A Complementary Toolbox of Iterative Methods for the Stereo­selective Synthesis of Heteroatom-Rich Motives from C₁-Building Blocks

Dedicated to Prof. Hans-Günther Schmalz on the occasion of his 60^th birthday.

Abstract

The ability to assemble organic molecules one carbon atom at a time has been a long-held dream for chemists. Modern boronate homologations with chiral carbenoids allow for the assembly-line synthesis of long chiral alkyl chains with excellent control over individual stereocenters. Nevertheless, heteroatom rich motives present a serious synthetic challenge to this approach. Interestingly, older methods based on substrate-controlled homologations of chiral boronic esters or umpolung of a carbonyl nucleophile can offer complementary solutions. A combination of these approaches might thus extend the range of possible targets currently within grasp of a C₁-based synthesis. Link to video abstract: https://www.youtube.com/watch?v=PH_HBrqQwtg .

1 Introduction

2 Substrate Control: Stereoselective Addition of d₁-Reagents to Aldehydes­

3 Stereocontrol by Chiral Auxiliary/Director: The Matteson Boronate Homologation

4 Reagent Control: Moving Chiral Information to the Carbenoid

5 Conclusions and Outlook

Key words

homologation - assembly-line synthesis - chiral carbenoid - boronic ester - Matteson homologation - Dondoni homologation - Aggarwal homologation

• References

• 1a Beld J. Lee DJ. Burkart MD. Mol. Biosyst. 2015; 11: 38
• 1b Ghazarian H. Idoni B. Oppenheimer SB. Acta Histochem. 2011; 113: 236
• 1c Zheng K. Xie C. Hong R. Front. Chem. (Lausanne, Switz.) 2015; 3: 32; DOI: org/10.3389/fchem.2015.00032
• 2a Lin L. Yamamoto K. Mitsunuma H. Kanzaki Y. Matsunaga S. Kanai M. J. Am. Chem. Soc. 2015; 137: 15418
• 2b Northrup AB. Mangion IK. Hettche F. MacMillan DW. C. Angew. Chem. Int. Ed. 2004; 43: 2152
• 2c Northrup AB. Science (Washington, D. C.) 2004; 305: 1752
• 2d Albert BJ. Yamamoto H. Angew. Chem. Int. Ed. 2010; 49: 2747
• 2e Alagiri K. Lin S. Kumagai N. Shibasaki M. Org. Lett. 2014; 16: 5301
• 3 Han SB. Hassan A. Kim IS. Krische MJ. J. Am. Chem. Soc. 2010; 132: 15559
• 4a Hanessian S. Wang W. Gai Y. Olivier E. J. Am. Chem. Soc. 1997; 119: 10034
• 4b Miyashita M. Hoshino M. Yoshikoshi A. J. Org. Chem. 1991; 56: 6483
• 5 To clarify: When referring to a ‘C_n-building block’ in this review, we only focus on the number of carbon atoms that are inserted into the alkyl chain in an iterative manner. From this perspective, the condensation of two propionates would be considered a C₂-based method, as the alkyl chain, which grows by the iterative process is elongated by two atoms.
• 6 Burns M. Essafi S. Bame JR. Bull SP. Webster MP. Balieu S. Dale JW. Butts CP. Harvey JN. Aggarwal VK. Nature (London) 2014; 513: 183
• 7 Dondoni A. Synthesis 1998; 1681

Recent reviews:
• 8a Matteson DS. J. Org. Chem. 2013; 78: 10009
• 8b Thomas SP. French RM. Jheengut V. Aggarwal VK. Chem. Rec. 2009; 9: 24

Original article:
• 8c Matteson DS. Majumdar D. J. Am. Chem. Soc. 1980; 102: 7588
• 8d Matteson DS. Ray R. J. Am. Chem. Soc. 1980; 102: 7590

Recent reviews:
• 9a Sandford C. Aggarwal VK. Chem. Commun. 2017; 53: 5481
• 9b Leonori D. Aggarwal VK. Acc. Chem. Res. 2014; 47: 3174
• 9c Scott HK. Aggarwal VK. Chem. Eur. J. 2011; 17: 13124
• 9d Collins BS. L. Wilson CM. Myers EL. Aggarwal VK. Angew. Chem. Int. Ed. 2017; 56: 11700
• 9e Pape F. Teichert JF. Nachr. Chem. 2017; 65: 879
• 10 Blakemore PR. Marsden SP. Vater HD. Org. Lett. 2006; 8: 773
• 11 Butlerov AA. C. R. Hebd. Seances Acad. Sci. 1861; 53: 145
• 12 Breslow R. Tetrahedron Lett. 1959; 1: 22
• 13a Fischer E. Ber. Dtsch. Chem. Ges. 1890; 23: 370
• 13b Fischer E. Ber. Dtsch. Chem. Ges. 1888; 21: 988
• 13c Fischer E. Passmore F. Ber. Dtsch. Chem. Ges. 1889; 22: 359
• 14a Dondoni A. Marra A. Chem. Rev. 2004; 104: 2557
• 14b Dondoni A. Franco S. Junquera F. Merchán FL. Merino P. Tejero T. Bertolasi V. Chem. Eur. J. 1995; 1: 505
• 15 Dondoni A. Orduna J. Merino P. Synthesis 1992; 201
• 16a Dondoni A. Junquera F. Merchán FL. Merino P. Tejero T. Tetrahedron Lett. 1992; 33: 4221
• 16b Dondoni A. Franco S. Merchan FL. Merino P. Tejero T. Tetrahedron Lett. 1993; 34: 5475 ; the stereochemical assignment of syn-12 made in ref. 16a was corrected in ref. 16b
• 17 Dondoni A. Perrone D. Aldrichimica Acta 1997; 30: 35
• 18 Ghorai P. Kraus A. Keller M. Götte C. Igel P. Schneider E. Schnell D. Bernhardt G. Dove S. Zabel M. Elz S. Seifert R. Buschauer A. J. Med. Chem. 2008; 51: 7193
• 19a Geraschenko OV. Khodakovskiy PV. Shivanyuk ON. Shishkin OV. Mykhailiuk PK. Tolmachev AA. Synthesis 2012; 44: 1263
• 19b Boga C. Micheletti G. Eur. J. Org. Chem. 2010; 5659
• 19c Ortiz P. del Hoyo AM. Harutyunyan SR. Eur. J. Org. Chem. 2015; 72
• 19d Li A. Kindelin PJ. Klumpp DA. Org. Lett. 2006; 8: 1233
• 19e Handlon AL. Schaller LT. Leesnitzer LM. Merrihew RV. Poole C. Ulrich JC. Wilson JW. Cadilla R. Turnbull P. ACS Med. Chem. Lett. 2016; 7: 83
• 19f Jiao X. Kopecky DJ. Fisher B. Piper DE. Labelle M. McKendry S. Harrison M. Jones S. Jaen J. Shiau AK. Escaron P. Danao J. Chai A. Coward P. Kayser F. Bioorg. Med. Chem. Lett. 2012; 22: 5966
• 19g Dondoni A. Catozzi N. Marra A. J. Org. Chem. 2005; 70: 9257
• 19h de la Campa R. Ortín I. Dixon DJ. Angew. Chem. Int. Ed. 2015; 54: 4895
• 19i Sun C. Lett. Drug Des. Discov. 2005; 2: 48
• 19j Dondoni A. Catozzi N. Marra A. J. Org. Chem. 2004; 69: 5023
• 20a Dondoni A. Fantin G. Fogagnolo M. Medici A. Pedrini P. J. Org. Chem. 1988; 53: 1748
• 20b Dondoni A. Fogagnolo M. Medici A. Pedrini P. Tetrahedron Lett. 1985; 26: 5477
• 20c Pop L. Lassalas P. Bencze LC. Toşa MI. Nagy B. Irimie FD. Hoarau C. Tetrahedron: Asymmetry 2012; 23: 474
• 21 When the 1,2-migration is too fast, over-homologation is possible. In an attempt to homologate the cyclic boronate shown below we observed double homologation followed by immediate β-elimination (Scheme 22). This can probably be attributed to the cyclic structure of the molecule and the high tendency of aryl substituents to undergo anionotropic 1,2-rearrangements. Terehina, V.; Hirschhäuser, C. unpublished results.
• 22 Corey EJ. Barnes-Seeman D. Lee TW. Tetrahedron: Asymmetry 1997; 8: 3711
• 23a Matteson DS. Erdik E. Organometallics 1983; 2: 1083
• 23b In our own experience, solutions of these compounds should be rigorously dried after aqueous workup. α-Haloboronic esters can be kept under argon in the freezer for only a few days. Under these conditions, complete epimerisation of formally diastereomerically pure α-bromopentyl pinanediol boronic ester was observed after several weeks.
• 24a Matteson DS. Beedle EC. Tetrahedron Lett. 1987; 28: 4499
• 24b Matteson DS. Kandil AA. Soundararajan R. J. Am. Chem. Soc. 1990; 112: 3964 ; here lower diastereoselectivities were observed with commercially available ZnCl₂ solutions, in other cases, these were used successfully though
• 25 Matteson DS. Peterson ML. J. Org. Chem. 1987; 52: 5116
• 26 Struth FR. Hirschhäuser C. Eur. J. Org. Chem. 2016; 958
• 27a Enolates: Matteson DS. Michnick TJ. Organometallics 1990; 9: 3171
• 27b Chiral carbanions: Matteson DS. Tripathy PB. Sarkar A. Sadhu KM. J. Am. Chem. Soc. 1989; 111: 4399
• 28a Matteson DS. J. Organomet. Chem. 1999; 581: 51
• 28b Matteson DS. Soundararajan R. Ho OC. Gatzweiler W. Organometallics 1996; 15: 152
• 29a Gorovoy AS. Gozhina O. Svendsen J.-S. Tetz GV. Domorad A. Tetz VV. Lejon T. J. Pept. Sci. 2013; 19: 613
• 29b Shi J. Lei M. Wu W. Feng H. Wang J. Chen S. Zhu Y. Hu S. Liu Z. Jiang C. Bioorg. Med. Chem. Lett. 2016; 26: 1958 ; it should be noted that homologation of the corresponding azide congener to 35a was attempted by the authors and led to decomposition to benzaldehyde, so homologation 35a was the only viable option in this case
• 30 Tripathy PB. Matteson DS. Synthesis 1990; 200
• 31 Jacobsen EN. Marko I. Mungall WS. Schroeder G. Sharpless KB. J. Am. Chem. Soc. 1988; 110: 1968
• 32 Bojaryn K. Hoffmann C. Struth FR. Hirschhäuser C. Synlett 2018; 29: 1092
• 33 Matteson DS. Beedle EC. Kandil AA. J. Org. Chem. 1987; 52: 5034
• 34 Thormeier S. Carboni B. Kaufmann DE. J. Organomet. Chem. 2002; 657: 136
• 35 Ho OC. Soundararajan R. Lu J. Matteson DS. Wang Z. Chen X. Wei M. Willett RD. Organometallics 1995; 14: 2855
• 36a Matteson DS. Liedtke JD. J. Org. Chem. 1963; 28: 1924
• 36b Matteson DS. Liedtke JD. J. Am. Chem. Soc. 1965; 87: 1526
• 36c Matteson DS. Acc. Chem. Res. 1970; 3: 186
• 36d Matteson DS. Sadhu KM. Peterson ML. J. Am. Chem. Soc. 1986; 108: 810
• 37 We found that the α-PMBO-congener of 21 decomposed upon fridge storage under argon after several weeks, most likely due to elimination.
• 38 Andrés P. Ballano G. Calaza MI. Cativiela C. Chem. Soc. Rev. 2016; 45: 2291
• 39 Matteson DS. Med. Res. Rev. 2008; 28: 233
• 40 Matteson DS. Majumdar D. J. Organomet. Chem. 1979; 170: 259 ; Quaternary ammonium derivatives of α-aminoboronic esters were synthesised early from pinacol (iodomethyl)boronate and tertiary amines. Matteson did not observe any deprotonation of the CH₂ group α to the boron, so it cannot be employed as a carbenoid
• 41 Matteson DS. Sadhu KM. Lienhard GE. J. Am. Chem. Soc. 1981; 103: 5241
• 42 Matteson DS. Kim GY. Org. Lett. 2002; 4: 2153
• 43 Coutts SJ. Adams J. Krolikowski D. Snow RJ. Tetrahedron Lett. 1994; 35: 5109
• 44 Inglis SR. Woon EC. Y. Thompson AL. Schofield CJ. J. Org. Chem. 2010; 75: 468
• 45 Matteson DS. Ray R. Rocks RR. Tsai DJ. S. Organometallics 1983; 2: 1536
• 46 Berry SC. Fink AL. Shenvi AB. Kettner CA. Proteins: Struct., Funct., Bioinform. 1988; 4: 205
• 47 Dembitsky VM. Srebnik M. Tetrahedron 2003; 59: 579
• 48 Singh RP. Matteson DS. J. Org. Chem. 2000; 65: 6650
• 49a Caselli E. Romagnoli C. Vahabi R. Taracila MA. Bonomo RA. Prati F. J. Med. Chem. 2015; 58: 5445
• 49b Gorovoy AS. Gozhina OV. Svendsen JS. Domorad AA. Tetz GV. Tetz VV. Lejon T. Chem. Biol. Drug Des. 2013; 81: 408
• 49c Matteson DS. Fernando D. J. Organomet. Chem. 2003; 680: 100
• 49d Matteson DS. Yang J. Tetrahedron: Asymmetry 1997; 8: 3855
• 50 Matteson DS. Maliakal D. Fabry-Asztalos L. J. Organomet. Chem. 2008; 693: 2258
• 51 Man HW. Hiscox WC. Matteson DS. Org. Lett. 1999; 1: 379
• 52 Wityak J. Earl RA. Abelman MM. Bethel YB. Fisher BN. Kauffman GS. Kettner CA. Ma P. McMillan JL. J. Org. Chem. 1995; 60: 3717
• 53 Kim BJ. Zhang J. Tan S. Matteson DS. Prusoff WH. Cheng Y.-C. Org. Biomol. Chem. 2012; 10: 9349
• 54 Matteson DS. Kandil AA. J. Org. Chem. 1987; 52: 5121
• 55 Matteson DS. Schaumberg GD. J. Org. Chem. 1966; 31: 726
• 56 Carmès L. Carreaux F. Carboni B. J. Org. Chem. 2000; 65: 5403
• 57 Noble A. Roesner S. Aggarwal VK. Angew. Chem. Int. Ed. 2016; 55: 15920
• 58 Hoyt AL. Blakemore PR. Tetrahedron Lett. 2015; 56: 2980
• 59 Blakemore PR. Burge MS. J. Am. Chem. Soc. 2007; 129: 3068
• 60a Hoppe D. Hintze F. Tebben P. Angew. Chem. Int. Ed. 1990; 29: 1422
• 60b Hoppe D. Hense T. Angew. Chem. Int. Ed. 1997; 36: 2282
• 60c Hoppe D. Synthesis 2009; 43 ; and references within
• 61 Stymiest JL. Dutheuil G. Mahmood A. Aggarwal VK. Angew. Chem. Int. Ed. 2007; 46: 7491
• 62a Dearden MJ. Firkin CR. Hermet J.-PR. O’Brien P. J. Am. Chem. Soc. 2002; 124: 11870
• 62b Dearden MJ. McGrath MJ. O’Brien P. J. Org. Chem. 2004; 69: 5789
• 62c Dixon AJ. McGrath MJ. O’Brien P. Org. Synth. 2006; 83: 141
• 62d O’Brien P. Chem. Commun. 2008; 655
• 63a Rasappan R. Aggarwal VK. Nat. Chem. 2014; 6: 810
• 63b Webster MP. Partridge BP. Aggarwal VK. Org. Synth. 2011; 88: 247
• 64 Blair DJ. Tanini D. Bateman JM. Scott HK. Myers EL. Aggarwal VK. Chem. Sci. 2017; 8: 2898
• 65 Balieu S. Hallett GE. Burns M. Bootwicha T. Studley J. Aggarwal VK. J. Am. Chem. Soc. 2015; 137: 4398
• 66 Matteson DS. Hurst GD. Heteroat. Chem. 1990; 1: 65
• 67a Sonawane RP. Jheengut V. Rabalakos C. Larouche-Gauthier R. Scott HK. Aggarwal VK. Angew. Chem. Int. Ed. 2011; 50: 3760
• 67b Stymiest JL. Bagutski V. French RM. Aggarwal VK. Nature (London) 2008; 456: 778
• 67c Bagutski V. French RM. Aggarwal VK. Angew. Chem. Int. Ed. 2010; 49: 5142
• 68 Pulis AP. Aggarwal VK. J. Am. Chem. Soc. 2012; 134: 7570
• 69 Partridge BM. Chausset-Boissarie L. Burns M. Pulis AP. Aggarwal VK. Angew. Chem. Int. Ed. 2012; 51: 11795
• 70 Blair DJ. Zhong S. Hesse MJ. Zabaleta N. Myers EL. Aggarwal VK. Chem. Commun. 2016; 52: 5289
• 71 Pulis AP. Blair DJ. Torres E. Aggarwal VK. J. Am. Chem. Soc. 2013; 135: 16054
• 72 Watson CG. Balanta A. Elford TG. Essafi S. Harvey JN. Aggarwal VK. J. Am. Chem. Soc. 2014; 136: 17370
• 73a Drago C. Caggiano L. Jackson RF. W. Angew. Chem. Int. Ed. 2005; 44: 7221
• 73b Cogan DA. Liu G. Kim K. Backes BJ. Ellman JA. J. Am. Chem. Soc. 1998; 120: 8011
• 73c Bolm C. Bienewald F. Angew. Chem. Int. Ed. 1996; 34: 2640
• 74 Satoh T. Oohara T. Ueda Y. Yamakawa K. Tetrahedron Lett. 1988; 29: 313
• 75a Emerson CR. Zakharov LN. Blakemore PR. Org. Lett. 2011; 13: 1318
• 75b Emerson CR. Zakharov LN. Blakemore PR. Chem. Eur. J. 2013; 19: 16342
• 76 Sun X. Blakemore PR. Org. Lett. 2013; 15: 4500
• 77 Possible explanation for the efficiency of different carbenoids of type 66f: R = Me, Et vs. i-Bu: Presumably the bulk of the i-Bu substituent on 66f(ii) AND 83(ii) protects the α-chloro sulfoxide 66f(ii) from deprotonation by its lithiated counterpart 83(ii) (increased kinetic acidity/basicity), while smaller substituents fail to achieve that. R = CH₂Bn vs. Bn: Here we suspected some additional stabilisation of the carbenoid through the aryl substituent (cation-π interaction) as the main reason for its reduced basicity. Thus, it was not obvious to us why the homobenzyl-substituted derivative gave significantly worse results. Calculations showed that the minimum structures of 66f with R = CH₂Bn and R = Bn were indeed thermodynamically more stable than their R = Et counterpart. Although both 66f with R = Bn and R = CH₂Bn showed comparable enthalpic stabilisation, the R = CH₂Bn structure was entropically less favourable. See Supporting Information.
• 78 Rayner PJ. O’Brien P. Horan RA. J. J. Am. Chem. Soc. 2013; 135: 8071
• 79 Casoni G. Kucukdisli M. Fordham JM. Burns M. Myers EL. Aggarwal VK. J. Am. Chem. Soc. 2017; 139: 11877
• 80 Andersen KK. Tetrahedron Lett. 1962; 3: 93
• 81a Faranal: Dutheuil G. Webster MP. Worthington PA. Aggarwal VK. Angew. Chem. Int. Ed. 2009; 48: 6317
• 81b Bisabolane: Aggarwal VK. Ball LT. Carobene S. Connelly RL. Hesse MJ. Partridge BM. Roth P. Thomas SP. Webster MP. Chem. Commun. 2012; 48: 9230
• 81c Tolterodin: Roesner S. Aggarwal VK. Can. J. Chem. 2012; 90: 965
• 81d Giganin: Fletcher CJ. Wheelhouse KM. P. Aggarwal VK. Angew. Chem. Int. Ed. 2013; 52: 2503
• 81e Sertraline: Roesner S. Casatejada JM. Elford TG. Sonawane RP. Aggarwal VK. Org. Lett. 2011; 13: 5740
• 81f Escitalopram: Partridge BM. Thomas SP. Aggarwal VK. Tetrahedron 2011; 67: 10082
• 81g Mycolacton: Brown CA. Aggarwal VK. Chem. Eur. J. 2015; 21: 13900
• 81h Aplypsin: Fletcher CJ. Blair DJ. Wheelhouse KM. P. Aggarwal VK. Tetrahedron 2012; 68: 7598
• 81i Phytophthora: Pulis AP. Fackler P. Aggarwal VK. Angew. Chem. Int. Ed. 2014; 53: 4382
• 81j Stemaphylline: Varela A. Garve LK. B. Leonori D. Aggarwal VK. Angew. Chem. Int. Ed. 2017; 56: 2127
• 82a Bootwicha T. Feilner JM. Myers EL. Aggarwal VK. Nat. Chem. 2017; 9: 896

Also see:
• 82b Hoyt AL. Blakemore PR. Org. Biomol. Chem. 2015; 13: 3781
• 83 Vedrenne E. Wallner OA. Vitale M. Schmidt F. Aggarwal VK. Org. Lett. 2009; 11: 165
• 84a Satoh T. Ozawa M. Takano K. Chyouma T. Okawa A. Tetrahedron 2000; 56: 4415
• 84b Hughes M. Boultwood T. Zeppetelli G. Bull JA. J. Org. Chem. 2013; 78: 844
• 85 Alwedi E. Zakharov LN. Blakemore PR. Eur. J. Org. Chem. 2014; 6643
• 86 Schmidt F. Keller F. Vedrenne E. Aggarwal VK. Angew. Chem. Int. Ed. 2009; 48: 1149
• 87 Casoni G. Myers E. Aggarwal V. Synthesis 2016; 48: 3241
• 88 Insertion of carbenoids with alkyl and silyl substituents into boronic esters: Aggarwal VK. Binanzer M. Ceglie MC. Gallanti M. Glasspoole BW. Kendrick SJ. F. Sonawane RP. Vazquez-Romero A. Webster MP. Org. Lett. 2011; 13: 1490
• 89 Schmidt J. Choi J. Liu AT. Slusarczyk M. Fu GC. Science (Washington, D. C.) 2016; 354: 1265
• 90 Jadhav PK. Man HW. J. Am. Chem. Soc. 1997; 119: 846

Conversions of alcohols into boronic esters:
• 91a Roesner S. Brown CA. Mohiti M. Pulis AP. Rasappan R. Blair DJ. Essafi S. Leonori D. Aggarwal VK. Chem. Commun. 2014; 50: 4053

Conversion of carboxylic acids into boronic esters:
• 91b Fawcett A. Pradeilles J. Wang Y. Mutsuga T. Myers EL. Aggarwal VK. Science (Washington, D. C.) 2017; 357: 283

Aldehyde homologation:
• 91c Levine SG. J. Am. Chem. Soc. 1958; 80: 6150