I. Total Syntheses of (–)-Hapalindole U and (+)-Ambiguine H
II. Progress Towards the Total Synthesis of Vinigrol
A thesis presented
by
Thomas J. Maimone
to
The Scripps Research Institute Graduate Program
in partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
in the subject of
Chemistry
for
The Scripps Research Institute
La Jolla, California
August 2009
UMI Number: 3378284
Copyright 2009 by Thomas J. Maimone
All rights reserved
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© 2009 by Thomas John Maimone
All rights reserved Dedication
This thesis is dedicated to my mom
and
In Loving Memory of
Joseph Anthony Vaiana (1955-2007)
1 ACKNOWLEDGEMENTS
Well, I don’t know where to start exactly because things have changed so much in the Baran lab since I started at Scripps in 2005; I guess I will begin in chronological order:
To the early members of the Baran lab, your dedication to science and work ethic were truly inspirational; I knew immediately after arriving that this was a “special place”
To Carlos Guerrero: People use this phrase liberally, but you truly are one of a kind not to mention one of the most decent persons I have ever met. Thank you for all the chemistry advice, late night conversations, Pink Floyd O’clock, F-1 racing gossip, and most importantly your friendship. I wish you all the best in science and life and am still sorry for giving you the finger that one day. I leave you the following: I told you the boron was still attached! and Who’s making the Cotixan run?
To Ryan Shenvi: I know we had a little bit of a bumpy road from time to time, but I want you to know how much I valued your opinions and viewpoints. Thank you for all of your advice on topics ranging from religious discussions to introductory chartello- plumbane chemistry. I am sure you will make an outstanding professor and I pray that I don’t pick any targets your group is working on. I wish you and Edna the best and will see you soon in boston.
To Ben Hafensteiner: You are perhaps the nicest person on planet earth don’t ever change. I wish you and Amanda the best.
To Mike Demartino: It was always great having a serious football fan two desks down from mine (even if they were an Eagles fan!). Best wishes to you and Jess.
2 To Jeremy Richter: Thank you for all technical tips and advice you gave me upon my arrival in lab. You are an exceptional, dedicated, and diligent chemists; I know you are kicking ass at BMS as we speak.
To the “Great Brandini” : I have never seen someone pick up laboratory technique as fast as you did. You went from a former Casino dealer to basically a post-doc in less than
6 months. Thanks for all those tasty beverages and the firehouse steak sandwiches from the UTC mall.
To Dave Lin: Thanks for putting up with me as a roommate these past 4 years. Some of my best memories in San Diego were those 3 Angels games you took me too against the
Red Sox. I wish you and Joanne all the best and good luck in your post-doc upstairs!
To Narendra Ambhaikar: You are truly an old-school rocker, thanks for all the tips you gave me early on, in chemistry and in life. Cover the face……….
To Noah Burns: Thanks for being such a good friend and hood-mate these past 4 years.
Your knowledge of chemistry has been humbling at times and I can’t imagine a person more suited for academia than you. You have been someone I can always tell my problems to and I hope that will never change between us. If there is anything I can ever do for you don’t hesitate to ask; I will always have your back. See you soon in Boston!
To Paul Krawczuk: My desk-mate, former hood-mate, hip-hop mate, north park-mate,
10’s mate, swingle-mate, and good friend; of anybody at Scripps I think I have spent the most time with you these past 4 years (I know this has resulted in me getting on your nerves more than a few times!) You are an extremely interesting person and I am lucky to get to call you my friend. I think you have an exciting life ahead of you and if you ever
3 need anything don’t hesitate to ask. I’ll leave you with this: “Do you think I can pour this without spilling?” and “Will’s gonna get steamed…….Bubba Gump style.”
To Tim Newhouse: My other desk, north-park, 10’s, and swingle-mate and good friend.
Getting to know you these past 4 years has been a truly valuable experience, one I will not soon forget. It seems your passion for chemistry grows with every day and I am positive you will make an excellent teacher and mentor to many future generations of students. It appears your work-ethic grows every year which is quite the opposite of the normal graduate student (myself included) who is typically on the decline. Best of luck to you and Anna and see you in Boston!
To Mikkel Jessing: your constant good mood and smile are contagious; your presence in the gym and lab made things easier for everyone I think. Thanks for all the funny looks when I come back from a “European break,” 80’s dance hits, and costumes theme parties.
I am sorry if I teased you a bit too much and I want you too remember two things: 1) there is only one form of football real men play and 2) I have spies everywhere………
Take care and Best of luck in Denmark!
To Jun “Cindy” Shi (Lil’ Bloom): You have been like my little sister these past four years and have truly become my super and team leader. I feel privileged to have worked with you on vinigrol and the 3-membered friend. You have a very bright future ahead of you and I wish you and Shun the best! See you in Boston and Big Bloom will miss you
To Ke Chen: You have been like a big sister to me you silly little pygmol. Thanks for putting up with all my buzzing, singing, and fake crying! BMS is lucky to get you and tell Sam I am able to go roller-blading this weekend. “Oh Ke don’t go, please don’t go
”
4 To Ian Young (I.Y.): You are a quality individual, super-star chemist, and pretty good rock band bassist. I am glad to have gotten to spend some time with you (albeit a pretty small amount) and wish you the best on the east coast. “WOOOO HOOOO, HELL
YEAH, I.Y., GO TO BMS, KICK ASS, CONQUER JERSEY, TAKE NAMES LATER.”
To Ian Seiple: Fellow Shiley gym rat extraordinaire and hip-hop specialist, good luck with your horrible project, I feel for you. Maybe we can grab a burger if you are ever in
Boston. P.S. Life’s a garden…..Dig it.
To Hans Renata: Your intellect is immense and can only be matched by your rock band drumming abilities and fashion sense. Take care and I am leaving you in charge of full
Cotixan duties …………..or maybe Siguaros?
To Emily: Sorry for scaring you when you arrived as well as my constant, relentless abuse. I know you can never tell when I am joking, but I will let you in on a little secret: I am always joking! You are the coolest female chemist at scripps and I know you will excel here (you are already three rings ahead of the competition). P.S. Good luck with your “sweet” new route and please try mCPBA.
To Will Gutekunst: Fellow numismatist, A.D. fan, and indole chemist. I knew when I first met you at recruiting week-end and you knew what a peace dollar, buffalo nickel, and mercury dime were that you are not the type of chap who comes around very often.
Good luck in grad school and beyond and I hope your target will be published someday.
Best Wishes to you and Taylor! P.S. there is a difference between collecting coins and collecting change.
To Taylor: Besides the times when we wanted to tear each others heads off, I had a great time whenever you were around, and am glad I got to know you better this past year.
5 Good luck with whatever life throws your way. Oh, I almost forgot, Can you place the orders this Friday? Thanks!
To Yoshi: Thanks for all the delicious Japanese treats as well as that “special” birthday present. Best of luck to you!
To Elena: Your smile can cheer up even the most stressed out grad student I am glad to have gotten a chance to meet you and I hope maybe sometime I can visit you in Italy.
Thanks again for the Limoncello! Buona fortuna per il futuro.
To Quentin: I would wish you good luck in grad school, but I know you don’t need it.
Take care and I have a feeling that we will cross paths in the future. I will keep an eye on
“things” until you return
To Brady Worrell: Your humor is infectious, and I have a rash developing on my big ol’ butt to prove it! Take care old friend and I am sure we will see each other in the future.
Keep that booty poppin’ P.S. Bendy in coming with me.
To Dave Sarlah: Thanks for all the chemistry tips, chemicals, and late-night discussions
(not to mention all those O2 sticks). I know we have had a little bit of a bumpy road, but I want to let you know I am glad we fixed things. Your dedication to chemistry is truly inspirational and I wish you the best both in your career as well as life. Take care you sleazy bastard and try to keep your DNA samples away from the French biologist.
To Marietta: You have made my life immensely more complicated and I am thankful everday for it! I will miss you so much. Il est trop tôt pour dire au revoir.
To Karen Downs: Thank-you for being there to guide me through RCIA, my life would surely not be the same had I not met you.
6 To Rocky: You have been a good friend these past 4 years and I will truly miss the work- outs, football/women chats, and PF Chang dinners. You made grad school a lot easier for a bunch of us and we will never forget it. Take care and I am sure we will cross paths again soon. Thanks for all the vitamin waters and I cant even imagine how much
Britain’s zoo fencing I owe you! I will leave you my Super bowl XLIV prediction:
Ravens 21, Vikings 17.
To Phil: I’ve never told you how appreciative I am for allowing me to join your lab and all the mentorship, in both science and life, you have given me. I know we didn’t always see eye-to-eye, but in the end I want you to know how much I respect you. Your lab has truly been an exciting place to conduct research and I have never questioned whether I made the right choice coming here. The only way I can sum up the first five years of your career is as follows: You came, you saw, you conquered. It seems as though synthetic chemists careers are judged by both the number and complexity of the targets that they have synthesized. I have a strong suspicion that in your rare case, however, natural products are just the beginning. Take care and best wishes to you, Anna, and Lucía.
To Andrew and Wendy, Tia, and Wally: Whether or not you know it, having you both so close has been immensely helpful during a difficult period in my life. I love you both and would do anything for you. Wherever you guys end up, I wish you the best!
To He-Haw: Thanks for never returing my phone calls. I love you and look forward to actually being able to see you on the east coast.
To Mom: Who could have ever imagined all the twist and turns life had in store for our family the past 10 years. I want you to know that it was your emails, phone calls, and sponge-Bob care packages that have gotten me through the most difficult period in my
7 life. Mom, you are my everything, without you I would be lost. My only real regret in life thus far, is that I haven’t been able to see you as often as we would like. But I feel your presence all around me. I love you more than anything and will always be your son no matter where I am. I want to wish you, Rick, and Maddie happiness forever. Say hi to
Benny for me!
8 Some Useful Quotes:
Then he said to Thomas, “Put your finger here and see my hands. Reach out your hand and put it in my side. Do not doubt but believe.” Thomas answered him, “My lord and my God!” Jesus said to him, “Have you believed because you have seen me? Blessed are those who have not seen and yet have come to believe.”
–John 20: 27-29
Everyone has a plan…..Until they get hit.
–Mike Tyson
Discipline is choosing between what you want now and what you want most.
If you do not know what light you are seeking, no light will be enough to guide you.
Kindness in words creates confidence. Kindness in thought creates profoundness.
Kindness in giving creates love.
–Tao Te Ching
Remember, you are dust and unto dust you shall return.
–God
9 Table of Contents
Dedication 1
Acknowledgements 2
Table of Contents 10
Abbreviations 12
Abstract 16
Chapter 1: Total syntheses of (–)-hapalindole U and (+)-ambiguine H 17
Section 1.1: Isolation and structures of complex cyanobacteria-derived indole
alkaloids...... 18
Section 1.2: Retrosynthetic analysis: Oxidative enolate coupling ...... 24
Section 1.3: Development of a gram-scale route to (–)-hapalindole U...... 27
Section 1.4: Total synthesis of (+)-ambiguine H...... 34
Section 1.5: Conclusion and distribution of credit ...... 43
Section 1.6: References...... 44
Section 1.7: Experimental section ...... 49
Section 1.8: Appendix to Chapter 1: Spectra ...... 74
Chapter 2: Progress towards the total synthesis of vinigrol ...... 137
Section 2.1: Isolation, biosynthesis, and background...... 138
Section 2.2: Retrosynthesis of vinigrol...... 142
Section 2.3: Rapid construction of the vinigrol core ...... 145
Section 2.4: Synthesis of the full vinigrol carbon skeleton...... 147
Section 2.5: Conclusion and distribution of credit 156
Section 2.6: References...... 157
10 Section 2.7: Experimental section ...... 162
Section 2.8: Appendix to chapter 2: Spectra ...... 194
Appendix: Curriculum Vitae and selected publications ...... 255
11 List of Abbreviations
Ac = acetyl acac = acetylacetonate
AIBN = azobis(iso-butyronitrile)
9-BBN = 9-borabicyclo[3.3.1]octane b = broad
BRSM = based on recovered starting material
CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine cat. = catalyst
COD = cyclooctadiene
Cy = Cyl = cyclohexyl
Crabtree’s catalyst = (tricyclohexylphosphine)(1,5-cyclooctadiene)(pyridine)iridium(I) hexafluorophosphate d = doublet dba = dibenzylideneacetone
DDQ =2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DIBAL = diisobutyl aluminum hydride
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
DCB = o-dichlorobenzene
DCE = 1,2-dichloroethane
DCM = dichloromethane (CH2Cl2)
DEAD = diethylazodicarboxylate
DMAP = (4-dimethylamino)pyridine
12 DMDO = dimethyl dioxirane
DMF = N,N’-dimethylformamide
DMP = Dess-Martin periodinane
DMSO = dimethylsulfoxide
ESI-TOF = electrospray ionization-time of flight
EDC = 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide equiv. = equivalents
Herrmann’s catalyst = trans-di(µ-acetato)bis[o-(di-o-tolylphosphino)benzyl] dipalladium(II) hν = UV irradiation
HMPA = hexamethylphosphoric triamide
HRMS = high resolution mass spectrometry
IBX = o-iodoxybenzoic acid
IR = infrared imid = imidazole
KHMDS = potassium hexamethydisilazide
LCMS = liquid chromatography mass spectrometry
LDA = lithium diisopropylamide
LAH = lithium aluminum hydride
LRMS = low resolution mass spectrometry
L-selectride = lithium tri-(sec-butyl)borohydride m = multiplet m-CPBA = m-chloroperoxybenzoic acid
13 Mont = montmorillonite mp = melting point
Ms = methansulfonyl
MTAD = 4-methyl-1,2,4-triazoline-3,5-dione
Mukaiyama’s reagent = N-tert-butylbenzenesulfinimidoyl chloride
MWI = microwave irradiation
NBS = N-bromosuccinimide
NCS = N-chlorosuccinimide
NMM = N-methylmorpholine
NMR = nuclear magnetic resonance
[O] = oxidant
PhH = benzene (C6H6)
PhMe = toluene (C7H8)
PMA = phosphomolybdic acid
PP = pyrophosphate
PTLC = preparative thin layer chromatography
Pyr. = pyridine (C5H5N) p-ABSA = para-acetamidobenzenesulfonyl azide prenyl = 3,3-dimethylallyl reverse prenyl = 1,1-dimethylallyl q = quartet s = singlet
SET = single electron transfer
14 t = triplet
TBAB = tetrabutylammonium bromide
TBAC = tetrabutylammonium chloride
TBAI = tetrabutylammonium iodide
TBAF = tetrabutylammonium fluoride
TEA = triethylamine (Et3N)
TEMPO = 2,2,6,6-tetramethyl-1-piperdinyloxy free radical
Tf = trifluoromethanesulfonate
TFA = trifluoroacetic acid
TFAA = trifluoroacetic anhydride p-TsOH = para-toluenesulfonic acid
THF = tetrahydrofuran (C4H8O)
TLC = thin layer chromatography
TBS = tert-butyldimethylsilyl
TMSOTf = trimethylsilyltrifluoromethane sulfonate
Ts = para-toluenesulfonyl
15 ABSTRACT
The Stigonemataceae family of cyanobacteria produces a class of over 60 biogenetically related, architecturally complex, topologically unique, and functionally rich indole natural products that form the basis of the hapalindole, fisherindole, ambiguine, and welwitindolinone indole alkaloids. Possessing a broad range of biological activity— including antifungal, antibacterial, and anticancer properties—such targets have served to stimulate the synthetic chemist for over a decade. Herein a practical and gram-scale route to the tetracyclic hapalindole alkaloid family is presented by way of an eight-step, enantiospecific, protecting group free total synthesis of (–)-hapalindole U.
With gram scale access to hapalindole U, the first total synthesis of an ambiguine alkaloid, namely (+)-ambiguine H was completed. This work was made possible through several recently discovered and powerful methodologies including: I) The first example of an oxidative coupling of a ketone with a brominated arene. II) A powerful reductive
Heck-type cyclization to forge the tetracyclic core. III) A novel, isonitrile-assisted prenylation of an indole. IV) A novel photofragmenation cascade to form an indole.
In 1987 Ando and co-workers isolated the unusual diterpene vinigrol from the fungal strain Virgaria nigra F-5408. The promising biological profile of vinigrol has attracted significant attention from the synthetic community. Herein we describe a simple and efficient synthetic route to the unusual decahydro-1,5-butanonaphthalene ring system found in vinigrol. In addition, synthetic routes are described to several advanced intermediates containing the entire carbon skeleton and full stereogenicity of this intriguing natural product.
16 Chapter 1
Total Syntheses of (–)-Hapalindole U
and (+)-Ambiguine H
17 1.1. Isolation and structures of complex cyanobacteria-derived indole alkaloids
The Stigonemataceae family of cyanobacteria has produced a class of over 60 biogenetically related, architecturally complex, topologically unique, and functionally rich indole natural products that form the basis of the hapalindole, fischerindole, welwitindolinone, and ambiguine alkaloids.1-15 Beginning in 1984, Moore and co- workers heroic isolation efforts have opened an exciting new door in marine natural products chemistry.1 Isolated from soil samples all over the world (Marshall Islands,
Everglades, Australia, Micronesia, Papua New Guinea, Israel), many of these compounds exhibit a broad range of bioactivities. In particular, many of the hapalindole,1,6,10,15-17 ambiguine,5,12,13 and welwitindolinone7 alklaloids have shown insecticidal, antialgal, antimycotic, or antibacterial properties. In addition, the hapalindolinones have been found to inhibit arginine vasopression binding.3 Finally, the welwitindolinones show anticancer activity against multiple drug resistant ovarian cancer cell lines.7,18
While the biological activity of many of these compounds is noteworthy, it is truly their molecular structures that piqued our groups interest as targets for total synthesis. All compounds shown in Figure 1.1 are related by the presence of an indole (or indole derived) subunit merged to a monoterpene fragment. In addition, a rather unusual isonitrile or isothiocyante group is present in nearly all of these compounds. Finally many of these natural products contain an asymmetric chlorine atom as well as multiple sites of further oxygenation. Moore has proposed that the entire core unit of these intriguing natural products (i.e. the tricyclic hapalindole core (3)) arises from an exotic chloronium
18 R X X X Cl Me Me Me Me Me H H H Me H Me Me H Me Me Me Me Me R NC NC R R H H H H H
NH NH N N N H H H R=NC, X=H: hapalindole C R=NC, X=H: 12-epi-hapalindole C R=NC, X=Cl: hapalindole A R=Cl: hapalindole G 12-epi-hapalindole G R=NCS, X=H: hapalindole D R=NCS, X=H: 12-epi-hapalindole D R=NCS, X=Cl: hapalindole B R=H: hapalindole U R=NC, X=Cl: hapalindole E R=NC, X=Cl: 12-epi-hapalindole E R=NC, X=H: hapalindole J R=NCS, X=Cl: hapalindole F R=NCS, X=Cl: 12-epi-hapalindole F R=NCS, X=H: hapalindole M R=NCS, X=OH: hapalindole O Cl R R Cl Me Me Me Me Me Me Me H H Me H Me H Me Me Me NC Me Me Me Me NC NCS NC NC NC H H H H H
N NH NH N N N H H H H hapalindole Q 12-epi-hapalindole Q 12-epi-hapalindole H hapalindole H hapalindole I hapalindole K R O Cl Cl Cl R R Me Me Me Me Me OH Me H Me H Me H Me Me Me Me Me Me Me NC Me NC NH NC CN Me H H H H S H O O O N N N N N H H H H H NHCHO R=Cl: hapalindole L hapalindole N/P hapalindole T hapalindole V R=Cl: hapalindolinone A R=H: dechlorofontonamide R=H: 12-epi-hapalindole J R=H: hapalindolinone B R=Cl: fontonamide X Cl Me Me Me Me Me Cl X R Me Me R Me H CN Me Me Me NC NC NC H H H H H H H O O Me O Me Me N Me N N NHCHO NHCHO H H H R=NC, X=Cl: anhydrohapaloxindole A R=H: hapalonamide G hapalonamide H fischerindole L R=NC, X=Cl: 12-epi-fischerindole G R=NCS, X=Cl: anhydrohapaloxindole B R=OH: hapalonamide V R=NC, X=H: fischerindole U isonitrile R=NCS, X=H: anhydrohapaloxindole M R=NCS, X=H: fischerindole U Cl isothiocyanate Cl Cl Cl Me Cl Me H Me Me CN H Me Me H H R Me 1 Me Me Me SCN O SCN CN Me H Me H O Me H O O H Me O O N O Me R N N N 2 N H H R H R1= NCS, R2=H: welwitindolinone C 12-epi-fisherindole I welwitindolinone A R=H: welwitindolinone B isothiocyanate 3-epi-welwitindolinone B R=Me: N-Me-welwitindolinone B R1=NCS, R2=Me: N-Me-welwitindolinone C Cl isothiocyanate R1=NC, R2=Me: N-Me-welwitindolinone C O isonitrile H Me H R Cl R Me Me Me H R Me O Me Me Me O Me OH NC SCN OH Me H OH Me Me Me O Me O NC Me NC H N H H O Me Me Me Me Me N R=NC: 3-OH-N-Me- Me Me N Me welwitindolinone C N N H N-Me-welwitindolinone D isonitrile H H R=NCS: 3-OH-N-Me- R=Cl: ambiguine A R=Cl: ambiguine B R=Cl: ambiguine K welwitindolinone C R=H: ambiguine H R=H: ambiguine C R=H: ambiguine L isothiocyante Cl R Cl R Cl R Me Me Me Me Me Me OH NC Me Me OH NC Me OH NC Me OH NC Me OH NC Me OH Me Me Me Me Me Me O O H H H H H H OH CN OH O OH Me Me Me Me Me Me Me Me N Me N Me N Me N N N Me H H H H H R=Cl: ambiguine M ambiguine O R=Cl: ambiguine E ambiguine F R=Cl: ambiguine D ambiguine G R=H: ambiguine N R=H: ambiguine I R=H: ambiguine J Figure 1.1 All known hapalindole-type family members.
19 Cl or H X X H X 13 14 Me Me 2 Me 15 Me Me R Me Me 15 11 Me Me Me 10 NC NC Cl 10 H OPP H NC 4 NC 3 or 5 C-4 C-2 reverse 2 cyclization 2 Me H 6 prenylation N N 1 N N Me H 7 H H H 1 tricyclic hapalindole tetracyclic hapalindole skeletal-types (3) tetracyclic ambiguine skeletal-types (8) skeletal-types (9) [O]-bond C-2 formation H [O]-bond cyclization formation
X Cl X Me Cl X Me H Me Me CN [O]-ring Me Me H R CN H [O] Me Me NC contraction R Me Me Me CN O H O Me Me O N O H N Me N Me H N H N Me H H hapalindolinone tricyclic fischerindole spirocyclic welwitindolinone tetracyclic skeletal-type (4) skeletal-types (5) skeletal-types (6) pentacyclic ambiguine welwitindolinone skeletal-types (10) skeletal-types (7) Figure 1.2. Moore's presumed biosynthetic relationship between all known hapalindole-type natural product skeletons.
(or proton) induced cyclization of tryptophan-derived isonitrile 1 with monoterpene 2
(Figure 1.2). This reaction forms the hallmark five continuous stereocenters unique to this alkaloid family. It should be noted, however, that nature makes many permutations of this stereochemical array. At present, it is unclear if this is due to “sloppy” biosynthetic machinery or a greater number of specific cyclases.12 Following the initial cyclization, an oxidative C-C bond forming between C-3 of the indole ring with the isonitrile bearing carbon (C-11) leads to the spiro-cyclopropane hapalindolinone framework (4). A cyclization between the isopropylidene group and C-2 of the indole ring furnishes the fischerindole family (5), which Jeremy Richter in this laboratory has shown compelling evidence to be the precursors to the spirocyclobutane natural product welwitindolinone A
(6) structure by way of an oxidative ring contraction.20 A further oxidative rearrangement then furnishes the remaining welwitindolinones (7) in Moore’s biosynthetic hypothesis.
The tetracyclic hapalindole nucleus (8) (which nature makes in both cis and trans-fused
20 forms across the C-10/15 bond) is presumably formed via cyclization of the isopropylidene onto the indole C-4 position. Further “reverse” prenylation of the tetracyclic hapalindoles leads to the basic ambiguine framework (9). It should be noted however, that Carmeli and co-workers have suggested that the entire framework may be formed in one single step rather than from the tricyclic hapalindoles in a separate step
(Figure 1.3).13
X X X 2 Me Me single Me H Me cyclase Me H Me Me –H Me Me NC NC NC H H H H H
N H N N H H 1 8 Figure 1.3. Carmeli's alternative 1-step enzymatic cyclization to the tetracyclic hapalindole core.
Finally, an enzymatic cyclization between the isonitrile bearing carbon (C-11) and the terminus of the reverse prenyl group leads to the pentacyclic ambiguine skeleton (10) which represents the pinnacle of complexity in this natural product family. A closer examination of the ambiguine family reveals hapalindoles U (11), G (12), and V (13) to be the likely biosynthetic precursors to the simplest ambiguines, namely ambiguines H
(14), A (15), B (16), and C (17) by way of C-2 reverse prenylation (Figure 1.4).
Ambiguines B and C are likely then processed to the complex pentacyclic ambiguines L
(18) and K (19). It currently appears that only ambiguines containing the tertiary hydroxyl group are enzymatically converted into the more complex 7-membered ring system. Nature then utilizes a plethora of oxidative manipulations on the di-substituted olefin to arrive at ambiguines F (20), O (21), M (24), N (25), I (26), and E (27).
Ambiguines I and E then likely undergo further oxidation of the indole moiety to arrive at
21 X X X X Me Me Me Me OH Me Me OH Me NC -H2O OH NC Me Me Me Me OH Me OH H H H H OH CN O CN Me Me N Me Me N H Me N Me Me N Me H H H X = Cl: ambiguine G (23) 22 X = Cl: ambiguine O (21) X = Cl: ambiguine F (20)
[O] [O] isonitrile to nitrile rearrangement X X X Me Me OH Me R Me NC Me [O] Me R C-2 reverse Me Me NC Cyclization H prenylation H H Me NC H H Me Me N Me N Me H N H H R = H, X = H: ambiguine H (14) X = H: ambiguine L (18) R = H, X = H: hapalindole U (11) R = H, X = Cl: ambiguine A (15) X = Cl: ambiguine K (19) R = H, X = Cl: hapalindole G (12) R = OH, X = Cl: ambiguine B (16) R = OH, X = Cl: hapalindole V (13) R = OH, X = H: ambiguine C (17 [O] +H2O
X X X Me Me Me OH Me NC Me OH Me OH NC Me NC Me [O] O Me O H H H OH OH Me Me N Me N Me N Me Me H H X = H: ambiguine I (26) X = H: ambiguine J (28) X = H: ambiguine N (24) X = Cl: ambiguine E (27) X = Cl: ambiguine D (29) X = Cl: ambiguine M (25)
Figure 1.4. Presumed biosynthesis within the ambiguine family. ambiguines J (28) and D (29) which represent the pinnacle of complexity within this class. Ambiguine G represents an oddity in this family since it contains a nitrile rather than isonitrile moiety. It seems logical that this group in installed via an enzymatic isonitrile to nitrile rearrangement (thus leading from ambiguine L (18) to putative intermediate 22 that then loses a molecule of water to form a conjugated π-system.
With so many diverse and unique structural types found in this natural product family it is not surprising that several synthesis have been reported for these natural products. Syntheses have been reported for hapalindoles G,21 H,22 J,23-25 M,23-25 Q,26-29
O,30 and U22 in addition to approaches to various hapalindoles.31-33 There have been many
22 reports of approaches to the welwitindolinones,34-44 however a total synthesis from this lab45,46 and the Wood group47,48 remain the only synthetic routes to these challenging molecules. At the start of this work, there was not a single report of an approach to an ambiguine alkaloid, since then a single report has surfaced.49 Our lab sought a flexible solution to all of the structural types in this family. Jeremy Richter’s pioneering work in this lab charted a route to the tricyclic hapalindoles, fischerindoles, and welwitindolinones. Chapter 1 of this thesis delineates our laboratory’s work in the area of tetracyclic hapalindoles and ambiguines; this work has resulted in the first total synthesis of an ambiguine alkaloid.50
23 1.2. Retrosynthetic analysis: Oxidative enolate coupling
The direct indole enolate coupling reaction initially discovered by Jeremy Richter in this lab stands as the key retrosynthetic disconnection to form the core of all of the structural types found in this family.26 Treatment of ketone, ester, or amide enolates with indole anion followed by the addition of a single electron oxidant (Cu(II)2- ethylhexanoate is optimal) allows for single-step access to a number of interesting heterocyclic structures (30-39) that would be difficult to access by other means (Figure
1.5).51
O i. LHMDS (3.3 eq.) THF, -78°C R O NH R' N ii. Cu(II)2-ethyl- H hexanoate (1.5 eq.) R ketone, amide, -78°C to 25°C indole R' or ester (2 eq.) (1 eq.) Indole (Isolated Yield %)
O O Me H N O NH Me Me Me O Me Me H NH Me H H Me NH MeO O
30 (50) 31 (48) 32 (30) 33 (51)
Me Me
Me Me Me Me O H Me O O Me O Me NH O NH H Me O NH X O NH NH
34 (44) 35 X = CH2 (43) 37 (42) 38 (61) 39 (51) 36 X = O (43) Figure 1.5. Oxidative indole enolate coupling: single-step formation of hindered heterocycles.
Mechanistically, this reaction is believed to proceed by initial enolate oxidation (single electron transfer process) to form an electron-deficient α-keto radical (40) which then reacts with indole anion to form radical anion (41). This high-energy species is then
24 OLi Cu(0) I Cu CuI H N R O N N O CuII O R i. [O] R R [O] R ii. tautomerization R R R N 40 41 42 Li Figure 1.6. Possible mechanistic pathway for the oxidative indole enolate coupling. further oxidized (again in a SET sense) and undergoes tautomerization to the coupled
51 product (42) (Figure 1.6). This powerful reaction allowed for 5-6 step syntheses of simple hapalindoles such as hapalindole Q (44),26 as well as exceedingly concise syntheses of fischerindoles U, G, I (43, 45, 46) and welwitindolinone A (47) by Jeremy
Richter in this group (Figure 1.7).45,46,50Ambiguine H (14), the simplest ambiguine
a. Me Me Me O H b. LHMDS; Me L-Selectride; H O carvone O Me a. LHMDS, CH CHO O d. TfOH H 3 H H then c. Martin H Cu(II) sulfurane NH NH Me N N Me H H indole e. NH4OAc NaBH3CN b. Cl f. CS(imid)2 Me Cl
O Me Me Me H a. LHMDS, Me H SCN O Me NCS H then H H Cu(II) H
NH Me N NH N Me H H b. Mont. K-10 ent-12-fischerindole U (43) hapalindole Q (44)
Cl
Me Me Me Me Cl Cl c. NaBH3CN Cl O CN f. DDQ, CN H NH4OAc H H H2O g. XeF2 CN Me H d. HCO H, H H Me 2 O Me DMT-MM Me Me N Me Me N e. COCl , Et N N Me N H H 2 3 H H 12-epi-fischerindole (45) fischerindole I (46) welwitindolinone A (47) Figure 1.7. a. Baran and Richter's gram-scale entry into the fischerindole and hapalindole alkaloids. b. Application to the protecting group-free total synthesis of welwitindolinone A (28).
25 natural product, was targeted for total synthesis and a retrosynthetic blueprint was developed (Figure 1.8). We hoped to be able to proceed via the tetracyclic hapalindole family (namely hapalindole U (11)) by way of a late-stage reverse prenylation.
Hapalindole U in turn could be traced back to tetracyclic ketone 48. We had hoped to form the tetracyclic core of 48 by a biomimetic type cyclization of compound 49, which would be the product of our oxidative coupling reaction. Ketone 50 in turn was hoped to arrive from manipulation of the chiral terpene pool.
Me Me Me Me H reverse Me H amination Me H Me NC prenylation Me NC H H H H Me O H
Me N Me N H H N H ambiguine H (14) hapalindole U (11) 48
Friedel- Crafts cyclization
Me oxidative Me Me enolate manipulations O H H coupling Me O 50 H
"chiral N N H terpene" H indole 49 Figure 1.8. Initial retrosynthetic analysis of the ambiguine and tetracyclic hapalindole alkaloids.
26 1.3. Development of a gram-scale route to (–)-hapalindole U
Our initial forays into the hapalindoles began with procuring large amounts of ketone 50 (Scheme 1.1). It should be mentioned that the chlorinated version of this ketone has already been prepared by Fukuyama and co-workers in their elegent synthesis of hapalindole G (12).21 Chemistry developed by Mehta52 was amenable to solve the problem at hand. Starting with the chiral terpene p-menth-1-en-9-ol, a dichloroketene
[2+2] cycloaddition (Cl3COCl, Zn, Et2O, sonication) followed by sodium methoxide- induced rearrangement led to compound 51 in 65% yield as an inconsequential mixture of four diastereomers. Dibal reduction, global mesylation, and cyclopropane fragmentation then arrived at ketone 52 in good yield (70% over 2 operations, again as an inconsequential mixture of diastereomers). Displacement of the primary mesylate with sodium iodide then furnished Ketone 50 after E2 elimination using DBU.
Me Me Me a. i. Cl3COCl, Zn Me OH Sonication OH b. DIBAL OMs d. NaI, acetone, Δ CO2Me c. MsCl, pyr. DBU, THF, Δ ii. MeONa/ OMe O O H MeOH, Δ H AcOH H Me Me Me 90% Me 65% 70% p-menth-1-en-9-ol 51 52 50 Scheme 1.1. Synthesis of ketone 50.
With compound 50 in hand, work on the key ring forming reactions could begin (Scheme
1.2). Oxidative coupling of indole with 50 proceeded smoothly and provided indole 49 as a single diastereomer in 61% yield on gram scale. As mentioned earlier, the simplest solution to the tetracyclic hapalindole skeleton would be via Friedel-Crafts type cyclization at the indole C-4 position. As the locus of reactivity resides in the indole C-
2,3 π-bond it was anticipated that this bond construction would be difficult, if not impossible. Furthermore, the undesired cyclization at the C-2 position had already been documented by Fukuyama and co-workers,21 as well as in our lab as this is one of the key
27 steps in the fischerindole syntheses (see Figure 1.7).20,26 Nevertheless, I had hoped that some combination of acids/temperatures might lead to at least some amounts of the desired cyclization product. I briefly screened an assortment of lewis acids and unfortunately never observed any of the desired compound 48. Not surprisingly, only C-2 cyclized ketone 53 was observed when cyclization proceeded.
Acids Screened Me AlCl3 AlCl :NaCl Me Me 3 O Me (molten) H a. i. LHMDS H FeCl /clay Me 50 Me H Me 3 ii. Cu(II) O conditions Me O ZnCl /clay O Me H 2 61% Me H NiCl2/clay HN CuCl2/clay N TfOH N H N H H aq. HCl indole 49 48 53 AcOH sole product Mont K-10 Scheme 1.2. Initial forays into forging the tetracyclic hapalindole skeleton. formed H3PO4
A logical solution to this problem was to remove the indole C-2,3 π-bond completely, thus arriving at indoline 54 (Scheme 1.3). Such a compound, if found to cyclize to structure 55, could then be oxidized back to the indole nucleus. Unfortunately, compound 54 proved troublesome to prepare via Gribble-type reduction.53 This fact coupled with an inelegant oxidation state fluctuation led me to move on to a more direct solution. A more attractive idea seemed to be to block the indole 2,3 π-bond with the bulky reverse prenyl moiety, thereby forcing bond formation to occur at the C-4 position
(Scheme 1.4). Although this strategy would rule out direct access to the tetracyclic hapalindoles, it would offer extremely expedient entry into the ambiguine carbon
Me Me Me Me NaCNBH3 AcOH H H Me Me H Me [O] Me O O O O Me H Me H complex mixture N N N N H H H 49 H 54 55 48 Scheme 1.3. Failed Gribble reduction route.
28 Me Me a. i. t-buOCl Me concentration THF, -78°C Me from CDCl3 Me O Me O Me O ii. Cl Me Me Me N B N N Me H Me H BR2 49 56 57 X-ray Scheme 1.4. Synthesis of compound 57. skeleton. Indole 49 was subjected to Danishefsky’s reverse prenylation protocol and furnished indole (57) in 75% yield (structure verified by x-ray crystallographic analysis).54 Interestingly, the compound first isolated after column chromatography appeared to still have the boron attached and was presumably the highly non-polar compound 56. After dissolution in CDCl3 for NMR analysis a new much more polar
Acids Screened
TfOH FeCl3/clay TFA Me Me ZnCl2/clay H TFA:MeSO3H CuCl /clay H 2 Me conditions Me TsOH NiCl2/clay O O TMSOTf Me H Mont K-10 AlCl3 TiCl4 AlCl :NaCl (molten) Me Me 3 AgOTf N Me N Me H2SO4 ZnCl2 H H HCl (gas) Dy(OTf)3 aq. HCl 57 58 YbCl3 5H2O BF3 OEt2 EtAlCl Scheme 1.5. Failed Friedel-Crafts cyclization of compound 57. 2 compound formed quantitatively, which turned out to be the desired product. Despite significant experimentation and a fairly extensive Lewis acid screen, I was unfortunately never able to realize the transformation 57 → 58 (Scheme 1.5) Under most conditions only starting material and decomposition were observed. In a few instance I observed very small amounts (~10%) of compounds tentatively appearing to be olefinic mixtures of the type 61. These compounds were presumably formed via initial protonation of the electron rich indole ring leading to intermediate 59, which is then trapped in a Prins-type fashion to tertiary carbocation 60, which ultimately suffers proton loss. It should be noted that this undesired mode of cyclization was also observed in our laboratory’s previous
29 studies toward the fischerindoles.46 Once again the electron rich nature of the indole 2,3
π -bond thwarts our attempts at C-4 cyclization. At this juncture
Me Me Me Me H H Me Me Me O O O H O –H H H H H
HN HN Me Me Me N N Me Me H Me Me Me H 61 57 59 60 (tentatively assigned) ~10% Figure 1.9. Undesired cyclization pathway. it seemed likely that our retrosynthesis needed to be revised to one in which the indole C-
4 position would possess greater reactivity. A logical solution would be to place a halogen at this position and thereby switch the reaction pathways from ones involving acid-catalyzed cyclizations to those involving radicals or transition metals. As a model study I prepared compound brominated indole 63 which resulted from the oxidative coupling of 4-bromoindole with known ketone 62 (Scheme 1.6). Significant optimization was required to coax the electron-deficient indole into coupling; in the end I found that 3 equivalents of the brominated indole and 2 equivalents of Cu(II)2-ethylhexanoate oxidant were required to obtain synthetically useful yields (50%). With compound 63 in hand, I
55 attempted a standard radical-based cyclization (Bu3SnH, AIBN, refluxing benzene).
Unfortunately, the reaction underwent a 7-endo type closure rather then the desired 6- endo pathway thus producing compound 64 as a roughly 2.5:1 mixture of diastereomers
(major isomer verified by X-ray crystallography). Molecular models suggest that the terminus of the isopropylidene group is probably closer to the indole C-4 position. This, coupled with the fact that a more stable tertiary radical is formed under the 7-endo
30 Me Me dr ~ 2.5:1 Me O Me Me b. AIBN, Me Me 62 (1 eq.) a. LHMDS (4 eq.) H Cu(II) (2 eq.) O Bu SnH 3 H Me Br Br Me 50% PhH, Δ O NH N H N H 63 64 X-ray 4-bromoindole (3 eq) Scheme 1.6. Model study radical cyclization. closure, makes the observed result not entirely surprising. I next turned my attention to palladium-based methods in the hope that I could elicit a reductive Heck-type cylization56,57 to form the desired 6-membered ring. Returning to the real system, I prepared compound 65 in 50% yield via oxidative coupling of 4-bromoindole and ketone
50 (Scheme 1.7). Our first attempt using literature conditions (Pd(OAc)2, NaO2CH, Et3N,
TBAC, DMF) were encouraging and formed tetracycle 48 in 25% yield. Although the yield was modest, this was the first time I observed the desired tetracyclic ring system
Me
Me Me O Me a. LHMDS (4 eq.) a. Pd(OAc)2 H 50 (1 eq.) n-Bu NCl Me Cu(II) (2 eq.) O 4 O Br H Br Me Me 50% NaO2CH NH Et3N DMF N H N 25% H 65 48 4-bromoindole (3 eq) Scheme 1.7. Reductive Heck cyclization: proof of concept. and I decided to undertake significant optimization of this reaction. It took extensive screening of reaction parameters (over 80 experiments performed) to optimize this reaction (65 → 48) to synthetically useful yields (Scheme 1.8). Catalyst destruction in the highly reducing formate environment, as well as debromination without cyclization were our biggest challenges. A large variety of bases were screened (see Scheme 1.8),
31 Bases examined Catalyst systems Me Me reductive Heck-type annulation Et3N Pd(OAc)2 H KHCO Pd(OAc) /PPh 10 mol. % Pd Me 3 2 3 O Na CO Herrmann's palladacycle Et3N (2.2 equiv) O 2 3 Br H Pd(PPh ) Me Me (Cy)2NMe 3 4 Pd dba CHCl HCO2Na (1.25 equiv) K2CO3 2 3 3 NH DMF, 80 °C DABCO Pd/C, PPh3 N Pd dba CHCl /P(Cyl) H Cs2CO3 2 3 3 3 65 48 NaOAc a Entry Pd-source, additives, time Yield (%) iPr2NEt Additives b morpholine 1 Pd(OAc)2, TBAC (1.0 equiv), Et3N (2.5 equiv), 15 h 18 n-Bu NCl c NaHCO3 4 2 Pd(OAc)2, Ph3P (0.2 equiv), 15 h 39 n-Bu4NBr 3 Pd (dba) , TBAB (2.0 equiv), Et N (2.2 equiv), 15 h 22 Solvents 2 3 3 n-Bu4NI 4 Pd(PPh3)4, TBAB (2.0 equiv), Et3N (2.2 equiv), 15 h 42 DMF 5 Herrmann's catalyst, TBAB (2.0 equiv), 15 h 50 DMF/H2O d 6 Pd(OAc)2, TBAB (2.0 equiv), Et3N (2.2 equiv), added over 5 h <10 PhMe d 7 Herrmann's catalyst, TBAB (2.0 equiv), Et3N (2.2 equiv), added over 5 h 65 PhH Formate source dioxane NaO2CH a isolated yield after chromatography; d isolated yield after 5 h (syringe pump) addition complete PhCF3 NH4O2CH
Scheme 1.8. Reductive Heck-type annulation: representative optimization. most of which were found to have a minimal impact on the reaction, thus I stuck with
Et3N. DMF and toluene emerged as the optimal solvents, and sodium formate as the ideal formate source. The additive TBAB was optimal over its chloro (TBAC) and iodo
(TBAI) counterparts. Catalyst screening showed the palladacycle of Herrmann and co- workers58 to be the most robust and even capable of forming product at room temperature! (albeit with low conversion). Even with many of these parameters somewhat optimized I was still faced with the trouble of catalyst turnover. Thus while
Herrmann’s catalyst was ideal at minimizing the amount of debrominated material, the reactions never reached completion with normal catalyst loadings (i.e 10% Pd). Perhaps my most important finding in the entire screening process was to add the catalyst slowly by syringe pump as a solution in DMF. To my satisfaction, when the 5 hour addition of 5 mol% of Herrmann’s dimeric palladacycle catalyst was finished, all of the starting material had been consumed. This reaction was robust and amenable to scale-up to the gram level with 65% yield. With ketone 48 available I could easily complete the synthesis of hapalindole U (11) (Scheme 1.9).50 A stereoselective microwave-assisted
32 reductive amination (NH4OAc, NaCNBH3) and formylation (HCO2H, CDMT, NMM,
DMAP) of the crude amine furnished compound 66 as a mixture of formamide rotamers.
It should be noted that diasterocontrol in this reaction without microwave assistance is
22 poor (~ 2.5:1 dr). Dehydration of formamide 66 (COCl2, Et3N) then furnished (–)- hapalindole U (11) in 62% overall yield from ketone 48. Pleasingly, this crystalline compound was amenable to single crystal X-ray diffraction analysis. The described route allowed for gram quantities of the natural product to be synthesized. This is fortunate because as we will see in the next section, the seemingly straightforward task of attaching the reverse prenyl group proved extremely challenging.
Me Me Me
H a. i. NH OAc Me 4 Me H Me H O NaCNBH3 b. COCl2, Me NHCHO Me NC H MWI Me H H Et3N H H ii. CDMT, NMM 62% (2 steps) NH HCO2H, DMAP NH NH
48 66 (–)-Hapalindole U (11) X-ray over 1 gram prepared Scheme 1.9. Completion of a gram-scale, enantiospecific hapalindole U synthesis.
33 1.4. Total synthesis of (+)-ambiguine H.
As mentioned, all that remained to bridge the gap between the hapalindole and ambiguine alkaloid families was the attachment of the reverse prenyl group at the indole
C-2 position. Given the early success of Danishefsky’s protocol in delivering a C-2 reverse prenylated indole, I returned to ketone intermediate 65 in the hope that I could prenylate and then cyclize with palladium to ketone 58 (Scheme 1.10). Unfortunately compound 65 was largely resistant to this methodology; it is likely that the electron withdrawing bromine inhibits the initial chloroindolenine formation at low temperature.
Me Me a. i. t-BuOCl Me Et3N Pd Me H O O O Me H Br ii. Me Br Me Me Me Me NH NH NH Me B
65 67 58
Scheme 1.10. Unsuccessful strategies toward the ambiguines.
This setback was insignificant because the Danishefsky reaction worked satisfactorily on cyclized ketone 48 (Scheme 1.11). Surprisingly this compound was formed in nearly equal quantities with its C-6 isomer (compound 68), which is presumably formed via the mechanism shown in Scheme Figure 10. The origins of selectively in this reaction were never fully explored; however, I have observed nearly complete formation of compound 68 under certain circumstances! We will see more unusual reactivity of the indole nucleus at this position later. Returning to compound 58, I was poised to complete the first ambiguine synthesis. Unfortunately I was never able to incorporate a nitrogen source into ketone 58 via reductive amination (58 → 59, NH4OAc,
NaCNBH3, 150°C, microwave), Leukart reductive amination (58 → 70, NH2CO2H,
34 Me Me Me Me H H H Me a. i. t-BuOCl Me O O Et N O Me H Me H 3 Me H ii. prenyl- 9-BBN Me NH NH 45% NH Me Me Me 48 58 68 X-ray
NH OAc, 4 HCO2NH2, NH2OMe HCl, pyr. Δ NaCNBH3 HCO2H Δ Δ Me Me Me
Me H Me H Me H OMe NH2 N Me H NHCHO Me H Me H
Me Me NH Me Me NH Me NH Me 69 70 71
Scheme 1.11. Successful arrival at the ambiguine framework and immediate problems.
HCO2H, 150°C) or even oxime formation (58 → 71, NH2OMe•HCl, pyridine, 120°C).
Molecular modeling suggests the terminus of the reverse prenyl group lies directly over the ketone moiety, thus sterically inhibiting the approach of the amine source. At this juncture, it became clear that the nitrogen functionality would have to be incorporated prior to the reverse prenyl group. Taking a variety of our previous nitrogen containing intermediates from the hapalindole U synthesis and subjecting them to the Danishefsky
Me Me Me Me H Me H Me H H Me t-BuOCl Me O O Me O taut. Me H Me H Me O H H Cl Et3N N NH NH N Me Me Me Me 48 Nu 72 73 68 Figure 1.10. Unusual reactivity of the hapalindole indole nucleus. protocol failed to afford any C-2 reverse prenylated product (Scheme 1.12). A variety of prenyl-based metal nucleophiles (see Scheme 1.12) were screened in addition to the
35 Me Me Me Me H Me H Me Me H a. i. X , THF Me H [1,2]-Cl R Me R -78 °C Me shift Me R H Me R H H H H H H Cl ii. Cl " " Me N NH NH NH M Me 74 Nu– attack 75 Nu– attack at Nitrogen + R = NH2 X = t-BuOCl, NBS, R = NH2 at Chlorine NHCHO NCS, MTAD, NHCHO Me Me NOMe M = B, In, Cu, Sn, Mg NOMe Ta, Zn, Si Me H Me H R R Me H H Me H H
N NH Nu Scheme 1.12. Failed prenylation and intelligence gathering. 76 77 standard prenyl-9-BBN reagent. In addition to the standard t-BuOCl reagent, several
“X+” activating reagents known to react with indoles were screened (NCS, NBS,
MTAD59). While disappointing, I did gain some intelligence into the shortcomings of this reaction. Analysis of the crude reaction mixtures indicated mixtures of C-2 chlorinated indole, recovered starting material, and at times even N-prenylated indoles (Scheme
1.12). The recovered starting material was suspicious since tlc analysis indicated that it had been completely consumed after addition of t-BuOCl. Thus, I believed the putative 3- chloroindolinine species (74) was forming, however it was either: a) rapidly undergoing a
[1,2] chloro shift (to afford structures of the type (75)), b) acting as a chlorinating agent to the prenyl nucleophile (thus returning starting material), or c) being attacked by the prenyl nucleophile at the 3-chloroindolinine nitrogen atom (thus leading to N-prenylated compounds of the form 77. I briefly diverged from the Danishefsky protocol and sought other means to incorporate the reverse prenyl group or at least a suitable precursor to one.
A very small summary of my failures can be seen in Scheme 1.13.
36 Me Me Me H H lewis Me Me acids Δ Me H Me NC Me NC H H NC H H Me H H Me Me N Me Me NH Me NH Me 78 14 14 a. NaH, prenyl bromide
Me 75% Me Me Me Me Me H Me Cl Me H Me O Me H Me NC 79 80 H H Me NC NC H H Me H H O Me silver lewis NH Me salts Me NH acids NH Me 14 11 81
HO a. i. LHMDS, Et3B CO2Et ii. Cu(II) 82 Pd(0)
Me Me Me
Me H Me H Me H [1,2]-shift NC Me NC Me NC H H H H Me H H CO2Et Me Me Me Me NH Me N NH Me 14 84 83 Scheme 1.13. Miscellaneous failed attempts to introduce the reverse prenyl group.
N-prenylated indoles are known to undergo acid-mediated rearrangement to mixtures of
C-2 reverse prenylated indoles and C-2 regular prenylated indoles.60 Thus, conversion of hapalindole (11) to N-prenyl compound 78 could be achieved with sodium hydride and prenyl bromide in 75% yield. Unfortunately, this compound failed to undergo the rearrangement to ambiguine H (14) both thermally and under Lewis acidic conditions.
Friedel-Crafts reactions of 14 with prenyl chloride (79) in the presence of silver salts also failed to furnish even trace quantities of ambiguine H. Michael-type reaction of hapalindole U with unsaturated aldehyde 80 failed to furnish aldehyde 81. In addition, an oxidative enolate coupling between hapalindole U and ester 82 was unsuccessful.
Although the oxidative enolate indole coupling at the C-2 position has never been
37 observed in this laboratory, we had hoped that the relatively electron-rich indole nucleus in 11 might allow the reaction to take place in this instance. The methods of Trost61 and
Tamaru62 for indole C-3 reverse prenylation also failed to afford any of compound 84, which we had hoped might rearrange to ambiguine 13. Returning to the Danishefsky protocol I attempted the reverse prenylation with the natural product hapalindole U itself and something interesting happened.
Me Me
H Me Me H H a. i. t-BuOCl Me N Me N H H C H ii. prenyl- Cl 9-BBN NH 60% N Me Me BR2 Hapalindole U (11) 85
X-ray
Me Me
+ Me H Cl H H Me Me Me B Me N Me N H C H Cl
NH N 86 Scheme 1.14. A novel isonitrile-assisted reverse prenylation of an indole.
The chlorinating reagent apparently reacted with the isonitrile moiety forming a highly reactive electrophile which was trapped by the neighboring indole π-bond presumably leading to intermediate imine 86. This imine then reacted with prenyl-9-BBN to afford pentacycle 85 which incorporated the entire prenyl-9-BBN reagent. This fortuitous reaction avoided the problems earlier since: a) intermediate 86 cannot undergo the [1,2]-shift reminiscent of the 3-chloro species, b) nucleophiles cannot attack at nitrogen since there is no leaving group at the C-3 position, and c) 86 cannot act as a
38 halogenating source to quench the prenyl nucleophile. It is worth noting that the 9-BBN group is strongly bound to the aniline-type nitrogen in 85 and all typical conditions for boron removal could not cleave it (Figure 1.11).
Me Me a. OH H2N Me H Me H THF, Δ Me N Me N H H Cl or Cl b. MeCHO, THF N Me NH Me or Me Me BR 85 2 c. NaOt-Bu THF, 80°C 87 Figure 1.11. Unusual heterolytic stability of the N–B bond in compound 85.
Although compound 85 incorporates the desired reverse prenyl group, it also has an unwanted quaternary C-C bond and is missing the key isonitrile group. We had hoped that it might be possible to cleave the unwanted C-C bond using photochemistry somewhat reminiscent of the venerable Norrish type-I process (albeit with an iminyl chloride rather than a ketone chromophore).63 Gratifyingly, when I irradiated
Me Me
Me H a. PhH, Me H Me N Et N H 3 NC Me H H Cl hν 66% N Me Me Me NH Me BR2 85 (+)-ambiguine H (14) x-ray
-Et NHCl hν 3 -HOBR2
Me Me Me Cl Cl Me H Me H Me H Me N Me N Me N H H H H H Cl H
N N N Me Me Me Me Me Me BR2 BR2 BR2 88 89 Scheme 1.15. A light-induced fragmentation cascade to furnish ambiguine H (14).
39 compound 85 in benzene with Et3N I observed direct formation of ambiguine H (14) which was confirmed by single crystal X-ray analysis (Scheme 1.15).
Me Me Me H Cl Cl Me H Cl Me H C-C Me scission Me N abstraction Me N Me N H H H H Me H N N Me N Me Me Me BR2 91 BR2 BR2 92 90 89 88
recombination –Et3NHCl at C-6 –HOBR2
Me Me Me H Cl Me i. aromatization Me H Me H Me NC Me N H H Me NC ii. –Et3NHCl H —HOBR2 NH N NH Me Me Me Me BR2 94 93 hapalindole U (11) Scheme 1.16. Side products formed in photofragmentation reaction: implications for benzylic radical intermediates.
A plausible mechanism is shown in Scheme 1.15. The intermediacy of a benzylic radical intermediate is strongly supported by the observation of minor by-products formed in this reaction, namely hapalindole U (11) and C-6 reverse prenylated compound 94 (Scheme
1.16). Benzyllic intermediate 88 can undergo homolytic C-C scission thus restoring aromaticity to the indole group and liberating tertiary allylic radical 91. The tertiary radical can then likely act as a hydrogen radical souce leading to hapalindole U (11) and isoprene (92). It can also however, recombine with the electron rich indole ring leading to intermediate 93, which leads to 94 after rearomatization. As we saw in the production of compound 68 (Figure 1.10), the hapalindole aromatic nucleus had significant reactivity at the unexpected C-6 position. It should be mentioned that heating of 85 (temperatures 180 to 250°C) fails to produce any ambiguine H. To probe the role of the boron atom in the fragmentation we needed to prepared non-boronated compound 87 (Scheme 1.17). As
40 Me Me Me a. i. t-BuOCl Me H Me H Me H DCM b. PhH, –78 °C Me N Et N Me NC NC H 3 H H Me H H ii. Cl hν 75% Me MgCl NH Me NH Me NH Me 45% (+)-ambiguine H (14) hapalindole U (11) 87
Scheme 1.17. Independent synthesis of non-boronated compound 87 and subsequent fragmenation. mentioned earlier, the 9-BBN group could not be removed in compound 85, therefore I had to independently synthesize indoline 87 from hapalindole U (11) by switching the nucleophile from prenyl-9-BBN to prenyl magnesium chloride (Scheme 1.17). Subjecting compound 87 to the photofragmentation conditions formed ambiguine H smoothly in both higher chemical yield and conversion and more interestingly, without the formation of C-6 reverse prenylated compound 94 and hapalindole U (11) (Scheme 1.17).
Assuming both intermediates 88 and 96 are formed in the reactions of 85 and 87 respectively, it is interesting to consider why intermediate 88 leads to 3 products (11, 14, and 94) while 96 produces only ambiguine H. It is tempting to consider that the resonance contributor 95 could play an electronic role in increasing the lifetime of radical
88, thereby allowing for alternative pathways to compete with hydrogen radical abstraction.
41 Me Me
Cl H Cl Me H Me Me N Me N H H multiple H H products
N N Me Me Me Me BR2 BR2 88 95
Me
Cl Me H Me N H H single product
N Me Me 96 H Figure 1.12. Boron substituent in influencing reaction pathways.
42 1.5 Conclusion and distribution of credit
In conclusion, we developed concise, enantiospecific syntheses of the alkaloids hapalindole U (11) and ambiguine H (14) without resorting to protecting group manipulations. While the avoidance of protecting groups is obviously beneficial in terms of streamlining syntheses (both by step count and atom economy), one could argue that in this work the real benefit to their exclusion was in the arena of discovery. Novel intermediates and cascade reactions would likely have not been observed in these instances had typical bond-constructions with protected heteroatoms been performed.
These syntheses also highlight the role serendipity plays in natural product endeavors, since one could argue that had our original retrosynthesis of ambiguine H worked as planned the resulting synthesis, albeit concise, might have been a bit “boring.” Work on the scope and mechanism of the oxidative indole coupling reaction, although mostly not included in this thesis, was performed by Dr. Jeremy Richter, Mr. Brandon Whitefield, and me, however the selected reactions shown in Figure 1.5 I performed alone. The hapalindole U and ambiguine H syntheses were designed by Dr. Phil Baran and myself and executed solely by me.
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48 1.7 Supplementary Information
General Procedures. All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran
(THF), triethylamine (TEA), dichloromethane (DCM), methanol (MeOH), dimethylformamide (DMF), diethyl ether (Et2O), and benzene were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Tetra-n-butyl ammonium bromide (TBAB), sodium formate, ammonium acetate, sodium iodide, and copper(II)-2-ethylhexanoate were dried and kept stored under high vacuum prior to use. Herrmann’s catalyst [Pd(P(o-tol)3)OAc]2 and Palladium tetrakis were prepared fresh according to standard procedures. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were monitored by thin- layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and p-anisaldehyde in ethanol/aqueous
H2SO4/CH3CO2H and heat as developing agents. NMR spectra were recorded on a
Bruker DRX 600, DRX 500, or AMX 400 spectrometer and were calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad. IR spectra were recorded on a Perkin-Elmer Spetrum BX spectrometer. High resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer (at Scripps) using ESI-TOF (electrospray ionization-time of flight) or a
ThermoFinnigan Mass spectrometer (at UCSD) using FAB (fast atom bombardment), or
49 EI (electron impact). Low resolution mass spectra (LRMS) were recorded on an Agilent
(at Scripps) or ThermoFinnigan Mass spectrometer (at UCSD) GC-MS. Photochemical reactions were conducted using a 450-watt Hanovia lamp with a quartz filter. Melting points (m.p.) are uncorrected and were recorded on a Fisher-Johns 12-144 melting point apparatus. Optical rotations were obtained on a Perkin-Elmer 431 Polarimeter. All microwave reactions were performed in a Biotage Initiator Microwave. Sonications were carried out in a Fisher Scientific FS30H Ultrasonic Cleaning Bath. Azeotroping refers to dissolving the compound to be dried in benzene and removing the solvent by rotary evaporation.
General Procedure for oxidative enolate/indole coupling: Synthesis of compounds
30-39. To a solution of carbonyl compound (1.0 equiv.) and indole (2.0 equiv.) in THF
(1.0 M) at –78°C in a flame-dried flask under a nitrogen atmosphere was added a 1.0 M solution of LHMDS (3.3 equiv.). After stirring for 30 minutes at –78°C, the septum was removed, solid copper(II)2-ethylhexanoate (1.5 equiv.) was rapidly added in one portion, and the septum quickly replaced. The flask was then removed from the cooling bath and allowed to warm to ambient temperature. Once the flask had reached ambient temperature, the reaction was partitioned between 1 N HCl and EtOAc. The organic layer was further washed with 1 N NaOH, water, then brine and dried (MgSO4), The solvent was removed in vacuo and the crude product purified by silica gel flash column chromatography.
Compound 30: yield = 41 mg, 50%; yellow solid, mp = 201 – 203°C: Rf = 0.24 (3:1 hexanes, EtOAc); [α]D = +45.1 (DCM, c = 1.98); IR (film) νmax = 3403, 2928, 1734,
50 -1 1 1609, 1499, 1457, 1254, 1016, 909 cm ; H NMR (600 MHz, CDCl3) δ 8.08 (bs, 1 H,
D2O exchangeable), 7.59 (d, J = 7.9 Hz, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 7.20 – 7.22 (m, 2
H), 7.14 (t, J = 7.3 Hz, 1 H), 6.95 (s, 1 H), 6.69 (dd, J = 8.5, 2.5 Hz, 1H), 6.64 (d, J = 2.2
Hz, 1 H), 4.14 (d, J = 9.5 Hz, 1 H), 3.78 (s, 3 H), 2.84 – 2.93 (m, 2 H), 2.41 – 2.44 (m, 1
H), 2.27 – 2.33 (m, 2 H), 2.20 – 2.23 (m, 1 H), 2.05 – 2.07 (m, 1 H), 1.92 – 1.95 (m, 1 H),
1.76 – 1.81 (m, 1 H), 1.56 – 1.68 (m, 3 H), 1.33 – 1.37 (m, 1 H), 1.11 (s, 3 H); 13C NMR
(150 MHz, CDCl3) δ 221.5, 158.5, 138.7, 137.3, 132.9, 127.9, 127.2, 123.1, 122.2, 120.3,
119.9, 115.7, 114.7, 112.5, 112.2, 56.1, 49.6, 49.5, 44.9, 43.5, 39.2, 32.9, 31.4, 30.5, 27.4,
26.8, 15.7; HRMS (ESI) calcd. for C27H30NO2 [M + H+] 400.2271, found 400.2280.
Compound 31: yield = 55 mg, 48%; yellow foam; Rf = 0.19 (1:1 hexanes:Et2O); [α]D =
-1 +156 (DCM, c = 0.596); IR (film) νmax = 3326, 2936, 1658, 1457, 1251, 1099, 909 cm ;
1 H NMR (600 MHz, CDCl3) δ 8.41 (bs, 1 H, D2O Exchangeable), 7.39 (d, J = 7.9 Hz,
1H), 7.21 (d, J = 8.1 Hz, 1 H), 7.11 (t, J = 7.2 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 6.70 (s,
1 H), 6.03 (s, 1 H), 4.76 (d, J = 4.6 Hz, 2 H), 3.61 (d, J = 13.1 Hz, 1 H), 2.61 (td, J =
13.8, 4.7 Hz, 1 H), 2.48 (dd, J = 11.9, 2.8 Hz, 1 H), 2.37 – 2.42 (m, 2 H), 1.97 – 2.03 (m,
2 H), 1.77 (s, 3 H), 1.47 (ddd, J = 25.9, 12.7, 3.9 Hz, 1 H), 1.27 (s, 3 H), 1.24 (t, J = 12.8
13 Hz, 1 H), 0.71 (d, J = 7.0 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 200.7, 170.7, 150.0,
137.6, 127.4, 125.6, 125.3, 122.4, 120.2, 119.8, 113.1, 112.6, 110.2, 49.2, 46.6, 45.3,
+ 41.2, 40.9, 33.9, 32.5, 21.7, 18.3, 14.4; HRMS (ESI) calcd. for C23H28NO [M + H ]
334.2165, found 334.2175.
Compound 32: yield = 40 mg, 30%; yellow oil; Rf = 0.32 (3:1 hexanes:Et2O); IR (film)
-1 1 νmax = 3326, 2930, 1675, 1576, 1457, 1093 cm ; H NMR (600 MHz, CDCl3) δ 8.11 (bs,
1 H, D2O exchangeable), 7.59 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 16.2 Hz, 1 H), 7.35 (d, J =
51 8.1 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H), 7.11 – 7.13 (m, 2 H), 6.23 (d, J = 16.2 Hz, 1 H),
3.97 (s, 2 H), 2.00 (t, J = 6.2 Hz, 2 H), 1.63 (s, 3 H), 1.55 – 1.58 (m, 2 H), 1.41– 1.43 (m,
13 2 H), 0.96 (s, 6 H); C NMR (150 MHz, CDCl3) δ 199.1, 143.5, 137.3, 137.0, 137.0,
130.1, 128.3, 123.8, 123.1, 120.6, 119.7, 112.0, 110.2, 40.6, 39.1, 34.9, 34.5, 29.6 (2 C),
+ 22.5, 19.7; HRMS (ESI) calcd. for C21H26NO [M + H ] 308.2009, found 308.2009.
Compound 33: yield = 128 mg, 51%; yellow solid, mp = 117 – 118°C; Rf = 0.12 (3:1 hexanes:EtOAc); IR (film) νmax = 3407, 2975, 1749, 1459, 1379, 1215, 1179, 1084, 1022,
-1 1 909 cm ; H NMR (600 MHz, CDCl3) d 8.45 (bs, 1 H, D2O exchangeable), 7.67 (d, J =
8.0 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 7.20 (t, J = 8.7 Hz, 1 H), 7.13 (t, J = 7.7 Hz, 1 H),
6.97 (d, J = 2.4 Hz, 1 H), 4.36 (dt, J = 13.9, 5.3 Hz, 1 H), 4.24 (dd, J = 16.1, 7.4 Hz, 1 H),
13 2.83 – 2.87 (m, 1 H), 2.38 – 2.42 (m, 1 H), 1.73 (s, 3 H); C NMR (150 MHz, CDCl3) δ
181.9, 138.1, 125.7, 123.1, 122.7, 120.5, 120.4, 116.3, 112.8, 66.6, 43.7, 38.0, 24.7;
+ HRMS (ESI) calcd. for C13H14NO2 [M + H ] 216.1024, found 216.1015.
Compound 34: yield = 54 mg, 44%; yellow solid, mp = 143 – 145°C; Rf = 0.18 (3:1
-1 1 hexanes:EtOAc); IR (film) νmax = 3330, 2958, 1652, 1457, 1363, 1273, 1100 cm ; H
NMR (600 MHz, CDCl3) δ 8.29 (bs, 1 H, D2O exchangeable), 7.55 (d, J = 7.9 Hz, 1 H),
7.27 (d, J = 8.1 Hz, 1 H), 7.14 (t, J = 7.3 Hz, 1 H), 7.09 (t, J = 7.7 Hz, 1 H), 6.82 (s, 1 H),
6.08 (s, 1 H), 3.72 (s, 1 H), 2.35 (d, J = 18.5 Hz, 1 H), 2.18 (d, J = 18.5 Hz, 1 H), 2.02 (s,
13 3 H), 1.08 (s, 3 H), 0.89 (s, 3 H); C NMR (150 MHz, CDCL3) δ 200.6, 160.7, 136.7,
129.3, 126.7, 123.3, 122.7, 120.2, 120.1, 112.0, 111.3, 55.5, 45.1, 38.4, 29.6, 26.2, 25.4;
+ HRMS (ESI) calcd. for C17H20NO [M + H ] 254.1539, found 254.1541.
Compound 35: yield = 58 mg, 43 %; white foam; Rf = 0.22 (3:1 hexanes:EtOAc); IR
-1 1 (film) νmax = 3357, 3052, 2932, 1676, 1597, 1457, 1299, 1219 cm ; H NMR (600 MHz,
52 CDCl3) δ 8.18 (bs, 1 Η, D2O exchangeable), 8.17 (d, J = 8.0 Hz, 1 H), 7.51 – 7.53 (m, 2
H), 7.37 (t, J = 7.5 Hz, 1 H), 7.28 – 7.30 (m, 2 H), 7.16 (t, J = 7.3 Hz, 1 H), 7.09 (t, J =
7.5 Hz, 1 H), 6.79 (s, 1 H), 4.13 (dd, J = 10.0, 4.4 Hz, 1 H), 3.02 – 3.12 (m, 2 H), 2.44
13 –2.56 (m, 2 H); C NMR (150 MHz, CDCL3) δ 199.5, 145.2, 137.2, 134.3, 133.7, 129.7,
128.7, 127.7, 127.6, 123.0, 122.8, 120.3, 120.0, 114.6, 112.3, 46.9, 31.3, 29.5; HRMS
+ (ESI) calcd. for C18H16NO [M + H ] 262.1226, found 262.1228.
Compound 36: yield = 45 mg, 43 %; clear oil; Rf = 0.20 (3:1 hexanes:EtOAc); IR
-1 1 (film) νmax = 3405, 1686, 1604, 1477, 1458, 1326, 1214 cm ; H NMR (500 MHz,
CDCl3) δ 8.15 (bs, 1 Η, D2O exchangeable), 7.96 (d, J = 8 Hz, 1 H), 7.68 (d, J = 8 Hz, 1
H), 7.50 (t, J = 8.5 Hz, 1 H), 7.37 (d, J = 8 Hz, 1 H), 7.27 (d, J = 2 Hz, 1 H), 7.21 (t, J =
7.5 Hz, 1 H), 7.15 (t, J = 8 Hz, 1 H), 7.02 – 7.06 (m, 2 H), 4.72 – 4.79 (m, 2 H), 4.30 (dd,
13 J = 5, 7.5 Hz); C NMR (100 MHz, CDCL3) δ 192.7, 162.3, 136.9, 136.7, 128.8, 127.5,
123.5, 123.4, 122.4, 121.5, 120.9, 119.9, 118.6, 112.2, 110.1, 72.2, 45.2; HRMS (ESI)
+ calcd. for C17H14NO2 [M + H ] 264.1024, found 264.1021.
Compound 37: yield = 38 mg, 42 %; white solid, mp > 250°C; R f = 0.19 (2:1
Et2O:hexanes); [α]D = +95.4 (DCM, c = 1.56) IR (film) νmax = 3324, 1773, 1660, 1628,
-1 1 1459, 1377, 1197, 1104, 1041, 990, 908 cm ; H NMR (600 MHz, CDCl3)
δ 8.48 (bs, 1 Η, D2O exchangeable), 7.68 (d, J = 8.1 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H),
7.24 (t, J = 9.7 Hz, 1 H), 7.14 (t, J = 7.4 Hz, 1 H), 6.99 (d, J = 2.5 Hz, 1 H), 6.60 (d, J =
9.8 Hz, 1 H), 6.22 (d, J = 9.8 Hz, 1 H), 4.87 (d, J = 11.5 Hz, 1 H), 2.26 (dd, J = 12.1, 3.5
Hz, 1 H), 2.22 (s, 3 H), 2.08 (dd, J = 6.0, 2.0 Hz, 1 H), 1.80 (s, 3 H), 1.76 (d, J = 13.2 Hz,
1 H), 1.49 (td, J = 13.3, 4.3, 1 H), 1.40 (td, J = 12.8, 3.7, 1 H), 0.98 (s, 3 H); HRMS (ESI)
+ calcd. for C23H24NO3 [M + H ] 362.1751, found 362.1760.
53 Compound 38: yield = 794 mg, 61 %; white solid, mp = 150 – 153°C; Rf = 0.33 (1:1
Et2O:hexanes); [α]D = +47.4 (DCM, c = 3.65) IR (film) νmax = 3369, 2931, 1701, 1642,
-1 1 1457, 1373, 1247, 1099, 1011, 914 cm ; H NMR (500 MHz, CDCl3) δ 8.14 (bs, 1 Η,
D2O exchangeable), 7.37 (d, J = 7.8 Hz, 1 H), 7.16 (d, J = 7.9 Hz, 1 H), 7.12 (t, J = 6.8
Hz, 1 H), 7.07 (t, J = 7.3 Hz, 1 H), 6.61 (d, J = 2.35 Hz, 1 H), 6.35 (dd, J = 11, 17.7 Hz, 1
H), 5.18 (d, J = 11.0 Hz, 1 H), 5.14 (d, J = 17.7 Hz, 1 H), 4.64 (s, 1 H) 4.57 (s, 1 H), 4.23
(d, J = 12.4 Hz, 1 H), 2.97 (td, J = 3.9, 12.0 Hz, 1 H), 2.18 – 2.27 (m, 1 H), 2.11 (td, J =
3.8, 13.4, 1 H), 2.02 (dt, J = 3.5, 13.5, 1 H), 1.91 – 1.96 (m, 1 H); 1.60 (s, 3H), 1.57 (s,
13 3H); C NMR (125 MHz, CDCl3) δ 212.2, 146.4, 143.0, 136.0, 127.1, 123.6, 121.2,
118.8, 118.7, 112.2, 112.0, 111.3, 110.8, 52.3, 50.6, 47.9, 36.7, 27.5, 22.9, 18.5; HRMS
+ (ESI) calcd. for C20H24NO [M + H ] 294.1852, found 294.1848.
Compound 39: yield = 58 mg, 51 %; white solid, mp = 145 – 147°C; Rf = 0.35 (3:1
Hexanes: EtOAc); [α]D = +80.4 (DCM, c = 1.79) IR (film) νmax = 3354, 2953, 2868,
-1 1 1702, 1457, 1366, 1097, 908 cm ; H NMR (600 MHz, CDCl3) δ 8.14 (bs, 1 Η ,D2O exchangeable), 7.43 (d, J = 7.9 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1
H), 7.07 (t, J = 7.6 Hz, 1 H), 6.98 (d, J = 2.2 Hz, 1 H), 3.52 (d, J = 11.8 Hz, 1 H), 2.29 –
2.33 (m, 1 H), 2.22 – 2.25 (m, 1 H), 2.14 – 2.18 (m, 2 H), 2.07 (td, J = 13.4, 3.4 Hz, 1 H),
1.56 – 1.65 (m, 2 H), 0.93 (dd, J = 6.5, 5.2 Hz, 6 H), 0.86 (d, J = 6.4 Hz, 3 H); 13C NMR
(150 MHz, CDCl3) δ 211.6, 137.1, 128.4, 124.0, 122.5, 120.2, 120.0, 113.0, 112.1, 57.9,
+ 57.7, 43.3, 35.8, 30.5, 27.4, 22.5, 22.3, 19.9; HRMS (ESI) calcd. for C18H24NO [M + H ]
270.1852, found 270.1864.
Compound 51: i. A flame-dried flask was charged with p-menth-1-en-9-ol (6.79 g, 44.1 mmol, 1.0 equiv., inseparable and inconsequential mixture of diastereomers), Zn dust
54 (11.5 g, 176.0 mmol, 4.0 equiv.), and Et2O (400 mL). The flask was placed in an ultrasound bath, and freshly distilled trichloroacetyl chloride (19.5 mL, 174.7 mmol, 4.0 equiv.) in Et2O (200 mL) was added drop-wise to the sonicating solution over the course of 1 hour at 25 °C. Sonication was continued for 6 hours while maintaining a bath temperature of 25 – 30 °C by the periodic addition of ice. The reaction mixture was filtered through a plug of celite and concentrated in vacuo. The dark red oil was partitioned between Et2O (350 mL) and water (350 mL). The aqueous layer was extracted with Et2O (100 mL, 4X). The combined organic layers were washed with saturated NaHCO3 (400 mL, 2X), brine (400 mL, 2X), and dried (Na2SO4). The solvent was removed in vacuo to give a dark red oil. Flash column chromatography (silica gel, gradient from 2:1 to 1:1 hexanes:DCM) gave a yellow oil (10.9 g, 66%). [NOTE: the intermediate cyclobutanone was prone to slight decomposition on silica gel. Using crude material for the next step gives a similar overall yield] ii. To a flame dried flask was added the aforementioned cyclobutanone (1.06 g, 2.82 mmol, 1.0 equiv.), NaOMe (765 mg, 13.4 mmol, 4.8 equiv.), and anhydrous MeOH (28 mL). The mixture was placed into a pre-heated oil bath at 65 °C and heated for 30 minutes. Upon cooling, the reaction mixture was poured into 1N HCl (100 mL) and extracted with EtOAc (100 mL, 3X). The combined organic layers were washed with 1N
HCl (200 mL, 2X), brine (200mL, 2X), and dried (Na2SO4). The solvent was removed in vacuo to give a red oil. Flash column chromatography (silica gel, gradient from 2:1 to 1:1 hexanes:Et2O) yielded a yellow oil (671 mg, 61% yield over 2 operations) as an inseparable and inconsequential mixture of four diastereomers (two at the ester bearing carbon, each of which is a mixture of two diastereomers at the α-hydroxy bearing
55 carbon).
Compound 52: Compound 51 (767 mg, 2.99 mmol, mixture of diastereomers) was dissolved in DCM (30 mL) and cooled to –78 °C. DIBAL (1.5 M solution in toluene,
10.0 mL, 15.0 mmol, 5.0 equiv.) was then added drop-wise at –78 °C. The reaction mixture was stirred for 30 minutes at –78 °C, then quenched by the drop-wise addition of
MeOH (5 mL). The reaction mixture was warmed to room temperature, diluted with
EtOAc (200 mL) and saturated Rochelle’s salt solution (200 mL) and vigorously stirred overnight. The layers were separated and the aqueous layer was extracted with EtOAc
(100 mL, 4X). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, gradient from 1:1 to 3:2 to 1:0
EtOAc:hexanes) furnished the diol (560 mg, 82%, inconsequential and inseparable mixture of diastereomers). The diol (540 mg, 2.36 mmol, mixture of diastereomers) was dissolved in anhydrous pyridine (25 mL) and cooled to 0 °C. Methanesulfonyl chloride
(0.55 mL, 7.10 mmol, 3.0 equiv.) was slowly added drop-wise to the solution at 0 °C and stirring was continued for 75 minutes at this temperature. The reaction mixture was then warmed to room temperature and stirred for an additional 30 minutes before pouring into a mixture of 1N HCl (100 mL) and Et2O (200 mL). The aqueous layer was extracted with
Et2O (100 mL, 4X). The combined organic extracts were washed with 1N HCl (200 mL,
2X) and brine (200 mL). The solvent was removed in vacuo to give an oil which was dissolved in 4:1 AcOH:H2O (35 mL) and stirred for 2.5 hours at 23 ºC (to hydrolyze any enol-ethers that are formed). The reaction mixture was diluted with Et2O (150 mL) and
H2O (150 mL) and the aqueous layer was extracted with Et2O (100 mL, 4X). The combined organic layers were washed with saturated NaHCO3 (500 mL, 4X, carefully),
56 brine (250 mL, 2X), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, gradient from 1:1 to 2:1 Et2O:hexanes) gave 52 as a clear oil
(576 mg, 89%, mixture of two diastereomers).
Compound 50: Compound 52 (485 mg, 1.76 mmol) was dissolved in acetone (10 mL).
Dry sodium iodide (2.63 g, 17.6 mmol, 10.0 equiv.) was added and the reaction mixture was heated at reflux for 15 hours. Upon cooling to ambient temperature, the reaction was partitioned between Et2O (100 mL) and H2O (100 mL) and the aqueous layer was extracted with Et2O (75 mL, 3X). The combined organic layers were washed with saturated Na2S2O3 (200 mL, 2X), brine (200 mL, 2X) and dried (Na2SO4). The solvent was removed in vacuo to give an oil which was azeotropically dried with benzene, then dissolved in THF (10 mL). To this solution was added DBU (1.33 mL, 8.82 mmol, 5.0 equiv.) and the reaction was degassed by bubbling argon through the mixture for 5 minutes in an ultrasound bath. The reaction mixture was then heated for 3 hours at 65 °C under an argon atmosphere. Upon cooling, the mixture was partitioned between 1N HCl
(50 mL) and Et2O (100 mL) and the aqueous layer was extracted with Et2O (50 mL, 4X).
The combined organic layers were washed with 1N HCl (200 mL, 2X), brine (200 mL,
2X), and dried (Na2SO4). The solvent was removed in vacuo to give a yellow liquid.
Flash column chromatography (silica gel, 15:1 hexanes:Et2O) gave 7 (272 mg, 87%) as a
–3 clear liquid; TLC (hexanes:Et2O, 2:1 v/v): RF = 0.66; [α]D = –24.9 (c = 2.4 g cm in
DCM); IR (film) νmax = 3082, 2932, 2359, 1707, 1643, 1453, 1311, 1269, 1246, 1096,
-1 1 999, 895, 668 cm ; H NMR (400 MHz, CDCl3) δ 6.04 (dd, J = 10.9, 17.6 Hz, 1 H), 5.09
(d, J = 10.9 Hz, 1 H), 4.98 (d, J = 18.2 Hz, 1 H), 4.77 (s, 1 H), 4.67 (s, 1 H), 2.40 – 2.54
13 (m, 3 H), 1.72 – 1.88 (m, 4 H), 1.70 (s, 3 H), 1.20 (s 3 H); C NMR (125 MHz, CDCl3,
57 APT) δ 213.1, 146.9, 142.6, 113.3, 110.6, 50.6, 44.8, 42.9, 35.9, 25.4, 22.8, 20.9; IR
(film): 3082, 2932, 1707, 1644, 1453, 1311, 1246, 1097, 1000, 896; HRMS (m/z):
+ [M+H] calcd for C12H19O, 179.1430; found, 179.1422.
Compound 49: Indole (1.00 g, 8.54 mmol, 1.9 equiv) was azeotropically dried with benzene (2X) and the residual solvent removed under high vacuum. ent-Compound 50
(792 mg, 4.44 mmol, 1.0 equiv.) and THF (25 mL) were then added, and the mixture was cooled to –78 °C under an atmosphere of dry nitrogen. Freshly prepared LHMDS (1.0 M in THF, 15 mL, 15 mmol, 3.4 equiv.) was added dropwise to the solution at –78 ºC and the reaction was stirred for 30 minutes at that temperature. Copper(II)-2-ethylhexanoate
(0.2 M solution in THF, 33 mL, 6.6 mmol, 1.5 equiv.) was added rapidly via syringe. The mixture was stirred for 5 minutes at –78 °C then warmed to room temperature and immediately poured into 1N HCl (150 mL) and EtOAc (150 mL). The aqueous layer was extracted with EtOAc (100 mL, 3X). The combined organic layers were washed with 1N
HCl (500 mL), 1N NaOH (500 mL), brine (500 mL), and dried (MgSO4). The solvent was removed in vacuo and the crude material was purified by flash column chromatography (silica gel, gradient from 10:1 to 5:1 hexanes:EtOAc) to give the title compound (794 mg, 61%) as a white solid. [Note: this compound was prepared with ent- compound 50 (which is opposite to the rest of the compounds in this series)]; m.p.: =
–3 151–153 ºC; TLC (hexanes:Et2O, 1:1 v/v): RF = 0.33; [α]D = +47.4 (c = 3.65 g cm in
DCM); IR (film) νmax = 3368, 2931, 2359, 1701, 1642, 1457, 1339, 1247, 1098, 1010,
-1 1 913, 892, 766, 668, 602 cm ; H NMR (500 MHz, CDCl3) δ 8.14 (bs, 1 H), 7.37 (d, J =
7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.12 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.3 Hz, 1H),
6.61 (d, J = 2.35 Hz, 1H), 6.35 (dd, J = 11.0, 17.7 Hz, 1H), 5.18 (d, J = 11.0 Hz, 1H),
58 5.14 (d, J = 17.7 Hz, 1H), 4.64 (s, 1H), 4.57 (s, 1H), 4.23 (d, J = 12.4 Hz, 1H), 2.97 (td, J
= 3.9, 12.0 Hz, 1H), 2.18 – 2.27 (m, 1H), 2.11 (td, J = 3.8, 13.4 Hz, 1H), 2.02 (dt, J = 3.5,
13 13.5 Hz, 1H), 1.91-1.96 (m, 1H), 1.60 (s, 3H), 1.57 (s, 3H); C NMR (125 MHz, CDCl3)
δ 212.2, 146 .4, 143.0, 136.0, 127.1, 123.6, 121.2, 118.8, 118.7, 112.2, 112.0, 111.3,
110.8, 52.3, 50.6, 47.9, 36.7, 27.5, 22.9, 18.5; IR (film): 3369, 2931, 1701, 1642, 1457,
+ 1373, 1340, 1247, 1099, 1011, 914, 893; HRMS (m/z): [M+H] calcd for C20H24NO,
294.1852; found, 294.1848.
Compound 53: Representative procedure for undesired cyclization: To a flame dried flask was added compound 49 (11.4 mg, 0.039 mmol, 1 equiv.), DCM (0.75 ml), and
MeOH (4.7 µl, 0.12 mmol, 3.0 equiv.). The flask was cooled to 0°C and TMSOTf (23 µl,
0.12 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, then quenched with saturated aqueous sodium bicarbonate (1 ml) at 0°C. DCM (5 mL) was added and the layers separated. The aqueous layer was extracted with DCM (5 mL, 3X). The combined organic layers were washed with brine (25 mL), and dried
(MgSO4). The solvent was removed in vacuo and the crude material was purified by preparative thin-layer silica gel chromatography (1:1 hexanes:Et2O) to give the title compound (2.0 mg, 66% BRSM) as a white foam and recovered starting material (8.4 mg). [Note: this compound was prepared with ent-compound 50 (which is opposite to the rest of the compounds in this series)]; TLC (hexanes:Et2O, 2:1 v/v): RF = 0.32; [α]D =
–3 –109.3 (c = 4.0 g cm in CHCL3); IR (film) νmax = 3393, 2958, 2927, 2864, 1705, 1449,
-1 1 1386, 1297, 1245, 1164, 1109, 1033, 1008, 918, 743 cm ; H NMR (600 MHz, CDCl3)
δ 7.86 (bs, 1 H), 7.76 (m, 1 H), 7.31 – 7.28 (m, 1 H), 7.12 – 7.10 (m, 2 H), 6.24 (dd, J =
12, 18 Hz, 1 H), 5.17 (d, J = 12 Hz, 1 H), 5.14 (d, J = 18 Hz, 1 H), 4.05 (d, J = 12 Hz, 1
59 H), 2.44 – 2.39 (m, 1 H), 2.03 – 1.91 (m, 3 H), 1.87 – 1.83 (m, 1 H), 1.47 (s, 3 H), 1.38
13 (s, 3 H), 1.16 (s, 3 H); C NMR (125 MHz, CDCl3) δ 211.9, 151.2, 143.0, 139.8, 124.6,
121.2, 120.5, 120.4, 113.2, 113.0, 111.5 63.13, 51.6, 51.3, 41.2, 39.0, 25.3, 23.8, 21.4,
+ 20.6; HRMS (m/z): [M+H] calcd. for C20H24NO, 294.1852; found, 294.1847.
Compound 57: ent-Compound 49 (26 mg, 0.09 mmol, 1 equiv.) was azeotropically dried with benzene. THF (0.85 ml) and Et3N (15 µl, 0.11 mmol, 1.2 equiv.) were added and the solution cooled to –78°C. Freshly prepared t-BuOCl (13 µl, 0.11 mmol, 1.3 equiv) was added and the reaction mixture stirred for 30 minutes at –78°C. Prenyl 9-BBN (1.0 M solution in THF, 0.18 ml, 0.18 mmol, 2 equiv.) was added dropwise at –78°C and the mixture stirred for 45 minutes at this temperature, then warmed to room temperature. The mixture was poured into saturated aqueous NaHCO3 (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (5 mL, 3X). The combined organic layers were washed with water (25 mL), brine (25 mL), and dried (MgSO4). The solvent was removed in vacuo and the crude material was purified by flash column chromatography
(silica gel, 15:1 hexanes:EtOAc) to give tentative intermediate 56. This compound was allowed to stand in CDCl3 for 30 minutes then concentrated in vacuo and dried under high vacuum. The material was re-purified by flash column chromatography (silica gel,
10:1 hexanes:EtOAc) to give ent-compound 57 (25.1 mg, 78%) as a white crystalline solid. Recrystallization from EtOAc gave slightly yellow cubes which were suitable for
X-ray diffraction; m.p.: = 170 – 173 ºC; TLC (hexanes:Et2O, 2:1 v/v): RF = 0.23; [α]D =
–3 +13.6 (c = 4.2 g cm in CHCl3); IR (film) νmax = 3407, 2920, 2850, 1701, 1460, 1375,
-1 1 1012, 912, 739 cm ; H NMR (600 MHz, CDCl3) δ 7.85 ( bs, 1 H), 7.30 (d, J = 6 Hz, 1
H), 7.25 (d, J = 6 Hz, 1 H), 7.06 (t, J = 6 Hz, 1 H), 6.97 (t, J = 6 Hz, 1 H), 6.32 (dd, J =
60 12, 18 Hz, 1 H), 6.10 (dd, J = 6, 12 Hz, 1 H), 5.20 (dd, J = 18 Hz, 1 H), 5.11 (dd, J = 12
Hz, 2 H), 5.07 (dd, J = 18 Hz, 1 H), 4.53 (d, J = 24 Hz, 2 H), 4.48 (d, J = 12 Hz, 1 H),
3.26 (dt, J = 6, 12 Hz, 1 H), 2.18 – 2.05 (m, 2 H), 1.96 – 1.94 (m, 1 H), 1.91 – 1.87 (m, 1
13 H), 1.47 (s, 3 H), 1.46 (s, 3 H), 1.42 (s, 3 H), 1.41 (s, 3 H); C NMR (125 MHz, CDCl3)
δ 211.3, 146.8, 146.5, 143.6, 140.5, 134.7, 128.5, 121.0, 120.9, 119.0, 112.3, 112.1,
111.5, 110.7, 108.4, 50.5, 50.0, 49.8, 38.9, 36.8, 28.3, 27.7, 27.4, 23.0, 21.2; HRMS
+ (m/z): [M+H] calcd. for C25H32NO, 362.2478; found, 362.2475.
Compound 63: 4-Bromoindole (1.65 g, 8.4 mmol, 3.0 equiv.) was azeotropically dried with benzene (2X) and the residual solvent removed under high vacuum. Ketone 62 (465 mg, 2.80 mmol, 1.0 equiv.) and THF (2.8 mL) were then added, and the mixture was cooled to –78 °C under a dry nitrogen atmosphere. LHMDS (1.0 M in THF, 12.3 mL,
12.3 mmol, 4.4 equiv.) was added dropwise at –78 °C and stirring was continued for 30 minutes. The rubber septum was quickly removed and solid copper(II)-2-ethylhexanoate
(1.96 g, 5.6 mmol, 2.0 equiv.) was added rapidly in one portion at –78 °C followed by immediate replacement of the rubber septum. [Note: rapid stirring is essential and brief exposure of the reaction mixture to the atmosphere had a negligible effect on the overall outcome of the reaction]. The reaction was stirred for 5 minutes at –78 °C, then warmed to room temperature and immediately poured into 1N HCl (50 mL) and EtOAc (50 mL).
The aqueous layer was extracted with EtOAc (50 mL, 3X). The combined organic layers were washed 1N HCl (250 mL), 1N NaOH (250 mL), brine (250 mL), and dried
(MgSO4). The solvent was removed in vacuo and the crude material was purified by flash column chromatography (silica gel, gradient from 7:1 to 5:1 hexanes:EtOAc) to give the title compound (498 mg, 50%) as a white solid; m.p.: = 185 – 187 ºC; TLC
61 –3 (hexanes:Et2O, 1:1 v/v): RF = 0.22; [α]D = +50.9 (c = 4.3 g cm in CHCl3); IR (film) νmax
= 3340, 2967, 2932, 1701, 1645, 1471, 1337, 1187, 1075, 910, 756 cm-1; 1H NMR (600
MHz, CDCl3) δ 8.43 (bs, 1 H), 7.15 (d, J = 12 Hz, 1 H), 7.06 (t, J = 16 Hz, 1 H), 6.90 (m,
1 H), 6.86 (dt, J = 2, 8 Hz, 1 H), 5.25 (d, J = 12 Hz, 1 H), 4.76 (s, 1 H), 4.65 (s, 1 H),
2.81 (dt, J = 3, 12 Hz, 1 H), 2.26 – 2.18 (m, 1 H), 1.93 – 1.90 (m, 1 H), 1.82 – 1.75 (m, 2
13 H), 1.63 (s, 3 H), 1.49 (s, 3 H), 1.12 (s, 3 H); C NMR (125 MHz, CDCl3) δ 214.9,
147.4, 137.4, 125.6, 125.1, 124.0, 122.4, 113.6, 112.4, 112.2, 110.9, 53.5, 47.2, 45.5,
+ 40.8, 28.9, 26.0, 25.3, 18.7; HRMS (m/z): [M+H] calcd. for C19H23BrNO, 360.0957; found, 360.0957.
Compound 64: To a sealable vial was added compound 63 (15 mg, 0.04 mmol, 1 equiv.) and AIBN (5 mg, 0.04, 1.1 equiv.). The flask was then evacuated and back-filled with
Argon. Dry, degassed benzene (0.85 ml) and Bu3SnH (28 µl, 0.10 mmol, 2.5 equiv.) were added and the sealed vial placed into a 100°C oil bath for 1 hour. After cooling to room temperature, the volatiles were removed in vacuo and the crude material was purified by preparative thin-layer silica gel chromatography (2:1 hexanes:Et2O) to yield compound
64 upper diastereomer (2.6 mg,) as a white crystalline solid and 64 lower diastereomer
(6.2 mg) as a white crystalline solid, overall yield = 75%. The lower (major) diastereomer was recrystallized from cyclohexane/EtOAc to yield colorless needles suitable for X-ray diffraction; m.p.: = 185ºC; TLC (hexanes:Et2O, 2:1 v/v): RF = 0.24; [α]D = –190 (c = 6.2
–3 g cm in CHCl3); IR (film) νmax = 3383, 2928, 1716, 1458, 1329, 1249, 1123, 1064,
-1 1 1018, 776, 746 cm ; H NMR (600 MHz, CDCl3) δ 8.24 ( bs, 1 H), 7.18 (d, J = 6 Hz, 1
H), 7.15 (s, 1 H), 7.05 (t, J = 12 Hz, 1 H), 6.86 (d, J = 6 Hz, 1 H), 4.06 (d, J = 12 Hz, 1
H), 3.21 (d, J = 18 Hz, 1 H), 3.13 (dd, J = 6, 18 Hz, 1 H), 2.23 – 2.10 (m, 3 H), 1.90 –
62 1.87 (m, 1 H), 1.75 – 1.69 (m, 2 H), 1.34 (s, 3 H), 1.15 (s, 3 H), 1.01 (d, J = 6 Hz, 3 H);
13 C NMR (125 MHz, CDCl3) δ 215.2, 135.7, 132.3, 126.7, 125.0, 121.3, 120.2, 110.4,
108.6, 51.4, 47.3, 44.9, 43.4, 40.6, 37.5, 29.5, 26.2, 25.2, 12.8; HRMS (m/z): [M+H]+ calcd. for C19H24NO, 282.1852; found, 282.1846.
The upper (minor) diastereomer: white crystalline solid that can be recrystallized from cyclohexane/EtOAc to yield colorless needles; m.p.: = 129-131ºC; TLC (hexanes:Et2O,
–3 2:1 v/v): RF = 0.40; [α]D = +47.8 (c = 3.7 g cm in CHCl3); IR (film) νmax = 3400, 2959,
-1 1 2923, 1703, 1456, 1338, 1105, 746 cm ; H NMR (600 MHz, CDCl3) δ 7.96 (bs, 1 H),
7.66 (s, 1 H), 7.16 (d, J = 12 Hz, 1 H), 7.03 (t, J = 6 Hz, 1 H), 6.76 (d, J = 12 Hz, 1 H),
4.39 (d, J = 12 Hz, 1 H), 3.67 (dd, J = 3, 15 Hz, 1 H), 2.68 (dd, J = 5, 15 Hz, 1 H), 2.21 –
2.16 (m, 1 H), 1.92 – 1.78 (m, 3 H), 1.67 – 1.62 (m, 1 H), 1.38 – 1.34 (m, 1 H), 1.27 (s, 3
13 H), 1.15 (s, 3 H), 0.89 (d, J = 7 Hz, 3 Η); C NMR (125 MHz, CDCl3) δ 216.6, 135.0,
132.9, 127.5, 122.0, 119.6, 114.4, 108.9, 52.9, 47.6, 45.2, 39.6, 38.9, 38.1, 29.4, 26.3,
+ 25.8, 20.8; HRMS (m/z): [M+H] calcd. for C19H24NO, 282.1852; found, 282.1847.
Compound 65: 4-Bromoindole (3.13 g, 16.0 mmol, 2.8 equiv.) was azeotropically dried with benzene (2X) and the residual solvent removed under high vacuum. Compound 50
(1.00 g, 5.61 mmol, 1.0 equiv.) and THF (5.6 mL) were then added, and the mixture was cooled to –78 °C under a dry nitrogen atmosphere. LHMDS (1.0 M in THF, 24.6 mL,
24.6 mmol, 4.4 equiv) was added dropwise at –78 °C and stirring was continued for 30 minutes. The rubber septum was quickly removed and solid copper(II)-2-ethylhexanoate
(4.0 g, 11.4 mmol, 2.0 equiv.) was added rapidly in one portion at –78 °C followed by immediate replacement of the rubber septum. [Note: rapid stirring is essential and brief exposure of the reaction mixture to the atmosphere had a negligible effect on the overall
63 outcome of the reaction]. The reaction was stirred for 5 minutes at –78 °C, then warmed to room temperature and immediately poured into 1N HCl (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (125 mL, 3X). The combined organic layers were washed 1N HCl (600 mL), 1N NaOH (600 mL), brine (600 mL), and dried
(MgSO4). The solvent was removed in vacuo and the crude material was purified by flash column chromatography (silica gel, gradient from 4:1 to 3:1 to 2.5:1 to 1:1 hexanes:Et2O) to give the title compound (1.04 g, 50%) as a white solid [Note: excess 4-bromoindole can also be easily recovered]; m.p.: = 130–132 ºC; TLC (hexanes:EtOAc 1:1 v/v): RF =
–3 0.59; [α]D = –19.1 (c = 9.2 g cm in DCM); IR (film) νmax = 3349, 2934, 1699, 1426,
-1 1 1337, 1186, 1120, 910, 735, 610 cm ; H NMR (400 MHz, CDCl3) δ 8.41 (bs, 1H), 7.15
(d, J = 7.5 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.83 – 6.87 (m, 2H); 6.28 (dd, J = 11.0, 17.6
Hz, 1H), 5.30 (d, J = 12.6 Hz, 1H), 5.11 (d, J = 10.9 Hz, 1H), 5.06 (d, J = 17.8 Hz, 1H),
4.77 (s, 1H), 4.66 (s, 1H), 2.84 (td, J = 3.8, 12.3 Hz, 1H), 2.20 – 2.31 (m, 1H), 1.87 –
13 2.05 (m, 3H), 1.64 (s, 3H), 1.61 (s, 3H); C NMR (150 MHz, CDCl3) δ 212.8, 147.0,
143.2, 137.2, 125.4, 125.0, 123.9, 122.2, 113.4, 112.4, 112.0, 111.7, 110.7, 52.9, 50.7,
+ 47.2, 37.5, 28.4, 22.6, 18.5; HRMS (m/z): [M+H] calcd for C20H23BrNO, 372.0957; found, 372.0966.
Compound 48 (optimized procedure): Compound 9 (1.12 g, 3.03 mmol, 1.0 equiv.) was azeotropically dried with benzene. Dry sodium formate (258 mg, 3.79 mmol, 1.2 equiv) and dry TBAB (1.96 g, 6.08 mmol, 2.0 equiv.) were added and the flask was evacuated, then backfilled with argon. DMF (30 mL) was then added followed by TEA (0.94 mL,
6.74 mmol, 2.2 equiv.). This mixture was degassed by three freeze-pump-thaw iterations and finally back-filled with argon. A solution of Hermmann’s catalyst (142 mg, 0.15
64 mmol, 0.05 equiv.) in DMF (20 mL) was degassed by three freeze-pump-thaw iterations and added drop-wise over 5 hours (syringe pump) to the substrate at 80 °C. The mixture was heated for an additional 3 hours at 80 °C. Upon cooling, the reaction mixture was diluted with Et2O (100 mL) and filtered through a plug of celite. The mixture was poured into Et2O (100 mL) and H2O (100 mL) and the aqueous layer was thoroughly extracted with Et2O (100 mL, 5X). The combined organic layers were washed with 1N HCl (500 mL), 1N NaOH (500 mL), brine (500 mL), and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by flash column chromatography (silica gel, gradient from 8:1 to 5:1 hexanes:Et2O) to give the title compound (579 mg, 65%) as white crystals; m.p.: = 149–151 ºC; TLC (hexanes:Et2O 3:1 v/v): RF = 0.14; [α]D = –18.1
–3 (c = 1.7 g cm in DCM); IR (film) νmax = 3400, 3058, 2964, 1867, 1698, 1438, 1334,
-1 1 1175, 1044, 1019, 911, 745 cm ; H NMR (600 MHz, CDCl3) δ 8.08 (bs, 1H), 7.49 (t, J
= 1.9 Hz, 1H), 7.15-7.19 (m, 2H), 7.03 (dd, J = 1.0, 6.5 Hz, 1H), 6.24 (dd, J = 10.9, 17.6
Hz, 1H), 5.17 (d, J = 10.9 Hz, 1H), 5.11 (d, J = 17.7 Hz, 1H), 3.96 (dd, J = 1.0, 11.5 Hz,
1H) 1.92-2.11 (m, 5H), 1.54 (s, 3H), 1.48 (s, 3H), 1.24 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 212.3, 143.0, 139.9, 133.4, 125.2, 122.4, 120.7,
112.7, 112.6, 108.6, 108.2, 51.6, 50.3, 44.4, 38.0, 37.1, 24.7, 24.6, 23.0, 21.3, HRMS
+ (m/z): [M+H] calcd for C20H24NO, 294.1852; found, 294.1847.
Compound 66: A flame dried 20 mL Biotage microwave vessel was charged with dry
NH4OAc (750 mg, 9.7 mmol, 40.0 equiv.), NaCNBH3 (115 mg, 1.83 mmol, 9.3 equiv) and dry MeOH (10 mL) under a dry nitrogen atmosphere. Compound 48 (57.9 mg, 0.20 mmol, 1.0 equiv.) in THF (1 mL) was added to the MeOH solution and the mixture was exposed to microwave irradiation at 150 °C for 2.5 minutes [Caution: high pressures and
65 toxic gases are formed]. Upon cooling and venting the gases in a well-ventilated fume hood, the contents from 10 of these runs were combined, diluted with EtOAc (200 mL), poured into 1N NaOH (250 mL), and the aqueous layer was thoroughly extracted with
EtOAc (100 mL, 5X). The combined organic layers were washed with 1N NaOH (500 mL, 2X) and dried (Na2SO4). The solvent was removed in vacuo and the crude amine was passed through a short plug of silica gel eluting with a gradient from 1:1
EtOAc:hexanes to pure EtOAc to give a solid (430 mg) which was dissolved in DCM (20 mL). The following compounds were added sequentially to the mixture: formic acid (0.11 mL, 2.9 mmol, 2.0 equiv.), 2-chloro-4,6-dimethoxy-1,3,5-triazine (565 mg, 3.22 mmol,
2.2 equiv.), 4-dimethylamino pyridine (10 mg, 0.08 mmol, 0.056 equiv.), and N-methyl morpholine (0.36 mL, 3.28 mmol, 2.2 equiv.). The resulting slurry was stirred at room temperature for 2 h, diluted with DCM (100 mL), and poured into saturated NaHCO3
(150 mL). The aqueous layer was thoroughly extracted with CH2Cl2 (100 mL, 5X). The combined organic layers were washed with 1N HCl (500 mL, 2X), brine (500 mL, 2X), and dried (Na2SO4). The solvent was removed in vacuo to give a solid which was purified by flash column chromatography (silica gel, gradient from 2:1 to 4:1 Et2O:hexanes) to give the title compound (411 mg, 64 %, mixture of E and Z isomers) as a white solid;
–3 m.p.: > 250 ºC; TLC (Et2O): RF = 0.37; [α]D = –79.7 (c = 0.77 g cm in DCM:MeOH 2:1
-1 1 v/v); IR (film) νmax = 3402, 2961, 1672, 1517, 1393, 1100, 906, 769, 734, 581 cm ; H
NMR (600 MHz, CDCl3) δ 8.16 (bs, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.15 – 7.17 (m, 2H),
7.02 (dd, J = 1.8, 6.1 Hz, 1H) 6.96 (t, 1.86 Hz, 1H), 5.98 (dd, J = 10.9, 17.5 Hz, 1H), 5.51
(d, J = 10.7 Hz, 1H), 5.01 (dd, J = 1.0, 10.9 Hz, 1H), 4.98 (dd, J = 1.0, 17.5 Hz, 1H), 4.75
(dd, J = 3.4, 10.9 Hz, 1H), 3.42 (ddd, J = 1.4, 3.5, 12 Hz, 1H), 1.96 – 1.98 (m, 1H), 1.62
66 13 1.74 (m, 4H), 1.50 (s, 3H), 1.32 (s, 3H), 1.15 (s, 3H); C NMR (150 MHz, CDCl3) δ
161.4, 146.8, 140.6, 133.9, 125.5, 122.6, 117.3, 112.9, 112.6, 111.4, 108.3, 52.3, 44.7,
+ 40.1, 37.4, 33.6, 30.1, 24.9, 24.5, 23.6, 21.2; HRMS (m/z): [M+H] calcd for C21H27N2O,
323.2118; found, 323.2115.
Compound 11 (hapalindole U): A flame-dried flask was charged with formamide 66
(315 mg, 0.98 mmol, 1.0 equiv.) under an atmosphere of dry nitrogen. DCM (60 mL) and TEA (2.4 ml, 17.2 mmol, 17.6 equiv.) were added, and the mixture was cooled to 0
°C. Phosgene (20 wt% solution in toluene) was carefully added drop-wise until TLC analysis showed complete consumption of starting material [Note: Phosgene is highly toxic and this reaction should be performed with caution in a well ventilated fume hood].
The reaction was quenched at 0 °C by the drop-wise addition of saturated NaHCO3 (50 mL) and warmed to room temperature. The reaction mixture was thoroughly extracted with DCM (75 mL, 5X). The combined organic layers were washed with saturated
NaHCO3 (400 mL, 2X), brine (400 mL, 2X), and dried (Na2SO4). The solvent was removed in vacuo and the crude material purified by flash column chromatography (silica gel, gradient from 3:1 to 2:1 hexanes:Et2O) to give the title compound as a white solid
(277 mg, 93%). Crystallization from hexanes/Et2O/MeOH yielded white needles of suitable quality for X-Ray diffraction (CCDC# 623050, See Figure S2); m.p.: = 241 ºC
–3 (decomposition); TLC (hexanes:Et2O 1:1 v/v): RF = 0.32; [α]D = –2.0 (c = 0.6 g cm in
1 DCM); IR (film) νmax = 3378, 2962, 2142, 1602, 1437, 1334, 1173, 914, 771; H NMR
(600 MHz, CDCl3) δ 8.00 (bs, 1H), 7.18 – 7.19 (m, 2H), 7.03 – 7.04 (m, 1H), 6.90 (bt,
1H), 6.05 (dd, J = 10.92, 17.5 Hz, 1H), 5.19 (d, J = 10.9 Hz, 1H), 5.18 (d, J = 17.4 Hz,
1H), 4.10 (bd, 1H), 3.27 – 3.28 (m, 1H), 1.90 – 2.03 (m, 3H), 1.59 – 1.68 (m, 2H), 1.50
67 13 (s, 3H), 1.28 (s, 3H), 1.15 (s, 3H); C NMR (150 MHz, CDCl3) δ 156.4, 145.4, 140.9,
134.1, 125.6, 123.0, 116.3, 113.3, 112.9, 112.8, 108.2, 63.4, 43.4, 39.3, 37.1, 33.7, 30.0,
+ 25.2, 24.4, 21.6, 21.0; HRMS (m/z): [M+H] calcd for C21H24NaN2, 327.1832; found,
327.1846.
Compounds 58 and 68: compound 48 (29 mg, 0.10 mmol, 1 equiv.) was azeotropically dried with benzene and the residual solvent removed under high vacuum. THF (2.0 ml) and Et3N (16.5 µl, 0.12 mmol, 1.2 equiv.) were added and the mixture cooled to –78°C.
Freshly prepared t-BuOCl (13.5 µl, 0.12 mmol, 1.2 equiv.) was added to the cooled solution. After 25 minutes, Prenyl 9-BBN (1.0 M solution in THF, 0.20 ml, 2.0 equiv.) was added slowly dropwise over the course of 5 minutes to the solution at –78°C. The reaction color turned bright orange. The reaction mixture was stirred for 45 minutes at
–78°C then warmed to room temperature and immediately partitioned between 1N NaOH
(5 ml) and EtOAc (5ml). The reaction mixture was thoroughly extracted with EtOAc (5 ml, 5X). The combined organic layers were washed with 1N NaOH (25 ml, 2X), 1N HCl
(25 ml), brine (25 ml), and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by preparative thin-layer silica gel chromatography (5:1 hexanes:Et2O) to give compound 58 (9.3 mg) and 68 (7.0 mg) as white solids, overall yield = 45%. Compound 68 could be recrystallized from EtOAc to yield colorless needles suitable for X-ray diffraction; m.p.: = 162 – 165 ºC (decomposition); TLC (hexanes:Et2O
–3 2:1 v/v): RF = 0.30; [α]D = –7.6 (c = 4.6 g cm in CHCl3); IR (film) νmax = 3404, 2926,
-1 1 1707, 1464, 1362, 1011, 918, 862 cm ; H NMR (600 MHz, CDCl3) δ 7.98 (bs, 1 H),
7.43 (s, 1 H), 7.18 (s, 1 H), 7.04 (s, 1 H), 6.22 (dd, J = 6, 18 Hz, 1 H), 6.12 (dd, J = 6, 12
Hz, 1 H), 5.16 (d, J = 6 Hz, 1 H), 5.09 (d, J = 18 Hz, 2 H), 5.04 (d, J = 12 Hz, 1 H), 3.92
68 (d, J = 12 Hz, 1 H), 2.09 – 1.88 (m, 5 H), 1.52 (s, 3 H), 1.46 (s, 9 H), 1.22 (s, 3 H); 13C
NMR (150 MHz, CDCl3) δ 212.5, 149.2, 143.6, 143.2, 139.2, 133.5, 123.7, 120.6, 112.8,
112.1, 110.1, 108.6, 105.7, 51.9, 50.5, 44.6, 41.8, 38.4, 37.2, 29.1, 29.0, 24.8, 24.8 23.2,
+ 21.4; HRMS (m/z): [M+H] calcd for C25H32NO, 362.2478; found, 362.2478. Compound
1 58: H NMR (500 MHz, (CD3)2CO) δ 9.70 (bs, 1 H), 7.06 (d, J = 5 Hz, 1 H), 6.96 (t, J =
5 Hz, 1 H), 6.88 (d, J = 5 Hz, 1 H), 6.30 (dd, J = 15, 20 Hz, 1 H), 6.15 (dd, J = 10, 15 Hz,
1 H), 5.10 – 5.02 (m, 4 H), 4.42 (d, J = 15 Hz, 1 H), 1.97 – 2.12 (m, 3 H), 1.73 – 1.82 (m,
2 H), 1.57 (s, 3 H), 1.51 (s, 3 H), 1.48 (s, 3 H), 1.47 (s, 3 H), 1.09 (s, 3 H).
Compound 78: Hapalindole U (11) (6.0 mg, 0.02 mmol, 1 equiv.) was azeotropically dried with benzene and the residual solvent removed under high vacuum. DMF (0.50 ml) was added and the reaction cooled to 0°C. NaH (60% dispersion in mineral oil, 2.0 mg,
0.05 mmol, 2.5 equiv.) was added at which point the mixture became bright yellow. The solution was stirred for 15 minutes at 0°C, then prenyl bromide (10 µl, 0.09 mmol, 4.4 equiv.) was added and the solution became clear. After stirring for 7 minutes at 0°C, the reaction was quenched with 1N HCl (1 ml). The mixture was partitioned between saturated aqueous ammonium chloride (5 ml) and Et2O (2 ml) and the aqueous layer was extracted with Et2O (5 ml, 2X). The combined organic layers were washed with brine (10 ml), and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by preparative thin-layer silica gel chromatography (3:1 hexanes:Et2O) to give title compound 78 (5.5 mg, 75%) as a white solid; m.p.: = 115 ºC; TLC (hexanes:Et2O
–3 4:1 v/v): RF = 0.41; [α]D = +184 (c = 4.7 g cm in CHCl3); IR (film) νmax = 2928, 2137,
-1 1 1608, 1455, 1363, 1319, 1279, 1165, 1039, 918, 780 cm ; H NMR (600 MHz, CDCl3)
δ 7.17 (t, J = 12 Hz, 1 H), 7.11 (d, J = 12 Hz, 1 H), 7.0 (d, J = 12 Hz, 1 H), 6.8 (s, 1 H),
69 6.05 (dd, J = 12, 18 Hz, 1 H), 5.4 (t, J = 6 Hz, 1 H), 5.18 (d, J = 12 Hz, 1 H), 5.17 (d, J =
18 Hz, 1 H), 4.67 (d, J = 6 Hz, 2 H), 4.07 (s, 1 H), 3.27 (d, J = 6 Hz, 1 H), 2.02 – 1.88 (m,
3 H), 1.82 (s, 3 H), 1.76 (s, 3 H), 1.65 – 1.58 (m, 2 H), 1.49 (s, 3 H), 1.26 (s, 3 H), 1.14
13 (s, 3 H); C NMR (150 MHz, CDCl3) δ 155.5, 145.7, 141.1, 136.2, 134.6, 126.3, 122.5,
120.5, 119.7, 113.4, 112.5, 111.5, 107.0, 63.5, 44.5, 43.6, 39.4, 37.3, 33.9, 30.2, 25.8,
+ 25.4, 24.6, 24.6, 21.7, 21.1, 18.2; HRMS (m/z): [M+H] calcd for C26H33N2, 373.2638; found, 373.2635.
Compound 85: Hapalindole U (11) (100.0 mg, 0.33 mmol, 1.0 equiv.) was azeotropically dried with benzene (2X) and the residual solvent removed under high vacuum. DCM (5.0 mL) was added, and the solution was cooled to –78 °C under an argon atmosphere. Freshly prepared tert-butyl hypochlorite (43 µL, 0.38 mmol, 1.2 equiv.) was added drop-wise and the solution was stirred at – 78 °C for 12 minutes.
Freshly prepared prenyl 9-BBN (1.12 M solution in DCM, 600 µL, 0.672 mmol, 2.0 equiv) was slowly added drop-wise down the flask walls over the course of 5 minutes.
Stirring was continued for 40 minutes at –78 °C before the reaction was quenched at low temperature by quickly transferring the contents of the flask to a small plug of silica gel and eluting with EtOAc. The solvent was removed in vacuo and the crude material purified by flash column chromatography (silica gel, 20:1 hexanes:Et2O) to give the title compound (104 mg, 60%) as a white solid. Crystallization from Et2O/DCM yielded clear plates of suitable quality for X-Ray diffraction (CCDC# 623051). m.p.: = 244 ºC
–3 (decomposition); TLC (hexanes:Et2O 7:1 v/v): RF = 0.48; [α]D = +46.8 (c = 1.8 g cm in
-1 1 DCM); IR (film) νmax = 2927, 1596, 1452, 1405, 1340, 1006, 910 cm ; H NMR (500
MHz, CDCl3) δ 7.19 (t, J = 7.8 Hz, 1 H), 6.96 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.7 Hz,
70 1H), 6.33 (dd, J = 10.9, 17.7 Hz, 1 H), 5.73 (dd, J = 10.7, 17.4 Hz, 1 H), 5.14 (dd, J =
1.3, 10.9 Hz, 1 H), 5.11 (dd, J = 1.3, 17.6 Hz, 1 H), 5.00 (dd, J = 1.0, 17.5 Hz, 1 H), 4.96
(dd, J = 1.0, 10.7 Hz, 1 H), 4.10 (s, 1 H), 3.81 (d, J = 2.1 Hz, 1 H), 2.87 (dd, J = 3.5, 11.4
Hz, 1 H), 1.87 – 2.05 (m, 9H), 1.64 – 1.79 (m, 5H), 1.42 – 1.57 (m, 5H), 1.34 (s, 3 H),
13 1.14 (s, 3 H), 1.04 (s, 3 H), 0.99 (s, 3 H), 0.60 (s, 3 H); C NMR (150 MHz, CDCl3) δ
168.1, 150.3, 147.2, 145.8, 145.5, 129.3, 129.1, 119.8, 115.3, 112.2, 111.4, 75.9, 66.7,
44.3, 42.0, 41.2, 38.9, 36.0, 33.6, 33.5, 33.4, 33.3, 32.9, 30.2, 28.0, 27.6, 26.0, 24.6, 24.3,
+ 23.2, 22.9, 21.8, 21.1, 20.7; HRMS (m/z): [M+H] calcd for C34H47BClN2, 529.3515; found, 529.3526.
Compound 14 (ambiguine H): Compound 85 (22.5 mg, 0.04 mmol, 1.0 equiv.) was dissolved in degassed benzene (2.3 mL) and freshly distilled and degassed TEA (30 µL) was added in a 5-mL Biotage microwave vessel. The mixture was sealed under an atmosphere of argon and irradiated for 5 hours, at which point the solvent was decanted
(to remove the highly crystalline Et3NHCl that is formed). The crude material was purified by preparative thin layer chromatography to give recovered starting material (8.2 mg) along with ambiguine H (14) (6.5 mg, 63% BRSM) as a white solid. [Note: the reaction cannot be run to full conversion, since the product itself is photoreactive].
Crystallization from hexanes/Et2O yielded off-white plates suitable for X-Ray diffraction
(CCDC# 623052). [Note: under similar experimental conditions, de-boronated product 87 cleanly forms ambiguine H in ~75% isolated yield in 2.5 h]; m.p.: = 228–231 ºC; TLC
–3 (hexanes:Et2O 1:1 v/v): RF = 0.57; [α]D = +20.0 (c = 0.18 g cm in DCM); IR (film) νmax
-1 1 = 3345, 2923, 2362, 2134, 1636, 1444, 1327, 998, 915 cm ; H NMR (600 MHz, CDCl3)
δ 7.98 (bs, 1H), 7.09 – 7.13 (m, 2 H), 6.98 (d, J = 6.5 Hz, 1 H), 6.21 (dd, J = 10.6, 17.5
71 Hz, 1 H), 5.93 (dd, J = 10.9, 17.5 Hz, 1 H), 5.25 (d, J = 17.5 Hz, 1 H), 5.19 (d, J = 10.6
Hz, 1 H), 5.14 (d, J = 10.9 Hz, 1 H), 5.11 (d, J = 17.5 Hz, 1 H), 4.49 (s, 1 H), 3.16 – 3.18
(m, 1 H), 1.90 – 2.10 (m, 3 H), 1.50 – 1.60 (m, 2H), 1.58 (s, 3 H), 1.52 (s, 3 H), 1.50 (s, 3
13 H), 1.23 (s, 3 H), 1.02 (s, 3H); C NMR (150MHz,CDCl3)
δ 146.3, 145.8, 140.6, 136.7, 132.17, 127.3, 122.0 113.0, 112.9, 112.4, 107.5, 106.7, 65.1
,43.9, 39.9, 38.7, 36.3, 34.8, 30.6, 29.7, 29.2, 27.8, 24.9, 24.0, 21.71, 21.68; HRMS (m/z):
+ [M+H] calcd for C26H33N2, 373.2638; found, 373.2636. Compound 94: white solid, TLC
–3 (hexanes:Et2O 2:1 v/v): RF = 0.25; [α]D = –10.0 (c = 1.0 g cm in DCM); IR (film) νmax
= 3411, 2967, 2844, 2136, 1454, 1346, 1054, 1033, 1012, 911 cm-1; 1H NMR (600 MHz,
CDCl3) δ 7.92 (bs, 1H), 7.18 (d, J = 1 Hz, 1 H), 7.06 (d, J = 1 Hz, 1 H), 6.86 (t, J = 2 Hz,
1 H), 6.12 (dd, J = 12, 18 Hz, 1 H), 6.04 (dd, J = 12, 18 Hz, 1 H), 5.19 (d, J = 6 Hz, 1 H),
5.17 (d, J = 12 Hz, 1 H), 5.10 (dd, J = 1, 18 Hz, 1 H), 5.05 (dd, J = 1, 12 Hz, 1 H), 4.08
(s, 1 H), 3.25 (d, J = 6 Hz, 1 H), 2.01 – 1.88 (m, 4 H), 1.66 – 1.60 (m, 1 H), 1.48 (s, 3 H),
13 1.47 (s, 6 H), 1.27 (s, 3 H), 1.14 (s, 3 H); C NMR (150MHz,CDCl3) δ 156.6, 149.1,
145.6, 144.2, 140.2, 134.2, 124.0, 116.2, 113.4, 112.7, 112.2, 110.2, 105.7, 63.5, 43.8,
41.9, 39.4, 37.5, 33.9, 30.2, 29.0, 29.0, 25.4, 24.5, 21.7, 21.1; HRMS (m/z): [M+H]+ calcd for C26H33N2, 373.2638; found, 373.2634.
Compound 87: Hapalindole U (11) (10 mg, 0.03 mmol, 1.0 equiv.) was azeotropically dried with benzene and the residual solvent removed under high vacuum. DCM (0.6 mL) was added, and the solution was cooled to –78 °C under an argon atmosphere. Freshly prepared tert-butyl hypochlorite (4.5 µL, 0.04 mmol, 1.2 equiv.) was added drop-wise and the solution was stirred at – 78 °C for 15 minutes. Freshly prepared prenyl magnesium chloride (0.75 M solution in THF, 90 µL, 0.07 mmol, 2.1 equiv) was slowly
72 added drop-wise down the flask walls over the course of 2 minutes. Stirring was continued for 25 minutes at –78 °C before the reaction was warmed to 0°C and quickly transferred to a small plug of silica gel and eluted with EtOAc. The solvent was removed in vacuo and the crude material purified by preparative thin-layer silica gel chromatography (1:1 hexanes:Et2O) to give the title compound (5.3 mg, 40%) as an oil that slowly solidified to a white solid; TLC (hexanes:Et2O 1:1 v/v): RF = 0.50; [α]D =
–3 +144 (c = 4.6 g cm in CHCl3); IR (film) νmax = 3378, 2967, 2933, 1601, 1455, 1414,
-1 1 1363, 1246, 1098, 1064, 1013, 912, 788, 743 cm ; H NMR (600 MHz, CDCl3) δ 7.09 (t,
J = 6 Hz, 1 H), 6.69 (d, J = 6 Hz, 1 H), 6.46 (d, J = 6 Hz, 1 H), 6.33 (dd, J = 12, 18 Hz, 1
H), 5.72 (dd, J = 6, 12 Hz, 1 H), 5.13 – 5.01 (m, 4 H), 4.03 (bs, 1 H), 3.84 (d, J = 2 Hz, 1
H), 3.42 (s, 1 H), 2.86 (dd, J = 6, 12 Hz, 1 H), 1.76 1.73 (m, 1 H), 1.70 – 1.65 (m, 1 H),
1.58 – 1.52 (m, 2 H), 1.39 – 1.34 (m, 1 H), 1.32 (s, 3 H), 1.16 (s, 3 H), 1.00 (s, 3 H), 0.87
13 (s, 6 H); C NMR (150 MHz, CDCl3) δ 169.1, 151.9, 147.2, 145.5, 145.3, 129.9, 122.1,
115.1, 113.3, 111.5, 105.7, 76.7, 75.2, 67.3, 45.1, 42.5, 41.6, 39.1, 36.1, 34.2, 26.8, 24.9,
+ 24.1, 23.4, 22.5, 21.0; HRMS (m/z): [M+H] calcd. for C26H34ClN2, 409.2405; found,
409.2402.
73 1.8 Appendix to Chapter 1: Spectra
74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 Chapter 2
Progress Towards the Total
Synthesis of Vinigrol
137 2.1. Isolation, biosynthesis, and background
In 1987 Ando and co-workers isolated the unusual diterpene vinigrol (1) from the fungal strain Virginia nigra F-5408.1 Initial biological screens found that vinigrol possesses both antihypertensive and platelet aggregation-inhibitory properties; it is believed that vinigrol acts as a Ca+2 agonist, although more studies are required to define its mode of action on calcium channels.2,3 More recent studies have identified vinigrol as a tumor necrosis factor (TNF) antagonist.4 In addition, 1 has also been shown to be effective in the treatment of HIV5 and inflammation.6 Finally, there has been interest in vinigrol as a nerve stem cell proliferation promoter.7 The promising biologically properties of 1 combined with its unique terpene framework has attracted significant attention from the synthetic community. From a chemical standpoint, vinigrol provides a particularly difficult challenge, as it is the only natural product to contain the decahydro-
1,5-butanonaphthalene carbon skeleton (figure 2.1).
Me OH OH H H Me OH Me Me H vinigrol (1) 1,5-butanonaphthalene skeleton (2)
Figure 2.1. Vinigrol: the only known 1,5-butanonaphthalene natural product.
Corey and Goodman have proposed that this unusual diterpene framework may arise from a phenolic radical-based cyclization (figure 2.2).8 In particular phenol oxidation leading to radical 4, which is in resonance with structure 5, could cyclize with its own terminal olefin leading to radical 6. The starting phenolic coupling precursor 4, appears
138 Me Me Me Me Me Me O Me O H H O H Me H Me Me Me vinigrol
Me Me Me Me H Me erogorgiaene (3) 4 5 6
Figure 2.2. Corey and Goodman's radical-based biosynthetic proposal for the origins of the vinigrol skeleton. closely related to the known erogorgiaene family of terpenes.9 Even more convincing support to this biosynthetic proposal comes in the form of several diterpene families isolated after Corey’s initial proposal (Figure 2.3). In particular, the colombiasin10 (9), cumbiasin11 (7), and elisapterosin12 (10) family of terpenes all appear to arise from dearomatization/cycloaddition cascades of oxidized aromatic terpenes related to erogorgiaene as well as the well-known pseudopterosins13 (8). Interestingly, many of these compounds have even succumbed to biomimetic total syntheses along these lines.14-
20 A biomimetic vinigrol synthesis along these lines, however, may be the most challenging in the group to simulate in the synthetic laboratory due to the unusual conformation the terminal carbon chain would have to adopt, as well as the facile propensity of phenolic radicals to undergo para-para C-C coupling. Although 1 is relatively small in size (molecular weight < 325 Daltons), the presence of eight contiguous stereocenters and multiple sites of oxygenation makes it a particularly challenging synthetic problem. Despite significant efforts from the Paquette,21-24 Corey,8
Barriault,25-28 Hanna,29-32 Mehta,33 Matsuda,34-36 Fallis,37 and Njardarson38,39 groups, no total synthesis of vinigrol has been reported to date. One of the key synthetic challenges to date has been the construction of the vinigrol carbon framework. Elegant studies by the
Paquette group have vividly demonstrated the difficulty in forming the bridging 8-
139 membered ring of vinigrol from a pre-existing cis-decalin framework (see 12 to 13) utilizing a variety of approaches (Figure 2.4).21-24
Me Me Me H Me OH OH Me OH H H H Me Me
OH Me HO Me Me Me Me H Me H
vinigrol (1) erogorgiaene (3) bis-7-hydroxyerogorgiaene (7)
Me Me Me H Me Me Me Me Me Me O H O H O H Me Me Me Me Me OH OH O OH OH OH Me O Me OH Me O Me OH
pseudopterosin A colombiasin A (9) elisapterosin B (10) cumbiasin B (11) aglycon (8)
vinigrol "parent cumbianes skeleton"
pseudoterosins colombiasins elisapterosins
Figure 2.3. Vinigrol, related diterpenes, and likely biosynthetic ring closures.
140 R Me R H Me Me H Me H ΔE ~ 12.5 H Me R H (kcal/mole) R H H H H H Me H H Me Me Me Me Me Me O H O Me Me Me Me Me Me H Me H Me H H H 15 12 13 14 Figure 2.4. Vinigrol conformational conundrum and calculations by Paquette and co-workers.
Indeed, calculations by the Paquette lab on related model compound 14 point to a largely unfavorable equilibrium between two conformers (14 and 15, Δ E ~ 12.5 kcal/mol), with the major conformer (14) lacking the proximity needed for ring closure.
Chapter 2 of this thesis delineates progress in this area which has achieved syntheses of several advanced intermediates which may hold the key to synthesizing this interesting natural product.
141 2.2 Retrosynthesis of vinigrol
The vinigrol molecule can be depicted from several viewpoints (Figure 2.5).
Since it was known from the outset that direct construction of the vinigrol ring system would be difficult, I considered the construction of a simpler ring system that could perhaps fragment to desired 1,5-butanonaphthalene skeleton (Figure 2.6). Owing to the
Me Me Me H OH Me HO Me Me HO H H Me OH H OH HO HO Me Me H OH OH Me OH HO H H Me OH H H H Me Me Me Me Me
decalin "taxol-like" Figure 2.5. Views of vinigrol.
Me Me Me Me H OH 11 Me H 4 Me Me OH Me
OH Me Me H difficult easier easier
Figure 2.6. Retrosynthetic analysis of the vingrol skeleton: skeletal simplification. unusually close proximity of C-4 and C-11 in molecular models, a bicyclo [2.2.2] octane seemed like a likely candidate and two retrosynthetic disconnections were made. My first strategy involved targeting compound 16 as a suitable precursor to vinigrol and unveiling the vinigrol core using the venerable Grob-fragmentation (see 16 to 17), a reaction that
142 Me OMs OH Me Me Me H H O Grob Me H Me manipulations fragmentation H OH H Me Me H OR
OH Me Me H OH H Me 18 H 16 17
intramolecular Diels-Alder
O OH O Me Me M Me Me endo selective Me Me OR Diels-Alder OR OR Me organometallic H addition H 21 20 19 Figure 2.7. Vinigrol retrosynthesis I: Grob-/Intramolecular Diels-Alder strategy. has seen widespread use in terpene synthesis.40 It should be mentioned that Corey and
Goodman also sought to utilize this disconnection, but were unsuccessful in synthesizing their precursor.8 Compound 17 can be traced back to compound 18 via olefin manipulations. It seemed likely that compound 18 might be available via an intramolecular Diels-Alder reaction leading back to compound 19 which can be viewed as the product of an organometallic addition to aldehyde 20. Aldehyde 20 was envisioned to arise from an endo selective Diels-Alder reaction of diene 21 with a simple unsaturated aldehyde. The beauty of this approach is that only the preference of the Diels-Alder reaction to proceed is needed to set nearly all of the 8-contiguous stereocenters in vinigrol. Our second retrosynthetic plan utilized the anionic oxy-Cope rearrangement to forge the vinigrol core (Figure 2.8). Cope precursor 22 could be derived from compound
23 via simple manipulations. triol 23 could potentially be accessed from epoxide 24, via site-selective epoxide elimination with the primary alcohol potentially acting as an
143 Me Me Me Me HO anionic Me H H O Me manipulations OR oxy-cope O Me Me OH H OH Me Me OH H Me H 23 16 22 site-selective epoxide rupture
O Me Me OR OR CO2Me HO MeO Me Me manipulations OR 6-π OR
endo selective O Diels-Alder Me H Me Me Me H 27 26 25 24 Figure 2.8. Vinigrol retrosynthesis II: oxy-Cope/Diels-Alder strategy. internal base when deprotonated. Epoxide 24 can be traced back to tricycle 25 via standard oxidation state manipulations. Compound 25 was thought to be available via the endo Diels-Alder reaction of a simple unsaturated ester with diene 26. Diene 26 could potentially arise from a 6π electrocyclization of triene 27.
144 2.3. Rapid Construction of the Vinigrol Core.
Our initial synthetic attempts closely paralleled our first retrosynthetic analysis and we were easily able to construct the vinigrol core in a fairly concise, high-yielding fashion (Scheme 2.1).41 Thus, commercially available methyl 4-methyl-2-pentenoate and
1,3-disiloxycyclohexadiene 28 smoothly participated in an endo-selective Diels-Alder reaction to produce bicyclic ketone 29 in 65% yield (unoptimized, dr = 2:1).42 Triflation
OMgCl Me Me Me O MeO2C MeO2C OTBS a. LDA, a. DIBAL, DMP Me Me Me MeO AlCl3 then Tf2O 80 % OTBS OTBS OTBS b. Me 65 % b. Pd(PPh ) , 3 4 MgCl (~ 2:1 dr) O H LiCl, Δ TBSO Me H H Bu Sn 28 29 3 30 31 (77%) Δ
OMs OH OMgCl H H Me Me H O Me a. DMP KHMDS H H Me H Me TBAF H Me H OH H Me OH OTBS 0°C b. DIBAL, Δ Me 92% MsCl (75%) H H (79%) H H 35 34 33 32
m-CPBA (dr ~ 2.5:1) a. DMP H+ 87% b. DIBAL (81%) (87%)
H H O
Me
O Me H 36
Scheme 2.1. Synthesis of the vinigrol core structure. 37 38 of 29 and subsequent Stille Coupling formed requisite diene 30 in excellent yield.43 After an oxidation state adjustment, allyl magnesium bromide was added to the corresponding aldehyde, producing an intermediate alkoxide 31 which was directly heated to 105°C for
90 mins followed by treatment of intermediate 32 with TBAF to furnish tetracycle 33 in
75% overall yield. The structure of 33 and all previous intermediates were confirmed unequivically by X-ray crystallographic analysis of alcohol 38. Although the olefinic units of 31 are not electronically matched for a Diels-Alder reaction, it was anticipated
145 that a strong proximity effect would encourage bond formation to occur. Remarkably, as shown in Figure 2.9, this reaction even takes place at room temperature over the course of two weeks.
OH OH Me DCM Me Me or OTBS H H Me NEAT OTBS rt 2 weeks H quantitative H 39 38 Figure 2.9. A remarkable proximity-induced spontaneous Diels-Alder reaction.
Since alcohol 33 does not possess the correct anti-periplanar atomic arrangement required for Grob fragmentation, it was inverted by oxidation/reduction followed by mesylation to provide 34. The stereochemistry of the intermediate alcohol (37) was verified by X-ray crystallography. Deprotonation of 34 with KHMDS smoothly afforded the vinigrol core structure in high yield (93%). It should be noted that the conditions required are unusually mild for this type of bond cleavage. It is likely that strict enforcement of orbital alignment by the rigid bicyclic system greatly facilitates this process. A high-yielding chemo- and stereoselective epoxidation of the less hindered trisubstituted olefin in 34 completed the synthesis of 35, as confirmed by X-ray crystallography.
146 2.4 Synthesis of the full vinigrol carbon skeleton.
With a rapid route to the vinigrol core, we next turned our attention to installing the remaining two methyl groups as well as tertiary alcohol moiety. It should be noted that the cis arrangement of the methyl and tertiary alcohol groups pose a synthetic challenge because the methyl group cannot arise from the simple hydrogenation of an exocyclic olefin. This is due to the likelihood that reagent attack from the less hindered
(and wrong) diastereoface would predominate. I had hoped to be able to open the epoxide in compound 36 with either a one-carbon unit or halogen atom that could be elaborated into the methyl group with the desired stereochemistry. Unfortunately, direct nucleophilic opening of the epoxide in 36 was not possible with either cyanide nucleophiles or bromide sources (Figure 2.10).
H NaCN H O H H O H O H H O H or base Me Me Me Me Et AlCN 2 Me O Me OH OH Me OH Me H CN H CN H Me H 36 40 41 16
H O H H H O H O Br H Me Me Me OH Me Me OH Me O Br H Me H H 36 42 16 Figure 2.10. Unsuccessful epoxide opening attempts.
I next decided to install the tertiary alcohol group separately and could easily do so using the venerable singlet oxygen ene reaction44 (see 43 → 44) (Scheme 2.2). The resulting olefin could then serve as a handle to install the methyl group. My first strategy involved a Simmons-Smith cyclopropanation followed by site-selective hydrogenation of the cyclopropane ring. Unfortunately, while I was able to form cyclopropane 46 from compound 44 in moderate yield, conditions for cyclopropane cleavage (PtO2, H2, 1500
147 O O O Me Me Me b. ClSi(Me)2CH2Br H Me c. AIBN, Bu SnH H H Me a. O H 3 OTBS H H Me 2 OTBS OTBS methylene blue H OH H O H 54% BRSM Si 45 43 44 Me Me d. CH2I2 Et2Zn 63% BRSM O O O Me Me Me e. H2. PtO2 H H Me Me f. Hg(O2CCF3) H H H H Me OTBS OTBS OTBS TFAO
H Me OH H Me OH OH H 47 46 48 Scheme 2.2. Failed routes to install the methyl group. psi) were unsuccessful in delivering 47. In addition, the Hg(II) mediated cyclopropane cleavage methodology of Still and Collum45 failed to produce 48. We next turned to a silicon-tethered radical cyclization strategy as pioneered by Stork (see 44 → 45).46 While attachment of the silicon tether group was feasible, I was never able to cleanly form the desired C-C bond; only halogen reduction was observed. My next strategy hinged on a
47 ketyl-radical olefin cyclization (Scheme 2.3). Ozonolysis of 49 (O3, then DMS) proceeded smoothly to deliver aldehyde 50. While I was able to successfully olefinate 50 via the Wittig homologation (CH2PPh3), subjecting this compound to SmI2 resulted in no observable cyclization. A carbenoid C-H insertion route was also pursued (scheme 2.3).48
Thus, tertiary alcohol 52 was prepared according to the cobalt-mediated hydration
49 methods of Mukaiyama (Co(acac)2, PhSiH3, O2) in excellent yield (85%). Malonate ester attachment (HO2CCH2CO2Me, EDC, DMAP), diazo-transfer (p-ABSA, DBU), and rhodium-catalyzed carbenoid insertion (Rh2(OAc)4, PhH, Δ) afforded lactone 53. Despite
148 OH OH OH Me Me Me b. PPh3 Me Me Me H Me c. SmI H H Me H Me H 2 H a. O3, DMS OH OH OH 72% HMPA O H t-BuOH OH H H O Me 49 50 51
O O O O O Me Me Me a. HO OMe a. Co(acac) EDC, DMAP H H Me Me H H Me OTBS H H PhSiH OTBS 3 OTBS b. p-ABSA, DBU O c. Rh (OAc) 2 2 4 O H H MeO H 85% OH 56% O O 53 43 52 could not be elaborated to a Scheme 2.3. Failed stratagies toward methyl group installation. methyl group. several strategies, I was never able to realize the transformation of this lactone ring into the needed methyl group. I finally discovered that the key methyl group could be installed using a dipolar cycloaddition of a bromonitrile oxide50 (generated in situ from dibromofolmadoxime and KHCO3) and can be seen in our eventual route to the entire vinigrol skeleton (Scheme 2.4). Thus treatment of ketone 43 (from our original model study) with LDA and MeI cleanly afforded the upper methyl group as a single diastereomer in high yield. TBS removal and directed reduction according to the procedure of Evans51 furnished Diol 49. It should be noted that non-directed reductions
(i.e DIBAL) afforded mainly the wrong alcohol diastereomer due to the presence of the newly formed methyl group. Mesylation of 49 according to our model study conditions
(MsCl, Et3N, DCM) afforded mixtures of secondary and tertiary mesylates, however conducting the reaction in neat pyridine with MsCl smoothly mesylated only the desired secondary alcohol in high yield. Subsequent Grob fragmentation again proceeded smoothly and furnished bromoisoxazole 54 after the aforementioned [3+2] dipolar
149 O OH Me Me H Me a. LDA, Me H O e. MsCl, pyr. H H H Me MeI H H Me OTBS OH Me b. TBAF f. KHMDS c. Me4NBH(OAc)3 g. Br OH Me H O H N H 72% Br N 43 Br 49 54 KHCO3 75% Me Me H H j. i. NaH H OH ii. CS2 H Me iii. MeI Me h. DIBAL Me O k. Δ, 180°C i. Crabtree's H Me Br O N 85% H cat., Br N 56 B(O-iPr)3 55 83% l. i. LiAlH4 m. COCl2, ii. HCO2H, Et3N X-ray CDMT, 62% NMM, DMAP Me Me Me Me Me n. AIBN, p. H OMe Zn, Me H Bu3SnH H H N NH4Cl OH Me o. OH H H Br 92% CN N H Br H OH Me Br Me OH Me OH H CN 57 KHCO3 58 59 76% Scheme 2.4. Synthesis of the full vinigrol carbon skeleton with all stereocenters. cycloaddition.50 It is worth noting that this cycloaddtion occurs with both complete control over regio-and positional selectivity in nearly quantitative yield. Ketone reduction
(DIBAL) followed by olefin hydrogenation (20% Crabtree’s catalyst, B(O-iPr)3, DCE,
80°C) furnished compound 55.52 It should be noted that olefin hydrogenation was very difficult due to the methyl and isopropyl groups which flank the di-substituted olefin on the face which most hydrogenations would be expected to occur from. I attempted this hydrogenation on nearly all of our synthetic
150 Conditions (PPh3)3RhCl, DCM Me Me Me Me Pd/C, EtOAc Me Me Pd/C, EtOH H O H O "H2" Ra-Ni, EtOH H H Ra-Ni, AcOH:H2O Ra-Ni, NaH2PO2 Br O H H Br O PtO2, AcOH, 500 psi N N NH2NH2, EtOH TsNHNH2, EtOH Crabtree's cat, DCM Conditions Me Me Pd/C, EtOH Me Me Me Me Pd/C, MeOH "H2" H O H O PtO2, EtOH H H Rh/Al2O3, EtOH TsNHNH2, EtOH H Me OH H Me OH NH2NH2 (KO2CN)2, AcOH Crabtree's cat., DCM
Conditions Me Me Me Me Pd/C, EtOH Me "H2" Me Pt/C, Cyclohexane H H OH OH Rh/Al O H 2 3 H Crabtree's cat, DCM NiCl2/LiAlH4 OH H Me OH H Me CoCl2/NaBH4 TsNHNH2 Figure 2.11. Hydrogenation woes. intermediates with a variety of conditions. A partial list of failures can be seen in figure
2.11. Suffice it to say, only one compound could be hydrogenated and only with one catalyst. Returning to the synthesis, xanthate formation (NaH, CS2, MeI), and subsequent
Chugaev elimination (Δ, 180°C) furnished olefin 56 in excellent yield.53 The bromoisoxazole group was then fully reduced with LiAlH4 and the resulting crude amine was formylated (HCO2H, CDMT, NMM, DMAP) and the resulting formamide dehydrated with phosgene to produce isonitrile 57. Subjecting 57 to Saegusa’s radical
54 deamination procedure (Bu3SnH, AIBN, PhH, Δ) and a second dipolar cycloaddition afforded compound 58. Cleavage of bromoisoxazole 58 (Zn, NH4Cl) furnished hydroxy nitrile 59, which possesses the entire vinigrol framework and stereogenicity.
At this point all that is needed to complete the total synthesis of vinigrol is oxidation state manipulations, mainly the conversion of the nitrile moeity into a
151 hydroxymethyl group, and installation of the lone olefin. Conditions for typical nitrile group reduction utilizing both metal hydride sources (DIBAL), as well as heterogeneous catalysts (Ra-Ni, Pd/C), failed to deliver any quantities of aldehyde 61 (Scheme 2.5). It was possible to cleanly reduce the nitrile to primary amine 60, but we were unable to find conditions for amine dehydrogenation to an imine (see 60 → 61).55,56 Direct dehydrogenation alpha to the nitrile (59 → 62) also failed under standard conditions
(LDA, then PhSeBr or Mukaiyama’s reagent57); this may be due to the difficulty in deprotonating this postion as it would form a trianionic species.
Me Me Me Me Me Me Me Me Me H OH H OH i. LDA H OH LiAlH4 H H H CN NH CN 2 80% ii. PhSeBr H H H Me OH Me OH or Me OH 60 Mukaiyama's Dibal 59 reagent 62 or Ra-Ni, H+ or IBX, then H+ Pd/C, H+ Me or Me Me Me t-BuOCl, DBU, then H= Me Me H OH H OH H CHO H or O NBS, DBU, then H= H H Me OH Me OH 61 63 Scheme 2.5. Unsuccessful attempts at unsaturation.
We next turned to targeting exocyclic olefin 64 in the hopes that it could be transformed into vinigrol via a singlet oxygen ene reaction (Scheme 2.6).44 To this end, I sought to prepare the olefin via either a Cope58 or Hofmann59 type elimination of the amine. Reductive amination of primary amine 60 (CH2O, STAB-H), smoothly formed tertiary amine 61.60 Treatment of this amine with either DMDO or m-CPBA at –78°C formed a new compound (believed to be N-oxide 62) however heating this compound
152 failed to produce any quantities of olefin 64. Quaternary ammonium salt formation (MeI) followed by counterion swap of iodide to hydroxide (Ag2O, H2O) furnished compound
63 from amine 61. Again, I was unable to detect any quantities of 64 from heating this compound.
At this juncture we decided that we needed to try to install the vinigrol olefin by more reliable means (i.e. unsaturation of a ketone). Although this method suffers from inelegant oxidation state fluctuations, I decided to try it (Scheme 2.5). Thus, oxidation of hydroxycyanide 59 with DMP and treatment of the resulting ketone (which exists in solution with its enol tautomer) with PhSeBr in pyridine afforded enone 65. It is interesting to note that a separate oxidation state with H2O2 was not needed,
Me Me Me Me Me a. CH2O, Me Me Me NaBH(OAc)3 Me H OH H OH b. DMDO MgSO4 Me H OH H H O NH N H 2 N H H Me Me OH Me OH H Me OH 60 61 c. MeI 62 d. Ag O 2 Δ H2O
Me Me Me Me Me Me Me Me Δ 1 Me H OH H OH O2 H OH OH H H N H OH OH H H H Me Me OH Me OH
63 64 1 Scheme 2.6. Failed Hoffman and Cope elimination routes. as is typical of selenium unsaturation reactions.61 Dibal reduction of enone 65 proceeded fairly smoothly to form allylic alcohol 67, which as anticipated, possesses the incorrect alcohol stereochemistry. Unfortunately, this alcohol could not be inverted utilizing the
Mitsonobu protocol.62 It appears that the initial Mitsonobu adduct is formed, however the
153 intermediate rapidly undergoes elimination rather than displacement. This is likely a consequence of the unusual vinigrol ring system, which would likely prefer an olefin to relieve steric strain. I had hoped that samarium-mediated single electron reduction might lead to an opposite diastereomeric outcome in the reduction.63 Unfortunately the double bond in the enone is quickly reduced under these conditions and compound 66 could not be formed from enone 65.
At this point it became clear that the olefin must be incorporated into a compound already containing the correct alcohol stereochemistry. A logical solution would be to place another eliminateable group into the skeleton prior to the second dipolar cycloaddtion (Scheme 2.8). Allylic oxidation (SeO2, dioxanes, Δ) of compound 69 afforded allylic alcohol 70. Disappointingly, the subtle additional steric demands of this
Me Me Me Me Me Me Me Me SmI , Me a. DMP O 2 H H OH H Et N/H O OH b. PhSeBr CN 3 2 CN H H H CN 54% H H H Me OH Me OH Me OH 59 65 a. Dibal 66 57%
Me Me Me Me Me Me PMe3, DEAD H H OH O CN CN H H HO2C NO2 H OH H O Me OH Me NO2 67 68 Scheme 2.7. Unsuccessful attempts to introduce unsaturation with correct alcohol stereochemistry. compound inhibited the ensuing dipolar cycloaddition (see 70 → 71). Pleasingly, however, I was able to invert the newly formed alchohol via a TEMPO/bleach oxidation followed by DIBAL reduction.64 Compound 72 did sluggishly undergo the [3+2] cycloaddtion to form compound 73 (formed as an inseperable 3:2 mixture of
154 regioisomers), however the alcohol group could never be mesylated presumably due to the bulky isopropyl group which lies directly overtop of it.
Me Me Me Me Me Me Me Me Br N O Me H H O a. SeO2 H N H 53% H H Br OH H H H Me Me OH OH Me OH OH 69 b. NaOCl, TEMPO, 70 71 NaHCO3, KBr c. DIBAL 52% Me Me Ms2O Me Me Me or Me Me Me OMe O H H MsCl, Et3N H N d. Br2CNOH N H H H Br OMs OH KHCO3 OH Br H H H Me OH H 50% BRSM Me OH H Me OH H 3:2 dr 72 73 74 Scheme 2.8. Unsuccessful attempts to introduce olefin surrogates.
Our most recent result is the ability to convert the primary amine group directly into the primary alcohol via diazo chemistry explored by Ganem and co-workers.65 Thus treatment of primary amine 60 with NaNO2 in Ac2O/AcOH forms triol 75 in ~20% yield.
Although the yield of this reaction remains quite low, and is capricious upon scale-up, this compound may hold the key to the completion of the synthesis of vinigrol (1) as it is only lacking a single olefin unit.
Me a. i. NaNO Me Me Me 2 Me Me Me Ac2O: Me Me H OH AcOH H OH ? H OH H H H OH NH2 ii. K2CO3, OH MeOH OH H H H Me ~ 20% Me OH Me OH 60 75 1 Scheme 2.9. Synthesis of triol 75.
155 2.5 Conclusion and distribution of credit
In conclusion, we have developed a fairly concise and high yielding route to the entire vinigrol carbon skeleton without excessive protecting group manipulations.
Significant reconnaissance gathered has identified the key challenges, particularly late- stage, that need to be overcome before this challenging target can succumb to efficient total synthesis. In addition I have documented an unusual example of a spontaneous
Diels-Alder reaction of two unactivated π-systems which proceeds at room temperature.
The initial synthetic planning of this project was conducted solely by myself. Florina
Voica contributed technical assistance to the early model study by further examining the initial intermolecular Diels-Alder reaction of siloxydiene 28. Dr. Shinji Ashida carried out much of the advanced work with me and is responsible for several key developments, namely: optimization of the Crabtree hydrogenation, discovering that the second dipolar cycloaddition proceeds with the correct regiochemistry, as well as preparing compound
70. Dr. Ashida and I also explored several routes that are not described within this thesis.
Recently Jun “Cindy” Shi has become my teammate on this project and is working to optimize the final diazonium reaction leading to our most advanced compound 75.
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462-466.
(65) Nikolaides, N.; Ganem, B. J. Org. Chem. 1989, 54, 5996-5998.
161 2.7 Supplementary Information
General Procedures. All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran
(THF), triethylamine (TEA), dichloromethane (DCM), methanol (MeOH), dimethylformamide (DMF), diethyl ether (Et2O), and benzene were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated.
Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm
E. Merck silica gel plates (60F-254) using UV light as visualizing agent and p- anisaldehyde in ethanol/aqueous H2SO4/CH3CO2H and heat as developing agents. NMR spectra were recorded on a Bruker DRX 600, DRX 500, or AMX 400 spectrometer and were calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, b = broad. IR spectra were recorded on a Perkin-
Elmer Spetrum BX spectrometer. High resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer (at Scripps) using ESI-TOF (electrospray ionization- time of flight) or a ThermoFinnigan Mass spectrometer (at UCSD) using FAB (fast atom bombardment), or EI (electron impact). Low resolution mass spectra (LRMS) were recorded on an Agilent (at Scripps) or ThermoFinnigan Mass spectrometer (at UCSD)
GC-MS. Photochemical reactions were conducted using a 450-watt Hanovia lamp with a quartz filter. Melting points (m.p.) are uncorrected and were recorded on a Fisher-Johns
162 12-144 melting point apparatus. Optical rotations were obtained on a Perkin-Elmer 431
Polarimeter. All microwave reactions were performed in a Biotage Initiator Microwave.
Sonications were carried out in a Fisher Scientific FS30H Ultrasonic Cleaning Bath.
Azeotroping refers to dissolving the compound to be dried in benzene and removing the solvent by rotary evaporation.
Compound 29: i. Dry 1,3 cyclohexanedione (1.0 g, 8.9 mmol, 1 equiv) was dissolved in ofollowed by dropwise addition of TBSOTf (4.1 ml, 17.8 mmol, 2.0 equiv). The mixture was stirred for 2 hours at 0°C, then concentrated in vacuo (at 15°C) to afford a cloudy yellow oil that was redissolved in Et2O (15 ml) to give a biphasic mixture. Under an atmosphere of N2, the upper organic layer was transferred to a dry flask. This process was repeated (2X) and the combined organic layers were concentrated in vacuo (at 15°C) to give the known diene 28 (2.8 g, purity > 90% by 1H NMR, 95%) as yellow oil which was used in the Diels-Alder reaction without further purification. ii. A flame dried flask was charged with AlCl3 (447 mg, 3.35 mmol, 1.5 equiv.) in DCM
(12.5 ml) and cooled to –78°C. Methyl 4-methyl-2-pentenoate (286 mg, 2.23 mmol, 1 equiv.) in DCM (9 ml) was added dropwise to the stirring suspension, and the resulting mixture stirred at –78°C for 20 minutes. Diene 28 (1.52 g, 4.46 mmol 2 equiv) in DCM
(1.1 ml) was added dropwise, followed by a 0.5 ml DCM rinse. The mixture was stirred at –78°C for 1 hour, then warmed to – 45°C and stirred 3 hours. After 3 hours, the reaction mixture was quenched at –45°C with saturated aqueous NaHCO3 (10 ml) and warmed to room temperature. DCM (50 ml) and saturated aqueous Rochelle’s salt (75ml) were added and the mixture was vigorously stirred for 8 hours. The layers were partitioned and the aqueous layer was extracted with DCM (50 ml, 2X). The combined
163 organic layers were dried (MgSO4) and concentrated in vacuo to give a yellow oil. Flash column chromatography (silica gel, 10:1 hexanes:Et2O) afforded the bicyclic ketone (506 mg, 64%, ~2:1 mixture of endo:exo) as a white solid. Endo isomer: TLC (hexanes: Et2O
1 4:1 v/v): RF = 0.32; H NMR (600 MHz, CDCl3) δ 3.66 (s, 3H), 3.14 (dd, J = 2.4, 18 Hz,
1 H), 2.52 (d, J = 7.2 Hz, 1 H), 2.37 (s, 1 H), 2.20 (d, J = 18.5 Hz, 1 H), 1.90 – 1.95 (m, 1
H), 1.71 – 1.79 (m, 3 H), 1.61 – 1.67 (m, 2 H), 0.92 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6
13 Hz, 3 H), 0.83 (s, 9 H), 0.10 (s, 3 H), 0.05 (s, 3 H); C NMR (150 MHz, CDCl3) δ 212.2,
175.4, 75.2, 56.0, 51.9, 47.1, 45.1, 44.3, 34.8, 31.1, 25.6, 21.1, 20.7, 18.0, 17.7, -1.9, -2.0;
IR (film) νmax 2953, 2856, 2359, 2340, 1732, 1473, 1363, 1327, 1253, 1165, 1130, 836,
-1 + 775 cm ; HRMS (m/z): [M+H] calcd. for C19H35O4Si, 355. 2299; found, 355. 2311.
Compound 30: i. Ketone 29 (4.0 g, 11.23 mmol, 1 equiv.) was azeotropically dried with benzene and then dissolved in THF. The solution was cooled to –78°C and a 1.0 M LDA solution (13.5 ml, 1.2 equiv.) was added dropwise to the cooled solution. After stirring 30 minutes, freshly distilled Tf2O (2.5 ml, 14.9 mmol, 1.3 eq.) was slowly added dropwise over 5 minutes. The solution was stirred for 1 hour at –78°C then slowly warmed to 0°C over approximately 1 hour. After stirring 15 minutes at 0°C, the solution was warmed to room temperature and quenched with a saturated aqueous sodium bicarbonate solution
(100 ml) and Et2O (100 ml). The layers were separated and the aqueous phase was extracted with ether (75 ml, 3X). The combined organic layers were washed with 1N
HCl, saturated aqueous NH4Cl, brine, and dried (MgSO4). Concentration in vacuo yielded a yellow oil. Flash column chromatography (silica gel, 50:1 hexanes:Et2O afforded the corresponding vinyl triflate (4.17 g, 76%, 87% BRSM) as a pale yellow oil as well as recovered starting material (490 mg).
164 ii. Anhydrous LiCl (1.83g, 43.2 mmol, 5 equiv.) was flame dried under high vacuum and allowed to cool under vacuum. The process was repeated three times. Pd(PPh3)4 (1.0 g,
0.86 mmol, 0.1 equiv.) was then added and the flask was evacuated and then backfilled with argon. The aforementioned vinyl triflate (4.2 g, 8.64 mmol, 1 equiv.) in THF (70 ml), was added, followed by vinyltributyltin (3 ml, 10.27 mmol, 1.2 equiv.). The mixture was heated to reflux for 3 hours, then cooled to room temperature and partitioned between Et2O (75 ml) and saturated aqueous NH4Cl (100 ml). The aqueous layer was extracted with Et2O (75 ml, 3X) and the combined organic layers were washed with 1N
HCL (300 ml, 1X), saturated aqueous NaHCO3 (300 ml, 1X), brine (300 ml, 1X), and dried (MgSO4). The solvent was removed in vacuo to give nearly colorless oil. Flash column chromatography (silica gel, gradient from pure hexanes to 50:1 hexanes:Et2O) gave the corresponding diene (2.83 g, 90%) as a colorless oil. iii. The aforementioned diene (2.3 g, 6.07 mmol, 1 equiv.) was azeotropically dried with benzene and then dissolved in DCM (40 ml). The solution was cooled to -78°C and
DIBAL (1.5 M solution in toluene, 10ml, 15 mmol, 2.5 equiv.) was added dropwise.
After stirring 30 minutes at –78°C the reaction was quenched by dropwise addition of
EtOAc (5 ml) followed by saturated aqueous Rochelle’s salt (20ml). The mixture was warmed to room temperature, diluted with additional EtOAc (100 ml) and Rochelle’s salt solution (100 ml) and stirred for 5 hours. The organic layer was separated and the aqueous layer was thoroughly extracted with EtOAc (50 ml, 3X). The combined organic layers were washed with 1N HCL (250 ml, 1X), saturated aqueous NH4Cl (250 ml, 1X), brine (250 ml, 1X) and dried (MgSO4). The solvent was removed in vacuo to give a colorless oil. Flash column chromatography (silica gel, gradient from 30:1 to 10:1
165 hexanes:Et2O) gave the corresponding alcohol (1.66 g, 82 %) as a colorless oil which slowly solidified to a waxy solid. iv. The aforementioned alcohol (685 mg, 2.04 mmol, 1 equiv.) was dissolved in wet
DCM (20 ml). The Dess-Martin reagent (1.08 g, 2.55 mmol, 1.25 equiv.) was added in one portion to the rapidly stirring solution at room temperature. After TLC analysis indicated complete consumption of starting material, the mixture was partioned between
Et2O (100 ml) and saturated aqueous Na2S2O3 (150 ml) and the aqueous layer was extracted with Et2O (25 ml, 3X). The combined organic layers were washed with saturated aqueous NaHCO3 (150 ml, 2X), brine (150 ml, 1X), and dried (MgSO4). The solvent was removed in vacuo to give a pale yellow oil. Flash chromatography (silica gel,
20:1 hexanes:Et2O) gave aldehyde 30 as a colorless oil (666 mg, 98%); TLC
1 (hexanes:Et2O, 5:1 v/v): RF = 0.67; H NMR (500 MHz, CDCl3) δ 9.45 (d, J = 4.0 Hz, 1
H), 6.27 (dd, J = 11, 17.5 Hz, 1 H), 6.03 (s, 1 H), 5.27 (d, J = 17.5 Hz, 1 H), 5.02 (d, J =
10.5 Hz, 1 H), 2.94 (s, 1 H) 2.27 (t, J = 4.5 Hz, 1 H), 1.79 – 1.85 (m, 1 H), 1.69 (dt, J =
5.0, 11.5 Hz, 1 H), 1.54 (dt, J = 4.5, 12.0 Hz, 2 H), 1.24 – 1.27 (m, 1 H), 1.17 – 1.23 (m,
1 H), 0.95 (d, J = 6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H), 0.86 (s, 9 H), 0.11 (s, 3 H), 0.11
13 (s, 3 H); C NMR (125 MHz, CDCL3) δ 204.0, 144.4, 134.2, 133.9, 112. 2, 77.9, 66.1,
45.8, 45.8, 35.2, 32.2, 30.2, 25.8, 22.0, 20.9, 20.2, 18.1, -2.0, -2.3; IR (film) νmax 2955,
2358, 1726, 1589, 1471, 1387, 1328, 1251, 1197, 1118, 1085, 1008, 988, 896, 870, 836,
-1 + 774 cm ; HRMS (m/z): [M+H] calcd. for C20H35O2Si, 355. 2401; found, 355. 2411
Compound 38: Aldehyde 30 (230 mg, 0.69 mmol, 1.0 equiv.) was dissolved in toluene
(6.8 ml) and cooled to –78°C under an atmosphere of argon. Allylmagnesium chloride
(1.7 M in THF, 0.41 ml, 0.70 mmol, 1.01 equiv.) was added dropwise at –78°C and the
166 solution was stirred at that temperature for 15 minutes, then warmed to room temperature. After stirring for 5 minutes at ambient temperature, the reaction was heated to 105°C for 90 minutes. Upon cooling, the mixture was partitioned between saturated aqueous NH4Cl (25 ml) and Et2O (25 ml) and the aqueous layer was extracted with Et2O
(15 ml, 3X). The combined organic layers were washed with brine (100 ml) and dried
(MgSO4). The solvent was removed in vacuo to give a white solid. Flash column chromatography (silica gel, gradient from 25:1 to 15:1 hexanes:Et2O) afforded the title compound (210 mg, 81%) as a ~ 5:1 mixture of alcohol diastereomers. Preparative thin layer chromatography afforded analytically pure major isomer as a white crystalline solid. Crystallization from cyclohexane yielded white cubes of suitable quality for X–ray
1 diffraction; m.p.: 152-154°C; TLC (hexanes:Et2O 3:1 v/v): RF = 0.58; H NMR (600
MHz, CDCl3) δ 5.28 – 5.29 (m, 1 H), 4.54 (d, J = 9.6 Hz, 1 H, D2O exchangeable), 3.54
(d, J = 9.6 Hz, 1 H) 2.40 – 2.42 (m, 1 H), 2.09 – 2.18 (m, 3 H), 2.00 – 2.05 (m, 1 H), 1.39
– 1.79 (m, 10 H), 0.96 (d, J = 6.6 Hz, 3 H), 0.91 (s, 9 H), 0.86 (d, J = 6.6 Hz, 1 H), 0.63
(d, J = 10.8 Hz, 1 H), 0.17 (s, 3 H), 0.16 (s, 3 H); IR (film) νmax 3510, 2929, 2359, 2341,
-1 + 1471, 1252, 1077, 961, 836 cm ; HRMS (m/z): [M+H] calcd. for C23H41O2Si, 377.287; found 377.2875.
Compound 33: Aldehyde 30 (105 mg, 0.31 mmol, 1.0 equiv.) was dissolved in toluene
(3.1 ml) and cooled to –78°C under an atmosphere of argon. Allylmagnesium chloride
(1.7 M in THF, 0.19 ml, 0.32 mmol, 1.01 equiv.) was added dropwise at –78°C and the solution was stirred at that temperature for 15 minutes, then warmed to room temperature. After stirring for 5 minutes at ambient temperature, the reaction was heated to 105°C for 90 minutes. Upon cooling to 65°C, THF (1 ml) was added followed by
167 TBAF (1.0 M in THF, 1.5 ml, 1.5 mmol, 4.8 equiv.) and the resulting solution was stirred for 45 minutes at 65°C. Upon cooling to room temperature, the mixture was partitioned between saturated aqueous NH4Cl (10 ml) and EtOAc (10 ml) and the aqueous layer was extracted with EtOAc (5 ml, 3X). The combined organic layers were washed with 1N
HCl (25 ml, 1X), saturated aqueous NaHCO3 (25 ml, 1X), brine (25 ml) and dried
(Na2SO4). The solvent was removed in vacuo to give a yellow oil. Flash column chromatography (silica gel, gradient from 2:1 to 1:1 hexanes:Et2O) afforded the title compound (62 mg, 75%) as a white foam. Major isomer: TLC (hexanes:Et2O 1:5 v/v): RF
1 = 0.55; H NMR (500 MHz, CDCl3) δ 5.29 – 5.30 (m, 1 H), 3.77 (s, 1 H), 3.62 (bs, 1 H),
3.08 (bs, 1 H), 2.44 (bd, J = 10 Hz, 1 H), 2.05 – 2.10 (m, 3 H), 1.99 – 2.04 (m, 1 H), 1.70
– 1.82 (m, 3 H), 1.59 – 1.62 (m, 4 H), 1.43 – 1.49 (m, 2 H), 1.35 – 1.37 (bd, J = 14.5 Hz,
1 H), 0.94 (d, J = 6.0 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 3 H), 0.65 (d, J = 10.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 142.1, 116.8, 74.7, 73.1, 50.9, 48.4, 45.0, 36.6, 33.7, 32.7,
29.4, 26.0, 23.9, 21.6, 21.1, 21.0, 20.1; IR (film) νmax 3301, 2930, 1468, 1432, 1076, 948
-1 + cm ; HRMS (m/z): [M+Na] calcd. for C17H26O2Na, 285.1825; found, 285.1820.
Compound 37: i. Diol 33 (100 mg, 0.38 mmol, 1 equiv.) was dissolved in wet DCM (4 ml) and the Dess-Martin reagent (180 mg, 0.42 mmol, 1.1 equiv) was added at room temperature. After TLC analysis indicated complete consumption of starting material, the mixture was partitioned between Et2O (25 ml) and saturated aqueous Na2S2O3 (25 ml) and the aqueous layer was extracted with Et2O (10 ml, 3X). The combined organic layers were washed with saturated aqueous NaHCO3 (50 ml, 2X), brine (50 ml, 1X) and dried
(MgSO4). The solvent was removed in vacuo and the crude material purified by silica gel
168 flash chromatography (gradient from 1:1 to 2:1 Et2O:hexanes) to give the corresponding hydroxyketone (91 mg, 92%) as a white solid. ii. The aforementioned hydroxyketone (91 mg, 0.35 mmol, 1.0 equiv.) was dissolved in
DCM (3.5 ml) and cooled to –78°C. DIBAL (1.5M in toluene, 0.75 ml, 1.13 mmol, 3.2 equiv.) was added dropwise at –78°C and the mixture was stirred for 30 minutes at that temperature. EtOAc (1 ml) was added dropwise followed by saturated aqueous
Rochelle’s salt (2 ml). The mixture was warmed to room temperature and additional
EtOAc (10 ml) and Rochelle’s salt (15 ml) were added. The biphasic mixture was vigorously stirred for 3 hours then partitioned and the aqueous layer was extracted with
EtOAc (10 ml, 3X). The combined organic layers were washed with 1N HCl (50 ml), brine (50 ml), and dried (Na2SO4). The solvent was removed in vacuo to give a white foam which was judged to be a ~2.5: 1 mixture of isomers by 1H NMR (nearly analytically pure, quantitative yield). Flash column chromatography (silica gel, gradient from 3:1 to 2:1 hexanes:Et2O) yielded undesired diol isomer (26 mg) followed by the title compound (62 mg, 68% of desired, 96% combined yield) as a white crystalline solid.
Crystallization from cyclohexane yielded white cubes of suitable quality for X–ray
1 diffraction; m.p.: 161-163°C; TLC (Et2O:hexanes, 5:1 v/v): RF = 0.35; H NMR (600
MHz, CDCl3) δ 5.30 – 5.31 (m, 1 H), 4.21 – 4.24 (m, 1 H), 2.18 – 2.20 (m, 2 H), 2.11
(ddd, J = 1.8, 9.0, 18.0 Hz, 1 H), 2.01 – 2.07 (m, 1 H), 2.00 (m, 1 H), 1.82 – 1.86 (m, 1
H), 1.72 – 1.79 (m, 1 H), 1.67 (m, 1 H), 1.59 – 1.63 (m, 1 H), 1.48 – 1.52 (m, 1 H), 1.41 –
1.43 (m, 2 H), 1.28 (m, 1 H), 1.10 – 1.14 (m, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 0.93 (d, J =
13 6.6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 141.7, 116.8, 73.4, 68.2, 49.7, 46.1, 44.1,
36.2, 34.8, 32.1, 30.7, 27.3, 25. 9, 21.9, 21.6, 21.5, 20.6; IR (film) νmax 3361, 2929, 1470,
169 -1 + 1331, 1032, 907, 733 cm ; HRMS (m/z): [M+H] calcd. for C17H27O2, 263.2005; found,
263. 2004.
Compound 34: i. Diol 33 (100 mg, 0.38 mmol, 1 equiv.) was dissolved in wet DCM (4 ml) and the Dess-Martin reagent (180 mg, 0.42 mmol, 1.1 equiv) was added at room temperature. After TLC analysis indicated complete consumption of starting material, the mixture was partitioned between Et2O (25 ml) and saturated aqueous Na2S2O3 (25 ml) and the aqueous layer was extracted with Et2O (10 ml, 3X). The combined organic layers were washed with saturated aqueous NaHCO3 (50 ml, 2X), brine (50 ml, 1X) and dried
(MgSO4). The solvent was removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 1:1 to 2:1 Et2O:hexanes) to give the corresponding hydroxyketone (91 mg, 92%) as a white solid. ii. The aforementioned hydroxyketone (25 mg, 0.10 mmol, 1.0 equiv.) was dissolved in
DCM (1.0 ml) and cooled to –78°C. DIBAL (1.5M in toluene, 0.2 ml, 0.30 mmol, 3.1 equiv.) was added dropwise at –78°C and the mixture was stirred for 20 minutes at that temperature. EtOAc (0.2 ml) was added followed by saturated aqueous Rochelle’s salt (1 ml) and the mixture was warmed to room temperature. Once the mixture had reached room temperature, additional EtOAc (5 ml) and Rochelle’s salt solution (2 ml) were added and the biphasic mixture was stirred vigorously for 1 hour. The reaction mixture was then partitioned and the aqueous layer extracted with EtOAc (5 ml, 3X). The combined organic layers were washed with 1N HCl (25 ml), saturated aqueous NH4Cl
(25 ml), brine (25 ml), and dried (Na2SO4). The solvent was removed in vacuo to yield a white foam (25 mg) that was re-dissolved in anhydrous DCM (1.0 ml). Et3N (0.02 ml,
0.14 mmol, 1.5 equiv) was added followed by methanesulfonyl chloride (0.01 ml, 0.12
170 mmol, 1.25 equiv) and the mixture was stirred for 20 minutes under an atmosphere of N2.
The mixture was partitioned between saturated NH4Cl (20 ml) and DCM (5 ml) and the aqueous layer was extracted with DCM (5 ml, 3X). The combined organic layers were washed with 1N HCl (25 ml), saturated aqueous NaHCO3 (25 ml), brine (25 ml), and dried (Na2SO4). The solvent was removed in vacuo and the crude material purified by flash column chromatography (silica gel, gradient from 3:1 hexanes:Et2O to 1:1 hexanes:Et2O) to afford the corresponding mesylate (28.2 mg, 86%, ~2.5:1 mixture of diastereomers). The major isomer is a white solid; TLC (Et2O:hexanes, 1:5 v/v): RF =
1 0.37; H NMR (600 MHz, CDCl3) δ 5.34 – 5.35 (m, 1 H), 5.22 – 5.26 (m, 1 H), 2.96 (s, 3
H), 2.27 – 2.30 (m, 1 H), 2.23 (m, 1 H), 2.11—2.14 (m, 1 H), 2.01—2.08 (m, 2 H), 1.88 –
1.89 (m, 1 H), 1.84 – 1.86 (m, 1 H), 1.74 – 1.81 (m, 1 H), 1.60—1.71 (m, 4 H), 1.50 –
1.54 (m, 1 H), 1.41 – 1.48 (m, 1 H), 1.22—1.24 (m, 1 H), 1.18 (s, 1 H), 0.98 (d, J = 6.6
13 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 141.0, 117.3, 80.6,
73. 4, 48.4, 46.6, 43.6, 38.5, 35.8, 34.6, 32.0, 28.6, 27.2, 25.5, 21.6, 21.5, 21.4, 20.5; IR
-1 + (film) νmax 3505, 2934, 1330, 1169, 928 cm ; HRMS (m/z): [M+Na] calcd. for
C18H28O4SNa, 363.160; found 363. 1606.
Compound 35: A flame-dried flask was charged with mesylate 34 (21 mg, 0.06 mmol, 1 equiv.). The flask was evacuated and then back-filled with dry argon. Freshly degassed
THF (1.0 ml) was added and the flask cooled to 0°C. KHMDS (0.5M solution in THF,
0.135 ml, 0.068 mmol 1.1 equiv.) was added dropwise and the solution was stirred for 15 minutes at 0°C, then warmed to room temperature and stirred 5 minutes. While still under an argon atmosphere, glacial acetic acid (0.05 ml) was added and the mixture stirred for 3 minutes, then partitioned between 1N HCl (10 ml) and Et2O (5 ml). The aqueous layer
171 was extracted with Et2O (5 ml, 3X) and the combined organic layers were washed with saturated aqueous NaHCO3 (25 ml, 2X), brine (25 ml), and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by flash column chromatography
(silica gel, gradient from 10:1 to 3:1 hexanes Et2O) to give the title compound (14 mg,
1 93%) as colorless oil; TLC (Et2O:hexanes, 1:1 v/v): RF = 0.52; H NMR (500 MHz,
CDCl3) δ 5.59 – 5.61 (m, 1 H), 5.40 (dddd, J = 1.5, 7.0, 11.0, 18.0 Hz, 1 H), 5.24 (dd, J =
7.5, 11.0 Hz, 1 H), 2.96 – 3.00 (m, 1 H), 2.89 (m, 1 H), 2.32 – 2.37 (m, 3 H), 2.19 – 2.27
(m, 1 H), 1.98 – 2.06 (m, 2 H), 1.89 – 1.95 (m, 1 H), 1.81 – 1.88 (m, 3 H), 1.61 – 1.71
(m, 2 H), 1.15 – 1.20 (m, 1 H), 1.00 (d, J = 6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H); 13H
NMR (125 MHz, CDCl3) δ 212.0, 141.0, 137.3, 133.6, 120.4, 53.1, 51.6, 41.5, 36.9, 36.5,
-1 31.5, 31.0, 24.9, 22.1, 21.4, 21.0, 21.0; IR (film) νmax 2934, 2866, 2359, 2341, 1700 cm ;
+ HRMS (m/z): [M+H] calcd. for C17H25O, 245.190; found 245.1906.
Compound 36: To a solution of ketone 35 (8.0 mg, 0.03 mmol, 1 equiv.) in DCM (1 ml) at -15°C was added NaHCO3 (5.5 mg, 0.065 mmol, 2 equiv.). Freshly purified m-CPBA
(8.5 mg, 0.05 mmol, 1.5 equiv.) was then added in small portions until TLC analysis indicated complete consumption of starting material (~45 minutes). The mixture was then partitioned between saturated aqueous Na2S2O3 (5 ml) and Et2O (5 ml) and the aqueous layer extracted with Et2O (5ml, 2X). The combined organic layers were washed with saturated aqueous NaHCO3 (25 ml), saturated aqueous NaHCO3 (25 ml, 2X), brine (25 ml), and dried (MgSO4). Concentration in vacuo yielded the title compound (8.5 mg,
95% purity by 1H NMR, 95% yield) as a white crystalline solid. [NOTE: The product is somewhat unstable to both acidic and basic conditions and purification often affords product of lower purity than the crude material]). Crystallization from cyclohexane
172 yielded white cubes of suitable quality for X–ray diffraction; m.p.: 117-120°C; TLC
1 (Et2O:hexanes, 1:1 v/v): RF = 0.34; H NMR (600 MHz, C6D6) δ 5.51 (m, 1 H), 4.98 (dd,
J = 7.8, 10.8 Hz, 1 H), 2.84 – 2.88 (m, 1 H), 2.74 (d, J = 4.2 Hz, 1 H), 2.19 – 2.22 (m, 2
H), 1.96 – 2.01 (m, 2 H), 1.78 – 1.86 (m, 2 H), 1.51 – 1.57 (m, 3 H), 1.45 – 1.48 (m, 1 H),
1.20 – 1.29 (m, 3 H), 1.13 – 1.17 (m, 1 H), 0.77 (d, J = 6.6 Hz, 3 H), 0.67 (d, J = 6.6 Hz,
13 3 H); H NMR (150 MHz, C6D6) δ 207.7, 136.1, 134.3, 61.7, 56.1, 54.8, 46.8, 42.7,
36.3, 34.3, 30.4, 27.5, 24.7, 22.0, 20.7, 19.9, 19.3; IR (film) νmax 2928, 2870, 2359, 2333,
-1 + 1699, 613 cm ; HRMS (m/z): [M+H] calcd. for C17H25O2, 261. 1849; found 261.1852.
Compound 44: Ketone 43 (11.1 mg, 0.03 mmol, 1 equiv.) was dissolved in MeOH/DCM
(10:1 v/v, 1.1 ml) and several drops of a methylene blue solution (prepared by dissolving
5 mg methylene blue in 1.0 ml DCM) were added. The solution was cooled to 0°C and placed near a 150 watt floodlamp. O2 was bubbled through the irradiated solution at 0°C with additional drops of methylene blue solution added as needed to maintain the deep blue color. After 2 hours, O2 bubbling and irradiation were stopped, and DMS (0.5 ml) was added and the reaction stirred for 8 hours at 0 °C. The reaction was partitioned between saturated aqueous NaHSO4 (5 ml) and Et2O (5 ml) and the aqueous layer extracted with Et2O (5ml, 2X). The combined organic layers were washed with brine (25 ml) and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by preparative thin-layer silica gel chromatography (1:1 hexanes:Et2O) to yield the title compound (4.8 mg, 54% BRSM) and recovered starting material (2.5 mg); 1H
NMR (600 MHz, CDCl3) δ 6.02 (t, J = 6 Hz, 1 H), 5.68 (dd, J = 3, 6 Hz, 1 H), 2.73 –
2.71 (m, 1 H), 2.42 (dd, J = 12, 16 Hz, 1 H), 2.35 – 2.32 (m, 1 H), 2.11 – 2.06 (m, 2 H),
2.01 (d, J = 6 Hz, 2 H), 2.01 (d, J = 6 Hz, 2 H), 1.95 (ddd, J = 2, 6, 16 Hz, 1 H), 1.90 –
173 1.87 (m, 1 H), 1.62 – 1.58 (m, 5 H), 1.16 (m, 1 H), 0.89 (d, J = 6 Hz, 3 H), 0.83 (d, J = 6
13 Hz, 3 H), 0.80 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H); C NMR (150 MHz, CDCl3) δ 213.5,
134.1, 131.2, 79.0, 72.0, 60.1, 51.9, 45.3, 39.2, 37.4, 32.9, 32.5, 31.2, 29.1, 26.0, 21.4,
21.2, 18.4, 16.4, -1.6, -1.8.
Compound 46: Compound 44 (4.5 mg, 0.01 mmol, 1 equiv.) was azeotropically dried with toluene and the residual solvent removed under high vacuum. Toluene (0.5 ml) was added and the mixture cooled to 0°C. Et2Zn (1.0 M solution in hexanes, 0.11 ml, 0.11 mmol, 10 equiv.) was added followed by CH2I2 (19 µl, 0.24 mmol, 20 equiv.). The reaction mixture was stirred at 0°C for 2 hours, then warmed to room temperature and stirred an additional 30 minutes. The reaction was partitioned between 1N HCl (5 ml) and
Et2O (5 ml) and the aqueous layer extracted with Et2O (5 ml, 2X). The combined organic layers were washed with brine (15 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by preparative thin-layer silica gel chromatography
(1:1 hexanes:Et2O) to afford cyclopropane 46 (1.0 mg, 63% BRSM) and recovered
1 starting material (3 mg); H NMR (600 MHz, CDCl3) δ 2.64 (dd, J = 12, 18 Hz, 1 H),
2.42 – 2.37 (m, 1 H), 2.17 – 2.03 (m, 4 H), 1.84 – 1.80 (m, 1 H), 1.70 (s, 1 H), 1.68 –
1.64 (m, 1 H), 1.60 – 1.58 (m, 4 H), 1.45 – 1.42 (m, 1 H), 1.37 (d, J = 6 Hz, 1 H), 1.31
(m, 1 H), 1.27 – 1.23 (m, 1 H), 1.05 – 1.01 (m, 1 H), 0.95 (d, J = 6 Hz, 3 H), 0.86 (d, J =
6 Hz, 3 H), 0.78 (s, 9 H), 0.57 (dd, J = 2, 6 Hz, 1 H), 0.08 (s, 3 H), 0.03 (s, 3 H). 13C
NMR (150 MHz, CDCl3) δ 214.4, 79.0, 71.1, 60.2, 51.4, 45.4, 40.6, 38.3, 32.9, 32.7,
30.2, 29.4, 26.6, 21.6, 21.3, 20.6, 18.4, 16.9, 13.6, 12.7, -1.6, -1.9.
Compound 50: Diol 49 (15 mg, 0.05 mmol, 1 equiv.) was dissolved in 2:1 MeOH/DCM
(v:v, 1.0 ml) and cooled to –78°C. O3 was bubbled through the cooled solution until a
174 faint blue color persisted. DMS (0.5 ml) was then added and the reaction mixture warmed to room temperature and stirred overnight. The mixture was partitioned between DCM (2 ml) and Brine (5 ml) and the aqueous layer extracted with DCM (5 ml). The combined organic layers were washed brine (10 ml), dried (MgSO4) and the solvent removed in vacuo to afford the title compound (12 mg, 72%) as an oil that was sufficiently pure for
1 the next step. H NMR (500 MHz, CDCl3) δ 9.80 (s, 1 H), 3.83 (dd, J = 2, 6 Hz, 1 H),
2.78 – 2.71 (m, 1 H), 2.47 – 2.41 (m, 1 H), 2.32 (m, 1 H), 2.15 – 2.14 (m, 1 H), 2.04 –
1.98 (m, 2 H), 1.96 – 1.87 (m, 2 H), 1.86 – 1.82 (m ,1 H), 1.80 – 1.74 (m, 1 H), 1.66 (dt, J
= 6, 18 Hz, 1 H), 1.59 – 1.50 (m, 3 H), 1.44 – 1.42 (m , 1 H), 1.05 (d, J = 6 Hz, 3 H), 1.04
(d, J = 6 Hz, 3 H), 0.90 (d, J = 6 Hz, 3 H).
Compound 52: To a solution of ketone 43 (10 mg, 0.03 mmol, 1 equiv.) in THF (0.6 ml) was added PhSiH3 (6 µl, 0.05 mmol, 1.8 equiv.) and Co(acac)2 (1.5 mg, 0.006 mmol,
0.22 equiv.). O2 was bubbled through the rapidly stirring solution until tlc analysis indicated complete consumption of starting material. DMS (0.1 ml) was added and the reaction stirred for 3 hours. Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 10:1 → 5:1 → 2:1 hexanes:Et2O) to afford tertiary alcohol 52 (8.5 mg, 81%) as an oil that slowly solidifies;
TLC (hexanes: Et2O 1:1 v/v): RF = 0.41; IR (film) νmax = 3444, 2951, 1701, 1471, 1388,
-1 1 1314, 1256, 1144, 1097, 1074, 975, 836, 774 cm ; H NMR (600 MHz, CDCl3) δ 2.50 –
2.46 (m, 2 H), 2.33 – 2.27 (m, 1 H), 2.18 – 2.09 (m, 3 H), 2.03 (d, J = 6 Hz, 1 H), 1.89 –
1.81 (m, 3 H), 1.72 – 1.69 (m, 1 H), 1.64 – 1.56 (m, 3 H), 1.28 – 1.18 (m, 3 H), 0.96 (d, J
= 6 Hz, 3 H), 0.84 (d, J = 6 Hz, 3 H), 0.78 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H); 13C NMR
(150 MHz, CDCl3) δ 213.4, 78.3, 74.7, 60.3, 50.1, 45.5, 42.5, 37.2, 33.2, 32.8, 31.3, 26.2,
175 26.0, 24.2, 21.6, 21.0, 18.4, 16.3, 14.5, -1.61, -1.82; HRMS (m/z): [M+Na]+ calcd. for
C23H40O3SiNa, 415.2639; found, 415.2648.
Compound 53: i. Tertiary alcohol 52 (430 mg, 1.1 mmol, 1 equiv.) was dissolved in
DCM (10 ml) followed by the addition of monomethyl malonate (250 mg, 2.1 mmol, 2.0 equiv.), EDC (420 mg, 2.1 mmol, 2.0 equiv.), and DMAP (260 mg, 2.1 mmol, 2.0 equiv.). The reaction mixture was stirred for 2.5 hours at room temperature, then partitioned between 1 N HCl (10 ml) and DCM (10 ml). The aqueous layer was extracted with DCM (25 ml) and the combined organic layers washed with 1N HCl (50 ml), saturated aqueous NaHCO3 (25 ml), brine (25 ml), and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (6:1 hexanes:Et2O) to afford the corresponding mixed malonate (426 mg, 79%) as a colorless oil. ii. To the aforementioned mixed malonate (89 mg, 0.18 mmol, 1 equiv.) in MeCN/DCM
(4:1 v:v, 1.5 ml) was added DBU (50 µl, 0.33 mmol, 1.9 equiv.) followed by p-ABSA
(54 mg, 0.23 mmol, 1.25 equiv.). The mixture was stirred at room temperature for 1 hour then partitioned between 1N HCl (5 ml) and DCM (5 ml). The aqueous layer was extracted with DCM (5 ml, 3X) and the combined organic layers were washed with brine
(25 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purfied by silica gel flash chromatography (5:1 hexanes:Et2O) to afford the
1 corresponding diazomalonate (81 mg, 86%) as an oil. H NMR (500 MHz, CDCl3) δ 3.85
(s, 3 H), 2.68 (s, 1 H), 2.57 – 2.46 (m, 2 H), 2.18 – 2.36 (m, 3 H), 2.09 (d, J = 6 Hz, 1 H),
2.00 – 1.89 (m, 2 H), 1.84 (d, J = 6 Hz, 1 H), 1.79 – 1.60 (m, 7 H), 1.49 – 1.43 (m, 1 H),
0.94 (d, J = 6 Hz, 3 H), 0.86 (d, J = 6 Hz, 3 H), 0.79 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H).
176 iii. The aforementioned diazomalonate (81 mg, 0.16 mmol, 1 equiv.) was placed in a sealable vial with Rh2(OAc)4 (3.5 mg, 0.008 mmol, 0.05 equiv.). The flask was evacuated, then back-filled with Argon. Dry, degassed benzene (3 ml) was added and the sealed vial placed into an 80°C oil bath. After 1 hour, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (gradient from 20:1→ 15:1 → 10:1 →5:1 → 3:1 → 1:1 → 1:2
1 hexanes:Et2O) to yield the title compound (63 mg, 82%) as a white foam; H NMR (400
MHz, CDCl3) δ 3.80 (s, 3 H), 3.46 (d, J = 8 Hz, 1 H), 2.97 (dd, J = 4, 12 Hz, 1 H), 2.70 –
2.67 (m, 1 H), 2.32 – 2.18 (m, 3 H), 2.09 (d, J = 8 Hz, 1 H), 2.00 – 1.92 (m, 3 H), 1.90 –
1.79 (m, 3 H), 1.69 – 1.58 (m, 4 H), 1.55 – 1.49 (m, 1 H), 0.92 (d, J = 6 Hz, 3 H), 0.84 (d,
J = 6 Hz, 3 H), 0.78 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H).
Compound 49: i. To a flame dried flask was added compound 43 (5.85 g, 15.6 mmol, 1 equiv.) and THF (150 ml) under Argon. The solution was cooled to –78° C and LDA (1.0
M in THF, 20.0 ml, 20.0 mmol, 1.3 equiv.) was added dropwise over 10 minutes. The mixture was stirred for 15 minutes at –78°C, warmed to 0°C and stirred for 10 minutes, then cooled back to –78°C and stirred for 5 minutes. MeI (1.6 ml, 25.6 mmol, 1.6 equiv.) was added dropwise at –78°C and the solution stirred for 30 minutes at –78°C. The mixture was then slowly warmed to 0°C and stirring continued for 2.5 hours at this temperature. The reaction was partitioned between saturated aqueous NH4Cl (250 ml) and Et2O (200 ml) and the aqueous layer extracted with Et2O (200 ml, 2X). The combined organic layers were washed with brine (500 ml), dried (MgSO4), and the volatiles removed in vacuo to yield the crude α-methyl ketone (6.1 g) as a single diastereomer.
177 ii. The aforementioned crude α-methyl ketone (6.1 g, 15.7 mmol, 1 equiv.) was dissolved in THF (125 ml) and TBAF (1.0 M solution in THF, 25 ml, 25 mmol, 1.6 equiv.) was added. The mixture was heated at 50°C for 1 hour at which point additional TBAF (25 ml) was added, and heating continued for 2 hours. Upon cooling, the reaction mixture was partitioned between saturated aqueous NH4Cl (150 ml) and Et2O (150 ml) and the aqueous layer extracted with Et2O (150 ml, 3X). The combined organic layers were washed with 1N HCl (500 ml), water (500 ml), brine (500 ml), and dried (MgSO4). The solvent was removed in vacuo to afford a yellow solid which was re-dissolved in
AcOH:MeCN:THF (1:1:1 v/v/v, 150 ml). Me4NBH(OAc)3 (16.5 g, 62.7 mmol, 4 equiv.) was added portion-wise to the rapidly stirring solution. The reaction mixture was stirred for 1.5 hours then carefully poured into saturated aqueous NaHCO3 (250 ml) and Et2O
(200 ml). The aqueous layer was extracted with Et2O (200 ml, 3X) and the combined organic layers carefully washed with saturated aqueous NaHCO3 (250 ml, 5X), brine
(250 ml), and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 2:1 to 1:1 hexanes:Et2O) to afford compound 49 (3.1 g, 72% over 3 steps) as a white solid; m.p.: 165°C; TLC
1 (Et2O:hexanes, 5:1 v/v): RF = 0.13; H NMR (600 MHz, CDCl3) δ 5.28 (dd, J = 3, 5 Hz, 1
H), 3.79 (dd, J = 5, 10 Hz, 1 H), 2.20 (s, 1 H), 2.15 – 2.10 (m, 1 H), 2.03 – 1.97 (m, 2 H),
1.86 – 1.77 (m, 3 H), 1.72 – 1.71 (m, 1 H), 1.67 – 1.58 (m, 5 H), 1.45 – 1.36 (m, 2 H),
1.15 – 1.13 (m, 2 H), 1.04 (d, J = 6 Hz, 3 H), 0.99 (d, J = 6 Hz, 3 H), 0.93 (J = 6 Hz, 1
13 H); C NMR (150 MHz, CDCl3) δ 142.5, 117.0, 74.3, 73.1, 50.3, 46.7, 45.1, 36.3, 34.8,
34.7, 32.6, 32.1, 23.8, 21.9, 21.9, 21.5, 20.5, 15.3; IR (film) νmax 3371, 2929, 1638, 1469,
178 -1 + 1368, 1326, 1227, 1034, 988 cm . HRMS (m/z): [M+Na] calcd. for C18H28O2Na, 299.
1981; found, 299.1969.
Compound 54: i. Diol 49 (3.1 g, 11.2 mmol, 1 equiv.) was dissolved in anhydrous pyridine (100 ml) and cooled to 0°C. MsCl (1.05 ml, 13.6 mmol, 1.2 equiv.) was added dropwise to the solution at 0°C, and stirring was continued for 2.5 hours at this temperature. The reaction was partitioned between 1N HCl (150 ml) and Et2O (150 ml).
The aqueous layer extracted with Et2O (100 ml, 3X). The combined organic layers were washed with 1N HCl (500 ml, 4X), water (500 ml), brine (500 ml), and dried (MgSO4).
Volatiles were removed in vacuo to yield the crude mesylate ii. The aforementioned crude mesylate (4.8 g, 13.5 mmol, 1 equiv.) was azeotropically dried with benzene and the residual solvent removed under high vacuum. Dry THF (110 ml) was added and the reaction cooled to 0°C under an atmosphere of argon. KHMDS
(0.5 M solution in THF, 30 ml, 15 mmol, 1.1 equiv.) was added dropwise over 15 minutes to the solution at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, then warmed to room temperature and quenched (while under argon) by the dropwise addition of AcOH (10 ml). The reaction mixture was partitioned between saturated aqueous NH4Cl (100 ml) and Et2O (100 ml) and the aqueous layer extracted with Et2O
(100 ml, 3X). The combined organic layers were washed with saturated aqueous
NaHCO3 (250 ml, 3X), water (250 ml), brine (250 ml), and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 10:1 → 5:1 hexanes:Et2O) to afford the Grob product
(2.5 g, 85% over 2 steps) as a colorless oil.
179 iii. The aforementioned Grob product (3.03 g, 11.7 mmol, 1 equiv.) was dissolved in
EtOAc (100 ml) and KHCO3 (3.5 g, 35 mmol, 3 equiv.) was added in one portion. To the rapidly stirring mixture was added dibromoformaldoxime (3.6 g, 17.6 mmol, 1.5 equiv.).
Stirring continued until TLC analysis indicated complete consumption of starting material [Note: sometimes addition portions of KHCO3 and dibromoformaldoxime are required to drive the reaction to completion]. The reaction was partitioned between saturated aqueous NH4Cl (150 ml) and DCM (100 ml) and the aqueous layer extracted with DCM (100 ml, 2X). The combined organic layers were washed with brine (300 ml), dried (MgSO4), and the volatiles removed in vacuo. The crude material was purified by silica gel flash chromatography (gradient from 20:1 → 10:1 → 5:1 hexanes:Et2O) to afford bromoisoxazole 54 (3.9 g, 88%) as a white crystalline solid; m.p.: 115°C; TLC
1 (Et2O:hexanes, 5:1 v/v): RF = 0.54; H NMR (600 MHz, CDCl3) δ 5.31 – 5.23 (m, 2 H),
3.2 (dd, J = 3, 6 Hz, 1 H), 2.67 – 2.63 (m, 1 H), 2.58 – 2.52 (m, 1 H), 2.45 (d, J = 6 Hz, 1
H), 2.40 – 2.33 (m, 2 H), 2.31 – 2.18 (m, 3 H), 2.09 – 2.01 (m, 2 H), 2.09 – 1.81 (m, 1 H),
1.76 – 1.72 (m, 1 H), 1.67 – 1.62 (m, 1 H), 1.55 – 1.51 (m, 1 H), 1.07 (d, J = 6 Hz, 3 H),
13 0.96 (d, J = 6 Hz, 3 H), 0.86 (d, J = 6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 211.6,
145.3, 141.9, 131.2, 92.0, 53.8, 53.7, 44.0, 43.5, 42.0, 36.3, 32.7, 30.2, 24.6, 21.5, 21.4,
-1 21.0, 20.6, 18.1; IR (film) νmax 2957, 1698, 1460, 1387, 1327, 1262, 1093, 840, 817 cm ;
+ HRMS (m/z): [M+H] calcd. for C19H27BrNO2, 380. 1220; found, 380.1223.
Compound 55: i. Bromoisoxazole 54 (1.0 g, 2.6 mmol, 1 equiv.) was dissolved in DCM
(20 ml) and cooled to –78°C. DIBAL (1.2 M solution in toluene, 2.6 ml, 3.1 mmol, 1.2 equiv.) was added dropwise to the cooled solution and the reaction mixture stirred for 1 hour at –78°C. EtOAc (25 ml) and saturated aqueous Rochelle’s salt solution (50 ml)
180 were added and the mixture warmed to room temperature and vigorously stirred for 8 hours. The reaction mixture was partitioned and the aqueous layer extracted with EtOAc
(25 ml, 3X). The combined organic layers were washed with brine (150 ml), dried
(MgSO4), and the solvent removed in vacuo. The crude material was purified by silica gel flash chromatography (2:1 hexanes:Et2O) to afford the corresponding alcohol (955 mg,
95%) as white foam. ii. To a flame dried flask was added the aforementioned alcohol (830 mg, 2.16 mmol, 1 equiv.) followed by Crabtree’s catalyst (350 mg, 0.43 mmol, 0.2 equiv.) and the flask was evacuated, then backfilled with argon. Degassed DCE (25 ml) was added followed by
B(O-iPr)3 (0.5 ml, 2.16 mmol, 1.0 equiv.). Hydrogen was bubbled through the solution for 10 minutes, then the flask was placed in an 80°C oil bath and heated under an atmosphere of H2 (non-bubbling) for 8 hours. Upon cooling, the reaction was partitioned between 1N HCl (25 ml) and DCM (25 ml), and the aqueous layer extracted with DCM
(20 ml, 3X). The combined organic layers were washed with 1N HCl (50 ml, 3X), brine
(50 ml), and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by silica gel flash chromatography (3:1 hexanes: Et2O) to afford title compound
1 55 (730 mg, 87%) as a white foam; TLC (Et2O:hexanes, 1:1 v/v): RF = 0.38; H NMR
(600 MHz, CDCl3) δ 4.45 (m, 1 H), 3.02 (t, J = 6 Hz, 1 H), 2.36 (dd, J = 6, 12 Hz, 1 H),
2.11 – 2.07 (m, 1 H), 2.04 – 1.99 (m, 1 H), 1.95 – 1.94 (m, 1 H), 1.93 – 1.85 (m, 3 H),
1.81 – 1.77 (m, 1 H), 1.75 – 1.69 (m, 3 H), 1.64 – 1.59 (m, 1 H), 1.56 – 1.37 (m, 7 H),
0.99 (d, J = 6 Hz, 3 H), 0.93 (d, J = 6 Hz, 3 H), 0.88 (d, J = 6 Hz, 3 H); 13C NMR (150
MHz, CDCl3) δ 146.3, 94.3, 67.2, 54.1, 45.7, 39.2, 39.0, 38.9, 37.4, 31.7, 30.5, 21.8,
28.7, 27.3, 25.8, 22.1, 21.4, 19.6; IR (film) νmax 3443, 2952, 1459, 1362, 1289, 1063,
181 -1 + 1033, 900, 753 cm ; HRMS (m/z): [M+H] calcd. for C19H31BrNO2, 384.1533; found,
384.1529.
Compound 56: i. To a flame dried flask was added NaH (60% dispersion in mineral oil,
1.28 g, 32mmol, 10 equiv.) and THF (25ml). The mixture was cooled to 0°C and alcohol
55 (1.24 g, 3.2 mmol, 1 equiv.) in THF (7 ml) was added dropwise over 5 minutes. The reaction mixture was stirred for 5 minutes at 0°C, then warmed to room temperature and stirred for 1 hour. CS2 (3.9 ml, 65 mmol, 20 equiv.) was added and stirring continued for
3 hours, followed by the addition of MeI (7.9 ml, 127 mmol, 40 equiv.) and an additional
12 hours of stirring. The reaction mixture was partitioned between 1N HCl (100 ml) and
Et2O (50 ml), and the aqueous layer extracted with Et2O (50 ml, 3X). The combined organic layers were washed with 1N HCl (250 ml), brine (250 ml), and dried (MgSO4).
Volatiles were removed in vacuo in a well-ventilated fume hood [Caution: MeI may still be present] and the crude material purified by silica gel flash chromatography (5:1 hexanes:Et2O) to afford the corresponding xanthate (1.35 g, 88%) as a yellow oil. ii. The aforementioned xanthate (1.35 g, 2.84 mmol, 1 equiv.) was dissolved in degassed o-DCB (55 ml) under an atmosphere of argon. The mixture was heated to 180 °C for 3 hours. Upon cooling, the reaction mixture was passed through a short plug of silica gel, eluting with hexanes (to remove o-DCB), followed by 1:1 hexanes:Et2O to afford title compound 56 (1.0 g, 96%) as a slightly yellow oil; TLC (Et2O:hexanes, 1:1 v/v): RF =
1 0.81; H NMR (600 MHz, CDCl3) δ 5.72 – 5.66 (m, 2 H), 3.03 (t, J = 6 Hz, 1 H), 2.52 –
2.48 (m, 1 H), 2.36 (s, 1 H), 2.16 – 2.04 (m, 5 H), 1.66 – 1.48 (m, 7 H), 1.41 – 1.34 (m, 1
H), 1.29 – 1.26 (m, 1 H), 0.94 (d, J = 6 Hz, 3 H), 0.93 (d, J = 6 Hz, 3 H), 0.85 (d, J = 6
13 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 144.9, 129.1, 124.8, 91.6, 54.0, 43.0, 41.6, 39.9,
182 39.0, 37.2, 32.6, 30.9, 27.7, 26.1, 25.5, 25.4, 22.0, 21.5, 19.6; IR (film) νmax 2953, 1575,
-1 + 1462, 1386, 1367, 1099, 1059, 899, 864, 810, 740 cm ; HRMS (m/z): [M+H] calcd. for
C19H29BrNO, 366.1427; found, 366.1430.
Compound 57: i. Olefin 56 (230 mg, 0.63 mmol, 1 equiv.) was azeotropically dried with benzene and the residual solvent removed under high vacuum. THF (3 ml) was added and the solution cooled to 0°C. LiAlH4 (1.0 M solution in THF, 12.5 ml, 12.5 mmol, 20 equiv.) was added drop-wise at 0°C over 15 minutes, and the mixture warmed to room temperature and stirred for 12 hours. The reaction mixture was cooled to 0°C, the septum removed, and 1N HCl (10 ml) was added very slowly dropwise [Caution: gas evolution occurs]. The reaction mixture was partitioned between saturated aqueous NaHCO3 (75 ml) and EtOAc (25 ml) and the aqueous layer thoroughly extracted with EtOAc (25 ml,
3X) and then DCM (25 ml, 3X). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo to yield the crude amine (180 mg) as a yellow foam. ii. The aforementioned crude amine (180 mg, 0.63 mmol, 1 equiv.) was dissolved in
DCM (7 ml). To this solution was added formic acid (47 µl, 1.25 mmol, 2.0 equiv.),
CDMT (230 mg, 1.3 mmol, 2.1 equiv.), NMM (220 µl, 1.6 mmol, 2.5 equiv.) and DMAP
(10 mg, 0.08 mmol, 0.13 equiv.) in that order. The mixture was stirred for 1 hour then partitioned between 1N HCl (25 ml) and DCM (15 ml). The aqueous layer was extracted with DCM (15 ml, 3X), and the combined organic layers washed with 1N HCl (50 ml), saturated NaHCO3 (50 ml), brine (50 ml), and dried (Na2SO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from
1:1 → 2:1 EtOAc:Hexanes → pure EtOAc) to afford the corresponding formamide (172 mg, 81% from bromoisoxazole 56) as a white foam.
183 iii. The aforementioned formamide (170 mg, 0.5 mmol, 1 equiv.) was dissolved in DCM
(5.0 ml) and Et3N (1.0 ml, 7.2 mmol, 15 equiv.) and cooled to –20°C. Phosgene (20 wt% solution in toluene, 0.25 ml, 0.5 mmol, 1 equiv.) was added very slowly dropwise over 5 minutes to the cooled solution. The reaction mixture was stirred for 20 minutes at –20°C, then quenched at this temperature by the dropwise addition of saturated aqueous NaHCO3
(5 ml). The reaction mixture was partitioned between saturated aqueous NaHCO3 (15 ml) and DCM (10 ml), and the aqueous layer extracted with DCM (10 ml, 2X). The combined organic layers were washed with 1N HCl (25 ml, 2X), saturated aqueous
NaHCO3 (25 ml), brine (25 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (1:1 hexanes:Et2O) to afford isonitrile 57 (122 mg, 76%) as a colorless crystalline solid: m.p.: 75 – 78°C; TLC
1 (Et2O:hexanes, 1:1 v/v): RF = 0.43; H NMR (600 MHz, CDCl3) δ 5.68 – 5.62 (m, 2 H),
3.6 (d, J = 18 Hz, 1 H), 3.34 – 3.30 (m, 1 H), 2.31 – 2.23 (m, 2 H), 2.19 (bs, 1 H), 2.11 –
2.03 (m, 2 H), 1.97 (d, J = 6 Hz, 1 H), 1.89 – 1.85 (m, 1 H), 1.73 – 1.66 (m, 1 H), 1.63 (s,
1 H), 1.61 – 1.49 (m, 4 H), 1.45 –1.29 (m, 5 H), 0.97 (d, J = 6 Hz, 3 H), 0.90 (d, J = 6 Hz,
13 3 H), 0.89 (d, J = 6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 155.5, 129.2, 124.1, 74.6,
46.6, 42.3, 41.6, 39.2, 37.3, 36.8, 36.1, 31.4, 28.7, 25.6, 24.1, 23.7, 22.1, 21.3, 20.5; IR
-1 (film) νmax 3450, 2953, 2145, 1660, 1462, 1366, 1233, 1136, 1064, 1033, 969, 760 cm ;
+ HRMS (m/z): [M+H] calcd. for C20H32NO, 302.2478; found, 302.2467.
Compound 58: i. To a re-sealable vial was added isonitrile 57 (244 mg, 0.81mmol, 1 equiv.) and AIBN (0.4 g, 2.4 mmol, 3.0 equiv.) and the flask was evacuated then back- filled with argon. Degassed benzene (15 ml) was added followed by Bu3SnH (2.1 ml, 7.9 mmol, 9.8 equiv.). The sealed vial was placed into a 100°C oil bath for 2.5 hours. After
184 cooling, all volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 10:1 → 5:1 hexanes:Et2O) to afford the corresponding deaminated product (204 mg, 91%) as a colorless oil. ii. The aforementioned deaminated product (200 mg, 0.72 mmol, 1 equiv) was dissolved in DCM (7 ml) and KHCO3 (2.17 g, 21.6 mmol, 30 equiv.) was added. To the rapidly stirring solution was added dibromoformaldoxime (2.2 g, 10.8 mmol, 15 equiv.) as a solution in DCM (7ml) over the course of 12 hours via syringe pump. The reaction was partitioned between saturated aqueous NH4Cl (25 ml) and DCM (10 ml) and the aqueous layer extracted with DCM (10 ml, 3X). The combined organic layers were washed with brine (50 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 2:1 → 1:1 hexanes:DCM → pure DCM) to yield recovered starting material (100 mg) and compound 58 (120 mg, 83% BRSM) as a white solid: m.p.: 123–125°C; TLC
1 (Et2O:hexanes, 2:1 v/v): RF = 0.73; H NMR (600 MHz, CDCl3) δ 4.79 (d, J = 12 Hz, 1
H), 3.15 (dd, J = 6, 18 Hz, 1 H), 2.26 (d, J = 2 Hz, 1 H), 2.10 – 2.05 (m, 2 H), 2.02 – 1.97
(m, 2 H), 1.94 – 1.85 (m, 2 H), 1.70 – 1.52 (m, 4 H), 1.45 – 1.36 (m, 4 H), 1.34 – 1.27
(m, 2 H), 1.08 – 1.01 (m, 1 H), 0.97 (d, J = 6 Hz, 3 H), 0.96 (d, J = 6 Hz, 3 H), 0.90 (d, J
13 = 6 Hz, 3 H), 0.90 (d, J = 6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 146.8, 87.4, 74.7,
47.4, 44.3, 44.2, 40.3, 37.6, 36.1, 35.1, 32.6, 30.7, 29.5, 27.8, 25.8, 24.5, 22.1, 21.5, 14.2;
-1 IR (film) νmax 3574, 2957, 1573, 1456, 1374, 1264, 1238, 1096, 959, 870, 847, 724 cm ;
+ HRMS (m/z): [M+H] calcd. for C20H33BrNO2, 398.1689; found, 398.1696.
Compound 59: Bromoisoxazole 58 (110 mg, 0.28 mmol, 1 equiv.) was dissolved in
MeOH:THF (5.5:1 v/v, 3.25 ml) and NH4Cl (220 mg, 4.15 mmol, 15 equiv.) was added.
185 The heterogeneous mixture was cooled to 0°C and Zn dust (90 mg, 1.38 mmol, 5 equiv.) was added. The reaction was stirred at 0°C for 1 hour at which point additional Zn dust
(90 mg) was added. After an additional 2 hours of stirring at 0°C, the reaction was warmed to room temperature and the liquids decanted off. The solids were washed with additional Et2O (15 ml, 3X) and the combined organic layers were washed with saturated aqueous NH4Cl (50 ml), brine (50 ml), and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (1:1 hexanes:Et2O) to afford the title compound (81 mg, 92%) as an oil which slowly
1 solidified to white solid: TLC (Et2O:hexanes, 2:1 v/v): RF = 0.29; H NMR (600 MHz,
CDCl3) δ 4.05 (d, J = 6 Hz, 1 H), 3.75 (bs, 1 H), 3.43 (m, 1 H), 2.41 (dt, J = 6, 12 Hz, 1
H), 2.27 (d, J = 6 Hz, 1 H), 2.13 – 2.10 (m, 1 H), 2.05 – 2.01 (m, 1 H), 1.95 – 1.89 (m, 1
H), 1.80 (bs, 1 H), 1.74 – 1.50 (m, 7 H), 1.45 – 1.40 (m, 1 H), 1.36 – 1.25 (m, 4 H), 0.99
(d, J = 6 Hz, 3 H), 0.96 (d, J = 6 Hz, 3 H), 0.94 (d, J = 6 Hz, 3 H), 0.84 (d, J = 6 Hz, 3 H)
13 ; C NMR (150 MHz, CDCl3) δ 121.7, 76.9, 70.2, 49.3, 42.6, 39.1, 37.3, 34.7, 32.5,
31.4, 31.2, 30.4, 25.9, 25.3, 23.5, 22.3, 21.5, 20.8, 13.2; IR (film) νmax 3423, 2956, 2242,
-1 + 1726, 1456, 1373, 1058, 952, 738 cm ; HRMS (m/z): [M+H] calcd. for C20H34NO2,
320.2584; found, 320.2589.
Compound 60: Cyanide 58 (30 mg, 0.075, 1 equiv.) was dissolved in THF (0.5 ml) and cooled to 0°C under argon. LiAlH4 (1.0 M solutione in THF, 1.5 ml, 1.5 mmol, 20 equiv.) added drop-wise at 0°C over 5 minutes, and the mixture warmed to room temperature and stirred for 12 hours. The reaction mixture was cooled to 0°C, the septum removed, and 1N HCl (2 ml) was added very slowly dropwise [Caution: gas evolution occurs]. The reaction mixture was partitioned between saturated aqueous NaHCO3 (10
186 ml) and EtOAc (5 ml) and the aqueous layer thoroughly extracted with EtOAc (5 ml, 3X) and then DCM (5 ml, 3X). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo to yield amine 59 (24 mg) as an oil which was ~90% pure by
1H NMR. [Note: The 1H and 13C NMR exhibit significant line broadening]: 1H NMR
(600 MHz, CDCl3) δ 4.17 (d, J = 2 Hz, 1 H), 3.40 (bs, 1 H), 3.07 (dd, J = 6, 18 Hz, 1 H),
2.98 (dd, J = 6, 18 Hz, 1 H), 2.23 – 2.20 (m, 1 H), 2.15 – 2.00 (m, 5 H), 1.65 – 1.20 (m,
15 H), 0.98 (d, J = 6 Hz, 3 H), 0.94 (d, J = 6 Hz, 3 H), 0.92 (d, J = 6 Hz, 3 H), 0.86 (d, J
13 = 6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ 76.8, 75.7, 50.9, 46.1, 42.9, 40.2, 38.0,
34.7, 34.3, 32.8, 31.3, 30.5, 29.8, 25.9, 23.2, 22.5, 21.8, 19.7, 13.7; IR (film) νmax 3397,
2956, 1720, 1583, 1452, 1376, 1274, 1111, 954, 712 cm-1; HRMS (m/z): [M+H]+ calcd. for C20H38NO2, 324.2897; found, 320.2901.
Compound 61: Amine 60 (15 mg, 0.04 mmol, 1 equiv.) was dissolved in DCM (1.5 ml) and MgSO4 (160 mg, 1.32 mmol, 29 equiv.) added. To the rapidly stirring solution was added formaldehyde (37% aqueous solution, 30 µl, 0.4 mmol, 10 equiv.) followed by
NaBH(OAc)3 (120 mg, 0.57 mmol, 12 equiv.). The reaction was stirred for 1.5 hours then partitioned between saturated aqueous NaHCO3 (10 ml) and DCM (5ml). The aqueous layer was extracted with DCM (5 ml, 3X) and EtOAc (5 ml, 3X) and the combined organic layers were washed with NaHCO3 (25 ml), brine (25 ml), and dried (Na2SO4) to
1 afford the crude dimethylamine (17 mg). H NMR (600 MHz, CDCl3) δ 4.03 (s, 1 H),
2.34 – 2.26 (m, 3 H), 2.23 (s, 6 H), 2.06 – 2.01 (m, 5 H), 1.72 – 1.70 (m, 2 H), 1.58 –
1.26 (m, 12 H), 1.01 (d, J = 6 Hz, 3 H), 0.97 (d, J = 6 Hz, 3 H), 0.94 (d, J = 6 Hz, 3 H),
0.89 (d, J = 6 Hz, 3 H).
187 Attempted Cope elimination: The aforementioned dimethylamine 61 (2.5 mg, 0.007 mmol, 1 equiv.) was dissolved in DCM (0.25 ml) and cooled to –78°C. DMDO (~ 0.095
M solution in acetone, 80 µl, 1.1 equiv.) was added dropwise to the solution at –78°C.
The solution was stirred 15 minutes at –78°C then warmed to room temperature and the volatiles removed in vacuo to yield a new compound tentatively assigned as amine N- oxide 62 (2.5 mg). Note: Heating of this compound in DMSO failed to produce any compound 64.
Attempted Hofmann elimination: i. Dimethylamine 61 (10 mg, 0.03 mmol, 1 equiv.) was dissolved in Et2O (0.5 ml) and MeI (20 µl, 0.32 mmol, 11 equiv.) added. The reaction mixture was stirred for 5 hours at which point additional MeI (20 µl) was added and stirring continued for 12 hours. Volatiles were removed in vacuo to afford the crude quaternary ammonium iodide salt (12.4 mg). ii. The aforementioned quaternary ammonium iodide salt (2 mg, 0.004 mmol, 1 equiv) was dissolved in EtOH:H2O (1:1 v/v, 0.5 ml) and Ag2O (~2 mg, 0.008 mmol, 2.0 equiv.) was added. The reaction mixture was stirred at room temperature for 4 hours, then filtered through a cotton plug, eluting with EtOH. Volatiles were removed in vacuo to yield the tentatively assigned quaternary ammonium hydroxide salt 63 (~ 2 mg). Note:
Heating of this compound failed to produce any of olefin 64.
Compound 65: i. Nitrile 59 (48 mg, 0.15 mmol, 1 equiv.) was dissolved in wet DCM
(1.5 ml). DMP (100 mg, 0.24 mmol, 1.6 equiv.) was added and the mixture stirred rapidly for 1 hour. The reaction mixture was partitioned between saturated aqueous Na2S2O3 (5 ml) and Et2O (5 ml) and the aqueous layer extracted with Et2O (5 ml, 3X). The combined organic layers were washed with saturated aqueous NaHCO3 (25 ml, 2X), brine (25 ml),
188 and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (1:1 hexanes:Et2O) to yield the corresponding ketone (30 mg, 63%) which exists in solution as a mixture of keto and enol tautomers. ii. The aforementioned ketone (3.5 mg, 0.01, 1 equiv.) was dissolved in DCM (0.25 ml) followed by the addition of pyridine (5 µl, 0.06 mmol, 5.6 equiv). The solution was cooled to 0°C and PhSeBr (7 mg, 0.03 mmol, 3 equiv.) added. The reaction mixture was stirred at 0°C for 15 minutes, then warmed to room temperature. The reaction mixture was directly loaded onto a preparatory thin-layer chromatography plate (developed with
2:1 Et2O:hexanes) to afford enone 65 (3.0 mg, 86%) as an oil: TLC (Et2O:hexanes, 1:1
1 v/v): RF = 0.14; H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 6 Hz, 1 H), 2.77 (d, J = 6 Hz,
1 H), 2.58 (d, J = 6 Hz, 1 H), 2.29 – 2.27 (m, 1H), 2.20 – 2.16 (m, 1 H), 2.06 – 1.98 (m, 2
H), 1.60 – 1.54 (m, 1 H), 1.48 – 1.21 (m, 9 H), 1.05 (d, J = 6 Hz, 3 H), 1.04 (d, J = 6 Hz,
13 3 H), 0.93 (d, J = 6 Hz, 3 H), 0.91 (d, J = 6 Hz, 3 H); C NMR (150 MHz, CDCl3) δ
195.5, 163.0, 118.5, 114.8, 76.2, 56.2, 46.1, 42.9, 41.8, 36.0, 34.7, 32.4, 30.0, 28.9, 28.6,
+ 25.9, 23.8, 21.9, 20.7, 13.9; HRMS (m/z): [M+H] calcd. for C20H29NO2Na, 338.2090; found, 320.2091.
Compound 67: Enone 65 (21 mg, 0.07 mmol, 1 equiv.) was dissolved in DCM (1 ml) and cooled to –78°C. DIBAL (1.5 M solution in toluene, 0.1 ml, 0.15 mmol, 2.3 equiv.) was added dropwise and the mixture stirred at –78°C for 1 hour. EtOAc (2.5 ml) and saturated aqueous Rochelle’s salt solution (2.5 ml) were added at –78°C and the reaction mixture was warmed to room temperature and stirred vigorously for 2 hours. The reaction mixture was partitioned between EtOAc (2.5 ml) and saturated aqueous Rochelle’s salt solution (5 ml) and the aqueous layer extracted with EtOAc (5 ml, 2X). The combined
189 organic layers were washed with brine (20 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by preparative thin-layer silica gel chromatography (3:1 Et2O:hexanes) to afford title compound 67 (12 mg, 57%) as a white solid.
Compound 70: Olefin 69 (125 mg, 0.45 mmol, 1 equiv.) was dissolved in dioxanes (10 ml) and SeO2 (100 mg, 0.90 mmol, 2.0 equiv.) added. The mixture was heated to 100°C under at atmosphere of N2 for 4 hours. Upon cooling, the reaction mixture was partitioned be 1N HCl (25 ml) and Et2O (25 ml), and the aqueous layer thoroughly extracted with Et2O (10 ml, 5X). The combined organic layers were washed with saturated aqueous Na2S2O3 (50 ml), saturated aqueous NaHCO3 (50 ml), brine (50 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 3:1 → 2:1 → 1:1 hexanes:Et2O) to afford the title diol 70 (70 mg, 53%) as a white foam: TLC (Et2O:hexanes, 2:1 v/v): RF = 0.39;
1 H NMR (600 MHz, CDCl3) δ 5.92 – 5.84 (m, 2 H), 4.19 (s, 1 H), 3.36 (bs, 1 H), 2.30 (s,
1 H), 2.19 (s, 1 H), 2.12 – 2.09 (m, 1 H), 1.97 – 1.93 (m, 2 H), 1.64 – 1.56 (m, 1 H), 1.55
– 1.51 (m, 1 H), 1.47 – 1.26 (m, 8 H), 1.20 – 1.13 (m, 1 H), 1.02 (d, J = 6 Hz, 3 H), 1.00
(d, J = 6 Hz, 3 H), 0.92 (d, J = 6 Hz, 3 H), 0.88 (d, J = 6 Hz, 3 H); HRMS (m/z): [M+H]+ calcd. for C19H32O2Na, 315.2294; found, 315.2297.
Compound 72: i. Diol 70 (72 mg, 0.25 mmol, 1 equiv.) was dissolved in DCM (2.5 ml) followed by the addition of 5% aqueous NaHCO3 (1.0 ml), KBr (3 mg, 0.025 mmol, 0.10 equiv.) and TEMPO (4 mg, 0.025, 0.10 equiv.). The biphasic mixture was cooled to 0°C and bleach (commercial bleach solution, 6% NaOCl, 0.61 ml, 0.5 mmol, 2 equiv.) was added dropwise to the rapidly stirring mixture. The reaction mixture was stirred for 45
190 minutes at 0°C, then partitioned between saturated aqueous Na2S2O3 (10 ml) and DCM
(10 ml). The aqueous layer was extracted with DCM (10 ml, 2X) and the combined organic layers were washed with brine (25 ml) and dried (MgSO4). Volatiles were removed in vacuo to yield the crude enone (71 mg) as a white foam that was sufficiently
1 pure for the next step. TLC (Et2O:hexanes, 2:1 v/v): RF = 0.27; H NMR (600 MHz,
CDCl3) δ 6.82 (dd, J = 6, 12 Hz, 1 H), 5.97 (dd, J = 2, 12 Hz, 1 H), 2.61 (s, 1 H), 2.54
(m, 1 H), 2.06 – 2.01 (m, 1 H), 1.73 – 1.68 (m, 1 H), 1.65 – 1.36 (m, 11 H), 1.02 (d, J = 6
Hz, 3 H), 0.95 (d, J = 6 Hz, 3 H), 0.94 (d, J = 6 Hz, 3 H), 0.89 (d, J = 6 Hz, 3 H); 13C
NMR (150 MHz, CDCl3) δ 203.6, 150.5, 126.5, 76.5, 55.7, 46.7, 41.8, 36.2, 34.7, 32.5,
31.0, 29.9, 28.7, 25.6, 25.0, 24.0, 21.5, 21.3, 13.5; IR (film) νmax = 3432, 2955, 1701,
1665, 1461, 1388, 1372, 1299, 1243, 1150, 1094, 1061, 971, 945, 774; HRMS (m/z):
+ [M+H] calcd. for C19H30O2, 291.2318; found, 291.2320. ii. The aforementioned enone (71 mg, 0.24 mmol, 1 equiv.) was dissolved in DCM (2.5 ml) and cooled to –78°C. DIBAL (1.5 M solution in toluene, 0.8 ml, 1.2 mmol, 5 equiv.) was added slowly dropwise and the solution stirred for 1 hour at –78°C. EtOAc (5 ml) and saturated aqueous Rochelle’s salt solution (5 ml) were added and the reaction warmed to room temperature and stirred vigorously for 2 hours. The reaction mixture was partitioned between EtOAc (10 ml) and saturated aqueous Rochelle’s salt solution (10 ml) and the aqueous layer extracted with EtOAc (5 ml, 3X). The combined organic layers were washed with brine (25 ml), dried (MgSO4), and the solvent removed in vacuo. The crude material was purified by silica gel flash chromatography (gradient from 3:1 → 2:1
→ 1:1 hexanes:Et2O) to afford title compound 72 (37 mg, 52%) as a white solid. m.p. =
1 160°C; TLC (Et2O:hexanes, 2:1 v/v): RF = 0.18; H NMR (600 MHz, CDCl3) δ 5.66 (m,
191 2 H), 4.91 (s, 1 H), 2.45 (d, J = 6 Hz, 1 H), 2.10 (m, 2 H), 1.94 – 1.89 (m, 1 H), 1.75 –
1.70 (m, 2 H), 1.56 – 1.51 (m, 1 H), 1.48 – 1.35 (m, 5 H), 1.31 – 1.22 (m, 4 H), 1.11 –
13 1.09 (m, 1 H); C NMR (150 MHz, CDCl3) δ 129.1, 129.1, 76.8, 69.4, 46.0, 42.6, 42.5,
36.7, 34.6, 32.6, 31.5, 30.5, 28.7, 26.6, 25.1, 24.3, 23.9, 23.3, 13.7; IR (film) νmax = 3476,
3300, 2957, 1706, 1459, 1372, 1296, 1274, 1225, 1145, 1052, 1033, 935, 867, 761;
+ HRMS (m/z): [M+H] calcd. for C19H32O2Na, 315.2294; found, 315.2292.
Compound 73: Diol 72 (37 mg, 0.13 mmol, 1 equiv.) was dissolved in DCM (2.5 ml) and KHCO3 (500 mg, 5.0 mmol, 40 equiv.) added. To the rapidly stirring solution was added dibromoformaldoxime (511 mg, 2.5 mmol, 20 equiv.) as a solution in DCM (2.0 ml) over the course of 10 hours via syringe pump addition. The reaction mixture was stirred an additional 4 hours before being partitioned between saturated aqueous NH4Cl
(10 ml) and DCM (5 ml). The aqueous layer was extracted with DCM (5 ml, 3X) and the combined organic layers washed with brine (25 ml) and dried (MgSO4). Volatiles were removed in vacuo and the crude material purified by silica gel to yield recovered starting material (20 mg) and title compound 73 (12 mg, 50% BRSM) as a white solid along with
1 it regioisomer (inseparable 3:2 mixture): TLC (Et2O:hexanes, 2:1 v/v): RF = 0.18; H and
13C NMR cannot be individually assigned due to severely overlapping regions, spectra are included; IR (film) νmax = 3497, 2956, 1576, 1457, 1374, 1261, 1226, 1117, 1060,
+ 991, 932, 840, 743; HRMS (m/z): [M+H] calcd. for C20H32O2BrNa, 436.1458; found,
436.1464.
Compound 75: Amine 60 (2.5 mg, 0.008 mmol, 1 equiv.) was dissolved in 1:2
AcOH:Ac2O (v:v, 0.3 ml) and cooled to 0°C. NaNO2 (11.0 mg, 0.16 mmol, 20 equiv) was added and the solution stirred for 2 hours at 0°C. The reaction was partitioned
192 between NaHCO3 (5.0 ml) and DCM (2.0 ml) and the aqueous layer extracted with DCM
(2.0 ml, 5X). The combined organic layers were washed with saturated aqueous NaHCO3
(10 ml, 3X), brine (10 ml), and dried (MgSO4). The solvent was removed in vacuo and the crude material re-dissolved in MeOH (0.5 ml). Dry, powdered K2CO3 (5.0 mg) was added and the mixture stirred for 1 hour at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl (2.5 ml) and DCM (1.0 ml) and the aqueous layer extracted with DCM (1.0 ml, 3X). The combined organic layers were washed with brine (5.0 ml) and dried (MgSO4). The solvent was removed in vacuo and the crude material purified by preparative thin-layer chromatography (developed with
1 Et2O) to yield the title compound (0.5 mg, ~20%) as a solid: H NMR (600 MHz, CDCl3)
δ 4.07 (s, 1 H), 3.94 (bs, 1 H), 3.87 (dd, J = 4, 12 Hz, 1 H), 3.72 (dd, J = 4, 12 Hz, 1 H),
2.84 (bs, 1 H), 2.30 – 2.27 (m, 1 H), 2.17 – 2.16 (m, 1 H), 2.15 – 2.11 (m, 1 H), 2.09 –
2.04 (m, 2 H), 1.96 – 1.94 (m, 1 H), 1.67 – 1.42 (m, 8 H), 1.33 – 1.25 (m, 5 H); HRMS
+ (m/z): [M+Na] calcd. for C20H36O3Na, 347.2556; found, 347.2554.
193 2.8 Appendix to Chapter 2: Spectra
194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 Appendix: Curriculum Vitae and Selected Publications
255 Curriculum Vitae
Thomas J. Maimone
Date/Place of Birth: 13 Feb 1982 / Warsaw, NY, USA Citizenship: United States
Education
2005 - 2009 Ph.D. Graduate Student in Chemistry
Advisor: Professor Phil S. Baran
The Scripps Research Institute
GPA (4.0/4.0)
2002 - 2004 B.S. with High Honors in Chemistry
Advisor: Professor Dirk Trauner
University of California, Berkeley
GPA (3.9/4.0)
2000 - 2002 Undergraduate Student in Chemistry
University at Buffalo, SUNY
GPA (4.0/4.0)
Awards & Honors
• NIH Ruth L. Kirschstein Postdoctoral Fellow, 2009
• Roche Excellence in Chemistry Award, Scripps, 2008
• ACS Division of Organic Chemistry Fellowship (Pfizer Sponsored), 2008
• Bristol-Myers Squibb Graduate Fellowship, Scripps, 2007
• Erich O. & Elly M. Saegebarth Prize in Chemistry, UC Berkeley, 2004
• Golden Key National Honor Society, UC Berkeley, 2003
• Summer Undergraduate Research Award, UC Berkeley, 2003
• Dr. M. Heger-Horst Scholarship, UC Berkeley, 2002
256 • Merck Index Award for Excellence in Organic Chemistry, SUNY Buffalo, 2002
• CRC Press Award for Excellence in General Chemistry, SUNY Buffalo, 2001
Publications
1. Maimone, T. J.; Voica, A. F.; Baran, P. S. A Concise Approach to Vinigrol. Angew.
Chem. Int. Ed. 2008, 47, 3054-3056.
2. Richter, J. M, Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.;
Baran, P. S. Scope and Mechanism of Direct Indole and Pyrrole Couplings Adjacent
to Carbonyl Compounds: Total Synthesis of Acremoauxin A and Oxazinin 3. J. Am.
Chem. Soc. 2007, 129, 12857-12869.
3. Baran, P. S.; Maimone, T. J.; Richter, J. M. Total Synthesis of Marine Natural
Product Without Using Protecting Groups. Nature. 2007, 446, 404-408.
4. Malerich, J. P.; Maimone, T. J.; Elliot, G. M.; Trauner, D. Biomimetic Synthesis of
Antimalarial Naphthoquinones. J. Am. Chem. Soc. 2005, 127, 6276 – 6283.
5. Maimone, T. J.; Baran, P. S.; Modern Synthetic Efforts Toward Biologically Active
Terpenes. Nat. Chem. Bio. 2007, 3, 396-407.
6. Baran, P. S.; Maimone, T. J. A Tuxedo for Iodine Atoms. Nature. 2007, 445, 826-
827.
257