Concise, stereodivergent and highly stereoselective synthesis of cis-and trans-2-substituted 3-hydroxypiperidines-development of a phosphite-driven cyclodehydration

Article abstract of DOI:10.3762/bjoc.10.35

A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.

Full text of DOI:10.3762/bjoc.10.35

Concise, stereodivergent and highly stereoselective
synthesis of cis- and trans-2-substituted 3-hydroxy-
piperidines – development of a phosphite-driven
cyclodehydration
Peter H. Huy*1,§, Julia C. Westphal2 and Ari M. P. Koskinen*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 369–383.
1Aalto University, School of Chemical Technology, Laboratory of
Organic Chemistry, Kemistintie 1, 02015 Espoo, Finland and
2University of Cologne, Department of Chemistry, Organic Chemistry,
Greinstrasse 4, 50939 Cologne, Germany
doi:10.3762/bjoc.10.35
Received: 18 November 2013
Accepted: 16 January 2014
Published: 11 February 2014
Email:
Peter H. Huy* - peter.huy@uni-saarland.de; Ari M. P. Koskinen* -
ari.koskinen@aalto.fi
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
* Corresponding author
Guest Editor: J. S. Dickschat
§ Current Address: Saarland University, Institute of Organic Chem-
istry, Mailbox 151150, 66041 Saarbrücken, Germany
© 2014 Huy et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amino acids; asymmetric synthesis; cyclodehydration;
hydroxypiperidines; natural products; one-pot
Abstract
A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis
(up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This
sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing
simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct
(triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually asso-
ciated to triphenylphosphine oxide.
Introduction
1,2-Amino alcohols of the type A (Figure 1) represent a products and other bioactive compounds [1-7]. Selected exam-
frequent core motif of many pharmacologically active natural ples are given in Figure 1: The non-peptidic human neurokinin-
products [1-9], chiral auxiliaries [10,11] and catalysts for asym- 1 (NK1) substance P receptor antagonists L-733,060 [15,16]
metric synthesis [12-14]. Especially the 2-substituted 3-hy- and CP-99,994 [17-19], the natural product febrifugine (antima-
droxypiperidine scaffold of the general structure B (as one type larial) [20,21] and antiprotozoal agent halofuginone (commer-
of an 1,2-amino alcohol) can be found in numerous natural cial trade names Halocur® (lactate salt) and Stenorol® (hydro-
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Beilstein J. Org. Chem. 2014, 10, 369–383.
Figure 1: Natural products and other bioactive piperidine derivatives of type B.
bromide salt)) [22]. Other relevant examples are 3-hydroxypipe- tile pharmacological activities of compounds based on the
colic acids, which serve as (conformationally restricted) substi- 3-piperidinol scaffold, a step-economic, scalable and stereodi-
tutes of proline and serine [23,24] and have been incorporated vergent synthesis of both cis- and trans-diastereomers of B in
into diverse bioactive peptidomimetics [25,26], and the good diastereoselectivities is highly desirable.
iminosugar swainsonine, a new potential chemotherapeutic
agent [27,28]. Recently, analogs of halofuginone were discov- In the syntheses of potentially new drug candidates scalability is
ered as inhibitors of tRNA synthetases [29-31].
a significant factor to provide sufficient substance amounts for
clinical tests [41,42]. Additionally, alternatives in reactions
The majority of the reported syntheses [2-4,32-35] are elabo- driven by the formation of phosphine oxides from phosphines
rate (far more than 10 steps), specific on one of the targets (e.g. the Appel and Mitsunobu reaction) are highly desired to
depicted in Figure 1 and therefore on one relative configuration improve atom economy (reduced waste amounts) and to
(either cis- or trans), and have not been proven to be scalable. circumvent difficulties in the separation of these by-products as
In our opinion the following examples represent the most effi- demonstrated by a number of reviews [43-45]. Numerous proto-
cient synthesis of 3-piperidinols of type B in terms of step- cols have been developed to improve these issues, mostly based
economy (<10 steps to establish the core motif B): 1. Charette on polymer supported or otherwise modified (more complex)
[36] prepared the less bioactive enantiomers of L-733,060 and phosphines [43-45]. Surprisingly, in this context simple and
CP-99,994 through nucleophilic additions to chiral pyridylium inexpensive phosphites (P(OR)3) have only been applied as
salts and subsequent hydrogenation. 2. Cossy and Pardo [37,38] phosphine substitutes in one single example: Beal [46] utilized
synthesized L-733,060 (formal total synthesis) and two tri-isopropylphosphite in a Mitsunobu condensation of a
(epimeric) hydroxypipecolic acid through ring expansions of guanine-derived nucleoside analog with benzylic alcohols
2-(α-hydroxyalkyl)pyrrolidines deduced to proline. 3. Based on providing simplified byproduct separation through improved
the ring expansion of Cossy and Pardo [37], O´Brien [39] real- water solubility (of O=P(OiPr)3). In our case we were not able
ized the synthesis of L-733,060 (80% ee). The 2-(α-hydroxyal- to remove stoichiometric amounts of OP(OEt)3 (which is more
kyl)pyrrolidine precursor was prepared from a protected pyrro- hydrophilic than OP(OiPr)3) through an aqueous work up
lidine through sparteine-mediated enantioselective lithiation and (without saponification). Moreover, pentavalent P(OEt)5
subsequent hydroxyalkylation. 4. Recently, Pansare [40] prepared from P(OEt)3 with diethylperoxide and ethylbenzene-
reported the synthesis of L-733,060, CP-99,994 and a hydroxy- sulfonate, respectively, in an additional step, was reported to
pipecolic acid through asymmetric organocatalytic vinylogous effect cyclodehydration of diols to furans and pyrans [47,48]
aldol addition as the key step.
(for recent examples for cyclodehydration protocols see
[49,50]). Thereby, the volatile products were separated from
While the syntheses by Charette [38] and Pansare [40] are O=P(OEt)3 through distillation.
restricted to piperidinols B in cis-configuration (dr >19:1 and
8:1, respectively), the sequences of Cossy and Pardo [35] and After our initial short communication [51] about the step-
O´Brien [39] are stereodivergent. Nevertheless, the observed economic and stereodivergent synthesis of trans- and cis-2-
diastereomeric ratios are low (1:1 and 2.3:1 for trans-B, res- substituted 3-piperidinols B, we want to report the development
pectively) at least for one of the epimers. Considering the versa- of this sequence in more detail with a focus on the phosphite-
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Beilstein J. Org. Chem. 2014, 10, 369–383.
Figure 2: Retrosynthetic analysis of piperidines B (X = OH or leaving group, PG = protecting group).
mediated cyclodehydration. Additionally, the synthesis of a side labile amino aldehyde intermediates [55,56]. Basically any
chain functionalized piperidinol derived from methionine and carbamate or amide protecting group (= PG) orthogonal to the
studies towards the preparation of glutamic and aspartic acid benzyl moiety would be suitable for this strategy. Furthermore,
derived heterocycles are presented.
we decided to surrender protection of the OH functions in the
synthesis of intermediates D and C in order to minimize the
Following the retrosynthetic analysis in Figure 2 the relative number of steps of the sequence. Thus far only four examples
configuration of B (cis/trans) should be controlled through following a related strategy to establish the syn- and anti-con-
targeted protecting group (PG) manipulation: Reduction of the figuration of 1,2-aminoalcohol motifs have been reported [57-
common precursor ketone D (derived from commercial avail- 60].
able amino acids) should deliver the syn-amino alcohol C
Results and Discussion
proceeding though a Felkin–Anh transition state [52,53] (due to
the sterically demanding –NBnPG function). Further PG Synthesis of hydroxyketone intermediates D
cleavage and cyclodehydration would give rise to cis-B. On the In the first step L-alanine, phenylalanine, phenylglycine and
other hand, initial deprotection of D (to liberate the Lewis-basic methionine 1a–d were converted to their N-benzyl-N-carba-
–NHBn moiety) and subsequent reduction passing through a mate-protected derivatives 2a–d (PG = Cbz, Boc) in a practical
Cram-chelate transition state [54] should deliver the anti-amino one pot procedure through combination of Quitt´s reductive
alcohol C.
benzylation protocol [61] and a Schotten–Baumann acylation
[62,63] in 70–95% yield (Scheme 1). While we choose a Cbz
After subsequent cyclisation trans-B would result. Noteworthy, protecting group for the amino acids 1a–c due to the mild
this strategy would completely circumvent configurationally cleavage conditions (hydrogenolysis), we decided to introduce a
Scheme 1: Synthesis of the protected amino acids 2. (a) KOH for 1b. b) PG–X = Cbz–Cl (1a–c), Boc2O (1d).
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Beilstein J. Org. Chem. 2014, 10, 369–383.
Boc group at the N-terminus of methionine 1d to avoid desulfu- the dibenzyl-protected derivatives 4 formed as side products
ration (–EtSMe → –Et) in the later deprotection.
(<10% referred to 2). The residual impurities (BnOH and 4)
were separated either through work up (of amide 5a) or
In order to suppress the formation of the only carbamate chromatographic purification (of amides 5b–d) after the
protected amino acid derivatives 3 (remaining as impurity in the following amidation (2→5).
isolated products 2), quantitative benzylation (1→I) was
ensured by successive addition of three portions of benzalde- Importantly, through this procedure not only one isolation step
hyde/NaBH4 (Quitt´s procedure [61] → two portions) and by was avoided, but also the overall yield was improved signifi-
maintaining the pH at a value of 10–11. The extractive sep- cantly: For the transformation from 1a to 2a (I isolated as free
aration (washing of a basic aqueous solution of the acids 2) of acid) under (optimized) literature conditions we achieved a
the two equivalents of BnOH formed during the reductive yield of 44% over two steps (59% and 74%, respectively)
amination (1→I) proved to be challenging: Due to the high compared to 70% according to our direct conversion from 1a to
amphiphilicity of carboxylate salts of 2, mixtures in water and 2a.
an organic solvent tend to form three distinct phases separating
poorly. Nevertheless, washing of an aqueous solution of the Next the carboxylic acids 2 were transformed to the Weinreb
polar lithium salts of 2 (crude 2 in aq. LiOH) with organic amides 5 with DCC and MeONHMe in 77–91% yield
solvents of increasing polarity (Et2O→EtOAc) allowed to (Scheme 2). While no racemisation occurred with substrates 2a,
remove BnOH almost completely (<10% of BnOH referred to 2b and 2d (Et3N/DMAP or NMM as bases; Table 1, entries 1
2). Residual benzyl alcohol diminished the yield in the and 2), the protected phenylglycine derivative 2c showed high
following amidation (2→5) due to competitive formation of the configurational lability: Under standard conditions (DCC/Et3N/
corresponding benzyl esters. Depending on the NaBH4 batch 0.3 equiv DMAP) the amide 5c was obtained in a diminished ee
Scheme 2: Synthesis of hydroxy ketones 7 (R = Me (a), Bn (b), Ph (c) and EtSMe (d); PG = Cbz (a–c), Boc (d)).
Table 1: Ees and isolated yields of Weinreb amides 5.
entry
substrate
R
reagents
eea
yield
1
2
2a
2b
–Me
–Bn
DCC, NMM
99%
99%
91%b
77%c
DCC, Et3N, DMAP (cat.)d
3
4
5
6
7
DCC, Et3N, DMAP (cat.)d
DCC, Et3N, HOBt (cat.)d
DCC, NMM, DMAP (cat.)d
DCC, NMM
49%
5%
n.d.
n.d.
2c
2d
–Ph
75%
95%
74%
n.d.
81%b
n.d.
T3P, pyridinee
8
–EtSMe
DCC, NMM
99%f
91%b
aThe ee was determined via HPLC on a chiral stationary phase. bIsolated crude yield, purity >90% according 1H NMR. cIsolated yield after chroma-
tography. dcat. = 0.3 equiv. eSolvent EtOAc instead of CH2Cl2. fThe ee was determined to be ≥99% at the later stage the piperidinol cis-11d. DCC =
N,N´-dicyclohexylcarbodiimide; NMM = N-methylmorpholine; DMAP = N,N-dimethylaminopyridine, HOBt = 1-hydroxybenzotriazole; T3P = n-propy-
lphosphonic acid anhydride; n.d. = not determined.
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Beilstein J. Org. Chem. 2014, 10, 369–383.
of 49% (Table 1, entry 3). HOBt as nucleophilic catalyst proved excess of MeMgBr in the deprotonation step of 3-chloro-
to be even worse than DMAP, because under otherwise iden- propanol was found to assist the Grignard formation. Notably,
tical conditions the product 5c was isolated almost as a race- with this strategy we saved additional protection and deprotec-
mate (5% ee, entry 4). By replacing Et3N with the less basic tion steps of the free hydroxy group of 7. Thereby, only the
NMM (in the presence of DMAP) the ee increased clearly phenylglycine derivative 7c displayed a slight decrease of ee
(49→75%, entry 5). However, without any nucleophilic cata- (95→92%), the other hydroxy ketones 7a, 7b and 7d did not
lyst the desired amide 5c was isolated with a very good ee of show any racemisation at all, not even after a longer time of
95% (entry 6) [64].
storage. For the latter three the enantiomeric excess was not
determined on this step: Further conversion as depicted in
The high racemisation sensitivity of 2c is further underlined by Scheme 4 and Table 2 delivered piperidinols 11a, 11b and 11d
a T3P/pyridine (n-propylphosphonic acid anhydride) [65,66] in ≥99% ee. As no intermediate in the conversion of 7 to 11 was
mediated amidation, which has been reported to suppress crystallized, the ketones 7a, 7b and 7d must have been enan-
racemisation [67]. With substrate 2c the condensation product tiopure.
5c was formed in a moderate ee of 74% (Table 1, entry 7). The
configurational lability of the phenylglycine derivative was not Residual 3-chloropropanol (<15 mol % referred to 7), which
surprising, as phenylglycine itself is 60 times more prone to was difficult to separate chromatographically, was removed
racemisation than alanine [68]. The optical purity of amides after the next step either during the work up (diols 9) or chro-
5a–c, hydroxyketone 7c and piperidins cis-11a–d and trans-11a matographically (on the sequence leading to 15a). Interestingly,
(Table 2, Scheme 6 and 7) was determined with HPLC on a the ketones 7a–d existed in an equilibrium with their cyclic
chiral stationary phase and comparison with racemic samples hemiacetal tautomers as shown in Scheme 2. The predominant
(alanine 1a and phenylglycine 1c derived substrates) or in keto form possessed a clear singlet around 205–210 ppm for the
analogy to the aforementioned amino acid derivatives (phenyl- quaternary carbonyl carbon and the furan form was indicated by
alanine 1b and methionine 1d deduced substrates).
two weak signals at 105–110 ppm for the hemiacetal carbon
(two diastereomers) in the 13C NMR.
In the next step, addition of a slight excess of the 3-chloro-
propanol-derived Grignard reagent 6 (final concentration Additionally, a short 3 step route to the functionalized glutamic
0.25–0.3 mol/L), which was found to be superior in the final and aspartic acid derived Weinreb amides 5e and 5f was coined
concentration to the reported ClMgnPrOMgCl derivative as outlined in Scheme 3: At the outset both amino acids (1e and
(0.1–0.2 mol/L in our hands) [69], to amides 5a–d resulted in 1f) were subjected to esterification of the sterically less
ketones 7a–d in good to excellent yields (86–97%, Scheme 2). hindered side chain carboxyl function with acetyl chloride in
In contrast to the reported procedure (2–3 h of reflux) [69], MeOH [70-72]. Neutralization of the reaction mixture with
short reflux times to form 6 (20–30 min) were crucial to avoid K2CO3 and reductive benzylation [73] in one-pot then deliv-
decomposition of this dianionic reagent. Furthermore, a slight ered the benzyl amines 8e and 8f. While glutamic acid showed
Scheme 3: Synthesis of amides 5e and 5f and ketone 7e.
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Beilstein J. Org. Chem. 2014, 10, 369–383.
selective mono esterification after 3 h at room temperature, the excellent yields and as pure diastereomers as indicated by
aspartic acid mono ester was obtained in a 5:1 ratio with the 400 MHz 1H NMR (Scheme 4). Unfortunately, L-Selectride
diester (not shown) after approximately 18 h of reaction time. proved to be too unreactive at low temperatures towards the
Shorter reaction times in the esterification step of 1f decreased phenylglycine derived ketone 7c, at higher temperatures mainly
the yield of 8f.
decomposition of the starting material was observed. Neverthe-
less, Superhydride [75,76] reduction and successive Cbz-
The amines 8e and 8f were converted in a straightforward cleavage gave the desired amino alcohol syn-9c in useful
manner to the carbamates 2e and 2f under Schotten–Baumann diastereomeric ratios of 3.7–4:1 syn/anti. The slightly dimin-
conditions [62,63]. Thus, K2CO3 (→ pH = 10) as the base ished yield of 9c (74–77%) compared to 9a and 9b (85–93%) is
prevented saponification of the side chain methyl ester func- rationalized by formation of the oxazolidinone 10c as side-
tions (as observed with hydroxide salts). Nevertheless, in the product. This cyclic carbamate results from the condensation of
acylation of the glutamic acid derivative 8e the corresponding the alcoholate moiety of II with the Cbz-function passing the
pyroglutamic acid derivative 2g resulting from lactamisation of syn-periplanar conformation indicated in Scheme 4. With a
the ester function was observed as a side product in traces bulky phenyl substituent (= R) this conformation is higher
(<5%). Next, amidation of the acids 2e and 2f gave the amides populated than with smaller R groups (e.g. Me and Bn) due to
5e and 5f in good yields under standard coupling conditions. increased steric repulsion between the n-PrOH and R moiety.
Unfortunately, the ketone 7e was obtained in only 24% yield This explains the more facile formation of oxazolidinones of
through addition of the Grignard reagent 6 to amide 5e (along type 10 with the phenylglycine derived carbamate 7c. Indeed, if
with 30% of reisolated starting material), illustrating the ten- the excess of Selectride was quenched with acetaldehyde after
dency of reagent 6 to attack the side chain ester moiety.
reduction of 7a, the oxazolidine 10a was obtained (under the
basic reaction conditions) as the major product.
Synthesis of syn-amino alcohols C
Already the NaBH4 reduction (in MeOH at −40/0 °C) of The outcome of the Cbz-cleavage strongly depended on the
ketones 7a and 7b and subsequent hydrogenolysis of the Cbz- activity of the commercial Pd/C batch: While an active catalyst
group in one-pot delivered the syn-amino alcohols 9a and 9b in led to a quantitative cleavage after 3 h (all substrates), less reac-
good diastereomeric ratios (around 11:1 syn/anti, compare tive batches led to considerably increased reaction times (2 d for
Scheme 4). In contrast the NaBH4 reduction of ketone 7c under 7a). For 7b and 7c the isolated yields of the amines 9 even
identical conditions gave diol 9c without any selectivity (dr = dropped to 10–20% after 2 d reaction time due to incomplete
1.3:1). To our delight, reduction of the ketones 7a and 7b with Cbz-cleavage. However, Pd/C freshly prepared from Pd(OAc)2
L-Selectride [74] (or N-Selectride) and subsequent hydrogenol- and activated charcoal according to Felpin [77] delivered
ysis of the Cbz-group in one-pot delivered the benzyl amines consistent results (reaction time < 3 h). Although the Cbz-
syn-9a and 9b in accordance with the Felkin–Anh model in cleavage beside a benzyl moiety in alcohols as solvent is known
Scheme 4: Synthesis of amino alcohols syn-9a–d and oxazolidinone 10a. (for 7a–c conditions A: H2 (1 atm), Pd/C, HCl, MeOH (THF/MeOH 1:1), rt,
3 h; for 7d conditions B: HCl (aq.; 4 N HCl in THF/H2O), rt, 6 h) aR´= sBu for 7a, 7b and 7d (L-Selectride); R´= Et for 7c (Superhydride). bdr ≥ 19:1.
cdr = 3.7–4:1.)
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Beilstein J. Org. Chem. 2014, 10, 369–383.
(for selected examples of the chemoselective Cbz-cleavage of acidic, aqueous phase of the products 9 resulting in the crude
Bn, Cbz-protected amines see [78-80]), we only achieved high diols 9a–d in a circa 90% purity according 1H NMR. Hence, the
chemoselectivities in the presence of an excess of HCl.
crude amino alcohols 9 were not further purified before the
following cyclodehydration.
In a similar manner the methionine derived Boc-protected
ketone 7d was converted through L-Selectride reduction and Synthesis of cis-piperidinols B
Boc-cleavage induced by aqueous HCl solution in one pot to the Cyclodehydration of amino alcohol syn-9a to piperidinol cis-
syn-aminoalcohol 9d as a single diastereomer according to 1H 11a under Appel conditions (I2, PPh3) [81,82] surpassed by far
NMR. Importantly for up-scaling, only a slight excess of Mitsunobu conditions and sulfonation (with MsCl, TsCl)
L-Selectride (1.3 equiv) or Superhydride (1.5 equiv), respect- induced cyclisations (see Supporting Information File 1 for
ively, was required for the quantitative conversion of 7a–d to more details): Under optimized conditions (1.1 equiv I2, Et3N in
the intermediate II. Therefore the deprotonation of the free MeCN at −40 °C) the cyclic products 11a–c were isolated in
OH-group of 7 must be significantly slower than the desired 68–77% yield and 90–99% ee (Table 2 entry 1, 10, 12). For
reduction of the carbonyl function. Practically, the residual work up the reaction mixture was simply absorbed on silica gel
3-chloropropanol remaining from the prior Grignard addition (ca. 9 fold amount of starting material 9) through evaporation of
5→7 step (vide supra) and sec-Bu3B/BEt3 from the reduction the solvent and directly subjected to chromatographic purifica-
were easily separated through washing with Et2O of an (HCl) tion.
Table 2: Cyclodehydration of amino alcohols 9a–d to piperidinols 11a–d.
entry
substrate
R
PR3
deviation from standard conditions
yield
1
2
3
4
5
6
7
8
9
PPh3
–
77%a,b,c
82%a,b,c (14 g)
52%a,c
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
–
reflux instead of rt in saponification
DIPEA instead of Et3Ne
lutidine instead of Et3Ne
imidazole instead of Et3Ne
Et3N/CH2Cl2 1:10
57%c,d
syn-9a
–Me
50%c,d
30%c,d
79%c,d
THF instead of CH2Cl2e
−20 °C then warming to 0 °C
58%c,d
41%a,c
10
11
PPh3
–
–
68%a,b,c
74%a,b,c
syn-9b
–Bn
P(OEt)3
12
13
14
15
PPh3
–
77%a,e,f (2.3 g)
68%a,e,f
P(OEt)3
P(OEt)3
P(OEt)3
Et3N/CH2Cl2 1:1.3
–
syn-9c
syn-9d
–Ph
49%a,f
Et3N/CH2Cl2 1:3
22%a,f
16
–EtSMe
P(OEt)3
–
74%a,b,c
aIsolated yield after chromatographic purification. bee ≥ 99%, determined by HPLC on a chiral stationary phase. cdr >19:1 cis/trans. dYield deter-
mined with naphthalene as NMR-standard. eRatio base/solvent 1:10. fee = 90%; dr = 4.0:1 (entry 12), 5.3:1 (entry 13), 3.7.1 (entry 14), 3.0:1 (entry
15) cis/trans. DIPEA = di-isopropylethylamine; lutidine = 2,6-dimethylpyridine. All reactions were run until full conversion of the starting material 9.
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Beilstein J. Org. Chem. 2014, 10, 369–383.
Unfortunately, the stoichiometric byproduct triphenyl phosphi- For both cyclodehydration methods (with PPh3 and P(OEt)3)
ne oxide was only separable by chromatography requiring neat iodine was simply added to a solution of the amino alco-
significantly increased amounts of silica gel (the crude product hols 9a–d, the phosphorus reagent and Et3N in the reaction
weight usually obtained 300–400% of the theoretical yield after solvent at the indicated temperature (−40 °C and −78 °C, res-
aqueous work up). Attempts to crystallize OPPh3 beside the pectively) and stirred at this temperature, until I2 had dissolved
piperidine 11a or of the fumaric acid salt of 11a for instance completely (1–2 h with PPh3 and 2–5 h with P(OEt)3). Then the
failed, only an oily mixture of 11a and OPPh3 precipitated. Sep- usually heterogeneous mixture (through precipitated
aration of OPPh3 through washing of an aqueous solution of Et3NH+Cl−) was allowed to warm to room temperature to reach
hydrochlorides of 11 led to a significant loss of piperidines 11 full conversion of the starting material 9. Due to the ammoni-
(especially with 11b and 11c bearing lipophilic side chains R). um salt precipitation and the solid iodine for the large scale
preparation of piperidinol 11a (14 g, Table 2, entry 2) mechan-
In general, the reaction of alcohols with alkyl phosphites ical stirring was preferred. For saponification, saturated KOH
(P(OR)3), activated through oxidants such as iodine, have been solution in MeOH (ca. 4 N) was chosen, because aqueous KOH
reported to give the corresponding phosphates in a or NaOH solution would result in biphasic mixtures. A quanti-
Michaelis–Arbuzow type reaction [83-85] (Scheme 5). In order tative hydrolysis of the triethylphosphate side product required
to improve atom economy and side product separation, we evaporation of CH2Cl2 and Et3N (and MeOH) after the add-
rationalized that in the phosphonium intermediate III (origi- ition of the methanolic KOH-solution in vacuo, dilution with
nating from activation of the diol/amino alcohol E) the MeOH, stirring at room temperature for ca. 1 h, and a second
intramolecular substitution by the amino function (delivering concentration under reduced pressure. Most likely, the solu-
the desired heterocycles of type G) should be significantly bility of KOH in the CH2Cl2/Et3N/MeOH mixture is too low
faster than the bimolecular reaction of the iodide ion with inter- resulting in incomplete hydrolysis of the phosphate without
mediate III as indicated (resulting in the formation of the evaporation of the solvent. Saponification at reflux on the other
corresponding undesired phosphates F). The formation of hand (in order to circumvent the solvent evaporations) led to
heterocycles G passing phosphates F through substitution of the partial decomposition of the product 11a (isolated yield 52%
phosphate leaving group by the nucleophilic YH moiety would after several hours of reflux, see Table 2, entry 3). Chromato-
be in principal also a plausible explanation for the formation of graphic purification of the crude piperidinols 11a–d, which
F, but can most likely be excluded (see Supporting Information were already isolated in 85–90% purity (from the phosphite
File 1).
cyclodehydration), was best achieved with halogen free iPrOH/
Et3N/hexane eluent mixtures (ratio 0.8–3:2–4:100 depending on
Indeed, under optimized conditions (1.2 equiv I2, P(OEt)3, Et3N the polarity of the product). Although the diastereomers of
(5–6 equiv)/CH2Cl2 1:2; −78 °C then warming to rt) the piperidinol 11c (dr ca. 4:1 cis/trans) were chromatographically
piperidinols 11a–d were isolated after saponification (during separable, we decided to separate them after protecting group
work up) of triethylphosphate and chromatographic purifica- exchange at the stage of the Boc carbamate 16c (see Scheme 8),
tion in 68–82% yield and high enantiomeric excess (90–99%) because the epimers of the latter one were much easier to
(Table 2, entries 2, 11, 13 and 16).
isolate.
Scheme 5: Competition between the Michaelis–Arbuzow process and the desired cyclodehydration of amino alcohols and diols E (Y = e.g. O, NBn).
376

Beilstein J. Org. Chem. 2014, 10, 369–383.
Interestingly, we observed a high specificity in the base: With Furthermore, in THF the yield of 11a decreased to 58%
pyridine, NMM, DMAP and DBU (1,8-diaza[5.4.0]bicyclo- (Table 2, entry 8), whereas in MeCN low conversions were
undec-7-ene), respectively, (instead of Et3N) the desired hetero- observed most likely through reaction of the solvent with the
cycle 11a was only formed in traces. DIPEA, lutidine and I–P(OEt)3+ intermediate and in Et3N as the sole solvent the
imidazole delivered 11a in clearly diminished yields of 30–57% solubility of iodine is too low. Even at room temperature iodine
(Table 2, entries 4–6) compared to Et3N (79%, entry 7). For did not dissolve (= react) completely. Also a larger excess of
comparison we ran the condensation of amino alcohol 9a to iodine (>1.2 equiv) has a negative effect on the yield, because
piperidinol 11a in the same concentration as in Table 2, entries the secondary hydroxy function probably is activated as well.
4–6 and 8 (as opposed to the standard conditions) and deter- With the more atom economic P(OMe)3 complex product
mined the yield also through NMR-standard: The yield assigned mixtures were obtained (in the case of substrate 9a). Most likely
in that way (79%, entry 7) shows a decent match to the 82% the differentiation between the Michaelis–Arbuzow and
isolated yield obtained under standard conditions (entry 2). cyclodehydration pathway (see Scheme 5) is declined. More-
Hence, the comparability of Table 2 entry 2 to entries 4–8 is over, the reaction temperature has a strong influence: When the
established. In conclusion NMM, pyridine and imidazole might condensation of 9a had been performed at −20 °C for instance,
be too weak bases, DBU might be too strong and a base piperidine 11a was isolated in only 41% yield (Table 2, entry
favoring other reaction pathways then the desired cyclodehydra- 9). Interestingly, the activation of the primary OH function of
tion. DIPEA and lutidine could be sterically too hindered and substrates 9 in the presence of the secondary OH group
DMAP too nucleophilic inducing side reactions.
proceeded (with PPh3 and P(OEt)3) in very high chemoselec-
tivity most likely due to steric effects. The corresponding aziri-
Moreover, we observed a strong influence of the ratio of Et3N/ dine of 9a clearly resulting from activation of the secondary
CH2Cl2 with substrate 9c: The phenylglycine-derived hydroxy- hydroxy group and subsequent fast 3-exo-trig cyclisation was
piperidine 11c was obtained in 68% yield in Et3N/CH2Cl2 in a only obtained as a sideproduct at higher temperatures (I2, PPh3,
1:1.3 ratio, while a 1:3 solvent mixture gave 11c in only 22% imidazole, CH2Cl2 at 0 °C; see Supporting Information File 1
yield (Table 2, entries 13–15). Indeed, the furan 13h (see for more details).
Table 2) resulting from nucleophilic substitution of the primary
(activated) OH-function through the secondary hydroxy group Significantly, 14 g of alanine derivative cis-11a were obtained
of 9c formed in significant amounts in the cyclisation of amino (cyclodehydration with P(OEt)3) in one batch with no purifica-
diol 9c. This is explained by steric shielding of the amino func- tion of the intermediates (2a, 5a, 7a and syn-9a) at all and an
tion (→ decreased nucleophilicity) through the bulky phenyl overall yield of 44%, demonstrating the scalability and high
group in α-position (compared to the less demanding Me and practicability of our sequence. The relative configurations of
Bn side chains R of substrates 9a and 9c). As the R-substituent compounds 9 and 11 were proven by NOE spectroscopy of
is in the β-position of the secondary OH-function of diols 9, this piperidinols cis-11a–d, trans-11a, cis- and trans-16c,
hydroxy moiety is less shielded. For substrate 9c the yield could L-733,060.HCl and of oxazolidinones trans-10a and trans-10c
not be improved further, because in higher ratios Et3N/CH2Cl2 (see Supporting Information File 1 for more details).
iodine did not completely dissolve (react) at −78 °C in a reason-
Synthesis of other heterocycles through
able time (<12 h).
phosphite-mediated cyclodehydration
This strong influence of the ratio of Et3N/CH2Cl2 can be attrib- We next wanted to demonstrate the generality of the phosphite-
uted to the lower solubility of iodine in Et3N (which leads to a mediated cyclodehydration (Table 3). Towards this end, a range
slower and thus more selective reaction) and general base catal- of amino alcohols and diols 12a,b and 12d–h were converted in
ysis: Simultaneous deprotonation (through Et3N) in the cyclisa- usually very good yields (>80%) to pyrrolidines, piperidines
tion step strongly favours the desired reaction pathway to and furans 13a,b and 13d–h. The established cyclodehydration
piperidines 11. Due to this effect we chose a ratio of Et3N/ procedure only had to be slightly modified regarding the work
CH2Cl2 1:2 as standard conditions for the phosphite mediated up: As most of the products 13a,b and 13d–h are volatile, the
cyclodehydration. Typically, 5 to 6 equivalents of Et3N crude reaction mixture was concentrated under reduced pres-
resulting in a reasonable concentration of the substrates 11 and sure (50 mbar) after quenching with the methanolic KOH solu-
12 (see Table 3) of 0.4–0.5 mol/L (in Et3N/CH2Cl2) were suffi- tion and kept at this pressure at the rotatory evaporator for ca.
cient enough to guarantee magnetically stirring, as the viscosity 0.5 h. Then the residue was portioned between water and
of the reaction mixture increases through ammonium salt n-pentane (high volatility and low solubility of OP(OEt)3!) and
precipitation during the preceding reaction. Noteworthy, Et3N is the organic phase was washed with five portions of water to
as cheap as common solvents such as THF and CH2Cl2.
remove the remaining phosphate (after saponification 13
377

Beilstein J. Org. Chem. 2014, 10, 369–383.
Table 3: Cyclodehydration of amino alcohols and diols 12a–h to heterocycles 13a–h.
entry
substrate
YH
R1
H
R2
H
n
deviation from standard conditions
yield
1
2
–
80%a
81%b
12a
NBn
1
washing of 13-HCl (aq.) with EtOAc instead of saponification
3
4
12b
12c
NBn
H
H
H
H
2
2
washing 13b-HCl (aq.) with EtOAc instead of saponification
63%b
n. r.
NBoc
2 d at rt
5
6
rac-12d
rac-12e
OH
OH
Ph
H
H
1
1
–
–
92%b
85%b
o-ClPh
7
8
9
–
83%b
67%a
83%a
rac-12f
OH
p-BrPh
H
1
P(OiPr)3 instead of P(OEt)3
P(OPh)3 instead of P(OEt)3
10
rac-12g
OH
OH
Mes
Ph
H
1
1
–
84%b
11
12
–
82%b
75%a
12h
Ph
PPh3/MeCN instead of P(OEt)3/CH2Cl2
aYield determined with naphthalene as NMR-standard. bIsolated yields, purity >90% according to crude 1H NMR.
contained 20–30 mol % of the phosphate). Finally, the hetero- The α-aryl furans 13d–f were formed in excellent yields
cycles 13 were isolated without a trace of the phosphoric acid (83–92%, Table 3, entries 5–7). Interestingly, the cyclodehydra-
ester (“traceless cyclodehydration”) in >90% purity according tion of rac-12f was also mediated by P(OiPr)3 and P(OPh)3 in
to 1H NMR.
67% and 83% yield, respectively (entries 8–9). Whereas
OP(OiPr)3 was hydrolyzed in the work up, OP(OPh)3 was not
We first investigated the amino alcohols 12a–c: Pyrrolidine 13a saponified and therefore still remained in the isolated product
was formed in 80% yield after hydrolysis of the phosphate and 13f. However, considering the atom economy these phosphites
in 81% yield after extraction of triethylphosphate with EtOAc do not represent an alternative to P(OEt)3. Even the diols rac-
(×5) while keeping the product 13a as the hydrochloride salt in 12g and 12h with a sterically demanding mesityl and two phe-
the aqueous phase (Table 3, entries 1 and 2). Surprisingly, with nyl substituents, respectively, gave cleanly the furans rac-13g
the higher homologue 12b the piperidine 13b was obtained in and 13h in good yields (Table 3, entries 10 and 11). Also in
only 63% yield (entry 3). The lower yield compared to the hy- terms of isolated yield the phosphite-mediated cyclodehydra-
droxypiperidines 11a,b and 11d (≥74%, see Table 2) might be tion of substrate 12h was superior (82%, Table 3, entry 11) to
explained by the preference of a conformation of the phospho- the phosphine driven conditions (75%, entry 12).
nium intermediate III of 11a,b and 11d (Scheme 5), which is
favourable for the cyclisation. This arrangement might be stabi- Synthesis of a trans-piperidinol B
lized through a hydrogen bridge between the NH proton and the We initially investigated the diastereoselectivity of the reduc-
O atom of the secondary OH group and a (weak) Thorpe–Ingold tion of the secondary benzylamino ketone 14a, which was
effect by the substituent R. The much less nucleophilic Boc- synthesized from hydroxyketone 7a through Cbz-cleavage and
carbamate 12c was not converted to the desired piperidine 13c basic work up (Scheme 6 and Table 4). According to 1H NMR
(entry 4). Here only starting material was re-isolated (probably the hemiacetal of 14a (ca. 1:1 ratio of its epimers) forms an
originating from hydrolysis of the corresponding phosphate of equilibrium with its ketone tautomer in a 1.8:1 ratio. In contrast
alcohol 12c).
to hydroxyketones 7a–d the furan tautomer of 14a is thermody-
378

Beilstein J. Org. Chem. 2014, 10, 369–383.
Scheme 6: Initial synthesis of the trans-piperidinol 11a in diminished enantiopurity. aThe amino alcohol 9a obtained through L-Selectride reduction
according to entry 6 in Table 4 (dr = 25:1) was subjected to cyclodehydration.
namically more stable than the keto form. This might be ratio- is in harsh contrast to previously reported reductions of related
nalized by a lower steric strain in the heterocyclic form due to para-methoxybenzylamino and benzylamino ketones with
the smaller NHBn side chain (compared to NBnCbz in 7a–d).
DIBALH giving rise of the best diastereoselectivities [59,60]).
Albeit up to four equivalents of DIBALH were utilized, only
Disappointingly, in the reduction with NaBH4 no selectivity 40–60% conversion of 14a was reached. Here the complexa-
was observed at all (dr = 1:1 anti/syn, Table 4, entry 1). tion by –AliBu2 after the initial deprotonation of the OH and
However, in the presence of one equivalent of HCl the diol 9a NH function of 14a might shield the carbonyl group and
was isolated in a moderate dr of 2.6:1 (entry 2), which demon- encumber reduction.
strated the formation of a Cram chelate transition state stabi-
lized through a hydrogen bond of the hydrochloride of 14a. However, L-Selectride reduction resulted in better stereoselec-
Under Luche conditions (NaBH4, CeCl3) [86] a similar result tivities with dr = 6:1 anti/syn (Table 4, entry 5). If the starting
was attained (dr = 2.9:1, Table 4, entry 3).
material 14a was dissolved in the less polar CH2Cl2 (rather than
THF), the dr further increased to >19:1 (entry 6). Moreover,
DIBALH delivered amino alcohol 9a (various solvents tested) N-Selectride provided the product 9a almost as a pure diastere-
only in poor selectivities (dr up 2.6:1, Table 4, entry 4), which omer (entry 7, solvent THF), only a very small trace of the syn-
diastereomer was visible in the 1H NMR (400 MHz). Neverthe-
less, even with 4 equivalents of Selectride conversions of only
Table 4: Diastereoselectivity in the reduction of ketone 14a.
up to 80% were observed. Unfortunately, subsequent Appel
reaction of the diol anti-9a (dr = 25:1), synthesized through
entry [H–]
solvent
T [°C] dr (anti/syn)
L-Selectride reduction in THF/CH2Cl2 (Table 4, entry 6), gave
piperidinol 11a in a significantly diminished ee of 32% (deter-
mined via HPLC on a chiral stationary phase and comparison
with a racemic sample). This racemisation might be rational-
ized by an intermolecular enamine formation of the secondary
amino ketone 14b as depicted in the intermediate IV, Scheme 6.
1
2
3
4
5
6
7
NaBH4
NaBH4, HCl
MeOH
MeOH
0
1:1a
0
2.6:1a
2.9:1a
1.4–2.6:1c
6:1d
NaBH4, CeCl3 MeOH
−78
−78
−78
DIBALH
diversb
THF
L-Selectride
L-Selectride
N-Selectride
CH2Cl2/THFd −78
THF −78
25:1e
>50:1e
At this point we realized that a hydrochloride of the secondary
amino ketone 14a or a derivative should be unable to racemise
through autocatalytic enamine formation (due to the protona-
tion of the amino function). However, the hydrochloride of
amine 14a was poorly soluble in organic solvents, so that its
isolation proved to be difficult. Straightforward, mesylation of
hydroxyketone 7a and subsequent Cbz-cleavage (H2, Pd/C) in
aThe amino alcohol 9a was isolated in 87% (entry 1), 85% (entry 2),
93% (entry 3) yield and >90% purity according to 1H NMR. bCH2Cl2,
n-Hex/THF or n-Hex/CH2Cl2. c40–60% conversion were achieved,
starting material was not separated. dA solution of the starting material
14a in CH2Cl2 was treated with a commercial solution of L-Selectride
in THF. e60–80% conversion were achieved, starting material was not
separated.
379

Beilstein J. Org. Chem. 2014, 10, 369–383.
Scheme 7: Synthesis of trans-piperidinol 11a in excellent ee.
the presence of HCl delivered the hydrochloride salt 15a, which tion in one pot, the diastereomers cis- and trans-16c were easily
was easily isolated through filtration and solvent evaporation separated by flash chromatography. Thereby, we found it ad-
(Scheme 7). To our delight, subsequent liberation of the free vantageous to perform the hydrogenolysis in the presence of
amine through DBU at low temperature, immediate L-Selec- HCl to protonate the released amine and then induce Boc
tride reduction (giving intermediate V), HCl quenching and protection after neutralisation of the acid by Et3N rather than to
Et3N-induced cyclisation afforded the piperidine trans-11a in run the hydrogenolysis in the presence of Boc2O. As already
an excellent ee (≥99%) and as a single diastereomer according observed in the reduction/Cbz-cleavage 7→9 (Scheme 4) the
to crude 1H NMR. Although the reduction is performed in the quality of the Pd/C batch had a high influence on the
presence of a secondary amino function bearing an N–H-proton hydrogenolysis: No Bn cleavage was observed with Pd/C
and one equivalent of DBU-H+, only 1.5 equivalents of charges of a low activity, more catalytically active batches and
L-Selectride were required for a quantitative conversion. Thus freshly prepared Pd/C [77] led to quantitative conversion within
we assume the Cram chelate transition state is formed through 1–2 d (1 atm H2). The resulting alcohol cis-16c was subjected to
an amine N–H proton rather than an amide N–Li lithium cation Williamson etherification and subsequently the Boc-group was
as shown in Scheme 7 (which would result from deprotonation cleaved under acidic conditions (HCl in dioxane). We decided
of the amino group by L-Selectride and would thus consume at to isolate L-733,060 as its hydrochloride salt, because it is a
least 2 equivalents of the reducing agent).
non-hygroscopic solid (rather than an oil) and can be easily
extracted with organic solvents (e.g. EtOAc) from an aqueous
phase. With 8 steps, our sequence represents one of the shortest
syntheses reported to date [38-40]. Additionally, with the carba-
mate cis-16c (synthesized in 6 rather than 8 steps) we also
achieved a formal total synthesis of CP-99,994 [87].
Synthesis of L-733,060
In order to probe the practicability of our sequence we synthe-
sized L-733,060 as shown in Scheme 8. After cleavage of the
Bn-group under 1 atm of hydrogen and subsequent Boc-protec-
Scheme 8: Synthesis of L-733,060·HCl.
380

Beilstein J. Org. Chem. 2014, 10, 369–383.
5. Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576.
Although the phenylalanine and phenylglycine-derived piperidi-
nols 11b and 11c bear “unfunctionalized” side chains, phenyl
groups represent masked carboxylic acid functions. For
instance, the enantiomers of piperidine cis-11c and its N-depro-
tected derivative were converted to (2S,3R)-3-hydroxypipecolic
acid through protecting group manipulation and oxidative
cleavage of the phenyl group with RuCl3 and NaIO4 [38,40].
doi:10.1016/S0040-4020(00)00149-6
6. Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R.
Drug Discovery Today 2011, 16, 107–118.
doi:10.1016/j.drudis.2010.08.017
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doi:10.1016/j.tetasy.2009.02.048
8. Pruett, S. T.; Bushnev, A.; Hagedorn, K.; Adiga, M.; Haynes, C. A.;
Sullards, M. C.; Liotta, D. C.; Merrill, A. H., Jr. J. Lipid Res. 2008, 49,
1621–1639. doi:10.1194/jlr.R800012-JLR200
Conclusion
9. Brunner, M.; Koskinen, A. M. P. Curr. Org. Chem. 2004, 8, 1629–1645.
doi:10.2174/1385272043369638
Herein we presented a highly stereodivergent (dr up to 19:1),
scalable and practical (up to 14 g of cis-11a without any purifi-
cation of intermediates) synthesis of cis- and trans-configured
3-piperidinols 11, which represent a key structural motive in
various natural products and other bioactive target compounds.
Moreover, a high step-economy (5–6 steps) was guaranteed by
several novel one-pot procedures (1→2, 7→syn-9, 15a→trans-
11a) and surrendering any protection of OH functions. To probe
the efficiency of this sequence piperidinol 11c was converted to
the NK-1 inhibitor L-733,060 in three further steps. Add-
itionally, a unique cyclodehydration procedure replacing PPh3
through P(OEt)3 to improve atom economy (166 compared to
262 g/mol) and to allow separation of the oxidized side product
(OP(OEt)3) by saponification (no similar literature precedents
known) was implemented. Ongoing research is focusing on the
transformation of the methionine-derived piperidinol 11d to
other pharmacologically relevant targets on a gram scale.
10.Zappia, G.; Cancelliere, G.; Gacs-Baitz, E.; Delle Monache, G.;
Misiti, D.; Nevolam, L.; Botta, B. Curr. Org. Synth. 2007, 4, 238–307.
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Supporting Information File 1
Experimental and characterisation data.
[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
We want to thank the German Academic Exchange Service
(DAAD) for a generous scholarship for P. H., and Prof. Dr.
H.-G. Schmalz for the very kind opportunity to perform a part
of the project at the University of Cologne. Additionally, we
want to thank Christopher Lood (Aalto University) for
recording analytical data.
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Kerry, M. A.; Krieger, F.; Meniconi, M.; Muñoz-Sanjuán, I.;
Palfrey, J. J.; Park, H.; Schaertl, S.; Taylor, M. G.; Weddell, D.;
Dominguez, C. Bioorg. Med. Chem. 2011, 19, 5833–5851.
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