Discoveries and Challenges en Route to Swinhoeisterol A

Chemistry - A European Journal

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Discoveries and Challenges en route to Swinhoeisterol A

[

a]

[a]

[b]

[a]

Fenja L. Duecker , Robert C. Heinze , Simon Steinhauer , and Philipp Heretsch*

[

a]

M.Sc. F. L. Duecker, Dr. R. C. Heinze, Prof. Dr. P. Heretsch

Institut für Chemie und Biochemie, Organische Chemie, Freie Universität Berlin

Takustrasse 3, 14195 Berlin, Germany

E-mail: philipp.heretsch@fu-berlin.de

[

b]

Dr. S. Steinhauer

Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin

Fabeckstrasse 34–36, 14195 Berlin, Germany

Supporting information for this article is given via a link at the end of the document.

Abstract: We here give a full account of our synthetic studies that

these natural products, dankasterone A (3) and B (4) show

significant cytotoxicity against the P388 lymphocytic leukemia test

system (ED50 2.2 and 2.8 µg/mL, respectively)^[whereas diabeo-

steroid swinhoeisterol A (2) exhibits a remarkable inhibition of the

histone acetyltransferase (h)p300 with an IC50 of 2.9µM.^[¹¹^a^]The

most recently isolated secondary metabolite, periconiastone A (5),

is reported to display intriguing antibacterial activity against two

Gram-positive microbial pathogens, namely S. aureus (MIC

4 µg/mL) and E. faecalis (MIC 32 µg/mL).^[¹²^]

culminated in the first synthesis of 13(14→8),14(8→7) diabeo-steroid

10]

swinhoeisterol A as well as the related dankasterones A and B,

13(14→8)abeo-steroids, and periconiastone A, a 13(14→8)abeo-

4,14-cyclo-steroid. We describe in detail experiments that provided

further insight into the mechanism of our switchable radical framework

reconstruction approach. By discussing failed strategies and tactics

towards swinhoeisterol A, we eventually present the successful route

that also allowed an access to structurally closely related analogues

22

as  -24-epi-swinhoeisterol A.

Herein, we want to report on the evolution of our synthetic studies

towards swinhoeisterol A (2) and its 24-epi-isomer (24-epi-2) as

well as present experimental support for our mechanistic proposal

for our radical framework reconstruction approach.

Introduction

Traditionally, the majority of bioactive compounds has been

isolated from terrestrial plants and fungi, whereas the marine

biosphere was more difficult to access. Undersea organisms often

produce structurally highly complex, rearranged secondary

metabolites with unique bioactivities.^[¹^]

An increasing number of chemical syntheses relies on biogenetic

information, gaining access to natural products via biomimetic

approaches.^[Still, many of the proposed pathways are

established without the support of co-isolated biosynthetic

precursors from the producing organism. Commonly, biogenetic

proposals anticipate polar pathways to account for skeletal

rearrangements and radical routes are rarely considered.^[³^]One

class of steroidal natural products with such rearranged skeletons

are the so-called abeo-steroids, which display one or several C–

C bond migrations with respect to the classic, tetracyclic steroid

backbone.^[

2]

4]

In recent years, our group as well as others have demonstrated

that key synthetic transformations (possibly biomimetic in nature)

can indeed be carried out using radical reactivity, giving the

desired skeletal modifications with high selectivity as shown in the

Scheme 1. Structures of the abeo-steroids swinhoeisterol A (2), dankasterone

A (3) and B (4), and periconiastone A (5), their common synthetic starting

material, ergosterol (1), as well as their generic classes.

syntheses of rearranged steroids cortistatin A,^[⁵^]aplysiasecosterol

_A_,_[6] strophasterol_A_,[7] pleurocin A/matsutakone,^[⁸^]and

Results and Discussion

herbarulide.^[⁹^]It was also a cascade of rearrangements initiated

by an alkoxy radical that cleared the way to the dankasterone

₁₃₍₁₄_→₈₎_a_b_e_o_-_s_t_e_r_o_i_d_s_]_[10] and the swinhoeisterol class of

Our rationale to gain synthetic access to the rearranged skeletons

of abeo-steroids relied on the initial generation of an alkoxy radical.

The following radical rearrangement (Scheme 2) enabled the

synthesis of the above-mentioned natural products and selective

access to either the mono- or diabeo-skeleton was gained by

[

_n_a_t_u_r_a_l_p_r_o_d_u_c_t_s_[₁₃₍₁₄_→₈₎_,₁₄₍₈_→₇₎_d_i_a_b_e_o_-_s_t_e_r_o_i_d_s_]_._[11] Only

recently, we achieved the synthesis of swinhoeisterol A (2), its 24-

epi-counterpart (24-epi-2), dankasterone A (3) and B (4), and

_p_e_r_i_c_o_n_i_a_s_t_o_n_e_A₍₅₎_,_[12] the 4,14-cyclo aldol product of the latter,

starting from commercial ergosterol (1) by exploiting a radical

_c_a_s_c_a_d_e₍_S_c_h_e_m_e₁₎_._[13] Regarding the biological activities of

2 2

adapting the reaction conditions (PhI(OAc) /I for the former;

HgO/I for the latter) to generate B – starting from a γ-hydroxy

2

enone A. Subsequent β scission of the C13–C14 bond in B would

1

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form an intermediary 14-oxo functionality along with a stabilized

7

tertiary radical at C13 (C). An attack onto the  -bond generates

α-keto radical D, which is either quenched reductively to give the

1

3(14→8)abeo skeleton (E)^[¹⁴^]as present in the dankasterone

class of natural products, or further reacts in a Dowd–Beckwith

rearrangement.^[¹⁵^]This comprises of an attack of the C7-centered

radical to the 14-oxo functionality to give alkoxy radical F. Another

β

scission,

this

time

of

C8–C14,

yields

the

1

3(14→8),14(8→7)diabeo core (G) of the swinhoeisterols after

abstraction of an H atom (G→H).

Scheme 3.

3(14→8),14(8→7)diabeo structures 8, 9, and 10. ORTEP plots of 9 and 10.

Thermal ellipsoids are drawn at 50% probability. Reagents and conditions: a)

Zn (29 eq.), HOAc, 90 °C, 3 h, 47%; b) SeO (4.75 eq.), tBuOH/pyridine (4:1),

(2.0 eq.), CaCO (2.0 eq.), C , 85 °C,

h, 8: 18%, 9: 59%, 10: traces. CCDC 1991055 (compound 9) and 1991054

Radical

rearrangement

of

7

leading

to

the

1

2

80 °C, 4 h, 59%; c) Pb(OAc)

4

(2.0 eq.), I

2

3

6 6

H

2

(compound 10) contain the supplementary crystallographic data.

Scheme 2. Mechanistic proposal for the alkoxy radical initiated framework

reconstruction leading to the structural precursors of the dankasterones E and

swinhoeisterols G.

was used leading to a different product distribution for “open flask”

and “degassed” conditions (see Scheme 4). Tetraene dione 13

was isolated as the major product (31% yield) and its yield could

be improved to 44% when carefully degassing the reaction

mixture. Under “open flask” conditions, 4-iodo substituted

endoperoxides 16 and 17 were obtained in 12 and 23% yield,

respectively, or in 9 and 11% for the “degassed” experiment. The

formation of 16 and 17 presumably results from remaining traces

of oxygen in the reaction mixture. Interestingly, aerobic conditions

led to the isolation of 15β-iodo tetraene dione 14 (14%) whereas

oxygen-free conditions delivered the 13(14→8)abeo species 15

Initially, 5α-hydroxy enone 7 was chosen as a substrate for the

envisioned radical rearrangement (Scheme 3). As we described

_i_n_o_u_r_s_y_n_t_h_e_s_i_s_o_f_h_e_r_b_a_r_u_l_i_d_e_,_[9] the preparation of Burawoy’s

ketone (6) following reported procedures has proven to lack

reproducibility.^[¹⁶^]Aiming for a stepwise oxidation of ergosterol (1),

6

was available in 62% yield over 4 steps.^[⁹^]Reduction with zinc

in acetic acid provided 5α-enone (not shown) in 47% along with

0% of its 5β-epimer (not shown). While Riley oxidation

2

(

13%), instead, providing first conformation of our mechanistic

employing 1,4-dioxane as solvent gave the desired product in only

low and irreproducible yields, the solvent system

pyridine/tBuOH^[¹⁷^]allowed for the formation of alcohol 7 in an

acceptable yield of 59%. To generate the alkoxy radical at C14

proposal (Scheme 2).

Gaining synthetic access to the swinhoeisterols by further

processing one or several of the obtained products was tested on

tetraene dione 13 (Scheme 5) as well as epimeric 4-iodo

endoperoxides 16 and 17 (Scheme 6). For 13, we envisioned to

reduce the oxo-functionality at C6 to the corresponding allylic

alcohol, which could then be used to perform a sigmatropic

rearrangement, either directly (Johnson–Claisen), after

acetylation (Ireland–Claisen), or after methyl stannylation ([2,3]-

Wittig–Still), thereby installing a precursor for the exo-methylene

function at C4. However, no conversion of starting material was

observed when applying Johnson–Claisen conditions to the allylic

alcohol and in case of the [2,3]-Wittig–Still rearrangement,

addition of nBuLi to the methyl stannylated alcohol only resulted

in the formation of the 1,2-rearranged product. In case of the

Ireland–Claisen reaction, the allylic acetate was successfully

converted to the corresponding silyl ketene acetal as judged by

from alcohol 7, the literature-known combination of Pb(OAc)

4 2

, I

and CaCO

3

in benzene^[¹⁸^]was used and, indeed, all isolated

products showed the desired 13(14→8),14(8→7)diabeo-skeleton,

though in higher oxidation states than expected. Diene dione 9

was obtained as the major product (40%) along with

endoperoxide 10 (20%). When the reaction mixture was carefully

degassed prior to addition of Pb(OAc)

4

, 59% of 9, only traces of

1

0, and 18% of 15β-iodo diene dione 8 were obtained.

To prevent formation of the oxygen adduct and to keep options

for later A-ring functionalization, elimination of the tertiary alcohol

in Burawoy’s ketone (6) was carried out using thionyl chloride and

4

basic conditions to give  -enone 11 (75% yield). In this case,

4

standard Riley conditions gave  -hydroxy enone 12 as another

4 2

substrate for the radical cascade. Again, the Pb(OAc) /I -system

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Scheme 4. Radical rearrangement of 12 and product distributions depending on the reaction conditions. Reagents and conditions: a) SOCl

10 °C, 45 min, 75%; b) SeO (4.75 eq.), dioxane/H O (50:1), 65 °C, 5 h, 73%; c) Pb(OAc) (2.0 eq.), I (1.5 eq.), CaCO (2.0 eq.), C , 85 °C, 2 h, R as in

Scheme 3.

2

(4.5 eq.), pyridine,

–

2

4

2

3

6 6

H

¹H-NMR, but further reaction to the desired carboxylic acid was

not successful.

rearrangement ring contraction/expansion^[¹⁹^](see structure J)

yielding lactone 20, which features immense connectivity

changes in the A and B ring. To the best of our knowledge, this

structural motif has not been observed in any steroidal context,

before. Afore mentioned Wharton transposition was envisioned to

convert epoxide 18 to C4 allylic alcohol, but as the initial

conversion to the corresponding hydrazone was unsuccessful,

further studies employing iodo-endoperoxides 16 and 17 were

discarded.

Since the diastereomeric endoperoxides 16 and 17 contained the

7

structural motif of a Δ -9α-hydroxy ketone, which is also present

in other members of the swinhoeisterols, they were also assumed

valuable intermediates en route to 2 (Scheme 6). Thus, reduction

of the peroxide functionality to the corresponding 5,9-diol (as in

1

9) was carried out on both 4-iodo epimers using PtO

of 4β-iodo endoperoxide 16, a mixture of the diol (not shown) and

epoxide 18 resulting from concomitant S 2 reaction was obtained.

Full conversion was possible by treatment with Ag O and gave 18

2 2

/H . In case

N

2

in 56% over 2 steps. As 18 was deemed a suitable precursor for

further transformations (e.g. Wharton transposition), diol 19 was

to be transformed to 18 as well through a S

with Ag O showed no conversion at room temperature but after

6 h at 60 °C selective formation of a new product was observed.

N

1reaction. Treatment

2

1

Careful analysis of the NMR data obtained led us to propose the

structure of lactone 20, which was confirmed by X-ray single

crystal structure analysis. Presumably, formation of the expected

cation at C4 did indeed take place but was immediately or

concertedly followed by bond migration to give 10(5→4)abeo

intermediate I.

Scheme 6. Synthetic transformations of endoperoxides 16 and 17 and

mechanistic proposal for the rearrangement to 20. Reagents and conditions: a)

Scheme 5. Attempted sigmatropic rearrangements to introduce a synthetic

precursor for the desired exo-methylene unit.

PtO

(2 steps); c) PtO

0 °C, 16 h, 85%, R as in Scheme 3.

2

(0.2 eq.), H

2

(balloon), EtOAc, 25 °C, 4 h; b) Ag

2

O, THF, 25 °C, 1 h, 56%

2

(0.2 eq.), H (balloon), EtOAc, 25 °C, 4 h, 70%; d) Ag

2

O, THF,

6

Assumedly, this oxocarbenium facilitated an attack of the C9

hydroxyl and thereby set the stage for a benzilic acid-type

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Another compound isolated from the reaction of 12 with

4

Pb(OAc)

4

/I

2

was  -13(14→8)abeo-steroid 15. Although not

further employed in the synthesis of the swinhoeisterols, its

isolation supported our mechanistic proposal and transformation

to dankasterone A (3) in 56% yield over two steps (Scheme 7)

was successful. In the meantime, we were able to provide proof

of the cage-like 13(14→8)abeo-4,14-cyclo structure of

[

12]

periconiastone A (5) by X-ray single crystal analysis. Previously,

we had synthesized 5 from dankasterone B (4)^[and now set out

to explore the possibility to generate an enolate by 1,4-reduction

of dankasterone A (3), which would then undergo aldol addition

and give the desired 4,14-cyclo skeleton. Interestingly, reaction

with L-selectride only gave 3α-alcohol 21, the product of 1,2-

reduction, presumably due to steric inaccessibility of C5.

13]

Scheme 7. Synthesis of periconiastone A (5) (ORTEP plot of 5. Thermal

ellipsoids are drawn at 50% probability) and alternative synthetic access to

dankasterone A (3) and its reduction. Reagents and conditions: a) DBU (10 eq.),

PhMe, 25 °C, 12 h; b) K

CH Cl , 25 °C, 1 h, 56% (2 steps); d) L-selectride (2.0 eq.), THF, –78 °C, 1 h,

7%. DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMP Dess–Martin

2 3

CO (5.0 eq.), MeOH, 25 °C, 1 h; c) DMP (2.0 eq.),

2

8

=

periodinane, R as in Scheme 3. CCDC 1989984 contains the supplementary

crystallographic data for compound 5.

Scheme 9. Synthetic access to 14β-OH 34 and attempted rerarrangement.

Reagents and conditions: a) TMSOTf (1.5 eq.), Et

b) TPP (0.2 mol%), O , hν, CH Cl , –78 °C, 15 min, 32: 56%, 33: 12%; c)

FeSO •7 H O (1.05 eq.), acetic buffer (pH 3), THF/H O (1.5:1), 25 °C, 1 h, 38%;

d) PPh (1.0 eq.), CH Cl , 25 °C, 1 h, 71%; e) Pb(OAc) (2.0 eq.), I (2.0 eq.),

CaCO (2.0 eq.), 85 °C, 1 h, 42%. TMSOTf trimethylsilyl

3 2 2

N (2.0 eq.), CH Cl , 0 °C, 1 h;

2

4

2

3

2

4

2

3

C

6

H

6

,

=

trifluoromethanesulfonate, TPP = meso-tetraphenylporphyrin, R as in Scheme 3.

As so far, all our efforts to process any rearranged material

obtained towards swinhoeisterol, and for a further generalization

of the radical cascade, next γ-hydroxy enone 22 which was

accessible in 4 steps and 42% from ergosterol (1)^[⁷^]was to be

4 2

investigated. When treating 22 with Pb(OAc) /I , four main

products were obtained after careful separation (Scheme 8A).

Once more, two of those contained the diabeo-structure (triene

dione 25 and its 15β-iodo analogue 26); the other two being

1

3(14→8)abeo dione 23 and its 7α-iodo analogue 24. To further

substantiate our mechanistic proposal, 23 as well as 24 were both

separately treated with Pb(OAc) /I . As expected, no conversion

4

2

Scheme 8. A: Radical rearrangement of 22 leading to mono- and diabeo

structures 23, 24, 25 and 26. B and C: Attempted rearrangements using

of the starting material was observed in case of dione 23, but the

reaction of iodide 24 gave rise to 65% of diabeo-compound 25.

As we reported earlier, it was possible to selectively access either

the diabeo-framework (25, HgO/I , 68% yield) or the monoabeo-

2

skeleton (24, PhI(OAc) , 76% yield), depending on the conditions

to generate the initial alkoxy radical.^[¹³^]To test if the

alternative conditions. Reagents and conditions a) Pb(OAc)

2.0 eq.), CaCO (2.0 eq.), C , 85 °C, 2 h; b) HgO (2.7 eq.), I (2.4 eq.), C

05 °C (sealed tube), 2 h, 68%; c) PhI(OAc) (2.0 eq.), I (1.0 eq.), C , 25 °C,

0 min, 76%; d) Ag O (2.0 eq.), I (1.5 eq.), C , 85 °C, 2 h, 27: 37% (5α/5β

.3:1), 28: 19%; e) [Ir(dF(CF )ppy) (5,5’-d(CF )bpy)]PF (3 mol%),

)NO CCF (0.4 eq.), blue LEDs, PhMe, 35 °C, 3 d, 17% (40% brsm). brsm

based on recovered starting material, R as is Scheme 3.

4 2

(2.0 eq.), I

(

3

6

H

6

2

6 6

H ,

1

3

2

6 6

H

2

6 6

H

3

2

3

6

(

nBu

4

2

3

=

rearrangement to the diabeo-structures could be initiated without

employing toxic Hg or Pb reagents, 22 was treated with Ag

2

O and

.^[²⁰^]However, only elimination of the 14-hydroxyl was observed

to give 28) along with partial i-steroid opening to give iodide 27

I

2

(

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Chemistry - A European Journal

10.1002/chem.202001405

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Scheme 10. Analysis of synthetic challenges in swinhoeisterol A (2).

as a mixture of epimers (5α/5β 2.3:1).^[²¹^]Knowles’ photocatalytic

ring expansion conditions^[²²^]either did not yield any rearranged

product but resulted in the isolation of ⁸^,¹⁴-steroid 29.^[¹⁴^a^]Any

other attempts to initiate a radical-promoted cascade employing

other metal salts, did not lead to any conversion of the starting

material.

2

9α-hydroxy dione 37 presumably through attack of O by the

intermediary dienolate. Even though this was not the expected

product, the synthetic route was continued, since the obtained 9α-

hydroxy enone pattern is present in swinhoeisterol B (not shown).

4

Reduction with LiAlH gave de-silylated 6α-OH 38, which seemed

to be a suitable precursor for an i-steroid opening. However, when

3 2

treating 38 with acetic acid and BF •OEt

,^[²³^]unexpected

To further study the influence of the stereoconfiguration at C14 on

the radical cascade, we prepared14β-hydroxy enone 34

[24a,b]

anthrasteroid

39 was isolated in 87%. Presumably, the initial

i-steroid opening took place as expected (K) but was followed by

generation of cation L through loss of the hydroxy group.

(

Scheme 9). Since all Riley oxidations carried out resulted in 14α-

hydroxylation, a Schenck ene reaction followed by reduction of

the hydroperoxide was envisioned, instead. i-Steroid enone 30

was converted into TMS dienol ether 31, which was then treated

with oxygen and TPP as photosensitizer under irradiation with

white light to give 14α-hydroperoxide 32 and 14β-hydroperoxide

Stabilization of the cation by bond migration could then lead to

_s_p_i_r_o_-_c_o_m_p_o_u_n_d_M_,[24c,d] which, after formation of the C1–C6 bond,

gives Wheland complex N. Loss of a proton would generate

aromatic 39, whose 1(10→6)abeo-structure can be found in a

_n_u_m_b_e_r_o_f_n_a_t_u_r_a_l_p_r_o_d_u_c_t_s_.[24d–g]

3

3 (56 and 12% yield, respectively). While 14α-OOH 32 could be

converted to 13(14→8)abeo-dione 23 in a yield of 38% using

Danieli’s conditions (FeSO

),^[¹⁴^b^]14β-OOH 33 was reduced to the

2

corresponding alcohol 34, which was then exposed to Pb(OAc) /I .

4

This time, no rearrangement of the steroid skeleton was observed.

The alkoxy radical generated at C14 rather added to the double

bond at C8, giving rise to an epoxide and the C7 centered radical

was then quenched by iodine leading to 7α-iodo epoxide 35. This

difference in reactivity can be explained with an unfavorable

orbital overlap of the radical’s SOMO and the σ-orbital of the C13–

C14 bond so that no β scission could occur.

As the radical rearrangement was most selective on the i-steroid

system, it was chosen as starting material for our synthetic efforts

towards swinhoeisterol A (2) and analogues. In the following, we

want to discuss the major synthetic challenges that had to be

overcome en route to swinhoeisterol A (Scheme 10). Starting

from ergosterol (1), our synthetic approach consisted of an

oxidative cleavage/olefination/hydrogenation sequence of ²²to

introduce the desired (saturated) campestane side chain

(

Scheme 10, A). We envisioned to introduce the exo-methylene

moiety via elimination of a hydroxymethyl group at C4 at a late

stage of the synthesis making use of an enone functionality in the

A-ring (Scheme 10, B). This key intermediate was traced back to

a diene dione system from our radical cascade (Scheme 10, C).

Scheme 11. Transformations on i-steroid diene dione 25 and mechanistic

proposal for the formation of anthrasteroid 39. Reagents and conditions: a)

TESOTf (5.0 eq.), 2,6-lutidine (10 eq.), CH

3.0 eq.), THF, –78 °C, 1 h, 53%; c) LiAlH

BF •OEt /HOAc/Et (1:1:2), 0 °C, 1 h, 87%. TESOTf

trifluoromethanesulfonate, R as in Scheme 3.

2

Cl

(5.0 eq.). THF, 0 °C, 1 h, 40%; d)

triethylsilyl

2

, 0 °C, 1 h, 86%; b) L-selectride

(

4

3

2

O

=

Following these studies, we attempted a synthetic approach

towards swinhoeisterol A (2) making use of 25 (Scheme 11),

which was obtained in a good yield from 22 when applying HgO/I

68%). It was possible to differentiate the C6- and C14-oxo

functionalities of diene dione 25 by selective formation of C14 silyl

enol ether 36. We planned to adjust the oxidation state by 1,6-

reduction with L-selectride, which along with the expected

reduction involved the incorporation of an oxygen at C9 to give

2

(

Through these experiments, the tertiary alcohol at C9 had been

identified to be problematic in the cyclopropane opening reaction

of 38 and, thus, its formation was tried to be avoided by vigorous

exclusion of oxygen prior to reduction with L-selectride

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Chemistry - A European Journal

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(

Scheme 12). The so-generated ⁸-ene dione system

tautomerized (Scheme 10, C), leading to a tedious isolation

accompanied by decomposition. To prevent this problem, we

decided to add another reducing reagent to the reaction mixture

to convert one or both ketones to the corresponding alcohols.

Interestingly, the initially formed lithium enolate protected the

respective ketone against reduction with lithium aluminum hydride,

and only the 6-oxo moiety was reduced to give β-hydroxy ketone

4

3 2

0. Its treatment with BF •OEt and acetic acid again resulted in

an undesired side reaction, i.e., isomerization of ⁸into

conjugation with the ketone to give ⁵^,⁷-diene 41 as the major

product (51%) and only minor quantities (12%) of the desired ⁵^,⁸

-

diene 42. Saponification (K

2 3

CO , MeOH) proved to be difficult on

4

2, and de-acetylation could only be achieved under reductive

conditions (DIBAl-H) leading to concomitant reduction of the 14-

oxo functionality to furnish 43. To instead employ ⁵^,⁷-diene 41,

several approaches were investigated, but isomerization of one

or both of the two double bonds proved to be impossible. We

8

suspected that isomerization of  had occurred due to activation

3 2

of the ketone with BF •OEt , and, thus, reduced 40 to 6,14-diol 44.

Fortunately, this time no isomerization was observed during i-

steroid opening and subsequent de-acetylation (DIBAl-H) gave

3

,14-diol 43 in a convincing yield of 74% over 2 steps. Employing

Oppenauer conditions to achieve oxidation and isomerization to

enone 45 did not lead to any conversion. Hence, a stepwise

process using Dess–Martin periodinane and then DBU

established key-intermediate 45 with a yield of 79% over 2 steps.

Scheme 13. Attempted reductive alkylation of enone 45, successful conversion

to hydroxymethylated 49 via Nishiyama−Stork reaction and elimination of the

22

primary alcohol to  -24-epi-2. Reactions and conditions: Li•4 NH

3

, –78 to

N (1:2), –60 to –20 °C, 1 h;

(1.5 eq.), MeOH, –10 °C, 20 min; c)

chloromethyl)-chloromethylsilane (5.0 eq.), Et (10 eq.), DMAP (0.2 eq.),

CH Cl , 25 °C, 1 h; d) NaI (50 eq.), acetone, 60 °C, 16 h, 83% (3 steps); e)

nBu SnCl (0.2 eq.), NaBH CN (2.0 eq.), AIBN (0.1 eq.), tBuOH, 85 °C, 16 h;

then KF (10 eq.), KHCO (10 eq.), H /MeOH/THF (2:2:1), 25 °C, 30 min,

(2.5 eq.), 2,6-di-tert-butyl-4-methylpyridine (7.5 eq.), CH Cl

78 °C, 5 min; then MeOH (30 eq.), DBU (20 eq.), –78 to 25 °C, 2 h, 62%. TMS

trimethylsilyl, DMAP 4-(dimethylamino)pyridine, AIBN 2,2’-

azobis(isobutyronitrile), Tf = trifluoromethanesulfonyl, R as in Scheme 3.

2

5 °C; then 45, THF, –78 °C, 30 min; then TMSCl/Et

3

b) NaBH (0.6 eq.), CeCl •7

4

3

2

H O

(

3

N

2

3

2 2

O

3

6%; f) Tf

2

O

2

,

–

=

As a handle to construct the requisite exo-methylene group along

with the necessary trans ring junction of the A and B ring (Scheme

1

0, B), we envisioned the installation of a hydroxymethyl group at

C4 and elimination of the primary alcohol to furnish the methylene

unit. Initially, we intended to install the remaining carbon atom

through a reductive alkylation protocol under dissolving metal

conditions. As the direct addition of gaseous formaldehyde did not

yield any of the desired hydroxy methylated product,^[²⁵^]the

trapping as a silyl enol ether was investigated. We applied a

procedure described by Mueller and Gillick,^[²⁶^]which involved the

generation of so-called lithium bronze.^[²⁶^c^]Thus, enone 45 was

readily converted into silyl enol ether 46 (Scheme 13). To

introduce a suitable methylene precursor, a variety of conditions

to alkylate 46 were tested. Methods using aqueous formaldehyde

[

27]

either in combination with Lewis acids such as Sc(OTf)

3

or

Yb(OTf) ^[

28]

or by addition of a de-silylating reagent (e.g. TBAF^[²⁹^]

)

3

have been described. Even though addition of formaldehyde

could be detected by mass spectrometry, the isolation of the

desired γ-hydroxy ketone was unsuccessful and instead, ketone

Scheme 12. i-Steroid opening and synthesis of key fragment 45. Reagents and

conditions: a) L-selectride (1.5 eq.), LiAlH

b) BF •OEt /HOAc/Et O (1:1:2), 0 °C, 45 min, 41: 51%, 42: 12%; c) DIBAl-H,

THF, –78 °C, 1.5 h, 76%; d) NaBH (2.5 eq.), CeCl •7H (2.5 eq.),

MeOH/CH Cl (2:1), –10 °C, 30 min, 87%; e) BF •OEt /HOAc/Et O (1:1:2), 0 to

5 °C, 5 h, 88%; f) DIBAl-H, THF, –78 °C, 1.5 h, 89%; g) DMP, NaHCO , CH Cl

5 °C, 1 h, 82%; h) DBU, CH Cl 25 °C, 1 h, 91%. DIBAl-H

4

(2.5 eq.), THF, –78 to 0 °C, 2 h, 55%;

3

2

4

7 was obtained, the product of a retro-aldol reaction.^[³⁰^]To

4

3

2

O

2

3

2

circumvent this problem, we attempted to install a protected

hydroxy methyl moiety. However, when treating silyl enol ether 46

_w_i_t_h_B_O_M_C_l_a_n_d_v_a_r_y_i_n_g_L_e_w_i_s_a_c_i_d_s_,[31] only α-halogenated

2

3

2

,

2

,

=

diisobutylaluminum hydride, R as in Scheme 3.

ketones were isolated, yielding 4-chloro- and 4-fluoro-ketones

6

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

when using SnCl

4

, TiCl

4

, or BF

3

•OEt

2

, respectively. Consequently,

followed by Finkelstein reaction to give iodide 48. Radical

the introduction of other functional groups known to be convertible

into a methylene group was considered. Thus, treatment of silyl

enol ether 46 with ethyl bromo acetate to give the corresponding

ethyl ester^[³²^]or Eschenmoser’s salt to give the dimethylamine,^[³³^]

were attempted but did not yield any desired product other than

ketone 47.

cyclization was then achieved by treatment with catalytic

quantities of AIBN and nBu SnCl and stoichiometric amounts of

3

NaBH CN to result in the formation of a oxasilolane (not shown),

3

which, upon oxidative work up (H O , KF), delivered diol 49 in

2

36% yield along with 16% of its undesired 5β-epimer. Finally, the

primary alcohol was converted to the corresponding triflate with

Tf

2

O at –78 °C, which, upon warming to 25 °C, eliminated to yield

2

the desired exo-methylene group in  -24-epi-swinhoeisterol A

2

[37]



-24-epi-2.

With reliable route for swinhoeisterol A’s tetracyclic core, one last

synthetic challenge had to be overcome, i.e., the introduction of

the correctly configurated side chain (Scheme 10, A). It was

deemed strategically advantageous, to perform the necessary

modifications at a late stage. Since we envisioned a sequence of

oxidative C–C bond cleavage, olefination, and hydrogenation,

many synthetic intermediates bearing easily accessible double

bonds additional to ²²had to be excluded a priori. Thus, hydroxy

methylated 49 and enone 45 presented themselves as promising

candidates (Scheme 14). Oxidative ²²bond cleavage on the

stage of diol 49 was achieved through ozonolysis and reductive

work-up. Attempted Julia–Kocienski olefination proved

unsuccessful due to low solubility of the starting material. Thus,

the 1,3-diol functionality of 49 was protected as an acetonide,

which was processed to the corresponding aldehyde. Again, no

conversion of the starting material in an attempted

Julia−Kocienski reaction could be observed. We, thus, shifted our

attempts towards enone 45. Ozonolysis gave aldehyde 50, and

this time, Julia−Kocienski olefination using sulfone 51 indeed led

to conversion of starting material. Unfortunately, not the desired

olefin, but tetrazole 52, which presumably arose from aldol

reaction between enolizable C7 and the 22-oxo functionality

followed by trapping of the alcoholate by the tetrazole moiety of

sulfone 51, was isolated. As a consequence of this reactivity, i-

steroid diol 44, an intermediate without the oxo moiety at C14,

was anticipated to adopt a less reactive conformation and, thus,

seemed to be a better choice. However, treatment of the

corresponding aldehyde of diol 44 with LiHMDS and sulfone 51

only led to isolation of material with the C6 hydroxyl bearing a

tetrazole substituent. One of the few remaining intermediates to

conduct the ozonolysis/olefination approach was β-hydroxy

ketone 40, which, after conversion to aldehyde 53 eventually

afforded the desired olefin 55 (with the double bond being Z

configurated) along with small quantities of aldol product 54.

Fortunately, it was possible to almost suppress formation of 54

Scheme 14. Attempts to install the necessary campestane side chain.

Reagents and conditions: a) O

PPh (1.1 eq), –78 to 25 °C, 16 h, 92%; b) 51 (5.0 eq.), LiHMDS (5.0 eq.), THF,

78 to 25 °C, 22 h, 52%; c) O , CH Cl /pyridine (99:1), –78 °C, 45 min; then

PPh (2.0 eq.), –78 to 25 °C, 16 h, 73%; d) 51 (5.0 eq), LiHMDS (3.1 eq), THF,

78 to –65 °C, 2 h, 86%; e) NaBH (2.5 eq), CH Cl /MeOH (1:1), –10 °C, 30 min,

4%. HMDS = 1,1,1,3,3,3-hexamethyldisilazide, R as in Scheme 3.

3 2 2

, CH Cl /pyridine (99:1), –78 °C, 3 min; then

3

–

3

2

3

–

4

2

(

less than 5%) when increasing the amount of sulfone 51 (5.0 eq.).

9

That way, olefin 55 was obtained in 86% yield. To furnish the

desired saturated campestane side chain, hydrogenation

conditions were tested on olefin 55, but no conversion of starting

material was observed under the conditions employed. Further

reduction experiments were then carried out on diol 56, which was

Alternatively, the method by Nishiyama and Stork^[³⁴^]was

considered and successfully executed to introduce the C4

hydroxy methyl moiety. Thus, enone 45 was selectively reduced

under Luche conditions to the corresponding allylic alcohol, which

was then treated with chloro(bromomethyl)dimethylsilane and

triethyl amine to give the crucial precursor for a radical cyclization.

Initial results employing the (bromomethyl)silyl ether (not shown)

in the radical cyclization and subsequent Tamao oxidation^[³⁵^]

lacked reproducibility. An alternative procedure employing

substoichiometric amounts of the tin reagent required the

corresponding (iodomethyl)silyl ether 48.^[³⁶^]Hence, allylic alcohol

was converted to the (chloromethyl)silyl ether (not shown)

4

obtained by reduction with NaBH .

Hydrogenation of a 22Z double bond is known to be more difficult

than of the corresponding 22E isomer.^[³⁸^]In agreement, in most

experiments no conversion was achieved (Table 1, entries 3–9)

and only elevated hydrogen pressure (40–60 bar) led to complete

conversion to 57. Unfortunately, varying degrees of epimerization

at C24 occurred during the course of this reaction^[³⁹^]yielding up to

50% of the undesired ergostane product when using Pd/C (entry

1) and still 25% when Pt/C was used (entry 2). Attempted

7

Chemistry - A European Journal

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FULL PAPER

alternatives, such as Wilkinson’s (entry 6) or Crabtree’s catalyst

treatment with BF

3

•OEt

2

under acidic conditions gave the

(

entry 7) as well as Shenvi’s radical hydrogenation method

corresponding acetates 59 and 59a. De-acetylation was

accomplished using DIBAl-H giving rise to 43, 43a, and 43b.

Oxidation with DMP and subsequent isomerization of the  bond

entries 8 and 9)^[did not lead to any conversion of starting

40]

5

material.

with DBU yielded enones 45, 45a, and 45b. Luche reduction and

Table 1: Attempted hydrogenation of ²²in 56.

silylation

with

chloro(chloromethyl)-

or

pressure H

2

epimerization

at C24^[^a^]

(bromomethyl)chlorodimethylsilane gave (chloromethyl)silyl

ethers 60 and 60b, and (bromomethyl)silyl ether 61a, respectively.

As classic Nishiyama−Stork conditions (61a, AIBN, nBuSnH)

followed by Tamao oxidation gave crucial diol 49a only in low and

varying yields (15–34%), we adjusted the synthetic route towards

 -24-epi-2 and 2. (Chloromethyl)silyl ethers 60 and 60b were

transformed to the corresponding (iodomethyl)silyl ethers using

Finkelstein conditions and then treated with catalytic amounts of

entry

catalyst

conversion

[

bar]

40

60

-^[^c^]

1

2

3

4

5

6

7

8

9

Pd/C

Pt/C

~50%

complete

none

~25%

2

PtO

Ir

2

-

none

Rh/C

none

3 3

AIBN and nBu SnCl and a stoichiometric amount of NaBH CN

prior to oxidation, facilitating a reliable access to diols 49 and 49b.

[RhCl(PPh

3

)

3

]

none

Finally, triflation of the primary alcohol and subsequent

Crabtree^[^b^]

Mn(dpm)

Co(acac)

none

2

elimination afforded 2, 24-epi-2, and  -24-epi-2, respectively,

bearing the characteristic exo-methylene group of the

swinhoeisterols.

3

none

-^[^c^]

none

2

We herein detailed our efforts towards the synthesis of

swinhoeisterol A (2) and discussed major challenges that were

overcome during the development of a viable synthetic route.

[

a] Ratio of epimers determined from ¹³C NMR spectra (see SI of ref. 13). [b]

Crabtree catalyst: (SP-4)tris(cyclohexyl)phosphane[(1-2-η:5-6-η)-cycloocta-

,5-diene]pyridineiridium hexafluorophosphate. [c] 4.0 eq. of PhSiH ; acac =

acetylacetonate, dpm = 2,2,6,6-tetramethyl-3,5-heptanedionato.

1

3

22

Additionally, the synthesis of the first analogue,  -24-epi-

22

swinhoeisterol A ( -24-epi-2) was outlined as well as several

experiments that were carried out to support our mechanistic

proposal for the radical framework reconstruction. Two

unexpected rearrangements of the steroid skeleton were

observed, one of them leading to hydroxy lactone 20, which had

not been reported before. The synthesis of the remaining

members of the swinhoeisterol class and the biological evaluation

of all synthesized natural products are ongoing in our laboratory.

As hydrogenation of an 22E-configurated double bond without

epimerization of C24 was deemed more promising, we carried out

several isomerization experiments to convert 22Z to 22E, but

could eventually not succeed in identifying a viable method. At this

point, we turned our attention to rather functionalize the side chain

double bond and remove the thus-installed functional group

reductively in a separate step. Introduction of sulfur-containing

functionalities failed and halogenation with bromine to the

dibromide and subsequent treatment with AIBN/nBu

to a mixture of 22E- and 22Z-diol 56. To our delight, hydroboration

and subsequent oxidation with NaOH/H afforded primarily a

,14,23-triol (not shown) under concomitant reduction of C14.

3

SnH only led

2

O

2

6

Acetonide formation of the thus-obtained 1,3-diol unit and

functionalization of the side chain alcohol (predominantly 23-OH)

to a xanthate, followed by Barton–McCombie deoxygenation

eventually gave the desired saturated campestane side chain

without any epimerization (Scheme 15).

All synthetic challenges were thus coped with so that three very

similar approaches led to the synthesis of natural swinhoeisterol

A (2, b-series) and 24-epi-swinhoeisterol A (24-epi-2, a-series).

As it was initially uncertain at which stage an installation of the

correct side chain fragment would be feasible, the synthetic route

had also been carried out in the ergostane series, starting from

2

ergosterol (1) without hydrogenation of the  bond. This route

2

22

enabled access to  -24-epi-swinhoeisterol A ( -24-epi-2) in 16

steps and a total yield of 1.5%.

In summary, access to the diabeo-skeleton (25 and 25a) via γ-

hydroxy enones 22 or 22a was accomplished in 5 to 6 steps,

respectively, starting from ergosterol (1). β-Hydroxy ketones 40

and 40a, obtained after reduction, were further processed

following two different pathways. For the synthesis of

swinhoeisterol A (2), 40a was subjected to ozonolysis and Julia–

Kocienski olefination to give 55b, followed by a hydroboration,

oxidation/Barton–McCombie deoxygenation sequence to yield

the desired saturated campestane side chain as in 58b. Opening

of the i-steroid moiety led to acetate 59b. 40 and 40a, on the other

hand, were reduced to diols 44 and 44a and subsequent

8

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

Scheme 15. Overview of the synthetic routes to swinhoeisterol A (2, b series), 24-epi-swinhoeisterol A (24-epi-2, a series) and ²²-24-epi-swinhoeisterol A (²²-24-

epi-2) starting from ergosterol (1). Reactions and conditions: a) PtO (0.1 eq.), H (20 bar), EtOAc, 25 °C, 24 h, 22a: 88% b) HgO (2.7 eq.), I (2.4 eq.), C , 105 °C,

h, 25: 68%, 25a: 68%; c) L-selectride (2.0 eq.), THF, –78 °C, 1 h; then LiAlH (2.0 eq.), –78 to 0 °C, 1 h, 40: 55%, 40a: 54%; d) O , CH Cl /pyridine (99:1), –78 °C,

5 min; then PPh (2.0 eq.), –78 to 25 °C, 16 h; e) 51 (5.0 eq.), LiHMDS (3.1 eq.), THF, –65 °C, 1 h; then 40, –65 °C, 1 h, 55b: 63% (2 steps); f) BH •THF (10 eq.),

(1:1), 25 °C, 1 h; g) CSA (1.2 eq.), (MeO) CMe /CH Cl (1:5), 0 °C, 1 h; h) KHMDS (2.0 eq.), CS (5.0 eq.), THF, –78 to

5 °C, 1.5 h; then MeI (7.5 eq.), 25 °C, 45 min; i) AIBN (0.5 eq.), nBu SnH (5.0 eq.), C , 85 °C, 3 h, 58b: 54% (4 steps); j) BF •OEt /HOAc/Et O (1:1:2), 0 to 25 °C,

h, 59b: 82%; k) DIBAl-H, THF, –78 °C, 1 h, 43: 89%, 43a: 86% 43b: 83%; l) DMP (3.0 eq.), NaHCO (6.6 eq.), CH Cl , 25 °C, 1 h; m) DBU (0.2 eq.), CH Cl

5 °C, 1 h, 45: 75% (2 steps), 45a: 79% (2 steps), 45b: 73% (2 steps); n) NaBH (0.6 eq.), CeCl •7 (2.5 eq.), MeOH, –10 °C, 20 min; o)

N (10 eq.), DMAP (0.2 eq.), CH Cl , 25 °C, 1 h, 60: 83% (2 steps), 60b: 71% (2 steps); p) NaI (50 eq.), acetone,

CN (2.0 eq.), AIBN (0.1 eq.), tBuOH, 85 °C, 16 h; then KF (10 eq.), KHCO (10 eq.), H /MeOH/THF (2:2:1), 25 °C,

0 min, 49: 36% (2 steps), 49b: 39% (2 steps); r) Tf O (2.5 eq.), 2,6-di-tbutyl-4-methylpyridine (7.5 eq.), CH Cl , –78 °C, 5 min; then MeOH (30 eq.), DBU (20 eq.),

78 to 25 °C, 2 h, Δ -24-epi-2: 62%, 2: 73%; s) NaBH (2.5 eq.), CeCl •7 H O (2.5 eq.), MeOH, –10 °C, 30 min, 44: 86%, 44a: 87%; t) BF •OEt /HOAc/Et O (1:1:2),

to 25 °C, 5 h, 59: 88% 59a: 86%; u) NaBH (0.6 eq.), CeCl •7 H O (2.5 eq.), MeOH, –10 °C, 20 min; v) (bromomethyl)chlorodimethylsilane (15 eq.), Et N (20 eq.),

Cl , 25 °C, 1 h, 61a: 78% (2 steps); w) AIBN (1.0 eq.), nBu SnH (5.0 eq.), C , 85 °C, 16 h; then KF (10 eq.), KHCO (10 eq.), H /MeOH/THF

2:2:1), 25 °C, 2.5 h, 49a: 15–34%; x) Tf O (10 eq.), 2,6-lutidine (15 eq.), CH Cl , –78 °C, 10 min; then MeOH (10 eq.), DBU (20 eq.), –78 to –40 °C, 1.5 h, 24-epi-

: 72%. CSA = camphorsulfonic acid, py = pyridine, PT = 1-phenyl-1H-tetrazol-5-yl.

2

6 6

H

2

4

3

2

3

THF, 0 to 25 °C, 16 h; then NaOH/H

2

O

2

5

2

3

6

H

6

3

2

3

2

,

4

3

2

H O

chloro(chloromethyl)dimethylsilane (5.0 eq.), Et

3

2

6

3

–

0

0 °C, 16 h; q) nBu

3

SnCl (0.2 eq.), NaBH

3

2 2

O

2

4

3

2

3

2

4

3

2

3

DMAP (0.2 eq.), CH

2

3

6

H

6

3

2 2

O

(

2

was allowed to cool to 25 °C, diluted with EtOAc (15 mL) and filtered

Experimental Section

®

through a plug of Celite . The solvent was removed under reduced

(

22E)-6-Oxo-5α(H)-ergosta-7,22-dien-3β-yl acetate (S1)

pressure and column chromatography (silica gel, nhexane/EtOAc 9:1)

A suspension of Burawoy’s ketone (6) (366 mg, 778 µmol, 1.0 eq.) in

f

gave S1 (167 mg, 367 µmol, 47%) as a colorless solid. R = 0.22

acetic acid (26 mL) was heated to 90 °C and zinc dust (1.50 g, 22.9 mmol,

20

(

3

nhexane/EtOAc 5:1); m.p. 173–175 °C (CHCl ); [α]_D= –14.7 (c = 1.00,

29 eq.) was added to the mixture in three portions over 3 h. The mixture

9

Chemistry - A European Journal

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FULL PAPER

1

CHCl

3

); H NMR (500 MHz, CDCl

3

) δ [ppm] = 5.72 (t, J = 2.4 Hz, 1H), 5.24

18%) diene dione 9 (24.9 mg, 53.4 µmol, 59%) and traces of endoperoxide

10.

(

dd, J = 15.3, 7.5 Hz, 1H), 5.16 (dd, J = 15.3, 8.3 Hz, 1H), 4.76 – 4.68 (m,

1H), 2.30 (dd, J = 12.4, 3.7 Hz, 1H), 2.25 – 2.15 (m, 2H), 2.14 – 2.04 (m,

3H), 2.04 (s, 3H), 1.89 – 1.83 (m, 3H), 1.82 – 1.74 (m, 2H), 1.70 – 1.62 (m,

1H), 1.62 – 1.56 (m, 1H), 1.56 – 1.51 (m, 1H), 1.50 – 1.44 (m, 3H), 1.44 –

1.33 (m, 4H), 1.04 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (s,

3

H), 0.84 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.61 (s, 3H); ¹³C

15β-Iodo diene dione 8: light-yellow oil, R

f

= 0.29 (nhexane/EtOAc 3:1);

2

D

0

1

[α] = –25.9 (c = 0.75, CHCl ); H NMR (600 MHz, CDCl ) δ [ppm] = 6.31

3

(

t, J = 2.8 Hz, 1H), 5.34 – 5.23 (m, 2H), 4.87 (t, J = 3.9 Hz, 1H), 4.77 – 4.69

m, 1H), 2.96 (dd, J = 17.9, 2.5 Hz, 1H), 2.70 – 2.63 (m, 1H), 2.50 (dd, J =

(

8.9, 3.3 Hz, 1H), 2.47 (t, J = 3.5 Hz, 1H), 2.31 – 2.24 (m, 1H), 2.19 – 2.14

NMR (126 MHz, CDCl

3

); δ [ppm] = 199.3, 170.7, 163.8, 135.1, 132.6,

23.1, 73.0, 56.2, 55.8, 53.2, 50.1, 44.5, 42.9, 40.4, 38.8, 38.3, 36.7, 33.2,

8.0, 26.9, 26.5, 22.7, 21.9, 21.5, 21.2, 20.1, 19.8, 17.7, 13.3, 12.7; IR

(

m, 1H), 2.05 (s, 3H), 2.04 – 2.01 (m, 2H), 2.00 – 1.93 (m, 2H), 1.93 – 1.85

m, 1H), 1.80 – 1.71 (m, 1H), 1.64 – 1.57 (m, 1H), 1.51 – 1.44 (m, 1H),

1

2

(

1

.10 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.02 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H),

neat); ṽ [cm⁻¹] = 2953 (m), 2922 (s), 2852 (m), 1739 (w), 1677 (w), 1459

(

_.₈₄₍_d_,_J₌₆_.₈_H_z_,₄_H₎_,₀_.₈₂₍_d_,_J₌₆_.₇_H_z_,₃_H₎_;13C NMR (151 MHz,

0

(

m), 1377 (w). 1240 (w), 1038 (w), 970 (w), 722 (w); HRMS (ESI-TOF);

CDCl

3

); δ [ppm] = 193.9, 193.0, 170.6, 167.6, 148.5, 137.5, 136.1, 131.9,

+

46 3

m/z calcd. for C30H O Na [M+Na] : 477.3339, found: 477.3350.

1

2

27.6, 72.7, 52.2, 49.1, 47.7, 45.3, 43.4, 39.4, 38.9, 36.0, 34.5, 33.2, 31.5,

(

22E)-14-Hydroxy-6-oxo-5α(H)-ergosta-7,22-dien-3β-yl acetate (7)

₆_.₇_,₂₆_.₃_,₂₂_.₇_,₂₂_.₁_,₂₁_.₅_,₂₀_.₂_,₁₉_.₉_,₁₉_.₃_,₁₇_.₆_._;_I_R₍_n_e_a_t₎_;_v_̃_[_c_m−1] =

Selenium dioxide (83.4 mg, 752 µmol, 4.75 eq.) was added to a solution

956 (s), 2925 (s), 2871 (m), 2855 (m), 1735 (s), 1702 (s), 1590 (w), 1458

of 5α-enone S1 (71.8 mg, 158 mmol, 1.0 eq.) in tBuOH/pyridine (4:1,

(w), 1376 (m), 1291 (w), 1235 (s), 1185 (w), 1035 (m); HRMS (ESI-TOF);

2

.5 mL) and the reaction mixture was heated to 80 °C for 4 h. It was cooled

to 25 °C, the mixture was filtered through a plug of Celite^®and rinsed with

EtOAc (15 mL). The filtrate was washed sequentially with Na (sat.

aq., 10 mL), NaHCO (sat. aq., 10 mL) and brine (sat., 10 mL), dried over

MgSO , and the solvent was removed under reduced pressure. Column

chromatography (silica gel, nhexane/EtOAc 4:1 g 3:1) gave γ-hydroxy

enone 7 (43.7 mg, 92.8 µmol, 59%) as a colorless solid. R = 0.20

); [α] = +15.2 (c = 1.00,

+

41 4

m/z calcd. for C30H O INa [M+Na] : 615.1942, found: 615.1933.

Diene dione 9: colorless needles (recrystallized from pentane/Et

2

O),

₎_;1H NMR

f 3

R = 0.15 (nhexane/EtOAc 3:1); [α]_D= –79.5 (c = 1.00, CHCl

2

S

2

O

3

20

3

(

500 MHz, CDCl

3

) δ [ppm] = 6.30 – 6.22 (m, 1H), 5.36 (dd, J = 15.3, 8.5

4

Hz, 1H), 5.28 (dd, J = 15.3, 7.9 Hz, 1H), 4.75 – 4.64 (m, 1H), 2.83 (dd, J =

1

7.7, 2.4 Hz, 1H), 2.69 (ddd, J = 11.9, 7.0, 3.5 Hz, 1H), 2.61 – 2.50 (m,

H), 2.45 (dd, J = 17.6, 3.2 Hz, 1H), 2.40 (dd, J = 12.6, 3.4 Hz, 1H), 2.24

f

3

2

D

0

(

nhexane/EtOAc 3:1); m.p. 187–189 °C (CHCl

3

– 2.18 (m, 1H), 2.04 (s, 3H), 1.99 – 1.94 (m, 2H), 1.90 – 1.85 (m, 2H), 1.75

1.68 (m, 1H), 1.59 – 1.51 (m, 2H), 1.49 – 1.43 (m, 2H), 1.14 (s, 3H), 1.06

d, J = 7.0 Hz, 3H), 1.01 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8

_H_z_,₃_H₎_,₀_.₈₁₍_d_,_J₌₆_.₇_H_z_,₃_H₎_;13C NMR (126 MHz, CDCl

); δ [ppm] =

01.8, 193.6, 170.6, 170.2, 148.9, 136.3, 135.5, 131.8, 130.1, 72.7, 53.1,

1

CHCl

3

); H NMR (500 MHz, CDCl

3

) δ [ppm] = 5.90 (d, J = 2.8 Hz, 1H), 5.26

–

(dd, J = 15.3, 7.5 Hz, 1H), 5.19 (dd, J = 15.3, 8.2 Hz, 1H), 4.76 – 4.68 (m,

(

1H), 2.72 (ddd, J = 11.9, 7.2, 2.8 Hz, 1H), 2.34 (dd, J = 12.3, 3.8 Hz, 1H),

2.25 – 2.18 (m, 1H), 2.11 – 2.05 (m, 1H), 2.04 (s, 3H), 1.98 – 1.90 (m, 3H),

1.90 – 1.83 (m, 3H), 1.80 – 1.68 (m, 2H), 1.63 – 1.52 (m, 3H), 1.52 – 1.35

3

2

5

2

0.5, 49.6, 48.1, 45.1, 43.4, 39.8, 36.3, 34.5, 33.2, 26.7, 26.2, 23.6, 22.9,

(

m, 4H), 1.28 – 1.23 (m, 1H), 1.02 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.8 Hz,

H), 0.88 (s, 3H), 0.85 – 0.81 (m, 6H), 0.69 (s, 3H); ¹³C NMR (126 MHz,

CDCl ); δ [ppm] = 200.0, 170.7, 163.4, 135.4, 132.7, 122.9, 85.3, 72.9,

3.4, 50.4, 46.5, 46.1, 42.9, 40.1, 38.7, 36.7, 33.2, 32.1, 30.6, 26.9, 26.7,

₂_.₁_,₂₁_.₄_,₂₀_.₂_,₁₉_.₈_,₁₉_.₁_,₁₇_.₆_;_I_R₍_n_e_a_t₎_;_v_̃_[_c_m−1] = 2955 (m), 2924 (s),

3

854 (m), 1735 (m), 1704 (s), 1659 (w), 1590 (w),1457 (m), 1375 (m), 1234

3

_N_a+

42 4

s), 1186 (m), 1037 (m); HRMS (ESI-TOF); m/z calcd. for C30H O

(

5

2

_M₊_N_a_]+_:489.2975, found: 489.2992. CCDC 1991055 contains the

[

6.4, 21.5, 21.4, 20.6, 20.1, 19.8, 17.7, 16.2, 13.1; IR (neat); ṽ [cm⁻¹] =

supplementary crystallographic data for this paper. These data can be

obtained free of charge from The Cambridge Crystallographic Data

Centre.

953 (m), 2922 (s), 2853 (m), 1739 (w), 1459 (w), 1377 (w), 1240 (w), 1038

46 4

w), 972 (w); HRMS (ESI-TOF); m/z calcd. for C30H O

Na⁺[M+Na]⁺:

(

493.3288, found: 493.3287.

2

Endoperoxide 10: colorless needles (recrystallized from pentane/Et O)

(

22E)-15β-Iodo-6,14-dioxo-13(14→8),14(8→7)diabeo-5α(H)-ergosta-

,9(11),22-trien-3β-yl acetate (8),

22E)-6,14-Dioxo-13(14→8),14(8→7)diabeo-5α(H)-ergosta-7,9(11),22-

trien-3β-yl acetate (9) and

22E)-6,14-Dioxo-5α,9α-endoperoxide-13(14→8),14(8→7)diabeo-

1

R

f

= 0.24 (nhexane/EtOAc 3:1); H NMR (500 MHz, CDCl

3

) δ [ppm] = 6.26

7

(

t, J = 2.8 Hz, 1H), 5.36 (dd, J = 15.3, 8.6 Hz, 1H), 5.29 (dd, J = 15.2, 8.0

(

Hz, 1H), 4.71 (tt, J = 11.3, 4.5 Hz, 1H), 2.83 (dd, J = 17.6, 2.4 Hz, 1H),

2

.70 (ddd, J = 12.0, 7.2, 3.6 Hz, 1H), 2.63 – 2.52 (m, 2H), 2.46 (dd, J =

7.5, 3.2 Hz, 1H), 2.41 (dd, J = 12.6, 3.4 Hz, 1H), 2.26 – 2.19 (m, 1H), 2.05

(

1

ergosta-7,22-dien-3β-yl acetate (10)

(

s, 3H), 2.02 – 1.98 (m, 1H), 1.98 – 1.93 (m, 1H), 1.91 – 1.86 (m, 2H), 1.82

dt, J = 11.6, 2.4 Hz, 1H), 1.73 (td, J = 14.0, 13.1, 4.4 Hz, 1H), 1.55 – 1.50

m, 1H), 1.49 – 1.45 (m, 1H), 1.31 – 1.28 (m, 2H), 1.15 (s, 3H), 1.07 (d, J

To a solution of γ-hydroxy enone 7 (43 mg, 91 µmol, 1.0 eq.) in benzene

(

4 mL) were added CaCO

3

(18.2 mg, 182 µmol, 2.0 eq.) iodine (46.2 mg,

(80.7 mg, 182 µmol, 2.0 eq.), and argon

1

82 µmol, 2.0 eq.) and Pb(OAc)

4

=

3

1

4

2

7.0 Hz, 3H), 1.02 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz,

_H₎_,₀_.₈₂₍_d_,_J₌₆_.₈_H_z_,₃_H₎_;13C NMR (151 MHz, CDCl

); δ [ppm] = 201.8,

was bubbled through the solution via cannula for 15 min. The resulting

3

mixture was heated to 85 °C for 2 h. The reaction mixture was cooled to

93.6, 170.7, 148.9, 131.8, 131.1, 130.2, 129.0, 72.8, 53.1, 50.5, 49.7,

8.2, 45.2, 43.4, 39.8, 36.3, 34.5, 33.2, 29.8, 26.7, 26.3, 23.7, 22.9, 22.2,

®

25 °C, filtered through a plug of Celite , and rinsed with EtOAc (20 mL).

The organic phase was washed sequentially with Na

S O

2 2 3

(sat. aq.,

_N_a+

42 6

1.5, 20.2, 19.9, 19.2, 17.6; HRMS (ESI-TOF); m/z calcd. for C30H O

2

5 mL) and brine (sat., 25 mL), dried over MgSO , and the solvent was

4

_M₊_N_a_]+_:521.2874, found: 521.2892. CCDC 1991054 contains the

[

removed under reduced pressure. Column chromatography (silica gel,

supplementary crystallographic data for this paper. These data can be

nhexane/EtOAc, 5:1g3:1) gave 15β-iodo diene dione 8 (9.5 mg, 16 µmol,

1

0

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

obtained free of charge from The Cambridge Crystallographic Data

Centre.

(m), 1056 (w), 1021 (w), 969 (w); HRMS (ESI-TOF); m/z calcd. for

+

30 44 4

C H O Na [M+Na] : 491.3132, found: 491.3131.

(

22E)-6-Oxo-ergosta-4,7,22-trien-3β-yl acetate (11)

(22E)-6,14-Dioxo-13(14→8),14(8→7)diabeo-ergosta-4,7,9(11),22-

tetraen-3β-yl acetate (13),

Through a solution of Burawoy’s ketone (6) (1.00 g, 2.13 mmol, 1.0 eq.) in

pyridine (30 mL) was bubbled argon via cannula for 10 min and the mixture

(22E)-15β-Iodo-6,14-dioxo-13(14→8),14(8→7)diabeo-ergosta-

4,7,9(11),22-tetraen-3β-yl acetate (14),

was cooled to –15 °C. In a separate flask, SOCl

.5 eq.) was added to pyridine (5 mL) at 0 °C, which was then added to

the reaction mixture at –15 °C and the mixture was stirred at this

temperature for 45 min. The solution was carefully poured into H

30 mL) and the aqueous phase was extracted with EtOAc (3 × 25 mL).

The combined organic phases were washed sequentially with HCl (1 M in

O, 3 × 35 mL), H O (2 × 50 mL) and brine (sat., 50 mL), dried over

2

(694 µL, 9.56 mmol,

4

(22E)-6,14-Oxo-13(14→8)abeo-ergosta-4,22-dien-3β-yl acetate (15),

(22E)-4β-Iodo-6,14-dioxo-5α,9α-endoperoxide-

2

O

13(14→8),14(8→7)diabeo-ergosta-7,22-dien-3β-yl acetate (16) and

(22E)-4α-Iodo-6,14-dioxo-5α,9α-endoperoxide-

(

13(14→8),14(8→7)diabeo-ergosta-7,22-dien-3β-yl acetate (17)

4

H

2

To a solution of Δ -hydroxy enone 12 (60.0 mg, 128 µmol, 1.0 eq.) in

MgSO

4

, and the solvent was removed under reduced pressure. Column

benzene (3 mL) were added CaCO

3

(25.6 mg, 256 µmol, 2.0 eq.), iodine

(114 mg, 256 µmol, 2.0 eq.),

4

chromatography (silica gel, nhexane/EtOAc 7:1) gave Δ -enone 11

(49.0 mg, 192 µmol, 1.5 eq.) and Pb(OAc)

4

(

724 mg, 1.60 mmol, 75%) as a colorless solid. R

f

= 0.40 (nhexane/EtOAc

and the reaction mixture was heated to 85 °C for 2 h. The mixture was

2

D

0

1

®

cooled to 25 °C, filtered through a plug of Celite , and rinsed with EtOAc

3

:1); m.p. 127–129 °C (EtOAc); [α] = –100.7 (c = 1.00, CHCl

3

); H NMR

(

10 mL). The filtrate was washed sequentially with Na

2 2 3

S O (sat. aq.,

(

700 MHz, CDCl

3

) δ [ppm] = 6.37 (dd, J = 2.3, 1.5 Hz, 1H), 5.85 (t, J = 2.3

1

5 mL) and brine (sat., 15 mL), dried over MgSO , and the solvent was

4

Hz, 1H), 5.41 (ddd, J = 9.5, 6.0, 2.3 Hz, 1H), 5.24 (dd, J = 15.3, 7.7 Hz,

removed under reduced pressure. Column chromatography (silica gel,

1

2

1

H), 5.17 (dd, J = 15.2, 8.4 Hz, 1H), 2.28 (ddd, J = 11.7, 7.2, 2.5 Hz, 1H),

.14 (ddd, J = 12.9, 4.6, 2.5 Hz, 1H), 2.07 (s, 3H), 2.06 – 2.01 (m, 2H),

.93 – 1.89 (m, 1H), 1.88 – 1.84 (m, 1H), 1.81 – 1.78 (m, 1H), 1.77 – 1.70

nhexane/EtOAC , 5:1 g 4:1 g 3:1 g 2:1) gave 4β-iodo endoperoxide 16

4

(

9.9 mg, 16 µmol, 12%), 15β-iodo Δ -diene dione 14 (10.9 mg, 18.5 µmol,

4

1

4%), Δ -diene dione 13 (18.7 mg, 40.2 µmol, 31%) and 4α-iodo

(m, 1H), 1.67 – 1.63 (m, 2H), 1.53 – 1.46 (m, 2H), 1.46 – 1.40 (m, 1H),

endoperoxide 17 (18.5 mg, 29.6 µmol, 23%). When the reaction mixture

1.39 – 1.33 (m, 2H), 1.17 (s, 3H), 1.04 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.8

_H_z_,₃_H₎_,₀_.₈₄₍_d_,_J₌₆_.₇_H_z_,₃_H₎_,₀_.₈₂₍_d_,_J₌₆_.₈_H_z_,₃_H₎_,₀_.₆₅₍_s_,₃_H₎_;13_C

was subjected to three freeze-pump-thaw cycles prior to addition of

Pb(OAc)

4

and heating the following product distribution was obtained (15

NMR (126 MHz, CDCl

3

); δ [ppm] = 188.0, 170.8, 166.6, 145.0, 135.1,

32.8, 129.5, 123.9, 69.5, 56.2, 56.2, 47.7, 44.6, 43.0, 40.3, 38.7, 38.1,

4.5, 33.2, 27.9, 24.6, 22.7, 21.8, 21.3, 21.3, 20.9, 20.1, 19.8, 17.7, 12.9;

was isolated instead of 14): 16: 9%, 17: 13%, 15: 11%, 13: 44%.

1

4β-iodo endoperoxide 16: light-orange oil, R

f

= 0.24 (nhexane/EtOAc

3

20

1

_I_R₍_n_e_a_t₎_;_v_̃_[_c_m₋1] = 2955 (s), 2926 (m), 2871 (m), 1740 (s), 1666 (m), 1624

3:1); [α]

= +37.0 (c = 1.00, CHCl

D

3

); H NMR (500 MHz, CDCl ) δ [ppm] =

3

(

m), 1458 (w), 1371 (w), 1236 (s), 1057 (w), 1022 (w), 969 (w), 874 (w);

5.31 (dd, J = 15.3, 8.4 Hz, 1H), 5.25 (dd, J = 15.3, 7.6 Hz, 1H), 4.72 (dd, J

= 3.8, 1.7 Hz, 1H), 4.38 (dt, J = 11.1, 3.7 Hz, 1H), 2.72 (ddd, J = 11.7, 5.6,

2.8 Hz, 1H), 2.64 (dd, J = 12.8, 4.2 Hz, 1H), 2.62 – 2.55 (m, 1H), 2.11 (s,

3H), 2.08 – 2.05 (m, 2H), 2.04 – 1.99 (m, 2H), 1.97 – 1.93 (m, 3H), 1.91 –

1.85 (m, 2H), 1.82 – 1.76 (m, 2H), 1.49 – 1.42 (m, 1H), 1.39 (dt, J = 12.8,

3.3 Hz, 1H), 1.26 (s, 3H), 1.09 (s, 3H), 1.06 (d, J = 6.9 Hz, 3H), 0.90 (d, J

= 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); ¹³C NMR

+

44 3

HRMS (ESI-TOF); m/z calcd. for C30H O Na [M+Na] : 475.3183, found:

4

73.3183.

(

22E)-14-Hydroxy-6-oxo-ergosta-4,7,22-trien-3β-yl acetate (12)

Selenium dioxide (671 mg, 6.05 mmol, 4.75 eq.) was added to a solution

4

of Δ -enone 11 (574 mg, 1.27 mmol, 1.0 eq.) in dioxane/H

2

O (50:1,

4

0.8 mL) and the resulting mixture was heated to 60 °C for 5 h. The

mixture was cooled to 25 °C, filtered through a plug of Celite^®and rinsed

with EtOAc (25 mL). The filtrate was washed sequentially with Na

3

(126 MHz, CDCl ); δ [ppm] = 202.8, 185.5, 169.8, 166.9, 135.5, 134.4,

S O

2 2 3

131.6, 97.3, 89.6, 69.6, 53.0, 52.0, 51.9, 45.5, 43.4, 38.9, 38.7, 33.1, 28.3,

25.2, 24.4, 23.1, 22.9, 22.9, 21.3, 20.4, 20.2, 19.8, 19.1, 17.6; IR (neat); ṽ

[cm⁻¹] = 2955 (m), 2924 (s), 2854 (m), 1739 (m), 1714 (m), 1458 (w), 1376

(w), 1232 (m), 1067 (w), 1024 (w), 981 (w), 770 (w); HRMS (ESI-TOF);

3

(sat. aq., 40 mL), NaHCO (sat. aq., 40 mL) and brine (sat., 40 mL), dried

over MgSO

4

, and the solvent was removed under reduced pressure.

4

Column chromatography (silica gel, nhexane/EtOAc 4:1) gave Δ -hydroxy

+

enone 12 (434 mg, 922 µmol, 73%) as a yellow solid.

R

f

=

0.30

41 6

m/z calcd. for C30H O Ina [M+Na] : 647.1840, found: 647.1845.

20

4

20

(

nhexane/EtOAc 3:1); m.p. 165–167 °C (EtOAc); [α]_D= –50.5 (c = 1.00,

Δ -dione 15: light-orange oil, R

f

= 0.33 (nhexane/EtOAc 2:1); [α]_D= –26.2

1

CHCl

3

); H NMR (500 MHz, CDCl

3

) δ [ppm] = 6.36 (t, J = 1.8 Hz, 1H), 6.00

(c = 1.00, CHCl

3

); H NMR (600 MHz, CDCl

3

) δ [ppm] = 6.42 (dd, J = 3.1,

(

d, J = 2.6 Hz, 1H), 5.43 – 5.36 (m, 1H), 5.26 (dd, J = 15.2, 7.3 Hz, 1H),

1.0 Hz, 1H), 5.43 – 5.39 (m, 1H), 5.30 – 5.21 (m, 2H), 2.74 – 2.69 (m, 1H),

2.60 (d, J = 16.4 Hz, 1H), 2.53 – 2.47 (m, 2H), 2.39 – 2.31 (m, 2H), 2.04

(s, 3H), 1.99 – 1.93 (m, 1H), 1.91 – 1.80 (m, 4H), 1.78 – 1.67 (m, 5H), 1.58

– 1.55 (m, 1H), 1.50 – 1.43 (m, 1H), 1.30 (dt, J = 13.0, 2.8 Hz, 1H), 1.18

(s, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.97 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.83

5

–

1

0

1

4

2

.18 (dd, J = 15.3, 8.0 Hz, 1H), 2.77 (ddd, J = 10.5, 7.3, 2.7 Hz, 1H), 2.15

2.08 (m, 1H), 2.07 (s, 3H), 2.05 – 2.02 (m, 1H), 2.02 – 1.83 (m, 5H), 1.78

1.60 (m, 6H), 1.58 – 1.51 (m, 1H), 1.51 – 1.44 (m, 1H), 1.44 – 1.36 (m,

H), 1.15 (s, 3H), 1.02 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.86 –

.80 (m, 6H), 0.71 (s, 3H); ¹³C NMR (126 MHz, CDCl

(d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H); ¹³C NMR (151 MHz, CDCl

);

3

); δ [ppm] = 188.8,

70.8, 166.4, 144.6, 135.4, 132.6, 130.4, 123.5, 85.2, 69.5, 50.4, 46.4,

3.8, 42.9, 40.1, 38.1, 34.3, 33.2, 32.1, 30.4, 26.6, 24.5, 21.4, 21.3, 20.6,

0.5, 20.1, 19.8, 17.7, 16.2; IR (neat); ṽ [cm⁻¹] = 3458 (br w), 2954 (m),

924 (s), 2853 (m), 1739 (m), 1666 (w), 1625 (w), 1458 (w), 1374 (w), 1236

δ [ppm] = 214.9, 199.5, 170.5, 143.5, 135.0, 132.8, 130.7, 68.9, 62.1, 53.4,

50.4, 48.9, 43.4, 41.9, 39.8, 38.0, 37.7, 37.6, 35.3, 33.2, 25.2, 24.8, 24.4,

23.5, 22.6, 21.3, 20.2, 19.8, 17.8, 17.2; IR (neat); ṽ [cm⁻¹] = 2955 (s), 2925

(s), 2870 (m), 1737 (m), 1701 (m), 1631 (w), 1463 (w), 1371 (w), 1232 (s),

1

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

®

1

044 (w), 1016 (w), 970 (w); HRMS (ESI-TOF); m/z calcd. For

was filtered through a plug of Celite , rinsed with EtOAc (10 mL), and the

solvent was removed under reduced pressure. Column chromatography

(silica gel, nhexane/EtOAc 3:1) gave a mixture of diol S2 and epoxide 18

(6.9 mg, S2/18 3.1:1 determined by integration of 4H-signals δ [ppm] =

+

C

30 44 4

H O Na [M+Na] : 491.3132, found: 491.3134.

4

1

3

6

5β-iodo Δ -diene dione 14: light-yellow oil, R

f

= 0.26 (nhexane/EtOAc

); H NMR (600 MHz, CDCl ) δ [ppm] =

.53 – 6.48 (m, 1H), 6.35 (t, J = 2.8 Hz, 1H), 5.45 (ddd, J = 10.2, 6.3, 2.4

20

1

:1); [α]_D= –30.4 (c = 1.00, CHCl

3

4

.77(major), 3.80 (minor) in ¹H-NMR) as a light-yellow oil. R

f

= 0.26

); ¹H NMR (700 MHz,

3

CDCl ) δ [ppm] = 5.31 (dd, J = 15.4, 8.8 Hz, 1H), 5.26 (dd, J = 15.3, 7.9

20

Hz, 1H), 5.32 – 5.26 (m, 2H), 4.91 (t, J = 3.9 Hz, 1H), 2.93 (dd, J = 17.9,

(nhexane/EtOAc 2:1); [α] = –7.5 (c = 0.58, CHCl

3

D

2

.5 Hz, 1H), 2.70 – 2.63 (m, 1H), 2.50 (dd, J = 17.8, 3.2 Hz, 1H), 2.21 –

.14 (m, 2H), 2.11 – 2.09 (m, 1H), 2.08 (s, 3H), 2.06 – 2.03 (m, 3H), 1.89

2

Hz, 1H), 5.12 (d, J = 2.5 Hz, 1H), 5.08 – 5.05 (m, 1H), 4.77 (dd, J = 4.6,

1.7 Hz, 1H), 4.54 (dt, J = 12.3, 4.5 Hz, 1H), 2.74 – 2.67 (m, 1H), 2.66 –

2.62 (m, 2H), 2.56 (td, J = 13.9, 4.0 Hz, 1H), 2.32 – 2.25 (m, 1H), 2.11 (s,

3H), 2.03 – 1.95 (m, 3H), 1.89 – 1.85 (m, 2H), 1.83 – 1.77 (m, 3H), 1.71 –

1.68 (m, 1H), 1.48 (s, 3H), 1.47 – 1.43 (m, 1H), 1.41 (dt, J = 13.7, 3.6 Hz,

1H), 1.06 – 1.04 (m, 6H), 0.90 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H),

(q, J = 6.7 Hz, 1H), 1.79 (tdd, J = 13.6, 10.2, 3.5 Hz, 1H), 1.47 (dt, J = 13.4,

6

.7 Hz, 1H), 1.29 (s, 3H), 1.14 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 0.91 (d, J

6.7 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H); ¹³C NMR

=

(

3

151 MHz, CDCl ); δ [ppm] = 194.8, 183.5, 170.8, 168.0, 147.2, 140.3,

1

37.9, 136.1, 132.4, 131.8, 128.3, 69.5, 52.6, 47.6, 45.1, 43.4, 39.4, 38.4,

6.0, 33.2, 32.9, 31.4, 28.9, 24.6, 22.5, 22.0, 21.3, 20.2, 19.9, 17.6; IR

3

0.81 (d, J = 6.8 Hz, 3H); ¹³C NMR (176 MHz, CDCl

); δ [ppm] = 204.4,

3

neat); ṽ [cm⁻¹] = 2958 (m), 2927 (m), 2871 (w), 1737 (s), 1695 (s), 1625

(

189.6, 173.1, 171.0, 135.2, 132.1, 130.3, 84.1, 78.6, 70.8, 51.2, 50.9, 45.5,

43.4, 42.2, 38.7, 37.3, 33.2, 29.8, 26.4, 26.1, 24.2, 24.1, 23.6, 22.8, 21.5,

20.8, 20.2, 19.9, 17.6; IR (neat); ṽ [cm⁻¹] = 2953 (m), 2921 (s), 2852 (m),

1740 (w), 1460 (w), 1377 (w), 1243 (w), 759 (w); HRMS (ESI-TOF); m/z

w), 1589 (w), 1456 (w), 1365 (m), 1293 (w), 1234 (s), 1024 (m), 984 (w),

9

14 (w), 797 (w), 735 (w); HRMS (ESI-TOF); m/z calcd. for C30

H

39

O

4

INa⁺

+

[

M+Na] : 613.1785, found: 613.1801.

4

20

calcd. for C₃₀H₄₃O INa

+

[M+Na] : 649.1997, found: 649.2004.

+

Δ -diene dione 13: light-yellow foam, R

f

= 0.21 (nhexane/EtOAc 3:1); [α]_D

6

1

(22E)-4α,5α-Epoxy-9α-hydroxy-6,14-dioxo-13(14→8),14(8→7)diabeo-

ergosta-7,22-dien-3β-yl acetate (18)

=

6

5

=

2

1

2

7

6

1

4

1

–128.1 (c = 1.00, CHCl

3

); H NMR (600 MHz, CDCl

3

) δ [ppm] = 6.46 –

.41 (m, 1H), 6.31 (t, J = 2.8 Hz, 1H), 5.42 (ddd, J = 10.2, 6.4, 2.4 Hz, 1H),

.35 (dd, J = 15.3, 8.4 Hz, 1H), 5.28 (dd, J = 15.3, 7.8 Hz, 1H), 2.81 (dd, J

17.9, 2.5 Hz, 1H), 2.72 (ddd, J = 11.9, 6.5, 2.9 Hz, 1H), 2.60 – 2.53 (m,

H), 2.48 (dd, J = 17.8, 3.2 Hz, 1H), 2.19 – 2.13 (m, 1H), 2.11 – 2.09 (m,

H), 2.08 (s, 3H), 2.02 – 1.97 (m, 2H), 1.92 – 1.84 (m, 2H), 1.83 – 1.75 (m,

H), 1.47 (dq, J = 13.3, 6.7 Hz, 1H), 1.29 (s, 3H), 1.16 (s, 3H), 1.07 (d, J =

.0 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.81 (d, J =

To a solution of diol S2 and epoxide 18 (3.1:1, 6.90 mg.11.6 µmol, 1.0 eq.)

2

in THF (1.0 mL) was added Ag O (8.1 mg, 35 µmol, 3.0 eq.) and the

reaction mixture was stirred at 25 °C for 1 h. The mixture was filtered

®

through a plug of Celite , rinsed with EtOAc (10 mL), and the solvent was

removed under reduced pressure. Column chromatography (silica gel,

nhexane/EtOAc 3:1) gave epoxide 18 (5.0 mg, 10 µmol, 56% over 2 steps)

_.₈_H_z_,₃_H₎_;13_C_N_M_R₍₁₅₁_M_H_z_,_C_D_C_l

as a colorless solid. R

f

= 0.32 (nhexane/EtOAc 2:1); m.p. 169–171 °C

3

); δ [ppm] = 203.5, 183.5, 170.8,

2

D

0

); ¹H NMR (700 MHz, CDCl

69.6, 147.5, 141.3, 136.9, 135.6, 131.9, 131.0, 69.5, 53.2, 49.8, 48.2,

5.4, 43.4, 39.8, 36.1, 33.2, 32.9, 28.9, 24.6, 24.0, 23.0, 22.0, 21.3, 20.2,

9.9, 17.6; IR (neat); ṽ [cm⁻¹] = 2955 (m), 2922 (s), 2853 (m), 1739 (m),

(CH

2

Cl

2

); [α] = –53.7 (c = 0.35, CHCl ) δ

3

[ppm] = 5.32 (dd, J = 15.3, 8.6 Hz, 1H), 5.28 (dd, J = 15.3, 7.7 Hz, 1H),

5.07 (dd, J = 9.4, 8.0 Hz, 1H), 3.81 (d, J = 1.0 Hz, 1H), 2.78 (d, J = 2.6 Hz,

1H), 2.71 (tt, J = 9.1, 5.9 Hz, 1H), 2.66 (ddd, J = 11.7, 5.4, 3.2 Hz, 1H),

2.60 (ddd, J = 12.7, 11.6, 4.5 Hz, 1H), 2.33 – 2.27 (m, 1H), 2.15 (td, J =

14.2, 3.6 Hz, 1H), 2.11 (s, 3H), 2.09 – 2.01 (m, 2H), 2.01 – 1.95 (m, 1H),

1.91 – 1.85 (m, 1H), 1.84 – 1.77 (m, 3H), 1.75 (ddd, J = 12.7, 6.3, 2.8 Hz,

703 (w), 1458 (w), 1365 (w), 1234 (m), 1025 (w), 975 (w), 773 (w); HRMS

Na⁺[M+Na] : 487.2819, found:

+

(

ESI-TOF); m/z calcd. for for C30

H O

40 4

4

87.2809.

α-iodo endoperoxide 17: orange oil, R

4

f

= 0.17 (nhexane/EtOAc 3:1);

); H NMR (700 MHz, CDCl ) δ [ppm] = 5.34

dd, J = 15.3, 8.7 Hz, 1H), 5.31 – 5.25 (m, 2H), 4.14 (d, J = 10.7 Hz, 1H),

23

1

H), 1.50 – 1.43 (m, 2H), 1.22 – 1.18 (m, 4H), 1.09 (s, 3H), 1.07 (d, J = 7.0

Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7

Hz, 3H); ¹³C NMR (176 MHz, CDCl

); δ [ppm] = 203.9, 187.7, 175.0, 170.1,

35.4, 133.2, 131.9, 84.1, 66.6, 62.4, 56.1, 51.5, 51.1, 45.5, 43.4, 38.9,

[

α] = –64.7 (c = 1.00, CHCl

3

D

(

3

2

.77 (td, J = 12.0, 4.1 Hz, 1H), 2.71 (ddd, J = 11.6, 5.7, 2.8 Hz, 1H), 2.66

2.59 (m, 1H), 2.31 – 2.25 (m, 1H), 2.15 (s, 3H), 2.11 – 2.03 (m, 3H), 2.02

1.93 (m, 2H), 1.93 – 1.86 (m, 4H), 1.50 – 1.43 (m, 3H), 1.11 – 1.07 (m,

H), 1.04 (d, J = 0.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz,

1

3

1

–

7.9, 37.2, 33.2, 29.1, 23.9, 22.8, 22.4, 22.3, 21.2, 20.3, 20.2, 20.1, 19.9,

–

7.6; IR (neat); ṽ [cm⁻¹] = 2954 (m), 2922 (s), 2853 (m), 1740 (m), 1712

6

_H₎_,₀_.₈₃₍_d_,_J₌₆_.₈_H_z_,₃_H₎_;₁3C NMR (126 MHz, CDCl

3

); δ [ppm] = 201.4,

(m), 1458 (w), 1376 (w), 1233 (m), 1025 (w), 979 (w), 801 (w); HRMS (ESI-

3

+

TOF); m/z calcd. for C30

22E)-5α,9α-Dihydroxy-4α-iodo-6,14-dioxo-13(14→8),14(8→7)diabeo-

ergosta-7,22-dien-3β-yl acetate (19): To solution of 4α-iodo

endoperoxide 17 (6.9 mg, 11 µmol, 1.0 eq.) in EtOAc (1.5 mL) was added

PtO (0.5 mg, 2.2 µmol, 0.2 eq.). After stirring at 25 °C for 4 h under an

42 6

H O Na [M+Na] : 521.2874, found: 521.2877.

190.6, 170.1, 168.3, 135.6, 133.4, 131.6, 97.5, 92.0, 75.2, 56.2, 52.0, 51.9,

(

45.5, 43.4, 39.0, 38.7, 33.2, 28.5, 27.2, 25.0, 23.3, 22.9, 21.2, 21.2, 20.2,

₉_.₈_,₁₉_.₃_,₁₇_.₆_,₁₅_.₄_;_I_R₍_n_e_a_t₎_;_v_̃_[_c_m₋1] = 2955 (s), 2924 (s), 2854 (m),

a

1

1739 (m), 1718 (s), 1458 (m), 1376 (w), 1234 (m), 1041 (w), 983 (w);

+

2

41 6

HRMS (ESI-TOF); m/z calcd. for C30H O INa [M+Na] : 647.1840, found:

atmosphere of hydrogen (balloon), the mixture was filtered through a plug

6

47.1841.

®

of Celite , rinsed with EtOAc (10 mL), and the solvent was removed under

(

22E)-5α,9α-Dihydroxy-4β-iodo-6,14-dioxo-13(14→8),14(8→7)diabeo-

reduced pressure. Column chromatography (silica gel, nhexane/EtOAc

ergosta-7,22-dien-3β-yl acetate (S2)

3

:1) gave 4α-iodo diol 19 (4.8 mg, 7.7 µmol, 70%) as a colorless solid. R

f

To a solution of 4β-iodo endoperoxide 16 (11.1 mg, 17.8 µmol, 1.0 eq.) in

22

EtOAc (1.5 mL) was added PtO

2

(0.8 mg, 3.6 µmol, 0.2 eq.). After stirring

= 0.28 (nhexane/EtOAc 2:1); m.p. 237–239 °C (CHCl

3

); [α]

D

= –39.3 (c =

1

at 25 °C for 4 h under an atmosphere of hydrogen (balloon), the mixture

0.63, CHCl

3

); H NMR (600 MHz, CDCl

3

) δ [ppm] = 5.31 (dd, J = 15.3, 8.5

1

2

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

24.5, 23.5, 22.5, 20.2, 19.8, 17.8, 17.3; IR (neat); ṽ [cm⁻¹] = 3431 (br w),

2955 (s), 2925 (s), 2870 (m), 1737 (m), 1791 (s), 1625 (w), 458 (m), 1368

(m), 1267 (w), 1231 (m), 1079 (w), 974 (w), 756 (w); HRMS (ESI-TOF);

Hz, 1H), 5.28 – 5.24 (m, 1H), 5.24 – 5.19 (m, 1H), 4.91 (d, J = 2.5 Hz, 1H),

4

2

1

0

6

1

4

1

C

.57 (d, J = 11.1 Hz, 1H), 3.78 (s, 1H), 2.72 – 2.64 (m, 2H), 2.64 – 2.56 (m,

H), 2.36 – 2.29 (m, 1H), 2.12 (s, 3H), 2.06 – 2.00 (m, 3H), 1.90 – 1.84 (m,

H), 1.79 – 1.74 (m, 1H), 1.70 – 1.63 (m, 3H), 1.46 (dq, J = 13.3, 6.7 Hz,

H), 1.40 (dt, J = 14.0, 3.5 Hz, 1H), 1.07 (d, J = 6.9 Hz, 3H), 1.03 (s, 3H),

.95 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.81 (d, J =

+

42 3

m/z calcd. for C28H O Na [M+Na] : 449.3026, found: 449.3035.

Dankasterone A (3)^[¹⁰^a^,¹³^]

To a solution of 3β-allylic alcohol S3 (16.6 mg, 38.9 µmol, 1.0 eq.) in

.8 Hz, 3H); ¹³C NMR (151 MHz, CDCl

3

); δ [ppm] = 202.3, 190.2, 173.3,

CH

77.8 µmol, 2.0 eq.) and the reaction mixture was stirred at this temperature

for 1 h. The mixture was diluted with CH Cl (2 mL), Na (sat. aq.,

5 mL) was added and the mixture was vigorously stirred at 25 °C for

30 min. The aqueous phase was extracted with CH Cl (3 × 10 mL), the

combined organic phases were washed sequentially with NaHCO

aq., 20 mL) and brine (sat., 20 mL), and it was dried over MgSO

2 2

Cl (1.5 mL) at 25 °C was added Dess–Martin periodinane (33.0 mg,

70.1, 135.2, 132.2, 130.1, 83.3, 80.0, 75.4, 51.1, 50.9, 45.5, 43.7, 43.4,

0.1, 38.6, 37.6, 33.2, 29.6, 27.7, 25.8, 24.5, 22.8, 21.9, 21.3, 20.2, 19.9,

9.7, 17.6; IR (neat); ṽ [cm⁻¹] = 2952 (m), 2922 (s), 2852 (m), 1740 (w),

460 (w), 1377 (w), 1215 (w), 760 (w); HRMS (ESI-TOF); m/z calcd. for

2

2 2 3

S O

2

+

30

H

43

O

6

INa [M+Na] : 649.1997, found: 649.2021.

3

(sat.

2

Hydroxy lactone (20): Ag O (4.4 mg, 19 µmol, 3.0 eq.) was added to a

4

. The

solution of 4α-iodo diol 19 (4.0 mg, 6.4 µmol, 1.0 eq.) in THF (2.0 mL) and

solvent was removed under reduced pressure and column

chromatography (silica gel, nhexane/EtOAc 1:1) gave dankasterone A (3)

(16.5 mg, 38.9 µmol, quant.) as a colorless solid. ¹H NMR (700 MHz,

the reaction mixture was heated to 60 °C for 16 h. The mixture was cooled

®

to 25 °C, filtered through Celite , and it was rinsed with EtOAc (10 mL).

The solvent was removed under reduced pressure and column

3 3

CDCl ) δ [ppm] = (700 MHz, CDCl ); δ [ppm] = 6.36 (d, J = 0.8 Hz, 1H),

chromatography (silica gel, nhexane/EtOAc 3:1) gave hydroxy lactone 20

5.31 – 5.22 (m, 2H), 2.84 – 2.79 (m, 1H), 2.65 (dd, J = 16.8, 1.6 Hz, 1H),

2.56 – 2.43 (m, 5H), 2.41 (td, J = 7.4, 2.6 Hz, 1H), 2.10 – 1.98 (m, 3H),

1.92 – 1.82 (m, 3H), 1.77 (dt, J = 13.0, 7.4 Hz, 1H), 1.74 – 1.66 (m, 2H),

1.50 – 1.46 (m, 2H), 1.26 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H), 0.98 (s, 3H),

(2.7 mg, 5.4 µmol, 85%) as

a

crystalline solid (crystallized from

2

D

2

nhexane/EtOAc). R

f

= 0.28 (nhexane/EtOAc 2:1); m.p. 152–154 °C; [α]

1

=

1

+31.0 (c = 0.26, CHCl

3

); H NMR (700 MHz, CDCl

3

) δ [ppm] = 5.93 (s,

0.91 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H).

H), 5.40 (dd, J = 14.8, 8.9 Hz, 1H), 5.30 (dd, J = 15.3, 8.2 Hz, 1H), 5.19

All characterization data were consistent with those reported in the

literature.^[¹³^]

(

td, J = 5.1, 3.4 Hz, 1H), 2.80 (ddd, J = 12.4, 10.5, 8.5 Hz, 1H), 2.61 (ddd,

J = 12.4, 7.6, 2.8 Hz, 1H), 2.55 (ddt, J = 9.6, 7.0, 3.7 Hz, 1H), 2.29 (d, J =

(

22E)-3α-Hydroxy-13(14g8)abeo-ergosta-4,22-diene-6,14-dione (21)

3

2

=

.5 Hz, 1H), 2.17 (ddd, J = 13.4, 12.1, 6.8 Hz, 1H), 2.13 – 2.04 (m, 3H),

.04 – 1.98 (m, 6H), 1.93 – 1.86 (m, 2H), 1.85 – 1.79 (m, 1H), 1.61 (dt, J

13.1, 7.6 Hz, 1H), 1.50 – 1.45 (m, 2H), 1.27 (s, 3H), 1.23 (s, 3H), 0.98

L-Selectride (1 M in THF, 46µL, 46 µmol, 2.0 eq.) was added dropwise to

a solution of dankasterone A (3) (9.8 mg, 23 µmol, 1.0 eq.) in THF (1 mL)

at –78 °C and the reaction mixture was stirred at this temperature for 1 h.

After addition of MeOH (0.5 mL), the mixture was warmed to 0 °C before

(d, J = 7.0 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.83

_d_,_J₌₆_.₇_H_z_,₃_H₎_;13_C_N_M_R₍₁₇₆_M_H_z_,_C_D_C_l

(

3

); δ [ppm] = 201.4, 174.5,

NaOH (3 m in H

The mixture was vigorously stirred at 25 °C for 1 h and the aqueous phase

was extracted with Et O (3 × 10 mL). The combined organic phases were

washed with brine (sat., 25 mL), dried over MgSO , and the solvent was

2 2 2

O, 2 mL) and H O (35% w/w, 2 mL) were carefully added.

1

4

1

70.5, 170.0, 135.8, 132.7, 131.0, 95.2, 77.8, 77.1, 60.8, 52.8, 51.7, 48.7,

3.5, 42.8, 39.8, 38.7, 33.2, 33.0, 32.8, 28.3, 26.4, 22.7, 21.4, 21.3, 20.3,

₉_.₉_,₁₇_.₆_,₁₆_.₆_;_I_R₍_n_e_a_t₎_;_v_̃_[_c_m₋1] = 2953 (m), 2922 (s), 2853 (m), 1740

2

4

(w), 1460 (w), 1377 (w), 1246 (w), 1082 (w), 966 (w), 721 (w); HRMS (ESI-

+

removed under reduced pressure. Column chromatography (silica gel,

42 6

TOF); m/z calcd. for C30H O Na [M+Na] : 521.2874, found: 521.2881.

nhexane/EtOAc 1:1) gave 3α-allylic alcohol 21 (8.6 mg, 20 µmol, 87%) as

(

22E)-3β-Hydroxy-13(14→8)abeo-ergosta-4,22-diene-6,14-dione (S3)

To a solution of acetate 15 (33 mg, 70 µmol, 1.0 eq.) in MeOH (1.5 mL) at

5 °C was added K CO (49 mg, 0.35 mmol, 5.0 eq.) and the reaction

mixture was stirred at this temperature for 1 h. The mixture was diluted

with H O (3 mL) and EtOAc (5 mL), and the aqueous phase was extracted

with EtOAc (3 × 10 mL). The combined organic phases were washed with

brine (sat., 15 mL), dried over MgSO , and the solvent was removed under

reduced pressure. Column chromatography (silica gel, nhexane/EtOAc

21

f

a colorless oil. R = 0.23 (nhexane/EtOAc 1:1); [α] = +37.0 (c = 0.55,

D

1

2

3

CHCl

3

); H NMR (700 MHz, CDCl

3

) δ [ppm] = 6.43 (d, J = 2.9 Hz, 1H), 5.26

– 5.24 (m, 2H), 4.20 – 4.16 (m, 1H), 2.79 (t, J = 8.7 Hz, 1H), 2.53 – 2.50

(m, 2H), 2.48 (ddd, J = 15.8, 6.5, 2.3 Hz, 1H), 2.44 – 2.38 (m, 2H), 1.96 –

1.89 (m, 2H), 1.87 – 1.83 (m, 2H), 1.79 – 1.75 (m, 2H), 1.71 – 1.67 (m, 2H),

1.65 – 1.61 (m, 1H), 1.57 (dtd, J = 13.1, 6.9, 3.5 Hz, 1H), 1.48 – 1.45 (m,

1H), 1.43 – 1.41 (m, 1H), 1.39 (dt, J = 13.0, 2.7 Hz, 1H), 1.06 (t, J = 3.5

Hz, 6H), 0.95 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H),

2

4

1

:1) gave 3β-allylic alcohol S3 (16.6 mg, 38.9 µmol, 56%) as a colorless

22

1

0.81 (d, J = 6.8 Hz, 3H); ¹³C NMR (176 MHz, CDCl

oil. R

f

= 0.18 (nhexane/EtOAc 1:1); [α]_D= +7.0 (c = 0.90, CHCl

3

); H NMR

3

); δ [ppm] = 215.1,

2

3

1

01.3, 143.1, 135.0, 134.7, 132.7, 66.0, 61.9, 54.2, 49.7, 48.3, 43.4, 41.9,

(

600 MHz, CDCl ) δ [ppm] = 6.50 (dd, J = 2.9, 1.2 Hz, 1H), 5.30 – 5.20 (m,

3

9.5, 38.2, 37.5, 35.3, 35.0, 33.2, 28.4, 25.7, 24.7, 23.6, 23.1, 20.2, 19.8,

2

1

3

H), 4.35 (td, J = 7.0, 5.6, 2.6 Hz, 1H), 2.73 – 2.67 (m, 1H), 2.62 (d, J =

6.3 Hz, 1H), 2.54 – 2.46 (m, 2H), 2.40 – 2.29 (m, 2H), 1.98 – 1.91 (m,

H), 1.89 – 1.80 (m, 4H), 1.77 – 1.70 (m, 3H), 1.67 – 1.59 (m, 2H), 1.58 –

.52 (m, 1H), 1.46 (dq, J = 13.4, 6.7 Hz, 1H), 1.28 (dt, J = 12.9, 2.8 Hz,

H), 1.17 (s, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.97 (s, 3H), 0.91 (d, J = 6.9 Hz,

H), 0.83 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H); ¹³C NMR (151 MHz,

7.8, 17.2; IR (neat); ṽ [cm⁻¹] = 3458 (br w), 2954 (s), 2925 (s), 2855

(m),1736 (s), 1457 (w), 1366 (m), 1217 (m), 977 (w); HRMS (ESI-TOF);

+

42 3

m/z calcd. for C28H O Na [M+Na] : 449.3026, found: 449.3041.

(

22E)-3β-Iodo-5α(H)-ergosta-6,14,22-trien-6-one (27) and (22E)-3α,5-

Cyclo-5α-ergosta-6,14,22-trien-6-one (28)^[⁷^]

To a solution of γ-hydroxy enone 22 (80.0 mg, 195 µmol, 1.0 eq.) in

benzene (5 mL) were added iodine (74.1 mg, 292 µmol, 1.5 eq.) and

CDCl

3

); δ [ppm] = 215.2, 199.9, 141.9, 135.0, 134.7, 132.8, 66.9, 62.1,

53.3, 50.6, 49.1, 43.4, 42.1, 40.0, 38.1, 38.0, 37.6, 35.4, 33.2, 28.4, 25.3,

1

3

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

silver(I) oxide (90.4 mg, 390 µmol, 2.0 eq.) and the reaction mixture was

heated to 85 °C for 2 h. The mixture was cooled to 25 °C, filtered through

a plug of Celite^®and rinsed with EtOAc (10 mL). The filtrate was washed

(d, J = 6.8 Hz, 3H); ¹³C NMR (151 MHz, CDCl

); δ [ppm] = 210.5, 145.8,

3

135.5, 132.3, 121.6, 56.9, 47.1, 44.4, 43.3, 43.0, 42.7, 42.3, 39.5, 37.3,

36.8, 33.2, 32.2, 28.1, 25.9, 25.1, 21.3, 21.2, 20.1, 19.8, 18.9, 18.7, 17.8,

16.3; IR (neat); ṽ [cm⁻¹] = 2953 (m), 2922 (s), 2852 (m), 1460 (w), 1377

(w), 1246 (w), 1082 (w), 970 (w), 760 (w); HRMS (ESI-TOF); m/z calcd. for

sequentially with Na

2 2 3

S O (sat. aq., 15 mL) and brine (sat., 15 mL), dried

over MgSO , and the solvent was removed under reduced pressure.

4

+

Column chromatography (silica gel, nhexane/EtOAc 99:1 g 50:1) gave

iodide 27 (37.6 mg, 72.2 µmol, 37%) as a mixture of diastereomers (5α/5β

28

C H42ONa [M+Na] : 417.3128, found: 417.3143.

(22E)-14α-Hydroperoxy-3α,5-cyclo-5α-ergosta-7,22-dien-6-one (32)

and (22E)-14β-Hydroperoxy-3α,5-cyclo-5α-ergosta-7,22-dien-6-one

(33)

2.3:1 determined by integration of 15H-signals δ [ppm] = 6.16 (minor), 6.10

1

(

major) in H-NMR) and Δ¹⁴-enone 28 (14.6 mg, 37.2 µmol, 19%).

Iodide 27: light-yellow solid, R

f

= 0.29 (nhexane/EtOAc 12:1); m.p. 137–

39 °C, [α]_D= –251.6 (c = 1.00, CHCl ) δ

); ¹H NMR (500 MHz, CDCl

ppm] = 6.10 (d, J = 2.8 Hz, 1H), 5.95 – 5.89 (m, 1H), 5.28 (dd, J = 15.3,

2 2

To a solution of enone 30 (100 mg, 253 µmol, 1.0 eq.) in CH Cl (1 mL)

21

1

3

were added triethylamine (71 µL, 0.51 µmol, 2.0 eq.) and trimethylsilyl

trifluoromethanesulfonate (68 µL, 0.38 mmol, 1.5 eq.) at 0 °C and the

reaction mixture was stirred at this temperature for 1 h. It was diluted with

[

7

2

1

3

=

1

3

.8 Hz, 1H), 5.17 (dd, J = 15.1, 8.4 Hz, 1H), 4.14 – 4.01 (m, 1H), 2.73 –

.65 (m, 1H), 2.36 (dd, J = 12.0, 3.4 Hz, 1H), 2.32 – 2.18 (m, 5H), 2.13 –

.04 (m, 3H), 1.90 – 1.84 (m, 1H), 1.76 – 1.68 (m, 3H), 1.66 – 1.58 (m, 1H),

.51 – 1.43 (m, 2H), 1.36 (td, J = 13.5, 3.9 Hz, 1H), 1.03 (d, J = 6.7 Hz,

H), 0.93 – 0.91 (m, 6H), 0.90 (s, 3H), 0.83 (d, J = 7.0 Hz, 3H), 0.82 (d, J

CH

phase was extracted with CH

phases were washed with brine (sat., 30 mL), dried over MgSO

2

Cl

2

(5 mL) and NaHCO

3

(sat. aq., 15 mL) was added. The aqueous

Cl (3 × 10 mL), the combined organic

, and the

2

4

solvent was removed under reduced pressure. The crude product was

used in the next step without further purification.

₆_.₉_H_z_,₃_H₎_;13_C_N_M_R₍₁₂₆_M_H_z_,_C_D_C_l

3

); δ [ppm] = 198.1, 154.7, 149.4,

Crude silyl enol ether 31 (253 µmol, 1.0 eq.) was dissolved in CH

2 2

Cl

34.9, 132.9, 129.4, 121.5, 58.6, 57.0, 50.9, 46.5, 42.9, 40.6, 39.0, 39.0,

8.8, 36.7, 35.7, 34.8, 33.2, 27.3, 21.1, 20.6, 20.1, 19.8, 17.7, 17.4, 13.5;

(3.5 mL), meso-tetraphenylporphyrin (0.3 mg, 0.5 µmol, 0.2 mol%) was

_I_R₍_n_e_a_t₎_;_v_̃_[_c_m₋1] = 2955 (s), 2926 (s), 2870 (m), 1666 (s), 1615 (w), 1593

added, and the reaction mixture was cooled to –78 °C. Oxygen was

bubbled through the solution and the mixture was irradiated with white light

(300 W) for 15 min. The solution was allowed to warm to 25 °C, the solvent

was removed under reduced pressure, and the residue was adsorbed on

silica gel. Column chromatography (silica gel, nhexane/EtOAc 9:1) gave

(w), 1566 (w), 1457 (m), 1368 (w), 1330 (w), 1265 (m), 1121 (w), 971

41_O_I_N_a+ _[_M₊_N_a_]+_:

H

(w)823 (w); HRMS (ESI-TOF); m/z calcd. for C28

543.2094, found: 543.2118.

_Δ₁4_-_e_n_o_n_e₂₈[7]: R

₌₀_.₁₈₍_n_h_e_x_a_n_e_/_E_t_O_A_c₁₂_:₁₎_;1H NMR (600 MHz,

f

1

3

1

4β-hydroperoxide 33 (13.3 mg, 31.2 µmol, 12%) and 14α-hydroperoxide

CDCl

.29 (dd, J = 15.1, 7.8 Hz, 1H), 5.19 (dd, J = 15.4, 8.5 Hz, 1H), 2.36 (ddd,

J = 12.4, 5.9, 2.7 Hz, 1H), 2.33 – 2.23 (m, 2H), 2.10 (dt, J = 13.0, 3.4 Hz,

H), 2.07 – 2.01 (m, 1H), 1.97 (dtd, J = 12.3, 8.0, 4.0 Hz, 1H), 1.91 – 1.84

m, 1H), 1.84 – 1.79 (m, 1H), 1.77 – 1.68 (m, 6H), 1.52 – 1.46 (m, 1H),

.44 (dd, J = 13.4, 3.5 Hz, 1H), 1.16 – 1.11 (m, 1H), 1.09 (s, 3H), 1.05 (d,

J = 6.5 Hz, 3H), 0.96 (s, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.8 Hz,

H), 0.83 (d, J = 6.8 Hz, 3H), 0.78 (t, J = 4.7 Hz, 1H).

22E)-3α,5-Cyclo-5α-ergosta-8(14),22-dien-6-one (29)

3

) δ [ppm] = 6.24 (d, J = 2.7 Hz, 1H), 6.04 (dd, J = 3.7, 2.2 Hz, 1H),

2 (60.4 mg, 142 µmol, 56%).

5

4β-Hydroperoxide 33: light-yellow oil, R

f

= 0.26 (nhexane/EtOAc 5:1);

2

D

1

[α] = +17.9 (c = 1.00, CHCl

3

); H NMR (500 MHz, CDCl ) δ [ppm] = 7.71

3

(

(s, 1H), 6.38 (d, J = 2.7 Hz, 1H), 5.32 – 5.21 (m, 2H), 2.46 (ddd, J = 10.1,

5.5, 2.8 Hz, 1H), 2.31 – 2.24 (m, 1H), 2.03 – 1.95 (m, 2H), 1.90 – 1.84 (m,

2H), 1.79 – 1.69 (m, 4H), 1.67 – 1.62 (m, 3H), 1.57 – 1.52 (m, 3H), 1.50 –

1.44 (m, 2H), 1.14 (s, 3H), 1.11 – 1.08 (m, 1H), 1.06 (s, 3H), 1.01 (d, J =

6.7 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H), 0.83 – 0.81

1

3

(

(m, 4H); ¹³C NMR (126 MHz, CDCl

); δ [ppm] = 198.3, 160.8, 134.4, 133.3,

3

Through a solution of γ-hydroxy enone 22 (75.5 mg, 184 µmol, 1.0 eq.) in

toluene (5 mL) in a pressure tube was bubbled argon via cannula for

125.9, 95.5, 55.0, 49.1, 47.5, 44.1, 43.1, 42.0, 39.8, 39.2, 35.1, 34.1, 33.3,

33.0, 26.6, 26.5, 22.1, 20.9, 20.1, 19.8, 18.8, 18.3, 17.8, 14.4; IR (neat); ṽ

[cm⁻¹] = 3348 (br w), 2957 (s), 2925 (s), 2870 (m), 1737 (w), 1646 (m),

1

0 min. [Ir(dF(CF

and (nBu )NCOOCF

was sealed. The reaction mixture was irradiated with two Kessil lamps

Kessil H150B LED Grow Light) and stirred at 35 °C, which was the internal

3

)ppy)

2 3 6

(5,5’-d(CF )bpy)]PF (6.3 mg, 5.5 µmol, 0.03 eq.)

4

3

(26 mg, 74 µmol, 0.4 eq.) were added and the tube

42 3

1457 (w), 1379 (m), 974 (w); HRMS (ESI-TOF); m/z calcd. for C28H O

Na⁺

+

(

[M+Na] : 449.3026, found: 449.3006.

temperature of the reaction set up, for 3 d. The solvent was removed under

14α-Hydroperoxide 32: colorless solid, R

f

= 0.22 (nhexane/EtOAc 5:1);

); [α] = +87.3 (c = 1.00, CHCl

); ¹H NMR

) δ [ppm] = 7.90 (s, 1H), 5.93 (d, J = 2.6 Hz, 1H), 5.26

dd, J = 15.3, 7.6 Hz, 1H), 5.16 (dd, J = 15.2, 8.4 Hz, 1H), 2.65 (ddd, J =

0.5, 7.6, 2.6 Hz, 1H), 2.22 – 2.15 (m, 1H), 2.12 – 1.99 (m, 3H), 1.99 –

2

D

1

reduced pressure and the residue was purified by column chromatography

m.p. 184–186 °C (CHCl

3

(

silica gel, nhexane/EtOAc 50:1 g 9:1) to give Δ⁸⁽¹⁴⁾-ketone 29 (12.7 mg,

2.3 µmol, 17%) as a colorless oil and recovered starting material 22

(

500 MHz, CDCl

3

(42.5 mg, 103 µmol, 56%) as

a

light-yellow solid.

R

f

=

0.32

1

22

1

(

ⁿ^h^e^x^aⁿ^e^/^E^t^O^A^c¹⁹^:¹⁾^;^[^α^]D = –31.4(c = 1.00, CHCl

3

); H NMR (600 MHz,

1.89 (m, 3H), 1.89 – 1.83 (m, 2H), 1.79 (dt, J = 8.8, 4.5 Hz, 1H), 1.72 –

1.68 (m, 3H), 1.66 – 1.59 (m, 2H), 1.51 – 1.45 (m, 1H), 1.44 – 1.38 (m, 1H),

1.10 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H), 0.85 – 0.81

CDCl

3

) δ [ppm] = 5.24 – 5.19 (m, 2H), 3.03 (dt, J = 21.8, 1.4 Hz, 1H), 2.96

(dd, J = 21.7, 1.6 Hz, 1H), 2.30 – 2.23 (m, 1H), 2.23 – 2.18 (m, 1H), 2.18

(m, 9H), 0.80 – 0.77 (m, 2H); ¹³C NMR (126 MHz, CDCl

); δ [ppm] = 198.0,

3

– 2.13 (m, 1H), 2.13 – 2.08 (m, 2H), 2.08 – 2.03 (m, 1H), 2.01 (dt, J = 12.5,

3.4 Hz, 1H), 1.89 – 1.80 (m, 4H), 1.76 – 1.71 (m, 2H), 1.67 – 1.63 (m, 1H),

1.62 – 1.56 (m, 2H), 1.49 – 1.44 (m, 1H), 1.44 – 1.38 (m, 1H), 1.30 (td, J

= 13.4, 3.5 Hz, 1H), 1.20 – 1.14 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H), 0.94 (s,

3H), 0.92 (d, J = 6.8 Hz, 3H), 0.90 (s, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.82

159.2, 135.4, 132.7, 127.3, 97.1, 50.7, 47.8, 45.5, 44.1, 42.9, 40.0, 38.1,

35.6, 33.7, 33.2, 30.1, 26.9, 26.9, 24.9, 22.0, 21.4, 20.1, 19.8, 19.4, 17.6,

17.2, 13.8; IR (neat); ṽ [cm⁻¹] = 2952 (w), 2923 (m), 2852 (w), 1736 (s),

1

4

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

1634 (w), 1456 (w), 1371 (m), 1229 (m), 1217 (m), 887 (w); HRMS (ESI-

and the reaction mixture was stirred at this temperature for 1 h. The

+

TOF); m/z calcd. for C28

H

42

O

3

Na [M+Na] : 449.3026, found: 449.3012.

mixture was diluted with CH

added. The aqueous phase was extracted with CH

combined organic phases were washed with brine (sat., 30 mL), and dried

over MgSO . The solvent was removed under reduced pressure and

column chromatography (silica gel, nhexane/EtOAc 14:1) gave silyl enol

ether 36 (22.4 mg, 43 µmol, 86%) as a light-yellow solid. R = 0.53

); [α] = –83.1 (c = 1.00,

2

Cl

2

(5 mL), and NaHCO

3

(sat. aq., 10 mL) was

(

22E)-14β-Hydroxy-3α,5-cyclo-5α-ergosta-7,22-dien-6-one (34):

Triphenylphosphine (9.2 mg, 35 µmol, 1.0 eq.) was added to a solution of

4β-hydroperoxide 33 (15 mg, 35 µmol, 1.0 eq.) in CH Cl (1 mL) at 25 °C

2

Cl (3 × 10 mL), the

2

1

2

4

and the resulting mixture was stirred at this temperature for 1 h. The

solvent was removed under reduced pressure and the colorless residue

was adsorbed on silica gel. Column chromatography (silica gel,

nhexane/EtOAc 9:1 g 5:1) gave 14β-γ-hydroxy enone 34 (10.3 mg,

f

2

D

0

(

nhexane/EtOAc 5:1); m.p. 85–87 °C (CHCl

3

1

CHCl

3

); H NMR (500 MHz, CDCl

3

) δ [ppm] = 6.15 (t, J = 2.9 Hz, 1H), 5.39

2

5 µmol, 71%) as a colorless solid. R

f

= 0.18 (nhexane/EtOAc 5:1); m.p.

(

dd, J = 15.3, 8.2 Hz, 1H), 5.31 (dd, J = 15.3, 7.7 Hz, 1H), 5.07 (t, J = 6.8

2

D

2

1

136–138 °C (CHCl

3

); [α] = +13.1 (c = 0.72, CHCl

3

); H NMR (600 MHz,

Hz, 1H), 2.66 (dd, J = 18.6, 2.7 Hz, 1H), 2.53 – 2.46 (m, 1H), 2.38 (dd, J =

18.6, 3.2 Hz, 1H), 2.07 – 2.03 (m, 2H), 1.95 – 1.87 (m, 2H), 1.86 – 1.76 (m,

1H), 1.72 (dd, J = 8.3, 4.6 Hz, 1H), 1.66 – 1.62 (m, 1H), 1.55 – 1.47 (m,

1H), 1.46 – 1.38 (m, 1H), 1.22 – 1.19 (m, 6H), 1.03 (d, J = 6.8 Hz, 3H),

0.99 – 0.94 (m, 12H), 0.93 – 0.88 (m, 2H), 0.86 (d, J = 6.9 Hz, 3H), 0.85

(d, J = 6.7 Hz, 3H), 0.78 (t, J = 4.8 Hz, 1H), 0.72 – 0.67 (m, 6H); ¹³C NMR

CDCl

3

) δ [ppm] = 6.50 (d, J = 2.5 Hz, 1H), 5.40 (dd, J = 15.4, 8.2 Hz, 1H),

5

2

1

=

0

1

3

.35 (dd, J = 15.4, 7.7 Hz, 1H), 2.42 (ddd, J = 9.9, 7.2, 2.6 Hz, 1H), 2.39 –

.34 (m, 1H), 2.05 – 1.95 (m, 2H), 1.91 (q, J = 6.8 Hz, 1H), 1.85 – 1.79 (m,

H), 1.73 – 1.68 (m, 6H), 1.66 – 1.63 (m, 1H), 1.54 – 1.46 (m, 4H), 1.15 –

.11 (m, 1H), 1.06 (s, 3H), 1.05 (s, 3H), 1.01 (d, J = 6.7 Hz, 3H), 0.95 (d, J

6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.77 –

3

(126 MHz, CDCl ); δ [ppm] = 194.1, 169.9, 146.9, 146.7, 134.9, 134.2,

.74 (m, 1H); ¹³C NMR (151 MHz, CDCl

); δ [ppm] = 197.8, 165.1, 135.4,

3

133.7, 126.9, 108.5, 56.6, 51.6, 50.9, 43.3, 42.9, 41.7, 38.8, 36.1, 35.8,

33.3, 27.1, 26.3, 26.2, 22.6, 21.2, 20.1, 19.9, 17.5, 13.0, 7.0, 5.3; IR (neat);

ṽ [cm⁻¹] = 2955 (m), 2924 (s), 2853 (m), 1738 (w), 1658 (w), 1459 (w),

1378 (w), 1208 (w), 1173 (w), 1005 (w), 969 (w), 823 (w); HRMS (ESI-

33.2, 124.6, 84.7, 55.3, 49.4, 46.2, 43.5, 43.5, 41.1, 40.6, 40.5, 38.8, 35.0,

3.6, 33.2, 26.7, 25.7, 22.8, 22.1, 20.2, 19.9, 19.3, 17.9, 16.5, 13.7; IR

neat); ṽ [cm⁻¹] = 2953 (m), 2921 (s), 2852 (m), 1740 (w), 1459 (w), 1377

(

+

(w), 1168 (w), 1082 (w), 970 (w); HRMS (ESI-TOF); m/z calcd. for

52 2

TOF); m/z calcd. for C34H O SiNa [M+Na] : 543.3629, found: 543.3627.

+

C

28

H

42

O

2

Na [M+Na] : 433.3077, found: 433.3079.

(22E)-9α-Hydroxy-14-triethylsilyloxy-13(14→8),14(8→7)diabeo-3α,5-

cyclo-5α-ergosta-7,14,22-trien-6-one (37)

(

22E)-7α-Iodo-8β,14β-epoxy-3α,5-cyclo-5α-ergosta-22-en-6-one (35)

Through a solution of 14β-γ-hydroxy enone 34 (9.9 mg, 24 µmol, 1.0 eq.)

L-Selectride (317 µL, 317 µmol, 3.0 eq.) was added dropwise to a solution

of silyl enol ether 36 (55.0 mg, 106 µmol, 1.0 eq.) in THF (1.5 mL) at

–78 °C and the reaction mixture was stirred at this temperature for 1 h.

Methanol (0.2 mL) was added and the mixture was warmed to 0 °C before

in benzene (1 mL) was bubbled argon via cannula for 10 min. CaCO

3

(4.8 mg, 48 µmol, 2.0 eq.), iodine (12 mg, 48 µmol, 2.0 eq.) and Pb(OAc)

4

(

21 mg, 48 µmol, 2.0 eq.) were added and the reaction mixture was heated

to 85 °C for 2 h. The mixture was cooled to 25 °C, filtered through a plug

NaOH (3 M in H

The mixture was vigorously stirred at 25 °C for 1 h and the aqueous phase

was extracted with Et O (3 × 10 mL). The combined organic phases were

washed with brine, dried over MgSO , and the solvent was removed under

2 2 2

O, 2 mL) and H O (35% w/w, 2 mL) were carefully added.

®

of Celite , and rinsed with EtOAc (10 mL). The filtrate was washed

sequentially with Na

over MgSO , and the solvent was removed under reduced pressure.

Column chromatography (silica gel, nhexane/EtOAC 19:1) gave iodo-

epoxide 35 (5.5 mg, 10 µmol, 42%) as a colorless solid. R = 0.42

); [α] = –31.8 (c = 0.82,

S O

2 2 3

(sat. aq., 15 mL) and brine (sat., 15 mL), dried

2

4

reduced pressure. Column chromatography (silica gel, nhexane/EtOAc 7:1

f

g 5:1) gave 9-hydroxy silyl enol ether 37 (30 mg, 56 µmol, 53%) as a light-

1

D

9

19

(

nhexane/EtOAc 9:1); m.p. 113–115 °C (CHCl

3

yellow oil. R

¹H NMR (700 MHz, CDCl

) δ [ppm] = 5.40 (dd, J = 15.4, 8.7 Hz, 1H), 5.32

3

f 3

= 0.28 (nhexane/EtOAc 5:1); [α]_D= –49.1 (c = 0.67, CHCl );

1

CHCl

3

); H NMR (600 MHz, CDCl

3

) δ [ppm] = 5.26 (dd, J = 15.2, 7.5 Hz,

1

–

1

H), 5.20 (dd, J = 15.2, 8.4 Hz, 1H), 3.99 (s, 1H), 2.77 – 2.71 (m, 1H), 2.20

– 5.26 (m, 2H), 2.65 – 2.59 (m, 1H), 2.30 (dt, J = 17.8, 5.4 Hz, 1H), 2.20

(td, J = 12.5, 6.5 Hz, 1H), 2.13 (ddd, J = 17.8, 9.7, 6.0 Hz, 1H), 2.09 – 2.03

(m, 2H), 2.02 – 1.96 (m, 1H), 1.93 – 1.85 (m, 2H), 1.82 – 1.78 (m, 2H),

1.75 (dd, J = 12.0, 6.5 Hz, 1H), 1.68 (dd, J = 12.1, 8.8 Hz, 1H), 1.60 (ddd,

J = 8.2, 4.2, 1.3 Hz, 1H), 1.50 (dq, J = 13.3, 6.7 Hz, 1H), 1.24 – 1.20 (m,

1H), 1.15 – 1.12 (m, 3H), 1.07 (s, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.96 (d, J

= 7.0 Hz, 3H), 0.95 – 0.93 (m, 9H), 0.86 (d, J = 6.8 Hz, 3H), 0.84 (d, J =

6.8 Hz, 3H), 0.78 (dd, J = 5.2, 4.1 Hz, 1H), 0.69 – 0.58 (m, 6H); ¹³C NMR

2.12 (m, 2H), 2.04 – 1.98 (m, 1H), 1.98 – 1.95 (m, 1H), 1.91 – 1.85 (m,

H), 1.85 – 1.79 (m, 2H), 1.79 – 1.73 (m, 3H), 1.62 – 1.56 (m, 1H), 1.53 –

.45 (m, 2H), 1.45 – 1.39 (m, 3H), 1.22 (td, J = 12.8, 4.2 Hz, 1H), 1.08 –

.00 (m, 7H), 0.95 – 0.92 (m, 6H), 0.88 (t, J = 5.2 Hz, 1H), 0.85 (d, J = 6.9

Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H); ¹³C NMR (151 MHz, CDCl

3

); δ [ppm] =

2

3

1

04.3, 134.8, 133.1, 74.2, 67.5, 57.1, 47.7, 43.4, 43.0, 41.7, 40.7, 39.3,

7.7, 36.6, 34.3, 33.2, 30.5, 27.1, 26.0, 26.0, 21.5, 20.3, 20.1, 19.8, 18.0,

7.7, 15.0, 11.5; IR (neat); ṽ [cm⁻¹] = 2956 (s), 2925 (s), 2871 (m), 2853

3

(176 MHz, CDCl ); δ [ppm] = 196.1, 169.2, 143.7, 134.7, 132.4, 131.0,

(

m), 1692 (m), 1458 (w), 1370 (w), 1291 (w), 1143 (w), 974 (w), 878 (w),

113.6, 85.2, 54.2, 50.4, 46.8, 43.5, 42.4, 38.4, 37.9, 36.5, 34.0, 33.3, 31.3,

27.7, 25.5, 22.6, 22.6, 20.2, 19.9, 19.3, 17.6, 16.2, 7.0, 5.3; IR (neat); ṽ

[cm⁻¹] = 3455 (br w), 2954 (m), 2924 (s), 2872 (m), 2854 (m), 1737 (s),

1667 (w), 1456 (w), 1372 (s), 1217 (s), 1011 (w), 887 (w); HRMS (ESI-

+

7

41 2

56 (w); HRMS (ESI-TOF); m/z calcd. for C28H O INa [M+Na] :559.2043,

found: 559.2042.

22E)-14-Triethylsilyloxy-13(14→8),14(8→7)diabeo-3α,5-cyclo-5α-

(

+

ergosta-7,9(11),14,22-tetraen-6-one (36)

54 3

TOF); m/z calcd. for C34H O Na [M+Na] : 561.3734, found: 561.3727.

To a solution of diene dione 25 (20 mg, 50 µmol, 1.0 eq.) in CH

Cl

2 2

(22E)-6α,9α-Dihydroxy-13(14→8),14(8→7)diabeo-3α,5-cyclo-5α-

(1.25 mL) were added 2,6-lutidine (58 µL, 0.50 mmol, 10 eq.) and

ergosta-7,22-dien-14-one (38)

triethylsilyl trifluoromethanesulfonate (56 µL, 0.25 mmol, 5.0 eq.) at 0 °C

1

5

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

Lithium aluminum hydride (1 M in THF, 70 µL, 70 µmol, 5.0 eq.) was added

stirring for 45 min at this temperature, the reaction mixture was diluted with

dropwise to a solution of 9-hydroxy silyl enol ether 37 (7.5 mg, 14 µmol,

EtOAc (10 mL) and carefully added to NaHCO

The aqueous phase was extracted with EtOAc (3 × 15 mL) and the

combined organic phases were washed sequentially with NaHCO (5% aq.,

2 × 30 mL) and brine (sat., 30 mL), dried over MgSO , and the solvent was

3

(sat. aq., 50 mL) at 0 °C.

1.0 eq.) in THF (1.0 mL) at 0 °C and the reaction mixture was stirred at this

temperature for 1 h. EtOAc (5 mL) and Rochelle’s salt (½ sat. aq., 5 mL)

3

were carefully added and the resulting mixture was vigorously stirred at

4

2

5 °C for 5 h. The aqueous phase was extracted with EtOAc (3 × 10 mL),

the combined organic phases were washed with brine (sat., 25 mL), and

dried over MgSO . The solvent was removed under reduced pressure and

column chromatography (silica gel, nhexane/EtOAc 3:1) gave 6,9-diol 38

2.4 mg, 5.6 µmol, 40%) as a colorless oil. R = 0.32 (nhexane/EtOAc 3:1);

); H NMR (700 MHz, CDCl ) δ [ppm] = 5.34

dd, J = 15.3, 8.8 Hz, 1H), 5.28 (dd, J = 15.3, 8.0 Hz, 1H), 4.24 (s, 1H),

removed under reduced pressure. Column chromatography (silica gel,

nhexane/EtOAc 19:1 g 12:1 g 9:1) gave Δ⁵^,⁸-diene 42 (16.1 mg, 35.4 µmol,

12%) and Δ⁵^,⁷-diene 41 (69.3 mg, 152 µmol, 51%).

4

_Δ5,8-diene 42: colorless oil, R

23

f

= 0.38 (nhexane/EtOAc 5:1); [α]_D= –71.9

(

f

1

(

c = 1.02, CHCl

3

); H NMR (700 MHz, CDCl

3

) δ [ppm] = 5.24 (dd, J = 3.0,

2

D

0

1

[

α] = +37.3 (c = 0.21, CHCl

3

1.7 Hz, 1H), 4.61 (tt, J = 10.9, 5.1 Hz, 1H), 3.49 – 3.47 (m, 1H), 2.49 – 2.38

(m, 3H), 2.36 – 2.29 (m, 1H), 2.27 – 2.21 (m, 1H), 2.21 – 2.16 (m, 1H),

2.16 – 2.11 (m, 1H), 2.04 (s, 3H), 1.96 – 1.91 (m, 1H), 1.81 – 1.77 (m, 1H),

1.77 – 1.74 (m, 1H), 1.74 – 1.67 (m, 1H), 1.60 (dd, J = 10.7, 7.0 Hz, 1H),

1.56 – 1.52 (m, 1H), 1.51 – 1.44 (m, 2H), 1.44 – 1.38 (m, 2H), 1.34 (td, J

= 13.7, 4.1 Hz, 1H), 1.29 – 1.25 (m, 2H), 1.23 (s, 3H), 1.22 – 1.15 (m, 2H),

0.95 (d, J = 6.9 Hz, 2H), 0.91 (s, 3H), 0.90 – 0.87 (m, 1H), 0.84 (d, J = 6.8

Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H); ¹³C NMR

(

3

.72 (s, 1H), 2.74 – 2.68 (m, 2H), 2.62 (ddd, J = 13.2, 11.5, 4.7 Hz, 1H),

.17 – 2.11 (m, 1H), 2.02 – 1.95 (m, 2H), 1.91 – 1.79 (m, 3H), 1.79 – 1.74

2

(m, 3H), 1.59 (dd, J = 12.3, 8.9 Hz, 1H), 1.51 – 1.48 (m, 1H), 1.46 (dd, J =

1

3.1, 6.5 Hz, 1H), 1.28 – 1.26 (m, 1H), 1.20 – 1.14 (m, 1H), 1.08 (s, 3H),

.07 – 1.04 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H), 0.85 – 0.81 (m, 7H), 0.54 (dd,

1

J = 5.2, 3.7 Hz, 1H);¹³C NMR (176 MHz, CDCl

3

); δ [ppm] = 212.0, 163.6,

1

3

1

35.1, 132.2, 130.7, 85.6, 70.6, 52.8, 51.2, 45.7, 44.7, 43.5, 38.9, 37.7,

3

(126 MHz, CDCl ); δ [ppm] = 212.4, 170.5, 143.4, 141.4, 134.9, 119.0,

5.3, 33.3, 32.9, 29.9, 29.0, 28.0, 23.0, 22.9, 22.9, 22.3, 20.3, 19.9, 17.7,

73.7, 53.7, 51.3, 50.5, 40.8, 39.2, 38.2, 37.3, 36.9, 35.8, 35.5, 33.7, 31.8,

31.0, 27.5, 27.5, 22.8, 22.6, 21.5, 21.4, 20.5, 19.6, 17.9, 15.6; IR (neat); ṽ

[cm⁻¹] = 2955 (w), 2937 (w), 2870 (w), 1739 (m), 1713 (m), 1464 (w), 1373

(w), 1236 (s), 1162 (w), 1046 (m); HRMS (ESI-TOF); m/z calcd. for

1.5; IR (neat); ṽ [cm⁻¹] = 2953 (m), 2921 (s), 2852 (m), 1740 (w), 1460

(m), 1377 (w), 1238 (w), 1168 (w), 974 (w); HRMS (ESI-TOF); m/z calcd.

+

42 3

for C28H O Na [M+Na] : 449.3026, found: 449.3042.

+

(

22E)-14-Oxo-1(10→6),13(14→8),14(8→7)triabeo-anthraergosta-

C

30

H

46

O

3

Na [M+Na] : 477.3339, found: 477.3345.

_Δ5,7-diene 41: colorless oil, R

= 0.33 (nhexane/EtOAc 5:1); [α]_D= –30.9

₎_;1H NMR (600 MHz, CDCl

c = 1.01, CHCl ) δ [ppm] = 5.95 (d, J = 2.5

Hz, 1H), 4.67 (tt, J = 11.4, 4.5 Hz, 1H), 2.79 – 2.72 (m, 1H), 2.58 (ddd, J =

24

5

,7,9,22-tetraen-3α-yl acetate (39)

f

To a solution of 6,9-diol 38 (2.3 mg, 5.4 µmol, 1.0 eq.) in Et

°C were added acetic acid (0.2 mL) and BF •OEt (0.2 mL), and the

resulting mixture was stirred at this temperature for 1 h. The mixture was

diluted with EtOAc (5 mL) and carefully poured into NaHCO (sat. aq., 20

mL) at 0 °C. The aqueous phase was extracted with EtOAc (3 × 10 mL),

the combined organic phases were washed sequentially with NaHCO (sat.

aq., 25 mL) and brine (sat., 25 mL), and dried over MgSO . The solvent

2

O (0.4 mL) at

(

3

0

3

2

1

4.6, 4.9, 2.4 Hz, 1H), 2.51 (ddd, J = 13.9, 9.1, 5.3 Hz, 1H), 2.46 (dd, J =

1.4, 7.8 Hz, 1H), 2.32 – 2.25 (m, 1H), 2.03 (s, 3H), 1.96 – 1.87 (m, 2H),

.86 – 1.81 (m, 3H), 1.76 – 1.71 (m, 2H), 1.62 – 1.58 (m, 2H), 1.58 – 1.52

3

(

m, 4H), 1.45 – 1.36 (m, 2H), 1.24 – 1.18 (m, 1H), 1.11 (s, 3H), 0.93 (d, J

6.9 Hz, 4H), 0.91 – 0.87 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H), 0.79 – 0.75

_m_,₉_H₎_;13C NMR (151 MHz, CDCl

); δ [ppm] = 203.4, 170.6, 161.9, 141.6,

28.1, 120.3, 72.9, 55.8, 52.6, 51.3, 44.7, 40.3, 39.0, 38.0, 36.3, 36.3, 35.7,

4

=

was removed under reduced pressure and column chromatography (silica

(

3

gel, nhexane/EtOAc 7:1) gave anthrasteroid 39 (2.1 mg, 4.7 µmol, 87%)

1

22

as a colorless oil. R

f

= 0.24 (nhexane/EtOAc 7:1); [α]_D= –46.4 (c = 0.20,

33.5, 31.7, 29.8, 28.0, 22.1, 21.5, 21.5, 21.1, 20.7, 20.5, 17.8, 15.6, 15.2;

1

IR (neat); ṽ [cm⁻¹] = 2953 (m), 2922 (s), 2853 (m), 1739 (w), 1463 (w),

CHCl

3

); H NMR (700 MHz, CDCl

3

) δ [ppm] = 5.39 (dd, J = 15.3, 8.8 Hz,

46 3

1377 (w), 1241 (w), 759 (m); HRMS (ESI-TOF); m/z calcd. for C30H O

Na⁺

1

2

9

2

1

3

1

3

1

H), 5.29 (dd, J = 15.3, 8.5 Hz, 1H), 5.19 – 5.12 (m, 1H), 3.12 – 3.03 (m,

+

H), 2.90 (dd, J = 15.9, 9.0 Hz, 1H), 2.83 – 2.78 (m, 1H), 2.76 (dd, J = 16.5,

.5 Hz, 1H), 2.74 – 2.68 (m, 2H), 2.64 – 2.57 (m, 2H), 2.16 – 2.10 (m, 4H),

.06 (s, 3H), 2.05 – 1.99 (m, 2H), 2.00 – 1.95 (m, 2H), 1.92 – 1.85 (m, 1H),

.78 – 1.70 (m, 2H), 1.51 – 1.45 (m, 1H), 1.07 (s, 3H), 1.06 (d, J = 7.1 Hz,

H), 0.93 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.8 Hz,

[M+Na] : 477.3339, found: 477.3342.

3β,14α-Dihydroxy-13(14→8),14(8→7)diabeo-7β(H)-ergosta-5,8-dien-

3β-yl acetate (44)^[¹³^]

To a solution of Δ⁵^,⁸-diene 42 (75.0 mg, 165 µmol, 1.0 eq.) in THF (4 mL)

at –78 °C was added DIBAl-H (1 M in hexanes, 1.65 mL, 1.65 mmol,

10.0 eq.) and the resulting solution was stirred at this temperature for 1.5 h.

EtOAc (2.5 mL) and Rochelle’s salt (½ sat. aq., 5 mL) were added carefully

and the mixture was vigorously stirred for 30 minutes while warming to

25 °C. The aqueous phase was extracted with EtOAc (3 × 10 mL) and the

combined organic phases were washed with brine (sat., 15 mL), dried over

H); ¹³C NMR (176 MHz, CDCl

); δ [ppm] = 209.8, 170.9, 146.1, 139.6,

3

35.3, 134.9, 134.9, 132.5, 131.9, 130.9, 70.3, 54.1, 53.9, 46.3, 43.5, 40.5,

8.3, 33.3, 33.1, 29.0, 28.0, 25.3, 24.4, 23.3, 21.6, 20.7, 20.2, 19.9, 17.7,

6.1; IR (neat); ṽ [cm⁻¹] = 2954 (m), 2924 (s), 2853 (m), 1739 (w), 1684

(w), 1458 (w), 1377 (w), 1241 (w), 772 (w), 757 (w); HRMS (ESI-TOF); m/z

+

calcd. for C30

H

42

O

3

Na [M+Na] : 473.3026, found: 473.3029.

4

MgSO , and the solvent was removed under reduced pressure. Column

14-Oxo-13(14→8),14(8→7)diabeo-ergosta-5,7-dien-3β-yl acetate (41)

chromatography (silica gel, nhexane/EtOAc 1:1) gave 3,14-diol 44

1

and 14-Oxo-13(14→8),14(8→7)diabeo-7β(H)-ergosta-5,8-dien-3β-yl

acetate (42)

(51.8 mg, 125 µmol, 76%) as a colorless solid. H NMR (500 MHz, CDCl

3

)

δ [ppm] = 5.40 – 5.28 (m, 1H), 3.79 (d, J = 6.2 Hz, 1H), 3.61 – 3.52 (m,

1H), 3.03 – 2.95 (m, 1H), 2.41 (dd, J = 12.2, 5.0 Hz, 1H), 2.37 – 2.29 (m,

2H), 2.24 (dd, J = 15.5, 8.4 Hz, 1H), 2.00 – 1.93 (m, 1H), 1.93 – 1.86 (m,

2

To a solution of β-hydroxy ketone 40 (123 mg, 298 µmol, 1.0 eq.) in Et O

(

3 2

6 mL) at 0 °C were added acetic acid (3 mL) and BF •OEt (3 mL). After

1

6

Chemistry - A European Journal

10.1002/chem.202001405

FULL PAPER

2

D

2

1

–

6

1

H), 1.86 – 1.80 (m, 2H), 1.74 – 1.63 (m, 2H), 1.62 – 1.51 (m, 6H), 1.49 –

.44 (m, 2H), 1.41 (dt, J = 12.7, 4.1 Hz, 1H), 1.36 (d, J = 10.5 Hz, 1H), 1.24

1.16 (m, 2H), 1.14 (s, 3H), 0.96 (s, 3H), 0.95 – 0.91 (m, 1H), 0.89 (d, J =

.9 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.80 – 0.76 (m, 6H).

R = 0.25 (nhexane/EtOAc 3:1); [α] = +84.4 (c = 0.25, CHCl ); ¹H NMR

f

3

(

3

600 MHz, CDCl ) δ [ppm] = 5.35 (dd, J = 15.4, 7.8 Hz, 1H), 5.25 (dd, J =

1

5.3, 8.1 Hz, 1H), 5.09 (s, 1H), 4.69 (s, 1H), 4.05 (dd, J = 11.4, 5.8 Hz,

H), 3.19 – 3.15 (m, 1H), 2.55 (dt, J = 16.6, 4.1 Hz, 1H), 2.49 (p, J = 7.3

1

3(14→8),14(8→7)diabeo-5α(H),7β(H)-ergosta-8,22-diene-3,14-dione

Hz, 1H), 2.36 (dd, J = 9.3, 6.7 Hz, 1H), 2.34 – 2.26 (m, 2H), 2.20 (dtd, J =

5.7, 7.6, 2.9 Hz, 1H), 2.13 (d, J = 13.2 Hz, 1H), 2.07 – 2.01 (m, 2H), 1.87

h, J = 6.7 Hz, 2H), 1.72 – 1.67 (m, 2H), 1.57 (td, J = 12.8, 6.3 Hz, 3H),

(

47)

1

Lithium (3.0 mg, 0.43 mmol, 18 eq.) was added to liquid ammonia (3 mL)

at –78 °C before it was warmed to room temperature and the residual

ammonia was blown out with a stream of argon. To the resulting lithium

bronze, THF (1.5 mL) was added and the resulting suspension was cooled

to –78 °C. A solution of enone 45 (10 mg, 24 µmol, 1.0 eq) in THF

(

1

0

1

3

1

.49 – 1.44 (m, 2H), 1.36 (td, J = 12.8, 4.3 Hz, 1H), 1.04 – 1.01 (m, 6H),

.92 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H),

_.₇₈₍_s_,₃_H₎_;13C NMR (151 MHz, CDCl

3

); δ [ppm] = 213.3, 152.0, 146.8,

36.1, 134.7, 132.7, 102.9, 73.1, 55.6, 53.6, 45.4, 45.2, 44.3, 43.6, 38.8,

(0.75 mL) was added dropwise and the reaction mixture was stirred at this

8.4, 37.6, 34.8, 33.3, 32.5, 27.8, 24.3, 23.0, 20.9, 20.2, 19.9, 19.7, 17.9,

temperature until complete conversion was observed (0.5–1 h). Triethyl

amine (0.2 mL) and TMSCl (0.1 mL) were added at –60 °C and the

reaction mixture was allowed to warm to –20 °C. Phosphate buffer (2 mL)

in THF (2 mL) was added carefully and the aqueous phase was extracted

with EtOAc (3 × 10 mL). The combined organic phases were washed with

₇_.₈_;_I_R₍_n_e_a_t₎_;_v_̃_[_c_m−1] = 2954 (m), 2923 (s), 2853 (m), 1740 (w), 1459

(

w), 1377 (w), 1010 (w), 970 (w); HRMS (ESI-TOF); m/z calcd. for

+

C

29 44 2

H O Na [M+Na] : 447.3234, found: 447.3228.

4

brine (sat., 25 mL), dried over MgSO , and the solvent was removed under

Acknowledgements

reduced pressure. Crude silyl enol ether was used in the next step without

further purification.

Financial support for this work was provided by Deutsche

Forschungsgemeinschaft (Grant No. HE 7133/7-1), the

Boehringer Ingelheim Stiftung (exploration grant to P.H.), and

Studienstiftung des Deutschen Volkes (Ph.D. scholarship to

R.C.H.). We acknowledge the assistance of the Core Facility

BioSupraMol supported by the DFG.

Independent from the consecutive reaction conditions chosen, the only

isolable product was ketone 47, which was obtained as a colorless oil after

column chromatography (silica gel, nhexane/EtOAc 4:1). R

f

= 0.26

); H NMR (600 MHz,

); δ [ppm] = 5.26 (dd, J = 15.4, 7.7 Hz,

H), 5.20 (dd, J = 15.4, 7.7 Hz, 1H), 2.78 (dd, J = 14.1, 2.4 Hz, 1H), 2.63

td, J = 13.7, 7.1 Hz, 1H), 2.48 (d, J = 9.2 Hz, 1H), 2.46 – 2.45 (m, 1H),

.33 – 2.26 (m, 2H), 2.23 – 2.16 (m, 1H), 2.16 – 2.08 (m, 2H), 2.08 – 2.03

m, 1H), 1.95 – 1.89 (m, 2H), 1.89 – 1.82 (m, 2H), 1.73 (d, J = 8.9 Hz, 1H),

.50 – 1.40 (m, 4H), 1.38 (s, 3H), 1.31 – 1.22 (m, 2H), 1.02 (s, 3H), 0.98

d, J = 7.0 Hz, 3H), 0.95 (dt, J = 11.6, 2.1 Hz, 1H), 0.90 (d, J = 6.8 Hz, 3H),

.82 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); ¹³C NMR (151 MHz,

CDCl ); δ [ppm] = 212.2, 149.6, 136.3, 134.3, 133.1, 85.6, 60.8, 52.1, 51.9,

3.4, 42.7, 41.3, 40.6, 38.8, 38.7, 37.9, 37.7, 34.0, 33.3, 32.9, 26.5, 23.1,

22

1

(

nhexane/EtOAc 3:1); [α]_D= +66.3 (c = 0.39, CHCl

3

CDCl ) δ [ppm] = (600 MHz, CDCl

3

1

Keywords: biomimetic synthesis • natural product synthesis •

radical reactions • rearrangement • steroids

(

2

(

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42 2

HRMS (ESI-TOF); m/z calcd. for C28H O Na [M+Na] : 433.3077, found:

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O, 5 mL) was added.

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Chemistry - A European Journal

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FULL PAPER

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