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Published in final edited form as: Org Lett. 2011 December 16; 13(24): 6436–6439. doi:10.1021/ol202728v.
Gram-Scale Synthesis of the A’B’-Subunit of Angelmicin B
Benjamin C. Milgram, Brian B. Liau, and Matthew D. Shair* Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138
Abstract
A gram-scale enantiospecific synthesis of the A’B’-subunit of angelmicin B is reported. The synthesis involves a Lewis acid-catalyzed contrasteric Diels–Alder reaction and a tandem silyl zincate 1,6-addition/enolate oxidation sequence.
Angelmicin B (1, Figure 1) was isolated in 1993 by Uehara, Oki, and coworkers from the rare actinomycete Microbispora subsp. AA9966.1,2 Hibarimicin B, which was subsequently isolated along with hibarimicin A-G from the Microbispora rosea subsp. hibaria TP-A0121, shares an identical structure with 1. Angelmicin B (1) was originally identified as an inhibitor of Src tyrosine kinase (IC50 > 5800 nM),1a and was later found to inhibit proliferation and induce differentiation of HL-60 human leukemia tumor cells (IC50 = 58 nM).3 The discrepancy between these effective concentrations suggests that Src is perhaps not the target responsible for the anticancer activity of 1, and to date, the cellular target of 1 remains unidentified.
Angelmicin B (1) is a pseudo-C2-symmetric glycosylated type II polyketide. The two halves of its fascinating pseudo-C2-symmetric structure differ in the oxidation states of the B/B’, C/ C’, and D/D’ rings. Several questions concerning the absolute and relative configuration of 1 remain to be addressed.4 The absolute configuration of both halves of the aglycon and the carbohydrates as well as the relative stereochemistry of the C13′-carbinol are unknown. Additionally, it is unclear whether the compound exhibits atropisomerism as a result of potential hindered rotation about its C2–C2′ bond.5 A total synthesis of 1 or its aglycon would elucidate these stereochemical uncertainties, but has yet to be achieved.6 Intrigued by the biological properties, stereochemical ambiguities, and structural complexity of 1, we initiated a program aimed at its total synthesis. Herein we report a highly scalable enantiospecific synthesis of the orthogonally protected A’B’-subunit of angelmicin B (2, Scheme 1).
Our retrosynthesis of 2 is outlined in Scheme 1. We anticipated that the enone functionality in 2 could be generated by oxidation of allylic silane 3. Additionally, we envisioned that introduction of the n-propyl substituent in 2 could be accomplished through a diastereoselective organometallic addition to α-hydroxy ketone 3 from the convex face of the rigid cis-decalin carbon framework. Next, compound 3 would be accessed by means of a
*shair@chemistry.harvard.edu . Supporting Information Available: Experimental procedures, physical data, X-ray data for compound 2, and copies of 1H and 13C spectra for compounds 2–5, 7, 8, 11, 14, 15, and all synthesis intermediates. This material is available free of charge via the Internet at http://pubs.acs.org.

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regio- and diastereoselective 1,6-addition of a silyl zincate to dienone 4, followed by in situ oxidation of the resultant extended zinc enolate. A Lewis acid-catalyzed contrasteric Diels– Alder reaction between cyclohexenone 5 and 1,3-butadiene would then set the relative stereochemistry in 4, wherein the newly formed C–C bonds and the C4–OTBS substituent reside in a syn orientation. Finally, suitably protected cyclohexenone 5 would be prepared through ring-closing metathesis of a linear precursor accessed from readily available Dglucose derivative 6. The type and position of the hydroxyl protecting groups were chosen with respect to two criteria. First, a C4–OTBS group was deemed necessary for syn selectivity in the key Lewis acid-catalyzed contrasteric Diels–Alder reaction. Second, orthogonally deprotectable groups were selected to facilitate sequential introduction of the sugar residues surrounding angelmicin B. The ability to produce gram quantities of latestage intermediates is essential for a successful total synthesis of angelmicin B, one of the largest and most complex aromatic polyketides known. Recognition of the common stereochemical elements shared by 2 and D-glucose helped enable the realization of this requirement.
Our synthesis commenced with compound 6, which was obtained in three steps from methyl α-D-glucopyranoside on multigram scale according to a modified literature protocol (Scheme 2).7 A three-step procedure for the conversion of 6 to iodide 7 began with AcOHmediated hydrolysis of the benzylidene acetal, followed by selective Wittig iodination of the resultant primary hydroxyl group and TBS protection of the remaining secondary carbinol in 90% overall yield. Sonication of 7 with activated zinc powder promoted reductive fragmentation to generate an aldehyde intermediate,8 which upon treatment with an organocerium reagent derived from vinylmagnesium bromide furnished allylic alcohol 8 as an inconsequential diastereomeric mixture in 75% yield over two steps.9,10 Finally, exposure of 8 to first-generation Grubbs olefin metathesis catalyst11 in dilute CH2Cl2 followed by Parikh–Doering oxidation12 of the resulting diastereomeric cyclohexenols produced cyclohexenone 5 in 82% yield over two steps. Over thirty grams of 5 was prepared through this method.
Following our synthesis of 5, we next attempted the key Lewis acid-catalyzed contrasteric Diels–Alder reaction depicted in eq 1 of Scheme 3. Danishefsky and coworkers had previously demonstrated that 2-cyclohexenone 9, bearing a γ-OTBS group, participates in a contrasteric intermolecular Diels–Alder reaction with 1,3-butadiene when catalyzed by AlCl3 to provide cis-decalin 10 in 76% yield (eq 1, Scheme 3).13 In this transformation, the β-C–C bond is formed syn relative to the γ-OTBS group in high diastereoselectivity (>10:1 syn:anti). We anticipated similar stereoselectivity in our proposed Diels–Alder reaction, despite the additional Lewis basic groups in our substrate. Gratifyingly, treatment of 5 with 1,3-butadiene in the presence of TiCl4 at 5 °C for 3.5 h afforded a >10:1 mixture of adducts, favoring the desired syn diastereomer 11. This reaction, which can be performed on multigram scale with high diastereoselectivity, is to our knowledge the most complex example of a contrasteric Diels–Alder yet reported.
The stereoselectivity of this reaction is likely governed by subtle steric and stereoelectronic effects. Approach of 1,3-butadiene to 5 syn to the γ-OTBS substituent is sterically occluded by both the γ-OTBS and α-OPiv groups and thus counterintuitive (transition state 1, Scheme 3). However, stereoelectronic considerations suggest that pseudo-axial approach of 1,3butadiene to the β-carbon of the chair-like ground state conformation of 9 is kinetically favored.14 Additionally, the Cieplak model has been invoked to rationalize the stereochemical outcome for the aforementioned Diels–Alder reaction.15 In accordance with this line of reasoning, formation of the β-C–C bond syn with the electron-withdrawing γOTBS group stabilizes the forming σ*-C–C orbital through hyperconjugation with the electron-donating σ-C–H bond (transition state 2, Scheme 3). It is plausible that a synergism

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of individually small stereoelectronic effects bias the reaction pathway towards the observed product diastereomer 11.
The synthesis of 2 continued with a series of carefully controlled oxidations of the cisdecalin carbon skeleton of 11 (Scheme 4). Exposure of 11 to TMSI, generated in situ from TMSCl and NaI, promoted thermodynamic enolization of the ketone at C6 rather than at C2 to generate enol silane 12 as a single regioisomer.16 This regioselection is particularly noteworthy since C2–H is presumably more acidic than C6–H. Chemoselective oxidation of 12 was accomplished upon treatment of 12 with DDQ to afford dienone 4 in 78% overall yield, again as a single regioisomer.17 The mild nature of this procedure prevented overoxidation of the dienone moiety. Next, regio- and diastereoselective addition of dimethylphenylsilyl zincate to the δ-position of dienone 4 generated extended zinc enolate intermediate 13.18 In situ α-oxidation of 13 with MoO5•pyr•HMPA (MoOPH) delivered cisdecalin 3 as a single regio- and diastereoisomer in 82% yield. The one-pot 1,6-conjugate addition/enolate oxidation sequence was amenable to a variety of oxidants including Davis oxaziridine and DMDO; however, MoOPH proved the most efficient oxidant on largescale.19 Overall, the tandem reaction sequence generated the sterically congested C6-tertiary carbinol and an allylic silane, which was planned to serve as a latent enone surrogate.
Exposure of 3 to excess organocerium reagent derived from n-propylmagnesium chloride led to carbonyl addition exclusively from the convex face of the molecule and concurrent cleavage of the pivoyl ester (Scheme 4).20 The use of a mixed organocerium reagent was required to avoid ketone enolization and reduction.21 The resultant 1,2-diol was protected as an acetonide, affording 14 in 71% yield over two steps. Treatment of 14 with m-CPBA led to epoxidation of the allylic silane with in situ 1,5-silyl migration of silicon and concomitant epoxide opening to provide compound 15 in 85% yield.22 Chemoselective removal of the dimethylphenylsilyl group with TBAF at −78 °C and Swern oxidation23 of the resulting allylic alcohol delivered 2 in 91% yield over two steps on gram-scale, completing our synthesis of the protected A’B’-subunit of angelmicin B.
In summary, a scalable and enantiospecific synthesis of the protected A’B’-subunit of angelmicin B (2) has been accomplished starting from methyl α-D-glucopyranoside. This sequence has been utilized to prepare 3.2 grams of 2 to date. The synthesis features a Lewis acid-catalyzed contrasteric Diels–Alder reaction between cyclohexenone 5 and 1,3butadiene. Additionally, the synthesis further demonstrates the utility of silyl zincate reagents in organic synthesis through their application in a tandem 1,6-conjugate addition/ enolate oxidation sequence. Reports of our progress toward a total synthesis of angelmicin B will be forthcoming.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
We thank Dr. Shao-Liang Zheng (Harvard University) for his assistance with X-ray crystallography. Financial support from NIH (R01GM090068) is acknowledged. B.C.M. acknowledges AstraZeneca and Eli Lilly for financial support. B.B.L. acknowledges a NSF predoctoral fellowship for financial support.
References
(1)(a). Uehara Y, Li PM, Fukazawa H, Mizuno S, Nihei Y, Nishio M, Hanada M, Yamamoto C, Furumai T, Oki T. J. Antibiot. 1993; 46:1306–1308. [PubMed: 8407594] (b) Kajiura T, Furumai T, Igarashi Y, Hori H, Higashi K, Ishiyama T, Uramoto M, Uehara Y, Oki T. J. Antibiot. 1998;

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NIH-PA Author Manuscript

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51:394–401. [PubMed: 9630861] (c) Hori H, Kajiura T, Igarashi Y, Furumai T, Higashi K, Ishiyama T, Uramoto M, Uehara Y, Oki T. J. Antibiot. 2002; 55:46–52. [PubMed: 11918065] (d) Kajiura T, Furumai T, Igarashi Y, Hori H, Higashi K, Ishiyama T, Uramoto M, Uehara Y, Oki T. J. Antibiot. 2002; 55:53–60. [PubMed: 11918066] (e) Igarashi Y, Kajiura T, Furumai T, Hori H, Higashi K, Ishiyama T, Uramoto M, Uehara Y, Oki T. J. Antibiot. 2002; 55:61–70. [PubMed: 11918068] (f) Cho SI, Fukazawa H, Honma Y, Kajiura T, Hori H, Igarashi Y, Furumai T, Oki Y, Uehara Y. J. Antibiot. 2002; 55:270–278. [PubMed: 12014442]
(2)(a). For structural elucidation of angelmicin B, see: Hori H, Higashi K, Ishiyama T, Uramoto M, Uehara Y, Oki T. Tetrahedron Lett. 1996; 37:2785–2788. (b) Hori H, Igarashi Y, Kajiura T, Furumai T, Higashi K, Ishiyama T, Uramoto M, Uehara Y, Oki T. J. Antibiot. 1998; 51:402–417. [PubMed: 9630862]
(3). Yokoyama A, Okabekado J, Uehara Y, Oki T, Tomoyasu S, Tsuruoka N, Honma Y. Leuk. Res. 1996; 20:491–497. [PubMed: 8709621]
(4). For more information see: ref. 6e.
(5). Romaine IM, Hempel JE, Shanmugam G, Hori H, Igarashi Y, Polavarapu PL, Sulikowski GA. Org. Lett. 2011; 13:4538–4541. [PubMed: 21812391]
(6)(a). For studies towards angelmicin B or its related natural products, see: Lee CS, Audelo MQ, Reibenpies J, Sulikowski GA. Tetrahedron. 2002; 58:4403–4409. (b) Maharoof USM, Sulikowski GA. Tetrahedron Lett. 2003; 44:9021–9023. (c) Kim K, Mahroof SM, Raushel J, Sulikowski GA. Org. Lett. 2003; 5:2777–2780. [PubMed: 12889872] (d) Narayan S, Roush WR. Org. Lett. 2004; 6:3789–3792. [PubMed: 15469350] (e) Lambert WT, Roush WR. Org. Let. 2005; 7:5501–5504. [PubMed: 16288541] (f) Lee W, Kim K, Sulikowski GA. Org. Lett. 2005; 7:1687–1689. [PubMed: 15844881] (g) Li J, Todaro LJ, Mootoo DR. Org. Lett. 2008; 10:1337– 1340. [PubMed: 18324819] (h) Li J, Todaro L, Mootoo DR. Euro. J. Org. Chem. 2011:6281– 6287.
(7). Franais A, Urban D, Beau JM. Angew. Chem. Int. Ed. 2007; 46:8662–8665.
(8)(a). Skaanderup PR, Hyldtoft L, Madsen R. Monatsh. Chem. 2002; 133:467.(b) Bernet B, Vasella A. Helv. Chim. Acta. 1979; 62:1990–2016.(c) Bernet B, Vasella A. Helv. Chim. Acta. 1979; 62:2400–2410.(d) Bernet B, Vasella A. Helv. Chim. Acta. 1979; 62:2411–2431.(e) Nakane M, Hutchinson CR, Gollman H. Tetrahedron Lett. 1980; 21:1213–1216.(f) Fürstner A, Jumbam D, Teslic J, Weidmann H. J. Org. Chem. 1991; 56:2213–2217.
(9). Compound 8 was generated as a 3:1 mixture of diastereomers. See supporting information for more detail.
(10). Hyldtoft L, Madsen R. J. Am. Chem. Soc. 2000; 122:8444–8452.
(11)(a). Schwab P, France MB, Ziller JW, Grubbs RH. Angew. Chem., Int. Ed. 1995; 34:2039–2041. (b) Schwab P, Grubbs RH, Ziller JW. J. Am. Chem. Soc. 1996; 118:100–110.
(12). Parikh JP, Doering WE. J. Am. Chem. Soc. 1967; 89:5505–5507.
(13). Jeroncic LO, Cabal MP, Danishefsky SJ, Shulte GM. J. Org. Chem. 1991; 56:387–395.
(14). Angell EC, Fringuelli F, Pizzo F, Porter B, Taticchi A, Wenkert E. J. Org. Chem. 1986; 51:2642– 2649.
(15)(a). Cieplak AS, J Am. Chem. Soc. 1981; 103:4540–4552.(b) Ohkata K, Tamura Y, Shetuni BB, Takagi R, Miyanaga W, Kojima S, Paquette LA. J. Am. Chem. Soc. 2004; 126:16783–16792. [PubMed: 15612717] (c) Carreño MC, González MP, Houk KN. J. Org. Chem. 1997; 62:9128– 9137.
(16)(a). Miller RD, McKean DR. Synthesis. 1979; 9:730–732.(b) Moher ED, Collins JL, Grieco PA. J. Am. Chem. Soc. 1992; 114:2764–2765.(c) Krafft PA, Holton RA. Tetrahedron Lett. 1983; 24:1345–1348.
(17)(a). Ryu I, Murai S, Hatayama Y, Sonoda N. Tetrahedron Lett. 1978; 19:3455–3458.(b) Corey EJ, Guzman–Perez A, Loh T-P. J. Am. Chem. Soc. 1994; 116:3611–3612.
(18)(a). Dunn TB, Ellis JM, Kofink CC, Manning JR, Overman LE. Org. Lett. 2009; 11:5658–5661. [PubMed: 19904991] (b) Vaughan A, Singer RD. Tetrahedron Lett. 1995; 36:5683–5686.(c) Lipshutz BH, Sclafani JA, Takanami TJ. Am. Chem. Soc. 1998; 120:4021–4022.(d) Crump RANC, Fleming I, Urch CJ. J. Chem. Soc., Perkin Trans. 1994; 1:701–706.(e) Tckmantel W, Oshima K, Nozaki H. Chem. Ber. 1986; 119:1581–1593.

NIH-PA Author Manuscript

Org Lett. Author manuscript; available in PMC 2012 December 16.

NIH-PA Author Manuscript

Milgram et al.

Page 5
(19)(a). Vedejs E. J. Am. Chem. Soc. 1974; 96:5944–5946. (b) Vedejs E, Larsen S. Org. Synth. 1986; 64:127–132. and references therein.
(20)(a). Martin CL, Overman LE, Rohde JM. J. Am. Chem. Soc. 2010; 132:4894–4906. [PubMed: 20218696] (b) Trost BM, Waser J, Meyer A. J. Am. Chem. Soc. 2008; 130:16424–16434. [PubMed: 18998641] (c) Dimitrov V, Kostova K, Genov M. Tetrahedron Lett. 1996; 37:6787– 6790.
(21). Imamoto T, Takiyama N, Nakamura K, Hatajima T, Kamiya Y. J. Am. Chem. Soc. 1989; 111:4392–4398.
(22). Lee, K.-s.; Hoveyda, AH. J. Am. Chem. Soc. 2010; 132:2898–2900. [PubMed: 20148561] (23). Omura K, Swern D. Tetrahedron. 1978; 34:1651–1660.

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Figure 1. Structure of angelmicin B (1)

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Scheme 1. Proposed Synthesis of 2

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Scheme 2. Synthesis of Diels–Alder Substrate 5a a Reagents and conditions: (a) 80% aq AcOH, 80 °C, 1 h, 94%; (b) Ph3P (1.3 equiv), imidazole (3.0 equiv), I2 (1.3 equiv), PhMe, 23 to 45 °C, 1 h, 97%; (c) TBSOTf (2.0 equiv), 2,6-lutidine (1.0 M), 0 to 23 °C, 30 min, 99%; (d) Zn(0) (10 equiv), THF/H2O (4:1), sonication, 40 °C, 2 h; (e) CH2CHMgBr (1.2 equiv), CeCl3 (1.2 equiv), THF, −78 °C, 2 h, 75% (3:1 dr) for two steps; (f) Grubbs I (5 mol %), CH2Cl2, 23 °C, 18 h, 85%; (g) SO3•pyr (3.0 equiv), i-Pr2NEt (5.0 equiv), DMSO (10.0 equiv), CH2Cl2, 0 °C, 1.5 h, 97%. Abbreviations: TBS = tert-butyldimethylsilyl, Grubbs I =
bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride, DMSO = dimethyl
sulfoxide, pyr = pyridine.

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Scheme 3. Lewis Acid-Catalyzed Contrasteric Diels–Alder Reactiona a Reagents and condtions: (a) 1,3-butadiene (20 equiv), AlCl3 (0.9 equiv), PhMe, 23 °C, 1 h, 76% (>10:1 syn:anti ). (b) 1,3-butadiene (8.0 equiv), TiCl4 (1.0 equiv), PhMe, −78 to 5 °C,
3.5 h, 76% (>10:1 syn:anti). Abbreviations: TS = transition state.

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Scheme 4. Completion of the Synthesis of the A’B’-Subunit of Angelmicin B (2)a a Reagents and conditions: (a) TMSCl (10 equiv), NaI (15 equiv), HMDS (20 equiv),
MeCN, 82 °C, 3 h; (b) DDQ (3.0 equiv), CH2Cl2, 23 °C, 3 h, 78% for two steps; (c) Me2PhSiLi (1.0 M in THF, 1.5 equiv), ZnEt2 (1.0 M in PhMe, 1.5 equiv), THF, −78 °C, 30 min; then 4, −78 to 0 °C, 30 min; then MoOPH (2.6 equiv), −78 to −20 °C, 20 min, 82%; (d) CeCl3 (15 equiv), LiCl (30 equiv), THF, 23 °C, 12 h; then n-PrMgCl (1.6 M in Et2O, 12 equiv), −78 °C, 3 h; then 3, −78 to 0 °C, 2 h, 85%; (e) 2-methoxypropene (10 equiv), PPTS (10 mol %), PhH, 23 °C, 4.5 h, 84%; (f) m-CPBA (1.3 equiv), NaHCO3 (3.0 equiv), CH2Cl2, −78 to −5 °C, 7 h, 85%; (g) TBAF (1.0 M in THF, 1.5 equiv), THF, −78 °C, 1.5 h, 99%; (h) (COCl)2 (8.0 equiv), DMSO (16 equiv), CH2Cl2, −78 °C, 1 h; then diol, −78 °C, 4 h; then Et3N (32 equiv), −78 to 0 °C, 30 min, 92%. Abbreviations: TMS = trimethylsilyl, DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, MoOPH =
Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide), PPTS = pyridinium
p-toluenesulfonate, m-CPBA = meta-chloroperbenzoic acid, TBAF = tetrabutylammonium
fluoride.

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