Total synthesis of the lycopodium alkaloid serratezomine a using free radical-mediated vinyl amination to prepare a β-stannyl enamine linchpin

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Total Synthesis of the Lycopodium Alkaloid Serratezomine A Using

Free Radical-Mediated Vinyl Amination to Prepare a β‑Stannyl

Enamine Linchpin

Julie A. Pigza,^†,§Jeong-Seok Han,^†,⊥Aroop Chandra,^†,∥Daniel Mutnick,^†,#Maren Pink,^‡

and Jeﬀrey N. Johnston*^,†

^†Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822,

United States

^‡Indiana University Molecular Structure Center, Bloomington, Indiana 47405, United States

S

* Supporting Information

ABSTRACT: Serratezomine A is a member of the structurally diverse class of compounds known as the Lycopodium alkaloids.

The key supporting studies and successful total synthesis of serratezomine A are described in this account. Signiﬁcant features of

the synthesis include the ﬁrst application of free radical mediated vinyl amination and Hwu’s oxidative allylation in a total

synthesis and an intramolecular lactonization via a transannular S_Ni reaction. Minimal use of protecting groups and the highly

diastereoselective formation of a hindered, quaternary stereocenter using an umpolung allylation are also highlights from a

strategy perspective. Observation of quaternary carbon epimerization via a retro-Mannich/Mannich sequence highlights the

additional challenge presented by the axial alcohol at C8 in serratezomine A.

Lycopodium alkaloids, huperzine A (2, Figure 1), a constituent

alkaloid, has shown the most promising biological activity. It

has been used for the treatment of neurodegenerative disorders

relating to the neurotransmitter acetylcholine, including

myasthenia gravis and Alzheimer’s disease,⁴⁻⁶and is available

as a dietary supplement to enhance memory.

INTRODUCTION

■

Serratezomine A (1), a C₁₆N alkaloid belonging to the

fawcettimine class of Lycopodium alkaloids,^1,2was isolated

from the club moss Lycopodium serratum var. serratum in 2000

(Figure 1).³Serratezomine A exhibited moderate cytotoxicity

against murine lymphoma L1210 cells (IC₅₀= 9.7 μg/mL) and

human epidermoid carcinoma KB cells (IC₅₀>10 μg/mL) and

demonstrated strong anticholinesterase activity. Of the

The complex framework of the Lycopodium alkaloids makes

them challenging, yet attractive targets for total synthesis.

Serratezomine A contains six contiguous stereocenters

including a spirocyclic all-carbon center contained within a

tetracyclic ring system. The structure of 1 was determined by

¹H and ¹³C NMR, a combination of 2D NMR techniques, and

from data obtained by the structurally similar serratinine (3).³

In addition, serratinine (3) was converted to 1 via a biomimetic,

one-pot modiﬁed Polonovski rearrangement.⁷The ﬁrst total

synthesis of 1 was recently completed by us,⁸and elegant

syntheses of the structurally similar serratinine (3)^9,10and

fawcettimine (4)¹¹have also been accomplished. Still other

Lycopodium alkaloids have been the subject of recent

publications.¹²In this report, our complete study leading to

the successful preparation of (+)-serratezomine A through total

chemical synthesis is described. The steric inﬂuence of the axial

alcohol was evident in the discovery of an undesired

Figure 1. Serratezomine A (1) and representative Lycopodium

alkaloids.

Received: October 31, 2012

Published: December 28, 2012

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a

epimerization at the spirocyclic carbon, which was successfully

overcome in the ﬁnal synthetic route.

Scheme 2. Synthesis of Carboxylic Acid 19

Our retrosynthetic approach to serratezomine A (1) is

presented in Scheme 1. The ﬁrst two disconnects involve the

Scheme 1. Retrosynthetic Analysis of 1

a

(a) O₃, EtOH, −78 °C, then DMS, 93%: (b) (−)-Ipc-crotylborane,

BF₃·OEt₂, −60 °C, 7 d, then NaOOH, 79%, 93% ee, 11:1 dr; (c)

TBSCl, imidazole, DMF, 95%; (d) 2-methyl-2-butene, BH₃·DMS,

THF, 0 °C, 4 h, then NaOOH, 82%; (e) Dess−Martin periodinane,

CH₂Cl₂, 0 °C, 4 h, 97%; (f) NaClO₂, NaH₂PO₄, 2-methyl-2-butene

(95%).

alcohol was installed in the anti-conﬁguration using a Brown

crotylation. This reaction is especially diﬃcult with unsaturated

aldehydes and tends to provide lower yields and selectivities.¹⁸

Fortunately, using a modiﬁcation on multigram scale that

included a large dry ice bath that could be maintained for an

extended period, the desired product was formed with good

enantioselectivity and yield (14, 93% ee, 79% yield). Careful

temperature control was imperative to good stereoselection

since considerable conversion could occur as the reaction

mixture warmed during the quenching process. The structure of

the main diastereomer was conﬁrmed by formation of both

(R)- and (S)-Mosher esters in which NMR analysis led to the

determination of relative stereochemistry as depicted for

alcohol 14.¹⁹The majority of the terpene alcohol (15, a

byproduct from the chiral auxiliary oxidation) could be

fractionally distilled, and the crude reaction mixture containing

the two alcohols (14 and any remaining 15) was subjected to

TBS protection to aﬀord the mixture of TBS ethers. The TBS

group provided greater separation of the two products by

column chromatography and allowed for the isolation of pure

16. Using the optimized reaction conditions, the crotylation

reaction could be performed on a 50 g scale to provide the silyl

ether (16) in 75% yield over 2 steps.

After successful installation of the ﬁrst two stereocenters, our

attention focused on elaboration of the terminal alkene in 16.

Treatment with disiamylborane followed by oxidative work up

aﬀorded primary alcohol 17 in good yields (70−85%).²⁰

Subsequent oxidation of the primary alcohol 17 using Dess−

Martin periodinane²¹gave the desired aldehyde in a

quantitative yield, which then was carried through the Pinnick

oxidation²²to aﬀord carboxylic acid 19.

The stage was now set for the convergent coupling with a β-

stannyl enamine linchpin. Starting from pentynyl chloride 12, a

Gabriel amine synthesis was utilized to form primary amine 20

in 85% yield (Scheme 3).²³The protecting group on the amine

was formed via transimination with benzophenone imine to

form imine 11a.²⁴The protecting group on the nitrogen could

be varied and is an important aspect for success of the free-

piperidine and lactone rings. The piperidine ring formation is

evident after functionalization of the pendant alkene in 5 to

provide a leaving group for imine cyclization and reduction to

the bicyclic amine. The lactone ring is formed after

saponiﬁcation of the ester and displacement of the mesylate.

Target 5 provides an intermediate that contains all of the

carbons in the natural product. Installation of the allyl group

was to be attempted through a diastereoselective allylation of

vinylogous amide 6. The cyclohexanone ring in 6 was

anticipated to result from an intramolecular Michael addition

of the vinylogous amide and α,β-unsaturated ester in 7d.

Selectivity in this step was projected to be the result of A^1,3-

strain minimization¹³and favor an axial ethyl acetate

substituent as depicted in 7d. The N-protected vinylogous

amide represents the convergent point in our synthesis. It was

expected to be accessible via acylation of β-stannylenamine 9d

with acid chloride 8. The β-stannylenamine was synthesized by

methodology developed earlier by us, involving a nonconven-

tional radical-mediated 5-exo-trig cyclization of an imine.^14,15

The required imine (11d) is accessible in three steps from the

commercially available chloride 12 by a Gabriel amine

synthesis. The acid chloride portion (8) was anticipated to be

accessible from α,β-unsaturated aldehyde 10 using a Brown

crotylation. The two stereocenters in 8 would be used to direct

the formation of all remaining stereocenters in 1.

RESULTS AND DISCUSSION

■

The synthesis began with selective ozonolysis of the terminal

alkene in commercially available ethyl sorbate (13, Scheme

2).¹⁶The α,β-unsaturated aldehyde (10) was isolated after

vacuum distillation in up to 93% yield.¹⁷Next, the homoallylic

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Scheme 3. Synthesis of the β-Stannyl Enamine Linchpin

Table 1. Deprotection and Cyclization Attempts of

a

Vinylogous Amides

entry

vinylogous amide

reagent(s)

result

a

1

7a

7b

7c

7d

NH₃CO₂H, Pd/C

HCO₂H, Pd/C

Et₃SiH, TFA

Et₃SiH, TFA, PhSH

EtSH, AlBr₃(30 equiv)

BCl₃

22a

2

NR

3

4

22b

NR

5

6

7

BBr₃

NR

a

8

BBr₃(5 equiv)

DDQ

22b

22c

(a) phthalimide, DMF, 100%; (b) H₂NNH₂, MeOH, 85%; (c)

n

9

benzophenone imine, 4 Å MS, CH₂Cl₂, 99%; (d) Bu₃SnH, AlBN,

10

11

12

13

14

15

16

17

18

19

20

21

22

23

DDQ

22c

C₆H₆, 90 °C, 70%.

b

CAN

(PMP)₂CO

22c

DDQ (pH = 7)

80% AcOH

radical mediated amination and future deprotection reaction

(vide infra).

22b

NR

EtSH, AlBr₃(30 equiv)

KO^tBu, DMSO

Li, NH₃

KO^tBu, DMSO

EtSH, AlBr₃(30 equiv)

EtSH, AlBr₃(0.2 equiv)

Li, NH₃

Free radical-mediated aminostannation was carried out using

n

slow addition of Bu₃SnH and AIBN to a reﬂuxing, degassed

benzene solution of imine 11a (Scheme 3).¹⁴The stannane

radical adds to the terminal position of the alkyne (as in 21a) to

form the vinyl radical (21b). The 5-exotrig cyclization of the

vinyl radical onto the azomethine nitrogen provides a stabilized

tertiary carbon radical adjacent to two phenyl groups (21c).²⁵

This radical is quenched by ⁿBu₃SnH to form β-stannylenamine

9a, which is used in unpuriﬁed form for the subsequent

coupling reaction with acid chloride 8.

NR

22b

NR

DDQ

22c

CAN

Ph₃C⁺BF₄

6

−

NR

a

Deprotection only occurred post-reduction of the α,β-unsaturated

The acid chloride needed for the coupling was made by

treating acid 19 with oxalyl chloride (Scheme 4). After removal

b

system, as observed by crude ¹H NMR. This indicates that the

expected ketone from deprotection was isolated. However, the

corresponding enamine/cyclized product was not isolated.

a

Scheme 4. Synthesis of N-Protected Vinylogous Amides

ation with Lewis acids with or without hydride reducing agents

(entries 3−8) and metal-catalyzed reduction (entries 1−2).^19b

These reactions either did not occur or caused deprotection of

the TBS group (to form 22b). Oxidative removal of the N-

protecting group using DDQ led to cleavage of the vinylogous

amide to form lactam 22c (entry 9). Oxidative deprotection

methods attempted with the other vinylogous amides (7b−7d)

also resulted in lactam 22c (entries 10, 12, 21). Using CAN

instead of DDQ provided the most interesting results with both

7b (entry 11) and 7d (entry 22). In both cases, the N-

deprotection was successful and the ketone byproduct was

observed (bis(PMP) ketone in entry 11 and PMP-CH₃ketone

in entry 22), but none of the deprotected product could be

isolated (22a). Fortunately, using CAN with substrate 7d

(entry 22) provided the desired, cyclized product (6).

Only one diastereomer of the product (6) was observed, and

this was expected on the basis of examination of the

interactions within the transition state (Scheme 5). Developing

A^1,3-strain between the large ethyl acetate substituent and the

nitrogen protecting group in pretransition state assembly 23a

would disfavor the ethyl ester substituent in the equatorial

a

(a) oxalyl chloride, DMF, CH₂Cl₂, 0 °C; (b) 9a−d, THF. PMP = p-

MeOC₆H₄.

of volatile compounds, the crude acid chloride 8 was added to

the β-stannyl enamine (9a), and the resulting oil was

chromatographed to provide the coupled product (7a).

Vinylogous amides (7b, 7c, and 7d), with diﬀerent N-

protecting groups, were synthesized utilizing the same protocol

with β-stannyl enamines (9b, 9c,^14cand 9d, respectively).

With vinylogous amides 7a−d in hand, the intramolecular

conjugate addition was attempted (Table 1). Various methods

were initially investigated to eﬀect the deprotection/cyclization

using diphenylmethyl (DPM)-protected 7a, such as complex-

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using NaH and THF (80% yield) but can also occur simply by

chromatography of 6 on Et₃N-treated silica gel.

Scheme 5. Transition State Analysis of the Oxidative

Deprotection and Michael Addition

A plausible mechanism for formation of imide 26 is outlined

in Scheme 7. Deprotonation of the acidic pyrrolidine nitrogen

Scheme 7. Mechanism of the Base-Mediated Cyclization

in vinylogous amide 6 would lead to enolate 27a. Rotation

about the C−C σ-bond, nucleophilic attack by the vinylogous

amide on the ester, and a cyclohexanone ring ﬂip leads to 27b.

This ring ﬂip locates the nitrogen in proximity to the ester side

chain allowing for cyclization to form imide 26. The fact that

the transformation occurs on SiO₂treated with Et₃N suggests

the importance of base to enhance the nucleophilicity of the

nitrogen N−H.

While this reaction course was unplanned, imide 26 appeared

to be a viable intermediate to serratezomine A (1). Imide 26

was more stable over time, compared to 6, and provided a rigid,

tricyclic structure that might also be advanced to serratezomine

A. A comparison of the two routes is shown in Scheme 8 (new

position. Alternatively, pretransition state 23b containing the

axial ester would minimize this strain between the ester and the

pyrrolidine ring and also between the vinyl hydrogen and large

OTBS group. NOE studies were performed on the isolated

product (6) to conﬁrm the stereochemistry of the ester side

chain as well as those created by the Brown crotylation. The

vinylogous amide was established as Z on the basis of an NOE

correlation between the equatorial hydrogen and a methylene

of the pyrrolidine ring. Furthermore, the chair conformation of

the cyclohexanone ring in solution was determined on the basis

of coupling constant analysis. Under optimal conditions, the

desired vinylogous amide could be isolated in up to 46% yield.

The next desired step was the installation of an allyl group,

which would provide the three carbons in the piperidine ring of

serratezomine A. However, exposure of vinylogous amide 6 to a

Scheme 8. Evaluation of a Second Approach to 1

n

variety of bases (LDA, KO^tBu, KHMDS, BuLi) and allyl

halides did not provide any of the desired substrate (25,

Scheme 6). Under all conditions, either starting material was

recovered or a new product was formed containing a strong UV

active π-system and led to assignment of the new product as

vinylogous imide 26. The reaction gave the highest yield when

Scheme 6. Formation of a New Tricyclic Backbone (26)

= route 1, original = route 2).²⁶For route 1, a reductive

allylation (e.g., dissolving metal reduction) of vinylogous imide

26 would furnish 28. The amide bond could act as a protecting

group for the nitrogen until cyclization to form the piperidine

ring was necessary, at which time the amide would be

solvolyzed. Alternatively, if route 2 using vinylogous amide 6

was applied, then the ester functionality would have to be

reduced prior to allylation to prevent imide formation (as in

29). With 29 in hand, allylation would provide 30. Both routes

address the installation of the congested quaternary carbon,

which we anticipated would be among one of the most

challenging aspects of the synthesis, unusually so for

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serratezomine A relative to other Lycopodium alkaloids because

of its axial alcohol at C8. During the early studies investigating

route 2, any reagents used to eﬀect ester reduction still proved

too basic and instead caused cyclization to imide 26. At that

point, the decision was made to investigate route 1.

Claisen Approach to Establish the C12 Quaternary

Stereocenter (Route 1). To progress forward with this route,

an allyl group would need to be installed adjacent to the ketone,

as in 28. Alkene reduction of 26 and a subsequent allylation

provided a feasible sequence that might be adapted to a one

step process.²⁷Alkene reduction was achieved using metal-

catalyzed hydrogenation on either vinylogous amide 6 or imide

26 (Scheme 9). Hydrogenation of 6 over Pd/C provided a 56%

converted to the desired allylation product (28) via a Claisen

rearrangement.

Pursuing this course, ether 33 was heated to 170 °C in a

sealed tube. While the reaction was successful, it provided the

undesired allyl epimer with the trans-decalone ring system (34,

Scheme 10). The key NOESY correlation used in assigning the

Scheme 10. Claisen Rearrangement of 33

Scheme 9. Formation and Reactions of the Tricyclic

Backbone

conﬁguration was the 1,3-diaxial interaction between the

geminal hydrogen to the OTBS group and one of the

hydrogens of the methylene carbon in the allyl group. Modeling

studies using Pcmodel showed that while the energy diﬀerence

between non-allylated trans-decalone 31 and cis-32 was

relatively small (0.13 kcal/mol), the diﬀerence between

allylated trans-decalone 34 and cis-28 is much greater (2.4

kcal/mol) with trans-34 being favored. Inspection of the bond

angles in each 6-membered ring showed that the cyclohexanone

ring suﬀered the most torsional strain in cis-decalone 28 due to

the allyl group. This would explain why capture of a proton is

possible to form the cis-decalone (32) but allylation in this

same manner was never observed (28). It appeared that

substrate control would not be easily overcome to obtain the

desired allylation product. This realization encouraged us to

further consider route 2 involving reduction of the ester to

prevent cyclization to form imide 26 (see Scheme 8 for

comparison of the two routes).

Oxidative Allylation Approach to Establish the

Quaternary Stereocenter at C12 (Route 2). To explore

route 2, the ester in 6 would need to be reduced to prevent the

cyclization to the imide. As mentioned, many reducing agents

were also suﬃciently basic, causing cyclization to imide 26

(even NaBH₄/CeCl₃). The key reducing agent was eventually

identiﬁed as Red-Al in toluene. It allowed reduction of the ester

to form 35, which was then protected as pivalate 36 in good

yield (Scheme 11).

Diﬀerent allylation reaction conditions were then attempted

to install the three carbon chain necessary to form the

piperidine ring (36 → 37, Scheme 11). These attempts focused

on various base-mediated alkylation reactions but were not

successful despite the possibility of N, C, or O-alkylation. Even

metal-catalyzed hydrogenation, which worked well with imide

26, did not work to provide any alkene reduction (in which an

allyl group would be added in a second step). Unreacted

starting material was isolated in all cases. Interestingly, if the

allyl halide was exposed to Ag(I) salts, small amounts of

allylated products were observed, which indicates that the

vinylogous amide is inherently nucleophilic. An attempt to

capitalize on this behavior was tested via exposure of 36 to two

yield of ketone 31, while PtO₂provided over-reduction of the

ketone as well (to form the α-OH, not shown).²⁸Alternatively,

imide 26 could be reduced using catecholborane in the

presence of Wilkinson’s catalyst to form ketone 31.²⁹

Gratifyingly, the pyrrolidine stereocenter in both reductions

was set in the correct orientation as is required in serratezomine

A, indicating that substrate control provided the needed

conﬁguration.³⁰

The stereocenter of the hydrogen adjacent to the ketone in

31, however, is opposite to that of the desired allyl group (as in

28). Epimerization was possible in the presence of bases that

established thermodynamic conditions, such as NaH or ^tBuOK,

to provide the ketone epimer with a cis-orientation of the 6,6-

ring system (32, Scheme 9). Epimer 32 could also be formed in

one step using a solution of lithium in NH₃(26 → 32). If

allylation could occur from the same face as protonation (see

28), then successful installation of the quaternary center would

be achieved. However, attempts to capture the enolate with

allyl halides and a variety of bases did not result in any C-

allylation (28) starting from either ketone epimer (31 or 32).

Small amounts of O-allylated product 33 were isolated though

and could be enhanced using KO^tBu and HMPA (61% yield).

Allyl vinyl ether 33 is signiﬁcant since it could potentially be

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reaction because oxygen can react with a radical intermediate,

leading to oxidation byproducts (one of which was identiﬁed as

α-hydroxyketone 39). A further improvement was made by

switching CTAN to CAN, which gave the highest yields (58−

67%) and diastereoselection (23:1, assigned on the basis of

isolation of the minor diastereomer on large scale, epi-37).

The mechanism of the oxidative allylation is believed to

involve single electron oxidation of the vinylogous amide (36)

by cerium(IV), forming radical cation 40a (Scheme 13).^37a,39

Scheme 11. Ester Reduction and Alkene Functionalization

Scheme 13. Plausible Mechanism of the Cerium-Mediated

Allylation

a

(a) Red-Al, toluene, 0 °C to rt, 81%; (b) pivalic anhydride, Et₃N,

DMAP, CH₂Cl₂, rt, 40 h, 93%; (c) NCS, CH₂Cl₂, 15 min, 85% (38a);

(d) MCPBA, CH₂Cl₂, rt, 30 min, 42% (38b, 63% brsm). *Stereo-

center not conﬁrmed.

oxidants, NCS³¹and MCPBA, providing the α-chloro ketimine

(38)³²and α-hydroxy ketimine (39), respectively.³³

Both 38 and 39 were reasonable substrates to allow

introduction of an allyl group by reductive enolate formation.³⁴

However, exposure of either compound to SmI₂and

allylbromide provided intractable mixtures. The use of either

35

Fe(acac)₃or HMPA³⁶provided a cleaner reaction, but no

allylated product (37) was observed and only reduced

vinylogous amide 36 was isolated. This demonstrates that the

α-carbon-heteroatom bond was reductively cleaved, but

protonation followed rather than allylation.

The insight gained from exposure of 36 to oxidants led us to

the successful work from the Flowers’ group utilizing a cerium-

mediated oxidative allylation of vinylogous amides.³⁷Their

research used a more soluble source of Ce(IV) known as

CTAN³⁸(Ce(NBu₄)₂(NO₃)₆) along with allyl silane as the

source of the three carbon chain. Initial allylation attempts

using CTAN, allyl silane, and vinylogous amide 36 furnished a

C-allyl product in only 20% yield. However, 2D NMR analysis

indicated the product was indeed the desired diastereomer (37,

Scheme 12). Optimization included increasing the amount of

allyl silane to 2 equiv (45% yield) and degassing the CH₃CN

solvent (55% yield). Degassing of CH₃CN likely improved the

The radical cation then undergoes attack by the nucleophilic

allyl silane, forming the quaternary center and a new secondary

alkyl radical (40b). A second equivalent of Ce(IV) is then

needed to oxidize the radical to a cation (40c). It was then

proposed by the Flowers group that the nucleophilic solvent,

CH₃CN, plays a role in displacement of the trimethylsilyl

group, providing the terminal alkene in 37.^37a

The high diastereoselectivity observed during the allylation is

surprising (Scheme 13). It is likely that the cyclohexanone ring

ﬂip occurs as soon as the radical cation is formed since the π-

bond of the alkene in 36 is broken, resulting in the release of

A^1,3-strain and allowing the large OTBS group to be equatorial.

The main interactions an incoming allyl silane nucleophile

would experience from the bottom face are a 1,2-interaction

with an axial hydrogen in 40a. From the top face, there would

be two 1,3-diaxial interactions with hydrogen and a 1,2-

interaction with the side chain in 40a.

Scheme 12. Oxidative Allylation Using Cerium(IV)

The all-carbon quaternary stereocenter was now established,

and all carbons required in serratezomine A were in place. Our

attention was then turned to accessing the piperidine ring by

functionalizing the terminal alkene via hydroboration. To

prevent selectivity issues, the ketone had to be reduced prior to

hydroboration in which the β-alcohol was required as in the

natural product. Reduction with NaBH₄in THF at room

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temperature provided more of the undesired α-alcohol in yields

ranging from 45 to 58% (not shown), likely because of an

imine-directed borane delivery to the top face. To direct

hydride addition to the opposite face, chelating conditions were

used to engage the imine nitrogen and ketone since this would

eﬀectively block the top face. Gratifyingly, using a bidentate

Lewis acid (Et₂AlCl) and ⁿBu₃SnH as a reducing agent aﬀorded

the desired β-alcohol in good yield and moderate diaster-

Scheme 15. Alkene Conversions of 41

eoselectivity (41, Scheme 14).⁴⁰Rapid addition of Bu₃SnH

n

Scheme 14. Installation of the β-Alcohol

a

(a) NBS, CH₂Cl₂, rt, 51%; (b) BH₃·DMS, THF, 0 °C, then NaOH,

n

H₂O₂, H₂O, 35%; (c) Bu₃SnH, AlBN, 85 °C, 59%.

Wilkinson’s catalyst [RhCl(PPh₃)₃], did not provide the desired

hydroboration product (44). Increasing the borane amount,

reaction time, or temperature proved to be even more

detrimental to the yield. We thought that the imine may be

binding irreversibly to the borane, so Lewis acids were added

along with the borane. The primary alcohol was still formed but

without any improvement in the yield. Therefore, an alternative

approach was used with electrophilic bromination to form the

piperidine ring directly via a bromonium intermediate and 6-

endo cyclization (as in 47). Instead a 5-exo cyclization was

observed in the presence of NBS in either CH₂Cl₂or MeOH to

form 45.⁴⁴Eﬀorts to reduce the iminium ion with Bu₃SnH or

n

NaBH₃CN were unsuccessful but did reduce the primary

bromide in the former case. There is literature precedence for

conversion of the 5-exo to 6-endo product via an intermediate

aziridium ion (45 → 47), but attempts to implement this

approach were met with failure, likely due to the inability to

reduce the iminium ion in 45.⁴⁵

resulted in the simultaneous reduction of the ester to aﬀord the

diol (42) with similar diastereoselectivity. A two-step

reduction/deprotection to diol 42 was also developed using

the chelating reduction in the ﬁrst step and then sodium metal

in MeOH for the second step. The two-step protocol was

advantageous since the alcohol diastereomers (α and β-41)

could be separated by column chromatography after the

reduction, whereas it was not straightforward to separate the

diol diastereomers (α and β-42).

Having β-diol 42 in hand led to us to attempt lactone ring

formation, which would be followed by piperidine ring

construction in separate synthetic operations. However,

subjecting diol 42 to a variety of oxidation conditions including

Ag₂CO₃/C₆H₆(Fetizon oxidation),⁴¹Dess−Martin, PCC, and

TEMPO proved fruitless, as no oxidation products were

observed (43, Scheme 14). This was surprising since diol 42 is

in the correct chair conformation to undergo lactonization. Our

suspicion was that the nucleophilic imine nitrogen might be

involved in the formation of side products that result once the

primary alcohol in 42 is oxidized.^42,43

Despite low yields during the hydroboration, alcohol 41

provided our best access to serratezomine A and was carried

forward to form the piperidine ring. Conversion of the alcohol

to the primary bromide was successful using Br₂and PPh₃(48,

Scheme 16). After column chromatography to isolate bromide

48, a second compound of low R_fwas also observed that was

1

not initially seen by H NMR analysis of the crude reaction

mixture. This compound would form by allowing a pure sample

of bromide 48 to stand at room temperature in CDCl₃.

Surprisingly, the compound was not only cyclized to form the

Scheme 16. Unexpected Epimerization

Our attention was again focused on construction of the

piperidine ring before the lactone ring. This would functionalize

the nitrogen and allow us to proceed with the synthesis.

Treatment of the alkene in 41 with either BH₃·THF or

BH₃·DMS followed by oxidative workup provided the desired

primary alcohol 44, but in low yields (23−35% with up to 25%

recovered 41, Scheme 15). A survey of boron reagents,

including 9-BBN, disiamylborane, and catecholborane with

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piperidinium ring, but was also epimeric at the quaternary

center and was identiﬁed as epi-49 instead of the expected

product (49).

To ascertain the structure of epi-49, it was subjected to a

PtO₂-catalyzed reduction to provide the amine as a single

diastereomer (50, Scheme 17). At this point 2D NMR

of the α-OH (as an alternative strategy). The latter two are

discussed here.

Routes Investigated to Prevent Epimerization. Pro-

tection of β-alcohol 41 was unexpectedly complicated. While

silylation was successful (TESOTf or TIPSOTf), the addition

of a larger protecting group, along with the fact that four of the

six substituents were axial, provided compounds with broad

peaks by NMR analysis and unclear conformational prefer-

ences. An idea to tether the β-OH with the primary alcohol,

using diol 42, was also met with failure.⁴⁸A crystal structure of

diol 42 was obtained, which revealed that a hydrogen bond

existed between the imine nitrogen and the secondary alcohol

(Figure 2). This could explain the observed unreactivity of the

β-alcohol toward protecting group reaction conditions.

Scheme 17. Studies to Support Epimerization Conclusion

Figure 2. Crystal structure of diol 42.

Fortunately, the sulfonation of the alcohol could be

accomplished to form mesylate 53 in quantitative yield

(Scheme 18). In an eﬀort to increase the yield of the next

Scheme 18. Reactions of Mesylate 53

techniques more clearly highlighted the correlations with the

new methine CH adjacent to the nitrogen.⁴⁶Fortunately, a

crystal structure of epi-49 was also obtained by exchange of the

bromide counterion to a triﬂate (using TESOTf, 51). The

crystal structure unambiguously conﬁrmed the epimerization

and solidiﬁed our previous stereochemical assignments. The

epimerization likely occurs through an enamine retro-aldol

reaction of the expected cyclized product (49) (as in Scheme

17).⁴⁷First, a ring-opening of 49 forms the enamine-aldehyde

(52a). Rotation about the C−C σ-bond in 52a provides

intermediate 52b in which enamine addition to the aldehyde to

reclose the ring would give 52c. After protonation of the

enolate, epi-49 would result with an overall epimerization of the

spirocyclic carbon.

The driving force to epimerize is less apparent. The

isomerization may relieve some strain derived from the

interaction of the methylene carbon in the pyrrolidine ring

with the two axial hydrogens on the cyclohexanol ring in 49.

The epimerized product (epi-49) allows the pyrrolidine ring to

be further away and thus minimizes the steric strain. The

epimerization was an unfortunate ﬁnding so late in the

synthesis but seems to be favored on the basis of substrate

control. Several routes were then devised to prevent

epimerization: reduction of the imine (to prevent formation

of an iminium ion upon cyclization), protection of the β-OH

(to prevent opening of the cyclohexanone ring), and formation

step, hydroboration of the alkene, two tactics were pursued.

The ﬁrst was deprotection of the TBS group since it was

speculated that the terminal alkene was sterically hindered by

the large TBS group, thus leading to low yields of the primary

alcohol. Treatment of 53 with TBAF at 66 °C provided an

unexpected product, the bridged bicyclic ether (54), as a result

of an intramolecular S_N2 displacement of the mesylate by the

intermediate alkoxide formed from the TBS deprotection.

The second attempt to increase the yield of the hydro-

boration was to locate the mass balance. During chromatog-

raphy, more polar fractions were present and accounted for

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1

a

35−40% of the material. H NMR analysis revealed a set of

Scheme 20. Advancement of α-Alcohol 60

broad peaks diﬀerent from the primary alcohol. Upon storage

of this viscous oil for several days, the new compound

converted to primary alcohol 55. It was speculated that the

broadness of the peaks may be a result of borane binding with

the electron rich imine (as in 56, Scheme 18). Furthermore,

amine−borane complexes are known to be stable and isolable

compounds at room temperature.^49,50To test this hypothesis, a

solution of the oil (presumed to be 56) in CH₂Cl₂was treated

with an excess of DMAP for 7 days. DMAP, an electron rich

amine, was expected to bind more strongly to borane than to

the imine functionality, and thus would act as a borane

scavenger. Indeed, puriﬁcation of the resulting mixture aﬀorded

the pure primary alcohol (55). This study established the

feasibility of alkene conversion to the terminal alcohol, but

concerns related to sulfonate deprotection⁵¹and our inability to

make forward progress with β-alcohol (41) led us to a new

approach to serratezomine A, using the α-alcohol.

Originally, the β-alcohol was desired as an approach to

lactone ring formation, but our numerous strategies were

thwarted (vide supra). Since the alcohol was easily protected as

the mesylate, it was envisioned that the α-mesylate could be

used instead (57, Scheme 19).⁵²Conversion of 57 to the

a

(a) NaBH₄, THF, 0 °C to rt, 55% (>23:1 dr); (b) MsCl, Et₃N,

CH₂Cl₂, 0 °C to rt, 98%; (c) BH₃·DMS, THF, 0 °C, then NaOOH,

then DMAP, 7 d, 79%; (d) PPh₃, Br₂, imid., C₆H₆, rt, 76%; (e) PtO₂,

H₂, 57%; (f) NaBH₃CN, 45%.

Scheme 19. Advancement of the α-Alcohol

isomer, as a syn-pentane interaction between the pyrrolidine

ring and ester side chain would highly disfavor the undesired

isomer.⁵³

With the piperidine ring in place (58), our attention turned

toward oxidative adjustment of the primary alcohol to the

carboxylate functionality to allow formation of the lactone ring.

To accomplish this goal, deprotection of the pivalate protecting

group was required. Treatment of 58 with DIBAL aﬀorded the

desired alcohol in good yield (63, Scheme 21). The alcohol was

Scheme 21. Attempts at Lactone Ring Formation

piperidine ring could be accomplished in a similar manner as

before to form 58. Then a pivalate deprotection could be

carried out, and the primary alcohol could be oxidized to a

carboxylate (as in 59). Cyclization of the carboxylate could

occur via an S_Ni displacement of the mesylate to form the

lactone ring, leaving only a TBS deprotection to complete the

synthesis of 1.

Advancement of the α-Alcohol As a New Strategy. To

form the desired alcohol, ketone 37 was treated with NaBH₄in

THF to provide the α-alcohol (60, >23:1 dr), which was then

protected as the mesylate in excellent yield (57, Scheme 20).

The mesylate was subjected to the hydroboration conditions,

and the resulting crude oil was treated as before with DMAP.

Upon puriﬁcation, the desired primary alcohol (61) was

isolated. The alcohol was again treated with Br₂and PPh₃to

aﬀord the primary bromide, which cyclized slowly upon

standing to aﬀord the iminium salt (62). Subsequent reduction

of iminium 62 was investigated by utilizing both hydride

reducing agents and metal-catalyzed hydrogenation. The latter

then subjected to a variety of oxidation conditions including

Dess−Martin periodinane, Parikh−Doering,⁵⁴and Swern

oxidations. In all cases, decomposition of the starting material

was observed, and no oxidation product could be isolated (64).

It was believed that the lone pair of electrons on the nitrogen

still exerted its eﬀect by donating into the newly formed

aldehyde, and that the resulting strained hemiaminal underwent

a variety of fragmentation pathways, leading to the decom-

position of 64.⁴³

1

case proved superior in providing the amine (58). The H

NMR peaks of 58 were uniformly broad, suggesting two

interconverting chair conformations as shown. As a result, 2D

NMR analysis to determine the facial selectivity of the

reduction step could not be conducted. However, the presence

of only one set of peaks by NMR strongly suggested the

reduction was highly stereoselective to provide the desired

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It was reasoned that serratezomine A might be accessed by a

RuO₄-mediated oxidation of cyclic ether 65.⁵⁵The approach to

65 appeared straightforward via an intramolecular displacement

of the mesylate by an alkoxide, generated by deprotonation of

the primary alcohol. Surprisingly, alcohol 63 was inert to most

basic reaction conditions including potassium tert-butoxide,

sodium hydride, LiHMDS and LDA (Scheme 21). Exposure to

ⁿBuLi and ^tBuLi led to complete decomposition of the starting

material. On the basis of the model studies, it was believed that

the steric interactions between the two sp³-hybridized carbons

at C5 and C15 were too high to overcome in the cyclic ether

(65). The S_N2 displacement of the mesylate by an exogenous

oxygen nucleophile was also investigated to form diol 66. It was

hypothesized that the presence of the β-alcohol in diol 66

would lead to the formation of the desired lactone, via a lactol

intermediate, using a Fetizon oxidation. The mesylate was

treated with a variety of oxygen nucleophiles, including

Table 2. Optimization of Ketone Reduction

b

entry reducing agent

solvent

THF

time

α:β

conversion (%)

c

1

2

3

NaBH₄

3 d

>20:1

0.8:1

3:1

30−45

100

25

NaBH₄

MeOH

1-propanol

THF

1.5 h

2 d

NaBH₄

LiBH₄

c

4

5

6

7

>5:1

L-Selectride

KBH₄

THF

2 d

5

c

MeOH

THF

2 d

4:1

25

1 d

15

a

All reactions were performed at −3 °C and employed 1.4 equiv of

b

1

reducing agent. Conversions were measured using H NMR of the

crude reaction mixture. Decomposition of the starting material was

c

58

CsOAc,⁵⁶ⁿBu₄N⁺⁻NO₃,⁵⁷and KNO₂at elevated temper-

observed.

atures (>100 °C) and for a long duration (10−20 h). However,

the starting material was recovered in all cases. The inert nature

of mesylate 63 could be attributed to its sterically hindered

environment (both the adjacent quaternary center and the axial

alcohol side chain).

Completion of the Synthesis and Reduction of the

Overall Step Count. The use of an α-mesylate remained a

promising strategy, and we encountered diﬃculties only during

the late-stage oxidation in an attempt to form the lactone ring.

This could be avoided if the pivaloate side chain was not

reduced to the alcohol earlier in the synthesis (refer to Scheme

11). The ester reduction was used at the time to prevent

formation of the tricyclic imide under basic conditions. With

the cerium-mediated allylation developed, it was hypothesized

that the product might withstand the nonbasic conditions and

not undergo an undesired cyclization, thereby reducing the

total step count by two.

evaluated. Employing KBH₄, LiBH₄and L-Selectride as

reducing agents aﬀorded α-alcohol 68 in high diastereoselec-

tivity but with mainly decomposition of the starting material

(entries 4−7). Gratifyingly, treatment of ketone 25 with

NaBH₄in MeOH led to complete conversion to α-alcohol 68,

but in low diastereoselectivity (entry 2). The solvent that

ultimately provided the best combination of diastereoselectivity

and yield was 1-propanol (entry 3). Performing the reaction at

lower temperatures did not improve the diastereoselection in

favor of the α-alcohol.⁵⁹

With the ketone reduction in place, we turned toward

formation of the piperidine ring. After some experimentation,

we were pleased to ﬁnd that the desired iminium salt could be

formed in quantitative yield by mesylation of the primary

alcohol, rather than formation of the corresponding bromide,

followed by imine cyclization. After extended treatment of the

reaction mixture with aqueous NH₄Cl, the crude NMR

indicated complete conversion and cyclization to the iminium

salt (71, Scheme 23). The crude reaction mixture was then

treated with NaBH₃CN to aﬀord the tertiary amine (72) in

quantitative yield.⁶⁰The NMR peaks of 72 were uniformly

broad, as in 58, but indicated one diastereomer at C4 had

formed, and this was carried onto the next step.

The CAN-mediated oxidative allylation of vinylogous amide

36 was carried out as before, but now with the ethyl ester in

place to form 25 (Scheme 22). Fortunately, no cyclization of

Scheme 22. Cerium-Mediated Allylation with Ester Intact

The ﬁnal eﬀorts were focused on installing the bridged

lactone by a tandem saponiﬁcation/intramolecular cyclization

strategy (Scheme 23). Employing diﬀerent reagents for the

saponiﬁcation including NaOTMS,⁶¹K₂CO₃,⁶²and LiOH led

to either decomposition or formation of an alkene by facile

elimination of the mesylate (74). Success was ﬁnally realized by

treating 72 with aqueous NaOH at 34 °C for 10 h to aﬀord a

1.1:1 mixture of lactone 73 and alkene 74, as indicated by NMR

analysis. Puriﬁcation attempts of the crude mixture were

unsuccessful because of coelution of the products. Therefore,

the crude reaction mixture was instead exposed to TBAF at 40

°C for 20 h, which led to a separable 3:2 mixture of

(+)-serratezomine A (1) and the fused lactone (75, from

lactonization of 74). The spectral data (¹H NMR, ¹³C NMR,

and IR) and optical rotation of synthetic 1 (syn. [α]_D+9.5 (c

0.3, MeOH)), were in agreement with the reported values (nat.

[α]_D+13.0 (c 0.5, MeOH)), conﬁrming the structural and

absolute stereochemical assignments of 1 (for the complete,

total synthesis scheme of 1, see Scheme 24).

the imine onto the pendant ester was observed in the product

(67), and the high diastereoselectivity for the allylation was

maintained. The ketone was then treated with an excess of

NaBH₄in THF to form the α-alcohol (68). The reaction was

sluggish, but ultimately provided the desired alcohol in high

diastereoselectivity (>20:1), albeit in low yields (68, Table 2,

entry 1). In an attempt to increase the yield of the reduction

step, a variety of reducing agents and reaction conditions were

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a

Scheme 23. Completion of the Synthesis

EXPERIMENTAL SECTION

■

General Methods. All glassware used for reactions was ﬂame-dried

under a vacuum, and reactions were run under an inert atmosphere of

nitrogen or argon. All reagents and solvents were commercial grade

and puriﬁed prior to use when necessary. Diethyl ether (Et₂O),

tetrahydrofuran (THF), dichloromethane (CH₂Cl₂), benzene (C₆H₆),

and acetonitrile (CH₃CN) were dried by passage through a column of

activated alumina as described by Grubbs.⁶³Benzene was additionally

passed through a column containing activated Q-5 reactant. All other

solvents were distilled over calcium hydride before use or are

otherwise indicated diﬀerently. All organic layers collected from

extractions were dried over MgSO₄unless otherwise indicated.

Reagents were used from the bottle unless otherwise noted within

the experimental details. Thin layer chromatography (TLC) was

performed using glass-backed silica gel (250 μm) plates, and ﬂash

chromatography utilized 230−400 mesh silica. Products were

visualized using UV light and either ceric ammonium molybdate,

ninhydrin, p-anisaldehyde, potassium iodoplatinate, or potassium

permanganate solutions. Melting points were recorded on a capillary

melting point apparatus and are reported uncorrected. For FTIR,

liquids and oils were analyzed as neat ﬁlms on a NaCl plate

(transmission), whereas solids were applied to a diamond plate (ATR)

if a thin ﬁlm could not be prepared, and data are reported in

wavenumbers (cm⁻¹). NMR were acquired on either a 400, 500, or

600 MHz instrument. Chemical shifts are measured relative to the

residual solvent peaks as an internal standard set to δ 7.26 and δ 77.1

1

for H and ¹³C, respectively. Multiplicities are reported as singlet (s),

doublet (d), triplet (t), quartet (q) or combinations thereof, while

higher coupling patterns are written out explicitly. HRMS data was

obtained either by chemical ionization (CI), electron ionization (EI),

or electrospray ionization (ESI) using an ion trap or by matrix-assisted

laser desorption/ionization (MALDI) in either positive and negative

ion modes using TOF. Combustion data analyzing C, H, and N were

performed on select compounds. Compounds 5, 7d, 14, 16, 25, 68,

69, 70, and 72 were reported in an earlier publication⁸as well as 9c

and 11c.^14c

(+)-Serratezomine A (1) and (1S,5S,6S,7S,8′S,8a′R)-6-((tert-

Butyldimethylsilyl)oxy)-7-methylhexahydro-1′H-2-oxaspiro-

[bicyclo[3.3.1]nonane-9,8′-indolizin]-3-one (73). To a solution of

ester 72 (13.2 mg, 25.5 μmol) in MeOH (600 μL) at 0 °C was added

sodium hydroxide (220 μL, 0.1 M in H₂O). The reaction was stirred

for 30 min before being warmed to 34 °C and stirred for another 10 h.

The solvent was removed in vacuo, and the resulting residue was

dissolved in CH₂Cl₂. The organic layer was washed once with H₂O

and then satd aq NH₄Cl and dried, ﬁltered, and concentrated to a

yellow oil. The crude oil could be puriﬁed and was characterized as the

TBS protected intermediate (73, see data below). Alternatively, the

crude oil could be carried on directly by dissolving in THF (300 μL)

and adding TBAF (63.8 μL, 1.0 M in THF). The reaction was stirred

for 15 min before being warmed to 40 °C and stirred for another 20 h.

The solvent was evaporated, and the resulting crude oil was subjected

to mass directed LC puriﬁcation (15% CH₃CN/0.1% TFA) to aﬀord

(+)-serratezomine A 1 as a white solid (2.4 mg, 33%): R_f= 0.22 (10%

MeOH/CH₂Cl₂); [α]²_D⁴+9.5 (c 0.3, MeOH); IR (ﬁlm) 3423, 2920,

a

(a) MsCl, Et₃N, CH₂Cl₂, 0 °C to rt, 98%; (b) BH₃·DMS, THF, 0 °C,

then NaOOH, then DMAP, CH₂Cl₂, 51% brsm; (c) MsCl, Et₃N,

CH₂Cl₂, 0 °C, then satd aq NH₄Cl, rt, 20 h; (d) NaBH₃CN, MeOH,

98% over 2 steps; (e) NaOH, MeOH, 34 °C; (f) TBAF, THF, 40 °C,

33% over 2 steps.

CONCLUSIONS

■

In summary, the ﬁrst total synthesis of (+)-serratezomine A was

ultimately accomplished in 15 steps from a commercially

available aldehyde. Notably, this is the only member of the

Lycopodium alkaloids of the fawcettimine class bearing a

substituent (OH) at C8 to be prepared other than the early

synthesis of serratinine. The axial alcohol provided a powerful

driving force for quaternary carbon epimerization when oﬀered

a pathway (49 → epi-49). Fortunately, this challenge was

overcome without sacriﬁcing brevity in the current synthesis

but did require several investigational lines to probe the

reactivity inherent to this crowded system. Additional salient

features of this synthesis include the following: (a) application

of a free radical-mediated vinyl amination to construct the

pyrrolidine ring; (b) a highly stereoselective intramolecular

Michael addition to construct the cyclohexane ring; (c) the use

of an oxidative allylation promoted by cerium(IV) to establish

the all carbon quaternary stereocenter with the proper

conﬁguration; (d) a tandem saponiﬁcation/intramolecular S_Ni

cyclization to provide the bridged lactone; and (e) minimal use

of protecting groups. Access to the β-stannyl enamine was

particularly enabling, as it provided a platform for the

convergent assembly of each unit in a sequence of three steps.

1

2850, 1720, 1463, 1200, 1134 cm⁻¹; H NMR (400 MHz, MeOD) δ

4.32 (dd, J = 5.6, 2.8 Hz, 1H), 3.81 (dd, J = 11.2, 6.4 Hz, 1H), 3.77

(dd, J = 3.6, 3.6 Hz, 1H), 3.54 (ddd, J = 9.6, 9.6, 9.6 Hz, 1H), 3.36−

3.34 (m, 1H), 3.28−3.25 (m, 1H), 3.14 (dd, J = 20.0, 8.0 Hz, 1H),

2.98 (ddd, J = 13.2, 13.2, 3.6 Hz, 1H), 2.83 (br d, J = 13.6 Hz, 1H),

2.62−2.61 (m, 1H), 2.46 (d, J = 20.0 Hz, 1H), 2.29−2.13 (m, 4H),

2.05−1.99 (m, 1H), 1.85−1.74 (m, 4H), 1.40 (ddd, J = 13.6, 13.6, 3.2

Hz, 1H), 1.01 (d, J = 6.4 Hz, 3H); ¹³C NMR (125 MHz, MeOD) ppm

173.2, 83.5, 76.2, 66.7, 56.0, 48.7, 37.3, 37.1, 34.3, 34.2, 27.0, 23.6,

22.0, 20.6, 19.7, 17.3. Data for 73: R_f= 0.35 (10% MeOH/CH₂Cl₂);

[α]²_D⁴+3.5 (c 0.5, MeOH); IR (ﬁlm) 2927, 2855, 1738, 1672, 1196,

1039 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 4.18 (s, 1H), 3.75 (s, 1H),

3.57 (br d, J = 9.0, 1H), 3.48 (br d, J = 9.6, 1H), 3.37 (dd, J = 20.4, 7.8

Hz, 1H), 3.17 (br s, 1H), 2.87 (d, J = 13.8 Hz, 1H), 2.79 (br s, 1H),

2.72 (d, J = 14.4 Hz, 1H), 2.63 (d, J = 10.8 Hz, 1H), 2.37 (d, J = 20.4

Hz, 1H), 2.28−2.25 (m, 1H), 2.16−2.04 (m, 4H), 1.85−1.82 (m, 2H),

832

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Scheme 24. Total Synthesis of 1

1.79−1.74 (m, 2H), 1.63−1.60 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.89

(s, 9H), 0.14 (s, 3H), 0.07 (s, 3H); ¹³C NMR (150 MHz, CDCl₃)

ppm 170.0, 81.3, 75.9, 64.0, 53.9, 46.6, 45.8, 35.7, 35.4, 33.4, 30.7, 26.0,

22.4, 21.0, 19.5, 18.0, 16.9, 14.1, −4.3, −5.2.

to conﬁrm the new stereocenter and to establish the alkene geometry

are described in Supporting Information 2.

General Procedure for the Coupling Reaction to Prepare

Vinylogous Amides (7a−d). The crude acid chloride (8, 1 equiv)

was dissolved in THF (0.15 M), cooled to 0 °C, and then cannulated

at a quick dropwise rate to a stirring solution of the β-stannyl enamine

(9a−9c (1 equiv, small scale), 9d (1.8 equiv, large scale)) in THF

(0.14 M) also at 0 °C. After the addition was complete, the reaction

was allowed to stir an additional 5 min at 0 °C and was then warmed

to rt and stirred overnight (10−14 h). The solvent was removed in

vacuo, and the crude oil was puriﬁed by column chromatography on

SiO₂(0−40% ethyl acetate in hexanes), and the fractions containing

the product were resubmitted to a second column with 20−35% ethyl

acetate in hexanes) to provide the coupled product (7a−d).

(2E,4S,5S,8E)-Ethyl 8-(1-Benzhydrylpyrrolidin-2-ylidene)-4-

((tert-butyldimethylsilyl)oxy)-5-methyl-7-oxooct-2-enoate

(7a). According to the general coupling procedure, 9a was treated with

8 to provide the vinylogous amide as a brown viscous oil, which was

chromatographed on SiO₂(5−50% ethyl acetate in hexanes to provide

7a as a pale orange oil (534 mg, 56% yield): R_f= 0.21, (30% EtOAc/

hexanes); IR (ﬁlm) 3063, 1638 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

7.34 (m, 6H), 7.13 (m, 4H), 6.87 (dd, J = 15.6, 4.6 Hz, 1H), 5.99 (s,

1H), 5.93 (dd, J = 15.6, 1.8 Hz, 1H), 5.09 (s, 1H), 4.18 (m, 3H), 3.32

(t, J = 7.6 Hz, 2H), 3.09 (t, J = 7.3 Hz, 2H), 2.30 (dd, J = 14.5, 4.9 Hz,

1H), 2.19 (m, 1H), 2.00 (m, 1H), 1.93 (t, J = 7.3 Hz, 2H), 1.28 (t, J =

7.3 Hz, 3H), 0.89 (s, 9H), 0.81 (d, J = 6.7 Hz, 3H), 0.03 (s, 3H),

−0.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 196.3, 166.8, 165.3,

149.5, 138.5, 128.9, 128.8, 128.7, 128.1, 121.2, 91.6, 75.3, 63.3, 60.5,

49.9, 46.0, 36.9, 33.7, 26.1, 21.3, 18.4, 15.7, 14.5, −4.4, −4.7; HRMS

(CI) Exact mass calcd for C₃₄H₄₇NO₄Si [M]⁺, 561.3274. Found

561.3291.

Ethyl 2-((1S,2R,3S,Z)-2-((tert-Butyldimethylsilyl)oxy)-3-meth-

yl-5-oxo-6-(pyrrolidin-2-ylidene)cyclohexyl)acetate (6). Ceric

ammonium nitrate (16.8 g, 30.6 mmol) was added in one portion

to 7d (8.10 g, 15.3 mmol) in CH₃CN/H₂O (5:1, 765 mL) at rt. After

5 min, the reaction was quenched with satd aq NaHCO₃and extracted

with EtOAc. The combined organic layers were washed once with

brine, and dried, ﬁltered, and concentrated to an orange/brown oil.

The crude oil was subsequently chromatographed (SiO₂, 10−32−38%

ethyl acetate in hexanes) to provide 6 as a yellow/brown oil (2.8 g,

46%). This material was of suﬃcient purity to carry onto the next step,

but to obtain an analytically pure compound for characterization, a

second puriﬁcation was performed (SiO₂, 35−50% ethyl acetate in

hexanes) providing 6 as a dark yellow oil (2.5 g, 88% recovery, 40%

after two puriﬁcations): R_f= 0.20 (50% EtOAc/hexanes); [α]²_D¹+ 50.0

(c 1.0, CHCl₃); IR (ﬁlm) 2955, 2930, 2856, 1730, 1613, 1537 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 10.75 (br s, 1H), 4.17 (dq, J = 10.9,

7.1 Hz, 1H), 4.10 (dq, J = 10.8, 7.1 Hz, 1H), 3.66 (br s, 1H), 3.59 (dt,

J = 10.6, 6.9 Hz, 1H), 3.54 (dt, J = 10.6, 7.0 Hz, 1H), 2.95 (ddd, J =

9.4, 5.2, 2.8 Hz, 1H), 2.65−2.61 (m, 2H), 2.31−2.24 (m, 2H), 2.23

(dd, J = 17.0, 11.9 Hz, 1H), 2.18−2.05 (m, 2H), 2.05−1.96 (m, 2H),

1.26 (t, J = 7.1 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.81 (s, 9H), 0.05 (s,

3H), 0.03 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 194.7, 172.5,

167.8, 98.5, 72.6, 60.6, 47.7, 41.8, 41.0, 40.3, 30.6, 28.8, 25.9, 21.6,

18.7, 18.2, 14.4, −4.4, −4.8; HRMS (CI) Exact mass calcd for

C₂₁H₃₇NO₄Si [M]⁺395.2486, found 395.2502. 1D NOE NMR studies

833

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The Journal of Organic Chemistry

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(2E,4S,5S,8E)-Ethyl 8-(1-(Bis(4-methoxyphenyl)methyl)-

pyrrolidin-2-ylidene)-4-((tert-butyldimethylsilyl)oxy)-5-meth-

yl-7-oxooct-2-enoate (7b). According to the general coupling

procedure, 9b was treated with 8 to provide the vinylogous amide as a

brown viscous oil, which was chromatographed on SiO₂(5−50% ethyl

acetate in hexanes) to provide 7b as an orange oil (241 mg, 28%): R_f=

with stirring. The solution was concentrated, diluted with ether,

washed with water and then satd aq NaHCO₃, and then dried

(Na₂SO₄), ﬁltered, and concentrated. The residue was distilled (75

°C/15 Torr) to give aldehyde 10 as a light yellow oil (13.7 g, 75%). All

spectroscopic data was consistent with that reported in the literature.⁶⁶

N-(Diphenylmethylene)pent-4-yn-1-amine (11a). Alkynyl

amine 20⁶⁷(3.5 g, 42.1 mmol), benzophenone imine²⁴(7.25 g, 40.0

mmol), and 4 Å MS (2.0 g) were rapidly stirred in benzene (30 mL) at

rt for 36 h. The solution was ﬁltered through a pad of Celite, washed

with ether, and concentrated to yield imine 11a as a light yellow oil

(9.76 g, 99%): IR (ﬁlm) 3299, 3057, 1623 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.64 (m, 2H), 7.46 (m, 3H), 7.36 (m, 3H), 7.19 (m, 2H),

3.48 (t, J = 6.7 Hz, 2H), 2.33 (ddd, J = 7.3, 7.3, 2.7 Hz, 2H), 1.92 (m,

3H); ¹³C NMR (100 MHz, CDCl₃) ppm 168.7, 140.1, 137.1, 130.1,

129.0, 128.7, 128.6, 128.3, 128.0, 84.6, 68.6, 52.6, 30.3, 16.6; HRMS

(CI) Exact mass calcd for C₁₈H₁₆N [M − H]⁺, 246.1283, found

246.1283.

N-(Bis(4-methoxyphenyl)methylene)pent-4-yn-1-amine

(11b). Alkynyl amine 20⁶⁷(447 mg, 5.38 mmol), p-methoxybenzo-

phenone imine⁶⁸(865 mg, 3.60 mmol), and 4 Å MS (2.0 g) were

rapidly stirred in benzene (10 mL) at rt for 48 h. The solution was

ﬁltered through a pad of Celite, washed with ether, and concentrated

to yield imine 11b as a light yellow oil (1.59 g, 96%): IR (ﬁlm) 3297,

3002, 1604 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.9 Hz,

2H), 7.00 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.9

Hz, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 3.35 (dd, J = 6.7, 6.4 Hz, 2H),

2.18, (m, 2H), 1.79 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm

168.0, 161.3, 159.7, 134.2, 133.4, 132.5, 130.2, 129.6, 129.4, 128.6,

115.0, 114.0, 113.5, 84.7, 68.5, 55.6, 55.5, 52.5, 30.5, 16.6; HRMS (CI)

Exact mass calcd for C₂₀H₂₀NO₂[M − H]⁺, 306.1494, found

306.1484.

1

0.11, (30% EtOAc/hexanes); IR (ﬁlm) 2955, 1717 cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 7.03 (dd, J = 8.6, 1.3 Hz, 4H), 6.88 (m, 5H),

5.94 (dd, J = 15.6, 1.6 Hz, 1H), 5.88 (s, 1H), 5.07 (s, 1H), 4.18 (m,

3H), 3.80 (s, 3H), 3.30 (dd, J = 7.5, 7.5 Hz, 2H), 3.06 (dd, J = 7.0, 7.0

Hz, 2H), 2.30 (dd, J = 14.5, 4.8 Hz, 1H), 2.20 (m, 1H), 2.01 (dd, J =

14.2, 9.1 Hz, 1H), 1.90 (ddd, J = 14.7, 7.5, 7.5 Hz, 2H), 1.28 (t, J = 7.0

Hz, 3H), 0.89 (s, 9H), 0.82 (d, J = 6.7 Hz, 3H), 0.03 (s, 3H), −0.01 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) ppm 196.2, 166.8, 165.3, 159.3,

149.6, 130.9, 130.8, 129.8, 129.7, 121.2, 114.1, 91.3, 75.3, 62.1, 60.5,

55.5, 49.7, 46.0, 36.9, 33.8, 26.1, 21.2, 18.4, 15.7, 14.5, −4.3, −4.7;

HRMS (CI) Exact mass calcd for C₃₆H₅₁NO₆Si [M]⁺, 621.3486.

Found 621.3476.

(2E,4S,5S,8E)-Ethyl 4-((tert-Butyldimethylsilyl)oxy)-5-methyl-

7-oxo-8-(1-(1-phenylethyl)pyrrolidin-2-ylidene)oct-2-enoate

(7c). According to the general coupling procedure, 9c was treated with

8 to provide the vinylogous amide as a brown viscous oil, which was

chromatographed on SiO₂(5−50% ethyl acetate in hexanes) to

provide 7c as a pale orange oil (436 mg, 69%): R_f= 0.10 (30% EtOAc/

1

hexanes); IR (ﬁlm) 2955, 1718, 1544 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ (unable to separate diastereomers) 7.35 (m, 2H), 7.28 (m,

1H), 7.22 (d, J = 7.3 Hz, 2H), 6.90 (m, 1H), 5.97 (ddd, J = 15.6, 4.8,

1.6, 1H), 5.17, (s, 1H), 4.95 (q, J = 7.0 Hz, 1H), 4.11−4.27 (m, 3H),

3.32 (m, 2H), 3.18 (m, 1H), 3.08 (m, 1H), 2.36 (m, 1H), 2.25 (m,

1H), 2.07 (dd, J = 11.7, 9.1 Hz, 1H), 1.88 (m, 2H), 1.57 (d, J = 7.0 Hz,

3H), 1.28 (td, J = 7.3, 3.0 Hz, 3H). 0.90 (s, 9H), 0.87 (m, 3H), 0.04 (s,

3H), 0.00 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 196.1, 166.9,

165.4, 149.7, 140.2, 129.0, 127.9, 126.9, 126.8, 121.3, 90.6, 75.4, 60.5,

53.2, 47.3, 46.1, 37.0, 34.0, 26.1, 21.1, 18.4, 17.0, 16.9, 15.8, 14.5, −4.3,

−4.7; HRMS (CI) Exact mass calcd for C₂₉H₄₅NO₄Si [M]⁺, 499.3118.

Found 499.3112.

(4S,5S,E)-Ethyl 4-((tert-Butyldimethylsilyl)oxy)-7-chloro-5-

methyl-7-oxohept-2-enoate (8). To carboxylic acid 19 (1 equiv)

in CH₂Cl₂(0.1 M) at 0 °C was added oxalyl chloride (3 equiv). After

several minutes, catalytic DMF was added (5−10 μL). The reaction

was stirred for 30 min at 0 °C and 15 min at rt. The volatiles were

removed in vacuo, and the crude oil was placed under high vacuum for

a short time and then used immediately in the coupling reactions

above with 7a−7d.

(E)-N-(1-(4-Methoxyphenyl)ethylidene)pent-4-yn-1-amine

(11d). Alkynyl amine 20⁶⁷(23.0 g, 270 mmol) was added to a ﬂask

containing p-methoxyacetophenone (27.0 g, 180 mmol) and 4 Å

molecular sieves in C₆H₆(360 mL). After 24 h, the reaction was

ﬁltered through Celite using minimal C₆H₆, and then more sieves were

added, and the reaction was stirred another 24 h. The reaction was

ﬁltered, more sieves were added and also more amine 20 (4 g), and

the reaction was stirred 24 h, ﬁltered, more sieves added, 24 h, and

then ﬁltered and concentrated to a pale yellow oil. The crude oil (11d)

contains less than 5% of the starting ketone (36.5 g, 94%). The imine

1

was used crude below: IR (ﬁlm) 3292, 2933, 1603, 1252 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.9

Hz, 2H), 3.72 (s, 3H), 3.43 (t, J = 6.7 Hz, 2H), 2.27 (td, J = 7.0, 2.6

Hz, 2H), 2.12 (s, 3H), 1.87 (quintet, J = 6.8 Hz, 2H), 1.86 (t, J = 2.6

Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) ppm 164.8, 160.8, 134.1,

128.2, 113.6, 84.7, 68.4, 55.4, 50.5, 30.0, 16.5, 15.5; HRMS (FAB)

Exact mass calcd for C₁₄H₁₇NO [M + H]⁺, 216.1388. Found 216.1389.

(4S,5S,E)-Ethyl 4-((tert-Butyldimethylsilyl)oxy)-7-hydroxy-5-

methylhept-2-enoate (17). In a 200 mL round-bottom ﬂask

charged with BH₃·DMS (4.80 mL, 50.6 mmol) at 0 °C was added

2-methyl-2-butene dropwise (11.9 mL, 102 mmol). The colorless

mixture was stirred for 15 min, warmed to rt for 1.5 h, and then

recooled to 0 °C. To this mixture, a precooled solution of alkene 16

(12.6 g, 42.1 mmol) in THF (32.4 mL) was added slowly via cannula

addition. The reaction was stirred for 4 h at 0 °C, with the last 30 min

having minimal ice within the ice/water bath. The ice was recharged,

and the reaction was quenched by slow dropwise addition via addition

funnel of 3 N NaOH (36.2 mL, 1 drop per 3−4 s) and then addition

of 30% H₂O₂(25.1 mL) in the same fashion.⁶⁹The reaction was

stirred an additional 10 min and then allowed to warm to rt and stirred

overnight (at least 10 h). Saturated aq Na₂S₂O₃was added, and the

aqueous layer was extracted with EtOAc. The combined organic layers

were washed with satd aq NaCl, dried, ﬁltered and concentrated to a

cloudy white oil. Column chromatography (SiO₂, 5−10−20−30−45%

ethyl acetate in hexanes) provided 17 as a colorless oil (10.5 g, 79%)

along with a small amount of 18 as a colorless oil (1−5%). Data for

17: R_f= 0.11 (20% EtOAc/hexanes); IR (ﬁlm) 3442 (br), 2957, 2931,

General Procedure for β-Stannyl Enamine Formation (9a−

d). To a ﬂame-dried round-bottom ﬂask ﬁtted with a reﬂux condenser

was added the alkynyl imine (11a−11d, 1 equiv), and the ﬂask was

evacuated and backﬁlled with nitrogen three times. Benzene (0.04 M

n

in imine) and Bu₃SnH (0.22 equiv) were added, and the contents

were heated in an oil bath to 85−90 °C. In a separate ﬂask, AIBN (1

equiv)⁶⁴was added, and the ﬂask was evacuated and backﬁlled with

n

nitrogen three times. Then benzene (0.25 M in imine) and Bu₃SnH

(1.98 equiv) were added, and the resulting solution was cannulated

through the reﬂux condenser of the original reaction vessel at rate of

one drop every 3−4 s. After the addition was complete, the reaction

was stirred an additional 1 h before cooling to room temperature. The

solvent was removed in vacuo to provide the crude β-stannyl enamines

(9a−d), which were used in the coupling reaction with acid chloride

8.⁶⁵The scale varied between 1.5 and 15 mmol of 8.

(E)-Ethyl 4-Oxobut-2-enoate (10). A 500 mL round-bottom ﬂask

equipped with a magnetic stir bar and ozonolysis glass-adapter ﬁtting

was charged with freshly distilled ethyl sorbate 13 (15 g, 0.107 mol)

and absolute ethanol (430 mL). To this solution was added

approximately 6 drops of a saturated solution of Sudan Red 7B dye

in ethanol (resulting solution was magenta in color). The solution was

cooled to −78 °C, and then O₂was bubbled through the solution for

10 min, followed by the addition of O₃until the solution turned a faint

yellow color. At this point, the solution was purged with O₂for an

additional 10 min. Dimethyl sulﬁde (approximately 2.2 equiv) was

then added dropwise at −78 °C and allowed to warm to rt overnight

1

2858, 1722 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 6.92 (dd, J = 15.6,

4.9 Hz, 1H), 5.97 (dd, J = 15.6, 1.5 Hz, 1H), 4.25−4.20 (m, 1H), 4.21

834

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The Journal of Organic Chemistry

Featured Article

(qd, J = 7.1, 1.6 Hz, 2H), 3.77−3.69 (m, 1H), 3.66−3.58 (m, 1H),

1.90−1.81 (m, 1H), 1.68 (dtd, J = 13.9, 7.0, 4.6 Hz, 1H), 1.58 (br s,

1H), 1.44 (ddt, J = 14.4, 8.4, 6.2 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H),

0.95−0.91 (m, 3H), 0.93 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) ppm 166.4, 149.0, 121.2, 75.5, 60.5, 60.3, 36.1,

34.4, 25.8, 18.1, 15.4, 14.2, −4.5, −5.0; HRMS (ESI) Exact mass calcd

for C₁₆H₃₂O₄SiNa [M + Na]⁺339.1968, found 339.1951.

(1.7 mg) in MeOH (200 μL) were combined in a small vial, placed

into a metal chamber, and pressurized to 70 psi with hydrogen. The

reaction mixture was stirred for 72 h before it was ﬁltered,

concentrated, and puriﬁed via ﬂash column chromatography (SiO₂,

70−90−100% ethyl acetate in hexanes) to yield ketone 31 as a white,

crystalline solid (2.0 mg, 56%) as well as unreacted 6 (1.5 mg, 38%):

R_f= 0.43 (80% EtOAc/hexanes); mp 138.5−139.0 °C; IR (ﬁlm) 2956,

1

2930, 2856, 1715, 1642 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 4.12

Ethyl 2-((2R,3S,4S)-3-((tert-Butyldimethylsilyl)oxy)-4-methyl-

tetrahydro-2H-pyran-2-yl)acetate (18). Data is for the major

diastereomer only, ratio of major to minor is 3:1: R_f= 0.22 (10%

(ddd, J = 12.2, 9.7, 6.2 Hz, 1H), 3.87 (dd, J = 9.2, 4.2 Hz, 1H), 3.63

(ddd, J = 11.4, 5.5, 5.5 Hz, 1H), 2.96 (ddd, J = 11.1, 11.1, 5.4 Hz, 1H),

2.79−2.70 (m, 2H), 2.62 (dd, J = 15.2, 5.1 Hz, 1H), 2.45−2.38 (m,

1H), 2.37 (dd, J = 15.2, 2.8 Hz, 1H), 2.34−2.26 (m, 1H), 2.18−2.09

(m, 2H), 1.92−1.78 (m, 2H), 1.17 (dddd, J = 11.7, 11.7, 9.9, 9.9 Hz,

1H), 0.98−0.87 (m, 12H), 0.13 (s, 3H), 0.10 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) ppm 206.6, 168.9, 75.0, 57.3, 49.7, 46.3, 42.9, 38.9, 36.2,

34.3, 27.0, 26.0, 21.9, 18.3, 12.9, −4.0, −4.4. HRMS (EI) Exact mass

calcd for C₁₅H₂₄NO₃Si [M − C₄H₉]⁺294.1525, found 294.1530. An

X-ray crystal structure of 31 was obtained in which cocrystallization

occurred with an α-hydroxy compound (S4, not shown) as the minor

component. See Supporting Information 2 for more details as well as

detailed 2D NMR data.

Alternate Preparation of 31. Catecholborane (1.14 mL, 1.14

mmol) was added to a solution of vinylogous imide 26 (200 mg, 572

μmol) and Wilkinson’s catalyst (26 mg, 29 μmol) in THF (2 mL) at 0

°C. The reaction was quenched after 30 min by the addition of MeOH

and concentrated to a brown oil. Flash column chromatography (SiO₂,

60−80−100% ethyl acetate in hexanes) provided a ketone as a white

solid (170 mg, 84%) whose analytical data and ¹H NMR matched 31.

(6aS,7S,8S,10aS,10bR)-7-((tert-Butyldimethylsilyl)oxy)-8-

methyloctahydropyrrolo[2,1-a]isoquinoline-5,10(6H,10aH)-

dione (32). Oil-free NaH (700 μg, 28.4 μmol, oil was removed by

washing 3× with hexanes under an inert atmosphere) was added to a

stirred solution of ketone 31 (10.0 mg, 28.4 μmol) in benzene (280

μL), and the reaction was heated to 60 °C for 30 min. The reaction

was quenched with water and then extracted with EtOAc. The organic

layers were dried, ﬁltered, and concentrated to a yellow oil that was

puriﬁed via ﬂash column chromatography (70−90% ethyl acetate in

hexanes) to give ketone epimer 32 as a colorless oil (8.7 mg, 87%): R_f

= 0.20 (80% EtOAc/hexanes); IR (ﬁlm) 2955, 2928, 2889, 2856,

1715, 1653 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.19−4.12 (m, 1H),

3.78−3.69 (m, 2H), 3.40−3.32 (m, 1H), 2.96−2.94 (m, 1H), 2.54 (dd,

J = 13.2, 13.2 Hz, 1H), 2.43 (dddd, J = 13.3, 6.8, 6.8, 3.4 Hz, 1H), 2.26

(dd, J = 13.8, 4.4 Hz, 1H), 2.21 (ddd, J = 15.5, 3.2, 1.4 Hz, 1H), 2.16−

2.07 (m, 1H), 2.05−1.96 (m, 2H), 1.93 (dd, J = 14.3, 13.1 Hz, 1H),

1.90−1.81 (m, 1H), 1.46 (dddd, J = 11.4, 11.4, 11.4, 8.2 Hz, 1H), 1.04

(d, J = 6.7 Hz, 3H), 0.95 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) ppm 209.4, 168.6, 72.8, 54.2, 47.1, 44.0, 43.7, 41.6,

34.2, 34.2, 32.4, 26.0, 22.1, 18.3, 18.2, −4.2, −4.4; HRMS (CI) Exact

mass calcd for C₁₉H₃₄NO₃Si [M + H]⁺352.2310, found 352.2308.

Anal. calcd for C₁₉H₃₃NO₃Si: C, 64.91; H, 9.46; N, 3.98. Found: C,

65.01; H, 9.26; N, 3.70. Additional 2D data for 32 can be found in

Supporting Information 2.

1

EtOAc/hexanes); IR (ﬁlm) 2957, 2931, 2857, 1740 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 4.15 (q, J = 7.1 Hz, 2H), 3.83 (ddd, J = 9.4, 9.4,

3.1 Hz, 1H), 3.65−3.61 (m, 2H), 3.48 (dd, J = 9.0, 4.9 Hz, 1H), 2.72

(dd, J = 15.0, 3.1 Hz, 1H), 2.26 (dd, J = 15.0, 9.7 Hz, 1H), 2.15−2.08

(m, 1H), 1.93−1.85 (m, 1H), 1.48 (ddd, J = 13.8, 5.1, 2.3 Hz, 1H),

1.25 (t, J = 7.1 Hz, 3H), 1.05 (d, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.05 (s,

6H); ¹³C NMR (125 MHz, CDCl₃) ppm 172.3, 73.4, 73.2, 62.5, 60.6,

38.5, 32.6, 31.9, 36.0, 18.2, 14.4, 11.5, −4.0, −4.8; HRMS (CI) Exact

mass calcd for C₁₆H₃₃O₄Si [M + H]⁺317.2143, found 317.2136.

(3S,4S,E)-4-((tert-Butyldimethylsilyl)oxy)-7-ethoxy-3-methyl-

7-oxohept-5-enoic acid (19). Aldehyde 76 (9.7 g, 31 mmol) was

added to CH₃CN/^tBuOH/2-methyl-2-butene (3:3:1, 760 mL) and

cooled to 0 °C. In an Erlenmeyer ﬂask, NaH₂PO₄·H₂O (33.9 g, 245

mmol) was dissolved in H₂O (210 mL) via stirring, and then NaClO₂

(31.3 g, 277 mmol, 80% tech grade) was added in small portions until

it was completely dissolved (the solution turns from colorless to

yellow). The solution in the Erlenmeyer ﬂask was then poured into a

pressure addition funnel and added dropwise to the stirred aldehyde

solution. After 1 h at 0 °C, the reaction was warmed to rt for an

additional 2.5 h. Ether was added, and the two layers were separated.

The organic layer was washed once with satd aq Na₂S₂O₃and then

brine, and dried, ﬁltered, and concentrated to a crude oil. Column

chromatography (SiO₂, 10−15−25−40% ethyl acetate in hexanes)

provided carboxylic acid 19 as a pale yellow oil (9.1 g, 90% yield): R_f=

0.10 (20% EtOAc/hexanes); [α]²_D⁰+1.8 (c 0.8, CHCl₃); IR (ﬁlm) 3100

1

(br), 2957, 2932, 2858, 1714 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

6.86 (dd, J = 15.6, 5.1 Hz, 1H), 5.97 (dd, J = 15.6, 1.4 Hz, 1H), 4.22−

4.15 (m, 1H), 4.19 (qd, J = 7.0, 2.8 Hz, 2H), 2.50−2.43 (m, 1H),

2.20−2.12 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.2 Hz, 3H),

0.90 (s, 9H), 0.05 (s, 3H), 0.00 (s, 3H), OH hydrogen was not

observed; ¹³C NMR (125 MHz, CDCl₃) ppm 179.0, 166.2, 148.5,

121.7, 74.7, 60.4, 36.1, 35.9, 25.7, 18.0, 16.2, 14.1, −4.5, −5.1; HRMS

(ESI) Exact mass calcd for C₁₆H₃₀O₅NaSi [M + Na]⁺353.1760, found

353.1765.

(6aS,7S,8S)-7-((tert-Butyldimethylsilyl)oxy)-8-methyl-

2,3,6a,7,8,9-hexahydropyrrolo[2,1-a]isoquinoline-5,10(1H,6H)-

dione (26). To a solution of vinylogous amide 6 (280 mg, 530 μmol)

in toluene at 0 °C was added oil-free NaH (15.3 mg, 640 μmol, oil was

removed by washing 3× with hexanes under an inert atmosphere).

The reaction was stirred for 3 h at rt and then quenched with water.

The mixture was extracted with EtOAc, and the organic layers were

dried, ﬁltered, and concentrated to a brown oil. Flash column

chromatography (SiO₂, 50−65−100% ether in hexanes) yielded 26 as

a cream-colored, powdery solid (184 mg, 72%): mp 136.5−138.0 °C;

R_f= 0.47 (60% EtOAc/hexanes); IR (ﬁlm) 2947, 2931, 2886, 2857,

1696, 1669, 1586 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.82 (ddd, J =

11.7, 7.9, 6.1 Hz, 1H), 3.75 (dd, J = 9.5, 3.7 Hz, 1H), 3.62 (ddd, J =

11.6, 7.6, 7.6 Hz, 1H), 3.33−3.24 (m, 1H), 3.12 (dddd, J = 18.2, 8.9,

6.6, 2.6 Hz, 1H), 2.96−2.88 (m, 1H), 2.84 (dd, J = 16.1, 5.2 Hz, 1H),

2.50 (dd, J = 17.8, 5.3 Hz, 1H), 2.38 (dd, J = 17.7, 2.6 Hz, 1H), 2.19−

2.11 (m, 2H), 2.06−1.92 (m, 2H), 1.01 (d, J = 7.1 Hz, 3H), 0.91 (s,

9H), 0.09 (s, 3H), 0.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm

196.1, 169.5, 155.1, 106.6, 74.9, 45.6, 45.1, 36.0, 35.8, 33.7, 32.0, 25.7,

21.3, 17.9, 12.9, −4.4, −4.8; HRMS (CI) Exact mass calcd for

C₁₉H₃₂NO₃Si [M + H]⁺350.2151, found 350.2154. Anal. calcd for

C₁₉H₃₁NO₃Si: C, 65.29; H, 8.94; N, 4.01. Found: C, 65.34; H, 8.99; N,

3.99.

Alternate Preparation of 32. NH₃(9 mL) was condensed into a

two-necked ﬂask at −78 °C. Oil-free lithium wire (9 mg, washed once

with hexanes to remove the oil) was added, and the reaction was

stirred until a blue color persisted for at least 10 min. A solution of

t

vinylogous imide 26 (75.3 mg, 214 μmol), BuOH (20.5 μL, 214

μmol), and THF (600 μL) were added dropwise. After 20 min the

reaction was quenched by the addition of water and was warmed to rt

to evaporate the NH₃. The crude reaction was then extracted with

EtOAc, and the combined organic layers were dried, ﬁltered, and

concentrated to a pale yellow oil. Flash column chromatography (SiO₂,

70−90−100% ethyl acetate in hexanes) yielded a colorless oil identical

1

in analytical data and matching H NMR to ketone epimer 32 (47.3

mg, 63%).

(6aS,7S,8S,10bR)-10-(Allyloxy)-7-((tert-butyldimethylsilyl)-

oxy)-8-methyl-1,2,3,6a,7,8,9,10b-octahydropyrrolo[2,1-a]-

isoquinolin-5(6H)-one (33). Ketone 31 (20.0 mg, 56.9 μmol) was

added to a stirred mixture of KO^tBu (7.0 mg, 63 μmol) and HMPA

(49 μL, 284 μmol) in C₆H₆(600 μL) at 0 °C. After 10 min, the

(6aS,7S,8S,10aR,10bR)-7-((tert-Butyldimethylsilyl)oxy)-8-

methyloctahydropyrrolo[2,1-a]isoquinoline-5,10(6H,10aH)-

dione (31). Vinylogous amide 6 (4.0 mg, 10 μmol) and 10% Pd/C

835

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The Journal of Organic Chemistry

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reaction was warmed to rt and stirred for an additional 2 h before

quenching with satd aq NaHCO₃. The mixture was extracted with

EtOAc, and the combined organic layers were dried, ﬁltered, and

concentrated to a brown oil. Flash column chromatography (50−70−

100% ethyl acetate in hexanes) yielded 33 as a colorless oil (13 mg,

58%): R_f= 0.33 (65% EtOAc/hexanes); IR (ﬁlm) 2956, 2929, 2885,

354.2454. Anal. Calcd for C₁₉H₃₅NO₃Si: C, 64.54; H, 9.98; N, 3.96.

Found: C, 64.53; H, 10.04; N, 3.96.

2-((1S,2R,3S,Z)-2-((tert-Butyldimethylsilyl)oxy)-3-methyl-5-

oxo-6-(pyrrolidin-2-ylidene)cyclohexyl)ethyl pivalate (36). Tri-

methylacetic anhydride (2.02 mL, 10.0 mmol) was added to alcohol 35

(1.76 g, 4.98 mmol), DMAP (183 mg, 1.50 mmol), and Et₃N (4.2 mL,

30 mmol) in CH₂Cl₂(25 mL) at rt and stirred for ∼40 h. The reaction

was quenched with satd aq NaHCO₃and extracted with EtOAc. The

combined organic layers were washed with brine and then dried,

ﬁltered, and concentrated to a yellow oil. Flash column chromatog-

raphy (SiO₂, 50−70−90% ether in hexanes) provided pivalate 36 as a

yellow oil (2.04g, 93%), which upon standing in the refrigerator

became a cream-colored solid: R_f= 0.35 (60% EtOAc/hexanes); mp

54.5−57.0 °C; [α]²_D⁰+20.1 (c 1.0, CHCl₃); IR (ﬁlm) 2956, 2929, 2856,

1727, 1611, 1534 cm⁻¹. Data in CDCl₃: ¹H NMR (400 MHz, CDCl₃)

δ 10.76 (br s, 1H), 4.12 (ddd, J = 11.2, 7.7, 5.9 Hz, 1H), 4.09−4.01

(m, 1 H), 3.74 (dd, J = 2.7, 1.6 Hz, 1H), 3.61 (ddd, J = 10.4, 7.7, 6.1

Hz, 1H), 3.53 (ddd, J = 10.4, 7.9, 6.4 Hz, 1H), 2.64 (ddd, J = 16.7, 8.8,

6.6 Hz, 1H), 2.59−2.52 (m, 2H), 2.23 (dd, J = 17.6, 12.3 Hz, 1H),

2.19−2.06 (m, 2H), 2.03−1.93 (m, 2H), 1.75−1.56 (m, 2H), 1.22 (s,

9H), 0.96 (d, J = 6.5 Hz, 3H), 0.82 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) ppm 195.0, 178.9, 167.5, 99.7, 72.8,

1

2856, 1653, 1647, 1457 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.91

(dddd, J = 15.8, 10.5, 5.2, 5.2 Hz, 1H), 5.29 (dd, J = 17.2, 1.6 Hz, 1H),

5.20 (dd, J = 10.5, 1.4 Hz, 1H), 4.27−4.22 (m, 3H), 3.70 (ddd, J =

12.0, 8.7, 8.7 Hz, 1H), 3.43 (dd, J = 7.6, 3.6 Hz, 1H), 3.35−3.27 (m,

1H), 2.65 (dd, J = 15.2, 3.7 Hz, 1H), 2.44−2.30 (m, 3H), 2.11−2.07

(m, 1H), 2.04−1.98 (m, 1 H), 1.94−1.85 (m, 2H), 1.82−1.78 (m,

1H), 1.36 (dddd, J = 11.6, 11.6, 11.6, 8.2 Hz, 1H), 0.96 (d, J = 7.2 Hz,

3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) led to decomposition in the time needed to acquire the data

and did not allow for characterization; HRMS (CI) Exact mass calcd

for C₂₂H₃₈NO₃Si [M + H]⁺392.2621, found 392.2611.

(6aS,7S,8S,10aR,10bR)-10a-Allyl-7-((tert-butyldimethylsilyl)-

oxy)-8-methyloctahydropyrrolo[2,1-a]isoquinoline-5,10-

(6H,10aH)-dione (34). A solution of freshly prepared allyl vinyl ether

33 (37.0 mg, 94.5 μmol) in o-dichlorobenzene (1.2 mL) was heated at

170 °C in a sealed tube for 3.5 h. The reaction was concentrated, and

the crude oil was puriﬁed by ﬂash column chromatography (SiO₂, 40−

60% ethyl acetate in hexanes) to give 34 as a colorless oil (29 mg,

78%): R_f= 0.38 (60% EtOAc/hexanes); IR (ﬁlm) 2956, 2929, 2885,

2856, 1653, 1647 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.50 (dddd, J

= 17.1, 10.3, 7.2, 7.2 Hz, 1H), 5.13 (d, J = 9.4 Hz, 1H), 5.12 (d, J =

18.3 Hz, 1H), 4.16 (ddd, J = 12.2, 9.5, 5.6 Hz, 1H), 4.13−4.07 (m,

1H), 3.42 (dd, J = 11.7, 4.9 Hz, 1H), 2.88 (ddd, J = 11.9, 10.3, 6.3 Hz,

1H), 2.66 (dd, J = 14.8, 5.2 Hz, 1H), 2.70−2.61 (m, 1H), 2.57−2.53

(m, 2H), 2.37−2.27 (m, 4H), 2.25 (dd, J = 14.8, 2.4 Hz, 1H), 1.91−

1.75 (m, 2H), 1.27−1.14 (m, 1H), 0.94 (d, J = 7.1 Hz, 3H), 0.91 (s,

63.1, 47.8, 41.9, 50.7, 39.1, 35.6, 30.9, 29.1, 27.6, 26.0, 21.9, 19.1, 18.4,

1

−4.1, −4.4. Data in C₆D₆(for use with 2D NMR): H NMR (500

MHz, C₆D₆) δ 11.1 (br s, 1H), 4.21 (dt, J = 11.0, 6.6 Hz, 1H), 4.10

(dt, J = 11.3, 6.0 Hz, 1H), 3.75 (br s, 1H), 2.84 (dt, J = 10.6, 7.2 Hz,

1H), 2.75 (dt, J = 10.6, 7.2 Hz, 1H), 2.67 (ddd, J = 7.2, 7.2, 3.0 Hz,

1H), 2.62 (dd, J = 17.8, 12.1 Hz, 1H), 2.53 (dd, J = 17.4, 6.4 Hz, 1H),

2.45−2.38 (m, 2H), 2.01 (dddq, J = 6.3, 6.3, 6.3, 6.3 Hz, 1H), 1.62 (dt,

J = 6.8, 6.8 Hz, 2H), 1.36 (quintet, J = 7.1 Hz, 2H), 1.31 (s, 9H),

1.02−0.96 (m, 12H), 0.16 (s, 3H), 0.14 (s, 3H); HRMS (CI) Exact

mass calcd for C₂₄H₄₄O₄NSi [M + H]⁺438.3040, found 438.3023. 2D

NOESY data supporting the cis-assignment of the vinylogous amide

was performed and is in Supporting Information 2.

1

9H), 0.12 (s, 3H), 0.09 (s, 3H); H NMR (400 MHz, C₆D₆for use

with 2D NMR) δ 5.38 (dddd, J = 17.8, 10.0, 7.8, 6.8 Hz, 1H), 4.95 (d, J

= 9.5 Hz, 1H), 4.85 (dd, J = 16.8, 1.3 Hz, 1H), 4.30 (ddd, J = 13.1, 9.6,

5.2 Hz, 1H), 3.78 (dd, J = 9.9, 4.8 Hz, 1H), 3.27 (dd, J = 11.6, 4.9 Hz,

1H), 2.85−2.74 (m, 1H), 2.57 (ddd, J = 10.2, 10.2, 6.2 Hz, 1H), 2.32−

2.06 (m, 6H), 1.97 (dd, J = 14.8, 2.6 Hz, 1H), 1.93−1.86 (m, 1H),

1.38−1.15 (m, 2H), 0.95 (s, 9H), 0.80 (d, J = 7.1 Hz, 3H), 0.74−0.62

(m, 1H), 0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

ppm 208.9, 169.0, 131.3, 120.4, 71.0, 62.1, 51.8, 45.0, 43.1, 36.6, 36.4,

35.8, 32.8, 26.7, 26.2, 22.2, 18.4, 13.1, −3.9, −4.3; HRMS (EI) Exact

mass calcd for C₂₂H₃₈NO₃Si [M + H]⁺392.2621, found 392.2611. 2D

NMR data was obtained to support the assignment of the allyl group;

see Supporting Information 2 for details.

2-((1S,2S,5S,6S)-2-Allyl-6-((tert-butyldimethylsilyl)oxy)-2-

(3,4-dihydro-2H-pyrrol-5-yl)-5-methyl-3-oxocyclohexyl)ethyl

pivalate and epimer (37 and epi-37). Ceric ammonium nitrate⁶⁴

(2.5 g, 4.6 mmol) was added to a stirring solution of vinylogous amide

36 (1.0 g, 2.3 mmol) and allyltrimethylsilane (3.6 mL, 23 mmol) in

degassed CH₃CN⁷¹(76 mL) at 0 °C. The reaction was quenched after

10 min by the addition of satd aq NaHCO₃and extracted three times

with EtOAc. The combined organic layers were dried, ﬁltered, and

concentrated to provide a crude brown oil. Subsequent column

chromatography (SiO₂, 8−15% ethyl acetate in hexanes) yielded the

major diastereomer (37) as a colorless oil (750 mg, 67%), as well as a

small amount of the allyl diastereomer (epi-37) as a colorless oil (22

mg, 2% yield). Data for major diastereomer 37: R_f= 0.55 (20%

EtOAc/hexanes); [α]²_D⁰−83.9 (c 1.0, CHCl₃); IR (ﬁlm) 2957, 2931,

2858, 1727 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.68 (dddd, J = 17.0,

9.4, 5.1, 5.1 Hz, 1H), 5.14 (d, J = 17.0 Hz, 1H), 5.09 (d, J = 10.1 Hz,

1H), 4.65 (dd, J = 9.4, 3.9 Hz, 1H), 4.06−4.00 (m, 2H), 3.89−3.77

(m, 2H), 3.01 (dd, J = 13.9, 5.1 Hz, 1H), 2.84 (dd, J = 15.2, 6.2 Hz,

1H), 2.50−2.32 (m, 3H), 2.25−2.18 (m, 2H), 2.00−1.94 (m, 1H),

1.84−1.63 (m, 4H), 1.17 (s, 9H), 0.92−0.86 (m, 3H), 0.90 (s, 9H),

0.11 (s, 3H), 0.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 208.9,

178.4, 176.5, 134.1, 118.8, 73.9, 64.7, 71.8, 60.9, 43.9, 40.4, 38.5, 37.5,

36.4, 35.4, 29.2, 27.1, 25.9, 22.0, 18.0, 13.4, −4.4, −4.6; HRMS (CI)

Exact mass calcd for C₂₇H₄₈NO₄Si [M + H]⁺478.3347, found

478.3335. Data for minor diastereomer (epi-37): R_f= 0.32 (20%

EtOAc/hexanes); [α]²_D⁰−3.3 (c 1.0, CHCl₃) IR (ﬁlm) 2958, 2931,

2858, 1728, 1714 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.80−5.70 (m,

1H), 4.98 (d, J = 17.0 Hz, 1H), 4.93 (d, J = 10.1 Hz, 1H), 4.06 (dd, J =

8.1, 3.8 Hz, 1H), 4.00 (t, J = 7.5 Hz, 2H), 3.93−3.74 (m, 2H), 2.90−

2.81 (m, 1H), 2.70−2.61 (m, 1H), 2.52−2.34 (m, 4H), 2.32−2.23 (m,

2H), 1.97−1.77 (m, 2H), 1.74−1.59 (m, 1H), 1.67 (dddd, J = 14.3,

14.3, 7.3, 7.3 Hz, 1H), 1.18 (s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.91 (s,

9H), 0.14 (s, 3H), 0.12 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm

209.7, 178.5, 177.7, 134.8, 116.7, 73.9, 63.9, 60.8, 60.5, 44.8, 42.2, 38.8,

36.0, 35.9, 35.1, 27.6, 27.4, 26.2, 22.9, 18.4, 14.7, −4.1, −4.0; HRMS

(CI) Exact mass calcd for C₂₇H₄₈NO₄Si [M + H]⁺478.3347, found

(3S,4R,5S,Z)-4-((tert-Butyldimethylsilyl)oxy)-3-(2-hydrox-

yethyl)-5-methyl-2-(pyrrolidin-2-ylidene)cyclohexanone (35).

A 1.67 M stock solution of Red-Al (13 mL, 65 wt % in toluene) in

toluene (13 mL) was cooled to 0 °C. Of this stock solution, a portion

(18.5 mL, 30.9 mmol) was added rapidly to ester 6 (5.10 g, 12.9

mmol) stirring in toluene (103 mL) also at 0 °C.⁷⁰After 30 min, the

reaction was warmed to rt and stirred an additional 30 min. It was then

cooled to 0 °C before quenching with Rochelle’s salt (200 mL) and

then warmed again to rt for 20 min. The crude reaction was extracted

with EtOAc, and the combined organic layers were washed with brine,

dried, ﬁltered, and concentrated to a yellow/green oil. Column

chromatography (SiO₂, 50−70−90% ethyl acetate in hexanes)

provided alcohol 35 as a yellow, ﬂaky solid (3.2 g, 70%): R_f= 0.18

(90% EtOAc/hexanes); mp 87.9−89.5 °C; IR (ﬁlm) 3269 (br), 2953,

1

2928, 2856, 1603, 1514 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 10.74

(br s, 1H), 3.72 (br s, 1H), 3.69 (t, J = 6.3 Hz, 2H), 3.59 (ddd, J =

10.5, 7.8, 6.2 Hz, 1H), 3.52 (ddd, J = 10.4, 7.3, 7.3 Hz, 1H), 2.72 (ddd,

J = 16.7, 8.7, 6.5 Hz, 1H), 2.62−2.58 (m, 1H), 2.57 (ddd, J = 16.7, 8.6,

7.1 Hz, 1H), 2.22 (dd, J = 17.5, 12.1 Hz, 1H), 2.14 (dd, J = 17.3, 5.7

Hz, 1H), 2.13−2.06 (m, 1H), 2.01−1.92 (m, 2H), 1.66−1.52 (m, 3H),

0.95 (d, J = 6.5 Hz, 3H), 0.83 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) ppm 194.9, 167.6, 99.9, 73.0, 61.2, 47.6,

41.4, 40.6, 39.5, 30.8, 29.0, 25.9, 21.9, 18.9, 18.3, −4.2, −4.5; HRMS

(CI) Exact mass calcd for C₁₉H₃₆NO₃Si [M + H]⁺354.2464, found

836

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478.3352. 2D NMR data supporting the assignments of both the major

and minor diastereomers is discussed in Supporting Information 2.

2-((1R,5S,6S)-6-((tert-Butyldimethylsilyl)oxy)-2-chloro-2-(3,4-

dihydro-2H-pyrrol-5-yl)-5-methyl-3-oxocyclohexyl)ethyl piva-

late (38). N-Chlorosuccinimide (6.1 mg, 45.7 μmol)⁶⁴was added to a

stirring solution of the vinylogous amide 36 (20.0 mg, 45.7 μmol) in

CH₂Cl₂(450 μL) at rt. After 15 min, the reaction was quenched with

satd aq NaHCO₃and extracted with EtOAc. The combined organic

layers were dried, ﬁltered, and concentrated to a white oily solid. Flash

column chromatography (SiO₂, 5−10% ethyl acetate in hexanes)

provided the α-chloro ketone 38 as a colorless oil and single

diastereomer (18.3 mg, 85%). However, while the chair conformation

could be determined by ¹H NMR and 2D NMR, the newly set

stereocenter could not be identiﬁed by NOESY correlations: R_f= 0.69

59.8, 48.8, 44.8, 41.9, 38.9, 34.0, 30.4, 29.9, 27.5, 26.2, 25.4, 20.1, 18.7,

18.3, −3.5, −4.6; HRMS(CI) exact mass calcd for C₂₇H₅₀NO₄Si [M +

H]⁺480.3504 Found 480.3521. Anal. calcd for C₂₇H₄₉NO₄Si: C,

67.59; H, 10.29; N, 2.92. Found: C, 67.37; H, 10.23; N, 2.86. 2D

NMR data of 41 supporting the assignment of the stereochemistry of

the reduction is presented in Supporting Information 2.

(1S,2S,3S,4S,5S)-2-Allyl-4-((tert-butyldimethylsilyl)oxy)-2-

(3,4-dihydro-2H-pyrrol-5-yl)-3-(2-hydroxyethyl)-5-methylcy-

clohexanol (42). Na metal (72 mg, 3.1 mmol, washed 3× with

hexanes prior to use under an inert atmosphere) was added to pivalate

41 (150 mg, 313 μmol) in MeOH (6.3 mL) at 0 °C. The reaction was

stirred an additional 10 min at 0 °C before warming to rt and stirring

for 16 h. The reaction was quenched with 1 N HCl until a pH of 5−6,

and then the MeOH was removed in vacuo. The remaining oil was

extracted with ether, and the combined organic layers were dried,

ﬁltered, and concentrated. Column chromatography (SiO₂, 40−65%

ethyl acetate in hexanes) provided the desired β-diol (42) as a

colorless, thick oil (108 mg, 87%): R_f= 0.16 (40% EtOAc/hexanes);

[α]²_D¹+44.3 (c 0.7, CHCl₃); IR (ﬁlm) 3400 (br), 2954, 2930, 2859

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.58 (br s, 1H), 5.48−5.38 (m,

1H), 4.96 (d, J = 17.2 Hz, 1H), 4.92 (d, J = 10.1 Hz, 1H), 4.20 (br s,

1H), 3.93−3.85 (m, 1H), 3.80−3.72 (m, 1H), 3.74 (br s, 1H), 3.66

(ddd, J = 10.7, 6.8, 4.6 Hz, 1H), 3.57−3.50 (m, 1H), 3.28 (dd, J = 14.7,

8.3 Hz, 1H), 2.60−2.45 (m, 2H), 2.28−2.13 (m, 2H), 1.89−1.69 (m,

5H), 1.63 (br s, 1H), 1.48 (br d, J = 13.4 Hz, 1H), 1.34−1.26 (m, 1H),

0.94−0.90 (m, 12H), 0.10 (s, 3H), 0.06 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) ppm 184.3, 135.0, 116.9, 74.4, 69.9, 62.1, 59.7, 48.8, 44.4,

41.9, 34.3, 34.1, 30.5, 26.2, 25.4, 22.2, 18.7, 18.3, −3.6, −4.8; HRMS

(CI) Exact mass calcd for C₂₂H₄₂NO₃Si [M + H]⁺396.2934, found

396.2916. See Supporting Information 2 for X-ray data of 42

supporting an intramolecular hydrogen bond between the β-OH

hydrogen and imine nitrogen.

1

(40% EtOAc/hexanes); IR (ﬁlm) 2959, 2931, 2859, 1727 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 4.12 (dd, J = 8.7, 3.6 Hz, 1H), 4.11−4.05

(m, 1H), 4.01 (ddd, J = 10.6, 8.9, 6.4 Hz, 1H), 3.97−3.91 (m, 2H),

3.24 (dd, J = 14.3, 5.4 Hz, 1H), 2.87 (ddd, J = 9.7, 5.4, 5.4 Hz, 1H),

2.76−2.59 (m, 2H), 2.38−2.26 (m, 1H), 2.30 (dd, J = 13.6, 4.6 Hz,

1H), 1.96 (quintet, J = 7.8 Hz, 2H), 1.84−1.76 (m, 2H), 1.16 (s, 9H),

0.96 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); ¹³C

NMR (100 MHz, CDCl₃) ppm 201.6, 178.6, 175.1, 74.2, 63.9, 61.6,

48.7, 42.9, 41.9, 39.0, 37.1, 35.5, 30.1, 27.6, 26.2, 23.3, 18.4, 13.7, −4.0,

−4.2; HRMS (CI) Exact mass calcd for C₂₄H₄₃ClNO₄Si [M + H]⁺

472.2650, found 472.2632.

2-((1R,5S,6S)-6-((tert-Butyldimethylsilyl)oxy)-2-(3,4-dihydro-

2H-pyrrol-5-yl)-2-hydroxy-5-methyl-3-oxocyclohexyl)ethyl

pivalate (39). MCPBA⁶⁴(30.0 mg, 171 μmol) was added to

vinylogous amide 36 (75.0 mg, 171 μmol) in CH₂Cl₂(1.7 mL) at rt.

After 25 min, the reaction was quenched with satd aq NaHCO₃and

extracted with EtOAc. The combined organic layers were dried,

ﬁltered, and concentrated to an oil. Flash column chromatography

(SiO₂, 5−10−20% ethyl acetate in hexanes) furnished α-hydrox-

yketone 39 as a colorless oil as one diastereomer (32.7 mg, 42%),

along with recovered starting material (25 mg, 33%). As with the 38

above, the exact diastereomer could not be established: R_f= 0.69 (50%

Alternate Preparation of 42 along with (1R,2S,3S,4S,5S)-2-

Allyl-4-((tert-butyldimethylsilyl)oxy)-2-(3,4-dihydro-2H-pyrrol-

5-yl)-3-(2-hydroxyethyl)-5-methylcyclohexanol (S2). To a

stirred solution of ketone 37 (125 mg, 262 μmol) in CH₂Cl₂(4.0

mL) at −78 °C was added Et₂AlCl (728 μL, 1.31 mmol, 1.8 M

solution in toluene) slowly dropwise. The reaction mixture was stirred

1

EtOAc/hexanes); IR (ﬁlm) 3464, 2958, 2930, 2858, 1727 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 4.70 (dd, J = 10.3, 4.6 Hz, 1H), 4.42 (br s,

1H), 4.19 (ddd, J = 10.6, 8.7, 6.5 Hz, 1H), 4.12 (ddd, J = 10.6, 8.9, 6.1

Hz, 1H), 4.04−3.85 (m, 2H), 3.38 (dd, J = 13.4, 5.8 Hz, 1H), 2.76−

2.66 (m, 1H), 2.47−2.34 (m, 2H), 2.30 (dd, J = 13.4, 2.9 Hz, 1H),

1.99 (ddd, J = 11.3, 7.0, 4.9 Hz, 1H), 1.95−1.66 (m, 4H), 1.18 (s, 9H),

0.95−0.87 (m, 12H), 0.09 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) ppm

209.4, 178.7, 178.2, 83.4, 72.2, 64.5, 62.6, 48.3, 41.7, 39.0, 37.3, 36.8,

28.0, 27.6, 26.2, 21.8, 18.4, 13.0, −3.9, −4.4; HRMS (CI) Exact mass

calcd for C₂₄H₄₄NO₅Si [M + H]⁺454.2989, found 454.2976.

n

for 30 min at −78 °C, and then Bu₃SnH (282 μL, 1.05 mmol) was

added rapidly. The reaction mixture was stirred for 30 min at −78 °C

and then for 3 h at rt (with slow warming of the reaction from −78 °C

to rt) before being treated with NH₄OH with stirring for 30 min. The

aluminum salt was ﬁltered oﬀ and washed with CH₂Cl₂. The resulting

solution was concentrated, and the residue was puriﬁed by column

chromatography (SiO₂, 30−50 ethyl acetate in hexanes) to furnish β-

diol 42 as a colorless oil (86 mg, 83%) along with the α-diol

diastereomer (S2) as a colorless oil (8 mg, 8%). Data for α-diol S2: R_f

= 0.08 (33% EtOAc/hexanes); IR (ﬁlm) 3410 (br), 2953, 2928, 2855

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.03−5.93 (m, 1H), 4.84 (d, J =

17.2 Hz, 1H), 4.78 (d, J = 10.0 Hz, 1H), 4.16 (dd, J = 12.1, 4.1 Hz,

1H), 3.77 (br t, J = 7.6 Hz, 2H), 3.70−3.58 (m, 2H), 3.69 (br s, 1H),

3.41 (dd, J = 15.2, 6.0 Hz, 1H), 2.58−2.39 (m, 2H), 2.19 (dd, J = 15.2,

8.8 Hz, 1H), 2.04−1.89 (m, 2H), 1.85−1.70 (m, 2H), 1.69−1.56 (m,

2H), 1.44−1.21 (m, 4H), 0.95 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.12

(s, 3H), 0.06 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 184.1,

138.3, 114.1, 73.7, 71.7, 61.9, 59.4, 51.2, 45.7, 39.6, 34.3, 32.3, 32.0,

31.5, 26.0, 22.1, 18.3, 18.1, −3.8, −5.0; HRMS (CI) Exact mass calcd

for C₂₂H₄₂NO₃Si [M + H]⁺396.2928 Found 396.2948.

2-((1S,2S,3S,5S,6S)-2-Allyl-6-((tert-butyldimethylsilyl)oxy)-2-

(3,4-dihydro-2H-pyrrol-5-yl)-3-hydroxy-5-methylcyclohexyl)-

ethyl pivalate (41). To a solution of ketone 37 (1.18 g, 2.47 mmol)

in CH₂Cl₂(25 mL) at −78 °C was added Et₂AlCl (3.43 mL, 6.18

mmol, 1.8 M in toluene) slowly via syringe. The reaction mixture was

n

stirred for 30 min at −78 °C, and then Bu₃SnH (1.33 mL, 4.94

mmol) was added over 45 min via syringe pump. The reaction mixture

was stirred for 1 h at −78 °C, warmed gradually to rt over 1 h, and

then for another 1.5 h at rt. The reaction mixture was cooled to 0 °C,

quenched with satd aq NH₄OH, and stirred for an additional 30 min at

rt. Water was added, and the crude reaction was extracted with EtOAc,

and the combined organic layers were washed with brine and then

dried, ﬁltered, and concentrated to a pale yellow oil. Flash column

chromatography (2× SiO₂, 4−10−20% ethyl acetate in hexanes)

yielded the desired β-alcohol (41) as a colorless oil (900 mg, 76%): R_f

= 0.65 (50% EtOAc/hexanes); [α]²_D⁰+48.9 (c 1.0, CHCl₃); IR (ﬁlm)

3515−3234, 3076 (w), 2957, 2929, 2857, 1729, 1621, 1463, 1282,

1251, 1154, 1051, 1031 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.62 (br

s, 1H), 5.50−5.38 (m, 1H), 5.02−4.91 (m, 2H), 4.23 (br s, 1H), 4.06−

3.98 (m, 2H), 3.97−3.88 (m, 1H), 3.82−3.73 (m, 2H), 3.37−3.27 (m,

1H), 2.62−2.44 (m, 2H), 2.30−2.21 (m, 1H), 2.18−2.09 (m, 1H),

1.92−1.76 (m, 5H), 1.58−1.47 (m, 1H), 1.44−1.34 (m, 1H), 1.20 (s,

9H), 0.94 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H), 0.07 (s, 6H); ¹³C NMR

(100 MHz, CDCl₃) ppm 184.0, 178.7, 134.8, 117.0, 73.9, 69.7, 63.7,

2-((1S,2S,3S,5S,6S)-6-((tert-Butyldimethylsilyl)oxy)-2-(3,4-di-

hydro-2H-pyrrol-5-yl)-3-hydroxy-2-(3-hydroxypropyl)-5-

methylcyclohexyl)ethyl pivalate (44). BH₃·DMS (116 μL, 1.25

mmol) was added to alkene 41 (300 mg, 625 μmol) in THF (6.3 mL)

at 0 °C. After 3.5 h, the reaction was quenched by the addition of 3 N

NaOH (2.3 mL) and 30% H₂O₂(1.5 mL) and was allowed to stir at rt

overnight. The reaction was extracted with EtOAc, and the combined

organic layers were dried, ﬁltered, and concentrated to an oily solid.

Column chromatography (SiO₂, 15−30−45−60% ethyl acetate in

hexanes) yielded alcohol 44 as a colorless oil (87.1 mg, 28%), as well

as recovered starting material (41) (65.8 mg, 22%). Data for 44: R_f=

0.21 (50% EtOAc/hexanes); [α]²_D⁰+28.6 (c 1.8, CHCl₃); IR (ﬁlm)

837

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The Journal of Organic Chemistry

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3403 (br), 2956, 2930, 2856, 1729 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 5.30 (br s, 1H), 4.30 (br s, 1H), 4.07−4.00 (m, 2H), 4.00−

3.92 (m, 1H), 3.80 (ddd, J = 15.3, 7.7, 7.7 Hz, 1H), 3.77 (br s, 1H),

3.61 (ddd, J = 12.3, 6.4, 6.4 Hz, 1H), 3.55−3.47 (m, 1H), 2.68−2.56

(m, 2H), 2.53−2.44 (m, 1H), 2.32−2.23 (m, 1H), 1.96−1.75 (m, 5H),

1.57−1.44 (m, 2H), 1.43−1.33 (m, 2H), 1.22 (s, 9H), 1.12−1.01 (m,

1H), 0.97−0.90 (m, 12H), 0.08 (s, 6H), primary OH hydrogen was

not observed; ¹³C NMR (125 MHz, CDCl₃) ppm 184.0, 178.5, 73.6,

69.0, 63.5, 63.2, 59.6, 48.7, 45.2, 38.6, 33.6, 33.4, 30.4, 30.3, 28.3, 27.2,

25.9, 25.3, 21.8, 18.4, 18.0, −3.9, −5.0; HRMS (EI) Exact mass calcd

for C₂₇H₅₂NO₅Si [M + H]⁺498.3610, found 498.3609.

(1S,2S,3S,3′R,4S,6S)-3′-(Bromomethyl)-3-((tert-butyldi-

methylsilyl)oxy)-6-hydroxy-4-methyl-2-(2-(pivaloyloxy)ethyl)-

3′,5′,6′,7′-tetrahydro-2′H-spiro[cyclohexane-1,1′-pyrrolizin]-

4′-ium bromide (45). NBS (83.0 mg, 463 μmol) was added to

alkene 41 (117 mg, 244 μmol) in CH₂Cl₂(2.4 mL) at 0 °C, and the

reaction was stirred for 25 min. The solvent was concentrated in

vacuo, and the residual oil was puriﬁed via ﬂash column

chromatography (SiO₂, 7−15% ethyl acetate in hexanes) to yield 45

as a colorless oil (72 mg, 46% yield): R_f= 0.54 (30% EtOAc/hexanes);

IR (ﬁlm) 2958, 2931, 2857, 1726 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 4.39−4.33 (m, 1H), 4.34 (dd, J* = 10.2, 5.4 Hz, 1H), 4.11−4.04 (m,

2H), 3.89−3.76 (m, 2H), 3.81 (dd, J* = 13.4, 3.8 Hz, 1H), 3.52 (dd, J

= 10.1, 5.6 Hz, 1H), 3.39 (dd, J = 10.1, 6.6 Hz, 1H), 2.68−2.59 (m,

1H), 2.52−2.44 (m, 1H), 2.47 (dd, J = 9.6, 6.6 Hz, 1H), 2.22−2.14

(m, 1H), 2.07−1.98 (m, 1H), 2.01 (ddd, J* = 12.8, 12.8, 5.2 Hz, 1H),

1.85−1.73 (m, 4H), 1.70 (dd, J = 12.7, 8.1 Hz, 1H), 1.67 (ddd, J =

10.2, 4.8, 4.8 Hz, 1H), 1.20 (s, 9H), 1.03 (d, J = 7.6 Hz, 3H), 0.88 (s,

9H), 0.04 (s, 3H), 0.02 (s, 3H), OH hydrogen was not observed; ¹³C

NMR (100 MHz, CDCl₃) ppm 178.8, 176.9, 81.8, 78.1, 73.8, 65.2,

60.7, 56.0, 44.8, 43.3, 38.9, 38.4, 36.1, 34.2, 30.5, 29.5, 27.5, 26.2, 22.4,

18.3, 13.6, −4.0, −4.5; HRMS (CI) Exact mass calcd for

C₂₇H₄₈Br⁸¹BrNO₄Si [M − H]⁺638.1693, found 638.1696. J* indicates

that the coupling constant was obtained using a 1D-TOCSY to

separate overlapping peaks. 2D NMR assignments of 45 can be found

in Supporting Information 2.

(until TLC revealed the disappearance of the primary bromide, 48, not

isolated). Column chromatography (SiO₂, 80% ethyl acetate in

hexanes then 5−12% methanol in dichloromethane) provided epi-49

as a colorless oil (21.8 mg, 78%): R_f= 0.15 (10% MeOH/CH₂Cl₂); IR

1

(ﬁlm) 3417 (br), 2958, 2930, 2857, 1721, 1669 cm⁻¹; H NMR (500

MHz, CDCl₃) δ 5.55 (br s, 1H), 4.89−4.81 (m, 1H), 4.39 (br t, J = 7.5

Hz, 1H), 4.24−4.12 (m, 2H), 4.11 (ddd, J = 10.3, 10.3, 6.5 Hz, 1H),

3.99 (ddd, J = 10.1, 10.1, 5.3 Hz, 1H), 3.87−3.80 (m, 1H), 3.68 (dd, J

= 10.5, 4.9 Hz, 1H), 3.57−3.49 (m, 1H), 3.30−3.20 (m, 1H), 2.80−

2.72 (m, 1H), 2.58−2.49 (m, 1H), 2.32 (ddd, J = 13.9, 6.5, 6.5 Hz,

1H), 2.26−2.16 (m, 1H), 2.13−2.06 (m, 1H), 1.98−1.93 (m, 1H),

1.90−1.81 (m, 3H), 1.75−1.67 (m, 1H), 1.57 (ddd, J = 14.3, 9.7, 4.8

Hz, 1H), 1.16 (s, 9H), 1.04 (d, J = 7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s,

3H), 0.06 (s, 3H), OH not observed; ¹³C NMR (125 MHz, CDCl₃)

ppm 194.2, 178.6, 73.5, 68.2, 64.2, 63.1, 53.2, 48.5, 38.8, 38.7, 36.0,

34.7, 33.9, 29.9, 27.1, 25.9, 20.5, 19.4, 18.2, 18.1, 11.9, −4.2, −4.8;

HRMS (CI) Exact mass calcd for C₂₇H₅₀NO₄Si [M]⁺480.3504, found

480.3519.

2-((1R,2S,4S,5S,6S,8a′R)-5-((tert-Butyldimethylsilyl)oxy)-2-

hydroxy-4-methylhexahydro-1′H-spiro[cyclohexane-1,8′-in-

dolizin]-6-yl)ethyl pivalate (50). PtO₂(8.0 mg, 36 μmol) was

added to salt epi-49 (10.0 mg, 17.8 μmol) in MeOH (500 μL), and 1

atm of hydrogen (H₂) was administered via a balloon. After 5 h, the

reaction was complete as indicated by TLC and was ﬁltered through

Celite, rinsing with MeOH and then concentrated. The crude oil was

chromatographed (SiO₂, 5−10% methanol in dichloromethane) to

provide amine 50 as a colorless oil (7.2 mg, 83%): R_f= 0.30 (10%

MeOH/CH₂Cl₂); IR (ﬁlm) 3380 (br), 2957, 2929, 2856, 1726 cm⁻¹;

¹H NMR (800 MHz, CDCl₃) δ 12.10−11.75 (br s, 1H), 4.89−4.83 (s,

1H), 4.06 (ddd, J = 11.2, 5.9, 5.9 Hz, 1H), 4.02−3.92 (m, 2H), 3.71 (s,

1H), 3.39−3.28 (m, 2H), 3.13−3.06 (m, 1H), 2.62−2.56 (m, 1H),

2.42−2.35 (m, 1H), 2.33 (d, J = 13.4 Hz, 1H), 2.25−2.14 (m, 2H),

2.14−2.09 (m, 1H), 2.07−1.96 (m, 3H), 1.96−1.90 (m, 1H), 1.74−

1.69 (m, 1H), 1.66−1.61 (m, 1H), 1.58−1.52 (m, 2H), 1.20 (s, 9H),

1.10 (dd, J = 13.2, 12.9 Hz, 1H), 0.93−0.88 (m, 12H), 0.10 (s, 3H),

0.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 178.5, 74.7, 67.3,

66.2, 64.0, 54.2, 46.0, 44.1, 39.6, 38.7, 31.9, 27.9, 27.2 (3C), 26.0 (3C),

24.6, 23.1, 22.0, 18.35, 18.31, 18.2, 17.9, −3.3, −4.5; HRMS (CI)

Exact mass calcd for C₂₇H₅₁NO₄Si [M]⁺481.3582, found 481.3589.

(1R,2S,3S,4S,6S)-3-((tert-Butyldimethylsilyl)oxy)-6-hydroxy-

4-methyl-2-(2-(pivaloyloxy)ethyl)-1′,2′,3′,5′,6′,7′-hexahydro-

spiro[cyclohexane-1,8′-indolizin]-4′-ium triﬂuoromethanesul-

fonate (51). Upon stirring epi-49 in CH₂Cl₂with excess TESOTf, the

bromide counterion could be exchanged for a triﬂate counterion

resulting in 51: R_f= 0.20 (10% MeOH/CH₂Cl₂); [α]²_D⁰+4.0 (c 0.05,

CHCl₃); IR (ﬁlm) 3424 (br), 2959, 2932, 2858, 1722 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 4.69−4.61 (m, 1H), 4.30 (dd, J = 10.2, 6.2 Hz,

1H), 4.29−4.20 (m, 1H), 4.10 (ddd, J = 10.3, 10.3, 6.3 Hz, 1H), 3.99

(ddd, J = 10.2, 10.2, 5.4 Hz, 1H), 3.90−3.83 (m, 1H), 3.78−3.67 (m,

1H), 3.70 (dd, J = 10.4, 5.0 Hz, 1H), 3.59−3.51 (m, 1H), 3.36−3.27

(m, 1H), 2.70−2.60 (m, 1H), 2.50−2.41 (m, 1H), 2.37−2.26 (m, 2H),

2.17−2.10 (m, 1H), 1.96−1.86 (m, 4H), 1.76−1.67 (m, 1H), 1.53

(ddd, J = 14.7, 10.8, 4.6 Hz, 1H), 1.20 (s, 9H), 1.09−1.03 (m, 1H),

1.07 (d, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), OH

not observed; ¹³C NMR (125 MHz, CDCl₃) ppm 193.8, 178.7, 73.3,

68.6, 64.2, 62.5, 53.0, 48.5, 39.0, 38.6, 34.9, 34.5, 33.8, 29.5, 27.1, 25.8,

20.2, 19.3, 18.0, 17.8, 11.8, −4.3, −4.8. The CF₃SO₃⁻(triﬂate) carbon

was not observed by ¹³C NMR, but a peak was observed at −76.5 ppm

in the ¹⁹F NMR. HRMS (ESI) Exact mass calcd for C₂₇H₅₀NO₄Si

[M]⁺480.3509, found 480.3510. A crystal structure of triﬂate salt 51,

which supports the expected epimerization at the spirocyclic carbon,

can be found in Supporting Information 2.

(1S,2S,3S,3′S,4S,6S)-3-((tert-Butyldimethylsilyl)oxy)-6-hy-

droxy-3′,4-dimethyl-2-(2-(pivaloyloxy)-ethyl)-3′,5′,6′,7′-tetra-

hydro-2′H-spiro[cyclohexane-1,1′-pyrrolizin]-4′-ium bromide

(46). To a stirred solution of bromide 45 (6.0 mg, 9.4 μmol) in

n

C₆H₆(1 mL) was added Bu₃SnH (7.6 μL, 28 μmol) and AIBN (3.1

mg, 18.8 μmol), and the reaction mixture was heated at 80 °C for 30

min. After cooling to rt, the reaction mixture was treated with 1 N

NaOH (0.5 mL) with vigorous stirring for 30 min. The product was

extracted with Et₂O, and the combined organic layers were dried,

ﬁltered and concentrated to yellow oil. Flash column chromatography

(SiO₂, 8−15% ethyl acetate in hexanes) yielded 46 as colorless oil (2.7

mg, 59%): R_f= 0.55 (25% EtOAc/hexanes); [α]²_D²+18.0 (c 0.3,

CHCl₃); IR (ﬁlm) 2960, 2925, 2858, 1730 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 4.41 (dd, J = 10.4, 5.6 Hz, 1H), 4.31−4.24 (m, 1H), 4.12−

4.02 (m, 2H), 3.89−3.78 (m, 2H), 3.77 (dd, J = 13.2, 3.6 Hz, 1H),

2.69−2.61 (m, 1H), 2.52−2.44 (m, 1H), 2.38 (dd, J = 12.4, 6.8 Hz,

1H), 2.21−2.14 (m, 1H), 2.05−1.97 (m, 2H), 1.86−1.79 (m, 1H),

1.78−1.70 (m, 3H), 1.67−1.61 (m, 1H), 1.57 (br s, 1H); 1.48 (dd, J =

12.4, 8.0 Hz, 1H), 1.29 (d, J = 6.2 Hz, 3H), 1.20 (s, 9H), 1.04 (d, J =

7.2 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) ppm 178.8, 177.6, 80.1, 74.8, 73.8, 65.4, 60.7, 56.1, 46.0,

45.0, 38.9, 38.4, 34.3, 30.7, 29.4, 27.5, 26.2, 22.6, 22.4, 18.4, 13.7, −4.0,

−4.5; HRMS (CI) Exact mass calcd for C₂₇H₅₀NO₄Si [M − Br]⁺

480.3504, found 480.3506. 2D NMR assignments of 46 can be found

in Supporting Information 2.

(1R,2S,3S,4S,6S)-3-((tert-Butyldimethylsilyl)oxy)-6-hydroxy-

4-methyl-2-(2-(pivaloyloxy)ethyl)-1′,2′,3′,5′,6′,7′-hexahydro-

spiro[cyclohexane-1,8′-indolizin]-4′-ium bromide (epi-49). Bro-

mine (4.9 μL, 97 μmol) was added to a stirred solution of alcohol 44

(24.1 mg, 48.4 μmol), PPh₃(25 mg, 97 μmol), and imidazole (6.6 mg,

97 μmol) in benzene (1 mL) at rt. After 8 min, the reaction was

quenched with satd aq Na₂S₂O₃and extracted with EtOAc. The

combined organic layers were dried, ﬁltered, and concentrated in

vacuo to provide a colorless oily solid. The crude was dissolved in

2-((1S,2S,3S,5S,6S)-2-Allyl-6-((tert-butyldimethylsilyl)oxy)-2-

(3,4-dihydro-2H-pyrrol-5-yl)-5-methyl-3-((methylsulfonyl)oxy)-

cyclohexyl)ethyl pivalate (53). To a stirred solution of alcohol 41

(400 mg, 834 μmol) and triethylamine (255 μL, 1.83 mmol) in

CH₂Cl₂(8 mL) at 0 °C was added methanesulfonyl chloride (124 μL,

1.08 mmol). The reaction was stirred for 30 min before it was warmed

to rt and stirred for 15 min. The reaction was quenched with satd aq

NH₄Cl and extracted with CH₂Cl₂. The combined organic layers were

1

CDCl₃for H NMR analysis and after was allowed to sit for 1−2 d

838

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The Journal of Organic Chemistry

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dried, ﬁltered, and concentrated to a pale yellow oil. Column

chromatography (SiO₂, 10−20% ethyl acetate in hexanes) provided

the mesylate 53 as a pale yellow oil (464 mg, 100%): R_f= 0.70 (50%

EtOAc/hexanes); [α]²_D⁴+18.0 (c 1.0, CHCl₃); IR (ﬁlm) 3396 (br),

20% ethyl acetate in hexanes) provided mesylate 57 as a thick colorless

oil (291 mg, 89%): R_f= 0.68 (50% EtOAc/hexanes); [α]²_D⁴−44.8 (c

1

1.45, CHCl₃); IR (ﬁlm) 3396 (br), 2956, 2928, 2858, 1628 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 5.73 (dddd, J = 17.0, 10.0, 8.0, 6.0 Hz,

1H), 5.31 (dd, J = 12.0, 5.0 Hz, 1H), 4.94 (d, J = 16.5, Hz, 1H), 4.87

(d, J = 10.0 Hz, 1H), 3.98−3.95 (m, 2H), 3.84−3.70 (m, 2H), 3.65 (br

s, 1H), 3.48 (br s, 1H), 3.07 (s, 3H), 2.55 (ddd, J = 8.5, 8.5, 8.5 Hz,

1H), 2.40 (ddd, J = 8.5, 8.5, 8.5 Hz, 1H), 2.33 (dd, J = 8.5, 8.0 Hz,

1H), 2.10−1.88 (m, 3H), 1.84−1.78 (m, 2H), 1.65 (br s, 1H), 1.50−

1.38 (m, 2H), 1.19 (s, 9H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (s, 9H), 0.09

(s, 3H), 0.05 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) ppm 178.4 (2C),

136.9, 115.5, 83.1, 72.5, 62.1, 59.6, 49.6, 47.9, 40.4, 39.3, 38.7, 34.6,

32.7, 31.1, 27.9, 27.2, 26.0, 22.4, 18.0 (2C), −3.8, −4.9; HRMS (ESI)

Exact mass calcd for C₂₈H₅₂NO₆SSi [M + H]⁺558.3285, found

558.3287.

1

2956, 2928, 2858, 1628 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 5.48−

5.38 (m, 1H), 5.20 (br s, 1H), 4.98−4.90 (m, 2H), 4.10−3.98 (m,

2H), 3.89−3.80 (m, 1H), 3.78 (br s, 1H), 3.78−3.71 (m, 1H), 3.34

(dd, J = 15.0, 9.0 Hz, 1H), 3.07 (s, 3H), 2.71−2.62 (m, 1H), 2.41

(ddd, J = 8.0, 8.0, 8.0 Hz, 1H), 2.30 (br s, 1H), 2.17 (dd, J = 15.0, 4.0

Hz, 1H), 1.98 (br d, J = 11.5 Hz, 1H), 1.93−1.82 (m, 3H), 1.81−1.64

(m, 2H), 1.50−1.40 (m, 1H), 1.20 (s, 9H), 0.96 (d, J = 7.0 Hz, 3H),

0.91 (s, 9H), 0.07 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) ppm 178.4,

177.0, 133.2, 117.6, 83.3, 73.1, 63.3, 59.7, 49.0, 44.5, 41.4, 38.8, 38.7,

33.7, 30.3, 30.0, 27.2, 25.9, 25.7, 22.4, 18.0 (2C), −3.9, −4.9; HRMS

(ESI) Exact mass calcd for C₂₈H₅₂NO₆SSi [M + H]⁺558.3285, found

558.3278.

2-((1S,2R,4S,5S,6S,8a′R)-5-((tert-Butyldimethylsilyl)oxy)-4-

methyl-2-((methylsulfonyl)oxy)-hexahydro-1′H-spiro[cyclo-

hexane-1,8′-indolizin]-6-yl)ethyl pivalate (58). PtO₂(71.0 mg,

313 μmol) was added to salt 62 (91.1 mg, 143 μmol) in MeOH (4.0

mL), and a balloon atmosphere of hydrogen (H₂) was administered.

After 5 h, the reaction was complete as indicated by TLC and was

ﬁltered through Celite using MeOH and then concentrated. The crude

oil was chromatographed (SiO₂, 5−10% methanol in dichloro-

methane) to provide amine 58 as a colorless oil (45.3 mg, 57%): R_f

= 0.30 (10% MeOH/CH₂Cl₂); [α]²_D⁴−11.4 (c 1.4, CHCl₃); IR (ﬁlm)

3396 (br), 2956, 2928, 2858, 1628 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 5.24 (br s, 1H), 4.14−4.06 (m, 2H), 3.88 (dd, J = 7.8, 3.6

Hz, 1H), 3.09 (s, 3H), 3.05 (br s, 1H), 2.15−2.14 (m, 1H), 2.12−2.06

(m, 1H), 2.02 (ddd, J = 14.4, 4.2, 4.2 Hz, 1H), 1.95 (ddd, J = 6.6, 6.6,

6.6 Hz, 1H), 1.91−1.70 (m, 12H), 1.59 (br s, 1H), 1.49 (dddd, J =

13.8, 7.2, 7.2, 4.8 Hz, 1H), 1.19 (s, 9H), 1.09 (d, J = 6.6 Hz, 3H), 0.93

(s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); ¹³C NMR (150 MHz, CDCl₃)

ppm 178.6, 82.0, 71.6, 64.8, 63.6, 53.1, 46.7, 42.0, 40.9, 39.2, 31.3, 30.2,

29.7, 27.2, 25.9, 25.8, 25.7, 23.7, 18.9 (2C), 18.5, 17.9, −3.6, −4.9;

HRMS (ESI) Exact mass calcd for C₂₈H₅₄NO₆SSi [M + H]⁺560.3434,

found 560.3441.

2-((1S,2S,3S,4R,6S)-3-Allyl-3-(3,4-dihydro-2H-pyrrol-5-yl)-6-

methyl-7-oxabicyclo[2.2.1]heptan-2-yl)ethyl pivalate (54).

TBAF (80.0 μL, 80.0 μmol) was added to silyl ether 53 (15.0 mg,

26.8 μmol) in THF (0.5 mL), and the reaction was reﬂuxed for 2 h,

quenched with satd aq. NaHCO₃, and extracted with ether. The

combined organic layers were dried, ﬁltered, and concentrated to a

crude oil that was puriﬁed via column chromatography (SiO₂, 12−25−

50% ethyl acetate in hexanes) to furnish cyclic ether 54 as a yellow oil

(7.5 mg, 81%): R_f= 0.60 (50% EtOAc/hexanes); [α]²_D⁴−12.6 (c 1.5,

CHCl₃); IR (ﬁlm) 2956, 2928, 2858, 1744, 1709 cm⁻¹; ¹H NMR (600

MHz, CDCl₃) δ 5.56 (dddd, J = 16.8, 10.2, 7.8, 6.6 Hz, 1H), 5.04 (d, J

= 16.8 Hz, 1H), 5.01 (d, J = 10.2 Hz, 1H), 4.28 (d, J = 5.4 Hz, 1H),

4.07 (d, J = 4.8 Hz, 1H), 4.04−3.95 (m, 2H), 3.84−3.74 (m, 2H),

2.55−2.49 (m, 2H), 2.33−2.25 (m, 3H), 2.13 (dddd, J = 9.0, 6.6, 6.6,

3.6 Hz, 1H), 2.06 (ddd, J = 5.4, 5.4, 5.4 Hz, 1H), 1.95 (dd, J = 12.0, 8.4

Hz, 1H), 1.81−1.70 (m, 3H), 1.20 (s, 9H), 1.16 (ddd, J = 12.6, 5.4, 4.2

Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm

178.7, 177.7, 133.8, 117.8, 86.8, 84.2, 64.3, 60.5, 53.6, 47.2, 45.4, 38.7,

37.5, 35.5, 29.7, 27.4, 27.2, 22.2, 21.2; HRMS (ESI) Exact mass calcd

for C₂₁H₃₄NO₃[M + H]⁺348.2539, found 348.2533.

2-((1S,2S,3R,5S,6R)-2-Allyl-6-((tert-butyldimethylsilyl)oxy)-2-

(3,4-dihydro-2H-pyrrol-5-yl)-3-hydroxy-5-methylcyclohexyl)-

ethyl pivalate (60). To ketone 37 (100 mg, 209 μmol) in THF (2

mL) at 0 °C was added NaBH₄(40 mg, 1.1 mmol), and the reaction

was stirred for 10 min before being warmed to rt and stirred for 72 h.

The reaction was cooled to 0 °C, quenched with butyraldehyde (103

μL, 1.20 mmol), and allowed to warm to rt for 20 min before adding

satd aq NH₄OH. The reaction mixture was extracted with EtOAc, and

the combined organic layers were dried, ﬁltered, and concentrated to a

pale yellow oil. Column chromatography (SiO₂, 10−15−20−25%

ethyl acetate in hexanes) provided α-alcohol 60 (55.5 mg, 55%), the

epimeric β-alcohol (41) (12 mg, 12%), and recovered starting material

(37) (5.4 mg, 5%). Data for 60: R_f= 0.27 (30% EtOAc/hexanes);

2-((1S,2S,3S,5S,6S)-6-((tert-Butyldimethylsilyl)oxy)-2-(3,4-di-

hydro-2H-pyrrol-5-yl)-2-(3-hydroxypropyl)-5-methyl-3-

((methylsulfonyl)oxy)cyclohexyl)ethyl pivalate (55). BH₃·DMS

(34.1 μL, 353 μmol) was added to alkene 53 (93.0 mg, 168 μmol) in

THF (1.7 mL) at 0 °C. The reaction was stirred for 2 h before being

warmed to rt and stirred for another 1 h. The reaction was cooled to 0

°C, quenched by the addition of 3 N NaOH (650 μmol) and 30%

H₂O₂(500 μmol) and was allowed to stir at rt overnight. The reaction

was extracted with EtOAc, and the combined organic layers were

dried, ﬁltered, and concentrated to an oily solid. The residue was

redissolved in CH₂Cl₂(1 mL) and treated with DMAP (205 mg, 1.68

mmol) at rt for 7 d before it was ﬁltered, concentrated, and puriﬁed via

ﬂash column chromatography (SiO₂, 20−35%-50% ethyl acetate in

hexanes) to aﬀord alcohol 55 as a colorless oily solid (48 mg, 50%) in

addition to recovered starting material (53) (22 mg, 23%): R_f= 0.30

(50% EtOAc/hexanes); [α]_D²⁴−20.0 (c 0.6, CHCl₃); IR (ﬁlm) 2956,

2928, 2858, 1744, 1709 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.27 (br

s, 1H), 3.96 (br s, 1H), 3.85−3.81 (m, 2H), 3.68−3.63 (m, 2H), 3.48

(br s, 1H), 3.08 (s, 1H), 3.07 (br s, 1H), 2.81 (br s, 1H), 2.55−2.50

(m, 2H), 2.50−2.45 (m, 1H), 2.07−2.84 (m, 7H), 1.87−1.84 (m, 1H),

1.40−1.36 (m, 1H), 1.19−1.16 (m, 10H), 0.95−0.91 (m, 15H), 0.06

(s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 178.4 (2C),

83.6, 72.5, 63.5, 63.0, 59.8, 48.5, 39.3, 38.7, 34.2, 32.9, 32.0, 31.3, 30.3,

28.1, 27.2, 26.0, 22.3, 18.0, 17.9, 14.2, −3.8, −4.9; HRMS (ESI) Exact

mass calcd for C₂₈H₅₄NO₇SSi [M + H]⁺576.3390, found 576.3378.

2-((1S,2S,3R,5S,6R)-2-Allyl-6-((tert-butyldimethylsilyl)oxy)-2-

(3,4-dihydro-2H-pyrrol-5-yl)-5-methyl-3-((methylsulfonyl)oxy)-

cyclohexyl)ethyl pivalate (57). To a solution of alcohol 60 (283

mg, 590 μmol) and triethylamine (181 μL, 1.30 mmol) in CH₂Cl₂(7.0

mL) at 0 °C was added methanesulfonyl chloride (60.1 μL, 767 μmol).

The reaction was stirred for 30 min at 0 °C and then for 15 min at rt.

The reaction was quenched with satd aq NH₄Cl, extracted with

CH₂Cl₂, and the combined organic layers were dried, ﬁltered, and

concentrated to a pale yellow oil. Column chromatography (SiO₂, 10−

1

IR(ﬁlm) 2956, 2932, 2855, 1727 cm⁻¹; H NMR (500 MHz, CDCl₃)

δ 6.02−5.93 (m, 1H), 4.96 (br s, 1H), 4.85 (d, J = 17.0 Hz, 1H), 4.78

(d, J = 9.9 Hz, 1H), 4.17 (dd, J = 12.1, 3.9 Hz, 1H), 4.05−4.00 (m,

2H), 3.84−3.71 (m, 2H), 3.68 (br s, 1H), 3.40 (dd, J = 15.3, 5.7 Hz,

1H), 2.56 (ddd, J = 16.4, 9.4, 5.4 Hz, 1H), 2.43 (ddd, J = 16.8, 9.4, 7.6

Hz, 1H), 2.17 (dd, J = 15.3, 8.8 Hz, 1H), 1.99−1.88 (m, 2H), 1.87−

1.79 (m, 1H), 1.76 (ddd, J = 12.7, 12.7, 12.7 Hz, 1H), 1.76−1.70 (m,

1H), 1.60 (ddd, J = 12.8, 3.8, 3.8 Hz, 1H), 1.47 (dddd, J = 16.0, 11.7,

4.8, 4.8 Hz, 1H), 1.37−1.30 (m, 1H), 1.20 (s, 9H), 0.96 (d, J = 6.7 Hz,

3H), 0.92 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) ppm 184.0, 178.7, 138.4, 114.4, 73.3, 71.7, 63.5, 60.7, 51.3,

46.2, 39.9, 39.0, 34.3, 32.1, 31.7, 38.7, 27.5, 26.2, 22.3, 18.6, 18.3, −3.5,

−4.7; HRMS (CI) Exact mass calcd for C₂₇H₅₀NO₄Si [M + H]⁺

480.3504, found 480.3501. 2D NMR spectra of α-alcohol 60 are

described in the Supporting Information 2.

2-((1S,2S,3R,5S,6R)-6-((tert-Butyldimethylsilyl)oxy)-2-(3,4-di-

hydro-2H-pyrrol-5-yl)-2-(3-hydroxypropyl)-5-methyl-3-

((methylsulfonyl)oxy)cyclohexyl)ethyl pivalate (61). BH₃·DMS

(102 μL, 1.06 mmol) was added to alkene 57 (279 mg, 504 μmol) in

THF (5.0 mL) at 0 °C. The reaction was stirred for 2 h before being

warmed to rt and stirred for another 1 h. The reaction was cooled to 0

839

dx.doi.org/10.1021/jo302333s | J. Org. Chem. 2013, 78, 822−843

The Journal of Organic Chemistry

Featured Article

°C, quenched by the addition of 3 N NaOH (2.0 mL) and 30% H₂O₂

(1.5 mL) and was allowed to stir at rt overnight. The reaction was

extracted with EtOAc, and the combined organic layers were dried,

ﬁltered, and concentrated to an oily solid. The residue was redissolved

in CH₂Cl₂(3 mL) and treated with DMAP (610 mg, 5.01 mmol) at rt

for 7 d before it was ﬁltered, concentrated, and puriﬁed via ﬂash

column chromatography (SiO₂, 20−40−60% ethyl acetate in hexanes)

to yield alcohol 61 as a colorless, thick oil (228 mg, 79%): R_f= 0.24

(50% EtOAc/hexanes); [α]_D²⁴−18.2 (c 0.55, CHCl₃); IR (ﬁlm) 2956,

2928, 2858, 1744, 1709 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.29 (br

s, 1H), 3.96 (br s, 1H), 3.85−3.81 (m, 2H), 3.68−3.63 (m, 2H), 3.48

(br s, 1H), 3.08 (s, 1H), 3.07 (br s, 1H), 2.81 (br s, 1H), 2.55−2.50

(m, 2H), 2.50−2.45 (m, 1H), 2.07−2.84 (m, 7H), 1.87−1.84 (m, 1H),

1.40−1.36 (m, 1H), 1.19−1.16 (m, 10H), 0.95−0.91 (m, 15H), 0.06

(s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 178.4 (2C),

83.6, 72.5, 63.5, 63.0, 59.8, 48.5, 39.3, 38.7, 34.2, 32.9, 32.0, 31.3, 30.3,

28.1, 27.2, 26.0, 22.3, 18.0, 17.9, 14.2, −3.8, −4.9; HRMS (ESI) Exact

mass calcd for C₂₈H₅₄NO₇SSi [M + H]⁺576.3390, found 576.3395.

(1S,2S,3R,4S,6R)-3-((tert-Butyldimethylsilyl)oxy)-4-methyl-6-

((methylsulfonyl)oxy)-2-(2-(pivaloyloxy)ethyl)-1′,2′,3′,5′,6′,7′-

hexahydrospiro[cyclohexane-1,8′-indolizin]-4′-ium bromide

(62). Bromine (25.2 μL, 493 μmol) was added to a solution of

alcohol 61 (142 mg, 247 μmol), PPh₃(67 mg, 249 μmol), and

imidazole (33.5 mg, 493 μmol) in benzene (8 mL) at rt. After 10 min,

the reaction was quenched with satd aq Na₂S₂O₃and extracted with

EtOAc. The combined organic layers were dried, ﬁltered, and

concentrated in vacuo to provide a pale yellow oily solid. The crude

was dissolved in CHCl₃(5 mL) and allowed to sit for 1 d (until TLC

revealed the disappearance of the primary bromide). The solvent was

removed, and the resulting crude oil was puriﬁed by column

chromatography (SiO₂, 80% ethyl acetate in hexanes then 5−12%

methanol in dichloromethane) to aﬀord 62 as a colorless oil (120 mg,

76%): R_f= 0.12 (10% MeOH/CH₂Cl₂); [α]²_D⁴−21.4 (c 1.05, CHCl₃);

(4S,5S,E)-Ethyl 4-((tert-Butyldimethylsilyl)oxy)-5-methyl-7-

oxohept-2-enoate (S1). Dess−Martin periodinane⁷²(30.5 g, 71.9

mmol) was added to alcohol 17 (11.4 g, 36.0 mmol) in CH₂Cl₂(200

mL) at rt and stirred for 2 h. By TLC, the reaction was complete and

therefore quenched by the addition of an aqueous solution containing

2:1 satd aq Na₂S₂O₃:NaHCO₃and was stirred until both layers

became clear (∼20 min). The two layers were separated, and the

aqueous layer was extracted with CH₂Cl₂. The combined organic

layers were washed with brine, dried, ﬁltered, and concentrated to a

cloudy oil (S1), which was pure enough for characterization and could

be carried on directly to form 19 (11.0 g, 97%). Data for S1: R_f= 0.40

(20% EtOAc/hexanes); [α]_D²⁰−5.1 (c 0.5, CHCl₃); IR (ﬁlm) 2957,

2932, 2887, 1724 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.79−9.77 (m,

1H), 6.88 (dd, J = 15.6, 5.2 Hz, 1H), 6.00 (dd, J = 15.6, 1.6 Hz, 1H),

4.23 (qd, J = 7.1, 1.7 Hz, 2H), 4.22−4.19 (m, 1H), 2.57−2.50 (m,

1H), 2.31 (ddd, J = 16.1, 8.4, 2.1 Hz, 1H), 2.31−2.24 (m, 1H), 1.33 (t,

J = 7.1 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.94 (s, 9H), 0.09 (s, 3H),

0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 201.9, 166.2, 148.6,

121.8, 75.1, 60.4, 45.8, 34.1, 25.8, 18.1, 16.6, 14.1, −4.4, −5.0; HRMS

(CI) Exact mass calcd for C₁₆H₃₀O₄NaSi [M + Na]⁺337.1811, found

337.1798.

ASSOCIATED CONTENT

■

S

* Supporting Information

1

Includes H and ¹³C NMR spectra of all new compounds not

previously reported including the title compound (1), S1

(precursor to 19), and S2 (formed along with 42), along with

X-ray data (CIF) for 31 (co-crystallized with S4), 42, and 51,

and select 2D data used for structural assignments. This

material is available free of charge via the Internet at http://

pubs.acs.org.

1

IR (ﬁlm) 2956, 2928, 2858, 1744, 1709 cm⁻¹; H NMR (500 MHz,

AUTHOR INFORMATION

■

CDCl₃) δ 5.22 (dd, J = 9.0, 4.0 Hz, 1H), 4.85 (dd, J = 12.5, 9.0 Hz,

1H), 4.34−4.20 (m, 2H), 4.18 (ddd, J = 12.0, 6.0, 6.0 Hz, 1H), 4.10

(ddd, J = 12.0, 6.0, 6.0 Hz, 1H), 3.98 (dd, J = 16.0, 7.0 Hz, 1H), 3.75

(br s, 1H), 3.75−3.62 (m, 1H), 3.39 (s, 3H), 3.35−3.22 (m, 1H), 3.01

(br d, J = 13.5 Hz, 1H), 2.52−2.40 (m, 2H), 2.34−2.26 (m, 1H), 2.22

(ddd, J = 12.5, 9.0, 9.0 Hz, 1H), 2.18−2.11 (m, 2H), 2.07 (ddd, J =

13.5, 3.0, 3.0 Hz, 1H), 2.03−1.90 (m, 2H), 1.82−1.73 (m, 1H), 1.71−

1.63 (m, 1H), 1.19 (s, 9H), 0.99 (d, J = 6.0 Hz, 3H), 0.98 (s, 9H), 0.13

(s, 3H), 0.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) ppm 193.0,

178.3, 78.2, 72.2, 62.9, 62.3, 49.6, 47.4, 45.8, 40.9, 39.1, 38.7, 31.0,

30.4, 29.7, 28.7, 27.1, 25.7, 19.9, 19.0, 17.9, 16.8, −3.7, −5.0; HRMS

(ESI) Exact mass calcd for C₂₈H₅₂NO₆SSi [M − Br]⁺558.3285, found

558.3292.

Corresponding Author

*E-mail: je ﬀ rey.n.johnston@vanderbilt.edu.

Present Addresses

^§Department of Chemistry, Queensborough Community

College, Bayside, New York 11364, United States.

^⊥DongWoo Pharm. Co., Ltd., Gyeonggi-Do, Korea.

^∥Department of Chemistry, Princeton University, Princeton,

New Jersey 08544, United States.

^#Genomics Institute of the Novartis Research Foundation, San

Diego, California 92121, United States.

Notes

(1S,2S,3S,4S,6R,8a′R)-3-((tert-Butyldimethylsilyl)oxy)-2-(2-

hydroxyethyl)-4-methylhexahydro-1′H-spiro[cyclohexane-

1,8′-indolizin]-6-yl methanesulfonate (63). To a solution of

pivalate 58 (42.2 mg, 75.0 μmol) in CH₂Cl₂/toluene (1:1, 4.0 mL) at

78 °C was added DIBAL (375 μL, 375 μmol, 1.0 M solution in

toluene). The reaction was stirred for 30 min before being warmed to

−5 °C and stirred for 5 h. The reaction was quenched with satd aq

NH₄Cl and extracted with CH₂Cl₂. The combined organic layers were

dried, ﬁltered, and concentrated to a pale yellow oil. Column

chromatography (SiO₂, 10−15% methanol in dichloromethane)

provided alcohol 63 as a yellow oil (18.0 mg, 54%): R_f= 0.11 (10%

MeOH/CH₂Cl₂); [α]²_D⁴−32.1 (c 0.95, CHCl₃); IR (ﬁlm) 3396 (br),

2956, 2928, 2858, 1628 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 4.72 (br

d, J = 6.0 Hz 1H), 3.82 (br d, J = 10.8 Hz 1H), 3.70 (s, 1H), 3.65 (dd,

J = 7.8, 2.4 Hz, 1H), 3.40 (br s, 1H), 3.35−3.31 (m, 1H), 3.06 (s, 3H),

2.79 (br d, J = 18.0 Hz, 1H), 2.71 (br s, 1H), 2.60 (br t, J = 10.8 Hz,

1H), 2.35−2.28 (m, 2H), 2.22−1.85 (m, 7H), 1.72−1.60 (m, 5H),

0.94 (d, J = 6.0 Hz, 3H), 0.91 (s, 9H), 0.88−0.81 (m, 1H), 0.28 (s,

3H), 0.08 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) ppm 82.2, 73.4, 65.2,

60.6, 53.0, 46.8, 42.0, 41.4, 40.8, 31.9, 31.3, 31.2, 30.4, 26.0, 22.7, 19.1,

18.0 (2C), 14.1, −3.9, −5.0; HRMS (EI) Exact mass calcd for

C₂₃H₄₆NO₅SSi [M + H]⁺476.2866, found 476.2863.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We are grateful to Professors Gilbert and Gajewski (Indiana

University) for their assistance using Pcmodel v.8 (developed

by Dr. Kevin Gilbert, Serena Software, Bloomington, IN).

Research reported in this publication was supported by the

National Institute of General Medical Sciences of the National

Institutes of Health under Award No. R01 GM 063557.

REFERENCES

■

(1) For a review of the Lycopodium alkaloids see: Ayer, W. A.;

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(16) Ethyl sorbate (sorbic acid ethyl ester) was purchased at 500

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lycoposerramines X and Y: Tanaka, T.; Kogure, N.; Kitajima, M.;

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(19) (a) Using Kakisawa analysis. Ohtani, I.; Kusumi, T.; Kashman,

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analysis are given in the Supporting Information 2 and were adapted

from: (b) Mutnick, D. M. M.S. Thesis, Indiana University,

Bloomington, IN, 2003.

(20) A side product containing a mixture of two diastereomers (18)

was also observed and was determined to result from conjugate

addition of the alkoxide formed during basic workup onto the

unsaturated ester. Maintaining the temperature at 0 °C by a slow,

dropwise quench during the oxidative work up was necessary to

minimize the amount of the undesired cyclization product (18).

(21) (a) IBX was prepared according to: Frigerio, M.; Santagostino,

M.; Sputore, S. J. Org. Chem. 1999, 64, 4537. (b) Dess−Martin was

prepared from IBX using (step B only): Boeckman, R. K.; Shao, P.;

Mullins, J. J. Org. Syn. 2000, 77, 141.

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(23) Continuous extraction of the amine with benzene using a

liquid−liquid extractor was utilized because of the high solubility of the

amine in water. An alternative workup approach was also successful.

After quenching the reaction, the aqueous phase was made basic by

addition of excess KOH (5−7 equiv). The aqueous phase was

subsequently extracted with DCM 3 times. The combined organic

layers were dried over Na₂SO₄, and the solvent was evaporated. The

crude amine was puriﬁed by distillation to provide the product as a

light yellow oil.

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(30) Using ^L-Selectride, a bulky hydride reducing agent, gave the

epimer at the pyrrolidine stereocenter (^L-Selectride, BF₃·OEt₂, THF,

−78 °C, 48% yield).

(31) For chlorination/bromination of vinylogous amides in a similar

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1988, 53, 5287.

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(33) While only one diastereomer was formed in each case, the

stereocenter of the newly installed functionality could not be

conﬁrmed by 2D NOESY measurements, as no cross peaks were

observed between the cyclohexanone and pyrrolidine rings. The

cyclohexanone ring conformation could be ascertained from 2D NMR

measurements and coupling constants. In all schemes, the chair

conformation shown is that which was observed on NMR analysis of

that compound in solution.

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A. J. Org. Chem. 1991, 56, 4112.

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(51) All attempts led to decomposition of the starting material. These

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2006, 69, 1531. (c) NaI, Zn, DMF: Lui, H.-J.; Wynn, H. Can. J. Chem.

1986, 64, 658.

(37) (a) Zhang, Y.; Raines, A. J.; Flowers, R. A., II J. Org. Chem. 2004,

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mesylate) was carried through to the piperidinium ring, it still

underwent an epimerization of the spirocyclic stereocenter and gave

the same product as before (epi-49), indicating that during the

epimerization, the α-alcohol was also epimerized to the β-alcohol.

(53) The one-step Polonovski rearrangement by Kobayashi, which

contains the reduction of a similar iminium ion, supports this

prediction. See reference 7.

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(39) This also demonstrates that during the CAN-mediated amine

deprotection in the earlier stages of the synthesis, the low yield could

also be a result of the vinylogous amide in either the starting material

or product being further oxidized with CAN and leading to side

products and/or degradation.

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primary alcohol was converted to either a leaving group or a carbonyl-

containing functional group. This work is described in more detail in

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(43) In their synthesis of (−)-sarain A, Overman et al. reported a

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amine in the molecule: Garg, N. K.; Hiebert, S.; Overman, L. E. Angew.

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(59) When β-OH 69 was treated with NaH in DMF, the imine

cyclized onto the ester (instead of the β-OH) reforming a similar

tricyclic system that was observed before (26) but ﬁnally had the allyl

group in the correct orientation, which we were not to accomplish

previously (see 28 for example). Also, β-OH 69 was recycled using

Dess−Martin periodinane to reform the ketone.

(60) The pure tertiary amine was isolated in 53% yield. In addition,

an amine:borane complex was isolated as well in 44% yield. This amine

borane complex could also be used in the next reaction.

(61) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.

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(64) Puriﬁed according to the procedure in Perrin: Armarego, W. L.;

Perrin, D. D. Puriﬁcation of Laboratory Chemicals, 4th ed.; The Bath

Press: Bath, England, 1996.

(65) An NMR of the β-stannylenamine was checked. The aryl peaks

are integrated to see the ratio of product to starting material, which is

usually around 75:25. If the ratio is less than 3:1 (product enamine to

starting imine), then the amount of carboxylic acid (19) used for the

coupling step is decreased so the yield of the coupling reaction is not

adversely aﬀected.

(66) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807.

(67) Prepared according to Li, Y.; Marks, T. J. J. Am. Chem. Soc.

1996, 118, 9295.

(46) Both 2D NOESY and HMBC correlations were needed to

assign the new structure (epi-49). The diﬃcult part was in

distinguishing the 3 methylene carbons in the 5-membered ring

versus the 3 methylene carbons in the 6-membered ring of the

indolizidine. The details of the 2D NMR structure elucidation will be

published elsewhere.

(47) (A) Atarashi, S.; Choi, J.-K.; Ha, D.-C.; Hart, D. J.; Kuzmich, D.;

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́

(b) Hemelin, O.; Depres, J.-P.; Greene, A. E.; Tinant, B.; Declercq, J.-

(68) Pickard, P. L.; Tolbert, T. L. Org. Syn. 1964, 44, 51.

(69) It was observed that if the NaOH was added too fast (more than

1 drop/3 s), then a side product was observed corresponding to

intramolecular alkoxide addition to the unsaturated ester (see

P. J. Am. Chem. Soc. 1996, 118, 9992.

(48) Using dimethoxypropane, carbonyl diimidazole, and

^tBu₂Si(OTf)₂, the latter of which actually added two silyl groups

842

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characterization for 18). The H₂O₂addition also was monitored

carefully because of an exotherm and bubbling. Use of a thermometer

inside the reaction during the workup is recommended.

(70) To add the Red-Al/toluene rapidly, after pulling the correct

amount of stock solution into the syringe, the needle was removed as

well as the septum from the reaction ﬂask, and the Red-Al was added

directly to the reaction in one portion. The 1.67 M stock solution

manages to dilute the Red-Al some, but it is still a relatively thick

solution, and best yields were obtained by this method.

(71) CH₃CN was degassed by three cycles of freeze−pump−thaw

under a high vacuum and back-ﬁlling with either argon or nitrogen.

(72) (a) IBX prep: Frigerio, M.; Santagostino, M.; Sputore, S. J. Org.

Chem. 1999, 64, 4537. (b) Dess−Martin periodinane formation from

IBX, see step B of Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Syn.

2000, 77, 141.

843

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Article Doi

Total synthesis of the lycopodium alkaloid serratezomine a using free radical-mediated vinyl amination to prepare a β-stannyl enamine linchpin

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