A synthesis of cephalostatin 1

Accepted Manuscript

Yong Shi, Qing Xiao, Quan Lan, Da-Hai Wang, Lan-Qi Jia, Xiao-Hu Tang, Tao Zhou,

Min Li, Wei-Sheng Tian

PII:

S0040-4020(18)31337-1

https://doi.org/10.1016/j.tet.2018.11.010

TET 29921

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To appear in: Tetrahedron

Received Date: 30 September 2018

Revised Date: 29 October 2018

Accepted Date: 5 November 2018

Please cite this article as: Shi Y, Xiao Q, Lan Q, Wang D-H, Jia L-Q, Tang X-H, Zhou T, Li M, Tian W-S,

A synthesis of cephalostatin 1, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.010.

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A Synthesis of Cephalostatin 1

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Yong Shi*, Qing Xiao, Quan Lan, Da-Hai Wang, Lan-Qi Jia, Xiao-Hu Tang, Tao Zhou, Min Li and Wei-Sheng

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Tetrahedron

journal homepage: www.elsevier.com

A Synthesis of Cephalostatin 1

Yong Shi , Qing Xiao, Quan Lan, Da-Hai Wang, Lan-Qi Jia, Xiao-Hu Tang, Tao Zhou, Min Li and Wei-

Sheng Tian

CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,

Shanghai 200032, China

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

A synthesis of cephalostatin 1 from hecogenin is described in detail. The gram-scale synthesis of

south part features a Baeyer–Villiger oxidation of hecogenin to 16,20-diol, a selective oxidation

of C16-OH with Dess–Martin periodinane, a Rh(I)-catalyzed C15–C16 double bond shift to

C14–C15 position, and a Hg(OAc)₂-mediated spiroketal formation from cyclic enol ethers with

alkenyl side chain at 2-position. Key transformations in the synthesis of north part, also on gram

scale, include an abnormal Baeyer–Villiger oxidation of hecogenin to the corresponding

dinorcholanic lactone, where a catalytic amount of iodine acts as a traceless and catalytic switch,

an umpolung of steroidal 22-aldehyde to forge C22–C23 bond with good stereochemical control,

a cascade spiroketal-forming process to establish DEF rings in one operation, and a selective

oxidation of C3-OH. There are also other noteworthy transformations that, although not used in

our final route, are valuable and could be applied to other syntheses, including: intra- or

intermolecular S_N2’ processes of C14-heteroatom-substituted C15–C16 alkenes, an

unprecedented rearrangement of β-adduct of D-ring dienes and singlet oxygen, a chelation-

controlled methylallylation of C23 aldehyde, and so on.

Available online

Keywords:

cephalostatin 1

Baeyer-Villiger Oxidation

dinorcholanic lactone

singlet oxygen

Spiroketal Formation

.

———

Corresponding author. e-mail: chemyshi@hotmail.com (Y. Shi)

Corresponding author. e-mail: wstian@sioc.ac.cn (W.-S. Tian)

2

Tetrahedron

ACCEPTED MANUSCRIPT

1. Introduction

Searching for natural products possessing anti-tumor effects,

the Pettit group from Arizona State University isolated 20

cephalostatins^1-9from the marine worm Cephalodicsus gilchristi

(represented by cephalostatin 1 (1), Figure 1), and the Fusetani

group from Tokyo University isolated 26 ritterazines^10-13from the

tunicate Ritterella tokioka (represented by ritterazine B (2)). The

cephalostatins and ritterazines formed

a

family of 46

trisdecacyclic bissteroidal pyrazines with striking cytotoxicity

against human tumors at low nanomolar level, hence ranking

them among the most powerful anticancer agents ever tested by

the US National Cancer Institute.¹⁴Although an increasing

amount of research is being focused on these issues, the cellular

target and mechanism of them have not been fully elucidated.^15-20

Unlike the taxol, growing in large and easy-to-harvest forests, the

limited availability of marine organisms are scattered on the

bottom of the ocean and makes it impossible to obtain large

amounts of cephalostatins or ritterazines by harvesting. Chemical

synthesis is the only resort.

With up to thirteen rings annulated to the pyrazine with a C2-

symmetry in the lipophilic bissteroidal core moiety and highly

oxygenated outer spiroketal areas, cephalostatins/ritterazines

represent some most fascinating and challenging structural

elements, stimulating a broad spectrum of organic synthesis

efforts in a number of laboratories.^21-33These endeavors have put

forward elegant and creative solutions to some long-standing

synthetic problems, such as, three processes of preparing

unsymmetrical pyrazines developed by Heathcock³⁴, Fuchs³⁵, and

Winterfeldt³⁶, and an unprecedented oxidation of C18-Me from

C14-C15 double bond developed by Shair.

Three groups (the Fuchs group from Purdue University^37-38

,

the Shair group from Harvard University³⁹, and our group⁴⁰)

accomplished the synthesis of cephalostatin 1. Some key

transformations in these syntheses were listed in Figure 1b. All

the syntheses started with hecogenin (3), a cheap steroidal

sapogenin, or its derivatives, except the synthesis of the north

part of 1 by Shair, which started with epiandrosterone (4). Both

Fuchs and Shair used Marker degradation⁴¹to transform the

spiroketal of hecogenin derivatives to steroidal 16,17-en-20-ones,

which set the stage for introducing other functionalities. In our

synthesis, we employed 3,12,16,20-tetraol 7 and lactone 8, both

prepared from hecogenin, to synthesize south part (5) and north

part (6) of 1, respectively. In our previous communication⁴⁰, only

the final route was briefly reported, leaving most of the details

undiscussed. This article describes in detail our synthesis of

cephalostatin 1.

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Figure 1. A Brief Overview of Three Syntheses of Cephalostatin 1

commercially available 30% H₂O₂and formic acid) followed by

saponification furnished 7 in 93% yield after recrystallization.

2. Results and Discussions

2.1. Synthesis of the South Part of Cephalostatin 1

The intramolecular remote functionalization of C18 methyl

group from C20-OH was routinely accomplished by trapping the

δ-carbon radical generated by 1,5-hydrogen transfer to alkoxyl

free radical with iodine.^54-56The presence of unprotected

hydroxyls might cause severe side reactions, selective protection

of hydroxyl groups at C3, C12 and C16 was therefore needed.

Two basic problems in the synthesis of the south part (5) are

the transformation of the EF rings from a 5/6 system, which is

present in the starting material, to a functionalized 6/5 system

and the introduction of C14-C15 double bond in the D ring.

Starting with 7, we needed to functionalize the C18 angular

methyl group with the C20-OH, install the C14–C15 double bond

with the C16-OH, and assemble the spiroketal with desired

stereochemistry.

By stirring 7 in dry acetone at room temperature in the

presence of TsOH (20 mol%), its C16-OH and C20-OH were

protected as acetonide, and then the C3-OH and the C12-OH of

11 were protected as acetates to give the fully protected tetraol in

95% yield after recrystallization from EtOAc/hexane. Removal

of the acetonide with 80% aqueous HOAc at 60 °C gave 12 in

high yield (86%, 98% brsm). Although the C16-OH of 12 could

be selectively protected as pivalate or t-butyldimethylsilyl ether

in good yields, the steric crowdedness at the upper face of the D

ring made the remote functionalization impossible.

Our synthesis of south part (5) thus started with the

preparation of the tetraol 7. The transformation of the EF-ring

spiroketal of steroidal sapogenins into 16,20-diol via Baeyer–

Villiger oxidation was first reported by Marker in 1940⁴²and

developed as a useful degradation tool by Morita and co-workers

in 1960s^43-47. Our group have independently developed a similar

procedure without knowing the Morita’s report.⁴⁸The reactivities

of these OHs and their use in natural product synthesis have been

explored in our laboratory.^49-53

Selective oxidation of C16-OH was considered a good option

because the resultant C16 ketone could minimize the steric

interference and be used to install the C14–C15 double bond.

Interestingly, Dess–Martin oxidation of 12 proved superior to

other typical oxidations (NBS, PDC, Swern, etc.), and delivered

the desired ketone 13 in excellent yield. It was noteworthy that

running the oxidation at low concentration was crucial for the

high selectivity of this oxidation, with the ratio of C16 ketone to

C20 ketone being ca. 3/1 at 0.17 M and 86/3 at 0.08 M. Then,

As in Scheme 1, the C12 ketone of hecogenin (9) was reduced

by NaBH₄in MeOH/THF to yield C12 alcohol as a mixture of

epimers in a ratio of 7–8/1 (β/α). The undesired C12α epimer was

removed through acetylation and recrystallization from ethanol to

afford rockogenin diacetate (10) in 76% yield. Baeyer–Villiger

oxidation of 10 with performic acid (generated in situ from

4

Tetrahedron

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Scheme 1. Toward south part: functionalization of the C18 angular methyl group

Scheme 2. Introduction of the C14–C15 double bond from C16-ketone.

according to Meystre’s hypoiodite method⁵⁷(lead tetraacetate/I₂,

hv), proximal functionalization of the C18 methyl group in 13

proceeded smoothly, providing lactone 14 in 73–79% yield after

Jones oxidation, along with ether 15 in 8–10% yield. Oxidation

of ether 15 with RuCl₃/NaIO₄failed to convert it into 14.⁵⁸

Further investigation revealed that the C18 functionalization of

C20S-alcohols, as in 13, is of faster reaction rate and higher yield

than that of their C20R-counterparts. The ease of preparation also

made them good choices for this type of reaction.

C16-carbonyl group via forming a thioketal and Raney Ni-

mediated reduction. We assumed that an allylic

bromination/debromination sequence would be the solution.

Treating 18 with N-bromosuccinimide (NBS) and benzoyl

peroxide (BPO) in refluxing tetrachloromethane produced a less

polar product 21 (TLC), which was unstable and converted into

allylic alcohol 22 in 89% yield after aqueous workups,

presumably via an allylic bromination/S_N2’ reaction. Attempt to

reduce the crude bromide 21 in situ with Zn/HOAc in MeOH

formed only the C16α methyl ether; and treatment of the crude

21 with EtSH in the presence of DBU formed thioether 23 as a

mixture of C16 epimers, the reduction of which with Raney

Ni/H₂system could not remove the thioether group at C16. Albeit

not usable in this synthesis, this reaction was successfully

adopted in our glaucogenin project.⁵²

Various methods have been reported to introduce the C14–

C15 double bond from suitable precursors,^59-62but none from the

C16 ketone. Direct dehydrogenation of 14 with DDQ and

(PhSeO)₂O was infeasible, presumably due to the difficulty in

forming enolate at the D ring. We then tried to introduce the

C15–C16 double bond and to migrate it to C14–C15 position

(Scheme 2). Shapiro reaction, a straightforward method to

convert ketones into double bonds, was also infeasible because

the tosylhydrazone of 14 was difficult to prepare. Finally, a

stereoselective reduction of 14 with NaBH₄in MeOH–THF

afforded the C16β-OH, which underwent mesylation (optimal

condition: 3.0 equiv MsCl, 6.0 equiv pyridine, DMAP, CH₂Cl₂,

rt) and iodination-elimination (NaI, HMPA, 110–120 °C, 4 h) to

introduce the C15–C16 bond, giving 18 in 92% yield over three

steps.

To migrate the double bond of 18 from the disubstituted C15–

C16 position to the trisubstituted C14–C15 position, we

63

investigated several typical conditions (TsOH, HCl,⁵⁹I₂

,

PdCl₂(PhCN)₂and RhCl₃^65-67). All failed. However, although

RhCl₃-catalyzed double bond migration (10 mol% RhCl₃in

EtOH, 72–78 °C, 24 h) did not work on 18, it worked well on 24,

whose C3 and C12 hydroxyl groups were exposed, giving the

desired ꢀ¹⁴-lactone 26 in 82% yield on multigram scale, along

with a small amount of 3-oxo byproduct 25 (ca. 5%). This result

indicated that the rhodium(I) (generated by oxidizing the

substrate) might be the real active catalyst and that ethanol could

not be oxidized to generate the Rh(I). To test this hypothesis, we

64

Allylic oxidation of 18 with CrO₃in the presence of a catalytic

amount of N-hydroxysuccinimide (NHS) delivered the

unsaturated enone 19 in good yield, but we failed to remove its

ACCEPTED MANUSCRIPT

Scheme 3. Completion of the synthesis of the protected south part 41.

used isopropanol as solvent; the reaction of 18 indeed took place,

but could only reach 90% conversion rate after heating at 100 °C

for 24 h. Furthermore, adding a small amount (5–10 mol%) of

dihydropregnenolone to the reaction mixture could dramatically

accelerate the reaction of 18 and progesterone was isolated as

byproduct.

To introduce the C24–C27 unit and the C23R-OH, we

examined various methylallylation procedures and none of them

exhibited apparent selectivity. The optimal condition was the

reaction with methylallylmagnesium chloride at 0 °C, affording

separable 33 and 34 (23-epi-33) as a 1.1/1 mixture in nearly

quantitative yield. The C23 stereochemistry of 33 was secured by

X-ray crystallography of its 3-hydroxyl derivative to be the

desired R. Reaction at lower temperature (−20 °C) gave a 2/3

mixture favoring the unwanted 34. Unable to achieve by

Mitsunobu inversion, converting 34 into 33 was realized by

Dess–Martin oxidation and NaBH₄reduction in 43% yield (with

56% 34 recovered). The poor stereoselectivities observed herein

indicated no dominant inherent facial bias in substrates like 32,

which were in agreement with the results reported by Fuchs and

Shair.

With the C14–C15 double bond being installed, focus turned to

facile construction of the

E

ring. When synthesizing

cephalostatin 1, Fuchs and co-workers have developed an elegant

and unified procedure to build the E ring, from 16,20-diol for

north part and from 18,20-diol for south part, namely employing

a sequence involving selective Rh-mediated insertion reaction of

α-diazophosphate ester, Jones oxidation, and intramolecular

Horner–Wadsworth–Emmons (HWE).⁶²Finding no better

approach, we borrowed this strategy.

We then focused on the construction of the spiroketal moiety

from 33. Mundy and co-workers have reported a tandem

oxymercuration-solvomercuration protocol to construct bicyclic

ketals from enol ethers (Scheme 3).⁶⁹We envisaged that a similar

procedure performed on cyclic enol ethers with alkenyl side

chain at 2-position would provide best chance to yield spiroketals

in single operation. As we expected, treatment of 33 with 2.2

equiv of mercuric acetate in a solution of degassed THF followed

by reduction with NaBH₄in aqueous NaOH solution afforded 35

in 93% yield. The stereochemistries at C20 and C22 of 35 were

confirmed by X-ray crystallography of its 3-silyl ether derivative,

which were similar to those reported by Fuchs (via acid-mediated

Diol 26 was protected as MOM ethers and treated with

LiAlH₄to furnish 18,20-diol 27 in high yield (Scheme 3). Direct

introduction of the side chain to diol 27 by selective oxidation of

C20-OH and intra- or intermolecular HWE reaction was fruitless.

Reaction of 27 with 28 afforded the desired product in low yield.

We thus referred to Fuchs’ procedure and prepared pentacyclic

aldehyde 32 from diol 27. Reaction of α-diazophosphate ester 29

with diol 27 smoothly provided the desired insertion product 30

as a mixture of diastereomers which was subjected to Jones

oxidation to give C20 ketone in high yield. Treatment of the

crude ketone with sodium hydride in THF for four hours (Fuchs’

condition) did not afford the desired 31 in our hands. Instead, we

found t-BuOK to be a better base for our substrate, furnishing 31

at 0 °C in 30 min and 87% yield. Meanwhile, Masamune–Roush

condition (DBU, LiCl, CH₂Cl₂)⁶⁸was equally effective for this

HWE reaction. Reduction of 31 with LiAlH₄followed by Dess–

Martin oxidation gave 32 in 97% yield.

cyclization) and Shair (via

a bromoetherification/reductive

debromination sequence). The observed stereochemical outcome

at C20 might result from oxymercuration from the less hindered

convex face of the dihydropyran E-ring. It was noteworthy that

reaction of 34 under the same condition was much slower and

with poor selectivity, giving a mixture of many isomers,

suggesting that the C23R-OH might play an important role on the

6

Tetrahedron

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formation of C22-configuration, presumably via the interaction

another Criegee intermediate 51. Migration of the iodinated C23

between the C21 methyl group and the C23R-OH.

in 51 led to the formation of 52, which, upon hydrolysis, released

lactone 8, iodide ion, and aldehyde 53. The iodide ion and 53

were oxidized by peracid to regenerate iodine and to provide acid

54, respectively. Therefore, at least 3 equiv of the peracid was

needed.

Another observation on this reaction worth further

investigation was that only 50% of 33 was transformed into 35

when 1.1 equiv of Hg(OAc)₂was used. We assumed that the

reaction might not simply proceed via an oxymercuration of enol

ether-solvomercuration of the C25–C26 double bond-spiroketal

formation sequence, but via some more complex mode.

The C22 spiroketal of south part 41 is in a thermodynamically

favorable configuration, therefore, the S-configured C22 of 35

could epimerize to the more stable R-configuration under suitable

acidic conditions. After protecting its C23-OH as acetate, 35 was

submitted to a series of acid-catalyzed equilibration conditions.

Some reagents (BF₃•Et₂O, Tr⁺BF⁻, BBC, Dowex-50W, etc.) gave

complex mixtures of partially deprotected (of the acid-labile

MOM ethers) and epimerized products, and some (PPTS or CSA

in t-BuOH) resulted in partial deprotection of C23 acetate.

Finally, treating 35 with LiBF₄in refluxing aqueous acetonitrile

for 4 h removed the MOM ethers and epimerized the C22

stereocenter in one pot, leading to an inseparable 3/1 equilibrium

mixture of 40 (C22R) and its C22-epimer (22-epi-40, C22S) in

93% yield. Longer reaction time or higher temperature could not

improve the ratio, indicating a relatively stable equilibrium. Jones

oxidation of the mixture provided south part 41 (less polar

product) and its C22-epimer 42 in 65% and 24% yield,

respectively. Our procedure for establishing the spiroketal of 41

from 33 required only four steps.

Scheme 4. Synthesis Plans for North Part 6 from Lactone 8

(protecting groups are omitted)

2.2. Synthesis of the North Part of Cephalostatin 1

The north part 6 exists in 18 cephalostatins and, indicated by

the structure-activity relationship (SAR) research, is strongly

associated with the most potent antitumor activity of these

natural products. An efficient synthesis is thus important. As

mentioned above, our synthetic studies started with the steroidal

lactone 8, whose functionalities at C16 and C22 were considered

as good handles to build the DEF-ring functionalities of 6.

During our course of studies, two routes have been explored

(Scheme 4). In route a, we first introduced the C14–C15 double

bond and C17α-OH, reaching another lactone 44, from which we

established stepwise the needed C23-OH and F ring. In route b,

we tried to prepare a well-tailored substrate 45 and to construct

the EF rings simultaneously from it.

Since the oxidation of 10 could go both directions to give 7

and 8, how could catalytic amount of iodine switch the reaction

direction so thoroughly that no 7 was detected? The accepted

two-step mechanism of Baeyer–Villiger oxidation tells that

formation of Criegee intermediate is reversible and migration is

rate determining.^83-84We thus assumed that the migration of C23

in 51 was much faster than the migration of C20 in 47. As the

generations of Criegee intermediates 47 and 51 were reversible,

the reaction was therefore driven to the formation of 8.

With lactone 8 in hand, we first tried to introduce the required

functional groups on its D ring. Its C3-OH and C12-OH were

protected as MOM ethers under standard condition (MOMCl,

Bu₄NI, i-Pr₂NEt, DCM, reflux) to afford 56, which could be

easily recrystallized from ethanol/hexane. Various conditions

were investigated to open the lactone ring directly, however, all

of them met with failure. Therefore, 56 was reduced with LiAlH₄.

The primary C22-OH of the resultant diol was selectively

protected as acetate, and the C16-OH was converted into

mesylate in pyridine, which, at elevated temperature,

spontaneously underwent elimination in the same pot to furnish

steroid-16-en-22-acetate 57 in 76% yield. Attempting to

introduce a bromine atom at the allylic C15, we treated 57 with

N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN)

in refluxing tetrachloromethane for 10 hours, and found that the

reaction introduced not the allylic bromide but a conjugated

double bond at C14–C15 via a one-pot allylic bromination-

elimination process. Because the reaction released hydrogen

bromide that would pull the acid-sensitive MOM ethers down,

cyclohexene oxide was added as an acid scavenger. This

improvement allowed us to obtain diene-22-acetate 59 in 87%

yield on the 20 g scale.

A robust method of preparing lactone 8 from hecogenin 9 was

thus crucial for us. Dinorcholanic lactones, to which 8 belongs,

are versatile intermediates that preserve all the stereocenters on

the ring E of steroidal sapogenins, and thus received much

attention from synthetic chemists. Several methods were

reported^70-81and our solution is an abnormal Baeyer–Villiger

oxidation of steroidal sapogenins⁸². In the presence of a catalytic

amount of iodine and H₂SO₄, oxidation of rockogenin diacetate

10 with freshly prepared peracetic acid afforded the desired 8

after a sequential saponification on 200 g scale and in 84% yield

(Scheme 5).

A plausible mechanism of this oxidation is illustrated in

Scheme 6. We reasoned that the iodination at C23 during the

reaction elevated the migratory aptitude at C23, hence altered the

inherent regioselectivity of the oxidation. In acidic medium, the F

ring of steroidal sapogenin (10 as example) was opened to form

an oxonium ion 46, to which the addition of peracid generated a

Criegee intermediate 47. Then migration of the tertiary C20 from

carbon to oxygen gave 16,20-diol 7 (as esters) and acid 48. In the

presence of iodine, however, 46 was first iodinated at the C23

and the resultant 50 was then attacked by peracid, forming

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Scheme 5. Synthesis of north part.

Scheme 6. Plausible mechanism of abnormal Baeyer–Villiger oxidation of steroidal sapogenins

Selective oxidation of the C16–C17 double bond in diene 59,

either via direct epoxidation or with C22-OH as directing group,

suffered from low yield and poor selectivity. Treatment of 59

with singlet oxygen (O₂, TPP, sunlamp) also exhibited poor facial

selectivity, giving the desired α-adduct 60 in 42% yield. The β-

adduct 61, however, disappeared during the reaction, and a

rearrangement product 62 was isolated in 46% yield instead. We

assumed that the O–O bond of 61, with high structural tension,

underwent homogeneous cleavage to generate two oxygen

radicals, which triggered the another homogeneous breakage of

C14–C8 and C17–C13 bonds to form ketones at C14 and C17,

and the union of resultant radicals at C8 and C13 formed this

exquisite tricyclic framework. We also tested the facial

selectivity of the [4+2] cyclization on dienes with different

protecting group at C22-OH and found that most of them

(acetate, benzoate, benzyl ether, TBS ether, etc.) exhibited poor

selectivity. As the reaction could be performed at multigram

scale, we accepted this result.

Reduction of the α-adduct 60 with Zn/HOAc system in

CH₂Cl₂gave ꢀ¹⁴,16α-OAc product 63 in moderate yield. We

reasoned that an intermolecular S_N2' reaction occurred at C16

between the resultant 14,16-diol and acetate acid, and we wanted

to make it intramolecular. Therefore, 60 was hydrolyzed with

LiOH in MeOH/THF, then submitted to Dess–Martin oxidation

and Pinnick oxidation to afford the corresponding acid 65.

Treatment of 65 with Zn/HOAc in reflux CH₂Cl₂triggered an

intramolecular S_N2' reaction, furnishing lactone 66 in 74% yield

from 60.⁸⁵

We then investigated the installation of C23–C27 side chain

on 66 via a nucleophilic addition with 67 (Scheme 7). As 66

enolizes easily under basic conditions, it resists nucleophilic

addition of metallic reagents. After much optimization on

metallic reagents, the desired 68 was isolated in low yield, along

with substantial amount of 20-epi-66 (61%). Treatment of 68

with 65% aqueous solution of HOAc at room temperature

provided 5/5-spiroketal product 69 (26%), 5/6-spiroketal product

8

Tetrahedron

70 (north part of cephalostatin 7 and ritterazine K, 34%), and

more candidate reactions and better control on the stereochemical

ACCEPTED MANUSCRIPT

diketone 71 (34%).

outcome.

Addition of aldehyde 64 with the lithio anion of 1,3-dithiane

provided the desired Felkin–Anh adduct 75 in 78% yield over

two steps (from alcohol, as 64 is unstable, it was used without

purification), on multigram scale. Treatment of 75 with

Zn/HOAc in CH₂Cl₂did not lead to 76 or 77, but gave a complex

mixture. We reasoned that the acidity of the reaction medium

might be the main cause, which could be buffered with solvents

having certain Lewis basicity. As expected, carrying out the

Zn/HOAc reduction of 75 in ether or THF at room temperature

cleanly provided the 14α,17α-diol 76 in high yield. It was

noteworthy that 76 was stable enough in this reduction system

that it could stand refluxing for several hours. Treating 76 with

pyridinium p-toluenesulfonate (PPTS) or TMSCl in CH₂Cl₂

triggered the intramolecular S_N2’ reaction to give the desired

cyclization product 77. The C22-stereochemistry was verified as

R through a 2D NOESY analysis.

Hydrolysis of 77 to aldehyde 78 posed some difficulties.

Commonly reported conditions such as HgCl₂/CaCO₃, NBS,

NCS/AgNO₃, PhI(TFA)₂, and MeI/CaCO₃were unsuccessful and

failed to produce any aldehyde signal (NMR analysis) from 77.

When using PhI(TFA)₂and MeI conditions, 77 disappeared on

TLC but no aldehyde detected, presumably due to the formation

of corresponding oxidized and methylated derivatives which

resisted hydrolysis. Finally, the deprotection was accomplished

in 95% yield by treating 77 with HgO/BF₃•Et₂O in reflux THF.⁸⁷

The stereochemistry at C22 retained during the deprotection step

and no isomerization was observed during several-month storage.

Scheme 7. Attempts of introducing ring F from lactone 61

Further treatment of 69 with NaNO₂/BF₃•Et₂O, a routine

process to introduce a ketone at C23 of steroidal sapogenins,⁸⁶

resulted in the excision of the F ring, returning to lactone 66.

Although both 69 and 70 were useful in the cephalostatin

synthesis, the addition reaction was low-yielding and the product

distribution of the following cyclization was uncontrollable,

hence, prompting us to explore a more efficient route. With these

concern, we went back to aldehyde 64 for further investigation.

Aldehyde 64 underwent nucleophilic addition with lithium

reagents derived from dithiane 72 and iodide 67 to provide 73

and 74 in moderate yields (Scheme 8). Because reduction of their

O–O bonds gave complex mixtures and deprotection of S,S-ketal

of 73 was problematic, we decided to adopt a stepwise strategy

that introduces functional groups separately. This alteration

would simplify the functional-group manipulations and give us

With aldehyde 78 in hand, focus was turned to stereoselective

introduction of the C23-OH and the 25,26-vicinal diol unit. We

envisioned that a chelation-controlled methylallylation would

give 78, a α-chiral aldehyde, the chiral C23-OH, which in turn

Scheme 8. First-generation synthesis of the north part.

configurations of these products were unable to assign. Hydroxyl

^{would serve as a handle to control the stere}A^ochC^emCⁱE^strP^yT^ofE^tD^heMANUSCRIPT

25,26-vicinal diol (Scheme 9). Treatment of 78 with 2-

methylallylic Grignard reagent in THF at −78 °C afforded an

inseparable 1.0/3.3 mixture of isomers favoring the undesired

23S-stereoisomer 23-epi-79 in 90% yield (Table 1, entry 1).

Elevating the reaction temperature or premixing the aldehyde

with MgBr₂slightly improved the 23R-selectivity (entries 2–4),

but the inherited 23S product still dominated. A changeover of

the selectivity was made by performing the reaction in DCM,

affording a 7.3/1 mixture of isomers favoring the desired 23R-

isomer 79.

group-directed epoxidation and intramolecular halogenation of

the homoallylic alcohol unit (79), and Mukaiyama aldol of 78

with hydroxyacetone derivative and asymmetric methylation of

the resulting β-chiral ketone also failed to achieve the desired

stereochemical control.

Our stepwise strategy had all kinds of selectivity issues, and

this detour provided an opportunity to scrutinize our original

design concept. As depicted in Scheme 10, to establish the EF-

spiroketal unit of 6 from intermediate 82, exchanging the

oxidation states at C22 and C23 was required, which not only

brought about many unexpected difficulties but also was not

attractive in strategic level. To elevate the redox-economy⁹⁰, we

put on schedule the preparation of compounds 83, which has the

correct oxidation states at C22 and C23, through the coupling of

dithiane 84 and a properly protected β-chiral aldehyde.

Scheme 9. Methylallylation Models for Aldehyde 78

Table 1. Methylallylation of aldehyde 78

Results (R:S by

Entry Conditions

NMR)

1

2

3

methylallyl-MgCl, THF, −78 °C, 14 h

methylallyl-MgCl, THF, 0 °C, 10 h

methylallyl-MgCl, THF, reflux, 2 h

90% (1.0:3.3)

100% (1.0:1.8)

93% (1.0:1.3)

Scheme 10. Concerns about Oxidation States at C22, C23

Our preparation of the β-chiral aldehyde 89 started with the

known diol 86 (Scheme 11).⁹¹The primary OH was protected as

a TBDPS ether and the PMP group was removed by CAN

oxidation. Then, the exposed OHs were protected as TES ethers,

and the primary one was removed upon treating with PPTS in

MeOH/DCM (1/40). Dess–Martin oxidation of the resulting 88

provided 89 in 54% yield from 86. Similar aldehydes with the

vicinal diol being protected as isopropylidene, cyclopentylidene,

or cyclohexylidene ketals were also prepared.

methylallyl-MgCl, MgBr₂•Et₂O, THF, −78

°C, 2 h to RT

4

5

6

100% (1.0:2.3)

90% (1.0:1.0)

83% (7.3:1.0)

methylallyl-MgCl, DCM, −78 °C, 6 h

methylallyl-MgCl, MgBr₂•Et₂O, DCM,

−78 °C, 6 h

methylallyl-TMS, MgBr₂•Et₂O, DCM,

−78 °C to RT

7

No Reaction

8

9

methylallyl-TMS, SnCl₄, DCM, −78 °C

methylallyl-TMS, TiCl₄, DCM, −78 °C

40% (5–6:1)

< 20% (10:1)

To prepare dithiane 84, compound 60 was subjected to

hydrolysis and Dess–Martin oxidation. Treatment of the resultant

22-aldehyde 85 with 1,3-propanedithiol in the presence of 0.1

equiv of TsOH in CH₂Cl₂at 0 °C for 4 h, without affecting the

acid-labile MOM ethers, afford 84 in 87% on the multigram

scale.

methylallyl-SnMe₃, MgBr₂•Et₂O, DCM,

RT, 3 h

10

95% (>19:1)

Sakurai allylation and Keck allylation were also evaluated, as

shown in entries 7–10. Due to the low reactivity of trimethyl(2-

methylallyl)silane, relatively strong Lewis acids (SnCl₄and

TiCl₄)⁸⁸should be used to activate the aldehyde group, which

brought about deprotection of acid-labile MOM ethers and

epimerization of C22. On the other hand, under the activation of

MgBr₂•Et₂O in CH₂Cl₂, treating 78 with trimethyl(2-methylallyl)

stannane provided 79 in high yield and stereoselectivity.

As the bulkiness of the steroidal skeleton might make the

metalation of 84 difficult, to probe the efficiency of forming the

desired lithiated derivative, we performed a D₂O quenching

experiment, leading to the conclusion that the lithiated species

was short-lived and required quick trapping with the nucleophilic

partners. After treating 84 with n-BuLi at 0 °C for 5–10 min, 89

was added to the reaction mixture, delivering an inseparable 5–

6/1 mixture of epimers. The major epimer was assigned as 23R-

configured by a late-stage intermediate; the stereochemical

outcome could be rationalized by Cram–Reetz steric model.^92-95

When other aldehydes (isopropylidene, cyclopentylidene, or

cyclohexylidene ketals) were used, the reaction gave a ca. 1/1

mixture of the inseparable diastereomeric alcohols.

We then evaluated several asymmetric dihydroxylation

systems to install the last two hydroxyl groups on 79 and

disappointingly found that none of them gave usable

stereochemical selectivity and the isomers were inseparable (best

result: 2/3, the stereochemistry was not identified). After

acetylation of C23-OH and C26-OH, the inseparable mixture of

89

epimers 80 could undergo Suárez iodine(III) oxidation^25,to

form a mixture of 5/5-spiroketals in moderate yield, but the

10

Tetrahedron

ACCEPTED MANUSCRIPT

OTBDPS

S

23

Et₃SiO ₂₅

a. 1,3-propanedithiol

TsOH, CH₂Cl₂, 0 °C

4 h, 87% (20 g scale)

O

OSiEt₃

a. K₂CO₃, MeOH, 97%

b. Dess-Martin [O], 91%

22

b. n-BuLi, 0 °C

5 min, then 89

c. PhI(OTFA)₂

d. Ac₂O

22

23

22

OH

dr: 5-6/1

OTBDPS

OAc

84

O

68%, 91% brsm

97%

85

90

91

60

e. O₂, TPP, hv

f. Zn, HOAc, THF

62%

68% brsm

Nu

Fuchs' substrate

Structures we wanted to convert 91 to

OR

Me

H

O

Me

TBDPSO

OTBDPS

O

OR

O

C

O

MeO

Et₃SiO

H

Et₃SiO

O

H

O

HO

Cram-Reetz Steric Model

OH

OAc

OH

17

14

O

16

I

II

III

IV

OH

92

a. TBDPSCl, imidazole

b. CAN, NaHCO₃, 10 min

c. TESCl, imidazole

d. PPTS, MeOH/DCM

OSiEt₃

OH

OSiEt₃

e. Dess-Martin [O]

79%

O

OTBDPS

OH

OTBDPS

PMPO

HO

84%

82%

86

87

88

89

Scheme 11. Synthesis of the north part.

In a synthesis of cephalostatin 7, Fuchs and co-workers

submitted several substrates, represented by diene I in Scheme

11, to [4+2] cycloaddition with singlet oxygen, and found that

C22 ketal rings could shield the upper face of the D-ring dienes

to achieve the exclusive α-facial selectivity control in

cycloaddition reactions.²⁷It was desirable to employ the C22

thioketal ring in 90 to do the same job. Moreover, considering

that thioketal could also be unmasked with oxygen and

irradiation (the cycloaddition condition), and that both reductive

cleavage of the O–O bond and the EF-ring spiroketalization

could take place in acidic medium, we hypothesized that these

steps could be compressed in one pot to convert 90 into 6

directly. But, the reality was not as attractive as the hypothesis.

Treatment of diene 90 with singlet oxygen delivered a very

complex mixture. Reasoning that the complexness might be

caused by incomplete oxidation of sulfur atoms, we performed an

extra dethioketalization step but isolated no identifiable product.

We had to perform these reactions step by step.

form hemiketal) to generate an E-ring hemiketal 96, and its TES

ether was deprotected and the F ring was closed to yield 97.

Oxidative dethioketalization of 90 (PhI(OCOCF₃)₂, CaCO₃,

MeCN/water) followed by acetylation of the C23-OH afforded

91 in 97% yield. The cycloaddition of 91 with singlet oxygen

(TPP in CH₂Cl₂, sunlamp, −78 °C) delivered a readily separable

1

2.5–4.5/1 mixture of isomers (by H NMR analysis of the crude

product) favoring the desired α-adduct. In THF, reduction of the

crude product with Zn/HOAc gave 92 (dr 10/1) in 62% yield on

the multigram scale. In order to improve the facial selectivity of

the cycloaddition, we also tried to transform the side chain of 91

to cyclic systems II–IV, an interesting attempt which proved

difficult and inefficient and was abandoned quickly.

With multigram of 92 in hand, we turned to construct the 5/5

spiroketal. As 92 already contains all the functionalities that

needed to build the desired spiroketal, we conceived two paths to

reach the protected north part 97, as depicted in Scheme 12. Path

A was an F-ring-then-E-ring tactic, where the TES ether was

selectively deprotected and, under acidic medium, the exposed

C25-OH would attack the C22 ketone either to trigger a cascade

ketalization/intramolecular S_N2’ process to reach 97 (via 93), or

to form a F-ring hemiketal which reacted with C16-OH,

generated by intermolecular S_N2’ reaction on D ring with water,

to form the E ring (via 94). In contrast, path B featured an E-ring-

then-F-ring tactic, in which 92 initially underwent intramolecular

S_N2’ reaction (or intermolecular S_N2’ reaction with water then

Scheme 12. Possible Paths of Spiroketal Formation

Selective deprotection of the TES ether of 92 without

affecting the adjacent TBDPS ether proved quite challenging

(Table 2). Treatment of 92 with tetrabutylammonium fluoride

(TBAF) in THF showed no selectivity, and running the reaction

at low temperature showed no improvement (entry 1). When

buffering TBAF with acetic acid or employing other deprotection

conditions (Et₃N·3HF, HF·pyridine, SiO₂, etc.), we recovered 92

completely (entries 2–5).

C22-H and C24α-H, along with the fact that the configuration of

Table 2. Conditions for Spiroketal Formation

ACCEPTED MANUSCRIPT

entry

Conditions

Results ^(a)

C25 was known, confirmed that the C23 was R-configured,

which also supported the structural assignment of 90. The

crosspeaks between C21-methyl group and C23-H and between

C16-H and C23-OAc led to the conclusion that the configuration

at C22 was S. These assignments were further confirmed by

TBAF (1.0–2.0 or 5.0 equiv), THF,

−78 to 0 °C

1

nonselective desilylation

2

3

TBAF, HOAc, THF, rt, 24 h

No Reaction

1

Et₃N·3HF (22 equiv), THF, rt, 6 d

comparing the H NMR resonance signals of methyl groups in

100 with those of the known sample and cephalostatin 1.

Et₃N·3HF (22 equiv), THF, 55 °C,

15 h

4

5

6

No Reaction

TBDPSO

Silica gel, DCM, rt, 24 h

Et₃SiO

OH

20 equiv HOAc, DCM or DCM/i-

PrOH, rt, 24 h

MOMO

1.0 M HCl/THF (1/10)

0 °C to rt, 2 h, 90%

HO

E

OAc

92

O

H

MeOH anticipated S_N2’,

TES retained

7

8

PPTS, DCM/MeOH (20:1), rt

H

1.0 M HCl/THF (1/10)

rt, 2 h; then 45 °C, 45 h

MOMO

complex (S_N2’, TES

retained)

2 equiv PPTS, THF/H₂O, rt to 40 °C

96

9

HOAc:THF:H₂O (8:1:1), rt

HOAc:THF:H₂O (3:3:1), rt

complex (96)

TBDPSO

O

10

clean (50% 96 isolated)

O

OH

HO

22

HO

22

23

CH₃CN, HF (1.2 to 12 equiv), 0 °C

to rt

11

12

13

complex (96)

O

OH

+

OH

H

CH₃CN, HF (12 equiv), 60 °C, 1.5 h

97 (23-OAc, mixture)

complex, all PGs cleaved

R/S up

H

to 15/1

HO

98

HO

97

PPTS (10 to 20 equiv), t-BuOH, rt to

80 °C, 10 h

H

(23S)/(23R): 5/4

(22S,23R) natural

15-21%

59-68%

1 M aqueous HCl/THF (1/10), 0 °C

to rt, 2 h

Ac₂O, DMAP

DCM, 92%

14

15

16

17

96 (90%)

TBAF, THF

reflux, 4 h, 98%

1 M aqueous HCl/THF (1/10), 0 °C

2 h; 45 °C, 27 h

27 (s, 1.65 ppm)

97 (5/1 dr)

97 (15/1 dr)

HO

(d, 1.35 ppm) 21

TBDPSO

O

1 M aqueous HCl/THF (1/10), 45

°C, 40–50 h

HO

AcO

₁₈HO

HO

(s, 1.32 ppm)

22

23

12

H

O

OH

OAc

H

96, 1 M aqueous HCl/THF (1/10), 45

°C, 40–50 h

H

^(a)Based on thin layer chromatography (TLC) and ¹H NMR

analysis of the crude product.

HO

AcO

100

99

H

OTBDPS

H

NOE analysis of 99

C20 not changed

C23 is R-configured

C22 is S-configured

O

Several acidic conditions triggered the intramolecular or

intermolecular S_N2’ reaction with solvent (methanol and water)

on D ring, with the acid-labile protecting groups (MOM ethers,

TES ether, and acetate) being deprotected in different degree,

therefore producing complex mixtures in most cases (entries 7–

13). Further optimization revealed that treatment of 92 in THF

with 1 M HCl solution at 0 °C for two hours cleanly afforded 96

in 90% isolated yield (entry 14, and Scheme 13). Elevating the

temperature to 45 °C produced a complex mixture (more than

eight spots on TLC plate) in two hours; longer reaction time

greatly simplified the reaction, showing two spots on TLC plate

after 24 hours. The major spot (more polar) was assigned as an

inseparable mixture of C22S isomers (97/23-epi-97: 5/1), and the

minor one an inseparable mixture of the former’s C22R

counterparts (entry 15). Reacting for another 20–24 hours at 45

°C, the ratios of the products were improved (97/23-epi-97: up to

15/1, 98 as a ca. 1/1 mixture) and stayed stable (entries 16, 17).⁹⁶

Higher temperature and longer time would result in dramatic

drop in yield; hence, the optimal condition was therefore set as: 1

M aqueous HCl/THF (1/10), 45 °C, 40–45 h. The reaction was

performed on the multigram scale to give 97 in 59–68% yield.

Me

O

AcO

H

Me

O

AcO

Me

O

H

Me

99

Scheme 13. Synthesis of North Part

Having four acid-labile protecting groups (C26 TES ether,

C23 acetate, and C3/C12 MOM ethers) removed and the EF-ring

spiroketal established in the correct configuration, our protocol

represented the most efficient way to this challenging structural

unit.

Both the configurations of C23 and C25 contribute to the

excellent stereochemical outcome of the spiroketal-forming step,

we anticipated, as illustrated in Scheme 14. The stereochemistry

of C23 would determine from which face of the E-ring

oxocarbenium ion the C25-OH would attack C22 to close the F

ring, which is the kinetic aspect of the reaction. The 23S-

configured substrate prefers the lower-face attack, where the

repulsive force between the C21 methyl group and the C23

acetate group is minimized, to form the 22R-configured

spiroketal (via up TS I to 98R), whereas its 23R counterpart

prefers the upper-face attack to form the 22S-configured

spiroketal (via down TS II to 97). Since 96 was mainly 23R-

configured, the spiroketal would be mainly assembled as the

needed 22S. On the other hand, the products would adopt

The stereochemistries of 97 was identified through 2D-

NOESY analysis of its triacetate 99 to be C22S- and C23R-

configured. The crosspeak between C18-methyl group and C20-

H indicated that the configuration at C20 did not change. The

crosspeaks between C27-methyl group and C24β-H and between

12

Tetrahedron

ACCEPTED MANUSCRIPT

conformations that better minimize the interactions among

substitution of the resultant α-bromo ketone with

substituents at C20, C22, and C25. To lower the interaction

between the C21 methyl group and the C26-OTBDPS group, the

C22S-configured isomers would adopt the bent conformation,

which possesses two anomeric effects, and the C22R-isomers

adopt the extended conformation, which possesses one anomeric

effect. As the 22-epimers were inseparable, 97 and 98, and 97R

and 98R were collected separately. According to our results,

compound 97 is both the kinetic and the thermodynamic product.

However, attempts to convert other isomers to 97 could not give

97 in synthetically usable yields.

tetramethylguanidinium azide (TMGA) in MeNO₂⁹⁷provided the

α-azido ketone 101 in good yield. In a similar way, we prepared

the α-amino methoxime 102 in good yield through a sequence

involving bromination at the C2 of 6 with PTAB, substitution

with sodium azide in DMF, formation of the C3 methoxime with

O-methylhydroxylamine, and Staudinger reduction of the azide

group. Treatment of the pyrazine coupling partners, 101 and 102,

with polyvinylpyridine (PVP) and Bu₂SnCl₂in refluxing benzene

delivered the protected cephalostatin 1 (103) in 67% yield.

Removal of the TBDPS group with TBAF and hydrolysis of

three acetates with K₂CO₃/MeOH gave (+)-cephalostatin 1 (1) in

86% yield. The spectroscopic properties of our synthetic 1 are

consistent with those reported in the literature.

Selective hydrolysis of the C3 acetate in triacetate 99 failed

because the C23 acetate was also hydrolyzed easily. We

investigated selective oxidation of the C3-OH in 97 and found

that treatment of 97 with freshly prepared Ag₂CO₃/Celite in

refluxing toluene provided the north part 6 in 92% yield after

acetylation of other two secondary hydroxyl groups (Scheme 15).

In 13 steps with an overall yield of 18%, we accomplished the

synthesis of 6 from 8 and prepared more than 2.5 g of 6 for

further exploration.

3. Conclusion

To summary, we have developed efficient, gram-scale routes

to south part 42 and north part 6, respectively, and thus

accomplished a synthesis of cephalostatin 1. Our synthesis

presented two controllable and regiodivergent Baeyer-Villiger

oxidations of steroidal sapogenins, which could efficiently

convert hecogenin either to tetraol 7 or to lactone 8, both on more

than 100 g scale, hence laying a solid foundation for subsequent

exploration. In the latter oxidation, iodine tracelessly switches the

reaction direction: entering the reaction via in situ iodination,

being released as iodide ion, and being recycled through

oxidation of peracid. Our method provides not only an excellent

2.3. Completion of the Synthesis of Cephalostatin 1

With subunits 42 and 6 in hand, we reached the final stage of

the synthesis. Having been extensively investigated and used by

Fuchs et al., the pyrazine synthesis was easy to perform, as

illustrated in Scheme 15.³⁵Adjacent to the easily enolized C3

ketone, the C2 of south part 42 was easily brominated by treating

with phenyltrimethylammonium tribromide (PTAB) in THF, and

Scheme 14. Rational Pathways for Spiroketal Formation (R = TBDPS)

Scheme 15. Completion of the synthesis of cephalostatin 1.

ACCEPTED MANUSCRIPT

20

example of using chemical method to alter the inherent migratory

preference of Baeyer-Villiger oxidation without adding extra

steps, but also a practical and scalable method for preparing

dinorcholanic lactones. The lactones prepared through our

method have been used in the syntheses of several natural

products by us and others.^98-101

mg, 82%) as a white solid. Mp 175-176 °C; [α]_D+6.3 (c 1.05,

CHCl₃); IR (KBr): 1767, 1747, 1729, 1713, 1614, 1234 cm⁻¹; H

1

NMR (300 MHz, CDCl₃) δ 5.93 (m, 1H), 4.77 (dd, J = 11.7, 6.8

Hz, 1H), 4.74 (m, 1H), 4.72 (m, 1H, 1H), 3.02 (d, J = 9.0 Hz,

1H), 2.88 (m, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.45 (d, J = 5.9 Hz,

3H), 1.00 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 203.3, 181.1,

172.8, 171.3, 170.8, 129.3, 77.5, 76.5, 73.7, 61.5, 55.3, 50.5,

44.6, 37.5, 37.1, 37.0, 34.4, 29.9, 28.1, 28.0, 26.7, 22.1, 21.8,

18.3, 12.7; Anal calcd for C₂₅H₃₂O₇: C, 67.55; H, 7.26. Found: C,

67.55; H, 7.24.

Key steps in the south part synthesis include Rh(I)-catalyzed

migration of the C15–C16 double bond to C14–C15 and

Hg(OAc)₂-mediated spiroketal formation of cyclic enol ethers

with alkenyl side chain at 2-position. Key steps in the north part

synthesis include umpolung of steroidal moiety to form the C22–

C23 bond, [4+2]-cycloaddition of D-ring dienes with singlet

oxygen combined with intramolecular/intermolecular S_N2’

process to establish the functional groups on D ring, and one-pot

construction of the DEF rings. Successful application of cascade

reactions (construction of both spiroketals) and one-pot reactions

(removal of MOM ethers of 35 together with spiroketal

epimerization, allylic bromination and elimination of 57, etc.)

made our synthesis flask-economic and efficient.

4.1.2. Allylic alcohol 22

A solution of 18 (43 mg, 0.10 mmol), cyclohexene oxide (88

mg, 0.9 mmol), dibenzoyl peroxide (BPO, 1.2 mg, 0.005 mmol)

and NBS (18 mg, 0.10 mmol) in dry CCl₄(2.0 mL) was stirred at

reflux under an argon atmosphere for three hours. TLC showed

the generation of a less polar product. The mixture was subjected

to flash column chromatography on silica gel (PE/EA: 1/1) to

20

provide the more polar product 22 (40 mg, 89%). [α]_D-33 (c

1

0.85, CHCl₃); H NMR (300 MHz, CDCl₃) δ 5.45 (m, 1H), 5.02

(brs, 1H), 4.91 (dd, J = 11.4, 4.9 Hz, 1H), 4.69 (m, 1H), 4.68 (m,

1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.50 (d, J = 5.9 Hz, 3H), 0.91 (s,

3H); LRMS-ESI (m/z): 325 ([M-H-2AcOH]⁺).

In the course of our synthesis, two transformations, although

not used in the final route, are notable. First, the C14–C15 double

bond, when there is a leaving group at C14, tends to undergo

S_N2’ reaction, either inter- or intramolecularly (from 21 to 22 and

23, from 60 to 63, 65 to 66, 76 to 77, and 92 to 96). Second, the

rearrangement of the β-adduct of D-ring diene with singlet

oxygen would form an unprecedented tricyclic structure (from 59

to 62).

4.1.3. Allylic sulfide 23

A solution of 18 (128 mg, 0.30 mmol), cyclohexene oxide (88

mg, 0.9 mmol), dibenzoyl peroxide (BPO, 4.0 mg, 0.016 mmol)

and NBS (53 mg, 0.30 mmol) in dry CCl₄(4.0 mL) was stirred at

reflux under an argon atmosphere for 24 h. Another portion of

NBS (37 mg, 0.20 mmol) was added and the reaction was kept at

reflux for 12 h. The mixture was cooled to 40 °C; EtSH (2.6 mL)

and DBU (0.03 mL) were added. The reaction was stirred for 18

h, then cooled to ambient temperature and filtered and washed

with CCl₄. The filtrate was concentrated and purified through

flash column chromatography on silica gel (PE/EA: 7/1) to afford

16α-23 (55 mg, 37%) as a white solid and 16β-23 (68 mg, 46%)

4. Experimental section

General Methods: All reactions sensitive to air or moisture were

performed in flame-dried round bottom flasks with rubber

septum under

a positive pressure of argon or nitrogen

atmosphere, unless otherwise noted. Air and moisture-sensitive

liquids and solutions were transferred via syringe and stainless

steel cannula. Tetrahydrofuran (THF) and diethyl ether (Et₂O)

were distilled from sodium/benzophenone, methylene chloride

(DCM), toluene, and 2,6-lutidine from calcium hydride, N,N-

dimethylformamide (DMF) and dimethylsulfoxide from calcium

hydride under reduced pressure, acetone from K₂CO₃onto

activated 3Å molecular sieves, others according to the standard

procedures described in Purification of Laboratory Chemicals.

Yields refer to chromatographically and spectroscopically (¹H

NMR) homogeneous materials, unless otherwise stated.

Reactions were monitored by thin-layer chromatography (TLC)

carried out on silica gel plates using UV light as visualizing agent

and an ethanolic solution of phosphomolybic acid, and heat as

developing agents. NMR spectra were recorded on 300 MHz or

400 MHz instrument and calibrated using residual undeuterated

solvent as an internal reference [¹H NMR: CHCl₃(7.26), DMSO-

d₆(2.50); ¹³C NMR: CDCl₃(77.16)]. The following abbreviations

were used to explain the multiplicities: s = singlet, d = doublet, t

= triplet, q = quartet, br = broad.

20

as a white solid. Compound 16α-23: mp 108-109 °C; [α]_D-45

1

(c 0.60, CHCl₃); IR (KBr): 1746, 1726, 1540, 1246 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 5.36 (m, 1H), 4.87 (dd, J = 11.4, 4.9

Hz, 1H), 4.68 (m, 1H,), 4.67 (m, 1H), 3.96 (m, 1H), 2.86 (t like, J

= 6.4 Hz, 1H), 2.55 (q, J = 7.4 Hz, 1H), 2.07 (s, 3H), 2.02 (s,

3H), 1.47 (d, J = 6.6 Hz, 3H), 1.28 (t, J = 7.4 Hz, 3H), 0.92 (s,

3H); LRMS-EI m/e: 429 (4.2, M⁺-SEt), 297 (100). Compound

20

16β-23: mp 99-100 °C; [α]_D-81 (c 0.90, CHCl₃); IR (KBr):

1

1745, 1732, 1540, 1234 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

5.45 (m, 1H), 4.75 (dd, J = 10.4, 4.7 Hz, 1H), 4.73 (m, 1H), 4.68

(m, 1H), 3.96 (br d, J = 8.0 Hz, 1H), 3.11 (m, 1H), 2.53 (q, J =

7.5 Hz, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.72 (d, J = 6.9 Hz, 3H),

1.24 (t, J = 7.5 Hz, 3H), 0.92 (s, 3H); LRMS-EI m/e: 430 (0.87,

M⁺-AcOH), 429 (2.52, M⁺-SEt), 297 (100).

4.1.4. Dinorcholanic lactones and (R)-4-

methyldihydrofuran-2(3H)-one (55)through iodine-

catalyzed abnormal Bayer-Villiger oxidation of

steroidal sapogenin: general procedure

To a 2000 mL flask was added HOAc (300 mL), H₂SO₄(4.6

mL, cat.), iodine (2.60 g, 0.10 equiv.) and the mixture was stirred

at room temperature for 30 min before substrates (steroidal

sapogenin, 100 mmol) was added. A peracetic acid solution

(freshly prepared, ca. 1 M, 600 mL) was added. The temperature

of the mixture rose to ca. 60 °C in one hour and another 3-4

hours was needed for fully consumption of the starting material

at this temperature (in some cases, an oil bath was needed). The

reaction was cooled with a water/ice bath and quenched carefully

by addition of a saturated aqueous Na₂SO₃solution, and then

concentrated in vacuo. The residue was filtered and washed with

4.1.1. Enone 19

To a solution of alkene 18 (200 mg, 0.47 mmol) in

acetone/H₂O

(1.8

mL/0.20

mL)

were

added

N-

hydroxysuccinimide (59 mg, 0.51 mmol) and a solution of CrO₃

(186 mg, 1.86 mmol) in acetone/H₂O (5.6 mL/0.60 mL). The

mixture was stirred at 40-45 °C for 20 h, filtered, and washed

with acetone. The filtrate was concentrated; the residue was

dissolved with DCM and filtered through celite. The filtrate was

washed with brine, dried over Na₂SO₄, filtered, and concentrated

under reduced pressure. Purification through flash column

chromatography on silica gel (PE/EA: 2/1) gave enone 29 (170

14

Tetrahedron

ACCEPTED MANUSCRIPT

toluene and the filtrate was concentrated under reduced

1.07 (d, 3H, J = 8.1 Hz), 1.01 (s, 3H), 0.84 (s, 3H); ¹³C NMR (75

pressure (co-evaporation with toluene would minimize the

residual HOAc, the presence of which would slow the hydrolysis

and increase the use of KOH). The crude was dissolved in EtOH

(400 mL) and KOH was added slowly (pH > 14). The reaction

was stirred vigorously at reflux for five hours and cooled to

ambient temperature. A diluted aqueous HCl solution (pH < 3)

was added to give a copious yellow-white precipitate. The solid

was collected by filtration, washed by water, and then dried in

vacuo overnight. The crude lactone could be used in the next step

without further purification (typical yield: 80-95%). The analytic

sample was obtained by recrystallization with EtOH as white

microcrystal. The aqueous layer was extracted with DCM to

MHz, CDCl₃) δ 170.6, 170.0, 156.0, 117.1, 96.9, 94.3, 84.1, 81.7,

75.8, 68.0, 57.9, 55.2, 54.9, 49.7, 43.8, 37.9, 36.5, 35.4, 34.8,

34.1, 29.5, 29.2, 28.4, 28.3, 27.9, 21.0, 20.8, 15.4, 12.9, 11.6;

HRMS-EI (m/z): calcd for C₃₀H₄₈O₉Na⁺: 575.3191, found:

575.3190.

4.1.7. Aldehyde 64

To a solution of C22-OH (2.06 g, 4.42 mmol) in CH₂Cl₂(40

mL) was added Dess–Martin periodinane (2.44 g, 5.74 mmol, 1.3

equiv) and t-BuOH (1.2 mL). the reaction mixture was stirred for

10 hours at room temperature, quenched with saturated

Na₂S₂O₃/saturated NaHCO₃(v/v: 4/1) and diluted with ether (200

mL). The organic layer was separated, washed with brine and

dried over Na₂SO₄. Concentration in vacuum afforded the crude

aldehyde 64 (2.05 g, 100%). The aldehyde was partially

decomposed during flash column chromatography on silica gel to

24

provide lactone 55. 55: bp: 92–94 °C/16 mmHg; [α]_D+ 27 (c

0.64, CHCl₃); IR (film): 2971, 1780, 1460, 1242, 1174, 1018,

838, 601, 499 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 4.37 (dd, J =

1

8.9, 7.1 Hz, 1H), 3.83 (dd, J = 8.9, 6.3 Hz, 1H), 2.69 – 2.50 (m,

2H), 2.10 (q, J = 10.5 Hz, 1H), 1.11 (d, J = 6.5 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 177.5, 74.8, 36.1, 30.4, 17.9; Anal.

Calcd for C₅H₈O₂: C, 60.00; H, 8.00. Found: C, 60.05; H, 7.85.

20

afford a β-elimination product. mp 101–102 °C; [α]_D+70 (c

0.145, CH₂Cl₂); IR (film): 2979, 2927, 2881, 1718, 1456, 1442,

1148, 1102, 1043, 915, 743, 709 cm⁻¹; H NMR (300 MHz,

1

CDCl₃) δ 9.88 (d, 1H, J = 1.8 Hz), 6.44(s, 2H), 4.72, 4.71 (AB,

2H, J_AB= 6.9 Hz), 4.68 (s, 2H), 4.08 (dd, 1H, J = 12, 4.8 Hz),

3.50 (m, 1H), 3.372 (s, 3H), 3.367 (s, 3H), 3.25 (m, 1H), 1.25 (d,

3H, J = 6.9 Hz), 0.94 (s, 3H), 0.83 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 200.7, 134.1, 133.9, 98.4, 96.3, 94.5, 75.9, 75.4, 64.4,

55.8, 55.1, 45.6, 44.7, 44.0, 36.8, 35.6, 34.9, 33.2, 28.5, 28.4,

27.3, 26.7, 13.1, 11.5, 10.8; HRMS-ESI (m/z): calcd for

C₂₆H₄₀O₇Na⁺: 487.2664, found: 487.2666.

4.1.5. Cycloaddition with singlet oxygen to adduct

60 and 62

A solution of 59 (3.113 g, 6.5 mmol) and 5,10,15,20-

tetraphenylporphine (TPP, 20 mg, 0.32 mmol, 0.5 mol%) in dry

CH₂Cl₂(130 mL) was purged with oxygen at 0 °C for 5 min. The

reaction was stirred with irradiation by a sunlamp (200 W) at 0

°C for 7.5 h until TLC showed that the 59 was completely

consumed. The reaction mixture was concentrated under reduced

pressure, purified though flash column chromatography on silica

gel (PE/EA: 12/1–10/1–7/1) to provide α-adduct 60 (1.134 g,

42%) as a white crystal, and 62 (1.242 g, 46%, more polar) as a

4.1.8. Acid 65

To a solution of crude aldehyde (4.42 mmol) in t-BuOH/H₂O

(v/v: 5/1, 78 mL) was added 2-methyl-2-butene (3.28 mL, 31

mmol, 7 equiv), NaClO₂(0.594 g, 5.28 mmol, 1.2 equiv) and

NaH₂PO₄•2H₂O (1.373 g, 8.8 mmol, 2.0 equiv) sequentially. The

mixture was allowed to stir at room temperature for two hours

and diluted with ethyl acetate (300 mL). The organic layer was

separated, washed with brine and dried over Na₂SO₄. Filtration,

concentration under reduced pressure afforded the acid 65 (2.18

g, 99%) which was used directly in the next step without

purification. The analytic sample was obtained by

recrystallization with acetone as a white crystal. mp 143–144 °C

20

brownish oil. 60: mp 96–97 °C; [α]_D+30 (c 0.90, CHCl₃); IR

1

(film): 3059, 2941, 2866, 1743, 1231, 1039, 917 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 6.14 (d, 1H, J = 2.1 Hz), 5.85 (dd, t like,

1H, J = 2.1 Hz), 4.70, 4.65 (AB, 2H, J_AB= 6.6 Hz), 4.68 (s, 2H),

4.20 (m, 1H), 3.89 (m, 1H), 3.45 (m, 1H), 3.38 (s, 3H), 3.37 (s,

3H), 3.07 (dd, 1H, J = 13.2, 6.6 Hz), 2.87 (dd, 1H, J = 11.7, 4.2

Hz), 2.04 (s, 3H), 1.15 (d, 3H, J = 6.9 Hz), 1.06 (s, 3H), 0.92 (s,

3H); Anal. Calcd for C₂₈H₄₄O₈: C, 66.12; H, 8.72. Found: C,

66.15; H, 8.72. 62: [α]_D²⁰–44.4 (c 0.82, CHCl₃); IR (film): 2937,

20

1

2860, 1745, 1699, 1606, 1451, 1374, 1234, 1044 cm⁻¹; H NMR

(acetone); [α]_D+33.6 (c 0.176, CHCl₃); IR (film): 3438, 3060,

2942, 2930, 2830, 1740, 1464, 1184, 1149, 1105, 1046, 927, 919

(300 MHz, CDCl₃) δ 6.49 (d, 1H, J = 6.1 Hz), 6.44 (d, 1H, J =

6.1 Hz), 4.68 (s, 2H), 4.62, 4.55 (AB, 1H, J_AB= 6.6 Hz), 4.20 (dd,

1H, J = 11.0, 4.4 Hz), 4.06 (dd, 1H, J = 10.7, 6.0 Hz), 3.45-3.55

(m, 2H), 3.36 (s, 3H), 3.32 (s, 3H), 2.32-2.43 (m, 1H), 2.06 (s,

3H), 1.11 (d, 3H, J = 6.7 Hz), 1.06 (s, 3H), 0.85 (s, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 203.7, 200.6, 170.8, 135.1, 134.5,

96.2, 94.7, 80.0, 76.4, 65.0, 58.8, 55.5, 55.2, 51.1, 51.0, 45.0,

44.4, 37.7, 35.4, 34.5, 32.2, 29.3, 28.4, 27.9, 20.9, 18.0, 13.3,

11.4; Anal. Calcd for C₂₈H₄₄O₈: C, 66.12; H, 8.72. Found: C,

66.04; H, 8.78.

1

cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.66 (d, 1H, J = 6.0 Hz),

6.40 (d, 1H, J = 6.0 Hz), 4.77 (s, 2H), 4.69 (s, 2H), 4.09 (q, 1H, J

= 4.8 Hz), 3.46–3.55 (m, 1H), 3.43 (s, 3H), 3.38 (s, 3H), 3.17

(dd, 1H, J =10.2, 6.9 Hz), 1.40 (d, 3H, J = 6.6 Hz), 0.92 (s, 3H),

0.83 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.0, 134.4, 132.7,

98.4, 96.3, 96.2, 94.4, 75.9, 75.4, 64.6, 55.9, 45.6, 44.0, 37.6,

36.7, 35.6, 34.9, 33.4, 28.5, 28.4, 27.2, 26.6, 14.9, 12.1, 11.5;

HRMS-ESI (m/z): calcd for C₂₄H₄₀O₈Na⁺: 503.2615, found:

503.2615.

4.1.9. C17-OH lactone 66

4.1.6. Compound 63

To a solution of acid 65 (1.80 g, 3.75 mmol) in DCM (35 mL)

was added acetic acid (1.50 mL, 26.0 mmol, 7 equiv) and zinc

powder (1.50 g, 22.5 mmol, 6 equiv). The resulting suspension

was warm to reflux for 4 hours until the starting material was

fully consumed. The reaction mixture was filtrated through a

short pad of silica gel, and diluted with ethyl acetate (150 mL).

The organic layer was washed with diluted brine, saturated

aqueous NaHCO₃solution, brine, and dried over Na₂SO₄.

Filtration, concentration and flash column chromatography on

silica gel (PE/EA: 8/1) furnished lactone 66 (1.10 g, 63%) as a

wax. The reaction was performed at 50 mg scale to give a yield at

To a solution of 60 (80 mg, 0.16 mmol) in CH₂Cl₂(15 mL)

was added zinc powder (103 mg, 1.6 mmol, 10 equiv) and acetic

acid (20 ꢁL, 2.5 equiv). The reaction was stirred at room

temperature for five hours, filtered through short pad of silica and

washed with CH₂Cl₂. The filtrate was neutralized with saturated

aqueous NaHCO₃solution, washed with brine and dried over

Na₂SO₄. Concentration under reduced pressure and flash column

chromatography on silica gel (PE/EA: 2/1) afforded 63 (56 mg,

65%) as a pale yellow oil. [α]_D²⁰–41.9 (c 0.56, CHCl₃); IR (film):

1

3500, 2933, 2860, 1742, 1467, 1375, 1242, 1041, 917 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 5.53 (d, 1H, J = 1.2 Hz), 5.24 (s, 1H),

4.81, 4.58 (AB, 2H, J = 6.3 Hz), 4.68 (s, 2H), 4.08 (m, 3H), 3.45

(m, 1H), 3.37 (s, 6H), 2.87 (s, 1H), 2.06 (s, 3H), 2.05 (s, 3H),

20

77%. [α]_D+40 (c 0.11, DCM); IR (film): 3459, 2933, 1772,

1

1715, 1647, 1195, 1147, 1102, 1040, 915, 415 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 5.43 (s, 1H), 5.00 (s, 1H), 4.72, 4.62(AB,

11.5 Hz), 3.49 (m, 1H), 3.39 (d, 1H, J = 11.4 Hz), 3.38 (s, 3H),

3.37 (s, 3H), 3.30 (s, 1H), 1.13 (s, 3H), 1.09 (s, 3H), 1.07 (d, 3H,

J = 7.0 Hz), 0.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 157.0,

117.7, 107.4, 96.2, 94.6, 93.7, 90.8, 79.7, 76.0, 69.3, 66.6, 58.6,

55.4, 55.2, 51.7, 47.5, 44.4, 36.9, 36.0, 35.1, 34.2, 32.3, 29.3,

28.6, 28.2, 27.7, 27.28, 24.8, 16.2, 12.0, 7.5; HRMS-ESI (m/z):

[M+Na]⁺calcd for C₃₁H₅₀O₈: 573.3395, found: 573.3397. 71:

[α]_D²⁰+79.7 (c 0.80, CH₂Cl₂); IR (film): 3450, 2964, 2932, 1692,

ACCEPTED MANUSCRIPT

2H, J_AB= 6.0 Hz), 4.66 (s, 2H), 4.28 (s, 1H), 3.84 (dd, 1H, J

=11.1, 4.8 Hz), 3.44-3.53 (m, 1H), 3.39 (s, 3H), 3.34 (s, 3H),

2.76 (q, 1H, J = 7.5 Hz), 1.28 (d, 3H, J = 7.5 Hz), 1.09 (s, 3H),

0.85 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 179.0, 158.9, 117.1,

95.6, 94.5, 91.4, 87.1, 79.5, 75.7, 55.8, 55.2, 55.1, 51.7, 44.3,

42.0, 36.7, 36.0, 34.9, 34.3, 28.8, 28.4, 27.9, 26.4, 15.2, 11.9,

10.8; HRMS-ESI (m/z): [M+Na]⁺calcd for C₂₆H₄₀O₇: 487.2668,

found: 487.2666.

1637, 1609, 1376, 1262, 1147, 1102, 1031, 915 cm⁻¹; H NMR

1

(500 MHz, CDCl₃) δ 5.94 (s, 1H), 4.69, 4.62 (AB, 2H, J_AB= 6.3

Hz), 4.68 (s, 2H), 3.42 (m, 4H), 3.37 (s, 3H), 3.36 (s, 3H), 2.18

(s, 3H), 1.41 (s, 3H), 1.18 (s, 3H), 0.94 (s, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 212.5, 194.6, 185.3, 148.1, 137.8, 125.6, 96.0,

94.6, 82.2, 75.8, 72.2, 69.7, 55.7, 55.2, 51.5, 51.2, 44.1, 36.7,

36.4, 35.4, 35.2, 34.9, 31.5, 29.0, 28.5, 27.8, 27.4, 23.6, 18.0,

15.8, 11.9; HRMS-ESI (m/z): [M+Na]⁺calcd for C₃₁H₄₈O₈:

571.3242, found: 571.3241.

4.1.10. Addtion of lithium reagent to give adduct 68

To a solution of iodide 67 (82 mg, 0.32 mmol) in anhydrous

pentane/ether (1.5 mL, v/v: 3/2) under argon atmosphere was

slowly added t-BuLi (1.5 M in pentane, 0.44 mL, 0.66 mmol) at

−78 °C. The resulting solution was stirred for another hour, and

added slowly a solution of lactone 66 (49 mg, 0.11 mmol) in

anhydrous THF. Methanol (0.80 mL) was added to quench the

reaction after 15 minutes, and the mixture was diluted with ethyl

acetate. The organic layer was washed with saturated aqueous

NH₄Cl solution and brine, dried over Na₂SO₄. Filtration,

concentration and flash column chromatography on silica gel

(PE/EA: 3/1–1/1) furnished the desired adduct 68 (7 mg, 25%

brsm) as a pale yellow oil, 20-epi-66 (8 mg), and the starting

4.1.12. Adduct 73

To a solution of 72 (372 mg, 1.5 mmol) in HMPA/THF (0.15

mL/2.5 mL) at -70 °C was slowly added a solution of t-BuLi in

pentane (1.50 M, 1.10 mL, 1.65 mmol) under argon. The mixture

was stirred at -70 °C and a solution of aldehyde 64 (348 mg, 0.75

mmol) in THF was added slowly. After one hour, a saturated

aqueous NH₄Cl solution was added to quench the reaction and

the mixture was allowed to warm to ambient temperature. The

mixture was diluted with ethyl acetate and separated; the organic

layer was washed with brine, dried over Na₂SO₄, filtered,

concentrated under reduced pressure. Purification through flash

column chromatography on silica gel (PE/EA: 25/1 to 6/1)

afforded 73 (250 mg, 51%) as a wax. [α]²_D⁰+ 35.7 (c 0.66,

20

material 66 (30 mg, 61%). Adduct 68: [α]_D+27 (c 0.25,

CH₂Cl₂); IR (film): 3500, 2933, 1458, 1377,1214, 1148, 1106,

1044, 912, 411 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.34 (s, 1H),

4.84 (brs, 1H), 4.76, 4.70 (AB, 2H, J_AB= 6.6 Hz), 4.68 (s, 2H),

4.33 (s, 1H), 4.21 (s, 1H), 3.82, 3.71 (AB, 2H, J_AB= 8.4 Hz),

3.76–3.84 (m, 1H), 3.43–3.56 (m, 1H), 3.42 (s, 3H), 3.37 (s, 3H),

1.40 (s, 6H), 1.29 (s, 3H), 1.12 (s, 3H), 1.08 (d, 3H, J = 6.9 Hz),

0.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 153.5, 119.7, 109.2,

108.6, 95.6, 94.6, 92.4, 92.1, 80.9, 80.7, 75.9, 74.1, 56.3, 55.2,

54.3, 52.6, 45.9, 44.6, 36.8, 36.2, 35.1, 33.9, 33.2, 31.5, 29.0,

28.6, 28.2, 27.3, 27.0, 26.6, 25.0, 14.5, 12.0, 7.9; HRMS-ESI

(m/z): calcd for C₃₄H₅₆O₉Na⁺: 631.3822, found: 631.3817. 20-epi-

66: [α]_D²⁰−9 (c 1.00, CH₂Cl₂); IR (film): 3459, 2929, 2859, 1775,

1716, 1558, 1379, 1216, 1189, 1147, 1104, 1041, 991, 966, 915,

CHCl₃); IR (KBr film) 3464, 2982, 2931, 2863, 1466, 1374,

1

1105, 1043, 914 cm^-; ¹H NMR (300 MHz, CDCl₃) δ 6.63 (d, 1H,

J = 6.0 Hz), 6.31 (d, 1H, J = 5.7 Hz), 4.77 (s, 2H), 4.67 (s, 2H),

4.38 (s, 1H), 4.18 (d, 1H, J = 4.2 Hz), 4.11 (dd, 1H, J =11.4,

4.2Hz), 3.88 (d, 1H, J = 8.1 Hz), 3.83 (d, 1H, J =8.1 Hz), 3.50

(m, 1H), 3.37 (s, 3H), 3.35 (s, 3H), 3.06-2.65 (m, 6H), 1.08 (s,

3H), 0.80 (s, 3H); LRMS-ESI (m/z): 735.4 ([M+Na]⁺); Anal.

Calcd for C₃₇H₆₀O₉S₂: C, 62.33; H, 8.48. Found: C, 62.22; H,

8.61.

1

820, 757 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 5.51 (s, 1H), 4.89

(s, 1H), 4.77 (d, 1H, J = 2.7 Hz), 4.71, 4.65 (AB, 2H, J_AB= 7.5

Hz), 4.68 (s, 2H), 3.90 (dd, 1H, J =11.7, 3.9 Hz), 3.44-3.55 (m,

1H), 3.41 (s, 3H), 3.37 (s, 3H), 3.13 (q, 1H, J = 7.2 Hz), 1.44 (d,

3H, J = 7.2 Hz), 1.10 (s, 3H), 0.86 (s, 3H); HRMS-ESI (m/z):

calcd for C₂₆H₄₀O₇Na⁺: 487.2664, found: 487.2666.

4.1.13. Adduct 74

At -70 °C, to a solution of (S)-4-(2-iodoethyl)-2,2,4-trimethyl-

1,3-dioxolane (67, 209 mg, 0.77 mmol) in ether/pentane (0.64

mL/0.96 mL) was added a solution of t-BuLi in pentane (1.50 M,

1.0 mL, 1. 5 mmol) under argon. After 30 min, to the resulting

white suspension was added a solution of 64 (232 mg, 0.50 mmol)

in THF (4.0 mL). After TLC showed complete consumption of

64, a saturated aqueous NH₄Cl solution was added to quench the

reaction and the mixture was allowed to warm to ambient

temperature. The mixture was diluted with ethyl acetate and

separated; the organic layer was washed with brine, dried over

Na₂SO₄, filtered, and concentrated under reduced pressure.

Purification through flash column chromatography on silica gel

(PE/EA: 5/1) afforded 74 (145 mg, 48%) as a wax. IR (KBr film)

4.1.11. Treatment of 68 with HOAc

The solution of adduct 68 (26 mg, 0.43 mmol) in HOAc (65%

aqueous solution, 2.0 mL) was stirred at room temperature for 3

hours. The reaction was diluted with ethyl acetate, washed with

saturated aqueous NaHCO₃solution and brine, dried over

Na₂SO₄. Filtration, concentration and flash column

chromatography on silica gel (PE/EA: 10/1) provided 69 (6 mg,

20

26%), 70 (8 mg, 34%), and 71 (8 mg, 34%). 69: [α]_D+19.2 (c

0.50, CH₂Cl₂); IR (film): 2451, 2927, 2858, 1462, 1374, 1210,

1

1147, 1109, 1045, 920 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 5.31

(d, 1H, J = 1.8 Hz), 4.77, 4.67 (AB, 2H, J_AB= 6.0 Hz), 4.72 (s,

1H), 4.68 (s, 2H), 3.80 (dd, 1H, J = 11.7, 4.8 Hz), 3.60 (d, 1H, J

= 11.4 Hz), 3.49 (m, 1H), 3.384 (s, 3H), 3.382 (d, 1H, J = 11.4

Hz), 3.37 (s, 3H), 1.18 (s, 3H), 1.11 (s, 3H), 1.03 (d, 3H, J = 6.9

Hz), 0.86 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 155.9, 118.5,

118.1, 96.3, 94.6, 93.2, 91.0, 86.7, 80.4, 76.0, 68.6, 55.9, 55.2,

55.2, 52.1, 44.5, 44.1, 36.8, 36.0, 35.1, 34.4, 34.2, 30.3, 29.2,

28.6, 28.2, 27.7, 23.8, 15.6, 12.0, 7.7; HRMS-ESI (m/z):

[M+Na]⁺calcd for C₃₁H₅₀O₈: 573.3395, found: 573.3395. 70:

[α]_D²⁰+17,5 (c 0.50, CH₂Cl₂); IR (film): 3495, 2927, 1701, 1460,

1

3437, 2934, 1380, 1260, 1211, 1148, 1039, 897; cm^-; H NMR

(300 MHz, CDCl₃) δ 6.59 (1H, d, J = 6.0 Hz), 6.33 (1H, d, J =

5.7 Hz), 4.69 (s, 2H), 4.68 (s, 2H), 4.05 (m, 1H), 3.78 (s, 2H),

3.51 (m, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 1.11 (d, 3H, J = 6.9 Hz),

1.07 (s, 3H), 0.83 (s, 3H); HRMS-ESI (m/z): [M+Na]⁺calcd for

C₃₄H₅₄O₉: 631.3817, found: 631.3817.

4.1.14. Adduct 75

To a solution of 1,3-dithiane (716 mg, 5.97 mmol) in

anhydrous THF (30 mL) under argon atmosphere was added n-

BuLi (3.50 mL, 1.60 M in hexane, 5.60 mmol) at −78 °C. The

resulting mixture was stirred for additional 40 min, then added a

1

1376, 1149, 1107, 1043, 936 cm⁻¹; H NMR (500 MHz, CDCl₃)

δ 5.35 (s, 1H), 4.78, 4.66 (AB, 2H, J_AB= 6.0 Hz), 4.68 (s, 2H),

4.62 (s, 1H), 3.83 (dd, 1H, J = 11.5, 8.0 Hz), 3.84 (d, 1H, J =

16

Tetrahedron

solution of aldehyde 64 (crude product from Dess–Martin

([M+Na]⁺); Anal. Calcd for C₃₀H₄₈O₆S₂: C, 63.34; H, 8.51.

ACCEPTED MANUSCRIPT

oxidation, 1.58 g, 3.29 mmol) in THF. The reaction was kept at

−78 °C until the aldehyde was completely consumed (by TLC),

and saturated NH₄Cl aqueous solution was added to quench the

reaction. Brine (30 mL) was added to the mixture at room

temperature and the solution was extracted with ethyl acetate for

three times, the combined organic layer was dried over Na₂SO₄.

Filtration, concentration, and flash column chromatography on

silica gel (PE/EA: 4/1) afforded 75 (1.534 g, 78% from C22-OH)

as a white foam. [α]²_D⁰+ 40.0 (c 0.45, CHCl₃); IR (KBr film)

Found: C, 61.24; H, 8.34.

4.1.17. Aldehyde 78

To a suspension of red HgO (65.2 mg, 0.30 mmol) in

THF/water (3.0 mL/3.0 mL) was added BF₃•Et₂O (27.5 ꢁL, 0.305

mmol) at room temperature. The mixture was stirred for 10 min,

then added a solution of dithiane 77 (56.9 mg, 0.10 mmol) in

THF (3.0 mL) and the system was warmed to reflux for 2 h. The

solid was filtered, the filtrate was quenched with saturated

NaHCO₃solution and extracted with ethyl ether for several

times. The combined organic layer was washed with brine and

dried over Na₂SO₄. Filtration, concentration, and flash column

chromatography on silica gel (PE/EA: 3/1) provided the desired

aldehyde 78 (45.6 mg, 95%) as a white foam. [α]²_D⁰+ 60.7 (c 0.52,

2936, 2857, 1466, 1449, 1388, 1245, 1147, 1103, 1033, 913 cm^-

1

;

¹H NMR (300 MHz, CDCl₃) δ 6.63 (d, 1H, J = 6.0 Hz), 6.30

(d, J = 6.0 Hz), 4.74 (d like, 2H, J = 2.1 Hz), 4.68 (s, 2H), 4.32

(d, 1H, J = 10.5 Hz), 4.07 (dd, 1H, J = 10.4, 4.5 Hz), 3.73 (d, 1H,

J = 10.2 Hz), 3.46-3.57 (m, 1H), 3.36 (s, 3H), 3.35 (s, 3H), 1.12

(s, 3H), 1.05 (d, 3H, J = 7.2 Hz), 0.83 (s, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 135.9, 131.3, 99.6, 98.3, 96.9, 94.6, 76.5, 76.0,

68.1, 64.2, 55.5, 55.1, 47.8, 45.8, 44.1, 36.8, 35.7, 35.0, 33.2,

33.1, 28.7, 28.5, 27.3, 27.0, 26.6, 25.9, 25.2, 13.0, 11.6, 8.6;

LRMS-ESI (m/z): 607.0 ([M+Na]⁺); Anal. Calcd for C₃₀H₄₈O₇S₂:

C, 61.61; H, 8.27. Found: C, 61.55; H, 8.01.

CHCl₃); IR (KBr film) 3511, 2930, 1721, 1648, 1467, 1450,

1

1385, 1311, 1149, 1103, 1037, 951, 937, 915 cm^-

;

¹H NMR (500

MHz, CDCl₃) δ 9.76 (d, 1H, J = 3.0 Hz), 5.40 (s, 1H), 5.05 (s,

1H), 4.75 (d, 1H, J = 6.6 Hz), 4.67 (d, 1H, J = 6.6 Hz), 4.68 (s,

2H, J = 2.1 Hz), 4.21 (dd, 1H, J = 3.0, 5.4 Hz), 3.79 (dd, 1H, J =

5.1, 7.8 Hz), 3.43-3.55 (m, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 2.61

(qui., 1H), 1.16 (s, 3H), 1.07 (d, 3H, J = 7.2 Hz), 0.88 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 203.95, 154.2, 119.8, 95.6, 95.5,

94.6, 91.2, 87.7, 75.9, 56.2, 55.1, 54.0, 52.6, 44.5, 44.2, 36.8,

36.2, 35.0, 33.98, 28.9, 28.5, 28.1, 26.5, 13.9, 12.0, 7.5; LRMS-

ESI (m/z): 501.2 ([M+Na]⁺), 533.3 ([M+MeOH +Na]⁺); Anal.

Calcd for C₂₇H₄₂O₇: C, 67.76; H, 8.84. Found: C, 67.65; H, 8.68.

4.1.15. Triol 76

To a solution of peroxide 75 (1.534 g, 2.62 mmol) in THF (35

mL) embedded in an ice/water bath was added Zn powder (not

activated, 1.712 g, 26.3 mmol) and acetic acid (4.50 mL, 4.68 g,

78 mmol). The reaction was aged for 2 h to consume the starting

material completely. The mixture was filtered through a short pad

of silica gel and washed with ethyl acetate (160 mL). The filtrate

was washed with saturated aqueous NaHCO₃solution (2 × 100

mL) and brine, dried over Na₂SO₄. Filtration, concentration, and

flash column chromatography on silica gel (PE/EA: 3/1) afforded

the desired 14,17,22-triol 76 (1.433 g, 93%) as a white foam.

4.1.18. Methylallylation of aldehyde giving the

acetates of 79 and 23-epi-79

To a suspension of aldehyde 78 (95.7 mg, 0.20 mmol) and

MgBr₂•Et₂O (153 mg, 0.60 mmol) in dry CH₂Cl₂(10 mL) was

added trimethyl(2-methylallyl)stannane. The mixture was stirred

at ambient temperature for two hours and quenched with 1N HCl

aqueous solution, diluted with ether. The organic layer was

separated and washed with brine, dried over Na₂SO₄. Filtration,

concentration, and flash column chromatography on silica gel

(PE/EA: 2/1-1/1) provided 79 (101 mg, 95%) as a colorless oil.

NMR indicated that the aldehyde was completely converted and

[α]²_D⁰+ 37.8 (c 0.40, CHCl₃); IR (KBr film) 3415, 2934, 2862,

1

1468, 1415, 1385, 1148, 1104, 1042, 961, 934, 913 cm^-

;

¹H

NMR (300 MHz, CDCl₃) δ 6.29 (d, 1H, J = 5.7 Hz), 6.23 (d, J =

6.0 Hz), 4.68 (s, 2H, J = 2.1 Hz), 4.78 (d, 1H, J = 6.0 Hz), 4.62

(d, 1H, J = 6.0 Hz), 4.37-4.41 (m, 3H), 3.90 (d, 1H, J = 10.2 Hz),

3.44-3.55 (m, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.84-3.02 (m, 2H),

2.69-2.76 (m, 2H), 2.32 (qu., 1H, J = 7.0 Hz), 1.16 (s, 3H), 0.92

(d, 3H, J = 7.2 Hz), 0.87 (s, 3H); LRMS-ESI (m/z): 609.0

([M+Na]⁺); Anal. Calcd for C₃₀H₅₀O₇S₂: C, 61.40; H, 8.59.

Found: C, 61.42; H, 8.41.

no 23-epimer formed. [α]²_D⁰+ 33.7 (c 1.00, CHCl₃); IR (KBr film)

1

3383, 2931, 1467, 1454, 1145, 1108, 1044 cm^-

;

¹H NMR (300

MHz, CDCl₃) δ 5.36 (s, 1H), 4.90 (s, 1H), 4.84 (br s, 2H), 4.72

(s, 2H), 4.67 (s, 2H), 4.62 (br s, 1H), 4.08 (br s, 1H), 4.10 (d, 1H,

J = 8.1 Hz), 3.75-3.82 (m, 2H), 3.42-3.56 (m, 1H), 3.38 (s, 3H),

3.36 (s, 3H), 2.54 (p like, 1H, J = 7.5 Hz), 2.42 (dd, 1H, J = 8.1,

13.8 Hz, C₂₄H_a), 2.24 (dd, 1H, J = 5.1, 13.8 Hz, C₂₄H_b), 1.78 (s,

3H), 1.17 (s, 3H), 1.10 (d, 3H, J = 6.9 Hz), 0.86 (s, 3H); ¹³C

NMR (75 MHz, CDCl₃) δ 153.7, 143.0, 120.4, 112.9, 95.6, 95.0,

94.6, 91.5, 85.2, 81.0, 75.9, 68.1, 56.1, 55.2, 54.8, 52.4, 44.5,

42.3, 41.7, 36.7, 36.1, 35.0, 33.8, 28.9, 28.5, 28.1, 27.0, 22.6,

14.2, 12.0, 8.7; LRMS-ESI (m/z): 557.3 ([M+Na]⁺); HRMS-

MALDI (m/z): calcd for C₃₁H₅₀O₇Na⁺: 557.3449. Found:

557.3460.

4.1.16. Cyclization Product 77

To a solution of diol 76 (234 mg, 0.40 mmol) in dry CH₂Cl₂

(20 mL) immersed in an ice/water bath was added TMSCl (50.0

ꢁL, 0.40 mmol). The mixture was quenched with saturated

aqueous NaHCO₃solution after TLC indicated that the diol was

completely consumed. The solution was diluted with ethyl

acetate (160 mL) and the organic layer was washed with brine

and dried over Na₂SO₄. Filtration, concentration, and flash

column chromatography on silica gel (PE/EA: 3/1) afforded the

cyclized product 77 (164 mg, 72%) as a white foam. The C22

The crude product of aldehyde 78 (216 mg, 0.452 mmol) with

(2-methylallyl)magnesium chloride (prepared from 3-chloro-2-

methylprop-1-ene) was dissolved in dry CH₂Cl₂(10 mL). To the

resulting solution were added AC₂O (0.16 mL, 1.7 mmol), Et₃N

(0.30 mL, 2.14 mmol) and DMAP (26.0 mg, 0.21 mmol), and the

mixture was stirred until the disappearance of the starting

material. The mixture was directly concentrated and purified

through flash column chromatography on silica gel (PE/EA: 5/1–

4/1) to provide 23R-acetate (60.4 mg, 25%, white foam) and 23S-

acetate (146 mg, 59%, white foam). Acetate of 79 (23R-epimer):

¹H NMR (400 MHz, CDCl₃) δ 5.32 (s, 1H, C₁₅H), 5.18-5.25 (m,

1H, C₂₃H), 4.77-4.82 (2H, C₂₆H), 4.76 (s, 1H, C₁₆H), 4.73, 4.65

(AB, 2H, J = 6.3Hz, 12-OMOM), 4.68 (s, 2H, 3-OMOM), 3.99

configuration was assigned as R through H-¹H COSY and 2D

1

NOESY. [α]²_D⁰+ 33.9 (c 0.86, CHCl₃); IR (KBr film) 3513, 2932,

1

1466, 1449, 1375, 1147, 1103, 1044, 1027, 974 cm^-

;

¹H NMR

(400 MHz, CDCl₃) δ 5.30 (s, 1H), 4.75 (d, 1H, J = 6.3 Hz), 4.65

(d, 1H, J = 6.3 Hz), 4.70 (s, 1H), 4.68 (s, 2H), 4.37 (d, 1H, J =

10.2 Hz), 3.95 (dd, 1H, J = 10.2, 5.4 Hz), 3.90 (dd, 1H, J =5.7,

4.8 Hz), 3.44-3.54 (m, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 2.79-2.92

(m, 4H), 2.48-2.53 (m or dq, 1H), 1.14 (s, 3H), 1.12 (d, 3H, J =

7.2 Hz), 0.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 156.3, 118.5,

95.7, 94.5, 93.4, 91.6, 81.9, 81.1, 75.9, 56.0, 56.0, 55.1, 51.4,

47.4, 44.3, 42.2, 36.8, 35.97, 34.98, 34.1, 29.4, 29.2, 29.0, 28.5,

28.1, 26.9, 25.9, 15.4, 11.99, 9.2; LRMS-ESI (m/z): 591.0

19. Rudy, A.; Lopez-Anton, N.; Barth, N.; Pettit, G. R.; Dirsch, V. M.;

(dd, 1H, J = 4.5, 7.2 Hz, C₂₂H), 3.87 (dd, 1H, J = 4.5, 11.7 Hz,

C₁₂H), 3.43-3.56 (m, 1H, C₃H), 3.53 (s, 1H), 3.38 (s, 3H, 12-

ACCEPTED MAN_SU_chS_ulC_ze-R_OsI_thP_ofT_{f, K.; Rehm, M.; Prehn, J. H. M.; Vogler, M.; Fulda, S.;}

Vollmar, A. M., Cell Death and Differentiation 2008, 15 (12), 1930-

1940.

OMOM), 3.36 (s, 3H, 3-OMOM), 2.48 (p like, 1H, J = 7.2 Hz,

C₂₀H), 2.24-2.38 (m, 1H, C₂₄H), 2.04 (s, 3H, 23-Ac), 1.77 (s, 3H,

27-Me), 1.13 (s, 3H, 18-Me), 1.02 (d, 3H, J = 7.2 Hz, 21-Me),

0.86 (s, 3H, 19-Me); ¹³C NMR (100 MHz, CDCl₃) δ 170.5,

155.5, 141.5, 119.3, 113.7, 95.5, 94.6, 94.3, 91.6, 83.4, 80.7,

76.0, 70.3, 56.0, 55.1, 51.8, 44.5, 41.5, 40.8, 36.9, 36.0, 35.0,

34.1, 29.3, 28.5, 28.2, 26.8, 22.4, 21.4, 15.3, 12.0, 9.0; Acetate of

20. Burgett, A. W. G.; Poulsen, T. B.; Wangkanont, K.; Anderson, D. R.;

Kikuchi, C.; Shimada, K.; Okubo, S.; Fortner, K. C.; Mimaki, Y.;

Kuroda, M.; Murphy, J. P.; Schwalb, D. J.; Petrella, E. C.; Cornella-

Taracido, I.; Schirle, M.; Tallarico, J. A.; Shair, M. D., Nature Chemical

Biology 2011, 7 (9), 639-647.

21. Lee, S.; LaCour, T. G.; Fuchs, P. L., Chem. Rev. 2009, 109 (6), 2275-

2314.

1

23-epi-79 (23S-epimer): H NMR (400 MHz, CDCl₃) δ 5.37 (dt,

22. Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E., Cephalostatin

Analogues — Synthesis and Biological Activity. In Progress in the

Chemistry of Organic Natural Products, Herz, W.; Falk, H.; Kirby, G.

W., Eds. Springer Vienna: 2004; Vol. 87, pp 1-80.

23. Gryszkiewicz-Wojtkielewicz, A.; Jastrzebska, I.; Morzycki, J. W.;

Romanowska, D. B., Curr. Org. Chem. 2003, 7 (12), 1257-1277.

24. Tian, W.-S., Chin. J. Org. Chem. 2000, 11-21.

25. Betancor, C.; Freire, R.; Pérez-Martín, I.; Prangé, T.; Suárez, E., Org.

Lett. 2002, 4 (8), 1295-1297.

26. Li, W.; LaCour, T. G.; Fuchs, P. L., J. Am. Chem. Soc. 2002, 124 (17),

4548-4549.

27. Lee, J. S.; Fuchs, P. L., J. Am. Chem. Soc. 2005, 127 (38), 13122-13123.

28. Lee, S.; Jamieson, D.; Fuchs, P. L., Org. Lett. 2009, 11 (1), 5-8.

29. Jeong, J. U.; Sutton, S. C.; Kim, S.; Fuchs, P. L., J. Am. Chem. Soc.

1995, 117 (40), 10157-10158.

“m” like, 1H, J = 2.7, 8.4 Hz, C₂₃H), 5.28 (s, 1H, C₁₅H), 4.63-

4.77 (7H, C₂₆H, C₁₆H, 3/12-OMOM), 3.95 (t, 1H, J = 7.2 Hz,

C₂₂H), 3.84 (dd, 1H, J = 4.5, 8.2 Hz, C₁₂H), 3.64 (s, 1H), 3.41-

3.55 (m, 1H, C₃H), 3.38 (s, 3H, 12-OMOM), 3.36 (s, 3H, 3-

OMOM), 2.47 (p-like, 1H, J = 7.2 Hz, C₂₀H), 2.49-2.56 (1H,

C₂₄H_a), 2.22 (dd, 1H, J = 9.6, 14.1 Hz, C₂₄H_b), 2.00 (s, 3H, 23-

Ac), 1.77 (s, 3H, 27-Me), 1.13 (s, 3H, 18-Me), 1.00 (d, 3H, J =

7.2 Hz, 21-Me), 0.86 (s, 3H, 19-Me); ¹³C NMR (100 MHz,

CDCl₃) δ 170.0, 155.6, 142.1, 119.0, 113.3, 95.6, 94.6, 93.6,

91.7, 83.0, 75.9, 70.9, 56.0, 55.6, 55.1, 51.9, 44.4, 41.8, 40.4,

36.8, 36.0, 35.0, 34.0, 29.6, 28.5, 28.2, 26.8, 22.5, 21.1, 15.0,

12.0, 8.7; LRMS-ESI (m/z): 599.2 ([M+Na]⁺).

30. Jeong, J. U.; Guo, C.; Fuchs, P. L., J. Am. Chem. Soc. 1999, 121 (10),

2071-2084.

31. Phillips, S. T.; Shair, M. D., J. Am. Chem. Soc. 2007, 129 (20), 6589-

6598.

Acknowledgments

32. Taber, D. F.; Joerger, J.-M., J. Org. Chem. 2008, 73 (11), 4155-4159.

33. Shi, Y.; Jiang, X.-L.; Tian, W.-S., J. Org. Chem. 2017, 82 (1), 269-275.

34. Heathcock, C. H.; Smith, S. C., J. Org. Chem. 1994, 59 (22), 6828-6839.

35. Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd, M. R., J. Am. Chem. Soc.

1996, 118 (43), 10672-10673.

We thank the National Natural Science Foundation of

China (21072210) for financial support.

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Highlights

1. Mercuric acetate promotes cyclic enol ethers with alkenyl side chain at

2-position to form spiroketals.

2. Iodide-catalyzed abnormal Baeyer-Villiger oxidation of a steroidal

sapogenin deliveres the corresponding dinorcholanic lactone.

3. β-Adduct of D-ring diene with singlet oxygen would rearrange to form an

unprecedented tricyclic structure.

4. When a leaving group present at C14, C14ꢀC15 double bond tends to

undergo S_N2ꢁ reaction inter- or intramolecularly.

5. Both spiroketals of cephalostatin 1 are thermodynamically favorable.

Article Doi

A synthesis of cephalostatin 1

DOI: 10.1016/j.tet.2018.11.010

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Article abstract of DOI:10.1016/j.tet.2018.11.010

Full text of DOI:10.1016/j.tet.2018.11.010

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