Stereoselective Syntheses of (+)-2- epi -Deoxoprosopinine, (-)-Deoxoprosophylline, (+)- cis -195A, and 2,5-Di- epi - Cis -195A from a Common Chiral Nonracemic Building Block

Article abstract of DOI:10.1021/acs.joc.5b00621

Approaches toward the syntheses of alkaloids belonging to the 2,6-disubstituted 3-hydroxypiperidine and cis-decahydroquinoline (cis-DHQ) classes of alkaloids are developed, starting from a common chiral nonracemic bicyclic lactam lactone (BLL). Two key δ-

Full text of DOI:10.1021/acs.joc.5b00621

Article
pubs.acs.org/joc
Stereoselective Syntheses of (+)-2-epi-Deoxoprosopinine,
(−)-Deoxoprosophylline, (+)-cis-195A, and 2,5-Di-epi-cis-195A from a
Common Chiral Nonracemic Building Block
Krishna Annadi and Andrew G. H. Wee*
Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan S4S 0A2, Canada
S
* Supporting Information
ABSTRACT: Approaches toward the syntheses of alkaloids
belonging to the 2,6-disubstituted 3-hydroxypiperidine and cis-
decahydroquinoline (cis-DHQ) classes of alkaloids are developed,
starting from a common chiral nonracemic bicyclic lactam
lactone (BLL). Two key δ-lactam intermediates, (5S,6S)-5-
hydroxy-6-hydroxymethyl- and (5S,6S)-5-hydroxy-6-methyl-
piperidin-2-ones, are prepared; the latter δ-lactam is obtained
via a direct decarbonylation of a bicyclic lactam lactol. The BLL is
also used to prepare (4aR,5R,8aS)- and (4aR,5S,8aS)-5-methyl-
octahydroquinolin-2-ones, which involved a 6-exo-trig free-radical
conjugate addition reaction. The stereoselectivity observed in the
free-radical cyclization step is found to be governed by allylic 1,2-strain arising from the interaction of the N-(p-methoxybenzyl)
group and the C6 substituent in the lactam ring of the free-radical intermediate. The effectiveness of the developed approaches is
demonstrated by the asymmetric syntheses of (+)-2-epi-deoxoprosopinine, (−)-deoxoprosophylline, (+)-cis-195A, and 2,5-di-epi-
cis-195A.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The piperidine ring is an important feature that is commonly
found in alkaloids isolated, typically in minute amounts, from
marine and terrestrial plants and animals.1 Many of these
alkaloids exhibit not only diverse structures that contain
interesting stereochemistries but also biological activities that
have potential applications in medicine.2 For these reasons,
piperidine-containing alkaloids are attractive targets for syn-
thesis, and much interest has been aimed at developing
approaches and methodologies for their stereoselective
construction.1e,3
The 2,6-disubstituted 3-hydroxypiperidine structure is com-
monly encountered in alkaloids of the Prosopis and Cassia
families (Figure 1; 1−6).1a These alkaloids are characterized by
a long-chain, structurally varied hydrophobic group at C6 and a
polar C2 methyl or hydroxymethyl substituted 3-hydroxypiper-
idine unit. Consequently, these alkaloids are sometimes referred
to as alkaloid lipids. In addition to their unique structures, these
We previously described a method for the preparation of
bicyclic lactam lactones (BLLs) in both enantiomeric forms4
and showed that the BLLs are versatile building blocks for
application in the synthesis of piperidine and indolizidine
alkaloids. Accordingly, we have reported the enantioselective
total syntheses of (+)-isofebrifugine, (−)-sedacryptine,
(+)-(8S,8aS)-octahydroindolizidin-8-ol, and (+)-(1S,8aS)-
octahydroindolizidin-1-ol.4,5 Now, we describe approaches
toward piperidine-containing alkaloids belonging to two
different structural classes, the 2,6-disubstituted 3-hydroxypi-
peridines and the 2,5-disubstituted decahydroquinolines,
starting from a common BLL building block. The realization
of these two approaches is shown by the total syntheses of
(−)-deoxoprosophylline and (+)-2-epi-deoxoprosopinine, and
(+)-cis-195A (pumiliotoxin C) and its 2,5-di-epi diastereomer.
These syntheses also demonstrate the synthetic flexibility
afforded through the use of BLLs in readily preparing chiral
nonracemic δ-lactam intermediates.
Figure 1. Representative examples of alkaloid lipids.
Received: March 18, 2015
© XXXX American Chemical Society
A
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alkaloids exhibit a range of interesting biological activities such
as antioxidant properties,6a anti-inflammatory activity,6b ace-
tylcholinesterase,6c and plant growth inhibitory6d activities.
Because of these attributes, the alkaloid lipids are often chosen
as synthetic targets for evaluating new approaches and
methodologies.7
yield. Subsequent ozonolysis of 9 followed by reductive workup
yielded the diol (5S,6S)-13 in 78% yield.
The chemoselective reduction of BLL-10 with Red-Al, using
slightly modified reaction conditions to our previously reported
procedure4 (see Experimental Section), furnished the lactol 14,
which was treated with 1 equiv of Wilkinson’s catalyst12 in N,N-
dimethylacetamide (DMA) at 120 °C. Efficient decarbonylation
of 14 was observed, which led directly to the formation of
(5S,6S)-15. The conversion of 14 to (5S,6S)-15 represents one
of the few examples of the direct decarbonylation reaction of
lactols,12,13 and the first to be used on a bicyclic lactam lactol.
With ready access to the key δ-lactam intermediates 13 and
15, we turned our attention to the syntheses of (−)-deox-
oprosophylline (16) and (+)-2-epi-deoxoprosopinine (17)
starting from δ-lactam 13 to demonstrate its synthetic utility.
Enantioselective syntheses of deoxoprosophylline14 and 2-
epi-deoxoprosopinine14k,15 were reported previously starting
from either chiral pool14a−k,15b or synthesis-derived14l−s,15a
starting materials. Our retrosythetic plan for (−)-16 and (+)-17
is shown in Scheme 2. (−)-Deoxoprosophylline (16) can be
A survey of the literature indicated that 6-substituted-5-
hydroxy δ-lactams, such as 13 and 15 (Scheme 1), are often
Scheme 1. Preparation of BLL-10 and δ-Lactam
Intermediates 13, 15
Scheme 2. Retrosynthetic Plan of (−)-16 and (+)-17
obtained via C3 epimerization of alkaloid 17. Alkaloid 17 is to
be formed from amino ketone 18, which is to be prepared from
the δ-lactam diol 13; the δ-lactam carbonyl unit will serve as the
chemical handle for installing the dodecyl side chain.
The synthesis of (+)-2-epi-deoxoprosopinine (17) began
with the preparation of the N-Boc δ-lactam 21 (Scheme 3)
from 13 in order to enhance the electrophilicity16 of the lactam
carbonyl unit for installation of the dodecyl side chain. First, we
investigated the removal of the N-PMB group under Birch17
conditions (Na, liq. NH3; NH4Cl), which turned out to be
unproductive. A 36% yield of the 1,4-cyclohexadiene derivative
2518 was isolated, and the remainder of the material balance
was an intractable mixture of polar components. Thus, diol 13
was converted to the dipivalate 19 in 91% yield, and the N-
PMB group in 19 was removed by CAN oxidation (3:1 v/v
MeCN−H2O) under optimized conditions,19 to give a 1:1
mixture of the δ-lactams 20a,b which, without separation, was
treated with Hunig’s base in MeOH at 55 °C. This yielded 20a
in an overall yield of 75%.
The lithio anion derived from 20a was acylated (Boc2O) to
give the N-Boc derivative 21, which was reacted with freshly
prepared n-C12H25MgBr in THF to furnish the acyclic ketone
18 as the only product in 72% yield. No products that could
arise from nucleophilic acyl substitution at either one or both of
the pivalate groups were detected.
used as advanced intermediates in the synthesis of the alkaloid
lipids.8 However, some of the routes reported for their
preparation are not flexible8b and suffer from regio-8c and
stereoselectvity8d issues. In this context, we have investigated a
route to readily prepare the δ-lactam intermediates 13 and 15
from the BLL-10 (Scheme 1).
The bicyclic lactam lactone 10 required for the synthesis of
δ-lactam intermediates 13 and 15 was prepared using a route
that is similar to the one we had reported4 for the N-benzyl
analog. Thus, the known4 δ-lactam alcohol 7a was first
converted to the N,O-di(p-methoxybenzyl) derivative 7b in
86% yield. Selective removal of the O-PMB group in 7b was
effected by CAN oxidation in a 9:1 v/v MeCN−H2O mixture
to give 8 (79%). Treatment of 8 with the House−Blankley9,4b
reagent gave the diazoacetate 9, which upon exposure to
Rh2(4S-MPPIM)4 underwent efficient intramolecular C−H
insertion to give BLL-10.
Reduction10 of the lactone moiety in 10 to the diol was
accomplished using NaBH4 in refluxing THF containing
MeOH. The diol was subjected to regioselective o-nitro-
phenylselenation followed by oxidation−o-nitrophenyl-
selenoxide elimination11 to provide the alkenol 12 in 76%
Reductive cyclization of 18 to form the trisubstituted
piperidine 22 was achieved via concomitant acid mediated N-
Boc removal and condensation of the released primary amino
function with the ketone carbonyl to give the corresponding
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carbamate 24 gave (−)-deoxoprosophylline (16) in 92% yield.
Its [α]D24 −14.2° (c 0.45, CHCl3) {lit.14h [α]D24 −14.2° (c 0.58,
Scheme 3. Synthesis of (−)-16 and (+)-17
CHCl3); lit.14e [α]D −15.2° (c 0.55, CHCl3); lit.14a [α]D
22
24
1
−14.0° (c 0.24, CHCl3)} and H and 13C NMR data are in
excellent agreement with reported data.14
Having demonstrated the utility of BLL-10 in the synthesis
of 2,6-disubstituted 3-hydroxypiperidine, we turned our
attention toward the use of BLL-10 in the synthesis of the
decahydroquinoline (DHQ) alkaloids. The DHQ ring system is
a central feature found in many alkaloids that have been
isolated from frogs (Dendrobatidae and Mantellidae), ants
(Myrmicinae), toads (Bufonidae), marine tunicates, and
flatworms.1d,22 Structurally, 2,5-disubstituted DHQ alkaloids
are the most commonly encountered ones wherein the
decahydroquinoline ring can have either a cis- or trans- ring
junction (Figure 2). Biological activity studies on several DHQ
Figure 2. Representative examples of DHQ alkaloids.
alkaloids revealed that they act as noncompetitive blockers of
nicotinic acetylcholine receptors.23 These alkaloids are often
only obtained in minute quantities from animal sources (some
of which may be endangered) and, consequently, are available
in insufficient amounts for more comprehensive biological
studies. These limitations have spurred the development of
many methods for their synthesis.24−32
Many ingenious methods have been devised with a focus on
the synthesis of cis-DHQ alkaloids on account of the fact that
cis-195A (pumiliotoxin C), a cis-DHQ alkaloid, was the first of
the DHQ family of alkaloids to be isolated and structurally
characterized.24g,33 The reported approaches for constructing
cis-DHQ alkaloids were based on Diels−Alder24 and 1,3-dipolar
cycloadditions,25 intramolecular cyclizations (enamine-cycliza-
tion,26c,d,g,h aza-annulation,26b,f,i,j reductive amino-cyclizatio-
n26a), ring closing and ring rearrangement metathesis,27 tandem
reactions,28 metal catalysis,29 free-radical cyclizations,30 and N-
heterocyclic intermediates.31 However, some of these methods
are limited by low stereoselectivity,26a lack of flexibility,26c and
low yield30a and, therefore, new methods are constantly being
sought.
The use of appropriately substituted cis-octahydroquinolin-2-
ones30a,32 as intermediates for the synthesis of cis-DHQ
alkaloids has received less attention, but offers a practical
alternative method. In this context, we reasoned that BLL-7
would be especially suited for the asymmetric construction of
the cis-octahydroquinolin-2-one (32) (Scheme 4). The
presence of the phenylsulfonyl group in 32 allows for
functionalization or chain extension31d,34 at the α-methylene
position. The lactam carbonyl and phenylsulfonyl units,
together, would provide increased options for further synthetic
transformations thereby increasing the synthetic utility of 32.
cyclic iminium triflate salt. Hydrogenation (1 atm, balloon) of
the crude salt over 10% Pd/C gave only 22 in 92% yield. H
1
NMR analysis of the crude reaction mixture indicated that the
hydrogenation of the cyclic iminium salt had proceeded with
excellent cis-diastereoselectivity; the C6 epimer was not
detected. The C2/C6 relative stereochemistry and the absolute
configuration of C6 were confirmed by the conversion of 22 to
(+)-17, whose [α]D +3.0° (c 0.84, MeOH) {lit.14k [α]D
24
28
+3.3° (c 0.6, MeOH) lit.15a [α]D +3.0° (c 0.6, MeOH)} and
1H and 13C NMR data are in accord with those reported in the
literature.14k,15
20
To prepare (−)-deoxoprosophylline (16), the configuration
at C3 in (+)-2-epi-deoxoprosopinine (17) was inverted, and
this was achieved by first converting 17 to the cyclic carbamate
23 by treatment with triphosgene. Epimerization of hydroxyl
groups in bicyclic carbamates similar to 23 via an oxidation−
reduction protocol has precedence in the literature.14r,20 Thus,
heating a solution of 23 and IBX in ethyl acetate at reflux for 7
h cleanly gave the corresponding ketone,14r which was not
purified but was immediately reduced20b with NaBH4 in
methanol to afford a separable mixture of the desired epimer 24
(82%) and starting 23 (6.5%). We found that the oxidation of
23 with the Dess-Martin periodinane21 (1.6 mol equiv, CH2Cl2,
0 °C to rt) was “not clean” as judged by TLC analysis; the
overall yield of the desired alcohol 24 (39%) after NaBH4
reduction was low, and 12% of starting alcohol 23 was
regenerated. Subsequent base hydrolysis (KOH, EtOH) of the
C
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Scheme 4. Retrosynthetic Plan for cis-Octahydroquinolin-2-
one (32)
Scheme 6. Synthesis of cis-Octahydroquinolin-2-one from
Lactol 14
cis-Octahydroquinolin-2-one (32) is to be formed from a 6-
exo-trig, free-radical cyclization of the precursor 33. The free-
radical precursor 33 is to be made by (phenylsulfonyl)-
vinylation of the terminal double bond in 34, and the C5
hydroxyl group will serve as a latent carbon-centered free
radical. Terminal alkene 34 is to be obtained via olefination of
lactol 14.
The crucial step in this plan is the formation of 32 by the
free-radical mediated cyclization of 33. In 2008, Spino and co-
workers had reported an intramolecular free-radical cyclization
route to the cis-decahydroquinoline ring of cis-195A (Scheme
5).30a Although highly stereoselective, they found the
Scheme 5. Spino’s Free-Radical Cyclization Route to cis-
DHQ
was recovered. Thus, we investigated the hydroboration36 of 35
with pinacolatoborane (HBPin) catalyzed by [Ir(cod)Cl]2
36a
(1.5 mol %), and in the presence of 3 mol % of dppe. The
reaction was found to proceed with high regioselectivity to give
the pinacolboronic ester 36a but only in 62% yield. After
further investigations of reaction conditions to improve the
yield of 36a we found that hydroboration of 35 catalyzed by 2
mol % of Wilkinson’s catalyst36b afforded the desired 36a in
high yield (92%).
cyclization to be inefficient and was plagued by competing
reduction, dimerization, and aromatization of the free-radical
intermediate. Nonetheless, their work represents the only
report, to date, of a free-radical cyclization approach to
construct the cis-decahydroquinoline ring system of cis-
195A.30b In our plan, the free-radical center is potentially
nucleophilic in character and we reasoned that the use of an
electrophilic double bond should facilitate and improve the
efficiency of cyclization. Further, we were also interested in
determining the diastereoselectivity of the cyclization especially
with regard to the formation of the two new stereocenters at
C4a and C5 in the presence of the pre-existing, stereochemi-
cally defined C8a.
The synthesis of the octahydroquinolin-2-one ring com-
menced with the Wittig olefination of lactol 14 (vide supra,
Scheme 1) using methylidene(triphenyl)phosphorane to give
alkene alcohol 34 in 96% yield (Scheme 6), which was then
converted to the corresponding MOM-ether 35 in quantitative
yield. With alkene 35 in hand, the preparation of the α,β-
unsaturated phenylsulfone 37 was undertaken and we chose to
investigate the use of a B-alkyl Suzuki−Miyaura coupling
reaction for this purpose.35
Informed by the studies37 of Suzuki and co-workers, who
found that organoboronates are ineffective in B-alkyl coupling
reactions, pinacolboronic ester 36a was, therefore, first
converted to the potassium trifluoroborate salt 36b in 77%
yield by treatment with 4.5 M aqueous KHF2.38 Subsequent
Suzuki−Miyaura coupling39 of 36b with (E)-(2-bromovinyl)
phenyl sulfone40 using 10 mol % of Pd(dppf)Cl2 in the
presence of 3 equiv of Cs2CO3 gave the desired product 3741 in
80% yield. Hydrolytic removal of the MOM protecting group in
37 followed by reaction of the corresponding alcohol with
N,N′-thiocarbonyldiimidazole efficiently provided the free-
radical precursor 33 (Scheme 6). Thioimidazolide 33 was
then treated with AIBN and Bu3SnH (80 °C, 3 h, degassed
toluene, slow addition) to effect cyclization42 leading to two
major diastereomers, 38 and 39, and two minor diastereomers,
40 and 41, in 75% combined yield and in a ratio of
12.6:5.8:1.6:1.0. Compounds 39 and 41 were closely moving
(Rf [39] = 0.22, Rf [41] = 0.26; 5 × Et2O), but were separable
by careful chromatography. Compounds 38 and 40 were
obtained as an 8:1 mixture, but because 38 was the major
product we were able to obtain an analytically pure sample of
38 after repeated careful chromatographic separation of the
mixture.
Attempts at the hydroboration of alkene 35 with 9-BBN-H,
under a variety of conditions (e.g., different solvents and
reaction temperatures), were in vain, and only starting alkene
D
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All of the four possible octahydroquinolin-2-one diaster-
eomers were formed in the free-radical cyclization of
thioimidazolide 33. The stereochemistries of the ring junction
(C8a/C4a) in diastereomers 38, 39, 40, and 41 were assigned
energy than via TS-46b indicating that formation of 38 is more
favored. The minor diastereomers, 40 and 41, are formed via
TS-46e and TS-46f, respectively.
As mentioned above, cis-195A is the first of the DHQ family
of alkaloids to be isolated and characterized. As a result, cis-
195A is often a target of choice for synthetic chemists to
develop and test new methods for the stereoselective
construction of DHQs. Many syntheses of cis-195A and/or
its stereoisomers have been reported in both racemi-
c 2 4 a − f , 2 5 , 2 6 a − d , 2 8 , 3 2 a − g a n d e n a n t i o m e r i c a l -
ly24g−i,26d−f,29,30a,31a−c,32h,i pure forms. With the cis-octahydro-
quinolin-2-ones 38 and 39 in hand, the enantioselective
syntheses of (+)-cis-195A (26)24c,30a and 5-epi-cis-195A
(47)26b,43 were examined, and the retrosynthetic plan is
summarized in Scheme 7.
1
on the basis of H NMR spectral data analysis, and using the
stereochemically well-defined C8a as a reference point. In
particular, the H8a signal appeared as a ddd (δ 3.14 in 38, δ
3.16 in 39, δ 3.24 in 40, and δ 2.74 in 41) and was found to be
diagnostic. The stereochemistry at C5 of 38, 39, 40, and 41 was
assigned by converting them (desulfonylation and N-PMB
deprotection; see Supporting Information) to the known
compounds 42,26b,32c,43 43,24c,d,29a,32c,e 44,24c,29a,32c and 45,24d
1
respectively (Figure 3); the H and 13C NMR spectral data of
each of the four octahydroquinolin-2-ones are in good
agreement to those reported in the literature.
We first investigated the synthesis of (+)-cis-195A (26,
Scheme 8). Initially, an approach similar to the one used in the
synthesis of (+)-2-epi-deoxoprosopinine (17, Scheme 3, 21 →
18) was investigated in order to install the n-propyl substituent.
Therefore, the octahydroquinolin-2-one 43 was converted to
the N-Boc derivative and then subjected to reaction with n-
PrMgBr. Surprisingly, preferential addition of n-PrMgBr
occurred mainly at the N-Boc carbonyl moiety resulting in
the regeneration of starting 43. As a result, the route originally
reported by Oppolzer was used (Scheme 8). Thus, the
octahydroquinolin-2-one 43 was converted to the correspond-
ing methyl imidate24c with freshly washed Me3OBF4. Due to
the instability of the methyl imidate toward hydrolysis, it was
not isolated but used crude in its reaction with n-PrMgBr to
form the imine 48. Hydrogenation of the crude imine 48 over
10% PtO2 (1 atm H2, balloon) in the presence of 2 M aqueous
HCl in ethanol was found to be stereospecific and yielded
(+)-cis-195A (26) in 45% yield over three steps; some
Figure 3. N-Deprotected−desulfonylated octahydroquinolin-2-ones
42−45.
To gain an understanding of the observed distribution of
products 38, 39, 40, and 41 in the free-radical cyclization step,
gas-phase DFT computational studies were performed to
model the transition states involved in the reaction pathway.
We used the N-benzyl instead of the N-(p-methoxybenzyl) in
46 for our calculations. The six transition state structures, TS-
46a−f, were obtained, and the Gibbs free energies of activation
(ΔG‡) were derived from the difference in the free energies of
each of the six transition state structures and the most stable
free-radical precursor (local minima) which had resulted from
the “plus-and-minus-displacement”44 minimization calculations
performed on the six transition state structures (Figure 4). The
computed transition state structures revealed the δ-lactam unit
has adopted a half-chair conformation in 46, and the cyclization
of the C5-centered radical onto the phenylsulfonylvinyl moiety
has occurred via six-membered, chairlike transition states.45 For
TS-46a,b, the C6 α,β-unsaturated phenylsulfonyl side chain is
located in the pseudoaxial position, which alleviates A1,2-strain
interaction between the N-PMB group and the C6 side chain.
However, TS-46b is destabilized by a nonbonding interaction
between the vinylic α-hydrogen and the pseudoaxial δ-
hydrogen (side chain labeling) in the incipient six-membered
ring. With TS-46c−f, the C6 α,β-unsaturated phenylsulfonyl
side chain occupies the pseudoequatorial position and,
consequently, these transition states are destabilized by an
inherent A1,2-strain between the N-PMB group and the C6
substituent. Moreover, in each of the TS-46c,f, a destabilizing,
nonbonding interaction identical to the one found in TS-46b is
present. Transition state 46c is also further destabilized due to
the orientation of the phenylsulfonylvinyl unit on the concave
side of the forming bicycle. The calculated ΔG‡ for cyclization
proceeding via each of the six transition states supports our
experimental results regarding product distribution. The major
diastereomers, 38 and 39, are formed via TS-46a and TS-46b,
respectively. Reaction via TS-46d may be a very minor
contributor toward the formation of 39, and the involvement
of TS-46c is expected to be negligible. Further, the ΔG‡ for
free-radical cyclization via TS-46a is 1.3 kcal/mol lower in
21
unreacted 43 (13%) was also recovered. The [α]D −2.1° (c
0.33, MeOH) [lit.29d [α]D −2.2° (c 1.34, MeOH)] and H
and 13C NMR spectral data of 26 are in excellent agreement
with those reported in literature.29d We also prepared the
hydrochloride salt of (+)-cis-195A by treating a solution of 26
20
1
in methanol with concentrated HCl. The H and 13C NMR
1
22
spectral data of 26·HCl and its [α]D +12.9° (c 0.34, MeOH)
[lit.29d [α]D +12.9° (c 0.36, MeOH)] are also in accord with
20
the reported data.29d
For the synthesis of 5-epi-cis-195A (47) from octahydroqui-
nolin-2-one 42 the same steps as those described for the
synthesis of cis-195A were used. Thus, 42 was converted via the
methyl imidate (Scheme 9) to imine 49 followed by
1
hydrogenation of 49 over 10% PtO2. However, the H and
13C NMR spectral data of the product were found to be
incongruent with the data reported by Stille and Paulvan-
nan26b,43 for their synthesis of 5-epi-cis-195A, which was
prepared from ( )-42. In their studies, reduction of 49 with
DIBAL-H was reported to occur from the sterically less
hindered Si-face of the imine π-bond to give 5-epi-cis-195A as
the only product. Puzzled by this outcome, we revisited the
reduction of the imine 49, but employing DIBAL-H as the
reductant under the reported26b,43 conditions. In our hands, the
DIBAL-H reduction step resulted in a mixture of products,
which after careful chromatographic purification afforded a
compound with 1H and 13C NMR spectral data that were again
not in agreement with the reported data for 47. Reduction of
imine 49 with Na(OAc)3BH46 in the presence of AcOH in
THF also gave the same product as that obtained from the
DIBAL-H reduction. These results suggested that the reduction
E
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Figure 4. Transition state structures for the free-radical cyclization of 46.
Scheme 7. Retrosynthetic Approach to (+)-cis-195A and 5-
epi-cis-195A
Scheme 9. Synthesis of 2,5-Di-epi-cis-195A from (−)-42
Scheme 8. Synthesis of (+)-cis-195A from (+)-43
of 49 in our case must have occurred from the sterically more
hindered Re-face of the imine π-bond. This product was
1
assigned as 2,5-di-epi-cis-195A (50) based on the H NMR
spectral data analysis.
F
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In particular, the H8a in 50 showed a characteristic ddd signal
hydroxy-6-methylpiperidin-2-one (15). The (5S,6S)-13 was
successfully converted to (+)-2-epi-deoxoprosopinine (17) and
(−)-deoxoprosophylline (16). The overall yields of (+)-17 and
(−)-16 starting from the BLL-10 are 16% (10-steps) and 10%
(13-steps), respectively. For the synthesis of cis-DHQs, BLL-10
was transformed to the cis-octahydroquinolin-2-ones 38 and 39
using an intramolecular free-radical conjugate addition reaction
as the key step. A rationalization of the observed stereo-
selectivity and product distribution in the free-radical
cyclization is proposed and is supported by the Gibbs free
energies of the computed transition state structures leading to
cis- and trans-octahydroquinolin-2-ones. Compounds 38 and 39
were converted to octahydroquinolin-2-ones 42 and 43, which
are advanced intermediates used in the syntheses of (+)-cis-
195A (26) and 2,5-di-epi-cis-195A (50). Compounds (+)-26
and 50 were obtained in overall yields of 2.2% (14-steps) and
4% (14-steps), respectively, starting from the BLL-10.
The overall yields realized for (+)-2-epi-deoxoprosopinine
(17) and (−)-deoxoprosophylline (16) are comparable to the
yields reported in the literature. On the other hand, the overall
yields of (+)-cis-195A (26) and 2,5-di-epi-cis-195A (50) were
slightly lower and this is attributed to the modest
diastereoselectivity realized during the formation of the C5
stereocenter bearing the (phenylsulfonyl)methyl group in the
octahydroquinolin-2-ones 38 and 39. Nonetheless, the
synthetic approaches developed here have the advantage of
flexibility. The functionalized lactam intermediates 13, 15, 38,
and 39 prepared from BLL-10 will find applications in the
syntheses of other members of these two classes of alkaloids.
Further, either of the enantiomers of BLL-10 is readily
accessible,4 which would allow the syntheses of the 2,6-
disubstituted-3-hydroxypiperidine and cis-DHQ alkaloids in
either of their enantiomeric forms.
3
at δ 2.88 with Jvic values of 12.1, 3.9, and 3.9 Hz. The large
3
3
3J8a‑8ax and two small J8a‑8eq and J8a‑4a couplings are indicative
of the expected coupling behavior of H8a in the preferred
conformer 50a. If the reduced product were 5-epi-cis-195A
(47), as shown24h,47 in its preferred conformer 47a (Scheme
9), H8a is not expected to show a large vicinal coupling
constant. Further support for the assigned structure of 50 was
deduced from NOESY1D experiments, which showed signal
enhancement of H2 when H8ax was irradiated and vise versa.48
1
In addition to these studies, a comparison of the H and 13C
NMR data of hydrochloride salt of 50 with those reported by
Husson and co-workers32d for ( )-50·HCl also showed very
good agreement. Hsung et al. also had reported26f the synthesis
of (−)-4a,8a-di-epi-pumiliotoxin C, which is equivalent to 2,5-
1
di-epi-cis-195A. The H and 13C NMR spectral data of (−)-50·
HCl reported by Hsung et al. were not in accord with our and
Husson’s spectral data. Interestingly, 2,5-di-epi-cis-195A (50)
21
showed [α]D21 0.0 (c 0.69, MeOH) and 50·HCl showed [α]D
+0.4 (c 0.73, MeOH).
The observed stereoselectivity in the reduction of imines 48
and 49 leading to (+)-cis-195A (26) and 2,5-di-epi-cis-195A
(50), respectively, is interesting and can be understood by
considering the reaction conformers of 48a and 49a (Scheme
10) in which the C5-methyl substituent occupies the equatorial
Scheme 10. Proposed Stereochemical Course of Reduction
of Imines 48 and 49
EXPERIMENTAL SECTION
■
General. Only the diagnostic absorptions in the infrared spectrum
1
are reported. H (300 or 500 MHz) and 13C{1H} (75 or 125 MHz)
NMR spectra were recorded in CDCl3 unless stated otherwise. The
residual CHCl3 singlet at δH = 7.26 and the CDCl3 triplet centered at
δC = 77.0 were used as internal references for 1H and 13C NMR
spectra, respectively. 11B{1H} (96.3 MHz) and 19F{1H} (282.4 MHz)
NMR spectra were recorded in either CDCl3 or CD3CN and were
calibrated with reference to δB = 0.0 and δF = −153.0 using BF3·Et2O
as the external standard. High-resolution mass spectra in electron
impact (EI) and chemical ionization (CI) modes were recorded on a
double focusing sector field mass spectrometer and in the electrospray
ionization (ESI) mode using a quadrupole time-of-flight mass
spectrometer. Optical rotations were recorded at the NaD line.
Reaction progress was monitored by thin-layer chromatography on
silica gel 60F254 precoated (0.25 mm) on aluminum backed sheets. Air
and moisture sensitive reactions were conducted under a static
pressure of argon. All organic extracts were dried over anhydrous
Na2SO4. Chromatographic purification implies flash column chroma-
tography, which was performed on silica gel 60 Å (230−400 mesh).
Dichloromethane, DMF, DMA, toluene, chloroform, methanol, and
acetonitrile were dried by distillation from calcium hydride. THF and
diethyl ether were dried by distillation from sodium using sodium
benzophenone ketyl as the indicator. Ethanol was dried by distillation
form Mg(OEt)2. The commercial trimethyloxonium tetrafluoroborate
obtained was washed successively with CH2Cl2 and Et2O prior to use.
Computational Methods. Geometry optimizations and vibra-
tional frequency DFT calculations were conducted using the
Gaussian09 (revisions B.01/D.01) program suite49 using the
unrestricted B3LYP/6-31G(d) level of theory.50 All optimizations
used tight convergence criteria and an ultrafine grid. Transition state
structures were located using opt = (ts, noeigentest, calcFC)
position. For 48a, the delivery of hydrogen or hydride (“H”)
occurs from the less hindered Si-face of the imine π-bond via a
chairlike transition state leading to the formation of (+)-26. On
the other hand, the delivery of “H” to reaction conformer 49a
preferentially occurs from the Re-face of the imine π-bond to
form 50 as our results indicate. The approach of “H” from the
Si-face of 49a is favored on steric grounds, but would lead to an
energetically less stable twist boat transition state whereas the
“H” approach from the Re-face, although sterically hindered,
proceeds via a lower energy chairlike transition state24e to give
50.
CONCLUSIONS
■
The utility of the BLL-10 as a chiral building block is
demonstrated by the approaches that have been developed for
the syntheses of alkaloids belonging to two structural classes,
the 2,6-disubstituted-3-hydroxypiperidines and the cis-
decahydroquinolines (cis-DHQs). Our studies on the synthesis
of 2,6-disubstituted-3-hyroxypiperidines involved the efficient
conversion of BLL-10 to the advanced intermediates (5S,6S)-5-
hydroxy-6-hydroxymethylpiperidin-2-one (13) and (5S,6S)-5-
G
DOI: 10.1021/acs.joc.5b00621
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
algorithms.51 Optimized transition state structures were submitted to
vibrational frequency analysis to confirm that they had only one
imaginary frequency. Further, each of the transition states was
confirmed to be on the correct reaction coordinate by “plus-and-
minus-displacement”43 minimization runs: the transition state was
displaced ∼0.05 Å along the imaginary frequency normal mode in both
directions, and the two displaced structures (starting free-radical and
product free-radical intermediates) were optimized to the nearest
minima structures.
(S)-1-(p-Methoxybenzyl)-5-(p-methoxybenzyloxy)piperidin-
2-one (7b). Sodium hydride (1.95 g, 46.8 mmol, 60% dispersed in
mineral oil) was washed with hexane and dried. It was suspended in
DMF (34 mL) and then treated with the known4 lactam alcohol 7a
(2.0 g, 17.4 mmol) in DMF (16 mL) via cannula at 0 °C under Ar. To
this brown colored reaction mixture was added sodium iodide (260
mg, 10 mol %), and the mixture was stirred at rt for 30 min. Then p-
methoxybenzyl chloride (6.70 mL, 48.6 mmol) was added dropwise to
the brown mixture, and the resulting light yellow suspension was
stirred overnight at rt. DMF was removed by Kugelrohr distillation,
and the oily residue was diluted with Et2O and washed with brine. The
organic layer was dried over sodium sulfate, filtered, and concentrated.
Purification by chromatography (1:4 petroleum ether/EtOAc then
EtOAc) afforded 7b (5.31 g, 86%) as a white solid: mp 37−40 °C;
[α]D24 +23.2° (c 1.35, CHCl3); IR (CH2Cl2) νmax 1676, 1644 cm−1; 1H
NMR (CDCl3, 300 MHz) δ 7.12−7.20 (m, 4 H), 6.78−6.87 (m, 4 H),
4.54 (d, J = 14.5 Hz, 1 H), 4.46 (d, J = 14.5 Hz, 1 H), 4.38 (d, J = 11.4
Hz, 1 H), 4.31 (d, J = 11.4 Hz, 1 H), 3.69−3.81 (m, 7 H), 3.18−3.32
(m, 2 H), 2.58−2.73 (m, 1 H), 2.39 (ddd, J = 17.5, 6.2, 6.2 Hz, 1 H),
1.85−2.05 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 169.2, 159.2,
158.9, 130.0, 129.3, 128.9, 113.9, 113.8, 70.2, 69.9, 55.1(9), 55.1(7),
50.4, 49.2, 28.2, 25.8; HRMS (EI-double focusing sector field) m/z:
[M]+ Calcd for C21H25NO4 355.1784; Found 355.1776.
2115, 1700, 1686, 1654, 1637 cm−1; H NMR (CDCl3, 300 MHz) δ
7.08−7.17 (m, 2 H), 6.76−6.87 (m, 2 H), 5.11−5.2 (m, 1 H), 4.69 (s,
1 H), 4.58 (d, J = 14.4 Hz, 1 H), 4.38 (d, J = 14.4 Hz, 1 H), 3.75 (s, 3
H), 3.39 (dd, J = 13.1, 4.1 Hz, 1 H), 3.24 (ddd, J = 13.1, 3.8, 1.5 Hz, 1
H), 2.39−2.64 (m, 2 H), 1.90−2.11 (m, 2 H); 13C NMR (CDCl3, 75
MHz) δ 168.5, 159.0, 129.3, 128.6, 114.0, 66.6, 55.2, 50.4, 49.2, 46.4,
46.3, 27.7, 25.6; HRMS (EI-double focusing sector field) m/z: [M]+
Calcd for C15H17N3O4 303.1219; Found 303.1214.
1
(3aS,7aS)-4-(p-Methoxybenzyl)tetrahydrofuro[3,2-b]-
pyridine-2,5(3H,6H)-dione (10). Rh2(4S-MPPIM)4 (4S-MPPIM =
methyl 1-(3-phenylpropanoyl)-2-oxoimidazolidine-4(S)-carboxylate)
(30 mg, 2 mol %) was dried under vacuum at 80 °C for 1 h and
then cooled to rt. CH2Cl2 (5 mL) was added, and the mixture was
heated (oil bath) to reflux under argon. A solution of the diazoacetate
9 (310 mg, 1.02 mmol) in CH2Cl2 (10 mL) was added dropwise, via
syringe pump, over a period of 3 h. After addition was complete, the
mixture was refluxed for an additional 1 h and then cooled to rt. The
solvent was removed under reduced pressure to give crude product 10
as a light purple oil. The crude product was purified by
chromatography (1:1 petroleum ether/EtOAc) to afford BLL-10
24
(260 mg, 92%): [α]D +52.1° (c 1.66, CHCl3); IR (CH2Cl2) νmax
1784, 1654, 1643 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.11−7.18 (m,
2 H), 6.82−6.89 (m, 2 H), 5.17 (d, J = 15.9 Hz, 1 H), 4.81 (ddd, J =
7.5, 3.7, 3.7 Hz, 1 H), 4.08 (ddd, J = 7.5, 7.5, 3.7 Hz, 1 H), 3.90 (d, J =
15.9 Hz, 1 H), 3.79 (s, 3 H), 2.72 (dd, J = 17.8, 7.5 Hz, 1 H), 2.40−
2.63 (m, 3 H), 2.21−2.35 (m, 1 H), 1.88−2.05 (m, 1 H); 13C NMR
(CDCl3, 75 MHz) δ 173.9, 169.0, 159.3, 129.5, 128.0, 114.3, 75.6,
55.2, 54.4, 47.0, 35.6, 26.5, 24.0; HRMS (EI-double focusing sector
field) m/z: [M]+ Calcd for C15H17NO4 275.1158; Found 275.1164.
(5S,6S)-5-Hydroxy-6-(2-hydroxyethyl)-1-(p-methoxybenzyl)-
piperidin-2-one (11). BLL-10 (57 mg, 0.21 mmol) was dissolved in
THF (1 mL) and NaBH4 (20 mg, 0.52 mmol) was added at rt, under
argon. The resulting white suspension was allowed to reflux (65 °C, oil
bath), and MeOH (0.17 mL, 4.2 mmol) was added dropwise over a
period of 1 h. The mixture was stirred for an additional 1 h at the same
temperature. The reaction mixture was cooled to 0 °C, and 1 M
aqueous HCl was added until the gas evolution was subsided. All the
volatiles were evaporated under reduced pressure, and the crude
residue obtained was diluted with CH2Cl2. The organic layer was
washed once with 10% aqueous NaOH. The aqueous layer was
saturated with solid NaCl and back-extracted into CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated. Purification by chromatography (10:1 EtOAc/MeOH)
afforded the diol 11 (55 mg, 95%) as a colorless oil: [α]D21 −83.1° (c
(S)-5-Hydroxy-1-(p-methoxybenzyl)piperidin-2-one (8). To
7b (510 mg, 1.44 mmol) in a mixture of MeCN and distilled water
(9:1 v/v, 20 mL) at 0 °C was added CAN (1.58 g, 2.88 mmol) in one
portion, and the resultant yellow-orange solution was stirred at 0 °C
for 1.5 h and then at rt for 1 h. The reaction mixture was recooled to 0
°C, a few drops of distilled water were added, and the reaction mixture
was diluted with EtOAc. The mixture was washed successively with
saturated aqueous NaHCO3(2 × 5 mL) and distilled water (1 × 5
mL). The organic layer was separated, and the aqueous layer was
saturated with solid NaCl and re-extracted with EtOAc. The combined
organic layers were dried over Na2SO4, filtered, and concentrated. The
crude product was purified by chromatography (1:4 petroleum ether/
EtOAc, then 10:1 EtOAc/MeOH) to give the N-PMB alcohol 8 (270
mg, 79%) as white crystals. Starting 7b (25 mg, 5%) was also
1
2.10, CHCl3); IR (CH2Cl2) νmax 3517−3096, 1654, 1636 cm−1; H
NMR (CDCl3, 300 MHz) δ 7.06−7.16 (m, 2 H), 6.75−6.86 (m, 2 H),
5.20 (d, J = 15 Hz, 1 H), 3.90 (ddd, J = 8.7, 4.3, 4.3 Hz, 1 H), 3.71−
3.82 (m, 6 H), 3.49−3.6 (m, 1 H), 3.40 (ddd, J = 8.7, 4.3, 4.3 Hz, 1
H), 2.34−2.63 (m, 2 H), 1.72−2.09 (m, 4 H); 13C NMR (CDCl3, 75
MHz) δ 169.8, 159.0, 129.2, 129.0, 114.0, 66.7, 60.2, 58.6, 55.2, 47.5,
31.9, 28.8, 25.2; HRMS (EI-double focusing sector field) m/z: [M]+
Calcd for C15H21NO4 279.1471; Found 279.1472.
24
recovered: mp 97−100 °C; [α]D −12.4° (c 2.04, CHCl3); IR
1
(CH2Cl2) νmax 3518−3178, 1654, 1636 cm−1; H NMR (CDCl3, 300
MHz) δ 7.08−7.17 (m, 2 H), 6.76−6.85 (m, 2 H), 4.51 (d, J = 14.5
Hz, 1 H), 4.36 (d, J = 14.5 Hz, 1 H), 3.97−4.0 (m, 1 H), 3.74 (s, 3 H),
3.23−3.35 (m, 2 H), 3.09 (dd, J = 12.4, 5.1 Hz, 1 H), 2.59 (ddd, J =
18.0, 7.1, 7.1 Hz, 1 H), 2.34 (ddd, J = 18.0, 6.2, 6.2 Hz, 1 H), 1.76−
1.96 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 169.4, 158.9, 129.3,
128.7, 113.9, 63.6, 55.2, 53.4, 49.5, 28.6, 28.1; HRMS (EI-double
focusing sector field) m/z: [M]+ Calcd for C13H17NO3 235.1208;
Found 235.1207.
(5S,6S)-5-Hydroxy-1-(p-methoxybenzyl)-6-vinylpiperidin-2-
one (12). To the diol 11 (56.2 mg, 0.20 mmol) in THF (4 mL) under
argon was added 2-nitrophenylseleno cyanate (56 mg, 0.24 mmol),
and the mixture was cooled to 0 °C. To this brown colored reaction
mixture was then added tributylphosphine (60 μL, 0.24 mmol)
dropwise, and the solution was allowed to rt. After stirring the reaction
mixture for overnight, THF was removed under reduced pressure. The
crude product was purified by chromatography (10:1 EtOAc/MeOH)
to afford the selenide (74 mg, 80%) as a yellow oil. To a solution of
the crude selenide in THF (4 mL) at 0 °C, under argon, was added
30% aqueous H2O2 (0.2 mL, 2.0 mmol) dropwise, and the mixture was
stirred at rt for 5 h. The reaction mixture was cooled to 0 °C, saturated
aqueous NaHSO3 solution was added to quench excess H2O2, and
THF was evaporated. Dichloromethane was added, and the organic
layer was successively washed with saturated aqueous NaHCO3 (2 × 5
mL) and brine (1 × 5 mL) and dried over Na2SO4. The crude mixture
was purified by chromatography (1:4 petroleum ether/EtOAc then
EtOAc) to give 12 (40 mg, 76% over two steps) as a colorless oil:
(S)-5-(α-Diazoacetoxy)-1-(p-methoxybenzyl)piperidin-2-one
(9). The secondary alcohol 8 (0.75 g, 3.19 mmol) and α-(p-
toluenesulfonylhydrazone)acetyl chloride (1.25 g, 4.78 mmol) were
dissolved in CH2Cl2 (25 mL) under argon, and the solution was
cooled to 0 °C. N,N-Dimethylaniline (0.73 mL, 5.73 mmol) was added
dropwise, and the mixture was stirred for 40 min at rt. Then, the
mixture was cooled to 0 °C, N,N-diisopropylethylamine (2.8 mL, 15.9
mmol) was added and stirred for 30 min. The reaction mixture was
diluted with CH2Cl2, washed with saturated aqueous NaHCO3(3 × 20
mL), water (2 × 20 mL), aqueous citric acid (3 × 20 mL), and finally
water (20 mL), and dried over Na2SO4. The filtered solution was
evaporated, and the crude residue was purified by chromatography
(2:1 petroleum ether/EtOAc) to afford the diazoacetate 9 (0.88 g,
90%) as a yellow oil: [α]D23 +24.2° (c 2.07, CHCl3); IR (CH2Cl2) νmax
H
DOI: 10.1021/acs.joc.5b00621
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The Journal of Organic Chemistry
Article
21
[α]D −182.9° (c 0.68, CHCl3); IR (neat) νmax 3573−3108, 2953,
diastereomer) 170.9, 158.9, 129.4, 128.7, 113.9, 97.7, 75.3, 57.2, 55.2,
46.6, 39.0, 27.1, 24.4; HRMS (EI-double focusing sector field) m/z:
[M]+ Calcd for C15H19NO4 277.1314; Found 277.1313.
2837, 1643 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.09−7.17 (m, 2 H),
6.79−6.87 (m, 2 H), 5.86 (ddd, J = 17.2, 10.3, 6.7 Hz, 1 H), 5.45 (d, J
= 10.3 Hz, 1 H), 5.39 (d, J = 14.6 Hz, 1 H), 5.25 (d, J = 17.2 Hz, 1 H),
3.83−3.97 (m, 2 H), 3.78 (s, 3 H), 3.59 (d, J = 14.6 Hz, 1 H), 2.60
(ddd, J = 18.2, 5.2, 5.2 Hz, 1 H), 2.47 (ddd, J = 18.2, 8.8, 8.8 Hz, 1 H),
2.18 (br s, 1 H), 1.80−1.92 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ
169.2, 159.0, 133.2, 129.5, 129.2, 120.6, 114.0, 67.4, 61.9, 55.2, 47.1,
29.3, 25.9. HRMS data for compound 12 were obtained after
converting it to the corresponding pivalate derivative; HRMS (EI-
double focusing sector field) m/z: [M]+ Calcd for C20H27NO4
345.1940; Found 345.1937.
(5S,6S)-5-Hydroxy-6-(hydroxymethyl)-1-(p-methoxybenzyl)-
piperidin-2-one (13). An ozone/oxygen stream was bubbled into a
solution of olefin 12 (33 mg, 0.13 mmol) in EtOH (4 mL) at −40 °C.
After about 2 min, TLC analysis showed the absence of starting
material. Argon was bubbled into the reaction mixture to remove
excess ozone, and then the mixture was warmed to 0 °C. NaBH4 (20
mg, 0.50 mmol) was added, and the mixture was allowed to warm
slowly to rt with stirring. After 2 h at rt, the reaction mixture was
recooled to 0 °C and glacial AcOH was added dropwise to destroy
excess NaBH4, followed by evaporation of EtOH. The mixture was
diluted with CH2Cl2, and distilled water (1 mL) was added. Aqueous
NaOH (5%) was added, and the two layers were separated. The
aqueous layer was saturated with solid NaCl and back-extracted into
CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated. Purification by chromatography (10:1
EtOAc/MeOH) afforded 13 (26 mg, 78%) as a thick colorless oil:
[α]D22 −58.8° (c 0.84, CHCl3); IR (neat) νmax 3578−3065, 2947, 1615
cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.06−7.15 (m, 2 H), 6.76−6.85
(m, 2 H), 5.22 (d, J = 14.9 Hz, 1 H), 4.04−4.14 (m, 1 H), 3.87−3.98
(m, 2 H), 3.74−3.82 (m, 1 H), 3.74 (s, 3 H), 3.32−3.40 (m, 1 H), 2.61
(ddd, J = 18.0, 6.5, 6.5 Hz, 1 H), 2.39 (ddd, J = 18.0, 6.3, 6.3 Hz, 1 H),
1.94−2.10 (m, 1 H), 1.77−1.93 (m, 1 H); 13C NMR (CDCl3, 75
MHz) δ 170.8, 158.9, 129.0, 128.9, 114.0, 67.6, 60.4, 58.6, 55.2, 46.9,
28.3, 26.0. HRMS data for compound 13 were obtained after
converting it to the corresponding dipivalate derivative 19.
(3aS,7aS)-2-Hydroxy-4-(p-methoxybenzyl)hexahydrofuro-
[3,2-b]pyridin-5(6H)-one (14). A stock solution of 0.15 M Red-Al in
toluene was made by diluting Red-Al (3.0 mL, 65% w/w in toluene)
with toluene (60 mL). To a stock solution of Red-Al (20.4 mL, 3.17
mmol) at −78 °C was added, under Ar, THF (1 mL), followed by a
solution of BLL-10 (1.23 g, 4.47 mmol) in THF (33 mL) via syringe
pump (rate of addition ∼4 mL/min; the flask that held the solution of
10 and the syringe were rinsed with another 8.0 mL of THF). The
reaction mixture was stirred at −78 °C for 1 h. The reaction mixture
was quenched with a few drops of MeOH, followed by saturated
aqueous NH4Cl (4 mL), and allowed to warm to rt. All the volatiles
were evaporated under reduced pressure; the remaining residue was
diluted with CH2Cl2 (40 mL) and filtered through a pad of Celite. The
two layers were separated, and the organic layer was washed once with
brine. The aqueous layer was saturated with solid NaCl and back-
extracted into CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated. Careful chromatography purifica-
tion (packed with 1:4 petroleum ether/EtOAc, then EtOAc, followed
by 10:1 EtOAc/MeOH) afforded the lactol 14 (997 mg, 80.5%; 93.5%
based on recovered starting material) as an off-white solid; the diol 11
(31 mg, 2.5%) and starting material 10 (172 mg, 14%) were also
recovered. The ratio of the diastereomeric lactols was ∼2.8:1, based on
integration of the benzylic methylene protons at 5.04 and 5.32 ppm:
(5S,6S)-5-Hydroxy-1-(p-methoxybenzyl)-6-methylpiperidin-
2-one (15). To the lactol 14 (22 mg, 0.08 mmol) was added
Rh(PPh3)3Cl (83 mg, 0.09 mmol) and the flask was evacuated and
flushed with nitrogen three times. DMA (1 mL) was added, and the
resulting brown color solution was stirred at 120 °C (oil bath) for 12
h. After cooling the reaction mixture to rt, DMA was removed by
Kugelrohr distillation. Purifaction by chromatography (1:4 petroleum
22
ether/EtOAc) gave 15 (14.6 mg, 74%) as a colorless oil: [α]D
−112.7° (c 1.56, CHCl3); IR (neat) νmax 3563−3092, 2955, 1613
cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.10−7.17 (m, 2 H), 6.79−6.86
(m, 2 H), 5.22 (d, J = 14.8 Hz, 1 H), 3.86−3.95 (m, 1 H), 3.83 (d, J =
14.8 Hz, 1 H), 3.77 (s, 3 H), 3.35−3.46 (m, 1 H), 2.57 (ddd, J = 18.3,
7.4, 4.0 Hz, 1 H), 2.42−2.53 (br m, 1 H), 2.44 (ddd, J = 18.3, 9.0, 8.0
Hz, 1 H), 1.77−2.05 (m, 2 H), 1.19 (d, J = 6.6 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 169.1, 158.9, 129.4, 129.2, 114.0, 67.4, 55.2, 54.5,
47.0, 29.0, 24.8, 13.1; HRMS (EI-double focusing sector field) m/z:
[M]+ Calcd for C14H19NO3 249.1365; Found 249.1358.
(5S,6S)-1-(p-Methoxybenzyl)-5-pivaloyloxy-6-(pivaloyl-
oxymethyl)piperidin-2-one (19). To the diol 13 (26 mg, 0.13
mmol) in CH2Cl2 (3 mL), under argon at rt, were added DMAP (15
mg, 0.13 mmol), N,N-diisopropylethylamine (0.11 mL, 0.65 mmol),
and pivaloyl chloride (40 μL, 0.32 mmol) successively, and the
solution was stirred overnight. The reaction mixture was cooled to 0
°C, distilled water (1 mL) was added, and the mixture was stirred for
20 min. The mixture was washed with saturated aqueous NaHCO3,
dried over Na2SO4, filtered, and concentrated. The crude residue was
purified by chromatography (1:1 petroleum ether/EtOAc) to afford
23
dipivalate 19 (39 mg, 91%) as a colorless oil: [α]D −25.5° (c 2.57,
CHCl3); IR (CH2Cl2) νmax 1734, 1654, 1648 cm−1; 1H NMR (CDCl3,
300 MHz) δ 7.12−7.19 (m, 2 H), 6.81−6.87 (m, 2 H), 5.18 (d, J =
15.0 Hz, 1 H), 5.05 (ddd, J = 9.2, 4.6, 4.6 Hz, 1 H), 4.30 (dd, J = 11.7,
5.3 Hz, 1 H), 4.19 (dd, J = 11.7, 3.9 Hz, 1 H), 4.06 (d, J = 15.0 Hz, 1
H), 3.78 (s, 3 H), 3.64−3.72 (m, 1 H), 2.5−2.72 (m, 2 H), 1.9−2.18
(m, 2 H), 1.18 (s, 9 H), 1.17 (s, 9 H); 13C NMR (CDCl3, 75 MHz) δ
177.9, 177.0, 169.3, 159.0, 128.9, 128.7, 114.2, 67.3, 60.9, 55.7, 55.2,
47.4, 38.8, 38.7, 28.7, 27.1, 27.0, 23.6; HRMS (EI-double focusing
sector field) m/z: [M]+ Calcd for C24H35NO6 433.2464; Found
433.2463.
(5S,6S)-5-Pivaloyloxy-6-(pivaloyloxymethyl)piperidin-2-one
(20a). To the N-PMB lactam 19 (34.5 mg, 0.08 mmol) in acetonitrile
(0.95 mL) at 0 °C was added aqueous cerium(IV) ammonium nitrate
(0.32 mL, 1 M) dropwise (final MeCN/H2O = 3:1 v/v). The resulting
orange solution was stirred at the same temperature for 30 min,
followed by 1 h at rt. The reaction mixture was diluted with EtOAc,
and saturated NaHCO3 was added. The resulting suspension was
stirred for 30 min at rt and then was vacuum filtered through a pad of
Celite. After the two layers were separated, the organic layer was
washed once with brine. The combined aqueous layers were saturated
with solid NaCl and back-extracted into EtOAc. The two organic
layers were combined and dried over Na2SO4, filtered, and
concentrated. Purification by chromatography (1:1 petroleum ether/
EtOAc then 25:1 EtOAc/MeOH) afforded 20a and 20b (20 mg) in a
ratio of 1:1, and in a combined 76% yield.
The mixture of 20a and 20b (20 mg) was treated with N,N-
diisopropylethylamine (0.06 mL, 0.32 mmol) in MeOH (2 mL) at 55
°C (oil bath) for 1 h. After evaporating the solvent under reduced
pressure, the crude product was purified by chromatography (1:4
petroleum ether/EtOAc) to afford 20a (25 mg, 75%) as a colorless oil.
Characterization data for compounds 20a and 20b were previously
reported.19
23
mp 144−146 °C; [α]D +27.4° (c 1.53, CHCl3); IR (CH2Cl2) νmax
3505−3104, 1653 cm−1; 1H NMR (CDCl3, 300 MHz) δ (major
diastereomer) 7.10−7.17 (m, 2 H), 6.77−6.87 (m, 2 H), 5.51−5.58
(m, 1 H), 5.04 (d, J = 14.6 Hz, 1 H) 4.44−4.51 (m, 1 H), 3.98−4.21
(m, 2 H), 3.95 (d, J = 14.6 Hz, 1 H), 3.76 (s, 3 H), 2.27−2.49 (m, 2
H), 1.94−2.25 (m, 2 H), 1.68−1.95 (m, 2 H); δ (discernible signals
for minor diastereomer) 5.48 (m, 1 H), 5.32 (d, J = 14.8 Hz, 1 H),
4.24−4.33 (m, 1 H), 3.72−3.82 (m, 4 H), 2.65−2.79 (m, 1 H); 13C
NMR (CDCl3, 75 MHz) δ (major diastereomer) 171.0, 159.0, 129.5,
128.9, 114.0, 97.0, 72.5, 57.2, 55.2, 47.5, 41.7, 27.5, 24.8; δ (minor
(5S,6S)-1-(tert-Butyloxycarbonyl)-5-pivaloyloxy-6-(pivaloyl-
oxymethyl)piperidin-2-one (21). To the lactam 20a (27.2 mg, 0.08
mmol) in THF (4 mL) at −78 °C under argon were added a few
crystals of 2,2′-bipyridine indicator, followed by dropwise addition of
n-BuLi (0.05 mL, 0.09 mmol, 1.9 M in hexanes) until a bright red
solution resulted. The mixture was stirred for 10 min, and then a
solution of Boc2O (29 mg, 0.13 mmol) in THF (2 mL) was added via
I
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The Journal of Organic Chemistry
Article
cannula. The mixture was stirred at −78 °C for 30 min and then at
−20 °C for 30 min. The reaction mixture was recooled to −78 °C,
quenched with saturated aqueous NH4Cl, and warmed slowly to rt.
THF was evaporated, the crude residue was diluted with EtOAc,
washed once with brine, and dried over Na2SO4. EtOAc was removed
under reduced pressure, and the crude product was purified by
chromatography (9:1 petroleum ether/EtOAc, then 8:1 petroleum
The organic layer was dried over Na2SO4 and filtered. Removal of the
solvent under reduced pressure gave 17 (26.5 mg, 89.5%) as an off-
1
white solid whose H and 13C NMR spectra showed it to be pure.
Recrystallization from aqueous MeOH afforded 20.5 mg (77%) of the
pure (+)-2-epi-deoxoprosopinine: mp 55−57 °C (lit.14k mp 57−58 °C;
lit15a mp 56−57 °C); [α]D +3.0° (c 0.84, MeOH), {lit.14k [α]D
24
28
+3.3° (c 0.6, MeOH); lit.15a [α]D +3.0° (c 0.6, MeOH)}; IR
(CH2Cl2) νmax 3548−3188, 3056 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 3.59−3.90 (m, 3 H), 2.12−2.92 (m, 5 H), 1.77−1.99 (m, 1 H),
1.09−1.70 (m, 25 H), 0.74−1.00 (m, 3 H); 13C NMR (CDCl3, 75
MHz) δ 66.2, 64.7, 61.1, 56.8, 37.0, 31.9, 31.87, 29.8, 29.66, 29.65,
29.63, 29.61, 29.3, 26.5, 25.8, 22.7, 14.1; HRMS (CI-double focusing
sector field) m/z: [M + H]+ Calcd for C18H38NO2 300.2903; Found
300.2902.
20
23
ether/EtOAc) to afford 21 (24.7 mg, 69%) as a colorless oil: [α]D
+25.2° (c 2.32, CHCl3); IR (CH2Cl2) νmax 1773, 1732 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 5.16−5.27 (m, 1 H), 4.39−4.52 (m, 2 H), 4.15−
4.26 (m, 1 H), 2.57−2.68 (m, 2 H), 1.95−2.19 (m, 2 H), 1.50 (s, 9 H),
1.20 (s, 9 H), 1.17 (s, 9 H); 13C NMR (CDCl3, 75 MHz) δ 177.9,
177.1, 169.9, 152.1, 83.8, 67.0, 61.3, 54.8, 38.9, 38.8, 31.9, 27.9, 27.05,
27.02, 23.9; HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd for
C21H35NO7Na 436.2305; Found 436.2300.
(5R,8S,8aS)-5-Dodecyl-tetrahydro-8-hydroxy-1H-oxazolo-
[3,4-a]pyridin-3(5H)-one (23). To the 2-epi-deoxoprosopinine (17)
(32 mg, 0.10 mmol) in a 1:1:1 ratio of 1,4-dioxane (1.4 mL), distilled
water (1.4 mL), and saturated aqueous NaHCO3 (1.4 mL) at 0 °C
triphosgene (36 mg, 0.11 mmol) in toluene (2.8 mL) was added
dropwise via syringe. The resulting biphasic solution was vigorously
stirred at rt overnight. The reaction mixture was then cooled to 0 °C,
and saturated aqueous NaHCO3 (1 mL) was added. This mixture was
gradually warmed to rt and repeatedly extracted with CH2Cl2. The
aqueous layer was saturated with solid NaCl and back-extracted into
CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated. The crude product was purified by
chromatography (1:2 petroleum ether/EtOAc) to give the carbamate
(2S,3S)-2-(tert-Butyloxycarbonylamino)-6-oxo-1,3-di-O-
pivaloyloctadecane-1,3-diol (18). To a solution of the N-Boc
lactam 21 (148 mg, 0.35 mmol) in THF (7 mL) at −78 °C under
argon was added freshly prepared n-C12H25MgBr in THF (1.2 mL,
0.46 mmol, 0.39 M) dropwise, and the reaction mixture was stirred at
the same temperature for 2.5 h. The reaction was quenched with 0.5 M
aqueous HCl at −78 °C, and the solution was concentrated under
reduced pressure. The resulting mixture was diluted with CH2Cl2 (5
mL) and washed with saturated aqueous NaHCO3 (1 × 5 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated. The
crude product was purified by chromatography (10:1 petroleum ether/
EtOAc then 6:1 petroleum ether/EtOAc) to give starting 21 (10 mg,
7%) and the desired N-Boc ketone 18 (150 mg, 72%; 77% based on
23
23 (29 mg, 83%) as a white crystalline solid: mp 108−110 °C; [α]D
24
1
recovered 21) as a colorless oil: [α]D −8.1° (c 2.34, CHCl3); IR
+9.2° (c 0.5, CHCl3); IR (CH2Cl2) νmax 3520−3240, 1724 cm−1; H
(CH2Cl2) νmax 3434, 1736, 1718 cm−1; 1H NMR (CDCl3, 300 MHz) δ
4.98 (ddd, J = 7.9, 6.3, 3.9 Hz, 1 H), 4.50−4.63 (br d, 1 H), 3.84−4.16
(m, 3 H), 2.26−2.56 (m, 4 H), 1.74−1.97 (m, 2 H), 1.37−1.59 (m, 12
H), 1.14−1.32 (m, 35 H), 0.86 (t, J = 6.7 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 209.4, 178.1, 177.7, 155.4, 79.9, 71.2, 63.0, 51.8,
42.9, 39.0, 38.8, 38.0, 31.9, 29.6, 29.59, 29.58, 29.4, 29.3, 29.2, 28.3,
27.3, 27.2, 27.1, 25.1, 23.8, 22.7, 14.1; HRMS (CI-double focusing
sector field) m/z: [M + H]+ Calcd for C33H62NO7 584.4526; Found
584.4531.
NMR (CDCl3, 300 MHz) δ 4.16−4.31 (m, 2 H), 3.74−3.84 (m, 1 H),
3.63 (ddd, J = 8.1, 6.3, 1.8 Hz, 1 H), 3.00−3.14 (m, 1 H), 2.35−2.51
(m, 1 H), 2.13−2.28 (br m, 1 H), 1.95−2.07 (m, 1 H), 1.50−1.82 (m,
4 H), 1.12−1.44 (m, 20 H), 0.86 (t, J = 6.4 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 156.5, 64.9, 62.9, 60.9, 57.5, 31.9, 31.3, 31.0,
29.68, 29.67, 29.64, 29.3, 26.7, 24.8, 22.7, 14.1; HRMS (EI-double
focusing sector field) m/z: [M]+ Calcd for C19H35NO3 325.2617;
Found 325.2610.
(5R,8R,8aS)-5-Dodecyl-tetrahydro-8-hydroxy-1H-oxazolo-
[3,4-a]pyridin-3(5H)-one (24). To the carbamate 23 (18.5 mg, 0.05
mmol) in EtOAc (1.5 mL) at rt was added 2-iodoxybenzoic acid (40
mg, 0.14 mmol) in one portion. The resulting white suspension was
refluxed at 80 °C for 7 h, by which time the reaction was complete as
indicated by TLC analysis. The reaction mixture was allowed to cool
to rt, and it was filtered through a pad of Celite. Ethyl acetate was
evaporated under reduced pressure to give the crude product as an off-
white solid (20 mg), which was immediately reduced in the next step.
The ketone (20 mg) was dissolved in MeOH (1 mL) and cooled
(−10 to −5 °C) in an ice−salt bath. NaBH4 (3.3 mg, 0.08 mmol based
on starting 23) was added in one portion, and the mixture was stirred
at 0 °C for 1 h. Distilled water (0.5 mL) was added, and the reaction
mixture was slowly allowed to warm to rt. Methanol was evaporated,
and the resulting residue was diluted with CH2Cl2. The organic layer
was washed once with brine, and the aqueous layer was saturated with
solid NaCl and extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4, filtered, and concentrated. The crude product
was purified by chromatography (4:1 petroleum ether/EtOAc then 3:1
petroleum ether/EtOAc) to give the desired alcohol 24 (15 mg, 81%)
as an off-white solid, and starting alcohol 23 (1.2 mg, 6.5%) was also
(2S,3S,6R)-6-Dodecyl-3-pivaloyloxy-2-(pivaloyloxymethyl)-
piperidine (22). To the N-Boc ketone 18 (26 mg, 0.04 mmol) in
CH2Cl2 (0.5 mL) at 0 °C under argon was added trifluoroacetic acid
(0.17 mL, 2.21 mmol) dropwise, and the reaction mixture was stirred
at rt for 3 h. CH2Cl2 and TFA were evaporated under reduced
pressure, and the crude residue was dried over P2O5 under high
vacuum. The crude iminium salt was dissolved in MeOH (3 mL) and
subjected to the catalytic hydrogenation (1 atm H2, balloon) over 10%
palladium on carbon (18 mg). After stirring overnight, the mixture was
filtered through a pad of Celite, and MeOH was evaporated under
reduced pressure. The reaction mixture was diluted with CH2Cl2 (5
mL), washed with saturated aqueous NaHCO3 (2 × 5 mL), and dried
over Na2SO4. The filtered solution was evaporated under reduced
pressure, and the crude product was purified by chromatography (9:1
petroleum ether/EtOAc) to afford 22 (19.3 mg, 92.5%) as a colorless
24
oil: [α]D +21.7° (c 1.08, CHCl3); IR (neat) νmax 2926, 2853, 1734
cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.82−4.90 (m, 1 H), 3.95 (dd, J
= 10.7, 7.5 Hz, 1 H), 4.01 (dd, J = 10.7, 7.5 Hz, 1 H), 3.08 (ddd, J =
6.3, 6.3, 1.4 Hz, 1 H), 2.47−2.61 (m, 1 H), 1.94−2.07 (m, 1 H), 1.11−
1.66 (m, 44 H), 0.86 (t, J = 6.5 Hz, 3 H); 13C NMR (CDCl3, 75 MHz)
δ 178.1, 177.6, 66.5, 64.2, 57.1, 56.1, 39.1, 38.7, 37.2, 31.9, 29.7, 29.66,
29.65, 29.62, 29.61, 29.3, 28.7, 27.5, 27.2, 27.1, 25.9, 22.7, 14.1; HRMS
(CI-double focusing sector field) m/z: [M + H]+ Calcd for
C28H54NO4 468.4053; Found 468.4063.
23
regenerated. Compound 24: mp 68−70 °C; [α]D −24.6° (c 1.42,
CHCl3); IR (CH2Cl2) νmax 3560−3200, 1735 cm−1; 1H NMR (CDCl3,
300 MHz) δ 4.30 (dd, J = 8.8, 7.3 Hz, 1 H), 4.18 (dd, J = 8.8, 3.8 Hz, 1
H), 3.43−3.58 (m, 1 H), 3.29 (ddd, J = 9.5, 7.3, 3.8 Hz, 1 H), 2.95−
3.08 (m, 1 H), 2.19−2.44 (m, 2 H), 2.07−2.18 (m, 1 H), 1.60−1.83
(m, 2 H), 1.17−1.54 (m, 22 H), 0.86 (t, J = 6.5 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 156.1, 69.5, 65.1, 62.7, 57.3, 33.5, 31.9, 30.9, 29.9,
29.67, 29.65, 29.63, 29.62, 29.60, 29.56, 29.3, 27.0, 22.7, 14.1; HRMS
(EI-double focusing sector field) m/z: [M]+ Calcd for C19H35NO3
325.2617; Found 325.2610.
(+)-2-epi-Deoxoprosopinine (17). Sodium (18 mg, 0.8 mmol)
was washed with hexanes, weighed into a flask to which MeOH (2
mL) was added at 0 °C under argon. The dipivalate 22 (46.2 mg, 0.1
mmol) in MeOH (1 mL) was added to the above solution via cannula
at the same temperature, and the resulting mixture was stirred at rt
overnight. The reaction was quenched with water at 0 °C, and MeOH
was evaporated under reduced pressure. The aqueous layer was
saturated with solid NaCl and was repeatedly extracted into CH2Cl2.
(−)-Deoxoprosophylline (16). To a solution of carbamate 24 (13
mg, 0.04 mmol) in 95% EtOH (1 mL) was added aqueous KOH (0.5
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The Journal of Organic Chemistry
Article
mL, 8 M), and the reaction mixture was heated to 95 °C (oil bath) for
18 h. The reaction mixture was cooled to rt, and EtOH was evaporated
under reduced pressure. The crude residue was diluted with CH2Cl2
(6 mL), and the organic layer was washed once with distilled water.
Dichloromethane was removed under reduced pressure, the residue
was dissolved in EtOH (2 mL), and a few drops of concentrated HCl
were added. Ethanol was evaporated under reduced pressure, the
resulting white solid was taken into CH2Cl2 (5 mL), and aqueous
NaOH (5 mL, 2.5 M solution) was added. The organic layer was
separated, and the aqueous layer was repeatedly extracted into CH2Cl2
(4 × 5 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated. Purification by chromatography (6:1
CH2Cl2/MeOH) afforded (−)-deoxoprosophylline (11 mg, 92%) as
THF (24 mL), and it was cooled to 0 °C under argon. KOt-Bu (639
mg, 5.41 mmol) was added, in one portion, to the above suspension to
give a bright yellow suspension. After 45 min at 0 °C a solution of the
lactol 14 (600 mg, 2.16 mmol) in THF (16 mL) was added, via
cannula, and the reaction mixture was stirred for 1 h. Saturated
aqueous NH4Cl (5 mL) was added, and the THF was evaporated
under reduced pressure. The aqueous layer was extracted with CH2Cl2
(3 × 20 mL), dried over Na2SO4, filtered, and concentrated. The crude
product was purified by chromatography (1:1 petroleum ether/
EtOAc) to afford 34 (572 mg, 96%) as a white crystalline solid: mp
23
83−85 °C; [α]D −78.9° (c 2.01, CHCl3); IR (CH2Cl2) νmax 3543−
3110, 1653 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.04−7.12 (m, 2 H),
6.75−6.82 (m, 2 H), 5.74−5.90 (m, 1 H), 5.28 (d, J = 14.8 Hz, 1 H),
5.01−5.17 (m, 2 H), 3.82−3.92 (m, 1 H), 3.78 (d, J = 14.8 Hz, 1 H),
3.74 (s, 3 H), 3.30−3.38 (m, 1 H), 3.18 (br d, 1 H), 2.49−2.64 (m, 2
H), 2.25−2.46 (m, 2 H), 1.75−2.01 (m, 2 H); 13C NMR (CDCl3, 75
MHz) δ 169.7, 158.8, 135.6, 129.1, 117.6, 113.9, 66.9, 58.8, 55.1, 47.7,
33.5, 28.6, 25.3; HRMS (EI-double focusing sector field) m/z: [M]+
Calcd for C16H21NO3 275.1521(4); Found 275.1521(3).
1
a white solid, whose H and 13C NMR spectra showed it to be pure.
Recrystallization (Et2O/hexanes) gave (−)-deoxoprosophylline (16)
as a white crystalline solid: mp 89−90 °C (lit.14h mp 88−89 °C, lit.14e
mp 85−86 °C, lit.14a mp 90.5 °C); [α]D −14.2° (c 0.45, CHCl3)
24
{lit.14h [α]D −14.2° (c 0.58, CHCl3); lit.14a [α]D −14.0° (c 0.24,
CHCl3); lit.14e [α]D22 −15.2° (c 0.55, CHCl3)}; IR (KBr) νmax 3567−
3042, 2921, 2851 cm−1; 1H NMR (CDCl3, 300 MHz) δ 3.82 (dd, J =
10.7, 4.9 Hz, 1 H), 3.69 (dd, J = 10.7, 5.4 Hz, 1 H), 3.39−3.50 (ddd, J
= 9.1, 9.1, 4.6 Hz, 1 H), 2.09−2.64 (m, 5 H), 1.98−2.09 (m, 1 H),
1.68−1.79 (m, 1 H), 1.01−1.50 (m, 24 H), 0.87 (t, J = 6.6 Hz, 3 H);
13C NMR (CDCl3, 75 MHz) δ 70.8, 64.8, 63.2, 56.0, 36.6, 34.0, 31.9,
24
24
(5S,6S)-6-Allyl-1-(p-methoxybenzyl)-5-(methoxymethoxy)-
piperidin-2-one (35). To the alcohol 34 (1.18 g, 4.29 mmol) in
DCE (30 mL) under Ar at rt were added tetrabutylammonium iodide
(24 mg, 1.5 mol %), N,N-diisopropylethylamine (4.50 mL, 25.71
mmol), and MOM-Cl (0.98 mL, 12.86 mmol) successively, and the
resulting solution was allowed to reflux, overnight. The reaction
mixture was cooled to 0 °C and diluted with CH2Cl2 (10 mL), and
saturated aqueous Na2CO3 (10 mL) was added. After the mixture
stirred for 15 min at the same temperature, the biphasic solution was
transferred into a separatory funnel. The two layers were separated,
and the organic layer was washed once with brine. The aqueous layer
was saturated with solid NaCl and back-extracted into CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated. Purification by chormatography (2:1 petroleum ether/
EtOAc) afforded 35 (1.37 g, 100%) as a colorless oil: [α]D21 −74.8° (c
31.2, 29.8, 29.67, 29.66, 29.64, 29.60, 29.58, 29.3, 26.2, 22.7, 14.1;
HRMS (CI-double focusing sector field) m/z: [M + H]+ Calcd for
C18H38NO2 300.2903; Found 300.2893.
(5S,6S)-1-[(4-Methoxycyclohexa-1,4-dienyl)methyl]-5-
pivaloyloxy-6-(pivaloyloxymethyl)piperidin-2-one (25·dipiva-
late). Na metal was cut into small pieces and washed three times
with hexanes. To the liquid NH3 (5 mL) at −78 °C under argon was
added Na metal (58 mg, 2.5 mmol) portionwise (∼5 min), and the
resulting blue colored solution was stirred at −78 °C for 30 min. To
the above solution was then added the diol 13 (33.6 mg, 0.13 mmol)
in THF (2 mL) via cannula, and the reaction mixture was stirred at the
same temperature for 6 h. Solid NH4Cl (60 mg) was added to the
above solution at −78 °C, and the reaction temperature was allowed to
gradually warm to rt, by which time all of the ammonia had
evaporated. The crude residue was extracted with CH2Cl2 (3 × 5 mL),
followed by 4:1 v/v CH2Cl2/MeOH (3 × 5 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated.
Purification by chromatography (10:1 EtOAc/MeOH) afforded 25
(12 mg, 36%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.48−
5.56 (m, 1 H), 4.67 (d, J = 15.1 Hz, 1 H), 4.56−4.61 (m, 1 H), 4.24
(ddd, J = 8.7, 4.1, 4.1 Hz, 1 H), 3.98 (dd, J = 11.9, 6.7 Hz, 1 H), 3.84
(dd, J = 11.9, 2.4 Hz, 1 H), 3.53 (s, 3 H), 3.41−3.51 (m, 2 H), 2.55−
2.79 (m, 5 H), 2.43 (ddd, J = 17.9, 7.4, 7.4 Hz, 1 H), 2.01−2.17 (m, 1
H), 1.86−1.99 (m, 1 H). The diol 25 was fully characterized after
converting it to the corresponding dipivalate derivative.
1
1.05, CHCl3); IR (CH2Cl2) νmax 3054, 2951, 1636 cm−1; H NMR
(CDCl3, 300 MHz) δ 7.09−7.17 (m, 2 H), 6.78−6.86 (m, 2 H), 5.74−
5.90 (m, 1 H), 5.34 (d, 1 H, J = 14.8 Hz), 5.01−5.16 (m, 2 H), 4.56
(d, 1 H, J = 6.9 Hz), 4.51 (d, 1 H, J = 6.9 Hz), 3.81 (d, J = 14.8 Hz, 1
H), 3.76 (s, 3 H), 3.69−3.77 (m, 1 H), 3.42 (dd, J = 11.1, 5.5 Hz, 1
H), 3.27 (s, 3 H), 2.41−2.69 (m, 3 H, H-3), 2.31 (ddd, J = 14.4, 7.2,
7.2 Hz, 1 H), 1.85−2.07 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ
169.2, 158.8, 135.5, 129.2, 129.1, 117.5, 95.6, 72.9, 57.5, 55.5, 55.1,
48.0, 33.8, 28.8, 23.2; HRMS (EI-double focusing sector field) m/z:
[M]+ Calcd for C18H25NO4 319.1784; Found 319.1780.
(5S,6S)-1-(p-Methoxybenzyl)-5-(methoxymethoxy)-6-(3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)piperidin-
2-one (36a). To the alkene 35 (1.41 g, 4.43 mmol) in CH2Cl2 (25
mL) under argon at rt was added [Rh(PPh3)3Cl] (82 mg, 2 mol %) in
one portion resulting in an orange-red color solution. Pinacolborane
(1.32 mL, 8.86 mmol) was added dropwise to the above mixture,
during which time the color of solution has changed to yellow-orange.
After the reaction mixture was stirred at the same temperature
overnight, it was cooled to 0 °C and distilled water (5 mL) was added.
The organic layer was separated, and the aqueous layer was saturated
with solid NaCl and back-extracted into CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered, and concentrated. The
crude residue was purified by chromatography (Et2O) to afford
To the diol 25 (12 mg, 0.045 mmol) in CH2Cl2 (2 mL), under
argon at rt, were added DMAP (5.5 mg, 0.045 mmol), N,N-
diisopropylethylamine (47 μL, 0.27 mmol), and pivaloyl chloride (16
μL, 0.13 mmol) successively, and the solution was stirred overnight.
The reaction mixture was cooled to 0 °C, distilled water (1 mL) was
added, and the mixture was stirred for 20 min. The mixture was
washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered,
and concentrated. Purification by chromatography (2:1 petroleum
ether/EtOAc) afforded 25·dipivalate (16.5 mg, 85%) as a colorless oil:
22
1
IR (CH2Cl2) νmax 2973, 2875, 1732, 1648 cm−1; H NMR (CDCl3,
boronate ester 36a (1.82 g, 92%) as a colorless oil: [α]D −48.4° (c
0.67, CHCl3); IR (CH2Cl2) νmax 2943, 1642 cm−1; 1H NMR (CDCl3,
300 MHz) δ 7.10−7.17 (m, 2 H), 6.76−6.83 (m, 2 H), 5.35 (d, J =
14.7 Hz, 1 H), 4.52 (d, J = 6.8 Hz, 1 H), 4.47 (d, J = 6.8 Hz, 1 H), 3.74
(s, 3 H), 3.74 (d, J = 14.7 Hz, 1 H), 3.65−3.75 (m, 1 H), 3.26−3.33
(m, 1 H), 3.24 (s, 3 H), 2.57 (ddd, J = 18.2, 7.9, 5.0 Hz, 1 H), 2.44
(ddd, J = 18.2, 7.9, 7.9 Hz, 1 H), 1.69−2.03 (m, 3 H), 1.40−1.62 (m, 3
H), 1.20 (s, 12 H), 0.75 (t, J = 7.4 Hz, 2 H); 13C NMR (CDCl3, 75
MHz) δ 169.2, 158.7, 129.3, 129.1, 113.8, 95.2, 82.8, 72.8, 57.4, 55.4,
55.0, 48.1, 32.0, 30.1, 28.7, 24.69, 24.67, 23.0, 21.9; 11B NMR (CDCl3,
96.3 MHz) δ 33.5; HRMS (EI-double focusing sector field) m/z: [M]+
Calcd for C24H38BNO6 447.2792(2); Found 447.2792(4).
300 MHz) δ 5.49−5.55 (m, 1 H), 5.13 (ddd, J = 9.7, 4.6, 4.6 Hz), 4.62
(d, J = 15.1 Hz, 1 H), 4.57−4.61 (m, 1 H), 4.38 (dd, J = 11.8, 5.2 Hz, 1
H), 4.18 (dd, J = 11.8, 3.8 Hz, 1 H), 3.67−3.74 (m, 1 H), 3.53 (s, 3
H), 3.49 (d, J = 15.1 Hz, 1 H), 2.52−2.79 (m, 4 H), 1.92−2.18 (m, 4
H), 1.21 (s, 9 H), 1.19 (s, 9 H); 13C NMR (CDCl3, 75 MHz) δ 177.9,
177.2, 169.2, 152.6, 130.6, 120.8, 89.9, 67.3, 60.7, 55.4, 53.9, 49.1, 38.9,
38.7, 29.0, 28.6, 27.4, 27.1, 27.0, 23.5; HRMS (ESI-QTOF) m/z: [M +
Na]+ Calcd for C24H37NO6Na 458.2513; Found 458.2530.
(5S,6S)-6-Allyl-5-hydroxy-1-(p-methoxybenzyl)piperidin-2-
one (34). Ph3P+MeBr− (1.93 g, 5.41 mmol) was dried under vacuum
at 110 °C for 1 h and cooled to rt. The above salt was suspended in
K
DOI: 10.1021/acs.joc.5b00621
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Potassium (5S,6S)-1-(p-Methoxybenzyl)-5-(methoxy-
methoxy)-6-(3-(trifluoroborato)propyl)piperidin-2-one (36b).
To the boronate ester 36a (1.82 g, 4.03 mmol) in MeOH (26 mL)
at rt was added aqueous KHF2 (4.10 mL, 4.5 M) dropwise, and the
resultant solution was vigorously stirred at the same temperature,
overnight. All the volatiles were removed under reduced pressure, and
the crude residue was dissolved in a mixture of MeOH and water (2:1
v/v, 20 mL) for azeotropic evaporation of the pinacol byproduct. The
solvent was removed, and the evaporation cycles were continued until
TLC showed the absence of the pinacol (6 cycles). The crude residue
was washed with acetone (4 × 20 mL), dried over Na2SO4, filtered,
concentrated, and redissolved in CH2Cl2. To this solution was added
Et2O down the sides of the flask to effect the precipitation of
potassium trifluoroborate salt. The solvent was decanted carefully from
the flask, and the remaining white precipitate was washed with Et2O (3
× 10 mL). Evaporation of Et2O under reduced pressure gave the
trifluoroborate salt 36b (1.33 g, 77%, 70.5% from 35) as a white solid:
−32.6° (c 0.93, CHCl3); IR (neat) νmax 3650−3109, 2946, 1616 cm−1;
1H NMR (CDCl3, 300 MHz) δ 7.85 (d, J = 7.4 Hz, 2 H), 7.47−7.66
(m, 3 H), 7.03−7.15 (m, 2 H), 6.92 (dt, J = 15.1, 6.7 Hz, 1 H), 6.76−
6.86 (m, 2 H), 6.30 (d, J = 15.1 Hz, 1 H), 5.23 (d, J = 14.7 Hz, 1 H),
3.86−3.98 (m, 1 H), 3.77 (d, J = 14.7 Hz, 1 H), 3.76 (s, 3 H), 3.16−
3.28 (m, 1 H), 2.64−2.77 (br m, 1 H), 2.55 (dt, J = 18.2, 6.0 Hz, 1 H),
2.42 (dt, J = 18.2, 7.7 Hz, 1 H), 2.19 (dt, J = 6.7 Hz, 2 H), 1.70−1.96
(m, 3 H), 1.40−1.68 (m, 3 H); 13C NMR (CDCl3, 75 MHz) δ 169.6,
158.6, 146.2, 140.2, 133.1, 130.4, 129.1, 128.8, 128.8, 127.2, 113.8,
66.3, 59.0, 55.0, 47.7, 31.3, 28.6, 28.4, 25.4, 25.0; HRMS (EI-double
focusing sector field) m/z: [M]+ Calcd for C24H29NO5S 443.1766;
Found 443.1769.
To the above alcohol (1.12 g, 2.53 mmol) in DCE (30 mL) under
argon at rt was added 1,1-thiocarbonyldiimidazole (1.0 g, 5.05 mmol)
in one portion, and the resultant reddish brown solution was stirred at
85 °C (oil bath) overnight. The reaction mixture was cooled to rt,
distilled water (5 mL) was added, and the mixture was stirred for 10
min. The two layers were separated, and the organic layer was diluted
with CH2Cl2 and washed successively with cold aqueous HCl (2 × 5
mL, 0.5 M), saturated aqueous NaHCO3 (1 × 5 mL), and brine (1 × 5
mL). The organic layer was dried over Na2SO4, filtered, and
concentrated. Purification by chromatography (EtOAc, then 20:1
23
mp 72−74 °C; [α]D −45.9° (c 0.44, CHCl3); IR (CH2Cl2) νmax
1
3055, 2943, 1625 cm−1; H NMR (CD3CN, 300 MHz) δ 7.12−7.21
(m, 2 H), 6.81−6.90 (m, 2 H), 5.16 (d, J = 14.9 Hz, 1 H), 4.54 (d, J =
6.8 Hz, 1 H), 4.49 (d, J = 6.8 Hz, 1 H), 3.86 (d, J = 14.9 Hz, 1 H), 3.75
(s, 3 H), 3.69−3.79 (m, 1 H), 3.31−3.40 (m, 1 H), 3.22 (s, 3 H), 2.49
(ddd, J = 18.0, 8.5, 5.3 Hz, 1 H), 2.34 (ddd, J = 18.0, 7.7, 7.7 Hz, 1 H),
1.78−2.02 (m, 2 H), 1.64−1.77 (m, 1 H), 1.48−1.63 (m, 1 H), 1.32
(tt, J = 7.8, 7.8 Hz, 2 H), 0.00−0.21 (m, 2 H); 13C NMR (CD3CN, 75
MHz) δ 170.8, 160.2, 131.8, 130.4, 118.8, 115.2, 96.5, 74.0, 59.7,
56.35, 56.33, 49.4, 34.4, 29.9, 24.5, 24.4 (q, J = 8.9 Hz, 13C-11B); 11B
NMR (CD3CN, 96.3 MHz) δ 2.9; 19F NMR (CD3CN, 282.4 MHz) δ
−141.0; HRMS (ESI-QTOF) m/z: [M − K+]− Calcd for
C18H26BF3NO4 388.1912; Found 388.1928.
23
EtOAc/MeOH) afforded 33 (1.22 g, 87%) as a thick foamy oil: [α]D
−2.3° (c 0.57, CHCl3); IR (CH2Cl2) νmax 3047, 2951, 1636 cm−1; 1H
NMR (CDCl3, 300 MHz) δ 8.21−8.25 (m, 1 H), 7.80−7.87 (m, 2 H),
7.45−7.65 (m, 4 H), 7.09−7.18 (m, 2 H), 6.98−7.02 (m, 1 H), 6.77−
6.90 (m, 3 H), 6.24 (dd, J = 15.1, 0.9 Hz, 1 H), 5.65 (ddd, 1 H, J = 8.7,
4.3, 4.3 Hz, 1 H), 5.23 (d, J = 14.9 Hz, 1 H), 3.96 (d, J = 14.9 Hz, 1
H), 3.77 (s, 3 H), 3.62−3.72 (m, 1 H), 2.62 (t, J = 7.2 Hz, 2 H), 2.06−
2.35 (m, 4 H), 1.54−1.81 (m, 2 H), 1.35−1.52 (m, 2 H); 13C NMR
(CDCl3, 75 MHz) δ 182.3, 168.7, 159.1, 144.9, 140.3, 136.8, 133.3,
131.5, 131.3, 129.2, 129.1, 128.5, 127.5, 117.4, 114.2, 77.3, 56.1, 55.2,
47.9, 31.2, 29.3, 28.0, 24.6, 22.0; HRMS (ESI-QTOF) m/z: [M + Na]+
Calcd for C28H31N3O5S2Na 576.1597; Found 576.1614.
(5S,6S)-1-(p-Methoxybenzyl)-5-(methoxymethoxy)-6-((E)-5-
(phenylsulfonyl)pent-4-enyl)piperidin-2-one (37). Cs2CO3 (3.0
g, 9.21 mmol), [Pd(dppf)Cl2] (251 mg, 0.31 mmol), and (E)-(2-
bromovinyl) phenyl sulfone (835 mg, 3.38 mmol) were successively
added to the trifluoroborate salt 36b (1.31 g, 3.07 mmol), and the flask
was evacuated and flushed with nitrogen. To the above reaction flask
under argon at rt was added a degassed mixture of toluene and water
(3:1 v/v, 26 mL), and the suspension was allowed to warm to 85 °C
(oil bath). The solution is orange-red in color at the beginning and was
turned into dark brown within 2 h, by which time all of the
trifluoroborate was consumed. The reaction mixture was diluted with
EtOAc (20 mL) and washed successively with water (1 × 5 mL) and
brine (1 × 5 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated. Purification by chromatography (1:2 petroleum
ether/EtOAc, then 1:4 petroleum ether/EtOAc) afforded 37 (1.19 g,
80%) as a yellow oil: [α]D21 −21.6° (c 0.63, CHCl3); IR (CH2Cl2) νmax
2947, 2900, 1636 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.84−7.91 (m,
2 H), 7.49−7.66 (m, 3 H), 7.07−7.17 (m, 2 H), 6.94 (dt, J = 15.1, 6.8
Hz, 1 H), 6.79−6.88 (m, 2 H), 6.31 (d, J = 15.1 Hz, 1 H), 5.26 (d, J =
14.8 Hz, 1 H), 4.55 (d, J = 6.8 Hz, 1 H), 4.50 (d, J = 6.8 Hz, 1 H),
3.70−3.80 (m, 1 H), 3.79 (d, J = 14.8 Hz, 1 H), 3.78 (s, 3 H), 3.22−
3.34 (m, 1 H), 3.26 (s, 3 H), 2.40−2.65 (m, 2 H), 2.20 (dt, J = 6.8, 6.8
Hz, 2 H), 1.70−2.0 (m, 3 H), 1.43−1.64 (m, 3 H); 13C NMR (CDCl3,
75 MHz) δ 169.2, 158.9, 145.9, 140.5, 133.2, 130.9, 129.2, 129.1,
129.0, 127.5, 114.0, 95.3, 72.9, 57.6, 55.6, 55.2, 48.5, 31.6, 29.1, 28.7,
25.5, 22.9; HRMS (EI-double focusing sector field) m/z: [M]+ Calcd
for C26H33NO6S 487.2029; Found 487.2021.
Formation of Octahydroquinolin-2-ones 38−41 from Thio-
imidazolide 33. To a solution of the thioimidazolide 33 (483 mg,
0.87 mmol) in degassed toluene (30 mL) under argon at 85 °C (oil
bath) was added a mixture of AIBN (45 mg, 0.17 mmol) and Bu3SnH
(0.36 mL, 1.31 mmol) in degassed toluene (30 mL) via syringe pump
over 3 h. The reaction mixture was stirred at the same temperature for
another 30 min and was allowed to reach rt. Toluene was evaporated
under reduced pressure, and the crude residue was diluted with
EtOAc. Aqueous KF (10 mL, 10% w/v) was added, and the biphasic
mixture was vigorously stirred for 30 min. The solution was vacuum
filtered through a pad of Celite, and the two layers were separated. The
aqueous layer was re-extracted into EtOAc, and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. The crude
residue was carefully purified by chromatography (Et2O, then 1:4
petroleum ether/EtOAc) to give 38 + 40 (189 mg, 38:40 = 8:1), 39
(58.6 mg), 41 (6.2 mg), and 39 + 41 (25 mg, 39:41 = 2.5:1) in an
overall yield of 75%. The ratio of the mixture of 38 and 40 was
determined based on the integration of benzylic methylene proton
doublets at 3.89 and 4.25 ppm, whereas the ratio of the mixture of 39
and 41 was based on the integration of benzylic methylene proton
doublets at 5.21 and 4.98 ppm. For characterization purposes,
compound 38 was obtained after repeated chromatographic
purification (1:4 petroleum ether/EtOAc) of the 8:1 mixture of 38
and 40.
(5S,6S)-1-(p-Methoxybenzyl)-6-((E)-5-(phenylsulfonyl)pent-
4-enyl)-5-(thiocarbonylimidazolyl)-piperidin-2-one (33). Com-
pound 37 (1.24 g, 2.54 mmol) was dissolved in HCl−MeOH (26 mL,
1 M), and the solution was heated to 60 °C (oil bath) for 3 h. The
reaction mixture was cooled to 0 °C, and solid NaHCO3 (2.18 g, 26
mmol) was added to quench the excess acid. MeOH was evaporated
under reduced pressure, and the crude residue was diluted with
CH2Cl2. The organic layer was washed once with brine. The aqueous
solution was saturated with solid NaCl and back-extracted into
CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated. The crude residue was purified by
chromatography (EtOAc, then 10:1 EtOAc/MeOH) to give the
(4aR,5R,8aS)-1-(p-Methoxybenzyl)-5-((phenylsulfonyl)methyl)-
22
octahydroquinolin-2-one (38). White solid: mp 52−54 °C; [α]D
−38.6° (c 0.28, CHCl3); IR (CH2Cl2) νmax 3047, 2940, 1629 cm−1; 1H
NMR (CDCl3, 300 MHz) δ 7.86 (d, J = 7.5 Hz, 2 H), 7.64 (t, J = 7.3
Hz, 1 H), 7.53 (t, J = 7.3 Hz, 2 H), 7.07−7.17 (m, 2 H), 6.79−6.89
(m, 2 H), 5.21 (d, J = 14.8 Hz, 1 H), 3.84 (d, J = 14.8 Hz, 1 H), 3.80
(s, 3 H), 3.14 (ddd, J = 11.4, 4.0, 4.0 Hz, 1 H), 3.04 (dd, J = 14.0, 6.2
Hz, 1 H), 2.93 (dd, J = 14.0, 6.8 Hz, 1 H), 2.53 (dd, J = 18.0, 6.2 Hz, 1
H), 2.18−2.43 (m, 2 H), 1.99−2.12 (m, 1 H), 1.70−1.98 (m, 3 H),
1.58−1.70 (m, 1 H), 1.45−1.58 (m, 1 H), 1.09−1.44 (m, 3 H); 13C
NMR (CDCl3, 75 MHz) δ 169.0, 158.9, 140.0, 133.8, 129.5, 129.3,
129.03, 127.6, 114.0, 59.4, 57.2, 55.2, 47.0, 37.6, 34.7, 30.9, 26.4, 26.1,
22
deprotected alcohol (1.06 g, 94%) as a thick colorless oil: [α]D
L
DOI: 10.1021/acs.joc.5b00621
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
24.0, 16.1; HRMS (EI-double focusing sector field) m/z: [M]+ Calcd
for C24H29NO4S 427.1817; Found 427.1813.
EtOAc, then 1:4 petroleum ether/EtOAc) afforded an inseparable 8:1
mixture of the corresponding desulfonylated products (414 mg, 76%,
84% brsm) as a colorless oil. Some unreacted mixture of 38 and 40 (74
mg, 9%) was also recovered. The diastereomeric ratio of the
desulfonylated products was determined based on integration of the
(4aR,5S,8aS)-1-(p-Methoxybenzyl)-5-((phenylsulfonyl)methyl)-
23
octahydroquinolin-2-one (39). Colorless oil: [α]D −36.0° (c 1.60,
CHCl3); IR (CH2Cl2) νmax 3057, 2941, 1630 cm−1; 1H NMR (CDCl3,
300 MHz) δ 7.84 (d, J = 7.6 Hz, 2 H), 7.62−7.70 (m, 1 H), 7.55 (t, J =
7.6 Hz, 2 H), 7.05−7.14 (m, 2 H), 6.80−6.88 (m, 2 H), 5.19 (d, J =
15.0 Hz, 1 H), 3.89 (d, J = 15.0 Hz, 1 H), 3.80 (s, 3 H), 3.16 (ddd, J =
10.9, 4.4, 4.4 Hz, 1 H), 3.04 (dd, J = 14.2, 6.5 Hz, 1 H), 2.96 (dd, J =
14.2, 6.5 Hz, 1 H), 2.32−2.58 (m, 3 H), 2.0−2.17 (m, 1 H), 1.80−1.92
(m, 2 H), 1.51−1.74 (m, 3 H), 1.33−1.52 (m, 2 H), 1.14−1.29 (m, 1
H); 13C NMR (CDCl3, 75 MHz) δ 169.3, 158.8, 139.6, 133.9, 129.5,
129.4, 128.8, 127.8, 114.0, 59.3, 55.3, 53.4, 47.0, 38.4, 33.7, 31.2, 26.7,
25.2, 22.5, 19.9; HRMS (EI-double focusing sector field) m/z: [M]+
Calcd for C24H29NO4S 427.1817; Found 427.1801.
1
benzylic methylene proton doublets at 5.27 and 4.37 ppm in the H
NMR spectrum.
Pure 38 (43 mg, 0.1 mmol), previously obtained by repeated
chromatographic purification of the mixture of 38 and 40, was also
treated with Na−Hg amalgam to obtain the corresponding
desulfonylated product (21 mg, 73%, 89% based on recoverd 38)
which was used for spectral characterization. (4aR,5R,8aS)-1-(p-
23
Methoxybenzyl)-5-methyloctahydroquinolin-2-one. Colorless oil: [α]D
−66.5° (c 1.94, CHCl3); IR (neat) νmax 2933, 2865, 1631 cm−1; H
1
NMR (CDCl3, 300 MHz) δ 7.13−7.20 (m, 2 H), 6.80−6.87 (m, 2 H),
5.27 (d, J = 14.9 Hz, 1 H), 3.85 (d, J = 14.9 Hz, 1 H), 3.79 (s, 3 H),
3.12 (ddd, J = 11.7, 4.1, 4.1 Hz, 1 H), 2.51−2.63 (m, 1 H), 2.34−2.49
(m, 1 H), 1.54−1.97 (m, 6 H), 0.99−1.43 (m, 4 H), 0.89 (d, J = 6.9
Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 169.8, 158.7, 123.0, 129.0,
113.9, 58.2, 55.2, 47.0, 39.6, 34.4, 31.3, 28.2, 26.3, 24.6, 19.1, 15.4;
HRMS (EI-double focusing sector field) m/z: [M]+ Calcd for
C18H25NO2 287.1885; Found 287.1886.
(4aS,5R,8aS)-1-(p-Methoxybenzyl)-5-((phenylsulfonyl)methyl)-
octahydroquinolin-2-one (40). 1H NMR (CDCl3, 300 MHz) δ
(discernible signals for 40 in a 8:1 mixture of 38 and 40) 4.94 (d, J =
15.6 Hz, 1 H), 4.34 (d, J = 15.6 Hz, 1 H), 3.24 (d, J = 13.7, 13.7, 2.6
Hz, 1 H).
(4aS,5S,8aS)-1-(p-Methoxybenzyl)-5-((phenylsulfonyl)methyl)-
octahydroquinolin-2-one (41). White solid: mp 205−208 °C
22
(EtOAc); [α]D +18.7° (c 0.98, CHCl3); IR (CH2Cl2) νmax 3058,
(4aS,5R,8aS)-1-(p-Methoxybenzyl)-5-methyloctahydroquinolin-
2-one. 1H NMR (CDCl3, 300 MHz) of 8:1 product mixture, δ
(discernible signals for desulfonylated compound formed from 40)
4.96 (d, J = 15.6 Hz, 1 H), 4.37 (d, J = 15.6 Hz, 1 H), 2.81−2.91 (m, 1
H).
2931, 2858, 1634 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.85−7.92 (m,
2 H), 7.63−7.71 (m, 1 H), 7.53−7.62 (m, 2 H), 7.03−7.10 (m, 2 H),
6.78−6.85 (m, 2 H), 4.98 (d, J = 15.3 Hz, 1 H), 4.25 (d, J = 15.3 Hz, 1
H), 3.78 (s, 3 H), 2.98 (dd, J = 14.5, 8.3 Hz, 1 H), 2.92 (dd, J = 14.5,
3.1 Hz, 1 H), 2.74 (ddd, J = 11.2, 11.2, 3.4 Hz, 1 H), 2.57 (ddd, J =
18.0, 4.5, 3.0 Hz, 1 H), 2.35−2.52 (m, 2 H), 2.11−2.22 (m, 1 H),
1.85−1.95 (m, 1 H), 1.60−1.76 (m, 2 H), 1.16−1.52 (m, 4 H), 1.02
(dddd, J = 12.3, 12.3, 12.3, 3.5 Hz, 1 H); 13C NMR (CDCl3, 75 MHz)
δ 170.1, 158.6, 139.3, 133.8, 129.6, 129.4, 128.5, 128.0, 114.0, 56.4,
55.2, 53.9, 44.9, 43.6, 33.6, 32.9, 31.7, 29.1, 24.6, 19.5; HRMS (EI-
double focusing sector field) m/z: [M]+ Calcd for C24H29NO4S
427.1817; Found 427.1820.
The 8:1 product mixture from the desulfonylation of 38 and 40
(414 mg, 1.44 mmol) was subjected to Birch reduction according to
the general procedure. Purification by chromatography (20:1 EtOAc/
MeOH) afforded an 8:1 mixture of octahydroquinolin-2-ones 42 and
44 (212 mg, 88%) as a white solid. Single recrystallization of the above
mixture from Et2O afforded pure 42 (144 mg) as a white solid: mp
145−146 °C (Et2O) {lit.32c for ( )-42, mp 133−134 °C}; [α]D
23
−14.7° (c 2.20, CHCl3); IR (CH2Cl2) νmax 3201, 3051, 2932, 2865,
1
1659 cm−1; H NMR (CDCl3, 500 MHz) δ 6.50−6.75 (br s, 1 H),
Desulfonylation and Birch Reduction of Octahydroquinolin-
2-ones 38−41. General Procedure for Desulfonylation. To the
octahydroquinolin-2-ones 38−41 (1 mmol) in MeOH (30 mL) under
argon at rt was added freshly dried Na2HPO4 (1.92 g, 13.5 mmol) in
one portion. Na−Hg (14.5 g, 6% Na) amalgam was added to the
above solution in three equal portions over 30 min. The resultant
cloudy solution was stirred overnight at rt, after which time mercury
was seen to settle at the bottom of the reaction flask. The reaction
mixture was cooled to 0 °C in a salt−ice bath, and distilled water (8
mL) was added. To the above mixture was then added EtOAc (20
mL), and the resulting solution was vigorously stirred for 15 min at rt.
The solution was carefully decanted into a separatory funnel leaving
behind the mercury in the reaction flask. The organic and aqueous
layers were separated, and the aqueous layer was saturated with solid
NaCl and back-extracted into EtOAc. The combined organic layers
were dried over Na2SO4, filtered, and concentrated to give the crude
desulfonylated products.
General Procedure for Birch Reduction. Na metal was cut into
small pieces and washed three times with hexanes. To the liquid NH3
(15 mL) at −78 °C under argon, was added Na metal (276 mg, 12
mmol) portion wise (∼5 min) and the resulting blue colored solution
was stirred at −78 °C for 30 min. To the above solution was then
added the desulfonylated compounds (1 mmol) in THF (7 mL) via
cannula and the reaction mixture was stirred at the same temperature
for 5 h. Solid NH4Cl (280 mg) was added to the above solution at −78
°C and the reaction temperature allowed to gradually warm to rt, by
which time all of the ammonia had evaporated. The crude residue was
extracted with CH2Cl2 (3 × 12 mL), followed by 4:1 v/v CH2Cl2/
MeOH (3 × 5 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated to afford the crude octahydroqui-
nolin-2-ones 42-45.
3.29 (ddd, J = 12.3, 8.4, 4.2 Hz, 1 H), 2.43 (ddd, J = 18.0, 4.7, 2.3 Hz,
1 H), 2.27 (ddd, J = 18.00, 8.3, 8.3 Hz, 1 H), 1.89−1.97 (m, 1 H),
1.61−1.75 (m, 5 H), 1.34−1.48 (m, 2 H), 1.18−1.30 (m, 1 H), 1.03
(dddd, J = 13.0, 13.0, 13.0, 3.6 Hz, 1 H), 0.95 (d, J = 6.9 Hz, 3 H); 13C
NMR (CDCl3, 75 MHz) δ 172.2, 54.1, 38.4, 34.2, 31.2, 30.5, 28.2,
24.3, 19.3, 15.0; HRMS (EI-double focusing sector field) m/z: [M]+
Calcd for C10H17NO 167.1310; Found 167.1309. Racemic 42 has been
reported32c,43 in the literature.
(4aS,5R,8aS)-5-Methyloctahydroquinolin-2-one (44). To ob-
tain pure 44 for characterization purposes, the mixture of 42 and 44
(enriched in 44) obtained in the desulfonylation−Birch reduction of
an 8:1 mixture of 38 and 40 was converted to the corresponding N-
Boc derivatives by treatment with n-BuLi and Boc2O in THF at −78
°C. Gratifyingly, N-Boc-44 was readily separated from N-Boc-42 by
column chromatography. Treatment of N-Boc-44 with 1 M HCl−
MeOH gave pure 44 as a white solid: IR (CH2Cl2) νmax 3202, 3054,
2959, 2930, 2861, 1660 cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.50 (br
s, 1 H), 2.97 (ddd, J = 10.5, 10.5, 3.5 Hz, 1 H), 2.48 (ddd, J = 18.1, 6.4,
1.9 Hz, 1 H), 2.34 (ddd, J = 18.1, 11.9, 6.8 Hz, 1 H), 2.03−2.13 (m, 1
H), 1.66−1.83 (m, 3 H), 1.15−1.44 (m, 4 H), 0.94−1.10 (m, 2 H),
0.96 (d, J = 6.4 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 57.5, 46.2,
35.09, 35.11, 33.7, 31.6, 24.8, 24.0, 19.1 (the amide carbonyl signal was
not detected due to low sample concentration); HRMS (EI-double
focusing sector field) m/z: [M]+ Calcd for C10H17NO 167.1310;
Found 167.1306.
The mp and [α]D of 44 were not measured due to insufficient
amounts of material. Racemic 4424c,32c and (+)-4429a have been
described in the literature.
(4aR,5S,8aS)-5-Methyloctahydroquinolin-2-one (43). Desulfo-
nylation of 39 (355 mg, 0.83 mmol) was conducted according to the
general procedure. Purification by chromatography (1:1 petroleum
ether/EtOAc then 1:4 petroleum ether/EtOAc) afforded the
desulfonylated compound (181 mg, 76%). Starting 39 (28.4 mg,
8%) was also recovered. (4aR,5S,8aS)-1-(p-Methoxybenzyl)-5-methyl-
(4aR,5R,8aS)-5-Methyloctahydroquinolin-2-one (42). The
desulfonylation of an 8:1 mixture of 38 and 40 (810 mg, 1.89
mmol) was conducted according to the above described general
procedure. Purification by chromatography (1:2 petroleum ether/
M
DOI: 10.1021/acs.joc.5b00621
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
21
octahydroquinolin-2-one. Colorless oil: [α]D −47.3° (c 1.22, CHCl3);
IR (neat) νmax 2932, 2873, 1637 cm−1; 1H NMR (CDCl3, 300 MHz) δ
7.12−7.20 (m, 2 H), 6.80−6.88 (m, 2 H), 5.22 (d, J = 15.0 Hz, 1 H),
3.96 (d, J = 15.0 Hz, 1 H), 3.79 (s, 3 H), 3.38 (ddd, J = 8.9, 4.2, 4.2
Hz, 1 H), 2.39−2.61 (m, 2 H), 2.03−2.18 (m, 1 H), 1.36−1.89 (m, 8
H), 1.21 (ddd, J = 13.2, 8.8, 4.6 Hz, 1 H), 0.95 (d, J = 7.1 Hz, 3 H);
13C NMR (CDCl3, 75 MHz) δ 170.3, 158.7, 130.0, 128.8, 113.9, 55.2,
54.0, 46.7, 40.3, 32.2, 31.0, 28.0, 27.8, 23.0, 19.7, 19.1; HRMS (EI-
double focusing sector field) m/z: [M]+ Calcd for C18H25NO2
287.1885; Found 287.1888.
cooled to 0 °C, and cold saturated aqueous NaHCO3 (2 mL) was
added. The two layers were separated, and the aqueous layer was re-
extracted with Et2O. The combined organic layers were dried over
anhydrous K2CO3, filtered, and concentrated. The crude imine (36
mg) was hydrogenated in the next step without any further
purification.
To the imine (36 mg) in 95% EtOH (1 mL) was added aqueous
HCl (0.2 mL, 2 M), followed by PtO2 (6 mg), and the mixture was
stirred under H2 (1 atm, balloon) for 8 h. The reaction mixture was
filtered through a pad of Celite followed by washing with 95% EtOH,
and the solvent was removed under reduced pressure. The crude
hydrochloride salt was diluted with CH2Cl2 (10 mL) and aqueous
NaOH (5 mL, 6 M) was added; the mixture was then stirred for 30
min. The two layers were separated, and the aqueous layer was re-
extracted with CH2Cl2 (4 × 5 mL). The combined organic layers were
dried over anhydrous K2CO3, filtered, and concentrated. The crude
residue (22 mg) was purified by chromatography (10:1 CH2Cl2/
MeOH, then 80:20:1 CH2Cl2/MeOH/iPrNH2) to give 26 (15.5 mg,
45% over 3 steps, 52% based on recovered 43) as a pale yellow oil.
The starting octahydroquinilin-2-one 43 (3.8 mg, 13%) was also
recovered. Addition of concentrated aqueous HCl (2 drops) to a
methanolic solution of 26, followed by evaporation, gave the
corresponding hydrochloride salt (18.8 mg) as an off-white solid.
Birch reduction of the desulfonylated compound obtained from 39
(130 mg, 0.45 mmol) was conducted according to the general
procedure. Purification by chromatography (1:4 petroleum ether/
EtOAc) afforded the cis-octahydroquinolin-2-one 43 (65 mg, 86%) as
a white solid: mp 143−144 °C (Et2O) {lit.29a for ent-43, mp 146.5−
147.5 °C}; [α]D +65.3° (c 0.88, CHCl3); {lit.30a for (+)-43; [α]D
23
20
+33.8° (c 0.08, CHCl3); lit.29a for ent-43; [α]D −60.4° (c 1.00,
25
CHCl3)}; IR (CH2Cl2) νmax 3195, 3054, 2932, 1659, 1450 cm−1; H
1
NMR (CDCl3, 500 MHz) δ 5.44−5.60 (br s, 1 H), 3.63 (ddd, J = 3.4,
3.4, 3.4 Hz, 1 H), 2.26−2.33 (m, 2 H), 2.05 (ddd, J = 13.7, 9.3, 4.2 Hz,
1 H), 1.39−1.74 (m, 8 H), 0.96−1.08 (m, 1 H), 0.93 (d, J = 6.4 Hz, 3
H); 13C NMR (CDCl3, 75 MHz) δ 172.9, 52.2, 39.7, 33.7, 31.8, 27.6,
27.3, 23.1, 20.0, 19.3; HRMS (EI-double focusing sector field) m/z:
[M]+ Calcd for C10H17NO 167.1310; Found 167.1308. Compounds
( )-43,24c,d,32c,e (+)-43,30a and (−)-4329a have been reported in the
literature.
(4aS,5S,8aS)-5-Methyloctahydroquinolin-2-one (45). Desulfo-
nylation of a 2.5:1 mixture of 39 and 41 (131 mg, 0.31 mmol) was
conducted according to the general procedure. Purification by
chromatography (1:1 petroleum ether/EtOAc) afforded an inseparable
mixture of the corresponding desulfonylated compounds (70 mg,
80%) in a 2.5:1 ratio. Characterization data for the major product,
which was formed from the desulfonylation of 39, is reported under
the preparation of 43 described above. (4aS,5S,8aS)-1-(p-Methoxy-
Data for 26: [α]D −2.1° (c 0.33, MeOH) {lit29d [α]D −2.2° (c
1.34, MeOH)}; IR (CH2Cl2) νmax 3317, 3047, 2928, 2864, 1450, 1373,
1265 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.84 (q, J = 2.5 Hz, 1 H),
2.48−2.58 (m, 1 H), 1.77−2.00 (m, 2 H), 1.50−1.71 (m, 4 H), 1.23−
1.49 (m, 7 H), 1.04−1.17 (m, 2 H), 0.88−1.03 (m, 2 H), 0.90 (t, J =
6.4 Hz, 3 H), 0.83 (d, J = 6.0 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ
57.7, 56.0, 42.6, 39.8, 35.9, 33.4, 27.4, 27.1, 21.3, 19.9, 19.1, 14.3.
Data for 26·HCl: mp 280−282 °C (sealed capillary) {lit31a mp
21
20
29d
22
20
285−286 °C}; [α]D = +12.9° (c 0.34, MeOH) {lit [α]D +12.9°
(c 0.36, MeOH)}; IR (KBr) νmax 3173, 3121, 2969, 2955, 2930, 2872,
1
benzyl)-5-methyloctahydroquinolin-2-one. H NMR (CDCl3, 300 MHz)
1
of the 2.5:1 product mixture, δ (discernible signals for desulfonylated
compound formed from 41) 4.90 (d, J = 15.3 Hz, 1 H); 4.39 (d, J =
15.3 Hz, 1 H), 3.08 (ddd, J = 11.5, 11.5, 3.4 Hz, 1 H), 0.81 (d, J = 7.3
Hz, 3 H).
2821, 1584 cm−1; H NMR (CDCl3, 300 MHz) δ 9.50 (br s, 1 H),
8.40 (br s, 1 H), 3.23−3.36 (m, 1 H), 2.86−3.05 (m, 1 H), 2.26−2.54
(m, 2 H), 1.97−2.25 (m, 4 H), 1.69−1.92 (m, 2 H), 1.31−1.67 (m, 6
H), 1.14−1.31 (m, 1 H), 0.92−1.04 (m, 1 H), 0.90 (t, J = 6.9 Hz, 3
H), 0.88 (d, J = 5.6 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 60.2,
58.1, 40.9, 34.8, 34.3, 29.1, 27.1, 25.2, 23.1, 20.5, 19.7, 19.1, 13.7.
HRMS (EI-double focusing sector field) m/z: [M]+ Calcd for
C13H26N 196.2060; Found 196.2063.
Birch reduction of the 2.5:1 desulfonylated products prepared from
the mixture of 39 and 41 (70 mg, 0.24 mmol) was performed
according to the general procedure. Purification by chromatography
(1:4 petroleum ether/EtOAc) afforded an inseparable 2.5:1 mixture of
43 and 45 (20 mg, 50%). Characterization data for the major product
43 (from 39) is described above: 1H NMR (CDCl3, 300 MHz) of the
2.5:1 mixture of 43 and 45, δ (discernible signals for minor 45) 6.05
(br s, 1 H), 3.20 (ddd, J = 11.0, 11.0, 3.9 Hz, 1 H), 2.46 (ddd, J = 17.8,
5.4, 2.9 Hz, 1 H), 1.74−1.83 (m, 1 H), 0.89 (d, J = 7.3 Hz, 3 H); 13C
NMR (CDCl3, 75 MHz) of the 2.5:1 mixture of 43 and 45, δ
(discernible signals for minor 45) 172.1, 51.6, 42.6, 34.2, 32.7, 31.9,
31.7, 25.5, 18.8, 12.8. Compound 45 was inseparable from 43, which
prevented its full spectral characterization and measurement of its
optical rotation. Racemic 45 has been reported24d in the literature.
(+)-cis-195A (26). A solution of the octahydroquinolin-2-one 43
(30 mg, 0.18 mmol) in CH2Cl2 (1 mL) was added to a stirred mixture
of trimethyloxonium tetrafluoroborate (55 mg, 0.36 mmol) and N,N-
diisopropylethylamine (1 drop) in CH2Cl2 (1 mL) under argon at 10
°C, and the solution was allowed to stir at rt for 1.5 h. The reaction
mixture was cooled to 0 °C, and cold aqueous saturated NaHCO3 (2
mL) was added. The two layers were separated, and the aqueous layer
was re-extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated. 1H NMR of the crude
product (38 mg) showed the presence of the imidate ether and
unreacted starting material in a 4:1 ratio. The crude product was used
in the next step without any purification to avoid degradation.
A freshly prepared solution of n-C3H7MgBr in Et2O (0.48 mL, 1.32
M) was added to benzene (1 mL) under argon, and the mixture was
heated to 85 °C (oil bath) for 10 min. The imidate ether (38 mg) in
benzene (2 mL) was added to the Grignard solution via cannula and
refluxed for 12 h. The reaction mixture was diluted with Et2O and
2,5-Di-epi-cis-195A (50). 2,5-Di-epi-cis-195A was synthesized
from the cis-octahydraquinolin-2-one 42 (30 mg, 0.18 mmol)
according to the same procedure described above for preparation of
cis-195A; purification by chromatography (10:1 CH2Cl2/MeOH, then
80:20:1 CH2Cl2/MeOH/iPrNH2) afforded 2,5-di-epi-cis-195A (13.2
mg, 38% over three steps, 51% based on recovered 42) as a pale yellow
oil. The starting lactam 42 (7.6 mg, 25%) was also recovered. Addition
of concentrated aqueous HCl (2 drops) to a methanolic solution of
50, followed by evaporation of the solvent, gave the corresponding
hydrochloride salt (15.5 mg) as an off-white solid.
21
Data for 50: [α]D 0.0° (c 0.69, MeOH); IR (neat) νmax 3298,
2928, 2865, 1458 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.88 (ddd, J =
11.6, 3.4, 3.4 Hz, 1 H), 2.67−2.79 (m, 1 H), 1.89 (m, 1 H), 1.65−1.80
(m, 3 H), 1.14−1.65 (m, 11 H), 0.91−1.10 (m, 2 H), 0.88 (t, J = 6.0
Hz, 3 H), 0.86 (d, J = 6.4 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ
56.3, 49.0, 41.6, 40.0, 35.3, 33.3, 28.5, 26.3, 25.5, 19.3, 19.1, 18.4, 14.2.
21
Data for 50·HCl: mp 178−182 °C (decomp); [α]D +0.41° (c
1
0.73, MeOH); IR (CH2Cl2) νmax 3051, 2955, 2870, 1588 cm−1; H
NMR (CDCl3, 300 MHz) δ 9.42 (br s, 1 H), 9.30 (br s, 1 H, NH),
3.40−3.54 (m, 1 H), 3.00−3.18 (m, 1 H), 2.15−2.27 (m, 1 H), 2.05−
2.16 (m, 1 H), 1.90−2.05 (m, 2 H), 1.23−1.89 (m, 11 H), 0.97−1.13
(m, 1 H), 0.93 (t, J = 7.0 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 3 H); 13C
NMR (CDCl3, 75 MHz) δ 55.7, 51.0, 37.4, 35.3, 34.1, 28.1, 27.9, 22.0,
18.8, 18.6, 16.9, 13.9. HRMS (EI-double focusing sector field) m/z:
[M]+ Calcd for C13H26N 196.2060; Found 196.2061.
N
DOI: 10.1021/acs.joc.5b00621
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Tetrahedron 2003, 59, 6445. (c) Wei, B.-G.; Chen, J.; Huang, P.-Q.
Tetrahedron 2006, 62, 190. (d) Liu, L.-X.; Xiao, K.-J.; Huang, P.-Q.
Tetrahedron 2009, 65, 3834. (e) Xiao, K.-J.; Liu, L.-X.; Huang, P.-Q.
Tetrahedron: Asymmetry 2009, 20, 6181. (f) Xiao, K.-J.; Wang, Y.; Ye,
K.-Y.; Huang, P.-Q. Chem.Eur. J. 2010, 16, 12792.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of the H and 13C NMR spectra for all products,
stereochemical assignment data for compounds 38−41 and
42−45, and Cartesian coordinates for computed structures 46.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b00621.
(9) House, H. O.; Blankley, C. J. J. Org. Chem. 1968, 33, 53.
(10) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem. Soc.
Jpn. 1984, 57, 1948.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: Andrew.Wee@uregina.ca.
Notes
■
(13) Nygaard, R.; Madsen, R. J. Org. Chem. 2007, 72, 9782.
(14) From chiral pool starting material: (a) Saitoh, Y.; Moriyama, Y.;
Hirota, H.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. Jpn. 1981,
54, 488. (b) Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
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1999, 1407. (e) Datta, A.; Kumar, J. S. R.; Roy, S. Tetrahedron 2001,
57, 1169. (f) Dransfield, P. J.; Gore, P. M.; Prokes, I.; Shipman, M.;
Slawin, A. M. Z. Org. Biomol. Chem. 2003, 1, 2723. (g) Jourdant, A.;
Zhu, J. Heterocycles 2004, 64, 249. (h) Fuhshuku, K.-i.; Mori, K.
Tetrahedron: Asymmetry 2007, 18, 2104. (i) Andres, J. M.; Pedrosa, R.;
Perez-Encabo, A. Eur. J. Org. Chem. 2007, 1803. (j) Arevalo-Garcia, E.
B.; Colmenares, J. C. Tetrahedron Lett. 2008, 49, 6792. (k) Kokatla, H.
P.; Lahiri, R.; Kancharla, P. K.; Doddi, V. R.; Vankar, Y. D. J. Org.
Chem. 2010, 75, 4608. From synthesis-derived starting material:
(l) Yang, C.-F.; Xu, Y.-M.; Liao, L.-X.; Zhou, W.-S. Tetrahedron Lett.
1998, 39, 9227. (m) Yang, C.; Liao, L.; Xu, Y.; Zhang, H.; Xia, P.;
Zhou, W. Tetrahedron: Asymmetry 1999, 10, 2311. (n) Ma, N.; Ma, D.
Tetrahedron: Asymmetry 2003, 14, 1403. (o) Chavan, S. P.; Praveen, C.
Tetrahedron Lett. 2004, 45, 421. (p) Sim, I. S.; Ryu, C. B.; Li, Q. R.;
Zee, O. P.; Jung, Y. H. Tetrahedron Lett. 2007, 48, 6258. (q) Liu, R.-C.;
Wei, J.-H.; Wei, B.-G.; Lin, G.-Q. Tetrahedron: Asymmetry 2008, 19,
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(s) Abraham, E.; Brock, A.; Candela-Lena, J. I.; Davies, S. G.;
Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell,
A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.; Thomson,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council, Canada and the University of Regina for financial
support. Mr. A. Jayaraman of this department is thanked for his
assistance in the “plus-and-minus-displacement” calculations;
the calculations (Gaussian09, D01) were enabled in part by
support provided by WestGrid (www.westgrid.ca) and
Compute Canada/Calcul Canada (www.computecanada.ca).
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