Collective synthesis of lycopodium alkaloids and tautomer locking strategy for the total synthesis of (-)-lycojapodine A

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Collective Synthesis of Lycopodium Alkaloids and Tautomer Locking

Strategy for the Total Synthesis of (−)-Lycojapodine A

Houhua Li,^†,‡Xiaoming Wang,^§,‡Benke Hong,^§and Xiaoguang Lei*^,†,§

^†National Institute of Biological Sciences (NIBS), Beijing 102206, China

^§College of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China

S

* Supporting Information

ABSTRACT: The collective total synthesis of Lycopodium

alkaloids (+)-fawcettimine (1), (+)-fawcettidine (2), (+)-alo-

pecuridine (4), (−)-lycojapodine A (6), and (−)-8-deoxy-

serratinine (7) has been accomplished from a common

precursor (15) based on a highly concise route inspired by

the proposed biosynthesis of the fawcettimine- and serratinine-

type alkaloids. An intramolecular C-alkylation enabled eﬃcient

installation of the challenging spiro quaternary carbon center

and the aza-cyclononane ring. The preparation of the tricyclic

skeleton as well as the establishment of the correct relative stereochemistry of the oxa-quaternary center were achieved by

hydroxyl-directed SmI₂-mediated pinacol couplings. An unprecedented tandem transannular N-alkylation and removal of a Boc

group was discovered to realize a biosynthesis-inspired process to furnish the desired tetracyclic skeleton. Of particular note is the

unique and crucial tautomer locking strategy employed to complete the enantioselective total synthesis of (−)-lycojapodine A

(6). The central step in this synthesis is the late-stage hypervalent iodine oxidant (IBX or Dess−Martin periodinane)/TFA-

mediated tandem process, which constructed the previously unknown carbinolamine lactone motif and enabled a biomimetic

transformation to generate (−)-lycojapodine A (6) in a single operation.

INTRODUCTION

■

The Lycopodium alkaloids¹are a family of structurally diverse

and complex natural products. To date, more than 250

Lycopodium alkaloids have been isolated and characterized.

The combination of fascinating molecular architectures and

signiﬁcant biological activities of the Lycopodium alkaloids has

provoked long-term interest in their total syntheses.²Among

them, the fawcettimine-type alkaloids, including fawcettimine

(1),³fawcettidine (2),^3,4lycoﬂexine (3),⁵alopecuridine (4),⁶

sieboldine A (5),⁷and lycojapodine A (6)⁸(Figure 1), have

attracted broad attention worldwide in recent years and have

been the subject of a number of remarkable total syntheses.⁹Of

particular note is lycojapodine A (6), which was isolated by

Zhao and co-workers in early 2009. While the relative structure

of lycojapodine A (6) was secured by X-ray analysis, its absolute

structure was still unknown. Compound 6 possesses a unique

6/6/6/7 tetracyclic skeleton with an unprecedented carbinol-

amine lactone motif, which renders it a striking synthetic target.⁸

Indeed, the carbinolamine lactone motif also exists in

aspidophytine,¹⁰haplophytine,¹¹and zoanthamine alkaloids¹²

and was proved to be a great synthetic challenge which

Figure 1. Representative Lycopodium alkaloids.

Received: August 17, 2012

stimulated signiﬁcant eﬀorts to advance methodologies for their

total syntheses. Because of the challenging carbinolamine

lactone motif, not surprisingly, the total synthesis of 6 still

remains elusive.¹³

The serratinine-type Lycopodium alkaloids, such as 8-

deoxyserratinine (7),¹⁴serratinine (8),¹⁵serratine (9),¹⁶and

serratanidine (10),¹⁴represent another major class of

A

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Scheme 1. Proposed Biogenetic Pathways for the Fawcettimine and Serratinine-Type Lycopodium Alkaloids

Lycopodium alkaloids, which are structurally relevant to the

fawcettimine-type alkaloids. However, this family of natural

products possess a more complex molecular architecture

including a challenging 6/5/6/5 tetracyclic framework with

two contiguous quaternary stereogenic centers. Not surpris-

ingly, these intriguing molecular architectures served well to

invite a number of synthetic studies.¹⁷However, relatively little

progress and limited success for their total synthesis have been

disclosed so far.

From a biosynthetic point of view, the fawcettimine-type

alkaloids are unique in comparison with any other types of

Lycopodium alkaloids because of the widespread ring−chain

tautomerism (inset A, Scheme 1),¹⁸which is crucial to their

biogenesis. Based on the biogenetic pathway proposed by

Inubushi,¹⁹fawcettimine (1) could be derived from lycodoline

(11) (lycopodine-type) through carbon-skeleton rearrange-

ment (Scheme 1). Fawcettimine (1) exists as either the

carbinolamine tautomer or the ketoamine tautomer.^9l,m,20The

carbinolamine form of 1 could undergo either dehydration to

yield fawcettidine (2)²¹or further oxidation to produce

alopecuridine (4). On the other hand, the ketoamine form of

1 could either react with formaldehyde to generate an iminium

species, which subsequently undergoes a transannular Mannich

reaction to furnish lycoﬂexine (3)^5,9d,ior ﬁrst epimerize to 4-

epi-fawcettimine, which allows a transannular N alkylation

(S_N2) to construct the C4−N bond and furnish 8-deoxy-13-

dehydroserratinine (12), which has the tetracyclic skeleton of

the serratinine-type alkaloids. Further selective reduction of 12

would aﬀord 8-deoxyserratinine (7). Conceivably, we propose

that the serratinine-type skeleton could also be transformed to

the fawcettimine-type framework by selective C−N bond

cleavage. Similar to fawcettimine (1), alopecuridine (4) is also

present as carbinolamine form or keto-amine form. The keto-

amine form of alopecuridine could generate the unstable imine

B

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Scheme 2. Retrosynthetic Analysis for the Collective Synthesis of Fawcettimine and Serratinine-Type Lycopodium Alkaloids

a

Scheme 3. Eﬃcient Syntheses of C-Alkylation Precursors 21 and 22

a

Reagents and conditions: (a) (i) 18, CuBr, Me₂S, LiCl, THF, −78 °C; (ii) 19, −78 °C, 75%; (b) Et₃N·HF, MeCN, rt, 94%; (c) collidine, MsCl,

CH₂Cl₂, 4 °C; (d) Dess−Martin periodinane, CH₂Cl₂, rt, 80% (two steps); (e) NaI, acetone, rt, 84%.

species (13) via tautomerization/oxidation sequence or vice

versa. Further oxidation of imine 13 could aﬀord sieboldine A

(5).²²Furthermore, according to the biogenetic pathway for

lycojapodine A (6) proposed by Zhao et al.,⁸the carbinolamine

form of 4 might undergo an oxidative cleavage to generate acid

14 (Scheme 1, carbinolamine form), which could furnish

lycojapodine A (6) through further lactonization. However,

acid 14 would also exist as either the carbinolamine form or

ketoamine form due to the ring−chain tautomerism. Accord-

ingly, the ﬁnal lactonization was conceivably problematic

because of the existence of the ketoamine tautomer of 14.

Inspired by the intriguing biogenetic pathways for both

fawcettimine- and serratinine-type alkaloids, we have been

engaged in their total syntheses since 2009. In the previous

communication, we reported the total syntheses of (+)-faw-

cettimine, (+)-fawcettidine, and (−)-8-deoxyserratinine

through a highly concise route involving an intramolecular C

alkylation to install the challenging spiro-conﬁgured quaternary

carbon center and a hydroxyl-directed SmI₂-mediated pinacol

coupling to construct the tricyclic skeleton and establish the

correct stereochemistry.²³The previous study also demon-

strated the feasibility of biomimetic interconversions between

the fawcettimine and serratinine-type alkaloids. However, the

crucial “ring−chain tautomerism” issue involved in the

biosynthesis had not been fully addressed. In addition, the

scope of current strategy for the eﬃcient synthesis of other

Lycopodium alkaloids with distinct frameworks, especially

(−)-lycojapodine A, remained to be further explored. Herein,

we describe the full details of our investigation on the evolution

of our synthetic strategy and the discovery of new method-

ologies that should have potential applications. Ultimately, our

synthetic endeavors have led to the collective synthesis²⁴of both

fawcettimine- and serratinine-type alkaloids, including the

enantioseletive total synthesis of (−)-lycojapodine A relying

on a remarkable tautomer locking strategy.

RESULTS AND DISCUSSION

■

Synthesis Plan. The retrosynthetic analysis that guided our

eﬀorts to develop a uniﬁed route to achieve the collective total

synthesis of both fawcettimine- and serratinine-type alkaloids is

depicted in Scheme 2. We envisioned that 1−7 could be

accessed from a common intermediate (15), which has

C

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included the requisite functionality for expedient conversion to

each of the target molecules. The key spiro-conﬁgured

quaternary carbon center at C12 in diketone (15) could be

installed through intramolecular C alkylation. We expected that

intermediate (16) could be eﬃciently prepared via a tandem

conjugate addition/aldol reaction from three readily available

starting materials, including optically active enone (5R)-5-

methylcyclohex-2-enone 17,²⁵allylmagnesium bromide 18, and

aldehyde 19.

Initial Attempts with Diketo Aldehyde 25 and Diketo

Acid 26. Having established the spiro-conﬁgured quaternary

carbon center and the aza-cyclononane ring, we initially

attempted to access fawcettimine-type alkaloids from the

common intermediate 15 in a straightforward fashion.

Speciﬁcally, Lemieux−Johnson oxidation of diketone 15

aﬀorded aldehyde 25,³²which was subjected to Pinnick

oxidation conditions to give acid 26 in quantitative yield

(Scheme 5). Since 25 and 26 shared the same oxidation state

Eﬃcient Synthesis of the Common Intermediate 15.

As shown in Scheme 3, our synthesis commenced with a

tandem conjugate addition/aldol reaction sequence.²⁶This

three component reaction was initiated by the treatment of

enone 17 with freshly prepared allylcuprate at −78 °C followed

by aldehyde 19²⁷to aﬀord alcohol 16 as an inconsequential

diastereomeric mixture. Desilylation of 16 under mild

conditions smoothly generated keto diol 20. Selective primary

mesylation of 20 using Burke’s protocol²⁸followed by oxidation

of the second alcohol with Dess−Martin periodinane (DMP)

furnished diketo mesylate 21. Iodination of 21 provided diketo

iodide 22.

Scheme 5. Syntheses of Diketo Aldehyde 25 and Diketo Acid

26

a

We next investigated the challenging intramolecular C

alkylation to install the C12 spiro-conﬁgured quaternary carbon

center (Scheme 4). Although the C alkylation of 1,3-dicarbonyl

Scheme 4. Intramolecular C-Alkylation To Yield Spiro-

diketone 15

a

Reagents and conditions: (a) OsO₄, NaIO₄, DABCO, dioxane−H₂O

(2/1), rt, 15 h, 92%; (b) NaClO₂, NaH₂PO₄, t-BuOH−H₂O−2-

methyl-2-butene, rt, 5 h, quant.

with (+)-alopecuridine (4) and (−)-lycojapodine A (6),

respectively, further eﬀorts were made to synthesize either 4

from aldehyde 25 or 6 from acid 26.

We ﬁrst examined the feasibility of constructing the 5-

membered ring and the oxa-quaternary carbon center at C4

with diketo aldehyde 25. Upon treatment of 25 with SmI₂,

intramolecular pinacol coupling occurred to yield keto diol 27

exclusively in excellent yield (81%), and none of the other

isomer (the desired C4−C5 coupled product) was detected

during the reaction. The stereochemistry of 27 was conﬁrmed

by 2D NMR analysis.³³Although the rationale for the

regioselectivity observed herein was still unclear, the high

stereoselectivity of 27 observed during the coupling reaction

could be attributed to the chelate eﬀect of the C4 carbonyl

upon the formation of ketyl radical 28. Further oxidation of

vicinal diol 27 proved to be challenging, and several oxidation

conditions were screened (Scheme 6, entries 1−3). When

Dess−Martin periodinane (DMP) that has been known to be

capable of oxidatively cleaving vicinal diols³⁴was used, the

oxidatively cleaved product 25 was obtained as the major

product in 48% yield (Scheme 6, entry 1). On the other hand,

α-ketol 29 was obtained as the major product in good yield

(53%) along with a small amount (17%) of diketo aldehyde 25

when using 2-iodoxybenzoic acid (IBX) as an oxidant (Scheme

6, entry 2), which presumably was due to hindrance of vicinal

diol 27.³⁵Finally, the Ley oxidation condition³⁶was examined

and proven to be the optimum condition. As a result, α-ketol

29 was generated as a single product in 63% yield (Scheme 6,

entry 3). Aside from SmI₂-mediated pinacol coupling, we also

studied intramolecular crossed benzoin reaction³⁷with 25

catalyzed by Rovis’s NHC (N-heterocyclic carbene) catalyst

30,³⁸with the hope of switching the regioselectivity. Although

diketo aldehyde 25 underwent intramolecular crossed benzoin

a

Reagents and conditions: (a) DBU, MeCN (0.014 M), rt.

compounds represents a powerful means for the synthesis of α-

substituted 1,3-dicarbonyl substrates, previous examples of its

intramolecular form to install a spiro-conﬁgured quaternary

carbon center are relatively rare.²⁹In our case, after extensive

reaction condition screening (base, solvent, temperature, and

concentration), we found that, while diketo mesylate 21 only

yielded O-alkylation product 23, the desired C-alkylation

product 15 was smoothly generated in good yield (65%) by

the treatment of diketo iodide 22 with DBU in acetonitrile.³⁰

The spiro quaternary carbon center at C12 was created

eﬃciently in this remarkable transformation. The rationale for

the high stereoselectivity of 15 observed in this reaction could

be attributed to the steric eﬀect caused by the axial allylic group

at C7 (see transition state 24).³¹

D

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a

Scheme 6

a

Reagents and conditions: (a) SmI₂, HMPA, −78 °C to rt, THF, 81%; (b) Dess−Martin periodinane, CH₂Cl₂, rt; (c) IBX, DMSO, rt; (d) TPAP,

NMO·H₂O, 4 Å MS, CH₂Cl₂, rt; (e) catalyst 30 (20 mol %), Et₃N, CHCl₃, rt, 12 h, 66%.

a

Scheme 7. Approaches toward the Synthesis of (−)-Lycojapodine A (6) via Biomimetic Cyclization

a

Reagents and conditions: (a) TFAA, CHCl₃, 50 °C, 12 h.

reaction smoothly with catalyst 30, the undesired isomer 29

was obtained in 66% yield as the sole product.

Yang and co-workers.^13aCompound 36 was generated in good

yield (56%) exclusively upon the treatment of 26 with TFAA

(triﬂuoroacetic anhydride) in chloroform (Scheme 7). Mech-

anistically, mixed anhydride 31 was initially formed upon the

treatment of 26 with TFAA; thus, 1 equiv of TFA was released,

which triggered the deprotection of the Boc group at 50 °C and

gave intermediate 32. Conceivably, two diﬀerent reaction

pathways could be expected at this stage: (1) keto amine 32

could attack the carbonyl at C13 and tautomerize to the

carbinolamine tautomer 33, which would undergo further

When our synthetic endeavors toward (+)-alopecuridine (4)

using diketo aldehyde 25 failed, we then turned our attention to

diketo acid 26. Inspired by the proposed biogentic pathway for

(−)-lycojapodine A (6), 26 could potentially be the proper

substrate for a biomimetic cyclization that ultimately led to 6.

Unfortunately, after extensive screening of reaction conditions,

we only obtained the unnatural alkaloid 36 rather than the

desired (−)-lycojapodine A (6), which was also observed by

E

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Scheme 8. Evolved Synthetic Strategy

lactonization to furnish the desired (−)-lycojapodine A (6)

(Scheme 7, path a). Tautomerization between keto amine 32

and carbinoamine 33 would be a reversible equilibrium. (2)

Alternatively, keto amine 32 could easily undergo transannular

cyclization due to the ring strain of 9-membered aza-

cyclononane ring, followed by dehydration to yield enamine

34. Further intramolecular nucleophilic substitution could be

expected to yield tetracyclic iminium salt 35, which would

eventually transform to the thermodynamically stable enamine

36 (Scheme 7, path b). Due to the irreversible transannular

cyclization/dehydration in path b, compound 36 was obtained

as the sole product during this reaction. Based on this result, we

concluded that we might not be able to access (−)-lycojapo-

dine A (6) unless we could ﬁnd solutions to suppress the

competitive transannular cyclization and drive the keto amine−

carbinolamine equilibrium to favor the formation of carbinol-

amine form.

C4 in 15 would be blocked, thus the carbonyl group at C13

could be selectively reduced to provide 13-hydroxy ketone

(Scheme 9). Gratifyingly, upon treatment of diketone 15 with

a

Scheme 9. Selective Reduction

Evolved Synthetic Strategy. While direct transformations

of neither diketo aldehyde 25 nor diketo acid 26 proved to be

successful, we evolved a new synthetic strategy for the

syntheses of 1-7 from the common intermediate 15 (Scheme

8). With the aim of exploring the potential biomimetic

interconversions between fawcettimine and serratinine-type

alkaloids, we envisioned that target alkaloids 1−3 and 7 would

be derived from a common scaﬀold 8-deoxy-13-serratinine 12,

and the key aza-quaternary carbon center at C4 in 12 could be

installed through a biomimetic transanular N alkylation from

37. As mentioned previously, 4 served as the biogenetic

precursor for both 5 and 6; thus, 4−6 could be derived from

the common intermediate 38. The challenging oxa-quaternary

carbon centers at C4 in both α-ketols 37 and 38 could be

assembled by SmI₂-mediated pinacol coupling of diﬀerent

aldehyde precursors,³⁹while the C4 carbon center in α-ketol 37

was expected to be installed by Matsuda’s hydroxyl-directed

SmI₂-mediated pinacol coupling of 13-hydroxy aldehydes 39 or

40.⁴⁰We envisioned that without the chelate eﬀect of free

hydroxyl group at C13, the relative stereochemistry at C4 in α-

ketol 38 could also be ﬁxed correctly during SmI₂-mediated

pinacol coupling of 13-OTMS aldehydes 41 or 42. Finally, all

four aldehydes 39-42 would be smoothly generated from the

common intermediate 15 through selective reduction and

oxidative alkene cleavage.

a

Reagents and conditions: (a) NaBH₄, MeOH, rt, 43, 87%; (b)

NaBH₄, CH₂Cl₂/MeOH (10/1), rt, 43, 29%, 44, 63%; (c) TMSOTf,

2,6-lutidine, CH₂Cl₂, −78 °C; (d) OsO₄, NaIO₄, DABCO, dioxane/

H₂O (2/1), rt, for 39, 86% from 43; for 40, quant from 44; for 41,

96% for two steps from 43; for 42, 46% for two steps from 44.

NaBH₄in methanol, 43 was generated exclusively in 87% yield.

Interestingly, a solvent eﬀect was observed for this reduction

reaction,⁴¹and the other stereoisomer 44 could also be isolated

as the major product in 63% yield along with 29% of 43, when a

mixture of CH₂Cl₂/MeOH (10/1) was used. The structures of

43 and 44 were unambiguously conﬁrmed by X-ray diﬀraction

analysis⁴²and NOE analysis,³³respectively. Further Lemieux−

Johnson oxidation of 43 aﬀorded 39 in 86% yield. Substrate 44

was also transformed into 40 in quantitative yield. Moreover, a

two-step procedure was developed for the syntheses of another

two TMS (trimethylsilyl)-protected aldehydes 41 and 42.

Speciﬁcally, trimethylsilylation of the secondary alcohol at C13

and subsequent Lemieux−Johnson oxidation provided 41 and

42 in 96% and 46% yield from 43 and 44, respectively.

SmI₂-Mediated Intramolecular Pinacol Coupling. We

next initiated studies on SmI₂-mediated pinacol coupling of all

four aldehyde precursors 39−42 with the hope of setting up the

correct stereochemistry of oxa-quaternary carbon centers at C4

for both α-ketols 37 and 38. In the early 1990s, Matsuda and

co-workers observed that the conﬁguration of the hydroxyl

Selective Reduction and Syntheses of Four Pinacol

Coupling Precursors 39−42. Because of the steric hindrance

of the axial allylic group at C7 and the torsional strain of the

aza-cyclononane ring, we anticipated that the carbonyl group at

F

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a

Scheme 10. SmI₂-Mediated Intramolecular Pinacol Coupling with Aldehydes 39 and 41

a

Reagents and conditions: (a) SmI₂(5 equiv), THF, rt; (b) SmI₂(5 equiv), HMPA (20 equiv), THF, −78 °C to rt.

a

Scheme 11. Hydroxyl-Directed SmI₂-Mediated Intramolecular Pinacol Coupling with Aldehydes 40 and 42

a

Reagents and conditions: (a) SmI₂(5 equiv), THF, rt; (b) SmI₂(5 equiv), HMPA (20 equiv), THF, −78 °C to rt.

group in the starting material had some inﬂuence in controlling

the stereochemical outcome of the SmI₂-mediated coupling

reactions.^40,43Later they developed various types of hydroxyl-

directed SmI₂-mediated transformations and also demonstrated

its applicability to complex natural product synthesis.^43c

furnish the ﬁrst total synthesis of ( )-alopecuridine.^9jWhile the

conﬁguration at C5 in 47 was conﬁrmed by NOE analysis,³³the

stereochemistry at C4 was later conﬁrmed by subsequent

converting diol 47 to the known α-ketol 38 (see Scheme 12).^9j

The high stereoselectivity of 47 observed during pinacol

couplings may be attributed to the steric eﬀect caused by the

axial trimethylsilyl ether group at C13 in the formation of ketyl

radical 48.

Aldehydes 40 and 42 were also subjected to the pinacol

coupling reaction mediated by SmI₂(Scheme 11). We observed

that pinacol coupling of 40 occurred smoothly and provided

interesting stereochemical outcomes under diﬀerent conditions.

Speciﬁcally, treatment of 40 with SmI₂gave two coupling

products 4,5-cis diol 49 in 72% isolated yield and 4,5-trans diol

50 in 18% isolated yield (Scheme 11, entry 1). However, when

the pinacol coupling was carried out in the presence of HMPA,

50 was isolated as the sole product in 67% yield (Scheme 11,

entry 2). Subsequent oxidation of 49 and 50 aﬀorded the

known α-ketol 37,⁹ⁱwhich conﬁrmed the oxa-quaternary

stereocenters at C4 in 49 and 50 (see Scheme 14). Acetylation

of 49 and 50 generated two diacetate derivatives 51 and 52,

Inspired by Matsuda’s studies, we envisioned the free

hydroxyl group at C13 in starting materials 39 or 40 could

completely control the formation of the desired quaternary

stereocenter at C4 with the required stereochemistry for α-

ketol 37. In contrast, without the stereoinduction of hydroxyl

group at C13 in the substrates 41 or 42, the oxa-quaternary

carbon center at C4 in α-ketol 38 would also be set up correctly

during SmI₂-mediated pinacol coupling reactions due to the

steric eﬀect. Initially, 39 and 41 were used as coupling

substrates in our investigation. While 39 failed to aﬀord any

coupled products under various conditions (Scheme 10, entry

1), we were pleased to ﬁnd that pinacol coupling of 41 occurred

smoothly with SmI₂either in the presence (Scheme 10, entry

2) or absence of HMPA (Scheme 10, entry 3) and furnished 47

as the sole product in excellent yields. Tu and co-workers had

adopted a similar intramolecular pinacol coupling strategy to

G

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a

Scheme 12. Total Synthesis of (+)-Alopecuridine (4)

a

Reagents and conditions: (a) TBAF, THF, rt, 92%; (b) TPAP, NMO·H₂O, 4 Å MS, CH₂Cl₂, rt, 4 h, 50% for 38, 28% for 57; (c) TFA, CHCl₃, rt,

then NaHCO₃, 94%.

Scheme 13. Oxidation of Triol 56

H

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Scheme 14. Oxidation of Vicinal Diols to the Corresponding α-Ketols

respectively. The stereochemistry at C5 in 51 and 52 was

determined by NOE analysis,³³and thus, the relative

conﬁgurations of 49 and 50 were established as 4,5-cis and

4,5-trans, respectively. Finally, the reaction of 42 with SmI₂

either in the absence or presence of HMPA resulted in the

reduction of aldehyde to aﬀord alcohol 55 instead of producing

any desired products (Scheme 11, entry 3).

The observed stereochemical outcome was consistent with

Matsuda’s ﬁnding,^40,43and could be rationalized by two

proposed chelation models, in which the pinacol couplings in

the absence or presence of HMPA are likely to generate

diﬀerent cyclic ketyl radicals and produce distinct products. In

the absence of HMPA, the single ketyl radical was generated

through reduction of the aldehyde moiety, followed by

chelation of the Sm^IIIcation with the δ hydroxyl group to

form the 8-membered ketyl 53, which ultimately produced 4,5-

cis diol 49 as the major product. In the presence of HMPA,⁴⁴a

ketyl radical pair was produced, which likely further formed a 6-

membered ketyl radical transition state 54 by chelation of the

Sm^IIIcation with the β hydroxyl group. Presumably due to the

strong dipole−dipole repulsion between the two cationic Sm^III

complexes, the pinacol coupling proceeded through the diketyl

coupling pathway to aﬀord the 4,5-trans diol 50 as the sole

product.

from those reported for the natural product.⁴⁵Thus, the

asymmetric total synthesis of (+)-alopecurdine (4) was

accomplished in 13 steps, and the absolute conﬁguration of 4

was also established by total synthesis.

Oxidation of Vicinal Diols. During Ley oxidation of triol

56, an undesired lactone 57 was also isolated as the minor

product in 28% yield (Scheme 13, entry 1), which provoked

our interest to further investigate this oxidation reaction. The

results are summarized in Scheme 13. Interestingly, oxidation of

56 with PCC and hypervalent iodine oxidants (DMP, IBX, etc)

only gave oxidative cleavage products 25 and lactone 57

without any desired α-ketol 38 (Scheme 13, entries 2−4). A

plausible mechanism was proposed in order to rationalize the

formation of three products: Based on the previous studies by

Frigerio and Santagostino, DMP would easily react with vicinal

diol to form a 5-membered cyclic diolate irreversibly (58,

Scheme 13).^34fTherefore, intermediate 58 could undergo

oxidative cleavage smoothly to aﬀord aldehyde 39, which would

either be further oxidized to generate diketo aldehyde 25 or

tautomerize to give lactol 62, which was further oxidized to

furnish lactone 57. More recently, Moorthy and co-workers³⁵

demonstrated that IBX exhibited similar reactivity as DMP with

strained and sterically hindered vicinal diols due to the

formation of a similar 5-membered cyclic diolate (59, Scheme

13). In the PCC case, we supposed similar 5-membered cyclic

diolate (60, Scheme 13) could exist and lead to the ﬁnal

oxidized products 25 and 57. Finally, when 56 was treated with

Ley conditions, aside from the formation of desired α-ketol 38,

a reversible formation of 5-membered cyclic diolate 61 could

also occur, further oxidative cleavage of 61 would aﬀord

aldehyde 39, at which point, both 25 and 57 could be generated

theoretically. However, only 57 was obtained after the reaction,

presumably due to the presence of 4 Å MS (molecular sieves).

This postulation was further supported by the following control

experiments (Scheme 14, entries 5 and 6), where the isolated

yields of lactone 57 were signiﬁcantly improved in the presence

Total Synthesis of (+)-Alopecuridine (4). With diol 47 in

hand, we were able to access alopecurdine (4) within several

steps (Scheme 12). Removal of the trimethylsilyl group with

TBAF aﬀorded triol 56 in 92% yield. On the basis of our

pervious results (see Scheme 6), Ley oxidation proved to be

suitable for the substrates containing a vicinal diol moiety.

Herein, the desired α-ketol 38 was generated in moderate yield

(50%) upon Ley oxidation, with 28% byproduct 57. Finally,

(+)-alopecurdine·TFA (4) was obtained after removal of the

Boc group from 38 with TFA followed by neutralization with

NaHCO₃. Synthetic alopecuridine·TFA (4), [α]_D+69.8 (c 0.50,

1

MeOH), exhibited H and ¹³C NMR spectra indistinguishable

I

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a

Scheme 15. Synthesis of 8-Deoxy-13-dehydroserratinine (12)

a

Reagents and conditions: (a) TFA, CHCl₃, rt, 92%; (b) SOCl₂/Et₃N, THF, −78 to 0 °C, for 12, 98%; for 65, 53%.

a

Scheme 16. Total Syntheses of (+)-Fawcettimine (1), (+)-Fawcettidine (2), and (−)-8-Deoxyserratinine (7)

a

Reagents and conditions: (a) NaBH₄, dry EtOH, 0 °C, 98%; (b) Zn, HOAc, 140 °C, 95%; (c) SmI₂, H₂O, THF, 0 °C, 51%.

of 4 Å MS. In order to better understand the role of 4 Å MS

during this process, we repeated the Ley oxidation of triol 56 in

the absence of 4 Å MS (Scheme 14, entry 7). To our surprise,

α-ketol 38 was obtained exclusively in excellent yield (89%).

Thus, 4 Å MS was proved to be crucial in the formation of

lactone 57, which might play dual roles: (1) favor the formation

of cyclic diolates 58−61 and consequently prompt the oxidative

cleavage of the vicinal diol and (2) drive the aldehyde−lactol

tautomerism to favor the formation of lactol tautomer 62.

Finally, during the oxidation of 56 with DMP in the presence of

H₂O (5 equiv), aldehyde 39 was generated as the sole product

(Scheme 14, entry 8), which provided direct evidence to

support our proposed mechanism.

Since the TPAP/NMO·H₂O conditions represented the

optimal oxidation conditions for triol 56, we applied this

improved protocol to the oxidations of other vicinal diols, and

the results are summarized in Scheme 14. Each substrate was

oxidized by TPAP both in the presence (Scheme 14, conditions

A) and absence of 4 Å MS (Scheme 14, conditions B) for

comparison. We ﬁrst revisited the oxidation of diol 27. In

comparison to 63% yield under normal Ley conditions

(Scheme 14, entry 1), the desired α-ketol 29 was obtained in

78% yield using the improved protocol (Scheme 14, entry 2).

We later tried to convert triols 49 and 50 to the known α-ketol

37,⁹ⁱand in both cases, oxidation reactions using the improved

protocol furnished the desired α-ketol 37 in greater yield than

those in the presence of 4 Å MS (Scheme 14, entries 3−6). We

expect this protocol could serve as a general and eﬃcient

method for oxidizing vicinal diols to the corresponding α-

ketols.

Synthesis of 8-Deoxy-13-dehydroserratinine (12).

With α-ketol 37 in hand, we then focused on the construction

of the C4−N bond by using transannular N alkylation (Scheme

15). In initial attempts, we conducted a two-step protocol:

removal of the Boc group to furnish compound 63 followed by

transannular N alkylation.⁴⁶However, due to the intra-

molecular carbinoamine formation of 64, further attempts to

use the free amine for the transannular N alkylation failed.⁹ⁱ

J

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Scheme 17. Tautomer Locking Strategy in the Total Synthesis of (−)-Lycojapodine A (6)

Surprisingly, upon treatment of α-ketol 37 with SOCl₂and

Et₃N in THF, the desired 8-deoxy-13-dehydroserratinine (12)

was obtained in nearly quantitatively yield (98%). In order to

elucidate the mechanism of this remarkable process, we

conducted several control experiments: (1) upon treatment

of 37 with either SOCl₂or Et₃N alone in THF, no reaction

occurred and 37 was recovered; (2) Boc-protected piperidine

was also subjected to the same reaction conditions; as a result,

no reaction was observed; (3) the reaction of 38 with SOCl₂/

Et₃N in THF resulted in the dehydration of hydroxyl group at

C4 to form enone 65 (Z/E mixture) in 53% yield without any

transannular N alkylation products. Based on these results, we

speculated that the cascade might be involved with (1) SOCl₂

reacting with the C4 hydroxyl group of 37 in the presence of

Et₃N to form intermediate 66 as a good leaving group at C4;

(2) transannular nucleophilic attack of the lone pair on the

nitrogen atom from the back face to aﬀord the ionic acyl

ammonium intermediate 67; and (3) base-triggered removal of

the Boc group in 67 furnishing the desired N alkylation product

12. On the contrary, when 38 was reacted with SOCl₂/Et₃N in

THF, the similar intermediate 68 was also formed. However,

the nitrogen lone-pair electrons in 68 were oriented in the syn

position to the leaving group at C4, in which case only

dehydration occurred to yield enone 65.

Total Syntheses of (+)-Fawcettimine (1), (+)-Fawcetti-

dine (2), and (−)-8-Deoxyserratinine (7). Having estab-

lished the key aza-quaternary carbon center at C4 in 12, we

were able to access both fawcettimine- and serratinine-type

Lycopodium alkaloids from the common intermediate 12

(Scheme 16). Selective reduction of the carbonyl group at

C13 with NaBH₄at 0 °C smoothly aﬀorded (−)-8-

deoxyserratinine (7) in 98% yield. Furthermore, under harsh

reducing conditions (Zn/HOAc, 140 °C, 8 h), reductive

cleavage of the C4−N bond of 12 followed by dehydration to

form the enamine moiety occurred and furnished (+)-fawcetti-

dine (2) in excellent yield (95%).⁴⁷Finally, we attempted to

selectively cleave the C4−N bond under mild conditions to

furnish fawcettimine (1).⁴⁸Since the two carbonyl groups at C5

and C13 were also likely to be reduced as well under reductive

conditions, the late-stage reductive carbon−nitrogen bond

cleavage proved to be challenging. Delightfully, by treatment of

substrate 12 with SmI₂in THF and 2.5 equiv of water as a

proton source at 0 °C, (+)-fawcettimine (1) could be obtained

in moderate yield (51%). With (+)-fawcettimine (1) in hand,

(+)-lycoﬂexine (3) could be easily obtained in a single

operation based on previous studies reported by both the

Mulzer group^9dand the Yang group.⁹ⁱThe spectroscopic data

of these synthetic samples 1, 2, and 7 fully matched with those

previously reported.³³

Tautomer Locking Strategy in the Total Synthesis of

(−)-Lycojapodine A (6). With the proposed biogenetic

precursor (+)-alopecurdine (4) in hand, we ﬁnally turned our

attention to (−)-lycojapodine A (6), the remaining member

that has not been synthesized so far. As mentioned previously

(see Scheme 7), we realized that it would be extremely crucial

to develop an eﬀective tautomer locking strategy to favor the

formation of the carbinolamine tautomer and sequester the

competitive irreversible transannular cyclization/dehydration

for the endgame steps (Scheme 17). According to the proposed

biogenetic pathway for (−)-lycojapodine A (6) as well as our

unsuccessful biomimetic cyclization attempts using diketo acid

26, carbinolamine 69 would be essentially considered as the key

intermediate to access 6 (see Scheme 1, carbinolamine form of

acid 14, and Scheme 7, carbinolamine mixed anhydride 33).

However, because of the reversible tautomerism, carbinolamine

69 could also isomerize to keto amine 70, which would

subsequently undergo irreversible transannular cyclization/

dehydration to aﬀord enamine 71. In the previous synthetic

studies we observed that upon treatment of carbinolamine 69

with acid (i.e., TFA) carbinolammonium salt 72 was

generated.⁴⁹It seemed likely that this would oﬀer us a solution

to lock the carbinolamine tautomer. Thus, the desired reaction

pathway for intermediate 72 could occur to furnish

(−)-lycojapodine A (6). Therefore, we envisioned that both

basic conditions and basic workup should be avoided to prevent

neutralizing carbinolammonium salt 72 and subsequently

releasing the carbinolamine tautomer 69 during the trans-

formations to generate 6.

Biomimetic Studies Based on the Modiﬁed Biogenetic

Pathway. Based on the tautomer locking strategy, we further

proposed a modiﬁed biogenetic pathway for (−)-lycojapodine

A (6) (Scheme 18) where we expected the alopecuridinium

acid derivative, i.e. carbinolammonium triﬂuoroacetate form of

4, would be the proper biogenetic precursor compared to the

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a

Scheme 18. Biomimetic Studies Based on the Modiﬁed

Scheme 20. Rapid Synthesis of Tautomer-Locked Diol 74

Biogenetic Pathway

a

Reagents and conditions: (a) 2,2-dimethoxypropane, p-TSA, acetone,

quant; (b) TBAF, THF, rt, 99%; (c) TPAP, NMO·H₂O, 4 Å MS,

CH₂Cl₂, rt, 95%; (d) concd HCl, MeOH, reﬂux then TFA, quant.

carbinolamine form of 4. Next we attempted to examine our

biogenesis hypothesis with synthetic (+)-alopecurdine·TFA (4)

yield. Removal of the trimethylsilyl group with TBAF and

subsequent oxidation of the secondary alcohol using Ley

oxidation provided ketone 79. At this point, the only step

remaining to give diol 74 was to remove both 1,2-acetonide and

Boc protecting groups. Initial attempts using TFA resulted in

selective removal of the Boc group with the acetonide

functionality remaining intact. Finally, diol 74 was obtained

quantitatively by the treatment of substrate 79 with

concentrated HCl in methanol under reﬂux overnight, and

the deprotected product was further dissolved in TFA to aﬀord

the tautomer-locked diol 74 (carbinolammonium triﬂuoroace-

1

(carbinolammonium triﬂuoroacetate form, secured by H and

¹³C NMR spectra³³). Although 4 was subjected to various

reaction conditions which were known to be eﬀective for

oxidative cleavage of the α-hydroxy ketone moiety (Pb-

(OAc)₄,⁵⁰NaIO₄,⁵¹RuCl₃/NaIO₄,⁵²etc), unfortunately, no

desired product 6 was observed, nor could we recover starting

material 4, which was presumably due to the facile

decomposition of 4 under these conditions.

Total Synthesis of (−)-Lycojapodine A (6). Since initial

biomimetic transformation of (+)-alopecurdine·TFA (4) had

failed, at this point, inspired by the formation of lactone 57

during the oxidation reaction of triol 56 (see Scheme 13), we

envisioned that the carbinolamine lactone motif of 6 could also

be assembled via a similar tandem oxidative cleavage/lactol

formation/oxidation process with proper oxidants. Thus, the

revised endgame strategy to access (−)-lycojapodine A (6) was

proposed in Scheme 19. Compound 6 could be derived from

diol 74 via a tandem reaction with the intermediates aldehyde

75 and lactol 76, while the locked tautomer 74 would be

eﬃciently generated from the diol 47 within several operations.

As depicted in Scheme 20, protection of the 4,5-cis diol

moiety of diol 47 aﬀorded 1,2-acetonide 77 in quantitative

33

1

tate form, conﬁrmed by H and ¹³C NMR spectra ).

With diol 74 in hand, the late-stage tandem oxidation process

was investigated (Scheme 21). Since this unprecedented

tandem process was supposed to be triggered by oxidative

cleavage of the 4,5-cis diol moiety, diol 74 was treated with

various oxidants (Pb(OAc)₄, NaIO₄, TPAP/NMO, DMP/

CH₂Cl₂, IBX/DMSO, etc.). However, the desired product 6

was not detected using these oxidants either in the presence or

absence of 4 Å MS, and in most cases starting material 74 was

decomposed (Scheme 21, entries 1−4). Finally, we were able to

isolate (−)-lycojapodine A (6) for the ﬁrst time in 9% yield

applying Moorthy’s conditions (Scheme 21, entry 5).³⁵The

solvent TFA presumably stabilized the carbinolammonium

triﬂuoroacetates 74−76 by preventing the release of the

corresponding carbinolamine tautomers. Furthermore, when 4

Å MS was added to the reaction (Scheme 21, entry 6), 6 was

isolated in moderated yield (38%). Eventually, prolonging the

reaction time with elevated reaction temperature could also

increase the isolated yield to 54% (Scheme 21, entry 7), which

represented the best result for this reaction by far. However,

when IBX was replaced by DMP, no reaction occurred and the

starting material 74 was recovered (Scheme 21, entry 8).

Biomimetic Transformation of (+)-Alopecuridine (4)

into (−)-Lycojapodine A (6). After establishing a feasible

route to access (−)-lycojapodine A (6) via our tandem

oxidation endgame strategy, with an aim to prove the

biogenesis hypothesis for (−)-lycojapodine A (6), we revisited

our modiﬁed biogenetic pathway using (+)-alopecuridine·TFA

(4) (Scheme 22). Gratifyingly, upon the treatment of 4 with

IBX and 4 Å MS in TFA (Scheme 22, entry 1),

(−)-lycojapodine A (6) was isolated in 51% yield. Moreover,

when IBX was replaced by Dess-Martin periodinane (Scheme

Scheme 19. Revised Synthetic Plan Based on Tautomer

Locking Strategy

L

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subsequent biomimetic transformation into (−)-lycojapodine A

(6) were successfully merged into a single and more eﬃcient

operation (Scheme 23). Speciﬁcally, α-ketol 38 was ﬁrst

dissolved in TFA at rt, while Boc was removed in less than 2 h,

and the keto ammonium triﬂuoroacetate form of alopecuridine

(4) was formed. At this stage, the attempt to add DMP and 4 Å

MS into the reaction only resulted in the recovery of

alopecuridine (4) without obtaining any desired (−)-lycojapo-

dine A (6). In order to completely lock the carbinolamine

tautomer, the keto ammonium triﬂuoroacetate form of

alopecuridine (4) was allowed to stay in TFA for additional

16 h at rt. Subsequently, DMP and 4 Å MS were added into the

solution, and the reaction was quenched after an additional 4 h

to furnish (−)-lycojapodine A (6) in excellent yield (83%).

Synthetic lycojapodine A (6), [α]_D−137 (c 0.20, CHCl₃),

Scheme 21. Late-Stage Tandem Oxidation Process To

Access (−)-Lycojapodine A (6)

1

exhibited H and ¹³C NMR spectra indistinguishable from

those reported for the natural isolate.³³Thus, the total synthesis

of (−)-lycojapodine A (6) was accomplished either in 15 steps

through late-stage tandem oxidation process or 13 steps

through one-pot biomimetic transformation, and the absolute

conﬁguration of 6 was also established.

CONCLUSION

■

Collective total syntheses of both fawcettimine- and serratinine-

type Lycopodium alkaloids (+)-fawcettimine (1), (+)-fawcetti-

dine (2), (+)-alopecuridine (4), (−)-lycojapodine A (6), and

(−)-8-deoxyserratinine (7) were accomplished from a common

precursor on the basis of a highly concise route (all were

accomplished in either 12 or 13 steps).

A number of synthetic steps in the syntheses are noteworthy:

(a) the intramolecular C-alkylation was applied to install the

challenging spiro quaternary carbon center and the aza-

cyclononane ring; (b) the hydroxyl-directed SmI₂-mediated

pinacol coupling was used to establish the correct relative

stereochemistry of the oxa-quaternary center; (c) the

unprecedented tandem transannular N-alkylation and removal

of Boc group realized a biosynthesis-inspired process to aﬀord

the desired tetracyclic skeleton; (d) the unprecedented, late-

stage IBX/TFA-mediated tandem oxidation process through a

novel tautomer locking strategy was used to aﬀord

(−)-lycojapodine A (6) eﬃciently; (e) a biomimetic trans-

formation into (−)-lycojapodine A (6) from (+)-alopecurdine

(4) was also achieved based on a modiﬁed biogenetic pathway

for (−)-lycojapodine A.

Scheme 22. Biomimetic Transformation of

(+)-Alopecuridine (4) into (−)-Lycojapodine A (6)

Moreover, the combination of a tautomer locking protocol

and a remarkable late-stage IBX/TFA-mediated tandem

oxidation process for the eﬀective construction of the

challenging carbinolamine lactone motif, our improved Ley

oxidation protocol for oxidation of vicinal diols, as well as the

use of hypervalent iodine oxidants like IBX or DMP for

oxidative cleavage of α-ketol into keto acid may ﬁnd further

synthetic applications.

22, entry 2), the biomimetic transformation of (+)-alopecur-

idine·TFA (4) occurred smoothly and furnished 6 in excellent

yield (86%). To the best of our knowledge, these results

represent the ﬁrst example of oxidative cleavage of an α-ketol

into a keto acid using hypervalent iodine oxidants.⁵³On the

other hand, when (+)-alopecuridine·TFA (4) was subjected to

either IBX/DMSO (Scheme 22, entry 3) or DMP/CH₂Cl₂

(Scheme 22, entry 4), in both cases starting material 4 was

decomposed without producing any desired product. These

control experiments exhibited the crucial roles of TFA and 4 Å

MS for this biomimetic process.

EXPERIMENTAL SECTION

■

General Experimental Methods. ¹H NMR and ¹³C NMR

spectra were recorded on a 400 MHz spectrometer at ambient

temperature with CDCl₃as the solvent unless otherwise stated.

Chemical shifts are reported in parts per million relative to chloroform

(¹H, δ 7.26 ppm; ¹³C, δ 77.00 ppm). Data for ¹H NMR are reported as

follows: chemical shift, integration, multiplicity (s = singlet, d =

doublet, t = triplet, q = quartet, m = multiplet), and coupling

constants. Infrared spectra were recorded on a Fourier transform

infrared spectrophotometer. High-resolution mass spectra were

Finally, after careful examination, removal of the Boc group

from α-ketol 38 to aﬀord (+)-alopecurdine·TFA (4) and its

M

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Scheme 23. One-Pot Operation to (−)-Lycojapodine A (6)

obtained on a FT-ICR spectrometer. Optical rotations were recorded

7.64 (m, 4H), 7.43−7.36 (m, 6H), 3.67 (t, J = 6.1 Hz, 2H), 3.27 (s,

2H), 3.21 (s, 2H), 2.42 (t, J = 7.1 Hz, 2H), 1.84−1.79 (m, 2H), 1.76

(m, 2H), 1.41 (s, 9H), 1.05 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

201.4, 155.4, 135.3, 133.4, 129.4, 127.5, 79.1, 61.4, 46.1, 44.2, 40.9,

31.5, 30.9, 28.2, 26.6, 20.6, 19.0; IR (neat) ν_max2931, 2858, 1692,

1558, 1541 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₈H₄₂NO₄Si

484.2878, found 484.2876.

on a digital polarimeter at 589 nm and are recorded as [α]²¹

D

(concentration in grams/100 mL solvent). Analytical thin-layer

chromatography was performed using 0.25 mm silica gel 60-F plates.

Flash chromatography was performed using 200−400 mesh silica gel.

Yields refer to chromatographically and spectroscopically pure

materials, unless otherwise stated. Methylene chloride, toluene, and

1,2-dichloroethane were distilled from calcium hydride; tetrahydrofur-

an were distilled from sodium/benzophenone ketyl prior to use. All

reactions were carried out in oven-dried glassware under an argon

atmosphere unless otherwise noted.

Compound 16. Lithium chloride (2.20 g, 55 mmol) was ﬁrst

heated at 110 °C under high vacuum in a 500 mL ﬂask for 2−3 h,

copper bromide (7.34 g, 51.0 mmol), anhydrous THF (230 mL), and

methyl sulﬁde (4.53 mL, 61 mmol) were added sequentially, and the

mixture was stirred for 30 min until the formation of a yellow solution.

Then the reaction mixture was cooled to −78 °C, and allylMgBr 18 (1

M in Et₂O, freshly prepared, 44 mL, 44 mmol) was added dropwise.

The solution was stirred for 1 h, (5R)-5-methylcyclohex-2-enone 17

(4.79 mL, 41 mmol) was added, and the mixture was stirred for an

additional 1 h at −78 °C before a solution of aldehyde 19 (9.0 g, 18.6

mmol) in anhydrous THF (20 mL) was added. The ﬁnal mixture was

stirred at −78 °C for an additional 3 h before being quenched by

addition of satd aq NH₄Cl at −78 °C and then warmed to rt. The

aqueous layer was extracted with CH₂Cl₂, the combined organic

extracts were dried over Na₂SO₄, and the ﬁltrate was concentrated in

vacuo. The residue was puriﬁed by ﬂash chromatography on silica gel

(PE/EtOAc = 5/1) to aﬀord two diastereomeric mixtures 16 (8.96 g,

Aldehyde 19. To a stirred solution of TBDPS-protected 3-

hydroxypropanal (13.2 g, 42.3 mmol)⁵⁴in chloroform (180 mL) was

added 4-amino-1-butanol (3.90 mL, 42.3 mmol) dropwise. The

mixture was stirred at rt for 2 h under argon, and then sodium

borohydride (8.25 g, 211 mmol) was added in one portion, followed

with anhydrous methanol (18 mL), and the reaction mixture was

stirred at rt for an additional 40 h. The reaction was quenched with

water and extracted with EtOAc, and the combined extracts were

washed with saturated NaHCO₃solution, dried over anhydrous

Na₂SO₄, and concentrated in vacuo to give the crude product (16.3 g),

which was redissolved in chloroform (165 mL). Di-tert-butyl

dicarbonate (9.33 g, 42.3 mmol) was added to the solution, and the

reaction mixture was stirred overnight at rt and then concentrated in

vacuo to aﬀord a crude oil residue, which was puriﬁed by ﬂash silica gel

chromatography (PE/EtOAc = 4/1) to aﬀord primary alcohol 80

1

73%) as a slightly yellow oil. Data for two isomers: H NMR (400

MHz, CDCl₃) δ 7.66−7.61 (m, 4H), 7.43−7.36 (m, 6H), 5.74−5.66

(m, 1H), 5.05−5.01 (m, 2H), 3.86 (s, 1H), 3.67 (t, J = 5.9 Hz, 2H),

3.27−3.15 (m, 4H), 2.40 (s, 1H), 2.16 (s, 6H), 1.76 (s, 3H), 1.64−

1.59 (m, 4H), 1.52 (s, 2H), 1.41 (s, 9H), 1.05 (s, 9H), 0.98 (d, J = 6.5

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 214.3, 155.9, 135.5, 133.7,

129.6, 127.6, 117.2, 79.3, 70.9, 61.6, 60.0, 48.7, 46.5, 44.2, 37.9, 37.0,

34.8, 32.8, 31.7, 29.7, 28.4, 28.4, 26.8, 24.7, 21.2, 19.2; IR (neat) ν_max

3420, 2928, 2858, 1694, 1473 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

C₃₈H₅₈NO₅Si 636.4079, found 636.4079.

Keto Diol 20. The substrate 16 (8.90 g, 14 mmol) was dissolved in

100 mL of anhydrous CH₃CN, and Et₃N·3HF (11.76 mL, 70 mmol)

was added at rt. After being stirred for 70 h at rt, the reaction mixture

was concentrated in vacuo and puriﬁed on silica gel (PE/EtOAc = 1/1

to 1/2) to provide keto diol 20 (5.24 g, 94%) as a slightly yellow oil:

¹H NMR (400 MHz, CDCl₃) δ 5.74−5.64 (m, 1H), 5.05−5.00 (m,

1

(16.5 g, 80%) as a colorless oil: H NMR (400 MHz, CDCl₃) δ 9.76

(s, 1H), 7.70−7.67 (m, 4H), 7.42−7.36 (m, 6H), 3.70−3.69 (m, 2H),

3.64 (t, J = 6.1 Hz, 2H), 3.30−3.23 (m, 4H), 1.79 (s, 2H), 1.61−1.53

(m, 4H), 1.42 (s, 9H), 1.08 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

155.6, 135.3, 133.5, 129.5, 127.5, 79.1, 62.0, 61.5, 46.7, 44.2, 31.6, 29.5,

28.4, 28.3, 28.2, 26.7, 24.4, 19.0, 19.0; IR (neat) ν_max3415, 2928, 2857,

1691, 1670 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₈H₄₄NO₄Si

486.3034, found 486.3043. The primary alcohol 80 (14.5 g, 30 mmol)

was dissolved in 250 mL anhydrous CH₂Cl₂, pyridium chlorochromate

(9.65 g, 45 mmol) and silica gel (9.65 g) were added sequentially, and

the reaction mixture was stirred at rt for 4 h. The reaction was

concentrated in vacuo and puriﬁed by silica gel column chromatog-

raphy (PE/EtOAc = 7/1 to 4/1) to aﬀord aldehyde 19 (13.2 g, 92%)

as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 9.76 (s, 1H), 7.66−

N

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2H), 3.78 (s, 2H), 3.53 (s, 2H), 3.34 (s, 2H), 3.14 (s, 2H), 2.50−2.39

(m, 2H), 2.15 (m, 7H), 1.64 (m, 5H), 1.51−1.49 (s, 2H), 1.44 (s, 9H),

0.96 (d, J = 6.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 214.5, 157.0,

135.4, 117.4, 80.0, 70.6, 59.5, 58.3, 48.6, 47.0, 42.6, 37.9, 36.9, 35.0,

33.5, 30.6, 29.7, 29.6, 29.5, 28.4, 25.1, 20.8; IR (neat) ν_max3421, 2924,

1691, 1665, 1479 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₂H₄₀NO₅

398.2901, found 398.2899.

115.2, 79.3, 67.6, 66.9, 48.8, 48.1, 47.0, 42.1, 38.8, 34.4, 33.1, 32.6,

29.6, 28.5, 28.3, 25.9, 25.3, 23.8, 21.8; IR (neat) ν_max2923, 2869, 1691,

1635, 1600, 1459 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for

C₂₂H₃₅NO₄Na 400.2458, found 400.2456; [α]²¹+57.4 (c 1.0,

D

CHCl₃).

Aldehyde 25. To a solution of 15 (45 mg, 0.119 mmol) in

dioxane/water (v/v = 2/1, totally 9 mL) were added DABCO (69.0

mg, 0.597 mmol), NaIO₄(258 mg, 1.19 mmol), and OsO₄(1.2 mL,

0.0119 mmol, 2.5 wt % solution in tert-butyl alcohol) sequentially, and

the reaction was stirred at rt and monitored by TLC. After the reaction

was complete, EtOAc and satd aq Na₂S₂O₃were added, the aqueous

phase was separated and extracted with EtOAc, the combined organic

extracts were dried over Na₂SO₄, and the ﬁltrate was concentrated in

vacuo and puriﬁed on silica gel (PE/EtOAc = 4/1) to aﬀord aldehyde

Diketo Mesylate 21. To a solution of keto diol 20 (4.69 g, 11.7

mmol) in CH₂Cl₂(230 mL) was added collidine (4.70 mL, 35.2

mmol) at rt. The solution was cooled to 0 °C, and methanosulfonyl

chloride (1.0 mL, 12.9 mmol) was added dropwise. After being stirred

at 4−7 °C for 24 h, the reaction mixture was quenched with water and

extracted with CH₂Cl₂, the combined organic extracts were washed

with 0.5% HCl (aq) and dried over Na₂SO₄, and the ﬁltrate was

concentrated in vacuo to provide a crude residue, which was used

directly in the next step. The crude compound was redissolved in

CH₂Cl₂(200 mL), and the solution was cooled to 0 °C. Dess−Martin

periodinane (7.46 g, 17.6 mmol) was added, and the reaction mixture

was warmed to room temperature and stirred at rt for 3 h. Then satd

aq NaHCO₃and satd aq Na₂S₂O₃were added to the mixture at 0 °C,

and the solution was stirred for additional 1 h. The aqueous phase was

separated and extracted with CH₂Cl₂, the combined organic extracts

were dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo

and puriﬁed on silica gel (PE/EtOAc = 2/1) to provide diketo

1

25 (38.0 mg, 81%) as a colorless oil: H NMR (400 MHz, CDCl₃) δ

9.72 (s, 1H), 3.45−3.28 (m, 1H), 3.10−2.85 (m, 3H), 2.83−2.54 (m,

3H), 2.51−2.17 (m, 6H), 2.16−1.82 (m, 4H), 1.80−1.59 (m, 3H),

1.48 (s, 9H), 1.04 (d, J = 6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

211.5, 210.8, 200.9, 157.1, 79.9, 70.1, 47.8, 46.9, 44.7, 37.5, 34.4, 34.4,

30.8, 29.7, 28.4, 23.4, 21.5, 21.0; IR (neat) ν_max2928, 1721, 1691,

1480, 1410, 1229, 1166 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

C₂₁H₃₄NO₅: 380.2432, found 380.2436; [α]²¹+11.3 (c 1.0, CHCl₃).

D

Diketo Acid 26. To a stirred solution of aldehyde 25 (13 mg,

0.034 mmol) and 2-methyl-2-butene (40 μL) in t-butyl alcohol/water

(v/v = 3/1, totally 2.0 mL), was added a solution of NaClO₂(12 mg,

0.103 mmol) and NaH₂PO₄(12.5 mg, 0.103 mmol) in 0.5 mL of

water dropwise at 0 °C, and the resulting solution was stirred at 0 °C

for 0.5 h, warmed to rt, and stirred for additional 5 h. The reaction was

quenched by addition of satd aq NH₄Cl at 0 °C, warmed to rt, and

extracted with EtOAc. The combined organic extracts were dried over

Na₂SO₄, and the ﬁltrate was concentrated in vacuo to aﬀord diketo

1

mesylate 21 (4.43 g, 80%) as a colorless oil: H NMR (400 MHz,

CDCl₃) δ 5.72 (m, 1H), 5.03−4.97 (m, 2H), 4.21 (t, J = 6.1 Hz, 2H),

3.29−3.21 (m, 4H), 2.99 (s, 3H), 2.58−2.38 (m, 4H), 2.15−1.76 (m,

9H), 1.41 (s, 9H), 1.22−1.14 (m, 2H), 0.95 (d, J = 5.3 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 208.3, 200.0, 183.0, 155.4, 136.6, 135.2,

117.6, 116.4, 111.0, 79.8, 67.5, 48.5, 46.8, 44.8, 43.5, 40.1, 40.0, 39.4,

38.3, 37.3, 35.7, 34.6, 33.9, 33.0, 28.9, 28.8, 28.3, 22.5, 22.1, 21.9, 20.7;

IR (neat) ν_max2927, 1691, 1639, 1602, 1456, 1414 cm⁻¹; HRMS (ESI)

acid 26 (14 mg, quant) as a colorless solid:¹³mp 62.5−63.5 °C; H

1

[M + H]⁺calcd for C₂₃H₄₀NO₇S 474.2520, found 474.2519; [α]²¹

NMR (400 MHz, CDCl₃) δ 3.46 (s, 1H), 3.24 (s, 1H), 3.01 (s, 2H),

2.89 (s, 1H), 2.67 (m, 3H), 2.46−2.36 (m, 2H), 2.35−2.09 (m, 6H),

2.03 (d, J = 14.7 Hz, 1H), 1.91 (s, 1H), 1.73 (d, J = 5.1 Hz, 3H), 1.49

(d, J = 19.5 Hz, 9H), 1.03 (d, J = 6.5 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 211.6, 210.7, 176.7, 157.1, 80.0, 76.7, 70.1, 47.7, 46.9, 37.1,

34.8, 33.7, 30.5, 29.7, 28.5, 23.4, 21.4, 21.0; IR (neat) ν_max2928, 1695,

1482, 1414, 1366, 1166 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for

D

+115.0 (c 2.0, CHCl₃).

Diketo Iodide 22. The diketo mesylate 21 (4.19 g, 8.85 mmol)

was dissolved in anhydrous acetone (170 mL), and sodium iodide

(13.4 g, 88.5 mmol) was added in one portion at rt. After being stirred

for 19 h at rt, the reaction mixture was concentrated in vacuo and

puriﬁed on silica gel (PE/EtOAc = 4/1) to aﬀord two inseparable

1

diastereomers (3.77 g, 84%) as a yellow oil. Data for two isomers: H

C₂₁H₃₃NNaO₆418.2200, found 418.2209; [α]²²−30.0 (c 0.1,

D

NMR (400 MHz, CDCl₃) δ 5.81−5.63 (m, 1H), 5.06−4.98 (m, 2H),

3.31−3.11 (m, 7H), 2.62−2.37 (m, 4H), 2.16−1.65 (m, 9H), 1.44−

1.43 (m, 9H), 1.27−1.15 (m, 1H), 0.97 (d, J = 6.5 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 208.2, 155.5, 136.6, 135.3, 117.6, 116.5, 111.0,

79.7, 67.6, 48.6, 47.6, 40.1, 40.0, 39.5, 38.3, 35.8, 34.6, 34.0, 33.0, 32.4,

29.0, 28.4, 22.5, 22.0, 20.8; IR (neat) ν_max2955, 2926, 1694, 1591

cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₂H₃₇INO₄506.1762, found

CHCl₃).

Diol 27. To a solution of aldehyde 25 (40 mg, 0.105 mmol) and

HMPA (370 μL, 2.11 mmol) in THF (degassed, 10 mL) at −78 °C

was added SmI₂(0.1 M in THF, freshly prepared, 5.3 mL, 0.527

mmol). The resulting mixture was stirred at −78 °C for 1 h, warmed

slowly to rt, and stirred at this temperature for additional 12 h. The

reaction mixture was quenched with satd aq Rochelle’s salt at 0 °C and

diluted with EtOAc. The aqueous layer was separated and extracted

with EtOAc. The organic extracts were combined and dried over

Na₂SO₄, and the ﬁltrate was concentrated in vacuo and puriﬁed by

silica gel column chromatography (PE/EtOAc = 4/1) to aﬀord 27 (32

mg, 81%) as a white solid. The relative stereochemistry of 27 was

determined by 2D-NMR analysis; see the Supporting Information for

details: mp 173.5−174.7 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.72 (d, J

= 5.4 Hz, 1H), 3.32 (d, J = 10.5 Hz, 1H), 3.23−2.98 (m, 2H), 3.01 (s,

1H), 2.82 (s, 1H), 2.52 (s, 1H), 2.37 (s, 2H), 2.26−2.10 (m, 2H),

2.01−1.73 (m, 5H), 1.73−1.53 (m, 4H), 1.51−1.33 (m, 12H), 0.94 (d,

J = 5.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.9, 155.8, 81.0,

79.6, 75.4, 41.3, 41.2, 36.5, 35.9, 34.1, 29.7, 28.5, 24.8, 23.3, 22.6, 22.4,

21.4; IR (neat) ν_max3420, 2927, 2868, 1681, 1412, 1365, 1168, 1088

cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₁H₃₆NO₅382.2588, found

382.2586; [α]²²+2.40 (c 0.5, CHCl₃).

506.1772; [α]²¹+133.0 (c 1.0, CHCl₃).

D

C-Alkylation Product 15. To a solution of diketo iodide 22 (2.15

g, 4.25 mmol) in anhydrous MeCN³⁰(300 mL, concentration: 0.014

M) was added DBU (2.59 mL, 17 mmol) at rt, and the reaction was

stirred for 40 h until the reaction was complete. The reaction mixture

was concentrated in vacuo and puriﬁed on silica gel (PE/EtOAc = 10/

1 to 4/1) to aﬀord O-alkylation byproduct 23 (225 mg, 14%) and C-

alkylation product 15 (1.04 g, 65%) both as white powder. For C-

alkylation Product 15: mp 79.5−82.5 °C; ¹H NMR (400 MHz,

CDCl₃) δ 5.76−5.65 (m, 1H), 4.98−4.94 (m, 2H), 3.38 (s, 1H),

3.14−2.96 (m, 4H), 2.72−2.55 (m, 1H), 2.42−1.91 (m, 10H), 1.78−

1.55 (m, 4H), 1.47 (s, 9H), 0.99 (d, J = 6.4 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 211.3, 157.1, 137.3, 115.9, 79.8, 70.4, 47.6, 47.0, 40.0,

37.7, 33.2, 31.2, 29.8, 28.5, 23.3, 21.7, 21.0; IR (neat) ν_max2928, 1684,

1480 cm⁻¹; HRMS (ESI) [M + Na]⁺calculated for C₂₂H₃₅NO₄Na

400.2458, found 400.2459; [α]²¹−11.8 (c 1.0, CHCl₃). For O-

Ketol 29 fro^Dm Keto Diol 27. To a stirred solution of keto diol 27

(25 mg, 0.066 mmol) in anhydrous CH₂Cl₂(3.5 mL) at rt were added

4-methylmorpholine N-oxide monohydrate (27 mg, 0.20 mmol), 4 Å

MS (54 mg), and TPAP (1.2 mg, 0.033 mmol) sequentially. The

resulting mixture was stirred at rt for 3 h. After the reaction was

complete, the reaction mixture was directly puriﬁed by silica gel

chromatography (PE/EtOAc = 2/1) to aﬀord ketol 29 (15 mg, 63%)

as a light yellow solid: mp 65.3−67 °C; ¹H NMR (400 MHz, CDCl₃)

D

alkylation product 23, the structure was determined by 2D-NMR

analysis; see the Supporting Information for details: mp 126.5−129.1

1

°C; H NMR (400 MHz, CDCl₃) δ 5.70 (m, 1H), 4.87 (d, J = 13.2

Hz, 2H), 4.04−3.93 (m, 2H), 3.35−3.22 (m, 4H), 2.83 (s, 1H), 2.66−

2.62 (m, 1H), 2.55−2.42 (m, 2H), 2.13−2.06 (m, 3H), 1.87−1.61 (m,

6H), 1.37 (s, 9H), 0.93 (d, J = 6.1 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 201.9, 201.6, 164.0, 163.3, 156.3, 156.0, 138.0, 119.8, 118.9,

O

dx.doi.org/10.1021/jo3017555 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

δ 4.00−3.47 (m, 1H), 3.25−2.78 (m, 4H), 2.51 (s, 1H), 2.32 (s, 2H),

2.23−2.11 (m, 1H), 2.05 (dt, J = 8.3, 6.9 Hz, 4H), 1.86 (m, 2H),

1.84−1.54 (m, 7H), 1.47 (s, 9H), 0.97 (d, J = 5.3 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 219.0, 216.6, 156.8, 82.3, 79.8, 63.3, 49.3, 45.5,

39.3, 39.1, 34.1, 33.7, 33.1, 32.9, 29.7, 28.5, 24.8, 24.0, 23.7, 23.0, 22.2,

21.5, 21.4; IR (neat) ν_max3515, 2928, 2870, 1754, 1686, 1413, 1367,

1165 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₁H₃₄NO₅380.2431,

found 380.2421; [α]²²+15.0 (c 0.02, CHCl₃).

2H), 0.92 (d, J = 6.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 220.1,

220.0, 157.1, 136.7, 116.3, 116.2, 79.6, 69.4, 69.3, 60.0, 59.6, 49.5, 48.3,

45.2, 43.6, 41.4, 37.3, 34.3, 32.6, 31.7, 30.6, 29.7, 28.5, 27.3, 25.3, 23.8,

23.3, 23.2, 22.4, 22.1; IR (neat) ν_max3560, 2926, 1684, 1480 cm⁻¹;

HRMS (ESI) [M + Na]⁺calcd for C₂₂H₃₇NO₄Na 402.2615, found

402.2614; [α]²¹−14.2 (c 1.0, CHCl₃).

D

Aldehyde 39. To a solution of 43 (30.2 mg, 0.08 mmol) in

dioxane/water (v/v = 2/1, totally 9 mL) were added DABCO (46.0

mg, 0.40 mmol), NaIO₄(171.9 mg, 0.80 mmol), and OsO₄(100.8 μL,

0.008 mmol, 2.5 wt % solution in tert-butyl alcohol) sequentially, and

the reaction was stirred at rt and monitored by TLC. After the reaction

was complete, ethyl acetate and satd aq Na₂S₂O₃were added, the

aqueous phase was separated and extracted with EtOAc, the combined

organic extracts were dried over Na₂SO₄, and the ﬁltrate was

concentrated in vacuo and puriﬁed on silica gel (PE/EtOAc = 3/2)

to aﬀord aldehyde 39 (26.0 mg, 86%) as a colorless oil: ¹H NMR (400

MHz, CDCl₃) δ 9.68 (s, 1H), 4.27−4.09 (m, 1H), 3.49 (s, 1H), 3.30−

2.90 (m, 5H), 2.62 (s, 1H), 2.34−1.69 (m, 8H), 1.63−1.47 (m, 11H),

1.33−1.22 (m, 3H), 0.95−0.87 (d, J = 6.5 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 201.5, 157.0, 79.9, 68.7, 58.9, 58.4, 49.2, 47.9, 47.1,

44.2, 36.2, 33.3, 32.4, 31.8, 31.5, 29.6, 29.1, 28.5, 26.7, 23.5, 23.1, 22.2,

21.8, 21.0, 20.3, 14.1; IR (neat) ν_max3441, 2925, 1692, 1481, 1456

cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for C₂₁H₃₅NO₅Na 404.2407,

Ketol 29 from Di^Dketo Aldehyde 25. To a solution of diketo

aldehyde 25 (28.4 mg, 0.0748 mmol) and triethylamine (10.2 μL,

0.0748 mmol) in CHCl₃(4 mL) was added NHC catalyst 30 (5.4 mg,

0.015 mmol) at rt. The resulting mixture was stirred at rt for 12 h. The

mixture was concentrated in vacuo and puriﬁed by silica gel column

chromatography (toluene/acetonitrile = 9/1) to aﬀord compound 29

(18.6 mg, 66%) as a light yellow solid.

Compound 36. To a solution of compound 26 (4.2 mg, 0.011

mmol) in CHCl₃(1 mL), was added triﬂuoroacetic anhydride (20 μL,

0.143 mmol) dropwise at 0 °C. The resulting mixture was stirred at 50

°C for 12 h. The reaction mixture was concentrated in vacuo and

dissolved in CH₂Cl₂(5 mL). To this solution was added solid sodium

bicarbonate (50 mg, 0.6 mmol). The resulting mixture was stirred at rt

for 1 h. After ﬁltration and concentration in vacuo, compound 36 (1.6

mg, 56%) was gained as a light yellow oil: ¹H NMR (400 MHz,

CDCl₃) δ 3.78 (td, J = 10.6, 5.5 Hz, 1H), 3.42−3.20 (m, 2H), 2.91−

2.70 (m, 3H), 2.53 (dd, J = 18.9, 15.8 Hz, 2H), 2.42 (dd, J = 12.4, 7.9

Hz, 2H), 2.37−2.31 (m, 1H), 2.25−2.15 (m, 1H), 1.9−1.82 (m, 2H),

1.70−1.57 (m, 2H), 1.53 (dd, J = 13.5, 2.5 Hz, 1H), 1.45−1.39 (m,

3H), 1.08 (d, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 210.0,

188.8, 166.4, 109.5, 54.2, 52.8, 46.6, 45.0, 44.3, 40.1, 33.3, 30.0, 29.9,

23.8, 22.3, 19.3; IR (neat) ν_max3395, 2917, 2866, 1705, 1605, 1561,

1520, 1455, 1266, 1187 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

found 404.2410; [α]²¹+34.4 (c 1.0, CHCl₃).

D

Aldehyde 40. To a solution of 44 (140 mg, 0.368 mmol) in

dioxane/water (v/v = 2/1, totally 18 mL) were added DABCO (211

mg, 1.84 mmol), NaIO₄(795.8 mg, 3.68 mmol), and OsO₄(467 μL,

0.0368 mmol, 2.5 wt % solution in tert-butyl alcohol) sequentially. The

reaction was stirred at rt and monitored by TLC. After the reaction

was complete, ethyl acetate and satd aq Na₂S₂O₃were added. The

aqueous phase was separated and extracted with EtOAc, the combined

organic extracts were dried over Na₂SO₄, and the ﬁltrate was

concentrated in vacuo and puriﬁed by silica gel column chromatog-

raphy (PE/EtOAc = 1/1) to aﬀord aldehyde 40 (140.5 mg, quant) as a

C₁₆H₂₂NO₂260.1645, found 260.1643; [α]²¹−87.0 (c 0.1, CHCl₃).

D

Procedures for the Syntheses of Hydroxyl Ketones 43 and

44. Method A: NaBH₄/MeOH. To a solution of the C-alkylation

product 15 (380 mg, 1.01 mmol) in 15 mL of anhydrous MeOH, was

added sodium borohydride (77.7 mg, 2.01 mmol) at rt. The reaction

mixture was stirred at rt for 3.5 h. The reaction mixture was

concentrated in vacuo, diluted with CH₂Cl₂and quenched by satd aq

NaHCO₃. The aqueous phase was separated and extracted with

CH₂Cl₂, and the combined organic extracts were dried over Na₂SO₄,

and the ﬁltrate was concentrated in vacuo and puriﬁed on silica gel

(PE/EtOAc = 10/1 to 1/1) to aﬀord hydroxy ketone 43 (333 mg,

87%) as a colorless solid.^9j

1

colorless oil: H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 4.10−4.07

(m, 1H), 3.54 (t, J = 12.1 Hz, 1H), 3.36−3.27 (m, 1H), 3.14 (m, 2H),

3.03−2.96 (m, 2H), 2.85−2.81 (m, 1H), 2.69−2.60 (m, 2H), 2.38 (dd,

J = 17.8, 7.4 Hz, 1H), 2.18−2.15 (m, 1H), 2.00−1.93 (m, 2H), 1.79−

1.62 (m, 4H), 1.53−1.38 (m, 10H), 1.31−1.17 (m, 3H), 0.92 (d, J =

6.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 219.4, 199.9, 157.0, 79.7,

69.7, 69.5, 59.4, 58.9, 49.8, 48.5, 45.9, 44.7, 44.0, 37.0, 34.1, 33.8, 33.1,

32.6, 32.2, 28.4, 26.9, 25.6, 23.6, 23.2, 23.2, 22.5, 21.8; IR (neat) ν_max

3544, 2927, 2868, 1723, 1684, 1558, 1481, 1412 cm⁻¹; HRMS (ESI)

[M + Na]⁺calcd for C₂₁H₃₅NO₅Na 404.2407, found 404.2410; [α]²¹

Method B: NaBH₄/MeOH/CH₂Cl₂. The C-alkylation product 15

(396 mg, 1.05 mmol) was dissolved in 80 mL of anhydrous CH₂Cl₂,

sodium borohydride (81.0 mg, 2.10 mmol), and anhydrous methanol

(8 mL) were added sequentially. The reaction mixture was stirred at rt

for 5 h before quenched by satd aq NaHCO₃. The aqueous phase was

separated and extracted with CH₂Cl₂, and the combined organic

extracts were dried over Na₂SO₄, and the ﬁltrate was concentrated in

vacuo and puriﬁed on silica gel (PE/EtOAc = 10/1 to 1/1) to aﬀord

hydroxyl ketone 43 (114 mg, 29%) as a colorless solid and hydroxy

ketone 44 (250 mg, 63%) as a colorless oil. For hydroxyl ketone 43, its

structure was determined by X-ray diﬀraction analysis; see the

D

−7.7 (c 1.0, CHCl₃).

Aldehyde 41. Compound 43 (309.7 mg, 0.816 mmol) was

dissolved in 40 mL of anhydrous CH₂Cl₂, the resulting solution was

cooled to −78 °C, then 2,6-lutidine (387 μL, 3.264 mmol) was added

dropwise, followed by TMSOTf (297 μL, 1.632 mmol). After being

stirred at −78 °C for 3 h, the reaction was quenched by addition of

satd aq NaHCO₃at −78 °C and then warmed to rt. The aqueous layer

was extracted with CH₂Cl₂, the combined organic extracts were dried

over Na₂SO₄, and the ﬁltrate was concentrated in vacuo to give a crude

oil, which was used directly in the next step. The crude compound

(0.816 mmol) was redissolved in dioxane/water (v/v = 2/1, totally 60

mL), and then DABCO (467 mg, 4.08 mmol), NaIO₄(1.763 g, 8.16

mmol), and OsO₄(4.14 mL, 0.0816 mmol, 2.5 wt % solution in tert-

butyl alcohol) were added sequentially. The reaction mixture was

stirred at rt and monitored by TLC. After the reaction was complete,

ethyl acetate and satd aq Na₂S₂O₃were added. The aqueous phase was

separated and extracted with EtOAc, the combined organic extracts

were dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo

and puriﬁed by silica gel column chromatography (PE/EtOAc = 4/1)

to aﬀord aldehyde 41 (354.6 mg, 96% for two steps) as a colorless oil:

¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1H), 4.31 (s, br, 1H), 3.63 (m,

1H), 3.32 (m, 1H), 3.15 (m, 1H), 3.04 (d, J = 17.7 Hz, 1H), 2.91 (d, J

= 12.7 Hz, 1H), 2.75 (s, 1H), 2.56−2.31 (m, 2H), 2.15 (s, 1H), 2.10−

1.73 (m, 4H), 1.73−1.58 (m, 3H), 1.49 (s, 9H), 1.42−1.23 (m, 4H),

0.86 (d, J = 6.4 Hz, 3H), 0.07 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

213.7, 204.2, 157.2, 79.6, 74.0, 67.0, 59.4, 46.2, 37.4, 35.3, 28.8, 28.4,

1

Supporting Information for details: mp 122.3−123.5 °C; H NMR

(400 MHz, CDCl₃) δ 5.70−5.59 (m, 1H), 4.98−4.94 (m, 2H), 4.10 (s,

1H), 3.64−3.60 (m, 2H), 3.44−3.38 (m, 1H), 3.25−3.20 (m, 1H),

3.06−2.64 (m, 4H), 2.18−1.86 (m, 6H), 1.74−1.60 (m, 5H), 1.49 (s,

9H), 1.33−1.25 (m, 3H), 0.89 (d, J = 6.5 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 220.0, 157.1, 138.2, 115.8, 79.8, 68.7, 59.6, 48.7, 47.5,

45.2, 43.7, 39.9, 36.4, 36.4, 32.1, 31.5, 31.3, 29.5, 28.5, 23.0, 22.1, 21.8,

21.1, 20.2; IR (neat) ν_max3547, 2925, 1688, 1638, 1481, 1456 cm⁻¹;

HRMS (ESI) [M + Na]⁺calcd for C₂₂H₃₇NO₄Na 402.2615, found

402.2613; [α]²¹+71.2 (c 1.0, CHCl₃). For hydroxyl ketone 44, the

D

relative stereochemistry was determined by 2D-NMR analysis; see the

1

Supporting Information for details: H NMR (400 MHz, CDCl₃) δ

5.68−5.58 (m, 1H), 5.00−4.94 (m, 2H), 4.22 (dd, J = 12.0, 3.6 Hz,

1H), 3.62 (t, J = 13.0 Hz, 1H), 3.42−3.15 (m, 2H), 3.07−2.76 (m,

3H), 2.41 (dd, J = 18.1, 7.7 Hz, 1H), 2.20−2.03 (m, 3H), 1.96−1.90

(m, 2H), 1.81−1.62 (m, 5H), 1.52−1.45 (m, 10H), 1.29−1.16 (m,

P

dx.doi.org/10.1021/jo3017555 | J. Org. Chem. XXXX, XXX, XXX−XXX

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22.7, 21.8, 20.9, 20.6, 20.2; IR (neat) ν_max2951, 2914, 1720, 1692,

separated and extracted with EtOAc, the combined organic extracts

were dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo

and puriﬁed by silica gel column chromatography (PE/EtOAc = 2/1

to 1/1) to aﬀord triol 49 (79.0 mg, 72%) as a slightly yellow oil and

triol 50 (19.0 mg, 18%) as a slightly yellow powder.

1410, 1365 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for C₂₄H₄₃NO₅SiNa

476.2802, found 476.2807; [α]²¹+11.2 (c 1.0, CHCl₃).

D

Aldehyde 42. Compound 44 (39.9 mg, 0.105 mmol) was dissolved

in 10 mL of anhydrous CH₂Cl₂, the resulting solution was cooled to

−78 °C, then 2,6-lutidine (49 μL, 0.420 mmol) was added dropwise,

followed by TMSOTf (38.4 μL, 0.210 mmol). After being stirred at

−78 °C for 3 h, the reaction was quenched by addition of satd aq

NaHCO₃at −78 °C and then warmed to rt. The aqueous layer was

extracted with CH₂Cl₂, the combined organic extracts were dried over

Na₂SO₄, and the ﬁltrate was concentrated in vacuo to give a crude oil,

which was used directly in the next step. The crude compound (30 mg,

0.07 mmol) was redissolved in dioxane/water (v/v = 2/1, totally 9

mL), and then DABCO (40 mg, 0.35 mmol), NaIO₄(151 mg, 0.70

mmol), and OsO₄(88.7 μL, 0.007 mmol, 2.5 wt % solution in tert-

butyl alcohol) were added sequentially. The reaction mixture was

stirred at rt and monitored by TLC. After the reaction was complete,

ethyl acetate and satd aq Na₂S₂O₃were added. The aqueous phase was

separated and extracted with EtOAc, the combined organic extracts

were dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo

and puriﬁed by silica gel column chromatography (PE/EtOAc = 4/1)

to aﬀord aldehyde 42 (21.9 mg, 46% for two steps) as a colorless oil:

¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 4.08 (dd, J = 10.6, 4.2

Hz, 1H), 3.53−3.15 (m, 2H), 2.90−2.87 (m, 1H), 2.75−2.72 (m, 2H),

2.54−2.39 (m, 2H), 2.29−2.03 (m, 5H), 1.70−1.58 (m, 4H), 1.47 (s,

9H), 1.35−1.22 (m, 4H), 0.90 (d, J = 5.9 Hz, 3H), 0.11−0.10 (s, 9H);

¹³C NMR (100 MHz, CDCl₃) δ 214.9, 201.0, 157.1, 79.5, 70.6, 69.1,

59.7, 48.8, 47.9, 44.8, 44.3, 43.2, 40.1, 33.8, 33.2, 32.3, 28.5, 26.4, 25.6,

23.8, 23.2, 22.3, 21.9, 14.1, 0.7, 0.6; IR (neat) ν_max2953, 2927, 1724,

1692, 1482, 1454, 1411 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for

Method B. To a solution of aldehyde 40 (17.0 mg, 0.044 mmol)

and HMPA (156.6 μL, 0.891 mmol) in anhydrous THF (degassed, 4.0

mL) at −78 °C was added SmI₂(0.1 M in THF, freshly prepared, 2.23

mL, 0.223 mmol). The resulting mixture was stirred for 1 h at −78 °C,

and then warmed to rt and stirred for additional 1 h. The reaction

mixture was quenched with satd aq Rochelle’s salt and diluted with

EtOAc. The aqueous phase was separated and extracted with EtOAc,

the combined organic extracts were dried over Na₂SO₄, and the ﬁltrate

was concentrated in vacuo and puriﬁed by silica gel column

chromatography (PE/EtOAc = 2/1) to aﬀord triol 50 (11.4 mg,

1

67%) as a slightly yellow powder. For triol 49: H NMR (400 MHz,

CDCl₃) δ 4.52 (t, J = 8.0 Hz, 1H), 4.16 (d, J = 10.1 Hz, 1H), 3.95 (s,

1H), 3.67−3.20 (m, 5H), 2.88−2.67 (m, 3H), 2.22−2.04 (m, 5H),

1.81 (s, br, 3H), 1.64 (d, J = 10.4 Hz, 4H), 1.46−1.31 (m, 10H), 1.03−

1.01 (m, 1H), 0.92 (d, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

δ 157.3, 87.0, 79.8, 79.5, 73.7, 50.8, 47.6, 44.7, 39.7, 38.3, 33.6, 32.3,

31.9, 29.7, 29.3, 28.6, 26.4, 24.6, 23.1, 22.7, 21.9, 20.5, 14.11; IR (neat)

ν_max3375, 2924, 1666, 1480, 1454, 1414 cm⁻¹; HRMS (ESI) [M +

Na]⁺calcd for C₂₁H₃₇NO₅Na 406.2564, found 406.2562; [α]²¹+5.0

D

(c 1.0, CHCl₃). For triol 50: mp 76.0 °C; ¹H NMR (400 MHz,

CDCl₃) δ 4.90 (s, 1H), 4.42−4.27 (m, 2H), 3.58−3.10 (m, 6H), 2.75

(s, 1H), 1.97−1.78 (m, 7H), 1.65−1.58 (m, 4H), 1.45 (s, 9H), 1.29−

1.18 (m, 2H), 1.08−1.01 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 156.7, 83.8, 80.0, 79.6, 79.3, 71.8, 71.3, 68.0,

51.1, 50.6, 47.5, 46.6, 46.1, 38.9, 38.5, 38.2, 34.9, 32.2, 29.7, 28.5, 25.8,

23.3, 22.8, 22.2, 22.0, 21.6, 14.1; IR (neat) ν_max3351, 2920, 1661,

1478, 1454, 1417 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for

C₂₁H₃₇NO₅Na 406.2564, found 406.2563; [α]²¹_D−6.8 (c 1.0, CHCl₃).

Diacetate 51. The triol 49 (17.2 mg, 0.045 mmol) was dissolved in

0.7 mL of anhydrous pyridine, then DMAP (2.7 mg, 0.023 mmol) and

Ac₂O (21.0 μL, 0.225 mmol) were added sequentially. The reaction

mixture was stirred at rt and monitored by TLC. After the reaction was

complete, the reaction mixture was concentrated in vacuo and puriﬁed

by silica gel column chromatography (PE/EtOAc = 4/1) to aﬀord

diacetate 51 (17.5 mg, 83%) as a colorless oil. The relative

stereochemistry of 51 was determined by 2D-NMR analysis; see the

C₂₄H₄₃NO₅SiNa 476.2803, found 476.2810; [α]²¹+7.0 (c 0.1,

D

CHCl₃).

SmI₂-Mediated Intramolecular Pinacol Coupling Protocol

for Diol 47. Method A. To a solution of aldehyde 41 (262 mg, 0.58

mmol) in anhydrous THF (degassed, 35 mL) at −78 °C was added

SmI₂(0.1 M in THF, freshly prepared, 29.0 mL, 2.90 mmol).⁵⁵The

resulting mixture was quickly warmed to rt and stirred for an

additional 3 h. The reaction mixture was quenched with satd aq

Rochelle’s salt at 0 °C and diluted with EtOAc. The aqueous phase

was separated and extracted with EtOAc, the combined organic

extracts were dried over Na₂SO₄, and the ﬁltrate was concentrated in

vacuo and puriﬁed by silica gel column chromatography (PE/EtOAc =

5/1) to aﬀord diol 47 (227 mg, 86%) as a colorless oil: ¹H NMR (400

MHz, CDCl₃) δ 4.18 (s, 1H), 4.12 (s, 1H), 3.57 (m, 2H), 3.10−2.94

(m, 2H), 2.83 (dd, J = 17.1, 6.7 Hz, 1H), 2.74 (s, 1H), 2.05 (m, 8H),

1.82−1.61 (m, 5H), 1.51 (s, 9H), 1.30−1.16 (m, 2H), 1.16−1.04 (m,

1H), 0.85 (d, J = 6.3 Hz, 3H), 0.03 (s, 9H); ¹³C NMR (100 MHz,

CDCl₃) δ 157.1, 82.8, 81.7, 79.8, 69.9, 52.8, 50.8, 49.9, 41.2, 38.4, 37.8,

33.0, 31.0, 28.6, 28.4, 24.0, 22.0, 19.5, 0.5; IR (neat) ν_max3413, 2948,

2923, 2359, 2340, 1677, 1482 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

C₂₄H₄₆NO₅Si 456.3140, found 456.3145; [α]²¹_D+11.0 (c 0.5, CHCl₃).

Method B. To a solution of aldehyde 41 (160 mg, 0.352 mmol) and

HMPA (618 μL, 3.52 mmol) in THF (degassed, 20 mL) at −78 °C

was added SmI₂(0.1 M in THF, freshly prepared, 17.6 mL, 1.76

mmol). The resulting mixture was stirred at −78 °C, slowly warmed to

rt, and stirred for 3 h at rt. The reaction mixture was quenched with

satd aq Rochelle’s salt and diluted with EtOAc. The aqueous layer was

separated and extracted with EtOAc, the combined organic extracts

were dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo

and puriﬁed by silica gel column chromatography (PE/EtOAc = 5/1)

to aﬀord 47 (128 mg, 80%) as a colorless oil. The relative

stereochemistry of 47 was determined by 2D-NMR analysis; see the

Supporting Information for details.

1

Supporting Information for details: H NMR (400 MHz, CDCl₃) δ

5.30 (dd, J = 11.7, 4.5 Hz, 1H), 5.23−5.19 (m, 1H), 4.02−3.97 (m,

1H), 3.78 (t, J = 12.3 Hz, 1H), 3.72 (t, J = 12.8 Hz, 1H), 3.67−3.44

(m, 1H), 3.28 (dd, J = 13.9, 6.2 Hz, 1H), 3.10−3.03 (m, 1H), 2.82−

2.73 (m, 1H), 2.50 (s, 1H), 2.19−2.15 (m, 1H), 2.09−2.07 (m, 3H),

1.98 (s, 5H), 1.80−1.73 (m, 2H), 1.67−1.55 (m, 4H), 1.47 (s, 9H),

1.33−1.25 (m, 3H), 1.07 (dd, J = 17.7, 8.6 Hz, 1H), 0.90 (d, J = 6.3

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.1, 170.7, 157.5, 85.2,

85.0, 79.0, 72.8, 51.0, 50.8, 48.3, 47.7, 44.5, 43.9, 41.5, 41.4, 37.2, 32.7,

32.5, 29.6, 28.6, 26.2, 26.0, 25.7, 23.1, 22.0, 21.7, 21.6, 21.4, 21.1, 21.0,

20.9; IR (neat) ν_max3446, 2926, 1732, 1692, 1558, 1540, 1487 cm⁻¹;

HRMS (ESI) [M + Na]⁺calcd for C₂₅H₄₁NO₇Na 490.2775, found

490.2784; [α]²¹−72.5 (c 0.4, CHCl₃).

D

Diacetate 52. The triol 50 (9.6 mg, 0.025 mmol) was dissolved in

1.0 mL of anhydrous pyridine, and then DMAP (1.5 mg, 0.013 mmol)

and Ac₂O (12.0 μL, 0.125 mmol) were added sequentially. The

reaction mixture was stirred at rt and monitored by TLC. After the

reaction was complete, the reaction mixture was concentrated in vacuo

and puriﬁed on silica gel (PE/EtOAc = 2/1) to aﬀord diacetate 52 (9.8

mg, 84%) as a colorless oil. The relative stereochemistry of 52 was

determined by 2D-NMR analysis; see the Supporting Information for

1

details: H NMR (400 MHz, CDCl₃) δ 5.67 (dd, J = 11.7, 4.7 Hz,

1H), 4.70 (dt, J = 10.6, 5.3 Hz, 1H), 3.74−3.45 (m, 2H), 3.31−3.25

(m, 1H), 3.15−3.08 (m, 1H), 2.94−2.87 (m, 1H), 2.79−2.66 (m, 1H),

2.30−2.29 (m, 1H), 2.22−1.76 (m, 11H), 1.62−1.51 (m, 4H), 1.46 (s,

9H), 1.40−1.25 (m, 4H), 1.15−1.07 (m, 1H), 0.91 (d, J = 6.4 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 171.1, 157.2, 83.7, 82.2,

82.1, 79.1, 73.0, 72.9, 50.1, 50.0, 47.7, 47.2, 45.0, 44.4, 41.3, 37.5, 32.3,

32.2, 32.0, 31.6, 31.0, 30.4, 28.6, 25.6, 25.5, 25.1, 22.6, 22.4, 21.8, 21.6,

Hydroxyl-Directed SmI₂-Mediated Intramolecular Pinacol

Protocol from 40. Method A. To a solution of aldehyde 40 (106 mg,

0.288 mmol) in anhydrous THF (degassed, 10 mL) at −78 °C was

added SmI₂(0.1 M in THF, freshly prepared, 14.4 mL, 1.44 mmol).

The resulting mixture was quickly warmed to room temperature and

stirred for an additional 5 h. The reaction mixture was quenched with

satd aq Rochelle’s salt and diluted with EtOAc. The aqueous phase was

Q

dx.doi.org/10.1021/jo3017555 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

21.4, 21.2, 14.1; IR (neat) ν_max3502, 2921, 1717, 1686, 1486, 1455,

Improved Ley Oxidation for the Synthesis of Ketol 38. To a

stirred solution of triol 56 (32 mg, 0.083 mmol) in anhydrous CH₂Cl₂

(3.5 mL) at rt were added 4-methylmorpholine N-oxide monohydrate

(29 mg, 0.21 mmol) and TPAP (1.4 mg, 0.0042 mmol) sequentially.

The resulting mixture was stirred at rt for 3 h. After the reaction was

complete, the reaction mixture was directly puriﬁed by silica gel

chromatography (PE/EtOAc = 2/1) to aﬀord ketol 38 (27.9 mg, 89%)

as a colorless oil.

1412 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for C₂₅H₄₁NO₇Na

490.2775, found 490.2782; [α]²¹+8.5 (c 0.4, CHCl₃).

D

Compound 55. To a solution of aldehyde 42 (21.9 mg, 0.048

mmol) and HMPA (84.8 μL, 0.480 mmol) in THF (degassed, 5.0 mL)

at −78 °C was added SmI₂(0.1 M in THF, freshly prepared, 2.4 mL,

0.24 mmol). The resulting mixture was stirred for 1 h before being

warmed to rt and stirred for additional 2 h. The reaction mixture was

quenched with satd aq Rochelle’s salt and diluted with EtOAc. The

aqueous layer was separated and extracted with EtOAc, the combined

organic extracts were dried over Na₂SO₄, and the ﬁltrate was

concentrated in vacuo and puriﬁed by silica gel column chromatog-

raphy (PE/EtOAc = 6/1) to aﬀord 55 as inseparable mixtures of

primary alcohol and hemiketal (ratio = 10/1, total 7.4 mg, 34%) as a

slightly yellow oil. Data for inseparable mixtures: ¹H NMR (400 MHz,

CDCl₃) δ 4.18 (dd, J = 11.4, 4.0 Hz, 2H), 3.64−3.22 (m, 4H), 2.84−

2.59 (m, 3H), 2.33−2.19 (m, 1H), 2.08−1.96 (m, 5H), 1.67−1.37 (m,

14H), 1.27−1.21 (m, 3H), 0.90 (d, J = 6.1 Hz, 3H), 0.11−0.06 (m,

9H); ¹³C NMR (100 MHz, CDCl₃) δ 215.0, 157.2, 98.4, 79.4, 69.6,

68.8, 61.2, 60.4, 49.7, 48.8, 48.0, 44.3, 43.0, 40.6, 37.3, 32.2, 31.2, 28.6,

28.6, 27.1, 25.4, 23.1, 22.1, 1.0, 0.6; IR (neat) ν_max3462, 2951, 2918,

2868, 2850, 1697, 1482, 1456, 1415 cm⁻¹; HRMS (ESI) [M + H]⁺

calcd for C₂₄H₄₆NO₅Si 456.3140, found 456.3142; [α]²¹_D+2.5 (c 0.32,

MeOH).

(+)-Alopecuridine (4). To a solution of ketol 38 (12.8 mg, 0.034

mmol) in anhydrous chloroform (3 mL) was added triﬂuoroacetic acid

(300 μL) dropwise at 0 °C. The resulting mixture was stirred at rt for

0.5 h. The reaction mixture was concentrated in vacuo and dissolved in

CH₂Cl₂(5 mL).To this mixture was added NaHCO₃solid (240 mg).

The resulting mixture was stirred at rt for 2 h and ﬁltered. The ﬁltrate

was concentrated in vacuo to aﬀord (+)-alopecuridine (4) (12.3 mg,

94%) as a pale white solid. Spectroscopic data are in accordance with

literature reported values: mp 78.6−80 °C; ¹H NMR (400 MHz,

CDCl₃) δ 11.47 (s, 1H), 8.55 (s, 1H), 3.90−3.78 (m, 1H), 3.53 (td, J

= 14.3, 4.2 Hz, 1H), 3.21 (dd, J = 13.7, 5.1 Hz, 1H), 3.02−2.93 (m,

1H), 2.87 (dd, J = 16.6, 13.4 Hz, 1H), 2.64−2.52 (m, 1H), 2.38−2.08

(m, 9H), 2.07−1.95 (m, 1H), 1.94−1.76 (m, 3H), 1.76−1.64 (m, 1H),

1.43 (ddd, J = 18.5, 10.9, 5.7 Hz, 1H), 0.98 (d, J = 8.6 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 215.7, 95.0, 80.4, 76.7, 53.9, 50.0, 49.8,

41.3, 40.6, 40.5, 36.1, 31.9, 31.3, 29.7, 29.6, 29.4, 25.0, 23.8, 22.7, 21.9,

21.5, 19.3; ¹H NMR (400 MHz, CD₃OD) δ 3.75−3.54 (m, 3H),

3.23−3.13 (m, 1H), 2.39 (m, 3H), 2.37−1.87 (m, 9H), 1.75 (ddt, J =

16.1, 12.5, 7.2 Hz, 3H), 1.54−1.42 (m, 1H), 1.02 (d, J = 6.5 Hz, 3H);

¹³C NMR (100 MHz, CD₃OD) δ 216.0, 95.5, 89.2, 81.2, 56.2, 55.7,

54.1, 52.6, 52.0, 51.8, 50.3, 46.9, 41.8, 41.6, 40.2, 35.5, 32.8, 32.0, 26.5,

25.3, 24.9, 23.7, 23.0, 22.1, 21.6, 20.8, 19.4; IR (neat) ν_max2924, 1741,

1660, 1459, 1260, 1197 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

Triol 56. To a solution of diol 47 (57 mg, 0.125 mmol) in

anhydrous THF (6 mL), was added TBAF (0.626 mL, 0.626 mmoL)

dropwise at 0 °C. The resulting mixture was stirred at rt for 45 h. The

reaction mixture was concentrated in vacuo and puriﬁed directly by

silica gel column chromatography (PE/EtOAc = 10/1) to aﬀord triol

1

56 (44 mg, 92%) as a colorless oil: H NMR (400 MHz, CDCl₃) δ

4.32−4.30 (m, 1H), 4.15 (s, 1H), 3.41 (t, J = 13.7 Hz, 2H), 3.17−2.94

(m, 3H), 2.65 (s, 1H), 2.19 (m, 3H), 2.15−1.74 (m, 5H), 1.65 (m,

3H), 1.59−1.39 (m, 10H), 1.39−1.22 (m, 3H), 1.22−1.04 (m, 2H),

0.88 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.2, 82.0,

81.9, 79.9, 68.5, 51.5, 50.0, 49.5, 41.0, 39.6, 37.2, 32.9, 30.5, 28.6, 28.5,

25.6, 23.3, 22.2, 19.4; IR (neat) ν_max3450, 2925, 1668, 1414, 1264

cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₁H₃₈NO₅384.2744, found

C₁₆H₂₆NO₃280.1907, found 280.1911; [α]²⁵+69.8 (c 0.5, MeOH).

D

Normal Ley Oxidation for the Synthesis of Ketol 37. To a stirred

solution of triol 49 (38.0 mg, 0.0991 mmol) in anhydrous CH₂Cl₂(5

mL) at rt were added 4-methylmorpholine N-oxide monohydrate

(68.3 mg, 0.495 mmol), 4 Å MS (136.6 mg), and TPAP (7.2 mg, 0.020

mmol) sequentially. The resulting mixture was stirred at rt for 4−5 h.

After the reaction was complete, the reaction mixture was directly

puriﬁed on silica gel (PE/EtOAc = 2/1) to aﬀord ketol 37 (28.0 mg,

384.2749; [α]²¹+17.6 (c 0.5, CHCl₃).

D

Normal Ley Oxidation for the Synthesis of Ketol 38. To a stirred

solution of triol 56 (32 mg, 0.083 mmol) in anhydrous CH₂Cl₂(3.5

mL) at rt were added 4-methylmorpholine N-oxide monohydrate (29

mg, 0.21 mmol), 4 Å MS (58 mg) and TPAP (1.4 mg, 0.0042 mmol)

sequentially. The resulting mixture was stirred at rt for 5 h. After the

reaction was complete, the reaction mixture was directly puriﬁed by

silica gel chromatography (PE/EtOAc = 2/1) to aﬀord ketol 38 (15.7

mg, 50%) as a colorless oil⁷and lactone 57 (8.8 mg, 28%) as a white

solid. Data for ketol 38: ¹H NMR (400 MHz, CDCl₃) δ 3.74 (dd, J =

13.6, 3.5 Hz, 1H), 3.70−3.60 (m, 1H), 2.90−2.79 (m, 2H), 2.71−2.61

(m, 1H), 2.59−2.47 (m, 1H), 2.47−2.41 (m, 1H), 2.41−2.37 (m, 1H),

2.37−2.29 (m, 1H), 2.15 (m, 1H), 2.12−1.96 (m, 4H), 1.93−1.86 (m,

1H), 1.86−1.73 (m, 3H), 1.73−1.62 (m, 2H), 1.45 (s, 9H), 1.33−1.40

(m, 1H), 1.07 (d, J = 6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

215.3, 211.4, 156.7, 79.7, 78.7, 64.9, 49.8, 48.5, 47.9, 41.5, 36.0, 33.6,

31.2, 28.5, 26.3, 23.9, 23.2, 22.8, 22.3; IR (neat) ν_max3392, 2925, 2870

1747, 1690, 1478, 1414 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for

1

74%) as a slightly yellow oil: H NMR (400 MHz, CDCl₃) δ 5.26−

5.20 (m, −OH, 1H), 3.82 (dt, J = 13.4, 4.4 Hz, 1H), 3.60−3.50 (m,

1H), 3.39−3.35 (m, 1H), 3.24−3.16 (m, 1H), 2.88−2.84 (m, 1H),

2.55−2.33 (m, 4H), 2.20 (d, J = 12.7 Hz, 1H), 2.08−1.88 (m, 5H),

1.84−1.67 (m, 4H), 1.47 (s, 9H), 1.37−1.31 (m, 1H), 1.08 (d, J = 6.3

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 220.6, 216.8, 157.5, 83.2,

79.5, 59.3, 47.0, 46.4, 44.7, 39.6, 35.0, 31.4, 31.3, 29.7, 28.6, 26.4, 24.5,

23.3, 22.0, 18.9; IR (neat) ν_max3467, 2924, 1753, 1684, 1558, 1540,

1486, 1456, 1410 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for

C₂₁H₃₃NO₅Na 402.2251, found 402.2254; [α]²¹+103.0 (c 1.0,

D

CHCl₃).

Improved Ley Oxidation for the Synthesis of Ketol 37. To a

stirred solution of triol 49 (28.0 mg, 0.073 mmol) in anhydrous

CH₂Cl₂(4 mL) at rt were added 4-methylmorpholine N-oxide

monohydrate (50.5 mg, 0.365 mmol), 4 Å MS (101 mg), and TPAP

(3.0 mg, 0.0073 mmol) sequentially. The resulting mixture was stirred

at rt for 3 h. After the reaction was complete, the reaction mixture was

directly puriﬁed on silica gel (PE/EtOAc = 2/1) to aﬀord ketol 37

(21.0 mg, 76%) as a slightly yellow oil.

8-Deoxy-13-dehydroserratinine (12). To a stirred solution of ketol

37 (21.6 mg, 0.057 mmol) and Et₃N (119.1 μL, 0.854 mmol) in

anhydrous THF (4.0 mL) at −78 °C was added SOCl₂(62.2 μL, 0.854

mmol) dropwise. The reaction mixture was stirred for 1 h at −78 °C,

warmed to 0 °C, and stirred for additional 1.5 h. After the reaction was

complete (monitored by TLC), the reaction mixture was quenched

with satd aq NaHCO₃and diluted with CH₂Cl₂. The aqueous layer

was separated and extracted with CH₂Cl₂, the combined organic

extracts were dried over Na₂SO₄, and the ﬁltrate was concentrated in

vacuo and puriﬁed by silica gel column chromatography (CH₂Cl₂/

MeOH = 10/1) to aﬀord 8-deoxy-13-dehydroserratinine (12) (14.6

mg, 98%) as a colorless oil:^17c¹H NMR (400 MHz, CDCl₃) δ 3.36−

C₂₁H₃₃NO₅Na:402.2251, found 402.2256; [α]²¹+88.0 (c 0.1,

D

CHCl₃). The relative stereochemistry of 57 was determined by 2D-

NMR analysis; see the Supporting Information for details. Data for

1

lactone 57: mp 193.1−195 °C; H NMR (400 MHz, CDCl₃) δ 4.86

(dd, J = 5.7, 2.5 Hz, 1H), 3.31 (s, 1H), 3.07 (dd, J = 12.5, 6.9 Hz, 5H),

2.45 (dd, J = 7.0, 3.2 Hz, 1H), 2.39 (s, 1H), 2.34 (s, 1H), 2.22 (d, J =

23.6 Hz, 2H), 2.16−2.13 (m, 1H), 2.11−1.99 (m, 2H), 1.96−1.86 (m,

1H), 1.76 (m, 2H), 1.60−1.54 (m, 2H), 1.52 (d, J = 2.0 Hz, 1H), 1.49

(s, 9H), 0.99 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

211.9, 171.4, 156.9, 155.8, 79.9, 79.7, 79.1, 54.0, 53.6, 49.3, 48.3, 45.4,

35.5, 34.8, 32.1, 28.4, 26.9, 22.9, 22.0, 21.5, 21.2, 20.5, 19.8; IR (neat)

ν_max2919, 1731, 1691, 1410, 1365, 1169, 1109 cm⁻¹; HRMS (ESI) [M

+ H]⁺calcd for C₂₁H₃₄NO₅380.2432, found 380.2436; [M + Na]⁺

calcd for C₂₁H₃₃NNaO₅402.2251, found 402.2249; [α]²⁶+21.6 (c

D

0.5, CH₂Cl₂).

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The Journal of Organic Chemistry

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3.32 (m, 1H), 2.84 (m, 1H), 2.71−2.60 (m, 2H), 2.52 (dd, J = 19.4,

9.0 Hz, 1H), 2.44−2.32 (m, 2H), 2.20 (dd, J = 12.7, 4.2 Hz, 1H),

2.14−2.05 (m, 2H), 2.02−1.88 (m, 4H), 1.78−1.70 (m, 4H), 1.61−

1.53 (m, 2H), 1.05 (d, J = 6.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

δ 213.4, 213.0, 76.1, 57.7, 51.4, 49.1, 47.0, 37.6, 37.2, 32.0, 30.8, 25.0,

24.7, 22.0, 21.4, 20.7; IR (neat) ν_max2918, 2849, 1739, 1698, 1455,

1410 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₁₆H₂₄NO₂262.1802,

THF, freshly prepared, 590 μL, 0.0593 mmol). The resulting mixture

was stirred for 40 min at 0 °C, quenched with satd aq Rochelle’s salt,

and diluted with CH₂Cl₂. The aqueous layer was separated and

extracted with CH₂Cl₂, the combined organic extracts were dried over

Na₂SO₄, and the ﬁltrate was concentrated in vacuo and puriﬁed by

silica gel column chromatography (CH₂Cl₂/MeOH = 1/1) to aﬀord

(+)-fawcettimine (1) (1.6 mg, 51%) as a colorless oil. Spectroscopic

data are in accordance with literature reported values:^9f¹H NMR (400

MHz, CDCl₃) δ 3.50−3.43 (m, 1H), 3.26 (dt, J = 14.1, 3.9 Hz, 1H),

2.91 (dd, J = 14.8, 5.4 Hz, 1H), 2.77−2.71 (m, 1H), 2.62 (dd, J = 17.7,

13.8 Hz, 1H), 2.29−2.08 (m, 8H), 1.98−1.83 (m, 5H), 1.63 (d, J =

14.4 Hz, 1H), 1.50−1.47 (m, 2H), 1.43−1.35 (m, 1H), 0.95 (d, J = 6.0

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 220.1, 105.0, 60.1, 53.5,

50.0, 48.2, 44.2, 43.2, 41.9, 35.7, 31.9, 28.5, 28.1, 23.7, 22.3, 21.8; IR

(neat) ν_max2917, 2849, 1730 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

C₁₆H₂₆NO₂264.1958, found 264.1956; [α]²⁵_D+81.7 (c 0.18, MeOH).

Ketal 77. To a solution of diol 47 (83.2 mg, 0.183 mmol) and p-

TsOH (3.17 mg, 0.018 mmol, 0.1 equiv) in dried acetone (15 mL)

was added 2,2-dimethoxypropane (0.937 mL) at 0 °C. The resulting

mixture was stirred at rt for 3.5 h. The reaction was quenched with

Et₃N, concentrated in vacuo and puriﬁed on silica gel (PE/EtOAc =

10/1) to aﬀord the ketal 77 (91 mg, quant.) as a white solid: mp

found 262.1796; [α]²¹−2.0 (c 0.2, CHCl₃).

D

Enone 65. To a stirred solution of 38 (8.2 mg, 0.022 mmol) and

Et₃N (45 μL, 0.324 mmol) in anhydrous THF (3.0 mL) at −78 °C

was added SOCl₂(24 μL, 0.324 mmol) dropwise. The reaction

mixture was stirred for 1 h at −78 °C, warmed to 0 °C, and stirred for

an additional 1.5 h at 0 °C. After the reaction was complete

(monitored by TLC), the reaction mixture was quenched with satd aq

NaHCO₃and diluted with CH₂Cl₂. The aqueous layer was separated

and extracted with CH₂Cl₂, the combined organic extracts were dried

over Na₂SO₄, and the ﬁltrate was concentrated in vacuo, and puriﬁed

by silica gel column chromatography (CH₂Cl₂/MeOH = 10/1) to

1

aﬀord enone 65 (4.2 mg, 53%) as a light yellow oil: H NMR (400

MHz, CDCl₃) δ 6.98 (ddd, J = 15.3, 12.0, 7.0 Hz, 1H), 3.96−3.52 (m,

1H), 3.46−3.20 (m, 2H), 3.08 (ddd, J = 53.4, 17.8, 8.5 Hz, 2H), 2.78−

2.61 (m, 2H), 2.48 (m, 1H), 2.42−2.20 (m, 3H), 2.06 (m, 5H), 1.79

(dd, J = 9.4, 4.0 Hz, 2H), 1.42 (d, J = 2.5 Hz, 9H), 1.06 (d, J = 6.3 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 210.4, 202.8, 155.1, 141.4,

140.3, 138.9, 79.8, 79.6, 60.6, 59.8, 48.1, 47.0, 46.7, 46.6, 45.4, 44.5,

41.1, 41.0, 38.6, 38.3, 31.3, 31.2, 30.0, 29.9, 29.4, 28.7, 28.6, 28.5, 28.4,

23.0, 22.3, 22.2; IR (neat) ν_max2956, 2916, 2848, 1698, 1646, 1472,

1458 cm⁻¹; HRMS (ESI) [M + Na]⁺calcd for C₂₁H₃₁NO₄Na

1

110.8−111.7 °C; H NMR (400 MHz, CDCl₃) δ 4.27 (d, J = 8.0 Hz,

1H), 4.07 (s, 1H), 3.67−3.39 (m, 3H), 2.96 (d, J = 20.9 Hz, 1H), 2.89

(dd, J = 14.1, 9.6 Hz, 2H), 2.15 (dd, J = 14.0, 7.4 Hz, 3H), 1.98−1.73

(m, 6H), 1.61−1.50 (m, 5H), 1.48 (s, 9H), 1.40 (s, 3H), 1.38 (s, 3H),

0.86 (d, J = 6.5 Hz, 3H), 0.10 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

174.1, 157.0, 108.1, 94.5, 89.8, 78.9, 70.4, 50.7, 48.7, 47.8, 47.6, 42.7,

37.6, 36.5, 32.4, 29.4, 28.9, 28.70, 28.4, 28.4, 24.4, 22.0, 21.4, 19.5, 0.7;

IR (neat) ν_max2928, 1697 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for

384.2145, found 384.2147; [α]²²+50 (c 0.1, CHCl₃).

D

(−)-8-Deoxyserratinine (7). To a solution of 8-deoxy-13-

dehydroserratinine (12) (4.4 mg, 0.0168 mmol) in anhydrous ethanol

(2.0 mL) was added sodium borohydride (1.3 mg, 0.0337 mmol) at 0

°C. The resulting solution was stirred at 0 °C for 30 min, and then 0.2

mL of acetone was added to quench the reaction. The reaction mixture

was concentrated in vacuo and puriﬁed by silica gel column

chromatography (CH₂Cl₂/MeOH = 20/1) to aﬀord (−)-8-deoxy-

serratinine (7) (4.3 mg, 98%) as a white solid. Spectroscopic data are

in accordance with literature reported values:^17cmp 226.5−228.2 °C;

¹H NMR (400 MHz, CD₃OD) δ 3.51 (s, 1H), 2.95 (dd, J = 21.2, 9.1

Hz, 1H), 2.85 (m, 1H), 2.71−2.62 (m, 2H), 2.48 (dd, J = 18.7, 11.1

Hz, 1H), 2.37−2.28 (m, 2H), 2.17−2.11 (m, 1H), 2.04−1.97 (m, 2H),

1.92−1.78 (m, 4H), 1.62−1.55 (m, 3H), 1.49−1.47 (m, 1H), 1.42−

1.29 (m, 3H), 1.15−1.08 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H); ¹³C NMR

(100 MHz, CD₃OD) δ 218.0, 78.8, 74.5, 53.4, 51.2, 49.6, 49.4, 49.2,

49.0, 48.8, 48.6, 48.4, 45.9, 39.9, 39.0, 34.1, 33.0, 25.8, 22.8, 22.5, 21.8,

21.5, 21.0; IR (neat) ν_max2949, 2919, 2849, 1735, 1458 cm⁻¹; HRMS

(ESI) [M + H]⁺calcd for C₁₆H₂₆NO₂264.1958, found 264.1955;

C₂₇H₅₀NO₅Si 496.3452, found 496.3451; [α]²¹+7.8 (c 1.0, CHCl₃).

D

Alcohol 78. To a solution of ketal 77 (70 mg, 0.141 mmol) in

anhydrous THF (5 mL) was added TBAF (0.71 mL, 0.71 mmoL)

dropwise at 0 °C. The resulting mixture was stirred at rt for 45 h. The

reaction mixture was concentrated in vacuo and puriﬁed directly by

silica gel column chromatography (PE/EtOAc = 10/1) to aﬀord

alcohol 78 (58 mg, 99%) as a white solid: mp 104−106 °C; ¹H NMR

(400 MHz, CDCl₃) δ 4.32 (d, J = 7.9 Hz, 1H), 3.87 (m, 2H), 3.81 (m,

1H), 3.76−3.66 (m, 1H), 3.63 (d, J = 13.3 Hz, 1H), 3.50 (d, J = 13.8

Hz, 1H), 2.84−2.61 (m, 2H), 2.15 (m, 2H), 2.13−1.93 (m, 5H), 1.84

(m, 3H), 1.52(m, 2H), 1.47 (s, 9H), 1.37 (s, 6H), 1.24 (m, 1H), 0.87

(d, J = 6.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 157.1, 108.1,

94.6, 89.0, 79.3, 68.2, 60.3, 49.5, 47.9, 47.7, 42.7, 39.2, 36.0, 32.4, 31.5,

29.5, 29.1, 28.5, 28.4, 28.0, 24.5, 23.3, 22.6, 22.2, 21.7, 21.1, 19.2, 14.2,

14.1; IR (neat) ν_max3468, 2923, 2968, 2866, 1671 cm⁻¹; HRMS (ESI)

[M + H]⁺calcd for C₂₄H₄₂NO₅424.3057, found 424.3049; [α]²¹_D+6.5

(c 1.0, CHCl₃).

[α]²¹−12.0 (c 0.1, EtOH).

Ketone 79. To a stirred solution of alcohol 78 (32.2 mg, 0.76

mmol) in anhydrous CH₂Cl₂(5 mL) at rt were added 4-

methylmorpholine N-oxide monohydrate (31.4 mg, 0.228 mmol), 4

Å MS (62.8 mg), and TPAP (1.3 mg, 0.0038 mmol) sequentially. The

resulting mixture was stirred at rt for 7 h. After the reaction was

complete, the reaction mixture was directly puriﬁed by silica gel

column chromatography (PE/EtOAc = 2/1) to aﬀord ketone 79 (30.5

D

(+)-Fawcettidine (2). To a solution of 8-deoxy-13-dehydroserrati-

nine (12) (5.4 mg, 0.0207 mmol) in anhydrous AcOH (4.0 mL) was

added active zinc powder (400 mg). The resulting mixture was heated

to 140 °C and stirred for 8 h at the same temperature. After cooling,

the excess Zn powder was removed by ﬁltration and washed several

times with methanol. The ﬁltrate was concentrated in vacuo, diluted

with water, and extracted with EtOAc, the combined organic extracts

were washed with satd aq NaHCO₃, dried over Na₂SO₄, and the

ﬁltrate was concentrated in vacuo to aﬀord (+)-fawcettidine (2) (4.8

mg, 95%) as a colorless oil. Spectroscopic data are in accordance with

literature reported values:^9b¹H NMR (400 MHz, CDCl₃) δ 5.71 (d, J

= 5.2 Hz, 1H), 3.14−3.10 (m, 1H), 3.07−2.97 (m, 2H), 2.73 (ddd, J =

16.6, 7.5, 1.4 Hz, 1H), 2.33−2.23 (m, 2H), 2.19−2.04 (m, 2H), 1.99−

1.82 (m, 4H), 1.79−1.55 (m, 5H), 1.39−1.32 (m, 2H), 1.05 (d, J = 7.1

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 218.9, 145.7, 127.3, 60.3,

56.2, 51.9, 46.1, 44.1, 39.0, 37.2, 34.1, 31.2, 29.1, 27.7, 23.7, 20.8; IR

(neat) ν_max2922, 2850, 1737, 1662, 1455 cm⁻¹; HRMS (ESI) [M +

1

mg, 95.3%) as a white solid: mp 71.4−73 °C; H NMR (400 MHz,

CDCl₃) δ 4.24 (t, J = 9.0 Hz, 1H), 3.41−3.29 (m, 2H), 3.08−2.97 (m,

2H), 2.97−2.85 (m, 1H), 2.73−2.62 (m, 1H), 2.53 (dd, J = 15.9, 8.2

Hz, 1H), 2.34−2.16 (m, 3H), 2.16−1.99 (m, 5H), 1.91 (dt, J = 15.6,

5.1 Hz, 1H), 1.79−1.65 (m, 1H), 1.54 (dt, J = 14.0, 5.5 Hz, 2H), 1.45

(s, 9H), 1.41 (s, 3H), 1.33 (d, J = 4.9 Hz, 3H), 0.98 (d, J = 5.5 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ 215.3, 214.8, 156.5, 155.9,

109.9, 109.7, 93.0, 92.8, 87.0, 86.9, 79.0, 78.9, 65.0, 64.8, 49.3, 48.1,

48.1, 47.5, 47.3, 47.0, 47.0, 34.3, 34.2, 32.9, 32.7, 31.8, 31.7, 31.0, 30.8,

29.5, 29.4, 28.5, 28.2, 25.3, 25.1, 24.8, 24.5, 23.5, 22.6, 22.4, 22.3; IR

(neat) ν_max2926, 2869, 1688, 1455, 1410, 1364, 1233, 1200, 1159,

1055, 918, 731 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₂₄H₃₉NO₅:

H]⁺calcd for C₁₆H₂₄NO 246.1852, found 246.1850; [α]^24.5+65 (c

D

0.24, EtOH).

422.2901, found 422.2899; [α]²¹+27.1(c 10.0, CHCl₃).

D

(+)-Fawcettimine (1). To a solution of 8-deoxy-13-dehydroserra-

tinine (12) (3.1 mg, 0.0119 mmol) and water (0.534 μL, 0.0296

mmol) in THF (degassed, 1.5 mL) at 0 °C was added SmI₂(0.1 M in

Diol 74. To a solution of ketone 79 (18.5 mg, 0.049 mmol) in

MeOH (2.5 mL) at rt, was added concd HCl (250 μL). The reaction

mixture was stirred at reﬂux for 12 h. The reaction mixture was

S

dx.doi.org/10.1021/jo3017555 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

concentrated in vacuo to remove the solvent, diluted with EtOAc, and

washed with satd aq NaHCO₃solution, and the aqueous layer was

extracted with EtOAc (10 mL × 3). The combined organic layers were

dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo to aﬀord

the crude product. The crude product was dissolved in 2 mL of

anhydrous TFA, and the resulting mixture was stirred at rt for 2 h. The

reaction mixture was concentrated in vacuo to aﬀord diol 74 (17.4 mg,

quant) as a colorless solid: mp 74−76 °C; ¹H NMR (400 MHz,

CDCl₃) δ 10.25 (s, 1H), 7.74 (s, 1H), 4.33 (d, J = 3.3 Hz, 1H), 3.92−

3.77 (m, 2H), 3.48 (d, J = 14.7 Hz, 2H), 3.33 (d, J = 9.0 Hz, 1H), 3.04

(d, J = 14.2 Hz, 1H), 2.80 (t, J = 13.8 Hz, 1H), 2.40−2.26 (m, 3H),

2.10 (d, J = 18.1 Hz, 4H), 1.97 (d, J = 12.4 Hz, 1H), 1.77 (t, J = 12.2

Hz, 2H), 1.67 (d, J = 10.6 Hz, 2H), 1.63−1.53 (m, 1H), 0.97 (d, J =

6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 110.3, 95.7, 94.5, 88.0,

53.1, 52.2, 50.5, 45.7, 41.7, 38.8, 35.2, 32.0, 29.7, 27.9, 27.0, 26.4, 25.0,

22.6, 21.5, 20.0; IR (neat) ν_max2918, 1780, 1654, 1247, 1152 cm⁻¹;

HRMS (ESI) [M + H]⁺calcd for C₁₆H₂₈NO₃282.2063, found

282.2062; [α]²¹+4.3 (c 10.0, CHCl₃).

was concentrated in vacuo and puriﬁed by silica gel column

chromatography (CH₂Cl₂/MeOH = 100/1 to 60/1) to aﬀord

(−)-lycojapodine A (6) (2.1 mg, 83%) as a white solid.

ASSOCIATED CONTENT

■

S

* Supporting Information

NMR spectra of all new compounds reported and X-ray data of

compound 43. This material is available free of charge via the

Internet at http://pubs.acs.org.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: leixiaoguang@nibs.ac.cn.

Author Contributions

^‡These authors contributed equally.

Procedures ^Dfor the Synthesis of Lycojapodine A. Method A.

To a solution of diol 74 (6.8 mg, 0.017 mmol) in anhydrous

triﬂuoroacetic acid (1 mL) were added IBX (57 mg, 0.204 mmol) and

4 Å MS (14 mg) at rt. The resulting mixture was stirred at 30 °C for 1

d and 40 °C for 1 d. The reaction mixture was concentrated in vacuo

and dissolved in EtOAc (5 mL). To this solution was added satd aq

NaHCO₃. The aqueous layer was extracted with EtOAc (5 mL × 3).

The combined organic layers were dried over Na₂SO₄, and the ﬁltrate

was concentrated in vacuo and puriﬁed by silica gel column

chromatography (CH₂Cl₂/MeOH = 100/1 to 60/1) to aﬀord

lycojapodine A (6) (2.6 mg, 54%) as a white solid. Spectroscopic

data are in accordance with literature reported values: mp 164−165

°C; ¹H NMR (400 MHz, CDCl₃) δ 3.84 (t, J = 14.1 Hz, 1H), 3.40 (m,

1H), 3.07 (dd, J = 15.4, 4.4 Hz, 1H), 2.94 (d, J = 14.4 Hz, 1H), 2.73

(m, 1H), 2.68 (m, 1H), 2.48 (m, 1H), 2.45 (m, 1H), 2.31 (m, 1H),

2.22 (m, 1H), 2.10 (m, 1H), 2.04 (m, 1H), 2.02 (m, 1H), 1.81 (m,

1H), 1.73 (m, 1H), 1.69 (m, 1H), 1.54 (m, 1H), 1.50 (m, 1H), 1.48

(m, 1H), 1.44 (m, 1H), 0.99 (d, J = 6.1 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 217.4, 170.7, 93.4, 55.0, 50.5, 49.2, 46.7, 41.4, 36.5,

36.0, 35.0, 31.5, 26.7, 24.4, 24.0, 21.2; IR (neat) ν_max2926, 2869, 1737,

1685, 1180, 1129 cm⁻¹; HRMS (ESI) [M + H]⁺calcd for C₁₆H₂₄NO₃

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank Prof. Richard Hsung, Dr. Mingji Dai, and Dr.

Zhengren Xu for helpful discussions, Ms. Mingyan Zhao and

Ms. Xiuli Han (NIBS) for NMR and HPLC−MS analysis, and

Dr. Jiang Zhou (Peking University) for HRMS analysis.

Financial support from the NSFC (21072150) and the Program

for New Century Excellent Talents in University (NCET-10-

0614) is gratefully acknowledged.

REFERENCES

■

(1) For recent reviews of the Lycopodium alkaloids, see: (a) Ayer, W.

A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A.; Brossi, A., Eds.;

Academic Press: New York, 1994; Vol. 45, p 233 and earlier reviews in

this series; (b) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752.

(c) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.;

Academic Press: New York; 2005; Vol. 61, p 1; (d) Hirasawa, Y.;

Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679. (e) Kitajima, M.;

Takayama, H. Top. Curr. Chem. 2012, 309, 1.

278.1750, found 278.1752; [α]²⁵−137.0 (c 0.2, CHCl₃).

D

Method B for (−)-Lycojapodine A. To a solution of (+)-alopecur-

idine (4) (4.5 mg, 0.0114 mmol) in anhydrous triﬂuoroacetic acid (1

mL) were added IBX (38 mg, 0.137 mmol) and 4 Å MS (9 mg) at rt.

The resulting mixture was stirred at 30 °C for 28 h. The reaction

mixture was concentrated in vacuo and dissolved in EtOAc (5 mL). To

this solution was added satd aq NaHCO₃. The aqueous layer was

extracted with EtOAc (5 mL × 3). The combined organic layers were

dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo and

puriﬁed by silica gel column chromatography (CH₂Cl₂/MeOH = 100/

1 to 60/1) to aﬀord (−)-lycojapodine A (6) (1.6 mg, 51%) as a white

solid.

Method C for (−)-Lycojapodine A. To a solution of (+)-alopecur-

idine (4) (4.0 mg, 0.011 mmol) in anhydrous triﬂuoroacetic acid (1

mL) were added Dess−Martin periodinane (26 mg, 0.060 mmol) and

4 Å MS (15 mg) at rt. The resulting mixture was stirred at rt for 4 h.

The reaction mixture was concentrated in vacuo, dissolved in EtOAc

(5 mL), and quenched with satd aq NaHCO₃at rt. The aqueous layer

was extracted with EtOAc (5 mL × 3). The combined organic layers

were dried over Na₂SO₄, and the ﬁltrate was concentrated in vacuo

and puriﬁed by silica gel column chromatography (CH₂Cl₂/MeOH =

100/1 to 60/1) to aﬀord (−)-lycojapodine A (6) (2.6 mg, 86%) as a

white solid.

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Method D (“One-Pot”) for (−)-Lycojapodine A. A solution of ketol

38 (3.4 mg, 0.009 mmol) in anhydrous triﬂuoroacetic acid (1 mL) was

stirred at rt for 18 h. To the above mixture were added Dess−Martin

periodinane (23 mg, 0.054 mmol) and 4 Å MS (7 mg) sequentially at

rt. The resulting mixture was stirred at rt for 4 h, concentrated in

vacuo, diluted with EtOAc (5 mL), and quenched with satd aq

NaHCO₃. The aqueous layer was extracted with EtOAc (5 mL × 3).

The combined organic layers were dried over Na₂SO₄, and the ﬁltrate

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1

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́

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V

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Collective synthesis of lycopodium alkaloids and tautomer locking strategy for the total synthesis of (-)-lycojapodine A

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