Chiral Allylic and Allenic Metal Reagents for Organic Synthesis | The

VOLUME 72, NUMBER 22

OCTOBER 26, 2007

© Copyright 2007 by the American Chemical Society

Chiral Allylic and Allenic Metal Reagents for Organic Synthesis‡ James A. Marshall Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904 [email protected] ReceiVed April 15, 2007

This account traces the evolution of our work on the synthesis of chiral allylic and allenic organometal compounds of tin, silicon, zinc, and indium and their application to natural product synthesis over the past quarter century.

My apprenticeship in synthetic organic chemistry began with a senior thesis project at the University of Wisconsin with S. Morris Kupchan and continued throughout my Ph.D. studies with Robert E. Ireland at the University of Michigan and at Stanford University, as an NIH postdoctoral fellow, with William S. Johnson. Through these experiences, I learned to appreciate simple solutions to seemingly complex synthetic problems, and I have endeavored to adopt this approach in my own research programs beginning with my first academic position, at Northwestern University. Having previously worked on the synthesis of steroids and diterpenes, I decided to initiate my first independent program in the relatively unexplored areas of hydroazulene and medium ring natural products. Fortuitously, NIH funding for this work was considerably enhanced by the findings of my undergraduate mentor Morris Kupchan, after his move to the University of Virginia, that hydroazulene lactones held some promise as antitumor compounds. I was also fortunate to attract a number of talented graduate students, three of whom joined my “group” while I was still at Stanford completing my postdoctoral work. After 18 productive years at Northwestern, I was seduced in 1980 by the mild winters and high field NMR facilities at the University of South Carolina, where I started a program aimed at an emerging class of macrocyclic marine natural products named “cembranes”. This account highlights our discoveries ‡ Dedicated to Professor Robert E. Ireland, an inspiring mentor and a good friend.

FIGURE 1. Representative cembrane natural products.

of simple solutions to problems in that area and extensions of those discoveries to other areas. The first cembrane natural products were isolated in the early 1960s, but they attracted little interest among synthetic chemists.1 In subsequent years, soft corals were found be a rich source of cembranoid lactones (Figure 1), a number of which were reported to possess significant antitumor activity.2 Interestingly, scientists at the Japan Tobacco Company identified the tobaccoderived cembrane R-CBT as an effective inhibitor of tumor promotion.3 As synthetic targets, cembranes pose the obvious problems associated with large rings and multiple stereocenters. Meth-

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FIGURE 2.

Synthesis of desoxyasperdiol by internal sulfone

alkylation.

odology for large ring carbocyclic synthesis was still at a highly formative stage in the early 1980s, and methods for stereoselective synthesis, particularly in acyclic or large ring compounds, were practically nonexistent. At the time, it was common practice to apply the conformational preferences of cyclohexanes to introduce stereocenters in precursors of acyclic intermediates. While it was possible to imagine that the cembrane ring system might exhibit certain conformational preferences that could similarly be used for stereochemical control, the lack of suitable molecular modeling programs limited the application of these techniques for predictive purposes when this work was initiated. Later developments allowed us to employ computational modeling with good success.4 One of my first South Carolina graduate students, Darryl Cleary, completed our inaugural synthesis of a cembranoid natural product in 1986. The route involved Wittig coupling of two main fragments, aldehyde 1 incorporating the two contiguous stereocenters, and phosphonium ylide 2 containing two of the three double bonds of the targeted compound, desoxyasperdiol (Figure 2).5,6 Aldehyde 1 was prepared from the mesoepoxide of (Z)-2-butene-1,4-diol acetonide, and the phosphonium ylide 2 was derived from farnesol. Reduction of the Wittig product and protection of the derived alcohol produced the acyclic precursor 3, which cyclized in 53% yield by intramolecular sulfone alkylation. Concurrent removal of the sulfonyl group and the benzyl ethers was effected with sodium in ammonia.6 Concomitant with the Cleary synthesis, Brad DeHoff was exploring a potentially more efficient approach to cembrane lactones in which an (E)-double bond or, more interestingly, the contiguous C1/C2 stereocenters would be introduced in the macrocyclization step. The targets of this approach were anisomelic acid7 and an unnamed cembranolide isolated by Coll and co-workers from an Australian soft coral (Figure 3).8 In our plan for anisomelic acid, we envisioned an intermolecular allylic stannane addition for the stereoselective introduction of a potential γ-lactone precursor with the correct relative stereochemistry. Macrocyclization would be achieved through an intramolecular Horner-Emmons condensation. Our proposed route to the unnamed cembrane lactone featured an intramolecular allylic stannane addition as the ring closure step. When these plans were formulated, the only example of such an addition was that of Denmark and Weber in connection with their 1984 study designed to probe the preferred arrangement of the double bond and aldehyde carbonyl in allylstannane reactions (Figure 4).9 Intermolecular additions of crotylstannanes to aldehydes had been shown by Keck and others to proceed readily in the 8154 J. Org. Chem., Vol. 72, No. 22, 2007

FIGURE 3. Alternative synthetic strategies for cembrane synthesis.

FIGURE 4. The first intramolecular allylstannane addition.

FIGURE 5. Acyclic and cyclic transition states for allylstannane additions to aldehydes.

presence of a Lewis acid promoter such as BF3•OEt2.10 Interestingly, syn adducts were formed as major products from both (E)- and (Z)-crotylstannanes in these reactions (Figure 5). On the other hand, when subjected to hyperbaric conditions in the absence of Lewis acids, (E)-crotylstannanes afforded anti adducts while the (Z)-isomers gave mainly syn adducts.11 Yamamoto reconciled these findings by suggesting an acyclic transition state for the Lewis acid reactions and a cyclic transition state for the hyperbaric reactions.11 Both types of additions could be of value in our planned syntheses. The addition reactions could also be effected thermally. Thomas and co-workers reported that upon extended heating at temperatures in excess of 100 °C, (E)-R-oxygenated crotylstannanes afford anti, (Z)-adducts with various aldehydes (Figure 6).12 These thermal reactions were also thought to proceed through cyclic transition states. Yet a third option for syn/anti selectivity was discovered by Keck and co-workers who found that TiCl4, when used in excess, favored anti adducts from an (E)-crotylstannane but gave the syn adducts when equimolar amounts were employed.13 Evidently, the anti products derive

FIGURE 6. Thermal reaction of oxygenated allylstannanes and aldehydes leading to anti products.

FIGURE 9. Additions of an R-oxygenated allylic stannane to conjugated aldehydes.

FIGURE 7. Keck allylstannane additions and transmetalation.

FIGURE 10. Synthesis of a cembranolide prototype by intramolecular allylstannation.

FIGURE 8. Allylstannane additions to conjugated aldehydes.

from an allylic TiCl3 reagent formed in situ from the stannane prior to aldehyde addition (Figure 7). The foregoing studies were conducted with crotylstannanes and relatively simple aldehydes. In order to evaluate the effects of chain length and branching, we felt the need to test these reactions on stannanes and aldehydes more closely related to our intended applications. Brad DeHoff’s initial results were quite promising. He found that the allylic stannane 4 affords the syn adduct 5 with crotonaldehyde in the presence of 1.1 equiv of BF3•OEt2 in CH2Cl2 at -78 °C (Figure 8).14 In accord with the findings of Keck et al., prior addition of TiCl4 to the stannane 4 followed by the aldehyde afforded the anti adduct (not shown). Surprisingly, an extension of the BF3 reaction to geranial failed completely. Even with a large excess of BF3•OEt2, none of the expected adduct 6 was produced. At temperatures below -30 °C, starting material was recovered, and above -30 °C, decomposition was observed. Apparently, hyperconjugative stabilization of the aldehyde-BF3 complex

by the β-methyl substituent of geranial lowers the electrophilicity of the carbonyl carbon center below the threshold required for the addition reaction. Concordant with this rationale, the β-iodo enal 7 afforded the adduct 8 with stannane 4, albeit as a 3:1 syn/anti mixture. Additions to the alkynal 9 also took place readily and with somewhat higher selectivity. While the unreactivity of geranial was disappointing, we nonetheless decided to proceed with these studies. As our ultimate goal involved conversion of the alcohol adducts to γ-lactones, we directed our efforts to reactions of R-oxygenated crotylstannanes and homologues with enals and ynals because the resultant enol ether adducts could be easily converted to such lactones. As previously noted, Thomas and co-workers found that R-oxygenated stannanes add to aldehydes at temperatures in excess of 100 °C. Brad and postdoc Steve Crooks attempted a thermal addition of the MOM stannane 11 with geranial but obtained only decomposition products. However, they found that the reaction with ynal 9 readily afforded the adduct 12, albeit as a nearly 1:1 mixture of anti and syn adducts (Figure 9). The BF3 reaction was somewhat more selective, producing adduct 13 as a 2.5:1 mixture of syn and anti isomers, each of which was a 1:1 mixture of (E)- and (Z)-isomers.15 This result was not highly promising, but we elected to pursue the intramolecular addition with ynal 14 in the hope that conformational constraints might improve the isomer ratio (Figure 10). In fact, when Steve Crooks performed this reaction, he obtained the cyclic adduct 15 in 88% yield as an 88:12 mixture of syn and anti adducts.16 Upon hydrolysis and oxidation, the syn adduct was converted to the cis-lactone 16, a cembranolide prototype. The foregoing additions were conducted with racemic stannanes. We next began to consider the possibility of using an enantiomerically enriched stannane. Thomas had previously J. Org. Chem, Vol. 72, No. 22, 2007 8155

FIGURE 11. Synthesis of enantioenriched R-hydroxystannanes and

FIGURE 13. BF3-promoted addition of an enantioenriched allylic

their BOM ethers.

stannane to achiral aldehydes.

FIGURE 14. BF3-promoted addition of an enantioenriched allylic stannane to a chiral aldehyde.

FIGURE 12. Application of intramolecular allylstannane addition to cembranolide synthesis.

shown that nonracemic menthyloxy crotylstannanes yield enantioenriched adducts in thermal reactions (Figure 6).12 In that study, the stannane was prepared by separation of diastereomeric menthyloxymethyl ethers of the racemic R-hydroxy crotylstannane. This constitutes the first ever synthesis of a nonracemic allylic stannane. Postdoc Ben Gung took on the task of developing an alternative synthesis of chiral oxygenated allylic stannanes through reduction of an acylstannane precursor with chiral hydride reagents.17 This effort proved unexpectedly difficult owing to the instability of allylic R-hydroxystannanes. Unlike their alkyl counterparts, allylic hydroxystannanes show a strong tendency to decompose under acidic conditions and revert to their conjugated aldehyde and Bu3SnH precursors under basic conditions. To further complicate matters, acylstannanes are highly susceptible to air oxidation. These properties posed severe limitations on our choices of oxidizing and reducing conditions and reagents. Ben examined the standard oxidizing agents for alcohols, but none was suitable. Eventually, the Mukaiyama protocol18 involving treatment of the alcohol with t-BuOMgBr and azodicarbonyl dipiperidide (ADD) saved the day. Ben developed a convenient sequence by adding LiSnBu3 to the enal and then introducing ADD to the reaction mixture to effect oxidation of the intermediate alkoxide, thereby circumventing the labile R-hydroxystannane intermediate (Figure 11).19 Reduction of the acylstannanes with Noyori’s (S)- and (R)-BINAL-H reagents gave the enantiomerically enriched (R)or (S)-R-hydroxystannanes,20 which were converted to the stable BOM or MOM ethers with BOMCl or MOMCl in the presence of Hunig’s base. When Ben carried out the BF3-promoted cyclization of the (S)-R-OMOM allylstannane aldehyde 17, he obtained an 88:12 mixture of syn and anti adducts in high yield (Figure 12). The major adduct 18 was subsequently converted to the cembranoid 8156 J. Org. Chem., Vol. 72, No. 22, 2007

FIGURE 15. Intramolecular allylstannylation preceded by 1,3-stannane isomerization.

lactone 20 identical in spectral properties and rotation to those reported for Coll’s “no name” lactone.21 Ben’s synthesis of chiral alkoxystannanes had ramifications well beyond cembrane natural products. In addition to applications in asymmetric synthesis, the general availability of chiral stannanes enabled explorations of several interesting mechanistic questions relating to allylstannane additions and transmetalation reactions. Ben found that the R-OBOM-substituted allylic stannane 19, upon addition to 2-heptynal, afforded a mixture of four diastereomeric adducts favoring the syn, (E)-isomer A (Figure 13).17 However, the diastereoselectivity was rather low. Somewhat improved selectivity was observed in additions to heptanal and (E)-2-heptenal, and reaction with the R-branched aldehyde 20 was highly stereoselective (Figure 14). Consistent with the Yamamoto acyclic transition state, these findings underscore the strong stereoelectronic control exerted by the allylic stannane stereocenter. Our work in this area took an unexpected turn when Ben attempted to extend intramolecular alkoxystannane additions to the ynal 21 in an effort to obtain the cyclodecyne 22, a prototype of the germacranolide sesquiterpenes. This product was not formed. Instead, he obtained the cyclododecyne 24 in 25% yield as a single diastereomer (Figure 15).22 We surmised that ring strain in the expected cyclodecyne product increases the transition state energy of the direct addition, thus allowing isomerization of the R-oxygenated allylic stannane to the γ-isomer 23, which leads to the less strained larger ring adduct. This assumption was confirmed by experiments with the enantiomeric R-OBOM allylic stannanes 25 and 27, which were converted to the enantiomeric γ-OBOM stannanes 26 and 28

FIGURE 16. 1,3-Isomerization of enantiopure (E)-R-OBOM allylic stannanes.

FIGURE 19. Synthesis and reactions of γ-OTBS allylic stannanes.

FIGURE 17. Additions of a γ-OBOM allylic stannane to aldehydes. FIGURE 20. Equilibration of γ-OTBS allylic stannanes.

FIGURE 18. Transition state for additions of γ-OBOM allylic stannanes to aldehydes.

on treatment with BF3•OEt2 in the absence of an aldehyde reaction partner (Figure 16).23 The (S)-γ-isomer 26 afforded the (E,R,R)-1,2-diol derivatives 29 with various aldehydes in the presence of BF3•OEt2 (Figure 17). Minor amounts of the 1,2diols 30 were also produced by an apparent BF3-catalyzed cleavage of the BOM ethers in the initial adducts. We surmised that the γ-OBOM stannane 26 was most probably the (Z,S)isomer. The conclusion followed that the 1,3-stannane isomerization must proceed by an enantioselective intermolecular anti pathway. Kevin Gill studied the 1,3-isomerization reaction in greater detail by means of low temperature 119Sn and F NMR experiments employing (C6F5)3B as the catalyst for the isomerization and for additions to aldehydes.24 From these studies, we concluded that a carbocation intermediate such as A is involved in the isomerization reaction. Such cations should be configurationally stable owing to hyperconjugative stabilization by the adjacent tin substituents, as illustrated in Figure 16. We have previously shown that the γ-oxygenated stannanes are highly favored in these isomerizations (see Figure 20). A likely transition state for the aldehyde additions is depicted in Figure 18. Attempts to prepare alkyl ethers of the R-hydroxy allylic stannanes with even the most reactive alkylating agents (allyl iodide, methyl triflate, Meerwein’s reagent) failed. These efforts yielded mainly enals and tributyltin hydride. However, Greg Welmaker discovered that R-hydroxystannanes could be silylated in high yield.25 Interestingly, upon treatment with TBSOTf and Hunig’s base, these stannanes underwent both silylation and rearrangement to (Z)-γ-stannyl enol ethers (Figure 19). The racemic (E)-isomers could be prepared by 1,4-addition of a Lipshutz stannylcuprate reagent26 to crotonaldehyde and in situ trapping of the enolate with TBSCl. The (E)-silyl ethers showed enhanced selectivities in addition reactions. Based on the foregoing observations, we speculated that the R-γ isomerization of alkoxy allylic stannanes is a highly

FIGURE 21. Additions of enantiomeric (E)- and (Z)-γ-OTBS crotylstannanes to aldehydes.

favored process. Decomposition of the stannanes upon prolonged exposure to Lewis acids frustrated our initial efforts to study this equilibration. However, after testing a number of Lewis acids, Jill Jablonowski and Michelle Elliott discovered that the γ-OTBS ether 31 survived prolonged exposure to Yb(OTf)3, which caused equilibration to a 3:1 mixture of (Z)- and (E)-γisomers with inversion of configuration (Figure 20).27 No R-OTBS isomer was formed in these experiments. The preference for the (Z)-isomer suggests a possible internal association of the stannane with the ether oxygen. The enantiomerically enriched (E)- and (Z)-γ-stannyl enol silanes afford syn adducts with aldehydes in BF3-promoted additions (Figure 21). As expected from the Yamamoto transition state model, the (S,Z)- and the (R,E)-stannanes both give the (R,R)-adduct with virtually complete stereoselectivity. This selectivity stems from a favorable confluence of a strong stereoelectronic anti preference for the tributylstannane substituent, a preferred anti arrangement of the aldehyde and OTBS substituents, and favored formation of an (E)-double bond in the transition state. Exploring a potential application to carbohydrate synthesis, George Luke found that BF3-promoted addition of the MOM stannane 33 to the benzyl ether of (S)-lactic aldehyde proceeds readily to afford the (E) syn, anti adduct 34 together with a small amount of the cyclopropane 35 in the matched addition (Figure 22).28 Addition of the OTBS stannane 31 in a mismatched BF3-promoted pairing affords the (E) syn, syn adduct J. Org. Chem, Vol. 72, No. 22, 2007 8157

FIGURE 24. A bidirectional synthesis of polyols.

FIGURE 22. Comparison of OTBS and OMOM allylic stannane additions to O-benzyl lactic aldehyde.

FIGURE 23. “Kinetic resolution” in additions of a racemic OTBS allylic stannane to a protected threonine aldehyde.

FIGURE 25. Transmetalation of R-OMOM allylic stannane with InCl3.

38 in low yield and a significant amount of the cyclopropane 39. Interestingly, MgBr2-promoted additions show a strong preference for the (E) syn, syn adduct 37 with the MOM stannane 36 in the reagent controlled pairing, whereas the OTBS reagent 40 leads to the (Z) syn, syn isomer 41 in a substratecontrolled (chelation) pairing. The cyclopropanes result from attack of the enol ether double bond on the aldehyde-BF3 complex followed by internal alkylation of the intermediate oxo cation by the alkylstannane with inversion of configuration. Because of the strong substrate control observed for MgBr2promoted additions to R-oxygenated aldehydes, George was able to prepare the matched adducts through use of excess racemic stannane, thereby circumventing the need to prepare the enantiopure reagent. This concept was utilized to advantage in postdoc Serge Beaudoin’s synthesis of a polyoxamic acid derivative.29 By using an excess of the racemic allylic stannane, he obtained the matched syn, anti adduct of an isopropylideneprotected threonine aldehyde in high yield (Figure 23). In a separate bidirectional application of the methodology, Serge converted the acetonide diene dialdehyde 42, derived from diethyl tartrate, to the bis-adduct 43 (Figure 24).30 Dihydroxylation of the four double bonds with OsO4 gave the syn,anti,syn,anti, syn,anti,syn,anti,syn,anti,syn,anti,syn polyol 44 with 14 contiguous hydroxy substituents in 55% yield. The high stereoselectivity of the dihydroxylation reaction can be attributed to a strong conformational bias in tetraene 43 resulting from steric interactions between the adjacent TBS ethers, thereby forcing the attached diene chains to assume a parallel arrangement in a hairpin-type conformation.31 Dihydroxylation occurs from the outside faces of the two hairpins. As previously noted, premixing crotylstannanes with TiCl4 before adding a substrate aldehyde leads to anti adducts. It was of interest to explore this modification with R-oxygenated allylic stannanes as a means of accessing anti-1,2-diol derivatives. However, we discovered that the labile oxygenated stannanes

decomposed when treated with TiCl4 or SnCl4. Kevin Hinkle found that InCl3 in acetone or, better, ethyl acetate affords isomerized γ-alkoxy allylic indium reagents, which react in situ with aldehydes to produce anti adducts in high yield (Figure 25).32 Surprisingly, premixing the aldehyde and InCl3 before addition of the stannane gave the best results. Assuming a cyclic transition state for the aldehyde addition reaction, it follows that the transmetalation proceeds by an anti process as indicated in Figure 25. In an early application of diversity-oriented synthesis, George Luke and postdoc Boris Seletsky used this methodology to synthesize eight diastereomeric hexose precursors through additions of the (R)- and (S)-R or γ-stannane reagents derived from crotonaldehyde to the erythrose and threose aldehydes 45 or 46 (Figures 26 and 27). Each of the diastereomeric adducts was obtained in high yield and isomeric purity from matched reagent and substrate combinations.33 In the 1980s, polyketide natural products emerged as the synthetic targets du jour, and the aldol reaction rose to prominence as the workhorse methodology for constructing the signature sequence of alternating methyl and hydroxyl substituents that characterize this important class of natural products.34 Initially, we attempted to adapt chiral allylic stannane methodology to the synthesis of these compounds, but our efforts were only marginally successful owing to modest levels of diastereoselection obtained with the requisite stannane reagents. In considering other alternatives, we were attracted to allenylstannanes. While little was known about these compounds, a 1983 paper of Ruitenberg et al. described a straightforward preparation of an enantioenriched allenylstannane by reaction of a triphenylstannylcuprate with a chiral propargylic mesylate (Figure 28).35 The configuration of the allene product was tentatively assigned from the optical rotation by application of Brewster’s rules for allene configuration, but the enantiomeric purity could

8158 J. Org. Chem., Vol. 72, No. 22, 2007

FIGURE 29. Reactions of allenyl/propargylstannanes with chloral.

FIGURE 26. Matched pairings for γ-OMOM crotylstannane and indium additions to a protected erythrose.

FIGURE 30. In situ generation of propargyl/allenylstannyl halides and additions to aldehydes.

FIGURE 27. Matched pairings for γ-OMOM crotylstannane and indium additions to a protected threose.

FIGURE 31. Synthesis of a racemic allenylstannane and Lewis acid promoted addition to achiral and racemic aldehydes.

FIGURE 28. Ruitenberg synthesis of a chiral allenylstannane.

not be determined. The possible use of these reagents for synthetic applications was not explored. As early as 1973, Lequan and Guillerm reported that the reaction of racemic 1-trimethylstannyl-1,2-butadiene with chloral affords an 80:20 mixture of diastereomeric propargylic alcohols (Figure 29).36 They also examined reactions of chloral with other allenic and propargylic stannanes resulting in homopropargylic alcohols and allenic carbinols. Kinetic parameters were measured for several of these reactions, and the interconversion of the propargyl and allenylstannane compounds was studied. Nothing further was done along these lines until 1981 when Mukaiyama and Harada described a reaction of propargylic iodides with aldehydes in the presence of excess stannous chloride to afford mixtures of allenyl and propargylic carbinols (Figure 30).37 These products were assumed to arise from propargylic and allenic stannanes formed in situ. Various modifications of this reaction subsequently appeared.38 With these results in mind, we reasoned that chiral allenylstannanes might be induced to react with aldehydes analogously

to allylstannanes. To test this hypothesis, postdoc Xiao-jun Wang prepared an allenyltin intermediate from the tosylate of racemic 3-undecyn-2-ol along the lines of Ruitenberg, but with Bu3SnLi in place of Ph3SnCu.39 Upon stirring with an excess of BF3•OEt2 in CH2Cl2 at -78 °C for 30 min, this stannane afforded syn adducts in high yield with isobutyraldehyde and pivalic aldehyde (Figure 31). Wang also examined the racemic β-oxygenated aldehyde 47, a prototype for our planned polyketide applications. By using BF3•OEt2 as the Lewis acid, he obtained the syn, syn adduct 48 as the major product of an 86:14 mixture of diastereoisomers. When he employed MgBr2, the diastereomeric syn, anti adduct 49 constituted the major component of a 90:10 mixture. The selectivity of these additions can be attributed to Felkin-Anh and chelation control. In a study related to pseudopterolide natural products, Wang also explored a number of intramolecular allenylstannane additions leading to homopropargylic cyclododecynols, one of which is illustrated in Figure 32.40 These 12-membered ring closures proceeded in nearly 90% yield to afford mixtures of diastereomers. Upon oxidation with the Dess-Martin reagent, the alcohols were converted to allenyl ketones in over 90% yield. These ketones, in turn, afforded bridged furans, also in high yield, upon exposure to AgNO3. Furan 50 is related to the marine pseudopterolide natural product kallolide B.41 J. Org. Chem, Vol. 72, No. 22, 2007 8159

FIGURE 35. Transition states for chelation-controlled additions to O-benzyl lactic aldehyde.

FIGURE 32. Synthesis of macrocyclic bridged furans by sequential intramolecular allenylstannane addition and allenone cyclization.

FIGURE 36. Felkin-Anh selectivity in additions of enantiomeric allenylstannanes to (R)-3-benzyloxy-2-methylpropanal.

FIGURE 33. Synthesis of enantioenriched allenylstannanes from chiral propargylic mesylates.

FIGURE 34. Additions of enantioenriched allenylstannanes to Obenzyl lactic aldehyde.

Wang next directed his efforts at the preparation of nonracemic allenylstannanes.42 He found that the enantioenriched propargylic mesylates 51 and 52 are converted to the chiral allenylstannanes 53 and 54 with the cuprate derived from Bu3SnLi and CuBr•SMe2 (Figure 33). The configuration of the stannanes, determined unambiguously by independent synthesis, confirmed the surmise of Ruitenberg et al. that stannylcuprate reactions with propargylic mesylates proceed by an anti SN2′ process. Wang’s first studies with nonracemic allenylstannanes involved additions to the benzyl ether of (S)-lactic aldehyde with promotion by MgBr2 or BF3•OEt2 (Figure 34). The former reactions were highly diastereoselective for both enantiomeric stannanes, suggestive of a substrate-controlled chelation process. The outcome is consistent with attack by the allenylstannane on the face of the chelated aldehyde opposite the R-methyl 8160 J. Org. Chem., Vol. 72, No. 22, 2007

substituent (Figure 35). The allene attack occurs anti to the stannane substituent (a stereoelectronic effect) in an orientation that places the hydrogen substituent of the attacking allenic carbon over the face of the five-membered chelate. The BF3promoted reactions, on the other hand, were strongly reagent controlled. Addition of the (P)-reagents was mismatched favoring the syn, syn adduct by only 70:30 (R ) CH2OAc) or 87:13 (R ) Et), whereas the (M)-reagent favored the syn, anti adduct (not shown) by 97:3 (R ) CH2OAc) or 99:1 (R ) Et). These additions evidently proceed under Felkin-Anh control. In work more closely aligned with polypropionate applications, Wang found that the aldehyde 55, derived from 2-methyl3-hydroxypropionic acid, showed typical matched-mismatched selectivity in BF3-promoted additions (Figure 36).43 The related MgBr2-promoted reactions were highly diastereoselective, except for a pairing with the (M)-ethylstannane which afforded a 1:1 mixture of the syn, syn and anti, anti adducts (not shown). Evidently, in this case, competing Felkin-Anh and chelation transition states, leading to the former and latter isomers, are equally favored. The foregoing BF3-promoted additions favor production of syn diastereomers through an acyclic Felkin-Anh transition state. By analogy with allylic stannanes, we reasoned that access to anti adducts might be possible by exchanging the tributyltin group with a more electropositive metal substituent in order to favor a cyclic transition state. This possibility was examined by Jolyon Perkins with the (P)-allenylstannane 56 and isobutyraldehyde (Figure 37).44 Promotion with BF3 yielded, as before, the syn adduct 57. However, when the addition was conducted at -78 °C with SnCl4 as the Lewis acid promoter, the (M)-allenylcarbinol 58 was formed as the sole product. By premixing the allenylstannane with SnCl4 prior to aldehyde addition, Jolyon obtained the desired anti homopropargylic alcohol 59. Each of these additions proceeded with high

FIGURE 39. Synthesis of syn, anti and anti, syn stereotriads from a common allenylstannane precursor.

FIGURE 37. Alternative reaction outcomes for additions of a chiral allenylstannane to isobutyraldehyde.

FIGURE 40. Stereoselective synthesis of syn- and anti-allenylcarbinols from a common allenylstannane precursor.

FIGURE 38. Proposed pathways for the formation of allenylcarbinols and diastereomeric homopropargylic alcohols from a common chiral allenylstannane.

diastereoselectivity and gave adducts of enantiomeric purity comparable to that of the starting stannane, suggestive of a stereospecific process. A consideration of these observations led to the mechanistic rationale outlined in Figure 38. The BF3-promoted reaction proceeds through an acyclic Yamamoto transition state in which the preferred anti relationship between the allenyl methyl and the aldehyde isopropyl substituents results in formation of the syn adduct 57. The addition of SnCl4 to the stannane results in an anti SE2′ substitution leading to the propargylic trichlorostannane 60. Reaction of this stannane with the aldehyde affords the allenylcarbinol 58. Alternatively, in the absence of aldehyde, the propargylic stannane undergoes a second SnCl4initiated rearrangement to the allenyl trichlorostannane 61, which in turn reacts with added aldehyde to yield the homopropargylic alcohol 59. These latter two additions proceed through cyclic transition states. This pathway was verified by an independent synthesis of the various products to confirm the stereochemical assignments and by NMR studies, which tracked the allenylpropargyl-allenyl isomerization sequence in the absence of aldehyde. Allenylstannane methodology can thus be employed to access all isomeric stereotriads related to polypropionate segments by appropriate combinations of allenyl tin reagent and chiral aldehyde substrate. The tributyltin reagent affords the syn, syn isomer with BF3 promotion under Felkin-Anh control or the syn, anti isomer with MgBr2 under chelation control (Figure 36). The anti, anti (not shown) and anti, syn triads (Figure 39) derive from the trichlorotin reagent, prepared in situ. While it is also possible to utilize allenylstannane methodology for the synthesis of allenylcarbinols with the in situ generated propargylic trichlorotin reagent, the homopropargylic alcohol can be formed as a byproduct, or even a major product,

FIGURE 41. Ag+-catalyzed conversion of allenylcarbinols to 2,5dihydrofurans.

FIGURE 42. Synthesis of enantiomeric anti adducts from a common allenylstannane by transmetalation.

owing to a competing propargyl-allenyl isomerization of the trichlorotin intermediate. Postdoc Richard Yu discovered a solution to this problem through use of BuSnCl3 in place of SnCl4 (Figure 40).45 The butyl substituent appears to markedly retard the rate of propargyl isomerization, and the allenylcarbinols thus become highly favored products. These reactions also show a high level of enantio- and diastereospecificity. The allenylcarbinols can be stereoselectively converted to 2,5dihydrofurans by treatment with AgNO3 in acetone (Figure 41). After a productive 15 years at South Carolina, I once again yielded to the temptation of improved facilities. This time, the seduction came from the University of Virginia and offered a new research building and laboratories along with the congenial environment of Mr. Jefferson’s University and historic Charlottesville. At Virginia, we continued our allenyl metal work with postdoc Mike Palovich, who examined the in situ conversion of allenyl tributyltin compounds to allenylindium chloride reagents (Figure 42).46 This variation proved successful, but surprisingly, the anti homopropargylic alcohol adduct 62 was enantiomeric to the adduct 63 obtained from the in situ SnCl4 reaction. Evidently, the InCl3 metal exchange proceeds with net retention and the SnCl4 exchange with net inversion (Figure J. Org. Chem, Vol. 72, No. 22, 2007 8161

FIGURE 43. In situ generation of enantiomeric allenyltin and indium reagents from a common allenylstannane.

FIGURE 46. Two-step conversion of a chiral homopropargylic mesylate to a chiral butenolide by sequential Pd-catalyzed hydrocarbonylation and Ag+-catalyzed cyclization.

FIGURE 44. Synthesis of anti, syn stereotriads from a chiral allenylstannane precursor.

FIGURE 45. Additions of chiral allenic and propargylic trichlorosilanes to aldehydes.

43). The former likely involves consecutive anti SE2′ processes, while the latter proceeds by an initial anti and a subsequent syn substitution (Figure 38). The indium reagent provides ready access to anti, syn stereotriads (Figure 44). Both the indium and tin exchanges occur with minimal racemization. However, in certain cases, Mike found that InBr3 or InI3 affords products of higher enantiopurity than those obtained with InCl3. In the early stages of these transmetalation investigations, Nick Adams briefly explored an in situ preparation of chiral trichlorosilanes through CuCl-catalyzed addition of trichlorosilane to chiral propargylic mesylates.47 This study was based on a 1995 report of Kobayashi and Nishio who prepared achiral propargyl trichlorosilane and allenyl trichlorosilane from propargyl chloride and studied their reactions with achiral aldehydes.48 Nick found that the mesylate of (R)-3-butyn-2-ol (64), upon treatment first with CuCl, HSiCl3, and Hunig’s base followed by addition of various aldehydes and DMF, afforded anti homopropargylic alcohols with excellent diastereo- and enantioselectivity (Figure 45). Interestingly, when the procedure was applied to the TMS butynyl mesylate 66, allenylcarbinols were highly favored. Evidently, the silylcuprate reacts with the unsubstituted propargylic mesylate by a preferential SN2′ pathway leading to the allenylsilane reagent 65, which then 8162 J. Org. Chem., Vol. 72, No. 22, 2007

affords anti adducts through a cyclic transition state, whereas cuprate addition to the TMS mesylate 66 proceeds by a net SN2 pathway, presumably because of steric effects. The propargylic silane 67 adds to aldehydes, with promotion by DMF, to afford allenylcarbinols. Although steric interactions between the allenyl Me and the aldehyde R groups, as illustrated in transition state diagram A, nicely accommodate the observed stereoselectivity of the allenylsilane addition, the preferred formation of the (R,M)-allenylcarbinol product through the analogous transition state B is less obvious and may involve interactions of the propargyl and aldehyde substituents with the silicon ligands.49 The configuration of the allene in the benzaldehyde adduct 68 was shown to be (M) by Ag+-catalyzed cyclization to the dihydrofuran followed by benzylic ether hydrogenolysis to produce the (R)-allylic alcohol 69. Though interesting, this study was dropped in favor of an alternative allenylzinc route to anti homopropargylic alcohols. The second phase of our chiral allenyl metal studies, like the first, had its origins in cembranolide natural products. The object of these efforts was a total synthesis of the marine furanocembrane rubifolide. Our plan involved an extension of the Ag+catalyzed synthesis of 2,5-dihydrofurans from allenylcarbinols (Figure 41) to a construction of the bridged butenolide moiety of rubifolide (Figure 1) from a chiral allenic acid. We hoped to prepare a suitable allenic acid precursor from a chiral propargylic mesylate through a type of SN2′ palladium insertion followed by in situ carbonylation and hydration. Unknown at the time was the overall stereochemistry of the process and the configurational stability of the presumed intermediate palladium species. After some effort, postdocs Eli Wallace and Mark Wolf developed a workable set of conditions for the two-step process (Figure 46).50 Stereochemical analysis indicated that palladation takes place with inversion of stereochemistry and subsequent carbonylation with retention. Clark Sehon utilized this methodology to good advantage in a remarkably efficient synthesis of rubifolide (Figure 47).51 In this synthesis, he also employed an intramolecular allenyltin-aldehyde reaction and an intraannular Ag+-catalyzed allenone cyclization to prepare the bridged furan precursor of the butenolide in an impressive application of allene synthetic chemistry. Although our results with allenyltin reagents provided straightforward solutions to the problems of stereotriad synthesis, we were not completely satisfied with the methodology because of the central role of tin. While tributylstannanes are much safer to handle than the trimethyl derivatives, the removal of tin byproducts and disposal of residues diminish the general appeal of the methodology. We formulated a partial solution to the problem based on a 1995 paper in which Tamaru and co-workers showed that allylic zinc compounds can be prepared from allylic benzoates by a Pd(0)-catalyzed metalation with diethylzinc.52 Our studies with Pd(0)-catalyzed carbonylations had demonstrated that chiral allenic palladium compounds could be

FIGURE 50. Catalytic cycle for oxidative transmetalation leading to allenylzinc reagents.

FIGURE 47. Clark Sehon’s allene-inspired synthesis of (+)-rubifolide.

FIGURE 48. Pathway for in situ Pd-catalyzed formation of allenylzinc reagents from propargylic mesylates and their addition to aldehydes.

FIGURE 51. Catalytic cycle for oxidative transmetalation leading to allenylindium reagents.

FIGURE 49. Synthesis of anti, syn and anti, anti stereotriads by in situ allenyl Pd-Zn exchange and addition to (S)- and (R)-3-benzyloxy2-methylpropanal.

FIGURE 52. Additions of in situ generated enantiomeric allenylindium reagents to a chiral aldehyde.

generated from chiral propargylic mesylates with minimal racemization. It therefore seemed possible that the Tamaru zincation reaction might follow a similar course. Nick Adams reduced this plan to practice employing the propargylic mesylate 70 and various aldehydes to prepare anti adducts with excellent enantioselectivity and diastereoselectivity (Figure 48).53 As expected, anti/syn ratios were highest for R-branched aldehydes. Matching/mismatching was minimal, as evidenced by the selective formation of the anti, syn and anti, anti adducts as sole products with the aldehydes 55 and its enantiomer (Figure 49). Reactions were initially performed with Pd(PPh3)4, but Nick later found 5 mol % of an equimolar mixture of Pd(OAc)2 and PPh3 to be more effective. A key feature of a possible catalytic cycle for the Pd-Zn exchange reaction involves reductive regeneration of the active Pd(0) catalyst from a Pd(II) intermediate through extrusion of ethylene (Figure 50). In considering other applications of this concept, we perceived that multivalent metals might undergo a formally related “oxidative transmetalation”. Our previous

experience with allenylindium reactions prompted us to investigate this possibility with commercially available InI. Here, a direct metal-metal exchange could take place without the involvement of an alkyl ligand since the requisite two electrons for regeneration of Pd(0) would come directly from In(I) to give stable In(III) intermediates (Figure 51). After surveying a number of Pd catalysts, Charsetta Grant verified the concept and found that the bidentate diphenylphosphinoferrocene ligand was quite effective (Figure 52).54 With this catalyst, the reaction proceeded in high yield with excellent stereoselectivity on a variety of aldehydes. As our studies with chiral allenic tin, zinc, and indium reagents were evolving, we increasingly recognized the need for reliable and efficient large-scale production of enantiopure propargylic alcohols. Several solutions to this problem ultimately emerged. The first of these was an adaptation of lipase-resolution methodology reported by Burgess and Jennings in 1991.55 With encouragement from Jim Panek, who had employed the lipase J. Org. Chem, Vol. 72, No. 22, 2007 8163

FIGURE 53. Lipase resolution of racemic 4-TMS-3-butyn-2-ol.

FIGURE 55. Synthesis of (S)-4-TIPS-3-butyn-2-ol and (S)-4-TMS3-butyn-2-ol by Noyori transfer hydrogenation.

FIGURE 54. Addition of allenylindium reagents from (R)-3-butyn2-ol mesylate and the related 4-TMS analogue.

methodology for resolutions of the closely related 4-DPS-3butyn-2-ol,56 Matt Yanik and Harry Chobanian subjected racemic 4-TMS-3-butyn-2-ol to the procedure with several modifications (Figure 53).57 In their resolution of this compound, Burgess and Jennings used hexane as the solvent and separated the resolved (S)-alcohol and (R)-acetate by column chromatography. Because of its volatility, the alcohol was recovered in only 27% yield. Matt and Harry chose pentane as the reaction solvent and converted the alcohol component of the crude resolved mixture to the base-soluble half-succinate for separation from the acetate by extraction. After extraction of the (S)-acetate and acidification of the aqueous phase to liberate the (R)-halfsuccinate from its sodium salt, the two esters were reduced with DIBAL-H to the respective alcohols. In this way, yields of 8590% were routinely obtained.58 They were able to reuse the insoluble lipase reagent several times with only modest loss of activity. An unexpected bonus of the process was the increased diastereoselectivity of the TMS allenylzinc and indium reagents with aldehydes over those of the unsubstituted allenyl reagents (Figure 54). The difference was especially notable with the indium reagents. Also notable was the use of Pd(OAc)2•PPh3 as the catalyst precursor in place of Pd(dppf)2Cl2. Hilary and Patrick Eidam developed an alternative route to enantiopure silyl-substituted propargylic alcohols through use of Noyori’s transfer hydrogenation methodology.59 As these reductions are typically conducted in isopropyl alcohol, they recognized that separation of the volatile TMS derivative might be problematic and selected the TIPS derivative of 3-butyn-2one as the silylated alkynone substrate. The reductions proved highly successful, and they were able to prepare both enantiomeric alcohols of >95% enantiomeric purity in high yield (Figure 55).60 The TIPS propargylic mesylates were comparable to their TMS counterparts in allenylzinc and indium additions to chiral and achiral aldehydes, and they proved superior in additions to R-branched conjugated aldehydes (Figure 56). Desilylations of the homopropargylic adducts were readily achieved with TBAF. Martin Herold, one of my current Ph.D. students, utilized a more recent Noyori modification of the 8164 J. Org. Chem., Vol. 72, No. 22, 2007

FIGURE 56. In situ additions of allenylzinc reagents to conjugated aldehydes.

FIGURE 57. Synthesis of chiral allenylsilanes and additions to chiral aldehydes.

transfer hydrogenation, in which triethylammonium formate is the hydride source, to prepare enantiopure 4-TMS-3-butyn-2ol mesylates in 70% overall yield from the racemic alcohol.61 The use of CH2Cl2 as the solvent in this reduction minimizes volatility losses of the alcohol precursor. Allenylzinc and indium reagents provide convenient alternatives to tin reagents for the synthesis of anti adducts. However, syn adducts are still best prepared with allenyltributyltin reagents. In our quest for alternative methodology, we briefly explored the use of chiral allenylsilanes. These are much weaker nucleophiles and require strong Lewis acids, such as TiCl4, as the Lewis acid promoter, thus limiting the range of aldehydes that can be employed for the additions. Following the method of Fleming,62 postdoc Karin Maxson prepared (M)- and (P)phenyldimethylsilylallenes by SN2′ displacement of propargylic mesylates with the silylcuprate reagent (Figure 57).63 Addition

R-chiral aldehyde.

their presence at the R- or β-position of the aldehyde led to varying amounts of chelation-controlled anti adducts (Figure 58). In accord with the findings of Danheiser and co-workers, allenylsilanes lacking a terminal substituent gave rise to adducts with an (E)-β-chlorovinylsilane substituent rather than the expected alkyne (Figure 59).64 However, these were readily converted to the alkynyl products with TBAF. Natural products provided the original impetus for our studies on chiral allylic and allenic organometallic reagents. In recent years, the allenyl reagents have proven especially useful for the synthesis of polyketides. Figure 60 summarizes applications that have resulted in completed or nearly completed total syntheses.65 In addition to these, a number of other applications have proven serviceable for the synthesis of polypropionate segments, mainly stereotriads. Although both syn and anti adducts can be prepared with high stereoselectivity, the former still require the use of tin reagents. In this account, I have chronicled the evolution of our synthetic work on cembranes and polyketides over the past two decades. It has been my great pleasure during those years to have been associated with a dedicated and highly skilled group of graduate students and postdocs. Their efforts have contributed immeasurably to the success of these ventures, and I acknowledge their contributions with the utmost gratitude.

of the (M)-allenylsilane to the (R)-aldehyde 71 afforded the syn, syn adduct, while addition to the (S)-aldehyde 72 led to a 4:1 mixture of the syn, anti and anti, syn products. The DPS protecting group was compatible with the Lewis acid, but the TBS- and PMB-protected analogues of these aldehydes were extensively cleaved. While benzyl ethers withstood cleavage,

Acknowledgment. We gratefully acknowledge research grants from the NIH and NSF for support of these programs over the past 25 years. Special thanks to Dr. Ray Conrow for correcting numerous typographical errors and calling our attention to a number of inconsistencies in a late stage draft version of the manuscript.

FIGURE 58. Chelation control in additions of allenylsilanes to chiral β-benzyloxy aldehydes.

FIGURE 59. Addition of chiral monosubstituted allenylsilanes to an

FIGURE 60. Applications of chiral allenyl metal reactions for natural product synthesis. J. Org. Chem, Vol. 72, No. 22, 2007 8165

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