Total Synthesis of Palau amine

Total Synthesis of Palau amine Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed. 2009, early view. 2 2 2 2 2 2 Chad opkins Wipf Group Literature Presentation 1-23-10 Chad opkins @ Wipf Group Page 1 of 14 1/27/2010

Stylotella aurantium Palau Isolation and Biological Activity Meaning of awaiian word palau: war club 2 2 2 2 2 2 Isolated in 1993 from the sea sponge Stylotella agminata collected from the Western Caroline Islands in the Republic of Palau Low acute toxicity (LD 50 13mg/kg, mice) Significant immunosuppressive and antitumor activities (IC 50 s for P-388 and A-549 were 0.1 and 0.2 µg/ml, respectively) Displays antifungal and antibacterial activities Authors note that the dust from the sponge caused allergic reactions consisting of severe shortness of breath lasting for about 4 h and skin rashes. (revised structure) Kinnel, R. B.; Gehrken,.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376. Kinnel, R. B.; Gehrken,.-P.; Swali, R.; Skoropowski, G.; Scheuer, P. J. J. rg. Chad opkins @ Wipf Group Chem. 1998, 63, Page 3281. 2 of 14 1/27/2010

Synthetic Challenges 2 2 2 A Formidable pponent.. Synthetic Publications: 34 PhD. Dissertations: 26 Total Synthesis: 1 (title paper) 2 2 2 cis-5,5 trans-5,5 original structure (incorrect) Unusually high nitrogen content (/C ~ 1 : 2) ighly strained core with 8 contiguous stereocenters igh polarity translates into difficulty in performing manipulations (solubility, purifications, etc.) p stability (decomposes under basic conditions above p 6.5) Absolute stereochemistry is unknown Structure revision: Grube, A.; Kock, M. Angew. Chem. Int. Ed. 2007, 46, 2320. Buchanan, M. S.; Carroll, A. R.; Quinn, R. J. Tetrahedron Lett. 2007, 48, 4573. revised structure (correct) Kobayashi,.; Kitamura, K.; agai, K.; akao, Y.; Fusetani,.; van Soest, W. M.; Matsunaga, S. Tetrahedron Lett. 2007, 48, Chad opkins @ Wipf Group Page 3 of 14 1/27/2010 2127.

ypothetical Biosynthesis 2 istidine C 2 C 2 2 C 2 2 2 2 2 clathrodin 2-2 2 Proline 2 2 2 2 2 2 [] 2 2 2 Mourabit, A. A.; Potier, P. Eur. J. rg. Chem. 2001, 237. Palau'amine Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G. Tetrahedron Lett. 1999, 40, 4775. Chad opkins @ Wipf Group Page 4 of 14 1/27/2010

roidin-derived Alkaloids Figure blatantly stolen from: Disclaimer: Relative stereochemistry unrevised Du,.; e, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965. Chad opkins @ Wipf Group Page 5 of 14 1/27/2010

2 C ighlights of Selected Previous Efforts Towards Palau amine (Romo) (s)-pyroglutamic acid 2 C 2 2 2 C TIPS Tsv Ts 1) 2, Li 4 2,6-lutidine, 170 o C 45 min,µw 2) TBDPS, Et3 DMAP, DCM 48% (2 steps) TIPS Tsv Ts TBDPS 2 Pd() 2 /C 93% TIPS Tse Ts TBDPS tartaric acid Tsv = Ts DMD, MgS 4-50 o C, DCM 99% TIPS Tse Ts TBDPS chloramine-t C 6 10, DCM -50 to rt 65-70% TIPS chlorination followed by a 1,2-migration/ring contraction Tse Ts TBDPS 1) TBAF, TF -40 o C, 79% 2) Mea, Me 65 o C, 76% correction of stereochemistry Tse Ts C 2 Me TBDPS x-ray obtained of p-bromobenzoyl derivative 1) TIPSTf, 91% 2) DIBAL-, -78 o C 3) ab 4, rt, (70%, 2 steps) TIPS Tse Ts TBDPS PPh 3, DIAD 74% TIPS Dilley, A. S.; Romo, D. rg. Lett. 2001, 3, 1535. Dransfield, P. J.; Wang, S.; Dilley, A.; Romo, D. rg. Lett. 2005, 7, 1679. Wang, S.; Dilley, A. S.; Poullenec, K. G.; Romo, D. Tetrahedron 2006, 62, 7155. Tse Ts TBDPS 2 Dransfield, Chad P. opkins J.; Dilley, @ Wipf A. S.; Group Wang, S.; Romo, D. Tetrahedron 2006, Page 62, 6 5223; of 14 Zancanella, M. A.; Romo, D. rg. Lett. 2008, 10, 1/27/2010 3685. 2 palau'amine 2

Me ighlights of Selected Previous Efforts Towards Palau amine (verman) Me 2 C 2 TBS PMB TBS Me 2 C PMB Me SEM Me 2 C C 2 Me SEM TBS 13 steps from comm. material Grubbs' II (5 mol%) DCM, 40 o C 0.1M, 2 d 75-80% SEM Me 2 C TBS C 2 Me S 2 2 Et, 110 o C sealed tube 2 d, 69-71% SEM S TBS 4 steps C 2 Me SmI 2 - cleavage S-methylation -protection thiourea formation SEM Teoc MeS TBS C 2 Me S Cbz 5 steps Ac guanidine formation Teoc protecting group manipulations reduction of carbonyls acetylation MeS TBS Ac Cbz 2 3 steps eacetylation/cyclization lcohol inversion SMe Cbz 2 4 steps guanidine formation deprotection/debromination 2 2 CF 3 C 2-2 2 2 CF 3 C 2-2 : 1 mixture palau'amine Katz, J. D.; verman, L. E. Tetrahedron 2004, 60, 9559. original structure (incorrect) Lanman, Chad B. opkins A.; verman, @ Wipf L. Group E.; Paulini, R.; White,. S. J. Am. Page Chem. 7 of 14 Soc. 2007, 129, 12896. 1/27/2010 2 2

Synthesis of Functionalized Cyclopentane Core Et Et 3 steps TIPS C 2 Me Me 2 C 150 o C TIPS C 2 Me C 2 Me (x-ray) single diastereomer 1) LA 2) Ms 3) a 3 4) TBAF 64% (5 steps) 3 3 1) PMB 2) 3 85% (2 steps) PMB 3 3 1) TMSTf i-pr 2 Et then BS 2) Si 2 57% (2 steps) single diastereomer 3 3 PMB 1) Li 2) TFA 78% (2 steps) 3 3 attenuate reactivity S 2 2 2,6-lutidine 38-43% 3-3 X X B: 3 3 3 3 13 1) ab 4 Ce 3 2) DBU 2 Boc Boc 55% (2 steps) Chlorination Side Products 3 3 ~ 15% ~ 15% 13 3 3 Boc Boc avoids intramolecular epoxidation and/or guanidine cyclization Gosselin, P.; Bourdy, C.; Mille, S.; Perrotin, A. J. rg. Chem. 1999, 64, 9557. Yamaguchi, J.; Seiple, I. B.; Young, I. S.; Malley, D. P.; Maue, M.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578. Su, S.; Seiple, I. B.; Young, I. S.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 16490. Chad opkins @ Wipf Group Page 8 of 14 1/27/2010 IBX 70% (dr 1.3 : 1) 3 3 14 Boc Boc other oxidation conditions afforded incorrect spirodiastereomer at C14 a(c) 2 72% 3 3 Boc Boc ~ 2g prepared 19 steps, 1% overall (C) 2

3 3 Boc Boc (C) 2 3 Pyrrole-Acid Intermediate Boc Boc 50% aq. TFA 3 2 3 3 (C) 2 3 crude Ag II 10% TFA 64% 17% rec. interm. (2 steps, 1 pot) - Addition of TFA accelerates reaction (5 min) - Completely chemoselective(!) 3 2 3 3 Me 2 C brine 65% minimizes choride displacement 3 3 2 2 TFAA/TFA then 2 54% 3 3 2 2 Me Me 2 (pyrrole surrogate) Ac, 38 o C, 6 h then TFA, rt, 12 h C 2 t-bu 44% (overall) TM-mediated coupling conditions were unsuccessful Me Me 3 Me 3 C 2 t-bu 2 2 TFA -Me Me Me 3 3 C 2 t-bu 2 2-2 Me - 3 3 C 2 2 2 t-bu 2 C t-bu 2 C P()(Me) 2 Me 3 Me Me Me Me Kt-Bu 92% 10% Pd/C 80% t-bu 2 C Me t-bu 2 C 2 Me Me 1) DMD, acetone, 41% 2) a 3, 4, 83% 3) MeI, Ag 2 76% Me Me Seiple, Chad I. B.; opkins Su, S.; @ Young, Wipf Group I. S.; Lewis, C. A.; Yamaguchi, J.; Page Baran, 9 of 14 P. S. Angew. Chem. Int. Ed. 2009, Early View. 1/27/2010

Completion of Racemic Palau amine 3 3 C 2 2 2 2, Pd(Ac) 2 2 2 C 2 2 2 EDC Bt 2 2 2 TFA 70 o C 17% (from azide) 2 2 2 2 2 2 2 2 2 (/-)-Palau'amine 0.6 mg as 2TFA salt The following was taken from the SI: Attempted purification of intermediates (in the above sequence) led to a reduced yield of final product due to their extreme polarity leading to difficulty in separation Purification of final product had to be performed twice on two columns (RP PLC) in 5-8 batches each Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed. 2009, Early View. what was the inspiration for the trans-annular cyclization? Chad opkins @ Wipf Group Page 10 of 14 1/27/2010

Spectroscopic Comparison ( 1 MR) Buchanan, M. S.; Carroll, A. R.; Quinn, R. J. Tetrahedron Lett. 2007, 48, 4573. Kinnel, R. B.; Gehrken,.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376. Chad opkins @ Wipf Group Page 11 of 14 1/27/2010

Spectroscopic Comparison ( 13 C MR) Buchanan, M. S.; Carroll, A. R.; Quinn, R. J. Tetrahedron Lett. 2007, 48, 4573. Kinnel, R. B.; Gehrken,.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376. Chad opkins @ Wipf Group Page 12 of 14 1/27/2010

Inspiration for Macro-Palau amine? 2 2 - CF 3 C 2 - CF 3 C 2 2 TFA 70 o C 2 2 - CF 3 C 2 - CF 3 C 2 2 Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed. 2009, Early View. 2 3 100 o C - 2 2 2-2 additional unknown prdts ~ equal amounts Sharma, G. M. Drugs, Food, Sea, Myth, Reality [Intl. Symp. Proc.] 1978, 203. akadai, M.; arran, P. G. Tetrahedron Lett. 2006, 47, 3933. exemplifies the innovative retrosynthetic analysis and mechanistic thinking that underpins the Baran group s remarkable string of total synthesis - C&E, 2010, 88(2), 5. the macro-intermediate is just off the charts, and alone places Baran in rarified territory. It is not just non-obvious, it is totally counter intuitive on many levels Chad opkins www.totallysynthetic.com, @ Wipf Group blogpost, Jan. 2, Page 2010. 13 of 14 1/27/2010

Summary First synthesis of Palau amine completed over 16 years after initial isolation Minimal protecting group operations Functionalized cyclopentane core prepared using strategic Diels-Alder, intramolecular aldol, and tandem oxidation/spirocyclization reactions Late stage chemoselective Ag(II)-picolinate oxidation installs key hemiaminal Uncatalyzed coupling of pyrrole surrogate gives access to pyrrole acid intermediate Intriguing trans-annular cyclization establishes elusive trans-5,5 ring core and completes the synthesis According to Baran, an enantioselective, scalable variant is coming soon please stay tuned. Chad opkins @ Wipf Group Page 14 of 14 1/27/2010