Stereocontrolled Generation of α-Metalated S, O-Acetals by Sulfoxide

Communication pubs.acs.org/Organometallics

Stereocontrolled Generation of α-Metalated S,O-Acetals by Sulfoxide-Ligand Exchange from Cyclic Dithioorthoformate Monooxides† Adam L. Barsamian and Paul R. Blakemore* Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003, United States S Supporting Information *

ABSTRACT: Treatment of trans or cis 2-isopentoxy-1,3-benzodithiolane-Soxides with EtMgCl gave configurationally stable (≥2.5 h, at −78 °C) stereodefined α-magnesiated S,O-acetals that incorporated D atoms in a stereospecific manner upon reaction with CD3OD. α-Lithiated S,O-acetals generated in the same fashion using PhLi were found to be less configurationally stable. Sp3-hybridized stereogenic carbanions present a myriad of tantalizing possibilities for asymmetric synthesis;1 however, few methods exist for their stereocontrolled synthesis.2 In a significant advance, Hoffmann et al. reported the generation of stereodefined α-haloalkyl Grignard reagents via sulfoxideligand (or “sulfoxide-metal”) exchange from scalemic α-halosulfoxides.3 Capitalizing on this discovery, we established that such carbenoid reagents,4a and their lithiated counterparts,4a−c can be used to chain extend boronic esters in a stereospecific manner. When applied in an iterative sense, this stereospecific reagent-controlled homologation (StReCH) process offers a programmable “assembly line” approach to synthesis in which the carbenoid presentation sequence uniquely determines the constitution and stereochemical configuration of an emerging polysubstituted alkyl chain (1 + 2 → 3 →→ 4, Scheme 1).5 In

Brown and Imai concerning the homologation of boronates by methoxy(phenylthio)methyllithium (5)9 drew our attention to α-metalated S,O-acetals. It was observed that ate-complexes generated by the interception of 5 by boronic esters (e.g., 6) rearrange to give α-alkoxyboronates upon treatment with thiophile HgCl2 (Scheme 2). Assuming that 1,2-metalate Scheme 2. Representative Example of Chain Extension of a Boronic Ester with Methoxy(phenylthio)methyllithium (5) As Reported by Brown and Imai9a

a

Scheme 1. Stereospecific Reagent-Controlled Homologation (StReCH) of Organoboron Compounds 1 with Enantioenriched Chiral Carbenoids 2

rearrangement occurs with high stereochemical fidelity,10 the Brown−Imai process could form the basis of a new StReCH manifold, providing it can be established that α-metalated S,Oacetals are configurationally stable and that a means to access them in a stereodefined form can be devised. Addressing these particular issues, herein it is reported that α-magnesiated S,Oacetals (and, to a lesser extent, their lithiated congeners) retain stereochemical integrity during addition to hard electrophiles and that these carbenoids are generated in a stereocontrolled fashion by sulfoxide-ligand exchange from cyclic dithioorthoformate monooxides. Carbenoid 5 was generated in a racemic form by Brown and Imai by s-BuLi-mediated deprotonation of MeOCH2SPh.9 It is conceivable that metalation of such prochiral methylene S,Oacetals could be achieved in an enantioselective manner using a chiral base;2,11 however, to avoid an unnecessary reliance on stereoinduction,4a we elected instead to focus on an inherently

addition to α-chloroalkylmetal species,4 the StReCH paradigm has now also been successfully implemented with other types of chiral carbenoids, including α-lithiocarbamates,6 α-lithio-epoxides/-aziridines,7 and α-lithio-N-Boc amines.8 The synthetic utility of StReCH would be further enhanced if a viable configurationally stable oxygen-bearing carbenoid 2 (Ri = OR′) could be identified that is capable of net stereospecific insertion into a C−B σ-bond. The existence of such a reagent would permit targeting of stereochemically complex oxygenated compounds, e.g., polyketides and carbohydrates, by iterative StReCH cycles. With this ultimate goal in mind, a report from © 2011 American Chemical Society

hex = n-C6H13, Bpin = B(OCMe2CMe2O).

Received: September 12, 2011 Published: December 19, 2011 19

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stereospecific route to the organometallic reagents of interest. On the basis of our experiences with sulfoxide-ligand exchange,4,12 and the suggestive work of Nell,13 it seemed likely, albeit not certain, that dithioorthoformate monooxides 9 would provide stereodefined α-metalated S,O-acetals 10 upon treatment with organolithium and Grignard reagents (Scheme

Scheme 5. Synthesis of 2-Isopentoxy-1,3-benzodithiolane-Soxides 18

Scheme 3. Proposed Route to Stereodefined α-Metalated S,O-Acetals 10 via Sulfoxide-Ligand Exchange from Dithioorthoformate Monooxides 9

Oxidation of dithioorthoformate 17 with m-CPBA14a afforded a mixture of separable S-oxides 18t and 18c (dr > 20:1, respectively), the major diastereoisomer of which was assumed to be trans configured.18 Regardless of the fact that the materials obtained were racemic, a legitimate means to assess the configurational stability of α-metalated S,O-acetals was now available to us. Sulfoxide-ligand exchange from either 18t or 18c would lead to carbanions (19t/19c) with different relative stereochemistry (Scheme 6). Intermediates 19 could therefore

3). In addition, it was recognized that the little investigated14 and intrinsically chiral functional group cluster in 9 would emerge naturally from the corresponding prochiral dithioorthoformate 8 upon oxidation. This tactic is synthetically attractive, creating two new stereogenic centers in a single operation; however, issues of both diastereo- and enantioselectivity must eventually be managed in any optimal conversion of 8 to 9. With this plan in mind, the preparation of acyclic dithioorthoformates and their subsequent oxidation was initially investigated. Eschewing the more elaborate protocols to prepare acyclic dithioorthoformates,15 we devised two methods to access test substrates (Scheme 4). In the first, S,O-acetal 12 was lithiated

Scheme 6. Experiments to Establish Configurational Stability of α-Metalated S,O-Acetals (19t/c) Derived from Distinct Diastereomers of 18

Scheme 4. Two Simple Syntheses of Acyclic Dithioorthoformates

be gauged to be configurationally stable (on the time scale of a reaction with a given test electrophile) if otherwise identical sulfoxide-ligand exchange experiments from 18t and 18c led to distinguishable isomeric products 20t and 20c upon electrophilic quench.19 In a scenario of configurational lability, isomeric organometals 19t and 19c would experience a period of equilibration prior to quench and net nonstereospecific reactions would be noted. Given the precedented sulfoxide-magnesium exchange from dithioacetal monooxides,13 the generation of magnesiated S,Oacetals from substrates 18t/c was investigated first (Table 1). Deprotonation can compete with sulfoxide-ligand exchange,12 and this side-reaction was considered as a potential risk given the high acidity of the central C−H bond in dithioorthoformate monooxides 18. In the event, treatment of 18t with EtMgCl (1 equiv, THF, −78 °C) followed by methanolysis after 15 min gave the ring-opened adduct 21 (R = Et) in a high yield, consistent with the generation of the desired metalate 19t (M = MgCl) without significant intervention by deprotonation (entry 1). Repetition of the experiment but with quenching by CD3OD gave monodeuteride 20t (E = D) as a single diastereoisomer (entry 2). The comparable experiment from 18c resulted in a less efficient sulfoxide exchange reaction, but, crucially, the monodeuterides obtained showed a strong preference for the opposite isomer (20c, E = D) (entry 3). Allowing the putative organomagnesiums 19t/c (generated as before) to incubate for an additional 2.25 h (at −78 °C) prior to quench with CD3OD gave product deuterides in lower yield

with s-BuLi and then sulfenylated to give 13;16 in the second, more concise approach, triethylorthoformate was subjected to acid-catalyzed ligand metathesis with p-thiocresol to provide dithioorthoformate 15 in addition to the separable trithioorthoformate. No examples of acyclic dithioorthoformate monooxides have been reported,14 and the oxidation of compounds 13/15 was approached with some trepidation. Indeed, after surveying numerous oxidation protocols (see Supporting Information for details), no traces of S-monooxide adducts were ever identified. It was concluded that acyclic dithioorthoformate monooxides likely fragment into thioxacarbenium ion and sulfenate species upon their genesis; decomposition pathways available to the latter presumably led to the principle observed products, which were mixtures of disulfide oxides (ArS(O)nS(O)mAr; m, n = 0, 1, 2). Whatever the precise nature of the oxidative decomposition pathways encountered, it became evident that simple acyclic dithioorthoformate monooxides are not viable molecules. Focus was next directed to 2-alkoxy-1,3-benzodithiolanes, a well-described class of cyclic dithioorthoformates that have been successfully converted into the corresponding S-oxides. 2Isopentoxy-1,3-benzodithiolane (17) was synthesized from anthranilic acid by isoamyl nitrite-initiated benzyne formation in the presence of CS2 and isoamyl alcohol (Scheme 5).17 20

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oxygen-bearing carbenoids for StReCH. Work to address such issues is in progress and will be reported in due course.

Table 1. Sulfoxide-Ligand Exchange (SLE) by RM from Dithioorthoformate Monooxides 18t/c and Trapping with Probe Electrophiles (EX)

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yield/dr of SLE adductsa reagent

quench

no.

S.M.

R−M

E−X

20t/c

nontrivial quench 20t:20c

21

1b 2b 3b 4c 5c 6d 7d

18t 18t 18c 18t 18c 18t 18c

Et−MgCl Et−MgCl Et−MgCl Et−MgCl Et−MgCl Ph−Li Ph−Li

H−OCH3 D−OCD3 D−OCD3 D−OCD3 D−OCD3 D−OCD3 D−OCD3

n/a 78% 20% 52% 9.4% 7.1% 5.7%

n/a >99:01 07:93 96:04 15:85 66:34 19:81

84% 10% 26% 24% 21% 2.9% 1.3%

ASSOCIATED CONTENT

S Supporting Information *

protonat.

All synthetic procedures, characterization data, and 1H and 13C NMR spectra for relevant compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].

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ACKNOWLEDGMENTS Financial support for this study from the National Science Foundation is gratefully acknowledged (CHE-0906409). The National Science Foundation (CHE-0722319) and the Murdock Charitable Trust (2005265) are also thanked for their generous support of the OSU NMR spectroscopy facility.

a

SLE adducts isolated from other components by SiO2 chromatography and then yield/dr determined by 1H NMR spectral analysis. b R−M (1 equiv) added to 18 (1 equiv) in THF, −78 °C, 15 min, then E−X. cR−M (1 equiv) added to 18 (1 equiv) in THF, −78 °C, 2.5 h, then E−X. dBarbier conditions: R−M (1 equiv) added to a mixture of 18 (1 equiv) + E−X (2.5 equiv), THF, −78 °C.

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(indicating a degree of chemical instability) but with only slightly diminished stereoselectivity (entries 4 and 5). On the basis of this series of experiments, it was concluded that αmagnesiated S,O-acetals are configurationally stable on a macroscopic time scale (at −78 °C) and that an ample temporal window potentially exists for their coalescence with electrophiles before stereofidelity is significantly eroded. Unfortunately, our attempts to intercept putative metalate 19t (M = MgCl) with a variety of other simple electrophiles revealed its poor nucleophilicity. Thus, no significant bond formation resulted from treating 19t (M = MgCl) with MeI, MeOTf, MOMCl, allyl chloride, or allyl bromide.20 It did, however, prove possible to intercept this species with benzaldehyde to afford the expected addition adduct in a good yield as a mixture of two diastereoisomers (52%, dr = 2:1).21 By contrast to the Grignard series, generation of α-lithiated S,O-acetals by PhLi-mediated sulfoxide-ligand exchange from substrates 18t/c was problematic. Deprotonation of 18t/c was now a dominant pathway, and any initially generated adducts 19t/c (or 21 formed from internal proton transfer) experienced significant secondary sulfoxide exchange with PhLi, leading to PhSCH2OAm and Ph2SO. Some useful data were obtained by separately treating 18t and 18c with PhLi in the presence of CD3OD (entries 6, 7). Deuterides 20t/c (E = D, R = Ph) were formed via this “Barbier”-type protocol in a low yield; in each case, the expected diastereoisomer predominated but both reactions were far from stereospecific, suggesting that αlithiated S,O-acetals 19 have poor configurational stability.22 In summary, it has been established that stereodefined αmagnesiated S,O-acetals are available in excellent yield by sulfoxide-ligand exchange between a class of readily prepared cyclic dithioorthoformate monooxides (e.g., 18t) and EtMgCl. These species are configurationally stable on a macroscopic time scale but possess low nucleophilicity. More reactive αlithiated S,O-acetals are similarly generated using PhLi, but side-reactions accompanying the sulfoxide-metal interchange limit the synthetic usefulness of the process. It remains to be discovered whether the favorable attributes identified for αmagnesiated S,O-acetals (i.e., configurational stability, ease of stereocontrolled generation) can be reconciled against their poor nucleophilicity in the context of potential deployment as

DEDICATION Dedicated to Prof. Philip J. Kocienski on the occasion of his 65th birthday. †

REFERENCES

(1) (a) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 716. (b) Organolithiums: Selectivity for Synthesis; Clayden, J., Ed.; Pergamon: New York, 2002. (2) Prevalent methods involve deprotonation; see: (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282. (b) Beak, P.; Basu, A.; Gallagher, D. J.; Sun Park, Y.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. (3) (a) Hoffmann, R. W.; Nell, P. G.; Leo, R.; Harms, K. Chem. Eur. J. 2000, 6, 3359. (b) Hoffmann, R. W. Chem. Soc. Rev. 2003, 32, 225. For earlier work with racemic sulfoxide precursors, see: (c) Durst, T.; LeBelle, M. J.; van den Elzen, R.; Tin, K.-C. Can. J. Chem. 1974, 52, 761. (d) Satoh, T.; Takano, K. Tetrahedron 1996, 52, 2349. (4) (a) Blakemore, P. R.; Marsden, S. P.; Vater, H. D. Org. Lett. 2006, 8, 773. (b) Blakemore, P. R.; Burge, M. S. J. Am. Chem. Soc. 2007, 129, 3068. (c) Emerson, C. R.; Zakharov, L. N.; Blakemore, P. R. Org. Lett. 2011, 13, 1318. (5) For an introduction to the related substrate-controlled chain extension process developed extensively by Matteson, see: (a) Matteson, D. S. Tetrahedron 1998, 54, 10555. (b) Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal, V. K. Chem. Rec. 2009, 9, 24. (6) Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2007, 46, 7491. (7) (a) Vedrenne, E.; Wallner, O. A.; Vitale, M.; Schmidt, F.; Aggarwal, V. K. Org. Lett. 2009, 11, 165. (b) Schmidt, F.; Keller, F.; Vedrenne, E.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48, 1149. (8) Coldham, I.; Patel, J. J.; Raimbault, S.; Whittaker, D. T. W.; Adams, H.; Fang, G. Y.; Aggarwal, V. K. Org. Lett. 2008, 10, 141. (9) Brown, H. C.; Imai, T. J. Am. Chem. Soc. 1983, 105, 6285. An essentially identical chain extension of Ph(CH2)2Bpin using carbenoid 5 was successfully conducted in our laboratory. (10) It was previously noted by Matteson et al. that ate-complexes closely related to 6 but lacking the alkoxy group fail to rearrange (and often fragment) under similar conditions. Thus, 1,2-metalate rearrangement from 6 likely involves oxacarbenium ion character in the transition state; however, this fact does not preclude inversion of configuration at the migratory terminus upon 1,2-nucleophilic rearrangement; see: (a) Mendoza, A.; Matteson, D. S. J. Org. Chem. 1979, 44, 1352. (b) Matteson, D. S.; Majumdar, D. Organometallics 1983, 2, 230. 21

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(11) Direct lithiation of S,O-acetal 12 with a combination of s-BuLi and (−)-sparteine was briefly explored, but modest enantioselectivity was observed. In the best result, p-TolSCH(Li)OMe generated with this reagent pair (in PhMe at −78 °C) gave the expected addition adduct upon treatment with PhCHO in 55% yield with dr = 74:26; the major diastereoisomer exhibited 24% ee; see Supporting Information for details. (12) Blakemore, P. R.; Burge, M. S.; Sephton, M. A. Tetrahedron Lett. 2007, 48, 3999. (13) Seminal work from Nell (aspects of which were later expanded on by Satoh et al.) established that ArSCHRMgX species (R = alkyl) offer excellent chemical and configurational stability and that such αthio-alkylmetals can be generated in enantiopure form by sulfoxideligand exchange from dithioacetal monooxides; see: (a) Nell, P. G. New J. Chem. 1999, 23, 973. (b) Satoh, T.; Akita, K. Chem. Pharm. Bull. 2003, 51, 181. (14) Only five examples of dithioorthoformate monooxides are known, all are cyclic; see: (a) Seio, K.; Sasaki, T.; Yanagida, K.; Baba, M.; Sekine, M. J. Med. Chem. 2004, 47, 5265. (b) Bulman Page, P. C.; Wilkes, R. D.; Namwindwa, E. S.; Witty, M. J. Tetrahedron 1996, 52, 2125. (c) Larkin, J. P.; Wyatt, J. A.; Hawkes, D. J. U.S. Patent 5026874 A 19910625, 1991. (15) For a general method and leading references, see: Takeda, T.; Sato, K.; Tsubouchi, A. Synthesis 2004, 1457. (16) A related method has been previously reported: Fuji, K.; Ueda, M.; Sumi, K.; Fujita, E. J. Org. Chem. 1985, 50, 662. (17) (a) Nakayama, J. Synthesis 1975, 38. (b) El-Wareth Sarhan, A.; Izumi, T. J. Chem. Res., Synop. 2002, 11. (18) The analysis that follows, and the conclusions drawn, do not depend on this assignment; however, given the near planarity of the five-membered-ring system in 17, it is likely that oxidation occurred preferentially from the face opposite the isopentyloxy substituent. In addition, we observe that 18c rearranges to 18t under mildly acidic conditions, bolstering the tentative assignment that 18t is the trans isomer and that 18c is the cis isomer. (19) For an analogous experiment to establish configurational stability for an α-bromoalkyllithium reagent, see: Hoffmann, R. W.; Ruhland, T.; Bewersdorf, M. J. Chem. Soc., Chem. Commun. 1991, 195. (20) Poor nucleophilicity was also noted by Satoh and co-workers for α-thioalkylmagnesium halides; see ref 13b. (21) See Supporting Information for details. Addition adducts of this type [RCH(OH)CH(SAr)OR′] have found utility in a connective synthesis of enol ethers (RCHCHOR′) via radical elimination from the corresponding xanthate derivatives; see: Vatele, J.-M. Tetrahedon Lett. 1984, 25, 5997. (22) α-Thioalkyllithiums generally lack good configurational stability at −78 °C (e.g., a, b), but there are notable exceptions (e.g., c, d); see: (a) Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1995, 117, 6621. (b) Hoffmann, R. W.; Dress, R. K.; Ruhland, T.; Wenzel, A. Chem. Ber. 1995, 128, 861. (c) Hoppe, D.; Kaiser, B.; Stratmann, O.; Frohlich, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 2784. (d) Hoffmann, R.; Koberstein, R. J. Chem. Soc., Perkin Trans. 2000, 2, 595.

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