2. Kinetic Resolution 2502 asymmetric reactions have emerged as a result of the growing need to develop efficient and practical syn- 2.4. Asymmetric Dihydroxylation of 2503 Polyunsaturated Substrates theses of biologically active compounds. Catalytic asymmetric reactions provide an especially practical 2.4.1. Formation of Polyols from Conjugated 2504 and Nonconjugated Polyenes entry into the chiral world due to their economical use of asymmetry inducing agents.l A number of 2.4.2. Selective Mono-dihydroxylation of 2506 Polyenes processes have gained wide acceptance, and some of them are even used on an industrial scale. Among 2.4.3. Asymmetric Dihydroxylation of Cyclic 2508 Polyenes the most prominent examples are the “Monsanto Process” for the asymmetric of dehy- 2.4.4. Asymmetric Dihydroxylation of Enynes 2509 droamino acids2 and the enantioselective isomeriza- 2.5. Influence of Acidic Hydrogens in the 2510 tion of allylic amine^,^ used in the “TakasagoProcess’’ Substrate on Rates, Chemoselectivity, and Stereoselectivity for the manufacture of (-)-menthol. The asymmetric 2.5.1. Influence on Regioselectivity epoxidation of unfunctionalized olefins, catalyzed by 251 1 manganese-salen complexes, also has considerable 2.5.2. Influence on Stereoselectivity 251 2 p~tential.~Our own efforts in the field of asymmetric 2.5.3. Influence on Rates 251 3 oxidation of olefins5have led to two useful reactions, 2.5.4. Summary 251 3 the asymmetric epoxidation6 (AE)and the osmium- 3. Synthetic Applications for 1,2-Diols 251 3 catalyzed asymmetric dihydr~xylation~(AD). While 3.1. Methods for the Differentiation of the 2514 the former reaction requires the presence of a direct- Hydroxyl Groups of a Diol ing functional group in the substrate (allylic ), 3.1.1. Selective Arenesulfonylation 251 4 the dihydroxylation process is much less limited in 3.1 -2. Cyclic Sulfites and Sulfates as 251 5 the choice of substrate, since it does not need any -like Synthons directing functional group to be present. Strikingly, 3.1.3. Conversion of Diols into Halohydrin 251 8 both processes crucially depend on the ligand ac- Esters and celeration effect (LAE),6b-dJ?which ensures that the reaction is funneled through a pathway involving the * The author to whom corres ondence should be addressed. Fax chiral catalyst. The principle of ligand acceleration no.: 619-554-6406. E-mail achress: [email protected] s.edu. is illustrated in Scheme 1 for the AD reaction. t Current address: CIBA-GEIGY, Zentrale Forschungslaiorato- In his pioneering work on the stoichiometric reac- rien, R-1060.3.10, CH-4002 Basel, Switzerland. 1: Current address: Lilly Research Laboratories, Eli Lilly and Co., tion of os04 with olefins, Criegee showed that pyri- Lilly Corporate Center, Indianapolis, IN 46260. dine accelerates the reaction con~iderably.~However, 0009-2665/94/0794-2483$14.00/00 1994 American Chemical Society 2484 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. I

HarbnuM C. Kolb did his undergraduate studies at Me University of K. rry Sharpless (b. 1941), W. M. Kwk )lessor of Chemistry at the Hannover, Germany, where he obtained his diploma in 1989. For his Scripps Research Institute. was deflected hom pre-med to chemishy alter Ph.D. he moved to London to work with S. V. Ley on the synthesis of the doing research in Thomas A. Spencer's laboratory at Dartmoulh College. limonoid azadirachtin. Two years later he joined K. B. Sharpless's Following a Stanford Ph.D. with E. E. van Tamelen and postdoctoral years research group at Scripps as a postdoctoral fellow. Initial research on wiih James P. Collman at Stanford and Konrad Bloch at HaNard, synthetic applications of the asymmetric dihydrovlation was followed by Sharpless joined the M.I.T. faculty. He taught there, as well as at Stanford studies on the mechanism of the same reaction. In November 1993, he in the 197oS, until moving to Scripps in 1990. Finding new metalcatalyzed joined the central research laboratories 01 ClBA in Basle. where he is transformations of use in organic synthesis is the main goal of his research. currently working in the carbohydrate section. His research interests include organic synthesis, molecular recognition and molecular modeling. Scheme 1. The Osmylation of Olefins

Initial efforts by Sharpless and Hentges to induce enantioselectivity in the osmylation with chiral py- Michael S. VanNieuwenhze (b. 1962) received his undergraduate education ridine derivatives failed due to the low affinity of at Kalamazoo (MI) College. He then spent two years as an organic these ligands for 0~04.'~~It was found that the chemist in the Parke-Davis Pharmaceutical Research Division of Wamer- binding constant of a ligand is extremely sensitive Lambert, Inc. After an appointment in the laboratory of Professor Samuel to the steric hindrance near the reacting center. Danishefsky at Yale University, Michael obtained the Ph.D. degree in Consequently, quinuclidine derivatives were used 1992 under the direction of Professor William R. Roush at Indiana instead of pyridines for further investigations due to University. Upon completion of his graduate study, he joined the research group of Professor K. Barry Sharpless at the Scripps Research Institute their intrinsically higher affinity for OSO~.'~This as a National Institutes of Health postdoctoral lellow. He is presently logic proved correct, and in 1979 it allowed Hentges employed by Eli Lilly and Company. His research interests include to isolate diols with moderate to good enantiomeric asymmetric synthesis, carbohydrate chemistry, and metalmediated excesses using acetate esters of cinchona alkaloids asymmetric transformations. as chiral ligand@ (Figure la, R = Ac). cost considerations make the stoichiometric osmyla- Apart from the cinchona alkaloid catalyzed asym- tion uneconomical. Not surprisingly, catalytic vari- metric dihydroxylation, there are very few other ants of the reaction, which employ relatively inex- catalytic systems. Recently, Hirama et al. employed pensive reagents for the reoxidation of the osmium(VI) a monodentate 1,4-diazabicyclo[2.2.2loctane (DAB glycolate products, greatly enhance its synthetic CO) derivative (Figure lb) to effect dihydroxylation utility.'O Inorganic cooxidants, such as sodium or of olefins under catalytic conditions16' (1mol % 0~04, potassium chlorate" or hydrogen peroxide,I2were the 5 mol % ligand). Unfortunately, the enantiomeric first to be introduced, but in some cases these excesses are far from satisfactory (541% ee) even reagents lead to diminished yields due to over- with stilbene. Better results were achieved by Mu- oxidation. Much better results are obtained with rahashi and co-workers16"who employed chiral isox- alkaline tert-butyl hydroperoxide, introduced by Sharp- azolidines (Figure 1)to effect the same transforma- less and Akashi,13 or N-methylmorpholine N-oxide14 tion in up to 73% ee. (Upjohn Process). Recently, Minato, Yamamoto, and A number of recent methods employ chiral diamine Tsuji demonstrated that &Fe(CN)c in the presence ligands for the asymmetric osmylation of 01efins~J~~-" of KzC03 provides a powerful system for the osmium- (Figure le). Good results have been achieved very catalyzed dihydroxylation of 01efins.l~ recently by Hanessian et al. with a simple, trans-1,2- Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2485

(a) Cinchona Alkaloid Ligands for AD under Catalytic Condition~~~~J~J~J~

Me0

Dihydroquinidine (R = H) j Dihydroquinine (R = H) DHQD DHQ (b) Recent Monodentate Ligands for AD under Catalytic Conditions

R = ’BuPh2Si-OR Hirama et al. Murahashi et a1.I6” (c) Chiral Diamine Ligands for AD under Stoichiometric Conditions P-4-

Snyder et a1.16m

Hanessian et al. 16b

Corey et aZ.16~ p’?. ph,

Ar L\SN*Ar Pr1-N n h WN-NWN--’Pr Ar = Ph, 3,5-~ylyl ’,,ar Tomioka et al. 16d-g Fuji et

I I R R R = neohexyl Nap = a-naphthyl Hirama et al. 16Jqk Narasaka et ~1.l~~ Figure 1. Some ligands for asymmetric dihydroxylation.16 Only monodentate ligands allow a reaction under catalytic conditions. Note that DHQD and DHQ are diastereomers and not enantiomers due to the presence of the ethyl group at C3. Although ligands derived from these two “pseudoenantiomeric”alkaloids lead to diols of opposite configuration, the ee’s are usually not identical. diaminocyclohexane derived ligand.16b Despite the of this discrepancy was found to be the presence of a good to excellent enantioselectivities that can be second catalytic cycle,19 which exhibited only low or obtained with diamine ligands, a serious drawback no enantioselectivity (Scheme 2). A partial remedy results from their bidentate nature; they form very was discovered by Wai in the slow addition of the stable chelate complexes with the osmium(VI) gly- olefin. 19 colate products which leads to inhibition of hydrolysis While the rate of progress in the development of and as a consequence prevents in situ recycling of this reaction was initially only moderate, our recent the osmium and the ligand. Thus, all the reactions work has led to a dramatic increase ?n momentum. involving bidentate ligands are stoichiometric in both This was due mainly to three key discoveries in our OsOl and the chiral ligand. group. First, Kwong found that the participation of Initially, the asymmetric dihydroxylation using the second catalytic cycle can be virtually eliminated derivatives of cinchona alkaloids was performed by performing the reaction under two-phase condi- under stoichiometric conditions, but in 1987 Marko tions with &Fe(CN)6 as the stoichiometric reoxidant and Sharpless found that the process became cata- (Scheme 3).20 lytic when N-methylmorpholine N-oxide was em- Under these conditions there is no oxidant other ployed as the cooxidant.18 However, the enantiomeric than Os04 in the organic layer, in contrast to the excesses of the diol products obtained under these homogeneous NMO conditions (cf. Scheme 2). Since catalytic conditions were initially lower than those the actual osmylation takes place in this layer, the produced by the stoichiometric reaction. The origin resulting osmium(VI)monoglycolate ester undergoes 2486 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. Scheme 2. The Two Catalytic Cycles for the Asymmetric Dihydroxylation Using NMO as Cooxidantls

high ee

0’ 0’ trioxo Os(VIII) glycolate

(high enantioselectivity) (low enantioselectivity)

L

Rf L L -R low ee

Scheme 3. Catalytic Cycle of the AD Reaction Second Generation Ligands with &Fe(CN)e as the CooxidantZ0 Alk‘-0 0-Alk‘

Ph Phthalazine (PHAL) Diphenylpyrimidine (PYR) Ligandsz3 (1) Ligandsz4 (2)

First Generation Ligands

GI‘ -

Chlorobenzoate (CLB) Phenanthryl Ether 4-Methyl-2-quinolyl Ligands (3) (PHN) Ligandszs (4) Ether (MEQ) Ligandsz5 (5) Figure 2. The latest generation of “dimeric” PHAL and PYR ligands and their predecessors (Alk* = DHQD or DHQ).

2 OH x2 HzO at room temperature, which normally has a beneficial 2 Fe(CN)6’- 2 Fe(CN)64- influence on the selectivity.22 We routinely add 1 equiv of MeSOzNHz to the reaction mixture,23aexcept hydrolysis, releasing diol and ligand to the organic for terminal olefins (Le., monosubstituted and 1,l- layer and Os(VI) to the aqueous layer before its disubstituted olefins). Surprisingly, terminal olefins reoxidation can occur, and consequently entry of the actually react slightly slower in the presence of osmium glycolate into the second cycle is prevented. MeS02NH2. However, this weak inhibitory effect is The use of K20s02(OH)4as a nonvolatile Os source noticeable only if a very small amount of os04 (ca. in combination with an inorganic cooxidant [&Fe- 0.2 mol %) is employed. (CN),J has allowed us to formulate a premix contain- Third, the discovery of ligands with two indepen- ing all reagents, including the ligand. With this dent cinchona alkaloid units by HartungZ3(phthala- premix, which is commercially available under the zine core) and crisp in^^^ (diphenylpyrimidine core), name of “AD-mix”,the reaction is extremely easy to attached to a heterocyclic spacer (Figure 21, has led carry out (cf. section 2.2.1). to a considerable increase in both the enantioselec- The second key discovery was made by Amberg and tivity and the scope of the reaction. Due to these Xu, who found that the hydrolysis of the osmium- improvements it is now possible to obtain high (VI) glycolate product can be accelerated considerably enantioselectivities with a broad range of (see by MeS02NH2. The reaction time can be as much section 2). These two ligand classes have superseded as 50 times shorter in the presence of this additive.21 our previous chlorobenzoate (CLB), phenanthryl This allows high catalytic turnovers even with steri- ether (PHN), and 4-methyl-2-quinolyl(MEQ) ligands cally encumbered substrates, and tetrasubstituted (Figure 2).25 olefins are now within the scope of the reaction (cf. The osmium-catalyzed dihydroxylation reaction section 2.2.2). Due to this “sulfonamide effect”, most has been the center of extensive mechanistic inves- AD reactions can be carried out at 0 “C rather than tigations and two different mechanisms have been Catalytic Asymmetric Dihydroxylalion Chemical Reviews, 1994, VoI. 94, No. 8 2407

Scheme 4. Schematic Presentation the of Its p-nce has a Concerted [3 + 21 Mechanismse (Path A) and the I rmalleffcfonlhe I\ Stepwise Osmaoxetane Mechanism"g (Path B) 1, rates; however. i! p- mcrea~e~ule binding uN) nature has a The of R only rryrhro allows high rates, but only a mal1 ram and binding intluence on @hebindins 94

oxygenation is essential to allow binding lo OrO, - B carbon Substituent is fm bulb binding to .. as rates v ,' U-T.0' ' Path9 - o'/ The presace Of B nu, ammatic L tinog system inceases binding and rales: @henitroogen has no E3innvence suggested Boseken and Criegee originally proposed Figure 4. Relationship between ligand structure and a concerted [3 + 21 path~ay~"-~(Scheme 4, path A), binding and ceiling rate constants.26 The alkaloid core is while Sharpless et al. suggested a stepwise reaction"g ideally set up to ensure high rates, binding, and solubility. which is initiated by a [2 + 21-like addition of the The rates and enantioselectivitiesare influenced consider- olefin across an Os=O bond (path B), followed by ably by the nature of the 09 substituent, while the binding rearrangement of the resulting osmaoxetane inter- to OsOI is almost independent of that substituent. mediate to the glycolate product. The recent observation of a nonlinear Eyring rate accelerations for aromatic olefins. Further relationship between ee and temperaturezzis incon- evidence from binding data suggests that the rate sistent with Criegee's one-step [3 + 21 mechanism, enhancement is not a ground-state effect, but rather but it can be explained by a reaction pathway with caused by a stabilization of the transition state due at least two selectivity determining steps which are to aromatic stacking interactions. Although this kind weighted differently according to temperature, owing of stabilization is operative even in our monomeric to their different activation parameters, HandAS*. first generation ligands (Figure 21, it is most effective Hence, this observation suggests that the stepwise in the dimeric second generation ligands due to the [Z + 21-like mechanism is operative. High level ab presence of a binding pocket or cleft. Thus, the initio calculations have indeed shown that osmaox- almost perfect match between the phthalazine ligands etanes are energetically accessible minima on the and aromatic olefins with respect to rates and enan- potential energy surface.2'a.c tioselectivities can be readily explained by an espe- Recent ligand structure-activity studies have shed cially good transition-state stabilization resulting light on the origin of the enantioselectivity in the AD from offset-parallel interactions between the aromatic reactionz6 and demonstrated the importance of an substituent of the olefin and the phthalazine floor of enzyme-like binding pocket present in the "dimeric" the ligand, as well as favorable edge-to-faceinterac- cinchona alkaloid kands.- . e.e.,-. the uhthalazine limds- tions with the "bystander" methoxyquinoline ring (Figure 3). (Figure 3). The geometry of the binding pocket is The cinchona alkaloid backbone is ideally suited such that it tolerates one large substituent in the for providing high ligand acceleration as well as meta position of the substrate's phenyl ring, since enantioselectivity and the relationship between ligand this substituent can be readily positioned away from structure and activitv is summarized in Firmre 4.26 the bystander methoxyquinoline ring without lower- The investigations" have further shown ihat the ing the edge-to-face attractions. Thus m-tert-butyl- reaction rates are influenced chiefly by the nature styrene gives enantioselectivities comparable to sty- of the 09 substituent of the cinchona alkaloid, with rene itself.36 However, a second large meta certain aromatic appendages giving especially large substituent seriously interferes with the perpendicu-

ON

Figure. 3. Structure of the osmaoxetane intermediate derived from styrene and (DHQDhPHAL, calculated using a modified MM2 force field.27bThe aromatic portion of the olefin is positioned inside a chiral binding pocket. 2400 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et at.

Derivatives “HO OH

NE

sw I a-i‘lcc “HO OH”

Derivatives

Major pathway Minor pathway

Best isomer (A), leads to (Rkdiol, : Steric repulsion destabilizes this good attractive stabilization and minimal repulsion j isomer (B), an (9-diol precursor

The interplay of two crucial inreractions, one aluactive, the other repulsive, provides a simple rationale for the face Selectivity in the AD reaction27b Figure 5. Rationalization for enantiofacial selectivity in the AD reaction (top left, empirical mnemonic device; top right, the proposed osmaoxetane intermediate with the sterically nonequivalent positions around the four membered ring and with trimethylamine in place of the alkaloid ligand; bottom, molecular mechanics model for explaining the enantioselectivity). lar wall of the binding pocket, thereby disrupting it Predictions for 1,l-disubstituted olefins using the and leading to lower selectivities. These results are empirical mnemonic device are not always unam- inconsistent with an alternative mechanistic proposal biguous?* since it may be difficult to judge which of by Corey and NO^:^^^^ which invokes sandwich-like the two substituents prefers the attractive, southwest stacking of the olefin between the methoxyquinolines quadrant. For a group to be well suited for this of the ligand. quadrant it has to be “soft”, large and/or flat. Thus, The above observations have led to a revised aryl groups are the ideal candidates, followed by alkyl mnemonic devicez6 (Figure 5) for predicting the groups. In contrast, oxygen-containing substituents enantiofacial selectivity in the reaction. The south- normally have a relatively low tendency to occupy east quadrant and to a much lesser extent the this position. Our results and a recent study by Hale northwest quadrant of this device present steric et a1?* suggest the trend shown in Scheme 5 for the barriers, whereas the northeast quadrant is relatively tendency of a substituent to occupy the southwest open for olefin substituents of moderate size. The quadrant. southwest quadrant is special in that it is regarded It should be noted, however, that predictions are as being an attractive area, especially well-suited to less reliable for cases where methyl groups are in accommodate flat, aromatic substituents or, in their competition with ROCHz groups, and low enantiose- absence, “large” aliphatic groups. An olefin posi- lectivities are normally obtained (entries 4-61. tioned according to these constraints will be attacked Recently, a molecular mechanics model for explain- either from the top face (i.e., the B-face), in the case ing the facial selectivity and rate trends has been of dihydroquinidine (DHQD) derivatives, or from the developed based on experimental observations (rate bottom face (i.e., the a-face), in the case of dihydro- and ee data, X-ray crystal structures) as well as ab quinine (DHQ) derived ligands. Recent studies have initio calculations.27b This model assumes that the shown, however, that the northwest quadrant, which reaction proceeds through the stepwise [Z + 21-like is normally considered to present a modest steric pathway (cf. Scheme 4, path B), involving an os- barrier (vide supra), also can play an attractive role maoxetane as an intermediate, since this is the for certain allylic and homoallylic alcohols (see sec- mechanism which fits the experimental observations tion 2.5). best?2 The molecular mechanics model suggests that Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2489 Scheme 5. Application of the Mnemonic Device to with the central aromatic nucleus of the bis(dihyd- 1,l-Disubstituted Olefinsz8 roquinidyl) terephthalate ligand. However, no con- ,,- (DHQDPHAL vincing evidence for such a mode of reaction was offered. AD Several stereochemical models have been devel- R’ oped for the rationalization of the stoichiometric (DHQI~PHAL asymmetric dihydroxylation with chiral diamine Tendency for a substituent to occupy the SW quadrant: Aryl > Alkyl > Me BoOCHz, PivOCH2, RsSiOCHz ligands. Tomioka et al. have concluded that the selectivity using their pyrrolidine ligands (cf. Figure Entry Olefin R Ligand %ee Product 1)can be understood best on the basis of the osmaox- etane mechanism.16d-g In contrast, Houk et al. have developed a molecular mechanics model which is ...... I based on a [3 + 21 transition state.27dTheir model is useful for explaining the stereoselectivity observed with various chiral diamine ligands. Both the catalytic and stoichiometric versions of the asymmetric dihydroxylation have been reviewed re~ently.~However, the rapid progress in this area makes an update necessary, and this review deals the enantiofacial selectivity is governed mainly by with new developments in the field of catalytic two factors; stabilizing stacking interactions between asymmetric dihydroxylation. The next chapter ad- one of the substituents (R)on the oxetane and the dresses the enantioselective preparation of 1,2-diols OR substituent on C9 of the ligand, and destabilizing employing the AD reaction, and is followed by repulsive interactions between another oxetane sub- another chapter covering synthetic applications for stituent (a hydrogen) and H9 of the ligand. These these chiral diols. effects are depicted in structures A and B at the bottom of Figure 5. A and B are diastereomers whose only essential difference is that the carbon and 2. Enantioselective Preparation of Chiral oxygen atoms connected to osmium in the metallaox- 7,BDiols from Olefins etane have been interchanged. Both A and B are in rotameric forms which allow engagement of the This section presents our current knowledge re- attractive interactions between R and the C9 OR garding the preparation of chiral 1,2-diols from substituent, leading to overall enhancement of reac- olefins. In five different subsections we will address tion rate in each case (ligand acceleration). However, (1) our currently recommended “best” AD ligands, partaking of these attractive interactions comes at a including their strong points and their weaknesses; greater cost for B than for A because of an attendant (2) reaction conditions for “standard” substrates as repulsive interaction between the ligand’s C9 hydro- well as for olefins that require special treatment; (3) gen and the proximate oxetane substituent. For A double diastereodifferentiation and kinetic resolution; this repulsion is minimal since the C9 hydrogen is (4) the dihydroxylation of polyunsaturated sub- juxtaposed with the oxetane oxygen. But due to the strates; and (5) the influence of free OH groups in aforementioned oxetane “interchange”, relating struc- the substrate on rate, stereoselectivity and chemose- tures A and B,the C9 hydrogen in B experiences a lectivity. bad repulsive interaction with an oxetane hydrogen. This section is intended to illustrate the broad This model provides a simple rationale for the AD’s scope of the AD reaction and the ease with which this face selectivity. If it is correct, then intriguingly the reaction can be carried out. It is hoped that this AD is primarily dependent on a noncovalent attrac- information will be helpful to anyone interested in tive interaction for its high selectivity. The role of performing an AD reaction. the attractive interaction is to favor a transition state arrangement where a repulsive steric effect presents a substantial problem for one diastereomer (B),but 2.1. Preparation of Ligands, Choice of Ligand, not for the other (A). In this scenario, the AD’s Scope, and Limitations enantioselectivity arises from the interplay of two simple effects, attraction and repulsion. Primacy is In recent years approximately 350 cinchona-based assigned to the attractive effect since it ordains the ligands have been tested for the AD reaction. It was decisive role played by the repulsive interaction. found that the enantioselectivity is influenced mainly An alternative mechanism was proposed by Corey by the nature of the 09 substituent of the cinchona et ~1.~~9~~~who suggested that a p-oxo-bridged bis- alkaloid backbone (vide supra). A number of differ- Os04 complex is involved as the active component. ent ligands were proposed as the “best” ligand over However, this hypothesis is inconsistent with the the years (see Figure 21,’ but our efforts have kinetics of the reaction, which clearly show a first- converged on only three different classes of ligands, order behavior in [OSO~I.~”>~Additionally, ab initio which taken together are very effective for the calculations by Frenking and Veldkamp have dem- dihydroxylation of almost any olefin. Scheme 6 onstrated that Corey’s dimer is not a minimum on shows our current ligand recommendations for each the potential energy hypersurface.27c Lohray et aL31 of the six olefin classes. It should be pointed out that have proposed an alternative model which envisages five out of six olefin classes are well served by the stacking of the olefinic double bond of the substrate PHAL (1) and PYFt (2) ligands, and only cis-olefins 2490 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. Scheme 6. The Recommended Ligands for Each Scheme 7. Preparation of the AD Ligands (A&* = Olefin Class DHQD or DHQ)34 Preparation of Phthalazine Ligands:23 CI 0-Alk'

Preferred PYR j I PYR PHAL I IND I PHAL j PHAL 1 1 ligand PHAL I I PHAL 0-Alk' PHAL eerange I 30-97 o/c i 70-97 % j 2040% i 90-99.8 o/c i 90-99 % ~ 20-97% 1 Preparation of Ligand+ mh 1. POCll or PClS EtO*EI 2. Alk*-OH, 2.HCI1. NaOMe Ho&H toluene.KOH, K2CO3, reflux Alk*.O&-Alk'

+ 48 - 58 W PHAL-classZ3(1) PYR-cI~~(2) IND-classZ9(6) H~N+~NH~ I Ph Ph Ph require a unique ligand [IND (611. Thus, the ph- PYR thalazines and are by far the most Preparation of IND ligands:z9 general ligands. 0. 0 Triphosgene. YO-AIk' In several recent reports from other laboratories, EtiN, THF, yc'Alk*-OH, EtJN. the use of other "dimeric" ligands, featuring a py- -'\ 0°C to 1.t.. 3 h_ w)CH&. 1.t. ridazine30 and a terephthalate spacer31 have been loo% w754% proposed for the AD reaction.32 However, a compara- IND tive study has shown that these ligands are inferior to the phthalazine- and pyrimidine-based ligands.33 a mixture of solid K2C03 and KOH as the (Scheme 7). The indoline ligands are readily avail- 2.1.1. Preparation of the Ligands able by reaction of N-indolinecarbonyl chloride (7) Most ligands are commercially available,34but they with the alkaloid in the presence of trieth~lamine.~~ are also easily prepared from relatively inexpensive 2.1.2. Ligand Choice and Enantioselectivity Data starting materials. The dimeric ligands are obtained by condensation of the alkaloid with the dichloride One striking feature of the PHAL and PYR ligands of the heterocyclic spacer in refluxing toluene using is their "dimeric" structure, which is in contrast to

Table 1. Asymmetric Dihydroxylation of Monosubstituted Olefins'

PHAL PYR PHAL PYR Olefin Olefin DHQD DHQ DHQD DHO Entry DHQD DHO DHQD DHO

20' 90(Sj Me0no-/-'.

27dJ ov77(Si 70(R) BnO

28'

' The ee value obtained with the best ligand for a given substrate is printed in bold. The reactions were carried out in t-BuOW HzO at 0 "C with &Fe(CN)Gas the cooxidant. All AD's with PHAL ligands were performed using the AD-mixes. AD's with PYR ligands were performed with 1.0 mol % of Os04 and 1.0 mol % of ligand. a See ref 37. See ref 38. See ref 39. See refs 23a and 24. e Vinyl- and allylsilanes only give moderate enantioselectivities with phthalazine ligands, due to branching in close proximity to the double bond. Interestingly, DHQD-PHN and (DHQDIzPYR give better results in these cases, see ref 40. f See ref 41. g See ref 42. See ref 43. See ref 44. j See ref 45. See ref 46. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2491

Table 2. Asymmetric Dihydroxylation of Table 3. Asymmetric Dihydroxylation of 1,l-DisubstitutedOlefinst trans-l,2-DisubstitutedOlefinst PHAL Entry Olefin (DHQD)zPYR Entry Olefin DHQD DHQ DHQD DHQ

26 Ph

3c Phck 4c MexPh

5c PhcHz%Ph

6b9d

+ The reactions were carried out in the presence of 1 equiv lof PhCHzO) of MeSOzNHz in t-BuOWHzO (1:l)at 0 “C with AD-mix-a [(DHQ)2PHALl and AD-mix-P [(DHQDhPHAL], respectively. See ref 37. See ref 23a. The reaction was performed at room temperature. See ref 49. e See ref 50. f See ref 51.8 See + The ee value obtained with the best ligand for a given ref 39. The reaction mixture was buffered with 3 equiv of substrate is printed in bold. The reactions were carried out NaHC03. See ref 52. in t-BuOWHzO at 0 “C with &Fe(CN)G as the cooxidant. All AD’s with PHAL ligands were run using the AD-mixes. AD’s with PYR ligands were performed with 1.0 mol % of Os04 and data in Table 2 (entries 2 and 6) and Table 3. The 1.0 mol % of ligand. (I See ref 37. * See refs 23a and 24. See diphenylpyrimidines 2 complement the phthalazines ref 47. See ref 45. e See ref 48. f See ref 28. and they are the ligands of choice for the important class of monosubstituted terminal olefins, especially all our previous ligands and the indolines 6. Al- those with branching in the substituent (see Table though it has been proposed that both alkaloids in 1, entries 1-3,6-11, and 16-18). As demonstrated these ligands act in c~ncert,~~,~~a recent study has in Figure 6, the enantioselectivities with n-l-alkenes shown that they have independent functions,8bwith strongly depend on the chain length, and “saturation only one alkaloid moiety being directly involved in behavior” is observed. Thus, the ee initially increases the reaction with Os04 and the olefin (the “working with the number of carbon atoms (cf. to alkaloid unit”). The function of the other, “by- ) but then reaches a “ceiling”, i.e., saturation stander”, alkaloid unit in combination with the value when the chain length is greater than 5. heterocyclic spacer appears to be to set up a chiral Although the pyrimidine ligands give the best selec- binding pocket for the olefinz6(see section I, Figure tivities with aliphatic olefins (Figure 6),the phthala- 3). zines perform better with olefins bearing aromatic Kinetic measurements,26enantioselectivity studies, substituents (Table 1, entries 13, 14, and 19, and and molecular mechanics calculation^^^ have shown Table 2, entry 2). Both PHAL and PYR derivatives that the binding pocket of the phthalazine ligands are useful for tetrasubstituted olefins (see Table 6). (1) is especially well suited to accommodate ole- fins with flat, aromatic substituents, making 2.1.3. Limitations (DHQD)zPHAL and (DHQ)zPHAL the preferred Among the substrates that remain problematic are ligands for these olefins (cf. data in Tables 1-5 czs-olefins as they have provided no examples exceed- concerning aromatic olefins). A recent study has ing 90% ee, even when IND ligands are employed. revealed that increasing the size of the ring substitu- Thus, cis-@-substitutedstyrenes yield products in the ents on styrene disrupts the favorable stacking range of 70-80% ee (Table 7, entries 1-41, while interactions within this binding pocket, leading to aliphatic substrates give even lower selectivities reduced enantiosele~tivities.~~ (entry 5).29 The phthalazine ligands 1 are also recommended It should be pointed out, however, that certain for the 1,l-and 1,2-trans-disubstitutedas well as the cyclic cis-olefins give satisfactory results with the trisubstituted classes of olefins, as revealed by the PYR ligands, even in those cases where IND ligands 2492 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et at. Table 4. Asymmetric Dihydroxylation of Trisubstituted Olefins? n-alkyl PHAL Entry Olefin DHQD DHQ f

-+- Wee [(DHQD) PYR] rb ee [(DHQD) PHAL] I I 2

“3 4 5 6 i 8 9 io Total Chain Length Figure 6. Dependence of the enantiomeric excess on the chain length of aliphatic n-~.~~ this olefin class cause problems. Thus, alkenes with a single, small substituent, e.g., allyl derivatives CHz-CHCHs CX = H, CH3,OC(O)R,OR, OTS,halo], normally give <70% ee (Table 1, entries 1-7 and 24). However, the propensity of PHAL ligands (1) to “recognize” flat, aromatic surfaces can be utilized even here. Thus, aryl allyl ethers are excellent starting materials for chiral glycerin synthons41 (Table 1, entries 19, 20, and 23), provided the + The reactions were carried out in the presence of 1 equiv aromatic group lacks substituents in the ortho posi- of MeSOzNHz in t-BuOHiHzO (1:l) at 0 “C with AD-mix-a [(DHQ)zPHAL]and AD-mix+?[(DHQDlzPHAL], respectively. tions (entries 21 and 22). These compounds are See ref 23a. See ref 36. (DHQD)zPYR provides the diol in interesting C3 building blocks and some of them 90% ee with this substrate. See ref 53. e See ref 54. f See ref are intermediates in the synthesis of /3-adrenergic 55.8 The diol is obtained in 86% ee with (DHQDIzPYR. blockers.41a In certain cases the use of other AD Table 5. Asymmetric Dihydroxylation of Enol Ethers ligands can also lead to improved enantioselectivities Leading to a-Hydroxy ? for these difficult olefins. For instance, the modified PHAL “phthalazine”ligand 8 gives higher enantioselectivi- Entry Olefin EIZ ratio DHQD DHQ ties than the original38 (eq 1). However, 8 is less Me0 1 phA/Ph I/ >99 99 (R) 98 fS) K3Fe(CN)6, K2CO3, NaHC03, K20~02(OH)4(0.2 mol W), Ph OH 2 &Ph >99/1 90 fR) ‘BuOH-H~O(lrl), 0°C Me0 eBrODHQD * HOABr Me0 95(R) 96 (S) 3 4/96 yield: 61-74% Phphjf$z (0.36 mol %) 72% ee ‘BuMe2Si0 4- \ 25/75 89 (R) 86 (Si 8 ODHQD Me0 Equation 1. Asymmetric dihydroxylation of allyl bromide 5 33/67 85(R) 84(S) P hk using the improved ligand 8. The reaction mixture is ‘BuMs2Si0 buffered with 3 equiv of NaHC03 to prevent epoxide 6 I/ >99 97 (R) formation.38 PhA

7 6/94 91 fR) 93 (S) readily available, and it is therefore used only for m certain problematic olefins, such as allyl bromide. ‘BuMelSiO In rare situations, the phenanthryl ether ligand 4 8 12/88 79 (R) can provide a solution. Thus, DHQD-PHN gives glyceraldehyde synthon 10 with much higher enan-

+ The reactions were carried out in the presence of 1 equiv tioselectivity than phthalazine or pyrimidine ligandsu of MeSOzNHz in t-BuOH/HzO (1:l) at 0 “C with AD-mix-a [(DHQ)zPHAL]and AD-mix+ [(DHQD)2PHALl,re~pectively.~~ (eq 2). Glyceraldehyde acetal 10 is an intermediate fail (Table Interestingly, the dihydroquinine- Ligand (2 - 5 mol %), K3Fe(CN)6. K2CO3, based pyrimidine ligand, (DHQIzPYR, gives products K20~02(OH)4(0.2 mol %), with higher enantiomeric excesses than the cor- - responding dihydroquinidine ligand (DHQDkPYR, 9 ~BuOH-HZO(1 : 1). 0°C 90% yield whereas the reverse is true for most other olefins (see DHQD-PHN 86% ee (97%ee, 60% yield after recrystallization) Tables 1-6). I (DHQD)*PHAL 67% ee 1 While most terminal olefins yield good results with Equation 2. DHQD-PHN gives superior results to PYR or PHAL ligands (Table 11, a few members of (DHQD)2PHAL with acrolein acetal 9.44 Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2493 Table 6. Asymmetric Dihydroxylation of Tetrasubstituted Olefins, Including Enol Ethers579t

PHAL PYR Entry Olefin isolated DHQD DHQ DHQD DHQ yield (a:

39 (R,J 47 (R) 80-82 1 o-”, 20 (R) 22 (R) 5 1-55

29 (R, R) 31 (R,R) 85-87

59 (lR,2S) 56 (IR,2S) 23-24

83 (R,R) 85 (SS) 85 (R,R) 89 (S,S 29-3 1

75 (R,RI 82 (RN 16-19

64(S) 60(R) 41 (S) 62 (R) 79-95+

67(S) 65(R) 6(R) 37(R) 89-92t

9 93(R) 95(S) 95(R) 97(S) 94-98+

‘BuMe2SiO 85(S) 81 (R) 59(S) SO(R) lo 6 64-85+ ‘BuMepSiO 89 (R) 84 (R) 23-32? l1 12 ‘Bu Mw Mw 15(R) 81 (S) 79(R) 19(S) 15-22t

13 53 (R) 63(S) 60(R) 33 (S) 46-60t

$ The ee value obtained with the best ligand for a given substrate is printed in bold. The reactions were carried out with 1mol % of os01 and 5 mol % of the ligand in t-BuOWHzO (1:l) in the presence of 1 equiv of MeSOzNHz (enol ethers) or 3 equiv (all carbon substituted olefins). The reaction temperature was 0 “C (enol ethers) or room temperature (tetrasubstituted alkenes). + The product is an a-hydroxy .

in the enzyme-mediated synthesis of fructose and 2.2. Reaction Conditions other sugars by W~ng.~~ This section is divided into four parts. The first We are aware of only a few cases where the original part addresses the optimum reaction conditions for p-chlorobenzoate ligand 3 gives higher selectivities “standard AD substrates”, Le., terminal, 1,l-disub- than the current generation of ligands. Thus, the AD stituted, truns-l,2-disubstituted,and trisubstituted of allyl silane 11 in the presence of 25 mol % of olefins. The second part provides the special reaction DHQD-CLByields a diol of 48% ee, while only 35% conditions that tetrasubstituted olefins require, and ee and 13% ee are obtained in the presence of the the third part deals with the AD of unreactive, corresponding phenanthryl ether (13 mol %) and electron-deficient olefins. In the fourth part, chemose- phthalazine (10 mol %) ligands, respectively.40a lectivity aspects in the AD of sulfur-containing olefins are discussed. 2.2.1. Asymmetric Dihydroxylation of the ‘Standard Substrates” 23a 2.2.1.1. Choice of Solvent and Stoichiometric Additives. The catalytic asymmetric dihydroxyla- 2494 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Table 7. Enantioselectivities Obtained with Table 9. The Use of Sodium Peroxodisulfate as an ~is-Olefins~~~+ Alternative Reoxidantel 1 mol % (DHQD)2PHAL, % ee HO 0.2 mol 9c OsO,, Entry Olefin DHQD-IND DHQ-IND nC4Hs-"4H9 3 eq. K2CO3.1-2 eq. MeS02NH:, "C& 12 1 :I 'BuOWH~O OH Temp. reactiontime % ee %yield 12(IR, 2s) 59 (IS, 2R) Reoxidant 3 eq. K,Fe(CN), 0°C 15.5h 97 96 2 0.4 eq. K3Fe(CN),, 1 eq. Na2S208 0°C 15.5 h 97 97 12 (IR, 2s) 3 0.2 eq. K3Fe(CN),, 1 eq Na2S208 r.t. 6.5 h 94-95 100 4 1 S eq. NazS2O8 r.t. 2days 94-95 98

I8 (2R, 3R) While the reaction is normally run under basic conditions (Kzc03, pH 12.2, aqueous layer), it is 80 (2R, 3R) 12 (2S,3S) possible to buffer the system with 3 equiv of NaHC03 (pH 10.3, aqueous la~er).~~,~~Buffering of the reac- tion mixture does not affect the ee, but it can have a beneficial effect on the yield when base-sensitive 56 (IR,2s) 44 (lS,2R) substrates are used or base-sensitive products are d' formed. Thus, the AD of allyl or cinnamyl halides (cf. eqs 1 and 3) should be performed under buffered 16 (IR,2s) conditions to minimize epoxide formation (see eq 1, (9 the yield with allyl bromide as substrate is between 61 and 74% under buffered conditions; in the absence The AD reactions were carried out at 0 "C in 1:l t-BuOW of NaHC03 only 4040% of diol is obtained38). HzO in the presence of 2 mol % of ligand 6 (DHQD-IND or DHQ-IND), 0.2 mol % of os04 and 1 equiv of MeSOzNHz. Unfortunately, the AD reaction does not turn over if K&03 is replaced entirely by NaHC03. Table 8. The AD of Cyclic ~is-Olefins~*J~~J AD-mix$, 3 eq. NaHCO3, DHQD-IND (DHQD)zPYR cis-Olefin 1 eq. CHsS02NH2, (see) (see) 1: 1 'BuOH-H20, 0°C R-Cl * JpCI 16 I OH I a 32 67 (67) 2 Me0 a Equation 3. The AD of allylic halides gives better yields 60 under buffered reaction c~nditions.~~~~~ 3aNC Normally, the reaction is performed with 3 equiv of potassium ferricyanide as the reoxidant. The large xm quantity of salt (due to its high molecular weight, 4 X= CN 58 (63) 5 Br 59 (74) about 1 g of &Fe(CN)6 is required per 1 mmol of 6 CF3 66 (14) olefin) may be disadvantageous for large-scale ap- 7 Et 76 (84) plications. In a study with trans-5- (12)as the substrate we found that ferricyanide can be largely + The numbers in parentheses are the enantiomeric excesses replaced by sodium peroxodisulfate without an ad- obtained with the dihydroquinine based ligand. The reactions verse effect on enantioselectivity or reaction rate61a were performed at 0 "C in 1:l t-BuOWHzO in the presence of (Table 9). Thus, at room temperature the reaction 1 mol % of both ligand and Os01 as well as 3 equiv of &Fe(CN)G and KzCO3. gives good results in the presence of only 0.2 mol % of &Fe(CN)6 (0.066 g per 1 mmol of olefin) and 1 tion of olefins is one of the easiest metal-catalyzed equiv of Na2S208 (0.24 g per 1 mmol of olefin) with reactions to perform. Water and oxygen pose no comparable reaction rates to the original conditions, problems, since the reaction is actually performed in However, complete replacement of ferricyanide re- sulted in much lower rates (entry 4). This use of a solvent mixture containing 50% water, and is best peroxodisulfate was discovered independently by carried out under heterogeneous conditions with 3 Bittman et equiv of both &Fe(CN)6 and K2C03 in order to avoid 2.2.1.2. Concentration of Os04 and Ligand. the second catalytic cycle20 (uide supra). Optimiza- Usually, the reaction is performed with very small tion studies have revealed that a 1:1 mixture of water amounts of the key reagents. Thus, only 0.2 mol % and tert-butyl is the solvent system of choice, of Os reagent,62added to the reaction mixture either and less polar solvents can result in inferior enan- as Os04 or as the nonvolatile K2OsOa(OH)r, and 1 tioselectivities. Methyl tert-butyl ether has been mol % of ligand, i.e., PHAL or PYR ligands, are successfully employed in an industrial application.60 sufficient for most olefinic substrates.23a Interest- The olefin concentration in the tert-butyl alcohoUH20 ingly, the enantioselectivity of the AD reaction has solvent mixture is usually 0.1 M.23a proven quite insensitive to variations in the relative Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2495 amounts of osmium and ligand. In some cases, the A representative procedure for the dihydroxylation low ligand loading mentioned above can be dropped of 1 mmol of olefin with AD-mix is given below. even further without much loss in the enantioselec- Under these conditions, 0.4 mol % of Os and 1mol % tivity. For example, stilbene still gives 96% ee when of ligand, i.e. (DHQD)zPHAL or (DHQ)gPHAL, are 1/100 of 1 mol % of (DHQDIzPHAL is used, as used with respect to the alkene. compared to the 99.8% ee obtained under normal A 25-mL round-bottomed flask, equipped with a condition^.^^" Alternatively, it is possible to increase magnetic stirrer, is charged with 5 mL of tert-butyl the amount of Os to 1mol %, while maintaining the alcohol, 5 mL of water, and 1.4 g of AD-mix-a or ligand concentration at the same level. This is useful AD-~~x-/?.~~[MeS02NH2 (95 mg, 1 equiv) based for accelerating the reaction rate of relatively unre- on 1 mmol of olefin) should be added at this point active olefins (vide infra). for all 1,2-disubstituted, trisubstituted, and tetra- Additionally, the ligand can be recovered from the substituted olefins.] The mixture is stirred at room reaction mixture by extraction with dilute sulfuric temperature until both phases are clear, and then acid and reused without p~rification.~~This should cooled to 0 “C, whereupon the inorganic salts prove important for very large-scale reactions and the partially precipitate. (For olefins which react procedure is described in section 2.2.1.4, below. sluggishly at 0 “C, e.g., ethyl cinnamate, the 2.2.1.3. The “AD-Mixes”.Terminal, 1,l-disub- reaction should be performed at room temperature. stituted and truns-1,2-disubstituted as well as trisub- Normally, this results in only a small loss in stituted olefins can be regarded as the “standard” enantioselectively.) One mmol of olefin is added substrates for the AD reaction. Since these sub- at once, and the heterogeneous slurry is stirred strates require very similar reaction conditions, it is vigorously at 0 “C until TLC or GLC reveal the possible to use a premix of all reactants [i.e., K2- absence of the starting olefin (ca. 6 to 24 h). The OS02(OH)4 as a nonvolatile Os04 source, (DHQDh- reaction is quenched at 0 “C by addition of sodium PHAL or (DHQ)2PHAL, K2CO3 and &Fe(CN)61 for sulfite (1.5 g) and then warmed to room tempera- convenient dihydroxylations on a small scale. These ture and stirred for 30-60 min. The reaction “AD-mixes” can be readily prepared,64and they are mixture is extracted several times with ethyl also commercially available34as AD-mix-/?[(DHQDh- acetate or CHzCl2 (when MeSOzNH2 is used, the PHAL] and AD-mix-a [(DHQ)zPHALI. The currently combined organic layers should be washed with 2 recommended contents in 1 kg of AD-mix are as N KOH to remove most of the sulfonamide) and follows: &Fe(CN)6,699.6 g; K2CO3, 293.9; (DHQDh- then dried (MgS04) and concentrated to give a mix- or (DHQh-PHAL, 5.52 g; and KzOs02(OH)4, 1.04 g.64 ture of the crude diol and the ligand. Purification [The ligand/Os molar ratio is 251.1 The standard by flash chromatography (silica gel, EtOAdhexane; AD procedure calls for 1.4 g of this AD-mix per the ligand does not elute under these conditions) millimole of olefin. gives the pure diol in typically excellent yield. Note that the above recipe corresponds to 0.4 mol The following paragraph provides a representative % of Os with respect to the olefin in contrast to our procedure for the AD with separate addition of the original of 0.2 mol %. The reagents. This procedure is used typically on a large adjustment was made to guarantee reproducible scale and/or when PYR24(2) or INDZ9(6) ligands are reaction times, since rate variations, caused by employed. Note that 2 mol % of the latter ligand is inhomogeneities in the AD-mix, had been observed required for the AD of &-olefins. with our original formulation. The higher concentra- tion of Os has the additional advantage that it leads The ligand [i.e., PHAL ligands (7.8 mg, 1.0 mol %), to shorter reaction times than those reported in our or PYR ligands (8.8 mg, 1.0 mol %), or IND ligands original paper,23aand it also means that less ad- (10.0 mg, 2 mol %)I, &Fe(CN)6 (990 mg, 3 mmol), ditional Os need be added to reach the 1mol % level K2C03 (420 mg, 3 mmol), and os04 (40 pL of a 0.1 that some unreactive olefins require (vide infra). M solution in toluene, 0.4 mol %) or K2Os02(OH)4 Representative Procedures for the AD (1.4 mg, 0.004 mmol) are dissolved in a 1:l mixture 2.2.1.4. of water and tert-butyl alcohol (5 mL of each, 10 of the Standard substrate^.^^ The following points mL total) at room temperature. [MeS02NH2 (95 should be observed when choosing the optimum mg, 1 equiv based on 1 mmol of olefin) should be reaction conditions for the First, 1 equiv of AD. added at this point for all 1,2-disubstituted and MeS02NH2 should be employed for all substrates trisubstituted olefins.] The vigorously stirred mix- other than terminal alkenes to enhance hydrolysis ture is then cooled to 0 “C and the olefin (1.0 mmol) of the osmate(VI) ester and hence the rate of catalytic is added in one portion. After complete consump- turnover; no MeS02NH2 should be added for mono- tion of the starting material (TLC or GLC), the substituted or 1,l-disubstituted olefins except in reaction is worked up as described above (when special cases where turnover is noted be very slow to MeS02NH2 is used, the combined organic layers due to the presence of chelating functionality and/or should be washed with 2 N KOH to remove most steric problems in the substrate. Second, for small- of the sulfonamide). scale reactions (-4mmol) it is most convenient to use the AD-mixes, since only trace amounts of the For large-scale preparations it is advisable to key components are needed. However, for large-scale recover the ligand.63 For the PHAL ligands this may reactions it is more economical to add the reagents be accomplished by extracting the combined organic separately, and since the PYR or IND ligands are not layers with 3% aqueous HzS04 saturated with K2- available in premade mixes the latter procedure is SO4(ca. 40 mL per 1g of ligand), followed by a second necessary when their use is called for. extraction of the organic solution with saturated K2- 2496 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. SO4(ca. 40 mL per 1 g of ligand). The ligand enters Table 10. The AD of Amides‘ the aqueous phase as the hydrogen sulfate salt and teaction the solution can be reused directly for the subsequent Entry Olefin %ee Config. Temp, Yield, B AD reactions without further purification. Note, however, that the amount of K2C03 in the subsequent Phdf 98 (2S, 3Ri r.t. 95 AD reaction should be increased in order to neutral- ize excess H2S04 and also to release the ligand salt as its free base. Additionally, the amount of water 96 f2S, 3Rj r.t. 92 should be decreased by the volume of aqueous ligand solution added to the reaction mixture. 0°C 81 2.2.2.As mmetric Dihydroxylation of Tetrasubstituted 93 f2Si Olefins, Yncluding Enol Etherg7 The hydrolysis of osmate esters derived from tet- 98 (3R,4Ri r.t. 91 rasubstituted olefins is very slow, resulting in serious turnover problems. Consequently, the catalytic di- I hydroxylation of this class of olefins has been ex- 5 PhyNxOMe 98 (3R4R) r.t. 81 tremely rare.13 However, recent studies have led to 0 a much better process for this challenging class of substrates and the main improvements are as fol- 96 f3Rs4RJ 0°C 84 lows: (1) MeS02NH2 speeds up hydrolysis and hence catalytic turnover. One equivalent of this additive + Carried out in the presence of 1mol % of OsO1,5 mol % of should be employed for the enol ethers, while 3 (DHQDIzPHAL, and 1 equiv of MeSOzNHz in 1:l t-BuOW equivalents are required for the “all-carbon”-substi- HzO.~~ tuted cases. This sulfonamide effect can be dramatic what surprising, since a belief had gradually evolved as shown by the following example. In the presence in our laboratory that nothing larger than a hydrogen of 1equiv of MeS02NH2, the AD of enol ether 13 was would fit into the “southeast” quadrant of the cata- complete within 24 h at 0 “C, giving a-hydroxy ketone lytic site (see Figure 5 and discussion). The face 14 in 97%isolated yield (eq 4). However, the reaction selectivity of the AD on tetrasubstituted olefins can is incomplete even after 70 h in the absence of this be predicted with our mnemonic device, and only one additive, and the product is isolated in only 53%yield exception [Table 6, entry 8 with (DHQD)zPYRI has along with the starting material (44%). been encountered so far. Thus, the olefinic substitu- ent which is recognized as the smallest is placed in 5 mol % (DHQD)*-PHAL, the southeast quadrant, as a hydrogen surrogate. The 1 mol % 0~04, data for cyclic enol ethers show that the cyclic Ph 1 eq. MeSOZNH2, methylene is more suitable for this hindered quad- 3 eq. KJFe(CN)6, rant than the OR group. 3 eq. K2C03, 14 13 ‘BuOH-H~O(1 : l), 0°C 97% yield, 93% ee 2.2.3.As mmetric Dihydroxylation of Electron-Deficient Equation 4. The AD of enol ethers gives access to optically O/efin@r 6/ active a-hydroxy ketones.57 Since Os04 is an electrophilic reagent, the rate of (2) The amount of os04 should be increased to 1 osmylation of electron-deficient olefins, such as a,B- mol % and the amount of ligand to 5 mol %. unsaturated carbonyl compounds, can be very low. (3) Whereas the more reactive enol ethers give While unsaturated esters still give satisfactory reac- satisfactory turnovers at 0 “C, the AD of the “all- tion rates at room temperature under the standard carbon”-substituted olefins should be performed at AD conditions (Le., 0.2-0.4 mol % os04 and 1 mol room temperature. Under these conditions, most % ligand), unsaturated amides, although more elec- “all-carbon”-substitutedcases give satisfactory reac- tron rich than the corresponding ester, react slug- tion rates, except cyclic ones (Table 6, entries 4-6). gishly, presumably due to osmate ester hydrolysis The optimized procedure is as follows: problems. However, a dramatic increase of the turnover rate can be achieved by increasing the The olefin is added in one portion to a mixture amount of os04 to 1 mol %. Thus, a,P-unsaturated consisting of 3 equiv each of &Fe(CN)G and KzCO3, amides can be dihydroxylated in the presence of 1 1mol % of OsO4,5 mol % of ligand (PHAL or PYR mol % 0~04,5 mol % ligand and 1 equiv of MeS02- derivatives) and 1 molar equiv (for enol ethers) or NH2, to give the corresponding diols in good to 3 molar equiv (for all-carbon-substituted olefins) excellent yields and enantiomeric excesse@ (Table of MeS02NH2 in 1:l tert-butyl alcohoVwater (5 mL 10). The reaction is typically carried out as described of each per mmol of olefin) at 0 “C (for enol ethers) for the tetrasubstituted olefins (section 2.2.2), except or at room temperature (for olefins). The reaction that 1 equiv of MeS02NH2 is generally sufficient. A is monitored by TLC or GLC, and the workup is few representative examples for the AD of unsatur- carried out as usual. ated amides are shown in Table 10. Under these conditions the AD of a number of Since N-methoxy-N-methyl amides (Weinreb tetrasubstituted olefins gives the corresponding diols amides) lead readily to or ketones,68 the in good yields and with good to excellent enantiose- products from the dihydroxylation of unsaturated lectivities when PHAL (1) or PYR (2) ligands are Weinreb amides can be regarded as masked dihy- employed (see Table 6). This observation is some- droxy aldehydes or dihydroxy ketones. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2497

Table 11. Asymmetric Dihydroxylation of Enonest Table 12. The AD of Sulfur-Containing Olefins43

Entry Substrate Product Yield %ee Entry Substrate Product Yield %ee (%) HO 0 "C5H11 "C5Hqlw 87 98 A PhH&S,ph 75 98 OH OH

Ph phHq 69 92 2 Ph-S-Ph PhH&SAPh 72 98 OH OH

89 68 84 OH

4 -'.Ph &'.ph 74 96 OH

fi 78 98 HO 0 PhHwH OH 6+t pod61 99 HO P = 'BuMezSi (PhHkSb 80 99

t The reactions were performed in 1:l t-BuOWHzO at 0 "C in the presence of 1 equiv of MeSOzNHz using modified AD- + %de. mix$ [l mol % of K~Os02(OH)4],buffered with 3 equiv of NaHC03. tt This particular reaction was carried out with regular AD-mix+ [0.4mol % of KzOs02(OH)41, and it took 4 2.3. Double Diastereoselection and Kinetic days at 0 "C (Marshall, J. A., personal communication). Resolution 2.3.1, Double Diastereoselection Even enones can be dihydroxylated with a fortified AD-mix, containing 1 mol % of KzOs02(OH)4 and 1 Given the high levels of enantioselectivity observed mol % of ligand l.67However, in order to prevent in the asymmetric dihydroxylation of prochiral ole- base-induced epimerization, the reaction mixture fins, we were optimistic that the AD would also be should be buffered with 3 equiv of NaHC03. In this effective with chiral olefins. For a given case, a way it is possible to obtain keto diols in good yields determination of the intrinsic diastereofacial selectiv- (Table 11). So far, this method has failed only ity of a chiral substrate is helpful in order to estimate with chalcone, which underwent epimerization and the likelihood of success, especially in the "mis- partial retro-aldol cleavage even under buffered matched" pairing.72 This is most easily accomplished conditions. by carrying out the osmylation in the absence of chiral ligand.70 However, this control experiment 2.2.4. Chemoselectivity in the AD of Olefins Containing SUlfUP may not be necessary for rigid cyclic olefins or for olefins bearing an allylic heteroatom as several In a recent study of the scope of the AD reaction, accounts regarding the osmylation of such species the chemoselectivity in the reaction of sulfur-contain- have been published along with analyses for the ing olefins with os04 was in~estigated.~~Kaldor and observed diastereo~election.~~A few examples of Hammond had previously shown that an OsOdN- matched and mismatched double dia~tereoselection~~ methylmorpholine N-oxide system is able to oxidize in the asymmetric dihydroxylation of chiral olefins sulfides directly to sulfones,69although competitive have been reported and are summarized in the dihydroxylation of a C-C double bond was also following paragraph^.^^!'^ observed. Interestingly, however, the catalytic AD system displays very high chemoselectivity for the In his studies on the stereoselective synthesis of double bond in the presence of sulfur-containing amino sugars, Wade investigated the asymmetric functionality, and sulfoxide- or sulfone-containing dihydroxylation of the 4,5-dihydroisoxazoles 15 and side products were not detected. Thus, it is possible 16 shown in Table 13.75 The reactions employing the to dihydroxylate allylic and homoallylic sulfides phthalazine class of ligands displayed useful levels (Table 12, entries 1-51, dithianes (entry 6, the of matched and mismatched diastereoselectivity (en- reaction does not give satisfactory results with tries 6-9). Thus, in the mismatched reactions (en- dithianes derived from 3-butenal and 3-methyl-3- tries 7 and 9), the reagent was able to strongly butenal, probably due to insufficient activation of the override the intrinsic diastereofacial bias of the olefin double bond),43band even disulfides (entry 7) to the substrate. It should be noted that these reactions corresponding diols in good yield and high enantio- use quantities of potassium osmate and ligand that meric excess. exceed the amounts in our recommended pr~cedure.~~ The finding that sulfides, disulfides, and certain Since the reaction rate with AD-mix-a (entry 7) was dithianes are unaffected under the AD conditions very slow, it seems likely that turnover is being considerably broadens the scope of this reaction, since suppressed as a result of chelation by the dihy- sulfur-containing functional groups are commonly droisoxazole at the osmate(VI1 ester stage used in organic synthesis. of the catalytic cycle. The added ligand and potas- 2498 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Table 13. Asymmetric Dihydroxylation of choice for the matched reaction (entry 4). Whereas, 4,5-Dihydroisoxazole Derivatives 15 and 16 in spite of their poor performance in the matched reactions, the pyrimidine derivatives (DHQ)zPYR and (DHQ)zPYR(OMe)3 gave the best results in the mismatched examples (entries 7 and 9). A mismatched double diastereoselective asym- metric dihydroxylation played a key role in a recently published synthesis of the polyhydroxylated indolizi- Entry Substrate Ligand Conditions AntUSyn Yield,% 1 dine alkaloid ca~tanospermine~~(Scheme 8). In the asymmetric dihydroxylation of epoxy ester 20,79Cha observed a 1O:l preference for the syn diastereomer 21 in reactions employing the (DHQ)zPHAL ligand. A complete reversal of selectivity was observed in the matched case as the anti product 22 was the major product with > 20: 1 diastereoselectivity. The major product 21 from the mismatched reaction was sub- sequently converted to (+)-castanospermine in what a 0.1 equiv of os&, 3 equiv NMO, THF/water, 9:1,20 "C. is one of the most concise syntheses of this target to 0.4 equiv of chiral aux. 3 equiv of chiral am, 1equiv 0~04, toluene, 20 "C. 0.08 equiv of KzOsO4-2Hz0, 3 equiv &Fe(CN)e, date.a1,a2 3 equiv of KzC03, 0.4 equiv of chiral aux, 1 equiv MeS02NH2, The asymmetric dihydroxylation was used to set t-BuOH&IzO, 1:1, 20 "C. e Use of AD-mix-a under recom- the stereochemistry of the final two stereocenters of mended conditions gave only 20% reaction after 22 h. an advanced intermediate used in the preparation Table 14. Asymmetric Dihydroxylation of Olefin 17 of squalestatin la3(Scheme 9). Thus, the tetrahy- drofuran derivative 23 was dihydroxylated in the presence of the DHQD-CLB ligand to provide diol 24 as a single diastereomer which was subsequently converted to the dioxabicyclo[3.2.lloctane derivative 25, a late-stage precursor to squalestatin 1. Entry Ligand (mol%) Ratio(l8: 19) Yield The asymmetric dihydroxylation of the following

1 quinuclidine (10) 2.6 : 1 85% a$-unsaturated ester derivatives has also been 2 DHQD-CLB (10) IO: 1 87% studieda4(Table 15). The reactions of 26 and 27 3 DHQ-CLB (10) 1 : 10 85% using the DHQ-CLB ligand are matched since the 4 (DHQD)z-PHAL (1j 39 : 1 84% 5 (DHQj2-PHAL (I) 1 : 1.3 52% diastereoselectivity is enhanced relative to the case 6 (DHQD)z-PYR (5) 6.9 : 1 90% without chiral ligand. Analogously, the reaction 7 (DHQIz-PYR (5) 1 : 4.1 86% between ester 28 and Os04 using the DHQD-CLB 8 (DHQD)2-PYR(OMe)3(5) 12 : 1 89% also constitutes a matched pair. One notes, however, 9 (DHQj2-PYR(OMe)3(5) 1 : 7.0 90% that in each mismatched example, the dihydroxyla- tion reagent is unable to override the intrinsic Scheme 8. Application of the AD for the Synthesis diastereofacial preference of the ester.85 It would be of (+)-Castanospermine'O interesting to see how the new phthalazine and/or HO OH pyrimidine ligands would fare in these challenging mismatched cases. The asymmetric dihydroxylation has also proven dihydroxylation-asymmetric 21 to be very useful for the synthesis of biologically EtO& 4 + active steroids having a vicinal diol in the side chain 20 N3 HO such as brassinoster~ids,~~-~~potent plant growth EtOZC regulators, ecdysteroid, an insect moulting hor- m~ne,~~as well as active metabolites of vitamin D.95 22 The AD has provided a direct method for the instal- r 1 Ligand Ratio (21 : 22 lation of the hydroxyl groups of the steroidal side chain with the correct relative and absolute configu- none 1.2 ration. This could not be accomplished in the absence (DHQM'HAL 10: 1 (+)-castanospermine of the chiral ligand. (DHQD)*PHAL

oxidized to tetrols 36 and 37 in a ratio of 1:1.6 in the

St = steroid nucleus ,,,, &j+ + ,,,,,, absence of ligandegoaKim then established that the 22 24 & 22 24 diastereomer ratio could be shifted to 3.4:l in favor St bH ' St OH ' of the natural (22R,23R) tetrol36 by performing the (22R,23R) (22S.238 "natural" "unnatural" reaction with DHQD-CLB using the NMO cooxidant system.g1 Subsequently, McMorris demonstrated (22R,23R)- and the unnatural (22$,23S)-isomers that the ratio in favor of the natural diastereomer36 while those with the (24R)-methylgroup gave a 1:l could be increased to 9: 1through use of DHQD-CLB mixture of natural and unnatural isomers. Steroidal with the ferricyanide cooxidant system and that Scheme 11. Asymmetric Dihydroxylation of A22(2s)-MethylHyodeoxycholate &/pC0&\$*;I;HO K3Fe(CN)6, Os04 "natural" ligand 31 MOMO"" * H! t-BuOWHzO + OMOM

Ligand 31 : 32

DHQD-CLB 4: 1 \' 32 2500 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Scheme 12. Asymmetric Dihydroxylation of 245 and 24R Steroidal Olefins

Os04, K,Fe(CN)6 DHOD-CLB - ,,,,,,* 33 t-BuOH/HzO St 0 22R,23R "natural" ''>,,,~ 8 : 1 diastereoselectivity ' 0~04,K3Fe(CN),j DHQD-CLB * t-BuOWH20

Hi 22R,23R OMOM "natural" 8 : 1 diastereoselectivity

Scheme 13. Asymmetric Dihydroxylation of Sa-Ergost-2,22-en-6-one

@ I - asymmetric dihydroxylation 0 Ligand 36: 37

DHQD-CLB 9 : 192 (DHQDI~PHAL io : 192

Scheme 14. Asymmetric Dihydroxylation for Structure Elucidation of Gerardiasteronene

OH

HO

HO 0 38 HO dihydroxylationasymmetric& HP HO OH

0 HO HI OH HO 0 39

1 Conditions Yield 38: 39 1 Os04,pyridine 85% 76 : 24 Os04, DHQ-CLB 80% 91 : 9 Os04,DHQD-CLB 87% 13 : 87 Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2501 Scheme 16. Asymmetric Dihydroxylation of the (24S)-diol40 as the major product of a 94:6 dia- Desmosterol Benzoate stereomer mixture while the reaction with (DHQD)z- PHAL provided the (24RI-diol 41 as the major product of a 955 mixture. The (24R)-diol is a potential precursor for the synthesis of (2422)-24,25- (DHQ)zPHAL dihydroxyvitamin D3.95a Lanosterol acetate bears an /--%/ isopropylidene side chain like that in desmosterol I 40 benzoate and has been found to give the same high 94 : 6 diastereoselecrivi!y diastereoselectivity in both the matched and mis- matched cases (24R:24S = 50:l and 1:23) with AD- mix-D and AD-mix-a, respectively.95b One of the more intriguing examples of double diastereoselection with the asymmetric dihydroxy- lation is shown below:97

K2C03 F’h K3Fe(CN)6 &H ;;);h b ’BU replacing DHQD-CLB with (DHQDIzPHAL gave an 42 ‘BuOH-H~O additional slight increase in the ratio (1O:l) favoring quinuclidine the natural diastereomer 36.92 Ph In another application in the steroid area, Honda OH utilized a matched double diastereoselective asym- ‘Bu + ‘Bu metric dihydroxylation to prove the absolute stereo- H structure of the C(19) side chain of the ecdysteroid, + enantiomers gerardiasterone (Scheme 14). Thus, experiments 1 :6 diastereofacialpreference performed in the absence of a chiral ligand revealed the anti,syn diastereomer 38 to be intrinsically favored. The matched reaction with DHQ-CLB en- In these experiments, the osmium-catalyzed dihy- hanced the selectivity to 91:9.93 The major diaste- droxylation in the absence of a chiral ligand displayed reomer 38 was found to be identical to gerardiaster- a 6:l preference for equatorial dihydroxylation. In one thus establishing the structure of the natural the double diastereoselective reactions of the enan- product. A good level of mismatched double diaste- tiomerically pure olefins, the levels of diastereose- reoselection was also observed as the all syn diaste- lectivity in both the matched and mismatched reac- reomer 39 was found to be the major product of an tions employing the (DHQDlzPHAL and (DHQ)zPHAL 87:13 mixture with DHQD-CLB as the ligand.94 ligands were equal in magnitude and opposite in As a final example in the steroid area, Ikekawa has directiong8(Scheme 16). investigated the asymmetric dihydroxylation of des- To date there have been several additional applica- mosterol benzoate as a means of preparing an tions of the asymmetric dihydroxylation reaction in intermediate useful for the preparation of (24R)- the double diastereoselective manifold. Among the 24,25-dihydroxyvitamin D3,95 a compound effective reported examples are the preparation of intermedi- for the treatment of osteoporosisg6 (Scheme 15). ates for the synthesis of the immunosuppressant FK- Thus, the asymmetric dihydroxylation of desmosterol 506,74athe preparation of intermediates in the syn- benzoate using (DHQ)zPHAL as chiral ligand gave theses of mycalamide B,99 insect juvenile hormone Scheme 16. Double Diastereoselection in the AD of 4-tert-Butylbenzylidenecyclohexane

HYOHPh , HOiHph,

tguHoH HOslBu AD-mix-a 78% yield matched i matched Ph

‘BU dH 98% e.e. 98% e.e.

AD-mix-p AD-mix-a 67% yield\ /60% yield mismatched mismatched ‘BU H H

[31:lds) [ 35:lds) 2502 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Scheme 17. Kinetic Resolution of C76 by Scheme 19. Kinetic Resolution of Olefin 42 via Asymmetric Dihydroxylation Asymmetric Dihydroxylation CPh

AD-mix-a H

-30%conversion I 20:+Q ‘Bu 4 : I selecriviry for , ‘Bu axial dihydroxylation lBu bisepoxide,loOand the preparation of modified pyri- 42 olefin enriched in midine nucleobases.lo1 (aR)-enantiomer 2.3.2. Kinetic Resolution Several applications of the asymmetric dihydroxy- lation for the kinetic resolution of chiral racemic olefins have appeared. In spite of the fact that the AD generally gives higher enantioselectivities than the AE, the asymmetric dihydroxylation has not olefin enriched in achieved the high levels of kinetic resolution ef- (as)-enantiomer ficiency observed with the asymmetric epoxidation The major dihydroxylation product in each case arises from preferential axial (AE).lo2J03 The generally superior chiral discrimina- I dihvdroxvlation: a result omosite to that observed in the absence of the chiral limnd! I tion for the AD over the AE and the known effective- ness of the AE in kinetic resolution applications lead one to expect that the AD will exhibit excellent two of the 30 double bond types were pyramidalized kinetic resolution discrimination when presented to a greater extent (i.e. possessed greater curvature) with a racemic chiral olefin. To date, however, with than all the others. Osmylation occurred preferen- a few notable exceptions, the AD has generally tially at one of these two sites thus making the proven to be ineffective for kinetic resolutions. resolution p0ssib1e.l~~ At present, we have no explanation for this differ- The Sharpless group has also investigated the ence between the AE and AD. Nevertheless, the kinetic resolution of racemic olefins with an axial coordination of the alkoxy group of the allylic alcohol chirality element. In these experiments, it was found to titanium in the AE greatly limits the possible that the resolution proceeded by dihydroxylation transition state geometries for the AE. The absence through an unexpected manifold.97 For example, of such a “restricting tether” in the AD process would when the dihydroxylation of olefins 42 and 43 was seem to be implicated in the unusually small rate performed in the absence of a chiral ligand, it was differences seen between enantiomers in the later found in each case that equatorial dihydroxylation process. was favored for each substrate (Scheme 18). In what is to date the most interesting demonstra- In the kinetic resolution experiments, however, it tion of kinetic resolution using the AD, Hawkins has was found that the fastest forming diol in each case resolved the enantiomers of c76, thus preparing the was that arising from axial dihydroxylation (Scheme first known example of an enantiomerically pure 19). Since the resolution itself is a double asym- allotrope of an elementlo4(Scheme 17). An obvious metric process, the dihydroxylation that makes the potential problem facing the use of the AD in a resolution possible is a mismatched double asym- resolution of c76 is that the molecule contains 30 metric reacti~n.~~~J~~The results of these experi- different types of double bonds, each of which is ments are summarized in Table 16. capable of dihydroxylation, thus raising the specter In addition to those mentioned above, several of enantiomeric discriminations that could oppose one additional olefin classes were investigated as poten- another. It was noted from ab initio calculations that tial substrates for kinetic resolution experiments. Scheme 18. Intrinsic Diastereoselection in the Dihydroxylation of Exocyclic Olefins 42 and 43

42 H quinuclidine + enantiomers I 1 : 6 diastereofacial preference I

43 ‘BuOH-Hzb H quinuclidine + enantiomers

I 1 : 1.2 diastereofacialpreference I Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2503 Table 16. Summary of Kinetic Resolution lution applications with studies on racemic allylic Experiments with Exocyclic Olefins 42 and 43 acetates. Several reaction variables including sub- Recovered strate to catalyst ratio, reaction temperature, and ole- Olefin Ligand kr,i Olefin fin substitution patterns were systematically inves- tigated. Each of the reactions was carried out using the bis(dihydroquinidiny1) terephthalate (DHQD)2- (DHQ)2PHAL 5.0 (aR) TP as the chiral ligand. Best results were obtained (DHQD)*PHAL 9.1 (as) with l-acetoxy-l-cyclohexyl-3-phenyl-2-propene(e.g. 1-Bu t-Bu 1-BU 42 entries 4 and 5).ll1 These data are summarized in Table 18.'12

C02Et Recently, a comparative study of the relative ef- ficiency of the (DHQD)zPHAL, (DHQD)zTP, and (DHQ)2PHAL 26.5 (aR) DHQD-CLB ligands for the kinetic resolution of (DHQD)*PHAL 32.0 (as) l-acetoxy-l-cyclohexyl-3-phenyl-2-propenewas re- t-Bu 43 ported.33 Each of the resolutions was carried out to 4 -60% conversion. This is most conveniently ac- complished by simply limiting the amount of cooxi- Table 17. Relative Rate Data from Kinetic Resolution dant and running the reaction until there is no Fe(1II) Experiments with 3-Substituted Cyclohexenol present in the reaction mixture.l13 The enantiomeric Derivatives excesses were then determined by chiral HPLC and the relative rates calculated using the Kagan equa- (DHQD)*PHAL tion.logJl0 These data are presented in Table 19. + dihydroxylation kinetic resolution Ph products In summary, the performance of the AD reaction Ph +& recovered in kinetic resolution applications is generally poor. olefin This is surprising given the high levels of enantio- facial selectivity observed with prochiral olefins. At present we do not have an explanation for the poor performance of the AD in kinetic resolutions, and it !: appears unlikely that the AD will ever approach the TBDMS 25.5 1 effectiveness of the AE in kinetic resolution applica- tion~.~~~On the other hand, the scope of the AD is , enormous compared to that for the AE, which works These investigations focused exclusively on allylic only for allylic alcohols. Therefore, one can imagine alcohol derivatives and the following trends emerged that the kinetic resolution version of the AD will often from these experiments. First, racemic acyclic allylic prove useful as a fast route to a chiral olefin and/or alcohols and their protected derivatives were gener- for establishing absolute configurations. ally poor substrates for kinetic resolution via the asymmetric dihydroxylation. Second, variously sub- stituted cyclopentenols and cyclohexenols were in- 2.4. Asymmetric Dihydroxylation of vestigated with the latter showing greater rate Polyunsaturated Substrates differences (i.e. higher Kfllz, ratios). Third, within the cyclohexenol substrate class, 3-substituted deriva- Polyunsaturated olefins have considerable syn- tives were superior to 2-substituted derivatives with thetic potential, since they are highly functionalized phenyl being the optimal substituent for the 3-posi- compounds and each sp2 center may in principle be tion.107J08J09For example, the kinetic resolution of prochiral. Thus, the face-selective manipulation of the TBDMS ether of 3-phenyl-2-cyclohexen-1-01was the double bonds in these substrates yields valuable allowed to proceed to 15%conversion using (DHQD)2- chiral building blocks. The AD reaction has several PHAL as chiral ligand. Analysis of the recovered virtues which make it especially useful for this kind of strategy, the most important being exquisite selectivity coupled with great reliability. Thus, the AD stereospecifically adds two hydroxyl groups in Ph suprafacial fashion across each double bond and the Ph 16% ee enuntiofucial selectivity of the initial dihydroxylation krlk, = 25.5 step can be confidently predicted based on the starting material revealed the R-isomer to be present mnemonic device (see section 1). The diastereofucial in 16% enantiomeric excess thus giving a kf/k, for selectivity of the subsequent dihydroxylation steps the resolution process of 25.5.109J10Shown in Table may also be controlled by the choice of the appropri- 17 are kinetic resolution data obtained from a series ate ligand. The reaction can be directed to effect of experiments utilizing 3-phenyl-substituted cyclo- either poly-dihydroxylation or regioselective mono- hexenol derivatives as substrates where kf/k, is the dihydroxylation of polyenes, leading to valuable poly- ratio of rate constants for the dihydroxylation of each 01s or ene diols, respectively. Most importantly, the of the enantiomers. regioselectivity of the dihydroxylation of unsym- Lohray has also investigated the utility of the metrical polyenes can generally be predicted based asymmetric dihydroxylation reaction in kinetic reso- on a simple set of rules (vide infra). 2504 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. Table 18. Kinetic Resolution of sec-Allylic Acetates via AD with (DHQD)zTP C02DHQD

K3Fe(CN)6, K2C03 t-BuOH:HZO (1:l) Ho oAc

OH

Entry R1 R2 Substrate/ Conversion %ee (Config.) S Catalyst (S) of recovered (kfk,)

1 Me C-C~HI~ 100 60 6.1 2 250 83 12.0 3 500 15 9.5 4 Ph C-C~HI~ 500 60 24.5 5 100 70 25.0 6 Ph Me 500 40 6.4 1 500 80 1.6 8 500 90 8.8 9 Me n-CgH17 250 70 6.8 10 250 88 9.1 11 Ph Ph 250 70 4.8 12 250 92 3.0

Table 19. Kinetic Resolution of Scheme 20. Diastereoselective 1-Acetoxy-1-cyclohexyl-3-phenyl-2-propene Bis-dihydroxylation of Conjugated Dieneslls

Ligand 0~01,NMO, .., .., ph Hz0,Acetone F]Ph- (DHQD)zPHAL (DHQDhTP 70% HO OH DHQD-CLB 81% phvPh+ ph*Ph 2.4.1. Formation of Polyols from Conjugated and HO OH HO OH Nonconjugafed Polyenes 1,2-syn-2,3-anti-3,4-syn1,2-syn-2,3-syn-3,4-syn The exhaustive dihydroxylation of polyenes can be No ligand present: 16 1 performed either in a single step by employing the DHQD-CLB present: 6 1 homogeneous N-methylmorpholine N-oxide (NMO) Further experiments, not shown in Table 20a, process115 or stepwise by carrying out sequential revealed that, in the absence of ligand, stoichiometric mono-dihydroxylations using the heterogeneous fer- osmium tetraoxide reacts much faster with the par- ricyanide condition^.^^ ent diene than with the ene diol intermediate, which Treatment of conjugated dienes or trienes with is consonant with the fact that the ferricyanide AD catalytic amounts of os04 in the presence of NMO process stops at the ene diol stage. Hence, the culprit as the stoichiometric reoxidant results in almost in these exhausitve dihydroxylations of conjugated exclusive formation of tetrols and hexols, respec- polyenes appears to be the trioxoosmium(VII1) gly- tively, as shown for a diene case in Scheme 20. colate complexes which are present in the NMO The poly-dihydroxylation in the NMO reaction, as system, but not the ferricyanide or the stoichiometric opposed to the single dihydroxylation in the ferri- Os04 systems. Our current hypothesis is that the cyanide system,116ais thought to result from the trioxoosmium(VII1) glycolate can attain favorable, participation of the second catalytic cycle oxidant, the transition state hydrogen bonding interactions be- trioxoosmium(VII1)glycolate (Scheme 2). Extensive tween its oxo ligand(s) and the ene diol hydroxyls, control experiments established that the 1,2-dihy- interactions which either do not exist or are less droxy 3-ene class of ene diols is uniquely reactive favorable with free 0~04.~~~~These interactions toward further oxidation in the NMO-based catalytic cannot occur if the two hydroxyl groups of the ene osmylation system, thus explaining the propensity diol are protected, leading to lower reaction rates for for exhaustive dihydroxylation116b(cf. relative rates these substrates (Table 20a, compare entry 5 with for entries 1 and 5, Table 20a). entries 6 and 7). This hypothesis of stabilizing Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2505 Table 20 too weak to overcome the strong anti diastereoselec- a. Relative Rates of Reaction in NMO-Based tivity exhibited by the trioxoosmium(VII1) glycolate Catalytic Osmylations (no ligand present)116b oxidant with ene diols and merely results in reduced Encry Substrate Relative Rate 2,3-antito 2,3-synratios in the presence of the chiral ligand (DHQD-CLB, Scheme 20). 1 Ph-Ph 1.o Since the unselective second cycle is avoided under the heterogeneous ferricyanide ~onditions,~~~~J~~it is Ph Ph 4.0 possible to obtain satisfactory enantio- and diaste- reoselectivities by performing a stepwise poly-dihy- dr~xylation.~~The diol obtained from a mono- PhAPh 5.2 dihydroxylation can then be used as a stereochemical template for exhaustive dihydroxylation (i.e. a “zip- dihydroxylation”) of the remaining double bonds Ph-Ph 6.0 using the NMO oxidant system. Each successive OH dihydroxylation event will occur from the olefin diastereoface that is anti to its nearest hydroxyl 5 ph&ph 9.2 neighbor. The great anti diastereoselectivity for dihydroxylation of ene diols in the NMO system is OH unique and should be synthetically useful.116d Alternatively, a polyene can be exhaustively dihy- 6 ph&Ph 0.4 droxylated by performing one AD reaction at a time OMe and protecting the intermediate diols as, for example, acetonides. This procedure enables better control of the diastereofacial selectivity of the subsequent di- PhdJgph 0.3 hydroxylation steps as well as simplifying the isola- tion of the final product. 2.4.1.1. Asymmetric Dihydroxylation of Divi- b. Diastereoselective Formation of Polyols nyl Ketals. A stepwise dihydroxylation strategy has (no ligand present)l15 been employed in the enantio- and diastereoselective Ratio preparation of protected keto tetrols 45 and 46 ?ntry Substrate Major Product (2,3-anti/2,3-syn) % Yield derived from diene ketals 44118 (Scheme 21 and Table HO OH 1 ph-ph Ph+Ph 16: 1 87 Scheme 21. Enantio- and Diastereoselective HO OH Exhaustive Dihydroxylation of Divinyl Ketals118 OH i. AD-mix+ 2 % HO+OH 5:1 80 1 eq. MeS02NH2, HO

nmRono 31:l eq. ‘BuOH/H~O. KSFe(CN)6,OT,3 eq. K2C03. ~ Rffk 3 qz/ 1O:l 72 ea ii. acetone, 2,2-dimethoxypropane HO OH pTSA i. AD-mix-p, 1:1 ‘BuOWH~O. 4- % 2:1 95 0°C.MeS02NH2 HO OH ii. acetone, pTSA HO HO OH 5 ph-Ph phwPh 7:4: 1‘ 95 HO HO OH

+ Ratio (2,3-anti-4,5anti)l(2,3-anti-4,5-syn)/(2,3-syn-4,5-syn). All product polyols are racemic. AD-mix-a [(DHQ)2PHAL] 4.0 1 .o hydrogen-bonding interactions accounts for the ten- AD-miX-p [(DHQD)zPHAL] 1 .O 3.5 dency for each new dihydroxylation event to occur adjacent to the previous site of attack, and from the 21). As discussed in the previous section, dihydroxy- opposite face, leading to 1,2-syn-2,3anti-3,4-syntetrols lations employing the ferricyanide oxidant system and 1,2-syn-2,3-anti-3,4-syn-4,5-unti-5,6-synhexols stop at the ene diol stage, presumably due to elec- (Table 20b) with conjugated dienes and trienes, tronic deactivation of the remaining olefin. respectively. Unfortunately, the selectivity drops Ketal-protected divinyl ketones 44 are readily considerably when the starting material has four or available from the corresponding saturated ketones more double bonds, not a surprising outcome given by ketalization followed by a,a’-dibromination and the increasing opportunities for nonadjacent oxida- bis-dehydrobr~mination.’~~Treatment with 1 equiv tion in extended conjugated polyenes. of AD-mix results in selective mono-dihydroxylation It should be noted that the intrinsic diastereofacial with high enantioselectivity in most cases (Table 21). preference described above mismatches the selectiv- One of the strong points of this reaction sequence ity imposed on the system by a cinchona ligand, since is that it not only provides control over the absolute the ligand-mediated reaction would require attack of configuration (in the first AD reaction), but also over the two double bonds of a trans,trans diene from the the relative stereochemistry (in the second dihy- same face. However, the induction by the ligand is droxylation reaction). Thus, depending on the choice 2506 Chemical Reviews, 1994,Vol. 94, No. 8 Kolb et al. Table 21. The Mono-dihydroxylation of Protected Table 22. Mono-dihydroxylation of Symmetrical Divinyl Ketones1lB9t Conjugated Dienes"& %ee with %ee with ( Entry Substrate Product 9c yield % ee Substrate 1 :nny (DHQD1zPHAL (DHQDIzPYR

1 ph-Ph phvph 84 99 1- 00A 93 12 * HO OH - 2- + 78 93

94 93 -. . 3 HO!HO A + 4 . OH OH 2 : 1 OH material over the ene-diol product is most likely due to the electron-withdrawing, and therefore deactivat- t The AD reactions were performed under standard condi- ing properties of the two OH groups of the latter. In tions in t-BuOWH20 employing 1equiv of AD-mixand 1equiv the NMO system, the favorable H-bonding effects of MeS02NH2. (No MeSOzNHz was used in entry 2.) provided by these same OH groups to the trioxoos- Scheme 22. Exhaustive Dihydroxylation of mium(VII1) glycolate oxidant are thought to over- Squalenes1 whelm their inherent electronic deactivating effects. Polyenes with isolated double bonds may also be mono-dihydro~ylated,~~~J~~~J~~J~~-~~~but the yields tend to be lower if the double bonds are electronically and sterically very similar, no doubt a result of competitive poly-dihydroxylation. i. 3 x AD mix-p, followed by acetonide 2.4.2.1. Regioselectivity. The regioselectivity of formation and recrystallization the mono-dihydroxylation of a polyene is determined ii. acetonide hydrolysis both by electronic and by steric effects. Recently, it was shown that the rate constants of the dihydroxy- lation of isolated double bonds are much larger with trum-1,2-disubstituted and trisubstituted olefins than with cis-1,2-disubstituted and terminal alkenes.125 Similar trends are also observed with polyenes, and Yield: 78% the factors governing the regioselectivity are dis- enantiomeric purity -100% diasteremeric punty -1 00% cussed in more detail in the following paragraphs. Electronic factors greatly influence the regioselec- tivity, and the osmylation of unsymmetrical polyenes of the ligand, either diastereomer 45 [with (DHQk- preferentially occurs at the more electron-rich double PHALI or diastereomer 46 [with (DHQDIzPHALl bond. This is true for conjugated polyenes (Table 23) may be obtained as the main product. as well as substrates with isolated double bonds The stepwise poly-dihydroxylation strategy has (Table 24). been taken to the extreme with the enantio- and Steric effects may play a decisive role in systems diastereoselective, exhaustive dihydroxylation of with electronically very similar double bonds, and squalene51 (Scheme 22). The dodecaol was obtained generally the sterically most accessible site is osmy- as essentially a pure enantiomer of a single diaste- lated preferentially (Table 25). reomer in 78% yield. The osmylation of methyl farnesoate 47 (Table 25, The high overall yield and stereoisomeric purity entry 4) proceeded with the highest preference for requires that each of the six dihydroxylation events, the l0,ll-double bond when carried out in the pres- of which the first one is enantioselective and the ence of (DHQDhPHAL, affording the 10,ll- and 6,7- remaining ones are diastereoselective, occurs with at diols in a 20:l ratiolzl [9:1 in the presence of least 96% ee or de, respectively, and an average (DHQ)zPHAL]. In contrast, only a 3:l selectivity was chemical yield of 98%. obtained in the absence of the ligand. The higher 2.4.2. Selective Mono-dihydroxylation of Polyenes sensitivity of the Os04 ligand system for steric effects may be due to the greater steric demand of a As mentioned earlier, under the heterogeneous transition state complex involving both Os04 and ferricyanide conditions, the asymmetric dihydroxy- ligand. A similar enhancement of the positional lation may be controlled to selectively produce ene selectivity by the ligand has been noticed in the diols from conjugated p~lyenesll~*J~~(Tables 22 and mono-dihydroxylation of squalenelzO(Scheme 23). In 23), since the second cycle, trioxoosmium(VII1) gly- the absence of a ligand, a 1:l:l mixture of the three colate oxidants are never produced in this system. regioisomeric diols 48,49, and 50, along with polyols, The latter oxidants cause the rapid perhydroxylation was obtained. However, a slight preference for the of conjugated polyenes which is an unavoidable less hindered double bonds was observed when the feature of the NMO-based system (vide supra). In reaction was carried out in the presence of 5 mol % the ferricyanide system, which involves free oso4, of (DHQD)zPHAL, affording the diols 48,49, and 50 the preferential osmylation of the polyene starting in a 2.4:l.B:l.O ratio. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2507 Table 23. Regioselective Mono-dihydroxylation of Table 25. The Influence of Steric Effects on the Conjugated Dienes and Trie~tes~~~~J~~J Regioselectivityt

Entry Substrate Products Ratio %e@ % yiell

2 82

36 5:1 92 80 22 1 94 OH

HoWCOzMe20 98 UCOzMe1 40

OH

The AD reactions were performed under standard condi- tion~~~~using (DHQD)zPHAL and 0.2-1.0 mol % of 0~01.a % ee of the major product. See ref 117. See ref 121.

The AD reactions were performed under standard condi- tion~~~~using (DHQDlzPHAL and 0.2-1.0 mol % of 0~04.

Table 24. Regioselective Mono-dihydroxylation of 1 mol% OsO4,5 mol% (DHQD)2PHAL, Dienes with Isolated Double Bondst 32 % yield 3 q.K3Fe(CN)6,3 e¶. K2CO3, 1 eq. MeS02NH2, 1:l BuOWH20, Entry Substrate Products Ratio O/o ee %yield 0°C. 24 h

98 I3

98 70

3b \ / HO- 94c 77 HO

97 94

the presence of the PHAL and PYR ligands. The cis- 13 94 double bond(s) of a czs,truns-polyene will not be attacked to an appreciable extent during asymmetric ,A+-./ OH 56 54 + dihydroxylation of the trans-double bond(s) with : OH 1 these 1igand~ll~"J~~(Table 26). OH Another selectivity-determining factor is the pres- 74 ervation of conjugation in trienes and in dienes which 42 are conjugated with aromatic groups. The examples in Table 27 (entries 1 and 2) demonstrate that generally one of the terminal double bonds of a conjugated system is attacked in order to maintain The AD reactions were performed under standard condi- a maximum degree of c~njugation.'~'This effect is tion~~~~using (DHQDIzPHAL and 0.2-1.0 mol % Of 0504. a See probably also partially responsible for the selective ref 116a. See ref 122. % de. See ref 126. attack of the double bond farthest away from the The geometry of the double bond also has an carbonyl group of the polyunsaturated carbonyl important influence on its reactivity toward Os04 in compounds in Table 23 (entries 4, 5, and 6). 2508 Chemical Reviews, 1994,Vol. 94, No. 8 Kolb et al. Table 26. Selective Mono-dihydroxylation of nylnaphthalene has a five times larger saturation cis,trans-Dienes and Trienes? rate constant than styrene in the presence of Entry Substrate Products Ratio % ee %yield (DHQD)zPHAL.~~ 2.4.3.Asymmetric Dihydroxylation of Cyclic Polyenes & 15 98 2.4.3.1. Small Ring Dienes. Recently, the asym- metric dihydroxylation of cyclic dienes was investi- gated,117J27since the products may provide useful synthetic building blocks and precursors for a num- ber of biologically active compounds, such as sugar analogs, inositols, conduritols, etc. Unfortunately, most cyclopentadienes and other 6- to 8-membered ring dienes are poor substrates for the AD reaction, probably a result of the cis geometry of the double bonds (Table 28). As shown in Tables 28 and 29, the phthalazine ligand gives the best results with most The AD reactions were performed under standard condi- substrates, and the enantiomeric excesses of the tion~~~~using (DHQD)2PHAL and 0.2-1.0 mol % of 0904. a See products are normally between 30 and 60% ee. ref 116a. See ref 117. Certain substituents lead to improved selectivities, and aromatic groups have an especially beneficial Table 27. The Selective Mono-dihydroxylation of influence. Thus, an almost enantiomerically pure Highly Conjugated Systems1l7?+ ene diol was obtained in the AD of phenylcyclopen- tadiene (Table 28, entry 3). Entry Substrate Products Ratio % ee %yield 1 Interestingly, the asymmetric dihydroxylation of benzylidene-protectedcis-cyclohexa-3,5-diene-1,2-diol (54)(Table 28, entry 13) proceeds in a highly enan- tioselective manner, providing the exo-diols 55 and ent-55 (both in about 85% ee) with AD-mix-a and AD- mix$, respectively. The improved enantiomeric excess compared to that of 1,3-cyclohexadiene(Table 28, entry 10) may be due to the increased steric bulk on one side of the cis-double bond thereby resulting in better enantioselection. Ene diol 55 is the penul- 68 timate intermediate in a recent synthesis of condu- ritol (Scheme 24), and simple recrystallization from CC14-CH2C12 raises its enantiopurity to ’99% ee. It is important to note that all of the configura- &4 98 tional assignments in this reference128are reversed due to a comparison with an incorrect literature 87 assignment. The authors have corrected their assignment,12sband they now agree with the outcome predicted by the AD mnemonic device. In fact, it was our inability to fit their results to the mnemonic + The AD reactions were performed under standard condi- which led us to question their original assignments. tions23a using (DHQDIzPHAL and 0.2-1.0 mol % of 0~04. Scheme 24. Asymmetric Synthesis of Conduritol E128 Interestingly, however, 1-(2-naphthyl)penta-l,3- AD-mix-P diene (53)reacts mainly at its internal double bond )asowPh QaLB’O ““0 in the presence of the phthalazine ligand (Table 27, - HO entry 3), leading to disruption of conjugation. In OH 55 contrast, the phenyl analog 51 (entry 2) reacts in a recryst. 85% ee ->99% ee “normal” fashion to give mainly ene diol 52, thereby AD-mix-a 85% yield maintaining a maximum degree of conjugation. The preference for the internal double bond in the naph- n,o+,n20 thalene system may be due to especially favorable I stacking interactions between the naphthyl group ,+o ),,,,Ph and the binding pocket of the phthalazine ligand26p27 Ho6<#,,oHOgCHH (cf. section 1, Figure 3). Molecular mechanics simu- ent-55 lations indicate that such stacking is not as feasible recryst. OH 87% ee ->99% ee (+)-condunto1 E in the transition state involving the external double 81% yield bond. Apparently, a phenyl group does not provide enough “binding energy” to compensate the energy 2.4.3.2. Asymmetric Dihydroxylation of Mid- loss caused by interruption of conjugation and/or the sized and Large-Ring Polyenes. As expected, conjugation is worth less in the naphthyl case. This even if they are tied into a ring, trans double bonds finding parallels the earlier observation that 2-vi- are dihydroxylated with considerably higher enan- Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2509 Table 28. Asymmetric Dihydroxylation of 6- and 6-Membered Ring Dienes and Trienes?

Product (DHQD)zPHAL (DHQD)*PYR DHQD-IND 2ntry Substrate 8ee bee %ee 1" 0 38 (37)

56 (14) '" OMe

99 (50) 3a OPh

4" 9 53 (38)

70 (7 1)

6" 80 (60)

%Hi5

83 (58) 61 (61)

30 (50)

47 (80) 9a p C02Me 10" 0 37 (97) 23 (88) 24 (82)

11" OPh 91 (42) 10 (57)

31 (84)

85 (85)

+ The numbers in parentheses are isolated yields. The absolute configurations were assigned tentatively based on the mnemonic device. The AD reaction was carried out at 0 "C in the presence of 5 mol % of the ligand and 1equiv of MeSOzNHZ. a See ref 127. The dihydroxylation was carried out at 0 "C with AD-mix$ in the presence of 1 equiv of MeSOzNHZ, and it occurred from the sterically less hindered face and anti to the adjacent oxygen substituent (cf. Scheme 24). The product was isolated as the diacetate; subsequent LiAlH4 reduction and recrystallization gave the optically pure diol in an overall yield between 55 and 65%; see ref 128. The absolute configuration of entries 10, 12, and 13 have been established, the rest are tentatively assigned based on the mnemonic device. tioselectivities than cis double bonds. A recent reactivity than do double bonds. Consequently, the study117has revealed that the pyrimidines 2 are the asymmetric dihydroxylation of enynes occurs exclu- ligands of choice, and the results are summarized in sively at the double bond, affording yne diols in Table 30. excellent yields. However, since triple bonds are The remaining double bonds can be dihydroxylated among the sterically least demanding functional in a highly diastereoselective fashion117(Table 3 1), groups, the enantioselectivities obtained with enynes and the intrinsic diastereofacial preference (cf. data (Table 32) are generally lower than with the cor- obtained with quinuclidine) can either be enhanced responding saturated olefins. AS expected, trans- [matched pair, (DHQ)zPYRl 01 ~h-"t completely olefins give enantioselectivities in the 90% ee range, reversed [mismatched pair, (DHQD)zPYRl depending while cis-olefins are much poorer substrates. The on the choice of ligand. The pyrimidines 2 are again results in Table 32 demonstrate that the the optimal ligands for this application. phthalazines are the ligands of choice for this class 2.4.4. Asymmetric Dihydroxylation of Enyne~'~~ of substrates. Although it is possible for Os04 to oxidize triple This methodology has been employed in the syn- bonds to 1,2-diketone~,~~J~~they have a much lower thesis of optically active furfuryl alcohols and hy- 2510 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Table 29. Asymmetric Dihydroxylation of 7- and Table 31. Influence of the Ligand on the 8-Membered Ring Dienes and Trienesla7" Diastereofacial Selectivity of the Second Dihydroxylation117J (DHQDhPHAL (DHQD)zPYR DHQD-IND Entry Substrate Product ~____ B ee W ee % ee Ligand Entry Substrate Products Quinuclidine (DHQ)2PYR (DHQD)zPYF "n 99.7 25 2 oph~~~ph 41 (46)

0.3 75

__._.- ...... - .. - . 4 0 5 (7-9) 99 11 'The numbers in parentheses are isolated yields. The absolute configurations were assigned tentatively based on the mnemonic device. The AD reaction was carried out at 0 "C in the presence of 5 mol % of the ligand and 1 equiv of MeSOzNH2. 1 89 Table 30. Asymmetric Dihydroxylation of Cyclic P01yenesl'~~t _...... _._. .- .- . - . (DHQD)*PYR (DHQD)zPHAL Entry Substrate Product 99 4.5 %. PP %. PP

la-94 51 3 QJ0/

HO 1 95.5

The dihydroxylation reactions were performed under the ferricyanide conditions using 1 mol % of quinuclidine, 1 mol % of (DHQlzPYR, and 5 mol % of (DHQDkPYR, respectively. The diol in entry 2 is protected as the acetonide, and in entry 3 as the carbonate.

Table 32. Asymmetric Dihydroxylation of Enynesla8J Ligand Entry Substrate 'yields DHQD-PHN (DHQD)*PHAL % ee Z ee 1 Ph-. 91 53 13

t The reactions were carried out in the presence of 1mol % 2 'C6Hll-*\ 67 44 I2 of Os01 and 1 mol % of the ligand. The ee was determined at low conversion. 3 "C6H13-N 76 38 54

4 Ph-4 91 48 19 droxybuten01ides.l~~Thus, hydromagnesiation of yne-diol56 gives the corresponding Grignard reagent 5 Ph=< 98 73 57 in good yield. Furfuryl alcohols 58 are formed upon acylation of the organometallic reagent with a nitrile and subsequent acid-mediated hydrolysis, resulting in cyclization and aromatization (Scheme 25, path A). Hydroxybutenolide 59 is accessible in a sequence involving carboxylation of the Grignard reagent with COZ,followed by hydrolysis (path B).

2.5. Influence of Acidic Hydrogens in the Substrate on Rates, Chemoselectivity, and

Stereoselectivity + The reactions were performed in 1:l t-BuOHIHzO at 0 "C in the presence of 0.2 mol % of Os04 and 1mol % of the ligand using &Fe(CN)G as the reoxidant. a Isolated yield of yne diol Several groups have reported the ability of certain from the AD with DHQD-PHN. The reaction was performed functional groups to affect the stereoselectivity of the on a mixture of geometric isomers of 1-phenyl-3-hexen-1-ye osmium-mediated dihydroxylation process.132 Sul- (cisltrans 25:75). Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2511 Scheme 26. Synthesis of Optically Active Furfuryl Table 33. Os04-Catalyzed Dihydroxylation of Alcohols and Butenolides from Enynes131 Geraniol and Derivatives HO Os04

+x +x + HO ..:

6H OH (6,7-&01) (2.3-diol)

57 OMgBr

i. 41.t.. eq. 2 R'CN,h ,".A Patl~~~,~$~~~

ii. 0.5 M HCI. 0°C 4 NHMs B 67 : 33 NHTs B 60 : 40 Me3Si 6 NHNs B 60 : 40

R' hCSH13 aMs = methanesulfonyl, Ts = p-toluenesulfonyl, Ns = 58 OH 59 OH p-nitrobenzenesulfonyl. * Conditions: (A) 5% oso4,3 equiv of R' = CZHS: 67 9O yield, 95 %ee 85 9% yield &Fe(CN)e, 1 equiv of MeSOgNHZ, 3 equiv KzCO3, 1:l (v/v) ph: 73 9O yield, 96 %ee t-BuOWHzO, RT; (B) 1 equiv of 0~04,PhMe, RT. Scheme 26. Hydroxyl-Directed Osmylations acidic hydrogen atoms (e.g., OH, NHTs, NHMs, NHTf), particularly when they occupy the allylic position, can influence the regio- and stereochemical course of the osmium-mediated dihydroxylation as well as exert significant rate enhancements when compared to electronically similar substrates. 1 86 : 14 diasrereoselecrivity I 2.5.1. influence on Regioselectivity To probe the effect exerted by allylic hydroxyl groups and other functional groups with acidic hy- drogens on the regioselectivity of the osmium-medi- pyridine ated dihydroxylation, a series of experiments were performed with geraniol derivatives141 (Table 33). 61 Under both stoichiometric and catalytic conditions, dihydroxylation of geraniol gives an 80:20 mixture favoring the 1,6,7-triol. Dihydroxylation of the cor- responding methyl ether and acetate derivatives resulted in almost exclusive oxidation at the remote TMSO"" double bond. On the basis of the electron-withdraw- ing effect of the allylic substituents, a preference for dihydroxylation at the remote double bond was [-I [-I anticipated. However, the increased propensity for f~xides,'~~s~lfoximines,~~~ nitro groups,135 as well as dihydroxylation of the proximal double bond in un- carbamates and acetates,136have been implicated in derivatized geraniol suggests an attractive interac- directing the stereochemical course of the dihydroxy- tion between the hydroxyl group and OSOS(possibly 1ati0n.l~~In contrast, functional groups with acidic a hydrogen bond) which partially offsets the elec- hydrogens have received little notice regarding their tronic deacti~ati0n.l~~Even higher selectivity was directing effects on the osmylation event. We are observed for oxidation of the proximal double bond aware of two citations for possible hydroxyl-directed of sulfonamido derivatives of geranylamine, this in dihydroxylati~ns.~~~J~~There are no doubt other spite of both more unfavorable electronic and steric examples which we have missed, but the main point influences for the sulfonamido substituents vis-a-vis is that the hydroxyl-directing effect which is ubiqui- the hydroxyl substituent. The increase in selectivity tous in olefinic alcohol epoxidations is almost un- relative to geraniol may be due to the increased known in osmylations of the same substrate class. acidity of the sulfonamido protons relative to a In the first example, the bicyclic system 60, having hydroxyl proton. The increased acidity may enhance a free hydroxyl group, was dihydroxylated from the the strength of the hydrogen bond thus enhancing concave face with 86:14 diastereoselectivity (Scheme allylic selectivity. 26).138 Similarly, allylic alcohol 61 showed a 3:l The magnitude of this hydroxyl-directing effect preference for dihydroxylation from the concave face may be influenced by performing the dihydroxylation while the corresponding silyl ether 62 was dihy- in the presence of ligand. For example, the dihy- droxylated exclusively from the convex face.139~140 droxylation of geraniol in the presence of quinuclidine In the remainder of this section, we will present suppressed oxidation of the 2,3 double bond giving data which suggest that functional groups bearing the 1,6,7-triol as the major product of a 9:l mixture 2512 Chemical Reviews, 1994,Vol. 94, No. 8 Kolb et al. Scheme 27. Dihydroxylation of Geraniol in the Presence of Ligand 3eq K3Fe(CN),, 3eq K2C03

leq MeS02NH2 ~ uoH 1 : l(v/v) t-BuOH/H20 OH OH OH

5 mol % Os04,NO ligand, RT 4:1 1 mol % 0~01,5% quinuclidine, RT 9:1 1 mol % 0~00.5%(DHQD)rPHAL, 0 “C 249 : 1 (1,6,7: 89% yield, 94% ee) Table 34. Dihydroxylation of 1-Substituted Table 35. Enantiomeric Excesses Obtained in the AD 2-C yclohexenes of cis-Allylic and -Homoallylic Alcohols with Various Chiral Ligands 9 :::el::TD qc X X X

1 on 1 : 3.3 2 NHTs 1 2.5 3 NHTf 1.1 : 1 4 N(Me)Tf 0 : 1

(Scheme 27). This ratio increased to 249:l when performed with (DHQDlzPHAL.

2.5.2.Influence on Stereoselectivity Functional groups in the allylic (or homoallylic) position bearing acidic hydrogens can also have a marked influence on the stereoselectivity of the dihydroxylation reaction. For example, the diaste- reofacial selectivity in the dihydroxylation of 1-sub- 63 with AD-mix-a proceeded in 74% ee.146 Thus, stituted 2-cyclohexenes was found to be dramatically influenced by the acidity of the allylic substituent in agreement with the proposed hydrogen bonding interaction between os04 and the allylic substituent (Table 34).143An increase of syn vs anti attack was 82% yield observed as the allylic substituent was changed from 74% ee hydroxyl to p-toluenesulfonamido to trifluoromethane- sulfonamido (entries 1-3). Complete anti selectivity when compared to cis-2-hexen-1-01, an increase in was observed in the absence of an acidic hydrogen enantioselectivity of 10% is realized when the ter- (entry 4). minal n-propyl substituent is replaced by n-decyl (cf. More recently, it was found that free hydroxyl cis-2-hexen-1-01gave 64% ee with (DHQ)zPHAL,see groups have a beneficial effect on the enantioselec- Table 35). tivities observed in the asymmetric dihydroxylation Hydrogen bonding of the free hydroxyl to an oxo of cis-allylic and -homoallylic alcohols, especially group on osmium may account for the enhanced when using the phthalazine ligands, (DHQDlzPHAL enantioselection observed with this special class of and (DHQ)zPHAL.lu This result was rather surpris- cis-olefins. The final entry in Table 35 also appears ing given that previous investigations had shown this to support this hypothesis. Although the enantiose- ligand class to be very poor for the asymmetric lectivity observed with this substrate was modest dihydroxylation of simple hydrocarbon cis-olefins, [54% ee with (DHQD)zPHALI, it is nonetheless especially those bearing alkyl groups at each termi- surprising given that the environment near the olefin nus.145 In addition, previous studies with truns- unit is nearly The catalyst is somehow allylic alcohols had suggested that a free allylic able to differentiate the two ends of the olefin even hydroxyl has a slight deleterious effect on enantiose- though the hydroxyl group is fairly remote from the 1e~tivity.l~~The asymmetric dihydroxylations of cis- reaction center. allylic and homoallylic alcohols were performed using To further test the hypothesis regarding the ben- the phthalazine ligands under standard conditions eficial effects of a free, proximate hydroxyl group, (i.e. t-BuOWHzO 1:1,0 “C). For some substrates, the asymmetric dihydroxylation experiments were per- enantioselectivities were comparable to those ob- formed on the corresponding methyl ethers. The data tained using the IND ligand ~1ass.l~~These data are obtained from these experiments are summarized in summarized in Table 35. Table 36. When compared to the corresponding In a subsequent experiment, it was found that the alcohols in Table 35, a dramatic drop in enantiose- asymmetric dihydroxylation of the C13 allylic alcohol lectivity is evident in each case. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2513 Table 36. AD Data of Methyl Ether Derivatives and the SW quadrants has a deleterious effect on the AD cis-/3-Methylstyrene with (DHQD)%PHAL process. More specific suggestions for the role of these putative hydrogen bonding effects are discussed Substrate Bee Major Fmduct elsewhere.26~27b

25.4. Summary

The data presented in this section reveal that an allylic hydroxyl group, or other allylic functional groups with acidic hydrogens, can exert an influence Meow 0 ... on the regia- and stereochemistry of dihydroxylation as well as enhance the reaction rate in comparison Me Ph 35” (lR.29 to other functional groups of similar electronic de- w mand. Although the magnitude of the effect may be small when compared to effects seen in other func- tional group directed reactions, there are instances, An attractive feature of this methodology is that as in the asymmetric dihydroxylation of cis-allylic the crude triol products tend to be crystalline, alcohols, where the effect is of sufficient magnitude presenting the opportunity for enantiomeric enrich- to be synthetically useful. ment. For example, the enantiomeric purity of the triol obtained from cis-2-hexen-1-01increased from 74% to 96% ahra single recrystallization.’” 3. Synthetic App/ications for 1,2-Dio/s

25.3. Influence on Rates The chemistry of carbohydrates and polyols is as old as the field of organic chemistry. Consequently To further examine the notion that a hydrogen there is a wealth of chemical knowledge on this class bond may be responsible for the enhanced enantio- of compounds and many transformations which were selection observed in the asymmetric dihydroxylation originally developed for Carbohydrates are also ap- of cis-allylic alcohols, the rates of formation of the plicable to diols derived from the AD of olefins. osmium(VI) glycolate of a-substituted styrene deriva- Polyols play an important role not only in biological tives were measured using stopped flow methods systems, they have also found frequent use as start- under pseudo first-order condition^.'^^ Calculation ing materials for the enantiospecific synthesis of of the ceiling rate constants for each of the substrates natural products and (“The Chiron Ap- provided the data shown in Figure 7. proach”). However, the AD reaction offers some Since the addition of Os04 to olefins is known to important advantages over the use of sugars as chiral be a mildly electrophilic process,1° one would expect building blocks in enantioselective synthesis. First, the reaction rates for the hydroxyl- and methoxyl- the AD, catalytic in both Os04 and the chiral auxil- substituted cases to be slower than that for the iary, provides either enantiomer of the product with parent a-methylstyrene. The rate data bear this out almost equal efficiency. Second, the AD is not limited for the methyl ether, however, when compared to to a certain number of standard starting materials a-methylstyrene, the compound with an allylic hy- (e.g. carbohydrates, tartrates, etc.), since virtually droxyl group is, by some mechanism [perhaps a any olefin can be regarded as a substrate. Thus, the hydrogen bond to an osmium oxo ligand (Os=O)], synthetic strategy is left almost entirely to the almost able to overcome the deactivating effect of the imagination of the chemist and not restricted by the allylic oxygen. Finally, it is worth noting that ee and availability of certain starting materials. Third, most rate-enhancing effects for an acidic functional group enantiospecificsyntheses from the chiral pool require seem to require that it reside in the NW quadrant of an elaborate protecting group strategy. This does not the AD mnemonic device (cf. section 1, Figure 5). In necessarily apply to syntheses involving the AD, since contrast, earlier res~lts~~J~~J~~indicate that the the diol can be carried through the synthesis “masked” presence of such a group in the NE and, perhaps also, as an olefin, ready to be released at any point.

5WO This section is intended to concentrate specifically I on chemical transformations of diols prepared by the 4000 AD reaction and their application in the synthesis of natural products and biologically active compounds k 3W0 as well as chiral building blocks and auxiliaries. In Mh-‘ most instances, diols are not the final products and 2WO their synthetic elaboration requires some further transformations. Commonly, these involve the selec- 1WO tive manipulation of one of the two OH groups either by protecting it or by converting it into a leaving group, suitable for displacement by a nucleophile. In the first section of this chapter, some recent methods for the differentiation and manipulation of Figure 7. Saturation rates with (DHQDIzPHAL in t- the hydroxyl groups of a diol are reviewed. The BuOH at 25 “C. second section describes the preparation of chiral 2514 Chemical Reviews, 1994, Vol. 94,No. 8 Kolb et al, building blocks using the AD reaction. The AD has Table 38. Selective Arenesulfonylation with Various also been used for the preparation of chiral auxilia- Arenesulfonyl ChlorideslWJ ries for other asymmetric transformations. These applications are discussed in the third section.

3.1. Methods for the Differentiation of the Hydroxyl Groups of a Diol 1 2 j 63% 3.1.1. Selective Arenesulfonylation

Selective manipulations of diols may be based upon 2 1 I 68% steric effects, which render one hydroxyl group more reactive than the ~ther.'~lJ~~Additionally, electronic effects, which manifest themselves in different acidi- + The reactions were performed in CHzClz at 0 "C in the ties of the OH groups, influence the rea~tivity.'~~J~~presence of 2 equiv of pyridine and 1.1 equiv of the sulfonyl The primary OH group of a diol derived from a chloride. The initial diol concentration was between 0.35 and 0.4 M. The ratios were determined by weighing the isolated terminal olefin can be readily converted into a products. sulfonate leaving group by reaction with arenesulfo- nyl chlorides in the presence of a tertiary amine. Althoughp-toluenesulfonates are used in most cases Scheme 28. Potential Racemization during the due to their inexpensiveness, better results in the Formation of Epoxides via Hydroxytosylates subsequent nucleophilic displacement step are often OH obtained with p-nitrobenzenesulfonates (nosylates) due to their considerably higher reactivity as a R leaving gr0~p.l~~The formation of the bis-sulfonate R'& 'OTS 66 ...... as a side product can be minimized by using only a small excess of sulfonylating reagent (Table 37). However, lowering the reagent amount will also result in an increased amount of the starting mate- rial left over and commonly one has to settle for a compromise. Scheme 29. Synthesis of Glycidaldehyde Building The regioselectivity of the sulfonylation can be Block 68" enhanced further by using sterically more encum- p-TosC1, bered reagents. Thus, 2,4,64rimethylbenzenesulfo- nyl chloride (64) or the corresponding 2,4,6-triiso- propyl derivative 65 are the reagents of choice for 91 %ee diols with very small steric differences (Table 38).157 (cf. eqn. 2, section 2.1.3.) NaOMe. Frequently, hydroxy sulfonates are only intermedi- MeOH, ates on the way to chiral epoxides and the sequence reflux, 1 hr olefin - diol - monosulfonate - epoxide has been applied in a number of natural product and drug 85 % yield over 2 steps, syntheses.158 However, for this strategy to be suc- 97 Bee (99 %ee after 1 crystallization) cessful it is important to realize a high regioselec- tivity in the initial sulfonylation step, since the . dihydroxylation of the corresponding acrolein acetal cyclization of the regioisomeric sulfonates 66 and 67 (eq 2) and one recrystallization from ben~ene.~~J~~ leads to opposite enantiomers (Scheme 28) and Monotosylation and treatment with sodium methox- consequently a loss in optical purity. ide gives the glycidaldehyde building block 68. This An example for the usefulness of the olefin - diol compound has several advantages over other glycid- - monosulfonate - epoxide reaction sequence is synthons,160since it is readily available in shown in Scheme 29. Glyceraldehyde synthon 10 can enantiomerically pure form, crystalline and stable at be obtained in good enantiomeric excess by the ambient temperature. Additionally, the deprotection of the aldehyde function can be carried out under Table 37. The Formation of Mono- and Bistosylates neutral conditions by catalytic hydrogenolysis. in the Reaction of Phenylethylene Glycol with Varying Amounts of p-Toluenesulfonyl Tertiary hydroxyl groups can be readily differenti- ated from primary or secondary hydroxyl groups due to the former's low nucleophilicity. Mesyl chloride OH 4eq. Pyridine, is the reagent of choice in such cases as it is relatively CH2C12, 0 oc * phA.,~~~+phA.,~~~!Starting Material 1 phA.,~~ reactive and inexpensive. An AD, mesylation, and

1.3 eq. TsCl 0; ~ Rec1;;d cyclization sequence represents the key steps in recent syntheses of juvenile hormone I11 bisepoxide161 1.O eq. TsCl 18 23 % 1 (Scheme 30) and also 2,3-0xidosqualene.'~~ 0.5 eq. TsCl > 49 j 40% High selectivities can also be obtained by way of ' The initial diol concentration was 0.4 M. The product stannylene acetals of diols (Scheme 31).162Thus, 69 ratios were determined by 'H NMR analysis of the crude preferentially reacted at the least hindered oxygen product. center without affecting the primary OH group at the Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2515 Scheme 30. Synthesis of Juvenile I11 Bisepoxide Scheme 33. Some Synthetic Transformations with by an AD-Mesylation-Cyclization Sequence161 a-(Sulfonyloxy) -/?-hydroxy Esters l53

AD-mix-a I OS(02)Ph-X R20A0 X = NO? 74 NaN3, DMF, “UI \ \ C02Me SOT, 20-24 h 0 *“ ii) KzCO3, MeOH OH 82 %yield 94:6 ratio at C-10

73 N, 70 % yield Scheme 34. Asymmetric Synthesis of Chloramphenicol’w

57 % yield Juvenile Hormone I11 Bisepoxide 96 %ee, 89 % yield Scheme 31. Highly Selective Acetylation and Tosylation of Polyols via Stannylene Acetals’s3 i. TsCI, EqN, CH2C12, ii. K2CO3, MeOH “BU__ OH 1.1 eq. “BuzSn(OMe)z, “BU.&~ 4 steps HO&~~ Benzene or Toluene, Dean-Stark reflux, - d&~~ 5-15 min / 69 \ OnN 75 Chloramphenicol /AcCl ::: or TsC1,\ at a low concentration, typically between 0.2-0.3 M AcOAOHTS0AoH in diol ester. 71 % yield 72 % yield In most cases p-nitrobenzenesulfonyl chloride gives superior yields (57-91%) to tosyl chloride153(48- Scheme 32. Regioselective Arenesulfonylation of 76%), and it also leads to more reactive pr0d~cts.l~~ Dihydroxy Estersls3 Thus, the better leaving group character of the nosyl group has been utilized in the preparation of a-azido carboxylic acids 73 (Scheme 33), precursors for a-amino a~id~.~~~J~~~,~Also glycidic esters 74 are accessible by this method. so. Rao et al. prepared glycidic ester 75 by this method and converted it into the broad-spectrum antibiotic chl~ramphenicol~~~(Scheme 34).

Yields: 48-91% 3.1.2. Cyclic Sulfites and Sulfates as Epoxide-like Side Products: Synthons‘651166 ArS(02)0 Optically active epoxides play an important role in RlqOR2 RlqOR2 synthetic organic chemistry158 as they constitute electrophilic, chiral building blocks with an “un- 71 OS(02)Ar 72 OS(02)Ar natural” 1,a-functional group re1ation~hip.l~’Ad- other terminus.163 Peracylation, a common problem ditionally, elimination processes in small rings can in the reactions of polyhydroxylated compounds, was be stereoelectronically disfavored in certain situa- almost completely eliminated. Recently, Ley et al. tions,168thereby rendering epoxides more useful than published a simplified “one-pot” procedure, which their acyclic equivalents. Many of these beneficial allows the preparation of the acetal by reaction properties of epoxides are shared by cyclic sulfates of the diol with dibutyltin dimethoxide in benzene and sulfites, with the sometimes useful distinction under Dean-Stark conditions and its subsequent that cyclic sulfates are more reactive than 0~iranes.l~~ benzylation, acylation, or sulfonylation in the same Consequently, these compounds can be regarded as s01vent.l~~ synthetic equivalents of epoxides and a number of In certain cases modest differences in acidity can useful synthetic examples have appeared in the be the origin of selectivity. Thus, a,P-dihydroxy literature over the years.166 esters 70 are selectively sulfonylated at the a-OH 3.1.2.1. Preparation of Cyclic Sulfites and group with either tosyl chloride or nosyl ~hloridel~~J~~Sulfates. Whereas the reaction of diols with SOC12 (Scheme 32). The formation of a$-bissulfonates 71 in the presence of an amine base gives the cyclic and a-(sulfonyloxy)-a$-unsaturated esters 72 as side sulfites 76 directly in good yields,165the analogous products (the latter arising by elimination of the reaction with S02Cl~usually results in low yields of former) can be minimized by performing the reaction the corresponding sulfates 77. However, cyclic sul- 2516 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. Table 39. Preparation of Cyclic Sulfites 76 and cyclic sulfite (isolated from the reaction mixture by Sulfates 77 from Diols? an aqueous workup, since tertiary amines inhibit the (A) SOCIz, CCI4, NaI04, cat. RuCI3, oxidation catalysis) is subjected to oxidation as refluxa onss,o described above. .,%R2 01 0°C to r.t. Table 39 demonstrates the broad scope of the (B) SOC12, Et3NT RiJAR2 method and even acid-sensitive functionality is toler- 77 ib ated, provided a proton scavenger is present during Entrv Product the formation of the ~u1fite.l~~ A 3.1.2.2. The Chemistry of Cyclic Sulfites and lac R, j(F R1,R2 = n-Alkyl, Ph Sulfates.166Analogous to epoxides, cyclic sulfates and sulfites can be opened by attack of a nucleophile A 0 SO? at either carbon center (Scheme 35). The product, Zd P'O~($,.,op2 P'= CH?Ph, P2= SiMe2'Bu 0 Scheme 35. Some Representative Reactions of r Cyclic Sulfites 76 and Sulfates 7716sJsa

Path A n Path B

A 88-97 % NU Nu- B 95 % 76 (n=l) - 77 (n=2) A 63.93%

r ' R= n-Alkyl, c-C~HII.CHzPh 78 Nu 60,b e A >90% n=2: 'J'i;, CH20SiMe2'Bu B 87 7c cat. H2S04, A A 64% q

R' LRZ~ Rl+R2

+ Procedure (A) is normally used in the "one-pot" preparation 79 Nu 80 LNu of cyclic sulfates via the sulfites,165while procedure (B) is more NU F, C1, Br, N3, RNH?, PhC02, suitable for acid-sensitive substrates or when sulfites are the NO3, SCN. PhS, AcS, H, desired products.169a See ref 165. See ref 169. See ref 170. PhCHZ, RCS,(RS)?CH See ref 171. e See ref 172. however, is not an alcohol, but a sulfate monoester fates are readily available by the oxidation of cyclic (78, n = 2) in the case of cyclic sulfates as substrates. sulfites (Table 39). These sulfate monoesters allow some interesting Originally, stoichiometric quantities of reagents transformations, which make the chemistry of cyclic like potassium ~ermanganatel~~and R~04~~~were sulfates more versatile than that of epoxides. used for the oxidation of cyclic sulfites. However, Naturally, hydrolysis of the sulfate monoesters better yields and cost considerations make the cata- (Scheme 35, path A) leads to hydroxyl compounds 79 lytic "one-pot" process, developed by Gao and Sharp- that parallel those obtained from 0~iranes.l~~How- more economical (Table 39). This new pro- ever, the sulfate in 78 (n = 2) can also function as a cedure employs NaI04 as the stoichiometric reoxidant leaving group, leading to disubstitution products for Ru04,of which catalytic quantities are sufficient. (Scheme 35, path B). Thus, a solution of the diol in Cc4 is refluxed with a. Monosubstitution of Cyclic Sulfites and Sulfates SOClz to prepare the corresponding sulfite 76 (Table (Path A). As shown in Scheme 35 cyclic sulfites 39, conditions A). Although this reaction is fast even and especially sulfates react with a variety of nucleo- at room temperature, refluxing is desired to expel the philes and a few examples are C1- (LiC1),177Br- (m- HC1 that is formed in the reaction, since it would Br),177F- (Et4NFn2H20, ~-Bu~~F),~~~J~~N3- (LiN3, cause side reactions in the subsequent oxidation step. NaN3),165,169,172,175,176,178 RNH2,172J80PhC02- (PhC02- For certain unreactive diols it may be necessary to NH4),165J69J75ROH (intramolecular, ride add a small amount of DMF to promote the reaction NO3- (Bu~NNO~),~~~SCN- (NH4SCN),165J77 PhS- with SOC12.170 The crude cyclic sulfite is then (PhSNa),183AcS-,~~~ H- (NaBHsCN, NaBH4),165 oxidized in the same reaction vessel, following addi- PhCH2- (PhCHzMgBr, Li~CuC14),'~~RC=C- tion of acetonitrile and water as additional solvent (RC=CSiMe3 + MeLi),181 (RSIzCH- (with 1,Li-cyclic components, in the presence of a slight excess of sulfates).182 NaI04 and catalytic amounts of RuCly3HzO (ca. The hydrolysis of sulfate monoesters 78 (n = 2) to 0.1-1 mol %). Aqueous workup and purification by P-hydroxyl compounds 79 is carried out by treatment filtration through a small pad of silica gel gives the with a catalytic amount of sulfuric acid and 0.5-1.0 pure cyclic sulfate 77 in normally excellent yields. equiv of water in THF.169 These conditions are Slight modifications of the above procedure are sufficiently mild to tolerate even acid-sensitive func- required for acid-sensitive substrates. In these cases tionalities, such as acetonide and silyloxy groups the reaction with SOClz should be performed in the (Scheme 36). presence of a tertiary amine base to neutralize the It is well known that nucleophilic 5-endo cycliza- HC1 formed169(Table 39, conditions B). The crude tions of hydroxy epoxides are disfavored for steric and Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2517 Scheme 36. Nucleophilic Opening and Hydrolysis Scheme 39. Synthesis of D-Erythrose via an in the Presence of Acid-Sensitive Functi~nality~~~ Irreversible Payne Rearrangementl'l OH O&,oi( i. LiN3, DMF, 4 ? 0 6O-7O0C,5 h ii.OSeq.HZS04. HO (r 89% yield, >95% ee q; 1 .O eq. HzO, THF, ct., 20 min i. SOCII, I ii. NaI04, cat. RuCIJ stereoelectronic reasons.ls5 Interestingly, this does not apply for hydroxy cyclic sulfates, since the at- 6 'so, tacking oxygen, carbon, and leaving oxygen can be irreversible v collinear without imposing too much strain on the i.PhSNa. 1 Payne-Rearrangement 93% yield system. Thus, 5-endo opening of the hydroxy cyclic ii. cat. H~SO~1 sulfate, formed in situ by saponification of the acetate PH 81, leads to optically active tetrahydrofuran 82 with inversion of configuration at the reacting center179 HO HO (Scheme 37). 82% yield D-Erythrose

Scheme 37. Formation of Tetrahydrofurans by Scheme 40. Asymmetric Synthesis of 5-endo Opening of Cyclic Sulfates179 (fbDisparlure Employing an Irreversible Payne Rearrangement 0n sop "Bu4NF [Hplp:$] S Methyl (+)-Ricinoleate 81 02 OSiMep'Bu - NaOEt , irreversible Payne-Rearrangement I i. 'BuC=CLi, 1 EtOH 90% ee

_. . i. MeC(OMe)s, 66% yield from cyclic sulfate ii. AcBr. I iii. K2C03, MeOH Nucleophilic opening of cyclic sulfates by amines 78% yield provides /?-hydroxy amines in analogy to epoxide "~ClOHpl (+)-Disparlure opening. This transformation has been employed in a recent synthesis of the morphine precursor (R)- (+)-disparlure, the sex attractant pheromone of the reticulinelsO (Scheme 38). female gypsy moth186(Scheme 40). Scheme 38. Asymmetric Synthesis of Cyclic sulfites 76 react in a similar fashion as the (R)-Reticulinels0 sulfates 77,166J76-178and an additional hydrolysis step of the initial product is not necessary. However, in OBn I SOCI?. EtrN. Et-0. OBn contrast to the S(VI) esters, cyclic sulfites are Kineti- cally labile at the sulfur center which may lead to unwanted side reactions, e.g. hydrolysis. Addition- ally, cyclic sulfites are much less reactive at the carbon centers than cyclic sulfates and they tend to (neat) give good results only with good nucleophiles such 1.1. to 130 'C as bromide, thiocyanate, and azide in polar aprotic sol~ents.~~~J~~ The cyclic sulfite chemistry provides ready access

c to enantiomerically pure /?-lactam~l~~and a practical c synthesis of the unnatural D-enantiomer of malic acid (841, starting from L-tartaric acid has appeared HO (R)-Reticuline BnO 65%yield from the diol (83), recently177(Scheme 41). The sulfate group in intermediate 78 (n = 2) (see In analogy to the chemistry of epoxides, cyclic Scheme 35) formed as the initial product of the sulfites 85 derived from y,b-dihydroxy a,p-enoates nucleophilic opening of a cyclic sulfate may function can be opened in SN~'fashion with organocuprate as an in situ protecting group for the /?-hydroxyl reagents,187leading to allylic alcohols 86 (Scheme42). substituent. Thus, the nucleophilicity of this masked The 1,3-chirality transfer is almost complete and OH group is completely eliminated, a feature that reductive elimination, giving rise to dienoates 87 as causes Payne-type rearrangements to be irrevers- side products, can be suppressed by adding the ible171J86(Scheme 39). This behavior was utilized in cuprate reagent to the substrate (inverse addition). a recent synthesis of erythr0~e.l~~ This methodology has been employed in the syn- An irreversible Payne rearrangement was also the thesis of the carpenter bee sex pheromone (88) key step in a very efficient asymmetric synthesis of (Scheme 43). 2518 Chemical Reviews, 1994,Vol. 94, No. 8 Kolb et al. Scheme 41. Preparation of D-Malate Esters from Table 40. Double Displacement of Cyclic Sulfates L-Tartrate Esters177 HO SOC12, cat. DMF, 50 "C, 1 h R02CjC02R 83 OH Entry Bis-Nucleophile LiBr, acetone, and conditions Product R = Me, Et, 'Pr 50 "C, 7-12 h NH II Zn, acetone-H20 HO 10 Ph-NH2 HO or Ptl+Ph DME, reflux, R02C&C02R - Pd-C, MgO, R02c~Co'R then hydrolysis of the NH2 resulting imidazoline 84 acetone-H20, Br 7040% yield H2 (15-50 psi)

Scheme 42. Reaction of Cyclic Sulfites with Organocopper Reagents187 KzCS~*H~O, 3c 18-crown-6, 3 eq. BFpOEt2, THF inverse addition, THF, -78 "C 85 Yield: 72 - 90% 4d MeOzC,CO,Me NaH, DME R': Me, BnO R2: H, Me + R3: Me, Et R4:Me, "Bu R17C02R3 See ref 170. * See ref 184. See ref 189. See ref 165.

Scheme 43. Asymmetric Synthesis of the nucleophilic openings of epoxides, the p-sulfate in 78 Carpenter Bee Pheromone (88) by still is a leaving group that can be displaced by a Diastereoselective 8~2Opening of a Cyclic nucleophile in a second step. This allows an overall Sulfatele7 substitution of both OH groups of diols and consider- OSiMeZBu ably enhances their synthetic usefulness. However, i. Cuprate reaction, ' since a Sod2- dianion is a much worse leaving group ii. 'BuMe2SiC1, than a ROS03- anion (cf. the PKa values of H2S04, 05sIO imidazole 68% yield , W pK, << 0, and HOS03-, PKa = f1.92) the second displacement is much less facile than the first and has so far only succeeded in an intramolecular fashion. A variety of optically active products are available by this methodology as shown in Table 40. 3.1.3. Conversion of Diols info Halohydrin Esters and Scheme 44. Formal Synthesis of (+I-Coriolic Epoxides Acid" Despite the synthetic versatility of epoxides, there are very few methods available for the direct enan- tioselective epoxidation of olefin~.~~~J~~The titanium tartrate catalyzed asymmetric epoxidation (AE)is restricted to allylic and homoallylic alcohols only,6 while chiral manganese salen complexes give good i. 'BuPhzSiCl, results mainly with cis-olefin~.~J~~~-~Other methods use stoichiometric amounts of chiral reagents and/or suffer from low enantioselecti~ities.~~~Thus, there is no general epoxidation process available yet that 86% yield 0 THF 90 0 parallels the osmium-catalyzed asymmetric dihy- 90% yield HO droxylation in scope. Consequently, methods for the stereospecific con- L._.-___ :cLx (+)-CoriolicAcid version of diols into epoxides are of immense interest. However, cyclodehydration sequences via monoto- sylates may result in partial racemization, since the As with epoxides, p-elimination provides allylic overall process proceeds with inversion of configura- alcohols and the reaction becomes quite facile in the tion at only one carbon center (cf. Scheme 28). These presence of an activating carbonyl group. Thus, a problems are avoided in epoxidation procedures that recent formal synthesis of (+I-coriolic acid makes use involve two inversions and, therefore, net retention of the base-induced elimination of cyclic sulfite 89, of configuration (Scheme 45). Such reactions may to produce allylic alcohol 90 as a synthetic intermedi- proceed via halohydrin intermediates which are atelsa (Scheme 44). formed from the diol with inversion of configuration. b. Disubstitution of Cyclic Sulfates (Scheme 35, Since the subsequent base-mediated cyclization leads Path B). Unlike the /3-hydroxyl group, generated in to a second inversion, the epoxide is formed with Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2519 Scheme 45. Stereochemical Outcome of the chloride201(Viehe's salt, entry i), or stepwise via sta- Formation of Epoxides via Halohydrinsm ble, cyclic intermediates such as orthoesters50J92J96-1gg OH (entries b, f, and g), benzylidene acetals200(entry h), thiocarbonatesZo2(entry j), or 2-(N&-dimethylamino)- 1,3-dio~olanes~~~(entry a). Methods involving cyclic acyloxonium cations 93, formed by reaction of a diol with HBr/acetic acid (Scheme 46, path A) or via cyclic orthoesters 92 (path B), have frequently been used in conjunction with the AD reaction, since they 6H require inexpensive reagents. 3.1.3.1. Preparation of Bromohydrin Acetates overall retenti~n.~~The advantage of this strategy from Diols Using HBr-Acetic Acid (Scheme 46, is that the regioselectivity of the halohydrin forma- Path A). The reaction of a diol with 30% by weight tion is inconsequential, since both regioisomers pro- HBr in acetic acid is stereospecific and yields acetoxy duce the same epoxide upon cyclization (Scheme 45). bromides with inversion at the halide-bearing cen- Most commonly, a diol is activated toward nucleo- ter.153J93Thus, (5')-(+)-propyleneglycol reacted with philic attack via a reactive, cyclic intermediate. This HBr/HOAc to give a 94:6 mixture of regioisomeric has the advantage that bis-functionalization of the bromo acetates (Scheme 47), which upon treatment diol cannot occur. A variety of methods employ this with base afforded (5')-(-)-propene oxide in good strategy and some of them are shown in Table 41. overall yield.lg3 The majority of these processes utilize the high In the case of diol esters 94 the yields range from reactivity of 1,3-dioxolan-2-ylium cations 91 toward 72 to 96% and the halide is normally introduced in nucleophiles. These reactive species can either be the a-position to the carbonyl group, leading to 95153 formed in situ from the diol and a reagent such as (Scheme 48, path A). However, a phenyl group (i.e. HBr in acetic a~id~~~J~~(entry c), a-acetoxyisobutyryl 94, R1 = Ph) exerts a stronger directing influence bromidelg4(entry d), acetylsalicyloyl bromidelg5(entry than a carbonyl group, resulting in a-acetoxy-P- e), N-(dichloromethy1ene)-N&-dimethylammonium bromo-&phenyl esters (96, R1= Ph) (path B).

Table 41. Reagents for the Manipulation of 1,2-Diols via Cyclic Intermediates

Nu = C1, Br, I P = H, acyl, carbamoyl

Reagents which lead to 1,3-dioxolan-2-ylium cations as intermediates: I ;eR21 Y= H Ph Me2N MeS Thiocarbonyl j diimidazole, then Me1

Reagents which give dioxaphospholane intermediateck

PPhd(PhC02)2, or PPh3/ROzC-N=N-C02R, or PPh3/CCl&2C03, or Ph3P(OR)z

a See ref 191. See ref 192. See refs 153 and 193. See ref 194. e See ref 195. f See refs 50 and 196-198. g See ref 199. See ref 200. See ref 201.j See ref 202. See refs 203-205. 2520 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. Scheme 46. Formation of Acetoxy Halides and Scheme 49. Preparation of Glycidic Esters from Epoxides via Cyclic Acetoxonium Ions a&Dihydroxy EsterslS3@ i. 6 eq. HBrNOAc, 45 T. H? 30 min, then MeOH, n 45 "C, 24 h, /$,C02Me nC5H1lye a" ^.. ii. K2C03.~. MeOH, r.t., 20 mL "C5H11 r.0 YI un YO 61% yield 92 'R2 a Note that the intermediate bromohydrin acetate is saponified PathAa \ / PathBb in situ by addition of MeOH to prevent ,%elimination.

upon treatment with HBr/acetic acid and subsequent cyclization.193 In many cases it is advisable, therefore, to use more neutral and milder conditions for the preparation of acyloxy halides and epoxides. In 1958, Baganz and Domaschke reported that cyclic orthoformates yield halohydrin formates upon treatment with neat acetyl chloride or bromide.lS6 Although their method re- quired vigorous reaction conditions, later work by other groups showed that the same transformation could be achieved under milder conditions. Reagents, X = CI, Br, I such as trityl chloride,lS7Me3SiC1lS8 or PC15,'92 have Base, MeOH also been employed in place of acetyl halides to effect ! the same type of transformation. In a recent study, the scope and limitations of the reaction of cyclic orthoacetates, derived from chiral

a See refs 153 and 193. See refs 50 and 196-198. diols, with acetyl halides or MesSiCl have been in~estigated.~~It was found that the formation of the Scheme 47. Preparation of cyclic orthoester intermediate, its opening, and the (S)-( -)- 1,2-EpoxypropanelS3 subsequent base-mediated cyclization to the epoxide HO 6 M HBrIHOAc. AcO Br can be carried out in one reaction vessel. This has /\/OH pCtor.t.,30min * -Br + LOAc led to the development of a convenient "one-pot" 89% procedure for the conversion of diols into acetoxy 94 6 halides or epoxides. Thus, the asymmetric epoxida- KOCSHII, tion of olefins can now be realized in only two steps 85% HOCSHII. 1100°C (Scheme 50). Depending on the type of substrate, two different methods for the formation of acetoxy halides have been developed. In most cases, a solution of the diol Scheme 48. Regioselective Formation of Acetoxy in CHzClz is treated at room temperature with a Bromides from Diol Estersls3 slight excess of trimethyl orthoacetate in the presence of a catalytic amount of a mild acid (ca. 1 mol % of 1 pyridinium p-toluenesulfonate or p-toluenesulfonic acid) to effect transesterification. In rare cases warming to ca. 40 "C may be necessary to achieve complete reaction. The solution is then evaporated Br to remove most of the methanol formed during the reaction (a small amount of MeOH is actually ben- R2phenyl = methyl Path B Path A R2y;kiyyy= eficial for the next step), and the residue is taken up in a solvent, usually CHzCI:! (MeCN or c6H6 have also AcO Br been used). The acetoxy halide is formed upon ),-,C02R2 R' addition of MeaSiCl, acetyl chloride, or acetyl bromide R1YOZR2 95 ir 96 OAc (the latter reagent usually gives the best results). While this reaction is normally performed at room The a-bromo-/3-hydroxyester derived from 97 gave temperature, reduced temperatures (-20 to 0 "C) glycidic ester 98 upon treatment with base153(KzC03 may be advisable for very sensitive substrates or if in MeOH) (Scheme 49). high regioselectivities in the nucleophilic opening of 3.1.3.2. Preparation of Halohydrin Esters and the acetoxonium ion are required. The reaction Epoxides from Diols via Cyclic Orthoesters mixture may be buffered with up to 0.1 equivalents (Scheme 46, Path B). Naturally, the HBr/acetic of triethylamine so that even acid sensitive sub- acid procedure is only applicable to acid-stable com- strates give good results (Table 42, entries 3 and 5). pounds, and in certain cases partial racemization can After completion of the reaction, the volatiles are occur, due to opening of the intermediate 1,3-diox- evaporated to yield virtually pure acetoxy halides. olan-2-ylium ion with formation of an acyclic car- These are dissolved in MeOH and treated with base bocation. Thus, enantiopure (R)-(-)-1-phenylethane- [KzCO~or Amberlite IRA 410 (OH-)] to effect cycliza- 1,2-diol gave (R)-(+)-styreneoxide in only 88% ee tion to the corresponding epoxides, which are typi- Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, NO.8 2521 Scheme 50. Asymmetric Epoxidation of Olefins in Two StepsM -1 -1

'HO OH' I R; H i. MeC(OMe)3. PPTS. 1-BuOH-H20 (13) ii. A& or MegSiCI, iii. K2CO3. MeOH R, H Rs..h/ RM AD-mix-a HO OH me-par 0 "HO OH' -1 -1

Scheme 51. Formation of Hexadiene Oxidem Scheme 52. Prenaration of (S)-Pro~ranolol~~~and Ao-mix--P. MeS02NH2, SKF 104353" byway of Chiral Epokides 1BuOHH20.0 T,22 h. /+&,A&/ 88% yield I 99 OH I i. M~C(OM&. P~S. ii. AcBr. cat. Et3N. iii. NaOH. MeOWEI,O

12% peld 100 cally isolated in ea. 90% yield. For very volatile epoxides, e.g. 100, the cyclization may be carried out with solid NaOH in diethyl ether in the presence of 1.5 equiv of MeOHZo6(Scheme 51). The other procedure for formation of epoxides is even easier to perform and best suited for activated diols, i.e. benzylic diols50 (Table 42, entries 1and 2). In these cases acetoxy halides are formed directly by adding trimethyl orthoacetate and MesSiCl to a solution of the diol in CHZClz. The reaction is worked up by evaporating the volatiles to give almost pure chlorohydrin acetates. These may be cyclized as described above. As illustrated by the examples in Table 42, the reaction is of broad scope and even acid-sensitive substrates give good results. It should be pointed out that no racemization was observed even with (+)-(,S)- 1-phenylethane-1,2-diol (entry l), in contrast to the HBr-acetic acid reaction (vide supra). The special features of the procedure can be summarized as SKF 104353 follows.5" Depending on the choice of the reagent, Scheme 53. Regioselective Dihydroxylation of chlorohydrins (with MeaSiCl or AcCl), bromohydrins 2,4-Hexadienyl Benzoate (103)117and Conversion (AcBr), and even iodohydrins (AcCl-NaI in MeCN) into the Corresponding Vinyl Epoxide 104*08 may be prepared. The halide is introduced in a AD-mir-$. highly regioselectivefashion, i.e. at the least hindered -0Bz position (entry 61, and/or away from an inductively 94%yield 103 OH on electron-withdrawing functional group (entries 3,4, 1 and 71, or in the benzylic position (entries 1, 2, and i. MeC(OM&, PPTS, 8). Only a few limitations are known. Thus, steri- cally crowded diols derived from trisubstituted olefins normally give unsatisfactory results. However, these & 84% yield OH 96%ee diols are excellent substrates for the formation of 104 epoxides via mesylates (uide supra). Partial racem- ization may occur with electronically activated diols, esting chiral building blocks (Scheme 53, see also e.g. l-(p-methoxyphenyl)ethane-1,2-di01.~~~ Scheme 51). The asymmetric dihydroxylation-epoxidation se- Also acyloxy halides are useful synthetic interme- quence has found recent application in the syntheses diates as demonstrated by a recent synthesis of the of the 8-blocker (S)-propran~lol~~~and the leukotriene C13 phenylisoserine side chain of taxo1199~209(Scheme antagonist SKF 10435350(Scheme 52). 54). This new synthesis may be the most practical The regioselective AD and epoxidation of dienes for the large-scale preparation of phenylisoserine gives access to vinyl epoxides,2°6s208which are inter- derivatives, since it is free of chromatographic sepa- 2522 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Table 42. One-Pot Synthesis of EpoxidessoJ

OH 101 x 102 OAc * = inverted configuration

Of 9% Yield of Entry diol % ee" acetoxy halides 101 : 1026 (X) epoxideC OH < 4 : 96 (C1) PhA( 91 84d OH OH 0 : 100 Ph+ 91 (a) 92 OH OH TBDMSO+ 59 85 : 15 (Br) 83eJ OH OH

96 100 : 0 (Br) 9gdS8

COpiPr lOOh 100 : 0 (Br) (77)C.i

86 : 14 (CI) 89 911 88 : 12 (Br) 91 87 : 13 (I)

89 100 : 0 (Br) 91d

99 14 : 86 (Br) 82'

' For the diols in entries 1 and 2 the reactions were performed according to the procedure for activated diols (i.e. direct mixing of the diol, MeC(OMe)s, and MesSiCl). All other diols were converted into epoxides using the three step procedure for unactivated diols. a The enantiomeric excesses were determined by HPLC or GC analysis of the free diols or the bis-MTPA esters. Determined by integration of the 'H NMR spectra of the crude products. Isolated yields. The enantiomeric excess of the epoxide was found to be identical within the experimental error to that of the diol by HPLC analysis. e The preparation of the acetoxy bromides was performed at 0 "C in the presence of 10 mol % of Et3N. f Methanolysis of the acetoxy bromide was performed with Amberlite IRA 410 (OH-) as base, since K&o3 gave inferior yields due to artial cleavage of the silyl ether. g The preparation of the acetoxy bromide was performed in the presence of 2 mol % of Et3N. !The diol was prepared from D-Glyceraldehyde acetonide. I Yield of the acetoxy bromide. This compound decomposed on treatment with Kzc03, presumably due to p-elimination of acetate. j Prepared by hydrogenation of the diol in entry 2. Yield of acetoxy iodide. Treatment of the pure acetoxy bromide of type 102 with K&O3 in methanol provided the epoxide in entry 8 in 91%yield. Scheme 54. Large-Scale Synthesis of the Taxol Scheme 55. Some Biologically Active Compounds Side Chainzo9 Which Have Been Synthesized with the Orthoester MeC(OMe),, cat. pTSA, Methodology CH2C12, r.t., then AcBr, +=?H CH2C12,60% -15 yield "C * +OM. OAc Me3NAC02 +OMe/ OH (R)-(-)-camitineb 99% ee 1 i. NaN.. DMF. 50 "C. (Vitamin BT) 1 ii. H~.io% PUC, 0 MeOH i. 10% HCl,,,, reflux, a y 14% yield 0 H$N&CO; H20,1.t. NMe2'HC' (R)-(-)-y-amino-P-hydroxybutyric acidb 72% yield (+)-Diltiazem" (GABOB) 99% ee a See ref 198d. See ref 38a. N-Benzoyl-(2R,3S)-3-phenylisosenne (C13 Taxol side chain) more than 100 g of the enantiomerically pure taxol side chain (106)was prepared.209 Other biologically active compounds, such as (+I- rations and requires only minimal extraction pro- diltiazem,lgM(R>-(->-y-amino-B-hydroxybutyric cesses; all intermediates and the final product are and (R)-(-)-~arnitine,~~"have also been synthesized readily purified by recrystallization. In this manner using the orthoacetate methodology (Scheme 55). Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2523 Table 43. Preparation of Enantiomerioally Enriched Scheme 57. One-Step Cyclodehydration of Diolsaos Methyl Carbinols123 H AD-mix-p R 0 R- MeC(OEt)s, -0 (Retention) PITS, AcBr, v - RLoH-l or HBr, HOAc .OH Ph 109A 110 A' 111 Bu3SnH, C6H6 HL 11 fast equilibnum RXBr m OH 106

R Reagents: 109 B 110 B' ent-111 PP~~CC~&COI,OI R =Me : 82 - 85% retention PPh$Et02C-N=N-C02Et. or Ph : 50 - 55% retention I 1 93(89) 58 cyCH2 (RO)zPPh3 0 Scheme 68. Regioselective and Stereospecific NC-CHz 94 (87) Monosubstitution of Unsymmetrical l,2-Diols via Dioxaphospholanes2w ycHz99 (86) 0 5 ~UMe~SIO~CH292 (84) 85 77 HJoH 'Os R OH Scheme 56. Some Targets Prepared by PPh3/(PhC02)2,or Deoxygenation of Terminal Diols PP~~/RO~C-N=N-C~~R~HOZCP~(or p-TsOH) or (EtO)zPPh3/HOzCPh(or p-TsOH) OH 'H

- i."$ ,A =o u Antibiotic A26771Bb WCR sex pheromoneb I equilibrium e See ref 74c. See ref 123.

Another application has been for the preparation of enantiomerically pure methyl carbinol acetates 107 (Table 43).123 Thus, the AD reaction of terminal olefins gives the corresponding diols in good enan- tiomeric excess and the optical purity can be en- I Nu- (PhCOZ-, p-TsO-, N3-) hanced further by recrystallization. Subsequent 4 reaction via the cyclic orthoacetate of the diols gives acetoxy bromides 106 in good yield, even when an + poH acid-sensitive functionality is present. As expected, the bromide is introduced at the terminus and its I 112A I 112 B reductive removal with BusSnH leads to acetates of major minor methyl carbinols 107. Keinan et al. employed this strategy in syntheses since the two regioisomers A' and B give opposite of the macrolides (+)-a~picillin~~~and antibiotic enantiomers, i.e. 11 1 and ent-111, upon cyclization. A26771B as well as the four possible stereoisomers Thus, (S)-(+)-propane-1,2-diol(lOB,R = Me) afforded of the western corn rootworm (WCR) sex phero- the corresponding epoxide with ca. 8245%retention (Scheme 56). of configuration, while activated diols, e.g. (SM+)- 3.1.3.3. Cyclodehydration and Monosubstitu- phenylethane-l,2-diol(lOS,R = Ph), lead to complete tion of Diols via 1,3,2A5-Dioxaphospholanes.Cy- racemization (Scheme 57). The fact that the con- clodehydration of diols to epoxides can be effected in figuration of the stereogenic carbon center is retained one step by treatment with -based re- during cyclodehydration indicates that the collapse agents such as dialkoxytriphenylphosphoranes,PPhd of betaine llOA is faster than that of betaine B'. CC1&2C03, or PPh3/R02CN=NC02R.203 The ini- If a dioxaphospholane 109 is reacted with a nu- tially formed intermediate, a dioxaphospholane 109, cleophile in the presence of an acid, i.e. PhCOzH, may exist in two isomeric forms A and B which lead HOTS, or NaNaOTs in MeCN, the corresponding to regioisomeric betaines llOA and B' (Scheme 57). benzoates, tosylates, and azides 112 (Nu = PhCO2, Intramolecular substitution of triphenylphosphine TsO, N3), respectively, are obtained with essentially oxide results in the formation of the epoxide 111. complete inversion of the chiral carbon center204 However, as in the case of epoxidation via tosylates (Scheme 58). Interestingly, the nucleophile is intro- (vide supra), partial racemization usually occurs, duced at the more hindered carbon, leading to the 2524 Chemical Reviews, 1994,Vol. 94, No. 8 Kolb et al. Table 44. Regioselective and Stereospecific Scheme 59. Differentiation of Hydroxyl Groups by Functionalization of (S)-l,2-Propanediolwith Kinetically Controlled Cyclization114~F10*211 Trimethylsilyl Reagentsaos Me3SiX

rll R2 113 109 I BOC = 'butoxvcarbonvl I ,OSiMs3 X, 1 AD-mix-P. MeS02NH2, 90%

+ - I\" HA K2C03, K3Fe(CN)6, X Me Me OSiMea > "'7~ ee 1:l BuOH-H~O,

113 A 113 B 10 "C, 24 ~ 36 h major minor 0 0 0 I 113 MelSiX A : B %Yield" SPh 17 1 70 Br 51 77 114 QH 116 QH 118 I 81 60 R' = CH3, C2H5 R' = C2H5 n= 1,2 c1 1.6 1 61 (see table 45) R2 = C2H5 (96% ee) = C3H7 (98% ee) CN 1.9 1 60 RZ C6H13 (97% ee) CSHII (98% ee) N3' >99 <1 85 C6H5 (99% ee) C12H25 (96% ee) CH2Ph (97 Wee) a Isolated yields. 25 "C,1 h. These building blocks are obtained in excellent yield formation of 11!2A, which may be due to activation of the dioxaphospholane by complexation of an and enantiomeric purity by asymmetric dihydroxyl- 109 ation of or y,d-unsaturated esters and acid (i.e. PhCOzH orp-TSA) at the most basic apical P,y 113 115, oxygen of the complex which is also sterically least respectively, under the &Fe(CN)&C03 condi- tions210(Scheme 59). hindered. This may lead to an increased electron deficiency of the equatorial oxygen atom and conse- Muricatacin, an acetogenin derivative that shows some cytotoxicity toward human tumor cells, is quently the carbon atom attached to it, thereby activating it for nucleophilic displacement.204 readily accessible by this strategy210 (Scheme 59, compound 116, R2 = C12H25). Analogous chemistry has been observed with tri- In recent elegant syntheses of solamin and reticu- methylsilyl reagents instead of acids, again resulting latacin the lactonization was employed to enable in preferential substitution at the more hindered regioselective monotosylation of diol intermediate carbon with nearly complete inversion of configura- 119 as a key step212(Scheme 60). tionzo5(Table 44). Trimethylsilyl halides give rise to 3.1.4.2. Formation of Cyclic Carbamates dur- silyl ethers of halohydrins 113 (X = C1, Br, I), while ing the Asymmetric Dihydroxylation of BOC- MesSiNa, Me3SiCN, and Me3SiSPh afford the cor- Protected Allylic and Homoallylic Amines. Di- responding (trimethylsily1)oxy azides 113 (X = N3), ols derived from NJV-di(tert-butoxycarbony1)allylic or cyanides (X = CN), and thioethers (X = SPh), homoallylic amines 117 also cyclize spontaneously to respectively. cyclic carbamates 118 during the AD reaction, thereby 3.1.4. Differentiation of the Hydroxyl Groups by Selective, differentiating the two hydroxyl groups211(Table 45). Intramolecular Trapping The cyclic portion of the protecting group can be selectively removed under basic conditions, enabling In the previous chapters the differentiation of the synthesis of the highly functionalized chiral hydroxyl groups based on steric or electronic grounds building block 120 (eq 5). was discussed. Another strategy to achieve this goal is to effect cyclization involving only one of the two ?, OH groups. This approach may be adopted with AD substrates that contain a carbonyl group at an appropriate distance from the double bond. Under un kinetic conditions, 5-membered rings are favored over 95% ee, quantitative yield 6-membered rings (Scheme 59), and cyclization nor- mally occurs spontaneously during the AD reaction 3.1.4.3. Formation of Bicyclic Systems by of olefinic substrates that contain ester or carbamate Intramolecular Ketalization. The asymmetric functionality. dihydroxylation provides an efficient access to natu- 3.1.4.1. Formation of y-Lactones During the ral products with a 6,8-dioxabicyclo[3.2.lloctaneskel- Asymmetric Dihydroxylation of B,y- and y,6- eton. These bicyclic systems are formed by intramo- Unsaturated Esters. Functionalized y-lactones are lecular ketalization of dihydroxy ketones, derived important synthetic building blocks for a number of from unsaturated ketones or ketone equivalents. natural products, precursors for HIV-1 protease Thus, (+)-exo-brevicomin has recently been synthe- inhibitors and other biologically active compounds. sized214by a sequence involving asymmetric dihy- Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2525 Scheme 60. Asymmetric Synthesis of Solamin and Table 46. Formation of N-Protected Cyclic Reticulatacin21a Carbamates 118 in the AD Reaction of Allylic and Homoallylic Di(tert-butoxycarbony1)amines 1 17211 i. AD-mix+ 0 H25C12 ii. MezC(0Me)Zr AD-mix-P, MeSO2NH2, pTSA, acetone. 1:l BUOH/H20,0 "C y-p BodNP\R n= 1,2 BodN* 117 '18 OH Substrate Product %yield % ee 66% yield, ca. 90% de, > 95% edde afier 1 recrystn BocpNAPh 78 97

Boc~N- 80 90

OH

BOQN -a 80 95 OH BoczNT44 47

- Solamin (n = 11) HO 75% yield 93 34 Reticulatacin (n = 13) Boc~N- \

HO droxylation of the protected unsaturated ketone 121 BOQN 73 89 and subsequent acid-catalyzed transketalization of the resulting diol 122 (Scheme 61). Other bicyclic natural products that have been \ Ph prepared in similar fashion are the beetle aggregation BOC~N- 13 98 pheromone (-)-frontalin215 and 7,7-dimethyl-6,8- dioxabicyclo[3.2.110ctane,216a volatile component of the aroma of beer (Scheme 62). Scheme 62. Asymmetric Synthesis of (-) -Frontalin and Scheme 61. Asymmetric Synthesis of 7,7-Dimethyl-6,8-dioxabicyclo[3.2.lloctane (+)-e~o-Brevicomin~~~ n

(DHQWzPHAL, 121 i. chemoselective dihydroxylation 'iig7 K2C03.1 : 1 BUOwH20, K3Fe(CN)6, 96% yield, qH of the trisubstituted double bond c HO 95%ee i. AD with (DHQ)zPHAL, with AD-mix-a, MeS02NH2, 0~04, ii. pTSA, CH2C12 OU0 0 "C, 32 h 122 4 p ii. 03, then PPhq Y iii. cat. pTSA

4o'00,

(+)-em-brevicomin (-)-Frontaha 7,7-Dimethyl-6,8-dioxa- 90% vield I 68% yield, bicyclo[3.2. l]octaneb 35% ee 59% yield, 94% ee 3.1.5.Miscellaneous Transformations See ref 215. See ref 216. The hydroxyl groups of a diol can also be distin- guished based on the proximity to certain functional ment with a nucleophile in the presence of a pal- groups, i.e. silyl groups or double bonds. Thus, ladium(0) complex217(Scheme 63). Peterson elimination of dihydroxy silanes 124, in- 3.1.5.1. Preparation of Enantiomerically En- volving the OH group closest to the silicon, yield riched Secondary Allylic and Propargylic Al- enantiomerically enriched secondary allylic alcohols cohols. a. Allylic Alcohols. Optically active, sec- 125*O (Scheme 63). It is also possible to make use of ondary allylic alcohols 125 are useful chiral building the electronic activation of the allylic position by a blocks, and they are readily obtained from allylsi- double bond for selective manipulations. Thus, the lanes in only two steps: asymmetric dihydroxylation, single dihydroxylation of diene 126 and conversion followed by Peterson elimination40 (Scheme 63 and of both OH groups into leaving groups, e.g. carbam- Table 46). ates, leads to the activated system 127,which allows The starting silanes 123 are available by a variety selective substitution of the allylic group by treat- of reactions2l8 and they have been prepared in this 2526 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

Scheme 63. Selective Manipulation of Diols Based Scheme 66. Formation of Optically Active on the Proximity to a Functional Group Propargylic Alcohols by Base-Induced Fragmentation of l-Chloro-2,3-acetonides221 R'vSiR3 Rl-R2

i. asymmetric dihydroxylation; Asymmetric ii. conversion of the OH groups 0Y i. AD-mix-a, :/ Dihydroxylation into leaving groups HO xo "C5H11 ii. dimethoxypropa& "C5H11vC1 Hi '0 77% yield 129 , 12 eq. "BuLi, 12 eq. HMPA, Peterson [PdO], Nu- THF, -30°C Olefination' 1 H "Bu- 125 Nu I See ref 40. See ref 217

Table 46. Preparation of Allylic Alcohols from Allylsilanest AD with PHN or HO KH, THF or EtZO, PHAL Ligands -78 "C to r.t. R' vSiR3 it is best to use a trimethylsilyl group. Thus, allyl- 'R1+SiR3 77 -85% yield R1 * 123 *btrimethylsilane (123,R1 = H, R = Me) gives the iu OH 125 corresponding diol with AD-mix$ in only 13% ee, Entry Substrate Product Ligand % ee while allyltriisopropylsilane (123,R1 = H, R = i-Pr) HO 1" "C5H11-SiMe3 & DHQD-PHN 91' yields an almost racemic compound under identical %H11 conditions. This observation may be related to a HO general problem with the phthalazine ligands which ?La "C5H1,-SiMe3 DHQ-PHN 87c "C5H71- do not respond well to branching in close proximity to the double bond (for example, see Table 1, entry ll),especially if the branched substituent should reside in the binding pocket of the ligand (i.e. the southwest quadrant of the mnemonic device, cf. 40 pSiMe3$ DHQD-PHN 94c Figures 3 and 5). In certain cases, the phenanthryl / ether ligands 4 (DHQ-PHN and DHQD-PHN) give higher enantioselectivities than the phthalazine ligands 1 and the diol derived from allyltrimethylsi- lane (123,R1 = H,R = Me) has been obtained with 6b )"%Me3 (DHQ)zPHAL 68d 76% ee. As expected, trans-disubstituted olefins 123 (R1 f H) (Table 46, entries 1-4 and 6) are better +The reactions in entries 1-5 were performed at room substrates for the AD than terminal or trisubstituted temperature. a See ref 40a. See ref 40b. 13 mol % of the alkenes (entry 5). These trans-disubstituted allylic ligand was used. 2 equiv of AD-mix-a (Le. 2.8 g per 1 mmol silanes all offer a fair-to-good alternative group for of the olefin) was used. the binding pocket when the offending CH2SiMe3 Scheme 64. Preparation of Allylsilanes group resides in the relatively open NE quadrant of the mnemonic device (Figure 5). R1/\\/SnBu3 As mentioned above, the reason for the poor i. R3SiCHZMgCL performance of the phthalazine ligands with allyl- cat. Ni(PPh3)4, 1 12* and vinylsilanes is the presence of a bulky group in C6H,&tzO, I.t., R' ASnBu3 close proximity to the double bond. Generally, py- ii. RIMnBr, rimidine ligands perform better than the phthala- zines in such cases24and, not surprisingly, a much better enantiomeric excess was obtained with vinyl- trimethylsilane using (DHQD)zPYR~~(88% ee, cf. a See refs 40a and 219. See refs 40b and 220. Table 1, entry 12) compared to 46% ee, obtained with (DHQD)2PHAL40(Table 1, entry 12). context by two methods, starting either from (E)-1,2- b. Secondary Propargylic Base-in- dichlor~~~.~~~or from vinylstannanes 12840b220 duced fragmentation of l-chloro-2,3-acetonides (129) (Scheme 64). affords secondary propargylic alcohols 130221(Scheme Unfortunately, allylsilanes give only moderate 65). The reaction proceeds by a mechanism similar enantioselectivities under the normal AD conditions to that for the fragmentation of l-chloro 2,3-ep- and a recent optimization studPo"has uncovered the oxides,222by elimination of an intermediate a-chlo- following trends. Increasing the size of the silyl rocarbanion and subsequent dehydrochlorination of substituents causes the enantioselectivity to drop and the resulting vinyl chloride. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2527

Scheme 66. Formal Synthesis of Vitamin Eaal Table 48. Epoxide and Cyclic Sulfate Building Blocks

~ ~ ~~~ i. PPh?.CCh, Method of Entry Precursor Building Block heoaration Applications

iii. Me$(OMe)z, H' Epoxides 100% ee 12eqnBuLi, 1 , -. . 12 es. HMPA, _THF,-30°C 'gTrc, OH Orthoester + P-blofkeP R 2 methodb \\ O&OH 0Ao 1 89% yield 0 49% yield Vinyl Epoxides HO ;thohoy +allylic alcoholsd + &lactonesc OH Hydroxy Epoxides Vitamin E Table 47. Formation of Oxazolidin-2-onesfrom Dienesa1' general 2 eq. TsNCO, BCC~N,,A+-.~, m,!&o ADandbae building treatmenth 2 % Pd[P(O'Pr), 14, block R,/-b/+R2 AD .,&~z THF,reflux, 12-24 h Glvcidaldehvde Eauivalents' +. via OH cOpO tosylatdor 126 OH 132 general 6 orthoester building % yield '0 block' 3nq Olefinn Product (from enedioll31) % ee '- methodn O\f \;"-p SOZC12, Glycid- 1- 3Cns:cis 86 93 7 HOGCI aldehyde CI equivalent' 0 6:1 Glycidic Esters 0 Orthoestepor 2 ph-Ph Phxeph 81 99 8 R' aOR2HBrmOAc' Ts 133 methods intermediates 0 for drug OH via a-tosylate synthesis" 9 RIT or nosylatem 134 1320 O Cf. Table 42, Scheme 50, and refs 50, 197, and 198. Cf. mo Scheme 52 and ref 41a. Cf. Schemes 51 and 53 and ref 206. References 223-225. e Reference 226. f Reference 39.8 For reviews, see ref 6a and 158. Cf. eq 5 and ref 211. Reference 160. J Cf. Scheme 29 and ref 44a. Reference 227. Cf. Scheme a For the preparation of the ene diols in entries 1,2, and 4, 49 and refs 153 and 193. Cf. Schemes 33 and 34 and refs see ref 116a; for the diol in entry 3, see ref 217. 153 and 154. Cf. section 3.1.1. and refs 50, 154, 164, 198d, 228, and 229. An analogous reaction sequence has been used in 3.2. Preparation of Chiral Building Blocks a recent formal synthesis of vitamin E starting from (Scheme 66). The AD reaction is ideally suited for the prepara- tion of chiral building blocks for asymmetric synthe- 3.1.5.2. Selective Substitution of the Allylic sis, due to its wide scope and normally excellent OH Group of Ene Diols. As shown in section 2.4, enantioselectivity. A large number of chiral synthons the asymmetric dihydroxylation of conjugated dienes have been prepared via the AD in recent years and yields ene diols with high enantiomeric excess. The most of the synthetic applications have already been synthetic utility of these highly functionalized com- discussed in detail in the previous chapters. This pounds is enhanced further by the selective substitu- section briefly lists the most important chiral syn- tion of the allylic OH group via Pd-stabilized allyl thons and the discussion is focused on those com- cations.217 pounds which have not been mentioned earlier. Treatment of an ene diol 131 with 2 equiv of 3.2.1. Electrophilic Building Blocks p-toluenesulfonyl isocyanate in the presence of cata- lytic amounts of Pd(0) gives oxazolidin-2-ones (132) Chiral epoxides and their synthetic equivalents, via initial formation of the biscarbamate, ionization the cyclic sulfates, as well as halohydrins and glyc- to the Pd-stabilized allyl cation and subsequent eraldehyde derivatives are versatile chiral building intramolecular trapping by the nitrogen of the other blocks. Their electrophilic character facilitates bond- carbamate group. As shown in Table 47, this reac- forming transformations and these chiral synthons tion has a wide scope and double-bond isomerization have been extensively used in syntheses of natural only occurs to a limited extent in certain cases. products and other biologically active compounds. 3.2.1.1. Chiral Epoxides and Cyclic Sulfates. The vinyloxazolidin-2-ones, prepared by this meth- Some epoxide and cyclic sulfate building blocks which odology, are valuable chiral building blocks, since have recently been prepared using the AD reaction they constitute synthetic precursors to amino alco- are listed in Table 48. The formation and synthetic hols. applications of cyclic sulfates and epoxides are dis- 2528 Chemical Reviews, 1994,Vol. 94,No. 8 Kolb et al. Scheme 67. Some Synthetic Applications of Vinyl Table 49. Ambident Electrophiles Epoxides Method of 1 Entry Precursor Building Block Applications OH ~- EtO,C-OBn I Path AZ3O

Path B22' R'. R4 = H Path E226 R2, R3 = H, Me, i CsHii a Reference 39. Reference 231.

Scheme 69. Synthetic Applications for Bisepoxide 137 010 Carpenter bee Lo OJ pheromone R'- R4 = H. alkyl, cyclic crown-6, E = CO2Me. PhS02 + carcinostatics'~8 Scheme 68. Preparation of the Tax01 C13 Side Chain via Glycidic Esters

1. E~~NH~BI, Nas, EtzAlCl MeOH, HzO ii. NaN3, DMF N3 ph,-(?pOzMe -ph+C02Me * 95% yield 72% yield 133 ref 228 OH ref. 154a, 229 134 R (-)-DIoP~~~ MeLi i. PhCOCI, Et3N, 31 to 89 9% 92% yield DMAP; R= ii. %NO. ii. Hz. PdC, Me,lR, 'Bu, ethyl acetate Ph. PhCHz, iii. NaH, BnBr. "BuaI HO PhCONHI CsCc-E1 R' R2N 51% OH NR' RZ phj\/C02Me OH OH OB" R' =Me, Ph, R2 = Me taxol C-13 side chain 45 - 60 W Chiral modifier for + (-)-rhodinose, LiAIH4 reductions236 63% 0 + (+)-epimuacarine cussed in depth in chapters 3.1.2 and 3.1.3.,respec- + mycinolide IV234 tively. Vinyl epoxides 135 are precursors for homoallylic 3.2.1.2. Halohydrin Building Blocks. Vicinal alcohols, allylic alcohols, and &lactones. Thus, sN2 halohydrins may be regarded as synthetic equiva- opening with Meaprovides homoallylic alcoholsz30 lents of epoxides. However, in contrast to epoxides, (Scheme 67, path A), whereas SN~'opening, leading they are not ambident electrophiles, since the site of to allylic alcohols, can be effected with certain nucleophilic attack is already predetermined by the aluminum reagents223(path B), organocuprate re- position of the halogen (provided that in situ cycliza- agent~~~~(path C), and under Pd(0) catalysiszz5(path tion to the epoxide is prevented by appropriate choice D). In contrast, treatment with Fez(C0)g and car- of a hydroxyl protecting group and/or the reagent). bonylation of the resulting n-allyltricarbonyliron As described in sections 3.1.3.1 and 3.1.3.2,halohy- lactone 136, provides access to as ex- drin esters may be prepared from diols in a highly emplified by the synthesis of the carpenter bee pheromone (path E). regioselective fashion either by the HBrMOAc or by the orthoester proced~re~~J~~J~~ The glycidic esters 133 and 134 (Table 48, entries (Table 42). Some examples are shown in Table 50. 8 and 9) are useful intermediates in the synthesis of P-amino-a-hydroxy acids, for example phenyliso- Table 60. Chiral Halohydrin Building Blocks ~erine~~~~,~~~,~~~(taxol side chain) as shown in Scheme Method of 68. ~ Entry Precursor Building Block heoaration Applications 1 Additionally, certain biologically active compounds, precursor such as the antibiotic chl~ramphenicol,'~~the leu- Orthoester for methyl kotriene antagonist SKF 104353,50and the cardiac 1 ,EoH RKB' methodn carbinolsb drug (+)-diltia~eml~~~(a Ca-channel blocker), have Dihydroxylation general 2 R~XRHbx with'buffered' building been prepared via glycidic ester intermediates (cf. AD-mixC block OH Schemes 34, 52, and 55, respectively). X = CI, Br. I Highly functionalized, chiral C3 and Cq synthons densely OH OAC Orthoester functionalized 3 with more than two electrophilic centers are listed HoABr ClABr methodd C3 building in Table 49. 138 blockd Bisepoxide 137 (Table 49, entry 1) is a versatile Cf. Table 42 and refs 50, 197, and 198. Cf. Table 43 and chiral building block and some applications are ref 123. Cf. Tables 1 and 3, section 2.2.1.1, and ref 39. Cf. shown in Scheme 69. Scheme 70 and ref 38a. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2529 Scheme 70. Synthesis of Carnitine and GABOB Scheme 71. Preparation of Glyceraldehyde using the Building Block 138S8a Synthons 139 and 14OZ4l OH i. MeC(OMe)s, OH i:BuzSnO cat. pTSA HO-Br RT. 45 min. 11. allyl bromide, CsF * '":yo 72% ee ii. Me3SiC1, RT, 4h 138 phriii. mCPBA Ph"'" cf. Eqn. 1 Ph''''' OH 52-7690 yield Selective Substitution (R,R)-141 I CSA, of Bromide 1CsH6 1KCN, MeOH, RT, 17 h OH OH OH i. aq. Me3N, RT, 3 h CIACN ii. recrvst. 3x from EtOH I i. conc. HC1, RT, 8.25 h 3.8 1 ii. 28% NHfizO, RT, 14 h 142 iii. 10% HCl, reflux, 4.5 h iv. Amberlite IR 120 (H') 7445% yield Ph,;,cHo Ph,;,cHo Swem;y]."CHo 143 i. conc. HCI, 50-75 OC, 6 h v. recrystallization 2x, 1 I ii. Amberlite IRA 410 (OH) Et 0H - H 0 I Ph"'" 139 140 Scheme 72. Chemoenzymatic Synthesis of D-Fructose and Its Analogss9

PdlOHb. Hq. r 50 psi, MedH , Table 51. Glyceraldehyde Building Blocks HO Method of 25"C,2d * R+Hol145 OH Entry Precursor Building Block PreDaration Applications -0 1 1 OH chemo- 144a (R = H, > 95% ee) 0 \ I OH catalytic enzymatic 144b (R = Me, 79% ee) HO&OP03'- 1 HOqDHOG CHO hydrogenation0 syntheses of 144c (R = Ph, > 95% ee) pH 7.5,25 "C, 2 d 0' carbohydratesa ii. acid phosphatase PhyO +HO pH 4.5,37 "C, 2 d

FDP aldolase = D-Fructose diphosphate OH OH 0 aldolase R*H

OH bH 146a-e a Cf. eq 2, Scheme 72. and refs 44a and 59. Reference 241. Reference 239. zymatic synthesis of ~arbohydrates,~~e.g. L-fructose (146a)(Scheme 72). A large number of other ketoses The chloro bromo acetate 138 (Table 50, entry 3) have been prepared by this route. is a densely functionalized C3 building block with a different functional group attached to each carbon Chiral Diol and folyol Building Blocks atom. Intriguingly, the presence of two different 3.2.2. halides at the termini of 138 causes the molecule to Polyols are important precursors for carbohydrate be chiral and enables selective manipulation. Thus, derivatives, glycerolipids, and other biologically rel- 138 is the central intermediate in the syntheses of evant compounds. Some poly01 building blocks are (R)-(-)-carnitine and (R)-(-)-y-amino-P-hydroxybu- summarized in Table 52. tyric (GABOB) (Scheme 70). The AD reaction of aryl allyl ethers proceeds with 3.2.1.3. Glyceraldehyde Building Blocks. Glyc- high enantioselectivity (cf. Table 1) and leads to eraldehyde is a useful Cs-building block that has been chiral glycerol derivatives, intermediates in the employed in a number of natural product and drug preparation of /?-blockers41(cf. Scheme 52) and syntheses.239While the (R)-enantiomer of glyceral- gly~erolipids~l~,~~~(Scheme 73). dehyde may be prepared from D-mannit01,~~~~~~~the (SI-isomer is less readily available, due to the cost of Scheme 73. Synthesis of Dipalmitoylglycerols61b*M2 L-mannitol. Some (E)-and (SI-glyceraldehyde equiva- lents that have been synthesized using the AD reaction are shown in Table 51. The syntheses241of glyceraldehyde synthons 139 and 140 (Table 51, entries 2 and 3) start with (I?$)- stilbenediol [(R,R)-1411,which is available in greater Cd%iCOz than 99% ee from the AD of stilbene (Table 3, entry Ci&iCOz&OH 7). Selective monoallylation via the stannylene acet- 95% yield (> 95% ee after 2 al, followed by epoxidation and acid-catalyzed epoxide recrystallizations) opening affords a separable 3.8:l mixture of the diastereomeric alcohols 142 and 143, which are oxidized under Swern conditions to provide the 3.2.3. Chiral Monohydroxy Compounds Derived from Diols aldehydes 139 and 140, respectively (Scheme 71). Chiral allylic alcohols, propargylic alcohols, and Glyceraldehyde 145 (R = H), prepared by catalytic methyl carbinols are versatile building blocks for hydrogenolysis of 144a, has been used in the chemoen- natural product and drug synthesis. Table 53 sum- 2530 Chemical Reviews, 1994,Vol. 94, No. 8 Kolb et al. Table 62. Polyol Building Blocks cyclic sulfitesls8(cf. Scheme 44). Propargylic alcohols Method of are available by base-induced fragmentation of chloro Entry Precursor Building Block PreDaration Applications acetonidesZ2l (cf. Schemes 65 and 66) and methyl OH + P-hlockel-b carbinols may be prepared by tin hydride reduction 1 &-.~oAr HO&OAr AD reactionn + glycerolipidsC of bromohydrin esters123(cf. Table 43). 3.2.4. 5- and 6-Membered Heterocycles 2 AD reactiond + aminosugars The AD reaction has been employed for the prepa- RO RO ration of small heterocyclic compounds, which are RO RO useful building blocks for asymmetric synthesis (Table 54). 3& 60 lg!AD reaction‘ + Carbohydrates In summary, the great strength of the AD reaction is that it provides ready access to enantiomerically R R OH enriched building blocks for asymmetric synthesis, AD reactiodg + Azole Antifungals8 starting from simple and inexpensive olefinic precur- Ar ArhOH R = CH2OBn. CH2OMe. sors. In a number of cases, the AD reaction has CH2Br. CH,CI superseded natural products, such as carbohydrates, as a source of optically active compounds, since the use of “tailor made” starting materials greatly re- a Cf. Table 1and refs 41,61b, and 242. * Cf. Scheme 52. Cf. duces the number of synthetic transformations and Scheme 73. Cf. Table 13 and ref 75. e Cf. Scheme 21, Table protecting group manipulations. 21, and ref 118. f Cf. Table 2 and ref 47. g References 243 and 244. 3.3. Preparation of Chiral Auxiliaries for Other marizes some of the compounds that have been Asymmetric Transformations prepared using the AD reaction. 3.3.1. Preparation of (1R,ZR)-trans-Z-fhenylcyc/ohe~ano/ Allylic alcohols may be prepared by Peterson elim- ination of diols derived from allyl silanes*O (cf. section (1R,2S)-truns-2-Phenylcyclohexanol(147)was first 3.1.5.11,kinetic res01ution~~J~~(cf. section 2.3.21,sN2’ introduced by Whitesell as a chiral auxiliary for an addition of organocuprates to cyclic sulfites derived asymmetric glyoxalate .246 Since its from ene diolsls7 (cf. Scheme 42), and elimination of introduction, it has found many additional applica- Table 53. Chiral Monohydroxy Building Blocks Method of Entry Precursor Building Block Preparation Applications

Allylic Alcohols

AD and general 2 R-SiMe3 RL Peterson building R=”CsHii, ‘C3H7.CC6Hll.Ph eliminationb block

Me y-hydroxy enal Base induced equivalent RWN\o~eRTbhk eliminationC [+Coriolic o’-Eo 0 0 Acid] HO Cuprate carpenter bee R1,-&-y?R3 + Additiond pheromone R4 R’: Me, BnO R2:H, Me R3: Me, Et R4:Me, “Bu Propargylic Alcohols \/ Base induced + vitamin E, fragmentatione prostaglandins

Methyl Carbinols + Aspicillin, Orthoester antibiotic 6 RJoH method and A2677 1B, R = n-Alkyl reductionf WCR sex Dheromone

a Cf. section 2.3.2., Tables 18 and 19, and refs 33 and 111. Cf. section 3.1.5.1, Table 46, and ref 40. Cf. Scheme 44 and ref 188. Cf. Scheme 4’2 and ref 187. e Cf. Schemes 65 and 66 and ref 221. f Cf. Table 43 and ref 123. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2531 Table 54. Heterocyclic Chiral Building Blocks Method of Entry Precursor Building Block Preparation Applications

general AD Reactionu building block

+ Muricatacin, AD Reactiona Solamin, Reticulin

selectively protected AD Reactionb dihydroxy amine synthon

AD, cyclic Highly func- sulfate form., tionalized tetra- 5-endo cycli- hydrofurand sationC

Me3s&RR' AD reaction, ge neral OH hydromagne- building Me3Si PRMesSi siation, R'CN or block C02 trapppinge

AD reaction, reaction with amino alcohol TsNCO and synthon Ri W0)f Cf. section 3.1.4.1,and Schemes 59 and 60, and refs 114, 210, 212, and 213. * Cf. section 3.1.4.2,Table 45, and ref 211. Cf. Scheme 37 and ref 179. Reference 245. e Cf. section 2.4.4,Scheme 25, and ref 131. f Cf. section 3.1.5.2,Table 47, and ref 217. tions in asymmetric synthesis. A review detailing the Scheme 74. Preparation of development and uses of this as well as other cyclo- ( 1R,2S)-tran8-2-Phenylcyclohexano12s2 hexyl-based auxiliaries has recently appeared.247 3 eq. KzCO3,3 eq. KjFe(CN)6 Previous preparations of this compound in enantio- 0.2% K~OSO*(OH)~ P6HbOH * merically pure form have relied upon the copper- 1% (DHQDhPHAL catalyzed opening of cyclohexene oxide by a phenyl 'BuOH:H20 (l:l), RT 1 eq. MeSOzh'Hz 75% yield Grignard reagent248followed by enzymatic resolution >99% ee of the corresponding acetate esters246,249or prepara- after recrvst. tory scale separation of para-substituted benzoate RaNi, EtOH, esters by chiral HPLCZ5O In addition, a route has ireflux, 2 h been developed that relies upon the asymmetric 66% yield of phenylcyclohexene by monoisopino- 147 >99% ee campheylb~rane.~~~It is now possible to prepare this (lR,ZS)-trans- after recryst. auxiliary on a multigram scale in '99% ee in a two- 2-phenylcyclohexanol step synthesis from phenylcy~lohexene~~~(Scheme 3.3.2.Optically Pure Hydrobenzoin (Stilbenediol) and 74). Derivatives The asymmetric dihydroxylation of phenylcyclo- Enantiomerically pure Cz-symmetric 1,2-diols and using (DHQDlzPHAL as chiral ligand pro- their derivatives have proved useful as chiral ligands ceeded in 98% yield and 98% ee. After a single or ligand precursors for several asymmetric pro- recrystallization from EtOAc-hexane (1:5), solid diol cesses. In addition to the tartrate esters, stilbenediol- product could be isolated in 75% yield and >99%ee. based auxiliaries have also found wide use. Stilbene Reductive removal of the benzylic hydroxyl group by is the best substrate to date for the asymmetric Raney nickel proceeded very smoothly and provided dihydroxylation reaction (cf. Table 3, entry 7) and a pure (1R,2S)-truns-2-phenylcyclohexano1in 66% yield process has been developed for the production of and >99%ee after recrystallization from pentane.252 stilbenediol (>99% ee) on a kilogram scale, which is The identical sequence using (DHQ)zPHALgives the performed at room temperature in a 5-L flask and lS,2R-enantiomer ent-147 in essentially identical the insoluble, solid diol product is isolated by simple yields and enantiopurity. filtration of the reaction mixture.253 2532 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. The use of stilbenediol and its derivatives as chiral Scheme 76. Preparation of (RPbStilbenediamine auxiliaries has been reported for a variety of asym- Bishydrochloride [(R,Z2)-1501from metric reactions including asymmetric hydrogena- (S,S)-Hydrobenzoin2a ti~n,~~~asymmetric Michael addition,255,256,257asym- HO metric cyclopr~panation,~~~and asymmetric allyl and MsCWpyr crotyl b~ration.~~~Stilbenediol has also been used for ph-Ph OOC-RT, 23 h* the production of chiral crown ethers for asymmetric OH (S,S)-141 phase-transfer catalysis,260as well as serving as a (S,S)-hydrobenzoin precursor for the production of stilbene diamine261 >99% ee which itself is a valuable ligand for asymmetric MsO N, synthesis.262 While most of the results described below represent only preliminary studies, they are nonetheless indicative of the potential utility for OMS i3 stilbenediol-based derivatives as ligands or auxili- aries in asymmetric processes. 3.3.2.1. Preparation of Stilbenediamine. Enan- No purification of J'"AHCl/MeOH tiomerically pure C2-symmetric diamines are finding intermediates required. Ph 58% overall yield increasing application in asymmetric synthesis. after recrystallization NH3CI Among this class of compounds, stilbenediamine (149) has proven particularly valuable. Corey re- cently used this compound to prepare a chiral media- tor for asymmetric Diels-Alder, aldol, and allylmet- Recently, Chang has developed a route to the alation reactions.262 In addition, stilbenediamine, bishydrochloride salt (R&)-150of (R&)-stilbenedi- along with other C2-symmetric diamines, has been amine264(Scheme 76). In analogy to Salvadori's used for the preparation of the chiral salen ligands work, this synthesis proceeds via the diazide pre- which are highly effective for the asymmetric epoxi- pared from the activated diol. The diamine bishy- dation of isolated 01efins.~ drochloride is obtained after catalytic hydrogenation Previous routes to optically pure stilbenediamine in acidic methanol in 58%overall yield from stilbene. have entailed resolution of the racemic diamine.262a,263 No purification of intermediates is required and the Salvadori has developed a four-step procedure using final product can be easily recrystallized from metha- trans-stilbene as starting materiaP (Scheme 75). 1101.~~~ Thus, trans-stilbene is readily converted to the enan- This procedure offers advantages over earlier reso- tiomerically pure diol (S,S)-141by the asymmetric lution-based methods, since it uses only readily dihydroxylation reaction. merconversion to the bis- available starting materials and it is also suitable p-toluenesulfonate 148, double displacement with for the preparation of either enantiomer through sodium azide followed by reduction provides enan- proper choice of ligand for the AD step. In addition, tiomerically pure (+)-(R&)-stilbenediamine [(RJZ)- the method may be adapted for the preparation of 1491 in 32% overall yield. other enantiomerically pure diamines, provided the It should be noted that the dihydroxylation reaction corresponding AD substrates contain no functional in this sequence proceeded in >85% ee using the groups which are incompatible with osmium tetrox- DHQ-CLB ligand. The enantiomeric excess was ide. increased to >99% by recrystallization. The recrys- 3.3.2.2. Stilbenediol Derivatives in Asymmet- tallization step can be obviated by using the phthala- ric Michael Reactions. Stilbenediol derivatives zine class of ligands in the dihydroxylation step which have also found applications in asymmetric Michael reproducibly provides the diol in 299% ee. reactions. For example, Tomioka has used the dim- ethyl ether (S,S)-151of (S,S)-hydrobenzoin,prepared Scheme 75. The Preparation of Stilbenediamine according to eq 6, to mediate the enantioselective via Asymmetric Dihydroxylation261 conjugate addition of organolithium reagents to a,P- Os04, acetone unsaturated aldimines as well as to BHA esters of NMO, H20 naphthalenecarboxylic DHQ-CLB * ~8590ee HQ

HO 1. TsCVpyr,.. 0 OC TSO NaH, Me2S04, THF 2. rt,4d PhbPh - PhhPh 82% yield ph+Ph 708yield - OH OMe ($S)-141 &I OTs (S,S)-141 79% yield and 148 ~99%ee after NaN3IDMF recrystallization 90 OC, 5 h Examples of these Michael additions are shown 60% yield below. Conjugate addition, followed by imine hy- drolysis and reduction provided the desired optically

~ ph&Ph phqPh ''%?;; enriched alcohol products 152 and 153 in good 2. rt, 12 h yields256a(Scheme 77). Interestingly, it was found N Hz 97% yield N3 that the reactions do not proceed smoothly in the (t)-(RJ7)-149 absence of the chiral auxiliary. Thus, the auxiliary Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2533 Scheme 77. Asymmetric Conjugate Addition Scheme 79. Preparation of Acyl Ketene Acetal 156 Reactions Controlled by (S,S)-151aSsa via Chlorohydrin 15519ab267

1. CH(OEt)3 (94%) phqph 2. PC15KH2C12 (90%) 0I CHO CH20H / 1. ($S)-151, PhLi 3. Ti(i-OPr)@tOH (85%) toluene, -45 oc mph-Nab mph OH or HCVMeOH (83%) 2.HjOi / / MeOH (R,R)-141 152 82% yield 94%ee y 1. (S,S)-151, PhLi Cq CHzOH 1 ii. K2C03, DMF 'INtoo: -78OC Ph +ph 59% yield t MeOH .-. >99% ee ,Ph \ I BU Et not only controls the stereochemical course, but it 156 also promotes the addition. Scheme 80. Reaction of the Enantiopure Ketal A similar series of reactions was performed using Derived from (1S,2?l)-155257 the BHA esters of naphthalenecarboxylic (Scheme 78). Thus, addition of phenyllithium to the Scheme 78. Asymmetric Conjugate Addition Reaction Controlled by (5,S)-151266b 156 I - 157 158 OMe 42% vield I 1

'Bu+'BU (S,S)-151,PhLi toluene, -45 OC c 159 84% yield 28 : 1 diastereoselectivity \/ 154 05 alkylboronic esters.259 The diol was easily prepared CH20H 1. LiEt3BH by hydrogenation of hydrobenzoin (141) over 5% Ph 2. MeOH 3. NaBh rhodium on alumina catalyst259b(eq 7). - I 152 5% Rh/A1203 MeOH. 60 OC yield 80% Ho, 7atm.H2 84% ee FH Php*s$h 84% yield * BHA ester 154 in the presence of (S,S)-151in toluene (R,R)-160 (R,R)-141 (3% at -45 "C, followed by reduction of the intermediate ketene derivative provided alcohol 152 in 80% yield and 84% enantiomeric excess. Additional work in this area established that the conjugate addition Allylboronate 162 is formed by addition of vinyl- reactions of both the aldimine and ester substrates magnesium chloride to the alkylboronic ester 161 and could be carried out efficiently with substoichiometric subsequent ZnCl2-catalyzed rearrangement of the amounts of the chiral auxiliary.256 intermediate ate complex259(eq 8). Thus, chirality In a related endeavor Konopelski has prepared transfer from the auxiliary allows diastereoselective both enantiomers of access to a-substituted allylboronate reagents by 2-chloro-1,2-diphenylethanol asymmetric chain extension of alkylboronic es- (155) and used them to synthesize chiral acyl ketene ters.259,265 acetals 156192b,257(Scheme 79). The acyl ketene acetal 156 was used for diastereo- selective conjugate additiodalkylation sequences257 n (Scheme 80). Thus, treatment of 156 with ethyl- 0 N'u 1. CH2=CHMgC1 t lithium at 0 "C in THF followed by in situ methyla- 2. ZnClz tion with Me1 provided 157 as the major product of a 1O:l diastereomer mixture. Interestingly, the 161 major diastereomer 157 could be stereoselectively c'2cH-B"b reduced to the anti alcohol product 159, a stereo- chemical result which is difficult to achieve using conventional aldol technology. 3.3.2.3. Auxiliaries for Asymmetric Allylbo- 1 eq8 ration. Hoffman has used (R,R)-and (S,S)-1,2- dicyclohexylethanediol(160) as a chiral auxiliary for the diastereoselective asymmetric chain extension of 2534 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. Table 55. Enantioselective AUylboration of The allylboronate reagent 162 was used for the Aldehydes with Reagent (R,R)-162a6w enantioselective allylboration of aldehydes.266 The results are summarized in Table 55.259c Entry Aldehyde Product Yield(%) 7c ee I Matteson has used dicyclohexylethanediol to direct HO the asymmetric chain extension of alkyl boronic 78 >99 esters (Scheme 81). The ultimate synthetic targets 1 y 4 CI were aldehyde 165 and ketone 166, two key inter- HO mediates in the asymmetric synthesis of stegobiol 2 d? 7 81 >99 and stegobinone, pheromones of the drugstore CI beetle.267 Previous work had demonstrated that asymmetric chain extension reactions utilizing C2-symmetric y? +cl 89 >99 directing groups proceed with diastereoselectivities > 1000:l.268,269An added advantage of this approach 0 is that none of the intermediate compounds required 19 >99 any purification. The central aldehyde and ketone intermediates, 165 and 166, respectively, were puri- fied by distillation and then used in a fragment assembly aldol reaction and elaborated into the natural products stegobiol and stegobin~ne.~~~The only chromatographic separation required in the Scheme 81. Asymmetric Synthesis of Stegobiol and StegobinoneZs7

BnOLi, THF, -78 "C 0 1. LiCHCl,, -100 'C DMSO (4 eq.), 25 OC, 18 h. c w 2. ZnCl,, -100 lo +25 OC (R,R)-163

BnZ, BnQ 0 1. LiCHC12, -100 'C 1. LiCHCl,. -100 OC . 2. ZnC12. -100 to +25 OC 2. ZnCl,, -100 to +25 OC Me 3, CH,MgBr, -78 OC to 25 OC

1. HZ02,NaOH 2. TBDMS-Cl 3. cyclohexene/Pd(OH), CaC03, EtOH 4. PDC, CHzC12

qH165 Me

65% overall from 163 28% overall from 163

stegobiol stegobinone Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2535 Scheme 82. Hydrobenzoin-Derived Crown Ethers Used in Asymmetric Catalysis260

HoyoH HowoHPh'2' Ph Ph Ph (S,9-141 (R,R)-141 (S.5')-hydrobenzoin (R,R)-hydrobenzoin /\

(S,S)-DP18C6 (S,S,S,S)-TPl8C6 (R,R,R,R)-TP18C6

Table 56. Asymmetric Reduction of Aryl Ketones entire sequence was in the final purification of Mediated by (S,S,S,S)-TP18C62w*~b st egobiol . 3.3.2.4. Chiral Crown Ether Catalysts. Chiral Substrate Product Yield(%) % ee crown ethers270have been used in molecular recogni- I tion processes for the enantiomeric differentiation of racemic substrates as well as serving as chiral reagents or catalysts for asymmetric transformations. Several studies have utilized crown ether derivatives wherein chirality is introduced into the backbone through the incorporation of enantiomerically pure hydrobenzoin segments260(Scheme 82). QL"~.. 73 64 As an example of their use in asymmetric catalysis, Stoddart reported that (S,S)-DP18C6 mediated the asymmetric Michael addition of methyl phenylacetate to methyl acrylate, producing the diester product 167 3.3.2.5. Chiral Ligands for Asymmetric Cy. in 95% yield and 79% enantiomeric exce~~~~(eq 9). clopropanation. Enantiopure ketals formed with stilbene diol mediate the diastereoselective cyclopro- panation of a proximate olefinic bond258b(Table 57). moMe+VoMe%OK (0.5 eq.),toluene, / 0 (S,S)-DP18C6 (0.5 eq.) Previous work in this area had utilized ketals pre- -78 OC pared from 1,4-di-O-benzyl-~-threitoland the dias- (3.75 eq.) (2.5 eq.) tereoselectivities typically ranged from 7:l to 9:1.271 C02Me I However, the diastereomers produced were neither chromatographically separable nor crystalline, which precluded the isolation of enantiomerically pure cyclopropyl ketones. &167 Me Table 57. Diastereoselective of 95% yield 79% ee Enantiomerically Pure Ene KetalsZmb Equation 9. (S,S)-DPl€EG-mediated Michael addditon of methyl phenylacetate to methyl acrylate.255 Ene ketal Stoddart has also reported that catalytic amounts t-- of complexes of (R,R,R,R)-TP18C6with potassium cyanide promote the phase-transfer acylcyanation of benzaldehyde, when benzoyl chloride is used as a trapping reagent260b(eq 10). The optically active benzoylated cyanohydrin complex was obtained in 40% enantiomeric excess.

0 OCOPh (R,R,R,R)-TP18C6*KCN. H toluene, -78 "C --f 0 "C, PhCOCl

62% yield, 40% ee In addition, 1:l adducts of (S,S,S,S)-TP18C6with -borane mediate the enantioselective re- duction of prochiral aromatic ketones260a$b(Table 56). 2536 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. In contrast, good to excellent levels of diastereo- are crystalline, thereby offering a chance for optical selectivity were observed in the Simmons-Smith enrichment by recrystallization. In addition, any cyclopropanation reactions with ene ketals, formed number of diol derivatives (including Cz-symmetric by dehydrative ketalization of the corresponding diamines) may be prepared via the appropriate enones with (S,S)-(-)-hydr~benzoin.~~~~In each case manipulations described in previous sections, thus reported in Table 57, the mixtures of diastereomeric suggesting many ligand possibilities for use in future ketals were recrystallized from anhydrous ether to asymmetric reactions. give the major diastereomer as a pure compound. Removal of the ketal (2.7 M aqueous HC1 in MeOH) 4. Recent Applications: A Case Study provided a route to enantiomerically pure cyclopropyl ketones.258b (20s)-Camptothecin (168)is a pentacyclic alkaloid 3.3.2.6. Miscellaneous Applications. (R,R)-(+)- that was first isolated in 1966274and is currently one Hydrobenzoin derived ketals of cyclic ketones un- of the most important anticancer lead compounds dergo highly diastereoselective reductions to enan- discovered by screening natural products. In spite tiomerically pure secondary alcohols (Table 58). of the large number of synthetic analogs that have been prepared showing improved efficacy as potential Table 58. Diastereoselective Reduction of cancer treatments,275efficient synthetic routes to the Enantiopure Ketal~~'~ biologically active (20s)-camptothecinare fairly lim- ited.276Recently, Comins reported a highly conver- Ketal Major Diastereomeric Diastereomer Excess gent 10-step asymmetric synthesis of this target which utilizes the DE fragment 170 as the key chiral intermediate277(Scheme 83). Preparation of this in-

>98% 83% Scheme 83. Retrosynthetic Analysis of (2OS)-Camptothecin

>98% 86%

168 (20S)-camptothecin HOPhAph 0 >97% 86%

Hog aBr+ NO 298% 82% I H 169 170

termediate, however, required stoichiometric amounts Ketals of several cyclic ketones were prepared and of (-)-8-phenylmenthol, an expensive chiral auxil- then reduced under standard conditions (i.e. 6 equiv iary. Given this potential obstacle, two research of DIBAL-H, CH2C12, 0 "C). Excellent levels of groups have recently investigated the possibility of diastereoselectivity and good yields were observed in introducing chirality in the DE fragment using the all cases.272 asymmetric dihydroxylation. Their work is sum- 3.3.2.7. Summary. The preceding sections high- marized here. light the growing utility of enantiomerically pure CZ- With the goal of preparing optically active a-hy- symmetric diols and their derivatives as chiral ligands droxy lactones for use in a camptothecin synthesis, and auxiliaries in asymmetric reactions. Enan- Curran gained key insights through model studies tiopure hydrobenzoin and its derivatives have so far on closely related systems.278 This effort identified dominated these studies. This may be the result of three classes of alkenes: endocyclic ketene acetals, several factors. First, it is commercially available. endocyclic enol ethers, and exocyclic a,@unsaturated Second, it may be readily prepared in high enantio- lactones, all of which were new classes of olefins for meric excess273by asymmetric dihydroxylation of the AD reaction, while at the same time offering truns-stilbene, which to date is the best substrate for potentially attractive routes for an asymmetric syn- the AD reaction. Third, it can be released by hydro- thesis of the DE fragment. genolysis, a crucial advantage for substrates contain- Data obtained from the asymmetric dihydroxyla- ing acid-sensitive functionality. tion of ketene acetal derivatives are presented in In principle, however, any C2-symmetric diol may Table 59. Oxidation of 171a and 171b by the be prepared by asymmetric dihydroxylation of the standard procedure with commercially available AD- appropriate trans-olefin. In many instances the diols mix-@was slow, but acceptable rates were obtained Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2537 Table 59. The Asymmetric Dihydroxylation of Scheme 84. Asymmetric Dihydroxylation of Endocyclic Ketene Acetals278 Exocyclic a&Unsaturated Lactones278

AD-mix-P aOR a0 EtI Hd’ 171a-d (R)-172 E-174 Substrate R (R)-172, ee Yield 1 qodeoxygenation c q 171a TBDMS 40% 70% 0 OH 171b TIPS 30% 67% HO ’- OH 171c COPh 65 % 82% OH-. . 175 (8-172 171d CO(CH3)3 78% 100% 70% yield, 28% ee by increasing the concentration of Os and ligand to 0.5 and 2.5 mol %, respectively. Although the yields (67-70%) and ee’s (30-40%) for these substrates were disappointing, improvements in both yield and ee were realized on moving to enol ester derivatives. Dihydroxylation of 171c gave the desired a-hydroxy 2-176 ketone in 82% yield and 65% ee, and enol pivalate 171d gave the desired product in quantitative yield and 78% ee. However, for preparation of a DE ring fragment with the correct absolute configuration, dihydroxylations with this class of substrates would have to be carried out using AD-mix-a, which gener- 50% yield, 99% ee ally gives lower ee’s than AD-mix+ Scheme 85. Asymmetric Dihydroxylation Route to For this reason, the AD reactions of endocyclic enol the (2OS)-CamptothecinDE Ring Fragment ethers were investigated. A marked improvement in enantioselectivity was anticipated since this would require use of the more selective dihydroquinidine - ligands and enantioselectivities with trisubstituted KZC03 olefins are generally better than those obtained with MeS02NHz their tetrasubstituted counterparts. Dihydroxylation Et t-BuOH:HzO experiments carried out on 173 using the fortified 178 AD-mix-p provided the crystalline hydroxyladol which was immediately oxidized (IdCaC03). The desired 7(S)-hydroxy lactone, possessing the correct absolute configuration for the synthesis of (20S)-camptothecin was obtained in 90% yield and 74% ee.279 OH

179

2. I-JCaC03 Ligand Et HO ‘*Et (DHQD)zPHAL. 173 (9-172 (DHQD)zPYR 74% ee, 90% yield (AD-mix-a, (R)-172,63% ee, 89% yield) (DHQDhPHAL(i.e. AD-mix$) followed by oxidation, the hydroxylactone (S)-179was obtained in 26% eeZ8l The other substrates investigated by Curran were (Scheme 85). When the same reaction was carried the exocyclic alkenes 174 and 176 (Scheme 84). This out using (DHQD)z-PYR the same (S)-hydroxy lac- approach is attractive since conjugated alkenes often tone was produced in 94% ee! Even more impressive, give good results in the AD, however, extra synthetic conversion of (S)-179to the corresponding pyridone steps are now required to remove the unwanted (S)-170was carried out by refluxing in 1 N hydro- hydroxyl group. While the results with E-174were chloride acid after which crystalline enantiomerically disappointing, dihydroxylation of 2-176 with AD- pure (’95% ee) (SI-170was collected by filtration of mix-a provided the diol with the desired 7(S)con- the reaction mixture. figuration in 50% yield and 99% ee. It was subse- This AD route to (S)-179developed by Fang at quently found, however, that deoxygenation of the Glaxo is the one used to prepare a camptothecin diol was not straightforward. analog which is now in phase I1 clinical trials. As Independently, a group at Glaxo was also investi- such, it appears to be the best example of the AD in gating an AD route to a chiral DE ring fragment.280 a practical application. This camptothecin story also Their investigations focused on the asymmetric di- underscores another important trend in the AD’S hydroxylation of enol ether 178. When 178 was development, which is that the PYR ligands are an dihydroxylated under standard conditions with important complement to the PHAL ligands. While 2538 Chemical Reviews, 1994, Vol. 94,No. 8 Kolb et al. the PHAL ligands are certainly the best for typical Table 60. Comparison of the AD with Enzymatic trans-disubstituted, trisubstituted, and many tetra- Catalysts” substituted, as well as 1,l-disubstituted olefins, the catalyst turnover (min-l) PYR ligands exhibit dramatic improvements for chymotrypsin 6000 special cases in each of these classes. In fact, at the asymmetric dihydroxylation 3000 time of this writing, the most interesting AD results DNA polymerase 900 coming in from groups around the world are those tryptophan synthetase 120 which define the differences between the PHAL and lysozyme 30 PYR ligands. a AD value from the reaction of 2-vinylnaphthalene with Extensive structural and mechanistic studies have (DHQD)2PHAL in the original NMO system (acetone/water led to a good understanding of the nature of the (lO:l), room temperature). Enzyme values from ref 284. binding pocket in the PHAL ligand^^^,^^ (cf. section 1, Figure 3). A similar campaign is now underway binding effects seems to offer exciting prospects for to map out the more spacious binding pocket of the designing even better AD ligands as well as selective PYR ligands. catalysts for other transformations. The putative binding pocketkleft for which there 5. Conclusion is strong evidence26with the PHAL ligands (Figure 3) is, of course, reminiscent of the ubiquitous, non- The stoichiometric osmylation of olefins as per- covalent binding phenomena in enzymatic catalysis. fected by Criegee in the 1930s is generally regarded Since organic chemistry still trails its vitalistic as the most reliable synthetic transformation avail- origins, many will feel comfortable calling such able to organic chemists. The reasons are simple: binding “enzyme-like”. However, while these AD os04 reacts with all olefins, and it reacts only with catalysts share some properties with enzymatic cata- olefins. Admittedly, the “all” and “only”in this latter lysts, they have the distinctly nonenzymatic attribute statement are used with some poetic license; how- of combining high selectivity with enormous sub- ever, no other known organic reaction comes close to strate scope, as well as the ability to produce either achieving such enormous scope coupled with such enantiomer at will. Such features make these cata- great selectivity. lysts powerful tools, both for planning and for execut- Of course even a very reliable reaction will see little ing asymmetric syntheses of chiral organic molecules. use unless it provides a needed synthetic transforma- The ligand acceleration phenomenon can support tion. The stereospecific cis-dihydroxylation of olefins extremely efficient catalysis. For the AD of 2-vinyl- achieved by Os04 is one of the most valued trans- naphthalene in the homogeneous acetone/water sys- formations for introducing functionality into organic tem using NMO and (DHQD)zPHAL, a turnover molecules. The olefinic functional group is ubiqui- number of 3000/min at 25 “C has been determined.283 tous in organic synthesis because it is easy to This value is comparable to the turnover number of introduce, and because it is stable to the acidhase many enzymes (Table 60). The turnover number in catalysis generally employed to construct carbon the AD is often limited by the rate of hydrolysis of skeletons. Then, at just the right moment in a the intermediate osmate ester. The rate of formation synthetic sequence, the olefin’s presence is dramati- of the osmate ester from 24nylnaphthalene, 0~04, cally revealed by oxidative 1,2-addition of heteroat- and (DHQD12PHAL in tert-butyl alcohol has been oms. The ability to emplace heteroatoms in this shown to be extremely rapid (k, = 35600 M-l min-1),26 otherwise difficult to achieve2s2 1,2-relationship is and a turnover number much higher than the mea- another crucial reason why so many organic synthe- sured 3000/min would be possible if the hydrolysis ses employ one or more olefin oxidation steps. step were not rate limiting. From a process research With most olefins, the AD also provides the nearly perspective, one of the most important remaining quantitative yield of diol one has come to expect in challenges for improving the AD is to find yet better catalytic osmylations through experience with the ways to increase the rate of osmate ester hydrolysis Upjohn Process.14 [The latter process is renowned and thereby increase catalytic efficiency. for effecting “spot-to-spot” transformations yielding Finally, the discovery of a “binding pocket” in the pure diol without chromatography.] These high PHAL and PYR ligands anticipates limitations in yields taken together with the enormous scope docu- substrate scope. Such limitations have indeed been mented for the AD in this review make it easy to found with the parent ligands.36 New ligands with predict that henceforth olefins will be seeing more tighter binding pockets are now being synthesized of os04 than ever before. to see if we can add back to our catalysts some of the Regarding enantioselectivity and especially, scope, substrate-restrictiodrecognitionfeatures seen with the AD system is unique among selective man-made enzymes. These studies are more aimed at testing catalysts. Two factors in particular are believed to hypotheses about the mechanism and the binding contribute to the AD’S success: (1) it is the first pocket than at producing new ligands with tailored highly effective nonenzymic catalyst depending on “lock-and-key”properties. After all, from a synthetic noncovalent binding for rate acceleration and selec- chemist’s viewpoint, the most attractive feature of ti~ity,~~,~~and (2) it is the most dramatic example to man-made selective catalysts is their great scope. date of “ligand accelerated catalysis’’ (a term we coined while studying the phenomenon in this sys- Acknowledgments. We are especially grateful to tem9. The importance of the LAC phenomenon in the colleagues and friends who gave us excellent asymmetric catalysis is the subject of a recent advice and help during the writing of this review. review.8d The newer observation of “noncovalent” K.B.S. thanks the National Institutes of Health (GM- Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2539 28384), the National Science Foundation (CHE- H. C. Kolb, P. G. Andersson, and K. B. Sharpless, 92960551,and the W. M. Keck Foundation for finan- Towards an Understanding of the High Enantiose- cial support. H.C.K. and M.S.V. thank the Deutsche lectivity in the Osmium-Catalyzed Asymmetric Di- Forschungsgemeinschaft and the National Institutes hydroxylation (AD). Part 1: Kinetics (J.Am. Chem. of Health, respectively, for postdoctoral fellowships. SOC.1994, 116, 1278). P.-0. Norrby, H. C. Kolb, and K. B. Sharpless, Appendix Towards an Understanding of the High Enantiose- lectivity in the Osmium Catalyzed Dihydroxylation The following is a list of all the publications from (AD). Part 2. A Qualitative Molecular Mechanics the Sharpless group relating to osmium-catalyzed Approach (J.Am. Chem. SOC.,1994,116,8470). oxidations of olefins, including all the asymmetric H. Becker, P. T. Ho, H. C. Kolb, S. Loren, P.-0. dihydroxylation publications beginning with the Henb Norrby, and K. B. Sharpless, Comparing Two Models ges paper in 1980. It is hoped that access to the titles for the Selectivity in the Asymmetric Dihydroxylation will facilitate location of specific topics of interest. Reaction (Tetrahedron Lett., 1994, 35, 7315). Osmylation Process Development Asymmetric Dihydrox lation-Discovery, K. B. Sharpless and K. Akashi, Osmium Catalyzed Development, and Su1: strate Scope Vicinal Hydroxylation of Olefins by tert-Butyl Hy- S. G. Hentges and K. B. Sharpless, Asymmetric droperoxide Under Alkaline Conditions (J.Am. Chem. Induction in the Reaction of Osmium Tetroxide with SOC.1976, 98, 1986). Olefins (J.Am. Chem. SOC.1980,102,4263). K. Akashi, R. E. Palermo, and K. B. Sharpless, A E. N. Jacobsen, I. Markb, W. S. Mungall, G. Major Improvement in the Osmium Catalyzed Vici- Schroder, and K. B. Sharpless, Asymmetric Dihy- nal Hydroxylation of Olefins by tert-Butyl Hydro- droxylation via Ligand-Accelerated Catalysis (J.Am. peroxide (J.Org. Chem. 1978,43,2063). Chem. SOC.1988, 110, 1968). B. B. Lohray, T. H. Kalantar, B. M. Kim, C. Y. Kinetics and Mechanism Park, T. Shibita, J. S. M. Wai, and K. B. Sharpless, K. B. Sharpless and D. R. Williams, The Reactions Documenting the Scope of the Catalytic Asymmetric of Olefins with Permanganate, Ruthenium Tetroxide, Dihydroxylation (Tetrahedron Lett. 1989,30,2041). and Osmium Tetroxide; Dependence of Rate on H. Kwong, C. Sorato, Y. Ogino, H. Chen, and K. B. Degree of Substitution (Tetrahedron Lett. 1975, Sharpless, Preclusion of the “Second Cycle” in the 3045). Osmium-Catalyzed Asymmetric Dihydroxylation of E. N. Jacobsen, I. Markb, M. B. France, J. S. Olefins Leads to a Superior Process (Tetrahedron Svendsen, and K. B. Sharpless, Kinetic Role of the Lett. 1990,31,2999). Alkaloid Ligands in Asymmetric Catalytic Dihy- B. M. Kim and K. B. Sharpless, Heterogeneous droxylation (J.Am. Chem. SOC.1989,111, 737). Catalytic Asymmetric Dihydroxylation: Use of a J. S. M. Wai, I. Markb, J. S. Svendsen, M. G. Finn, Polymer-Bound Alkaloid (Tetrahedron Lett. 1990,31, E. N. Jacobsen, and K. B. Sharpless, A Mechanistic 3003.) Insight Leads to a Greatly Improved Osmium- T. Shibata, D. G. Gilheany, B. K. Blackburn, and Catalyzed Asymmetric Dihydroxylation Process (J. K. B. Sharpless, Ligand-Based Improvement of Enan- Am. Chem. SOC.1989,111, 1123). tioselectivity in the Catalytic Asymmetric Dihydroxy- K. B. Sharpless and I. E. Markb, Ligand-Acceler- lation of Dialkyl Substituted Olefins (Tetrahedron ated Catalytic Asymmetric Dihydroxylation (U.S. Lett. 1990,31,3817). Patent 4,965,364,1990 assigned to Massachusetts C. Park, B. M. Kim, and K. B. Sharpless, Catalytic Institute of Technology.) Osmylation of Conjugated Dienes: A One-Pot Ste- T. Gobel and K. B. Sharpless, Temperature Effects reoselective Synthesis of Polyols (Tetrahedron Lett. in Asymmetric Dihydroxylation: Evidence for a 1991,32,1003). Stepwise Mechanism (Angew. Chem., Int. Ed. Engl. B. McKee, D. Gilheany, and K. B. Sharpless, R,R- 1993,32,1329). 1,2-Diphenyl-l,2-ethanediol(stilbene diol) (Org. Synth. P. G. Andersson and K. B. Sharpless, A Dramatic 1991, 70, 47). Ligand Effect on the Relative Reactivities of Substi- Y. Ogino, H. Chen, H. L. Kwong, and K. B. tuted Alkenes with Osmium Tetroxide (J.Am. Chem. Sharpless, On the Timing of HydrolysisReoxidation SOC.1993, 115, 7047). in the Osmium-Catalyzed Asymmetric Dihydroxyla- H. C. Kolb, P. G. Andersson, Y. L. Bennani, G. A. tion of Olefins Using Potassium Ferricyanide as the Crispino, K.-S. Jeong, H.-L. Kwong, and K. B. Sharp- Reoxidant (Tetrahedron Lett. 1991, 32, 3965). less, On “The Origin of High Enantioselectivity in the K. B. Sharpless, W. Amberg, M. Beller, H. Chen, Dihydroxylation of Olefins Using Osmium Tetroxide J. Hartung, Y. Kawanami, D. Lubben, E. Manoury, and Cinchona Alkaloid Catalysts’’ (J.Am. Chem. SOC. Y. Ogino, T. Shibata, and T. Ukita, New Ligands 1993,115, 12226). Double the Scope of the Catalytic Asymmetric Dihy- P-0 Norrby, H. Kolb, and K. B. Sharpless, Calcula- droxylation of Olefins (J.Org. Chem. 1991,56,4585). tions on the Reaction of Ruthenium Tetroxide with Y. Ogino, H. Chen, E. Manoury, T. Shibata, M. Olefins Using Density Functional Theory (DFT). Beller, D. Lubben, and K. B. Sharpless, A Ligand Implications for the Possibility of Intermediates in Structure-EnantioselectivityRelationship for the Os- the Osmium-catalyzed Asymmetric Dihydroxylation mium-Catalyzed Asymmetric Dihydroxylation of Ole- (AD) (Organometallics 1994,13, 344). fins (Tetrahedron Lett. 1991,32, 5761.) 2540 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al. K. B. Sharpless, W. Amberg, Y. Bennani, G. Cris- Dihydroxylation of Tetrasubstituted Olefins (J.Am. pino, J. Hartung, K. Jeong, H. Kwong, K. Morikawa, Chem. SOC.1993,115, 8463). Z. M. Wang, D. Xu, and X. L. Zhang, The Osmium- K. Morikawa and K. B. Sharpless, Double Diaste- Catalyzed Asymmetric Dihydroxylation (AD): A New reoselection in Asymmetric Dihydroxylation (Tetra- Ligand Class and a Process Improvement (J. Org. hedron Lett. 1993,34, 5575). Chem. 1992,57,2768). Z.-M. Wang and K. B. Sharpless, Asymmetric K.-S. Jeong, P. Sjo, and K. B. Sharpless, Asym- Dihydroxylation of Tertiary Allylic Alcohols (Tetra- metric Dihydroxylation of Enynes (TetrahedronLett. hedron Lett. 1993,34,8225). 1992,33,3833). G. Crispino, A. Makita, Z.-M. Wang, and K. B. G. Crispino and K. B. Sharpless, Asymmetric Sharpless, A Comparison of Ligands Proposed for the Dihydroxylation of Squalene (TetrahedronLett. 1992, Asymmetric Dihydroxylation (TetrahedronLett. 1994, 33, 4273). 35, 543). L. Wang and K. B. Sharpless, Catalytic Asym- P. J. Walsh, P. T. Ho, S. B. King, and K. B. metric Dihydroxylation of Cis-Disubstituted Olefins Sharpless, Asymmetric Dihydroxylation of Olefins (J.Am. Chem. SOC.1992, 114, 7568). Containing Sulfur: Chemoselective Oxidation of C-C D. Xu, G. A. Crispino, and K. B. Sharpless, Selec- Double Bonds in the Presence of Sulfides, 1,3- tive Asymmetric Dihydroxylation (AD) of Dienes (J. Dithianes, and Disulfides (Tetrahedron Lett., 1994, Am. Chem. SOC.1992,114, 7570). 35, 5129). T. Hashiyama, K. Morikawa, and K. B. Sharpless, H. Becker, M. A. Soler, and K. B. Sharpless, a-Hydroxy Ketones in High Enantiomeric Purity Selective Asymmetric Dihydroxylation of Polyenes from Asymmetric Dihydroxylation of Enol Ethers (J. (Tetrahedron,in press). Org. Chem. 1992,57, 5067). D. J. Berrisford, C. Bolm, and K. B. Sharpless, Z. M. Wang and K. B. Sharpless, Asymmetric Ligand Accelerated Catalysis (Angew. Chem., Int. Ed. Dihydroxylation of a-Substituted Styrene Derivatives Engl., in press). (SynZett 1993,8, 603). P. J. Walsh and K. B. Sharpless, Asymmetric Synthetic Applications and Manipulation of Diol Dihydroxylation (AD) of a,P-Unsaturated Ketones Intermediates (Synlett 1993,8, 605). Y. Gao and K. B. Sharpless, Vicinal Diol Cyclic G. A. Crispino, P. T. Ho, and K. B. Sharpless, Sulfates: Like Epoxides Only More Reactive (J.Am. Selective Perhydroxylation of Squalene: Taming the Chem. SOC.1988, 110, 7538). Arithmetic Demon (Science 1993,259,64). B. B. Lohray, Y. Gao, and K. B. Sharpless, One Pot M. S. VanNieuwenhze and K. B. Sharpless, The Synthesis of Homochiral Aziridines and Aminoalco- Asymmetric Dihydroxylation of cis-Allylic and Ho- hols from Homochiral 1,2-Cyclic Sulfates (Tetrahe- moallylic Alcohols (TetrahedronLett. 1994,35,843). dron Lett. 1989,30, 2623). D. Xu, C. Y. Park, and K. B. Sharpless, Study of B. M. Kim and K. B. Sharpless, Cyclic Sulfates the Regio- and Enantioselectivity of the Reactions of Containing Acid-Sensitive Groups and Chemoselec- Osmium Tetroxide with Allylic Alcohols and Allylic tive Hydrolysis of Sulfate Esters (Tetrahedron Lett. Sulfonamides (Tetrahedron Lett. 1994,35, 2495). 1989,30, 655). K. P. M. Vanhessche, Z.-M. Wang, and K. B. B. M. Kim and K. B. Sharpless, A Short Route to Sharpless, Asymmetric Dihydroxylation of Primary P-Lactams: Use of Cyclic Sulfites From Syn-2,3- Allylic Halides and a Concise Synthesis of (-)- Dihydroxy Esters (TetrahedronLett. 1990,31,4317). Diepoxybutane (Tetrahedron Lett. 1993, 35, 3472). P. R. Fleming and K. B. Sharpless, Selective Y. L. Bennani and K. B. Sharpless, Asymmetric Transformation of threo-2,3-Dihydroxy Esters (J. Dihydroxylation (AD) of Nfl-Dialkyl and N-Methoxy- Org. Chem. 1991,56, 2869). N-methyl a,P-and P,y-Unsaturated Amides (Tetra- R. Oi and K. B. Sharpless, Stereospecific Conver- hedron Lett. 1993,34, 2079). sion of Chiral 1,2-Cyclic Sulfates to Chiral Imidazo- Z. M. Wang, X. L. Zhang, and K. B. Sharpless, lines (Tetrahedron Lett. 1991,32,999). Asymmetric Dihydroxylation of Aryl Allyl Ethers R. Oi and K. B. Sharpless, Facile Synthesis of (Tetrahedron Lett. 1993,34, 2267). Enantiopure trans-2,3-Diphenyl-l,4-Diazabicyclo- M.Arrington, Y. L. Bennani, T. Gobel, P. Walsh, [2.2.2.loctane (Tetrahedron Lett. 1991,32, 4853). S.-H. Zhao, and K. B. Sharpless, Modified Cinchona R. Oi and K. B. Sharpless, Asymmetric Dihydroxy- Alkaloid Ligands: Improved Selectivities in the Os- lation of Acrolein Acetals: Synthesis of Stable Equiva- mium Tetroxide Catalyzed Asymmetric Dihydroxy- lents of Enantiopure Glyceraldehyde and Glycidal- lation (AD) of Terminal Olefins (Tetrahedron Lett. dehyde (TetrahedronLett. 1992,33, 2095). 1993,34, 7375). T. Kalantar and K. B. Sharpless, Transformations G. Crispino, K.-S. Jeong, H. Kolb, Z.-M. Wang, D. of Hydroxy Cyclic Sulfates: Stereospecific Conversion Xu, and K. B. Sharpless, Improved Enantioselectivity to 2,3,5-Trisubstituted Tetrahydrofurans (Acta Chem. in Asymmetric Dihydroxylations of Terminal Olefins Scand. 1993,47, 307). Using Pyrimidine Ligands (J. Org. Chem. 1993,58, Z. M. Wang, X. L. Zhang, K. B. Sharpless, S. C. 3785). Sinha, A. Sinha-Bagchi, and E. Keinan, A General M. S.VanNieuwenhze and K. B. Sharpless, Kinetic Approach to y-Lactones via Osmium-Catalyzed Asym- Resolution of Racemic Olefins via Asymmetric Dihy- metric Dihydroxylation. Synthesis of (-1- and (+I- droxylation (J.Am. Chem. SOC.1993, 115, 7864). Muricatacin (Tetrahedron Lett. 1992,33, 6407). K. Morikawa, J. Park, P. G. Andersson, T. Hash- E. Keinan, S. C. Sinha, A. Sinha-Bagchi, Z. M. iyama, and K. B. Sharpless, Catalytic Asymmetric Wang, X. L. Zhang, and K. B. Sharpless, Synthesis Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2541 of All Four Isomers of Disparlure Using Osmium- of Osmium Tetroxide-Cinchona Alkaloid Complexes Catalyzed Asymmetric Dihydroxylation (Tetrahedron (J.Org. Chem. 1989,54, 2263). Lett. 1992, 33, 6411). G. D. H. Dijkstra, R. M. Kellogg, H. Wynberg, J. H. C. Kolb and K. B. Sharpless, A Simplified S. Svendsen, I. Markb, and K. B. Sharpless, Confor- Procedure for the Stereospecific Transformation of mational Study of Cinchona Alkaloids. A Combined 1,ZDiols into Epoxides (Tetrahedron 1992,48,10515). NMR, Molecular Mechanics and X-Ray Approach (J. G. A. Crispino and K. B. Sharpless, Enantioselec- Am. Chem. SOC.1989,111,8069). tive Synthesis of Both Enantiomers of 7,7-Dimethyl- R. M. Pearlstein, B. K. Blackburn, W. M. Davis, 6,8-dioxabicyclo-[3.2.lloctanevia Regioselective Asym- and K. B. Sharpless, Structural Characterization of metric Dihydroxylation (Synlett 1993, 1, 47). the Pseudoenantiomeric Cis-Dioxo Osmium(VI) Es- H. C. Kolb, Y. L. Bennani, and K. B. Sharpless, ters of Chiral Diols with Cinchona Alkaloid Ligands Short and Practical Syntheses of (R)-(-)-Carnitine (Angew. Chem., Int. Ed. Engl. 1990,29, 639). and (R)-(-)-y-Amino-P-hydroxybutyricAcid (GABOB) W. Amberg, Y. L. Bennani, R. J. Chadha, G. A. (Tetrahedron: Asymmetry 1993,4, 133). Crispino, W. D. Davis, J. Hartung, K.-S. Jeong, Y. D. Xu and K. B. Sharpless, A Simple Route to Ogino, T. Shibata, and K. B. Sharpless, Syntheses Enantiomerically Enriched Oxazolidin-2-ones (Tet- and Crystal Structures of the Cinchona Alkaloid rahedron Lett. 1993, 34, 951). Derivatives used as Ligands in the Osmium-Cata- Y. L. Bennani and K. B. Sharpless, Asymmetric lyzed Asymmetric Dihydroxylation (AD) of Olefins (J. Synthesis of y-Hydroxy a,P-Unsaturated Amides via Org. Chem. 1993, 58, 844). an AD-Elimination Process; Synthesis of (+)-Coriolic D. V. McGrath, G. D. Brabson, K. B. Sharpless, and Acid (Tetrahedron Lett. 1993, 34, 2083). L. Andrews, Reinvestigation of the Infrared Spectra S. Okamoto, K. Tani, F. Sato, K. B. Sharpless, and of Oxoosmium(VI) Esters by Isotopic Labeling (Inorg. D. Zargarian, Synthesis of Optically Active Secondary Chem. 1993,32, 4164). Allylic Alcohols from Allylsilanes via Successive Asymmetric Dihydroxylation (AD) and Peterson Ole- Oxyamination fination Reactions (Tetrahedron Lett. 1993,34,2509). K. B. Sharpless, D. W. Patrick, L. K. Truesdale, G. A. Crispino and K. B. Sharpless, Enantioselec- and S. A. Biller, A New Reaction. Stereospecific tive Synthesis of Juvenile Hormone I11 in Three Steps Vicinal Oxyamination of Olefins by Alkyl Imido from Methyl Farnesoate (Synthesis 1993, 8, 777). Osmium Compounds (J.Am. Chem. SOC.1975, 97, P. J. Walsh, Y. L. Bennani, and K. B. Sharpless, 2305). Asymmetric Dihydroxylation (AD)/Cyclization of N- K. B. Sharpless, A. 0. Chong, and K. Oshima, DiBoc Allylic and Homoallylic Amines: Selective Osmium Catalyzed Oxyamination of Olefins by Differentiation of the Hydroxyl Groups (Tetrahedron Chloramine-T (J.Org. Chem. 1976,41, 177). Lett. 1993, 34, 5545). I. Henderson, B. Sharpless, and C.-H. Wong, A. 0. Chong, K. Oshima, and K. B. Sharpless, K. Synthesis of and Synthesis of Carbohydrates via Tandem Use of the Dioxo(tert-alkylimido)Osmium(VIII) Osmium-Catalyzed Asymmetric Dihydroxylation and Oxotris(tert-alkylimido)Osmium(VIII) Complexes. Ste- reospecific Vicinal Diamination of Olefins (J. Am. Enzyme-Catalyzed Aldol Addition Reactions (J.Am. Chem. SOC.1994,116, 558). Chem. SOC.1977, 99, 3420). D. Xu and K. B. Sharpless, Synthesis and Stereo- D. W. Patrick, L. K. Truesdale, S. A. Biller, and K. chemical Assignments for Goniobutenolides A and B B. Sharpless, Stereospecific Vicinal Oxyamination of Olefins by Alkyl Imido Osmium Compounds (J.Org. (Tetrahedron Lett. 1994, 35, 4685). Chem. 1978,43,2628). R. Oi and K. B. Sharpless, 3-(1S,2-Dihydroxy- E. Herranz and K. B. Sharpless, Improvements in ethyl)-1,5-Dihydro-3H-2,4-Benzodioxepine (Org. Synth., in press). the Osmium Catalyzed Oxyamination of Olefins by Chloramine-T (J. Org. Chem. 1978, 43, 2544). Z.-M. Wang, H. C. Kolb, and K. B. Sharpless, A Large-Scale and Highly Enantioselective Synthesis E. Herranz, S. A. Biller, and K. B. Sharpless, of the Tax01 C-13 Side Chain Through Asymmetric Osmium-Catalyzed Vicinal Oxyamination of Olefins Dihydroxylation (AD) Org. Chem., 1994,59,5104). by N-Chloro-N-argentocarbamates(J. Am. Chem. (J. SOC.1978, 100, 3596). S. B. King and K. B. Sharpless, An Efficient Synthesis of Enantiomerically Pure trans-2-Phenyl- E. Herranz and K. B. Sharpless, Osmium-Cata- cyclohexanol (Tetrahedron Lett. 1994,35, 5611). lyzed Vicinal Oxyamination of Olefins by N-Chloro- N-metallocarbamates (J.Org. Chem. 1980,45,2710). Y. L. Bennani, K. P. M. Vanhessche, and K. Barry Sharpless, A Short Route to a Mosher’s Acid Precur- S. G. Hentges and K. B. Sharpless, Improved sor Via Catalytic Asymmetric Dihydroxylation (AD) Procedure for the Oxyamination of Olefins with (Tetrahedron: Asymmetry 1994, 5, 1473). Trioxo(tert-butylimido)osmium(VIII)(J. Org. Chem. 1980, 45, 2257). Z.-M. Wang and K. B. Sharpless, A Solid-to-Solid Asymmetric Dihydroxylation Procedure for Kilo-Scale E. Herranz and K. B. Sharpless, Osmium Cata- Preparation of Enantiopure Hydrobenzoin (J. Org. lyzed Vicinal Oxyamination of Olefins by Chlor- Chem., in press). amine-T: czs-2-(p-Toluenesulfonamido)cyclohexanol and 2-Methyl-3-(p-toluenesulfonamido)-2-pentanol Structural Data for Ligands and Complexes (Org. Synth. 1983, 61, 85). E. Herranz and K. B. Sharpless, Osmium Cata- J. S. Svendsen, I. Markb, E. N. Jacobsen, Ch. P. lyzed Vicinal Oxyamination of Olefins by N- Rao, S. Bott, and K. B. Sharpless, On the Structure Chloro-N-argentocarbamates: threo-N-(l-Hydroxy- 2542 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

1,2- diphenyl-2-yl ) Ethy 1 Carbamate ( 0rg . Syn t h . Tokles, M.; Snyder, J. K. Tetrahedron Lett. 1986,27, 3951. (n) Imada, Y.; Saito, T.; Kawakami, T.; Murahashi, S.-I. Tetrahedron 1981, 61, 93). Lett. 1992, 33, 5081. (17) (a) Cleare, M. J.; Hydes, P. C.; Griffith, W. P.; Wright, M. J. J. Reviews Chem. SOC.,Dalton Trans. 1977, 941. (b) Grifith, W. P.; Skapski, A. C.; Woode, K. A.; Wright, M. J. Inorg. Chim. Acta R. A. Johnson and K. B. Sharpless, Catalytic 1978,31, L413. Asymmetric Dihydroxylation (Catalytic Asymmetric (18) Jacobsen. E. N.: Marko. I.: Muneall. W. S.: Schroder. G.: Sharpless, K. B. 2. Am. &em. Soc.-1988, 110, '1968. Synthesis, Iwao Ojima, Ed.; VCH Publishers, 1993). (19) Wai, J. S. M.; Marko, I.; Svendsen, J. S.; Finn, M. G.; Jacobsen, K. B. Sharpless, Coelacanths and Catalysis (Tet- E. N.; Sharpless, K. B. J. Am. Chem. SOC.1989, 111, 1123. rahedron 1994,50, 4235). (20) Kwong, H.-L.; Sorato, C.; Ogino, Y.; Chen, H.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 2999. (21) For example, in the absence of MeSOzNH2, trans-5-decenewas 6. References and Footnotes only partially (70%) converted to the corresponding diol after 3 days at 0 "C, whereas the diol was isolated in 97% yield after (1) For recent reviews, see: Catalytic Asymmetric Synthesis; Ojima, only 10 h at 0 "C in the presence of this additive, see ref 23a. I., Ed.; VCH Publishers: New York, 1993. (22) Gobel, T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1993, (2) a-Acylaminoacrylic acids can be hydrogenated in high ee using 32, 1329. Rh(1) complexes with chiral diphosphine ligands; for a recent (23) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. review, see: Takaya, H.; Ohta, T.; Noyori, R. Asymmetric A,; Hartung, J.;Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Hydrogenation. In Catalytic Asymmetric Synthesis; Ojima, I., Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. For Ed.; VCH Publishers: New York, 1993; pp 1-39. simplified experimental procedures for the preparation of the (3) For a recent review, see: Akutagawa, S.; Tani, K. Asymmetric phthalazine ligands as well as an X-ray crystal structure, see: Isomerization of Allylamines. In Catalytic Asymmetric Synthe- (b) Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.; sis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 41- Davis, W. D.; Hartung, J.;Jeong, K.-S.; Ogino, Y.; Shibata, T.; 61. Sharpless, K. B. J. Org. Chem. 1993, 58, 844. (4) For a recent review, see: Jacobsen, E. N. Asymmetric Catalytic (24) Crispino, G. A,; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Epoxidation of Unfunctionalized Olefins. In Catalytic Asym- Sharpless, K. B. J. Org. Chem. 1993, 58, 3785. metric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, (25) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, 1993; pp 159-202. J.; Kawanami, Y.; Liibben, D.; Manoury, E.; Ogino, Y.;Shibata, (5) Sharuless, K. B. Tetrahedron 1994, 50, 4235 T.; Ukita, T. J. Org. Chem. 1991, 56, 4585. (6) (a) Fbr a recent review, see: Johnson, R. A,; Sharpless, K. B. Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Cuta- (26) Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. lytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New SOC.1994,116, 1278. York, 1993; pp 103-158. (b) For mechanistic details, see: (27, For a density functional theory (DFT) study on possible inter- Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. SOC. mediates in the reaction of Ru04 with olefins, see: (a) Norrby, 1991,113, 106. (c) Finn, M. G.; Sharpless, K. B. J.Am. Chem. P.-0.; Kolb, H. C.; Sharpless, K. B. Organometallics 1994, 13, SOC.1991,113,113. (d) Finn, M. G. Ph.D. Thesis, Massachusetts 344. For a modified MM2 force field for the calculation of Institute of Technology, 1985. osmaoxetane complexes, see: (b) Norrby, P.-0.; Kolb, H. C.; (7) For earlier reviews of the AD reaction, see: (a)Johnson, R. A,; Sharpless, K. B. J. Am. Chem. SOC.1994, 116, 8470. For Sharpless, K. B. Catalytic Asymmetric Dihydroxylation. In Hartree-Fock calculations on Os complexes using a quasirela- tivistic effective core potential for Os, see: (c) Veldkamp, A,; Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publish- Frenking, G. J. Am. Chem. SOC.1994, 116, 4937. For a ers: New York, 1993; pp 227-272. (b) Lohray, B. B. Tetrahe- molecular mechanics model for rationalizing the stereoselectivity dron: Asymmetry 1992,3, 1317-1349. of the AD with diamine ligands based on a [3 21 mechanism, (8) (a) Jacobsen, E. N.; Mark6, I.; France, M. B.; Svendsen, J. S.; + Sharpless, K. B. J.Am. Chem. SOC.1989,111, 737. (b) Kolb, H. see: (d) Wu, Y.-D.; Wang, Y.; Houk, K. N. J. Org. Chem. 1992, C.; Andersson, P. G.; Bennani, Y. L.; Crispino, G. A,; Jeong, K.- 57, 1362. S.; Kwong, H.-L.; Sharpless, K. B. J.Am. Chem. SOC.1993,115, (28) Hale, K. J.; Manaviazar, S.; Peak, S. A. TetrahedronLett. 1994, 12226. (c) Kwong, H.-L. Ph.D. Thesis, Massachusetts Institute 35, 425. of Technology, 1993. For a recent review of ligand accelerated (29) Wang, L.; Sharpless, K. B. J.Am. Chem. SOC.1992, 114, 7568. catalysis, see: (d) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. (30) Corey, E. J.;Noe, M. C.; Sarshar, S. J. Am. Chem. SOC.1993, Angew. Chem., in press. 115, 3828. (9) (a) Criegee, R. Justus Liebigs Ann. Chem. 1936, 522, 75. (b) (31) Lohray, B. B.; Bhushan, V. Tetrahedron Lett. 1992, 33, 5113. Criegee, R. Angew. Chem. 1937,50, 153. (c)Criegee, R. Angew. See also ref 111. Chem. 1938,51,519. (d) Criegee, R.; Marchand, B.; Wannowias, (32) Both of the ligands in question were prepared and tested by the H. Justus Liebigs Ann. Chem. 1942, 550, 99. The [3 + 21 Sharpless group at MIT as part of the screening process. They mechanism was originally proposed by Boseken: (e) Boseken, were rejected due to the observed superiority of the phthalazine J. Reel. Trau. Chim. 1922,41,199. For the [Z + 21 mechanism, class of ligands in virtually all applications of the AD reaction: see: (0 Sharpless, K. B.; Teranishi, A. Y.;Backvall, J.-E. J. Am. Hartung, J.; Jeong, K.-S.; Sharpless, K. B. Unpublished results. Chem. SOC.1977, 99, 3120. (g) Jorgensen, K. A,; Schiott, B. (The ligands are included in MIT's U.S. Pat. Appl. Chem. Reu. 1990,90, 1483. No. 077/775, 683, Oct 10, 1991.) (10) For a general review of the osmylation of olefins and the various (33) Crispino, G. A,; Makita, A,; Wang, Z.-M.; Sharpless, K. B. methods available for the reoxidation of Os(VI) glycolates, see: Tetrahedron Lett. 1994, 35, 543. Schroder, M. Chem. Rev. 1980, 80, 187. (34) The phthalazine ligands and the AD-mixes are available from (11) Hofmann, K. A. Chem. Ber. 1912,45, 3329. Aldrich Chemical Co. [AD-mix-a, no. 39,275-8;AD-mix$, no. 39,- (12) (ai Milas, N. A.; Sussman, S. J.Am. Chem. SOC.1936,58,1302. 276-6; (DHQ)2PHAL, no. 39,272-3; (DHQD)2PHAL, no. 39273- (bi Milas, N. A,; Trepagnier, J. H.; Nolan, J. T., Jr.; Iliopulos, 1;(DHQD)2-PYR, no. 41,895-1; (DHQ)*-PYR,no. 41,897-81. The M. I. J. Am. Chem. SOC.1959,81, 4730. cinchona alkaloids, needed for the preparation of these ligands (13) Sharpless, K. B.; Akashi, K. J. Am. Chem. SOC.1976, 98, 1986. are also sold by Aldrich [hydroquinidine, no. 35,934-3; hydro- (14) (a)Schneider. W. P.: McIntosh. A. V. U.S. Patent 2.769.824 Nov. quinine, no. 33,771-41. 6, 1956. (b) VanRheenen, V.;'Kelly, R. C.; Cha, D. Y.'Tetrahe- (35) See ref 30 and (a) Corey, E. J.; Lotto, G. I. Tetrahedron Lett. dron Lett. 1976. 1973. 1990,31, 2665. Corey has recently withdrawn his mechanistic (15) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, proposal which was based on a supposedly highly reactive p-oxo- 766. bridged bis-(Os04) species and proposed an alternative mecha- (16) (a) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. SOC.1980, nism which involves sandwich-like stacking of the olefin between 102, 4263. (bi Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, the two methoxyquinoline units of the "dimeric" ligand; see: (b) S.; Sanceau, J.-Y.; Bennani, Y. L. J. Org. Chem. 1993,58, 1991. Corey, E. J.; Noe, M. C. J. Am. Chem. SOC.1993, 115, 12579. (c) Corey, E. J.; Jardine, P. D.; Virgil, S.; Yuen, P.-W.; Connell, (c) Corey, E. J.;Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, R. D. J. Am. Chem. SOC.1989, 111, 9243. (d) Tomioka, K.; 35, 2861. Nakajima, M.; Koga, K. J.Am. Chem. SOC.1987,109, 6213. (e) (36) Becker, H.; Ho, P. T.; Kolb, H. C.; Loren, S.; Norrby, P.-0.; Tomioka, K.; Nakajima, M.; Iitaka, Y.; Koga, K. Tetrahedron Sharpless, K. B. Tetrahedron Lett. 1994, 35, 7315. Lett. 1988, 29, 573. (0 Tomioka, K.; Nakajima, M.; Koga, K. (37) Vanhessche, K. P. M.; Sharpless, K. B. Manuscript in prepara- Tetrahedron Lett. 1990, 31, 1741. (9) Nakajima, M.; Tomioka, tion. K.; Iitaka, Y.;Koga, K. Tetrahedron 1993, 49, 10793. (h) Fuji, (38) (a) Kolb, H. C.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron: K.; Tanaka, K.; Miyamoto, H. Tetrahedron Lett. 1992,33,4021. Asymmetry 1993, 4, 133. (b) Arrington, M. P.; Bennani, Y. L.; (i) Oishi, T.; Hirama, M. Tetrahedron Lett. 1992, 33, 639. (j) &bel, T.; Walsh, P. J.; Zhao, S.-H.;Sharpless, K. B. Tetrahedron Hirama, M.; Oishi, T.; It& S. J. Chem. SOC.,Chem. Commun. Lett. 1993, 34, 7375. 1989, 665. (k) Oishi, T.; Hirama, M. J. Org. Chem. 1989, 54, (39) Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron 5834. (1) Yamada, T.; Narasaka, K. Chem. Lett. 1986,131. (mi Lett. 1994, 35, 3469. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994, Vol. 94, No. 8 2543

(40) (a)Okamoto, S.; Tani, K.; Sato, F.; Sharpless, K. B.; Zargarian, (62) While we normally use 0.2 mol % of os04 in the reaction, the D. TetrahedronLett. 1993,34,2509. (b) Soderquist, J. A.; Rane, amount in the AD-mixes has been increased to 0.4 mol % to A. M.; Lbpez, C. J. Tetrahedron Lett. 1993, 34, 1893. (c) prevent variations in reaction rates due to potential inhomoge- Bassindale, A. R.; Taylor, P. G.; Xu, Y. J. Chem. SOC.,Perkin neities in the mixture. On the other hand, less than 0.2 mol % Trans. 1 1994, 1061. of os04 may be used in certain cases if one wishes to "optimize" (41) (a)Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. TetrahedronLett. the amounts of the key reagents for economic reasons in a large- 1993,34,2267. (b) Wang, Z.-M.; Sharpless, K. B. Unpublished scale process. results. (63) The procedure for the recovery and recycling of the ligand has (42) Hartung, J.; Loren, S.; Sharpless, K. B. Unpublished results. been developed by Dr. Yun Gao of Sepracor for the large-scale The enantiomeric excess was determined by HPLC analysis of AD of m-chlorostyrene (personal communication). the diol (Pirkle 1-A 25 cm x 10 mm, 2.5%i-PrOH in hexane, (64) Recipe for the preparation of 1 kg of AD-mix-a or AD-mix-/?: 1.5 mumin, 254 nm). Potassium osmate [&Os02(OH)41(1.04 g) and (DHQ)zPHAL (for (43) (a) Walsh, P. J.; Ho, P. T.; King, S. B.; Sharpless, K. B. AD-mix-a)or (DHQD)zPHAL(for AD-mix-/?)(5.52 g) were ground Tetrahedron Lett. 1994. 35. 5129. (b) Sammakia. T.: Hurlev. together to give a fine powder, then added to powdered &Fe- B.; Sammond, D.; Smith; R., University of Colorado,'unpublished (CN)6 (699.6 g) and powdered KzC03 (293.9 9). and finally mixed results. thoroughly in a blender for ca. 30 min. The resulting orange (44) The best enantiomeric excess is obtained with DHQD-PHN (86% powder should be kept dry and is ready to use. ee, 96% ee after recrystallization) in this particular case; see: (65) The 1.4 g of AD-mix, needed for the AD of 1 mmol of olefin, (a) Oi, R.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 2095. contains the following amounts of reagents: 1.46 mg (0.004 (b) Determination of the enantiomeric excess with phthalazine mmol) of KzOsOz(OH)4, 7.73 mg (0.01 mmol) of (DHQkPHAL and pyrimidine ligands: Wang, Z.-M.; Sharpless, K. B. Unpub- or (DHQD)zPHAL,980 mg (3 mmol) of &Fe(CN)e, and 411 mg lished results. (3 mmol) of KzCOs. (45) A number of ee determinations with pyrimidine ligands have (66) Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993,34,2079. not been published (Wang, Z.-M.; Sharpless, K. BJ. (67) Walsh. P. J.: Shamless. K. B. Srnlett 1993. 605. (46) The AD reactions were carried out with the AD-mixes at 0 "C (68) (a) Nahm, S:;Weinreb, 8. M. Tebahedron iett. 1981,22, 3815. under standard conditions. The enantiomeric excesses were For a review, see: (b) O'Neill, B. T. Nucleophilic Addition to determined by HPLC analysis of the bis[methoxy(trifluorom- Carboxylic Acid Derivatives. In Comprehensive Organic Syn- ethy1)phenylacetatel esters (Pirkle 1-A 25 cm x 10 mm, 2.5% thesis; Fleming, I., Trost, B. M., Eds.; Pergamon Press: New i-PrOH in hexane, 1 mumin, 254 nm) (Zhang, X.-L.; Sharpless, York, 1991; Vol. 1, pp 397-458. K. B., unpublished results). (69) Kaldor, S. W.; Hammond, M. Tetrahedron Lett. 1991,32, 5043. (47) Wang, Z.-M.; Sharpless, K. B. Synlett 1993, 603. (70) We feel that control experiments are best done in the presence (48) The AD reactions of these two olefins were carried out under of ligand (e.g., pyridine or quinuclidine) in order to better standard conditions at 0 "C using the AD-mixes; the enantio- simulate the asymmetric ligand-assisted osmylation process. It meric excesses were determined by GLC analysis of the diols is also necessary to perform these experiments using the same [(entry 7) J & W CDX-B (30 m x 0.32 mm i.d.), 120 "C, (entry 8) oxidant system and conditions that will be used in the asym- J & W CDX-B (30 m x 0.32 mm id.), 90 "C] (Morikawa, K.; metric version. If one were to compare the results obtained Sharpless, K. B., unpublished results). using Upjohn-type conditions with those obtained using the two- (49) The AD reaction of this substrate was carried out at room phase ferricyanide system, the results may be very different. This can be attributed to a "second catalytic cycle" that is present temperature using 1%of (DHQDIzPHAL and 1%of 0904; the enantiomeric excess was determined by GC analysis of the bis- under the Upjohn-type conditions (cf. Scheme 2, section 1). A (methoxy(trifluoromethy1)phenylacetate)esters (J & W DB-17 trioxoosmium(VII1)glycolate species is present in this cycle and (30 m x 0.32 mm ID), 230 "C) (Wang, Z.-M.; Sharpless, K. B., is capable of olefin osmylation. Such a species is very different unpublished results). from the free os04 and the Os04-ligand complex responsible for dihydroxylation in the ferricyanide system and may give very (50) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515. different diastereoselectivity results (as well as different regio- (51) Crispino, G. A.; Ho, P. T.; Sharpless, B. Science 1993,259, K. selectivity, etc., vide infra). 64. (71) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, (52) (a) KO, S. Y.;Malik, M. Tetrahedron Lett. 1993, 34, 4675. (b) 24, 3943. (b) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24, KO,S. Y.;Malik, M.; Dickinson, A. F. J. Org. Chem. 1994, 59, 3951. (c) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; 2570. Jager, V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. SOC.1984, (53) The AD reaction of this olefin was carried out with AD-mix$ at 106,3880. (d) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; 0 "C; the enantiomeric excess was determined by GC analysis Wu, Y.-D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; of the bis(methoxy(trifluoromethy1)phenylacetate)esters (J & W Loncharich, R. J. Science 1986,231, 1108. DB-5 (30 m x 0.32 mm ID), 160 "C) (Jeong, K.-S.; Sharpless, K. (72) For an excellent review of double asymmetric synthesis, see: B., unpublished results). Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. (54) The AD reactions of these substrates were carried out using 1% Chem., Int. Ed. Engl. 1986,24, 1. of (DHQDlzPHAL and 1% of os04 at 0 "C; the enantiomeric (73) Generally, the levels of matched and mismatched double dia- excess was determined by HPLC analysis of the cyclic carbonate stereoselection observed in the asymmetric dihydroxylation of (Chiralcel OD-H 25 cm x 4.6 mm, 2.5%i-PrOH in hexane, 0.8 chiral monosubstituted olefins are not as high as those observed mlimin, 254 nm) (Loren, S.; Sharpless, K. B., unpublished for the other olefin substitution classes. results). (74) For examples of doubly diastereoselective asymmetric dihy- (55) The AD reactions of these substrates were carried out using 1% droxylations of monosubstituted olefins, see: (a) Ireland, R. E.; of (DHQDIzPHAL and 1% of Os04 at 0 "C; the enantiomeric Wipf, P.; Roper, T. D. J. Org. Chem. 1980,55,2284. (b) Jirousek, excess was determined by HPLC analysis of the cyclic carbonate M. R.; Cheung, A. W.-H.; Babine, R. E.; Sass, P. M.; Schow, S. [(entry 5) Chiralcel OD-H 25 cm x 4.6 mm, 2.5% i-PrOH in R.; Wick, M. M. Tetrahedron Lett. 1993,34,3671. (c) Sinha, S. hexane, 0.8 mumin, 254 nm] and by HPLC analysis of the diol C.; Keinan, E. J. Org. Chem. 1994, 59, 949. (d) Hoffmann, R. (Chiralcel OD-H 25 cm x 4.6 mm, 10%i-PrOH in hexane (entry W.; Schlapbach, A. Tetrahedron Lett. 1993,34,7903. (e) Gurjar, 6) and 30% i-PrOH in hexane [(entry 7) 0.5 mumin, 254 nm] M. K.; Mainkar, A. S.; Syamala, M. Tetrahedron: Asymmetry (Loren, S.; Sharpless, K. B., unpublished results). 1993,4, 2343. (56) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. (75) Wade, P. A.; Cole, D. T.; D'Ambrosio, S. G. Tetrahedron Lett. 1992,57,5067. 1994, 35, 53. (57) Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.; (76) Experiments in this laboratory have determined that it is Sharpless, K. B. J. Am. Chem. SOC.1993,115, 8463. possible to carry out the AD at room temperature if the amounts (58) Wang, Z.-M.; Sharpless, K. B. Unpublished results, also see ref of ligand and potassium osmate are increased to 5 mol % and 1 127. mol %, respectively. We commonly refer to this as super AD- (59) Henderson, I.; Sharpless, K. B.; Wong, C.-H. J. Am. Chem. SOC. mix and have found that these revised concentrations and 1994, 116, 558. reaction temperatures do not adversely affect enantioselectivity. (60) Yun Gao of Sepracor has used methyl tert-butyl ether (MTB (77) Morikawa, IC; Sharpless, K. B. Tetrahedron Lett. 1993,34,5575. ether) instead of t-BuOH to simplify the product isolation on a (78) In double asymmetric reactions of olefins with an allylic het- large scale. No dramatic effect on the enantiomeric excess was eroatom, it is possible to predict which combination of reagents observed with m-chlorostyrene as the substrate (94%ee) (Yun will constitute a matched or mismatched pair by simply using Gao, personal communication). However, a considerable drop the AD mnemonic in conjunction with the Ki~hi/Stork~~~,~model in ee has been observed with allyl bromide as the substrate. for heteroatom-directed osmylation of olefins. Whereas 72%ee was achieved in 1:l t-BuOWHzO, using ligand (79) Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993,58,7096. 8, a considerably lower enantiomeric excess was obtained in 1:l (80) Katsuki, T.; Sharpless, K. B. J.Am. Chem. SOC.1980,102,5974. MTB etheriHzO (36%ee) (Kolb, H. C.; Sharpless, K. B., unpub- (81) For several recently published syntheses of castanospermine, lished results). see ref 79, footnote 5.~ (61) (a) Zhang, X.-L.; Sharpless, K. B. Unpublished results. (b) (82) For an additional application of the AD in efforts directed toward Byun, H.-S.; Kumar, E. R.; Bittman, R. J. Org. Chem. 1994,59, the synthesis of indolizidines related to castanospermine and 2630. swainsonine, see ref 74b. 2544 Chemical Reviews, 1994, Vol. 94, No. 8 Kolb et al.

(83) Abedel-Rahman, H.; Adams, J. P.; Boyes, A. L.; Kelly, M. J.; 110) that markedly different values were obtained for the Mansfield, D. J.; Procopiou, P. A.; Roberts, S. M.; Slee, D. H.; selectivity factor S (Le. kf lk. or k,~)than were reported in Table Sidebottom, P. J.; Sik, V.; Watson, N. S. J. Chem. Soc., Chem. 18. The revised values are presented here in the following Commun. 1993, 1841. format: Entry (kflk.): 1 (2.9),2 (5.21,3 (4.11,4 (10.71,5 (9.8),6 (84)Brimacombe. J. S.;McDonald, G.; Abdur Rahman, M. Carbohydr. (2.81,7 (3.3),8 (3.81,9 (2.91,10 (4.21,11 (1.3),12 (1.3). Res. 1990,205,422. (113) The presence of Fe(II1) can be easily detected by carrying out a (85)The AD has also been used for the preparation of other higher spot test with an aqueous solution of Fe(I1). See: (a) Brown, D. carbon sugars. See ref 74e. B., Ed. Mixed Valence Compounds;Reidel, Dordrecht, 1980. (b) (86) (a) Takatsuto, S.;Yazawa, N.; Ikekawa, N.; Morishita, T.; Abe, Ogura, K.; Takamagari, K. J. Chem. Soc., Dalton Trans. 1986, H. Phytochemistry 1983,22, 1393. (b) Takatsuto, S.;Yazawa, 1519. N.; Ikekawa, N.; Takematsu, T.; Takeuchi, Y.; Koguchi, M. 14) For an additional citation of the AD in a kinetic resolution Phytochemistry 1983,22,2437. application, see: Ward, R. A,; Procter, G. Tetrahedron Lett. 1992, (87) (a) Thompson, M. J.; Meudt, W. J.;Mandava, N.; Dutky, S. R.; 33, 3363. Lusby, W. R.; Spauding, D. W. Steroids 1981, 38, 567. (b) 15) Park, C. Y.; Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1991, Thompson, M. J.; Mandava, N.; Meudt, W. J.; Lusby, W. R.; 32, 1003. Spauding, D. W. Steroids 1982, 39,89. 16) (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. SOC. (88)Zhou, W.-S.; Huang, L.-F.; Sun, L.-Q.; Pan, X.-F. Tetrahedron 1992, 114, 7570. (b) Park, C. Y. Ph.D. Thesis, Massachusetts Lett. 1991,32, 6745. Institute of Technology, 1991. (c) For additional discussion of (89) Sun, L.-Q.; Zhou, W.-S.; Pan, X.-F. Tetrahedron: Asymmetry the AD with respect to the possible role of hydrogen bonds and 1991,2,973. their effect on reaction rates and stereoselectivities, see section (90) (a) Takatsuto, S.;Ikekawa, N. Chem. Pharm. Bull. 1984, 32, 2.5 and references cited therein. (d) The ene diol deriving from 2001. (b) Ikekawa, N.; Zhao, Y.-J. In Brassinosteroids: Chem- mono-dihydroxylation of 1,4-diphenyl-1,3-butadiene(e.g., entry istry, Bioactiuity, and Applications; Cutler, H. G., Yokota, T., 4, Table 20a) was dihydroxylated with 16:l anti diastereoselec- Adam, G., Eds.; ACS Symposium Series 474;American Chemical tivity in the NMO oxidant system while the reaction with Society: Washington, DC, 1990; Chapter 24, p 280. stoichiometric Os04 proceeded with only 3:l diastereoselectivity (91)Kim, B. M.; Ikekawa, N.; Sharpless, K. B. Unpublished results. in favor of the anti diastereomer. The lower levels of diastereoselection in the NMO system are (117) Becker, H. J.; Soler, M.; Sharpless, K. B. Tetrahedron, in press. likely the result of partial dihydroxylation via the secondary (118)Vanhessche, K. P. M.; Sharpless, K. B. Unpublished results. catalytic ~ycle.19>70J~~b (119) (a) Krabbenhoft, H. 0. J. Org. Chem. 1979, 44, 4285. (b) (92) McMorris, T. C.; Patil, P. A. J. Org. Chem. 1993,58, 2338. Garbisch, E. W., Jr. J. Org. Chem. 1965,30, 2109. (93) Honda, T.; Takada, H.; Miki, S.; Tsubuki, M. Tetrahedron Lett. (120) Crispino, G. A,; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 1993,34,8275. 4273. (94) For additional applications of double asymmetric dihydroxyla- (121) Crispino, G. A.; Sharpless, K. B. Synthesis 1993, 777. tions of steroidal olefins. see: Brosa. C.; Peracaula, R.; Puig, R.; (122) Vidari, G.; Giori, A,; Dapiaggi, A,; Lanfranchi, G. Tetrahedron Ventura, M. Tetrahedron Lett. 1992,33, 7057 and ref 88.- Lett. 1993,34, 6925. (95) (a) Ikekawa, N.; Fujimoto, Y. Personal communication. (b) (123) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Org. Chem. 1993, Morikawa, K.; Sharpless, K. B. Unpublished results. 58, 7789. (96) Ikekawa, N.; Ishizuka, S. In Molecular Structure and Biological (124) Corey, E. J.; Noe, M. C.; Shieh, W.4. Tetrahedron Lett. 1993, Activity of Steroids; Bohl, M., Duax, W. L., Eds.; CRC Press: 34, 5995. Boca Raton, 1992; p 293. (125) Andersson, P. G.; Sharpless, K. B. J.Am. Chem. SOC.1993,115, (97)VanNieuwenhze. M. S.:. Shamless, .. K. B. J.Am. Chem. SOC.1993, 7047. 115, 7864. (126)Vidari, G.; Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron (98) This result is very curious since it would only be expected in Lett. 1993,34, 6485. cases where the substrate shows no intrinsic diastereofacial bias. (127) Wang, Z.-M.; Kakiuchi, K.; Sharpless, K. B. J. Org. Chem., in (99) Hoffmann, R. W.; Schlapbach, A. Tetrahedron Lett. 1993, 34, press. 7903. (128) (a) Takano, S.;Yoshimitsu, T.; Ogasawara, K. J. Org. Chem. (100) Rickards, R. W.; Thomas, R. D. Tetrahedron Lett. 1993,34,8369. 1994,59, 54. (b) Takano, S. Personal communication. (101) Barvian, M. R.; Greenberg, M. M. J. Org. Chem. 1993,58,6151. (129) Jeong, K.-S.; Sjo, P.; Sharpless, K. B. Tetrahedron Lett. 1992, (102) (a) Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesis; 33. 3833. Morrison, J. D., Ed.; Academic Press: New York, 1985;Vol. 5, (130) Bassignani, L.; Brandt, A.; Caciagli, V.; Re, L. J. Org. Chem. p 247. (b) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, 1978,43,4245. Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. SOC.1981, 103, (131) Tani, K.; Sato,Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1993, 6237. 34,4975. (103) Reviews of kinetic resolution: (a)Kagan, H. B.; Fiaud, J. C. Top. (132) For a recent review of substrate-directed reactions, see: Hov- Stereochem. 1988, 18, 249. (b) El-Baba, S.; Nuzillard, J. M.; eyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,93,1307. Poulin, J. C.; Kagan, H. B. Tetrahedron 1986,42,3851.(c) Chen, (133) (a) Hauser, F. M.; Ellenberger, S. R.; Clardy, J. C.; Bass, L. S. C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989,28,695. J. Am. Chem. SOC.1984, 106, 2458. (b) Solladie, G.; Frechou, (104) Hawkins, J. M.;Meyer, A. Science 1993,260, 1918. C.; Demailly, G. Tetrahedron Lett. 1986,27,2867. (c) Solladie, (105)The enantiomeric excess reported at 95% conversion was '97%. G.; Frechou, C.; Hutt, J.; Demailly, G. Bull. SOC.Chim. Fr. 1987, This suggests the ratio of the relative rate constants to be %3. 827. (106) Scheme 19 only shows results for benzylidene derivative 42. (134) (a)Johnson, C. R. Pure Appl. Chem. 1987,59,969.(b) Johnson, Experiments with ester 43 showed a much greater preference C. R.; Barbachyn, M. R.; Meanwell, N. A,; Stark, C. J.,Jr.; Zeller, for axial dihydroxylation (Le.; a single dihydroxylation product J. R. Phosphorus Sulfur 1985, 24, 151. (c) Johnson, C. R.; was isolated) in the presence of a chiral ligand. This is likely a Barbachyn, M. R. J. Am. Chem. SOC.1984, 106, 2459. result of the lower intrinsic diastereofacial preference of 43 as (135) (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. J. Am. Chem. SOC. compared to 42. 1988,110, 621. (b) Poli, G. Tetrahedron Lett. 1989,30, 7385. (107) Kakiuchi, K.; Park, J.; Soler, M.; Vanhessche, K.; VanNieu- (136) King, S.B.; Ganem, B. J.Am. Chem. SOC.1991,113,5089. wenhze, M. Unpublished results. (137) Allylic sulfides and sulfones provide no evidence of heteroatom- (108) The benzyl ether of 3-methyl-2-cyclohexen-1-01was a notable assisted dihydroxylation; see: Vedejs, E.; McClure, C. K. J. Am. exception to this statement. For example, at 60% conversion Chem. SOC.1986,108, 1094. the R-substrate was recovered in 94% enantiomeric excess, (138) Kon, K.; Isoe, S. Tetrahedron Lett. 1980,21,3399. giving a kflk, of 14.9. (139) Smith, A. B., 111; Boschelli, D. J. Org. Chem. 1983,48,1217. (109) The relative rate can be calculated by use of the following (140) A steric argument could also account for these results. For the equation: homoallylic alcohol 60 it could be argued that dihydroxylation krel= ln(1 - C)(1 - ee)An(l - C)(1 + eel is occurring from the olefin diastereoface that is anti to the allylic methyl substituent. A similar situation exits for allylic alcohol This is an adaptation of an equation first presented by Kaganllo where C is the percent conversiod100 and ee is the percent 61 which has an allylic isopropyl group. In the case of silyl ether enantiomeric excessl100. This equation may also be used to 62 preferential dihydroxylation from the convex face may be the calculate the percent conversion necessary to achieve a desired result of the greater steric demands of the allylic silyl ether enantiomeric excess by substituting into the e uation the desired substituent. ee and the ratio of rate constants (i.e., krel orlflk,). Knowledge (141)Xu, D.; Park, C. Y.; Sharpless, K. B. Tetrahedron Lett. 1994, of any two of the reaction variables allows calculation of the 35,2495. third. (142) The directive effect of the allylic hydroxyl group is analogous to (110) Balavoine, G.; Moradpour, A.; Kagan, H. B. J. Am. Chem. SOC. that seen in epoxidation of olefins. See, for example: (a) 1974,96, 5152. Henbest, H. B.; Wilson, R. A. L. J. Chem. SOC.1957, 1958. (b) (111) Lohray, B. B.; Bhushan, V. Tetrahedron Lett. 1993,34, 3911. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. SOC.1973,95, (112)Very good relative rates were reported for several examples in 6136. this table. It was found, however, upon substituting the reported (143) Xu, D.; Park, C. Y.; Sharpless, K. B. Unpublished results. values for percent conversion and enantiomeric excess of recov- (144)VanNieuwenhze, M. S.;Sharpless, K. B. Tetrahedron Lett. 1994, ered starting material into the Kagan equation (refs 109 and 35,843. Catalytic Asymmetric Dihydroxylation Chemical Reviews, 1994,Vol. 94,No. 8 2545

(145) The best results with this ligand class are obtained when one of (170) Oi, R.; Sharpless, K. B. Tetrahedron Lett. 1991,32, 999. the olefin substituents is a phenyl group.29 (171) KO, S. Y.; Malik, M. Tetrahedron Lett. 1993, 34, 4675. (146) VanNieuwenhze, M. S.;Sharpless, K. B. Unpublished results. (172) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, (147) Replacement of the hydroxyl group by a hydrogen atom would 30, 2623. give a nonprochiral olefin and, therefore, a meso diol in the AD (173) For reviews, see: (a) Breslow, D. S.; Skolnik, H. Multi-Sulfur reaction. and Sulfur and Oxygen Five- and Six-Membered Heterocycles, (148) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Unpub- Part One; Wiley-Interscience: New York, 1966;p 17. (b) Fisher, lished results. G. W.; Zimmermann, T. In Comprehensive Heterocyclic Chem- (149) For example, the asymmetric dihydroxylation of trans-cinnamyl istry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, alcohol proceeded with 71% ee using DHQD-CLB while the 1984;Vol. 6, p 851. (c) Tillet, J. G. Phosphorus Sulfur 1976,1, dihydroxylation of the corresponding acetate proceeded with 91% 341. ee. See, for example: (a) ref 141. (b) Lohray, B. B.; Kalantar, (174) (a) Denmark, S. E. J. Org. Chem. 1981,46,3144. (b) Lowe, G.; T. H.; Kim, B. M.; Park, C. Y.; Shibata, T.; Wai, J. S. M.; Salamone, S. J. J. Chem. Soc., Chem. Commun. 1983, 1392. Sharpless, K. B. Tetrahedron Lett. 1989,30, 2041. (175) Vanhessche, K. P. M.; Van der Eycken, E.; Vandewalle, M.; (150) Hanessian, S. Total Synthesis ofNatural Products: The “Chiron” Roper, H. Tetrahedron Lett. 1990,31,2337. Approach; Pergamon Press: Oxford, 1983. (176) Lohray, B. B.; Ahuja, J. R. J. Chem. Soc., Chem. Commun. 1991, (151) For a recent review of protecting groups and their use for the 95. differentiation of the hydroxyl groups of diols, see: Kunz, H.; Gao, Zepp, C. M. Tetrahedron Lett. Waldmann, H. Protecting Groups. In Comprehensive Organic (177) Y.; 1991,32, 3155. Synthesis; Trost, B. M., Fleming, I., Ed.; Pergamon Press: New (178) Kim, B.M.; Sharpless, K. B. Tetrahedron Lett. 1990,31, 4317. York, 1991;Vol. 6,pp 631-701. (179) Kalantar, T. H.; Sharpless, K. B. Acta Chem. Scand. 1993,47, (152) For a recent review of acylation reactions, including the regi- 307. oselective mono-acylation of polyols, see: Mulzer, J. Synthesis (180) Hirsenkom, R. Tetrahedron Lett. 1990,31, 7591. of Esters, Activated Esters and Lactones. In Comprehensive (181) Bates, R. W.; Femandez-Moro, R.; Ley, S. V. Tetrahedron Lett. Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon 1991,32,2651. Press: New York, 1991; Vol. 6, pp 323-380. (182) Van der Klein, P. A. M.; de Nooy, A. E. J.;van der Marel, G. A,; (153) Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991,56, 2869. van Boom, J. H. Synthesis 1991, 347. (154) (a) Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1990, (183) Tomalia, D. A.; Falk, J. C. J. Heterocycl. Chem. 1972,9, 891. 55, 1957. (b) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. (184) Pilkington, M.; Wallis, J. D. J. Chem. Soc., Chem. Commun. J.; Jackson, W. R.; Gountzos, H.; Matthews, B. R. J. Chem. Soc., 1993, 1857. Chem. Commun. 1990, 1018. (185) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (155)A recent study with methyl and ethyl arenesulfonates has shown (186) KO, S. Y. Tetrahedron Lett. 1994,35, 3601. that the methanolysis and aminolysis rate constants are 210 (187) Kang, S.-K.; Park, Y.-W.; Lee, D.-H.; Sim, H.-S.; Jeon, J.-H. times larger with nosylates than with tosylates, see: (a) Lee, I.; Tetrahedron: Asymmetry 1992,3,705. Choi, Y. H.; Rhyu, K. W.; Shim, C. S. J. Chem. Soc., Perkin (188) Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993,34,2083. Trans. 2 1989, 1881. For kinetic studies of the reaction of Konradi, A. W.; Lerner, R. 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