Facile Access to Bridged Ring Systems via Point-to-Planar Chirality

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Facile Access to Bridged Ring Systems via Point-to-Planar Chirality Transfer: Unified Synthesis of Ten Cyclocitrinols Yu Wang, Wei Ju, Hailong Tian, Suyun Sun, Xinghui Li, Weisheng Tian, and Jinghan Gui J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00925 • Publication Date (Web): 03 Mar 2019 Downloaded from http://pubs.acs.org on March 3, 2019

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Journal of the American Chemical Society

Facile Access to Bridged Ring Systems via Point-to-Planar Chirality Transfer: Unified Synthesis of Ten Cyclocitrinols Yu Wang, Wei Ju, Hailong Tian, Suyun Sun, Xinghui Li, Weisheng Tian and Jinghan Gui* CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shang-hai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-ling Road, Shanghai 200032, China ABSTRACT: Bridged ring systems are found in a wide variety of biologically active molecules, including pharmaceuticals and natural products. However, the development of practical methods to access such systems with precise control of the planar chirality presents considerable challenges to synthetic chemists. In the context of our work on the synthesis of cyclocitrinols, a family of steroidal natural products, we herein report the development of a point-to-planar chirality transfer strategy for preparing bridged ring systems from readily accessible fused ring systems. Inspired by the proposed pathway for biosynthesis of cyclocitrinols from ergosterol, our strategy involves a bioinspired cascade rearrangement, which enabled the gram-scale synthesis of a common intermediate in nine steps and subsequent unified synthesis of 10 cyclocitrinols in an additional one to three steps. Our work provides experimental support for the proposed biosynthetic pathway and for the possible interrelationships between members of the cyclocitrinol family. In addition to being a convenient route to 5(10→19)abeo-steroids, our strategy also offers a generalized approach to bridged ring systems via pointto-planar chirality transfer. Mechanistic investigations suggest that the key cascade rearrangement involves a regioselective ring scission of a cyclopropylcarbinyl cation, rather than a direct Wagner–Meerwein rearrangement.



INTRODUCTION

Natural products have long been invaluable sources of inspiration for drug discovery.1 An estimated 49% of the cancer drugs approved from the 1940s to the end of 2014 were either natural products or their derivatives.2 However, the structural diversity and complexity of natural products often limits their therapeutic utility, owing to the lack of efficient syntheses and the resulting difficulty in obtaining sufficient quantities for clinical use.3 One strategy for addressing this challenge is to develop methods for a unified synthesis of a family of natural products and unnatural congeners in useful quantities. Successful execution of this strategy entails concise, large-scale preparation of a late-stage common intermediate that can then undergo various transformations to generate target molecules.4 Bridged ring systems are found in a wide variety of pharmaceuticals and biologically active natural products, including taxol (1),5 ingenol (2),6 berkeleyone A (3),7 CP263,114 (4),8 and N-methylwelwitindolinone C (5, 6)9 (Fig. 1A). It is noteworthy that although terpene natural products with bridged ring systems are common, steroidal natural products10 with bridged ring substructure are rare, with one exception being the cyclocitrinols (Fig. 1B, 7–16), which feature an intriguing bicyclo[4.4.1]undecane A/B ring system and a bridgehead double bond.11 In 2000, Gräfe and co-workers isolated the first member of this family, cyclocitrinol (7), from a terrestrial Penicillium citrinum, although the structure was incorrectly assigned at that time (not shown).12 The correct structure was determined by Crews and co-workers in 2003, who isolated isocyclocitrinol A (10) from a sponge-derived P. citrinum.13 Later, Zhu and co-workers isolated and elucidated the structure, biosynthetic pathway, and biological activities of a series of C25 steroids with the bicyclo[4.4.1]undecane A/B rings, including 24-epi-cyclocitrinol (8), 24-oxo-cyclocitrinol

(9), isocyclocitrinol B (11), and neocyclocitrinols A–D (12– 15).14 In addition, norcyclocitrinol (16), the first C25 steroid combining a bicyclo[4.4.1]undecane A/B ring system with a bisnor side chain, was isolated by Zhan and co-workers from the culture broth of P. chrysogenum P1X.15 Importantly, in vitro experiments showed that several cyclocitrinols (7, 8, 13, and 14) induce the production of cAMP in GPR12-transfected CHO cells at 10 μM, indicating the therapeutic potential of these compounds for various neurological disorders, including spinal cord injuries and stroke.14 Construction of the bridged ring system is clearly the central synthetic challenge posed by cyclocitrinols. Compared with fused ring systems, bridged systems are generally more difficult to access, owing to ring strain. Moreover, control of the planar chirality in bridged systems is a formidable task, especially in the context of the synthesis of complex natural products.16 Therefore, the development of practical methods for the preparation of bridged systems has been a focus of organic chemists for several decades, and a number of elegant strategies have been reported, including ring closing metathesis,17 intramolecular Diels–Alder reaction,18 intramolecular Michael addition,19 Pauson–Khand reaction,20 pinacol rearrangement,6d, 21 C–H bond insertion,22 and C–C bond activation.23 Nevertheless, general protocols for building bridged ring systems from readily accessible fused ring systems are scarce,24 particularly with concomitant installation of the planar chirality. Development of such protocols would simplify installation of the core framework of natural products via skeletal rearrangements of easily prepared precursors and would allow for establishment of the necessary planar chirality via point-toplanar chirality transfer.25 For this purpose, we have explored the preparation of bridged bicyclo compound 23 or 24 using fused bicyclo compound 17

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A. Selected natural products with bridged ring systems

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BzHN

Me

O

Ph

Me

O OH

O MeOH

Me

HO

H BzO AcO

Me

Me

O

Me

Me

O

HO HO HO

O O

COOMe

H

Cl

O

OH Me

H H

Me

Me

O

Me

H

AcO

H

O

O O

Me

Me 2

O

R H

O

Me

H Me Me H O

taxol (1)

ingenol (2)

berkeleyone A (3)

CP-263,114 (phomoidride B) (4)

N Me N-methylwelwitindolinone C R = NCS (5), NC (6)

bicyclo[5.3.1]

bicyclo[4.4.1]

bicyclo[3.3.1]

bicyclo[4.3.1]

bicyclo[4.3.1]

O

HO

OH

H Me Me

5

COOH

B. Structures of cyclocitrinol family natural products (bicyclo[4.4.1] steroids) Me OH Me H

H

Me OH Me H

OH Me

H

H HO

HO

HO

H

H

Me

HO

HO

Me

H

H

HO

OH

Me Me

H

H

HO

HO

Me

H

Me Me H

HO

10

cyclopropane well explored scission R

cyclopropane formation R

n

17 (n = 1, 2) (LG: leaving group)

n

a

b cyclopropylcarbinyl cation (18)

fused ring systems: readily accessible

n

H

n

H HO

R n

20

OH

O norcyclocitrinol A (16)

This work:  10 cyclocitrinols (7-16) synthesized  10-12 steps overall

21

X

 Scalable & concise & divergent  Amenable to the synthesis of analogs

path b underdeveloped

Me OH Me H

H

O

R or

19

O isocyclocitrinol B (11)

OH

neocyclocitrinol D (15)

R

Me

Me

C. Access to bridged ring systems via point-to-planar chirality transfer LG

HO

H

neocyclocitrinol C (14)

path a

H

H

HO

OH

O

neocyclocitrinol B (13)

Me

O isocyclocitrinol A (10)

H

O

neocyclocitrinol A (12)

H

OH Me OH Me H

H

HO

H

O

Me

O 24-oxocyclocitrinol (9)

Me

Me

OH

OH Me OH Me H

O

H

O 24-epi-cyclocitrinol (8)

H HO

Me

H

O cyclocitrinol (7)

Me Me

Me OH Me H

OH

R n

22

R  Regiocontrolled synthesis of 23 or 24  Point-to-planar chirality transfer

R or n

23

n

24

 Mechanistic studies

bridged ring systems: synthetically challenging

Figure 1. Representative natural products with bridged ring systems, including cyclocitrinols, and modular strategies for their synthesis. Previous Work and Key Considerations. The interesting as a starting material. This compound has a leaving group at the biological activity profile and structural complexity of the angular methyl position and is thus prone to undergo cyclocitrinols have drawn significant attention from synthetic cyclopropanation to afford cyclopropylcarbinyl cation 18,26 chemists over the past decade. Several elegant approaches to the which usually gives rise to ring-expanded fused bicyclo compound 20 or 21 via rearranged cyclopropylcarbinyl cation construction of the cyclocitrinol core framework have been 19 (Fig. 1C, path a).27 However, cyclopropylcarbinyl-homoallyl reported, including Schmalz’s SmI2-mediated cyclopropane fragmentation,31 Leighton’s tandem ring-contracting Ireland– cation isomerization28 of 18 would lead instead to 23 or 24 via homoallylic cation 22 (path b), a path that is much less Claisen/Cope rearrangement sequence,32 and Li’s type II intramolecular oxidopyrylium-mediated [5+2] cycloaddition developed, because of the ring strain in these bridged ring (Scheme 1).33 Li and co-workers recently reported the first total species.29 Of critical importance in this path is complete transfer of the point chirality of the quaternary carbon (C10) of 17 to the synthesis of cyclocitrinol, starting from a vitamin D2 planar chirality of 23 or 24. Recently, we reported a synthesis degradation product, highlighting the synthetic utility of of cyclocitrinol (7) via a bioinspired cascade rearrangement, a intramolecular cycloadditions for the synthesis of complex chemical transformation that proceeds by way of path b.30 natural products.34 Herein, we present our work on the development of a unified Our synthetic interest in cyclocitrinols derives from their synthesis of 10 cyclocitrinols (7–16) in only 10–12 steps from fascinating biosynthesis (see below) and a desire to procure a commercially available compound (pregnenolone). We useful quantities of various cyclocitrinols for investigation of describe the evolution of this bioinspired strategy, the synthesis their biological activity. To accomplish this goal, we sought (1) of various 5(10→19)abeo-steroids, and our studies of the to develop a concise, bioinspired, gram-scale route to a latemechanism of the key cascade rearrangement. Furthermore, we stage common intermediate bearing the core structure; (2) to demonstrate that point-to-planar chirality transfer can be transform this intermediate into a variety of cyclocitrinols and utilized as a general strategy for access to bridged ring systems. unnatural congeners; and (3) to extend the route to the synthesis  RESULTS AND DISCUSSION of other bridged ring systems.


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Journal of the American Chemical Society 2A).35 Alternatively, the migration of C5 could also proceed in two steps, via 5,19-cyclopropane formation to form 33 and subsequent cleavage of the C5–C10 bond. Likewise, activation of the C19 Me group combined with migration of C9 from C10 to C19 or stepwise 9,19-cyclopropane formation followed by fragmentation could lead to 9(10→19)abeo-steroid 36,36 which is the core structure of compounds such as cortistatin A (37)37 and propindilactone G (38).38 The landmark synthesis of 37 from prednisone by Baran and co-workers has validated the proposed route for biosynthesis of 9(10→19)abeo-steroids.37a However, experimental support for the biosynthesis of 5(10→19)abeo-steroids from classical steroids is lacking. Consistent with the above-described biosynthesis, the biosynthesis of cyclocitrinol (7) from ergosterol (39) has been proposed to start with enzymatic activation of the C19 Me group to afford 40 (Scheme 2B).35 The C5–C6 olefin of 40 can then act as a nucleophile in a C5–C19 bond-forming reaction facilitated by concomitant oxidation at C6 to give 41. Subsequent cyclopropane fragmentation induced by deprotonation at C1 gives rise to the core structure of 7. Oxidations at C22, C23, and C25 of 39 and elimination of acetone by C24–C25 bond cleavage generate the carbon skeleton of the cyclocitrinol side chain. Based on this proposed biosynthesis of 7, our initial retrosynthetic analysis is outlined in Scheme 2C. Because cyclocitrinols 7–16 possess a common parent skeleton (Fig. 1B), we devised a unified synthetic strategy for accessing all these compounds from enone 42. We envisioned that 42 could be prepared via a regioselective cyclopropane fragmentation reaction of cyclopropyl enone 43. Furthermore, we postulated that 43 could be

Scheme 1. Previous Synthetic Studies toward Cyclocitrinola Schmalz (2007): SmI2-mediated cyclopropane fragmentation Me O

Me O H

SmI2, THF r.t., 2 min

H H

H H

43%

O

O

25

O

H

26

O

Leighton (2014): tandem Ireland-Claisen/Cope rearrangement

Me

O O

H

H

O H

2) 1 N HCl 3) TMSCHN2

OH 27

TIPSO

Me

1) Me2PhSiCl, DBU PhCF3, 140oC

TIPSO

38%

O

OMe

28

Li (2015): type II intramolecular [5+2] cycloaddition Li (2018): first completed synthesis Me Me H

O

OMe OMe 1) Ac2O

H

2) TMP, 155 oC

OH

68%

H O

OH

OMe

Me Me H

O

OMe

H

O

OH

H

OH

OAc 30

H

29 a

Abbreviations: DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, TMP = 2,2,6,6tetramethylpiperidine.

Retrosynthetic Analysis. The inspiration for our initial retrosynthetic analysis was largely drawn from the biosynthesis of rearranged abeo-steroids. Biosynthetically, the 5(10→19)abeo-steroid skeleton (34), like that of cyclocitrinol (7), is thought to derive from enzymatic activation of the C19 Me group of classical steroidal skeleton 31 to give 32, followed by migration of C5 from C10 to C19 to afford 34 (Scheme Scheme 2. Proposed Biosynthesis and Unified Retrosynthetic Analysis of Cyclocitrinols A. Unified biosynthesis of abeo-steroid Me 19

Me

H

H

Representative 9(1019)abeo-steroids: Me

enzymatic activation of C19 Me

X 19 10

H

5

31 H classical steroid

19

H

H

10 5

5 34 5(1019)abeo-steroid

9H

10

H 32

H C9 migration from C10 to C19

N

Me HO

H

19 9 10

HO

35

cyclopropane fragmentation

O

Me2N

H

cortistatin A (37) O

Me


H

19 H

H

cyclopropane formation

Me 10


9H

H

C5 migration from C10 to C19

Me

Me

19

9H

10

H 19 33

O

H O

H 9

H H 36 9(1019)abeo-steroid

Me

1 0

HO 19

Me

Me

Me

9

H OH

H

MeH

O

O

O

propindilactone G (38)

B. Proposed biosynthesis of cyclocitrinol (5(1019)abeo-steroid) from ergosterol Me Me 19

H

23

24

25 Me

Me

C19 Me activation

X H HO

H

ergosterol (39)

H

40

C. Bioinspired and unified retrosynthetic analysis of cyclocitrinols Me O Me cyclopropane side chain fragmentation installation cyclocitrinols (7-16) H AcO

Me Me H

H O

42


H

HO [O]

O

H

O

41

cyclopropane formation & C6 oxidation

O 43

Me Me LG


O

O

cyclocitrinol (7)

Me Me Me

44 LG: leaving group

24 Me

C19 Me oxidation & introduction of C7-C8 olefin

8H 7

OH

H

HO

H AcO

H

& side chain oxidation

H 6

H AcO

Me OH Me H

Me

cyclopropane formation & C6 oxidation

Me

Me H

HO

Me

22

H

O

H H

HO

pregnenolone (45), $0.32/gram

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

46 to furnish 47 proved to be far from trivial (Scheme 3B). Surprisingly, when 46 was subjected to the standard Suárez conditions,42 iodide 54 was obtained in 84% yield. In contrast, treatment of 46 with Pb(OAc)4 and benzoyl peroxide (BPO) in refluxing benzene (Tanabe’s conditions) furnished 47 in only 16% yield (entry 1).43 Extensive optimization experiments revealed that 47 could be obtained in 58% yield by increasing the amounts of the two reagents (entry 2). Replacement of BPO with azobisisobutyronitrile or benzene with cyclohexane proved unfeasible (entries 3 and 4), and use of (diacetoxyiodo)benzene as the oxidant led to low conversion (entry 5). Ultimately we found that addition of Pb(OAc)4 (3 equiv total) and BPO (0.6 equiv total) in three portions separated by 1 h reproducibly afforded 47 in 62% yield on a gram scale (entry 6). Acidcatalyzed solvolysis of 47 then generated 48 in 49% yield over two steps. This improved four-step sequence constituted an efficient and scalable route to 48 with simplified purification and set the stage for introduction of the C7–C8 olefin in the B ring. We envisioned that the C7–C8 olefin could be introduced by allylic bromination of the C5–C6 olefin to give a C7 allylic bromide, followed by HBr elimination. To test the feasibility of this approach, we phosphorylated the C19 hydroxyl group of 48 (affording 49) to install a leaving group at this position. Although allylic bromination of 49 proceeded smoothly, subsequent HBr elimination under various conditions generated a mixture of the C4–C6 and C5–C7 dienes, with a preference for the former, undesired isomer. To address this issue, we treated the mixture obtained from the allylic bromination of 49 with tetra-n-butylammonium bromide and p-toluenethiol (Confalone’s conditions)44 to generate allylic sulfide 50 in 80% yield (on a 3 g scale), which was expected to produce the C7– C8 olefin via oxidation of the sulfide and subsequent sulfoxide elimination. Forays into the Bridged Ring System. Oxidation of 50 with m-chloroperoxybenzoic acid (m-CPBA) gave a pair of diastereomers, which were subjected to thermal elimination to afford diene 55 in 47% yield (Scheme 4). Treatment of 55 with

accessed by means of intramolecular cyclopropanation of diene 44, followed by C6 oxidation. Finally, 44 could be traced back to commercially available pregnenolone (45) via oxidation of the C19 methyl group and introduction of the C7–C8 olefin. Pregnenolone is an excellent starting material owing to its low cost ($0.32/gram), ready availability, and remarkable structural similarity to advanced intermediate 42, missing only the A/B ring system. The challenges posed by this strategy for cyclocitrinol synthesis are the skeletal rearrangement of the pregnenolone A/B ring system, including functionalization of the C19 Me group, oxidation of the B-ring, installation of the 5,19-cyclopropane, and its regioselective fragmentation. C19 Me Group Functionalization and B-Ring Oxidation. Selective oxidation of the C19 Me group is a classic problem in steroid semisynthesis, and several strategies for this transformation have been developed, including remote radical functionalization directed by the C1β, C6β, or C11β hydroxyl group and Norrish type II photochemistry of the C11 ketone.39 We posited that the C5–C6 olefin of 45 could be easily elaborated to the C6β hydroxyl group, which could then be used to affect oxidation of the C19 Me group via a 1,5-hydrogen atom transfer reaction of a C6β alkoxy radical. Indeed, Terasawa and Okada used this strategy to prepare desired intermediate 48 in three steps from pregnenolone acetate 51 (Scheme 3C).40 However, our attempts to repeat this route revealed scalability and purification issues; specifically, the poor regio- and stereoselectivities of the bromohydroxylation of the C5–C6 olefin led to the formation of multiple side products, which complicated purification when the reaction was carried out on a large scale. These issues deterred us from using this approach for the large-scale preparation of bromohydrin 52, thereby prompting us to develop an alternative route to 48. The alternative route involved introduction of the C6β hydroxyl group via a known two-step sequence consisting of tosylation of 45 and solvolysis under basic conditions, which afforded cyclopropylcarbinol 46 in 80% yield (on a 10 g scale) (Scheme 3A).41 Subsequent remote radical functionalization of Scheme 3. Synthesis of C19 Functionalized Allylic Sulfide 50 A. Synthetic route

Me Me

19

Me

1) TsCl, Py

H

H HO

pregnenolone (45)

Me (PhO)2OPO 19 H 4

5

O

H

6

8

H

50

3) Pb(OAc)4 BPO see Scheme 3B for optimization

H

6

H

Me H H

AcO

AcO pregnenolone acetate (51)

AcO

H Br

O

O

5) (PhO)2POCl 93%

H AcO

OH 52

Br

solvent

isolated yield of 47 (%)

1a

1.4

0.07

benzene

2

3

0.6

benzene

58

3

3

AIBN (0.6)

benzene

trace

16

4

3

0.6

cyclohexane

NRb

5

DIB (3)

0.6

benzene

19 (71)c

48

6d

1.0*3

0.2*3

benzene

62

Me H

H 54

H

Me

O

Bromohydroxylation issues: 3) Zn, HOAc

H O

AcO

O

H H

H 6

Me Me

HO 19

H

Pb(OAc)4 BPO (equiv) (equiv)

O

H

I

47 entry

Me

84%

Pb(OAc)4 BPO

H

[6.9 g scale]

49

bromohydroxylation

H

Me Me

DIB, I2, hv

46

4) BF3Et2O, AcOH 49% (2 steps) [4 g scale]

C. Terasawa: previous approach to the synthesis of C19 hydroxyl intermediate 48 Me Me O O Me Me 1) NBA, 2) Pb(OAc)4, I2 HClO4 (aq) hv, reflux Me H Me H H

19

47

Me 6) DBDMH TBAB, TolSH (PhO)2OPO

O

Me

46

OH

B. Optimization of the C19 Me oxidation

Me

O

H

80% [3 g scale]

H

7 STol

Me

2) K2CO3, H2O 80% (2 steps) [10 g scale]

H

Me

AcO

Me Me

O

Page 4 of 14

H 53

a

1) multiple side products 2) optimal yield: ca. 50%

35% (3 steps)

3) poor regio- and stereoselectivities 48

4) complicated product purification 5) bromohydrin 52 not stable

Reported condition in ref. 43. bNo reaction. cIsolated yield of recovered 46 shown in parenthesis. dReaction performed on gram scale. Abbreviations: Ts = tosyl, BPO = benzoyl peroxide, DIB = (diacetoxyiodo)benzene, AIBN = 2,2'-azo-bis-isobutyronitrile, DBDMH = 1,3-dibromo-5,5-dimethylhydantoin, TBAB = tetra-n-butylammonium bromide, TolSH = ptoluenethiol, NBA = N-bromoacetamide.


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Scheme 4. Initial Forays into Bridged Ring Systems Me

Me Me

O

Me

1) m-CPBA

(PhO)2OPO

H H

2) DABCO toluene, 70 oC 47%

H

AcO

STol

(PhO)2OPO 8

H

H

7) DBU toluene, 50 oC

AcO

6

O

43

86% (desired product 42 not obtained)

H

AcO

6

OH 5) CDCl3, rt 2 days >99%

O

6) BH3, NaBO3 7) DMP

H

21% (2 steps)

H 6

AcO

O

O

Me

H

H H

AcO

6

O 59

Me O H

BF3Et2O Ac2O DCM, 20 oC

Me

H

[X-ray]

57

various conditions

6

Me Me

desired product (not obtained):

H

90% AcO

O

6

60

61

Me Me

O

O

H H

H

H

AcO

OAc

43

O

Schmalz: attempted cyclopropyl ketone fragmentation Me

6

56

H

AcO

58

H AcO

Me Me

O

H

23% (4 steps)

H

55

O

H

4) Jones oxidation

H

44%

Me Me

Me Me

O

Me

3) K2CO3 Acetone/H2O

7

AcO

50

Me Me

Me O

AcO

OAc

H 6

O

6 2

H AcO

H 6

42

O

Abbreviations: m-CPBA = meta-chloroperbenzoic acid, DABCO = 1,4-diazabicyclo[2.2.2]octane, DMP = Dess-Martin periodinane.

base in aqueous acetone delivered cyclopropylcarbinol 56, which was oxidized with Jones reagent to generate desired enone 43 in 23% yield over four steps. After confirming the structure of 43 by X-ray crystallographic analysis, we investigated the key cyclopropane fragmentation to access the core bridged ring system. Disappointingly, desired product 42 was not observed under any of the various conditions we tried (including acidic or basic conditions and microwave heating conditions), with the only products being those resulting from epimerization at the allylic position. Schmalz and co-workers investigated a similar cyclopropyl ketone fragmentation, on compound 59:27d under acidic conditions, they obtained only Bring-expanded diene 61 (90% yield), possibly via 60. These failures led us to search for an alternative pathway. Fortuitously, during the NMR characterization of 56, we found that cycloheptatriene 57 was generated in quantitative yield when a solution of 56 in CDCl3 was allowed to stand at room temperature for 2 days. We attributed this unexpected result to the presence of trace acid in CDCl3. Although the mechanism for this ring expansion reaction deserved further investigation (see below), we proceeded to elaborate 57 into enone 42. Hydroboration-oxidation of 57, followed by Dess–Martin oxidation, yielded 58 in 21% yield over two steps. From here, the only remaining step was deconjugation of 58, but unfortunately we were unable to accomplish this transformation, despite extensive experimentation. Interestingly, when 58 was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene, cyclopropyl enone 43 was isolated in 86% yield, possibly via enolization of the C6 ketone and subsequent 6π electrocyclization. Although cycloheptatriene 57 could not be transformed into a compound with the cyclocitrinol skeleton, the formation of 57 from 56 under acidic conditions deserves further comment (Scheme 5A). We speculate that in the presence of an acid, 56 was first converted to cyclopropylcarbinyl cation 63, which then

rearranged to produce homoallylic cation 65 (rather than 64); cation 65 would in turn give rise to 57 after losing the proton at C9. Tadanier and co-workers reported a related reaction: specifically, upon treatment with acid, compound 66, which does not have the C7–C8 olefin of 56,27a affords ring-expanded fused product 70, possibly via 68. The reason for the difference between the rearrangement pathways of 56 and 66 is not clear. However, the likely formation of homoallylic cation 65 suggested that we could obtain our desired C1–C10 olefin if deprotonation of 65 could be made to occur at C1 rather than at C9. We were pleased to discover that careful purification of the mixture produced by the thermal elimination reaction of sulfoxide 71 (which was generated by m-CPBA oxidation of allylic sulfide 50) led to the isolation of a 1:0.7 mixture of desired triene 72 and cycloheptatriene 57 in 9% combined yield (Scheme 5B). We were particularly encouraged by the formation of the requisite C1–C10 olefin, which might have arisen from cation 65, and we focused our efforts on optimizing the yield of triene 72 (Scheme 5C). We found that in the absence of base, 57 was produced exclusively (entry 1), perhaps by release of diphenyl phosphate, as suggested by the fact that 72 could be converted to 57 in 92% yield by treatment with a catalytic amount of p-toluenesulfonic acid (PTSA) in CHCl3. Screening of various bases revealed 1,4-diazabicyclo[2.2.2]octane (DABCO) to be the optimal choice (entries 2–5). Increasing the reaction temperature to 130 °C resulted in complete conversion of diene 55 (entry 6), and decreasing the concentration of 71 dramatically affected the regioselectivity of the reaction: the 72:57 ratio improved to 86:14 when the concentration was decreased to 0.0025 mol/L. Finally, replacing DABCO with a derivative of a cinchona alkaloid (such as quinine or quinidine) resulted in slightly higher regioselectivity. O-Methylquinine was chosen as the optimal base owing to the low cost of the parent alkaloid (quinine), and 72 was obtained in 57% yield (54% on a gram scale) starting from sulfide 50.



Page 6 of 14

Scheme 5. Gram-Scale Synthesis of Enone 42 in Nine Steps A. Cyclopropylcarbinol rearrangement under acidic conditions Me O Me H H+ H 19

10

AcO

5

H

6

56

OH

H

1

or

10

AcO

AcO 63

19

10

MeO

5

H2SO4 (aq) acetone

H 8

H

reflux, 2 h

7

6

H

H

65 favored

MeO 67

Me

H

71

S O

Me

9

10

H

H AcO

Me Me 1

55

PTSA (0.1 equiv) CHCl3, rt, 3 h

9% (72:57 = 1:0.7)

92%

Me Me

O

O

+

H

H

AcO

H

AcO

57

72

68 favored

10

Me Me

AcO

H STol

50

Me Me

O 1) m-CPBA

H H

57

O

MeO

6

H

73% 10

H

H

H

69 disfavored

71

MeO

base

2) O-methylquinine toluene, 130 oC 54% (2 steps) AcO [gram scale]

H

H

entry

base

temp. (oC)

1 2 3 4 5 6 7a 8a 9a 10a

none Et3N DIPEA pyridine DABCO DABCO DABCO DABCO DABCO O-methylquinine

70 70 70 70 70 130 130 130 130 130

5

6 19

70 OH

72

H

+ 72 + 57

concentration time (mol/L) (h) 0.02 0.02 0.02 0.02 0.02 0.02 0.01 0.005 0.0025 0.0025

Me Me

O 3) BH3, NaBO3 then Jones 74% [gram scale]

55

toluene

D. Gram-scale, nine-step synthesis of the key intermediate 42

(PhO)2OPO

AcO

9H

1

or

O

Me

NEt3, toluene (PhO)2OPO 70 oC

H H

Me

O

Me

AcO

9

10

C. Optimization of the cascade rearrangement

B. Key observations

(PhO)2OPO

H

H

10

OH 66

1

H

O

H

AcO

64 disfavored

>99%

Me

H

MeO

9 10

Tadanier: conversion of 5,19-cyclo-steroid to B-homo steroid (well explored) Me O H

Me Me

H

5 12 12 12 12 1.5 2 2 2 2

1

H NMR ratio (55:72:57) 57 only 81:15:4 73:19:8 33:19:48 77:18:5 0:77:23 0:80:20 0:84:16 0:86:14

0:89:11 (57%)b

O

H

AcO

42 [X-ray] O  9 steps from pregnenolone  gram-scale synthesis  >1.5 g prepared

a71

was used as a crude mixture from the m-CPBA oxidation of 50. bIsolated yield of 72 shown in parenthesis. Abbreviations: PTSA = p-toluenesulfonic acid, DIPEA = diisopropylethylamine.

With an efficient route to triene 72 in hand, what remained for the construction of the cyclocitrinol skeleton was the selective oxidation of the C5–C6 olefin to obtain the C6 ketone (Scheme 5D). Gratifyingly, the C5–C6 olefin of 72 was innately more reactive toward oxidants than the C7–C8 and C1–C10 olefins. Thus, hydroboration-oxidation of 72 with concomitant reduction of the C20 ketone, followed by in situ oxidation with Jones reagent, delivered enone 42 in 74% yield on a gram scale. The structure of 42 was established by X-ray crystallographic analysis. Notably, this gram-scale route to 42 involved only nine steps from pregnenolone 45 and provided more than 1.5 g of 42, an amount that was sufficient for late-stage diversification studies to prepare various cyclocitrinols and unnatural congeners. Unified Synthesis of 10 Cyclocitrinols. As alluded to earlier, cyclocitrinols 7–16 differ only in their side chains (Fig. 1B). With the shared tetracyclic ring system in hand, we posited that cyclocitrinols 7–9 and norcyclocitrinol (16) could be synthesized via chemo- and diastereoselective addition of the necessary side chains to the C20 ketone of 42. Furthermore, we surmised that isocyclocitrinols 10 and 11 and neocyclocitrinols

12–15 could be prepared from 7 and 8 by regiocontrolled 1,3rearrangement of the allylic alcohols. On the basis of the proposed biosynthetic interrelationships between the cyclocitrinols (Scheme 6A),14 we expected that protonation of the C20 hydroxyl group of 7 under acidic conditions would afford C20 allylic cation 73. Trapping its resonance form 74 with H2O would produce neocyclocitrinols A (12) and D (15) after loss of a proton. Likewise, neocyclocitrinols B (13) and C (14) could be obtained from 8 in the same manner. Alternatively, protonation of the C24 hydroxyl group of 7 under acidic conditions would generate C24 allylic cation 77 or its resonance form 78, which could be trapped by H2O to give 24-epicyclocitrinol (8) or isocyclocitrinols A (10) and B (11), respectively.. It is worth mentioning that Zhu and co-workers explored the acid-catalyzed equilibrium and isomerization reactions of cyclocitrinols by means of HPLC and LC-MS analysis.14 However, regiocontrolled synthesis of isocyclocitrinols 10 and 11 and neocyclocitrinols 12–15 from 7 and 8 in synthetically useful yields would obviously be highly appealing (albeit challenging) in that it would facilitate evaluation of their biological activities and elucidation of their


Page 7 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 6. Bioinspired Unified Synthesis of 10 Cyclocitrinols A. Possible biosynthetic interrelationships between members of cyclocitrinols H 2O H + H + H 2O OH OH 22 OH Me Me 24 Me 24 Me 20 20 23

73

H 2O

H+

H 2O

H+

OH 23

Me

H+

cyclocitrinol (7)

Me

Me

H 2O

74

H+

Me

Me H 2O

78

neocyclocitrinol A, D (12, 15)

H

H

24-oxocyclocitrinol (9) O 11 steps from pregnenolone

HO 3 OH

I Me Me

H

OH

R1 R2 Me

H

2

HO

H HO

Me

73% (+ 19% C3-OH 42) Me Me

H

O 20

H

H

+

Me

H 2O

76

neocyclocitrinol B, C (13, 14) OH

Me 20 Me

H

23

H

Me

22

H 23R: neocyclocitrinol A (12) 23S: neocyclocitrinol D (15) O 11 steps from pregnenolone

OH I

Me (S)-79 Me Me

1) (S)-79, nBuLi then K2CO3 H

OH

OH

24

H

Me

H 24-epi-cyclocitrinol (8) O 10 steps from pregnenolone

HO 3

[regioselective 2) H2O/dioxane (5/1) 1,3-rearrangement 100 oC, 12 h of allylic alcohols] 56% (13:14 = 1.3:1) OH HO Me Me

H

H

O norcyclocitrinol A (16) 12 steps from pregnenolone

biosynthetic interrelationships. Our unified synthesis of cyclocitrinols commenced with the preparation of 7 (Scheme 6B). Treatment of 42 with a lithium reagent derived from allylic alcohol (R)-7945 provided 7 in 73% yield after in situ removal of the C3 acetyl group. Selective oxidation of 7 with MnO2 gave 24-oxocyclocitrinol (9) in 51% yield. Likewise, 24-epicyclocitrinol (8) was synthesized in 71% yield from 42 by reaction with (S)-79 and n-BuLi. A three-step sequence involving nucleophilic addition of an allylic zinc reagent to 42 followed by oxidative cleavage46 of the terminal olefin and selective reduction of the resulting aldehyde led to norcyclocitrinol (16), which has a hydroxyethyl side chain. With these four cyclocitrinols prepared, the next challenge was to accomplish the bioinspired synthesis of 10–15 from 7 and 8 via regiocontrolled 1,3-rearrangements of allylic alcohols. Although Zhu and co-workers reported the isomerization of cyclocitrinols under acidic conditions,14 we found that subjecting 7 to various acidic conditions led to complex mixtures, with the major products arising from uncontrolled dehydration. Eventually, we discovered that heating an aqueous mixture of 7 in the absence of acid47 successfully effected the

Me

2) H2O/dioxane (5/1) 100 oC, 12 h

1) allyl-MgBr, ZnCl2, 93% 3) LiAlH(OtBu)3, 2) OsO4, NaIO4, 2,6-lutidine then LiOH, 73% 43% (+ 21% SM) Me OH OH Me H

HO

Me

71% (+ 21% C3-OH 42)

H

OH

HO

42 AcO 3 O 9 steps from pregnenolone

H 22S: isocyclocitrinol A (10) O 22R: isocyclocitrinol B (11) 12 steps from pregnenolone

Me

75

H + H 2O

Me

57% (12:15 = 1.1:1) [regioselective 1,3-rearrangement of allylic alcohols] cyclocitrinol (7) O 10 steps from pregnenolone HO

2) PhSeCN, PBu3 then K2CO3

3) H2O2, py, 10: 56% (2 steps) 11: 56% (2 steps) OH OH Me 22 Me Me H

HO Me

H

n

R = SePh, R = H, 80 O R1 = H, R2 =SePh, 81

OH

Me

H 2O

OH

OH

1) (R) or (S)-79, BuLi C3-OAc 7: 51% (+ 15% 42) C3-OAc 8: 54% (+ 19% 42)

H 1

(R)-79

24-epi-cyclocitrinol (8)

H

1) (R)-79, nBuLi then K2CO3

H+

H+

Me Me

51% (+ 20% 7)

HO

OH

isocyclocitrinol A, B (10, 11)

B. Bioinspired unified synthesis of ten cyclocitrinols O OH Me Me Me H 2) MnO2 H

H+

OH Me

Me

OH

H+

H 2O

22

H 2O

H + H 2O

OH

OH

Me

Me

77

OH

Me

Me

24

H 2O

OH HO

Me

H+

H 2O

OH

HO

23

Me

H

H 23S: neocyclocitrinol B (13) 23R: neocyclocitrinol C (14) O11 steps from pregnenolone

desired 1,3-rearrangement of the C20 tertiary allylic alcohol, delivering a 1.1:1 mixture of neocyclocitrinols A (12) and D (15) in 57% combined yield (Scheme 6B). Notably, the C20–C22 olefins of 12 and 15 were exclusively in the E configuration. Under the same conditions, neocyclocitrinols B (13) and C (14) were obtained from 8 in 56% combined yield. These results provide important insights into the biosynthetic origin of the neocyclocitrinols. Attempts to synthesize isocyclocitrinols 10 and 11 using the same strategy (that is, direct 1,3-rearrangement of C24 secondary allylic alcohols) were unsuccessful under a variety of conditions. Ultimately, we found that 10 and 11 could be obtained in three steps from 42 by means of a seleno-Mislow– Evans rearrangement.48 Thus, cyclocitrinol protected with an acetyl group at C3 was converted to allylic selenide 80 by means of the Grieco protocol.49 Oxidation of 80 by H2O2 triggered a [2,3]-sigmatropic rearrangement of the resulting selenoxide, giving rise to isocyclocitrinol A (10) in 56% yield over two steps. Isocyclocitrinol B (11) was prepared by subjecting C3acetyl-protected 24-epi-cyclocitrinol to the same sequence. Thus, unified synthesis of 10 cyclocitrinols (7–16) was accomplished in one to three steps



Page 8 of 14

Table 1. Regiodivergent Synthesis of Functionalized 5(10→19)abeo-Steroids 1) m-CPBA, EtOAc (PhO)2OPO 2) O-methylquinine toluene (0.0025 M), 130 oC

H

condition A

AcO

Me Me H

O

AcO

82a Me H (PhO)2OPO

Me

H

Me

O

AcO

STol

Me AcO

82c a

Me

a

Me (PhO)2OPO

O

H

H AcO

a

72, 54% (11%)b, condition A Me O Me

H

AcO

O H

H H

Me O H

Me

83d, 56%a (9%)b, condition A Me O Me H Me

b

O

AcO

82d

83c, 52% (14%) , condition A

H H

H

H

Me O

AcO

H

H

STol

83a, 52%a (7%)b, condition A Me Me H

Me Me H

O O

H H

5(1019)abeo-Steroids Me

H

Me

82b

(PhO)2OPO

(PhO)2OPO

AcO

H

H

Me Me H

H

H

STol

57

O

H

H

H

H AcO

AcO

C19 Functionalized Steroids

5(1019)abeo-Steroids

O

H

condition B

STol 50 or 82a-82d

C19 Functionalized Steroids

(PhO)2OPO

H

AcO

72 or 83a-83d

Me Me H

condition A, then PTSA (0.2 equiv) CHCl3, rt

H

STol 50

H STol

H

H AcO

AcO 57, (57%)b, condition B

83b, 50%a (14%)b, condition A b

Isolated yields of non-conjugated triene products (in red color). Isolated yields of heptatriene products (in blue color) shown in parenthesis.

from enone 42 (that is, 10–12 steps from pregnenolone). Modular Approach to Bridged Ring Systems. Our concise, unified synthesis of cyclocitrinols hinged on a regioselective cascade rearrangement, which transformed classical steroids into 5(10→19)abeo-steroids. To facilitate investigation of the biological activities of this class of compounds, we used this strategy to synthesize various cyclocitrinol congeners (Table 1). Four allylic sulfides (82a–82d) with a variety of structural motifs were smoothly transformed into the corresponding bicyclo[4.4.1]undeca-5,7,10-triene products (83a–83d) under standard conditions (condition A) in 50–56% yields, attesting to the viability of our strategy for accessing 5(10→19)abeosteroids from C19-functionalized steroids. In addition, when the crude product mixture obtained by subjecting sulfide 50 to condition A was treated with catalytic PTSA in CHCl3 (condition B), 53 was formed exclusively in 57% yield starting from 50. This finding demonstrates that regioisomer 72 or 57 could be selectively prepared, each of which provides ready access to cyclocitrinol congeners with a nonconjuated triene or cycloheptatriene substructure. It should be noted that all the products shown in Table 1 were obtained as single atropisomers, and their planar chirality arose from the point chirality of the C10 quaternary carbon of 50 or 82. Therefore, our cascade rearrangement constitutes a facile method for installation of bridged ring systems with full control of the planar chirality via point-to-planar chirality transfer. Inspired by these results, we were interested in generalizing this strategy to prepare other bridged ring systems (Table 2). Specifically, we surmised that regioisomers 85 and 86 (the core structure of marine natural product spiniferin-1 (87)50) could be regiodivergently synthesized from bicyclic alcohol 84, which could in turn be easily synthesized via Robinson annulation (see Supporting Information for details). Under the previously described optimal conditions, 84 was converted to the corresponding phosphate, which was then treated with DABCO

in toluene at 155 °C (condition A, Table 2) to yield nonconjugated triene 85 as the major product. In addition, we were pleased to find that the desired cascade rearrangement also proceeded at 0 °C when a strong activating reagent, such as perfluoroalkylsulfonyl fluoride (condition B, Table 2), was used; this protocol resulted in the formation of a mixture of regioisomers 85 and 86. However, subsequent addition of PTSA to the reaction mixture delivered cycloheptatriene 86 exclusively in good yield. Using these two distinct sets of reaction conditions, we next examined the scope of the point-to-planar chirality transfer strategy to produce 85, starting with condition A. Gratifyingly, bicyclo[4.4.0] dienes 84a–84f, which have a variety of functional groups (e.g., anisole, aniline, ether, and pyridine), were found to be compatible substrates, delivering desired products 85a–85f in 53–82% yields with good regioselectivity. The presence of the pyridine ring in 84e reduced the conversion of the second step, but treatment of the recovered phosphate intermediate with DABCO in boiling toluene for 12 h gave 85e in 53% overall yield. Moreover, dienes 84g–84i, which have alkynyl and aryl substituents, afforded corresponding products 85g–85i with excellent regioselectivities; 85g was formed as a single regioisomer. The structure and relative configuration of 85i were unambiguously determined by X-ray crystallographic analysis, which confirmed that the point chirality of the C10 quaternary carbon of 84i were transferred with complete fidelity to the planar chirality of 85i. Diene 84j, which has an n-pentyl group at C9, also smoothly underwent the desired reaction to give rise to 85j in 87% yield with 9:1 regioselectivity. Surprisingly, 84k, which has no substituent at C9, afforded cycloheptatriene 86k as the only product, which indicates the importance of steric hindrance at C9 for the preferential formation of 85 over 86. Importantly, bicyclo[5.4.0] diene 84l was also amenable to this reaction,


Page 9 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 2. Regiodivergent Synthesis of Bridged Ring Systems via Point-to-Planar Chirality Transfera–c

R n

[X-ray of 85i]

C4F9SO2F, DBU DCM, 0 oC; then PTSA, rt

R

condition A

condition B

n

Products 86 (from condition B)

n

HO

86

85a, 73% (10.8:1)

84a HO

86a, 71%

cis

Me

Me

Me

e

R

HO 12

R

R

10 3

3

R = OMe, 84b R = NMe2, 84c HO

Me

Me

OBn

5

5

OBn

3

HO

3

85e, 53% (6:1)f

HO

Me

O

O

84f

R R = MOM, 85h, 76% (15:1) R = OMe, 85i, 73% (15:1) [X-ray]

R R = MOM, 86h, 71% R = OMe, 86i, 70%

C5H11

5

OBn

C5H11

5

OBn

5

OBn

86j, 76%

85j, 87% (9:1)

85k, 0% Me (86k, 67%d)

Me 84k

86e, 54%g

Me

Me

R

N

3

84e

12 7

6

9

N

N

Me

8

84j

HO

86g, 70%

11

cis

OBn

Me

85g, 59%h Me

C5H11

86d, 67%

Me

Me

84g

9

MOMO

MOMO

Me11

R= MOM, 84h R= OMe, 84i HO

5

85d, 77% (7.1:1)

84d HO

R = OMe, 86b, 61% R = NMe2, 86c, 60%g

R = OMe, 85b, 81% (6.8:1) R = NMe2, 85c, 76% (7:1)

Me

5

3

Products 86 (from condition B) Me

Me

Me

MOMO d

Me spiniferin-1 (87) (marine natural product)

Products 85 (from condition A)

Substrates

Me

Me

R

84, n = 1, 2

Me

HO

HO

85

Products 85 (from condition A)

Substrates

O

1) (PhO)2POCl 2) DABCO, 155 oC toluene (0.0025 M) 5.5 h - 16 h

Me

O

85f, 82% (6.7:1)

OMe

84l

86f, 68%

Me 86k, 93%i

bicyclo[5.4.1] Me

Me

OMe

85l, 75% (3.5:1)

86l, 68% (1:5)j

OMe

Condition A: 1) (PhO)2POCl (4 equiv), Et3N (5 equiv), DMAP (0.3 equiv), DCM, 0 oC, 50 min; 2) DABCO (2 equiv), toluene (0.0025 M), 155 oC. Condition B: C4F9SO2F (2 equiv), DBU (3 equiv), DCM, 0 oC, 50 min; then PTSA (1.5 equiv), rt, 1.5 h. bIsolated yields of purified products unless otherwise stated. cRatio of nonconjugated triene 85 and cycloheptatriene 86 shown in parentheses. dDue to low polarity of the product, 1H NMR yields using 1,3,5-trimethoxybenzene as the internal standard were used instead. eMsCl (4 equiv), Et3N (3 equiv), DCM, 0 oC to rt, 22 h. fSome unreacted phosphate was recovered and resubjected to the same condition for 12 h to get a combined yield of 53%. g PTSA (3 equiv). hSecond step: 165 oC. iMsCl (2 equiv), Et3N (4 equiv), DCM, 0 oC to rt, 1.5 h. jCondition A, then PTSA (0.7 equiv), CHCl3, rt, 12 h. a

Scheme 7. Investigation of the Cascade Rearrangement Mechanism Me

A.

Me

(PhO)2OPO

standard conditions no reaction

O

+

H

H 92% AcO (72:57 = 8.2:1) 55 standard conditions: O-methylquinine, toluene, 130 oC, 2 h H

AcO

C.

Me 56, CDCl3, 2d rt, >99%

57

Me H H

AcO

6 2 R1 R

B.

10

AcO

AcO

72

HO

72 + 57 from 56, 51% (72:57 = 1:1.3) from 88, 40% (72:57 = 1:1.2)

Me

6

19

H

Me 89

5

9

10 5

63

6

H

cyclopropane scission highly regioselective

1

AcO


46%

R=

R

base 1

Me

condition A Table 2

path a

6

55

5

65

Me

R1 = OH, R2 = H, 56 R1 = H, R2 = OH, 88

AcO

AcO

D. C4F9SO2F, DBU DCM, 0 oC


less likely

5

10 19

standard conditions no reaction

O

H AcO

H

H

55

57

E. Proposed mechanism (PhO)2OPO

H

Wagner-Meerwein rearrangement

(PhO)2OPO 19

standard conditions

H 10

65

R OBn

R

Me 90

91

path b 9

Path a  72 Path b  57

72

+

57


giving corresponding bicyclo[5.4.1] triene 85l in 75% yield, albeit with only moderate regioselectivity. Encouraged by the above-described results, we next examined the regioselective preparation of compounds 86 under condition B. To our delight, exclusive formation of 86 was observed for all of the tested bicyclo[4.4.0] substrates. Interestingly, 84a was very reactive, and MsCl was sufficient to initiate the reaction, leading to 86a in 71% yield. It should be noted that in this case, an excess of MsCl relative to NEt3 was used to maintain the acidity of the reaction system. Additionally, dienes 84b–84i, which bear a diverse array of primary and secondary alkyl, alkynyl, and aryl groups, proved to be viable substrates, furnishing desired products 86b–86i in 54–71% yields. Owing to the basicity of the pyridine and amine groups in 86c and 86e, 3 equiv of PTSA was required to drive the reactions of these substrates to completion. A longer-chain substituent at C9 was also compatible with condition B; 84j afforded corresponding product 86j in 76% yield. As expected, treatment of 84k with MsCl and NEt3 provided 86k in excellent yield. Owing to the formation of nonconjugated triene 85k even under condition A, an excess of NEt3 relative to MsCl could be employed in this case, in sharp contrast to the situation with the preparation of 86a. Finally, addition of PTSA in CHCl3 to the crude mixture obtained by subjecting 84l to condition A gave the desired bicyclo[5.4.1] cycloheptatriene 86l in 68% yield with moderate regioselectivity. Mechanistic Investigations. The mechanism of this cascade rearrangement was investigated by means of a series of control experiments (Scheme 7A). In results similar to those depicted in Table 2, steroidal diene 55 was shown to be the precursor of the cascade rearrangement, affording 72 and 57 in 92% combined yield with 8.2:1 regioselectivity under the standard conditions (Scheme 7A). In addition, we observed no interconversion between 72 and 57 under the standard conditions. In light of these results, we speculated that this pair of regioisomers might arise from homoallylic cation 65 (Scheme 7B) via two possible pathways: (1) direct migration of C5 of diene 55 from C10 to C19 via a Wagner–Meerwein rearrangement (Scheme 7B) or (2) a cyclopropane formation and scission cascade via cyclopropylcarbinyl cation 63 (Scheme 7E). The following experiments showed that the second pathway was more likely (Scheme 7C and 7D). First, cyclopropylcarbinol 56 was quantitatively transformed to 57 under acidic conditions. Additionally, treatment of 56 or 88 with perfluoroalkylsulfonyl fluoride and DBU afforded similar results, suggesting that the configuration of the C6 leaving group had little effect on the reaction outcome. Furthermore, subjecting diene 89, which bears a C6 methyl group, to condition A (Table 2) gave cyclopropyl diene 91 (46% yield), possibly via cyclopropylcarbinyl cation 90 (Scheme 7D). In light of the above-described observations, we propose a cascade mechanism involving cyclopropane formation and regioselective scission to generate 65, as shown in Scheme 7E. Subsequent regiodivergent deprotonation at C1 or C9 of 65 leads to 72 or 57, respectively.  CONCLUSION We have shown that consideration of the proposed pathway for biosynthesis of a family of complex natural products can facilitate the development of a concise, scalable method for preparation of a common intermediate bearing the core framework, which can then be divergently elaborated into a collection of structurally diverse family members as well as unnatural congeners. In this study, we used this strategy to

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accomplish a concise, unified synthesis of 10 cyclocitrinols in only 10–12 steps from an inexpensive commercially available starting material (pregnenolone). The strategy was also useful for the preparation of various 5(10→19)abeo-steroids. The salient features of our synthesis are as follows: (1) a bioinspired cascade rearrangement was used to establish the core bicyclo[4.4.1]undecane skeleton, (2) late-stage common intermediate 42 was obtained on a gram scale in only nine steps, and (3) 10 cyclocitrinols were divergently synthesized via chemo- and diastereoselective nucleophilic addition to the C20 ketone of 42 and regiocontrolled 1,3-rearrangement of the resulting allylic alcohols. Our work provides experimental evidence for the proposed biosynthesis of cyclocitrinols from ergosterol and the possible interrelationships between members of the cyclocitrinol family. More importantly, our point-toplanar chirality transfer strategy could be used to synthesize challenging bridged ring systems from readily accessible fused ring systems and can be expected to find additional applications for natural product synthesis. This work should facilitate investigation of the biological activities of this fascinating class of 5(10→19)abeo-steroids and may lead to the development of therapies for various neurological disorders. Work toward this end is currently being pursued in our laboratory and will be reported in due course.

ASSOCIATED CONTENT Experimental procedures, and NMR spectra for all new compounds (PDF) X-ray crystallographic data for 42, 43 and 85i (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This paper is dedicated to Prof. Qing-Yun Chen on the occasion of his 90th birthday. Financial support was provided by the “Thousand Youth Talents Plan”, the National Natural Science Foundation of China (21871289), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), CAS Key Laboratory of Synthetic Chemistry of Natural Substances, and Shanghai Institute of Organic Chemistry. We thank Prof. Reinhard W. Hoffmann for insightful suggestions on mechanistic studies, and Prof. Zha-Jun Zhan (Zhejiang University of Technology) for providing the original NMR spectra of the isolated norcyclocitrinol. We are grateful to Dr. Ming Yan and Prof. Tian Qin (UT Southwestern Medical Center) for helpful discussions.

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(27) (a) Tadanier, J. Homoallylic Rearrangements of 19-Substituted Steroids. J. Org. Chem. 1966, 31, 2124-2135. (b) Wolff, M. E.; Ho, W. Modified Cardenolides. III. Cyclocardenolides Obtained from 19Hydroxycardenolides. J. Org. Chem. 1967, 32, 1839-1843. (c) Knox, L. H.; Velarde, E.; Berger, S.; Delfín, I.; Grezemkovsky, R.; Cross, A. D. Steroids. CCLXXXIV. Reactions of 19-Hydroxy-Δ5-3-Acetoxy Steroids with Diethyl(2-chloro-1,1,2-trifluoroethyl)amine. J. Org. Chem. 1965, 30, 4160-4165. (d) Kranz, D. P.; Greffen, A. M. Z.; Sheikh, S. E.; Neudoerfl, J. M.; Schmalz, H.-G. Sn(OTf)2 as An Effective Lewis Acid in Reactions of Cyclopropyl Ketones with Acetic Anhydride: Application in the Synthesis of a 19-Nor-B-Homo Steroid. Eur. J. Org. Chem. 2011, 2860-2866. (e) Kranz, D. P.; Chiha, S.; Greffen, A. M. Z.; Neudörfl, J.-M.; Schmalz, H.-G. Synthesis of B-Ring-Modified Steroids through BF3-Promoted Rearrangement/Substitution of 6βHydroxy-5,19-Cyclosteroids. Org. Lett. 2012, 14, 3692-3695. (28) Poulter, C. D.; Winstein, S. Stereospecific Homoallylic Ring Expansions and Contractions. J. Am. Chem. Soc. 1970, 92, 4282-4288. (29) For relevant examples of the construction of bicyclo[4.4.1] ring systems via a cycloheptatriene-norcaradiene rearrangement under acidic conditions, see: (a) Knox, L. H.; Velarde, E.; Cross, A. D. Studies of the Cycloheptatriene-Norcaradiene Isomerism in Some Novel Steroids. J. Am. Chem. Soc. 1963, 85, 2533-2535. (b) Tian, W.-S.; Lei, Z.; Chen, L.; Huang, Y. Some New Reactions of Poly(per)fluoroalkanesulfonyl Fluorides with Steroidal Molecules. J. Fluorine Chem. 2000, 101, 305-308. (c) Knox, L. H.; Velarde, E.; Cross, A. D. Steroids. CCLXXIII. The Chemistry of Some Norcaradiene and Cycloheptatriene Analogs. J. Am. Chem. Soc. 1965, 87, 3727-3736. (d) Bentley, P. H.; Todd, M.; McCrae, W.; Maddox, M. L.; Edwards, J. A. Tetracyclic 1,6-Methano-[10]annulenes. A Novel Class of Steroidal Annulenes. Tetrahedron 1972, 28, 1411-1425. (30) Wang, Y.; Ju, W.; Tian, H.; Tian, W.; Gui, J. Scalable Synthesis of Cyclocitrinol. J. Am. Chem. Soc. 2018, 140, 9413-9416. (31) El Sheikh, S.; Meier zu Greffen, A.; Lex, J.; Neudoerfl, J.-M.; Schmalz, H.-G. Synthesis of the Core Structure of the Cyclocitrinols via SmI2-Mediated Fragmentation of A Cyclopropane Precursor. Synlett 2007, 1881-1884. (32) Plummer, C. W.; Wei, C. S.; Yozwiak, C. E.; Soheili, A.; Smithback, S. O.; Leighton, J. L. Design, Development, Mechanistic Elucidation, and Rational Optimization of A Tandem Ireland Claisen/Cope Rearrangement Reaction for Rapid Access to the (Iso)cyclocitrinol Core. J. Am. Chem. Soc. 2014, 136, 9878-9881. (33) Mei, G.; Liu, X.; Qiao, C.; Chen, W.; Li, C.-C. Type II Intramolecular [5+2] Cycloaddition: Facile Synthesis of Highly Functionalized Bridged Ring Systems. Angew. Chem. Int. Ed. 2015, 54, 1754-1758. (34) Liu, J.; Wu, J.; Fan, J.-H.; Yan, X.; Mei, G.; Li, C.-C. Asymmetric Total Synthesis of Cyclocitrinol. J. Am. Chem. Soc. 2018, 140, 5365-5369. (35) Marinho, A. M. d. R.; Rodrigues-Filho, E.; Ferreira, A. G.; Santos, L. S. C25 Steroid Epimers Produced by Penicillium Janthinellum, a Fungus Isolated from Fruits Melia Azedarach. J. Braz. Chem. Soc. 2005, 16, 1342-1346. (36) Watanabe, Y.; Aoki, S.; Tanabe, D.; Setiawan, A.; Kobayashi, M. Cortistatins E, F, G, and H, four novel steroidal alkaloids from marine sponge Corticium simplex. Tetrahedron 2007, 63, 4074-4079. (37) (a) Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. Synthesis of (+)-Cortistatin A. J. Am. Chem. Soc. 2008, 130, 72417243. (b) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. Enantioselective Synthesis of (+)-Cortistatin A, A Potent and Selective Inhibitor of Endothelial Cell Proliferation. J. Am. Chem. Soc. 2008, 130, 16864-16866. (c) Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y. K. Total Synthesis of (+)-Cortistatin A. Angew. Chem. Int. Ed. 2008, 47, 7310-7313. (d) Flyer, A. N.; Si, C.; Myers, A. G. Synthesis of Cortistatins A, J, K and L. Nat. Chem. 2010, 2, 886-892. (e) Nilson, M. G.; Funk, R. L. Total Synthesis of (±)-Cortistatin J from Furan. J. Am. Chem. Soc. 2011, 133, 12451-12453. (f) Yamashita, S.; Iso, K.; Kitajima, K.; Himuro, M.; Hirama, M. Total Synthesis of Cortistatins A and J. J. Org. Chem. 2011, 76, 2408-2425. (g) Fang, L.; Chen, Y.; Huang, J.; Liu, L.; Quan, J.; Li, C.-C.; Yang, Z. Formal Synthesis of Cortistatins. J. Org. Chem. 2011, 76, 2479-2487. (h) Kuang, L.; Liu, L. L.; Chiu, P. Formal Total Synthesis of (+)-


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Cortistatins A and J. Chem. Eur. J. 2015, 21, 14287-14291. (i) Simmons, E. M.; Hardin-Narayan, A. R.; Guo, X.; Sarpong, R. Formal Total Synthesis of (±)-Cortistatin A. Tetrahedron 2010, 66, 4696-4700. (38) You, L.; Liang, X.-T.; Xu, L.-M.; Wang, Y.-F.; Zhang, J.-J.; Su, Q.; Li, Y.-H.; Zhang, B.; Yang, S.-L.; Chen, J.-H.; Yang, Z. Asymmetric Total Synthesis of Propindilactone G. J. Am. Chem. Soc. 2015, 137, 10120-10123. (39) For an excellent summary of this issue, see: Renata, H.; Zhou, Q.; Dünstl, G.; Felding, J.; Merchant, R. R.; Yeh, C.-H.; Baran, P. S. Development of a Concise Synthesis of Ouabagenin and Hydroxylated Corticosteroid Analogues. J. Am. Chem. Soc. 2015, 137, 1330-1340. (40) Terasawa, T.; Okada, T. Convenient Preparative Routes to 19Hydroxy, 19-Oxo-, 19-Oic-, and 19-Nor-Deoxycorticosterone. Tetrahedron 1986, 42, 537-545. (41) Hazra, B. G.; Basu, S.; Bahule, B. B.; Pore, V. S.; Vyas, B. N.; Ramraj, V. M. Stereoselective Synthesis of A New Hexanor(C23– C28)Castasterone-20,22-Ethyl Diether from 16-Dehydropregnenolone Acetate and its Plant Growth Promoting Activity. Tetrahedron 1997, 53, 4909-4920. (42) Armas, P. d.; Concepción, J. I.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E. Intramolecular Hydrogen Abstraction. Hypervalent Organoiodine Compounds, Convenient Reagents for Alkoxyl Radical Generation J. Chem. Soc., Perkin Trans. 1 1989, 405411. (43) Tanabe, K.; Takasaki, R.; Sakai, K.; Hayashi, R.; Morisawa, Y.; Hashimoto, T. Steroid Series. XVI. The Preparation of 3α, 5α-Cyclo6β,19-Oxidosteroids and its Conversion to 19-Oxygenated Steroid Derivatives. Chem. Pharm. Bull. 1967, 15, 15-27. (44) Confalone, P. N.; Kulesha, I. D.; Uskokovic, M. R. A New Synthesis of 7-Dehydrocholesterols. J. Org. Chem. 1981, 46, 10301032. (45) Weber, F.; Brückner, R. Total Syntheses of the Dihydrofuranonecarboxylate Natural Products Gregatin B and E: GramScale Synthesis of (+)-Gregatin B and Unambiguous Assignment of the Stereostructure of (+)-Gregatin E. Org. Lett. 2014, 16, 6428-6431. (46) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Improved Procedure for the Oxidative Cleavage of Olefins by OsO4−NaIO4. Org. Lett. 2004, 6, 3217-3219. (47) Li, P.-F.; Wang, H.-L.; Qu, J. 1,n-Rearrangement of Allylic Alcohols Promoted by Hot Water: Application to the Synthesis of Navenone B, a Polyene Natural Product. J. Org. Chem. 2014, 79, 39553962. (48) (a) Evans, D. A.; Andrews, G. C. Allylic Sulfoxides. Useful Intermediates in Organic Synthesis. Acc. Chem. Res. 1974, 7, 147-155. (b) Reich, H. J. Organoselenium Chemistry. Synthetic Transformations Based on Allyl Selenide Anions. J. Org. Chem. 1975, 40, 2570-2572. (49) Grieco, P. A.; Gilman, S.; Nishizawa, M. Organoselenium chemistry. A Facile One-Step Synthesis of Alkyl Aryl Selenides from Alcohols. J. Org. Chem. 1976, 41, 1485-1486. (50) (a) Marshall, J. A.; Conrow, R. E. Total Synthesis of (±)Spiniferin-1, a Naturally Occurring 1,6-Methano[10]annulene. J. Am. Chem. Soc. 1983, 105, 5679-5688. (b) Ding, K.; Sun, Y.-S.; Tian, W.S. Total Synthesis of (±)-Spiniferin-1 via a Polyfluoroalkanosulfonyl Fluoride Induced Homoallylic Carbocation Rearrangement Reaction. J. Org. Chem. 2011, 76, 1495-1498. In these two reports, the core structure of spiniferin-1 was constructed via a cycloheptatriene-norcaradiene rearrangement (see ref. 29 for more examples), which is clearly distinct from the cyclopropane ring expansion cascade described in this work.



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Table of Contents (TOC) point-to-planar chirality transfer

LG R

n

n

R 30 examples up to 93% yield

readily accessible

synthetically challenging Me OH Me H

H

H HO

R n

O

cyclocitrinol

OH Me

10 cyclocitrinols 10-12 steps overall scalable & concise

bioinspired unified strategy


14

Facile Access to Bridged Ring Systems via Point-to-Planar Chirality

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