1
Introduction
Natural products continue to be the biggest source of inspiration[1] for synthetic chemists towards the development of various methodologies for C–C
and C–hetero bond formation. In this regard, chiral amines[2] have received wide attention in recent years because of their diverse applications
as chiral auxiliaries,[3] organocatalysts,[4] chiral ligands for metal-catalysis,[5] and also for the synthesis of pharmaceutically active natural and unnatural products.[6] Classical methods for asymmetric C–N bond formation, including Sharpless aminohydroxylation,
rely on nucleophilic amination reactions[7] (Scheme [1]).
Later, electrophilic enantioselective α-amination reactions were developed with azodicarboxylates,
using chiral auxiliary derivatized preformed enolates and enol ethers.[8] Despite the robustness of asymmetric C–N bond formation, all of the above methods
require either substrate controlled chiral induction or pre-functionalized substrates.
Recently, organocatalysis have played a major role in the development of one-pot asymmetric
approaches for direct α-amination of prochiral aldehydes and ketones to access chiral
α-branched amines in high enantiomeric excess,[9] using simple and readily available starting materials.
In this context, the enzyme mimetic ability of proline has elegantly been explored
by List, Lerner, and Barbas III for asymmetric C–C bond formation in aldol reactions.[10] Working on the same grounds, List[11] and Jørgensen[12] for the first time unraveled, proline-catalyzed direct electrophilic α-amination
of achiral carbonyl compounds with azodicarboxylates for asymmetric C–N bond formation
with >95% ee. The merit of this protocol is the use of an inexpensive chiral catalyst
and the easy access to gram-scale reactions that do not necessitate the maintenance
of highly anhydrous conditions and proceeds with predictable stereochemical outcome
based on the catalyst used. Later, Jørgensen and co-workers demonstrated that groups
capable of hydrogen bonding are not prerequisites for high catalytic efficiency and
enantioselectivity in reactions involving silyl-protected diarylprolinol catalyst.[13] Given that the reaction proceeds through an enamine mechanism,[14] the chair-like transition state 1 proposed by List closely resembles Houk’s transition-state model 4 used for proline-catalyzed Hajos–Parrish–Eder–Sauer–Wiechert reaction rather than
the boat-like transition state 2 proposed by Jørgensen. On the basis of a series of calculations, Houk and co-workers
showed that the N–H hydrogen bond with proline does not lower the transition-state
energy.[15] Whereas, for a non-hydrogen-bonding catalyst the observed enantioselectivities originated
from steric discrimination of two enamine faces formed as a result of interaction
between the catalyst and carbonyl compound (transition-state model 3; Scheme [2]).
Scheme 1 Methods for C–N bond formation
Scheme 2 Proposed transition state for C–N bond formation
Scheme 3 Synthesis of 1,3-amino alcohols and 1,3-diamines via an iterative strategy
1,3-Polyol containing compounds constitute a large number of natural products with
a wide variety of potent biological activities.[16] As part of our ongoing studies on proline-mediated reactions, our group has developed
an iterative approach for α-aminoxylation[17] and showed its application for the synthesis of various 1,3-skipped polyol containing
natural products.[18] Working on the same lines, our group has also explored the efficacy of proline-catalyzed
asymmetric α-amination in the stereoselective synthesis of 1,3-diamines,[19] employing sequential α-amination and Horner–Wadsworth–Emmons (HWE) olefination of
aldehydes,[20] maintaining high ee as well as good dr during each iteration. The approach furnished >40:1 dr for syn/anti 1,3-diamines using l-proline (matched case), whereas poor to moderate (2:3 to 3:1) dr ratio was found for anti/syn 1,3-diamines using d-proline (mismatched case) (Scheme [3]).[19] The syn/anti 1,3-diamines, however were found to show contrasting results compared with syn/anti 1,3-diol.[17] A plausible reason for poor diastereoselectivity could be accounted for by the steric
as well as hydrogen-bonding influence of the existing chiral center in the substrate
on the incoming electrophilic amine source. On the other hand, proline-catalyzed sequential
α-aminoxylation/α-amination and HWE olefination of aldehydes lead to the formation
of enantiomerically pure anti/syn 1,3-amino alcohols with a high degree of diastereoselectivity (Scheme [3]).[21] Thus, the use of either d- or l-proline in the α-aminoxylation/α-amination step determines the outcome of the syn/anti configuration of 1,3-amino alcohol moiety. The potential of this methodology is further
demonstrated in the short synthesis of a cyclic amino alcohol derivative; namely,
(R)-1-((S)-1-methylpyrrolidin- 2-yl)-5-phenylpentan-2-ol (12; Scheme [3]).[22] Compound 12 and its analogues have recently been shown to possess promising therapeutic potential
in the treatment of Alzheimer’s, Parkinson’s, and Huntington’s diseases, and several
other neurological disorders, including spinal cord injuries and strokes. This account
highlights our laboratory’s ongoing program and accomplishment on proline-catalyzed
iterative α-amination and α-aminoxylation or a combination of both, for asymmetric
C–N and C–O bond formation. We have also covered the methods of closely related work
carried out by others in the last five years. In principle, using this iterative strategy
along with a judicious choice of proline catalyst and electrophilic ‘O’ or ‘N’ source,
all possible combinations of 1,3-diamines as well as amino alcohols can be accessed.
We have demonstrated the potential and broad scope of the strategy, by accomplishing
the total synthesis of various alkaloids and bioactive compounds having 1,3-amino
alcohols/1,3-diamines framework.
2
Applications
2.1
Total Synthesis of (–)-Halosaline, Formal Synthesis of (+)-Elaeokanine-A, (±)-Elaeokanine-C,
and T-4 Tetraponerines Alkaloids
In a continuation of our work on asymmetric synthesis of substituted piperidine alkaloids
using organocatalysis,[23] we further considered extending the above protocol to develop a general flexible
approach for 2-substituted piperidines (–)-halosaline 13,[24] (–)-8-epi-halosaline 14,[25] T-4 tetraponerines 15,[26] Elaeokanine A 16, and Elaeokanine C 17.[27] Synthesis of (–)-halosaline 13 started from the commercially available valeraldehyde 18. It was subjected to α-aminoxylation using nitroso benzene and l-proline as catalyst. Subsequent Horner–Wadsworth–Emmons (HWE) olefination employing
an ylide derived from triethyl phosphonoacetate and hydrogenation with Pd/C produced
the γ-hydroxy ester 19 in 78% yield and 94% ee. The ester 19 was converted into aldehyde 20 through a silyl protection and reduction sequence. α-Amination of the corresponding
aldehyde 20 using dibenzyl azodicarboxylate (DBAD) as a nitrogen source and d-proline as catalyst furnished the α-amino aldehyde, subsequent in situ reaction of
ylide generated from triethyl phosphonoacetate (HWE olefination) in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished anti-1,3-amino alcohol 21 in 71% yield and 98:2 diastereomeric ratio. 1,3-Amino alcohol 21 served as an important and versatile building block, which underwent N–N bond cleavage
with concomitant reduction of the double bond, followed by Boc protection to furnish
ester 22 in 79% yield. Compound 22, on reduction using LiBH4, tosylation, and NaCN displacement, produced the cyano compound 23 in 85% yield. After one-carbon homologation, cyano compound 23 was converted into the target molecule (–)-halosaline 13 by functional group interconversion, the latter can be converted into the target
15 by a known procedure.[28] Similarly, (–)-8-epi-halosaline 14 can be prepared by using l-proline during the α-amination reaction. Having achieved the synthesis of (–)-halosaline
13, cyclic aminoalcohol 25 was considered as the next target for the formal synthesis of 16 and 17.
For this purpose, 1,3-anti-aminoalcohol 21 was converted into lactam 24 under hydrogenation conditions, which, on LAH reduction, gave the key precursor 25 in 83% yield. Given that the conversion of compound 25 into target molecule 16 and 17 has been reported,[29] this constitutes the formal synthesis of target molecules Elaeokanine A and Elaeokanine
C (Scheme [4]).[30]
Scheme 4
2.2
Synthesis of Protected (2S,4R)-4-Hydroxyornithine and (+)-Pseudohygroline
The nonproteinogenic amino acid (2S,4R)-4-hydroxyornithine 26 found in lentils[31] and pyrrolidine alkaloid (+)-pseudohygroline 27
[32a] isolated from Carallia brachiata, Erythroxylon coca, and Schizanthus hookeri
[32b]
[c]
[d] showed potent biological activity and fascinating structural features. So we became
interested in devising a strategy to access all these natural products from a single
building block. To this end, the synthesis of the target molecule started from aldehyde
28. Sequential α-aminoxylation in the presence of d-proline, followed by Wittig–Horner olefination and hydrogenation by Pd/C gave the
γ-hydroxy esters 29 (29a: 68% yield, 96% ee; 29b: 72% yield and 94% ee). The γ-hydroxy esters 29, on further silyl protection of hydroxy group, reduction and dibenzyl azodicarboxylate
(DBAD) mediated α-amination in presence of d-proline, gave the product α-amino aldehyde 30. Towards the synthesis of (2S,4R)-4-hydroxyornithine, aminoaldehyde 30a, on NaBH4 reduction, afforded the substituted hydrazine 31 as a separable diastereomers in 88:12 ratio. The N–N bond cleavage of 31 under hydrogenation followed by Boc protection and finally oxidation using TEMPO/NaOCl/NaClO2 gave the desired protected (2S,4R)-4-hydroxyornithine 26 in 82% yield (Scheme [5]).[33]
Scheme 5
With an aim to synthesize (+)-pseudohygroline, aminoaldehyde 30b was olefinated under HWE reaction conditions with ylide derived from triethyl phosphonoacetate
to yield the syn-1,3-amino alcohol 32 in 19:1 diastereomeric ratio. Further N–N bond cleavage of 32 under hydrogenation conditions gave free amine, which was converted into lactam 33 smoothly in refluxing ethanol in 72% yield (over two steps). Methylation, reduction,
and its subsequent desilylation furnished natural product 27 in 95% yield (Scheme [5]). The target molecule 26 was synthesized in 22% overall yield; whereas 27 was synthesized in 24% overall yield from aldehyde 28a and 28b, respectively.
2.3
Synthesis of (–)-Deoxoprosopinine and (+)-Deoxoprosophylline
Prosopis alkaloids such as deoxo analogues deoxoprosopinine 34 and deoxoprosophylline 35 isolated from the leaves of Prosopis afrikana Taub, containing 2,6-disubstituted
piperidin-3-ol framework, exhibit antibiotic, anaesthetic, analgesic and CNS stimulating
properties. These alkaloids have unique structural features similar to the acyclic
structure of sphingosine and safingol sphingolipids containing a hydrophobic aliphatic
tail.[34] These sphingolipid mimics are required to facilitate transfer across the lipid membrane
and a hydrophilic head group to enable glycosidase inhibition,[35] thus enhancing their therapeutic potential.
The stereoselective synthesis starts with myristyl aldehyde 36. By following the protocol for α-amination of aldehyde using d-proline as discussed in the foregoing section, 36 gave the γ-amino-α,β-unsaturated ester 37 in 82% yield and 94% ee. Further reduction of 37, with concomitant reduction of the double bond followed by Dess–Martin periodinane
(DMP) mediated oxidation furnished aldehyde 39. Subsequent Wittig olefination gave trans-olefin 40 as the major compound in 70% yield along with a small amount of cis-olefin 41 and cyclized product 42 (16% yield). The undesired cyclized product 42 was again converted back into valuable alcohol 38 using LiBH4. Furthermore, olefin 40, on asymmetric dihydroxylation with (DHQD)2PHAL ligand under the Sharpless AD conditions, furnished diol 43a in 95% yield and 92:8 dr ratio. Regioselective monotosylation followed by Raney-Ni mediated N–N bond cleavage
gave free amine, which, in the same pot, underwent nucleophilic displacement of α-tosylate
to set the piperidine core of the molecule. Finally, reduction of the ester group
attached to the piperidine framework using LiBH4 produced (–)-deoxoprosopinine 34 in 96% yield with an overall yield of ca. 37%.[36] In a similar way, (+)-deoxoprosophylline 35 was synthesized with an overall yield of ca. 36% using (DHQ)2PHAL as a ligand in Sharpless AD step and following a similar set of reactions used
for (–)-deoxoprosopinine (Scheme [6]).
Scheme 6
2.4
Synthesis of Indolizidine, Pyrrolizidine, and Quinolizidine Framework
Indolizidine 44, pyrrolizidine 45, and quinolizidine 46 skeletons are important structural motifs found in diverse alkaloids, which exhibit
a broad range of biological activity. As an extension of our work for the synthesis
of alkaloids,[37] we considered developing a general strategy to access [5/5], [5/6] and [6/6] azabicyclic
ring systems just by varying the number of carbon atoms of the aldehydes used as the
starting material and the proper choice of organocatalyst employed.
As illustrated in Scheme [7], aldehydes 47a and 47b, on sequential l-proline catalyzed α-amination/HWE olefination sequence, gave the γ-amino-α,β-unsaturated
esters 48a and 48b in excellent yields and high enantioselectivity. Compounds 48a and 48b, under reductive hydrogenation followed by subsequent lactamization deprotection,
tosylation and finally base treatment, gave fused lactams 49a and 49b in 74% yield. Compounds 49a and 49b, on LAH reduction, gave pyrrolizidine 45 and indolizidine 44 ring systems. By following a reported procedure,[38] the fused lactam 49a can be readily converted into pyrrolam.
Scheme 7
Towards the synthesis of quinolizidine 46, γ-amino-α,β-unsaturated ester 48b was first subjected to N–N bond cleavage followed by Boc protection. Further reduction,
tosylation, followed by one-carbon homologation using NaCN gave the cyano compound.
Subsequent diisobutylaluminium hydride (DIBAL-H) reduction gave one-carbon homologated
aldehyde 50. Compound 50, on subjection to NaBH4 reduction, gave alcohol 51, along with formation of 52 as a major product (Scheme [7]). The double-bond reduction along with desilylation of compound 52 was achieved in one pot under hydrogenation conditions. Subsequent tosylation and
Boc deprotection led to the formation of the amine. The nucleophilic displacement
of tosyl with the resultant amine in the presence of Hünig’s base gave the quinolizidine
ring system 46 (Scheme [7]).[39]
2.5
Total Synthesis of (–)-Lentiginosine, (–)-epi-Lentiginosine, and Dihydroxypyrrolizidine
Lentiginosine 53, isolated from astralaguslentiginosus,[40] is the most potent known inhibitor of amyloglycosidases, with IC50=5 μg/mL, in addition to exhibiting excellent anti-HIV, anti-tumor and immunomodulating
activities. Several other strategies employed for the synthesis of lentiginosine and
its derivatives were tartaric acid, carbohydrates, nitrones, and amino acids etc.
as a chiral pool starting material.
The synthesis started with aldehyde 57a. By following the protocol for α-amination as discussed above, the γ-amino-α,β-unsaturated
ester 58 was prepared in 68% yield and 91% enantioselectivity. Ester reduction and ensuing
double bond reduction and desilylation of 58 using LiBH4 in one step followed by di-tosylation and N–N bond cleavage employing Raney-Ni gave
the free amine. Nucleophilic displacement of the di-tosylate resulted in the formation
of indolizidine alkaloid (R)-coniceine 56 (Scheme [8]).
Scheme 8
Synthesis of target molecules (–)-lentiginosine 53 and its 1,2-epimer 54 started with γ-amino-α,β-unsaturated ester 58. At this stage, the application of Sharpless AD reaction for embedding two hydroxyl
groups in the substrate with the aim to install the three requisite stereocenters
in a highly stereoselective manner paved to be a general synthetic route to the polyhydroxylated
imino sugars. Dihydroxylation of 58 gave the predicted ‘syn facial selectivity’ in the formation of the major product 59 in the absence of ligands. H-bonding between the OsO4 and NCbz–NHCbz group could be a plausible reason, despite the steric effect of the
allylic -NCbz substituent. Thus, by using (DHQ)2PHAL and (DHQ)2AQN ligands, high diastereoselectivity (dr ca. 99:1) was achieved. The latter proved more effective in achieving the ‘anti facial selectivity’, as the dr for the anti compound 60 increased to 3:1 based on exhaustive screening of other ligands.
Diol 59 was reduced to tetrol followed by primary tosylation to give di-tosyl. Subsequent
Raney-Ni hydrogenation conditions delivered the free amine. The nucleophilic displacement
of di-tosylate under similar reaction conditions furnished the desired (–)-lentiginosine
53. In a similar way, (–)-epi-lentiginosine 54 was synthesized from diol 60 by following a similar sequence of reactions (Scheme [8]).
Successful synthesis of lentiginosine and its 1,2-epimer, further prompted us to generalize
the strategy to other derivatives. Thus, by simple alteration of the chain length
of the aldehyde, the synthesis of dihydroxy pyrrolizidine 55 was accomplished. The synthesis commenced with aldehyde 57b, and by following the protocol for proline-catalyzed α-amination, as discussed above,
the γ-amino-α,β-unsaturated ester was obtained in 68% yield and 94% enantioselectivity,
as illustrated in Scheme [8]. The olefinic compound, on subjecting to Sharpless asymmetric dihydroxylation conditions
using (DHQD)2AQN as ligand, gave diol 61. Diol 61 was converted into target compound 55 by using analogous reactions as described for the synthesis of 53 and 54. Extension of this versatile methodology led us to complete all the three target
molecules in an efficient and short synthetic steps.[41]
2.6
Synthesis of Clavaminols, Sphinganine, and (+)-Spisulosine, and a Theoretical Insight
into the Stereochemical Aspects of the Reaction
The strategy developed to prepare long-chain α-amino-alcohols families such as clavaminol
A-H, (+)-spisulosine, and sphinganine having potent bioactivities such as antitumor,
immunostimulatory, immunosuppressant as well as neuronal proliferation, is summarized
in Scheme [9]. The synthesis began with proline-catalyzed α-amination of propanal 68 followed by indium-mediated Barbier type allylation to give homoallylic alcohol 71/72 in 75% yields with dr >99:1. The newly generated stereocenter will be anti and is contradictory to the result obtained with respect to that generated by using
proline in case of tandem aminoxylation–allylation[42] reactions as well as chelation controlled allylation.[43] DFT calculations also showed a difference of 9.03 kcal/mole in favor of the anti transition state, leading to the preferential formation of the anti product (Figure [1]). The bulky NCbz–NHCbz group[44] exerts steric effects thus decreasing the stability of the syn product.
Scheme 9
Finally, cross metathesis of homoallylic alcohols 71 and 72 with olefins with varying chain length such as oct-1-ene and tetradec-1-ene followed
by N–N bond cleavage and reduction of the double bond furnished clavaminol A 62 and (+) spisulosine 63 in 99% yields. Next, the amine group of clavaminol A 62 was selectively acetylated in the presence of alcohols using pentafluorophenyl acetate
to produce clavaminol C 64 in 80% yield. Thus, the total synthesis of clavaminol A 62 and (+)-spisulosine 63 was accomplished in 63% overall yield and clavaminol C 64 in 51% overall yield; better than the previously reported synthesis.
Figure 1 Chelation controlled reaction pathway showing the relative stability of the syn and anti transition state
The synthesis of clavaminol H 67 and sphinganine 65 commenced from 3-(benzyloxy) propanal 73 using a similar reaction sequence, thus accomplishing the total synthesis of sphinganine
65 and clavaminol H 67 in three and four steps, respectively, with 61% and 45% overall yields (Scheme [9]).[45]
2.7
Synthesis of (2S,3S)-3-Hydroxypipecolic Acid and Formal Synthesis of (+)-Swainsonine
Hydroxylated piperidines 79, 80 and indolizidines such as swainsonine 78, a potent α-mannosidase inhibitor, exhibit antiproliferative, immunomodulatory, antimetastatic,
and anticancer activities making it an attractive synthetic target.
Scheme 10
Sudalai et al. reported the synthesis of chiral piperidine 84 starting from known aldehyde 81, which on l-proline-catalyzed α-amination followed by Zn-mediated Barbier allylation in situ
furnished the hydrazino alcohol 82 in 80% yield (single diastereoisomer; 96% ee). The anti stereoselectivity can be accounted for on the basis of sterically controlled Felkin–Ahn
transition state. The secondary alcohol 82 was subjected to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated intramolecular
diastereoselective oxidative acetalization followed by N–N bond cleavage, which, on
subsequent hydroboration–oxidation, gave primary alcohol 83 in 70% yield. Alcohol 83 was converted into mesylate, which underwent intramolecular N-alkylation, to give
the piperidine core unit 84, which on deprotection gave compound 80. Similarly, compound 84 delivered 3-hydroxypipecolic acid 79 by four-step functional group transformation, which includes deprotection, protection,
oxidation using cat. RuCl3, NaIO4 and its HCl salt formation (Scheme [10]).[46]
Chiral piperidine 84 served as an important building block for the formal synthesis of (+)-swainsonine
78. Piperidine 84 on hydrolysis of ethyl carbamate, followed by allyloxy protection and subsequent
benzylidene acetal deprotection and silyl protection afforded di-TBS ether 85. Selective deprotection of primary silyl ether, DMP oxidation and one-carbon Wittig
olefination gave the required diene 86 in 65% yield. Since the transformation of 86 into (+)-swainsonine has been reported,[47] this constitutes a formal synthesis of target 78 (Scheme [10]).
Scheme 11
2.8
Synthesis of 4-Hydroxypyrazolidine Derivatives via Organocatalytic Sequential α-Amination/Corey–Chaykovsky
Reaction
Chiral hydroxypyrazolidine derivatives serve as important building blocks for enantiopure
1,3-diamines as well as for the pharmaceutical industry. They are shown to exhibit
a wide variety of biological activities such as anticonvulsant, antitumor and antidepressant
properties.
In the past, various groups including our own have trapped reactive α-aminoaldehyde
intermediates with various other nucleophiles.[48] Recently, Sudalai et al.[49] developed tandem α-amination/Corey–Chaykovsky reaction for in situ trapping of amino
aldehyde 88 with Corey’s sulfur ylide (dimethyloxosulfonium methylide) so as to access 4-hydroxypyrazolidine
derivatives 89 in moderate to good yields (65–80%) with excellent enantio- and diastereoselectivities
(Scheme [11]). The reaction was compatible with a wide variety of aldehydes and electrophilic
amine sources. The synthetic utility of this method was demonstrated in the synthesis
of anti-1,2-aminoalcohol, which are common structural motifs present in phytosphingosines
and HIV protease inhibitors.
2.9
Synthesis of Diverse Iminocyclitols from D-Ribose
2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine (five-membered), 1- and 2-deoxynojirimycin
derivatives (six-membered) and polyhydroxyazepane derivatives (seven-membered) are
polyhydroxy N-heterocyclic frameworks that are generally referred to as iminosugars or azasugars.
They are key building blocks for drug development against a number of diseases including
cancer, diabetes, and viral infections such as AIDS. Ramapanicker et al. have developed
a versatile and stereoselective strategy using proline-catalyzed α-amination as a
key reaction to access this class of molecules.[50] Aldehydes 98, 99, 100, and 101, synthesized using chiral pool methods, have been successfully employed as starting
materials for proline-catalyzed α-amination reaction to access five-, six-, and seven-membered
azasugars after certain functional group transformation.
Aldehyde 98 gave DMDP derivatives 90 and 91, aldehyde 99 gave homonojirimycin derivatives 92 and 93, similarly, aldehyde 100 gave deoxynojirimycin derivatives 94 and 95 and finally aldehyde 101 gave azepanes derivatives 96 and 97 depending on the choice of proline catalyst used. This hydrazino alcohol, on further
functional group transformation, allowed easy access to iminocyclitols from d-ribose as a single starting material (Scheme [12]).
Scheme 12
2.10
Synthesis of C-Glycosyl Amino Acids via α-Amination of C-Glycosylalkyl Aldehydes
Scheme 13
Non-natural C-glycosyl α-amino acids constitute ubiquitous building blocks of natural glycopeptides
on co-translational modification and development of carbohydrate-based drugs. Dondoni
and Massi et al. have developed a proline-catalyzed asymmetric synthesis of carbon-linked
sugar amino acids.[51] The α-amination of sugar aldehyde with DBAD afforded the α-hydrazino aldehyde exclusively,
in the presence of 30 mol% of l-proline as catalyst. This product can either be reduced to hydrazino alcohol using
NaBH4 or can be smoothly converted into the α-amino ester target by sequential Jones oxidation
followed by esterification with diazomethane. A variety of substituted perbenzylated
C-glycosyl acetaldehydes and C-glucosyl alkylaldehydes underwent efficient amination with good to excellent yields
and high enantioselectivity >95% (Scheme [13]).
