NIH Public Access Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. NIH-PA Author Manuscript Published in final edited form as: J Org Chem. 2004 April 2; 69(7): 2569–2572. Unified Synthesis of C19–C26 Subunits of Amphidinolides B1, B2, and B3 by Exploiting Unexpected Stereochemical Differences in Crimmins’ and Evans’ Aldol Reactions Wei Zhang, Rich G. Carter*, and Alexandre F. T. Yokochi† Department of Chemistry, 153 Gilbert Hall, Oregon State University, Corvallis, Oregon 97331 Abstract NIH-PA Author Manuscript The efficient synthesis of the C19–C26 subunit of amphidinolide B1 and B2 has been completed using a boron-mediated aldol reaction. The synthesis of the C19–C26 subunit of amphidinolide B3 has also been accomplished through an unexpected anti aldol reaction using a titanium-mediated process. In addition, the first reported examples of a stereochemical discrepancy between the Evans’ boronmediated oxazolidinone and the Crimmins’ titanium-mediated oxazolidinethione aldol reactions are disclosed. A working hypothesis is put forth to explain the results. The synthetic utility of chiral oxazolidinones has been well-documented in the organic community.1 This powerful removable auxiliary has been shown to be effective in the construction of a wide variety of carbon–carbon and carbon–heteroatom bonds in a highly stereoselective fashion. Numerous working models have been put forth to explain and predict the resultant stereochemical outcome from these reactions. These models have proven to be highly reliable and general, with only isolated examples of anomalies having been reported.2 NIH-PA Author Manuscript In particular, the so-called “Evans-syn” aldol reactions with chiral oxazolidinones using dibutylboron triflate and the appropriate amine base have become the standard by which new asymmetric and diastereoselective reactions are judged against (Scheme 1).3 The recently developed titanium-mediated oxazolidinethione aldol reaction, from the Crimmins laboratory, has been shown to provide comparable levels of selectivity on a wide range of systems.4 There are several advantages to the Crimmins’ aldol methodology (e.g., relative ease of auxiliary cleavage and use of the logistically easier titanium enolates). One particularly attractive attribute is the flexibility imparted by Crimmins’ chelated and nonchelated models which is dependent on the amount of TiCl4 and amine base (normally (−)-sparteine) that is added. This modification provides access to both the Evans-syn product via the nonchelated model and the non-Evans-syn adduct via the chelated model (Scheme 1). The level of syn/anti selectivity is high (normally > 20:1) and comparable to traditional boron-mediated aldol reactions for both the chelated and nonchelated titanium-mediated conditions. It should be pointed out that Crimmins has shown that the chirality of (−)-sparteine does not influence the stereochemical outcome of the transformation.4 We were attracted to the application of the Crimmins and/or Evans methodologies for the construction the eastern subunit 15 of the cytotoxic macrolide amphidinolide B1 (11)5,6 rich.carter@oregonstate.edu. †Director of X-ray Crystallographic Facility, Department of Chemistry, Oregon State University, Corvallis, OR 97331. E-mail: alexandre.yokochi@oregonstate.edu. Supporting Information Available: Crystallographic data for aldol adduct 28 and experimental procedures, including copies of spectral data (1H and 13C NMR), for compounds 15, 16, 21, 23–25, 28, 29, 31–34, 36–38, 44–46, and 49. This material is available free of charge via the Internet at http://pubs.acs.org. Zhang et al. Page 2 NIH-PA Author Manuscript (Scheme 2). Amphidinolide B1 has attracted considerable synthetic interest,7 yet the total synthesis of 11 remains an elusive target.8 Two additional members of the amphidinolide B family, B2 (12) and B3 (13), have also been reported. These structures only differ from the parent B1 structure by alternate stereochemistries at C18 and/or C22. Compounds 11 and 12 should be accessible from a common subunit 15 while C22 epimer 13 should be accessible from the anti,anti adduct 16. While the application of the titanium-mediated aldol methodology has begun to appear,9 several important combinations have yet to be fully explored. One such example is the coupling of an O-benzyl-protected glycolate such as 2 or 8 with an α-chiral aldehyde 3 to provide a syn,syn coupled adduct such as 7 or 10 (Scheme 1). The stereochemical “Felkin” relationship of the C22 and C23 positions (amphidinolide B1 numbering) would appear to be ideally suited for this transformation as both the auxiliary and the aldehyde appear to be directing the outcome in a complementary fashion. Despite this combination, the examples of a syn,syn adduct from an O-benzyl-protected glycolate such as 1, 2, or 8 are surprisingly rare.10 In fact, no examples of the aldol reaction depicted with oxazolidinethione 2 or 8 have been reported with α-chiral aldehydes. In this paper, we disclose the first reported examples of these combinations and the resulting synthesis of the C19–C26 subunits 15 and 16 for all amphidinolides B1–B3. NIH-PA Author Manuscript Construction of the necessary aldehyde precursor 21 was accomplished in four steps from commercially available Myers auxiliary 18. The known alkylation11 with the commercially available (R)-propylene oxide provided the C23,24-coupled material 19 in 94:6 dr.12 Subsequent TES protection followed by reduction with BH3·NH3/LDA and Ley oxidation13 yielded the desired aldehyde 21 (Scheme 3). NIH-PA Author Manuscript Exploration into the aldol reaction commenced with the known oxazolidinethione auxiliary 2214 (Scheme 4). Treatment of the prescribed conditions for obtaining nonchelation or “Evanssyn” aldol adducts [TiCl4 (1.0 equiv), (−)-sparteine (2.5 equiv)] provided two diastereomeric aldol adducts 23 and 24 in a 1.5:1 ratio. Unlike as predicted in the Crimmins’ models for this transformation, none of the expected Evans-syn adduct was observed. Instead, the anti adducts 23 (H21–H22 J = 9.3 Hz) and 24 (H21–H22 J = 8.4 Hz) were isolated in nearly equal amounts. 15 The addition of additives such as NMP or alternate bases (e.g., TMEDA) did not affect the observed stereochemical outcome.4 Thwarted by this unexpected result, we turned to an achiral aldehyde (2-butenal) to ensure the protocol was performing as expected. Aldol reaction under the identical conditions [TiCl4 (1.0 equiv), (−)-sparteine (2.5 equiv)] provided solely the expected Evans-syn adduct 25 (H21–H22 J = 3.3 Hz) in a 17:1 ratio. One possible explanation would be a mismatched relationship between the directing effect of the auxiliary and the inherent stereochemical preference of the aldehyde. To this end, the experiment was conducted with the achiral auxiliary 26; however, equal amounts of the two previously observed anti stereochemistries (21R,22R and 21S,22S) were again the only observable products. Given that the nonchelation approach provided none of the desired syn adduct (e.g., compound 7), the complementary chelation aldol would appear to be the next logical step (Scheme 5). Using the enantiomeric oxazolidinethione auxiliary 27, treatment under the chelation conditions [TiCl4 (2 equiv), (−)-sparteine (1 equiv)] proceeded poorly and in low yield. Crimmins has also reported that the use of less TiCl4 [(1 equiv), (−)-sparteine (1 equiv)] proceeds via the chelated model.4 Treatment using these conditions provided some improvement in the selectivity of the transformation, yielding a more respectable 4:1 ratio of the two anti products (28/29) (28: H21–H22 J = 8.8 Hz; 29: H21–H22 J = 9.2 Hz) with none of the predicted syn adduct. It is important to note that despite the expected directing effect of the auxiliary (e.g., 22 should give the same absolute configuration at C21, C22 under nonchelation conditions as enantiomeric auxiliary 27 gives under chelation conditions), the major product 28 from the chelation-controlled conditions using 27 contained the 21R,22R stereochemistry J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 3 NIH-PA Author Manuscript of the minor product from the nonchelation conditions with 22. Alcohol 28 is synthetically useful as it possesses the correct anti,anti C21–23 stereochemistry for amphidinolide B3. Interestingly, use of the enantiomeric auxiliary 22 under chelation conditions led to an equal mixture of the adducts 23 and 24. A similar result was observed with the achiral auxiliary 26. It became apparent at this juncture that the titanium-based aldol were unable to provide the necessary stereochemical relationship (e.g., 7 or 10) for amphidinolides B1 and B2. We were gratified to observe that use of the auxiliary 3016 under boron-mediated conditions did yield the desired Evans-syn adduct 31 (H21–H22 J = 2.1 Hz) in a 95:5 syn,syn and syn,anti ratio (72% isolated yield of 31). To the best of our knowledge, these results represent the first reported examples of the stereochemical divergence between the titanium-mediated oxazolidinethiones and boron-mediated oxazolidinones.15 NIH-PA Author Manuscript Stereochemical assignment of the aldol products 23–25, 28–29, and 31 was accomplished via a series of degradation experiments and X-ray crystallographic analysis of 28 (Scheme 6). Reductive removal of the auxiliaries from adducts 24 and 28 yielded an identical diol 32, thereby confirming 24 vis-à-vis X-ray structure 28. An analogous path was followed for the adducts 23 and 29 to yield the diol 34. The stereochemistry of 31 was confirmed via conversion to the TBDPS ether 36 and correlation with the TBDPS ether 33 through TPAP oxidation to the ketone 37. This degradation also indirectly established one of the two unknown stereocenters of 23 and 29 as 21S by assignment of both aldol adducts 28 and 31 as the 21R configuration. The 22S configuration was confirmed by Mosher ester analysis of 35.17 Finally, the stereochemistry of 25 was confirmed by reduction to a known compound 38.18 NIH-PA Author Manuscript A working hypothesis for the observed stereochemical results invokes the use of the open transition state 40 and boat transition states19 41 and 43 to explain the observed stereochemistry (Scheme 7). One possible rational for the inability of these transformations to proceed through the chair transition states 39 and 42 could be an unfavorable interaction between the benzyloxy substituent and the α-position of the aldehyde.20 As steric bulk at these positions increase, this unfavorable interaction should become more significant. We also hypothesize that the bulk of the benzyloxy substituent may be increased by an aggregation effect. While additional studies are necessary to verify this aggregation effect, we do observe a modest correlation of concentration with diastereoselectivity [0.15 M, 4:1 dr; 0.05 M, 2:1 dr (28:29)]. A similar correlation is observed for this transformation by even a slight variation in the ratio of auxiliary to aldehyde. The use of 1.5 equiv of auxiliary 27 with 1 equiv of the aldehyde 21 yielded a 4:1 ratio (28/29), while 2.0 equiv of the same auxiliary 27 (1 equiv of 21) yielded a 2:1 ratio (28/29) under the described chelation conditions. Phillips and co-workers have also commented on the sensitivity of titanium-mediated aldol reactions to slight modifications.19a In contrast to the titanium enolates, the boron enolates are unable to aggregate in the Zimmerman–Traxler transition state due to the full valence shell on boron. This important difference does appear to agree with the observed stereochemical results. Finally, an open transition state 40 is put forth to justify the anti adduct 23.15 This proposed explanation allows for an approach of the aldehyde consistent with the Felkin model. Completion of the C19–C26 subunits of amphidinolide B1–B3 was accomplished in three steps (Scheme 8). Silylation using TESOTf provided the bissilylated compound 44. Conversion to the thioester using catalytic amounts of KSEt followed by cuprate coupling gave the methyl ketone 15.21 An analogous path was pursued with anti,anti adduct 28 to provide the methyl ketone 16. Interestingly, attempted introduction of TBS protecting group on the adduct 31 led to competitive silyl migration. This migration was not observed with the adduct 28. A unified strategy for the synthesis of the C19–C26 subunits of amphidinolide B1–B3 13–15 has been accomplished. The first reported examples of the divergence of the titanium-mediated J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 4 oxazolidinethione aldol reaction to provide the anti adducts 23–24 and 28–29 as the sole products have been reported. A working model is put forth to explain the stereochemical results. NIH-PA Author Manuscript Supplemental Material Refer to Web version on PubMed Central for supplementary material. Acknowledgements Financial support was provided by the National Institutes of Health (NIH) (GM63723) and Oregon State University. This publication was also made possible in part by a grant from the NIH–National Institute of Environmental Health Sciences (P30 ES00210). We thank Professor Max Dienzer (Mass Spectrometry Facility, Environmental Health Sciences Center, Oregon State University) and Dr. Jeff Morré (Mass Spectrometry Facility, Environmental Health Sciences Center, Oregon State University) for mass spectra data, Roger Kohnert (Oregon State University) for NMR assistance, and Dr. Roger Hanselmann (Rib-X Pharmaceuticals) for his helpful discussions. References NIH-PA Author Manuscript NIH-PA Author Manuscript 1. Evans, DA.; Kim, AS. Handbook of Reagents for Organic Synthesis: Reagents, Auxiliaries and Catalysts for C–C Bonds. Coates, RM.; Denmark, SE., editors. John Wiley & Sons; New York: 1999. p. 91-101. 2. (a) Clive DLJ, Yu M. Chem Commun 2002:2380–81. (b) Evans DA, Kaldor SW, Jones TK, Clardy J, Stout TJ. J Am Chem Soc 1990;112:7001–31. (c) Iseki K, Oishi S, Kobayashi Y. Tetrahedron 1996;52:71–84. 3. (a) Evans DA, Bartroli J, Shih TL. J Am Chem Soc 1981;103:2127–29. (b) Evans DA, Nelson JV, Taber TR. Top Stereochem 1982;13:1–115. 4. Crimmins MT, King BW, Tabet EA, Chaudhary K. J Org Chem 2001;66:894–902. [PubMed: 11430110] 5. Ishibashi M, Ishiyama H, Kobayashi J. Tetrahedron Lett 1994;35:8241–42. 6. (a) Kobayashi J, Ishibashi M, Nakamura H, Ohizumi Y, Hirata Y, Sasaki T, Ohta T, Nozoe S. J Nat Prod 1989;52:1036–41. [PubMed: 2607346] (b) Ishibashi M, Ohizumi Y, Hamashima M, Nakamura H, Hirata Y, Sasaki T, Kobayashi J. J Chem Soc Chem Commun 1987:1127–29. 7. (a) Cid B, Pattenden G. Tetrahedron Lett 2000;41:2573–76. (b) Ohi K, Nishiyama S. Synlett 1999:571– 72. (c) Ohi K, Nishiyama S. Synlett 1999:573–75. (d) Eng HM, Myles DC. Tetrahedron Lett 1999;40:2275–78. (e) Eng HM, Myles DC. Tetrahedron Lett 1999;40:2279–82. (f) Chakraborty TK, Thippewamy D. Synlett 1999:150–52. (g) Ishiyama H, Takemura T, Tsuda M, Kobayashi J. J Chem Soc Perkin Trans 1999;1:1163–66. (h) Chakraborty TK, Thippewamy D, Suresh VR, Jayaprakash S. Chem Lett 1997:563–64. (i) Chakraborty TK, Suresh VR. Chem Lett 1997:565–66. (j) Lee DH, Lee S-W. Tetrahedron Lett 1997;38:7909–10. (k) Ohi K, Shima K, Hamada K, Saito Y, Yamada N, Ohba S, Nishiyama S. Bull Chem Soc Jpn 1998;71:2433–40. 8. For total syntheses of other members of the amphidinolides: (a) Williams DR, Kissel WS. J Am Chem Soc 1998;120:11198–99. (b) Williams DR, Myers BJ, Mi L. Org Lett 2000;2:945–48. [PubMed: 10768193] (c) Williams DR, Meyer KG. J Am Chem Soc 2001;123:765–66. [PubMed: 11456603] (d) Lam HW, Pattenden G. Angew Chem Int Ed 2002;41:508–511. (e) Maleczka RE, Terrell LR, Geng F, Ward JS III. Org Lett 2002;4:2841–44. [PubMed: 12182569] (f) Trost BM, Chrisholm JD, Wrobleski ST, Jung M. J Am Chem Soc 2002;124:12420–21. [PubMed: 12381177] (g) Fürstner A, Aïssa C, Riveiros R, Ragot J. Angew Chem Int Ed 2002;41:4763–66. (h) Ghosh AK, Liu C. J Am Chem Soc 2003;125:2374–75. [PubMed: 12603108] 9. (a) Crimmins MT, King BW, Zuercher WJ, Choy AL. J Org Chem 2000;65:8499–09. [PubMed: 11112569] (b) Crimmins MT, Choy AL. J Am Chem Soc 1999;121:5653–60. (c) Crimmins MT, Katz JD, McAtee LC, Tabet EA, Kirincich SJ. Org Lett 2001;3:949–52. [PubMed: 11263923] 10. Only four reported examples of this combination have appeared in the literature: (a) Crimmins MT, Katz JD, McAtee LC, Tabet EA, Kirincich SJ. Org Lett 2001;3:949–52. [PubMed: 11263923] (b) Chakaborty TK, Suresh VR. Tetrahedron Lett 1998;39:7775–78. (c) Piscopio AD, Minowa N, Chakraborty TK, Koide K, Bertinato P, Nicolaou KC. J Chem Soc Chem Commun 1993:617–18. (d) Jones TK, Reamer RA, Desmond R, Mills SG. J Am Chem Soc 1990;112:2998–3017. J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 5 NIH-PA Author Manuscript NIH-PA Author Manuscript 11. Myers AG, McKinstry L. J Org Chem 1996;61:2428–40. 12. It should be noted that this stereochemical combination provides the epimeric stereochemistry at C25 versus the target 11; however, the alkylation of the enantiomeric (S)-propylene oxide proceeds in poor selectivity due to its mismatched relationship to the approaching enolate. This stereocenter will be inverted later in the synthetic sequence. 13. Ley SV, Norman J, Griffith WP, Marsden SP. Synthesis 1994:639–66. 14. Crimmins MT, McDougall PJ. Org Lett 2003;5:591–94. [PubMed: 12583777] 15. It should be noted that Crimmins has recently reported the development of a titanium-mediated oxazolidinethione method for the synthesis of anti aldol adducts through an open transition state; however, this reaction protocol requires the addition of an additional 2.5 equiv of TiCl4 immediately prior to addition of the aldehyde. See ref 14. 16. Evans DA, Gage JR, Leighton JL, Kim AS. J Org Chem 1992;57:1961–3. 17. (a) Ohtani I, Kusumi T, Kashman Y, Kakisawa H. J Am Chem Soc 1991;113:4092–96. (b) Dale JA, Mosher HS. J Am Chem Soc 1973;95:512–19. (c) Sullivan GR, Dale JA, Mosher HS. J Org Chem 1973;38:2143–47. 18. Reduction using lithium borohydride revealed the known diol which match the reported 1H NMR and 13C NMR spectrum. [[α]20D = +17.5 (c = 0.48, CHCl3) vs lit. +16.8 (c = 2.0 in CHCl3)]. Fuhry MAM, Holmes AB, Marshall DR. J Chem Soc Perkin Trans 1993;1:2743–46. 19. The preference for a boat transition state in oxazolidinethione aldol reactions has been proposed previously. (a) Guz NR, Phillips AJ. Org Lett 2002;4:2253–56. [PubMed: 12074680] (b) Evans DA, Downey CW, Shaw JT, Tedrow JS. Org Lett 2002;4:1127–30. [PubMed: 11922799] 20. For recent and somewhat related examples, see: (a) Evans DA, Siska SJ, Cee VJ. Angew Chem Int Ed 2003;42:1761–65. (b) Marco JA, Carda M, Díaz-Oltra S, Murga J, Falomir E, Roeper H. J Org Chem 2003;68:8577–82. [PubMed: 14575488] 21. White JD, Carter RG, Sundermann KF, Wartmann M. J Am Chem Soc 2001;123:5407–13. [PubMed: 11389619] NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 6 NIH-PA Author Manuscript Scheme 1. Generalized Examples of Crimmins’ and Evans’ Aldol Adducts NIH-PA Author Manuscript NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 7 NIH-PA Author Manuscript Scheme 2. Retrosynthetic Analysis of Amphidinolide B1 NIH-PA Author Manuscript NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 8 NIH-PA Author Manuscript Scheme 3. Key: (i) ref 11, (R)-propylene oxide, 92%, 94:6 dr; (ii) TESCl, Et3N, DMAP, CH2Cl2; (iii) LDA, BH3·NH3, THF, 0 °C, 78% over two steps; (iv) TPAP, NMO, CH2Cl2, 85%. NIH-PA Author Manuscript NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 9 NIH-PA Author Manuscript Scheme 4. NIH-PA Author Manuscript Key: (i) TiCl4 (1 equiv), (−)-sparteine (2.5 equiv), 21, CH2Cl2, 0.15 M, −78 °C, 40 min, 1.25:1 dr (23:24), 44% 23, 30% 24; (ii) TiCl4 (1 equiv), (−)-sparteine (2.5 equiv), 2-butenal, CH2Cl2, 0.15 M, −78 °C, 40 min, 80%. NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 10 NIH-PA Author Manuscript Scheme 5. NIH-PA Author Manuscript Key: (i) TiCl4 (1 equiv), (−)-sparteine (1 equiv), 21, CH2Cl2, 0.15 M, −78 °C, 40 min, 4:1 dr (28:29), 53% 28; (ii) Bu2BOTf (1 equiv), Et3N (1.1 equiv), PhMe, 0.15 M, −50 to −30 °C, 2 h, 72%. NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 11 NIH-PA Author Manuscript NIH-PA Author Manuscript Scheme 6. Key: (i) LiBH4, MeOH, THF, 0 °C to rt; (ii) TBDPSCl, imid, DMAP, CH2Cl2, 0 °C to rt; (iii) (R)/(S) Mosher acid chloride, DMAP, CH2Cl2; (iv) difference in ppm [(S)-Mosher ester–(R)Mosher ester, CDCl3, 400 MHz NMR] shown on structure 35; (v) TPAP, CH2Cl2, molecular sieves. NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 12 NIH-PA Author Manuscript NIH-PA Author Manuscript Scheme 7. Possible Explanation for Observed Stereochemical Outcome NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17. Zhang et al. Page 13 NIH-PA Author Manuscript Scheme 8. NIH-PA Author Manuscript Key: (i) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C; (ii) EtSH, KH (cat.), THF; (iii) Me2CuLi, Et2O, −50 °C; (iv) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C. NIH-PA Author Manuscript J Org Chem. Author manuscript; available in PMC 2008 June 17.