Studies toward norzoanthamine: Ireland–Claisen rearrangements of α,β-unsaturated esters in a stereocontrolled synthesis of trans-fused 2-cyclohexen-1-ones

Tetrahedron 95 (2021) 132354

Contents lists available at ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

Studies toward norzoanthamine: IrelandeClaisen rearrangements of

a,b-unsaturated esters in a stereocontrolled synthesis of trans-fused 2-

cyclohexen-1-ones

David R. Williams^*, Paul T. Gladen, Samarjit Patnaik

Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN, 47405-7102, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

The enantiocontrolled preparation of the trans-fused ABC ring system of norzoanthamine is described.

The synthesis strategy has incorporated studies of IrelandeClaisen rearrangements of esters derived

from 3,3-dimethylacrylic acid. Stereocontrol results from competing chair- and boat-like transition

states. Introduction of a nitroalkene by application of a modiﬁed Henry reaction facilitates an intra-

molecular DielseAlder cycloaddition for an effective and simple transformation to the desired conju-

gated decalone. A fully functionalized AB ring system leads to the cyclization of the trans-fused

cyclohexenone to complete the ABC system via ring-closing metathesis.

Received 11 March 2021

Received in revised form

12 July 2021

Accepted 14 July 2021

Available online 16 July 2021

Dedication: Dedicated to Professor Dale

Boger in celebration of the 2020 Tetrahe-

dron Prize for Creativity in the Chemical

Sciences and his many contributions for the

advancement of organic chemistry.

Keywords:

IrelandeClaisen rearrangements

Stereoselectivity

Modiﬁed Henry reaction

Nitroalkenes

4

p

þ2

p cycloaddition reactions

Oleﬁn metathesis

1. Introduction

norzoanthamine in 2004 [5], and this laboratory has also described

conversions to obtain zoanthamine (1) and zoanthenol (3) [6].

Zoanthus alkaloids represent a bioactive family of marine nat-

ural products which feature fused cyclic structures characterized by

the incorporation of a novel hemiaminal moiety. Examples include

zoanthamine (1), norzoanthamine (2), and zoanthenol (3) (Fig. 1)

[1]. Several studies have identiﬁed additional compounds of this

family [2]. Norzoanthamine (2) has gained particular attention

because of its potent antiosteoporotic effects which suppress the

loss of bone weight and bone strength in ovariectomized mice [3].

However, nearly all of the metabolites of this class show varying

levels of cytotoxicity, inhibition of human platelet aggregation, and

anti-inﬂammatory activities [4]. The complexity of these structures

has stimulated a number of synthesis studies. Notably Miyashita

and coworkers completed the ﬁrst total synthesis of

Kobayashi and coworkers have also achieved a successful synthesis

of norzoanthamine [7]. The unique architecture of these natural

products has inspired a number of focused studies pertaining to the

challenging issues of stereochemistry, functionalization, and cycli-

zation methodology [8]. We are among these practitioners who

have repeatedly found interesting, and occasionally valuable, re-

sults in our efforts [9].

In this account, we have described studies culminating in the

enantiocontrolled synthesis strategy toward substituted, highly

functionalized trans-decalin systems. Important aspects of these

investigations include [3,3]-Claisen rearrangements derived from

g-deprotonation of esters of 3,3-dimethylacrylic acid. This

approach provides the enantiocontrolled installation of a key chiral

quaternary carbon. Our application directly facilitates an endo-se-

lective, intramolecular DielseAlder reaction of an (E)-nitroalkene

as a general and effective methodology toward the preparation of

highly substituted, conjugated cyclohexenones. This effort has

* Corresponding author.

E-mail address: williamd@indiana.edu (D.R. Williams).

https://doi.org/10.1016/j.tet.2021.132354

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

CH₂Cl₂in the presence of a slight excess of DMAP (1.4 equiv) yiel-

ded an inseparable mixture of the conjugated and nonconjugated

esters 12 and 13 in a 3:1 ratio (90% yield) [13]. Treatment of the

mixture of esters with LDA (1.1 equiv) in THF at ꢀ78 ^ꢁC was fol-

lowed by the addition of freshly distilled TMSCl. After warming to

25 ^ꢁC, the desired acid 14 was isolated as the major product (dr 6:1).

Diastereoselectivity was substantially increased and afforded 14 as

a single diastereomer by the use of 45% DMPU in THF as the solvent

for this reaction. However, these conditions led to a diminished

yield of the desired carboxylic acid as well as the appearance of the

elimination product 15. Optimization of this IrelandeClaisen rear-

rangement utilized 20% DMPU in THF as the solvent to give an 18:1

ratio of isomers favoring 14 (84% yield) while minimizing produc-

tion (<5%) of diene 15. After puriﬁcation of 14, deprotection with

DDQ provided lactone 16 as a single diastereomer. NMR analysis of

16 identiﬁed key NOESY correlations as shown in Fig. 2, that sup-

ported the assigned stereochemistry of the Claisen rearrangement

product 14 arising from the nonracemic alcohol 11.

Fig. 1. Examples of Zoanthus alkaloids.

culminated in the enantiocontrolled synthesis of the trans-fused

ABC tricycle of norzoanthamine.

Our studies also examined the IrelandeClaisen rearrangement

from nonracemic 17 as shown in Scheme 3. This sample was pre-

pared, beginning with the alcohol 17, which was obtained in the

manner as described for 11, using the antipodal 9. Esteriﬁcation

with 3-methyl-3-butenoic acid (EDCI, DMAP, CH₂Cl₂) also resulted

2. Results and discussion

The impetus for this study began with the observation of the

IrelandeClaisen rearrangement of Scheme 1 [10]. The alkoxide

derived from the reaction of n-Bu₃SnLi and aldehyde 4 was

quenched with the 3-methyl-2-butenoic anhydride 5 to yield ester

6. An IrelandeClaisen rearrangement of 6 afforded an intermediate

in the thermodynamic 3:1 ratio of inseparable a,b- and b,g-unsat-

urated products 18 and 19. As in the prior example, this ratio was

determined by the integration of vinylic hydrogen signals in the ¹H

NMR spectrum of the mixture. IrelandeClaisen rearrangement of

this mixture in the absence of DMPU gave the carboxylic acid 20 as

the major diastereomer (dr 6:1) in 84% yield. Deprotection of the

puriﬁed 20 afforded lactone 21 which was utilized to support the

assignment of stereochemistry via NOESY techniques. The key

NOESY correlations are shown in Fig. 3.

silyl enol ether following the

g-deprotonation which, upon

warming, led to carboxylic acid 7 as a single diastereoisomer (86%

yield). The exclusive formation of the E-alkenylstannane in 7 pro-

vided a valuable extension of Claisen methodology for direct link-

age with Stille cross-coupling processes. DDQ deprotection of 7 was

accompanied by destannylation and produced the desired six-

membered lactone 8. NMR analysis of this lactone using NOESY

correlations supported the assignment of the relative

stereochemistry.

More than a decade after this initial study, we enlisted the use of

the IrelandeClaisen rearrangement of esters of 3-methyl-2-

butenoic acid to speciﬁcally address the chirality and substitution

of the trans-decalone of norzoanthamine (2). As summarized in

Scheme 2, the chiral, nonracemic allyl alcohol 11 was prepared in

standard fashion by application of a symmetric Evans aldol reaction

of aldehyde 4 with the Z(O)-boron enolate generated from 9 [1 1].

The syn-product 10 was obtained as a single diastereomer and

reductive cleavage of the auxiliary using LiBH₄was followed by

selective tert-butyldiphenylsilyl protection of the intermediate diol

to give 11. The stereochemistry of the secondary alcohol of 11 was

veriﬁed by an advanced Mosher ester analysis [12]. Esteriﬁcation of

this allylic alcohol with 3-methyl-2-butenoic acid using EDCI in

Generally four factors control the stereochemical outcome of

the [3,3]-Claisen rearrangement: (a) the conﬁguration of the C]C

alkene, (b) the chirality of starting allylic alcohol, (c) the geometry

of the enolate (silyl enol ether), and (d) steric factors [14]. Since our

starting esters were inseparable mixtures of conjugated and

nonconjugated isomers, the expectation of diastereoselectivity was

in doubt because we had little reason to anticipate the production

of identical ratios of E/Z-enolates from each contributing ester. The

kinetic deprotonation of alkyl esters with LDA in THF is known to

substantially favor formation of the E(O) enolate [15]. This fact has

t

been conﬁrmed by trapping enolates with BuMe₂SiCl to charac-

terize stable silylketene acetals. We have also recorded the pro-

duction of the E-trimethylsilyl ketene acetal (E/Z ratio 10:1) from

kinetic deprotonation of a closely-related ester in the course of our

australifungin studies [16]. On the other hand, Ireland's original

studies demonstrated kinetic enolate formation in a solvent

mixture of 23% HMPA in THF leading to Z(O)-enolate and the cor-

responding (Z)-TBS silylketene acetal [15b]. Weiler and coworkers

[1 7] have shown that ester derivatives of 3-methyl-2-butenoic acids

undergo selective g-deprotonation via lithium coordination of the

carbonyl oxygen to yield Z(O)-enolates, and several literature re-

ports support this observation in examples of stereoselective

Claisen rearrangements which are consistent with Z(O)-enolate

formation [18]. The results of our studies sound a cautionary note

regarding these assumptions and the expectation of reactions

proceeding via chair-like transition states. In fact, the carboxylic

acid 14 (Scheme 2) is envisioned from the chair-like transition state

22 which arises from the Z(O)-enolate via the TMS silylketene

acetal. The ratio of products (6:1 dr) indicates a modest enrichment

in the formation of Z(O)-enolate from the mixture of esters

featuring kinetic

g- and a-deprotonations of 12 and 13, respec-

tively. The inclusion of 20% DMPU has a dramatic effect on the

course of deprotonation and substantially favors production of the

Scheme 1. Claisen rearrangement of stannane 6.

2

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

Scheme 2. Preparation of unsaturated esters and studies of IrelandeClaisen stereocontrol.

Fig. 3. Featured 2D NOESY correlations in 21.

Fig. 2. Featured 2D NOESY correlations in lactone 16.

of conjugated and nonconjugated esters in each case. It is feasible

that the pseudoaxial substituents in 23 are destabilizing and the

observed product 20 is produced from the boat transition state 24

via the predominant formation of the Z(O)-enolate. While boat-like

transition states have been identiﬁed in Claisen processes [19], we

had not anticipated a change from chair to boat TS preferences

because of the apparent structural similarities of the esters of

Schemes 2 and 3 [20]. In fact, products resulting from boat-like

transition states have usually been observed for esters derived

Z(O)-enolate leading to 14 (>18:1 dr). We had theorized that DMPU

would produce similar results as observed in the use of HMPA for

kinetic a-deprotections. In fact, kinetic g-deprotonation must also

demonstrate highly selective Z(O)-enolate formation under these

conditions. On the other hand, product 20 (Scheme 3) can be

rationalized from the chair arrangement of 23 which must incor-

porate the TMS enol ether of the E(O)-enolate. This hypothesis

seems unlikely since we utilized identical conditions and mixtures

Scheme 3. Studies of IrelandeClaisen rearrangements of 18 and 19.

3

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

from substituted, cyclic allylic alcohols [19a,b,c,f]. Recent studies

ether (MOMCl) in the presence of DMAP furnished the desired

have detailed IrelandeClaisen rearrangements of

a

-hetero-

acetal without evidence of b-elimination, and immediate reduction

substituted esters via boat-like transition states [19d]. However,

acyclic esters are thought to predominantly give products via chair-

like arrangements. Indeed, we have concluded that this is not the

case for the rearrangement resulting in the major product 20. In

either case, the kinetic production of Z(O)- vs E(O)-enolates does

not reﬂect the composition of the starting conjugated and

nonconjugated esters under conditions of kinetic deprotonation.

Hence, it was important to effect the chemical transformation to

the six-membered lactones to establish the stereochemical

outcome of these sigmatropic processes (see Fig. 4).

Carboxylic acid 14 incorporated the desired C-12 and C-21

chirality of norzoanthamine and was transformed into the diene 33

to serve as a fully functionalized component for a subsequent

cycloaddition (Scheme 4). Upon deprotection of 26, derived from

the methyl ester 25, an efﬁcient conversion to the o-nitro-

phenylselenide 27 proceeded smoothly, and led to the conjugated

diene of 28 via facile oxidative syn-elimination [21]. This procedure

with LiAlH₄at 0 ^ꢁC cleanly gave the primary alcohol for IBX

oxidation to the aldehyde of 33 (95%).

The introduction of a nitroalkene as a reactive dienophile uti-

lized a modiﬁed Henry reaction of aldehyde 33 (Scheme 5) with

nitromethane at room temperature in the presence of potassium

ﬂuoride [28]. A mixture of diastereomeric alcohols 34 (dr 2:1) was

isolated in 84% yield, and elimination readily produced 35 upon

treatment with methanesulfonyl chloride and Et₃N at 0 ^ꢁC. Triene

35 was not stable at 22 ^ꢁC. We found that traces of acid in chloro-

form solutions of this material slowly produced the DielseAlder

products as well as other unidentiﬁed substances. Based on this

observation, crude triene 35 was directly reﬂuxed in benzene under

argon in the presence of butylated hydroxytoluene (BHT) to yield

decalins 37 and 38 as a 10:1 mixture of diastereomers (56%). Sep-

aration by ﬂash chromatography, and 1-D as well as 2-D NMR an-

alyses of each cycloaddition product led to the determination of

relative stereochemistry via extensive NOESY correlations.

avoided the

a

-epimerization seen under E₂elimination conditions

For the trans-fused 37, the NOESY correlations of axial hydro-

gens at C-13, C-17, C-19 and C-21 (norzoanthamine numbering) are

observed (Fig. 5), whereas the bottom face of 37 indicates cross-

peaks for C-18, C-20, and the methyl substituent located at C-22.

Support for the minor isomer 38 is summarized by the observed

NOESY correlations (Fig. 5) that indicate crosspeaks for axial hy-

drogens at C-18, C-20, and the methyl substituent at C-22. Other

NOESY correlations indicate the cis-fused ring system such as the

NOESY crosspeak for vinylic hydrogen at C-14 with the axial

hydrogen at C-21. As expected, the major isomer 37 is the result of

the favored endo-transition state 36 in which the B-ring sub-

stituents are pseudoequatorial in a chair-like conformation of this

facile intramolecular process. The alternative exo-transition state

accounts for the formation of cis-fused 38 [16,29].

The Nef reaction was then explored for conversion of the trans-

fused decalin 37 to directly produce the conjugated enone of 39

(Scheme 6). We have previously described the use of dime-

thyldioxirane (DMDO) for a similar transformation [30]. However,

the application of these conditions in the case of 37 led to low yields

and extensive decomposition. Ultimately, trans-2-(phenylsulfonyl)-

3-phenyloxaziridene [31] was found to be a very effective oxidant

for treatment of the potassium nitronate of 37, and warming to 0 ^ꢁC

prior to quenching, also resulted in the C]C isomerization to

exclusively afford the enone (83%). In tandem with the high endo

to afford diene 26 via the alcohol 24 by conversions to standard

leaving groups. The aldehyde 30 was obtained in two additional

steps using a high yielding DIBAL reduction and DesseMartin

oxidation sequence. The introduction of the desired C-20 stereo-

chemistry of 32 could not be achieved with a FelkineAnh prefer-

ence via nucleophilic addition to the carbonyl of 30 because of the

steric interactions imposed by the alkyl substituents of a-and b-

substitution. For example, a number of asymmetric acetate aldol

methods were attempted in conjunction with aldehyde 30. The

Nagao tin enolate methodology [22] and the titanium enolate

described by Villarasa [23] failed to form detectable quantities of

aldol adducts, and decomposition of 30 was observed upon

warming. The Braun methodology [24] gave 75% yield of aldol

adducts with low (3:2 dr) selectivity, whereas the lithium enolate

of methylacetate quantitively reacted with 30 in an unselective

manner (1:1 dr). As an alternative, we also explored the Brown

asymmetric allylation [25] of aldehyde 30. Reactions with either

(þ)-Ipc₂or (ꢀ)-Ipc₂allyl species resulted in 35%e50% yields of

homoallylic alcohols with low (3:2 dr) selectivity. Attempted

asymmetric allylations using nonracemic B-allyl-1,3-bis[(4-

methylphenyl)sulfonyl]-4,5-diphenyl-1,3,2-diazaborolidines [26]

led to the recovery of starting 30. After an examination of these

methods, the adoption of the Duthaler procedure [27] using tita-

nium enolate 31 afforded alcohol 32 as a single diastereomer

(dr > 19:1) in 70% yield over two steps from 29. While a detailed

analysis of asymmetric induction in this reaction is difﬁcult, our

modeling has suggested that access to boat-like transition states

selectivity of the [4

p

þ2

p] reaction of nitroalkenes, this two-step

process provided an effective and general strategy for the synthe-

sis of substituted trans-fused enones. This pathway was advanced

to complete the trans-fused ABC ring system of norzoanthamine as

documented in Scheme 6. Luche reduction [32] of 39 proceeded to

yield a single diastereomer. The equatorial alcohol was assigned by

may be essential for high stereoselectivity in

dehydes [16]. Exposure of 32 to an excess of methyl chloromethyl

a,b,b

⁰-branched al-

Fig. 4. Transition state analyses of IrelandeClaisen processes.

4

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

Scheme 4. Preparation of diene 33.

Scheme 5. Formation of IMDA products.

Fig. 5. Key NOESY correlations for structures 37 and 38.

5

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

Scheme 6. Synthesis of the ABC tricycle 42 of norzoanthamine.

the large (J ¼ 9.1 Hz) vicinal coupling of the axial hydrogen

appearing at 3.54, and was protected as its TBS silyl ether prior to

and ethyl acetate for chromatography were distilled prior to use.

Tetrahydrofuran (THF), dimethylformamide (DMF), toluene,

acetonitrile (AcCN), diethyl ether (Et₂O) and dichloromethane

(DCM) were obtained anhydrous by degassing with argon and then

passing through activated alumina columns to remove water.

d

exposure to Birch reduction conditions yielding the primary alcohol

40 (88%). Upon Swern oxidation, the resulting aldehyde 41 was

treated with vinylmagnesium bromide followed by a Ley oxidation

(TPAP, NMO) [33] to yield the enone of 42 (71% over 2 steps), and

the synthesis of the trans-fused ABC tricycle 44 was ﬁnalized by a

ring-closing metathesis (RCM) using the Grubbs II catalyst (43)

under standard conditions [34].

Triethylamine

(Et₃N),

1,3-dimethyl-3,4,5,6-tetrahydro-2-

pyrimidinone (DMPU), and diisopropylethylamine (DIPEA) were

distilled from CaH₂under dry argon immediately before use.

Commercial reagents were used as obtained unless otherwise

speciﬁed. Air-sensitive reagents were handled inside a glovebox.

Reactions were monitored by standard thin-layer chromatography

(tlc) techniques using EMD silica gel 60 F254 pre-coated plates

(0.25 mm thickness). Following the run, tlc plates were visualized

under UV light and/or by appropriate stains (p-anisaldehyde or

ceric ammonium nitrate or potassium permanganate). Flash col-

umn chromatography was performed with Silica-P Flash Silica Gel

3. Conclusion

In conclusion, an enantiocontrolled synthesis of the trans-fused

ABC ring system of zoanthamine has been described. Our study has

explored the diastereoselectivity for IrelandeClaisen [3,3]-

rearrangements of mixtures of

a,b- and b,g-unsaturated esters

(ultra-pure 40e63 mm) from Silicycle Chemical Division (Quebec

QC, Canada).

derived from 3-methyl-2-butenoic acid. Substituent effects play a

signiﬁcant role in determining chair versus boat-like transition

states, and the inclusion of DMPU improves the stereoselectivity of

the reaction. The [3,3]-transposition has established critical vicinal

stereochemistry, including asymmetry of a quaternary carbon. The

transformations to afford the nitroalkene, designed for an intra-

molecular DielseAlder cycloaddition, have featured the asym-

metric Duthaler condensation as the preferred method to install C-

Proton nuclear magnetic resonance (¹H NMR) spectra were

recorded on Varian VXR 400 (400 MHz), Varian INOVA 400

(400 MHz) or Varian 500 (500 MHz) instruments. Carbon nuclear

magnetic resonance (¹³C NMR) spectra were measured using Var-

ian VXR 400 (101 MHz), Varian INOVA 400 (101 MHz) or Varian 500

(125 MHz) instruments. NMR coupling constants and signal pat-

terns are reported as J values in Hz and d values in parts per million

(ppm). ¹H and ¹³C NMR spectra are internally referenced to residual

solvent signals (CDCl₃referenced to d 7.26 and 77.16 ppm respec-

tively). The following abbreviations were used to indicate the

multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multi-

plet. High resolution mass measurements (HRMS) were obtained

on Thermo Electron Corporation MAT 95XP (EI/CI) or Agilent 1200

HPLC-6130 MSD (ESI). Optical rotation data were obtained on Per-

kin Elmer Model S-3 343 polarimeter and are reported in terms of

degree of rotation of plane-polarized light. IR spectra were recor-

ded on a FTIR spectrometer and are reported in terms of frequency

of absorption (cm^ꢀ1).

20 stereochemistry. Subsequently the [4

p

þ2

p] reaction has proven

to be an endo-selective event, and our modiﬁcation of the Nef re-

action has provided an effective preparation of trans-fused 2-

cyclohexen-1-ones. Overall, this synthetic sequence has intro-

duced ﬁve contiguous chiral carbon centers within the cyclohexane

ring, and ring-closing metathesis has led to the trans-fused tricycic

ABC system of norzoanthamine.

4. Experimental section

4.1. General information

Common commercial reagents that are described with lettered

abbreviations include 4-dimethylaminopyridine (DMAP), dime-

thylformamide (DMF), t-butyldimethylsilyl chloride (TBSCl), t-

butyldiphenylsilyl chloride (TBDPSCl), trimethylsilyl chloride

(TMSCl), tert-butylammonium ﬂuoride (TBAF), methoxymethyl

chloride (MOMCl), pyridinium chlorochromate (PCC), butylated

Unless otherwise noted, all reactions were performed in ﬂame-

dried or oven-dried glassware under argon atmosphere. All non-

volatile samples were pumped to constant weight at ambient

temperature (0.2e0.1 mmHg) following removal of solvents by

rotary evaporation. Non-aqueous reagents were transferred using

syringe techniques under argon atmosphere. Bulk grade hexanes

6

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

hydroxytoluene (BHT), 1-ethyl-3-(3-dimethylaminopropyl)carbo-

diimide (EDCI), and 2-iodoxybenzoic acid (IBX).

2920, 1719, 1641, 1202, 1080 cm^ꢀ1; ¹H NMR (400 MHz CDCl₃)

d 5.98

(dd, J ¼ 17.6, 10.8 Hz, 1H), 5.17e5.07 (m, 2H), 5.04 (s, 1H), 4.84 (s,

1H), 4.52e4.38 (m, 2H), 3.04 (s, 1H), 2.02 (ddd, J ¼ 13.2, 6.6, 6.6 Hz,

1H), 1.82e1.74 (m, 4H), 1.22 (s 3H); ¹³C NMR (101 MHz, CDCl₃)

4.1.1. Preparation of allylstannane (6)

ⁿBu₃SnH (1.27 mL, 4.70 mmol) was dissolved in THF (11.0 mL),

cooled to 0 ^ꢁC and then freshly prepared LDA (1.0 M in THF, 4.70 mL,

4.70 mmol) was added to it. The light yellow solution was stirred

for 30 min at 0 ^ꢁC, cooled to ꢀ78 ^ꢁC and aldehyde 4 (1.00 g,

4.27 mmol) was added as a precooled (ꢀ78 ^ꢁC) solution in THF

(3.0 mL) via cannula. The mixture was stirred for 1 h and then a

precooled (ꢀ78 ^ꢁC) solution of 3-methyl-prop-2-enoic acid anhy-

dride 5 (700 mg, 3.84 mmol) in THF (3.0 mL) was added via cannula.

After stirring for 1 h, analysis by tlc revealed the consumption of the

anhydride. The reaction was quenched with saturated aq. NH₄Cl

(10 mL), warmed to room temperature, diluted with water (20 mL)

and then extracted with Et₂O (2 ꢂ 50 mL). The combined Et₂O

extracts were dried (MgSO₄), ﬁltered, concentrated, and puriﬁed

via ﬂash silica gel chromatography (gradient elution of 1.5e2.5%

EtOAc/hexanes) to yield 2.03 g (87%) of 6 as a clear oil which was

characterized as follows: R_f¼ 0.70 (25% EtOAc/hexanes); IR (neat)

2955, 2925, 2853, 1692, 1641, 1513, 1248, 1233, 1034 cm^ꢀ1; ¹H NMR

d 171.3, 142.1, 140.5, 117.7, 113.9, 66.1, 60.2, 38.9, 34.0, 25.1, 22.8;

HRMS m/z calcd for C₁₁H₁₆O₂(M)^þ180.1145, found 180.1142.

4.1.4. (R)-4-benzyl-3-((2R,3S,E)-3-hydroxy-7-((4-methoxybenzyl)

oxy)-2,5-dimethylhept-4- enoyl)oxazolidin-2-one (10)

To a 0 ^ꢁC solution of oxazolidinone 9 (0.625 g, 2.68 mmol) [1 1]

was added di-n-butylboron triﬂate (1 M solution in CH₂Cl₂,

2.93 mL, 2.93 mmol) dropwise followed by a slow addition of Et₃N

(0.44 mL, 3.17 mmol). The reaction was stirred at 0 ^ꢁC for 30 min

and cooled to ꢀ78 ^ꢁC. A solution of aldehyde 4 (0.540 g, 2.44 mmol)

in CH₂Cl₂(6 mL) was added slowly over 10 min. The reaction was

stirred at ꢀ78 ^ꢁC for 3 h, warmed to 0 ^ꢁC and quenched by

sequential dropwise addition of a 2:1 mixture of MeOH/pH 7.1 M

aqueous phosphate buffer (5 mL) and a 2:1 mixture of MeOH/30%

aqueous H₂O₂(5 mL). The mixture was stirred at 0 ^ꢁC for 30 min.

The layers were separated and the aqueous layer was extracted

with Et₂O (3 ꢂ 10 mL). The combined organic layers were dried

over MgSO₄, ﬁltered and concentrated. Puriﬁcation by ﬂash chro-

matography (gradient elution of 10e50% EtOAc/hexanes) gave

(400 MHz, CDCl₃)

d

7.24 (d, J ¼ 8.4 Hz, 2H), 6.87 (d, J ¼ 8.4 Hz, 2H),

5.66 (s, 1H), 5.57 (A of AB, J_AB¼ 10.4 Hz, 1H), 5.55 (B of AB,

J_AB¼ 10.4 Hz, 1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.51 (t, J ¼ 7.4 Hz, 2H),

2.33, (m, 2H), 2.15 (s, 3H), 1.88 (s, 3H), 1.64 (s, 3H), 1.56e1.40 (m,

6H), 1.28 (sext, J ¼ 7.2 Hz, 6H), 0.88 (m, 15H); ¹³C NMR (101 MHz,

0.94 g (82%) of alcohol 10 as a viscous, colorless oil: R_f0.12 (3:1

21

hexanes/EtOAc); [

a]

ꢀ26.5 (c 0.75, CHCl₃); IR (neat) 3499, 2967,

D

2918, 1780, 1698, 1613, 1512, 1254, 1383, 1246, 1211, 1094, 1034, 912,

CDCl₃)

d

166.6, 149.1, 155.3, 130.6, 129.2, 128.0, 126.3, 116.2, 113.7,

824, 756, 704 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.35e7.17 (m, 7H),

72.5, 69.1, 55.2, 39.6, 30.6, 29.7, 29.0, 27.4, 20.1,17.0,13.7,10.0; HRMS

6.86 (d, J ¼ 8.2 Hz), 5.32 (d, J ¼ 7.8 Hz, 1H), 4.71e4.36 (m, 2H), 4.43

(s, 2H), 4.19e4.13 (m, 2H), 3.90e3.87 (m, 1H), 3.79 (s, 3H), 3.53 (t,

J ¼ 7.1, 2H), 3.23 (dd, J ¼ 13.6, 3.5 Hz, 1H), 2.78 (dd, J ¼ 13.3, 9.4 Hz,

1H), 2.51 (br s, 1H), 2.33 (apparent t, J ¼ 5.5, 2H), 1.71 (s, 3H), 1.29 (d,

J ¼ 7.1, 3H); ¹³C NMR (100 MHz, 69.1, 68.4, 66.1, 55.2, 55.1, 43.0, 39.6,

37.8, 17.1, 11.9; HRMS m/z calcd for C₂₇H₃₃NO₆(M þ Na)^þ490.2206,

found 490.2226.

m/z calcd for C₃₁H₅₂O₄Sn (M)^þ608.2888, found 608.2885.

4.1.2. Carboxylic acid (7)

Stannyl ester 6 (509 mg, 0.838 mmol) was dissolved in THF

(4.00 mL), cooled to ꢀ78 ^ꢁC and LDA (0.5 M in THF, 3.35 mL,

1.68 mL) was added dropwise. After stirring for 10 min TMSCl

(214 mL, 1.68 mmol) was added and the reaction was allowed to

warm to room temperature gradually. It was quenched with aq. pH

7 phosphate buffer (10.0 mL) and then the mixture was extracted

with Et₂O (2 ꢂ 25 mL). The ethereal layers were combined, dried

(MgSO₄), ﬁltered and concentrated. The crude material was puri-

ﬁed by ﬂash silica gel chromatography (gradient elution 5e30%

EtOAc/hexanes to provide 435 mg (86%) of acid 7 as a colorless oil

which was characterized as follows: R_f¼ 0.46 (25% EtOAc/hexanes);

4.1.5. (2S,3S,E)-7.4((4-methoxybenzyl)oxy)-2,5-dimethylhept-4-

ene-1,3-diol

To a solution of 10 (9.1 g, 19.5 mmol) and Et₂O (160 mL) was

added MeOH (3.9 mL, 97.3 mmol). The solution was cooled to 0 ^ꢁ

C

and stirred for 30 min LiBH₄(2.12 g, 97.3 mmol) was added in one

portion. The reaction was slowly allowed to warm to room tem-

perature and stirred for 2 h. The reaction was quenched by a careful

addition of saturated NH₄Cl (50 mL). The reaction mixture was

stirred at room temperature for 1 h. The layers were separated and

the aqueous layer was extracted with Et₂O (3 ꢂ 75 mL). Combined

organic extracts were dried over Na₂SO₄, ﬁltered and concentrated

to yield the crude diol for conversion to 11. The crude material was

used in the next reaction without additional puriﬁcation. A small

IR (neat) 3400, 3072, 2957, 1705 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

;

d

8.65 (br s, 1H), 7.24 (d, J ¼ 8.5 Hz, 2H), 6.87 (d, J ¼ 8.5 Hz, 2H), 6.18

(d, J ¼ 19.4, 1H), 5.93 (d, J ¼ 19.4, 1H), 5.00 (br s, 1H), 4.95 (br s, 1H),

4.41 (A of AB, J_AB¼ 11.6 Hz,1H), 4.38 (B of AB, J_AB¼ 11.6 Hz,1H), 3.80

(s, 3H), 3.50e3.36 (m, 2H), 3.09 (S, 1H), 2.00e1.88 (m, 1H),

1.86e1.70 (m, 4H),1.54e1.42 (m, 6H),1.36e1.20 (m, 6H),1.12 (s, 3H),

0.98e0.76 (m, 15H); ¹³C NMR (101 MHz, CDCl₃)

d

172.4, 149.1, 153.4,

amount of this diol was puriﬁed for characterization: R_f0.15 (1:1

21

139.9, 130.6, 129.2, 126.3,117.0, 113.7, 72.7, 67.2, 62.1, 55.2, 51.2, 43.9,

38.5, 29.1, 27.3, 23.9, 19.8, 13.7, 9.4; HRMS m/z calcd for C₂₇H₄₃O₄Sn

(M ꢀ C₄H₉)^þ551.2178, found 551.2184.

hexanes/EtOAc); [

a

]

þ3.2 (c 0.57, CHCl₃); IR (neat) 3386, 2933,

D

1613, 1514, 1463, 1362, 1302, 1248, 1175, 1090, 1034, 821, 704 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d

7.22 (d, J ¼ 8.6 Hz, 2H), 6.85 (d,

J ¼ 8.6 Hz, 2H), 5.36 (d, 8.9 Hz,1H), 4.46 (m, 1H), 4.41 (s, 2H), 3.78 (s,

3H), 3.66e3.60 (m, 1H), 3.57e3.49 (m, 3H), 2.45 (br s, 1H),

2.37e2.24 (m, 2H), 1.97 (br s, 1H), 1.93e1.87 (m, 1H), 1.67 (s, 3H),

4.1.3. (3R,4S)-4-methyl-3-(prop-1-en-2-yl)-4-vinyltetrahydro-2H-

pyran-2-one (8)

To carboxylic acid 7 (25 mg, 41

mmol) in CH₂Cl₂(2.0 mL) was

0.87 (d, J ¼ 6.7 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 159.2, 136.4,

added tert-butanol (0.20 mL), aq. phosphate pH 7 buffer (1.0 mL)

and 2,3-dichloro-5,6-dicyanoquinone (37 mg, 0.17 mmol) in that

order. The red reaction mixture was stirred for 10 h and then

quenched with saturated aq. NaHCO₃(2.0 mL). The mixture was

extracted with Et₂O (2 ꢂ 10 mL), the ethereal layers were com-

bined, dried (MgSO₄), ﬁltered, and concentrated. Puriﬁcation by

ﬂash silica gel chromatography (gradient elution of 5e10% EtOAc in

hexanes) provided 4.0 mg (54%) of 8 as a white solid which was

characterized as followed: R_f¼ 0.30 (10% EtOAc/hexanes; IR (neat)

130.3, 129.3, 126.8, 113.8, 72.5, 71.9, 68.0, 66.2, 55.3, 40.9, 39.7, 16.8,

12.2; HRMS m/z calcd for C₃₃H₄₄O₄Si (M þ Na)^þ317.1729, found

317.1739.

4.1.6. (2S,3S,E)-1-((tert-butyldiphenylsilyl)oxy)-7-((4-

methoxybenzyl)oxy)-2,5-dimethylhept-4-en-3-ol (11)

To a solution of DMAP (0.542 g, 4.44 mmol), Et₃N (12.4 mL,

88.76 mmol) and the crude diol (13 g, 44.4 mmol) from 10 in CH₂Cl₂

(220 mL) was added TBDPSCl (12.7 mL, 48.8 mmol). The reaction

7

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

was stirred at room temperature for 48 h. Saturated aqueous NH₄Cl

(200 mL) was added, the layers were separated and aqueous layer

was extracted with Et₂O (3 ꢂ 150 mL). The combined organic layers

were dried over MgSO₄, ﬁltered and concentrated. Flash chroma-

tography gave the desired, pure silyl ether 11 (14.22 g, 78% over 2

stirred overnight. The reaction mixture was poured into H₂O

(50 mL), the layers were separated and the aqueous layer was

extracted with CH₂Cl₂(3 ꢂ 10 mL). The combined organic layers

were dried over MgSO₄and concentrated. The crude product was

puriﬁed by ﬂash chromatography (gradient elution of 5e30% EtOAc

in Hexanes) to yield 18.20 g (89%) of an inseparable 3:1 mixture of

oleﬁn isomers 12 and 13: R_f0.73 (3:1 Hexanes/EtOAc); IR (neat)

3071, 3048, 2933, 2857, 1716, 1651, 1613, 1513, 1463, 1428, 1380,

1360, 1302, 1247, 1172, 1148, 1109, 1036, 1008, 999, 924, 850, 823,

steps based on recovered diol) and starting diol (2.33 g, 18%):

21

Characterization of 11: R_f0.51 (4:1 Hexanes/EtOAc); [

a

]

D

þ4.4 (c

0.86, CHCl₃); IR (neat) 3445, 3071, 3048, 2958, 2931, 2857, 1613,

1588, 1531, 1463, 1389, 1361, 1302, 1248, 1173, 1112, 1036, 1007, 823,

741, 703, 613 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.69e7.65 (m, 4H),

741, 704, 691, 614 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d 7.67e7.63 (m,

7.46e7.37 (m, 6H), 7.24 (d, J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H),

5.33 (d, J ¼ 9.0 Hz, 1H), 4.58e4.53 (m, 1H), 4.42 (s, 2H), 3.79 (s, 3H),

3.66e3.64 (m, 2H), 3.52 (t, J ¼ 7.1 Hz, 2H), 2.63 (br s, 1H), 2.38e2.28

(m, 2H), 1.93e1.87 (m, 1H), 1.68 (s, 3H), 1.06 (s, 9H), 0.87 (d,

d 159.1, 135.63, 135.55,

135.5, 133.2, 130.5, 129.8, 129.7, 129.2, 127.7, 127.2, 113.7, 72.5, 70.7,

4H), 7.44e7.32 (m, 6H), 7.24 (d, J ¼ 8.6 Hz, 2H), 6.88e6.85 (m, 2H),

5.70 (dd, J ¼ 9.0, 5.8 Hz), 5.64 (s, 0.75H), 5.19e5.15 (m, 1H), 4.87 (s,

0.25H), 4.81 (s, 0.25H), 4.40 (s, 2H), 3.80 (s, 3H), 3.62e3.45 (m, 4H),

2.96 (s, 0.5H), 2.30 (app t, J ¼ 5.1 Hz), 2.14 (s, 2.25H),1.89 (s, 3H),1.77

(s, 3H), 1.06 (s, 9H), 0.97 (d, J ¼ 6.6 Hz); ¹³C NMR (125 MHz, CDCl₃)

J ¼ 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 170.5, 165.9, 159.1, 155.7, 138.8, 137.8, 137.0, 135.6, 135.5, 133.82,

68.8, 67.3, 55.2, 40.8, 39.7, 26.9, 19.1, 17.0, 11.5; HRMS m/z calcd for

C

133.76, 133.62, 133.58, 130.6, 130.5, 129.6, 129.52, 129.48, 129.1,

127.6, 127.5, 124.2, 123.6, 116.6, 114.4, 113.7, 72.5, 72.1, 70.8, 68.65,

68.58, 65.2, 65.1, 55.2, 43.7, 40.6, 40.5, 39.7, 27.3, 27.0, 26.8, 22.4,

20.2, 19.2, 17.2, 17.1, 12.2, 12.1; HRMS m/z calcd for C₃₃H₄₄O₄Si

(M þ Na)^þ637.3325, found 637.3326.

₃₃H₄₄O₄Si (M þ Na)^þ555.2906, found 555.2906.

4.1.7. General procedure for the formation of C14 Mosher esters of

alcohol 11

4.1.9. (2R,3S,6R,E)-7-((tert-butyldiphenylsilyl)oxy)-3-(2-((4-

methoxybenzyl)oxy)ethyl)-3,6-dimethyl-2-(prop-1-en-2-yl)hept-4-

enoic acid (14)

To

0.0132 mmol) in CH₂Cl₂was added EDCI (0.0094 g, 0.0489 mmol),

DMAP (0.0045 g, 0.0367 mmol) and (S)-(ꢀ)- -methoxy- -tri-

a room temperature solution of alcohol 11 (0.0054,

a

To a 0 ^ꢁC solution of diisopropylamine (1.57 mL, 11.22 mmol) in

THF (11 mL) was added n-BuLi (3.0 mL, 2.5 M in hexanes). The

mixture was stirred for 10 min at 0 ^ꢁC and cooled to ꢀ78 ^ꢁC. DMPU

(5.5 mL) was added and the mixture was stirred for 10 min. To this

mixture was added a solution of esters 12 and 13 (2.3 g, 3.74 mmol)

in THF (7 mL). The reaction was stirred for 5 min and freshly

distilled TMSCl (1.42 mL, 11.22 mmol) was added. The cooled bath

was removed and the mixture was allowed to stir at room tem-

perature overnight. Saturated aqueous NH₄Cl (30 mL) was added,

the layers were separated and the aqueous layer was extracted 3x

with EtOAc (15 mL). The combined organic layers were dried over

MgSO₄, ﬁltered and concentrated. The crude acid 14 was used in the

next step without further puriﬁcation. A small amount of 14 was

puriﬁed for characterization: R_f0.19 (3:1 hexanes/EtOAc);

ﬂuoromethylphenylacetic acid (S-MTPA) (0.0086 g, 0.0367 mmol).

The mixture was stirred overnight and diluted with water. The

layers were separated and the aqueous layer was extracted with

CH₂Cl₂(3 ꢂ 1 mL). The combined organic layers were dried over

MgSO₄, ﬁltered and concentrated. The crude oil was puriﬁed by

ﬂash chromatography (2 mL silica gel, 5% EtOAc/hexanes) to yield

the (S)-MTPA of 11 (0.0075 g, 91%). In a separate ﬂask the same

procedure was employed utilizing (R)-(ꢀ)-

a-methoxy-a-tri-

ﬂuoromethylphenylacetic acid to yield the (R)-MTPA of 11

(0.0051 g, 83%). The analysis [12b] is described using selected

proton shifts as listed below.

(R)-MTPA ester of 11: ¹H NMR (400 MHz, CDCl₃)

d 5.27 (d,

J ¼ 9.8 Hz, 1H, H(c)), 3.39 (d, J ¼ 5.5 Hz, 2H, H(a)), 2.34 (d, J ¼ 6.8 Hz,

2H, H(d)), 0.88 (d, J ¼ 6.3 Hz, 3H, H(b)).

[

a

]

²¹þ12.9 (c. 0.94, CHCl₃); IR (neat) 3340, 3070, 2931, 2857, 1705,

(S)-MTPA ester of 11: ¹H NMR (400 MHz, CDCl₃)

d 5.11 (d,

D

1613, 1513, 1463, 1383, 1362, 1302, 1248, 1173, 1112, 1037, 823, 741,

J ¼ 9.4 Hz, 1H, H(c)), 3.46 (d, J ¼ 5.9, Hz, 2H, H(a)), 2.32 (t, J ¼ 6.8 Hz,

703, 614 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

; d 7.69e7.66 (m, 4H),

2H, H(d)), 0.94 (d, J ¼ 6.6 Hz, 3H, H(b)).

7.44e7.36 (m, 6H), 7.20 (d, J ¼ 8.6 Hz, 2H), 6.84 (d, J ¼ 8.6 Hz, 2H),

5.73 (d, J ¼ 16 Hz, 1H), 5.32 (dd, J ¼ 16.0, 7.8 Hz, 1H), 5.00 (s, 1H),

4.95 (s, 1H), 4.30 (ABq, J_AB¼ 11.3 Hz, Dn_AB¼ 11.3 Hz, 2H), 3.78 (s,

3H), 3.56e3.35 (m, 4H), 3.04 (s, 1H), 2.45e2.38 (m, 1H), 1.94e1.86

(m, 1H), 1.82 (s, 3H), 1.79e1.70 (m, 1H), 1.10 (s, 3H), 1.07 (s, 9H), 1.00

(d, J ¼ 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 172.7, 159.1, 139.6,

135.6, 134.8, 133.9, 132.2, 130.4, 129.5, 129.3, 127.6, 117.4, 113.7, 72.6,

68.9, 67.0, 62.3, 55.2, 40.6, 39.7, 39.0, 26.9, 23.8, 20.8, 19.3, 16.9;

HRMS m/z calcd for C₃₈H₅₀O₅Si (M þ Na)^þ637.3325, found

637.3354.

Proton

d_S(ppm)

d_R(ppm)

d_Sed_R(ppm)

a

b

c

3.46

0.94

5.11

2.32

3.39

0.88

5.27

2.34

þ0.07

þ0.06

ꢀ0.16

ꢀ0.02

d

4.1.10. (3R,4R)-4-((R,E)-4-((tert-butyldiphenylsilyl)oxy)-3-

methylbut-1-en-1-yl)-4-methyl-3-(prop-1-en-2-yl)tetrahydro-2H-

pyran-2-one (16)

4.1.8. (2S,3S,E)-1-((tert-butyldiphenylsilyl)oxy)-7-((4-

To a room temperature solution of acid 14 (0.034 g, 0.055 mmol)

in CH₂Cl₂(2 mL) was added DDQ (0.063 g, 0.276 mmol) in one

portion. The mixture was stirred overnight and saturated NH₄Cl

(2 mL) was added. The layers were separated and the organic layer

was extracted with Et₂O (3 ꢂ 2 mL). The combined organic layers

were dried over Na₂SO₄, ﬁltered and concentrated. The crude oil

was puriﬁed by ﬂash chromatography (1 mL basic alumina, 5%

EtOAc/Hexanes) to yield lactone 16 (0.014 g, 56%) as a colorless oil:

R_f0.39 (3:1 hexanes/EtOAc); IR (neat) 3017, 2955, 2860, 1733,

methoxybenzyl)oxy)-2,5-dimethylhept-4-en-3-yl3-methylbut-2-

enoate (12) and (2S,3S,E)-1-((tert-butyldiphenylsilyl)oxy)-7-((4-

methoxybenzyl)oxy)-2,5-dimethylhept-4-en-3-yl 3-methylbut-3-

enoate (13)

DMAP (6.10 g, 49.89 mmol), EDCI (7.66 g, 39.91 mmol) and 3,3-

dimethylacrylic acid (3.66 g, 36.58 mmol) were dissolved in CH₂Cl₂

(18 mL) and stirred at room temperature for 15 min. A solution of

alcohol 11 (17.72 g, 33.26 mmol) in CH₂Cl₂(17 mL) was added and

8

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

1613 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d

7.66e7.63 (m, 4H),

1.86e1.80 (m, 1H), 1.72 (s, 3H), 1.07 (s, 9H), 1.01 (d, J ¼ 7.0 Hz, 3H);

7.45e7.35 (m, 6H), 5.58 (d, J ¼ 8.6 Hz, 1H), 5.45 (dd, J ¼ 16.0, 7.4 Hz,

1H), 5.00 (t, J ¼ 1.6 Hz, 1H), 4.80 (s, 1H), 4.43e4.34 (m, 2H), 3.50 (d,

J ¼ 6.6 Hz, 2H), 2.99 (s, 1H), 2.43e2.35 (m, 1H), 1.95e1.86 (m, 1H),

1.79e1.74 (m, 1H), 1.73 (s, 3H), 1.18 (s, 3H), 1.04 (s, 9H), 0.99 (d,

J ¼ 6.7 Hz, 3H); HRMS m/z calcd for C₃₀H₄₀O₃Si (M þ Na)^þ499.2644,

found 499.2631.

¹³C NMR (125 MHz, CDCl₃)

d 159.3, 136.1, 135.8, 135.7, 133.7, 133.6,

130.1, 129.8, 129.7, 129.5, 129.5, 127.8, 127.8, 113.9, 72.8, 69.1, 67.3,

66.9, 55.4, 41.0, 32.9, 27.0, 24.8, 23.7, 19.4, 12.3; HRMS m/z calcd for

C

₃₃H₄₃O₃Si (M^þꢀ OH) 515.2983, found 515.2979.

4.1.12. (2R,3R,Z)-1-((tert-butyldiphenylsilyl)oxy)-7-((4-

methoxybenzyl)oxy)-2,5-dimethylhept-4-en-3-yl-3-methylbut-2-

enoate (18) and (2R,3R,Z)-1-((tert-butyldiphenylsilyl)oxy)-7-((4-

methoxybenzyl)oxy)-2,5-dimethylhept-4-en-3-yl-3-methylbut-3-

enoate (19)

4.1.11. (2R,3R,Z)-1-((tert-butyldiphenylsilyl)oxy)-7-((4-

methoxybenzyl)oxy)-2,5-dimethylhept-4-en-3-ol (17)

The preparation of the mixture of nonracemic esters 18 and 19

followed the same sequence of reactions as described for 12 and 13.

Details and full characterizations of the starting alcohol 17 is

included here.

To a solution of DMAP (1.03 g, 8.42 mmol), and EDCI (1.29 g,

6.73 mmol) in CH₂Cl₂(3 mL) was added 3,3-dimethylacrylic acid

(0.62 g, 6.17 mmol) and the mixture was stirred at room temper-

ature for 15 min. A solution of the previously prepared secondary

alcohol 17 (2.99 g, 5.61 mmol) in CH₂Cl₂(2 mL) was added, and the

mixture was stirred overnight. The reaction mixture was poured

into H₂O (20 mL), the layers were separated and the aqueous layer

was extracted with CH₂Cl₂(3 ꢂ 20 mL)). The combined organic

layers were dried over MgSO₄and concentrated. The crude product

was puriﬁed by ﬂash chromatography (gradient elution of 5e30%

EtOAc in Hexanes) to yield an inseparable mixture of 18 and 19

(3.17 g, 92%) as a colorless oil: R_f0.78 (3:1 Hexanes/EtOAc); IR (neat)

3070, 3049, 2932, 2857, 1715, 1651, 1613, 1588, 1513, 1463, 1588,

1513, 1463, 1428, 1378, 1361, 1302, 1248, 1228, 1172, 1149, 1112, 1037,

1008, 981, 849, 823, 741, 703, 612 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

To a 0 ^ꢁC solution of (S)-4-benzyl-3-propionyloxazolidin-2-

one¹¹(2.4 g, 10.2 mmol) in CH₂Cl₂(33 mL) was added di-n-butyl-

boron triﬂate (1 M solution in CH₂Cl₂, 12.0 mL, 12.0 mmol) drop-

wise followed by a slow addition of Et₃N (2.4 mL, 17.1 mmol). The

reaction was stirred at 0 ^ꢁC for 30 min and cooled to ꢀ78 ^ꢁC. A

solution of (Z)-5-((4-methoxybenzyl)oxy)-3-methylpent-2-enal

(2.00 g, 8.54 mmol in CH₂Cl₂(17 mL) was added slowly over

10 min. The reaction was stirred at ꢀ78 ^ꢁC for 2 h, warmed to 0 ^ꢁC

and quenched by sequential addition of 2:1 MeOH/pH 7.1 M

aqueous phosphate buffer (15 mL) and 2:1 MeOH/30% aqueous

H₂O₂(15 mL). The mixture was stirred at 0 ^ꢁC for 30 min. The layers

were separated and the aqueous layer was extracted with Et₂O

(3 ꢂ 30 mL). The combined organic layers were dried over MgSO₄,

ﬁltered and concentrated. Puriﬁcation by ﬂash chromatography

(10e50% EtOAc/hexanes) gave 3.91 g (98%) of the desired aldol

adduct as a viscous, colorless oil: R_f0.16 (3:1 Hexanes/EtOAc); IR

(neat) 3449, 2967, 2918, 2864, 1780, 1698, 1613, 1512, 1454, 1383,

1246, 1211, 1094, 1034, 912, 824, 756, 704 cm^ꢀ1; ¹H NMR (400 MHz,

d

7.74e7.64 (m, 4H), 7.44e7.33 (m, 6H), 7.25e7.22 (m, 2H), 6.85 (d,

J ¼ 8.6 Hz, 2H), 5.74e5.70 (m, 1H), 5.63 (br s, 0.75H), 5.26e5.23 (m,

1H), 4.87 (s, 0.25H), 4.81 (s, 0.25H), 4.41e4.40 (m, 2H), 3.80 (s, 3H),

3.64e3.47 (m, 4H), 2.96 (s, 0.5H), 2.63e2.53 (m, 1H), 2.50e2.44 (m,

1H), 2.15 (s, 2.25H), 1.89 (s, 3H), 1.75 (s, 3H), 1.06 (s, 9H), 0.91e0.90

(m, 3H); ¹³C NMR (125 MHz, CDCl₃)

d 170.4, 165.8, 159.0, 155.5,

CDCl₃)

d

7.45e7.18 (m, 7H), 6.90 (d, J ¼ 8.6 Hz, 2H), 5.54 (d,

138.7, 138.2 137.6, 135.6, 135.54, 135.51, 134.8, 133.8, 133.6, 130.7,

129.6, 129.51, 129.46, 129.1, 127.64, 127.56, 127.52, 124.5, 123.9,

116.6, 114.4, 113.6, 72.30, 72.27, 70.3, 68.62, 68.57, 65.3, 55.2, 43.7,

40.78, 40.74, 32.71, 32.68, 27.3, 26.8, 26.5, 24.11, 24.09, 22.45, 20.2,

19.3, 12.0, 11.8; HRMS m/z calcd for C₃₈H₅₀O₅Si (M^þ) 613.3344,

found 613.3349.

J ¼ 8.2 Hz, 1H), 4.77e4.59 (m, 2H), 4.49e4.30 (ABq, J_AB¼ 11.9 Hz,

Dn_AB¼ 7.7 Hz, 2H), 4.26e4.13 (m, 2H), 3.98 (m, 1H), 3.83 (s, 3H),

3.65e3.42 (m, 2H), 3.37e3.17 (m, 2H), 2.81 (dd, J ¼ 9.6, 13.5 Hz, 1H),

2.73e2.62 (m, 1H), 2.22 (td, J ¼ 4.9, 13.7 Hz, 1H), 1.76 (s, 3H), 1.35 (d,

J ¼ 6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 176.0, 159.1, 153.0,

137.3, 135.2, 129.8, 129.4, 129.2, 128.8, 127.5, 127.2, 113.7, 72.6, 68.1,

66.9, 65.9, 55.2, 55.1, 42.7, 37.7, 32.7, 23.4, 12.4; HRMS m/z calcd for

C

4.1.13. (2S,3S,6S,E)-7-((tert-butyldiphenylsilyl)oxy)-3-(2-((4-

methoxybenzyl)oxy)ethyl)-3,6-dimethyl-2-(prop-1-en-2-yl)hept-4-

enoic acid (20)

₂₇H₃₄NO₆(M^þ) 468.2386, found 468.2389.

To a solution of the aldol adduct (4.0 g, 8.56 mmol) in Et₂O

(70 mL) was added MeOH (1.0 mL, 25.7 mmol). The solution was

cooled to 0 ^ꢁC and stirred for 30 min LiBH₄(0.056 g, 25.7 mmol) was

added in one portion. The reaction was slowly allowed to warm to

room temperature with stirring overnight. The reaction was

quenched by addition of saturated NH₄Cl (50 mL), and the mixture

was stirred at room temperature for 1 h. The layers were separated

and the aqueous layer was extracted with Et₂O (3 ꢂ 50 mL), and

combined organic extracts were dried over Na₂SO₄, ﬁltered and

concentrated. The crude material was diluted in CH₂Cl₂(43 mL) and

Et₃N (2.4 mL, 17.1 mmol), DMAP (0.10 g, 0.856 mmol) and TBDPSCl

(2.89 mL, 11.1 mmol) was added. The mixture was stirred at room

temperature for 24 h and saturated NH₄Cl (40 mL) was added. The

layers were separated and the aqueous layer was extracted with

CH₂Cl₂(3 ꢂ 40 mL). The combined organic layers were dried over

Na₂SO₄, ﬁltered and concentrated. The crude oil was puriﬁed by

ﬂash chromatography to yield the desired secondary alcohol 17 as a

pure diastereomer (2.99 g, 65% for 2 steps): R_f0.54 (4:1 Hexanes/

EtOAc); IR (neat) 3480, 2959, 2861, 1613, 1514, 1468, 1248, 1109,

To a ꢀ78 ^ꢁC solution of diisopropylamine (1.64 mL) in THF

(12 mL) was added n-BuLi (2.5 M in hexanes, 3.1 mL). The mixture

was warmed to 0 ^ꢁC for 30 min and cooled to ꢀ78 ^ꢁC. A 3:1 mixture

of esters 18 and 19 (2.4 g, 3.90 mmol) was slowly added as a so-

lution in THF (8 mL) at stirred at ꢀ78 ^ꢁC for 1 h. Freshly distilled

TMSCl was added and the mixture was stirred for 1 h at ꢀ78 ^ꢁC. The

cooling bath was removed and the mixture was allowed to warm to

room temperature and then reﬂuxed overnight. The mixture was

cooled to room temperature and saturated NH₄Cl was added. The

layers were separated and the organic layer was extracted with

Et₂O (3 ꢂ 20 mL). The combined organic layers were dried over

Na₂SO₄, ﬁltered and concentrated. The crude oil was puriﬁed by

ﬂash chromatography (300 mL silica gel, 2e30% EtOAc/Hexanes) to

yield acid 20 (2.01 g, 84%) from a 6:1 mixture of diastereomers. For

21

full characterization of 20: R_f0.22 (3:1 hexanes/EtOAc); [

a]

ꢀ8.1

D

(c. 1.34, CHCl₃); IR (neat) 3400, 3071, 2957, 2931, 2858, 1706, 1613,

1514, 1463, 1428, 1385, 1363, 1302, 1248, 1208, 1173, 1112, 1037, 824,

741, 703, 614 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d 7.68e7.65 (m, 4H),

1036, 824, 704, cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.5e7.84 (m, 4H),

7.44e7.36 (m, 6H), 7.22 (d, J ¼ 8.5 Hz, 2H), 6.85 (d, J ¼ 8.6 Hz, 2H),

5.46 (d, J ¼ 16.0 Hz, 1H), 5.32 (dd, J ¼ 16.0, 7.0 Hz, 1H), 4.95 (s, 1H),

4.93 (s, 1H), 4.36 (s, 2H), 3.79 (s, 3H), 3.54 (dd, J ¼ 9.8, 5.9 Hz, 1H),

3.47e3.41 (m, 3H), 3.02 (s, 1H), 2.43e2.33 (m, 1H), 1.94e1.77 (m,

7.32e7.53 (m, 6H), 7.24 (d, J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H),

5.46 (d, J ¼ 8.6 Hz, 1H), 4.45 (s, 2H), 4.44e4.42 (m, 1H), 3.79 (s, 3H),

3.58e3.71 (m, 2H), 3.39e3.54 (m, 2H), 3.08 (d, J ¼ 2.0 Hz, 1H), 2.66

(ddd, J ¼ 13.7, 8.6, 6.2 Hz, 1H), 2.14 (dt, J ¼ 13.6, 4.9 Hz, 1H),

2H), 1.76 (s, 3H), 1.15 (s, 3H), 1.06 (s, 9H), 1.00 (d, J ¼ 7.0 Hz, 3H); ¹³

C

9

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

NMR (100 MHz, CDCl₃)

130.4, 129.5, 129.3, 127.6, 117.0, 113.8, 72.6, 68.8, 66.9, 61.4, 55.2,

d

177.0, 159.1, 139.6, 135.6, 135.1, 133.9,131.6,

4.93 (s,1H), 4.37 (s, 2H), 3.78 (s, 3H), 3.58 (s, 3H), 3.50e3.40 (m, 3H),

3.32e3.27 (m, 1H), 3.02 (s, 1H), 2.34e2.29 (m, 2H), 1.80 (s, 3H),

1.78e1.71 (m, 2H), 1.08 (s, 3H), 0.93 (d, J ¼ 6.6 Hz, 3H); ¹³C NMR

40.6, 39.5, 38.3, 26.9, 24.5, 20.6, 19.3, 16.9; HRMS m/z calcd for

C

₃₈H₅₀O₅Si (M þ Na)^þ637.3325, found 637.3315.

(100 MHz, CDCl₃) d 172.6, 159.1, 139.5, 137.0, 131.2, 130.3, 129.3,

117.3, 113.7, 72.5, 67.3, 66.4, 62.0, 55.2, 51.3, 40.8, 40.2, 38.8, 24.0,

21.1, 16.3; HRMS m/z calcd for C₂₃H₃₄O₅(M þ Na)^þ413.2304, found

413.2308.

4.1.14. (3S,4S)-4-((S,E)-4-((tert-butyldiphenylsilyl)oxy)-3-

methylbut-1-en-1-yl)-4-methyl-3-(prop-1-en-2-yl)tetrahydro-2H-

pyran-2-one (21)

To a room temperature solution of carboxylic acid 20 (0.136 g,

0.221 mmol) in CH₂Cl₂(2 mL) was added DDQ (0.075 g,

0.332 mmol) in one portion. The mixture was stirred overnight and

saturated NH₄Cl (2 mL) was added. The layers were separated and

the organic layer was extracted with Et₂O (3 ꢂ 2 mL). The combined

organic layers were dried over Na₂SO₄, ﬁltered and concentrated.

The crude oil was ﬁltered through a plug of silica gel to yield lactone

21 (0.067 g, 65%) as a colorless oil: R_f0.39 (3:1 hexanes/EtOAc); IR

4.1.17. (2R,3S,6R,E)-methyl 3-(2-((4-methoxybenzyl)oxy)ethyl)-3,6-

dimethyl-7-((2-nitrophenyl)selenyl)-2-(prop-1-en-2-yl)hept-4-

enoate (27)

To a 0 ^ꢁC solution of alcohol 26 (0.209 g, 0.536 mmol) and o-

nitrophenyl selenocyanate (0.158 g, 0.697 mmol) in THF (5 mL) was

added tributylphosphine (0.201 mL, 0.805 mmol). The cooling bath

was removed and the mixture was stirred at room temperature for

4 h. The reaction was quenched with 5% Na₂CO₃(5 mL). The layers

were separated and the aqueous layer was extracted with ether

(3 ꢂ 5 mL). The combined organic layers were dried over Na₂SO₄,

ﬁltered and concentrated. The crude oil was puriﬁed via column

chromatography (30 mL silica gel, 2e10% EtOAc/Hexanes) to yield

(neat) 3068, 2961, 2858, 1735, 1615 cm^ꢀ1

CDCl₃)

;

¹H NMR (400 MHz,

d

7.66e7.44 (m, 4H), 7.44e7.35 (m, 6H), 5.57 (d, J ¼ 16 Hz,

1H), 5.48 (dd, J ¼ 15.6, 7.0 Hz, 1H), 4.99 (t, J ¼ 1.2 Hz, 1H), 4.80 (s,

1H), 4.48e4.34 (m, 2H), 3.55e3.46 (m, 2H), 2.99 (s, 1H), 2.42e2.36

(m, 1H), 1.99e1.84 (m, 1H), 1.77e1.71 (m, 1H), 1.71 (s, 3H), 1.18 (s,

3H), 1.05 (s, 9H), 1.02 (d, J ¼ 6.7 Hz, 3H); HRMS m/z calcd for

selenide 27 (0.298 g, 97%): R_f0.30 (3:1 Hexanes/EtOAc); [

(c. 1.17, CDCl₃); IR (neat); 3105, 2918, 2850, 1733, 1588, 1566, 1513,

a

]

²¹þ42.0

D

C

₃₀H₄₀O₃Si (M þ Na)^þ499.2644, found 499.2624.

1452, 1303, 1331, 1247, 1151, 1095, 1037 cm^ꢀ1

;

¹H NMR (400 MHz,

8.27 (d, J ¼ 8.2 Hz,1H), 7.52e7.47 (m, 2H), 7.30 (ddd, J ¼ 8.4,

CDCl₃)

d

4.1.15. (2R,3S,6R,E)-methyl 7-((tert-butyldiphenylsilyl)oxy)-3-(2-

((4-methoxybenzyl)oxy)ethyl)- 3,6-dimethyl-2-(prop-1-en-2-yl)

hept-4-enoate (25)

5.5, 3.1 Hz, 1H), 7.25 (d, J ¼ 8.2 Hz, 2H), 6.84 (d, J ¼ 8.6 Hz, 2H), 5.82

(d, J ¼ 16.0 Hz, 1H), 5.25 (dd, J ¼ 15.6, 8.2 Hz, 1H), 5.00 (s, 1H), 4.93

(s, 1H), 4.41 (ABq, J_AB¼ 11.7 Hz, Dn_AB¼ 15.6 Hz, 2H), 3.77 (s, 3H),

3.60 (s, 3H), 3.46 (t, 7.3 Hz, 2H), 3.02 (s, 1H), 2.89e2.84 (m, 2H),

2.64e2.54 (m, 1H), 1.87e1.82 (m, 1H), 1.81 (s, 3H), 1.76e1.68 (m,

1H), 1.17 (d, J ¼ 6.6 Hz, 1.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

To 0 ^ꢁC solution of crude acid 14 (9.75 mmol) in DMF (5 mL) and

traces of residual DMPU (10 mL) was added K₂CO₃(4.05 g,

29.3 mmol) followed by a dropwise addition of MeI (1.82 mL,

29.3 mmol). The reaction was allowed to slowly warm to room

temperature over 2 h, stirred overnight and quenched with satu-

rated aqueous NaHCO₃(100 mL). The layers were separated and the

aqueous layer was extracted 3x with Et₂O. The combined organic

layers were dried over MgSO₄, ﬁltered and concentrated. The crude

product was puriﬁed via ﬂash chromatography (5% EtOAc/Hexanes)

d

172.5, 159.1, 146.9, 139.7, 135.8, 134.0, 133.5, 133.1, 130.7, 129.3,

129.2, 126.4, 125.2, 117.3, 113.7, 72.3, 67.0, 62.3, 55.2, 51.3, 41.0, 39.4,

36.8, 33.8, 23.9, 21.6, 20.5.; HRMS m/z calcd for C₂₉H₃₇O₆NSeNa

(M þ Na)^þ598.1786, found 598.1779.

4.1.18. (2R,3S,E)-methyl 3-(2-((4-methoxybenzyl)oxy)ethyl)-3,6-

dimethyl-2-(prop-1-en-2-yl)hepta-4,6-dienoate (28)

providing ester 25 (4.91 g, 82%) as a colorless oil: R_f0.78 (3:1

21

Hexanes/EtOAc); [

a]

þ17.2 (c. 0.68, CHCl₃); IR (neat) 3019, 2956,

To a 0 ^ꢁC solution of 27 (0.021 g, 0.0366 mmol) in THF (0.4 mL)

was added H₂O₂(30% in H₂O, 0.1 mL, 1.1 mmol). The cooling bath

was removed and the mixture was stirred at room temperature for

18 h. The mixture was diluted with Et₂O (2 mL) and saturated so-

dium thiosulfate (2 mL) was added. The layers were separated and

the aqueous layer was extracted with Et₂O (3 ꢂ 2 mL). The com-

bined organic layer was dried over Na₂SO₄, ﬁltered and concen-

trated. The crude oil was puriﬁed via ﬂash chromatography to yield

diene 28 (0.011 g, 81%) as a single diastereomer: R_f0.46 (3:1 Hex-

anes/EtOAc); IR (neat) 3100, 2960, 2855, 1734, 1613, 1467 cm^ꢀ1; ¹H

D

2857, 1737, 1613, 1513, 1460, 1361, 1301, 1248, 1151, 1112, 1036, 823,

741, 703 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.70e7.68 (m, 4H), 7.45

(m, 6H), 7.20 (d, J ¼ 8.6 Hz, 2H), 6.85 (d, J ¼ 8.6 Hz, 2H), 5.73 (d,

J ¼ 15.7 Hz,1H), 5.32 (dd, J ¼ 16, 7.4 Hz,1H), 4.99 (s, 1H), 4.94 (s, 1H),

4.30 (ABq, J_AB¼ 11.3 Hz, Dn_AB¼ 11.3 Hz, 2H), 3.79 (s, 3H), 3.57 (s,

3H), 3.56e3.53 (m, 1H), 3.48e3.35 (m, 3H), 3.03 (s, 1H), 2.48e2.38

(m, 1H), 1.89e1.78 (m, 1H), 1.80 (s, 3H), 1.72e1.65 (m, 1H), 1.11 (s,

3H), 1.08 (s, 9H), 1.03 (d, J ¼ 6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d

177.3, 159.1, 139.6, 135.6, 134.8, 134.0, 132.2, 130.4, 129.5, 129.3,

127.6, 117.5, 113.7, 72.6, 68.9, 67.0, 62.3, 55.2, 40.7, 39.8, 39.0, 26.9,

23.9, 20.8, 19.3, 16.9; HRMS m/z calcd for C₃₉H₅₂O₅Si (M þ Na)^þ

651.3481, found 651.3461.

NMR (400 MHz, CDCl₃)

d

7.24 (d, J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.2 Hz,

2H), 6.00 (ABq, J_AB¼ 16.4 Hz, Dn_AB¼ 13.9 Hz, 2H), 4.99 (s, 1H), 4.93

(s, 1H), 4.91 (s, 1H), 4.90 (s, 1H), (ABq, J_AB¼ 12.5 Hz, Dn_AB¼ 0 Hz,

2H), 3.80 (s, 3H), 3.60 (s, 3H), 4.48e3.34 (m, 2H), 3.07 (s, 1H),

1.93e1.72 (m, 2H), 1.84 (s, 3H), 1.78 (s, 3H), 1.15 (s, 3H); ¹³C NMR

4.1.16. (2R,3S,6R,E)-methyl-7-hydroxy-3-(2-((4-methoxybenzyl)

oxy)ethyl)-3,6-dimethyl-2-(prop-1-en-2-yl)hept-4-enoate (26)

To a room temperature solution of silyl ether 25 (0.174 g,

0.277 mmol) in THF (3 mL) was added TBAF (0.55 mL, 1 M in THF)

and the mixture was stirred for 30 h. Saturated aqueous NH₄Cl

(3 mL) was added, the layers were separated and the aqueous layer

was extracted (3 ꢂ 5 mL) with Et₂O. The combined organic layers

were dried over MgSO₄, ﬁltered and concentrated. The crude

product was puriﬁed via ﬂash chromatography (15% EtOAc/Hex) to

(100 MHz, CDCl₃)

d 172.5, 159.1, 142.2, 139.7, 135.5, 131.4, 130.6,

129.2, 117.3, 115.0, 113.7; HRMS m/z calcd for C₂₃H₃₂O₄Na (M þ Na)^þ

395.2309, found 395.2300.

4.1.19. (2R,3S,E)-3-(2-((4-methoxybenzyl)oxy)ethyl)-3,6-dimethyl-

2-(prop-1-en-2-yl)hepta-4,6-dien-1-ol (29)

To a solution of ester 28 (0.220 g, 0.56 mmol) in Et₂O (10 mL)

at ꢀ78 ^ꢁC was added via syringe DIBAL (5.7 mL, 1 M in hexanes

5.7 mmol). The reaction was stirred at ꢀ78 ^ꢁC for 2 h and allowed to

warm to ꢀ30 ^ꢁC followed by careful addition of a saturated aqueous

solution of Rochelle salt. The mixture was allowed to warm to room

temperature with vigorous stirring overnight. After ﬁltration to

remove solids, the phases were separated, and the organic phase

yield alcohol 26 (0.107 g, 99%) as a colorless oil: R_f0.18 (3:1 Hex-

21

anes/EtOAc); [

a]

þ 38.9 (c. 0.82, CHCl₃); IR (neat) 3445, 2952,

D

2860, 1734, 1613, 1514, 1456, 1248, 1171, 1092, 1034; ¹H NMR

(400 MHz, CDCl₃)

7.22 (d, J ¼ 8.6 Hz, 2H), 6.85 (d, J ¼ 8.6 Hz, 2H),

5.73 (d, J ¼ 16 Hz, 1H), 5.11 (dd, J ¼ 15.6, 8.2 Hz, 1H), 5.00 (s, 1H),

d

10

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

was extracted with Et₂O (3 ꢂ 15 mL). The combined organic ex-

tracts were dried over anhydrous MgSO₄, ﬁltered, and concentrated

to yield crude product which was puriﬁed by ﬂash chromatography

113.7, 81.0, 72.6, 67.4, 67.2, 60.6, 55.2, 42.3, 41.6, 39.7, 28.1, 22.6,

20.8, 18.9; HRMS m/z calcd for C₂₈H₄₂O₅(M þ Na)^þ481.2930, found

481.2930.

(10% EtOAc/hexanes) to give alcohol 29 (0.208 mg, 97%). R_f0.17 (3:1

21

Hexanes/EtOAc) [

a]

ꢀ4.4 (c. 0.70, CDCl₃); IR (neat) 3435, 3075,

D

2917, 1640, 1612, 1586, 1514, 1464, 1363, 1302, 1248, 1174, 1093,

1035, 976, 891, 821; ¹H NMR (400 MHz, CDCl₃)

d

7.23 (d, J ¼ 8.6 Hz,

4.1.22. General procedure for the formation of C20 Mosher esters of

32

2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 6.03 (d, J ¼ 16 Hz, 1H), 5.56 (d,

J ¼ 16.4 Hz, 1H), 5.06 (s, 1H), 4.92e4.91 (m, 2H), 4.83 (s, 1H), 4.37 (s,

2H), 3.80 (s, 3H), 3.73 (dd, J ¼ 10.9, 4.7 Hz, 1H), 3.61 (t, J ¼ 10.6 Hz,

1H), 3.46e3.34 (m, 2H), 2.26 (dd, J ¼ 10.4, 4.3 Hz, 1H), 1.82 (s, 3H),

To a room temperature solution of (S)-(ꢀ)-

ﬂuoromethylphenylacetic acid (MTPA) (0.014 g, 0.0595 mmol) and

DMF (0.9 L, 1.2 mol) in hexanes (2 mL) was added oxalyl chloride

(24 L, 0.283 mmol). The mixture was stirred for 1 h, ﬁltered

through glass wool and concentrated. A solution of alcohol 32

(0.0058 g, 0.0126 mmol), DMAP (single crystal) and Et₃N (25 L,

0.1785 mmol) in CH₂Cl₂(2 mL) was added to the residue. The

mixture was stirred overnight and saturated NaHCO₃(1 mL) was

added. The layers were separated and the aqueous layer was

extracted with CH₂Cl₂(3 ꢂ 1 mL). The combined organic layers

were dried over Na₂SO₄, ﬁltered and concentrated. The crude oil

was puriﬁed by ﬂash chromatography (2 mL silica gel, 5% EtOAc/

hexanes) to yield (S)-MTPA-32 (0.0079 g, 93%). In a separate ﬂask

a-methoxy-a-tri-

m

1.78e1.74 (m, 5H), 1.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 159.1,

m

143.9, 141.8, 137.0, 131.2, 130.5, 129.2, 116.0, 115.3, 113.8, 72.7, 66.9,

m

61.5, 59.0, 55.3, 40.2, 39.7, 23.4, 20.2, 18.8; HRMS m/z calcd for

C

₂₂H₃₂O₃(M þ Na)^þ367.2249, found 367.2253.

4.1.20. (2R,3S,E)-3-(2-((4-methoxybenzyl)oxy)ethyl)-3,6-dimethyl-

2-(prop-1-en-2-yl)hepta-4,6-dienal (30)

To

a room temperature solution of alcohol 29 (1.39 g,

4.03 mmol) in DMSO (45 mL) was added IBX (2.26 g, 8.06 mmol).

The mixture was stirred for 1 h and water (50 mL) and Et₂O (50 mL)

were added. The layers were separated and the aqueous layer was

extracted with Et₂O (1 ꢂ 50 mL). The combined organic layers were

washed with brine (2 ꢂ 50 mL), dried over Na₂SO₄, ﬁltered and

the same procedure was employed utilizing (R)-(ꢀ)-

a-methoxy-a-

triﬂuoromethylphenylacetic acid to yield (R)-MTPA-32 (0.0072 g,

90%). Mosher ester analysis [12b] of selected proton shifts are listed

below.

concentrated. Crude aldehyde 30 was used in the next step without

(R)-MTPA ester of 32: ¹H NMR (400 MHz, CDCl₃)

d 5.99 (d,

21

further puriﬁcation: R_f0.78 (3:1 Hexanes/EtOAc); [

a]

ꢀ12.3 (c.

D

J ¼ 16.4 Hz, 1H, H(h)), 5.59 (d, J ¼ 16.0 Hz, 1H, H(g)), 4.34 (s, 2H,

H(f)), 2.56 (dd, J ¼ 15.8, 4.9 Hz, 1H, H(b)), 2.46 (dd, J ¼ 16.1, 8.3 Hz,

1H, H(c)), 2.38 (d, J ¼ 3.2 Hz, 1H, H(d)), 1.42 (s, 9H, H(a)), 0.98 (s, 3H,

H(e)).

0.42, CDCl₃); IR (neat); 3079, 2917, 2850, 2726, 1721, 1612, 1558,

1513, 1248, 1096, 977, 899, 821 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

;

d

9.63 (d, J ¼ 3.9 Hz, 1H), 7.21 (d, J ¼ 8.2 Hz, 2H), 6.85 (d, J ¼ 8.6 Hz,

2H), 6.08 (d, J ¼ 16.0 Hz, 1H), 5.74 (d, J ¼ 16.4 Hz, 1H), 5.12 (s, 1H),

4.94 (s, 1H), 4.92 (s, 1H), 4.83 (s, 1H), 4.36 (s, 2H), 3.78 (s, 3H),

3.48e3.34 (m, 2H), 2.85, (d, J ¼ 3.5 Hz, 1H), 1.88e1.84 (m, 2H), 1.81

(S)-MTPA ester of 32: ¹H NMR (400 MHz, CDCl₃)

d 5.83 (d,

J ¼ 16.0 Hz, 1H, H(h)), 5.45 (d, J ¼ 16.0 Hz, 1H, H(g)), 4.29 (s, 2H,

H(f)), 2.66 (dd, J ¼ 15.7, 4.7 Hz, 1H, H(b)), 2.54 (dd, J ¼ 15.7, 8.6 Hz,

1H, H(c)), 2.30 (d, J ¼ 2.8 Hz, 1H, H(d)), 1.44 (s, 9H, H(a)), 0.65 (s, 3H,

H(e)).

(s, 3H), 1.78 (s, 3H), 1.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 201.1,

159.0, 141.6, 138.9, 135.1, 132.0, 130.3, 129.1, 117.7, 115.8, 113.7, 72.6,

68.0, 66.5, 55.1, 41.3, 39.1, 25.1, 21.4, 18.7; HRMS m/z calcd for

C

₂₂H₃₀O₃(M þ Na)^þ356.0593, found 365.2083.

4.1.21. (3R,4R,5S,E)-tert-butyl-3-hydroxy-5-(2-((4-methoxybenzyl)

oxy)ethyl)-5,8-dimethyl-4-(prop-1-en-2-yl)nona-6,8-dienoate (32)

To a 0 ^ꢁC solution of diisopropylamine (3.15 mL, 22.5 mmol) in

Et₂O (75 mL) was added nBuLi (7.88 mL, 2.5 M in hexanes,

19.7 mmol). The mixture was stirred at 0 ^ꢁC for 10 min and cooled

to ꢀ78 ^ꢁC. To this solution ^tBuOAc (2.26 mL, 16.9 mmol) was added

dropwise. After 30 min, CpTi(diacetoneglucose)₂Cl [27]. (180 mL,

0.09 M in Et₂O) was added slowly. After stirring at ꢀ78 ^ꢁC for

30 min the mixture was allowed to slowly warm to ꢀ30 ^ꢁC, stirred

at that temperature for 30 min and cooled to ꢀ78 ^ꢁC. Crude alde-

hyde 30 (3.0 g, 9 mmol) was slowly added as a solution in Et₂O and

stirred for 1.5 h at ꢀ78 ^ꢁC. The reaction mixture was quenched by

slow addition of aqueous THF (10 mL, 5 M H₂O), allowed to warm to

room temperature and ﬁltered through a pad of celite. The ﬁltrate

was poured into H₂O (200 mL), the layers were separated and the

aqueous layer was extracted (3 ꢂ 15 mL) with Et₂O. The combined

organic layers were dried over MgSO₄, ﬁltered through a pad of

celite and concentrated. The crude product was puriﬁed via ﬂash

chromatography (gradient elution of 10e20% EtOAc in Hexanes) to

yield 2.89 g of alcohol 32 (70% for 2 steps): R_f0.79 (3:1 Hexanes/

Proton

d_S(ppm)

d_R(ppm)

d_Sed_R(ppm)

a

b

c

d

e

f

1.435

2.662

2.539

2.303

0.653

4.291

5.445

5.831

1.420

2.559

2.464

2.376

0.982

4.337

5.589

5.988

þ0.015

þ0.103

þ0.075

ꢀ0.074

ꢀ0.329

ꢀ0.046

ꢀ0.144

ꢀ0.157

g

h

4.1.23. (3R,4R,5S,E)-tert-butyl 5-(2-((4-methoxybenzyl)oxy)ethyl)-

3-(methoxymethoxy)-5,8- dimethyl-4-(prop-1-en-2-yl)nona-6,8-

dienoate

To a 0 ^ꢁC solution of alcohol 32 (0.205 g, 0.447 mmol) in CH₂Cl₂

was added iPr₂NEt (3.11 mL, 17.88 mmol), DMAP (0.055 g,

0.447 mmol) and MOMCl (0.72 mL, 8.94 mmol) sequentially and

allowed to warm to room temperature. After 24 h the solution was

cooled to 0 ^ꢁC and MOMCl (0.18 mL, 2.23 mmol) was added and the

solution was allowed to warm to room temperature and stirred for

24 h. The solution was cooled to 0 ^ꢁC, diluted with CH₂Cl₂and

quenched with aqueous NaHCO₃. The layers were separated and

EtOAc); [

a

]

D

²¹þ 5.6 (c. 1.90, CHCl₃); IR (neat) 3516, 3075, 2971, 2933,

1724, 1632, 1612, 1586, 1514, 1456, 1367, 1302, 1248, 1153, 1093,

1038, 976, 953, 888, 845, 821, 756 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.23 (d, J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 6.06 (d, J ¼ 16.4 Hz,

1H), 5.86 (d, J ¼ 16.0 Hz, 1H), 5.01 (s, 1H), 4.90 (m, 2H), 4.83 (s, 1H),

4.43e4.39 (m, 1H), 4.37 (s, 2H), 3.79 (s, 1.81 (m, 2H), 1.84 (s, 3H),

1.83 (s, 3H), 1.44 (s, 9H), 1.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d

172.4, 159.1, 143.0, 142.2, 138.3, 130.7, 130.6, 129.2, 116.9, 114.7,

11

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

the aqueous layer was extracted with equal portions of CH₂Cl₂

(3 ꢂ 10 mL) The combined organic layers were dried over MgSO₄

and concentrated. The crude residue was puriﬁed by ﬂash chro-

matography (gradient elution of 5e10% EtOAc in Hexanes) to yield

(M þ Na)^þ453.2617, found 453.2624.

4.1.26. (4R,5R,6S,E)-6-(2-((4-methoxybenzyl)oxy)ethyl)-4-

(methoxymethoxy)-6,9-dimethyl-1-nitro-5-(prop-1-en-2-yl)deca-

7,9-dien-2-ol (34)

To a room temperature solution of aldehyde 33 (1.60 g,

3.71 mmol) in i-PrOH (40 mL) was added KF (0.22 g, 3.87 mmol)

followed by MeNO₂(3.04 mL, 58.1 mmol). The solution was stirred

for 20 h, concentrated and puriﬁed by ﬂash chromatography (10%

EtOAc/hexanes) to yield a 2:1 mixture of diastereomeric alcohols 34

the desired MOM-protected ester of 32 (0.196 g, 87%): R_f0.85 (3:1

21

Hexanes/EtOAc); [

a]

þ36.7 (c. 0.15, CHCl₃); IR (neat) 2918, 2849,

D

1726, 1612, 1580, 1537, 1468, 1377, 1302, 1248, 1154, 1100,

1036 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.23 (d, J ¼ 8.6 Hz, 2H), 6.85

(d, J ¼ 8.6 Hz, 2H), 6.03 (d, J ¼ 16.0 Hz, 1H), 5.76 (d, J ¼ 16.4 Hz, 1H),

5.02 (s, 1H), 4.89 (m, 2H), 4.83 (s, 1H), 4.60 (s, 2H), 4.37 (s, 2H), 4.25

(ddd, J ¼ 7.8, 4.7, 2.3 Hz), 3.79 (s, 3H), 3.49e3.33 (m, 2H), 3.31 (s,

3H), 2.65 (dd, J ¼ 16.0, 5.1 Hz, 1H), 2.43 (dd, J ¼ 16.0, 8.6 Hz, 1H),

2.06 (d, J ¼ 2.0 Hz, 1H), 1.93e1.84 (m, 7H), 1.77e1.68 (m, 1H), 1.43 (s,

(1.60 g, 84%). For characterization of isomer 34a: R_f0.39 (3:1

21

Hexanes/EtOAc); [

a]

þ39.6 (c. 0.09, CHCl₃); IR (neat) 3424, 2937,

D

1612,1555,1513,1453,1373,1302,1248,1148,1094, 1035, 901 cm^ꢀ1

;

9H), 1.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d

170.8, 159.0, 142.4,

¹H NMR (400 MHz, CDCl₃)

d

7.23 (d, J ¼ 8.6 Hz, 2H), 6.86 (d,

142.2, 138.4, 130.7, 130.5, 129.2, 118.2, 114.5, 113.7, 97.5, 80.2, 72.6,

67.2, 59.6, 55.7, 55.2, 41.6, 40.7, 40.2, 28.1, 22.6, 20.6,18.9; HRMS m/z

calcd for C₃₀H₄₆O₆(M þ Na)^þ525.3192, found 525.3201.

J ¼ 8.6 Hz, 2H), 6.03 (d, J ¼ 16.0 Hz,1H), 5.66 (d, J ¼ 16.4 Hz,1H), 5.03

(s, 1H), 4.92 (s, 1H), 4.91 (s,1H), 4.86 (s,1H), 4.66 (d, J ¼ 6.7,1H), 4.56

(d, J ¼ 7.0 Hz, 1H), 4.57e4.46 (m, 1H), 4.39e4.25 (m, 4H), 4.07e4.05

(m, 1H), 3.80 (s, 3H), 3.72 (d, J ¼ 4.7 Hz, 1H), 3.42e3.31 (m, 2H), 3.40

(s, 3H), 2.00 (d, J ¼ 2.7 Hz,1H),1.91e1.80 (m, 1H),1.84 (s, 3H),1.82 (s,

3H), 1.70e1.64 (m, 2H), 1.46e1.39 (m, 1H), 1.12 (s, 3H); ¹³C NMR

4.1.24. (3R,4R,5S,E)-5-(2-((4-methoxybenzyl)oxy)ethyl)-3-

(methoxymethoxy)-5,8-dimethyl-4-(prop-1-en-2-yl)nona-6,8-dien-

1-ol

(125 MHz, CDCl₃)

d 159.3, 143.2, 141.9, 138.2, 131.0, 130.6, 129.5,

To a 0 ^ꢁC solution of MOM-protected ester of 32 (from the

previous experiment) (0.200 g, 0.398 mmol) in Et₂O (4 mL) was

added LiAlH₄(0.075 g, 1.99 mmol). The mixture was stirred at 0 ^ꢁC

for 15 min and Na₂SO₄ꢃ10H₂O (0.5 g) was added. The white sus-

pension was stirred at 0 ^ꢁC for 30 min and at room temperature for

an additional hour, ﬁltered, washed with brine (2 ꢂ 10 mL), dried

over Na₂SO₄, ﬁltered and concentrated to yield the expected

117.7, 115.4, 113.9, 99.2, 80.7, 78.2, 72.9, 67.1, 65.6, 61.2, 56.4, 55.4,

51.6, 40.4, 39.5, 25.9, 20.4, 19.0; HRMS m/z calcd for C₂₇H₄₁NO₇

(M þ Na)^þ514.2781, found 514.2806. For characterization of isomer

21

34b: R_f0.37 (3:1 Hexanes/EtOAc); [

a

]

þ37.0 (c. 0.10, CHCl₃); IR

D

(neat) 3407, 2936, 1612, 1554, 1514, 1441, 1377, 1302, 1248, 1148,

1093, 1035, 893 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

;

d

7.24 (d,

J ¼ 8.6 Hz, 2H), 6.87 (d, J ¼ 8.6 Hz, 2H), 6.02 (d, J ¼ 16.0 Hz, 1H), 5.83

(d, J ¼ 16.0 Hz, 1H), 5.00 (s, 1H), 4.90 (m, 2H), 4.79 (s, 1H), 4.62 (s,

2H), 4.41e4.26 (m, 5H), 4.12e4.08 (m, 1H), 3.80 (s, 3H), 3.51e3.35

(m, 3H), 3.34 (s, 3H), 2.18 (br s, 1H), 2.00e1.93 (m, 1H), 1.88e1.79

alcohol (0.161 g, 94%) as a colorless oil: R_f0.08 (3:1 Hexanes/EtOAc);

21

[

a

]

þ20.4 (c. 0.3, CHCl₃); IR (neat) 3456, 3073, 2923, 2851, 1632,

D

1612, 1514, 1464, 1374, 1302, 1149, 1036, 894, 820, 757 cm^ꢀ1

NMR (400 MHz, CDCl₃)

;

¹H

7.23 (d, J ¼ 8.2 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz,

d

(m, 1H), 1.84 (s, 3H), 1.82 (s, 3H), 1.67e1.64 (m, 2H), 1.12 (s, 3H); ¹³

C

2H), 6.02 (d, J ¼ 16.0 Hz, 1H), 5.74 (d, J ¼ 16.0 Hz, 1H), 5.00 (s, 1H),

4.89 (m, 2H), 4.82 (s, 1H), 4.62 (ABq, J_AB¼ 6.7 Hz, Dn_AB¼ 7.1 Hz, 2H),

4.36 (ABq, J_AB¼ 11.5 Hz, Dn_AB¼ 8.3, Hz, 2H), 3.99 (td, J ¼ 6.2, 2.7 Hz,

1H), 3.79 (s, 3H), 3.67 (dt, J ¼ 11.2, 5.9 Hz), 3.56 (dt, J ¼ 10.5, 5.3 Hz,

1H), 3.45e3.33 (m, 2H), 3.36 (s, 3H), 2.20 (br s, 1), 2.01 (d, J ¼ 2.3 Hz,

1H), 1.92e1.66 (m, 4H), 1.85 (s, 3H), 1.82 (s, 3H), 1.14 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) d 159.6, 143.3, 142.3, 138.6, 130.6, 130.4,

129.6, 118.4, 114.9, 114.1, 98.1, 81.0, 77.6, 73.0, 67.2, 67.0, 59.2, 56.0,

55.5, 51.6, 40.1, 38.6, 24.9, 21.7, 19.0; HRMS m/z calcd for C₂₇H₄₁NO₇

(M þ Na)^þ514.2781, found 514.2775.

4.1.27. (1S,2R,3R,4aS,5S,8aR)-1-(2-((4-methoxybenzyl)oxy)ethyl)-

3-(methoxymethoxy)-1,7-dimethyl-5-nitro-2-(prop-1-en-2-yl)-

1,2,3,4,4a,5,6,8a-octahydronaphthalene (37)

NMR (100 MHz, CDCl₃)

d 159.1, 143.2, 142.0, 138.5, 130.6, 130.4,

129.3, 117.6, 114.7, 113.7, 97.9, 77.8, 72.7, 67.1, 60.1, 59.7, 56.0, 55.2,

41.4, 40.1, 37.4, 25.3, 20.6, 18.9; HRMS m/z calcd for C₂₆H₄₀O₅

(M þ Na)^þ455.2773, found 455.2795.

To a 0 ^ꢁC solution of alcohol 34 (1.60 g, 3.25 mmol) in CH₂Cl₂

(32 mL) was added Et₃N (1.36 mL, 9.76 mmol) followed by MsCl

(0.38 mL, 4.88 mmol). The mixture was stirred at 0 ^ꢁC for 15 min,

saturated aqueous NaHCO₃(0.5 mL) was added and stirred at room

temperature for 15 min. The layers were separated and the aqueous

layer was extracted with CH₂Cl₂(3 ꢂ 1 mL), dried over Na₂SO₄,

ﬁltered and concentrated. The crude residue was immediately

dissolved in benzene (65 mL) and BHT (single crystal) was added.

The solution was placed under argon atmosphere and was reﬂuxed

for 16 h, cooled to room temperature and concentrated. The crude

oil was puriﬁed by ﬂash chromatography (gradient elution of

5e10% EtOAc/hexanes) to yield decalin 37 (0.783 g, 51% for 2 steps)

and 38 (80 mg, 5% for two steps) as colorless oils. For character-

4.1.25. (3R,4R,5S,E)-5-(2-((4-methoxybenzyl)oxy)ethyl)-3-

(methoxymethoxy)-5,8-dimethyl-4-(prop-1-en-2-yl)nona-6,8-

dienal (33)

To a room temperature solution of the alcohol described above

(1.67 g, 3.87 mmol) in DMSO (40 mL) was added IBX (2.17 g,

7.73 mmol). The solution was stirred at room temperature for 1.5 h,

diluted with cold water (200 mL) and extracted with Et₂O

(3 ꢂ 200 mL). The combined organic layers were washed with brine

(3 ꢂ 200 mL), dried with MgSO₄and ﬁltered through a plug of silica

gel to provide aldehyde 33 (1.60 g, 96%) without the need for

21

additional puriﬁcation: R_f0.71 (2:1 Hexanes/EtOAc [

a

]

þ29.3 (c.

ization of pure 37: R_f0.51 (3:1 Hexanes/EtOAc); [

CHCl₃); IR (neat) 2934, 1640, 1549,1441,1380, 1248, 1096, 1036, 916,

a

]

²¹ꢀ24.1 (c. 0.13,

D

0.63, CHCl₃); IR (neat) 2937, 2728, 1722, 1632, 1612, 1586, 1454,

1372, 1302, 1248, 1209, 1150, 1093, 1036, 978, 916, 822 cm^ꢀ^{1 1}H

NMR (400 MHz, CDCl₃)

9.66 (s,1H), 7.22 (d, J ¼ 8.3 Hz, 2H), 6.85 (d,

;

820 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.23 (d, J ¼ 8.6 Hz, 2H), 6.86

d

(d, J ¼ 8.6 Hz, 2H), 5.40 (s, 1H), 5.02 (s, 1H), 4.73 (s, 1H), 4.66e4.58

(m, 1H), 4.52e4.36 (m, 4H), 3.81 (s, 3H), 3.82e3.70 (m, 1H),

3.55e3.49 (m, 1H), 3.46e3.40 (m, 1H), 3.28 (s, 3H), 2.68e2.61 (m,

1H), 2.45 (dd, J ¼ 16.2, 5.7 Hz, 1H), 2.04e1.95 (m, 2H), 1.82e1.67 (m,

J ¼ 8.6 Hz, 2H), 6.03 (d, J ¼ 16.1 Hz, 1H), 5.76 (d, J ¼ 16.1 Hz, 1H), 5.01

(s,1H), 4.90 (s, 2H), 4.81 (s,1H), 4.60 (s, 2H), 4.43e4.30 (m, 3H), 3.78

(s, 3H), 3.47e3.33 (m, 2H), 3.28 (s, 3H), 2.75 (ddd, J ¼ 17.3, 5.2,

2.3 Hz, 1H), 2.61 (dd, J ¼ 17.3, 7.0 Hz, 1H), 2.00 (d, J ¼ 2.8 Hz, 1H),

1.95e1.86 (m,1H), 1.84 (s, 3H),1.83 (s, 3H),1.75e1.68 (m, 1H),1.15 (s,

3H),1.76 (s, 3H),1.73 (s, 3H),1.09 (q, J ¼ 12.1 Hz,1H), 0.80 (s, 3H); ¹³

C

NMR (125 MHz, CDCl₃)

d 159.6, 144.0, 132.0, 130.9, 129.3, 121.6,

3H); ¹³C NMR (100 MHz, CDCl₃)

d

200.6, 159.3, 142.7, 142.2, 138.3,

114.1, 96.0, 89.1, 74.8, 72.9, 65.3, 56.3, 55.7, 55.5, 45.8, 40.3, 36.8,

36.4, 35.8, 35.3, 23.1,19.3; HRMS m/z calcd for C₂₇H₃₉NO₆(M þ Na)^þ

496.2675, found 496.2681.

130.9, 130.8, 128.3, 118.5, 114.7, 113.9, 97.7, 75.4, 72.7, 67.2, 60.7, 55.7,

55.3, 49.3, 41.8, 40.3, 25.1, 21.0, 18.9; HRMS m/z calcd for C₂₆H₃₈O₅

12

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

For full characterization of (1S,2R,3R,4aS,5S,8aS)-1-(2-((4-

methoxybenzyl)oxy)ethyl)-3-(methoxymethoxy)-1,7-dimethyl-5-

Dn_AB¼ 11.8 Hz, 2H), 3.80 (s, 3H), 3.80e3.75 (m, 2H), 3.54 (td, J ¼ 9.1,

5.2 Hz, 1H), 3.48e3.44 (m, 1H), 3.34 (s, 3H), 2.72 (dt, 12.5, 4.3 Hz,

1H), 2.09 (d, J ¼ 10.9 Hz, 1H), 1.95e1.82 (m, 2H), 1.80 (s, 3H),

1.65e1.56 (m, 2H), 1.66 (s, 3H), 1.40e1.30 (m, 3H), 0.98 (q,

nitro-2-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene

21

(38): R_f0.39 (3:1 Hexanes/EtOAc); [

a

]

ꢀ6.6 (c. 0.76, CHCl₃); IR

D

(neat) 2938, 2890, 1613, 1544, 1513, 1443, 1363, 1248, 1097,

J ¼ 11.6 Hz, 1H), 0.88 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d 159.5,

1038 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃)

d

7.20 (d, J ¼ 8.5 Hz, 2H), 6.85

144.2, 136.3, 130.9, 129.3, 124.5, 114.1, 96.0, 75.3, 729, 65.5, 57.2,

55.8, 55.5, 41.6, 40.3, 40.1, 38.0, 37.1, 30.1, 23.3, 17.8; HRMS m/z calcd

for C₂₇H₄₀O₅(M þ Na)^þ467.2773, found 467.2757.

(d, J ¼ 8.3 Hz, 2H), 5.44 (s, 1H), 4.95 (s, 1H), 4.74 (s, 1H), 4.61 (br s,

1H), 4.54 (d, J ¼ 6.8 Hz, 1H), 4.47 (dd, J ¼ 6.1, 3.1 Hz, 1H), 4.36 (ABq,

J_AB¼ 11.5 Hz Dn_AB¼ 11.1 Hz, 2H), 3.80 (br s, 1H), 3.77 (s, 3H), 3.42 (t,

J ¼ 7.5 Hz, 2H), 3.30 (s, 3H), 2.77 (dd, J ¼ 13.8, 4.0 Hz, 1H), 2.69 (d,

J ¼ 19.5 Hz, 1H), 2.24 (d, J ¼ 19.6 Hz, 1H), 1.99e1.90 (m, 2H),

1.87e1.81 (m, 2H), 1.75 (s, 3H), 1.73 (s, 3H), 1.60 (d, J ¼ 14.4, 7.4 Hz,

1H), 1.29 (q, J ¼ 12.2 Hz, 1H), 1.03 (s, 1H); ¹³C NMR (125 MHz, CDCl₃)

4.1.30. Tert-butyl(((1R,4aR,5S,6R,7R,8aS)-5-(2-((4-methoxybenzyl)

oxy)ethyl)-7-(methoxymethoxy)-3,5-dimethyl-6-(prop-1-en-2-yl)-

1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)oxy)dimethylsilane

To a room temperature solution of the previously prepared

allylic alcohol of 39 (preceding experiment) (100 mg, 0.225 mmol)

in CH₂Cl₂(0.75 mL) was added Et₃N (0.25 mL, 1.8 mmol), DMAP (1

crystal) and TBSCl (170 mg, 1.12 mmol). The mixture was stirred at

room temperature for 40 h and quenched with saturated aqueous

NaHCO₃. The layers were separated and the aqueous layer was

extracted with CH₂Cl₂(2 ꢂ 2 mL). The combined organic layers

were dried with MgSO₄, ﬁltered and concentrated. Puriﬁcation by

silica gel chromatography (1%e3% EtOAc/hexanes) provided the

d

159.3, 130.69, 130.71, 129.1, 119.6, 113.9, 96.3, 84.8, 77.4, 728, 65.8,

55.6, 55.2, 38.9, 38.2, 33.2, 32.6, 28.9, 23.2, 21.0. HRMS m/z calcd for

C

₂₇H₃₉NO₆(M þ Na)^þ496.2675, found 496.2668.

4.1.28. (4aR,5S,6R,7R,8aS)-5-(2-((4-methoxybenzyl)oxy)ethyl)-7-

(methoxymethoxy)-3,5-dimethyl-6-(prop-1-en-2-yl)-4a,5,6,7,8,8a-

hexahydronaphthalen-1(4H)-one (39)

To a room temperature solution of 37 (0.485 g, 1.02 mmol) in

t

THF (10 mL) was added BuOK (276 mg, 2.46 mmol). The mixture

desired TBS silyl ether (100 mg, 92% brsm) characterized as follows:

21

was stirred for 5 min, cooled to ꢀ78 ^ꢁC and trans-2- (phenyl-

sulfonyl)-3-phenyloxaziridine [31] (533 mg, 2.04 mmol) was added

as a solution in THF (10 mL) dropwise down the side of the ﬂask.

The reaction was stirred for 1 h at ꢀ78 ^ꢁC then warmed to 0 ^ꢁC and

stirred for 30 min. The reaction was quenched with saturated

aqueous NH₄Cl (20 mL) and diluted with CH₂Cl₂(30 mL). The layers

were separated and the aqueous layer was extracted with CH₂Cl₂

(3 ꢂ 20 mL). The combined organic layers were dried with MgSO₄,

ﬁltered and concentrated. Puriﬁcation by silica gel chromatography

R_f0.82 (3:1 Hexanes/EtOAc); [

a

]

D

þ25.6 (c. 1.04, CHCl₃); IR (neat)

2928, 2856, 1640, 1613, 1513, 1463, 1362, 1301, 1249, 1150, 1071,

1040, 920, 892, 836, 774 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃)

d

7.22 (d,

J ¼ 8.2 Hz, 2H), 6.85 (d, J ¼ 8.3 Hz, 2H), 5.27 (s, 1H), 5.01 (s, 1H), 4.73

(s, 1H), 4.65 (d, J ¼ 6.9 Hz, 1H), 4.59 (d, J ¼ 6.9 Hz, 1H), 4.41 (ABq,

J_AB¼ 11.7 Hz, Dn_AB¼ 15.0 Hz, 2H), 3.83 (d, J ¼ 7.3 Hz, 1H), 3.79 (s,

3H), 3.75 (td, J ¼ 11.1, 5.1 Hz, 1H), 3.54 (td, J ¼ 9.1, 5.3 Hz, 1H),

3.49e3.41 (m, 1H), 3.33 (s, 3H), 2.69 (dt, J ¼ 12.8, 4.5 Hz, 1H), 2.06

(d, J ¼ 10.9 Hz, 1H), 1.91e1.84 (m, 2H), 1.79 (s, 3H), 1.64 (s, 3H),

1.61e1.55 (m, 2H), 1.48e1.29 (m, 2H), 0.93 (s, 9H), 0.87 (s, 3H), 0.10

(gradient elution of 15%e25% EtOAc/hexanes) provided enone 39

20

(375 mg, 83%): R_f0.18 (hexanes/EtOAc (2:1)); [

a]

ꢀ21.6 (c 0.73,

(s, 3H), 0.09 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d 159.4, 144.3, 134.7,

D

CHCl₃); IR (ﬁlm) 2930, 1663, 1613,1514,1441, 1380, 1248, 1096, 1037,

130.9, 129.3, 125.5, 114.0, 96.3, 76.0, 75.4, 72.8, 65.5, 57.3, 55.7, 55.4,

41.5, 50.3, 39.4, 38.6, 37.0, 30.0, 26.1, 23.4, 18.3, 17.7, ꢀ3.8, ꢀ4.3;

HRMS m/z calcd for C₃₃H₅₄O₅Si (M þ Na)^þ581.3638, found

581.3638.

821 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.19 (d, J ¼ 8.6 Hz, 2H), 6.48

(d, J ¼ 8.6 Hz, 2H), 5.84 (s, 1H), 5.04 (s, 1H), 4.74e4.72 (m, 2H), 4.56

(d, J ¼ 6.9 Hz, 1H), 4.37 (s, 2H), 3.83e3.77 (m, 1H), 3.79 (s, 3H),

3.56e3.44 (m, 2H), 3.35 (s, 3H), 2.79 (dt, J ¼ 13.4, 4.5 Hz, 1H), 2.35

(dd, 17.9, 4.4 Hz, 1H), 2.20e2.04 (m, 3H), 1.83 (s, 3H), 1.79 (s, 3H),

1.77e1.62 (m, 3H), 1.09 (q, J ¼ 12.2 Hz, 1H), 0.92 (s, 3H); ¹³C NMR

4.1.31. 2-((1S,2R,3R,4aS,5R,8aR)-5-((tert-butyldimethylsilyl)oxy)-3-

(methoxymethoxy)-1,7-dimethyl-2-(prop-1-en-2-yl)-

1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-yl)ethanol (40)

(100 MHz, CDCl₃)

d

200.3, 161.7, 159.6, 143.9, 130.7, 129.5, 125.7,

114.1, 95.8, 74.9, 73.1, 65.5, 56.5, 55.9, 55.5, 44.6, 43.2, 40.7, 36.9,

33.3, 31.7, 24.4, 18.5; HRMS m/z calcd for C₂₇H₃₈O₅(M þ Na)^þ

465.2617, found 465.2610.

To a two-neck ﬂask, charged with a stir bar and cooled by

a ꢀ78 ^ꢁC bath, NH_3(l)(10 mL) was condensed, and Na^ꢁ(40 mg

1.7 mmol) was added in small pieces directly into the ﬂask to

provide an inky blue solution. After 10 min, the previously prepared

TBS silyl ether (100 mg, 0.179 mmol) was added as a solution in THF

(1 mL, with 1 mL rinse). The reaction was stirred at ꢀ78 ^ꢁC for

10 min, then ⁱPrOH (3 mL) was added dropwise until the blue color

dissipated to provide a clear colorless solution. Saturated aqueous

NH₄Cl (3 mL) was added and the cooling bath was removed and

replaced with a warm water bath. Stirring for 30 min allowed for

the evaporation of NH_3(l), and the remaining liquid was concen-

trated under reduced pressure to an aqueous slurry. The slurry was

extracted with CH₂Cl₂(3 ꢂ 5 mL), dried with MgSO₄, ﬁltered and

concentrated. Puriﬁcation by silica gel chromatography (gradient

4.1.29. (1R,4aR,5S,6R,7R,8aS)-5-(2-((4-methoxybenzyl)oxy)ethyl)-

7-(methoxymethoxy)-3,5-dimethyl-6-(prop-1-en-2-yl)-

1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-ol

To a room temperature solution of 39 (375 mg, 849 mmol) in

MeOH (14.5 mL) was added CeCl₃ꢃ7H₂O (0.54 g, 1.45 mmol). The

reaction was stirred for 5 min at room temperature, cooled

to ꢀ78 ^ꢁC and NaBH₄(82 mg, 2.17 mmol) was added. After 1 h

at ꢀ78 ^ꢁC the reaction was quenched with acetone (1 mL) warmed

to room temperature and concentrated. The resulting crude

mixture was partitioned between EtOAc and a 1:1 mixture of

saturated aqueous NaHCO₃and brine. The layers were separated

and the aqueous layer was extracted with EtOAc (4 ꢂ 5 mL). The

combined organic layers were dried with MgSO₄, ﬁltered through a

plug of silica gel and concentrated to provide the desired allylic

elution of 5e40% EtOAc/hexanes) provided 40 (69.1 mg, 88%) as a

21

colorless oil: R_f0.29 (hexanes/EtOAc (2:1)); [

a

]

D

þ15.4 (c 0.88,

CHCl₃); IR (ﬁlm) 3268, 2930, 2857, 1472, 1369, 1255, 1104, 1073,

1040, 836, 771 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃)

d

5.27 (s, 1H), 5.04

alcohol of 39 (0.356 mg, 94%) as a single diastereomer: R_f0.22 (1:1

(s, 1H), 4.80 (s, 1H), 4.65 (d, J ¼ 6.9 Hz, 1H), 4.58 (s, J ¼ 6.9 Hz, 1H),

3.84 (d, J ¼ 7.3 Hz, 1H), 3.79e3.73 (m, 2H), 3.65 (td, J ¼ 9.8, 6.7 Hz,

1H), 3.33 (s, 3H), 2.69 (dt, J ¼ 12.7, 4.5 Hz, 1H), 2.10 (d, J ¼ 10.9 Hz,

1H), 1.89e1.86 (m, 2H), 1.83 (s, 3H), 1.66 (s, 3H), 1.59e1.52 (m, 2H),

1.44 (tdd, J ¼ 12.0, 8.1, 4.2 Hz, 1H), 1.36 (ddd, 12.2, 9.9, 6.4 Hz, 1H),

0.91 (s, 9H), 0.88 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H); ¹³C NMR

21

Hexanes/EtOAc); [

a

]

_Dþ3.1 (c. 0.14, CHCl₃); IR (neat) 3426, 2925,

1640, 1613, 1513, 1453, 1376, 1302, 1248, 1154, 1096, 1037, 920,

820 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃)

d

7.22 (d, J ¼ 8.8 Hz, 2H), 6.86

(d, J ¼ 8.8 Hz, 2H), 5.34 (s, 1H), 5.02 (s, 1H), 4.74 (s, 1H), 4.70 (d,

J ¼ 6.9 Hz, 1H), 4.57 (d, J ¼ 6.9 Hz, 1H), 4.40 (ABq, J_AB¼ 11.7 Hz,

13

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

(125 MHz, CDCl₃)

d

144.4, 134, 5, 125.7, 114.9, 96.3, 75.9, 75.2, 58.4,

485.3063, found 485.3079.

57.5, 55.7, 41.7, 40.4, 40.3, 39.4, 38.5, 30.0, 26.1, 23.4, 18.3,

17.7, ꢀ3.8, ꢀ4.4; HRMS m/z calcd for C₂₅H₄₆O₄Si (M þ Na)^þ

461.3063, found 461.3075.

4.1.34. (4aS,4bR,8R,8aS,10R,10aR)-8-((tert-butyldimethylsilyl)oxy)-

10-(methoxymethoxy)-1,4a,6-trimethyl-4,4a,4b,5,8a,9,10,10a-

octahydrophenanthren-3(8H)-one (44)

4.1.32. 2-((1S,2R,3R,4aS,5R,8aR)-5-((tert-butyldimethylsilyl)oxy)-

3-(methoxymethoxy)-1,7-dimethyl-2-(prop-1-en-2-yl)-

To a room temperature solution of 42 (19 mg, 0.045 mmol) in

toluene (1.8 ml) was added Grubbs II catalyst [34] (43) (3.8 mg,

0.0045 mmol) as a solution in toluene (0.5 mL). The reaction was

heated in a 70 ^ꢁC bath. After 30 min, the mixture was concentrated

and puriﬁed by silica gel chromatography (5e15% EtOAc/hexanes)

1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-yl)acetaldehyde (41)

To a ꢀ78 ^ꢁC solution of (COCl)₂(0.39

mL, 0.46 mmol) in CH₂Cl₂

(0.5 mL) was added dry DMSO (0.05 mL, 0.68 mmol). The mixture

was stirred for 10 min and 40 (21.7 mg, 0.0495 mmol) was added as

a solution in CH₂Cl₂(0.2 mL, with 0.2 mL rinse). After stirring

at ꢀ78 ^ꢁC for 20 min, Et₃N (0.54 mL, 3.86 mmol) was added, the

cooling bath was removed, and the reaction was allowed to warm

to room temperature. The solution was diluted with water (1 mL).

The layers were separated and the aqueous layer was extracted

with CH₂Cl₂(3 ꢂ 2 mL). The combined organic layers were dried

with MgSO₄, ﬁltered and concentrated. Puriﬁcation by silica gel

chromatography (10% EtOAc/hexanes) provided aldehyde 41

to provide the ABC tricycle 44 (14.4 mg, 74%) characterized as fol-

21

lows: R_f0.32 (3:1 Hexanes/EtOAc); [

a]

þ34.1 (c. 0.18, CHCl₃); IR

D

(neat) 2955, 2928, 2855, 1668, 1471, 1442, 1377, 1257, 1148, 1102,

1070, 1040, 835, 775 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃)

d

5.91 (s, 1H),

5.29 (s, 1H), 4.76 (ABq, J_AB¼ 8.3 Hz, Dn_AB¼ 6.9 Hz, 2H), 3.87 (br s,

1H), 3.65 (td, J ¼ 10.7, 5.1 Hz, 1H), 3.40 (s, 3H), 2.89 (ddd, J ¼ 13.3,

5.1, 3.3 Hz,1H), 2.48 (d, J ¼ 16.6 Hz,1H), 2.41 (d, J ¼ 10.3 Hz,1H), 2.11

(d, J ¼ 16.6 Hz, 1H), 2.11 (s, 3H), 1.84e1.79 (m, 2H), 1.66 (s, 3H),

1.49e1.45 (m, 2H), 1.11e1.04 (m, 1H), 0.93 (s, 9H), 0.87 (s, 3H), 0.11

(s, 3H), 0.10 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

d 198.3, 163.9, 134.4,

(20.2 mg, 93%) as a colorless oil: R_f0.68 (hexanes/EtOAc (2:1));

20

[

a

]

þ37.8 (c 0.21, CHCl₃); IR (ﬁlm) 2954, 2928, 2856, 1716, 1471,

128.3, 125.6, 97.1, 75.8, 75.3, 56.5, 53.2, 51.6, 45.5, 42.3, 39.3, 38.6,

D

1362, 1250, 1152, 1105, 1072, 1041, 836, 774 cm^ꢀ1

(500 MHz, CDCl₃)

;

¹H NMR

9.87 (dd, J ¼ 3.3, 1.6 Hz, 1H), 5.28 (s, 1H), 5.08 (s,

29.5, 26.1, 25.5, 23.4, 18.3, 14.0, ꢀ3.9, ꢀ4.4; HRMS m/z calcd for

C

₂₅H₄₂O₄Si (M þ H)^þ436.2959, found 436.3014.

d

1H), 4.84 (s, 1H), 4.68 (d, J ¼ 6.9 Hz, 1H), 4.61 (d, J ¼ 6.9 Hz, 1H), 3.87

(d, J ¼ 7.8 Hz, 1H), 3.80 (td, J ¼ 10.9, 4.9 Hz,1H), 3.34 (s, 3H), 2.74 (dt,

J ¼ 12.7, 4.6 Hz, 1H), 2.49e2.41 (m, 2H), 2.26 (dd, J ¼ 16.4, 3.3 Hz,

1H), 1.90e1.70 (m, 3H), 1.83 (s, 3H), 1.66 (s, 3H), 1.47 (tdd, J ¼ 12.8,

8.3, 4.3 Hz, 1H), 0.97 (s, 3H), 0.92 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H);

Declaration of competing interest

The authors declare the following ﬁnancial interests/personal

relationships which may be considered as potential competing

interests: David R Williams reports ﬁnancial support was provided

by National Science Foundation.

¹³C NMR (125 MHz, CDCl₃)

d 202.1, 144.4, 134.0, 125.9, 96.3, 75.7,

74.8, 58.5, 55.8, 51.1, 42.7, 51.9, 39.4, 38.4, 30.1, 26.1, 23.3, 18.3,

16.7, ꢀ3.8, ꢀ4.3; HRMS m/z calcd for C₂₅H₄₄O₄Si (M þ Na)^þ

459.2906, found 459.2914.

Acknowledgements

4.1.33. 1-((1S,2R,3R,4aS,5R,8aR)-5-((tert-butyldimethylsilyl)oxy)-

3-(methoxymethoxy)-1,7- dimethyl-2-(prop-1-en-2-yl)-

This material is based upon work supported in part by the Na-

tional Science Foundation under Grants CHE1055441 and

CHE1665356. The authors also acknowledge support from Indiana

University. This project was partially funded by the Vice Provost for

Research through the Research Equipment Fund.

1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-yl)but-3-en-2-one (42)

To a ꢀ78 ^ꢁC solution of aldehyde 41 (25 mg, 0.058 mmol) in THF

(1.2 mL) was added vinylmagnesium bromide (0.29 mL, 0.29 mmol,

1 M in THF). The mixture was stirred at 0 ^ꢁC for 15 min, quenched

with saturated aqueous NH₄Cl, diluted with CH₂Cl₂and allowed to

warm to room temperature. The layers were separated and the

aqueous layer was extracted with CH₂Cl₂(3 ꢂ 4 mL). The combined

organic layers were dried with MgSO₄, ﬁltered and concentrated to

provide the corresponding allylic alcohol as a 3:2 mixture of di-

astereomers which were utilized without additional puriﬁcation.

The crude oil was dissolved in CH₂Cl₂(1.2 mL) and TPAP [33] (2 mg,

0.0058 mmol) followed by N-methyl-morpholine-N-oxide (NMO)

(20 mg, 0.17 mmol) was added. The black mixture was stirred at

room temperature for 30 min, diluted with 20% EtOAc in hexanes,

ﬁltered through a plug of silica gel using 20% EtOAc in hexanes and

References

[1] a) For a review: P.O. Guillen, S. Gegunde, K.B. Jaramillo, A. Alfonso, K. Calabro,

E. Alonso, J. Rodriguez, L.M. Botana, O.P. Thomas Mar. Drugs 16 (2018) 242;

b) B. Rao, A.S.R. Anjaneyula, S.S. Sarma, Y. Venkatateswarlu, M. Chen, J. Clary,

R. Rosser, J. Faulkner, J. Am. Chem. Soc. 106 (1984) 7984;

c) M. Kuramoto, K. Hayashi, Y. Fujitani, K. Yamaguchi, T. Tsuji, K. Yamada,

Y. Ijuin, D. Uemura, Tetrahedron Lett. 38 (1997) 5683;

d) S. Fukuzawa, Y. Hayashi, D. Uemura, Heterocycl. Commun. 1 (1995) 207;

ꢀ

e) A.H. Daranas, J.J. Fernandez, J.A. Gavin, M. Norte, Tetrahedron 55 (1999)

5539.

[2] a) A. Atta-ur-Rahman, K.A. Alvi, A. Abbas, M.L. Choudhary, J. Clardy, Tetrahe-

dron Lett. 30 (1989) 6825;

ꢀ

b) F. Cen-Pacheco, M. Norte, J. Fernandez, A.H. Daranas, Org. Lett. 16 (2014)

concentrated to provide 42 (19 mg, 71% for two steps) as a colorless

2880;

21

oil: R_f0.72 (3:1 Hexanes/EtOAc); [

a

]

þ48.9 (c. 0.32, CHCl₃); IR

c) Y.-B. Cheng, J.-W. Lo, L.-F. Shyur, C.-C. Yang, Y.-M. Hsu, J.-H. Su, M.-C. Lu, S.-

F. Chiou, C.-C. Lan, Y.-C. Wu, F.-R. Chang, Tetrahedron 71 (2015) 8001;

D

(neat) 2955, 2928, 2856, 1708, 1685, 1639, 1611, 1471, 1400, 1250,

ꢀ

d) A.H. Daranas, J.J. Fernandez, J.A. Gavin, M. Norte, Tetrahedron 54 (1998)

1152, 1070, 1041, 836, 774 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃)

;

d

6.28

7891;

(dd, J ¼ 17.6, 10.5 Hz, 1H), 6.15 (d, J ¼ 17.6 Hz, 1H), 5.76 (d,

J ¼ 10.6 Hz, 1H), 5.27 (s, 1H), 4.97 (s, 1H), 4.72 (s, 1H), 4.69 (d,

J ¼ 6.8 Hz,1H), 4.61 (d, J ¼ 6.8 Hz, 1H), 3.90 (d, J ¼ 7.3 Hz, 1H), 3.80

(td, J ¼ 11.0, 4.9 Hz, 1H), 3.36 (s, 3H), 2.87 (d, J ¼ 10.7 Hz, 1H), 2.72

(dt, J ¼ 12.8, 4.6 Hz,1H), 2.58 (d, J ¼ 18.6 Hz,1H), 2.50 (d, J ¼ 18.4 Hz,

1H), 2.34 (td, J ¼ 11.6, 6.1 Hz, 1H), 1.85e1.79 (m, 1H), 1.75 (s, 3H),

1.67e1.56 (m, 1H), 1.62 (s, 3H), 1.44 (dddd, J ¼ 15.4, 11.4, 7.7, 3.6 Hz,

1H), 1.07 (q, J ¼ 12.0 Hz, 1H), 0.93 (s, 9H), 0.90 (s, 3H), 0.10 (s, 6H);

e) Y.-M. Hsu, F.-R. Chang, I.W. Lo, K.-H. Lai, M. El-Shazly, T.-Y. Wu, Y.-C. Du, T.-

L. Hwang, Y.-B. Cheng, Y.-C. Wu, J. Nat. Prod. 79 (2016) 2674.

[3] a) F. Yoshimura, K. Tanino, M. Miyashita, Acc. Chem. Res. 45 (2012) 746;

b) M. Farrokhnia, K. Mahnam, Iran. J. Pharm. Res. (IJPR) 16 (2015) 173;

c) T. Genji, S. Fukuzawa, K. Tachibana, Mar. Biotechnol. (2010) 81.

[4] a) For an overview: B. Stolz, D. Behenna, J. Stockdill Angew. Chem. Int. Ed. 47

(2008) 2365;

ꢀ

b) R. Villar, J. Gil-Longo, A. Daranas, M. Souto, J. Fernandez, S. Peixinho,

ꢀ

M. Barral, G. Santafe, J. Rodríguez, C. Jimenez, Bioorg. Med. Chem. 11 (2003)

2301.

¹³C NMR (125 MHz, CDCl₃)

d 199.2, 137.6, 134.1, 126.8, 126.1, 96.2,

[5] M. Miyashita, M. Sasaki, I. Hattori, M. Sakai, K. Tanino, Science 305 (2004) 495.

[6] a) F. Yoshimura, M. Sasaki, I. Hattori, K. Komatsu, M. Sakai, K. Tanino,

M. Miyashita, Chem. Eur J. 15 (2009) 6629;

75.9, 55.7, 46.2, 41.3, 39.8, 39.4, 38.2, 30.3, 29.8, 26.2, 23.4, 18.3,

17.5, ꢀ3.8, ꢀ4.3; HRMS m/z calcd for C₂₇H₄₆O₄Si (M þ Na)^þ

b) Y. Takahashi, F. Yoshimura, K. Tanino, M. Miyashita, Angew. Chem. Int. Ed.

14

D.R. Williams, P.T. Gladen and S. Patnaik

Tetrahedron 95 (2021) 132354

48 (2009) 8905.

rearrangements. Some examples include: a) R.E. Ireland, P. Wipf, J.-N. Xiang,

J. Org. Chem. 55 (1991) 3572;

[7] a) Y. Murata, D. Yamashita, K. Kitahara, Y. Minasako, A. Nakazaki, S. Kobayashi,

Angew. Chem. Int. Ed. 48 (2009) 1400;

b) R.E. Ireland, R.C. Anderson, R. Badoud, B.J. Fitzsimmons, G.J. McGarvey,

S. Thaisrivongs, C.S. Wilcox, J. Am. Chem. Soc. 105 (1983) 1988;

c) R.E. Ireland, J.-P. Vevert, Can. J. Chem. 59 (1981) 572;

d) T.J. Fulton, A.Q. Cusumano, E.J. Alexy, Y.E. Du, H. Zhang, K.N. Houk,

B.M. Stoltz, J. Am. Chem. Soc. 142 (2020) 21938;

e) P.A. Magriotis, K.D. Kim, J. Am. Chem. Soc. 115 (1993) 2972;

f) N. Soldermann, J. Velker, A. Neels, H. Stoeckli-Evans, R. Neier, Synthesis

(2007) 2379.

b) D. Yamashita, Y. Murata, N. Hikage, K.-i. Takao, A. Nakazaki, S. Kobayashi,

Angew. Chem. Int. Ed. 48 (2009) 1404.

[8] In addition to the citations contained in the review of reference 4a, recent

works also include:. a) H. Xue, J. Yang, P. Gopal, Org. Lett. 13 (2011) 5696;

b) T.X. Nguyen, M. Dakanali, L. Trzoss, E.A. Theodorakis, Org. Lett. 13 (2011)

3308;

c) J.L. Stockdill, D.C. Behenna, A. McClory, B.M. Stoltz, Tetrahedron 65 (2009)

6571;

d) N. Sugano, Y. Koizumi, G. Hirai, H. Oguri, S. Kobayashi, S. Yamashita,

M. Hirama, Chem. Asian J. 3 (2008) 1549;

[20] For a computational study of chair-like and boat-like transition states in

IrelandeClaisen rearrangements: S. Gül, F. Schoenebeck, V. Aviyente,

K.N. Houk J. Org. Chem. 75 (2010) 2115.

e) D.C. Behenna, J.L. Stockdill, B.M. Stoltz, Angew. Chem. Int. Ed. 46 (2007)

4077.

[21] P.A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 41 (1976) 1485.

[22] Y. Nagao, Y. Hagiwara, T. Kumagai, M. Ochiai, T. Inoue, K. Hashimoto, E. Fujita,

J. Org. Chem. 51 (1986) 2391.

[9] a) D.R. Williams, G.S. Cortez, Tetrahedron Lett. 39 (1998) 2675;

b) D.R. Williams, T.A. Brugel, Org. Lett. 2 (2000) 1023;

c) D.R. Williams, D.C. Ihle, T.A. Brugel, S. Patnaik, Heterocycles 70 (2006) 77;

d) D.R. Williams, S. Patnaik, G.S. Cortez, Heterocycles 72 (2007) 213.

[10] S. Patnaik, I. Formal Synthesis of Leucascandrolide A; II. Synthetic Studies

towards the Zoanthamine Alkaloids, Ph.D. Thesis, Indiana University, February

2006.

[11] For a detailed preparation and examples of related Evans aldol reactions a)

J.R. Gage, D.A. Evans, Org. Synth. Coll. 8 (1993) 339;

b) D.R. Williams, D.C. Ihle, S.V. Plummer, Org. Lett. 3 (2001) 1383.

[12] a) I. Ohtani, T. Kusumi, M.O. Ishitsuk, H. Kakisawa, Tetraheron Lett 30 (1989)

3147;

b) T. Hoye, C.S. Jeffery, F. Shao, Nat. Protoc. 2 (2007) 2451;

c) J.A. Dale, H.S. Mosher, J. Am. Chem. Soc. 95 (1973) 512.

[13] An identical 3:1 mixture of esters 12 and 13 was also produced in reactions of

11 with 3-methyl-3-butenoic acid under these conditions..

[14] For a review of the Claisen rearrangement: D.R. Williams, P.P. Nag, Claisen and

mologations e Part II, Wiley & Sons, Hoboken, NJ, 2009, pp. 33e87.

[15] a) For a review of conditions for enolate geometry pertaining to stereocontrol

in the IrelandeClaisen rearrangement, see: A.M.M. Castro Chem. Rev. 104

(2004) 2939;

[23] A. Gonzalez, J. Aiguade, F. Urpi, J. Vilarrasa, Tetrahedron Lett. 37 (1996) 8949.

[24] a) U. Mahler, R.M. Devant, M. Braun, Chem. Ber. 121 (1988) 2035;

b) M. Braun, B. Mai, D.M. Ridder, Synlett (1999) 1600.

[25] a) H.C. Brown, K.S. Bhat, R.S. Randad, J. Org. Chem. 54 (1989) 1570;

b) U.S. Racherla, H.C. Brown, J. Org. Chem. 56 (1991) 401.

[26] a) E.J. Corey, C.M. Yu, S.S. Kim, J. Am. Chem. Soc. 111 (1989) 5493;

b) D.R. Williams, D.A. Brooks, K.G. Meyer, M.P. Clark, Tetrahedron Lett. 39

(1998) 7251;

c) D.R. Williams, K.G. Meyer, K. Shamim, S. Patnaik, Can. J. Chem. 82 (2004)

120;

d) D.R. Williams, B.A. Atwater, S.A. Bawel, P. Ke, O. Gutierrez, D.J. Tantillo, Org.

Lett. 16 (2014) 468.

[27] a) R.O. Duthaler, P. Herold, S. Wyler-Helfer, M. Reidiker, Helv. Chim. Acta 73

(1990) 659;

b) R.O. Duthaler, A. Hafner, Chem. Rev. 92 (1992) 807.

[28] R.H. Wollenberg, S. Miller, Tetrahedron Lett. 19 (1978) 3219.

[29] Our early studies of stereoselectivity in the intramolecular DielseAlder cy-

cloadditions of nitroalkenes have noted this preference for the production of

trans-fused decalin systems. See: D.R. Williams, J.C. Klein, N.S.C. Chow Tet-

rahedron Lett. 52 (2011) 2120.

[30] D.R. Williams, J.C. Klein, L.C. Kopel, N. Nguyen, D.J. Tantillo, Org. Lett. 18 (2016)

424.

[31] F.A. Davis, S. Chattopadhyay, J.C. Towson, S. Lal, T. Reddy, J. Org. Chem. 53

(1988) 2087. L.C. Vishwakarma, O. D. Stringer, F. A. Davis, Org. Synth. 66

(1988) 203; Coll. Vol. 8, (1993) 546.

b) For a seminal study, see: R.E. Ireland, R.H. Mueller, A.K. Willard J. Am. Chem.

Soc. 98 (1976) 2868.

[16] D.R. Williams, J.C. Klein, Org. Lett. 18 (2016) 420.

[17] F.L. Harris, L. Weiler, Tetrahedron Lett. 25 (1984) 1333.

[18] a) T. Beetz, R.M. Kelogg, C.T. Kiers, A. Piepenbroek, J. Org. Chem. 40 (1975)

3309;

[32] J.L. Luche, J. Am. Chem. Soc. 100 (1978) 2226.

[33] S.V. Ley, J. Norman, W.P. Grif ﬁ th, S.P. Marsden, Synthesis (1994) 639.

[34] For a seminal publication a) M. Scholl, S. Ding, C.W. Lee, R.H. Grubbs, Org. Lett.

1 (1999) 953, for reviews:;

b) M. Brechbiel, H. Kwart, J. Org. Chem. 47 (1982) 5411;

c) S.R. Wilson, L. Jacob, J. Org. Chem. 57 (1992) 4380;

ꢀ

d) S. Gil, M.A. Lazaro, M. Parra, E. Breitmaier, R. Mestres, Synlett 1 (1997) 70;

b) R.H. Grubbs, Tetrahedron 60 (2004) 7177;

e) C. Fehr, N. Chaptal-Gradoz, Helv. Chim. Acta 85 (2002) 533.

c) K.C. Nicolaou, P.G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 44 (2005) 4490.

[19] Boat-like transition states are not uncommon in IrelandeClaisen

15

Article Doi

Studies toward norzoanthamine: Ireland–Claisen rearrangements of α,β-unsaturated esters in a stereocontrolled synthesis of trans-fused 2-cyclohexen-1-ones

DOI: 10.1016/j.tet.2021.132354

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2021.132354

Full text of DOI:10.1016/j.tet.2021.132354

Products guided by the article

R&D Labs maybe for 266675-80-3

Relevant to this article

Hot Product